Pub Date : 2026-03-01Epub Date: 2026-01-27DOI: 10.1016/j.mehy.2026.111892
S. Shyam Sundar , Sahith Kumar Shetty , K. Brindha
The long-term success of dental implants depends on adequate alveolar bone volume, often necessitating regenerative interventions such as guided bone regeneration and sinus augmentation. Accurate assessment of bone dimensions is critical for planning these procedures, yet manual methods are prone to operator variability and limited reproducibility. Artificial intelligence (AI) has shown promise in dental imaging, with systems such as Dental-YOLO and automated segmentation models achieving high precision in detecting anatomical landmarks. However, existing AI approaches are constrained by dataset diversity, generalizability, and interpretability. We hypothesize that a hybrid Generative Adversarial Network (GAN)–P-TransUNet framework could overcome these limitations by combining GAN-based synthetic data augmentation with transformer-enhanced segmentation for precise and reproducible alveolar bone measurement. This framework could standardize preoperative bone evaluation, optimize regenerative planning, minimize surgical risk, and provide educational value through synthetic datasets. If validated, it has the potential to transform precision-driven regenerative implantology, improving clinical outcomes and patient safety.
{"title":"Hybrid GAN–P-TransUNet framework for alveolar bone regeneration in dental implant planning: A hypothesis","authors":"S. Shyam Sundar , Sahith Kumar Shetty , K. Brindha","doi":"10.1016/j.mehy.2026.111892","DOIUrl":"10.1016/j.mehy.2026.111892","url":null,"abstract":"<div><div>The long-term success of dental implants depends on adequate alveolar bone volume, often necessitating regenerative interventions such as guided bone regeneration and sinus augmentation. Accurate assessment of bone dimensions is critical for planning these procedures, yet manual methods are prone to operator variability and limited reproducibility. Artificial intelligence (AI) has shown promise in dental imaging, with systems such as Dental-YOLO and automated segmentation models achieving high precision in detecting anatomical landmarks. However, existing AI approaches are constrained by dataset diversity, generalizability, and interpretability. We hypothesize that a hybrid Generative Adversarial Network (GAN)–P-TransUNet framework could overcome these limitations by combining GAN-based synthetic data augmentation with transformer-enhanced segmentation for precise and reproducible alveolar bone measurement. This framework could standardize preoperative bone evaluation, optimize regenerative planning, minimize surgical risk, and provide educational value through synthetic datasets. If validated, it has the potential to transform precision-driven regenerative implantology, improving clinical outcomes and patient safety.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111892"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-05DOI: 10.1016/j.mehy.2026.111898
Ayah Al-Qasrawi
Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes, marked by metabolic acidosis and elevated ketone levels. Euglycemic DKA (EDKA), often seen in type 2 diabetes patients on SGLT-2 inhibitors, occurs without severe hyperglycemia. We propose that the pyruvate dehydrogenase kinase-4 (PDK4) is one of the critical drivers of diabetic ketoacidosis (DKA). Elevated PDK4 inactivates the pyruvate dehydrogenase complex, promoting fat oxidation and ketogenesis through Acetyl-CoA. This suggests DKA is a biochemical event in addition to hormonal dysregulation. PDK4 is thus a key mediator of both classic and euglycemic DKA and could represent a promising therapeutic target. Pharmacologic modulation of PDK4 to restore pyruvate dehydrogenase complex (PDC) activity could prevent DKA, offering a novel strategy beyond insulin therapy or glucose control. Understanding PDK4′s role reframes DKA as a metabolic, hormonal, and enzyme-driven event.
{"title":"Diabetic ketoacidosis is not a simple consequence of hyperglycemia, it is biochemical event driven by PDK4-mediated inhibition of PDC","authors":"Ayah Al-Qasrawi","doi":"10.1016/j.mehy.2026.111898","DOIUrl":"10.1016/j.mehy.2026.111898","url":null,"abstract":"<div><div>Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes, marked by metabolic acidosis and elevated ketone levels. Euglycemic DKA (EDKA), often seen in type 2 diabetes patients on SGLT-2 inhibitors, occurs without severe hyperglycemia. We propose that the pyruvate dehydrogenase kinase-4 (PDK4) is one of the critical drivers of diabetic ketoacidosis (DKA). Elevated PDK4 inactivates the pyruvate dehydrogenase complex, promoting fat oxidation and ketogenesis through Acetyl-CoA. This suggests DKA is a biochemical event in addition to hormonal dysregulation. PDK4 is thus a key mediator of both classic and euglycemic DKA and could represent a promising therapeutic target. Pharmacologic modulation of PDK4 to restore pyruvate dehydrogenase complex (PDC) activity could prevent DKA, offering a novel strategy beyond insulin therapy or glucose control. Understanding PDK4′s role reframes DKA as a metabolic, hormonal, and enzyme-driven event.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111898"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-29DOI: 10.1016/j.mehy.2026.111895
Egarit Noulsri , Surada Lerdwana
Aggressive prostate cancer (PC) relies on lipid metabolic reprogramming and pathological iron (Fe) accumulation to drive disease progression. While peroxisome proliferator-activated receptor-gamma (PPARγ) is a master regulator of this lipid-addicted phenotype, direct therapeutic targeting remains clinically limited by systemic toxicity. We propose a novel therapeutic framework: the Fe- cyclooxygenase (COX)/lipoxygenase (LOX)- prostaglandins (PGs)/leukotrienes (LTs)-PPARγ signaling axis. This hypothesis identifies intracellular iron bioavailability as the critical catalytic switch for oncogenic PPARγ activity. Within this axis, Fe serves as an essential cofactor for COX and LOX enzymes that synthesize activating eicosanoid ligands, PGs and LTs, required for receptor transactivation. This model shifts the paradigm of iron chelation from traditional nutritional starvation to a sophisticated signal-transduction interference strategy. By deactivating COX/LOX through active-site coordination and peroxide tone modulation, iron chelators e.g., deferoxamine, deferiprone induce a ligand deficit that forces PPARγ into an inactive apo-conformation, silencing pro-survival genes such as FASN and CD36. To validate this axis, we propose a multi-faced roadmap. This involves in vitro rescue experiments confirming that exogenous ligands bypass chelation-induced silencing, paired with in vivo transcriptomic RNA-seq and cistromic ChIP-seq mapping to verify the global attenuation of the PPARγ regulation. This signaling interference model provides a mechanistic rationale for using iron chelators as indirect transcriptional modulators. Such a strategy may provide a precision-guided approach for sensitizing castration-resistant disease to conventional therapeutic regimens.
{"title":"Iron chelators reduce prostaglandins and leukotrienes by inhibiting cyclooxygenase and lipoxygenase: A hypothesis to attenuate PPARγ transcriptional activity in prostate cancer","authors":"Egarit Noulsri , Surada Lerdwana","doi":"10.1016/j.mehy.2026.111895","DOIUrl":"10.1016/j.mehy.2026.111895","url":null,"abstract":"<div><div>Aggressive prostate cancer (PC) relies on lipid metabolic reprogramming and pathological iron (Fe) accumulation to drive disease progression. While peroxisome proliferator-activated receptor-gamma (PPARγ) is a master regulator of this lipid-addicted phenotype, direct therapeutic targeting remains clinically limited by systemic toxicity. We propose a novel therapeutic framework: the Fe- cyclooxygenase (COX)/lipoxygenase (LOX)- prostaglandins (PGs)/leukotrienes (LTs)-PPARγ signaling axis. This hypothesis identifies intracellular iron bioavailability as the critical catalytic switch for oncogenic PPARγ activity. Within this axis, Fe serves as an essential cofactor for COX and LOX enzymes that synthesize activating eicosanoid ligands, PGs and LTs, required for receptor transactivation. This model shifts the paradigm of iron chelation from traditional nutritional starvation to a sophisticated signal-transduction interference strategy. By deactivating COX/LOX through active-site coordination and peroxide tone modulation, iron chelators e.g., deferoxamine, deferiprone induce a ligand deficit that forces PPARγ into an inactive apo-conformation, silencing pro-survival genes such as FASN and CD36. To validate this axis, we propose a multi-faced roadmap. This involves <em>in vitro</em> rescue experiments confirming that exogenous ligands bypass chelation-induced silencing, paired with <em>in vivo</em> transcriptomic RNA-seq and cistromic ChIP-seq mapping to verify the global attenuation of the PPARγ regulation. This signaling interference model provides a mechanistic rationale for using iron chelators as indirect transcriptional modulators. Such a strategy may provide a precision-guided approach for sensitizing castration-resistant disease to conventional therapeutic regimens.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111895"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-17DOI: 10.1016/j.mehy.2026.111885
Nazia Hassan , Ayan K. Das , Asgar Ali
Recurrent Vulvovaginal Candidiasis (RVVC) is characterised as four or more symptomatic episodes of vulvovaginal candidiasis in a year, with partial resolution between episodes and microbiologic confirmation in at least two episodes. The prominent symptoms include vaginal-itching, discharge, erythema, oedema, and burning sensation. Biofilm development and antifungal resistance perpetuate RVVC symptoms by seeding Candida colonisation, infection relapse, and persistence. The microbial landscape of RVVC is predominantly C. albicans (90%) and emerging non-albicans Candida (NAC) species, including C. tropicalis, C. parapsilosis, C. krusei, and C. dubliniensis. The rare isolates, C. auris and S. cerevisiae, also contribute to ecological complexity in multi-species biofilms by enhancing resilience and interfering with quorum sensing. This hypothesis proposes that RVVC persistence is sustained not only by species-specific biofilm traits and virulence gene expression (ALS3, HWP1, EFG1, TUP1, BEM2), but also by interspecies interactions within multispecies vaginal biofilms that augment antifungal resistance and persistence. We propose that profiling clinical isolates could help reveal correlations between antifungal susceptibility, biofilm architecture, and gene-level regulation. The hypothesis highlights the translational importance of multispecies, multidrug-resistant, and rare Candida biofilms as key modulators of resistance and virulence traits. The proposed framework includes culture-based identification, antifungal susceptibility testing, in vitro biofilm assays, confocal microscopy, and qPCR analysis. These approaches will define biofilm-associated resistance patterns and establish quantitative molecular biomarkers to guide novel formulation designs, in vivo validation, and species-specific antifungal stewardship.
{"title":"Species-specific biofilm traits and virulence gene expression in recurrent vulvovaginal candidiasis: a translational hypothesis","authors":"Nazia Hassan , Ayan K. Das , Asgar Ali","doi":"10.1016/j.mehy.2026.111885","DOIUrl":"10.1016/j.mehy.2026.111885","url":null,"abstract":"<div><div>Recurrent Vulvovaginal Candidiasis (RVVC) is characterised as four or more symptomatic episodes of vulvovaginal candidiasis in a year, with partial resolution between episodes and microbiologic confirmation in at least two episodes. The prominent symptoms include vaginal-itching, discharge, erythema, oedema, and burning sensation. Biofilm development and antifungal resistance perpetuate RVVC symptoms by seeding <em>Candida</em> colonisation, infection relapse, and persistence. The microbial landscape of RVVC is predominantly <em>C. albicans</em> (90%) and emerging non-albicans <em>Candida</em> (NAC) species, including <em>C. tropicalis</em>, <em>C. parapsilosis</em>, <em>C. krusei</em>, and <em>C. dubliniensis</em>. The rare isolates, <em>C. auris</em> and <em>S. cerevisiae,</em> also contribute to ecological complexity in multi-species biofilms by enhancing resilience and interfering with quorum sensing. This hypothesis proposes that RVVC persistence is sustained not only by species-specific biofilm traits and virulence gene expression (ALS3, HWP1, EFG1, TUP1, BEM2), but also by interspecies interactions within multispecies vaginal biofilms that augment antifungal resistance and persistence. We propose that profiling clinical isolates could help reveal correlations between antifungal susceptibility, biofilm architecture, and gene-level regulation. The hypothesis highlights the translational importance of multispecies, multidrug-resistant, and rare Candida biofilms as key modulators of resistance and virulence traits. The proposed framework includes culture-based identification, antifungal susceptibility testing, in vitro biofilm assays, confocal microscopy, and qPCR analysis. These approaches will define biofilm-associated resistance patterns and establish quantitative molecular biomarkers to guide novel formulation designs, in vivo validation, and species-specific antifungal stewardship.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111885"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-27DOI: 10.1016/j.mehy.2026.111891
Ning Li , Yumin Heng , Tianyang Lv , Xiaoyue Ge , Changkui Liu , Kaijin Hu
Traumatic temporomandibular joint ankylosis (TTMJA), with its high recurrence rate post-surgery, lacks a unifying pathogenesis theory, hindering effective prevention. We propose a novel four-stage cascade hypothesis that highlights early lymphatic dysfunction—rather than hematoma organization—as a key early determinant of pathological repair. High-energy trauma releases free fibrocartilage fragments into the joint space, where they may act as ’osteogenic seeds’. Subsequent mechanical zonation of the joint into micromotion and stable zones then drives spatially distinct osteogenic pathways (endochondral and intramembranous ossification), explaining the histopathological heterogeneity of the ankylotic mass. This process culminates in piezoelectric-guided vascular fusion and osteoclast-suppressed consolidation, forming a complete bony bridge. Empirically testable in established models, this hypothesis delineates clear therapeutic windows: early intervention targeting lymphatic repair and debris clearance (≤7 days), followed by mechanical modulation (7–21 days), and late osteoclast reactivation (>60 days). This framework reframes clinical management by advocating stage-specific interventions within defined therapeutic windows to shift from reactive surgery to mechanism-based prevention.
{"title":"A novel hypothesis on the pathogenesis of traumatic temporomandibular joint ankylosis","authors":"Ning Li , Yumin Heng , Tianyang Lv , Xiaoyue Ge , Changkui Liu , Kaijin Hu","doi":"10.1016/j.mehy.2026.111891","DOIUrl":"10.1016/j.mehy.2026.111891","url":null,"abstract":"<div><div>Traumatic temporomandibular joint ankylosis (TTMJA), with its high recurrence rate post-surgery, lacks a unifying pathogenesis theory, hindering effective prevention. We propose a novel four-stage cascade hypothesis that highlights early lymphatic dysfunction—rather than hematoma organization—as a key early determinant of pathological repair. High-energy trauma releases<!--> <!-->free fibrocartilage fragments into the joint space, where they may act as ’osteogenic seeds’. Subsequent<!--> <!-->mechanical zonation<!--> <!-->of the joint into micromotion and stable zones then drives spatially distinct osteogenic pathways (endochondral and intramembranous ossification), explaining the histopathological heterogeneity of the ankylotic mass. This process culminates in piezoelectric-guided vascular fusion and osteoclast-suppressed consolidation, forming a complete bony bridge. Empirically testable in established models, this hypothesis delineates clear therapeutic windows: early intervention targeting lymphatic repair and debris clearance (≤7 days), followed by mechanical modulation (7–21 days), and late osteoclast reactivation (>60 days). This framework reframes clinical management by advocating stage-specific interventions within defined therapeutic windows to shift from reactive surgery to mechanism-based prevention.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111891"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-17DOI: 10.1016/j.mehy.2026.111877
Bogdan-Alexandru Hagiu
The SARS-CoV-2 virus persists for up to 80 days in the brainstem of golden hamsters and this fact is correlated with dopaminergic dysfunctions and changes in the expression of some genes, including the suppression of DRD2. Since moderate-intensity physical exercise stimulates the expression of DRD2, it was hypothesized that this type of physical training can be used for the prophylaxis of neurological disorders in Long COVID. Testing the hypothesis can be performed on the same experimental animals and the results can be evidenced by histological and immunohistochemical analyses, transcriptomics, and behavioral tests. In this way, cases of Parkinson’s disease following SARS-C0V-2 infection could also be prevented, if this causal link is confirmed.
{"title":"Moderate-intensity exercise as a preventive strategy against dopaminergic dysfunction in Long COVID: A mechanistic hypothesis","authors":"Bogdan-Alexandru Hagiu","doi":"10.1016/j.mehy.2026.111877","DOIUrl":"10.1016/j.mehy.2026.111877","url":null,"abstract":"<div><div>The SARS-CoV-2 virus persists for up to 80 days in the brainstem of golden hamsters and this fact is correlated with dopaminergic dysfunctions and changes in the expression of some genes, including the suppression of DRD2. Since moderate-intensity physical exercise stimulates the expression of DRD2, it was hypothesized that this type of physical training can be used for the prophylaxis of neurological disorders in Long COVID. Testing the hypothesis can be performed on the same experimental animals and the results can be evidenced by histological and immunohistochemical analyses, transcriptomics, and behavioral tests. In this way, cases of Parkinson’s disease following SARS-C0V-2 infection could also be prevented, if this causal link is confirmed.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111877"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-17DOI: 10.1016/j.mehy.2026.111876
Nikola Todorovic
Physical performance in hot environments is compromised by a combination of cardiovascular strain, thermoregulatory challenges, and oxidative, metabolic, and neuromuscular disruptions. While conventional pre-cooling strategies offer partial benefits, they often fail to prevent performance decline during prolonged exercise in the heat. Molecular hydrogen (H2), particularly in the form of hydrogen-rich water (HRW), has emerged as a promising modulator of redox homeostasis and cellular signaling in thermally stressed states. Recent evidence suggests that HRW ingestion may attenuate lactate accumulation and perceived exertion during endurance exercise, pointing to broader physiological roles beyond simple antioxidant action. I hypothesize that H2 acts as a context-sensitive ergogenic aid by modulating redox-sensitive signaling pathways, supporting mitochondrial bioenergetics, and influencing neuromuscular and afferent signaling, including mechanisms related to thermal discomfort and fatigue. Declines in breath hydrogen levels following exhaustive exercise further support the concept of hydrogen depletion as a marker or contributor to impaired performance and recovery, suggesting that hydrogen supplementation may be a potential solution to mitigate this occurrence. However, current studies remain limited in scope, often lacking methodological rigor and mechanistic depth. This article outlines a research framework for investigating H2 in heat-stressed exercise, highlighting key areas such as dose optimization, redox chronobiology, sex-specific responses, and longitudinal outcomes, with the aim of positioning H2 as a viable strategy for enhancing thermotolerance and performance.
{"title":"Molecular hydrogen and heat-stressed exercise: a mechanistic hypothesis and framework for future investigation","authors":"Nikola Todorovic","doi":"10.1016/j.mehy.2026.111876","DOIUrl":"10.1016/j.mehy.2026.111876","url":null,"abstract":"<div><div>Physical performance in hot environments is compromised by a combination of cardiovascular strain, thermoregulatory challenges, and oxidative, metabolic, and neuromuscular disruptions. While conventional pre-cooling strategies offer partial benefits, they often fail to prevent performance decline during prolonged exercise in the heat. Molecular hydrogen (H<sub>2</sub>), particularly in the form of hydrogen-rich water (HRW), has emerged as a promising modulator of redox homeostasis and cellular signaling in thermally stressed states. Recent evidence suggests that HRW ingestion may attenuate lactate accumulation and perceived exertion during endurance exercise, pointing to broader physiological roles beyond simple antioxidant action. I hypothesize that H<sub>2</sub> acts as a context-sensitive ergogenic aid by modulating redox-sensitive signaling pathways, supporting mitochondrial bioenergetics, and influencing neuromuscular and afferent signaling, including mechanisms related to thermal discomfort and fatigue. Declines in breath hydrogen levels following exhaustive exercise further support the concept of hydrogen depletion as a marker or contributor to impaired performance and recovery, suggesting that hydrogen supplementation may be a potential solution to mitigate this occurrence. However, current studies remain limited in scope, often lacking methodological rigor and mechanistic depth. This article outlines a research framework for investigating H<sub>2</sub> in heat-stressed exercise, highlighting key areas such as dose optimization, redox chronobiology, sex-specific responses, and longitudinal outcomes, with the aim of positioning H<sub>2</sub> as a viable strategy for enhancing thermotolerance and performance.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111876"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-25DOI: 10.1016/j.mehy.2026.111889
Mohammed Abrahim , Brittany Abrahim
Rosacea is a common, chronic inflammatory skin condition primarily affecting the human face. Clinical manifestations range from mild erythema to disfiguring phymatous changes, such as rhinophyma. Despite extensive research, its primary etiology remains unclear. Current evidence suggests that the disease may begin with an initial vascular insult, which then triggers an inflammatory cascade modulated by genetic, environmental, and microbial factors. However, the mechanisms underlying this initial vascular dysfunction have yet to be elucidated.
We propose the “Cheeky Ape Hypothesis,” which offers a novel evolutionary and anatomical potential contributor to the pathophysiology of rosacea. This hypothesis posits that impaired venous return within the facial vein and its tributaries—resulting from bilateral venous compression within the buccal fat pad, a uniquely human anatomical feature—could play a contributory role in initiating of the disease. As deep buccal fat is specific to humans, this anatomical specialization may represent an evolutionary trade-off, which could partly help explain the distinctive prevalence of rosacea in humans. The hypothesis suggests that the interplay between facial venous flow and adipose tissue distribution underpins the pathogenesis of rosacea. Rigorous experimental and clinical studies will be required to investigate and validate the proposed mechanism.
{"title":"The cheeky ape hypothesis: Is rosacea the evolutionary price of human buccal fat?","authors":"Mohammed Abrahim , Brittany Abrahim","doi":"10.1016/j.mehy.2026.111889","DOIUrl":"10.1016/j.mehy.2026.111889","url":null,"abstract":"<div><div>Rosacea is a common, chronic inflammatory skin condition primarily affecting the human face. Clinical manifestations range from mild erythema to disfiguring phymatous changes, such as rhinophyma. Despite extensive research, its primary etiology remains unclear. Current evidence suggests that the disease may begin with an initial vascular insult, which then triggers an inflammatory cascade modulated by genetic, environmental, and microbial factors. However, the mechanisms underlying this initial vascular dysfunction have yet to be elucidated.</div><div>We propose the “Cheeky Ape Hypothesis,” which offers a novel evolutionary and anatomical potential contributor to the pathophysiology of rosacea. This hypothesis posits that impaired venous return within the facial vein and its tributaries—resulting from bilateral venous compression within the buccal fat pad, a uniquely human anatomical feature—could play a contributory role in initiating of the disease. As deep buccal fat is specific to humans, this anatomical specialization may represent an evolutionary trade-off, which could partly help explain the distinctive prevalence of rosacea in humans. The hypothesis suggests that the interplay between facial venous flow and adipose tissue distribution underpins the pathogenesis of rosacea. Rigorous experimental and clinical studies will be required to investigate and validate the proposed mechanism.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111889"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-12DOI: 10.1016/j.mehy.2026.111878
Yuri Cordeiro Szeremeta
Perceived control is a transdiagnostic feature across chronic pain. The Locus of Control is a patient’s personality trait that refers to a belief about the extent to which they have control over their health outcomes. From a phenomenological point of view, the prevalence of internal or external dimensions of Locus of Control indicates how individuals operate certain cognitive systems and how they perceive different forces that influence their lives. Consequently, it is a key indicator of whether treatment will be successful or unsuccessful. However, the neural pathways and belief systems that underlie this personality trait remain poorly understood. This article raises the hypothesis that the theoretical basis of Active Inference may explain a propensity for external Locus of Control in chronic pain sufferers.
{"title":"Active Inference as a theoretical framework for external locus of control in chronic pain: the role of aberrant interoceptive integration","authors":"Yuri Cordeiro Szeremeta","doi":"10.1016/j.mehy.2026.111878","DOIUrl":"10.1016/j.mehy.2026.111878","url":null,"abstract":"<div><div>Perceived control is a transdiagnostic feature across chronic pain. The Locus of Control is a patient’s personality trait that refers to a belief about the extent to which they have control over their health outcomes. From a phenomenological point of view, the prevalence of internal or external dimensions of Locus of Control indicates how individuals operate certain cognitive systems and how they perceive different forces that influence their lives. Consequently, it is a key indicator of whether treatment will be successful or unsuccessful. However, the neural pathways and belief systems that underlie this personality trait remain poorly understood. This article raises the hypothesis that the theoretical basis of <em>Active Inference</em> may explain a propensity for external Locus of Control in chronic pain sufferers.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111878"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-27DOI: 10.1016/j.mehy.2026.111893
Ayah Al-Qasrawi
Despite major advances in tumor cell biology, metastatic disease remains the principal cause of nearly 90% of cancer-related deaths. While the literature characterizes the pre-metastatic niche through processes such as angiogenesis and immune suppression, the molecular basis of organ-specific metastasis—the non-random spread of cancer—remains poorly understood. Traditional models focus on vascular or lymphatic dissemination; however, evidence suggests that biochemical communication between primary tumors and distant tissues is crucial for the selective colonization of metastases. This hypothesis proposes a novel molecular mechanism to explain organ-specific metastasis, mediated by tyrosine kinase (TK) signaling. We hypothesize that primary tumors secrete specific tyrosine kinase proteins in exosomes that interact with overexpressed receptors in secondary organs. This targeted signaling creates a molecular “pre-metastatic niche,” facilitating organ-specific metastasis beyond passive vascular models. Uncovering this signaling axis is essential for better understanding cancer pathophysiology and for developing more targeted therapeutic approaches. Clinical successes demonstrate the therapeutic relevance of TK pathways in managing organ-specific metastases. These include the CNS-penetrant EGFR inhibitor osimertinib in non–small cell lung cancer, the dabrafenib–trametinib combination in BRAF V600 mutant melanoma, and the HER2-targeted regimen incorporating tucatinib for metastatic breast cancers.
{"title":"Molecular signaling between primary tumor and secondary tumor through tyrosine kinase","authors":"Ayah Al-Qasrawi","doi":"10.1016/j.mehy.2026.111893","DOIUrl":"10.1016/j.mehy.2026.111893","url":null,"abstract":"<div><div>Despite major advances in tumor cell biology, metastatic disease remains the principal cause of nearly 90% of cancer-related deaths. While the literature characterizes the pre-metastatic niche through processes such as angiogenesis and immune suppression, the molecular basis of organ-specific metastasis—the non-random spread of cancer—remains poorly understood. Traditional models focus on vascular or lymphatic dissemination; however, evidence suggests that biochemical communication between primary tumors and distant tissues is crucial for the selective colonization of metastases. This hypothesis proposes a novel molecular mechanism to explain organ-specific metastasis, mediated by tyrosine kinase (TK) signaling. We hypothesize that primary tumors secrete specific tyrosine kinase proteins in exosomes that interact with overexpressed receptors in secondary organs. This targeted signaling creates a molecular “pre-metastatic niche,” facilitating organ-specific metastasis beyond passive vascular models. Uncovering this signaling axis is essential for better understanding cancer pathophysiology and for developing more targeted therapeutic approaches. Clinical successes demonstrate the therapeutic relevance of TK pathways in managing organ-specific metastases. These include the CNS-penetrant EGFR inhibitor osimertinib in non–small cell lung cancer, the dabrafenib–trametinib combination in BRAF V600 mutant melanoma, and the HER2-targeted regimen incorporating tucatinib for metastatic breast cancers.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111893"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号