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

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

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.

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

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 (=0.82), although trial-level surrogacy was only moderate and imprecise (=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).

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

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

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  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]

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

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

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.

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

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

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

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]

Raman Spectroscopy of Boric Acid Daughter Crystals with Different B-isotopes: H311BO3 and H310BO3, and Different Hydrogen and Deuterium Concentrations

DOI: 10.31038/GEMS.2025781

Abstract

First, we present Raman spectroscopic results for commercial boric acid [H3 nBO3] and for the boric acid end members containing 10B and 11B. Furthermore, we show in this short contribution, using boric acid as a daughter mineral in melt and fluid inclusions in pegmatite quard from Elba Island/Italy, that the isotopic composition of boric acid is determinable in situ with an acceptable error of 6%. As a result, we obtain an 11B concentration of 91.9 ± 7.4 %. To our surprise, we also found detectable amounts of D3BO3 in the inclusions, in addition to H3BO3. The very high D concentration clearly shows that a significant portion of the pegmatite-forming fluids originated in the deep mantle.

Keywords

Raman spectroscopy, Pegmatites, Boric acid, Bor isotopes, D3BO3, Supercritical fluids

Introduction

Boron is the fifth element (atomic number) in the periodic table of elements in the third main group. Boron is a rare element, and its concentration in the lithosphere is, according to Rösler and Lange (1975) [1], 12 ppm. In granitic rock, according to the same authors, the concentration is 15 ppm. In Sn-granites from Ehrenfriedersdorf, Central Erzgebirge/Germany, the B-concentration can increase to 132 ppm [2]. In melt and fluid inclusions related to the granites and pegmatites from the Ehrenfriedersdorf deposit, boron concentrations as boric acid increase significantly to 6.88 ± 0.40 % [3] Recent studies [4] showed an extreme rise in B2O3 to 16% (corresponding to nearly 50000 ppm B) with the introduction of supercritical fluids from the mantle. At such high concentrations, it should be possible to determine boron isotopes with Raman spectroscopy. The concentration of boric acid in fluid and melt inclusions in the studied pegmatite from Elba Island can reach up to 20% (vol/vol), corresponding to about 30%(g/g).

Methods and Samples

Methods

Generally, we used boron acid-bearing fluids and melt inclusions in pegmatite quartz from Elba Island. That means fluid- and melt- inclusion with sassolite [H3BO3] daughter crystals. 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 were 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.

Samples

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 the paragenesis and the melt and fluid inclusions is in Thomas et al. (2008) [5]. 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 1 shows such a fluid inclusion.

Figure 1: Fluid inclusion in pegmatite quartz from Elba Island. F -fluid, V – vapor, H3BO3 – boric acid (sassoline), PB – pentaborate: ramanite-(Cs).
Some inclusions also contain meta-boric acid crystals. Generally, the used samples are exceptionally rich in inclusions with soluble B-bearing phases

Basic Experimental Section

At first, we took Raman measurements of commercial boric acid (H3 nBO3 ) and of both pure B-isotopes of solid boric acid. The results are in Table 1.

Table 1: Raman of crystallized H3 nBO3 , H3 10BO3 , and H3 11BO3 (n = 20 measurements each).

Boric acid with different B-isotopes

Raman band (cm-1) H3nBO3  Raman band (cm-1)
10B-isotope
Raman band (cm-1)
11B-isotope

Irel

76.0 ± 1.6

74.2 ± 0.5 75.4 ± 0.2 w
119.1 ± 3.8 118.3 ± 1.0 118.2 ± 0.3

w

207.8 ± 1.6

211.0 ± 0.4 208.3 ± 0.2 m
497.2 ± 3.8 499.7 ± 0.4 498.3 ± 0.2

s

879.8± 0.3

880.1 ± 0.4 880.0 ± 0.2 vs
1092.0 ± 7.2

w

1166.6 ± 2.7

1171.6 ± 0.4 1166.4 ± 0.4 w
1383.5 ± 6.3 1411.9 ± 0.6 1381.8 ± 1.1

w

2294.1 ± 2.7

vw
3173.6 ± 4.2 3172.2 ± 1.3 3170.4 ± 0.2

w

3246.4 ± 4.1

3252.0 ± 0.6 3252.0 ± 0.1

w

nB refers to boron of natural abundance with 19.78 % 10B and 80.22% 11B.
Irel – relative intensity: vs – very strong, s – strong, m – medium, w – weak, vw -very weak.

Table 2 presents both Raman lines of boric acid, which show the most significant differences between the two B-isotopes.

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

Hilger quartz spectrograph: 253.7 nm

EnSpectr Raman: 532 nm
B-isotopes Raman band
(cm-1)
Raman band
(cm-1)
Raman band
(cm-1)

Raman band
(cm-1)

11B

1166 1373 1165.8 ± 0.3 1380.8 ± 0.9
nB 1168 1375 1166.6 ± 2.7

1383.5 ± 6.3

10B

1173 1422 1171.6 ± 0.4

1411.9 ± 0.6

n – refers to boron of natural abundance with 19.78% 10B and 80.22% 11B.

Results

The basis of the present study is the determination of the Raman spectra of commercial and isotope-pure boric acid. The obtained results were applied to the melt and fluid inclusion in quartz from a graphic pegmatite of the Island of Elba/Italy. The study shows that the ~1380 cm-1 Raman band yields the best results. From 27 studied inclusions, we obtained a mean value of 1383.3 ± 2.3 cm-1. Using the data from Table 2, we obtained a linear curve with a correlation coefficient (R2 = 0.99839) and an 11B concentration of 91.9 ± 7.4 %. For the other Raman line (1165.2 ± 1.65 cm-1), we obtained a similar mean, but with a larger standard deviation. This result may be that the deuterium content influences the position of the Raman line (Figure 2).

Figure 2: Correlation of the B-isotopes in daughter crystals of boric acid in quartz from an Elba Island pegmatite. 11B-isotope content = 4532.64139 – 3.21026 * RS. RS – Raman shift. The black points are the measured ones, and the open points are from Table 2. The data for commercial boric acid were not used for the correlation because of uncontrolled partial fractionation on the microscope specimen slide.

That means the 11B concentration is incredibly high (91.9 ± 7.4 %) in the boric acid samples from the studied Elba Island pegmatite. Besides the high 11B concentration, there are also, in part, very high deuterium concentrations in the boric acid daughter crystals, as shown in Figure 3. The key results are given in Thomas (2025) [6]. Almost every boric acid crystal shows the Raman band for D3BO3. An extreme example is shown in Figure 4, along with the corresponding Raman spectrum from Figure 3. That should be the first natural example of nearby pure D3BO3. Note that each Raman spectrum of pure H3BO3 daughter crystals shows a very weak Raman band at about 807 cm-1, caused by the quartz host.

Figure 3: Raman spectrum of H and D-rich boric acid crystals shown in Figure 4. A perfect separation of both phases (H3BO3 and D3BO3) is at the moment not possible with the used Raman spectrometer, because the solution also contains both components. In the case of D3BO3, the separation from the SiO2 host is not unambiguously possible. However, the intensity of the SiO2 band at 807 cm-1 is usually very low (about 5% of the whole band).

Figure 4 shows the two daughter crystals (D3BO3 and H3BO3), which differ slightly in color and represent different phases.

Figure 4: Fluid inclusion in quartz from the Elba pegmatite with H3BO3 and D3BO3 daughter mineral phases. L – liquid phase, V – vapor phase.
Both boric acid daughter crystals in Figure 4 (H3BO3 and D3BO3) have the same B-isotope composition: 11B is 91.9% and 8.1% 10B.

Discussion

We report here, for the first time, unusual boric acid daughter crystals with extremely high 11B and high deuterium content at the % level. Both findings underline the author’s view that, for some pegmatites, a significant part of the volatiles and rare elements comes via supercritical fluids from the, in part, deep mantle of the Earth (Thomas and Rericha, 2024). Furthermore, we demonstrate that B-isotopes can be determined using Raman spectroscopy. That provides an opportunity to directly and non-destructively explore B-isotope fractionation in mineral-forming fluids, because the boric acid daughter minerals in primary inclusions represent the isotope composition of this solution (see Roedder, 1984).

Acknowledgment

We thank in memory Prof. Ludwig Baumann (1929-2008), of the Mining Academy Freiberg, for the provision of the sample from the Island of Elba.

References

  1. Rösler HJ, Lange H (1975) Geochemische Leipzig. Pg: 675.
  2. Hösel G (1994) Das Zinnerz-Lagerstättengebiet Ehrenfriedersdorf/Erzgebirge. Pg: 195.
  3. 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.
  4. Thomas R, Rericha A (2024) Extreme element enrichment, according to the Lorenzian distribution at the transition of supercritical to critical and under-critical melt or Geol Earth Mar Sci. 6: 1-6.
  5. 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.
  6. Thomas R (2025) Behavior of deuterium on boric acid: Raman spectrometric measurements: Preliminary Geol Earth Mar Sci. 7(7): 1-4.
  7. Roedder E (1984) Fluid Reviews in mineralogy. 12.
  8. Gmelin L (1954) Gmelins Handbuch der anorganischen Chemie: Bor (Ergänzungsband). Verlag Chemie, Weinheim. Pg: 253.
  9. Krishnan K (1963) The Raman spectrum of boric acid. Proceedings of the Indian Academy of Sciences, Section 57: 103-108.

Economic Shockwaves and Extremist Pathways: A Dual-Perspective Analysis of the 2025 Trade War’s Psychological Impact

DOI: 10.31038/PSYJ.2025773

Abstract

Trade wars, though driven by economic objectives, had repercussions extending beyond the economy into social and political spheres. Using a qualitative research design, this study examines the connection between the 2025 trade war and the potential rise of violent extremism by interviewing two key groups: former terrorist offenders, who provide insider perspectives, and terrorism analysts, who offer outsider viewpoints on extremist groups. The findings reveal that contemporary extremists can be categorized by ideology, scope, generational cohort, and behavioral patterns. The study further highlights how global economic instability, which leads to local crises, can exacerbate extremism and criminal behavior, particularly within vulnerable communities. This study identifies three classifications of extremists based on their responses to economic crises: “deradicalized”, “exploiters”, and “vulnerable”.

Keywords

2025 Trade war, Economic crises, Extremism, Radicalism, Terrorism

Introduction

In 2025, the United States, under Donald Trump’s presidency, escalated trade tensions by imposing high tariffs on goods imported from major economies such as the European Union (EU), China, and several ASEAN countries [1]. While these protectionist policies aimed to bolster domestic industries, they inadvertently disrupted the global economy. Simultaneously, a surge in extremist activities worldwide sparked concerns that such economic measures might be fueling the spread of radical ideologies. The Trump administration adopted an aggressive trade policy approach in 2025, implementing tariffs as high as 50% on European products while significantly increasing import taxes on goods from China and ASEAN countries. These measures were originally aimed to address trade imbalances and protect domestic industries. However, the abrupt policy shifts created substantial market instability, strained international relations, and triggered retaliatory measures from affected nations. For instance, the EU considered imposing counter-tariffs targeting U.S. technology firms, while ASEAN nations sought to mitigate the economic impact by strengthening trade partnerships with China and members of the Gulf Cooperation Council [2]. The imposition of tariffs significantly disrupted global supply chains, leading to higher production costs and subsequent price increases for consumers. While U.S. consumer confidence showed modest improvement following the trade truce with China, broader economic uncertainty persisted. Internationally, economies such as Germany faced potential GDP contractions, while several African nations revised their growth forecasts downward due to tariff-related instability. These economic pressures exacerbated social tensions, creating conditions that extremist groups exploited to capitalize on public discontent [3,4].

Historical precedents demonstrate that economic hardships can fuel extremist ideologies. The economic fallout from the 2025 trade war appears to be replicating this pattern. In the United States, the Department of Homeland Security’s Homeland Threat Assessment 2025 emphasized the ongoing threat posed by domestic violent extremists, many of whom were motivated by anti-government sentiment and conspiracy theories [5]. Globally, regions experiencing economic downturns saw a resurgence of radical groups capitalizing on widespread public discontent, a pattern that, while complex, is supported by various studies. This is evident in the rise of Pentecostal affiliation and political representation in Brazil [6], the growth of radical nationalism in Finland amid economic uncertainty [7], and the “Age of Discontent” framework, which argues that economic crises trigger cultural discontent and fuel the rise of populism and the radical right across several countries [8]. The trade war’s transnational impacts have been particularly evident. In Southeast Asia, ASEAN nations grappling with economic challenges stemming from U.S. tariffs have pursued alternative alliances and trade agreements. These geopolitical realignments not only altered regional power dynamics but also created opportunities for extremist groups to exploit perceptions of Western economic aggression. Similarly, in the Middle East, economic destabilization caused by U.S. tariffs and declining foreign investment contributed to the revival of groups like the Islamic State, which strategically leveraged the resulting chaos to recruit members and expand their influence [9].

While empirical evidence on the direct impact of trade wars on extremism remains limited, economic crises are known to significantly influence political extremism and terrorism. Historical patterns demonstrate that economic downturns frequently correlate with increased support for far-right and anti-establishment movements. This phenomenon was evident in Europe during both the 1930s Great Depression and the recent global financial crisis. Supporting this observation, a longitudinal study across 23 EU countries (1995-2012) revealed that declining GDP and rising unemployment rates consistently corresponded with growing electoral support for extremist parties, particularly far-left groups [10]. However, the relationship between economic hardship and extremism demonstrates significant complexity. In the U.S. context, Republican donors residing in foreclosure-affected areas showed reduced support for Tea Party candidates during the housing crisis [11]. On the other hand, research on Russian terrorism reveals that economic crises may produce contradictory effects on extremist activities: while economic distress can fuel public anger and potentially increase terrorist motivations, it may simultaneously constrain operational capabilities by limiting available resources [12]. These findings collectively suggest that the nexus between economic crises and political extremism is context-dependent, with outcomes varying according to specific circumstances. This study seeks to examine the intricate relationship between the 2025 trade war and the potential resurgence of violent extremism, as there is currently no research on this connection, incorporating viewpoints from both extremist networks and external sources. This will constitute the novelty of this study. Through in-depth interviews with two key stakeholder groups—former terrorist offenders (providing insider perspectives) and counterterrorism experts (offering external analyses), this study examines whether the 2025 US trade war’s economic disruptions may catalyze extremist violence. By elucidating the potential correlation between trade-induced economic shocks and extremist escalation, this study hopes to contribute in the development of mitigation strategies during periods of global economic and geopolitical instability.

Trade Wars

Definition of a Trade War

Trade wars are economic conflicts where countries impose retaliatory tariffs or trade restrictions to protect domestic industries or address trade imbalances [13,14]. These conflicts can arise from various factors, including uneven trade benefits, technological rivalries, and protectionist policies. The US-China trade war demonstrates such conflicts, with the US seeing China’s growth as a threat to its trade supremacy [15]. Trade wars can significantly impact global trade, economic growth, and international relations. The dynamic process of trade wars involves gradual tariff rises by one country, eventually prompting retaliation from the affected nations [16]. Depending on market characteristics, retaliation may lead to liberalisation or escalate into a full-scale trade war. Economist Douglas A. Irwin’s definition of trade war is a situation in which countries attempt to damage each other’s economy, usually through the tariff’s imposition or quota restrictions. It often lead to economic inefficiencies and increased tensions between nations [17]. Trade wars emerge as a direct consequence of protectionist economic policies designed to shield domestic industries through import restrictions. These measures, which include tariffs, import quotas, and regulatory barriers, fundamentally alter global economic dynamics by creating uncertainty that affects business investment patterns, disrupts global value chains, and distorts market expectations.

According to Xu (2024), protectionist interventions not only impede international trade flows but also elevate production costs and generate inflationary pressures across economies. The Sino US trade war, initiated amid economic tensions and mutual allegations of unfair trade practices, has significantly impacted strategic industries and constrained international investment flows [18]. The resulting global economic uncertainty has transmitted through financial markets, affecting both advanced and emerging economies [19]. Although current protectionist measures have demonstrated limited economic disruption to date, potential escalation poses substantial risks to global growth prospects and the Euro area [20]. This protectionism induced uncertainty adversely affects economic sentiment and potentially undermines long term market confidence. Empirical evidence from microeconomic firm data and macroeconomic analyses confirms that heightened trade policy uncertainty consistently suppresses corporate investment activity [21].

Historical Overview of Trade Wars

1. The Anglo-Dutch Trade Wars (17th Century). One of the earliest examples of a trade war occurred between England and the Dutch Republic in the 17th century. These conflicts involved both military and economic rivalry, including naval battles and commercial competition. In 1651, England passed the Navigation Acts, which restricted the use of foreign ships for trade between England and its colonies. This legislation aimed to weaken Dutch maritime dominance and ultimately led to a series of naval conflicts known as the Anglo-Dutch Wars. The outcome of these trade wars helped England establish itself as a dominant maritime and commercial power for centuries to come [22].

2. The Smoot-Hawley Tariff Act (1930). One of the most infamous trade wars in modern history was triggered by the Smoot-Hawley Tariff Act during the Great Depression. Passed by the U.S. Congress in 1930, the act imposed steep tariffs on over 20,000 imported goods. In retaliation, many countries raised their own tariffs, leading to a sharp decline in global trade. As a result, world trade plummeted by an estimated 65% between 1929 and 1934, exacerbating the global economic downturn [23].

3. The Chicken War (1960s). In the early 1960s, a trade dispute known as the “Chicken War” erupted between the U.S. and the European Economic Community (EEC) over tariffs on American poultry exports. After the EEC imposed protective tariffs, the U.S. retaliated by levying duties on European imports, most notably a 25% tariff on light trucks, including the popular Volkswagen Type 2 van. This measure had lasting consequences, in which the light truck tariff, which remains in effect as of the 2020s, has profoundly influenced the structure of the U.S. automobile industry for decades [24].

4. U.S.-China Trade War (2018–2020). The most prominent and widely documented trade war in recent history began in 2018 under the Trump administration, as tensions escalated between the United States and China. The U.S. accused China of engaging in unfair trade practices, including intellectual property theft and forcing technology transfers from foreign firms. In retaliation, the U.S. imposed tariffs on hundreds of billions of dollars’ worth of Chinese imports, prompting China to respond with counter-tariffs on American goods. This trade conflict had far-reaching consequences: it disrupted global supply chains, increased costs for manufacturers and consumers, and amplified economic uncertainty worldwide [25]. Additionally, it sparked a reassessment of global trade dependencies and contributed to a resurgence of economic nationalism across multiple countries.

Consequences of Trade Wars

Trade wars typically result in several key consequences: 1) higher consumer prices due to increased costs of imported goods, 2) supply chain disruptions, reducing efficiency and eroding competitiveness, 3) retaliatory measures from trading partners, escalating international tensions, and 4) adverse effects on global economic growth, particularly in interconnected sectors such as technology, agriculture, and automotive industries. According to the International Monetary Fund [26], the trade tensions and tariffs imposed between 2018 and 2019 slowed global economic growth, ultimately reducing world GDP by approximately 0.8% by 2020.

1. Disruption of Global Supply Chains. One of the primary mechanisms through which trade wars trigger economic crises is by disrupting global supply chains. In today’s interconnected economy, production processes often span multiple countries before final assembly. Tariffs raise the cost of intermediate goods, increasing production costs and reducing operational efficiency. During the U.S.-China trade war (2018–2020), for instance, U.S. manufacturers faced higher input costs due to tariffs on Chinese components, while Chinese exporters experienced reduced demand for their goods. Sectors with complex supply chains, such as automotive and electronics, were particularly vulnerable. A Federal Reserve study found that U.S. tariffs led to significant cost increases for domestic manufacturers and a measurable decline in industrial output [27]. Long-term consequences included widespread corporate uncertainty. Many firms delayed investments, restructured operations, or relocated production, often at substantial expense, to mitigate political and trade risks. This reconfiguration of supply chains further strained global economic stability.

2. Consumer Price Inflation and Reduced Purchasing Power. Tariffs function as a tax on imported goods, typically leading to higher consumer prices. Research by Amiti et al. [28] revealed that during the 2018-2019 U.S.-China trade conflict, American consumers and firms absorbed most of the additional costs from tariffs. These price increases reduced household purchasing power, which is crucial for maintaining GDP growth. When consumers have less to spend, overall economic demand weakens, business revenues decline, layoffs often follow, and economic growth slows. Prolonged trade conflicts may even trigger stagflation, which is a dangerous combination of rising prices and economic stagnation that, while rare, can cause severe damage. Multiple studies have examined the economic consequences of the U.S.-China trade war and potential broader global trade conflicts. Simulation results indicate that in a scenario of widespread global trade tensions, world GDP could decline by up to 1.96% with global trade volumes falling by 17% over the medium term [29]. The immediate impact of the U.S.-China dispute alone reduced GDP by 0.1% in the United States and 0.2% in China. The long-term effects appear more substantial, with potential losses reaching 1.6% for the U.S. and 2.5% for China, primarily due to reduced capital investment and diminished technological collaboration between the two nations [30]. Both countries experienced decreased energy demand and slower economic growth, which could further disrupt global energy markets [31]. While some nations may benefit from trade diversion effects, the overall impact on the global economy tends to be negative [32]. The conflict altered relative prices, disrupting established production networks and shifting comparative advantages in key sectors including transportation, electronics, and machinery.

3. Investor Uncertainty and Capital Flight. Trade wars generate significant policy uncertainty that undermines investor confidence. When trade policies become unpredictable, businesses typically delay decisions regarding expansion, innovation, and workforce growth. This cautious “wait-and-see” approach reduces aggregate investment and slows productivity growth [33]. The financial repercussions extend further as international investors may divest from nations engaged in trade conflicts, particularly those exhibiting economic vulnerability or political instability. Such capital outflows can trigger currency depreciation, increase borrowing costs, and potentially spark financial crises—especially in developing economies dependent on foreign investment.

4. Vulnerability of Emerging Markets. Emerging markets face heightened vulnerability during trade wars. These economies typically depend on exports for growth and require imports for critical industrial inputs. When major economic powers like the U.S. and China engage in trade conflicts, the ripple effects are global. Nations across Africa, Southeast Asia, and Latin America frequently experience reduced demand for their exports, volatile capital flows, and currency depreciation. These combined factors significantly elevate the risk of economic crises [34].

5. Poverty. Trade wars may impact poverty levels in developing countries through complex and indirect mechanisms. While trade expansion generally promotes economic growth, its benefits are often unevenly distributed across societal groups [35]. Trade conflicts influence poverty through multiple channels: (1) price volatility for essential goods, (2) labor market disruptions, (3) reduced government fiscal capacity, (4) heightened economic uncertainty, and (5) constrained GDP growth [36]. The ultimate poverty effects depend on three key factors: the severity of market disruptions, institutional capacity for risk mitigation, and labor demand elasticity. Particular attention must be paid to vulnerable populations, including women, rural communities, informal sector workers, and other marginalized groups [37].

Extremism

Extremism represents a multifaceted threat to both societal cohesion and fundamental rights [38]. Defined by the use of coercive violence to impose ideological or belief systems [39], its manifestations challenge common assumptions—particularly regarding religious extremism’s prevalence, which stems from complex interplays between individual psychology and communal dynamics [40]. From a psychological perspective, extremism is viewed as a form of deviant behavior that arises when there is an imbalance in motivation, where one need becomes so dominant that it overrides other needs and behavioral norms [41]. To address violent extremism requires identifying the specific needs or motivations that contribute to it and recognizing the role of external agents influencing or managing the difficulty level in carrying out extremist activities [42].

Research suggests that extremism is motivated by several psychological factors. According to significance quest theory, there are three main causes: a strong need to feel important or meaningful, a belief system that justifies the use of violence, and support from others with the same views [43]. Relative deprivation – the feeling of being treated unfairly or having less than others – is identified as an important factor that helps to explain various forms of violent extremism. This includes actions to change or protect existing social or political systems [44]. Extremism can manifest in both destructive forms (such as terrorism) and constructive forms (such as scientific breakthroughs). It can influence different parts of culture as well as individual decision-making. Understanding the psychological factors that lead to extremism is important to develop effective interventions to reduce dangerous extremist behaviors and redirect them to more constructive directions. These psychological insights offer a clear framework for studying and responding to different forms of extremism in different cultural and social settings.

Methods

Design

This study employed a qualitative research design to examine the relationship between the 2025 trade war and violent extremism. The qualitative technique was employed to gather extensive information regarding the relationship between factors. Due to various challenges in terrorism research, including confidentiality concerns and skepticism from both authorities and terrorist perpetrator [45,46], a qualitative methodology is more suitable for investigating the connection between the 2025 trade war and violent extremism.

Participants

This study involved ten deradicalized Indonesian terrorist offenders, a foreign (American) terrorist suspect, and eleven analysts/experts on terrorism (Table 1). Their ages ranged from 30 to 75 years. The terrorist offenders faced charges that included the Bali bombing, robbery, obstruction of justice, financing terrorism, involvement in worldwide terrorist networks, espionage, recruitment, and military training for terrorism. They were affiliated with militant organizations such as Jamaah Islamiyah/JI/Al Qaeda, ISIS, and Hezbollah. The eleven experts comprised forensic psychologists/terrorist profilers, senior officers from the Special Task Force Anti-Terrorism/Detachment 88 of the National Police (Densus 88), and several American, Indonesian, Malaysian, and Singaporean government think tanks (security consultants and advisors working for anti-terrorism agencies and various ministries), all of whom possess esteemed credentials.

Table 1: Participants of this study.

Perspective

Initial Sex (M/F) Age Field of expertise/ Case

Nationality/Affiliation

Outsider (experts/)

 

ST

M

45

Intelligence Indonesia

N

M

62

Economics Indonesia

PI

M

63

International relations, military, and defence Indonesia

GI

M

55

Politics and religion studies Indonesia

R

M

44

Legal and human rights Indonesia

IS

M

58

Law and gender studies Indonesia

MS

M

41

Middle East Studies USA

KP

F

51

Psychology Indonesia

BS

M

75

Military and intelligence Singapore

DT

F

54

Journalism, gender, and human rights Indonesia

AA

M

47

Religious studies Malaysia
 
Insider (former terrorist offenders/ suspects in extremist network)

AN

M

48

Terrorist recruitment and training JI

AT

M

45

Obstruction of justice ISIS

AI

M

48

Bombing JI

AD

F

23

Foreign fighting in Syria ISIS

TA

F

32

Terrorism financing ISIS

TS

M

49

Military training/camp JI

GL

M

32

Terrorism financing ISIS

WT

M

53

Terrorism financing JI

MI

M

45

Robbery JI

JI

M

61

Hiding information JI

SM

M

41

Espionage (foreign fighting in Iraq) Hezbollah

The study participants were selected through purposive sampling. To mitigate bias in purposive sampling, we initially defined the experts in this study as those possessing over ten years of experience in economics, social sciences, and/or counterterrorism; whereas the former offenders/suspects as those who were already deradicalized and whose names were recommended/referenced by counter-terrorism agencies/organizations (e.g., BNPT, Densus 88, the Ministry of Religious Affairs, and others). Secondly, we utilized inter-rater assessment in coding, categorizing, and interpreting the data acquired from participant interviews.

Procedure and Materials

A review of participant names, initial outreach, and communication with potential participants was conducted, followed by organized interviews with individuals who consented to participate in this study. Before the interviews, participants who agreed to take part in the study provided verbal consent to be involved. Interviews were conducted in May and June 2025 by the principal researcher of this study in Indonesia and the United States. Each participant engaged in a single interview session lasting approximately 30 to 40 minutes. Interviews were conducted in Bahasa Indonesia or English, with the researcher recording responses manually as participants opted against digital recording. Prior to concluding each interview, the researcher verified the written notes with the participant for accuracy to prevent misunderstanding and bias.

Analysis

The participants’ answers were compiled in a table for qualitative analysis. This enabled researchers to identify key similar concepts. The researchers subsequently deliberated on the participants’ replies and coding to ensure inter-rater agreement. They subsequently analysed the data using an inductive approach to identify a general pattern.

Results and Discussion

Extremists’ Perspectives on the 2025 Trade War

The findings of this study suggest that up-to-date extremists can be classified based on their scope, gender, ideology, hierarchical position within terrorist organisations, role, occupation, motivations for joining terrorist groups, generational cohort, and behavioural changes (Table 2). Extremists can be categorised as female or male, leaders or non-leaders, entrepreneurs or labourers, economically or non-economically oriented, religion- or non-religion-based, non-deradicalized or deradicalized, and active or passive. Regarding scope, there exist both local/home-grown and global extremists. Generational classifications include non-Gen Z individuals, specifically Baby Boomers (born 1946–1964), Generation X (born 1965–1980), and Millennials (born 1981–1996), as well as Gen Z or younger (born 1997 or later). The participants emphasise the Gen Z and younger cohort to anticipate the post-Artificial Intelligence (AI) age, as Gen Z is seen as a ‘cyber/digital generation’, fundamentally differing from preceding generations in many aspects of life. Although previous studies have recommended many classifications of terrorists or extremists, the participants of this study advocate for more simplified categories for pragmatic investigative objectives following the disbandment of Jamaah Islamiyah (JI) and the ‘zero-attack’ phenomenon.

Table 2: Classifications of contemporary extremists.

Category

Type

Scope Home-ground/local vs global
Gender Female vs Male
Hierarchy in terrorist network High-ranked (e.g., leaders, commanders) vs lower-ranked (e.g., technicians, couriers)
Work Entrepreneurs vs non-businessmen/labourers
Ideology Religion vs non-religion based (e.g., separatism, socialism, communism)
Motives to join network Economic vs justice vs security vs social vs political vs adventure
Generation Gen Z vs others
Level of radicalism Low vs medium vs high
Change in behaviour Non-deradicalized vs deradicalized vs unstable
Role Active (i.e., recruiter, producer) vs passive

The findings demonstrate that local extremist networks possess a limited understanding of the 2025 trade war in comparison to their global counterparts. Furthermore, extremist leaders and businessmen possess a greater understanding of the 2025 trade war and its ramifications on the daily lives of individuals, in contrast to non-leaders and labourers. Interestingly, participants of this study explain that female extremists (umahat) lack comprehension of global trends and the conflict between nations (USA/allies and China/allies), in contrast to their male kins (husband, father, son). Moreover, Gen Z extremists comprehend global news, including the 2025 trade war and its ramifications, as they consistently engage with news and podcasts on various online.

“Terrorists might be either homegrown or global. The global ones know that big countries might use them as proxies, so they might know about trade conflicts and other global problems. They are well-informed and watch the news because they will utilize any chance they have to propagate their narratives. But the ones who are homegrown don’t know anything about trade wars or geopolitics.” (A political analyst and advisor).

“We, Gen Z, watch news and listen to podcasts on YouTube, Twitter, and other sites. We know what’s going on in the world, including the 2025 Trade War and how it will affect our economy. We even keep up with many trends and know that there are numerous layoffs and campus dropouts in Indonesia because of the economic crisis.” (A former suspect/extremist).

“Our forensic clinical examination shows that these extremists and terrorists have serious problems in two parts of their brains: the ventromedial prefrontal cortex (vmPFC) and the dorsolateral prefrontal cortex (DLPFC). This means they don’t understand global issues like the 2025 trade war between the US and China. The DLPFC is a very important part of the brain that helps with memory, decision-making, emotion management, executive functioning, and behavior that is focused on goals. The DLPFC has something to do with violent behavior and terrorism. The vmPFC is a critically important part of the brain for social and emotional functioning, like empathy, controlling emotions, and moral competence. It regulates anxiety and fear. The vmPFC mixes cognitive and affective information, which includes human values.” (A forensic clinical psychologist)

“Don’t underestimate us, we follow the news. We know what’s going on in the world. We know about the trade war and other conflicts between the US and China, which affect Indonesia’s economy in the end.” (A bombing perpetrator).

“I doubt that extremists know about this thing (trade war). Their paradigm is different unless the great powers (USA and China) attack Muslim states.” (A senior military and intelligence advisor for several governments).

“They know about the 2025 trade war because their groups have a Foreign Affairs division, meaning they always monitor developments that occur abroad, including the trade war between China and America. So, they study things like this, not only local politics but also global politics. I remember when I interviewed one of the leaders of JI, he said that his division monitors global political developments and with whom they must cooperate.” (A senior journalist and analyst for governments).

The Expected Relationship Between the 2025 Trade War and the Rise of Extremism

The findings in this study show that participants split in opinions about the impact of trade war to the rise of extremism. Most participants argue that global economic challenges resulting in crises may increase the rise of extremism and criminal behaviour, especially to at-risk communities or individuals. Many of them refer to pull and push factors in criminal studies, indicating that economic or financial crises can precipitate various societal issues. They elucidated that economic difficulties may serve as catalysts or supporting factors, among other variables such as socioeconomic disparity, injustice, political instability, and so forth, in the emergence of extremism. Nevertheless, a small contingent of four individuals argues that economic issues are irrelevant to extremism, asserting that ideology is the only driver of such behaviour. These participants were former leaders or high-ranking members of JI (Table 3).

Table 3: Participants’ opinions on economic crises’ impact to the rise of extremism.

Insider (former terrorist offenders/suspects in extremist network)

Outsider (experts/analysts)

Initial and rank

Statements Agreement that trade war can lead to extremism Initial Statements

Agreement that trade war can lead to extremism

AN (JI, high-ranked) “No, nothing to do with that. Because our actions are based on ideology.”

X

N

“It is agreed in many theories that economic inequality can lead to criminality.”

AT (ISIS, high-ranked) “Yes, it can, therefore it is used in violent extremist narratives.”

PI

“Economic hardships can stimulate the rise of extremism, because vulnerable people in such situation will go to two things: gambling or extremism.”

AI (JI, high-ranked) “For us, economic issues don’t affect us. But for vulnerable people, economic difficulties may increase extreme thoughts.”

GI

“Economic troubles can be a catalyst in the increase of extremism.”

AD (ISIS, lower-ranked) “Economic problems can lead to violent extremism, yet through a very long process.”

R

“Yes, because economic discrepancy is one of the push factors in extremism and terrorism.”

TA (ISIS, lower-ranked) “Yes, economic grievance can be a trigger to make someone extreme in mind.”

IS

“No, economic troubles don’t contribute to extremism, because the extremists witness that everyone also suffers, not only their network/ fellows. We all are suffering.”

X

TS (JI, high-ranked) “For sure, yes, it can. Just like what happened in Poso.”

MS

“Yes, it can lead to extremism. Just look at Yemen.”

GL (ISIS, high-ranked) “It can, because economic troubles can increase criminal activities.”

KP

“Economic factors can increase extremism, but not directly.”

WT (JI, high-ranked) “It can but economy is not the only factor.”

BS

“Economic hardships due to the trade war can enhance existing or create new grievances, hence increase extremism.”

MI (JI, high-ranked) “There is a possibility that trade war between USA and China and other countries will cause global economic crises, and lead to the rise of extremism everywhere.”

DT

“Extremists will do the acts of terror when they have monetary resources, regardless the circumstances.”

X

JI (JI, high-ranked) “No, economic issues have nothing to do with us. We act based on ideology.”

X

AA

“Global economic crises because of the 2025 trade war between the great powers can be used by terrorists and extremists to recruit more people into extremist groups.”

SM (Hezbollah, sympathiser) “Economic difficulties for sure can increase the level of extremism in people.”

ST

“Yes, it can, that’s why economic crises is effectively used by them for their propaganda to recruit more people.”

The present findings reveal a divergence in participant perspectives regarding the potential impact of the 2025 trade war on extremism. A majority of participants posit that global economic instability may exacerbate extremism and criminal behavior, particularly among vulnerable populations. Drawing upon criminological frameworks, respondents highlighted how economic crises may function as both push and pull factors, interacting with other psychosocial variables—including socioeconomic disparities, systemic injustice, and political instability—to facilitate radicalization. Notably, a minority subset (n=4) of former Jemaah Islamiyah (JI) leaders and high-ranking members maintained that economic factors bear no significant relationship to extremism, asserting ideological commitment as the sole determinant of such behavior (see Table 3). This dissenting perspective underscores the ongoing theoretical debate regarding the relative weights of material deprivation versus ideological conviction in radicalization processes.

“People in underdeveloped regions who are still struggling, poor, and starving are more likely to commit terrorist attacks and become radicalized. For example, Poso. That’s the fact. It’s not easy to get people to do violent things while their tummies are full.” (A high-ranked JI member).

“Everywhere, it has become a premise that the greater the socioeconomic inequality, the higher the crime rate.” (A senior economic advisor of the Indonesian government.

“We are really offended when our acts are linked to money issues. Not all poor individuals in developing nations become terrorists. Our acts were based on our beliefs and ideology.” (A bombing perpetrator, former JI member).

“Trade wars and economic crises cannot turn individuals into extremists, but tensions between India and Pakistan can, due to India’s attacks against Muslims in Pakistan. There is a growing argument right now among Afghanistan ex-combatants over how to get to Pakistan from Indonesia to help our brothers and sisters there.” (A former leader of JI).

“Economic crises can turn people to be extreme in mind. Financial issues are not the main driver, but can increase extremism – indirectly maybe, along with other issues such as injustice, discrepancy, and other grievances.” (A senior JI member).

“Economic crises can lead to the rise of extremism as these can enhance existing or create new grievances.” (A senior military and intelligence advisor for several governments).

“The worse the economy in a country, the higher the extremism in its people. When people have nothing to lose – poor and starving, it’s easier to provoke them and escalate extremism in them. Just look at Yemen.” (An American analyst).

This study reveals a typology of psychological responses to economic crises among individuals with extremist affiliations. The findings demonstrate three distinct patterns of reaction and adaptation. First, there are individuals who have undergone significant belief system modification, having disengaged from violence. These individuals exhibit marked affective distress when confronted with economic crises, including inflation, rising prices, increased poverty, and heightened taxation. Their distress extends beyond personal circumstances to encompass broader societal impacts, and they maintain a determined commitment to peace advocacy regardless of external conditions.

In contrast, the study identifies a second category of extremist actors who occupy leadership or senior positions within their organizations and display high levels of radicalization. These “exploiters”-typed extremists individuals strategically exploit economic difficulties, turmoil, and chaos to advance their ideological objectives. They actively disseminate propaganda and recruit new members by framing economic crises as divine punishment for societies that fail to adhere to their prescribed religious practices. This exploitative behavior reflects sophisticated cognitive framing techniques and deliberate manipulation of in-group/out-group dynamics.

A third, more passive group emerges from the findings – individuals who are ‘muted’ members on the periphery of extremist networks while experiencing significant economic hardship. These members demonstrate increased susceptibility to radicalization during periods of economic distress, though they typically refrain from active participation in organizational activities. Their vulnerability appears rooted in the intersection of material deprivation and pre-existing network affiliations.

The study’s typological framework contributes to our understanding of how economic crises function as psychological stressors that interact differentially with individuals’ positions within extremist hierarchies and their stages of radicalization. The findings suggest that economic instability does not produce uniform effects across extremist populations, but rather activates distinct psychological and behavioral patterns depending on individuals’ organizational roles, belief systems, and personal circumstances. Thus, the study has identified three classifications of extremists according to their reactions to economic crises: 1) disengaged from violence/’deradicalized’ individuals who persistently promote peace, 2) ‘exploiters’ who use economic challenges as a means to disseminate extremist narratives and recruit more followers, and 3) ‘vulnerable’ silent individuals who may adopt more radical ideologies in response to economic hardships.

“These economic issues are exploited by recruiters to spread their ideology. They argue that the crises happen because the government is secular or not applying certain religious practices across many aspects.” (A high-ranked JI member).

“Historically proven, economic crises can cause discontentment and anger against authorities which can lead to resistance, fighting, and expressions of dissatisfaction against governments. The extremists use the issue of economic crises to blame the small group of minorities, the top 10%, the capitalists who own all the land and resources, and to promote hate-filled narratives or propaganda to get more people to join them.” (A scholar of Islamic studies, high-ranked counselor to governments).

“High prices, low purchasing power of the people, and various manifestations of economic crises cause two things in vulnerable communities: 1) online gambling due to frustration, or 2) extremism as a means to transcend existence in this world and go to the afterlife.” (An eminent professor in International Relations, Military, and Defense).

“Economic crises can cause someone to become extreme, but this is a very long process. Economic motives are not the only ones; they interact with other factors that can eventually cause people to become extreme. I am one example.” (A young former ISIS member).

Urgent Policy Measures Needed to Mitigate Risks During the 2025 Trade War

The findings of this study reveal several threats that governments must confront following the 2025 trade war, based on perspectives from both internal and external extremist groups. Former terrorist offenders/suspects and experts in various fields highlight current threats/risks, including significant economic and social disparities, political instability, poverty, and the escalation of tensions between India and Pakistan into a religious conflict (Table 4).

Table 4: Current threats according to participants.

Insider

(extremist networks)

Outsider

(experts)

Initial and rank

View on current risks Initial

View on current risks

AN (JI, high-ranked) The escalation of tensions between India and Pakistan into a religious conflict

N

Governments’ uncertainty in responding to the USA-China trade conflict
AT (ISIS, high-ranked) A new growing wave of violent extremism

PI

Poverty
AI (JI, high-ranked) Injustice, corruption, oppression and economic disparities

GI

Governments’ lack of empathy to their own people
AD (ISIS, lower-ranked) Economic, politic, and social instability

R

Social Inequality (grievance/hatred)
TA (ISIS, lower-ranked) People’s frustration and distrust in administrations of governments globally

IS

Radical narratives, such as those about India vs Pakistan war which are often linked to religion
TS (JI, high-ranked) Hunger and safety issues

MS

Economic inequality within and across nations
GL (ISIS, high-ranked) Poverty and welfare issues

KP

Crimes and terrorism
WT (JI, high-ranked) Disinformation, hoax, and dangerous radical narratives

BS

The consequences from the Israeli genocide against Palestinians
MI (JI, high-ranked) Inequality and perceived injustice in society

DT

The birth of new cells of extremist groups post-2025
JI (JI, high-ranked) Economic instability, poverty and sharp decline of people’s purchasing power

AA

Economic inequality, disinformation, and extremist narratives are thriving during economic crises and are used to manipulate public sentiment
SM (Hezbollah, sympathiser) Socio-economic discrepancies and injustice

ST

Recruitment of extremist groups

“The current threat, in my opinion as an economist, is the governments’ confusion and uncertainty in responding to BRICS versus the USA. This confusion stems from a lack of capacity.” (A senior economic advisor to the Indonesian government).

“The current threat to handle is that the fallout from the Israeli genocide against Palestinians has radicalized several Salafi groups. Although the violence has not yet happened, a new leader or coalition could trigger future jihadi attacks.” (A senior military and intelligence advisor for several governments).

“I think the current risks now are people’s frustration and distrust in their governments’ administrations. In many countries, governments have failed to win people’s hearts. They fail us. People around the world feel ignored and disrespected by their governments. Governments see their people as stupid, but actually they are not.” (A young former female ISIS member).

“Terrorism financing is now a real threat. Extremist narratives and propaganda on social media are often sponsored by terrorist groups. These groups frequently pay to spread extremist stories and propaganda online. Indonesians are generally kind and generous people, which is why these organizations collect money by tricking or manipulating ordinary citizens. They also utilize digital or cryptocurrency to transfer funds to locations like Syria.” (A forensic clinical psychologist).

This study found recommended government responses and strategies to address current threats, as proposed by former terrorist offenders and experts. These include good governance, poverty eradication, effective counternarratives and deradicalization programs, and improvements in education and healthcare systems (Table 5).

Table 5: Participants’ opinions on prompt improvement by governments globally.

Insider (former terrorist offenders/suspects in extremist network)

Outsider (experts/analysts)

Initial and rank

Strategies to Overcome Current Threats (Governments’ Areas for Improvement) Initial

Strategies to Overcome Current Threats (Governments’ Areas for Improvement)

AN (JI, high-ranked) Deradicalization and counter-narratives programs to vulnerable people

N

Educating people and focusing on strategic resources and commodities
AT (ISIS, high-ranked) Continue deradicalization and counternarrative programs, maintaining the level of defence and security, and eradicating corruption in governments’ administration

PI

Erasing poverty by: 1) eliminating corruption, 2) promoting socioeconomic equality, 3) enhancing welfare through the creation of employment opportunities, among other measures
AI (JI, high-ranked) Implementing good governance, reducing inequality, as well as performing effective deradicalization and counter-narratives against extremism

GI

Constructing positive narratives through various ways, such as legislation, politics and community empowerment, that cultivate empathy; and improve the education curriculum
AD (ISIS, lower-ranked) Strengthening all key sectors, including ending corruption, improving the quality, affordability, and accessibility of education, and enhancing healthcare

R

Countering radical narratives
TA (ISIS, lower-ranked) Demonstrating respect and empathy to people and addressing public frustrations, especially in education and healthcare

IS

Suppressing radical narratives and educating vulnerable communities
TS (JI, high-ranked) Enhancing societal safety as well as increasing employment opportunities to ensure that people can fulfil their basic needs

MS

Reducing economic disparities inside and across nations
GL (ISIS, high-ranked) Improving general welfare, especially for individuals vulnerable to radicalisation, offering employment to disengage individuals from violence, as well as maintaining deradicalization efforts

KP

Establishing a banking and non-banking framework that inhibits the financing of terrorists, alongside media counternarratives to mitigate extremism
WT (JI, high-ranked) Adopting a persuasive and inclusive approach and avoiding aggression and repression to people

BS

Ceasing the Israeli genocide against Palestinians
MI (JI, high-ranked) Implementing good governance which is full of integrity and transparency

DT

Monitoring to religious parties, new cells of extremist groups, and social media propaganda, and making effective programs to address extremism
JI (JI, high-ranked) Improving law enforcement, legal system, and economic opportunities

AA

Addressing economic inequality, countering extremist narratives, and monitoring emerging extremist group that may arise during times of economic turmoil
SM (Hezbollah, sympathiser Addressing socio-economic inequality

ST

Fixing governments’ communication which promote empathy and reduce tension

“Governments everywhere should adopt a persuasive and inclusive approach, like those successfully used with Jemaah Islamiyah in Indonesia, which led to its disbandment, and should reduce counterproductive actions such as aggression and repression toward people.” (A senior former member of JI).

“The state should enhance all sectors, including eradicating corruption, advancing education to make it more affordable and accessible to the populace, and enhancing healthcare. Avoid creating frustration among people because frustration can lead to turbulence, chaos, criminality, extremism, and terrorism.” (A young former female member of ISIS).

“The dissolution of JI does not mean the end, because there is potential for new cells to emerge from those who disagree with JI’s dissolution. There are also internal dynamics within JI post-dissolution that could lead to dissatisfaction and the emergence of new cells. Additionally, JI could change its name and strategy, and infiltrate government or non-government agencies to influence policy. Regarding ISIS, it’s crucial to monitor overseas instructions, as they are still consolidating and actively recruiting at this time.” (A senior journalist and analyst for governments).

Conclusion

While trade wars may appear politically advantageous in the short term, they typically incur significant economic costs. These include disruptions to global supply chains, increased consumer prices, erosion of investor confidence, and destabilization of developing markets. The 2025 U.S. trade war, though economically motivated, produced effects extending beyond financial systems into social and political domains. The resulting economic deterioration not only exacerbated international tensions but also created conditions conducive to the proliferation of extremist ideologies. Employing a qualitative research design, this study examines the complex relationship between the 2025 U.S. trade war and potential escalations in violent extremism, incorporating both internal (terrorist group) and external (analytical) perspectives. Through in-depth interviews with former terrorist offenders (insider perspectives) and counterterrorism experts (outsider perspectives), the research investigates whether the 2025 trade war may intensify violent extremism by creating favorable sociopolitical conditions for radicalization.”

The findings have revealed that current extremists are categorised based on their role, scope, ideology, hierarchical position within terrorist organisations, occupation, drives for joining terrorist groups, generational cohort, gender, and behavioural changes. A key revelation concerns the demonstrable secondary effects of the 2025 U.S. trade war on extremism dynamics. The economic disruptions disproportionately impacted vulnerable populations, creating identifiable psychosocial conditions that facilitated radicalization among at-risk communities and individuals. This economic shock appeared to operate as both a structural enabler and psychological accelerant for extremist mobilization. Particularly salient was the emergence of three distinct behavioral phenotypes in response to economic crises. The first group comprised disengaged/“deradicalized” individuals who actively promoted peaceful alternatives despite economic hardships, representing persistent anti-violence voices. In contrast, a second category of strategic actors – termed “exploiters” – systematically leveraged economic distress to amplify extremist narratives and recruitment efforts. Perhaps most concerning was the identification of a third, “vulnerable” silent cohort characterized by heightened vulnerability to radicalization when facing economic deprivation, suggesting a latent risk pool requiring targeted intervention.

The study’s findings yield important implications for evidence-based policymaking informed by psychological principles of radicalization. Drawing on first-hand accounts from former extremists and counterterrorism specialists, the research underscores how multidimensional interventions addressing both socioeconomic conditions and individual psychological vulnerabilities may effectively counter extremist recruitment. At the core of these recommendations lies the need for poverty alleviation programs that target the sense of relative deprivation known to fuel grievances, combined with counter-narrative campaigns that apply principles of cognitive dissonance to disrupt extremist messaging. The findings further highlight the psychological importance of governance reforms that address fundamental human needs for system justification and fairness, alongside improvements to education and healthcare systems that can foster secure attachments and hopeful future orientations. These policy priorities emerge as particularly crucial in light of the socioeconomic disruptions caused by the 2025 U.S. trade war, which appear to have created fertile ground for extremist narratives targeting vulnerable populations.

From a research perspective, the study reveals critical gaps in our quantitative understanding of how macroeconomic shocks interact with known psychological risk factors for radicalization. Future investigations employing longitudinal designs and multilevel modeling could help disentangle the complex relationships between trade-induced economic indicators, individual-level radicalization processes, and community-level transmission of extremist ideologies. Such research would benefit from incorporating both behavioral measures of extremist engagement and emerging neurocognitive markers of vulnerability to radicalization, potentially yielding more precise predictive models for preventive intervention. This integrated approach, combining psychological theory with economic policy analysis, offers a promising framework for developing more effective counter-extremism strategies that address both the structural conditions and individual pathways that facilitate radicalization.

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