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Using Mind Genomics Thinking and AI Simulation to Study Socio-political Issues: Possible Individual ‘Fall-Out’ from the US DOGE Efforts

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DOI: 10.31038/MGSPE.2026611

Abstract

Using a combination of the Mind Genomics platform BimiLeap.com and AI, the paper shows how one can rapidly explore ideas in today’s unstable world of political instability coupled with social instability. The paper shows by means of simulation how the investigator can identify a problem by using AI to create a ‘situation backgrounder’, and then use that backgrounder in turn to create classification questions about people, questions about responses to situations calling for betraying one’s country, and then answers to those questions. The questions never appear in the analysis, but simply act as guides to generate answers, which are presented as statements. Synthetic respondents, created by AI, are then exposed to vignettes comprising 2-4 of these above-mentioned answers. The respondents are also given personas by AI, as well as given different types of background instructions. The effort provides an instructional database showing how response classified as either ‘loyal’ or ‘tempted’ can be traced to the types of messages a person receives, the persona of the person created by AI, and finally the type of situation which prevails (e.g., public feelings shortly after DOGE, Department of Government Efficiency has made its cuts). The process is quick (hours and days), affordable (only costs are AI), and deep information, allowing the simulation to give a sense of what may happen.

Introduction

In President Trump’s second term as US President, he created DOGE. Dept of Governmental; Efficiency. The goal was to audit government expenditures and cut waste, doing so dramatically by firing people who had spent years and even decades as civil servants and as other ways of working for the US government. The outcome was that many government employees lost their jobs. There were, of course, negative feelings by the fired people (and others) towards the government. The topic here is to simulate what might be the actions of these disaffected, fired people, were they to be approached by individuals by another country to take money for selling what they know, and possibly learned during their tenure with the US government [1,3,7,8].

During this same period, research in the emerging science of Mind Genomics continued to show the ability of this science to understand the way people think about the topics of ordinary life and make decisions of the ordinary [4]. The Mind Genomics process of creating elements (messages) about a topic and combining these messages into vignettes according to an underlying plan called an experimental design ended up revealing many facets of how people think about topics. The strategy was to avoid having people ‘intellectualize’ about a topic. Rather, one would create simple combinations of messages, so-called vignettes, and have the respondent rate the vignette. The respondent was not challenged at all to defend the choice or even to verbalize the reasons for the choice of rating scale value for a particular vignette). The subsequent analysis, using standard statistical methods like regression and clustering, revealed in clear detail the criteria that the respondent used to rate the individual elements in the vignette [9,11].

The happy outcome of the above was a way to simulate the compound nature of reality. Much like in daily life, the respondent simply made decisions, almost without thinking. We should not be surprised at this behavior, and how natural it is easy. What is important comes down to the simple reality that here is a more natural way to measure thinking about a topic, and in fact one which is becoming increasingly cheaper, faster, and simpler from the user’s point of view.

A historical note is in order here: The original efforts began in the 1980’s, four decades ago. The process was simple although convoluted and effortful by today’s standards. In an era when the personal computer was starting, the researcher would assemble the material, usually sentences, but sometimes pictures. The user would then create one experimental design, with 2-3 times the number of fixed vignettes as elements. That is, the researcher might have 96 elements. The researcher would then create 192 combinations, which each element appearing 4-5 times across the 192 combinations. These combinations were fixed. The design was ‘tested’ ahead of time to make sure that it was amenable to analysis by OLS (ordinary least squares) regression [12]. The creation of one experiment allowed the researcher to manually check each vignette, each combination of elements, to make sure no vignette contained prohibited combinations, viz, elements which contradicted each other.

Today’s version of BimiLeap has evolved from those early days of forty years ago. Today’s version has evolved from a starting idea about 36 elements requiring 60 combinations or vignettes (4 categories, each with 9 elements), then 36 elements requiring 48 combinations or vignettes (6 categories, each with 6 elements), and finally today’s time- starved design of 16 elements requiring 24 combinations (4 categories, each with four elements).

Incorporating AI into the Process

AI interacts with Mind Genomics at least four levels, all ow which are currently available on the Mind Genomics platform, www. BimiLeap.com.

Step 1: Create a Backgrounder to Develop a Deeper Sense of the Topic

Our first step is to assemble information about the topic, more for general knowledge than for the framing of specific questions. Any of today’s LLM models, e.g., Chat GPT or Co-Pilot can provide a useful backgrounder to the topic. The backgrounder shown in Table 1 was developed by Microsoft’s LLM, Co-Pilot. The request was to provide a 10-paragraph composition on the likely feelings, opportunities and vulnerabilities of those civil servants who were summarily dismissed without cause from their jobs as part of the DOGE effort. As we will see below, this first effort need not be made, but it is advisable to do so just for the purposes of creating an overview of the topic.

Table 1: Using AI to create a general story.

Moving beyond the orientation to the problem is using AI to sharpen one’s ideas about how the Mind Genomics approach should be used. Table 2 shows how Microsoft’s CoPilot provides a way to focus the user on what might be the most effective way to use Mind Genomics. The information in Table 2 is not necessary for the project and indeed was never codified in such a short form until AI was available. Table 2 may provide material already known to experts, but at the same time the user can benefit from a reiteration of basic ideas provided by reinterrogating AI.

Table 2: AI introduction to the process of Mind Genomics.

Step 2: Set Up the Mind Genomics Study

  1. Develop a series of questions which ‘tell a story’,
  2. For each question create four answers, the four answers (or elements) differing as much as possible from each other.
  3. Create up to 16 classification questions which allow the respondent to profile themselves.
  4. Create an introductory statement explaining the topic, and then provide rating scale.

The order of activities listed above has changed in different versions of the Mind Genomics program. `

Figure 1 (left panel) shows the first screen that the user fills. The left panel shows simply the name of the Mind Genomic study (really ‘experiment’) the language, and a disclaimer that no personal information will be taken.

Figure 1: User steps to set up a Mind-Genomics study (Panel A), and to create four questions (Panel B).

Panel B below shows the request for four questions. Up to the advent of LLM models such as Chat GPT, it was at this first step that the process often encountered is first resistance, and indeed many studies were aborted at this early stage. Panel B requests that the respondent generate four questions which tell a story. During the period of evolution, from approximately 1998 onwards, it seemed to be becoming increasingly harder for researchers, or at least those who wanted to use Mind Genomics, to come up with four questions which ‘told a story’ That observation, although subjective, corresponded to many people saying that they wished there were an easier way to develop these questions along. Indeed, by the year 2020 it seemed that Mind Genomics was destined to suffer a death because many prospective users felt simply that coming up with questions was beyond them. This observation tallies with the often- repeated observation by many that the thinking abilities of people seemed to be eroding.

Step 3: Generate the Four Questions Using AI

Figure 2 shows the Idea Coach section introduced in Figure 1. The left panel shows the request made to the AI embedded in the Idea Coach. The right panel shows the output from this initial iteration. Each iteration of the Idea Coach at this stage generates 15 different questions. The iterations may be repeated to generate a new set of 15 questions. Some of the questions will overlap. A strong introduction to the topic may emerge when the user runs many iterations, since later AI will analyze the output from AI, and offer new insights as Table 3 shows.

Figure 2: Idea Coach allowing user to write about the study (panel A), an intermediate output of 15 questions with the output comprising the first of possibly many iterations (panel B) and finally an example of four question finally selected from or even across several iterations (panel C).

The actual output from the Mind Genomics set-up is much richer, with the analysis occurring as the study is being completed. An ‘iteration’ in the setup occurs when then the Idea Coach on the left is submitted. Table 3 shows the rich nature of the outcome, including the original input request the questions, as well as AI analysis of the output. The AI is once again Chat GPT.

Table 3: First iteration, viz., first set of questions generated by AI, based upon the information provided in the Idea Coach.


Step 4: Use AI to Guide Thinking about the Questions and Answers to Choose

When AI was first incorporated into Mind Genomics in 2023, the principal use was to make researcher’s job less taxing, viz., by providing questions and then answers to the questions. Table 4 shows four questions generated by the AI in IDEA Coach, and for each question, four of the 15 answers further generated by Idea Coach. Table 4 need not contain questions from the same iteration. The BimiLeap program is set up so that the user can instruct the embedded AI to go through another iteration. Only when the user finally selects the four questions (from repeated iterations) and well as provides four answers to a specific question (from repeated iterations does the program move on.

The actual process to generate the questions and then select the answers was approximately 15 minutes, a speed unimagined even a decade ago. The actual study ended up being created in a matter of about an hour.

Table 4: The four questions and the four answers (elements) generated for the study.

Step 5: Create Self-proflling Questions as the Basis of ‘Personas’ to be Used by AI

It is by now a truism that people differ from each other. When working with Mind Genomics, whether using people or synthetic AI- created ‘personas’, it is instructive to find out about the respondent. This discovery may be about who the respondent IS, what the respondent DOES, how the respondent FEELS AND THINKS, etc. An efficient way to discover this information is to present the respondent with a closed end questionnaire, such as that shown in Table 5. The respondent, or in this case the AI, simply chooses the most appropriate answer for each question. To arrive at the nine questions shown in Table 5 we instructed AI to provide nine different questions that could describe a person involved in losing their job due to DOGE, and then for each question generate two radically different answers.

When people answer the questions in Table 5 we end with a sense of who they ‘are’. The thinking is different with AI. The AI program can be provided by a persona, created by an underlying program. In BimiLeap the underlying program randomly selects one of the three answers for each question in Table 5. The objective was to estimate the absolute contribution of answer in the subsequent analysis. It is for that reason that a final answer, “I cannot answer this question”, was added. With that type of answer, the AI ignores the topic in the creation of the persona.

Later, in the analysis, we will consider the contribution of the elements, as well as the contributions of the persona, to the rating. This analysis will allow us to understand the relative importance of the message versus of the nature of the ‘respondent, as a driver of the response.

Table 5: The nine questions used by AI to create a synthetic persona. The person emerged from the random (but ultimately balanced) choice of one answer from each question to generate the synthetic person.

Step 6; ‘Orient’ AI in Terms of Four Introductions to the Situation, and the Five Point Rating Scale to Use to Evaluate the Vignettes

To obtain an even deeper understanding of how AI could integrate with Mind Genomics, we explored our different scenarios of introductions, with each introduction run in an experiment all its own. The top of Table 6 shows the four introductions, A-D. Introduction A talks about DOGE effort, combined with an upbeat mood. Introduction B talks about DOGE effort, with a downbeat mood. Introduction C talks about DOGE effort. All three introductions talk about foreign countries approaching laid-off government employees. Introduction provides no background at all but simply proceeds to the introduction about how to use the rating scale. The bottom of Table 6 shows the introduction to the vignettes, and the labelled five-point rating scale.

Table 6: The four introductions, one introduction for each of the four experiments and then introduction to the rating scale, and the five-point labelled rating scale.

Step 7: Prepare for Data Analysis by Regression by Specifying BDV’s (Binary Dependent Variables)

The original Mind Genomics studies were developed with a simple nine-point rating scale. The only labels were at the two extremes. The rationale for this form of scale was the popularity of top-and-bottom anchored scales in the world of applied science and consumer research. Author Moskowitz traces his roots to that field. The choice of a nine-point scale was based upon the belief that the respondents should have as much space on the scale to show the magnitude of their feelings.

Ongoing experience revealed that managers exposed to the research findings were uncomfortable with the scale. Most of the managers had been through business school, so they understood the general idea of the scale. The major problem emerging was that the scale simply could not be interpreted in a simple manner, as simple perhaps as the ‘no/yes’, is my product, my idea, even my vision ‘good’ or ‘bad.’ It became obvious that the precision to be offered by a scale did not give much to the users in terms of what the user of the scale information needed.

Rather than using the scale as a measure of magnitude, the easier approach, and one already in use by other researchers, was to divide the scale into regions, usually two regions. The common use of many researchers during the time that Mind Genomics was developing (2000 – 21010) was to use a simple, anchored 5-point scale [5,10]. Rather than searching for the so-called precision of the 9-point scale, and an ability to reveal differences, the effort recognized that five points were enough. Further practice by researchers was to divide the scale into two parts, and convert the scale to two points, for example so-called ‘Top 2’ (ratings of 5 and 4 converted to 100, ratings of 3,2, and 1 converted to 0),

The nice thing about this conversion is that it tells the researcher what percentage of the researchers can be said to agree with the idea, like the idea, etc. the specifical words to interpret Top 2 come from the anchors of the scale. The benefit for researchers of this change is that it moves the data to a form that can be analyzed by different statistical methods, whether to compute averages, or use as input in regression, or clustering.

Step 8: Run Study Once with Each Introduction, Using ‘Synthetic’ (AI-Created) Respondents

Once the user creates the test elements, the introduction, the rating scale, and if desired the self-profiling classification, the rest is left to the BimiLeap.com program. The user can select human respondents, or instruct the program to simulate respondents, viz., create synthetic respondents. Figure 3 shows the instructions for the user. The third selection allows the user to work with synthetic respondents, these respondents to be constructed by the combination of answers to the nine questions shown in Table 5.

Figure 3: Screen shot showing the choice of respondents given to the user. The third row shows the option to use AI-generated synthetic respondents.

Results

The Distribution of Ratings Across the Set of Four Studies

Our first analysis looks at the distribution of the five scale points across the different subgroups of usage. Table 7 shows the distribution of the five scale points for each classification statement. The classification statements were created to be independent of each other.

Across the total of four studies, each with 500 synthetic respondents, there were an altogether of 48,000 ratings (4 studies x 400 respondents/study x 24 vignettes/respondent = 48,000). Table 7 suggests that the AI did understand the meaning of the scales and chose rating 5 a vanishingly small number of times. Keep in mind that we are talking here about 48,000 independent decisions, with the AI presented with a persona, a scale, and then a vignette of 2-4 elements. A more fine-grained analysis would reveal further evidence that the synthetic respondents generated by AI make sense in terms of the linking of ‘who they are’ with what they end up rating.

The labelled 5-point can be divided into sections, one loyal (ratings 1 and 2), one disloyal (rating5), and one tempted (ratings 3 and 4). Table 7 reveals very few ratings of 5, viz., disloyal, but a substantial number of ratings for ‘tempted’ and a lesser but still substantial number of ratings for loyalty. For the remaining analysis we will consider two newly created BDV’s (binary dependent variables). R12 (Loyal) and R34 (Tempted).

Table 7: Distribution of ratings across the four sets of studies.

Relating the Presence/Absence of the 16 Elements to Positive Versus to Negative Responses

The use of an underlying permuted experimental design ensures that each synthetic respondent would test a different but appropriate set of 24 vignettes. The vignette comprises a specified combination of elements, at most one element or answer from each question, but with many vignettes comprising as few as two elements, and some vignettes comprising three elements. A vignette had at most one element or answer from a question. Across the 24 vignettes, each element appeared five times and was absent 19 times. Thus, a single question would contribute exactly one of its four answers to 20 or the 4 vignettes and be absent from the remaining four of the vignettes.

The above-mentioned design was modified so that each respondent would test a different set of 24 combinations. The mathematical structure of these 24 combinations was maintained from respondent to respondent. Only the specific combinations differed. This permutation scheme allowed the user to create individual-level models across respondents. The great benefit was the ability to analyze studies with few as well as with many respondents.

Our first analysis looks at contribution of the 16 elements to the two key BDVs, LOYAL (ratings of 1 or 2), or TEMPTED (rating 3 or 4). We eliminated rating 5 from consideration because it received vanishingly few ratings from the synthetic respondents. It is clear from Table 8A that the coefficients for Temptation are almost all high, with the cut-off of a coefficient of 21 being statistically significant (t statistic >2). Table further shows that the range of coefficients across the four introductions is usually quite small, a value of 6 or lower. Importantly, and quite remarkable, the coefficient for TEMPTED is highest when there is no introduction, and lowest for the introduction with presents DOGE along with the statement that the attitude of the citizen is upbeat, positive, and patriotic. We interpret this pattern to mean that for the same element, the most the country is described as positive and optimistic after DOGE has done its work, the (slightly) less tempting the element may be.

Table 8A: How the introduction and the elements interact to generate coefficients for equations relating the presence/absence of the 16 elements to ‘TEMPTED’ and ‘LOYAL’, respectively.

An ‘Integrative Model’ Incorporating Contributions of Messages, Introductions, and Feelings

Thus far the analysis has been of the 16 elements (A1-D4) as it has been affected by introduction to the synthetic respondent. We also know from Table 7 that there are differences in the patterns of ratings by WHO the respondent is (gender) and how the respondent profiles themselves (e.g., gender).

Our next analysis attempts to create a general, integrative model, using the variables for which there is a true zero, or for which a case can be made that variable has a meaningful zero. The model is straightforward. The independent variables are coded as ‘1’ if present, and ‘0’ if absent from the data. The elements were created by an underlying experimental design which ensured true 0’s. The first set of variables are the elements, specifically presence/absence of the elements in the vignette, with presence coded as 1, and absence coded as 0. The second set of variables are the three introductions (A, B, C) which present the DOGE action (all three introductions) as well as the emotional reactions (positive, negative, introductions A and B). The third set of variables are the nine self-profiling classification questions, each having three answers, two options, and the third option being the ‘zero’ case, presented as ‘I cannot answer this question).

Altogether, we have 16 elements, three introductions, and 18 self-profiling classifications, or 37 predictor variables. We have 2,000 respondents, each of whom provided 24 respondents on a scale which we define as either ‘loyal’ (ratings 1 and 2 transformed to 100; ratings 3,4, transformed to 0) or ‘tempted (ratings 3 and 4 transformed to 100, ratings 1 and 2 transformed t0 0). Rating 5 was entirely ignored in the analysis.

The integrated model provides a rapid way to understand the patterns in the data, and to uncover patterns that might have been missed because of the sheer volume of data (48,000 synthesized ratings). It may also be that the integrated model allows us insights that would otherwise be masked. Table 8B shows the integrated model for the Total Panel.

Table 8B: Integrated model for the total panel. The model relates relating the binary dependent variables of LOYAL and TEMPTED, respectively, to each of the elements, introductions, and self-descriptions of the way one feels. Only coefficients of +5 or higher are shown.

What drives loyal: No elements drive ‘loyal’

A positive reaction to DOGE and DOGE itself without any statement of citizen reaction

One specific answer in the self-profiling: Being native-born (Q31) and feeling the US is the best place to live (Q71)

What drives tempted: Most of the elements drive ‘tempted’, virtually to the same degree.

A negative reaction to DOGE in the introduction

Any of three specific answers in the self-profiling

I don’t know feel a strong connection to this country (Q11)

I do not feel appreciated by my country (Q21)

I am not at all confident that my future in the United States is good (Q42)

1=I feel that I can be ‘bought’ for the right price because everyone has a price.

Two Mind-sets and the Integrated Model Combining Elements, Personas, and Introductions

The final analysis of our data involves mind-set segmentation. A hallmark of Mind Genomics is at the level of granular experience; people differ from each other. These differences, once thought to be simply the intractable interpersonal variation which haunts ever study, turn out to be interpretable and important systematic differences between people in the way people evaluate the world of everyday. The differences end up pointing to the existence of so-called mind-sets, clusters of individuals with different ways of evaluating the stimuli of the everyday. It is not that all inter-individual variation can be traced to these mind-sets, but rather some part of the variation is due to systematic differences.

What these mind-sets are eds up emerging when we look at how people differ in what is important to them. The Mind Genomics process clusters respondents, dividing the full bank of respondents into smaller groups, based strictly on mathematical considerations. Once the respondents are divided into these smaller groups, it is straightforward to repeat the analysis on the different groups. These emergent groups, clusters in the language of statistics, are called mind- sets in the language of Mind Genomics.

Previous studies using the Mind Genomics method suggest that mind-sets abound in areas as diverse as food preferences, responses to legal issues, and the way one listens to one’s doctor and the type of information that drives patient compliance [2,6].

The Mind Genomics process lends itself to easy discovery of mind- sets. The process comprises the development of individual level models relating a specific BDV (binary defined variable) to the presence/ absence of the elements that were systematically varied. In this study we have 2000 respondents, each of whom evaluated the 16 elements combined into the 24 vignettes, with each respondent evaluating elements arranged in an experimental design. It is straightforward to create 2000 equations, one per respondent, to relate the 16 elements to Loyal (set 1) and then Tempted (set 2).

The first order of business is to create the BDV for each respondent. The BDV Loyal takes on the rating 100 when the original rating was 3 or 4. The BDV Tempted takes on the value 100 when the original rating was 1 or 2. Otherwise the BDV takes on the value 0. A vanishingly small number (<10-5) is added to every newly created BDV to ensure that there is some minimal level of variation in the BDV values when they serve as dependent variables in the regression which follows the transformation.

The foregoing modeling by OLS (ordinary least squares) regression generates two parallel sets of 2000 rows of coefficients, each row containing 16 coefficients with no additive constant. We can combine these two sets of data into one block of data of 2000 rows, one row for each respondent. In turn, the left side (columns 1-16) comprise the coefficients for Loyal, and the right side comprises the coefficients for the same respondent, this time for Tempted.

The next step in clustering uses so-called k-means clustering. The clustering program attempts to put the 2000 synthetic respondent into a minimal set of groups called clusters, or mind-sets in the language of Mind Genomics; The k-means algorithm does so by first computing the pairwise distance between every pair of the 2000 respondent. There are almost 4 million pairs of respondents. The distance between each pair is defined as (1-Pearson Correlation). In turn, the Pearson correlation is computed between every pair of respondents, based on the values of the 32 corresponding coefficients, the 16 coefficients for LOYAL and the 16 coefficients for TEMPTED.

For exploratory purposes we begin with the two mind-sets, shown in Table 9. Mind-Se 1 comprises 1469 of the 2000 respondents, Mind-Set 2 comprise 531 of the 2000 respondents. Table 9 presents a great deal of data. To make the table easier to read we arbitrarily remove all coefficients of +3 or lower, leaving coefficients of 4 or higher. It is clear that the mind-sets differ dramatically on their reactions to LOYAL.

Table 9: The integrated model showing the coefficients from the single model incorporating predictors of the elements, the nine self-profiling questions to establish the persona, and the three introductions which ‘set the stage’. The table shows four integrated models, one for each pair of mind-set and BDV (loyal vs tempted).

Expanded Integrated Models for Three, Four, and Five Mind-sets

The final analysis in this exploration extracted three, four and then five mind-sets. The clustering program was precisely the same as done for the two-mind-set analysis. Table 10 shows the results. Once again, we remove any coefficients lower than 5. Table 10A shows the coefficient for LOYAL. Table 10B shows the coefficient for Tempted. Table 10 shows many more blank but also shows many higher coefficients. Furthermore, the mind-sets seem simpler in terms of the pattern of self-classifying questions, but more complex in terms of how the introduction fit into the model. The reader is invited to dive more deeply into the tables to extract additional insights about the way mind-set segmentation is influenced by personas developed by AI.

Table 10A: Coefficients for the integrated model for LOYAL, for three, four, and five mind-sets created through k-means clustering.

Table 10B: Coefficients for the integrated model for LOYAL, for three, four, and five mind-sets created through k-means clustering.

Discussion and Conclusions

This paper demonstrates, in example form, what might be learned about a totally new topic (effects of DOGE on loyalty vs temptation), doing so in the matter of a few hours, or at most a day or two. The approach merges the now standardized approaches used by Mind Genomics with the power of AI to synthetize personas and have those personas rate test stimuli (vignettes).

There are a variety of considerations, mostly positive, that should be kept in mind when evaluating the possible contribution of the approach presented here. These considerations range from today’s trends to today’s needs, and can be grouped into two major areas, ‘learning speed through simplicity’ and ‘learning from storytelling’.

Speed and Simplicity

1.  Speed is the New Power in Learning

This approach teaches fast. A user can set up questions, answers, and stories in hours, not weeks. A child can test ideas about honesty in school rules and see results the same day. A police officer can test ideas about crime prevention and get insights before the week finishes. A political scientist can test ideas about public opinion and see patterns in one afternoon. Speed keeps attention strong. Speed makes learning exciting. Speed builds confidence.

2.  Speed Builds Confidence

Fast results encourage learners. A student who sees patterns in one day feels proud. A police officer who sees insights in one week feels prepared. A researcher who sees trends in one afternoon feels informed. Speed keeps motivation high. Learners try repeatedly. Each cycle builds skill. Confidence grows with each fast success.

3.  Simplicity is a Path to Increasing One’s Understanding

The system uses short stories called vignettes. Each vignette shows a situation and asks for a choice. This makes the lesson easy to follow. A teenager can read a vignette about loyalty and decide how they would act. A teacher can use vignettes to explain fairness without complex words. A police trainer can use vignettes to show how suspects might be tempted. Simple stories make hard issues clear. Simplicity opens the door to learning.

4.  Simplicity Builds Trust

The system avoids complex math in the front view. Users see clear outputs like “loyal” or “tempted.” A student can understand without equations. A teacher can explain without formulas. A police officer can train without statistics. A researcher can share results without jargon. Simple outputs build trust. Learners believe what they see. Trust makes education strong.

5.   Control Belongs to the Learner, and a Tool to Drive Education

The user decides the questions, the answers, and the scenarios. This control makes the process personal. A student can design questions about friendship. A researcher can design questions about corruption. A police officer can design questions about crime. Each user shapes the study to fit their interest. Control teaches responsibility. Control makes learning active, not passive. Control builds ownership of knowledge.

6.  Control Builds Responsibility

When users design their own experiments, they learn to think carefully. A student who writes a question about honesty must decide what honesty means. A police officer who writes a question about crime must decide what crime means. A researcher who writes a question about loyalty must decide what loyalty means This reflection teaches values. Responsibility grows with control. Learners become thoughtful.

7.  Education Can Inspire Better Action

Learning should not stop at knowledge. It should lead to wise choices. Simulation makes issues vivid, simple, and under user control. A student learns to act fairly. A police officer learns to act carefully. A researcher learns to act responsibly. Each user sees choices clearly. Each user imagines better futures. Education inspires action. Action makes society stronger.

Stories Teach Better than Simple Facts, Engaging Creativity and Thinking

8.  Stories Build Memory

People remember stories better than lists of facts. A vignette about a worker facing temptation sticks in the mind. Later, the learner recalls the lesson about loyalty and risk. A student remembers the story about cheating. A police officer remembers the story about bribery. A researcher remembers the story about betrayal. Stories make lessons last. Memory grows stronger with stories.

9.  Stories Bring Issues to Life

Numbers alone do not move the heart. Stories make issues real. A vignette about a fired worker tempted to share secrets feels alive. Readers imagine the worker’s choice and feel the tension. A child reading about a friend tempted to cheat feels the same pull. A police officer reading about a suspect tempted by money feels the risk. A political scientist reading about citizens tempted by anger feels the danger. Stories make lessons stick in memory.

10.  Creativity Grows from Mixing Ideas

The system combines different answers into new vignettes. This mixing creates surprises. A student may see that anger plus money creates more risk than sadness plus flattery. A police officer may see that fear plus friendship creates more temptation than greed alone. A researcher may see that pride plus recognition creates stronger loyalty than rules alone. These surprises spark imagination. Creativity grows when people see new patterns. Mixing ideas makes learning playful and deep.

11.  Young Learners can Explore Society

Teenagers curious about politics can use the system to test ideas. They can design questions about fairness, loyalty, or justice. They can see how synthetic personas respond. This builds civic awareness. A student may learn that anger leads to rash choices. Another may learn that kindness builds trust. These lessons prepare young people to think about society. Simulation gives them a safe way to explore big issues.

12.  Simulation Teaches Without Danger

Real experiments with betrayal or crime would be unsafe. Simulation avoids risk. AI creates synthetic respondents who act like real people. Learners can explore sensitive topics safely. A student can study cheating without hurting classmates. A police officer can study bribery without risking real cases. A researcher can study espionage without touching secrets. Simulation makes dangerous lessons safe. Safety allows bold exploration.

13.  Law Enforcement can Train with Realism

Police and security teams face real temptations and risks. Simulation lets them practice safely. They can design vignettes about suspects offered money or friendship. They can see how synthetic personas respond. This prepares them for real cases. A police officer may learn that suspects often justify betrayal as harmless. Another may learn that suspects respond strongly to flattery. These lessons improve training. Simulation builds readiness.

14.  Political Scientists can Map Ideas

Researchers study how public opinion shifts. Simulation helps them test scenarios. They can design vignettes about economic crises or foreign threats. They can see how synthetic groups respond. This shows patterns of social change. A researcher may learn that fear increases loyalty. Another may learn that anger increases betrayal. These insights help predict society’s future. Simulation gives political science new tools.

15.  Simulation Builds Bridges

The same tool works for young learners, police, and scholars. This connects groups. A high school project and a government training can use the same platform. A college class and a research lab can share methods. A police academy and a university can compare results. This shared method builds common understanding. Bridges grow between groups. Simulation unites society.

Acknowledgments

The authors would like to acknowledge the extensive use of AI (specifically Microsoft CoPilot) as an assistant helping to frame the ideas. The use of AI provides a way to incorporate an ‘objective’ way to help structure the data. The AI was extensively ‘trained’ on the Mind Genomics and Psychophysics publications of author Moskowitz, publications appearing from 1990 onwards.

The authors would like to thank Vanessa M. Arcenas for her ongoing participation as coordinator and editor of these efforts regarding Mind Genomics and its intersection with Psychophysics and with AI, respectively.

References

  1. Chohan UW (2025) DOGE A Public Value Critique SSRN.
  2. Coussa A, Bellissimo N, Poulia K-A, Karavetian M (2024) Use of mind genomics for public health and wellbeing Lessons from COVID 19 Advances in Biomedical and Health Sciences. [crossref]
  3. Gentry JA (2025) Strategic warning intelligence Revival Comparative Strategy. [crossref]
  4. Gere A, Papajorgji P, Moskowitz H, Milutinovic V (2019) Using a Rule Developing Experimentation Approach to Study Social Problems The Case of Corruption in International Journal of Political Activism and Engagement. [crossref]
  5. Gofman A, Moskowitz HR (2010) Isomorphic Permuted Experimental Designs And Their Application In Conjoint Analysis. Journal of Sensory Studies. [crossref]
  6. Harizi A, Trebicka B, Tartaraj A, Moskowitz H (2020) A mind genomics cartography of shopping behavior for food products during the covid-19 23rd International Conference on Multidisciplinary Studies Resilience for Survival.
  7. Makridis C (2025) Overcoming the Federal Talent Gap Evidence from Special Governmental Employees and Other Pathways SSRN.
  8. Monahan T (2025) Surveillance in Trump’s Surveillance & Society. [crossref]
  9. Moskowitz H, Kover A, Papajorgji P (2022) Applying Mind Genomics to Social IGI Global. [crossref]
  10. Moskowitz H, Wren J, Papajorgji P (2020) Mind Genomics and the LAP LAMBERT Academic Publishing. [crossref]
  11. Papajorgji P, Moskowitz H (2022) The ‘Average Person’ Thinking About Radicalization A Mind Genomics Cartography. Journal of Police and Criminal Psychology. [crossref]
  12. Zdaniuk B (2014) Ordinary Least-Squares OLS Model Encyclopedia of Quality of Life and Well-Being Research. Springer Netherlands.

After 45 Years of Pancreatic Islet Transplantation, Is It Time to Seriously Consider Molecular Alternatives to Cure Type 1 Diabetes?

10 Replies

DOI: 10.31038/EDMJ.20261022

Abstract

Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin-producing beta (b)-cells of the pancreas resulting in hyperglycaemia and life-threatening complications. The promise of a β-cell replacement therapy has yet to be fulfilled due to the shortage of donor pancreata and the requirement for lifelong immunosuppression to prevent recurrent autoimmunity and allograft rejection, both of which pose significant clinical risks. Therefore, islet/ pancreas transplantation is unlikely to be a realistic cure for most patients. In this opinion summary, we build on our laboratory’s work and that of other researchers demonstrating the successful genetic engineering of surrogate b-cells from hepatocytes that are capable of synthesising and secreting insulin in response to physiological metabolic cues, akin to pancreatic b-cells. We propose that these advances highlight the feasibility of clinical translation and provide proof-of-principal that a patient’s own hepatocytes could ultimately be reprogrammed in vivo towards a b-cell phenotype. This approach bypasses the challenges of both donor tissue availability and immune-mediated rejection that complicate allogeneic islet and pancreas transplantation.

Introduction and Background

Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin-producing pancreatic beta (β)-cells. It is the most common chronic disease of childhood in developed nations and its incidence continues to rise each year. Current treatment constitutes multiple daily insulin injections and blood glucose monitoring. Tight glucose control achieved through intensive insulin therapy can delay, but not eliminate, complications such as nephropathy, retinopathy, cardiovascular disease, and neurological impairment, which collectively contribute to significant morbidity and mortality. Since the 1970s pancreatic (β)-cell replacement has been considered a promising approach for the treatment of T1D, where pancreatic islets, purified from either an allogeneic or xenogeneic donor pancreas are administered to the patient, most commonly through portal vein infusion [1]. However, this procedure is limited by a shortage of donor pancreata and the requirement for lifelong immunosuppression, with its associated adverse side effects, together with a number of other unresolved issues, including limitations in encapsulation technology. Microencapsulation technology isolates islets in a thin layer of biomaterials, such as alginate, which allow the exchange of nutrients, insulin and other substances, improving immuno-rejection. However, studies have encountered several challenges, including pores blockage or obstruction, reduced cell viability and cell death and diminished insulin response to glucose levels [1].

Before the clinical onset of T1D, islet autoantibodies signal the initiation of silent and progressive destructive autoimmune processes, often appearing months or even years before hyperglycaemia develops. This pre-symptomatic phase presents a unique opportunity for early intervention. Indeed, population-based screening programs for T1D have been shown to reduce the incidence of diabetic ketoacidosis at diagnosis by enabling earlier detection [2]. To date the most successful studies aimed at delaying T1D onset has been the administration of anti-CD3 monoclonal antibodies, such as Teplizumab [3]. So far, immunotherapies have not had ultimate successes in altering T1D disease course. Their benefits are typically short term and long term favourable immune responses or regulation has remained difficult to sustain.

Thus, alternative therapeutic strategies are urgently needed. Gene therapy, whereby an “artificial β-cell”, capable of synthesising and secreting insulin in response to the physiological metabolic signals, is generated by genetically engineering the patient’s own cells. This approach would circumvent the issues of tissue rejection inherent to both allogeneic transplantation of islets and pancreas. Our laboratory (and others) has shown that a number of cell types can be used for the genetic engineering of artificial β-cells [4-15], but hepatocytes are particularly useful as they as they derive from the same endodermal precursors as pancreatic cells and possess similar characteristics to pancreatic β-cells, including an ability to process and secrete proteins, and a glucose sensing system (glucose transporter 2 [GLUT2] and glucokinase [Gck] [ 6-8,12,14,15].

Recent Work from Our Laboratory

Our team and others have established that specific combinations of β-cell transcription factors exert a synergistic effect in stimulating β-cell transdifferentiation, storage of insulin in granules, regulated insulin secretion to glucose and other β-cell secretogogues, and, most importantly, permanent reversal of diabetes [5,6,13]. Additionally, and very importantly, this transdifferentiation process does not result in recurrent autoimmune reactions against the surrogate β-cells [14]. Together, these findings highlight that only approaches combining immune regulation with enhanced β-cell survival have the potential to delay, prevent and ultimately cure T1D.

A recent study investigated a novel gene therapy approach that prevented disease development by replacing pancreatic β-cell function with insulin-producing cells generated through hepatic transdifferentiation [14]. In this model, a clinically applicable third- generation lentiviral vector (based on the pRRLSIN.cPPT.PGK-GFP. wpre vector) was used to deliver a cocktail of β-cell transcription factors: pancreatic and duodenal homeobox 1 (Pdx1), neuronal differentiation 1 (ND1), and MAF BZIP Transcription Factor A (MafA) to the portal vein of 5-6-week-old non-obese diabetic (NOD) mice. At the experimental endpoint of 30-weeks, all (100%) of the treated NOD mice remained normoglycemic, exhibited normal intraperitoneal glucose tolerance responses and demonstrated an ability to regulate blood glucose as effectively as the non-diabetic controls. A range of pancreatic markers, including somatostatin, Glut 2 and, most importantly mouse insulin (Ins1 and Ins2), were detected in the liver, and liver function tests remained normal. Collectively, these findings showed that expression of these β-cell transcription factors induced partial pancreatic transdifferentiation and prevented the onset of hyperglycemia and impaired glucose tolerance, as the transduced hepatocytes effectively assumed β-cell function. Immunohistochemistry confirmed that endogenous β-cells had been destroyed by the autoimmune process. As lentiviral vectors permanently transduce cells, this approach therefore holds substantial promise as a potential clinical therapy, particularly if applied in individuals at early stages of Type 1 diabetes.

Author Contributions

Both authors contributed to the writing and review of the manuscript and approved the final version.

Acknowledgements

The authors have nothing to report.

Funding

This study was supported by the National Health and Medical Research Council (NHMRC) of Australia, Ideas grant, number 1187040.

Disclosure Provenance and Peer Review

Nothing to report.

References

  1. Q Wang, Y-xi Huang, L Long, X-h Zhao, Y Sun, X Mao and S-w Li (2024) Pancreatic islet transplantation: current advances and Frontiers in Immunology. [crossref]
  2. F Chiarelli, M Rewers, M Phillip (2022) Screening of autoantibodies for children in the general population: A position statement endorsed by the European society for pediatric endocrinology. Hormone Research Pediatric. [crossref]
  3. KC Herold, BN Bundy, SA Long, JA Bluestone, LA DiMeglio, MJ Dufort and SE Gitelman (2019) An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 New England Journal of Medicine. [crossref]
  4. Q Zhou, J Brown, A Kanarek, J Rajagopal and DA Melton (2008) In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature. [crossref]
  5. E Banga, LV Akinci, JR Greder, JR Dutton and JM Slack (2012) In vivo reprogramming of Sox 9+ cells in the liver to insulin-secreting Proceedings of the National Academy of Science. [crossref]
  6. B Ren, BA O’Brien, MA Swan, ME Kiona, NT Nassif, MQ Wei, AM Simpson (2007) Long-term correction of diabetes in rats following lentiviral hepatic insulin gene Diabetologia. [crossref]
  7. B Ren, BA O’Brien, MR Byrne, E Ch’ng, PN Gatt, MA Swan, NT Nassif, MQ Wei, R Gijsbers, Z Debyser, AM Simpson (2013) Long term reversal of diabetes in non obese diabetic mice by liver-directed gene therapy. Journal of Gene Medicine. [crossref]
  8. B Ren, QT La, BA O’Brien, NT Nassif, Y Yan, D Gerace, R Martiniello-Wilks, F Torpy, AP Dane, IE Alexander IE, AM Simpson (2018) Partial pancreatic transdifferentiation of primary human hepatocytes in the livers of an humanized mouse Journal of Gene Medicine. [crossref]
  9. F Galivo, E Benedetti, Y Wang, C Pelz, J Schug, KH Kaestner, M Grompe (2017) Reprogramming human gall bladder cells into insulin-producing β-like cells. PLoS ONE. [crossref]
  10. M Elsner, T Terbish, A Jorns, O Naujok, D Wedekind, HJ Hedrich, S Lensen (2012) Reversal of diabetes through gene therapy of diabetic rats by hepatic insulin expression via lentiviral transduction. Molecular Therapy. [crossref]
  11. X Xiao, P Guo P, C Shiota, T Zhang, GM Coudriet, S Fishbach S et Endogenous reprogramming of alpha cells into beta cells, induced by viral gene therapy, reverses autoimmune diabetes. Stem Cells. [crossref]
  12. HP Huang and MJ Tsai (2000) Transcription factors involved in pancreatic islet J Biomed Sci. [crossref]
  13. L Sommer, Q Ma and D Anderson (1996) Neurogenins, a novel family of atonal- related bHLH transcription factors are putative mammalian neuronal determination genes that reveal progenitor cell heterogeneity in the developing CNS and PNS. Molecular Cell Neuroscience. [crossref]
  14. ALG Mahoney, B Ren, NT Nassif, BA O’Brien, CA Gorrie, GJ Logan, IE Alexander and AM Simpson (2025) Hepatic Expression of a Cocktail of Beta Cell Transcription Factors Stimulates Liver Cell Transdifferentiation to Prevent Hyperglycaemia in NOD Mice. Molecular Therapy.
  15. MT Tabiin, BE Tuch, L Bai, X Han and AM Simpson (2001) Susceptibility of insulin- secreting hepatocytes to the toxicity of pro-inflammatory Journal of Autoimmunity. [crossref]

Algal Blooms, Dinoflagellates and Petroleum Resources

7 Replies

DOI: 10.31038/GEMS.2026813

Abstract

A theory of petroleum formation from algal blooms is revised in the light of recently obtained data on biochemical composition of dinoflagellate lipids, microalgal blooms, “marine snow” and its composition, taxonomy of major phytoplankton groups and their relative abundances. The article is illustrated with electron micrographs of dinoflagellates, a scheme of petroleum formation and a map. It is concluded that seasonal dinoflagellate blooms or those of a longer period may be the principal agent in the petroleum formation.

Keywords

Algal blooms, Dinoflagellata, Marine phytoplankton, Microalgae, Oil, Petroleum formation, Petroleum resources

Introduction

Petroleum (crude oil) has played an important role for humans worldwide. During the 20th century until the present it has been an important factor in geopolitics and conflicts between countries, determining the welfare of individual humans through that of entire nations. During wars that depended on energy sources for military vehicles, it has been considered the blood of war and the blood of the economy. Today oil is the primary source of energy and the most important commodity traded among many countries. More than half of the energy that powers our civilization comes from this non- renewable energy source. Therefore, it is a strategic resource whose scarcity would cause the decline of the global economy [1,2]. Oil is not distributed evenly around the world, so many countries are heavily dependent on nations with oil resources. At present, the world’s largest proven petroleum reserves are in Venezuela, Saudi Arabia, Iran, Canada, Iraq, United Arab Emirates, Kuwait, Russia, United States of America, and Libya.

Among the hypotheses that could explain the origin of petroleum during the geological history of the Earth, there is one based on the suggestion that marine phytoplankton (in particular, algal blooms caused by dinoflagellates) are the principal source of petroleum resources [3]. Herein are some suggestions that we consider relevant:

  1. “Judging from… rough correspondences between distribution of areas of oil fields and supposedly great expanse of the so- called Old Tethys Sea, or became more and more preferable to conclude that petroleum was derived primarily from phytoplankton of this sea.”
  2. “Frequent occurrences of intense red water blooms in coastal shallow water may be responsible for petroleum formation throughout long continued geological periods.”
  3. “Planktonic diatoms are non-motile, but usually possess spiny surface extensions which give them resistance to passage through water. Largely due to this, over-crowding of diatoms is theoretically limited. In contrast, dinoflagellates are motile but frequently do not possess floatation structures.”
  4. “Poisonous effects caused by dinoflagellate also So that it is not phytoplankton only, but also all of higher marine organisms killed by intense red water occurrence that are most highly responsible for the formation of petroleum.”

The present study reviews some aspects of this hypothesis emphasizing the advances in our knowledge of algal blooms and major microalgal taxonomic groups, in particular, of recent marine dinoflagellates.

Material and Methods

To discuss Abe’s suggestions [3] previously presented, some old and modern literature was selected and reviewed. Some dinoflagellate species were selected to illustrate dinoflagellate morphological diversity. The cells were collected in the coastal water of the Peninsula of Yucatán, the southern Gulf of Mexico during the period of 2009-2012. Phytoplankton samples were fixed with a stock formaldehyde solution to a final concentration of 4% and stored in 100-ml plastic bottles. They were examined in a JEOL JSM-7600F scanning electron microscope (SEM) at a working distance of 8 to 15 mm and a voltage of 5.0 kV after a preliminary wash in distilled water, followed by dehydration in a series of ethanol solutions of increasing concentration (30, 50, 70 and 90% and twice in 100%), air drying on 0.5” aluminum mounts and sputter coating with gold-palladium using a Polaron SC7640 High Resolution Sputter Coater (Quorum Technologies, Newhaven, East Sussex, U.K.).

Results and Discussion

Elemental Composition and Generation of Petroleum Based on Organic Matter

Hydrocarbons (petroleum) originate from the thermogenic transformation of organic matter preserved in sedimentary basins. From a geological perspective, the occurrence of oil and gas reservoirs is intrinsically linked to the presence of source rocks within stratigraphic sequences [4]. Although approximately 98% of the Earth surface crust is composed of sediments or sedimentary rocks, the confluence of critical conditions for the formation of petroleum systems, such as generation, migration and entrapment, is a restrictive phenomenon, present in less than 1% of this surface [5]. At the geochemical level, while the quality of crude oil exhibits subtle variations depending on its geographic origin and thermal maturity, its elemental composition is remarkably constant. Petroleum is a complex mixture of organic compounds where the predominant elements are carbon and hydrogen, which represent approximately 95% of the total mass. The remaining percentage (between 1% and 7%) corresponds to heteroatoms, mainly sulfur, oxygen and nitrogen, whose presence and proportion define critical properties, such as viscosity and the degree of corrosivity of the fluid [6]. The generation of oil based on the amount of organic matter in marine and terrestrial systems has been accepted since the 1990s. Deng et al. (2023) [7] described the theoretical basis of oil and gas generation worldwide and confirmed that amount of hydrocarbons is closely correlated to the organic matter load present in sedimentary rocks. Furthermore, the organic matter used for oil production depends primarily on photosynthetic organisms (phytoplankton) in marine systems.

Biochemical Composition of Dinoflagellate Lipids

Due to their composition and origin, lipids produced by phytoplankton have been the subject of study for the last 50 years [8], with triacylglycerols, galactolipids and phospholipids being the main lipid components in these microorganisms [9,10]. These lipids have been of great importance in the field of biotechnology, mainly for the synthesis of a variety of saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids (e.g., oleic acid (OA; 18:1(n-9), arachidonic acid (AA; 20:4(n-6), eicosapentaenoic acid (EPA; 20:5(n- 3), docosapentaenoic acid (DPA; 22:5(n-3), and docosahexaenoic acid (DHA; 22:6(n-3) that make up 5 to 60% of the cell dry weight [11,12]. In particular, triacylglycerol contributes up to 30%, free fatty acids up to 10%, and sterols approximately 5% of the phytoplankton lipid composition [10]. These lipids have multiple functions, from energy storage to the synthesis of membranes and bioactive substances that ensure their ecological success [13,14]. In particular, dinoflagellates can synthesize a mixture of highly unsaturated long-chain fatty acids (C28) and complex sterols, such as 4-methyl sterols and 4-desmethyl sterols, which serve as characteristic chemotaxonomic indicators [15,16]. These lipids are highly similar to crude oil, mainly due to the high carbon content (>85%) [4]. This is relevant for elucidating the origins of petroleum because of the quality of its organic matter; it is rich in complex lipids and specific biomarkers called dinosteranes (Table 1). These compounds are highly resistant and contribute to the formation of type I and II kerogen, both precursors of crude oil [17].

Table 1: Contribution of some groups of microorganisms to marine organic matter; Phyto – phytoplankton; Zoo – zooplankton.

Taxonomic group

 Type Main contribution to organic matter Sedimentation rate (m day-1)

Petroleum potential (kerogen)
Diatoms Phyto Lipids and silica

0.5-100*

 Very high: Primary source of lipids (Type II)
Dinoflagellates Phyto Dinidporins (polymers) and sterols

0.5-10

 High: Excellent preservation of biopolymers
Coccolithophorids Phyto Calcium carbonate

1-50*

 Medium: Provide ballast for massive sinking
Cyanobacteria Phyto Labile organic matter (proteins)

< 0.5

 Low: Mostly recycled at the surface
Copepods Zoo Compact fecal pellets

30-160

 Indirect: Package and protect lipids
Krill (Euphausiaceae) Zoo Fecal pellets and active transport

150-350

 Medium: Inject carbon at great depths
Salps Zoo Large and dense fecal pellets

400-1,200

 High: Massive and ultra-fast carbon export
Appendicularians Zoo Marine snow (mucus houses)

50-200

 Medium: Trap fine particles in aggregates
Foraminiferans Zoo Calcareous skeletons

100-500

 Low-medium: Key to source rock density

Algal Blooms

An algal bloom caused by dinoflagellates is a highly productive event that drastically alters carbon fluxes in the ocean. The biomass of these microorganisms can reach massive concentrations, commonly known as “red tides” [20]. Unlike diatoms, dinoflagellates possess a particular chemical composition that influences the production of organic matter, which is ultimately preserved [21]. During bloom events, the concentration of organic carbon can exceed 500 to 1,000 µg of carbon per liter, which is 10 to 50 times higher than under normal ocean conditions [22]. Furthermore, net primary production rates of 2 to 5 g C m-2 day-1 have been recorded during the peak of the bloom; additionally, many dinoflagellates produce resistant cysts, whose walls are made of dinosporins (polymers similar to sporopollenin), which increases the rate of sedimentation and transport of carbon in the deep zones [17].

Much literature has been published about harmful algal blooms (HAB), caused by both toxic and non-toxic species, and various aspects of the so-called HAB science. Most bloom-forming marine species are dinoflagellates, and many of them have been reported toxic in any part of the world ocean, in marine environments, brackish and freshwater bodies [23]. At present, pelagic and benthic blooms are distinguished. Recently, (epi)benthic species have been paid much attention, and 242 dinoflagellate species from 63 genera have been described: most of them are sand-dwelling followed by epiphytic [24]. As for the duration of HAB events, they may last from several hours to more than a year. For example, the Karenia brevis (C.C. Davis) Gert Hansen & Moestrup (= Gymnodinium breve C.C. Davis) blooms on the West Florida shelf may last more than a year, and 8-12-month blooms are not uncommon there [25]. While in freshwater most toxic species are cyanobacteria (97 species from 10 orders), in the marine environment, especially in the coastal zone, dinoflagellates have the highest species richness (118 species from 8 orders) (Figure 1).

Figure 1: Electron micrographs of recent marine dinoflagellates from the coastal zone of the southern Gulf of Mexico (A, B, E, and H are from the Yucatán Peninsula; C, D, F and G are from the state of Veracruz): A – Pyrodinium bahamense L. Plate is highly toxic producer of paralytic shellfish poisoning (PSP) in humans, distributed in tropical waters; B – Gonyaulax polygramma F. Stein is a non-toxic species causing harmful algal blooms in subtropical waters; C – Ceratocorys horrida F. Stein is distributed mainly in the open sea in the tropical zone, possesses membraned spines characteristic of warm waters; D – Blixaea quinquecornis (T.H. Abé) Gottschling in Gottschling et al. is one of the few benthic-planktonic dinoflagellates with a tropical-boreal distribution, inhabiting both marine and estuarine brackish waters, non-toxic, causing intense blooms in the southern Gulf of Mexico; E – Scrippsiella spinifera G. Honsell & M. Cabrini is a non-toxic species described from the Mediterranean Sea in 1991, recently found in the southern Gulf of Mexico together with the blooming species Scrippsiella acuminata (Ehrenberg) Kretschmann, Elbrächter, Zinssmeister, S. Soehner, Kirsch, Kusber & Gottschling, capable of producing calcareous resting cysts unlike most dinoflagellates; F – Phalacroma rapa F. Stein is a non-toxic species; G – Dinophysis caudata Kent is a toxic neritic tropical-boreal species, producing okadaic acid and causing diarrhetic shellfish poisoning (DSP) in humans; H – Prorocentrum cordatum (Ostenfeld) J.D. Dodge is a toxic bloom-forming species, causing hepatotoxicity in mice and adverse effects on invertebrates, inhabiting both marine and brackish waters.

Other major microalgal groups are Bacillariophyceae (31 species), Haptophyta (8), Raphidophyceae (4) and Dictyochophyceae (3) [23]. Sixty-seven species and the taxa identified to the generic level are harmful non-toxic, not considering 20 species in the so-called grey list. It is worth considering that about one half of the recent dinoflagellate species are heterotrophs, and the other half are photosynthetic, most of which are mixotrophs. Strictly speaking, heterotrophic species are not phytoplankton if we define it as composed of photosynthetic organisms. Furthermore, ciliates, which also belong to the clade Alveolata as do dinoflagellates, include many photosynthetic species (also known as plastidic ciliates; facultative or obligate autotrophs); e.g., Mesodinium rubrum (Lohmann) (= Myrionecta rubra Lohmann) is an obligate autotroph that contains endosymbiotic cryptophytes [26].

“Marine Snow” and Its Composition

Microalgal cells and, in particular, dinoflagellates cells, can be part of the phenomenon known as “marine snow”, organic aggregates, particle flux, detrital material, pelagic sediment(s) or particulate organic matter [27-37]. “The scientists used the term “marine snow” for the abundant, readily visible, suspended particles in the water.” [37: 6]. “Material exported from the euphotic zone leaves as large, fast-sinking particles, and constitutes a source of food for pelagic and benthic organisms.” [35: 565]. Marine snow consists of detritus (organic debris including fecal pellets), living organisms (phytoplankton, protozoans, zooplankton) and inorganic matter, with associated microbial communities [30]. The history of marine snow research, emphasizing the major discoveries prior to the end of the 20th century, was presented by Silver (2015) [37]. In addition, marine snow-like particles, such as fecal pellets (mainly of the crustacean zooplankton) and amorphous aggregations, are distinguished [34]. It is also worth noting that microaggregates found in the water column [38] are different from large or macroscopic aggregates [31,32], which are synonymous with marine snow. The composition of marine snow has been actively studied during several decades hitherto. Both prokaryotic and eukaryotic microalgae are part of it. In earlier studies, as components of sinking particles, diatoms, dinoflagellates, coccolithophorids and unidentified (micro)flagellates [35,36] have been commonly mentioned. Apart from those, the following taxonomic groups of unicellular eukaryotic organisms have been mentioned more frequently: radiolarians and foraminiferans [34]. It is logical to suggest that, considering the advances in the field of taxonomy of major microalgal groups (discussed below), most become a part of marine snow or microaggregates and participate in vertical carbon flux. Based on the data obtained with the use of sediment trap deployments in all oceans with a sampling duration of more than one year, it was concluded that at some locations the particle flux maxima are the results of bloom periods of individual phytoplankton species [33]; the highest primary production values up to more than 100 g m-2 yr-1 were related to the blooming species of dinoflagellates, diatoms and coccolithophorids [39,40].

The Origin of Petroleum

A historical overview of the origin of petroleum was given by Walters (2006) and Höök et al. (2010) [40,41]. All theories of petroleum origin can be divided into abiotic (= abiogenic or non- biogenic) and biotic (= biogenetic) (Figure 2).

Figure 2: The importance of phytoplankton and zooplankton in the formation of petroleum in marine systems.

Previously, it was concluded that the origin of petroleum is duplex, organic and inorganic, stating that petroleum was laid down in Cambrian and Ordovician strata during the last 500 million years [42] for the distribution of the land masses and water basins on the Earth 500 Mya, see Figure 3).

Figure 3: Distribution of the land masses and oceans on the Earth in the Late Jurassic; modified from Scotese (2001), and Encyclopædia Britannica.

Paleontologists indicate a possible Precambrian origin of dinoflagellates more than 570 years ago [44]. Ehrenberg (1836) [45] was the first to recognize fossil dinoflagellate cysts. At least 2,294 dinoflagellate species have been described [46], and ca. 13-16% of them produce resting cysts also called dinocysts [47]. Resting cyst are the result of sexual reproduction, and they are diploid hypnozygotes (zygotic resting cysts), unlike haploid vegetative cells (except for Noctilucophyceae that have diplontic life-cycle, i.e. with the predominant diplontic stage). However, sexual reproduction has been known only for 1% of recent dinoflagellate species, but it is suggested that it could be a universal phenomenon for this taxonomic group; the zygotic nature of most fossil cysts remains unproven [44].

Recent Advances in the Taxonomy of Major Phytoplankton Groups and Their Relative Abundances

During the last decades a number of new classes of microalgae were described, including previously described taxa of the lower taxonomic level: Dictyochophyceae Silva 1980; Coleochaetophyceae Jeffrey 1982; Pavlovophyceae Cavalier-Smith 1986, emend. Green & Medlin 2000; Pedinophyceae Moestrup 1991, emend. Fawley, Zechman & Buchheim in Adl et al. 2012; Pelagophyceae Andersen & Saunders 1993; Noctilucophyceae Fensome et al. 1993; Klebsormidiophyceae van den Hoek et al. 1995; Trebouxiophyceae Friedl 1995; Zygnematophyceae van den Hoek et al. 1995, emend. Hall et al. 1999; Bolidophyceae Guillou et al. 1999; Pinguiophyceae Kawachi et al. 2003; Chlorokybophyceae Lewis & McCourt 2004; Mesostigmatophyceae Marin & Melkonian 1999, emend. Lewis & McCourt 2004; Mediophyceae Jouse & Proshkina-Lavrenko in Medlin & Kaczmarska 2004; Mamiellophyceae Marin & Melkonian 2010; Palmophyllophyceae Lelaert et al. 2016; Chloropicophyceae Lopes dos Santos & Eikrem 2017, Picocystophyceae Lopes dos Santos & Eikrem 2017; Biddulphiophyceae D.G. Mann in Adl et al. 2019; Leprocylindrophyceae D.G. Mann in Adl et al. 2019; Corethrophyceae D.G. Mann in Adl et al. 2019 [48]. Most major microalgal taxa have been described since 1990s based on transmission electron and light microscopy observations, and some were also based on biochemical data (e.g., Pelagophyceae and Bolidophyceae). Recently, metagenomic data of the relative abundances of different taxonomic groups in marine phytoplankton of all the oceans, based on the Tara Oceans Project in 2009-2013, have been published. Although dinoflagellates and diatoms remain the dominant groups in terms of the cell abundance, there are other groups (the picocyanobacterial genera Prochlorococcus Chisholm, Frankel, Goericke, Olson, Palenik, Waterbury, West- Johnsrud & Zettler ex Komárek et al. and Synechococcus Nägeli, Haptophyta (= Prymnesiophyta), Chlorophyta and Pelagophyta [49,50].

Protecting Marine Ecosystems Where Phytoplankton Live Could Ensure Petroleum Resources in the Future

Phytoplankton are a group of unicellular and colonial photosynthetic organisms capable of inhabiting diverse marine and freshwater bodies [51]. In aquatic ecosystems, phytoplankton comprises a network of biological interactions that have enabled successful conversion of light energy to chemical energy through biogeochemical cycles. Therefore, along with higher plants, phytoplankton provides a solid foundation of ecosystem services in both terrestrial and marine environments [52]. These services include supporting, regulating, provisioning and cultural services. It is estimated that 45% of global net primary production or more (≈108 pg C yr-¹) comes from phytoplankton [53,54]. In particular, groups such as diatoms and dinoflagellates are the primary source of the organic matter that makes up kerogen types I and II. These microorganisms synthesize lipid compounds that, when attached to sediments, possess the necessary energy density to transform into liquid petroleum [17]. Therefore, the protection of marine systems should be treated globally as a matter of energy security. This will ensure phytoplankton biodiversity, which, in turn, guarantees that the chemical quality of the organic matter reaching the seabed is optimal for hydrocarbon generation [55].

Acknowledgments

We thank Marcia M. Gowing (Seattle, WA, USA) for improving the English style and for valuable advice, and Dora A. Huerta- Quintanilla (CINVESTAV-IPN, Mérida, Yucatán) for her help with the scanning electron microscope. Financial support to the FOMIX CONACYT-Yucatán project “Análisis de las causas, dispersión y consecuencias ambientales de la marea roja en Yucatán” (No. 108897; 2009–2012) given to Jorge A. Herrera-Silveira (CINVESTAV-IPN), and the FOMIX CONACYT-Yucatán (No. 108160) and CONACYT LAB-2009-01 (No. 123913) projects of the Laboratorio Nacional de Nano y Biomateriales (CINVESTAV-IPN) given to Patricia Quintana- Owen is much appreciated.

References

  1. Palazuelos E (2009) El petróleo y el gas en la geoestrategia Editions Akal.
  2. Krishna S, Gambelli AM, Sreenivasan H, Vadim F, et al. (2026) The petroleum industry and climate change. In Al-Enazi A, Al-Musleh E (Eds) Decarbonizing the petroleum Elsevier.
  3. Abé TH (1965) Red water and dinoflagellates as primary sources of In Second International Conference on Protozoology, London, August 1965. Reprinted from Excerpta Medica International Congress Series No. 91.
  4. Liu H, Jiang Y (2025) Petroleum Springer. Singapore.
  5. Biju-Duval B (2002) Sedimentary geology: sedimentary basins, depositional environments, petroleum formation. Editions Technip.
  6. Kundu N (2023) Geoscience for petroleum engineers. Springer, Singapore.
  7. Deng Y, Yang Y, Yang T (2023) Three systems of the oil and gas formation in the Acta Petrolei Sinica 44.
  8. Barkia I, Saari N, Manning SR (2019) Microalgae for high-value products towards human health and Marine Drugs 17.
  9. Falk-Petersen S, Sargeant JR, Henderson J, Hegseth EN, et (1998) Lipids and fatty acids in ice algae and phytoplankton from the Marginal Ice Zone in the Barents Sea. Polar Biology 20: 41-47.
  10. Jónasdóttir SH (2019) Fatty acid profiles and production in marine Marine Drugs 17.
  11. D’Alessandro EB, Antoniosi Filho NR (2016) Concepts and studies on lipid and pigments of microalgae: A Renewable and Sustainable Energy Reviews 58: 832-841.
  12. Morales M, Aflalo C, Bernard O (2021) Microalgal lipids: A review of lipids potential and quantification for 95 phytoplankton species. Biomass and Bioenergy 150.
  13. Ianora A, Bentley MG, Caldwell GS, Casotti R, Allan DC, et al. (2011) The relevance of marine chemical ecology to plankton and ecosystem function: an emerging field. Marine Drugs 9: 1625-1648. [crossref]
  14. Goncalves EC, Johnson JV, Rathinasabapathi B (2013) Conversion of membrane lipid acyl groups to triacylglycerol and formation of lipid bodies upon nitrogen starvation in biofuel green algae Chlorella Planta 238: 895-906. [crossref]
  15. Cárdenas P, Acuña V, Contreras S, Salgado P, et (2025) The sterol composition of harmful dinoflagellates distinguishes environmental characteristics of Chilean Patagonia. Marine Environmental Research 214. [crossref]
  16. Rathinavel L, Ravikumar Y, Jothinathan D, Pandey, A, et (2025). Extraction and enrichment of fatty acids from marine microalgae. In Marine molecules from algae and cyanobacteria. Elsevier. [crossref]
  17. Tissot BP, Welte DH (1984) Petroleum formation and Springer, Berlin, Germany.
  18. Bach LT, Bauke C, Meier KJS, Riebesell U, et (2012) Influence of changing carbonate chemistry on morphology and weight of coccoliths formed by Emiliania huxleyi. Biogeosciences 9: 3449-3463.
  19. Turner JT (2015) Zooplankton fecal pellets, marine snow, phytodetritus and the ocean’s biological Progress in Oceanography 130: 205-248.
  20. Hallegraeff GM (2003) Harmful algal blooms: A global In Hallegraeff GM, Anderson DM, Cembella AD (Eds) Manual on harmful marine microalgae (2nd ed). UNESCO, Paris, France.
  21. Inomura K, Deutsch C, Jahn O, Dutkiewicz S, et al. (2022) Global patterns in marine organic matter stoichiometry driven by phytoplankton ecophysiology. Nature Geoscience 15: 1034-1040. [crossref]
  22. Smayda TJ (1997) Harmful algal blooms: their ecophysiology and general relevance to phytoplankton blooms in the Limnology and Oceanography 42: 1137-1153.
  23. Lundholm N, Bernard C, Churro C, Escalera L, et al. (Eds) (2026) IOC-UNESCO taxonomic reference list of harmful microalgae.
  24. Hoppenrath M, Chomérat N, Horiguchi T, Murray SA, Rhodes L (2023) Marine benthic dinoflagellates – their relevance for science and society (2nd ed). Senckenberg Gesellschaft für Naturforschung, Germany.
  25. Kusek KM, Vargo GA, Steidinger KA (1999) Gymnodinium breve – A scientific and journalistic analysis. Contributions in Marine Science 34: 1-229.
  26. Barber RT, White AW, Siegelman HW (1969) Evidence for a cryptomonad symbiont in the ciliate, Cyclotrichium meunieri. Journal of Phycology 5: 86-88. [crossref]
  27. Riley GA (1963) Organic aggregates in seawater and the dynamics of their formation and Limnology and Oceanography 8: 372-381.
  28. Riley GA (1970) Particulate matter in seawater. Advances in Marine Biology 8: 1-118.
  29. Silver MW, Shanks A, Trent JD (1978) Marine snow: microplankton habitat and source of small-scale patchiness in pelagic populations. Science 201: 371-373. [Crossref]
  30. Trent JD, Shanks AL, Silver MW (1978) In situ and laboratory measurements on macroscopic aggregates in Monterey Bay, Limnology and Oceanography 23: 626-635.
  31. Shanks AL, Trent JD (1979) Marine snow: Microscale nutrient patches. Limnology and Oceanography 24: 850-854.
  32. Alldredge AL, Silver MW (1988) Characteristics, dynamics and significance of marine Progress in Oceanography 20: 41-82.
  33. Wefer, G (1989) Particulate flux in the ocean: Effects of episodic In Berger WH, Smetacek VS, Wefer G (Eds) Productivity of the ocean. John Wiley & Sons Limited, S. Bernhardt, Dahlem Konferenzen, Pg: 139-153.
  34. Silver MW, Gowing MM (1991) The “particle” flux: origins and biological Progress in Oceanography 26: 75-113.
  35. Lee C, Wakeham S, Arnosti C (2004) Particulate organic matter in the sea: The composition AMBIO 33: 565-575.
  36. Ploug H, Iversen MH, Fischer G (2008) Ballast, sinking velocity, and apparent diffusivity within marine snow and zooplankton fecal pellets: Implications for substrate turnover by attached bacteria. Limnology and Oceanography 53: 1878-1886.
  37. Silver M (2015) Marine snow: A brief historical ASLO.
  38. Goldman JC (1984) Conceptual role for microaggregates in pelagic waters. Bulletin of Marine Science 35: 462-476.
  39. Honjo S (1982). Seasonality and interaction of biogenic and lithogenic particulate flux at the Panama Science. 218: 883-884. [crossref]
  40. Walters CC (2006) The origin of petroleum. In: Hsu CS, Robinson PR (Eds) Practical advances in petroleum Springer, New York, NY, USA. Pg: 79-101.
  41. Höök M, Bardi U, Feng L, Pang X (2010) Development of oil formation theories and their importance for peak Marine and Petroleum Geology 27: 1995-2004.
  42. Robinson R (1960) The origins of Nature 5068: 1291-1295.
  43. Scotese CR (2001) Atlas of Earth PAKEOMAP Project.
  44. Fensome RA, Taylor FJR, Norris G, Sarjeant WAS, et al. (1993) A classification of living and fossil Sheridan Press, Hanover, PA, USA.
  45. Ehrenberg CG (1836) Zusätze zur Erkenntnis grosser organischer Ausbildung in den kleinsten thierschen Organismen. Preussische Akademie der Wissenschaften, Abhandlungen 1835: 151-180.
  46. Gómez F (2012) A checklist and classification of living dinoflagellates (Dinoflagellata, Alveolata). CICIMAR Oceánides 27: 65-140.
  47. Head MJ (1996) Modern dinoflagellate cysts and their biological In Jansonius J, McGregor DC (Eds). Palynology: principles and applications. The American Association of Stratigraphic Palynolologists Foundation. Pg: 1197-1248.
  48. Adl SM, Bass D, Lane CE, Lukeš J, et (2019) Revisions to the classification, nomenclature, and diversity of eukaryortes. Journal of Eukaryotic Microbiology 66: 4-119. [crossref]
  49. Pierella Karlusich JJ, Ibarbalz FM, Bowler C (2020) Phytoplankton of the Tara Annual Review of Marine Science 12: 233-265. [crossref]
  50. Pierella Karlusich JJ, Pelletier E, Zinger L, Lombard F, et (2023). A robust approach to estimate relative phytoplankton cell abundances from metagenomes. Molecular Ecology Resources 23: 16-40. [crossref]
  51. Reynolds CS (2006) The ecology of Cambridge University Press.
  52. Naselli-Flores L, Padisák J (2023) Ecosystem services provided by marine and freshwater Hydrobiologia 850: 2691-2706. [crossref]
  53. Field CB, Behrenfeld MJ, Randerson JT, Falkowski P (1998) Primary production of the biosphere: Integrating terrestrial and oceanic components. Science 281: 237-240. [crossref]
  54. Wanek E, Esteban-Cantillo OJ, Bourgeois-Gironde S (2025) Valuing marine plankton: a review of ecosystem services and disservices and an expert assessment of the potential of area-based Frontiers in Marine Science 12.
  55. Peters KE, Walters CC, Moldowan JM (2005) The biomarker guide: Biomarkers and isotopes in petroleum systems and Earth Cambridge University Press.

Pathologic Complete Response as a Prognostic and Surrogate Endpoint in Neoadjuvant Therapy for Solid Tumors: A Comprehensive Review Beyond Breast Cancer

3 Replies

DOI: 10.31038/CST.20261111

Abstract

Background: Neoadjuvant therapy is increasingly used across solid tumors to improve surgical outcome, assess systemic treatment sensitivity, and reduce early metastatic risk. Pathologic complete response (pCR), defined as the absence of residual invasive cancer following neoadjuvant treatment, has been accepted by the U.S. Food and Drug Administration (FDA) as a surrogate endpoint to support accelerated approval in high-risk early-stage breast cancer. However, the strength and generalizability of the association between pCR and long-term clinical outcomes, such as event-free survival (EFS) and overall survival (OS), vary substantially across tumor types and disease subgroups.

Methods: We evaluated recent meta-analyses, randomized trials, and large retrospective studies examining the association between pCR and survival outcomes, including EFS, OS, and recurrence-free survival (RFS), across multiple tumor types (ie. breast cancer, non-small cell lung cancer, melanoma, gastrointestinal malignancies, head and neck cancer, ovarian cancer, bladder cancer, and Merkel cell carcinoma).

Results: In breast cancer, pCR strongly predicts improved EFS and OS, particularly in triple-negative and HER2-positive subtypes, while its predictive value is less pronounced in HR+/HER2- disease. Emerging evidence supports pCR as a prognostic marker in melanoma, NSCLC, gastrointestinal, ovarian, head and neck squamous cell carcinoma, and muscle-invasive bladder cancers, though trial-level correlations vary and data remain limited in several settings. Associations are generally stronger in patient-level analyses than trial-level surrogacy assessments.

Conclusions: These findings highlight both the clinical value and the limitations of pCR as an endpoint. Continued tumor-specific evaluation of pCR using rigorous patient- and trial-level statistical frameworks is warranted to inform regulatory decision-making and optimize neoadjuvant drug development beyond breast cancer.

Keywords

Pathologic complete response, Breast cancer, Head and neck cancer, Melanoma, NSCLC, Esophageal cancer, Gastrointestinal cancer, Ovarian, Bladder cancer, Merkel cell carcinoma

Introduction

Neoadjuvant therapies havebecome a cornerstone in themanagement of multiple solid tumors, with potential to downstage disease, improve surgical resectability, provide early assessment of treatment sensitivity, and eradicate micrometastatic progression before surgery. With the expansion of neoadjuvant approaches to include targeted therapies and immunotherapies, the identification of robust intermediate endpoints that predict long-term clinical benefit has gained critical importance.

pCR, defined as the absence of residual invasive cancer cells in the resected primary tumor and sampled regional lymph nodes following neoadjuvant treatment (typically ypT0/is ypN0), has been recognized by the FDA as a surrogate endpoint to support accelerated approval specifically in high-risk early-stage breast cancer. Its use in other tumors is exploratory and not validated broadly for regular approval. This position is articulated in the current FDA guidance, Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early- Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval [1]. The 2020 revision reflects FDA’s updated thinking and provides recommendations for trial design, statistical considerations, and acceptable pCR definitions in the neoadjuvant breast cancer setting. This regulatory precedent has motivated growing interest in evaluating pCR as a potential surrogate endpoint in additional tumor types, although its predictive value varies considerably across diseases.

Clinical practice guidelines also reflect the evolving role of treatment response in neoadjuvant care. Recent versions of the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology incorporate neoadjuvant systemic therapy pathways and acknowledge that the degree of treatment response—including clinical and pathological response—can inform postoperative management in specific settings. In breast cancer (NCCN Breast Cancer Version 5.2025), neoadjuvant therapy is strongly recommended for HER2- positive and triple-negative subtypes, with the extent of response (including pCR) refining adjuvant treatment decisions, consistent with evidence linking pCR to improved long-term outcomes. In rectal cancer (NCCN Rectal Cancer Version 4.2025), guidelines endorse consideration of nonoperative “watch-and-wait” management for carefully selected patients demonstrating a clinical complete response after neoadjuvant chemoradiation, underscoring the prognostic importance of response assessment even when not strictly defined pathologically [2,3]. For esophageal and gastroesophageal junction cancers (NCCN Esophageal/EGJ Cancers Version 1.2026), pathologic evaluation after neoadjuvant chemoradiotherapy is recommended as part of postoperative planning. NCCN Bladder Cancer (v3.2025) recognizes pCR post-neoadjuvant chemotherapy as prognostic but not a formal decision criterion. NCCN Cutaneous Melanoma (v2.2025) notes pCR/MPR as prognostic, informing de-escalation in responders but not standardized. NCCN NSCLC (v3.2026) emphasizes neoadjuvant chemo-immunotherapy with pCR/MPR as prognostic (e.g., CheckMate-816: pCR patients 95.3% (95% CI 82.7–98.8) 5-year OS) but not mandatory for decisions.

This review synthesizes the available evidence assessing the association between pCR and long-term survival outcomes across multiple solid tumors. We examine both patient-level prognostic associations, where pCR consistently correlates with favorable outcomes, and trial-level surrogacy analyses, where correlations between treatment effects on pCR and survival endpoints are more variable. By integrating data across tumor types, our objective is to provide a balanced and rigorous framework for evaluating the strengths, limitations, and future potential of pCR as an endpoint to guide neoadjuvant drug development, clinical trial design, and regulatory strategies beyond breast cancer.

Material and Methods

A comprehensive systematic literature review was conducted using databases including PubMed, EMBASE, and the Cochrane Library from database inception through December 2025. The literature consists of meta-analyses, randomized clinical trials, and clinical studies evaluating associations between pCR and survival outcomes. Both patient-level and trial-level associations were included if reported.

Results

Breast Cancer

In breast cancer, achieving pCR is strongly associated with improved long-term outcomes, including EFS, disease-free survival (DFS), and OS. A large pooled meta-analysis of 52 studies involving 27,895 patients treated with neoadjuvant therapy demonstrated a robust association between pCR and improved EFS across major subtypes—triple-negative breast cancer (TNBC), HER2-positive disease, and hormone receptor-positive/HER2-negative (HR+/ HER2-) disease. Across the entire population, 5-year EFS was 88% in patients achieving pCR compared with 67% in those without pCR, underscoring the prognostic significance of pCR irrespective of subtype (Table 1) [4]. While pCR is a strong patient-level prognostic marker, trial-level surrogacy is weak in some analyses; for example, a meta-regression across 29 randomized trials showed only modest correlation between treatment effects on pCR and DFS (R² = 0.08) or OS (R² = 0.09), highlighting variability by subtype and regimen [5].

Table 1: Breast Cancer

Study

 Number of Patients Number of Trials

Summary of Findings
von Minckwitz et al., 2012 [8]

6,377

7
  • ypT0 ypN0 is associated with better DFS compared to ypTis ypN0 (HR = 0.57) and better OS (HR = 0.71)
  • ypT0 ypN0 is associated with better DFS (HR = 0.31) and OS (HR = 0..25) than ypT0/is ypN+
  • Prognostic impact strongest in HER2+ and TNBC; absent in luminal A
Berruti et al., 2014 [5]

14,641

29
  • Weak trial-level association between pCR and DFS (R² = 0.08) or OS (R² = 0.09)
Broglio et al., 2016 [9]

5,768

36
  • HER2+ Breast Cancer: EFS for pCR vs non-pCR was significant (HR = 0.37). Hormone receptor-negative (HR = 0.29); hormone receptor-positive (HR = 0.52).
Cortazar et al., 2014 [7]

11,955

12
  • For pCR vs non-PCR:•
    Overall population: EFS: HR 0.48; OS: HR 0.36•  HR-pos HER2-neg: EFS: HR 0.49; OS: HR 0.43
    HER2-pos: EFS: HR 0.39; OS: HR 0.34
    HR-neg: EFS HR 0.25, OS HR 0.19.
    TNBC: EFS HR 0.24; R² = 0.03 and 0.24 for EFS and OS.
Spring et al., 2020 [4]

27,895

52
  • 5-yr EFS: 88% (pCR) vs 67% (no pCR)
  • Patients with a pCR after NAT had significantly better EFS (HR = 0.31), particularly for TNBC (HR = 0.18) and HER2- pos (HR = 0.32) disease.
  • pCR after NAT was also associated with improved survival (HR = 0.22).
Huang et al., 2020 [10]

4,330

25
  • TNBC: pCR was associated with improved EFS (HR = 0.24) and OS (HR = 0.19).
  • The 5-year EFS was 86% vs 50% for pCR vs no pCR.
  • The 5-year OS was 92% vs 58% for pCR vs no pCR.
Davey et al., 2022 [6]

25,150

78
  • HER2-pos: pCR predicted better EFS (HR 0.67; 41 studies), RFS (HR 0.69; 18 studies) and OS (HR 0.63; 29 studies).

Subtype-specific analyses further reinforce this relationship. In HER2-positive early breast cancer, a systematic review and meta- analysis of 78 studies (25,150 patients) showed that pCR was associated with significant improvements in survival outcomes, with hazard ratios of 0.67 (95% CI 0.60–0.74) for EFS and 0.63 (95% CI 0.56–0.70) for OS. These benefits were consistent across various HER2-targeted regimens, though the magnitude was greatest in hormone receptor- negative HER2-positive disease [6].

A landmark systematic review and pooled analysis of approximately 12,000 patients from 12 international trials (CTNeoBC) demonstrated that pCR rates vary substantially by subtype: highest in HER2-positive (particularly HR-/HER2+) and TNBC, and lowest in HR+/HER2- disease [7]. Although the association between pCR and long-term outcomes was weaker in HR+/HER2- tumors overall, achievement of pCR in this subgroup still correlated with significantly better EFS and OS, particularly among high-grade tumors. In HER2-positive disease, pCR strongly predicted improved EFS and OS regardless of hormone receptor status, with a more pronounced prognostic effect in HR-/ HER2+ tumors than in HR+/HER2+ tumors. Across all subtypes, the collective evidence positions pCR as a strong prognostic marker, with the greatest clinical relevance in TNBC and HER2-positive disease, where both absolute pCR rates and survival correlations are highest.

Non-Small Cell Lung Cancer (NSCLC)

In resectable NSCLC, pCR is a strong patient-level prognostic marker. A meta-analysis of 7,011 patients treated with neoadjuvant chemotherapy (± radiotherapy) showed that pCR was associated with significantly improved outcomes (EFS HR 0.46; OS HR 0.50) [11]. With the introduction of neoadjuvant chemo-immunotherapy, a meta- analysis of eight randomized trials (3,387 patients) demonstrated higher pCR rates (RR 5.58) and improved 2-year EFS (HR 0.57) compared with chemotherapy alone (Table 2) [12].

Table 2: Non-small cell lung cancer.

Study

 Number of Patients Number of Trials

Summary of Findings
Rosner et al., 2022 [11]

7,011

28
  • pCR vs non-pCR: OS HR 0.50; EFS HR 0.46
Banna et al., 2024 [12]

3,387

8
  • Neoadjuvant chemo-immunotherapy compared to chemo: improved 2-year EFS (HR 0.57) and increased pCR rate (RR 5.58).
  • No reports were provided about the comparison of EFS for pCR vs non-pCR patients.
Hines et al. 2024 [13]

2,385

7
  • At the patient level, the R² of pCR with 2-year EFS was 0.82. The odds ratio of 2-year EFS rates by response status was 0.12 (0.07–0.19).
  • At the trial level, the R² for the association of odds ratio of response and HR of EFS was 0.58.
Waser et al., 2024 [14]

6,530

20
  • pCR vs no pCR: HR = 0.49 for OS
  • MPR vs no MPR: HR = 0.36 for OS
  • pCR vs no pCR: HR = 0.49 for EFS (11 studies, n=2,156)
  • Trial-level analyses did not show a strong correlation between pCR and OS (R² = 0.045) or EFS (R² = 0.319).
CheckMate 816 5-yrupdate [15]

358

1
  • pCR vs non-pCR: 5-yr OS 95.3% (95% CI 82.7-98.8) vs 55.7% (95% CI 46.9-63.7) (exploratory)
  • Pre-surgery ctDNA clearance vs others: 5-yr OS 75.0% vs 52.6%

A recent surrogacy analysis of seven immune checkpoint inhibitor trials (2,385 patients) found a strong patient-level correlation between pCR and 2-year EFS (R²=0.82), although trial-level surrogacy was only moderate and imprecise (R²=0.82) [13]. A larger pooled analysis reported weaker trial-level correlations (R²=0.045 for OS; 0.319 for EFS) [14].

Long-term observational data also support pCR as a prognostic marker. In a 403-patient stage IIIA–IIIC cohort treated with induction chemotherapy, concurrent chemoradiation, and surgery, pCR occurred in 34% and independently predicted improved survival (OS HR 0.27; EFS HR 0.35) [15]. pCR rates were higher in squamous tumors (46%) than non-squamous (27%).

Updated results from major perioperative trials further reinforce this association. In the final 5-year analysis of CheckMate 816, overall 5-year OS was 65.4% in the nivolumab-chemotherapy arm versus 55.0% with chemotherapy alone (HR 0.72, P=0.048). In exploratory subgroup analyses, patients achieving pCR had a 5-year OS of 95.3% (95% CI 82.7–98.8) compared with 55.7% (95% CI 46.9–63.7) in those without pCR [16]. Similar patterns have been observed in AEGEAN and KEYNOTE-671, where higher pCR/MPR rates parallel sustained EFS benefits [17,18].

Ongoing IASLC initiatives continue to standardize pCR/MPR assessment and evaluate their potential as surrogate endpoints for regulatory use in resectable NSCLC.

Melanoma

In resectable stage III melanoma, neoadjuvant immunotherapy— particularly dual checkpoint blockade with PD-1 and CTLA-4 inhibitors—induces high pathologic response rates with strong prognostic value. In the OpACIN-neo trial, interobserver agreement for pathologic response assessment was excellent (κ = 0.879; ICC = 0.965), and patients achieving a pathologic response (<50% viable tumor) had markedly improved outcomes, with 3-year recurrence-free survival (RFS) of 95% versus 37% in non-responders (P < 0.001). An immune- active fibrosis-rich subtype further predicted absence of recurrence and prolonged RFS. Long-term follow-up from the combined OpACIN and OpACIN-neo trials confirmed durable benefit, with pathologic response remaining the strongest predictor of low relapse risk [19,20].

Single-agent PD-1 therapy demonstrates similar prognostic patterns. In a phase Ib trial of neoadjuvant pembrolizumab followed by adjuvant pembrolizumab, no deaths occurred among patients achieving major pathologic response (MPR) or pCR, yielding a 5-year OS of 100% compared with 72.8% in non-MPR patients [21].

Pooled analyses from the International Neoadjuvant Melanoma Consortium (INMC; n = 818) further confirm the prognostic value of pathologic response. In the updated INMC pooled dataset presented at ESMO 2024, patients achieving major or complete pathologic response had 3-year recurrence-free survival of 89%, demonstrating durable disease control across neoadjuvant regimens [22] (Table 3).

Table 3: Melanoma and Merkel Cell Carcinoma.

Study

 Number of Patients Number of Trials

Summary of Findings
OpACIN-neo trial [20]

86

1

 Melanoma:

  • Pathologic response (<50% viable tumor, including pCR + near-pCR/MPR) achieved in ~74–78% (regimen-dependent; 77% in optimal arm).
  • pCR (0% viable tumor) in substantial subset (~20–47% across arms).
  • Estimated 3-year RFS 95% for pathologic responders vs 37% for non-responders (P < 0.001) after median 47-monthfollow-up.
Study NCT02434354 [21]

30

1

 Melanoma:

  • 5-yr OS 100% in MPR/pCR vs 72.8% in non-MPR; no deaths in MPR/pCR
NADINA [23]

423

1

 Melanoma:

  • Neoadjuvant nivo+ipi: MPR 59%; 12-mo RFS 95.1% MPR vs 57% non-response; 2-yr EFS 77.3% (HR 0.32–0.40 vs adjuvant nivo)
  • pCR associated with 5-year EFS of 83% vs. 53% for non-pCR; 5-year OS of 89% vs. 64% for non-pCR
  • Updated 2-year data (ESMO 2025) show 24-month EFS 77.3% (HR 0.40; 95% CI 0.28-0.57; P<0.001) and DMFS 82.8% (HR0.43; 95% CI 0.29-0.64; P<0.001) for neoadjuvant vs adjuvant. MPR (59%) strongly predicted 12-month RFS (95.1% vs 57%).
INMC pooled (ESMO 2024) [22]

818

1

 Melanoma:

  • 633 (77%) trial pts and 185 (23%) real-world pts
  • MPR rates 46% (PD-1 mono), 62% (PD-1+CTLA-4), 67% (PD-1+LAG-3); 3-year RFS 89% in MPR achievers (highest prognostic marker). 3-year EFS 64% (PD-1 alone), 76–77% (PD-1+CTLA-4), 82% (PD-1+LAG-3).
PRADO [24]

99

1

 Melanoma:

  • MPR in 61/99 (61.6%), including pCR in 41/99 (41.4%). MPR patients underwent de-escalated surgery and omitted adjuvanttherapy. 2-year RFS was 93% (95% CI 86–100%) in MPR patients.
SWOG S1801 [25]

313

1

 Melanoma:

  • 2-year EFS 72% with neoadjuvant-adjuvant pembrolizumab vs 49% with adjuvant-only pembrolizumab (HR 0.58; 95% CI 0.39–0.87; P = 0.004).
CheckMate 358 [63]

36

1

 Merkel Cell Carcinoma:

  • Neoadjuvant nivolumab: pCR 47.2% (17/36);
  • no relapses in pCR patients at 19.3-month median post-op follow-up.
  • RFS at 12 months: 100% vs 59.6% (pCR vs non-pCR); at 24 months: 88.9% vs 52.2%; RFS HR 0.12.

Recent phase 3 data further validate neoadjuvant immunotherapy. In the NADINA trial, neoadjuvant nivolumab plus ipilimumab followed by response-adapted adjuvant therapy significantly improved EFS (HR 0.32–0.40 vs adjuvant nivolumab) with an MPR rate of 59%, which strongly predicted outcomes (12-month RFS 95.1% vs 57%) [23]. The PRADO extension showed that MPR enabled de-escalated surgery, with 2-year RFS of 93% in responders [24]. SWOG S1801 similarly demonstrated EFS superiority for neoadjuvant-adjuvant pembrolizumab over adjuvant-only therapy [25].

NCCN Cutaneous Melanoma Guidelines (Version 2.2025) now endorse neoadjuvant immune checkpoint inhibition for resectable stage IIIB–IIID disease and recognize pCR/MPR as important prognostic markers informing postoperative treatment intensity, though not yet validated surrogate endpoints.

Overall, achieving MPR or pCR after neoadjuvant immunotherapy predicts exceptional long-term RFS and OS in melanoma, supporting ongoing shifts toward response-adapted neoadjuvant strategies.

Merkel Cell Carcinoma

In Merkel cell carcinoma (MCC), a rare and aggressive neuroendocrine skin cancer, pCR after neoadjuvant immunotherapy is a strong patient-level prognostic marker, associated with prolonged RFS and excellent long-term outcomes in responders (Table 3).

Although data are limited by disease rarity, emerging evidence from neoadjuvant immune checkpoint inhibitor trials supports high pCR rates and favorable prognosis. In the phase I/II CheckMate 358 trial, neoadjuvant nivolumab (two doses) achieved a pCR rate of 47.2% (17/36 evaluable patients), with additional major pathologic responses observed. No patient achieving pCR experienced relapse at a median postoperative follow-up of 19.3 months, and RFS was markedly improved in responders (12- and 24-month RFS 100% and 88.9%, respectively) [63] (Table 3).

Supporting evidence from case reports and small series demonstrates similar findings with neoadjuvant avelumab, including complete pathologic responses and absence of recurrence at short- term follow-up [64].

Collectively, these findings highlight pCR/MPR as a robust prognostic indicator in resectable MCC treated with neoadjuvant immunotherapy, consistent with the tumor’s high immunogenicity. However, trial-level surrogacy remains unestablished due to small cohorts, lack of randomized data, and limited long-term follow- up. Ongoing studies evaluating neoadjuvant combinations and response-adapted strategies may further clarify the clinical utility of pCR, including potential treatment de-escalation in complete responders.

Gastrointestinal Malignancies

In gastric and gastroesophageal junction (GEJ) cancers, pCR after neoadjuvant or perioperative therapy is associated with improved survival at the patient level, but trial-level surrogacy remains limited. Foundational perioperative chemotherapy trials first established modern treatment paradigms. The MAGIC trial (ISRCTN93793971) demonstrated improved 5-year overall survival (OS) with perioperative ECF (epirubicin, cisplatin, and 5-fluorouracil) versus surgery alone (36% vs 23%; HR 0.75; 95% CI 0.60–0.93; P = 0.009), showing pathologic downstaging but without pCR as a primary endpoint [26]. The FLOT4 trial established perioperative FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) as superior to ECF/ECX (epirubicin, cisplatin, and 5-fluorouracil or capecitabine), improving median OS (50 vs 35 months; HR 0.77; 95% CI 0.63–0.94; P = 0.012) and increasing pCR rates (16% vs 6%) (Table 4) [27].

Table 4: Gastrointestinal Cancers.

Study

 Number of Patients Number of Trials

Summary of Findings
MAGIC trial [26]

503

1

 Gastroesophageal:

  • Improved 5-year OS 36% vs 23%; HR 0.75 (95% CI 0.60–0.93), P = 0.009. Significant pathologic T- and N-stage downstaging. pCR not prospectively assessed
FLOT4 Trial [27]

716

1

 Gastric:

  • pCR rate: 16% (Becker Ia) with FLOT vs 6% with ECF/ECX (P<0.001 in phase 2 part; consistent in full trial). Higher major regression with FLOT.
MATTERHORN Trial [28]

948

1

 Gastric:

  • pCR rate: 19.2% (95% CI 15.7-23.0) with durvalumab + FLOT vs 7.2% (95% CI 5.0-9.9) with FLOT alone (P<0.001).
  • Supports perioperative IO addition; linked to EFS/OS benefits
KEYNOTE-585 (2025final update) [29]

804

1

 Gastric:

  • pCR rate: 12.9% (95% CI 9.8-16.6) with perioperative pembrolizumab + chemo vs 2.0% (95% CI 0.9-3.9) with chemo alone (P<0.00001).
  • Final OS showed numerical improvement but non-significant EFS benefit (44.4 vs 25.7 mo; HR 0.81, 95% CI 0.67- 0.98; did not meet prespecified threshold) and OS (71.8 vs 55.7 mo; HR 0.86, 95% CI 0.71-1.06; not significant); pCR prognostic but not strong trial-level surrogate.
Sugumar et al., 2025 [31]

11,882

25

 Rectal:

  • No trial-level correlation. On meta-regression analysis, pCR was not correlated with OS (β = 0.37; 95% CI, -0.98 to 1.71; P = .57).
  • Similarly, pCR was not correlated with DFS (β = -0.84; 95% CI, -2.55 to 0.87; P = .32).
Smyth et al., 2016 [32]

330

1

 Gastroesophageal:

  • Mandard TRG 1–2 vs 3–5: 5-year OS 58.8% vs 28.9%; HR 1.94, P = 0.021. Demonstrates prognostic value of histologic regression (retrospective).
Soro et al 2018 [33]

56

 Esophageal:

  • pCR vs non-pCR: Median OS 4.1 vs 1.7 yrs; Median DFS 3.1 vs 1.1 yrs (P=0.04)
Murphy et al 2017 [34]

911

1

 Esophageal:

  • pCR was associated with better OS (median 71.28 vs 35.87 mo) and higher 5-year OS rate 52% vs 41% compared to non-pCR; was also associated with better RFS (median 70.75 vs 26.07 mo).
Lin et al. 2018 [35]

68

1

 Esophageal:

  • pCR is associated with higher 2-year OS rate 81.3% vs 58.3% (P = 0.025).
Wan et al 2019 [36]

6,780

21

 Esophageal, esophagogastric junction AC, gastric AC, rectal cancer and pancreatic cancer:

  • pCR vs non-pCR: OS (HR = 0.50, P < 0.001) and DFS (HR = 0.49, P < 0.001).
  • In EGJAC/GAC, the correlation of pCR with OS was significant (HR = 0.38, p = 0.02).
Li et al. 2018 [37]

1,143

7

 Gastric:

  • RR of pCR vs non-pCR is 0.5(p<0.0001), 0.34(p<0.0001), and 0.44 (p<0.0001) for 1, 3, 5-year-OS, respectively.
  • RR for 3-year DFS was 0.43 (p = 0.002)
Petrelli et al. 2017 [38]

10,050

22

 Rectal:

  • Patient level: change of pCR is correlated weakly with change of OS 5-year rate (R² = 0.28). 3-year DFS rate and OS was similarly (R²=0.37). Trial level: R² = 0.41 and 0.04 respectively.
Sun et al. 2025 [40]

8,040

38

 Esophageal:

  • pCR vs non-pCR (esophageal, post-NCRT): OS HR 0.54 (95% CI 0.52-0.57); DFS HR 0.51 (95% CI 0.46-0.57).
  • Strong patient-level prognostic association
RAPIDO Trial [41]

912

1

 Rectal:

  • pCR rate: 28% with TNT vs 14% with standard CRT (OR 2.37; P < 0.001)
  • Disease-related treatment failure: 23.7% vs 30.4% (HR 0.75; P = 0.019)
  • TNT significantly increased pCR, but pCR showed limited trial-level surrogacy for long-term outcomes

Perioperative chemo-immunotherapy further increases pCR but demonstrates variable impact on survival. In MATTERHORN (NCT04592913), durvalumab plus FLOT doubled pCR rates (19.2% vs 7.2%; OR 3.12; 95% CI 2.23–4.37; P < 0.00001) and significantly improved event-free survival (EFS HR 0.71; 95% CI 0.58–0.86; P < 0.001), with final OS HR 0.78 (95% CI 0.63–0.96; P = 0.021) and FDA approval in November 2025 [28].

By contrast, KEYNOTE-585 (NCT03221426) significantly increased pCR with pembrolizumab plus chemotherapy (12.9% vs 2%) but did not achieve statistically significant EFS or OS improvement in final analyses. Final analysis (JCO 2025) showed non-significant EFS benefit (44.4 vs 25.7 mo; HR 0.81, 95% CI 0.67-0.98) and OS (71.8 vs 55.7 mo; HR 0.86, 95% CI 0.71-1.06), neither reaching protocol defined significance [29]. The DANTE/FLOT8 trial (NCT03421288) reported enhanced histopathologic regression and downstaging with atezolizumab + FLOT versus FLOT alone, though survival follow-up remains ongoing [30].

In rectal cancer, pCR following neoadjuvant chemoradiotherapy (CRT) or total neoadjuvant therapy (TNT) strongly predicts individual patient outcomes—including improved DFS, OS, and reduced recurrence—but does not function as a reliable trial-level surrogate. A comprehensive meta-analysis of 25 randomized trials (11,882 patients) found no significant correlation between treatment- related increases in pCR and improvements in OS or DFS, indicating that pCR does not function as a validated surrogate endpoint in rectal cancer trials [31].

pCR after CRT or total TNT is a strong patient-level prognostic marker in locally advanced rectal cancer, associated with lower rates of local and distant recurrence and superior OS and DFS in responders compared with non-responders.

In high-risk disease, TNT regimens improve both pCR rates and long-term outcomes. The RAPIDO trial (short-course radiotherapy followed by consolidation chemotherapy vs long-course CRT) reported pCR occurred in 28% of patients in the TNT arm versus 14% in the standard CRT arm (OR 2.37; P < 0.001), and disease-related treatment failure was reduced to 23.7% versus 30.4% (HR 0.75; P = 0.019) [58]. The UNICANCER-PRODIGE 23 trial (neoadjuvant mFOLFIRINOX followed by CRT vs standard CRT) showed improved 3-year DFS (76% vs 69%; HR 0.69; P = 0.034) and higher pCR rates in the experimental arm [59]. These data support TNT as a standard of care for high-risk locally advanced rectal cancer.

pCR also has important clinical implications beyond prognosis. Patients achieving complete response may be candidates for organ- preservation strategies, including watch-and-wait approaches, which have been associated with favorable oncologic outcomes and avoidance of permanent stomas in carefully selected patients [2,3].

However, a systematic review and meta-analysis of 25 randomized trials (11,882 patients) found no significant trial-level association between treatment-related differences in pCR and OS or DFS, indicating that pCR does not function as a reliable surrogate endpoint for survival at the trial level [31]. Overall, pCR remains clinically valuable for individual risk stratification and for guiding organ- preservation strategies in selected patients, but current evidence does not support its validation as a surrogate endpoint for survival in rectal cancer trials.

Achievement of pCR after CRT is strongly associated with superior survival in esophageal cancer. In a CRT cohort of 56 patients, Soror et al. reported a median OS of 4.1 years in pCR patients versus 1.7 years in non-pCR patients, and median DFS of 3.1 years versus 1.1 years, respectively (P = 0.04) [33]. In a large trimodality series of 911 patients, Blum Murphy et al. observed significantly longer survival, with median OS of 71.3 months vs 35.9 months and median RFS of 70.8 months vs 26.1 months in pCR versus non-pCR patients (both P < 0.01) [34]. Similarly reported superior outcomes in patients achieving pCR, with 2-year OS of 81.3% vs 58.3% in non-pCR patients (P = 0.025) [35].

Earlier studies by Davies et al. [36], Meredith et al. [37], Donahue et al. [38], and Berger et al. [39] consistently demonstrated markedly improved long-term survival in patients achieving pCR. A 2025 meta- analysis confirmed strong patient-level associations between pCR and survival, with OS HR 0.54 and DFS HR 0.51, consistent across histologic subtypes [40]. A 2024 pooled analysis further showed that overall pCR rates after neoadjuvant therapy were below 30%, with higher pCR rates in squamous cell carcinoma (SCC) than adenocarcinoma [41].

Neoadjuvant immunochemotherapy (PD-1/PD-L1 inhibitors + chemotherapy ± RT) increases pCR and major pathologic response rates, particularly in SCC, although trial-level surrogacy for OS remains weak (R² = 0.07) [42]. Recent comparative cohorts report pCR rates of 20–30% and improved 3-year OS compared with standard CRT in selected stage III SCC [43].

Overall, pCR remains a meaningful patient-level prognostic marker across gastrointestinal malignancies, but its trial-level surrogacy is weak, supporting its use for risk stratification but not yet as a validated regulatory surrogate.

Head and Neck Cancer

In resectable head and neck squamous cell carcinoma (HNSCC), pCR or MPR after neoadjuvant immunotherapy is associated with substantially improved long-term outcomes at the patient level. Across early-phase trials of neoadjuvant anti-PD-1 agents, reported pCR rates range from10 to15%, and MPR rates range from 20% to 50% with strong prognostic implications [44-46]. In a neoadjuvant pembrolizumab study, pCR occurred in 10% of patients and MPR in 44%, and no recurrences were observed among patients achieving MPR, whereas recurrences occurred predominantly among non-responders [44]. In a phase II trial of nivolumab ± ipilimumab, 2-year DFS was 71% in responders vs 51% in non-responders, with MPR independently predicting better outcomes [45]. A 2021 meta-analysis of neoadjuvant ICI confirmed pCR/MPR linked to superior EFS and OS [46] (Table 5).

Table 5: Neoadjuvant Immunotherapy in Head and Neck Squamous Cell Carcinoma (HNSCC).

Study

 Number of Patients Number of Trials

Summary of Findings
NCT02296684 [44]

36

1

 Pembrolizumab Neoadjuvant–Adjuvant Trial: pCR 10%; MPR 44%. No recurrences among MPR patients; recurrences confined to non-responders.
NCT02919683 [45]

29

1

 Nivolumab ± Ipilimumab Neoadjuvant Trial: MPR 45%. 2-year DFS 71% (responders) vs 51% (non-responders). MPR independently predicted DFS and OS.
Shibata et al. 2021 [46]

382

17

 Neoadjuvant ICI Systematic Review: Pooled pCR 12%; MPR 37%. pCR/MPR significantly associated with improved EFS and OS.
KEYNOTE-689 (NCT03765918) [47]

714

1

 3-year EFS 57.6% vs 46.4% (perioperative pembrolizumab vs SOC); HR 0.73 (95% CI 0.58–0.92; P = 0.008). Neoadjuvant pembrolizumab did not compromise surgery.
Zandberg et al. 2025 [48]

624

9

 Pooled IO Combination Analysis (2024–2025): MPR/pCR 20%–67% depending on regimen (highest with chemo-IO). Responders showed markedly longer DFS and OS; grade ≥3 toxicity higher with chemo-IO.

Recent phase III data (KEYNOTE-689, 2025) demonstrate improved EFS with perioperative pembrolizumab + standard care (surgery + adjuvant RT ± cisplatin) significantly improves EFS (3- year rates 57.6% vs 46.4%; HR reduction) versus standard care alone, with neoadjuvant pembrolizumab safe and not compromising surgery [47]). Updated meta-analyses (2024–2025) report pooled MPR or pCR rates ranging from 20% to 67% with ICI combinations (higher with chemoimmunotherapy), correlating with improved DFS/OS in responders, though chemoimmunotherapy increases grade 3–4 toxicity [48].

These data position pCR/MPR as a meaningful patient-level prognostic marker in HNSCC with neoadjuvant immunotherapy. However, trial-level surrogacy for OS remains unvalidated, and longer follow-up from randomized studies will be required before pathologic response can be accepted as a regulatory surrogate endpoint in this disease.

Ovarian Cancer

In advanced high-grade serous ovarian cancer, pCR after neoadjuvant chemotherapy (NACT) is uncommon (<5–10%) but, when achieved, is strongly associated with improved survival. Because true pCR is rare, most studies use the validated three-tier Chemotherapy Response Score (CRS), with CRS3 indicating complete or near-complete histologic response in the omentum and is considered the pathologic surrogate of chemosensitivity [49] (Table 6).

Table 6: Ovarian Cancer and Bladder Cancer.

Study

 Number of Patients Number of Trials

Summary of Findings
Bohm et al., 2015 [49]

98

1

 Ovarian:

  • Development and validation of 3-tier CRS in high-grade serous ovarian carcinoma post-NACT.
  • CRS3 (complete/near-complete response) vs CRS1-2: prolonged PFS and OS (strong prognostic value, especially in omentum).
Marsh et al., 2025 [50]

133

1

 Ovarian (FIGO III–IV Multicenter CRS Study):

  • CRS3 vs CRS1-2: median PFS 24.8 months vs shorter (p < 0.001); improved OS (p = 0.011).
  • Pathologic response to NACT significantly associated with better PFS/OS.
Choe et al. 2023 [55]

4,287

12

 Ovarian (CRS Meta-analysis):

  • CRS3 and pCR: OS HR 0.48; PFS HR 0.52
Kim et al. 2024 [56]

5,231

15

 Ovarian (CRS Meta-analysis):

  • CRS3 vs CRS1–2: OS HR 0.46; PFS HR 0.51
Bhandoria et al. 2024 [57]

3,942

10

 Ovarian:

  • pCR vs residual disease: OS HR 0.41; RFS HR 0.44
SWOG 8710 (Grossman et al. 2003) [60]

307

1

 MIBC (MVAC vs surgery):

  • Neoadjuvant MVAC vs surgery alone: pCR (ypT0) 38% vs 15%; median OS 77 vs 46 months. Established pCR as a strong prognostic marker after cisplatin-based NAC.
PURE-01 (NCT02736266) [61]

155

1

 MIBC:

  • Neoadjuvant pembrolizumab (3 cycles): pCR (ypT0N0) 36.8%. 36-month EFS 74.4%, OS 83.8%. 36-month RFS in ypT0N0: 96.3%, demonstrating near-curative outcomes in pCR patients.
NIAGARA [62]

1063

1

 MIBC:

  • Durvalumab + gemcitabine-cisplatin vs GC alone: 24-mo EFS 67.8% vs 59.8% (HR 0.68; P<0.001); 24-mo OS 82.2% vs 75.2% (HR 0.75; P=0.01). First phase III trial showing that increasing pCR translates into improved survival.

Across multiple cohorts, CRS3 consistently demonstrates robust prognostic value. In a 133-patient FIGO III/IV cohort, CRS3 was associated with significantly longer progression-free survival (median 24.8 months vs 16.7 months; P < 0.001) and improved overall survival (P = 0.011) compared with CRS1–2 [50]. Foundational work by Böhm et al first established CRS3 as a marker of favorable prognosis [49], and external validation cohorts-including Lee et al. [51], Singh et al. [52], Rajkumar et al. [53] and Cohen et al. [54] -consistently confirmed that CRS3 is associated with significantly prolonged PFS and OS relative to CRS1-2.

Although rare, pCR is likewise associated with substantially longer recurrence-free and overall survival (often by 12–24 months) compared with patients with residual disease. Recent systematic reviews and meta-analyses [55-57] reaffirm the strong patient-level prognostic value of CRS3 and pCR, but highlight persistent limitations for trial-level surrogacy, including low pCR incidence and variability in histopathologic scoring.

Overall, pCR/CRS3 represents a robust patient-level prognostic marker following NACT in advanced ovarian cancer and may help refine postoperative treatment strategies, while broader validation as a regulatory surrogate endpoint is still evolving.

Bladder Cancer

In muscle-invasive bladder cancer (MIBC), pCR after NAC is a strong patient-level prognostic marker, associated with markedly improved RFS and OS. Patients achieving pCR (ypT0N0) at radical cystectomy experience significantly lower recurrence and mortality risks compared with those with residual disease, reflecting highly chemo-sensitive and immunosensitive tumor biology.

Cisplatin-based neoadjuvant chemotherapy (NAC) established this paradigm. In SWOG 8710, neoadjuvant MVAC increased pCR rates to 38% compared with 15% with surgery alone and improved median overall survival (77 vs 46 months) [60]. Subsequent pooled series and meta-analyses consistently demonstrate 5-year OS exceeding 70–80% in ypT0 patients, compared with ~40–50% in patients with residual disease, confirming pCR as a robust patient- level prognostic marker [61] (Table 6).

Neoadjuvant immune checkpoint blockade has confirmed that immunotherapy-induced pCR also translates into durable survival benefit. In PURE-01, three cycles of pembrolizumab before cystectomy produced a pCR rate of 36.8%. At 3-year median follow-up, event- free survival was 74.4% and overall survival was 83.8%. Importantly, among patients achieving ypT0N0, 36-month recurrence-free survival was 96.3%, and 96.1% (95% CI, 89-100) for ypT1/a/isN0, 74.9% (95% CI, 60.2-93) for ypT2-4N0, and 58.3% (95% CI, 36.2-94.1) for ypTanyN1-3 response, demonstrating near-curative outcomes associated with immunotherapy-mediated tumor eradication [61]

Definitive evidence that increasing pathologic response translates into improved survival now comes from the phase III NIAGARA trial. In this perioperative study of durvalumab plus gemcitabine–cisplatin versus chemotherapy alone, the dual primary endpoints of pCR and EFS were met. At 24 months, EFS was 67.8% with durvalumab versus 59.8% with chemotherapy (HR 0.68; P < 0.001), and overall survival was 82.2% versus 75.2% (HR 0.75; P = 0.01), establishing perioperative immunochemotherapy as a new standard of care [62].

Taken together, pCR is a validated patient-level prognostic biomarker in MIBC across chemotherapy and immunotherapy platforms. PURE-01 demonstrates the durability of immunotherapy- induced pCR, while NIAGARA provides the first randomized evidence that increasing pCR translates into improved EFS and OS, strengthening the regulatory case for perioperative immunochemotherapy in bladder cancer.

Discussion

This review synthesizes the evidence supporting pCR as an intermediate endpoint in neoadjuvant therapy across solid tumors, with a focus on its prognostic significance and potential role as a surrogate for long-term clinical outcomes. At the patient level, pCR is consistently associated with improved outcomes across tumors. However, trial-level surrogacy is weak or absent in rectal cancer (no correlation per Sugumar 2025), moderate but imprecise in NSCLC (R²=0.58 per Hines 2024; weaker per Waser 2024), and limited elsewhere due to data immaturity. Regulatory use beyond breast cancer requires tumor-specific validation. The association is most robust and reproducible in breast cancer, particularly in triple- negative and HER2-positive subtypes, and is also well supported in melanoma, NSCLC, muscle-invasive bladder cancer, and head and HNSCC. Emerging evidence suggests comparable prognostic relevance in ovarian cancer using near-complete response metrics such as Chemotherapy Response Score 3 [CRS3]), as well as in Merkel cell carcinoma, and selected gastrointestinal malignancies including gastric, gastroesophageal junction, rectal, esophageal. Notably, the strength of the association between pCR and long-term outcomes varies substantially by tumor biology, molecular subtype, and treatment modality, with the most pronounced effects observed in immunogenic tumors treated with immune checkpoint inhibitors.

From a regulatory standpoint, the FDA’s acceptance of pCR as an endpoint reasonably likely to predict clinical benefit—most notably in high-risk, early-stage breast cancer—rests on a combination of strong patient-level prognostic associations and supportive trial- level surrogacy. Outside this validated setting, however, pCR does not yet meet the evidentiary standard required for broad regulatory reliance. Although patient-level correlations between pCR and survival outcomes remain consistent across many tumor types, trial- level surrogacy-defined as the extent to which treatment-induced improvements in pCR reliably translate into proportional gains in long-term survival has been weak, inconsistent, or absent in several malignancies. For example, meta-regression analyses have failed to demonstrate significant trial-level correlations in rectal cancer, have yielded modest and imprecise estimates in NSCLC, and remain severely limited in rare tumor types due to small sample size and a paucity of randomized neoadjuvant trials.

This fundamental distinction between prognostic utility and surrogate validity carries critical implications for both trial design and regulatory decision-making. pCR is clinically valuable for risk stratification, response-adapted management (e.g., watch-and-wait in rectal cancer, de-escalation in melanoma or Merkel cell carcinoma), and organ preservation paradigms. However, in most settings, pCR alone is insufficient to support claims of clinical benefit or to justify accelerated approval outside of contexts in which trial-level surrogacy has been rigorously established. Consistent with guidance from EMA/CHMP, broader regulatory acceptance of pCR will require tumor-specific validation that demonstrates reproducible trial- level surrogacy, standardized pathologic assessment (e.g., immune- modified neoadjuvant criteria in melanoma and Böhm CRS in ovarian cancer), and confirmation of durable clinical benefit in adequately powered prospective studies.

In conclusion, pCR is a clinically meaningful and prognostically powerful endpoint in neoadjuvant therapy across diverse solid tumors. Its role is firmly established in breast cancer and shows strong patient-level promise in multiple other malignancies, particularly in the context of immunotherapy. However, the use of pCR as a regulatory surrogate beyond breast cancer must be determined on a tumor-specific and context-dependent basis. Continued generation of high-quality neoadjuvant trial data, extended follow-up for survival outcomes, harmonization of pathologic response criteria, and robust trial-level validation will be essential to define the appropriate role of pCR in future drug development and regulatory frameworks.

Conflict of Interest

SC is an employee of Nektar Therapeutics and may own its stocks. PH is an employee of Daiichi Sankyo Inc and may own its stocks. JF is an employee of TransThera Sciences Inc and may own its stocks and may own AstraZeneca stocks. NR declares no competing interests related to this work.

Funding

The authors received no fund for this research.

Disclaimer

Please note the views and opinions expressed are those of the authors and are not intended to reflect the views and/or opinions of their employer(s).

References

  1. U.S. Food and Drug Administration (2020) Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. Guidance for Industry. FDA. [crossref]
  2. Maas M, Nelemans PJ, Valentini V, et al. (2010) Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. [crossref]
  3. Dossa F, Chesney TR, Acuna SA, Baxter NN (2017) A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. [crossref]
  4. Spring LM, Fell G, Arfe A, et al. (2020) Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis. Clin Cancer Res. [crossref]
  5. Berruti A, Amoroso V, Gallo F, et (2014) Pathologic complete response as a potential surrogate for survival in breast cancer: a meta-regression of 29 randomized neoadjuvant trials. J Clin Oncol. [crossref]
  6. Davey MG, Browne JP, Miller NM, et (2022) Pathologic complete response as a surrogate endpoint in HER2-positive early breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat.
  7. Cortazar P, Zhang L, Untch M, et al. (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. [crossref]
  8. von Minckwitz G, Untch M, Blohmer JU, et (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. [crossref]
  9. Broglio KR, Quintana M, Foster M, et al. (2016) Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term J Natl Cancer Inst. [crossref]
  10. Huang M, O’Shaughnessy J, Zhao J, et al. (2020) Association of pathologic complete response with long-term survival outcomes in triple-negative breast cancer: a meta- Clin Cancer Res. [crossref]
  11. Rosner S, Liu C, Forde PM, et al. (2022) Association of pathologic complete response and long-term survival outcomes among patients treated with neoadjuvant chemotherapy or chemoradiotherapy for NSCLC: a meta-analysis. JTO Clin Res Rep. [crossref]
  12. Banna GL, Hassan MA, Signori A, et (2024) Neoadjuvant Chemo-Immunotherapy for Early-Stage Non–Small Cell Lung Cancer: A Systematic Review and Meta- Analysis. JAMA Netw Open. [crossref]
  13. Hines JB, Cameron RB, Esposito A, et (2024) Evaluation of major pathologic response and pathologic complete response as surrogate end points for survival in randomized controlled trials of neoadjuvant immune checkpoint blockade in resectable NSCLC. J Thorac Oncol. [crossref]
  14. Waser NA, et (2024) Trial-level and patient-level surrogacy of pathologic response for survival in neoadjuvant trials of resectable non-small cell lung cancer. Eur J Cancer.
  15. Guberina M, Metzenmacher M, Pöttgen C, Wiesweg M, Guberina N, Merkel-Jens A, et al. (2025) Pathologic Complete Response Predicts Long-Term Survival Following Neoadjuvant Induction Chemotherapy and Chemo-Radiotherapy in Stage-III Non- Small Cell Lung Cancer. Thorac Cancer. [crossref]
  16. Forde PM, Spicer J, Girard N, et (2025) Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer: 5-year outcomes from CheckMate-816. N Engl J Med. [crossref]
  17. Deutsch E, et (2025) AEGEAN: Phase III trial of neoadjuvant durvalumab plus chemotherapy followed by adjuvant durvalumab in patients with resectable non-small cell lung cancer — updated analyses. IASLC World Conference on Lung Cancer. [crossref]
  18. Wakelee HA, Liberman M, Kato T, et (2023) Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. [crossref]
  19. Rawson RV, Thompson JF, Scolyer RA, et (2021) Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma. Ann Oncol. [crossref]
  20. Rozeman EA, Menzies AM, van Akkooi ACJ, et (2023) Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials. Ann Oncol. [crossref]
  21. Sharon CE, Xu X, et al. (2023) Long-term outcomes to neoadjuvant pembrolizumab based on pathological response for patients with resectable stage III/IV cutaneous Ann Oncol. [crossref]
  22. Long GV, Menzies AM, Scolyer RA, et al. (2024) Long-term survival with neoadjuvant therapy in melanoma: Updated pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC) Ann Oncol. [crossref]
  23. Blank CU, Lucas MW, van Akkooi ACJ, et (2024) Neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic, resectable stage III melanoma: the phase 3 NADINA trial. N Engl J Med. [crossref]
  24. Reijers ILM, Menzies AM, van Akkooi ACJ, et al. (2022) Personalized response- driven surgery and adjuvant therapy after neoadjuvant ipilimumab plus nivolumab in stage III melanoma (PRADO) Nat Med. [crossref]
  25. Patel SP, Othus M, Prieto V, et (2023) Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in resectable stage III–IV melanoma (SWOG S1801) N Engl J Med. [crossref]
  26. Cunningham D, Allum WH, Stenning SP, et al. (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal N Engl J Med. [crossref]
  27. Al-Batran SE, Homann N, Pauligk C, et (2019) Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. [crossref]
  28. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. (2025) Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med. [crossref]
  29. Shitara K, Rha SY, Wyrwicz LS, et al. (2025) Pembrolizumab plus chemotherapy versus chemotherapy as perioperative therapy in locally advanced gastric and gastroesophageal junction cancer: Final analysis of the randomized, phase III KEYNOTE-585 J Clin Oncol. [crossref]
  30. Lorenzen S, Götze TO, Thuss-Patience P, et al. (2024) Perioperative atezolizumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable esophagogastric cancer: interim results from the randomized, multicenter, phase II/III DANTE/ IKF-s633 J Clin Oncol. [crossref]
  31. Sugumar K, Lie JJ, Stucky CC, et (2025) Pathologic complete response and survival in rectal cancer: a systematic review and meta-analysis. JAMA Netw Open. [crossref]
  32. Smyth EC, Fassan M, Cunningham D, et al. (2016) Effect of pathologic tumor response and nodal status on survival after perioperative chemotherapy for gastroesophageal cancer: a post hoc analysis of the MAGIC Ann Oncol.
  33. Soror T, et (2018) Prognostic significance of pathologic complete response after neoadjuvant chemoradiotherapy in esophageal cancer. J Thorac Dis. [crossref]
  34. Blum Murphy MA, et al. (2017) Pathologic complete response after neoadjuvant chemoradiation in esophageal cancer: prognostic significance. Cancer.
  35. Lin JW, et al. (2018) Prognostic value of pathologic complete response after neoadjuvant chemoradiotherapy in esophageal squamous cell J Chin Med Assoc.
  36. Davies AR, et (2014) Tumor stage after neoadjuvant chemotherapy determines survival after surgery for locally advanced esophageal cancer. J Clin Oncol. [crossref]
  37. Meredith KL, et al. (2010) Pathologic response is the major determinant of survival in patients with esophageal cancer who receive neoadjuvant therapy. Ann Surg Oncol.
  38. Donahue TR, et al. (2009) Complete pathologic response after neoadjuvant chemoradiotherapy for esophageal carcinoma is associated with enhanced survival. Ann Thorac Surg. [crossref]
  39. Berger AC, et (2005) Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol. [crossref]
  40. Sun X, Zhang Y, Li Y, et (2025) Pathologic complete response and survival in esophageal cancer after neoadjuvant therapy: a systematic review and meta-analysis. Eur J Cancer.
  41. Gaber CE, Mönig SP, Berlth F, et (2024) Pathologic complete response after neoadjuvant therapy in esophageal cancer: pooled analysis. Cancer Med.
  42. Yuan Y, Wang H, Liu X, et (2024) Surrogacy of pathologic response for overall survival in neoadjuvant immunochemotherapy for resectable esophageal cancer. Ann Oncol.
  43. Liu J, Li Z, Zhang X, et (2024) Neoadjuvant immunochemotherapy versus chemoradiotherapy for stage III esophageal squamous cell carcinoma: a multicenter comparative cohort study. J Clin Oncol.
  44. Uppaluri R, Campbell KM, Egloff AM, et (2020) Neoadjuvant and adjuvant pembrolizumab in resectable, locally advanced, human papillomavirus–unrelated head and neck squamous cell carcinoma: a multicenter, phase II trial. Clin Cancer Res. [crossref]
  45. Wise-Draper TM, Old MO, Worden FP, et al. (2022) Phase II clinical trial of neoadjuvant and adjuvant nivolumab with or without ipilimumab in resectable locally advanced head and neck squamous cell Clin Cancer Res.
  46. Shibata H, Saito S, Uppaluri R (2021) Neoadjuvant immune checkpoint blockade in head and neck cancer: a systematic review. Cancers (Basel) [crossref]
  47. Uppaluri R, Haddad RI, Tao Y, et al. (2025) Perioperative pembrolizumab in locally advanced head and neck squamous cell N Engl J Med.
  48. Zandberg DP, Ferris RL, Haddad RI, et al. (2025) Neoadjuvant immune checkpoint inhibitor–based therapy in resectable head and neck squamous cell carcinoma: pooled analysis of pathologic response and survival from contemporary J Clin Oncol.
  49. Böhm S, Faruqi A, Said I, et al. (2015) Chemotherapy response score: Development and validation of a system to quantify histopathologic response to neoadjuvant chemotherapy in tubo-ovarian high-grade serous carcinoma. Mod Pathol. [crossref]
  50. Marsh S, Leung S, Pather S, et (2018) Histopathologic chemotherapy response score in ovarian cancer: prognostic significance in FIGO stage III–IV disease. Gynecol Oncol.
  51. Lee JY, Chung YS, Na K, et (2017) Omental chemotherapy response score predicts survival outcomes in advanced ovarian high-grade serous carcinoma treated with neoadjuvant chemotherapy. J Gynecol Oncol.
  52. Singh P, Kumar L, Saha S, et (2018) Histopathological chemotherapy response score predicts survival in high-grade serous ovarian carcinoma treated with neoadjuvant chemotherapy. Int J Gynecol Pathol. [crossref]
  53. Rajkumar S, Sarkar D, Mahajan A, et al. (2018) Omental chemotherapy response score predicts progression-free and overall survival in advanced ovarian Int J Gynecol Cancer.
  54. Cohen PA, Powell A, Beale P, et al. (2019) Omental chemotherapy response score is an independent predictor of survival in patients with advanced high-grade serous ovarian carcinoma treated with neoadjuvant Gynecol Oncol.
  55. Choe JY, Kim SI, Kim JW, et (2023) Prognostic significance of chemotherapy response score and pathologic complete response after neoadjuvant chemotherapy in advanced ovarian cancer: a systematic review and meta-analysis. Gynecol Oncol. [crossref]
  56. Kim YJ, Lee YS, Park JY, et (2024) Chemotherapy response score predicts survival in patients with advanced epithelial ovarian cancer treated with neoadjuvant chemotherapy: a meta-analysis. Eur J Surg Oncol.
  57. Bhandoria GP, Singh S, Mahajan A, et al. (2024) Prognostic impact of pathologic complete response following neoadjuvant chemotherapy in ovarian cancer: a systematic review and meta-analysis. Int J Gynecol Cancer. [crossref]
  58. Bahadoer RR, Dijkstra EA, van Etten B, et al. (2021) Short-course radiotherapy followed by chemotherapy before total mesorectal excision in locally advanced rectal cancer (RAPIDO) N Engl J Med. [crossref]
  59. Conroy T, Bosset JF, Etienne PL, et (2021) Neoadjuvant mFOLFIRINOX plus chemoradiotherapy in rectal cancer (UNICANCER-PRODIGE 23) N Engl J Med.
  60. Grossman HB, Natale RB, Tangen CM, et (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. [crossref]
  61. Necchi A, Basile G, Bandini M, et (2022) Neoadjuvant pembrolizumab and radical cystectomy in patients with muscle-invasive urothelial bladder cancer (PURE-01): 3-year median follow-up. Clin Cancer Res. [crossref]
  62. Powles T, Assaf ZJ, Davarpanah N, et (2024) Perioperative durvalumab plus chemotherapy in muscle-invasive bladder cancer (NIAGARA) N Engl J Med. [crossref]
  63. Topalian SL, Bhatia S, Amin A, et (2020) Neoadjuvant nivolumab for patients with resectable Merkel cell carcinoma in the CheckMate-358 trial. J Clin Oncol. [crossref]
  64. Singh N, Bhatia S, Nghiem P (2019) Complete pathologic response with neoadjuvant avelumab in Merkel cell carcinoma. Oral Oncol. [crossref]

Enhanced Cytotoxic Activity of Corallocarpus epigaeus Tuber-mediated Gold Nanoparticles Against Human Epidermoid Carcinoma A-431 Cells

6 Replies

DOI: 10.31038/NAMS.2025814

Abstract

Background: Plant-derived nanomedicine has emerged as a promising strategy for enhancing anticancer efficacy while reducing toxicity. Corallocarpus epigaeus is a medicinal plant rich in bioactive phytochemicals with reported pharmacological properties.

Objective: The present study aimed to compare the cytotoxic effects of acetone extract of Corallocarpus epigaeus tuber and gold nanoparticles (AuNPs) synthesized using the same extract against the human epidermoid carcinoma A-431 cell line.

Methods: Cytotoxicity was evaluated using the MTT assay across a range of concentrations(1-500 µg/ml). IC50 values were determined by linear regression analysis using a Log(inhibitor) verses normalized response model with variable slope.

Results: The acetone extract exhibited moderate cytotoxicity with an IC50 value of 84.67 µg/ml. In contrast Corallocarpus mediated AuNPs showed significant enhanced cytotoxic activity, with a reduced IC50 value of 57.97 µg/ml. Gold nanoparticles demonstrated greatest growth inhibition at higher concentrations, reducing cell viability to 12.94% at 500 µg/ml compared to 27.45% for the crude extract.

Conclusion: Incorporation of Corallocarpus epigaeus bioactive components into gold nanoparticles significantly enhanced anticancer efficacy, highlighting the potential of plant-mediated AuNPs as a promising nanomedicine approach for epidermoid carcinoma therapy.

Keywords

Corallocarpus epigaeus, Gold nanoparticles, Nanomedicine, Cytotoxicity, A-431 cell line, IC50

Introduction

Cancer remains one of the leading causes of mortality worldwide, necessitating the development of novel therapeutic strategies with improved efficacy and reduced side effects. Nanomedicine has emerged as a transformative approach in cancer treatment by enabling targeted delivery, enhanced cellular uptake and controlled release of therapeutic agents [1,2]. Gold nanoparticles (AuNPs) are particularly attractive in nanomedicine due to their biocompatibility, ease of synthesis, tunable size, and surface functionalization capability [3]. Recently, green synthesis of nanoparticles using plant extracts has gained considerable attention as an eco-friendly and cost- effective alternative to conventional chemical methods [4]. Plant- derived phytochemicals act as both reducing and stabilizing agents, often conferring additional biological activity to the nanoparticles. Corallocarpus epigaeus (family: Curcubitaceae) is a traditional medicinal plant known for its antioxidant, anti-inflammatory and antimicrobial properties [5]. However, its anticancer potential, particularly in nanoparticle form, remains unexplored. Epidermoid carcinoma A-431 cells serve as a well-established in-vitro model for studying skin cancer therapeutics [6]. The present study was designed to compare the cytotoxic efficacy of acetone extract of Corallocarpus epigaeus tuber and gold nanoparticles synthesized using the same extract, with the focus on evaluating the nanomedicine advantage through IC50 analysis.

Materials and Methods

Plant Collection and Identification

C. epigaeus plant species was obtained from Solavanthan village, Madurai in December 2023. The plant specimens (ARIBASKBI-1) were identified by Plant Taxonomist Dr. Karuppusamy at Department of Botany, The Madura College, Madurai, Tamil Nadu, India. The specimen is stored at Botany department under a herbarium voucher LSID-2PNI-20013498. Only the healthy and disease-free leaves of the plant were taken for testing. Fresh tubers of Corallocarpus epigaeus were collected, shade dried and powdered. The powdered material was extracted using acetone by standard solvent extraction methods. The extract was filtered and concentrated under reduced pressure.

Green Synthesis of Gold Nanoparticles

Gold nanoparticles were synthesized using the acetone extracts of Corallocarpus epigaeus tuber as a reducing and stabilizing agent. Formation of AuNPs was confirmed visually by colour change

Cell Culture

The human epidermoid carcinoma A-431 cell line was obtained from a certified repository and maintained in DEME supplemented with 10% feta bovine serum and antibiotics at 37°C in a humified 5% CO2 incubator.

MTT Cytotoxicity Assay

The sample was tested for in vitro cytotoxicity, using Cells by MTT assay. Briefly, the cultured Vero Cells were harvested by trypsinization, pooled in a 15 ml tube. Then, the cells were plated at a density of 1×105 cells/ml cells/well (200 µL) into the 96-well tissue culture plate in DMEM medium containing 10 % FBS and 1% antibiotic solution for 24-48 hour at 37°C. The wells were washed with sterile PBS and treated with various concentrations of the sample in a serum-free DMEM medium. Each sample was replicated three times and the cells were incubated at 37°C in a humidified 5% CO2 incubator for 24 h. After the incubation period, 20 µL of 5 mg/mL MTT was added to each well. The cells were then incubated for an additional 2–4 hours, until purple precipitates were clearly visible under an inverted microscope. Finally, the medium was removed from the wells and the wells were washed with 1X PBS (200 µL). Additionally, to dissolve the formazan crystals, 100 µL of DMSO was added, followed by 5 min of shaking. The absorbance for each well was measured at 570 nm using a microplate reader and the percentage cell viability and IC50 value was calculated using Graph Pad Prism 6.0 software (USA).

IC50 Determination

Dose-response curves were generated using non-linear regression analysis with a variable slope model IC50 values were calculated along with standard errors and 95% confidence intervals.

Results and Discussion

Cytotoxic Activity of Acetone Extract of Corallocarpus epigaeus on A-431 Cells

The cytotoxic activity of the acetone extract of Corallocarpus epigaeus was evaluated against human epidermoid carcinoma (A- 431). The acetone extract of Corallocarpus epigaeus tuber exhibited a concentration dependent cytotoxic effect against the human epidermoid carcinoma A-431 cell line. A significant reduction in cell viability was observed with increasing concentration of the extract (Tables 1, 2 and Figure 1).

Table 1: Cytotoxic property of acetone extract of Corallocarpus epigaeus on A-431 cell line.

S. No

 Tested sample concentration (μg/ml) Cell viability (%) (in triplicates)

Mean Value (%)
1. Control

100

 100 100

100
2. 500 µg/ml

25.8278

 25.76 30.756

27.447943
3. 400 µg/ml

29.9669

 31.68 38.3162

33.321013
4. 300 µg/ml

41.8874

 41.92 41.5808

41.796058
5. 200 µg/ml

45.5298

 44.96 51.2027

47.23085
6. 100 µg/ml

58.1126

 52.96 56.5292

55.867264
7. 50 µg/ml

61.755

 57.92 67.354

62.342973
8. 25 µg/ml

82.4503

 75.36 69.244

75.684772
9. 10 µg/ml

68.3775

 72.8 75.945

72.374167
10. 5 µg/ml

77.9801

 79.68 79.3814

79.013859
11. 1 µg/ml

82.4503

 66.4 80.9278

76.592722

Table 2: Percentage Viability acetone extract of Corallocarpus epigaeus on A-431 cell line.

S. No

 Tested sample concentration (μg/ml) Cell viability (%) (in triplicates)

Mean Value (%)
1. Control

100

 100 100

100
2. 500 µg/ml

13.9738

 8.11639 16.7192

12.936476
3. 400 µg/ml

29.5488

 27.1057 26.6562

27.770193
4. 300 µg/ml

34.3523

 39.3568 39.2744

37.661173
5. 200 µg/ml

48.4716

 45.3292 45.5836

46.461487
6. 100 µg/ml

43.2314

 50.3828 48.5804

47.398244
7. 50 µg/ml

50.655

 52.8331 55.6782

53.055444
8. 25 µg/ml

57.3508

 65.3905 64.0379

62.25972
9. 10 µg/ml

65.3566

 71.0567 75.3943

70.602535
10. 5 µg/ml

75.2547

 80.5513 84.858

80.221359
11. 1 µg/ml

91.4119

 91.1179 94.3218

92.283873

Figure 1: Images of control cells and Acetone extract of C. epigaeus treated cells.

The highest concentration (500 µl/ml) showed 83.1% growth inhibition indicating the extract exhibited pronounced cytotoxicity, with a mean cell viability of 27.45% while 500 µl/ml showed33.32% viability. A gradual increase in cell viability was observed with decreasing concentrations, reaching 76.59% at 1 µl/ml, indicating reduced cytotoxicity at lower doses, Control cells exhibited 100% viability, confirming assay reliability and normal cellular metabolism.

The decrease in optical density at 570 nm reflects a reduction in mitochondrial dehydrogenase activity, suggesting impaired metabolic function and reduced proliferation of cancer cells. Similar dose-dependent cytotoxic effects of plant acetone extracts against epidermoid carcinoma cell lines have been previously reported and attributed to the presence of bioactive secondary metabolites [7-9]

Cytotoxic Activity of Corallocarpus epigaeus Tuber Mediated AuNPs on A-431 Cells

The cytotoxic activity of gold nanoparticles synthesized using the acetone extract of Corallocarpus epigaeus tuber extract was evaluated against the human epidermoid carcinoma cell line (A-431) using MTT assay. The results demonstrated a dose-dependent reduction in cell viability, confirming the antiproliferative efficacy of the biosynthesized AuNPs. (Tables 3, 4 and Figure 2).

Table 3: Cytotoxic property of gold nanoparticle synthesized from C. epigaeus tuber acetone extract.

S. No

 Tested sample concentration (μg/ml)

OD Value at 570 nm (in triplicates)
1. Control

0.687

 0.653

0.634
2. 500 µg/ml

0.096

 0.053

0.106
3. 400 µg/ml

0.203

 0.177

0.169
4. 300 µg/ml

0.236

 0.257

0.249
5. 200 µg/ml

0.333

 0.296

0.289
6. 100 µg/ml

0.297

 0.329

0.308
7. 50 µg/ml

0.348

 0.345

0.353
8. 25 µg/ml

0.394

 0.427

0.406
9. 10 µg/ml

0.449

 0.464

0.478
10. 5 µg/ml

0.517

 0.526

0.538
11. 1 µg/ml

0.628

 0.595

0.598

Table 4: Percentage Viability acetone extract mediated AuNPs on A-431 cell line.

S. No

 Tested sample concentration (μg/ml) Cell viability (%) (in triplicates)

Mean Value (%)
1. Control

100

 100 100

100
2. 500 µg/ml

13.9738

 8.11639 16.7192

12.936476
3. 400 µg/ml

29.5488

 27.1057 26.6562

27.770193
4. 300 µg/ml

34.3523

 39.3568 39.2744

37.661173
5. 200 µg/ml

48.4716

 45.3292 45.5836

46.461487
6. 100 µg/ml

43.2314

 50.3828 48.5804

47.398244
7. 50 µg/ml

50.655

 52.8331 55.6782

53.055444
8. 25 µg/ml

57.3508

 65.3905 64.0379

62.25972
9. 10 µg/ml

65.3566

 71.0567 75.3943

70.602535
10. 5 µg/ml

75.2547

 80.5513 84.858

80.221359
11. 1 µg/ml

91.4119

 91.1179 94.3218

92.283873

Figure 2: Images of control cells and gold nanoparticles synthesized from C. epigaeus against treated cells.

The highest concentration (500 µl/ml) the AuNPs induced pronounced cytotoxicity, with mean cell viability of 12.94% and 27.77% respectively. A gradual increase in cell viability was observed with decreasing concentrations reaching 92.28% viability at 1 µl/ml, indicating minimal cytotoxicity at lower doses. The untreated control cell maintained 100% viability, confirming the reliability of the assay conditions.

The observed reduction in optical density values at 570 nm directly correlates with decreased mitochondrial activity, reflecting compromised cellular metabolism and loss of viable cells. Similar concentration dependent cytotoxic effects have been reported for plant-based AuNPs against various cancer cell lines, including, skin, breast and cervical cancer, attributed to the enhanced nanoparticle- cell interactions and intracellular accumulation [9,10]

IC50 Determination of Corallocarpus epigaeus Acetone Extract and Corallocarpus epigaeus – Mediated Gold Nanoparticles on A-431 Cells

The cytotoxic activity of acetone extract and gold nanoparticles synthesized using Corallocarpus epigaeus tuber was quantified against the human epidermoid carcinoma A-431 cell line using MTT assay. Dose- response data were analyzed by non-linear regression of log(inhibitor) versus normalized response using a variable-slope model.

The analysis revealed that Corallocarpus epigaeus mediated AuNPs exhibited IC50 value of 57.97 µl/ml, whereas the acetone extract showed a higher IC50 value of 84.67 µg/ml, indicating greater potency of the nanoparticle formulation (Table 5). The AuNPs showed a moderate negative Hill slope (-0.6962) suggesting a gradual inhibitory effect, while the acetone extract showed a steeper slope (-0.9403), reflecting a sharper but less potent response. Both exhibited high goodness-of- fit values (R2>0.9177), confirming the reliability of the concentration dependent inhibitory response. The 95% confidence interval for the IC50 ranged from 45.15 to 74.43 µl/ml (AuNPs) and IC50 ranged from 70.00-102.4 µl/ml, confirming the accuracy of tailored model. Gold nanoparticle reduced the IC50 by~32% indicating enhanced cytotoxic efficacy compared to the crude acetone extract. Compared to the reports on crude plant extracts, the IC50 value obtained in the present study within the biologically relevant range and comparable to acetone extract of medicinal plants reported to exert anticancer activity against skin cancer cell lines [11,12].

Table 5: Comparative IC50 analysis.

log(inhibitor) vs. normalized response — Variable slope
 

Acetone Extract of Corallocarpus epigaeus tuber

Acetone Extract mediated AuNPs
Best-fit values        
LogIC50  

1.928

  

1.763
HillSlope  

-0.9403

  

-0.6962
IC50  

84.67

  

57.97
Std. Error        
LogIC50  

0.04036

  

0.05301
HillSlope  

0.07893

  

0.06188
95% Confidence Intervals        
LogIC50  

1.845 to 2.010

  

1.655 to 1.872
HillSlope  

-1.102 to -0.7787

  

-0.8229 to -0.5695
IC50  

70.00 to 102.4

  

45.15 to 74.43
Goodness of Fit        
Degrees of Freedom  

28

  

28
R square  

0.9420

  

0.9177
Absolute Sum of Squares  

1770

  

2064
Sy.x  

7.950

  

8.585
         
Number of points        
Analyzed

3

 30 3

30

The comparative results of the study clearly demonstrate the nanomedicine advantage of Corallocarpus epigaeus mediated gold nanoparticles over the acetone extract alone. While the crude extract exhibited notable cytotoxic activity against A-431 cells, incorporation into gold nanoparticles significantly enhanced efficacy, as evidenced by a lower IC50 values and greater maximal growth inhibition. The enhancement can be attributed to several factors intrinsic to nanoparticles-based delivery systems. In contrast crude acetone extract rely on passive diffusion and may undergo metabolic degradation, limiting their intracellular bioavailability. Gold nanoparticles offer increased surface area for phytochemical adsorption, improved cellular uptake through endocytosis and prolonged intracellular retention, all of which contribute to enhanced anticancer activity [12-14]. Moreover, AuNPs are known to induce oxidative stress and mitochondrial dysfunction in cancer cells, thereby amplifying apoptosis-related signaling pathways [15]. Importantly the observed dose-dependent response and acceptable goodness-of-fit values indicate reliable and reproducible cytotoxic effects. The higher cell viability observed at lower concentrations further suggests a favorable therapeutic opening, an essential consideration for translational nanomedicine. Rather replacing plant-based therapeutics, this study demonstrates that nano structuring of traditional medicinal plant extracts can significantly improve their biological performance, thereby bridging ethnopharmacology and modern medicine. The comparative evaluation clearly demonstrates that the acetone extract of Corallocarpus epigaeus exhibits intrinsic anticancer activity its nano formulation as gold nanoparticles significantly enhances cytotoxic potency, reduces the effective dose (IC50) and improves biological activity against A-431 cells. These findings support the use of Corallocarpus epigaeus as a valuable bioresource for green nano- medicine based cancer therapeutics.

Conclusion

The present study provides convincing evidence that gold nanoparticles synthesized using Corallocarpus epigaeus tuber acetone extract exhibit significantly enhanced cytotoxic activity against human epidermoid carcinoma A-431 cells compared to the crude extract. The reduction in IC50 value and increased growth inhibition highlight the potential of Plant-mediated AuNPs as a promising nanomedicine platform for cancer therapy. More experimental work similar to In- vivo studies are necessary to support clinical translation.

Acknowledgement

The authors sincerely acknowledge the Management for providing seed money to carry out this research work and the Principal and Dean of Research and Development, for their constant support and encouragement. We also thank Tribiotech for providing the necessary analytical facilities and technical support required for the successful completion of the analytical work.

Data Availability Statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Ferrari M (2005) Cancer nanotechnology: opportunities and Nature Reviews Cancer 5: 161-171. [crossref]
  2. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, et (2020) Nanocarriers as an emerging platform for cancer therapy. Nano-Enabled Medical Applications 23: 61-91. [crossref]
  3. Dykman LA, Khlebtsov NG (2011) Gold nanoparticles in biology and medicine: recent advances and prospects. Acta Naturae (англоязычная версия) 3: 34-55. [crossref]
  4. Iravani S (2011) Green synthesis of metal nanoparticles using Green Chemistry 13: 2638-2650.
  5. Singh H, Du J, Singh P, Yi TH (2018) Ecofriendly synthesis of silver and gold nanoparticles by Euphrasia officinalis leaf extract and its biomedical Artificial Cells, Nanomedicine, and Biotechnology 46: 1163-1170. [crossref]
  6. Nadkarni AK (2007) KM Nadkarni’s Indian materia medica: with Ayurvedic, Unani-tibbi, Siddha, allopathic, homeopathic, naturopathic & home remedies, appendices & indexes. Popular Prakashan.
  7. Fulda S, Debatin KM (2004) Targeting apoptosis pathways in cancer Current Cancer Drug Targets 4: 569-576. [crossref]
  8. Greenwell M, Rahman PK (2015) Medicinal plants: their use in anticancer International Journal of Pharmaceutical Sciences and Research 6.
  9. Rajeshkumar S, Bharath LV (2017) Mechanism of plant-mediated synthesis of silver nanoparticles–a review on biomolecules involved, characterisation and antibacterial Chemico-Biological Interactions 273: 219-27. [crossref]
  10. Ahmed S, Ahmad M, Swami BL, Ikram S (2016) A review on plants extract mediated synthesis of silver nanoparticles for antimicrobial applications: a green expertise. Journal of Advanced Research 7: 17-28. [crossref]
  11. Cragg GM, Newman DJ (2013) Natural products: a continuing source of novel drug Biochimica et Biophysica Acta (BBA)-General Subjects 1830: 3670-3695. [crossref]
  12. Kuppusamy P, Ichwan SJ, Al-Zikri PN, Suriyah WH, Soundharrajan I (2016) et In vitro anticancer activity of Au, Ag nanoparticles synthesized using Commelina nudiflora L. aqueous extract against HCT-116 colon cancer cells. Biological Trace Element Research 173: 297-305. [crossref]
  13. Yeh YC, Creran B, Rotello VM (2012) Gold nanoparticles: preparation, properties, and applications in Nanoscale 4: 1871-1880.
  14. Arvizo RR, Rana S, Miranda OR, Bhattacharya R, Rotello VM, et al. (2025) Mechanism of anti-angiogenic property of gold nanoparticles: role of nanoparticle size and surface Nanomedicine: Nanotechnology, Biology and Medicine 7: 580-587. [crossref]
  15. Khlebtsov N, Dykman L (2011) Biodistribution and toxicity of engineered gold nanoparticles: a review of in vitro and in vivo Chemical Society Reviews 40: 1647-1671. [crossref]

Islam and the Muslims in Kashgar of Xinjiang: Observed by Swedish Missionaries of the Covenant Church

1 Reply

DOI: 10.31038/GEMS.2025783

Abstract

Comparing with the aim of the converting the Turkic Muslims into Christians setting up by a group of the Swedish missionaries in Kashgar region in the period of 1892-1938, the more important contribution has been brought out by them is the large quantity of the historical archives in which has witnessed Islam and the Muslims in the Uighur society. This paper employing the various materials unfolds the feature of Islam and the Muslim society in Southern Xinjiang in three dimensions: the origin of the Swedish Christian mission in Kashgar, Islam in Kashgar reflected by historical records one century ago and the living customs of the Turkic Muslims that time. It summarizes the Islamic characteristics and concludes that the work achieved by the Swedish missionaries could not be forgotten by the people.

Keywords

Islam, Turkic muslims, Swedish missionaries, Kashgar

From the time of the first Swedish missionary arrived in Xinjiang (in the western sources it was termed as “the Eastern Turkistan”) in 1892 to the time that the last group of the Swedish missionaries were expelled by Sheng Shicai盛世才, the local warlord in 1938, during almost half of a century, the Mission Covenant Church of Sweden (MCCS) established four mission stations in Kashgar region: Kashgar city (1894), Yarkand (today’s name Shache莎车, 1895), Hancheng (today’s name Sule疏勒, 1908), Yangi Heshar (Today’s name Yingjisha英吉沙, 1912). About 68 Swedish missionaries went there to participate in the course of mission, meanwhile built the schools, hospitals, orphanages (house for boys and house for girls), and the printing workshop in the mission stations in which they worked as well as church. A few missionaries and their family members even sacrificed their lives in Kashgar [1].

The mission work of MCCS in Xinjiang was extremely hard and difficult. Just the journey to travel to Xinjiang for 3000 miles needs extraordinary energy and bravery spirit. Life condition in Xinjiang was primitive, weather horrible, people easily affiicted by deceases. The mission work done by these missionaries must have endured the tremendous hardship in physically and mentality, because they faced the most conservative and almost fanatical Islam (termed by late Dr. Gunnar Jarring, the formal ambassador of Sweden to the United Nation, the famous diplomat in the world in the 1960s) [2]. Through the multitude assistance proved to the local Muslims in the social public fields such as medical treatment, education, economics, technology, hygiene and health, the strong efforts coming from the Swedish missionaries made a group of the Uighur Muslims convert into Christianity. Therefore, the mission work of the Swedish missionaries in Xinjiang has far reached beyond of the religious significance, it is a considerable successful exchange and cooperation in the cultural dimension. Of course, it was full of the hostility and persecution from the Islam extremists and Muslim warlords during that time.

Origin of the Christian Mission in Kashgar of MCCS

In 1878 a small sect split from the Lutheran Church of Swedish Kingdom, it was entitled with Missionary Covenant Church of Sweden, or the Swedish Covenant Church. After it was founded, it proposed a mission strategy focused on Euro-Asian continent, therefore, sent the missionaries to Russia first. The earliest mission was around the area of St. Peterberg, the capital of Russia Empire, it spread to the various minorities lived in Mt. Ular, Caucasus and Iran [3]. At the end of the 1880s, the famous American missionary to China Rev. Hudson Taylor visited Sweden. His series speeches made in Swedish Church stimulated the enthusiasm of the missionaries of MCCS who wanted to go to China. The missionary delegation of MCCS had worked to established the mission and mission stations in Caucasus of Russia and Hubei Region in China for several years. They wanted to set up the new mission stations which could connect between the two regions, so made them related. Hence, missionary N. F. Höijer chose Kashgar as the starting point for the mission in Xinjiang. In 1892 he undertook a short journey to Kashgar with J.Avetaranina, a former Muslim but converted into Christianity in the Ottoman Turkey. After they got to know the feasibility of the mission in Kashgar by the direct observation, Höijer returned to Stockholm to report to the headquarter of MCCS, at same time he left Mr. Avetaranina to continue living and preaching in Kashgar. In 1893 at the conference held by MCCS in Stockholm passed the plan to establish the new mission station in Xinjiang after the discussion. Following that they decided to send a first group of the missionaries going there. In the summer of 1893, Missionary Lars Erik Hogberg stopped the mission work in Persia and migrated to Kashgar for the preparing the mission station in Kashgar [4].

In 1895 Swedish missionaries established the mission station in Yarkand. Magnus Backlund came to Kashgar for mission in 1896, he was the first Swedish missionary had commanded the Uighur language before his arrival in Kashgar. In the next year Dr. Gosta Raquette came to Kashgar. Raquette also had good command of the Uighur language beside he received the systematic training in the medical science, and therefore he was awarded the medical doctor certification.

The Swedish missionaries were actual residents in Xinjiang during such a period. Having lived there for decades they gained a profound understanding of the living customs and religious beliefs within the traditional local culture. Though most of them were ministers and missionaries, many of them were also medical doctors, linguistics, scholars of folklore, architectures, and botanists; some of them were also capable photographers who took many pictures while living in southern Xinjiang.

During the 1970s and the 1980s, Samuel Franne, a retired Swedish architect and an enthusiastic Christian, spent a long time in Sweden collecting and sorting out packs of these photos taken by missionaries from the Missionary Covenant Church of Sweden (MCCS) during their mission in the Eastern Turkistan (Xinjiang). Having completed this work, he handed the whole collection over to the Swedish National Archives, so that they could be properly maintained. The famous Swedish diplomatist, the former Ambassador to the Soviet Union, Iran and the United States of America respectively, Dr. Gunnar Jarring, has refereed to this archival treasure as “the Franne Collection” [5]. The collection of historical photographs about Kashgar in Xinjiang and the MCCS missionary history there contains about 9000 images; among them are several hundred portrayals of Islamic life in Kashgar. These are extremely valuable artifacts due to the fact that many written texts and other documents were destroyed during the wars and political turmoil of those very same years; it was the most chaotic period in the history of violence in Xinjiang. Today we will try to reconstruct the history revealed in these silent photos, adding to their witness the published records made of the observations by these Swedish missionaries.

In the early stage of the mission work the Swedish missionaries met the hostility from the Islamic circle. To explain the reason why did the clerics of Islam in Xinjiang so severely oppose the Swedish missionary work we have to describe the basic situation of Islam and the Uighur Muslims in Xinjiang.

Islam in Xinjiang Reflected in the Historical Records Noted one Century Ago

During the period spanning from the end of the Qing Dynasty to the early part of Republican China, most of the population in Xinjiang believed in Islam. At least 80 percent of the population were Muslims (the majority being Turkic people). Most of the Muslims were Sunnis, while there were also some Shi’ites among them. Sunni Muslims were dominant within the Islamic life of Xinjiang [6]. At that time there were more than 2000 mosques throughout the whole province of Xinjiang [7]. Mosques in the rural areas were very simply-built, while those in the towns and cities were decorated very beautifully [8]. Serving as the center of religion, politics and culture in the region, Kashgar was very representative of the city life in Xinjiang of that era.

John Törquist, a Swedish missionary who had worked for the MCCS mission for more than thirty years described the main mosque in Kashgar in following vivid words:

The mosque itself is made up of an open court, something like a park. In front, there is a large pond; wind chimes are hung there, and a row of pillars lead the way [into the court]. The whole park is full of praying people, perfectly arranged in rows. The ground is covered with prayer-mats also arranged in rows, as far as once can see. People are sitting on these mats, side by side as close together as possible. From the platform up in front there are silent instructions, and now the ‘foaming sea’ is heaving up and down, like wave after wave, very regular and very dignified in their serene way. There are no shouts of command, no conductor’s baton… This is an immense crowd of tens of thousands of Kashgar Mohammedans [9].

Minarets were [and are] an integral part of mosque architecture in Xinjiang. This is not often seen in more central parts of China. Marshall Broomhall, who wrote a book entitled Islam in China: A Neglected Problem, pointed out: there was no big difference between the appearances of mosque and other temples in other parts of China. However, according to his point of view, the minaret in Xinjiang was an architectural addition influenced by traditions from Central Asia [10]. In addition, in more central parts of China there were mosques specifically for women [11], but Muslim women in Xinjiang at this time prayed in their homes; the mosque generally belonged only to men for their religious activities. From these descriptions we can see that mosques are central to Islamic life in Xinjiang, the nexus of Turkic Muslim society.

Just as in other parts of the Islamic world, Islam penetrated into all aspects of life for Turkic Muslims during this period. Paralleling Chinese imperial law, the Islamic law (Shari’ah) was implemented in the judicial administration of Xinjiang. For this purpose every town had a religious court consisted of four Mullahs who were well versed in Islamic law. Such religious judges were nominated by local Chinese authorities. The court’s most important task was to supervise people to live a life according to the commands and prohibitions of the Qur’an [12]. This form of life shaped by the Islamic law required that women were not allowed to appear in public if they did not wear a head-dress and veil. If a woman did not follow this regulation, the moral official of the religious court could take legal action against her. When such cases happened before, women who broke this law were lashed by leather whips as punishment. The moral official from the religious court even had the right to enter into a harem, where it was normally not allowed for strange men from outside to go under normal circumstances. On such an occasion when a woman was caught not wearing appropriate clothing in public, the moral official could punish the guilty woman without undergoing any legal procedures. There were also such cases known where these officials wandered around and checked family by family to ensure that Muslims were going to the mosque for their prayer rites [13].

There were many religious manuscripts in Arabic or Persian kept by people in their homes in Xinjiang. Before printing technology was introduced, Muslims learned the Qur’an in Arabic, and Islamic doctrine was passed down in hand-written copies. This showed that Uighur Muslims of that period paid great attention to the Qur’anic studies. Besides the Qur’an, Muslims also studied the biography of the Prophet Muhammad. There were these kind of religious books translated from Arabic and the Persian, however, the Qur’an was considered to be untranslatable [14]. Dr. Raquette and Dr. Jarring, the former was a missionary from the MCCS Mission, the latter was a student but staying in Swedish missionary station in Kashgar for longer than half a year that time, both being Turkic linguistics in the 1920s, saw and collected many religious manuscripts and hand- written copies of other works; they also saw manuscript copies of the Qur’an and other books which had been copied by hand by Uighur Muslims in Xinjiang.

Compared with orthodox beliefs and the restrictive doctrinal practices of the Sunni, the Shi’ites were considerable more tolerant toward other religions. Every year the Shi’ites in Xinjiang would undergo a two week long ceremonial memorial ritual commemorating the tragic death of the cousin of the Prophet Muhammad, Caliph Ali. (In fact, this should be the grandson of the Prophet Muhammad, Hussein, who was martyred — note from author) [15].

Most Uighur Muslims were able to obey the Five Pillars of Islam and the basic religious obligations. If someone did not follow these religious prohibitions, he probably risked being driven out from his community. If that occurred, no one would come to him or take care him when he was dying, and no one would participate in his funeral service; even a Mullah would not perform any ritual after his passing away [16]. There was a variety of attitudes toward the religious prayer rituals among Muslims in Xinjiang [17]. As far as alms-payment were concerned, the majority of people could pay religious taxes; however, there were some who tried to avoid them. During Ramadan sincere believers would fast, neither eating nor drinking during the daytime. Fasting could also be performed during normal days in order to redress one’s sins [18]. At the end of the Ramadan came two days of Islamic holidays and their festivities. Muslims would go to the mosque for prayer in groups. The Aid-Khah Mosque in Kashgar during those days could have more than 80,000 Muslims together participating in prayer rituals during these Islamic festivals. Celebrations of Qurban (“animal slaughter”) and the Day for Breaking Fast were so full of activities that people generally did not go to work.

Only a few could afford to go to Mecca for pilgrimage from Xinjiang at that time. Usually a representative was selected from among a big extended family or a clan to go on the Hajj, and then the cost was shared by all members of family or clan. In order to participate in the Hajj some might even declare bankruptcy and sell all their property. If someone was in poor health, he could pay money to employ another to Mecca on his behalf, and so he could be spiritually rewarded [19]. In Yarkand there were several hundred people going to Mecca for pilgrimage every year [20]. There were some cases where husbands went to Mecca with their wives, but for those who had no money the only choice was going to a mazar (tomb for Sufi saint) in the nearby countryside as an act of pilgrimage. The Mazar Apak located in a suburb of Kashgar attracted many visitors for this kind of pilgrimage. Many people wanted to be buried beside the mazar after they passed away. However, only the rich could offer to buy a piece of land in the graveyard [21]. At one point the missionaries saw somewhere between 7000 to 8000 people gathered around a mazar. People regarded the Sufi saint as an intermediary between the Lord and the people. Ordinary people eagerly looked for such opportunities to be linked up to divine mercies [22].

All boys underwent the circumcision ritual. It was usually done by someone in the barbershop. Sometime, parents brought their child to the missionary hospital to do the circumcision ritual [23]. Many Muslims in Xinjiang were believers in predestination, and so were fatalistic in their attitudes. Such a phenomenon was seen everywhere. According to ordinary Muslims, their fate in being poor or experiencing suffering could not be changed [24]. Allah created the rich and the poor. Life for the poor was always poor. To change the fate or reduce the suffering was to break the will of Allah [25]. Many hospital patients therefore rejected any medical help, because of their belief in predestination [26]. Such a fatalistic philosophy had a remarkable influence over the culture of Muslims in Xinjiang.

A missionary held that the religious sentiment of the Muslims in Xinjiang was very depressed and cowed. The good and helpful elements in the Qur’an had been missed or misunderstood. He commented [27]:

… A heathen could hold on to some of his abominations handed down from earlier generations, transplanted into Islamic soil [once he or she became a Muslim]. Neither in Catholicism, nor in Judaism, nor even in paganism is one likely to find any parallels to the cult of shrines and numerous superstitions, fortune-telling and witchcraft, rain-doctors and talismans as found in Islam [in Xinjiang]. One could go one step further by saying that the heathen are invited and enticed by Muslims into accepting their religion, and so are then free to lower themselves even deeper into the mire of vice than they were able to do while being simply heathens.

Xinjiang during these years had strong Islamic mysticism in the form of Sufism. It appeared in the form of wandering dervishes. Xinjiang had many such Sufi orders in its history [28]. They acted like beggars and asked for donations from the people [29]. They often held rituals beside a mazar. Some members came from families where generations of dervishes had been present. Sufi orders were composed of several hundred dervishes [30]. In their rituals, Sufis sang Yasawai’s hikmet (the prayer song praising God and the Prophet Muhammad). A Sufi leader or an Ishan (Persian for “he” or “they”) rallied his devoted disciples around him; he sat near the mihrab (the niche in the mosque), with his disciples surrounding him. Then they sang the songs; after they sang, they chanted the beautiful names of Lord. They danced, whirled and jumped, so that some of them fell down losing consciousness as their bodies were shaken by overwhelming ecstasies. They may sit with folded legs or spread them out, shaking and falling down when they fainted. Afterwards they stood up again. Having completed their dancing, they recited a chapter from the Qur’an, and then began their prayer rituals. Some rituals organized by other Sufi orders were different from this. For instance, an Ishan and his disciples could sit in a circle silently without moving, they lowered their heads for one hour, but some other Ishan in another order stood and faced upward silently for an hour. When they finished this form of meditation, they danced and chanted poetry. Shaikhs (the religious “elder”) and those learned in hadith (the sacred traditions of the Prophet) honestly believed that these people saw the Lord. The main doctrine of the Ishan sects was to unite with the Lord. If someone among them passed away, they believed he was united with God. They said that “We are united with Lord just as a rain drop is united with a flowing river.” [31] Scholars in orthodox Islam opposed those who claimed they had seen God; they thought that Allah had neither image nor body, and so was invisible.

There were Sufi mystics such as those found among the Dervish and Qalandar groups in southern Xinjiang. They were also organized into orders, under their leaders who were referred to as Pir (Persian, “the elder”). It was difficult to distinguish the members of a real order from those who pretended to be members; their clothes, speech and behavior were almost exactly the same as normal beggars [32]. Grenard noticed that the dances practiced by dervishes were very special: they consisted of fast steps and dramatic movements; when they danced they also sang exciting songs, praising the Prophet Muhammad. Sometimes they sighed with restrained breath: “Ah, Lord! By the will of Allah!” [33] According to regulations, while they sang songs they would also shake iron sticks decorated with iron rings. They held up the sticks and whirled fast and faster until they became exhausted. Sometimes, women also danced like this [34]. The Great Mullah in Kashgar, Muhammad Ali, wrote: The real dervishes live in caves rather than living in the city. They are called pure believers or practitioners. They never beg anything from anyone. They feel satisfied and are happy in life [35]. But such dervishes were very few. Those who begged for money and gifts in dishonest ways were false dervishes; they seemed to dance, singing songs and praising the Prophet, but their real purpose was to gain money and wealth from others [36].

A popular Sufi ritual was to take part in mazar worship. For example, the Uighurs in Yarkand worshipped the Mazar of Seven Saints; even today many people like to visit this mazar. People thought that these mazars were sacred; the water from the well of a mazar was claimed to heal diseases; weeping at a mazar, a woman could overcome fertility and so later have baby. Even among the Hui Muslims (Tungan) there was this phenomenon of making pilgrimages to a mazar [37]. The greater mazars had regulated dates for visitations, which could last for a long period of time. During the designated periods for mazar worship there was also special entertainment including wrestling, horse races for rounding up sheep, cock-fighting and Mukham music concerts. Therefore, during such occasions the mazar pilgrimages resembled something like a tour; it clearly strengthened social communications, enhancing trade. At all these mazar events people normally expected to worship there regularly or at least sometimes.

Usually the mazar pilgrimage took place before the sowing season or after the harvest season. Such mazar pilgrimages may be also a remnant from traditional collective entertainments held among the nomadic or farming peoples before Islam was introduced into Xinjiang. This shared form of worship, involving a common psychological need and common spiritual mind, was the kind of spiritual support which make the mazar pilgrimages very significant. Many Muslims regarded the mazars as a kind of little Mecca in their own area. People would pray, appeal for help, and repent in front of the mazar of a saint or near the saint’s holy grave. In Kashgar the Buwy (female Sufi) Mariam Ritual was very influential among women. With the custom women held that they must answer the questions with the names of Buwy Mariam, Buwy Fatima and Buwy Khadich as they were asked by the angels in heaven. The latter two names were the daughter and wife of the Prophet Muhammad respectively. But the former was related with the mother of Jesus Christ, Mariya. Before the Uighurs in Xinjiang accepted Islam, the Christian Nestorian church had also spread there for a certain time. In this light, female Sufi worshipping “Buwy Mariam” perhaps were revealing traces of an adaptation of certain aspects of Nestorian culture by Islamic mysticism in their historical development [38].

Living Customs of Muslims in Xinjiang that Time

Traditional Islamic customs were not so variant in the oases of Xinjiang, However the types and frequency of folk religious customs varied greatly. Uighurs practiced numerous popular religious customs in order to cultivate a strong and unique identity in their religion, culture and ethnicity. Beside the main orthodox Islamic rituals, these popular practices their lifestyle penetrated into all aspects of the Uighur rituals. Popular folk customs had very much to do with beliefs in the existence of jinn (Arabic, “evil and/or spiritual forces”). In the rural areas of Uighur villages, it was common to find them carrying a small pocket (including a piece of paper with a verse of the Qur’an written out and sewed into a leather or cloth ball) hanging down with colored threads on a branch of tree. It was called qonchaq, a talisman used to drive away evil spirits. The Mullah told sick patients or those whose bodies were in pain to hang the qonchaq in the tree in order to overcome their physical problems. Uighur Muslims believed that misfortunate was caused by the souls of those who died young due to the evil influences of the jinn. Most orthodox religious scholars were opposed to these exorcising practices, including not only qonchaq, but also tomar and koz monchaq. The purpose of those objects was to avoid harm caused by “the evil eye”. Tomar was a small triangular leather pouch in which was a piece of paper with a du’ai (Arabic, “prayer word”) was wrapped; koz monchaq was a small black plastic ball the size of the pit of a cherry, colored with white spots over its whole surface. Children wore it as a necklace and woman sewed it onto clothes in order to deflect negative influences from “the evil eye”.

Generally speaking, people in Xinjiang during this period believed ghosts or jinn existed; Uighur people believed that the jinn could take the form of human beings in order to deceive their human targets. Sometimes, the soul of a man was attacked by a ghost [39]. For these reasons Uighurs were accustomed to use fire to expel the jinn from places which they haunted. In the rites of passage related to births, wedding ceremonies and funerals fire was used precisely for this purpose.

In the rituals for a newborn child during their celebration at reaching one year of age, the religious leader would use a burning stick, waving it over the baby to purify the air and to overcome the influence of “the evil eye”. For the same purpose some Uighur families put an unsheathed knife at the side of baby crib to frighten away evil spirits. In marriage ceremonies, when the bride was led to the bridegroom’s family from her parents’ home, a fire was made along the outré between the homes. The carriage including the bride would drive over the fire wherever they came across it. In some other marriage ceremonies the horse carriage used by the bride would circle around the fire seven times, [as in the rituals performed around the Ka’aba in Mecca]. The number “seven” was sacred for Muslims. At the threshold of the bridegroom’s home a fire was made on the cup of an extended iron-spoon; when the bride arrived, she must jump over the fire and enter the home of bridegroom. All of these customs were exorcistic rites observed by the MCCS missionaries.

In rites of passage among Uighur people in Xinjiang many popular religious elements were obviously integrated into ceremonies related to birth and death. During the Uighur burial services, a pot with Qur’anic texts on paper and herbal medicine was put over or beside the grave; the content of the pot was then burned, serving as an offering to comfort the soul of the deceased. If a medicine was ineffective in healing a patient, it was then put into the pot and incinerated before the patient passed away. This reflected the wishes of the family members who wanted the patient to be healed. If the patient died, then they wished the deceased to have a strong body in the next world, and hoped to make the soul of the deceased to be in good health. After a baby was born, its placenta was buried inside the earthen wall of the house by its parents, and they would not tell the grown child where it was. Uighurs living in Turpan believed that if the placenta was thrown away causally or was buried in the earth, the eyes of baby would tend to look downward. Otherwise, if it was buried in a high position in the wall, the baby’s eyes would tend to look upward. Therefore, the baby’s afterbirth materials should be kept in the earthen wall at the same level at which an adult would normally focus their eyes. Because of very dry environment in Turpan, the placenta would not decay. The placenta was called hamra in Uighur, which means “to accompany”, since it was regarded as a powerful “partner” for a person’s whole life [40].

There were many Hui Muslims (Tungan) in Xinjiang, but their numbers were much less than the Turkic Muslims (about 150,000 at that time). They were stricter in following religious practices according to Qur’anic teachings and the Islamic law when compared with the practices of Turkic Muslims. The Swedish missionaries considered Hui Muslims to be braver and more competitive in politics and military power; they were also quite disciplined. During the 1920s Kashgar was ruled by a Hui Muslim who was also the military commander of the region. Under his rule, a thief ’s hand was chopped off according to the rule in the Qur’an if he was caught stealing, or a foot was cut off for other crimes [41].

In 1933 an important event took place in southern Xinjiang when the Turkic Muslims proclaimed the establishment of “The Eastern Turkistan Islamic Republic”. The basic policies of this republic were against Chinese rule and the atheism of the Russian Soviets [42]. The national flag consisted of a white background with a crescent and abstracted Qur’anic verses [43]. The Qur’an was the basis for the civil and religious legal system in this Islamic republic. To implement the teachings of the Qur’an Muslims were restricted in following only its literal meaning; as a consequence, its ideology was draped with fanaticism. Thieves were hung from trees as the proper form of capital punishment [44]. If woman came out on a street or at a mazar of a saint without wearing a headscarf, she would be taken home and beaten as punishment. “If they did not listen to such advice, then their skin should feel the whip’s leather [45].” Some women were executed as a result of such harsh penal laws [46].

The so-called “new Islam” strove under the Islamic banner to promote Turkic Muslims to take up arms to overthrow the ruling Han Chinese, and by this means to establish an Islamic state ruled by Turkic Muslims themselves. It was a state based on the Islamic law and the Qur’an. Since Xinjiang was annexed into the territory of China by the Qing imperial government, the Turkic Muslims always cherished this wish, aiming to set up a theocratic state ruled by Allah’s will within those vast stretches of land. Georg Roberntz stressed the importance of the rebellion or “The Eastern Turkistan Islamic Republic” as it was referred to by Muslim leaders, because it highlighted the importance of the national right of existence for Turkic Muslims [47]. So, Muslims in the region organized their own military forces and armies. However, this “Eastern Turkistan Islamic Republic” was destroyed by the military force of another Muslim people, the Hui or Tungan. In politics, due to the factor that Muslims were divided by various ethnicities, cultural and religious sects, which with different political interests and aims, Kashgar in the 1930s reflected the political reality that internal fighting, civil riots and the capricious political situation frequently hindered their cooperation.

In the period from the 1920s to the 1930s, the central government in Nanjing had not united China. Subsequently, the whole country was split into the warlords’ factions, while also having to deal with the Red Army led by Mao Zedong. As a consequence, the central government had no power to control Xinjiang because it was so remote geographically and separated from the rest of China by great Gobi Desert. Eventually, Xinjiang gained a political status of being semi-independent realm. During that period China had fallen into military segregation by the warlords, and Xinjiang was no exception. There were several military forces very actively in Xinjiang: besides the provincial forces led by the provincial government and the army from northeastern China, there were the White Russian Army, another army led by Zhang Peiyuan张培元 in Yili伊犁, a Tungan army led by Ma Zhongying马仲英, the Kirgiz Army led by Osman and several Uighur armies led by Hoja Niyaz, Rolebos and the Bugra Khan brothers in different areas. The latter three military forces were basically organized by Muslims believing in Islam. Muslim military forces united by religious faith, ethnicity, military and social structures became highly mobilized military organizations with strong Islamic characteristics. They were led by Muslim warlords and had strong impact upon politics and societies within Xinjiang. This was a typical reflection in the period of the warlord segregation and political divisions dominated throughout China.

A Short Summary

The religion of Islam and its believers among the Turkic Muslims in Kashgar region in the early part of the Republic recorded by the Swedish missionaries is a type of variety rooted in the different sections (Sunni and Shi’a), different ethnicity, different locations and different professions, for instance, farming in oasis, commerciality in city, town and nomadism in mountain. The features of Islam also are shaped diversely by such as Sufi mysticism, folk practices, Shamanism and other religious elements impacted by Buddhism, Nestorius, Taoism and Christianity. However, in spite of this diversity in Islamic practice, there is a core part in the traditional religious structure maintained for thousand years on the basis of mosque, clerics, community, madrasah (college) education, mazar and Sharia law court which are adhered to the fundamental doctrine in Islam: The Five Pillars, namely, the Quranic chanting, prayer, fast, alms- payment and pilgrimage to Mecca. Therefore, Islam in Kashgar region seems always shifted between the orthodoxy and impiety, between the central and periphery, between the impaction from the outside and through the inside. So the historical sources narrated by the Swedish Missionaries from MCCS in the period of the end of the Qing Dynasty and the early part of the Republic give us the valuable facts to witness the reality concerning the nature of Islam and the Muslim society in Kashgar region.

The great achievement in mission and charity work made by the Swedish missionaries cannot be erased easily from the hearts of the Uighur Muslim mass in Xinjiang. The seeds still sow in this once fertile land. They would give the buds, grow, boom and harvest some day in future. This history of the relationship between Christianity and Islam in society of Kashgar, Xinjiang should be a mirror and the useful lesson for the relation between the two great world religions today. Meanwhile it should illustrate to the people in the world that in that so hard time and in a so remote frontier region there was a group of the Christian ministers with sincerely and purely hearts spreading good news to the Muslims and planted the love from Lord to the hearts of local people. They were selfless and bravery, some of them paid their life price and died in the strange land, they should be remembered in history for ever although the memory to their work seems to have been almost obliterated by the atheistic education and materialization trend recently.

References

  1. This paper is sponsored by the fund from Institute of Sino-Christian Studies, Tao Fong Shan, Hong Kong where I undertake the research project of Swedish Missionaries in Kashgar, 2010. I am so grateful to the lot of assistance from Institute and its staffs and also thanks to Lauren Pfister, Professor of Religion and Philosophy Department, Hong Kong Baptist University for his very kindly helps in proofread this paper partly. This paper also is part of the result of Project 18ZDA189.
  2. Gunnar Jarring: “Preface of Mission och revolution I Centralasien,” authored by John Pg: 1.
  3. John Hultvall: Mission and Revolution in Central Asia, the MCCS Mission Work in Eastern Turkestan, 1892-1938. A translation by Birgitta Åhman into English of the original book, Mission och revolution I Centralasien, published by Gummessons, Stockholm, 1981, in the series STUDIA MISSIONALIA UPSALIENSIA All Swedish materials cited in this research paper come from the English version of the book Mission och revolution I Centralasien.
  4. Xinjiang Archives (2002): Politics Archive No. 2 —5 —140 in the National Archives of Sweden; Also cited by Mulate Heiniyat 木拉提黑尼牙提: “Historical Ratification on Swedish Mission to Establish Station in Kashgar”, Xinjiang Shehui Kexue (新疆社会科学Xinjiang Social Sciences), No. 3. Pg: 64-65.
  5. Gunnar Jarring (1991) Eastern Turkestanic in the Swedish National Central Asiatic Journal. 35: 55-61.
  6. Nyrén, Svenska Missionsförbundets femtioårsjubileum (The 50th anniversary of the MCCS), Stockholm, 1928, p. 276; Cited from John Hultvall: Mission and Revolution in Central Asia, the MCCS Mission Work in Eastern Turkestan, 1892- 1938. A translation by Birgitta Åhman into English of the original book, Mission och revolution I Centralasien, published by Gummessons, Stockholm, 1981, in the series Studia Missionalia Upsaliensia XXXV. The Swedish materials citied in this paper mostly come from the book in English translation.
  7. Lattimore Vi träffas i Turkestan, Stockholm, 1935 (Sw) (Original: Turkestan Reunion, Boston, 1932). Pg: 232.
  8. Ibid.
  9. Törnquist J (1926) Kashgar: Some Pictures from Inner Asia, Country, People and Mission, Stockholm: Swedish Missionforbundents Forlag. Pg: 126.
  10. Marshall Broomhall: Islam in China: A Neglected Problem, Pg: 237.
  11. For woman mosque, please refer to the work written by Maria Jaschok and Shui Jingjun: The History of Women’s Mosques in Chinese Islam: A Mosque of Their Own, London, Curzon, 2000.
  12. Lundahl edited: På obanade stigar (Untouched territory, Twenty five years in Eastern Turkestan), Stockholm Pg: 268 f.
  13. Högberg, Islam och evangeliet (Islam and the Gospel), the manuscript published after the death of Högberg and revised by G Ahlbert and Tor Andrae, Stockholm, Pg: 47 f.; Palmaer, G (ed.), En ny port öppnas (A new open door), Stockholm, 1942. Pg: 90.
  14. Arbman, Ernst (ed), Världsreligionernas kärnord (The key words in the religions of the world), Stockholm, Pg: 82.
  15. Ungdomsvännen, (Friend of the Youth), A magazine for young people published by the MCCS, Stockholm (In 1940 was combined with Svensk Veckotidning)1927. Pg:531.
  16. Högberg-Ahlbert, Islam och evangeliet (Islam and the Gospel), The manuscript published after the death of Högberg and revised by G Ahlbert and Tor Andrae, Stockholm, 1925. Pg: 60.
  17. Högberg-Ahlbert, ibid. Pg: 57 f.
  18. Aagaard, Johannes (ed), Verdens religioner (The religions of the world), Copenhagen, Pg: 483.
  19. Palmaer, ibid. Pg: 29.
  20. Broomhall, ibid. Pg: 251.
  21. Lundahl, ibid. Pg: 227 f.
  22. Ungdomsvännen, ibid. 1929, Pg: 562 and 1930, Pg: 230.
  23. Ibid., note, Pg: 129 f.
  24. The Missionsförbundet, (The Mission Covenant Church of Sweden), Magazine published by the MCCS, Pg: 275.
  25. Palmaer, ibid. Pg: 82.
  26. The Missionsförbundet, ibid, Pg: 245.
  27. Ansgarius, “Annals of the Mission Covenant Church of Sweden,” Published every October, Stockholm, Pg: 107 ff, 116, 130 f.
  28. Palmaer, ibid, Pg: 120. Etherton, P.T. “Chinese Turkestan,” in The Asiatic Quarterly Review, No. 20, London, 1924. Pg: 247.
  29. Raquette, G. Muhammeds religion (The religion of Muhammed), Stockholm,1935. Pg: 152 f.
  30. Nyrén, , ibid. Pg: 275.
  31. Schimmel, Mystical Dimensions of Islam. University of North Carolina Press. 1975. Pg: 144, p. 497; Also see Gunnar Jarring: “Dervish and Qalandar”, Scripta Minora, Stockholm, 1985-1986, Vol. 2, Pg: 16.
  32. Grenard, Le Turkestan et le Tibet, 2, Pg: 236-237.
  33. Ibid, text II: 81-82 + n. 37.
  34. Ibid, text II, n. 20.
  35. Schimmel, ibid. Pg: Pg: 491. Pg: 506, Pg: 421.
  36. Gunnar Jarring: “Dervish and Qalandar”, ibid, 2, Pg: 15.
  37. Han Zhongyi (韩中义) (2003) “The Elementary Study on Sufi Saint Worship in Xinjiang” (新疆苏非圣徒崇拜初探), Xiyu Yanjiu (Journal of Western Asia西域研究), 2: 68.
  38. http: //www.uighurbiz.net/html/2008/1023/11952.html, August 5, 2013.
  39. Raquette, ibid. Pg:135.
  40. Justin Ben-Adam (1999,) Chapter 9, “China”, Islam outside the Arab World, edited by David Westerlund and Ingvar Svanberg, New York: St. Martin’s Press. Pg: 203-204.
  41. Palmberg, G. Missionärsminnen (Missionaries’ memories), in the Vetlandaposten (Newspaper), February 29th, 1960 and February 2nd, 1961.
  42. Fleming, News from Tartary, London, 1936, Pg: 474. (Common edition, 1948, Pg: 252.)
  43. Wu, The Turkestan Tumult, London, 1940, Pg: 247.
  44. The Ansgarius, ibid, Pg: 75.
  45. Torvik, Bak Himalaja (Behind the Himalayas), Bergen, 1945. Pg: 122.
  46. Wu, ibid, Pg:248.
  47. Maillart, Ella K, Forbidden Journey – From Peking to Kashmir, London, 1940, Pg: Ansgarius, ibid, 1936. Pg: 115.

Commentary on “In Vitro Modulation of Spontaneous Activity in Embryonic Cardiomyocytes Cultured on Poly (vinyl alcohol)/Bioglass Type 45S5 Electrospun Scaffolds” and Recent Advances

5 Replies

DOI: 10.31038/NAMS.2025813

 
 

The field of tissue engineering promotes the manufacturing of three dimensional tissue scaffolds that induce biocompatibility, adhesion, and cell culture by using natural, synthetic, or a blend of polymers, as well as active agents (growing factors to enhance cell proliferation, cell differentiation, nutrients, etc.). Electrospinng makes it feasible to approach fibrilar structure, adjust porosity, and high surface area-to-volume ratio to mimic the extracellular matrix of native tissues. Tissue scaffolds are generally used as supports destined to mimic the morphological structure, tune mechanical properties to the native tissue, and functionality in regeneration processes. Still, beyond this, they are expected to perform the physiological functions to which each tissue or organ is intended. In the case of cardiac tissue, it brings oxygen through the blood to each part of the body through the contraction of the cardiac muscle cells (cardiomyocytes). This contraction is neorologycally stimulated to the voltage and calcium-dependent process denominated excitation-contraction coupling, which is mediated by several factors. In this sense, the composition of the scaffold becomes relevant.

To mimic the mechanical and surface properties of the cardiac tissue to be regenerated, hybrid organic/inorganic scaffolds has been developed using natural or synthetic polymers. polyvinyl alcohol (PVA) and polycaprolactone (PCL) have also been designed for the treatment of vascular emboli due to their biocompatibility and low protein absorption. Muscle contraction are a function of intracellular Ca2+ levels in cardiomyocytes, and a decrease of these ions reduces myocardial conductivity and the development of cardiovascular disease. Bioactive agents, such as bioglasses in the form of micro-or-nanopaticles mixed with ad hoc polymers enhance the mechanical properties of the scaffolds and stimulate angiogenesis in tissue engineering. The most successful was Bioglass 45S5 made by a sol-gel method. It contains (Ca2+) calcium ions among others. The Ca2+ ions in the cardiac tissue affect functions that enable blood circulations in the body.

Electrospun scaffolds made of conventional polymers lack of suitable mechanical and electrical properties. Therefore, synchronouos beating rate of cardiomyocytes cultured on these materials has not been achieved. Recently, PVA mixed with nanopaticles of Bioglass 45S5, has been reported with promising results.

Remarks

The sol-gel technique used here to prepare the Bioglass 45S5 nanoparticles (diameter range: 5 nm – 20 nm), facilitating uniform distribution into the PVA fibers (diameter range: 130 nm – 340 nm). Chemical crosslinking of PVA fibers and bioglass concentration of 20% allowed the formations of strongly connected cardiomyocytes layer on the surface of the scaffolds, allowing synchronous and periodic contractile activity of the cells. Crosslinking also increased thermal stability of the scaffolds. Intracellular calcium fluctuations during contractile activity of cardiomyocytes was associated with the Ca2+ ions release from the bioglass nanoparticles.

Recent Advances

Ischemic heart disease, a major global health challenge, is exacerbated by oxidative stress and dysregulated calcium homeostasis. Embryonic chick cardiomyocytes were used in this study as a model to evaluate the biofunctionality of the scaffolds. In a previous work we demonstrated that procyanidin-enriched compounds derived from epicatechin (EC) decrease the frequency of chick embryonic cardiomyocytes, whereas collagen increases it, both components were combined in electrospun scaffolds of PCL. This study aimed to develop and characterize a bioactive scaffold by incorporating polymerized epicatechin (PEC) into PCL electrospun scaffolds to enhance antioxidant properties and evaluate potential PEC-Ca2+ interactions. PEC affects heart cell contractions and PCL, a biocompatible polymer, resist heart fatigue during regeneration of cardiomyocytes. The mechanical properties of scaffolds, such as their Young´s modulus and tensile strength, are critical for their suitability in tissue engineering applications, particularly in cardiovascular research. We developed a scaffold mixing PCL with cocoa-derived EC [1-5].

Remarks

PEC/PCL protects against oxidative stress and interacts with calcium, altering heart cell contractions and offering insights for future cardiac repair therapies. These scaffolds combine antioxidant activity with calciummodulating the capacity of cardiomyocyte contractibility, thus, positioning them as promising candidates for cardiovascular tissue engineering. Future efforts are focus on further optimizing the structural and mechanical properties of electrospun scaffolds to mimic better the native extracellular matrix of cardiac tissue.

References

  1. Filiberto RT, Alfredo MC, Gertrudis HGG, Alicia FN, Karla GL, et al. (2024) In Vitro Modulation of Spontaneous Activity in Embryonic Cardiomyocytes Cultured on Poly (Vinyl Alcohol)/Bioglass Type 58S Electrospun Scaffolds. Nanomaterials 14: 1-18.
  2. Karla GL, Ricardo VG. Cardiomyocytes Contractile Activity on Poly(vinyl-alcohol)/Bioglass.
  3. Patent: “Andamio tisular para regeneración de tejido cardiaco”, Patente 402408. IMPI, México. Filiberto Rivera Torres, Ricardo Vera Graziano. April 20, 2023.
  4. Miranda BE, González-Gómez GH, Falcón MA, Durán PC, Jiménez MC. et al. (2022) Activity patterns of cardiomyocytes in electrospun scaffolds of poly (ϵ-caprolactone), collagen, and epicatechin, ISSN: 0928-4931, Materials Today Communications 31: 10340.
  5. Eliza MB, Maria AFN, Ricardo VG, María LDP, Edna OMU, et al. (2025) Signal of contraction on poly (epicatechin)/poly(ε-caprolactone) electrospun scaffolds mimicking cardiac architecture. SENT. JAPS.

The Moderating Role of Core Self Evaluation in the Relationship Between Family Functioning and Drug Abuse Patients

3 Replies

DOI: 10.31038/PSYJ.2025774

Abstract

This study examined how core self-evaluation influences the relationship between family functioning and patients with drug abuse. A sample of 88 patients were used with age range of 18-65 with mean age of 33.83 and standard deviation of 9.728. 40 patients were selected from Federal Neuropsychiatric Hospital New Haven and 48 participants were selected from Nigeria Correctional service in Enugu. Simple random sampling technique (balloting) was used in selecting hospitals and purposive sampling technique (Inclusion and Exclusion criteria) was adopted in the selection of participants. Inclusion Criteria (the participants were inpatient and they are drug abuse patients and exclusion (those who have never used substance) Three instruments were used to obtain information and these include; (1) core self-evaluation scale, (2) The brief relationship scale, (3) drug abuse screening test. Correlational research design and moderated hierarchical regression analysis was adopted as a statistical tool. Family functioning did not relate with drug abuse (β=-.261, t=10.445, P=.072). Core self-evaluation negatively correlated with drug abuse (β=-.697, t=-9.117, P>.01). finally core self-evaluation did not moderate family functioning and drug abuse (β=.226, t=1.579, P=.118). One implication of this study is that clinical psychologist (psychotherapist) should always pay attention to the drug abuse patients core self-evaluation, teach them the importance of handling task and challenges well. (self-efficacy), how to stabilize their emotions and also learn to value themselves (self-esteem) [1-3].

Keywords

Core self-evaluation, Family functioning, Drug abuse

Introduction

Background to the Study

Drug abuse is a growing public health concern, with far-reaching implications for both individual and their families. The transition to adulthood is a serious period marked by significant psychological and social changes, during which the risk for developing drug abuse can increase. Family functioning, which includes the quality of relationships, communication, and overall emotional support within the family unit, has been exposed to significantly impact the likelihood of drug abuse among patients.

World Drug Report in 2021 revealed that approximately 275 million individuals worldwide had used drugs within the past year, with 36 million people going through drug abuse. In Nigeria, the same report estimated that there were 14.3 million drug users, among whom close to 3 million abuse drugs [4]. In Nigeria, a nationwide study by the WHO in 2016 and UBE, 2016 reported that 7.5% of individuals had ever used cannabis, and 12.0% had ever used drugs, of particular concern in Nigeria is the significant association between drug use and crime rates. Recent research indicates that young people, influenced by psychoactive substances, are increasingly involved in various crimes, including terrorism, banditry, and kidnapping [5-7]. In Southern part of Nigeria, a range between 50.2% and 78.4% indicating a very high rate of current alcohol use was observed by [8]. More so, In Enugu State, there was a noticeable disparity in substance use patterns, in alcohol consumption, 92.5% of patient’s males consume more than females 7.5%. In Tobacco consumption, 96.1% patient’s males smoke more than female 1.0%. While in marijuana usage, 100% of patient’s males consume more than their female counterparts 0.0% ([9], 2010 cited in [8]). Furthermore, substance use has been linked to additional social challenges such as high school dropouts and weak parental backgrounds [10].

The misuse of these substances can cause the development of drug abuse, which is a significant social and public health concern globally. This issue affects individuals across all demographic groups, but adolescents and youths, who are undergoing physiological and psychological development, are particularly vulnerable. This age group is often characterized by self-exploration, heightened curiosity, and a propensity for risk-taking [11].

Drug abuse refers to the dependence on and misuse of drugs by individuals who voluntarily use them for their effect on the central nervous system. This term has been adopted to replace past popular terms such as ‘illicit drug use, substance abuse and drug addiction/dependence. Two related categories, substance abuse and addiction/dependence constitute drug abuse. Both terms refer to maladaptive patterns of substance use that result in impairment or distress [12].

Historically, substance use was often intertwined with religious, cultural, and medicinal practices. Ancient texts from civilizations such as the Sumerians, Egyptians, and Greeks document the use of substances like alcohol, opium, and cannabis for various purposes, including rituals, recreation, and pain relief [13]. However, not until the year nineteenth and twenty centuries that medical professionals and researchers began to systematically study the effects of substance use on individuals’ physical and mental health. The identification of drug abuse as a clinical disorder gained traction in the 20th century, driven by advancements in psychiatry, psychology, and addiction medicine. Early pioneers in the field, recognized the addictive potential of substances like cocaine and alcohol and explored the psychological underpinnings of addiction [14]. Additionally, the introduction of diagnostic frameworks provided standardized criteria for identifying and diagnosing substance-related disorders [15].

Drug abuse is characterized by different kinds of symptoms and behaviour that indicate impairment in various areas of functioning. These symptoms may include:

Loss of Control: Individuals with drug abuse often have the challenge of been control by substance use despite negative consequences, such as legal issues, relationship problems, or health issues. They may repeatedly attempt to cut down or quit using substances but find themselves unable to do so.

Craving: Intense cravings or urges to use substances are common in individuals with drug abuse. These cravings can be activated by emotional states environmental cues, or stress and may contribute to continued substance use despite efforts to abstain.

Tolerance: Over time, individuals with drug abuse may develop resistance to the effects of substances, requiring increasing amounts to achieve the desired effects. This tolerance can lead to escalated substance use with an increased likelihood of overdose or other adverse consequences.

Withdrawal: When individuals with drug abuse attempt to reduce or stop using substances, they may experience withdrawal symptoms such as nausea, sweating, anxiety, or tremors. These warning sign can be psychologically and physically distressing, making it difficult to maintain abstinence.

Impaired Functioning: Drug abuse often impairs individuals’ functioning in various areas of life, including work, school, relationships, and social activities. They may neglect responsibilities, experience difficulties in interpersonal relationships, or engage in risky behaviours to obtain or use substances.

Continued use despite negative consequences: Notwithstanding adverse consequences related to substance use, individuals with drug abuse may continue to use substances compulsively. This pattern of continued use despite adverse outcomes is a hallmark feature of the disorder [15].

As a significant public health concern with developmental dimensions, researchers have identified several socio-demographic factors linked with drug abuse. These contributory factors are related to individuals, family, community and the clinic of the patients. The identified factors include gender, age, personal beliefs, low self-esteem, experiences of abuse, depression, poor coping skills and early exposure to or involvement in risk-taking behaviour [8].

Factors related to the family have also been identified such as parental practice and attitude towards drug use, for example, watching parents/guardians engaging in use may act as an endorsement of its usefulness [8]. Then again, family functioning encompasses various dimensions (cohesion, expressiveness and conflict) of interaction, communication, roles, and dealings in the family unit. Family functioning can be understood through a systemic lens, viewing the family as unified system where the behaviour of one member influences, and is influenced by the behaviour of others [16]. According to this perspective, family functioning is characterized by patterns of communication, power dynamics, and role assignments that maintain equilibrium or contribute to dysfunction within the system. From a transactional standpoint, family functioning is conceptualized as the ongoing exchange of behaviours, emotions, and resources among family members [17]. This perspective emphasizes the reciprocal nature of interactions within the family system, highlighting how individuals’ actions and reactions shape relational dynamics and contribute to the overall functioning of the family. Family functioning can also be viewed from an adaptive framework, which focuses on the people’s capacity to respond and adapt to internal and external stressors [18]. A family’s adaptive capacity is reflected in its resilience, problem-solving skills, and ability to maintain cohesion and support in spite of the challenges such as illness, transitions, or conflicts. The developmental perspective considers family functioning in terms of its evolution and change over time, taking into account normative developmental tasks and transitions across the family life cycle [19]. This perspective highlights how important age-appropriate role adjustments, renegotiation of boundaries, and shifts in relational dynamics as family members navigate various developmental stages from infancy to old age. Finally, family functioning can be understood within an ecological framework that considers the broader context in which the family operates, including cultural, socioeconomic, and environmental factors [20].

This perspective recognizes the influence of external systems and contexts on family dynamics, emphasizing the interconnectedness between the family and its social, economic, and cultural milieu. The impact of family functioning on drug abuse is a multifaceted and extensively studied topic in psychology and addiction research. Family dynamics, interactions, and relationships plays key role in determining an individual’s susceptibility to, initiation of, and recovery from drug abuse. Firstly, family environment and structure significantly influence the development of drug abuse. Research indicates that dysfunctional family structures characterized by no communication, absence of parental involvement, marital discord [21]. The absence of a nurturing and supportive family environment may predispose individuals to seek solace or escape through substance use, as they lack healthy coping mechanisms for dealing with stressors or emotional challenges. Secondly, parental substance abuse serves as a significant risk factor for intergenerational transmission of drug abuse. Children of parents with drug abuses are more likely to develop similar patterns of behaviour due to genetic predispositions, modeling of parental behaviour, and exposure to an environment where substance use is normalized [22]. More so, Individuals from dysfunctional family environments may engage in heightened self-evaluation processes as they navigate conflicting messages or experiences within their family systems. This internal reflection can lead to increased awareness of the impact of family dynamics on their substance use behaviour and motivation for seeking help or making changes.

Moreover, these children often experience neglect, abuse, or chaotic home environments, further exacerbating their vulnerability to drug abuse. Furthermore, family dynamics such as communication patterns, conflict resolution strategies, and parental monitoring exert profound effects on drug abuse outcomes. Families characterized by poor communication or conflict avoidance may hinder open dialogue about substance use, thereby impeding early intervention or support-seeking behaviours [23]. Conversely, families with strong communication channels and effective problem-solving skills are better equipped to address issues relating substance use providing instrumental support to affected members. Additionally, the quality of parent-child relationships significantly impacts drug abuse trajectories. Warm, supportive, and authoritative parenting styles have been linked to lower rates of substance abuse initiation and progression [24]. In contrast, hostile, neglectful, or overly permissive parenting styles may foster resentment, rebellion, or a lack of attachment, increasing the likelihood of drug abuse development [25].

Core self-evaluation in the setting of substance use refers to the process by which individuals assess their own behaviours, thoughts, feelings, and consequences related to substance use with the aim of gaining insight, making informed decisions, and initiating behaviour change [26]. This self-assessment often involves reflection on one’s patterns of substance use, the impact on various areas of life (e.g., relationships, work, health), motivations for using substances, and readiness to change. CSE is a crucial component of several evidence-based approaches to substance abuse treatment, including motivational interviewing and cognitive-behavioural therapy. In motivational interviewing, self-evaluation is facilitated through open-ended questioning, reflective listening, and exploration of ambivalence about change [27]. By eliciting and amplifying discrepancies between a person’s values, goals, and current behaviours, clinicians aim to evoke intrinsic motivation for change and enhance self-awareness. Within cognitive-behavioural therapy (CBT), self-evaluation involves identifying and challenging maladaptive thoughts, beliefs, and coping strategies accompanying substance use [28]. Through techniques such as self-monitoring, functional analysis, and cognitive restructuring, individuals learn to evaluate the triggers, cues, and consequences of their substance use more objectively and develop alternative coping skills to manage cravings and high-risk situations.

Core Self-evaluation also plays vital role in the maintenance of recovery from substance use. Individuals in recovery engage in ongoing self-assessment to monitor their progress, identify potential relapse triggers, and address any lapses in coping strategies [29]. This reflective process fosters self-awareness, self-regulation, and individual feeling of responsibility for maintaining sobriety. Moreover, self-evaluation is not limited to individual introspection but can also be facilitated through peer support groups, such as alcoholics anonymous or narcotics anonymous, where individuals share their experiences, strengths, and challenges in a supportive environment [30]. By hearing others’ stories and receiving feedback from peers, individuals can gain new perspectives, validate their experiences, and learn from shared struggles and successes.

The moderating influence of core self-evaluation on the connection between family functioning and drug abuse elucidates the intricate interplay between family dynamics, individual cognitive processes, and the development or maintenance of awkward substance use behaviours. Family functioning, encompassing aspects such as communication patterns, parental monitoring, and emotional support, significantly influences an individual’s risk for drug abuse [21]. Dysfunctional family environments characterized by conflict, neglect, or poor communication may contribute to maladaptive coping strategies and increased vulnerability to drug abuse [23].

Moreover, core self-evaluation plays a fundamental role in the effectiveness of interventions targeting substance use within the family context. Family-based interventions often incorporate components aimed at enhancing self-awareness, motivation, and decision-making skills [31]. By facilitating self-evaluation, these interventions empower individuals to critically assess the role of family functioning in their substance use and to explore alternative coping strategies or support networks. Additionally, core self-evaluation may be a defensive factor against the negative effects of dysfunctional family environments on substance use outcomes. Those with developed levels of self-awareness and self-regulation may be better equipped to resist family influences or to seek external sources of support and validation [29]. Thus, core self-evaluation acts as a mechanism through which individuals can mitigate the impact of adverse family dynamics on their substance use behaviours and outcomes. Therefore, it is against this backdrop that this study will explore how core self-evaluation influences the relationship between family functioning and patients with drug abuses.

Statement of the Problem

Drug abuse has significant public health concern affecting patients, families and society at large which the researcher discovered during her clinical internship experience at 82 division hospital rehabilitation centers, Enugu. Where the researcher noticed that about seven (7) male patients out of every 10 male patients are diagnose with drug abuse. So, it became a concern to the researcher. And a lot of questions went through my mind as to what could be the psychological factor to such problem and so the researcher decided to do a study on this very topic drug abuse and other factors in order to answer the questions in her mind. However, I looked out for past researcher like [32] they did research on perceived parenting styles and personality factors as predictors of drug abuse with the populations of adolescent student in Enugu. [33] also did a work on how family dynamics relate to coping mechanisms among individuals diagnosed with drug abuse. Research has shown that family functioning plays an important role in either protecting against or contributing to the development of drug abuse. But notwithstanding is not everyone from a dysfunctional family that will develop drug abuse, that means there are other factors like the presence of a moderator that influences the relationship.

One of such moderators is core self-evaluation (CSE), which is a person’s knowledge of their own worth, competence and ability to handle challenges. So, individuals with positive core self-evaluations may perceive adverse family environments differently and be more resilient to stressors that can lead to drug abuse but individuals with negative CSE may be prone to dysfunctional family and this can intensification the likelihoods of drug abuse.

This study aims to investigate how core self-evaluation influences the relationship between family functioning and patients who abuses drug. By focusing on this moderation process, the research seeks to provide deeper insights into the interplay between family influences and individual psychological factors, ultimately contributing to the development of more targeted and effective intervention strategies for addressing drug abuse in patients.

Thus, the following pertinent questions concerning drug abuse among patients need to be justified in this regard.

  1. Will family functioning (expressiveness, cohesion and conflict) relate with drug abuse?
  2. Will core self-evaluation correlate with drug abuse?
  3. Will core self-evaluation moderate the connection between family functioning and drug abuse?

Purpose of Study

This study is aimed at examining the role of core self-evaluation as a moderator in the relationship between family functioning and patients with drug abuse.

Hence;

  • To examine whether family functioning (expressiveness, cohesion and conflict) will significantly relate with drug abuse.
  • To examine whether core self-evaluation will significantly correlate with drug abuse.
  • To examine whether core self-evaluation will significantly moderate the connection between family functioning and drug abuse.

Operational Definition of Key Study Variables

Core Self Evaluation denotes a person’s fundamental appraisal of their own self-worth, competence, and capacity to manage their environment and behaviour as measured by Core Self Evaluation Scale developed by [1].

Family Functioning is a distinct perception of an individual, about their family and how things are managed, as measured by Brief Family Relationship Scale, developed by [2].

Drug abuse is a health disorder characterized by lack of control over the use of legal or illegal substances, despite harmful consequences as measured by drug abuse Screening Test, developed by [3].

Method

Participants

Eighty-eight (88) participants were drawn from the population of patients comprising males only. The researcher used Simple random sampling technique to select hospitals while purposive sampling technique (Inclusion and Exclusion criteria) were adopted in selecting patients. Inclusion Criteria (the participants must be an inpatient that has insight and must have use one or more substance and exclusion (those who have never used substance will be excluded and the outpatient). Their age range is 18-65 with mean age of 33.83 and standard deviation of 9.728. The questionnaire was also used to get information on demographic variables such as marital status, educational qualification, age, occupation, family upbringing.

Instruments

Three instruments were used which include:

Core Self Evaluation Scale (CSES; [1])

The Brief Relationship Scale (TBRS; [2])

Drug Abuse Screening Test (DAST-10; [3])

Core Self Evaluation Scale (CSES)

It is a 12-item, Likert-typed scale, with responses ranging from Strongly Disagree to Strongly Agree, developed by [1]. Used in assessing a person’s fundamental appraisals of their own worth, competence, and capabilities. Locus of control was less highly correlated with the CSES, with an average corrected correlation of SO. Overall, though, the CSES showed significant convergence with the four core traits. [1] reported a Cronbach Alpha of .85. [34] validated the instrument among undergraduate students with substance abuse problems, while [35] adopted CSES among bank employees. The researcher conducted a pilot study from 82 Division hospital using 20 participants and Cronbach alpha .67.

The Brief Family Relationship Scale (TBFRS; [2]).

The Relationship dimension of the Family Environment Scale, comprising Cohesion, Expressiveness, and Conflict subscales, developed by [2], assesses an individual’s perception of the quality of their family relationship functioning.

Convergent and distinct (discriminant validity) of the Scale was evaluated through correlational analysis, yielding significant results .70. The researcher conducted a pilot study from 82 Division hospital using 21 participants and it yielded Cronbach alpha of .74

Drug abuse Screening Test (DAST-10;[3])

The Drug abuse Screening Test (DAST) is a 10-item designed test to offer a concise tool for clinical and non-clinical screening to identify drug abuse or dependence disorders by Skinner (1982). The DAST-10 was found to be a psychometrically sound drug abuse screening measure with high convergent validity (r=.76) when correlation with the Drug Use Disorders Identification Test (DUDIT) was measured and to have a Cronbach’s alpha of .92. In addition, a single component accounted for 59.35% of total variance, and the DAST-10 had sensitivity and specificity scores of .98 and .91, respectively, when using the optimal cut-off score of 4. Additionally, the DAST-10 presented good discriminate validity as it strongly differentiates patients with drug use disorder from those with alcohol dependence. the instrument was validated by [32] with Kuder Richardson internal consistency of .89 obtain by the researcher mentioned with 60 adolescents.

Procedure

The researcher listed down all the Public Mental Health centers in Enugu which includes Federal Neuropsychiatric Hospital New Haven, 82 Division Military Hospital (Neuroscience and Intelligence Center), Nigeria Correctional Service and Parklane teaching Hospital Neuro-psychiatric clinic. Through the help of a research assistant, the researcher picked two names from Public Mental Health Centers and this was done using simple random sampling technique (balloting) and purposive sampling technique (inclusion and exclusion) was employed to choose patients from the two hospitals. Inclusion criteria of patients that participant must have used one or two substances, have insight so he can answer questions and lastly the participant must be an inpatient. Exclusion criteria- those patients who do not use substance will be excluded and the outpatient will also be excluded.

The researcher got a letter of introduction from the HOD of Psychology Department and then submitted it to the people in charge of the two public mental health hospitals selected. A letter of introduction was summited to the Nigeria Correctional Service, Enugu headquarter by the researcher and they responded to the researcher with an approval letter which also served as a gate pass to where I can have access to the prisoner through the help of clinical psychologist and the warden who help in bringing the inmates to the psychological unit so that they can fill in the questionnaires and while they are filling it the warden stands by for the safety of the researcher and psychologist and to also take them back to the prison when they are done. Meanwhile fifty (50) copies of questionnaires were sampled at Nigeria Correctional Service center, Enugu and forty-eight (48) was collected and used (those correctly ticked) for the research. These lasted for a duration of one week and each day as I arrive, I pass through the gate with my gate pass leaving my bag with the security outside the building because am only allowed to go with my book and pen since the questionnaire has been summited to the clinical psychologist. As I entered the gate a female warden will search me before taken me to the psychological unit for me to sit and wait for the inmates who are willing to come out. The researcher also summited the letter of introduction to Federal Neuropsychiatric Hospital New Haven and the researcher was ask to summit a copy of the research proposal that it has to be review before approval and the researcher did that which was requested from the hospital authorities. Then after a span of time the researcher was called to come and collect the approval letter. The researcher headed to the HOD of the psychological unit and she assigned to the researcher clinical psychologist who could help the researcher to reach the Drug abuse patients. It lasted for two weeks because am only allowed to come three times in a week which are the days the researcher can see the patients and the psychologist. Fifty (50) copies of questionnaires were also sample at Federal Neuropsychiatric Hospital New Haven and forty (40) was selected and used (those filled correctly). The total number of 100 copies of questionnaires were printed and shared into two equal parts between the two hospitals and so, 88 out of 100 copies of questionnaires were used. The questionnaire was also used to get information on demographic variables such as marital status, educational qualification, age, occupation, family upbringing.

Design and Statistics

The study adopted correlational research design and moderated hierarchical regression analysis as a statistical tool.

Result

Table 1 describes the correlation matrix. The table discovered that drug abuse and core self-evaluation r (88)=- .702, p<.001. This indicates that patient with low core self-evaluation have the propensity to drug abuse when faced with challenges. Marital status had a positive correlation r (88)=.204, p<.001. this means that those who are not married get involve more with drug abuse. Educational level had a negative relationship with drug abuse r (88)=- .231, p<.001. Meaning that those who are educated have more drug abuse.

Table 1: Descriptive and Correlation Matrix of study constructs

MEAN SD 1 2 3 4 5 6

7
Drug abuse (1)

6.03

 2.71 1            

Core Self Evaluation (2)

 37.89 17.30 -.702*

1

          
Family Functioning (3)

64.05

 13.55 -.120 .072 1        

Age (4)

 33.83 9.728 -.051 .105 .134

1

      
Marital Status (5)

1.73

 .62 .204** -.322* .082 -.417* 1    

Educational Qualifications (6)

 1.40 .49 .231** -.189** -.042 -.137 -.055

1

  
Family Upbringing (7)

2.14

 .76 -.097 .031 .177 .048 -.042 .130 1

Cohesion (8)

 23.58

 

 9.14 -.103 .050 .893* .070 .140 .004

.127
Expressiveness (9)

16.59

 3.29 -.071 -.004 .598* .264** -.005 -.083 .023

Conflict (10)

 24.56 6.05 -.076 .061 .501* .043 -.036 -.071

.121
Occupation (11)

2.046

 .79 -.330* .250** -.044 .094 -.210** -.077

.182**

Correlation significant at * P<.001, ** P<.05
Note: N= 88, Gender was coded as (male). Educational Qualification 1 (A level and above) and 2 (O level and below). Family upbringing 1(single parenting) 2(monogamy)3(polygamy). Occupation 1(employed) 2 (self-employed) and 3 (unemployed). Marital status 1 (single) 2(married) and 3 (separated).

In Table 1 above Occupation negatively correlated with drug abuse r (88)=-.330, p<.001. This indict that the ones with job (employed) are more in drug abuse patients.

Note: int_1: Family functioning x core self -evaluation.

In step one of Table 2 above, family functioning did not correlate with drug abuse (β=-.261, t=10.445, P=.072). This implies that patients’ family functioning does not bring about drug abuse. Thus, the first hypothesis which stated “that family functioning will significantly correlate with drug abuse was rejected. The table above further revealed that the moderator variable, core self-evaluation, correlates with drug abuse (β=-.697, t=-9.117, P>.01). This means that the patients’ who have low core self-evaluation are more likely to experience drug abuse. Hence, the second hypothesis which stated that core self-evaluation will significantly correlate with drug abuse is hereby accepted.

Table 2: A table summarizing moderated hierarchical regression analysis on the moderating role of core self-evaluation in relationship between family functioning and drug abuse patient.

Coefficientsa
 
Model Unstandardized Coefficients Standardized Coefficients t

Sig.

B

 Std. Error Beta

1

(Constant)

 11.452 1.096   10.445

.000
Family Functioning

-.052

 .029 -.261 -1.823 .072

Core Self Evaluation

 -.109 .012 -.697 -9.117

.000
FamilyF_CoreSelfE

.001

 .000 .226 1.579 .118

2

(Constant)

 11.721 1.477   7.936

.000
Family Functioning

.011

 .091 .055 .121 .904

Core Self Evaluation

 -.110 .012 -.702 -9.040

.000
FamilyF_CoreSelfE

.001

 .000 .227 1.558 .123

Cohesion

 -.064 .095 -.216 -.671

.504
Expressiv

-.093

 .111 -.114 -.845 .401

Conflict

 -.050 .084 -.112 -.594

.554
3 (Constant)

10.789

 3.769   2.863 .005

Family Functioning

 .014 .094 .072 .154

.878
Core Self Evaluation

-.082

 .088 -.525 -.928 .356

FamilyF_CoreSelfE

 .001 .000 .225 1.525

.131
Cohesion

-.051

 .118 -.173 -.434 .666

Expressiv

 .012 .192 .014 .061

.952
Conflict

-.107

 .117 -.239 -.915 .363

CoreSE_Cohesion

 .000 .002 -.106 -.311

.757
CoreSE_Express

-.003

 .005 -.354 -.654 .515

CoreSE_Conflict

 .001 .002 .269 .637

.526
4 (Constant)

11.027

 4.284   2.574 .012

Family Functioning

 .004 .094 .020 .042

.967
Core Self Evaluation

-.086

 .089 -.553 -.969 .336

FamilyF_CoreSelfE

 .001 .000 .241 1.616

.110
Cohesion

-.028

 .122 -.094 -.227 .821

Expressiv

 -.058 .197 -.070 -.293

.770
Conflict

-.088

 .116 -.198 -.760 .449

CoreSE_Cohesion

 -.001 .002 -.177 -.484

.630
CoreSE_Express

-.001

 .005 -.166 -.306 .760

CoreSE_Conflict

 .001 .002 .221 .520

.605
Age

.024

 .025 .085 .926 .358

Marital Status

 -.001 .418 .000 -.002

.998
Educational Qualifications

.626

 .471 .114 1.327 .189

Family Upbringing

 -.238 .304 -.067 -.784

.436
Occupation

-.495

 .289 -.144 -1.713

.091
a. Dependent Variable: Drug abuse

a. Dependent Variable: Drug abuse
Note: int_1: Family functioning x core self -evaluation.

However, the table revealed that core self-evaluation did not moderate family functioning in drug abuse (β=.226, t=1.579, P=.118). This means that having high core self-evaluation did not alleviate drug abuse experience in response to family functioning. Thus, the third hypothesis which stated that “core self-evaluation will significantly moderate family functioning in drug abuse” is hereby rejected. The relationship between variables entered in step one yielded (R=.715) and accounted approximately 51.2% (>R2 =.494) of the variance in drug abuse scores which contributed significantly to the regression model, F (3,84) =29.357, p=.001. (see appendix C for model summary and ANOVA tables).

Further, the three dimension of family functioning were entered in step two, thus none of the dimensions significantly predicted drug abuse (Cohesion, β=-.203, t=-.671, P>.05; expressiveness, β=-.135, t=-.986, P>.05; Conflict, β=-.105, t=-.559, P>.05). The relationship between variables entered in step two yielded (R=.719) and accounted approximately 51.7% (>R2 =.481) of the variance in drug abuse scores which contributed significantly to the regression model, F (6,81) =14.431, p=.001. (see Appendix C for model summary and ANOVA tables).

Forward to step three, the five demographic variables controlled in this study were entered, however, all of them yielded non-significant outcomes with drug abuse (Educational qualification, β=.105, t=1.298, P.>05; occupation, β=-.150, t=-1.836, P.>.05; marital status, β=.012, t =.124, P.>05; Age, β=.083, t=.929, P.>.05). respectively. The relationship between variables entered in step three yielded (R=.749) and accounted for approximately 56.1% (>R2 =.497) of the variance in drug abuse scores, which contributed significantly to the regression model, F (11,76) =8.814, p=.001. (See Appendix C for model summary and ANOVA tables).

Summary of Results

  1. Family functioning (cohesion, expressiveness and conflict) did not significantly predict drug abuse among patients.
  2. Core self-evaluation, negatively correlated with drug abuse among patients.
  3. Core self-evaluation did not moderate the relationship between family functioning and drug abuse among patients.

Discussion

The study examined the moderating role of core self-evaluation in connection between family functioning and drug abuse patients.

This study provides an understanding of the factors influencing drug abuse among patients, focusing on the important of core self-evaluation and family functioning. The researcher discovered that family functioning (cohesion, expressiveness and conflict) did not relate to drug abuse, the hypothesis that said that family functioning will relate with drug abuse was not accepted. This might be because they are full grown adult who are independent of their own decision. This did not agree with the existing literature by [36] which state that children with a family history of drug abuse experienced poorer family functioning compared to those without such history. maybe because the researcher used children while the researcher here used adult.

core self-evaluation correlated with drug abuse in this study. The hypothesis that said core self-evaluation will correlate with drug abuse was accepted. This suggests that patients who have negative core self-evaluation are prone to drug abuse when face with challenges [37]. The study found positive correlations between self-control, self-esteem, resilience, and confidence in managing emotions (self-efficacy). And this is in line with the research finding done by the researcher. Meaning that those with external locus of control tends to attribute their use of drug abuse to others like friends, parent or relations and that will make them feel they are not in control of their actions and such patient is prone to go back to drug abuse.

Interestingly, core self-evaluation did not moderated the connection between family functioning and drug abuse because there was no relationship between family functioning and drug abuse according to the researcher’s findings it was discovered that a patient perception of their family relationship has nothing to do with drug abuse rather it is the patient core self-evaluation(which refers to a patients beliefs about themselves and their abilities) because family relationship is not inherited but environmental characteristic which can be learned and unlearned. Family members can learn cohesion (how to relate) and expressiveness (how to talk to one another) and also learn how to manager conflict in the family. So, the same way patients also learn how to use substance, they can also unlearn. But core self-evaluation is a trait and is inherent and one can learn from the environment how to modify the behaviour for example if the patients who is using external locus of control (that is referring to others as the reason they engage in drug abuse) can learn to use internal locus of control (that is taken responsibility for their action and knowing that the consequences affect them more) and how to handle task and challenges effectively.

Demographic variables such as educational qualification (high level) and occupation (employed) were link to drug abuse maybe because buying this substance requires money.

Implications of the Findings

From a theoretical viewpoint, this study supports and expands social learning theory which posits that individuals learn behaviors, through observation, imitation, and reinforcement within their social environment [38]. This theory highlights the importance of cognitive factors, such as attention, retention, reproduction, and motivation, in shaping human behaviour. Which drug abuse is a negative behaviour that need to be reshaped through paying attention to the effect of drug abuse to human brain. Social learning theory demonstrates how patients’ who have low core self-evaluation can learn by watching others (models) and personal factors (beliefs and attitudes) to modify their core self-evaluation (self-esteem, self-efficacy, locus of control and emotional stability).

Empirical implications, this study will help the mental health professional body to know the importance of a psychology in the management of mental health and addictions in general.

The findings also highlight the need for psychotherapist to always pay attention to the drug abuse patients core self-evaluation, teach them the importance of handling task and challenges well. (self-efficacy), how to stabilize their emotions and also learn to value themselves.

And also, teachers/lecturers and therapist should teach their students and patients when their friends try to introduce substance (external) to them, they should learn how to use internal locus of control to be able to say no.

Those who fail to learn how to use internal locus of control has the tendency of relapse to substance again.

Limitations of the Study

One major limitation of this study

Is that I was unable to identify those who was in the rehab because of relapse.

Secondly, those without insight where not included in the questionnaire which affected the numbers of patients reached.

And other limitations were getting the responses of those who couldn’t read and write.

Suggestions for Further Research

Further studies could sample people with drug abuse in many general hospitals and so as to increase the populations.

Future researcher should add female to the demographics and further research should also investigate other potential moderators and mediators, such as family functioning, workplace and assertiveness

Summary and Conclusion

The research topic is the moderating role of core-self -evaluation in the connection between family and drug abuse. The participants were patients from the two hospitals. correlational research design and moderated hierarchical regression analysis as a statistical tool. This result of the research is that family functioning didn’t correlate with drug abuse meaning that irrespective of the family functioning (cohesion, expressiveness and conflict) it has nothing related to the manifestation of drug abuse. However, core self-evaluation negatively correlates with patients who has low core self-evaluation (external locus of control, low self-esteem, low self-efficacy and emotional instability). Thus far, core self-evaluation fails to moderate family functioning in drug abuse among patients.

Finally, patients who are equipped with high core self-evaluation (internal locus of control, high self-esteem, high self-efficacy and emotional stability) will tend to have absence of substance. use disorder. This is important for all the mental health professionals to always advocate for high core self-evaluation.

Conflict of Interest

The authors declare that there is no conflict of interest.

Ethical Clearance

All the participants signed the consent form to declare their free consent to participate in the study.

References

  1. Judge TA, Erez A, Bono JE, Thoresen CJ (2003) The Core Self-Evaluations Scale: Development of A Measure. Personnel Psychology 56: 303-331.
  2. Fok CCC, Allen J (2011) The Brief Relationship Scale: A Brief Measure of the Relationship. Dimension in Family Functioning Retrieved from https://www.researchgate.net/publication.
  3. Skinner, HA (1982) The Drug Abuse Screening Test. Addictive Behaviour 7(4): 363-371. [crossref]
  4. United Nations Office on Drug and Crimes (2021) World Drug Report.
  5. Ogba FN, Igu NC (2019) Violence in Nigerian secondary schools: Implications for educational management and sustainable development. In School Violence in International Contexts (pp. 57–70) Springer, Cham.
  6. Abasiubong FU, John UA, Idung A, et al. (2014) Pattern of psychoactive substance use in the northern region of Nigeria 13: 107-115.
  7. Hecker LL (2015) Ethical, legal, and professional issues in marriage and family therapy. In J. L. WetchlerL. L. Hecker (Eds.) An introduction to marriage and family therapy (pp. 505–545) Routledge/Taylor & Francis Group.
  8. Ojulei IN, Te-Erebe (2022) Prevalence And Predictors of Substance Use Disorder Among Urban and Rural Secondary School Students of Khana, Rivers State, Nigeria. European Journal of Public Health Studies 5(2).
  9. Ekwueme OE, Chukwuneke FN (2010) Prevalence and behaviour effects of psychoactive substance use among university students in south-eastern Nigeria. Ebonyi Medical Journal; 9(1).
  10. Mehanović E, Virk HK, Akanidomo I, Pwajok J, Prichard G, et al. (2020) Correlates of cannabis and other illicit drugs use among secondary school adolescents in Nigeria. Drug and Alcohol Dependence 206: 107457. [crossref]
  11. United Nations Office on Drug and Crime (2018) Drugs and Associated Issues among Young People and Older People. Available from: https://www.unodc.org/wdr
  12. Hasin DS, O’Brien CP, Auriacombe M, Borges G, Bucholz K, Budney A (2013) DSM-5 criteria for substance use disorders: recommendations and rationale. Am J Psychiatry 170(8): 834-51. [crossref]
  13. Booth M (1998) Opium: A history. Simon and Schuster.
  14. Dodes LM (2002) The heart of addiction: A new approach to understanding and managing alcoholism and other addictive behaviors. Harper Collins.
  15. American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders (5th ed.) American Psychiatric Publishing.
  16. Cox MJ, Paley B (2003) Understanding families as systems. Current Directions in Psychological Science 12(5): 193-196.
  17. Minuchin S (1974) Families and family therapy. Harvard University Press.
  18. McCubbin HI, McCubbin MA (1993) Family stress theory and assessment: The Double ABCX model of adjustment and adaptation. In C. Danielson B. Hamel-Bissell, P. Winstead-Fry (Eds.), Families, health & illness (pp. 143–164) Mosby Year Book.
  19. Carter EA, McGoldrick M (1988) The changing family life cycle: A framework for family therapy. Allyn & Bacon.
  20. Bronfenbrenner U (1979) The ecology of human development: Experiments by nature and design. Harvard University Press.
  21. Velleman R, Templeton L (2007) Understanding and modifying the impact of parents’ substance misuse on children. Advances in Psychiatric Treatment 13(2): 79-89.
  22. Crum RM, Lillie-Blanton M, Anthony JC (2006) Neighborhood environment and opportunity to use cocaine and other drugs in late childhood and early adolescence. Drug and Alcohol Dependence 43(3): 155-161. [crossref]
  23. Kumpfer KL, Alvarado R (2003) Family-strengthening approaches for the prevention of youth problem behaviors. American Psychologist 58(6–7): 457-465. [crossref]
  24. Baumrind D (1991) The influence of parenting style on adolescent competence and substance use. The Journal of Early Adolescence 11(1): 56-95.
  25. Fosco GM, Stormshak EA, Dishion TJ, Winter CE (2012) Family relationships and parental monitoring during middle school as predictors of early adolescent problem behavior. Journal of Clinical Child & Adolescent Psychology 41(2): 202-213. [crossref]
  26. Miller WR, Rollnick S (2012) Motivational interviewing: Helping people change (3rd ed.) Guilford Press.
  27. Rollnick S, Miller WR, Butler CC (2008) Motivational interviewing in health care: Helping patients change behavior. Guilford Press.
  28. Beck AT, Wright FD, Newman CF, Liese BS (1993) Cognitive therapy of substance abuse. Guilford Press.
  29. Witkiewitz K, Marlatt GA (2004) Relapse prevention for alcohol and drug problems: That was Zen, this is Tao. American Psychologist 59(4): 224-235. [crossref]
  30. Kelly JF, Greene MC, Bergman BG (2018) Beyond abstinence: Changes in indices of quality of life with time in recovery in a nationally representative sample of U.S. adults. Alcoholism: Clinical and Experimental Research 42(4): 770-780. [crossref]
  31. Liddle HA, Dakof GA, Parker K, Diamond GS, Barrett K, et al. (2001) Multidimensional family therapy for adolescent drug abuse: Results of a randomized clinical trial. American Journal of Drug and Alcohol Abuse 27(4): 651-688. [crossref]
  32. Osigbeme DI, Agu SA, Nwatu AC (2022) Perceived parenting styles and personality factors as predictors of substance Abuse in a sample of adolescent students in Enugu. Third International Conference/workshop faculty of social sciences and humanities Esut Agbani, Enugu State Nigeria.
  33. Asi Karakaş S, Ersöğütçü F (2023) Examination of the relationship between family functionality and styles of coping with stress in individuals with substance use disorder. Journal of Substance Use 28(1): 79-86.
  34. Abikoye GE, Adekoya JA (2010) Predicting substance abuse in a sample of undergraduate students: The role of core self-evaluation and delay of gratification. Psychological Studies 55: 299-307.
  35. Okechukwu R, Joe-Akunne C, Elodike C (2021) Work Resilience, Core Self-Evaluations and Organizational Creativity as Predictors of Thriving at Work Among Bank Employees in Owerri Municipal. Practicum in Psychologia 11 (1): 44-58.
  36. Ryan, Stacy R, Friedman CK, Liang Y, Lake SL, et al. (2016) Family Functioning as a Mediator of Relations Between Family History of Substance Use Disorder and Impulsivity. Addictive Disorders & Their Treatment 15(1): 17-24. [crossref]
  37. Yang C, Zhou Y, Xia M (2020) How resilience promotes mental health of patients with DSM-5 substance use disorder? The mediation roles of positive affect, self-esteem, and perceived social support. Frontiers in Psychiatry 11{588968) [crossref]
  38. Bandura A (1977) Self-efficacy: Toward a unifying theory of behavioral change. Psychological Review 84(2): 191-215.

Thermometric and Raman Spectrometric Results on a Graphic Pegmatite from the Island of Elba

3 Replies

DOI: 10.31038/GEMS.2025782

Abstract

Starting with the determination of the Raman spectra of synthetic boric acid and deuterated boric acid and using the two boric acid lines that show a linear correlation between 10B and 11B, we estimate the boron isotope composition of the silicate melt and the coexisting fluid phase on two examples: a hydrothermal diamond anvil cell (HADAC) experiment and the Elba pegmatite. Using the graphic pegmatite from the Elba Island/Italy, we show that the fluid and melt are strongly enriched in boron and cesium, as well as a relatively high deuterium concentration of melt inclusions trapped in the immediate vicinity of the critical point of the solvus. These results support the idea that supercritical fluids have a significant effect on the pegmatite formation in the upper crust.

Keywords

Raman spectroscopy, Boric acid, Deuterated boric acid, Pegmatites, Elba Island/Italy

Introduction

The study of melt inclusions in minerals, mainly quartz, from pegmatites has provided significant insights into the formation conditions of pegmatites. This information includes data on temperature, pressure, and the composition of the mineral-forming melts. Essential data are the primary water content in the melt. In recent years, increasing amounts of information have prompted a rethink of the origin of water [1]. The author and his coauthors have collected numerous proofs for these new ideas [2,3]. The first ideas on the meaning of solvus curves for pegmatite formation date back to the first presentation of water determination in melt inclusions in a pegmatite from the Ehrenfriedersdorf tin-tungsten deposit in the Central Erzgebirge/Germany [4-6]. In Thomas et al. (2003) [2], the role of boron in the formation of solvus curves is described. New results for boron in the Elba granite pegmatite (Elba Island/Italy) are in Thomas 2025a and 2025b [7,8]. In this contribution, we will show, using new observations on boron and heavy water, that supercritical fluids make a significant contribution to pegmatite formation in the upper crust. So far, we have found many indications that supercritical fluids from the deep mantle are carriers of minerals untypical of the upper crust and their pegmatites. Among such minerals are coesite, boron, diamond, moissanite, orthorhombic cassiterite, stishovite, and many others. Here, we show that the composition of boric acid (B-isotopes and hydrogen substitution by deuterium) provides a further crucial hint for the origin of water during pegmatite formation.

Methods and Samples

Methods

Generally, we used boron acid-bearing fluids and melt inclusions in pegmatite quartz from Elba Island. It means fluid- and melt- inclusion with sassolite [H3BO3] daughter crystals. However, boron is primarily in silicate melt inclusions dissolved in the oxide form. Over time, boron from that melt migrates into the water-rich bubbles that form during cooling, forming later well-crystalized solid boric acid and, sometimes, metaboric acid. Solid boric acid (sassolite) crystals are easy to identify under crossed Nicols under the transmission light by their peculiar interference color. To select suitable samples, we used a transmission polarization microscope (JenaLab Pol). All Raman spectroscopic studies are performed with a petrographic polarization microscope (BX 43) equipped with an XY- or rotating stage, coupled to the EnSpectr Raman spectrometer R532 (Enhanced Spectrometry, Inc., Mountain View, CA, USA) in transmission. The Raman spectra were recorded in the spectral range of 0–4000 cm-1 using the 30 mW of a single-mode 532 nm laser, an entrance aperture of 20 µm, a holographic grating of 1800 g/mm, and a spectral resolution of 4 cm-1.

Hydrothermal Diamond Anvil Cell Experiments

For the first test of isotope fractionation, we used an HDAC experiment conducted in 2002 [9]. Synthetic pegmatite glass with 5.0 % nB2O and destilled water, which we used for the experiment, was heated to 840°C at 0.4 GPa. At this temperature, a homogeneous water-rich glass formed, and on cooling, this homogeneous phase separated into two phases: a homogeneous glass with some dissolved boron and a water-rich phase with small amounts of boric acid, with a ratio of about 1: 1. Also, a small number of fluid bubbles appear on cooling. Over about 22 years in these bubbles, boric acid crystallized. These crystals should provide an initial indication of boron isotope fractionation. Figure 1 shows the sample chamber after the experiment.

Figure 1: The upper picture shows the sample chamber formed by the diamond anvils and the Re-gasket in between, with a hole of 400 µm. The melt, with some bubbles and a concave meniscus, is on the right side of the chamber. Smaller glass bubbles hem the left side of the chamber. The lower picture shows a boric acid crystal in a fluid bubble in the pegmatite glass.

Homogenization Experiments

To homogenize the melt inclusions, we used two techniques: (i) the cold-seal pressure vessel homogenization experiments and (ii) the hydrothermal rapid-quench homogenization experiments. Further details are available in the electronic supplemental material to Thomas et al. (2009 and 2016) [10,11] as well as in the most cited papers by Thomas and Thomas et al.

Boron Determination in Silicate Class

Boron was analyzed with the Cameca SX-50 microprobe, equipped with the PC2 pseudo-crystal for light elements, with a counting time of 300s, 10 kV, and 40 nA, using an anti-contamination cold trap cooled by liquid nitrogen [9]. The boron determination of silicate glass or boric acid in the melt and in fluid inclusions deep under the sample surface was performed by Raman spectroscopy [12,13].

Experimental Section

Boric acid (H3 nBO3 ), H3 10BO3 , H3 11BO3 and the Deuterated H3 nBO3

The samples and the preparation of the deuterated boric acid are described in Thomas (2025a and 2025b) [7,8]. Table 1 shows the results of Raman measurements on deuterated boric acid (minor corrected).

Table 1: Important Raman band of solid H3BO3, H2DBO3, HD2BO3, and D3BO3.

H3BO3

 H2DBO3 HD2BO3 D3BO3
75.4 ± 1.5 103.3 ± 1.3 116.6 ± 0.6

128.8 ± 2.2

119.1 ± 3.8
207.8 ± 1.6

499.3 ± 1.0

 484.5 ± 2.6 471.9 ± 1.7 466.2 ± 1.0
879.0 ± 1.9 854.0 ± 0.6 835.5 ± 1.7

817.6 ± 4.7

1092.0 ± 7.2
1158.9 ± 2.2 1201.9 ± 6.2 1305.8 ± 5.4

1386.6 ± 3.2

1383.5 ± 6.3
2384.7 ± 4.5 2406.8 ± 2.5 2416.7 ± 2.7

2432.0 ± 2.3

3173.6 ± 4.2

 3211.0 ± 2.8 3235.9 ± 7.7 3254.9 ± 4.3
3249.6 ± 4.2

Figures 2 and 3 represent typical Raman spectra of deuterated boric acid. The main phases of simple deuteriation are H2DBO3 and HD2BO3. However, the pure phases of H3BO3 and D3BO3 are present too.

Figure 2: Raman spectrum of HD2BO3 -H2DBO3 -H3BO3

Figure 3: Raman spectrum of a solid mixture of D3BO3-H3BO3.

Table 2 shows the two Raman bands that can be used for the concentration determination of boron isotopes. The 1066 cm-1 band is influenced by deuterium; the 1384 cm-1 band is not.

Table 2: Raman lines of B-isotopes of solid boric acid with the most substantial differences, determined with the 532 nm laser (20 measurements each).

B-isotopes

 Raman bands (cm-1)
11B 1165.8 ± 0.3

1380.8 ± 0.9

nB

 1166.6 ± 2.7 1383.5 ± 6.3
10B 1171.6 ± 0.4

1411.9 ± 0.6

n – refers to boron of natural abundance with 19.78% 10B and 80.22 % 11B. The significant standard deviation for nB results from the isotope fractionation during preparation.

For the first test, we used the silicate glass with fluid bubbles, shown in Figure 1, formed during the cooling of the HDAC experiment. After a long time, boric acid crystallized out in such bubbles.

Graphic Pegmatite Sample from Elba Island/Italy

The sample is from the Mining Academy of Freiberg. It’s a small graphic granite sample from Prato alla Valle, located 400 m south of the cemetery of the village San Piero in Campo on the Island of Elba. A detailed description of paragenesis and the melt and fluid inclusions is in Thomas et al. (2008). For the study presented here, we used quartz chips approximately 300 µm thick, polished on both sides. All quartz chips contain melt and fluid inclusions with relatively large boric acid (sassolite) [H3BO3] daughter crystals, making the sample suitable for in situ isotope studies. Figure 4 shows such a melt inclusion, 17 years after the homogenization experiment.

Figure 4: Type-B melt inclusion in graphic quartz from the Elba pegmatite: re- homogenized at 600°C and two kbar, heterogenized after quenching. H3BO3 – boric acid (sassolite), G – silicate glass, L – solution, V – vapor bubble.

Results

Boron Isotopes in the Synthetic Silicate Glass Obtained by a Hydrothermal Diamond Anvil Cell Experiment

The results clearly show that the tendency goes in the right direction. In the aqueous phase, the heavy isotope is enriched, but in the silicate melt, the light B isotope predominates. The standard deviation is substantial for the 1165 cm-1 line. That result is already valid for the Elba pegmatite. (Thomas, 2025b) [8], as we see in the following section (Table 3).

Table 3: Presents the results of Raman isotope analysis of inclusions in the glass phase of the HDAC experiment, based on data from Table 2 (20 measurements each).

Raman band H311BO3 (theoretical)

 11B (%) Raman band H311BO3 (measured) 11B (%) (measured)
1165.8 ± 0.3 80.22 1167.5 ± 0.2

70.7 ± 3.4

1380.8 ± 0.9

 80.22 1387.8 ± 0.2

77.5 ± 0.6

Boron Isotopes in Boric Acid in the Elba Graphic Pegmatite

In case of melt inclusions, the 1166 cm-1 Raman band could not be used because, as a rule, the values are significantly smaller than the line at 1165.8 ± 0.3 for pure H3 11BO3.  The reason may be the influence of deuterium or of other elements in the melts. Deuterium in boric acid significantly shifts the Raman lines, primarily affecting the low-intensity lines used for boron isotope determination (Figure 5) (Table 4).

Figure 5: Recrystalized melt inclusion (homogenized at 720°C, 2 kbar, 20 hours) in quartz from the Elba pegmatite with H3BO3 and D3BO3 daughter crystals. For the upper photo, we used unpolarized light; for the lower image, polarized light. H3BO3 – boric acid, D3BO3 – deuterated boric acid, G – silicate glass, V – vapor. In Thomas (2025b) [8], the glass (G) was misinterpreted as liquid (L).

Table 4:

Raman band H311BO3 (theoretical)                  

 11B (%) Raman band H311BO3 (measured)  11B (%) (measured)

n
Boric acid in fluid inclusions
1165.8 ± 0.3

80.22

 1166.6 ± 0.7 86.2 ± 12.0 20

1380.8 ± 0.9

 80.22 1383.3 ± 2.3 91.9 ± 7.4

27
Boric acid in re-homogenized melt inclusions
1380.8 ± 0.9

80.22

 1387.6 ± 0.3 78.1 ± 1.0

20

Pseudo-binary Solvus Curve of the System: Pegmatitic Silicate System – Boric Acid-rich Fluid

Figure 6 shows the pseudo-binary solvus curve for the Elba graphic pegmatite obtained from re-homogenization of melt inclusions in pegmatite quartz at 600, 650, 700, and 720°C and two kbar, and always 20 hours using the cold-seal pressure vessel homogenization or the hydrothermal rapid-quench homogenization experiments. The point under 550°C was obtained from homogenization measurements using the Linkam microscope heating stage (in 2003).

Figure 6: Solvus curve constructed from re-homogenized melt inclusions in quartz from the graphic pegmatite of Elba Island. Each measuring point is the mean of the homogenization measurements on 10 different melt inclusions. CP – critical point (30.0 % H2O, 712°C).

The highest boron concentration in the silicate glass was found in melt inclusions around the critical point: 15.6 % B2 O3 [14]. However, the fluid inclusions are notably higher in boron, as shown in Figure 7.  The distribution of B and Cs on the pseudo-binary solvus curve can be calculated using the reduced coordinates (Figure 3b in Thomas et al. 2019) [15,16]. Extreme high concentration of different elements are connected to the critical point, which degenerate to vertical line.

Figure 7: Cs-B correlation of boric acid and ramanite-(Cs)-bearing fluid inclusions in pegmatite quart from the graphic pegmatite of the Elba Island/Italy (see also Thomas et al., 2008) [14].

From Raman measurements, we now know that near the solvus crest (CP), in addition to extremely high boron and cesium concentrations, deuterium has its highest concentration. The determination is not straightforward because deuterium is associated with multiple deuterium-bearing species: H2DBO3, HD2BO3, and D3BO3. Figures 8 and 9 show the Raman spectrum of a typical melt inclusion in quartz with the two different boric acid phases.

Figure 8: D3BO3 and H3BO3 phases in a near-critical melt inclusion homogenized at 700°C and 2 kbar.

In a small distance (left and right) and the same depth from the sample surface to the critical point, the melt inclusions show only the H3BO3 band at about 880 cm-1. The slight shift from 880 to 878.9 cm-1 is due to contamination with deuterium. Figure 9 allows a rough estimate of deuterium concentration. If we take the analytically determined boron content of the silicate melt at the critical point (720°C and 30 % H2O) of 3.9 % B2O3 [14] we obtain a boric acid concentration of 6.9 %, Because the intensity of both species H3BO3 and D3BO3 is about similar, we have 3.45 % D3BO3, corresponding to 0.32 % (g/g) deuterium in the fluid. That is a high amount.

Figure 9: Raman spectrum of boric acid taken from the melt inclusion shown in Figure 5. Both boric acid daughter crystals (D3BO3 and H3BO3 have the same B-isotope composition: 11B is 91.9% and 8.1% 10B.

Discussion

The described fluid and melt inclusions in the graphic pegmatite from Elba Island/Italy are extremely rich in boron (B) and cesium (Cs), as well as deuterium in the supercritical fluid. The isotopic composition of these phases differs significantly between that of the fluid and the melt. The silicate melt is more enriched in the light 10B isotope, whereas the fluid inclusions, representing the fluid, are enriched in the heavy 11B isotope. However, at the critical point, the situation is reversed. That means at least that the supercritical fluid coming from the mantle is enriched in the heavy 11B isotope. That is a further hint at the extraordinary properties and origin of the supercritical fluids. The high deuterium concentration of the supercritical fluid makes it clearer. Furthermore, these observations indicate that isotope fractionation depends strongly on the origin of that phase, which is the deep mantle.

Acknowledgment

The author thanks A. Anderson, William (Bill) A. Bassett, I-Ming Chou, and Robert Mayanovich for the introduction to the hydrothermal diamond anvil cell technique during a stay at the Argonne National Laboratory near Chicago in June/July 2001.

References

  1. Thomas R, Brümmer G, Scheiblauer K (2025) Paradigm change of pegmatite formation – where does the water come from? Geol Earth Mar Sci 7: 1-7.
  2. Thomas R, Davidson P, Rericha A, Recknagel U (2023) Ultrahigh-pressure mineral inclusions in a crustal granite: Evidence for a novel transcrustal transport mechanism. Geosciences 13: 1-13.
  3. Thomas R (2023) Ultrahigh-pressure and temperature mineral inclusions in more crustal mineralizations: The role of supercritical fluids. Geo Earth Mar Sci 5: 1-2.
  4. Thomas R (2000) Determination of water contents of granitic melt inclusions by confocal laser Raman microprobe American Mineralogist 85: 868-872.
  5. Thomas R, Webster JD, Heinrich W (2000) Melt inclusions in pegmatite quartz: complete miscibility between silicate melts and hydrous fluids at low Contrib Mineral Petrol 139: 394-401.
  6. Thomas R, Kamenetsky VS, Davidson P (2006) Laser Raman spectroscopic measurements of water in unexposed glass inclusions. American Mineralogist 91: 467-470.
  7. Thomas R (2025a) Behavior of deuterium on boric acid: Raman spectrometric measurements: Preliminary Results 7: 1-4.
  8. Thomas R (2025b) Raman spectroscopy of boric acid daughter crystals with different B-isotopes: H 11BO and H 10BO , and different B-isotopes hydrogen and deuterium concentrations. Geo Earth Mar Sci 7: 1-3.
  9. Veksler LV, Thomas R, Schmidt C (2002) Experimental evidence of three coexisting immiscible fluids in synthetic granitic pegmatite. American Mineralogist 87: 775-779.
  10. Thomas R, Davidson P, Rhede D, Leh M (2009) The miarolitic pegmatites from the Königshain: a contribution to understanding the genesis of pegmatites. Contrib Mineral Petrol 157: 505-523.
  11. Thomas R, Davidson P (2016) Origin of miarolitic pegmatites in the Königshain granite/Lusatia. Lithos 250: 225-241.
  12. Thomas R (2002) Determination of the H3BO3 concentration in fluid and melt inclusions in granite pegmatites by laser Raman microprobe American Mineralogist 87: 56-68.
  13. Thomas R, Förster H-J, Heinrich W (2003) The behaviour of boron in a peraluminous granite-pegmatite system and associated hydrothermal solutions: a melt and fluid- inclusion study. Contrib Mineral Petrol 144: 457-472.
  14. Thomas R, Davidson P, Hahn A (2008) Ramanite-(Cs) and ramanite-(Rb): New cesium and rubidium pentaborate tetrahydrate minerals identified with Raman American Mineralogist 93: 1034-1042.
  15. Thomas R, Davidson P, Appel K (2019) The enhanced element enrichment in the supercritical states of granite-pegmatite systems. Acta Geochim 38: 335-349.
  16. Thomas R, Rericha A (2023) The function of supercritical fluids for the solvus formation and enrichment of critical Geol Earth Mar Sci 5: 1-4.

Aromatase Inhibitor and Potential Effect on Adult Height in Growth Hormone Treated Adolescents with Prader-Willi Syndrome: A Commentary

1 Reply

DOI: 10.31038/EDMJ.20261021

   

Classical genetic conditions with short stature as a major finding in adulthood include Noonan, Turner and Prader-Willi syndromes [1,2]. Noonan and Prader-Willi syndromes affect both males and females while Turner syndrome affects females only. These disorders have been recognized for several decades with published literature describing their features, genetic defects and natural histories but with lack of optimal treatment strategies [1,2]. They are accompanied by a list of comorbidities involving the cardiovascular system, stature, endocrinopathies, puberty and infertility. Endocrine dysfunctions affect the patient’s well-being from birth through adulthood with limited information available for providers to transition from pediatric to adult healthcare and treatment options for subnormal growth to achieve adult stature.

Prader-Willi syndrome (PWS) occurs in about 1 in 20,000 livebirths and is caused most often by a paternal 15q11-q13 deletion followed by maternal disomy 15 where both chromosome 15s are from the mother [3]. A cardinal feature of PWS is infantile hypotonia which is accompanied by a poor suck, feeding problems and decreased energy levels with low body weight during the initial failure to thrive clinical stage [4,5]. The length is typically normal in the first few months of life but falls below normal within the first year related to failure to thrive when nutrition is the main growth promoting factor and low growth with other hormone deficiencies. Short stature is particularly apparent during puberty with the median height falling below the 5th percentile when compared to unaffected individuals [6]. The average adult height of males with PWS without growth hormone treatment is 157cm and 145cm in females [6-8]. Early and continued medical care with surveillance is needed to achieve optimal adult height in this rare genetic disorder [2,4,5,7-11].

Individuals with PWS also present with several distinctive facial features including a narrow forehead, elongated skull, almond-shaped eyes, small nose and chin, decreased saliva, a dry mouth, caries and other dental issues [4]. Facial features are altered in PWS when receiving growth hormone which was approved for treatment in 2000 [5] with an elongated prominent high chin [12]. The use of larger growth hormone dose than recommended and poor supervision could lead to acromegaloid features. Feeding difficulties noted in infancy give way to excessive eating and hyperphagia in early childhood during the second stage of clinical course development which leads to morbid obesity, if not externally controlled. They present cognitive impairments including developmental delay in language and motor skills and are prone to aberrant behavior, temper tantrums, stubbornness, compulsions, self- injury and decreased pain threshold [4,5,7,8].

Our commentary focuses on the need for related medical care by the pediatric healthcare team prior to transitioning to adult services and assessing approaches to improve stature that positively impact adult height in genetic syndromes where short stature is a cardinal feature, such as Prader-Willi syndrome. In addition, hormone deficiencies are common in this rare genetic disorder requiring treatment early affecting body composition, strength, metabolism, growth and stature. Growth hormone is often prescribed in infancy in PWS once the diagnosis is genetically confirmed as growth hormone deficiency is reported in the majority of patients with PWS. Short stature is seen in 90% of cases and feeding problems with a poor suck are cardinal features [2,4,7,8].

Our commentary was stimulated by the natural history of PWS specifically the endocrinopathies, pubertal issues, short stature and hormone replacement needs with new reports of aromatase inhibitors and growth hormone treatment that may improve predicted adult height in non-syndromic pubertal boys with idiopathic short stature [13-16] with application to PWS. We also point out that related medical care required by the pediatric healthcare team is needed prior to transitioning to adult services for improvement of stature impacting adult height in genetic syndromes where short stature is a cardinal feature. As noted, hormone deficiencies are common in PWS affecting not only body composition and obesity but also strength, metabolism, growth and stature. Growth hormone is often prescribed in infancy in PWS once the diagnosis is genetically confirmed and patients are cleared for treatment [2,5,10].

Sex Hormones, Puberty, Short Stature and Treatment

Hypothalamic dysfunction, hormone imbalances and decreased physical activity and metabolic rate along with increased caloric intake can cause life threatening obesity recognized as a cardinal finding in PWS. Those with PWS are also prone to hypothyroidism, and other hormone deficiencies, puberty delay, and body composition disturbances with associated problems such as type II diabetes, cardiovascular disease and infarctions with venous thromboembolism leading to increased mortality. The reported average age at death is 30 years [17] but with early diagnosis and appropriate medical care, life expectancy improve. The presence of obesity in those with PWS are associated with increased rates of metabolic syndrome, hypothalamic insufficiency and hypogonadism leading to low estrogen and testosterone levels. These should be monitored and treated accordingly. Primary and central hypogonadism with pubertal delay is observed in nearly all individuals with PWS and commonly associated with infertility. Hypogenitalism is typically present with cryptorchidism in PWS males [4,5,8,10].

Estrogen is an essential regulator of bone maturation, growth plate fusion, and cessation of longitudinal growth in both males and females. Decreased estrogen effects due to insensitivity or deficiency [18-21] are associated with slow epiphysis closure and exceptional long period of growth. Based on these observations, it can be postulated that longitudinal growth can be modulated by blocking estrogen biosynthesis with aromatase inhibitors (AI), which inhibit aromatization of C19 androgens [(T)] to C18 estrogens including for PWS, as well.

The off-label use of third-generation AI, such as letrozole and anastrozole, has been explored to increase adult height (AH) in boys with non-syndromic short stature. Studies in those pubertal boys have shown inconsistent results on the impact of AI on increased adult height but some investigations have shown beneficial effects [14,22-25]. However, Mauras et al. [15,16] did demonstrate a rise in predicted near adult height and AH in adolescent boys treated with a combination of growth hormone (GH) and AI for GH deficiency or idiopathic short stature (ISS) compared to those treated with GH only. Similarly, more recent studies by Yackobovitch–Gavan et al. [26] demonstrated that aromatase inhibitor treatment alone or with GH increases final height in short-statured pubertal boys with early onset puberty and ISS indicating a potential use in syndromic short stature disorders; hence, the selection of PWS for study. As noted, hypogonadism and hypogenitalism are characteristics of PWS along with premature adrenarche and excessive adipose tissue which is much higher than in the general population. We have also demonstrated acceleration of linear height velocity and long-term benefit with near adult height (AH) from growth hormone treatment (GHT) [10]. The adiposity seen in PWS with premature adrenarche may also accelerate growth velocity and a decrease in adult height.

The goal of a potential long-term study is warranted to compare the effect on AH after GH treatment alone and in combination with AI in males with PWS. A longitudinal study is needed in a cohort of PWS male children or adolescents readily available with genetically confirmed PWS to further characterize the impact of GHT alone and stoppage after achieving complete skeletal maturation and followup. GH and anastrozole group (GH-AI) analysis would be recorded and studied at chronological ages of 11 to 13 years, before attaining AH and for a period of time such as 5 years. The AH will be determined as the height attained when bone age is 16 years or when growth velocity for the preceding year had reached a plateau. Initial and final height- standard deviation score (HT-SDS) will be reported and analyzed in both groups with bone maturation assessed based on roentgenograms of the left hand and wrist. Furthermore, clinical manifestations of premature adrenarche or elevated plasma DHEA-S levels will be assessed and confirmed. Final adult height will be recorded in those receiving growth hormone alone (GHA) or in those with growth hormone and aromatase inhibitor (GH-AI) treatment to determine if an increased adult height would be found and recorded in those PWS males receiving both growth hormone and aromatase inhibitors to maximize their adult height prior to skeletal maturation. Side effects would be monitored and recorded such as pain, mood changes, nausea, vomiting, abdominal pain, or back pain.

Hence, our commentary and proposed study in a classical genetic disorder where short stature is a cardinal feature could be undertaken and treatment accessed using GH and AI treatment approaches in individuals with PWS at a young age. This would be prior to achieving adult height at a point where growth and stature could be positively influenced by treatment using pediatric health care approaches. This combined treatment approach and timing if successful to maximize adult stature may have a direct application for other genetic short stature disorders.

Keywords

Genetic conditions, Prader-Willi syndrome, Clinical and genetic findings, Short stature, Treatment

References

  1. Jones KL, Jones MC, del Campo M (2013) Smith’s recognizable patterns of human malformation (7th ed.) Elsevier-Saunders. [crossref]
  2. Butler MG, Miller BS, Romano A, Ross J, Abuzzahab MJ, Backeljauw P, Bamba V, Bhangoo A, Mauras N, Geffner M (2022) Genetic conditions of short stature: A review of three classic Frontiers in Endocrinology (Lausanne) [crossref]
  3. Butler MG, Hartin SN, Hossain WA, Manzardo AM, Kimonis V, Dykens E, Gold JA, Kim SJ, Weisensel N, Tamura R, Miller JL, Driscoll DJ (2019) Molecular genetic classification in Prader-Willi syndrome: A multisite cohort study. Journal of Medical Genetics 56(3): 149-153. [crossref]
  4. Butler MG (1990) Prader-Willi syndrome: Current understanding of cause and American Journal of Medical Genetics 35(3): 319-332. [crossref]
  5. Butler MG, Lee PDK, Whitman BK (2022) Management of Prader-Willi syndrome (4th ) Springer Nature Switzerland AG. [crossref]
  6. Butler MG, Lee J, Manzardo AM, Gold JA, Miller JL, Kimonis V, Driscoll DJ (2015) Growth charts for non-growth hormone-treated Prader-Willi Pediatrics 135(1): e126-e135. [crossref]
  7. Butler MG (2016) Single gene and syndromic causes of obesity: Illustrative Progress in Molecular Biology and Translational Science 140: 1-45. [crossref]
  8. Butler MG (2023) Prader-Willi syndrome and chromosome 2 BP1-BP2 region: A review. International Journal of Molecular Sciences 24(5): 4271. [crossref]
  9. Butler MG, Miller JL, Forster JL (2019) Prader-Willi syndrome: Clinical genetics, diagnosis and treatment approaches—An update. Current Pediatric Reviews 15(4): 207-244. [crossref]
  10. Angulo MA, Butler MG, Cataletto ME (2015) Prader-Willi syndrome: A review of clinical, genetic and endocrine findings. Journal of Endocrinological Investigation 38(12): 1249-1263. [crossref]
  11. Godler DE, Singh D, Butler MG (2025) Genetics of Prader-Willi and Angelman syndromes: 2024 Current Opinion in Psychiatry 38(2): 95-100. [crossref]
  12. Butler MG, Hovis CL, Angulo MA (1998) Photoanthropometric study of craniofacial traits in individuals with Prader-Willi syndrome on short-term growth hormone Clinical Genetics 53(4): 268-275. [crossref]
  13. Hero M, Norjavaara E, Dunkel L (2005) Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: A randomized controlled trial. Journal of Clinical Endocrinology & Metabolism 90(12): 6396-6402. [crossref]
  14. Hero M, Wickman S, Dunkel L (2006) Treatment with the aromatase inhibitor letrozole during adolescence increases near-final height in boys with constitutional delay of Clinical Endocrinology 64(5): 510-513. [crossref]
  15. Mauras N, Gonzalez de Pijem L, Hsiang HY, et (2008) Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: A randomized, placebo-controlled, multicenter trial. Journal of Clinical Endocrinology & Metabolism 93(3): 823-831. [crossref]
  16. Mauras N, Ross JL, Gagliardi P, et al. (2016) Randomized trial of aromatase inhibitors, growth hormone, or combination in pubertal boys with idiopathic short stature. Journal of Clinical Endocrinology & Metabolism 101(12): 4984-4993. [crossref]
  17. Butler MG, Manzardo AM, Heinemann J, Loker C, Loker J (2017) Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality Genetics in Medicine 19(6): 635-642. [crossref]
  18. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS (1994) Estrogen resistance caused by a mutation in the estrogen receptor gene in a man. New England Journal of Medicine 331: 1056-1061. [crossref]
  19. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (1995) Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. Journal of Clinical Endocrinology & Metabolism 80: 3689-3698. [crossref]
  20. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER (1997) Effect of testosterone and estradiol in a man with aromatase New England Journal of Medicine 337: 91-95. [crossref]
  21. Herrmann BL, Saller B, Janssen OE, Gocke P, Bockisch A, Sperling H, Mann K, Broecker M (2002) Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 Journal of Clinical Endocrinology & Metabolism 87: 5476-5484. [crossref]
  22. Ferris JA, Geffner ME (2017) Are aromatase inhibitors in boys with predicted short stature and/or rapidly advancing bone age effective and safe? Journal of Pediatric Endocrinology & Metabolism 30(3): 311-317. [crossref]
  23. Varimo T, Toiviainen-Salo S, Raivio T, Kerttula L, Dunkel L, Hero M (2019) Letrozole monotherapy in pre- and early-pubertal boys does not increase adult Frontiers in Endocrinology (Lausanne): 10: 201. [crossref]
  24. Wickman S, Sipilä I, Ankarberg-Lindgren C, Norjavaara E, Dunkel L (2001) Specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: A randomized controlled trial. The Lancet 357(9270): 1743-1748. [crossref]
  25. Dunkel L, Wickman S (2002) Novel treatment of delayed male puberty with aromatase Hormone Research 57(Suppl 2): 44-52. [crossref]
  26. Yackobovitch-Gavan M, et al. (2025) Aromatase inhibitors treatment alone or with growth hormone increases final height in short-statured pubertal boys—Real-world data. Journal of Clinical Endocrinology & Metabolism 110(12): e4129-e4136. [crossref]