Medical hypotheses最新文献

{"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}

{"title":"Endogenous Mirroring Phenomena (EMP): a paradigm shift in biological sciences","authors":"Mahdieh Emadi","doi":"10.1016/j.mehy.2026.111888","DOIUrl":"10.1016/j.mehy.2026.111888","url":null,"abstract":"<div><div>The dynamic interaction between organisms and their environment has been a cornerstone of biological research, yet the mechanisms underlying this relationship remain incompletely understood. Recent advances in fields such as enactivism and ecological psychology have emphasized the active role organisms play in shaping their environments, suggesting that perception and action are deeply intertwined. However, existing theories often limit their focus to cognitive or passive reactive processes. This manuscript introduces Endogenous Mirroring Phenomena (EMP) as a novel theoretical framework, positing that biological systems possess intrinsic mechanisms that actively mirror environmental stimuli across the molecular, cellular, and systemic levels. Unlike biophotonic emissions or mirror neuron activity, which primarily address localized or specific reactive processes, EMP proposes a comprehensive, organized reflection of environmental cues that influences physiological regulation, adaptation, and evolution. This concept not only broadens our understanding of biological complexity but also offers new avenues for research on cellular communication, signaling, and evolutionary biology. By establishing EMP as a unifying principle, this work challenges traditional views and sets the stage for future interdisciplinary exploration.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111888"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079817","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}

{"title":"Stress-conditioned small extracellular vesicles from young cells to restore resilience in aging","authors":"Julio Buñay,&nbsp;Philippe de Medina,&nbsp;Marc Poirot,&nbsp;Sandrine Silvente-Poirot","doi":"10.1016/j.mehy.2026.111886","DOIUrl":"10.1016/j.mehy.2026.111886","url":null,"abstract":"<div><div>Aging is characterized by a progressive decline in cellular stress responses, including oxidative stress resistance, mitochondrial quality control, DNA repair, and autophagy. Small extracellular vesicles (sEVs) released by all cell types are now recognized as key mediators of intercellular communication, particularly under stress conditions. sEVs derived from cells exposed to controlled, non-lethal stressors (e.g., hypoxia, oxidative, mitochondrial, or genotoxic stress) can carry protective molecules that promote stress adaptation and repair in recipient cells. We propose that stress-conditioned sEVs from young cells can restore adaptive stress responses and repair capacity in aging tissues by delivering molecular mediators that are diminished or dysregulated in aged cells. This concept builds on three well-established principles: (1) the content of sEVs reflects the physiological or stress state of the donor cell; (2) sEVs released from stressed cells convey adaptive mediators that promote resilience and repair in recipient cells; and (3) both stress-adaptive responses and intercellular communication are altered in the elderly. This hypothesis proposes that sEVs released by stress-conditioned young cells could constitute a novel gerotherapeutic approach capable of restoring adaptive stress responses and exerting beneficial effects on multiple hallmarks of aging in aged organisms. We discuss the biological rationale, supporting evidence, and experimental models to test this concept.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111886"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036239","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}

{"title":"Comment on: Refinements to the hypothesis of climate-driven decline in human core body temperature","authors":"Fèlix Faming Wang","doi":"10.1016/j.mehy.2026.111890","DOIUrl":"10.1016/j.mehy.2026.111890","url":null,"abstract":"","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111890"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079815","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}

{"title":"The brain as a self-monitoring system: Recursive instability and AI-augmented control","authors":"Charles Okanda Nyatega ,&nbsp;Qiang Li ,&nbsp;Mohammed Jajere Adamu ,&nbsp;Deogratias Mzurikwao","doi":"10.1016/j.mehy.2026.111897","DOIUrl":"10.1016/j.mehy.2026.111897","url":null,"abstract":"<div><div>We propose that failures of biological self-regulation across systems such as Parkinsonian motor rigidity and septic immune collapse can be understood as violations of a shared recursive control condition that governs stable inference: <span><math><mrow><mrow><mo>|</mo><mn>1</mn><mo>-</mo><mi>α</mi><mi>g</mi><mo>′</mo></mrow><msub><mrow><mo>(</mo><mi>ε</mi></mrow><mi>t</mi></msub><mrow><mo>)</mo><mo>|</mo></mrow><mo>&lt;</mo><mn>1</mn></mrow></math></span>. This hypothesis reframes perception, introspection, physiological feedback, and AI inference loops as structurally equivalent recursive controllers whose stability depends on how strongly prediction errors update internal models. When this balance is distorted, systems become either over-stable (rigid, unresponsive) or unstable (runaway over-correction). If correct, this framework yields specific implications for translational neuromodulation. Adaptive deep brain stimulation should monitor stability-related quantities—prediction-error gain, update sensitivity, and latent causal structure—rather than relying solely on biomarker thresholds. Causal-latent controllers (e.g., SCDM-like disentanglement models) are predicted to outperform conventional controllers by maintaining stable recursion under perturbation. Conversely, empirical conditions that fail to show improved stability would count against the hypothesis. We outline the theoretical motivation, provide neural and immunological examples, and propose concrete, falsifiable predictions for testing the hypothesis in Parkinson’s disease and sepsis modeling. Finally, we discuss implications for designing AI-augmented closed-loop neuromodulation systems that remain robust under recursive self-monitoring. We hypothesize that failures of biological and artificial self-regulation can be explained by violations of a shared recursive stability condition, in which imbalances between prediction and correction drive systems into rigid or unstable feedback states.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111897"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189372","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}

{"title":"Thermal Compartment Syndrome: A hypothesis of iatrogenic intracranial heat entrapment during neurosurgical procedures","authors":"Marko Puljiz ,&nbsp;Darko Orešković ,&nbsp;Marko Moretti ,&nbsp;Andrija Bitunjac ,&nbsp;Vjenceslav Vrtarić ,&nbsp;Šimun Puljiz ,&nbsp;Fani Puljiz ,&nbsp;Anđelo Kaštelančić ,&nbsp;Fadi Almahariq ,&nbsp;Tonko Marinović ,&nbsp;Darko Chudy","doi":"10.1016/j.mehy.2026.111899","DOIUrl":"10.1016/j.mehy.2026.111899","url":null,"abstract":"<div><div>During cranial neurosurgical procedures, anesthetic blunting of thermoregulation, sealed draping, reduced scalp perfusion and evaporation, and exposure to radiant and convective heat sources can create a localized imbalance between cerebral heat production and dissipation. Cerebrospinal fluid (CSF) normally contributes to intracranial thermal buffering via convective redistribution; surgical CSF loss, ventricular collapse, and/or cisternal isolation may reduce this buffering and permit steeper local temperature gradients. In addition, endotracheal intubation bypasses upper-airway heat-and-moisture exchange, potentially reducing a physiologic cooling route. We propose the term “Thermal Compartment Syndrome” (TCS) to describe iatrogenic intracranial heat entrapment arising when exogenous heat inputs coincide with concurrent constraint of multiple physiologic heat-clearance pathways, producing focal intracranial temperature elevations that may occur despite normal systemic temperatures. TCS is a compartmental framing that predicts spatially heterogeneous “hot spots” near illuminated or cauterized cortex and in settings where internal convective buffering is reduced. We outline testable predictions, measurement approaches, and falsification criteria, emphasizing paired local and global thermometry to distinguish true parenchymal heat retention from surface-cooling artifacts. Recognizing TCS as a plausible intraoperative state could motivate targeted monitoring and systematic evaluation of modifiable heat inputs and heat-clearance constraints, with the goal of clarifying whether focal intracranial temperature exposure is clinically meaningful.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111899"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189361","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}

{"title":"The Stage 1 Plus hypothesis in status epilepticus: predicting resistance before it happens","authors":"Giuseppe Magro","doi":"10.1016/j.mehy.2026.111894","DOIUrl":"10.1016/j.mehy.2026.111894","url":null,"abstract":"<div><div>The traditional four-stage model of status epilepticus (SE) classifies treatment based on clinical response rather than underlying pathophysiology. However, growing evidence from experimental and clinical studies indicates that resistance to benzodiazepines (BDZs) can often be predicted, especially in patients experiencing prolonged SE, those with acute symptomatic causes, or nonconvulsive presentations with coma. This is why the author hypothesizes a Stage 1 Plus: an umbrella term to predict early BDZ resistance in treatment-naïve SE, as in any of the already-mentioned conditions.</div><div>Here, the author explores some of the mechanistic basis, preclinical validation, and emerging clinical support for SE’s Stage 1 Plus hypothesis. Time-dependent GABA-A receptor internalization and NMDA receptor upregulation drive BDZ resistance within minutes of SE onset, increasing over time. Preclinical models consistently demonstrate that simultaneous polytherapy, including midazolam and ketamine, is more effective than sequential drug administration.</div><div>Stage 1 Plus identifies SE patients who, although treatment-naïve, are likely to be BDZ-refractory. For these patients, early polytherapy may be essential. Future trials should be designed to test the hypotheses of early polytherapy rather than the current sequential drug administration approach in those situations.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111894"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189380","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}

{"title":"A neuromechanical hypothesis of compensatory arm assistance as a biomarker of lower-limb weakness in aging","authors":"Noppharath Sangkarit,&nbsp;Weerasak Tapanya","doi":"10.1016/j.mehy.2026.111904","DOIUrl":"10.1016/j.mehy.2026.111904","url":null,"abstract":"<div><div>Age-related decline in lower-limb strength is a major determinant of mobility loss and fall risk among older adults. As neuromuscular coordination and torque capacity deteriorate with aging, the body often recruits compensatory strategies to maintain postural control and movement feasibility. One such strategy involves the use of the upper limbs to provide mechanical assistance during rising or balance tasks. Emerging biomechanical evidence indicates that greater reliance on arm support commonly accompanies lower-limb weakness, suggesting that this behavior may reflect a neuromechanical adaptation rather than mere dependence. A neuromechanical hypothesis of compensatory arm assistance is proposed, suggesting that upper-limb loading represents an adaptive redistribution of mechanical demand in response to diminished lower-limb strength. The concept reframes arm support as a biomechanical signature of neuromuscular decline, potentially quantifiable through the proportion of assistive ground-reaction force relative to body weight (%Assistive GRF/BW). This measure could serve as a low-cost, mechanistically interpretable biomarker of lower-limb performance, bridging the gap between biomechanical understanding and community-level screening for functional decline. If verified, this paradigm would transform compensatory behavior—traditionally viewed as a limitation—into a diagnostic window on neuromechanical health and the aging motor system.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111904"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189360","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}

{"title":"The Voided Volume Transit Point (VVtrans): a novel functional biomarker for staging bladder decompensation in bladder outlet obstruction","authors":"Yu-Hsiang Lin,&nbsp;Po-Ting Lin,&nbsp;Kuo-Jen Lin,&nbsp;Tzu-Chi Teng,&nbsp;Yu-Ting Chen,&nbsp;Chen-Pang Hou,&nbsp;Chien-Lun Chen","doi":"10.1016/j.mehy.2026.111903","DOIUrl":"10.1016/j.mehy.2026.111903","url":null,"abstract":"<div><div>Clinical management of lower urinary tract symptoms (LUTS) caused by bladder outlet obstruction (BOO) is hampered by its reliance on subjective symptom scores, which correlate poorly with the progressive functional decline of the bladder. This disconnect often delays intervention and risks irreversible detrusor damage. We propose the Voided Volume Transit Point (VVtrans)—the inflection point on an individual’s longitudinal voided volume (VV) versus peak flow rate (Qmax) curve where Qmax plateaus—as a non-invasive biomarker for staging bladder decompensation. Derived from multiple home-uroflowmetry measurements, a declining VVtrans value reflects the continuum of bladder remodeling from a compensated, hypertrophic state to a decompensated, fibrotic bladder with reduced functional reserve. This hypothesis is supported by physiological evidence that detrusor contractility depends on bladder volume, pathophysiological studies of BOO-induced remodeling, and the feasibility of capturing real-world voiding dynamics with home-based monitoring. If validated through <strong>prospective clinical studies</strong>, VVtrans could provide an objective measure for early diagnosis, guide the timing of intervention to preserve detrusor function, and serve as a quantitative indicator of therapeutic success. Such an approach would represent a paradigm shift towards a more precise, bladder-centric model of patient care.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111903"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189422","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}

{"title":"Hypoxia-induced mitochondrial silencing as a proposed third axis of apoptosis control in solid tumors: a dual hypothesis linking initiation–promotion transition to hypoxic niche maintenance","authors":"Masato Hiki","doi":"10.1016/j.mehy.2026.111887","DOIUrl":"10.1016/j.mehy.2026.111887","url":null,"abstract":"<div><div>Cancer initiation and progression have traditionally been interpreted primarily through the accumulation of genetic mutations and the dysregulation of intracellular signaling pathways. At the same time, increasing evidence indicates that the tumor microenvironment—particularly hypoxia and pathological angiogenesis—plays a critical role in tumor cell survival, clonal selection, and therapeutic resistance. However, how genetic alterations and hypoxia-driven metabolic adaptation are functionally integrated during stepwise tumor progression remains incompletely understood.</div><div>In this manuscript, we propose a dual hypothesis framework in which hypoxia-induced mitochondrial silencing and hypoxic niches maintained by pathological angiogenesis cooperatively shape cancer progression in hypoxia-prone solid tumors. Mitochondrial silencing is defined here as a functional mitochondrial state in which oxidative metabolism is suppressed and the executional capacity of mitochondria-dependent apoptosis is attenuated, despite the structural persistence of mitochondria. We further propose that this state functions as a third regulatory layer of apoptosis control, distinct from classical pro- and anti-apoptotic signaling pathways.</div><div>As a second component of the hypothesis, we suggest that structurally and functionally abnormal tumor neovasculature generates spatially heterogeneous microenvironments characterized by limited red blood cell–mediated oxygen delivery but relatively preserved diffusion of glucose. Such hypoxic, glucose-accessible niches are predicted to preferentially select for and maintain cell populations adapted to mitochondrial silencing and glycolysis-dominant metabolism, thereby supporting clonal persistence, heterogeneity, and progression.</div><div>Although this work does not present experimental data, it provides a testable conceptual framework that repositions mitochondrial functional state as a central integrator of genetic alterations and microenvironmental constraints, and offers new perspectives on apoptosis resistance and metabolic adaptation in hypoxic solid tumors.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"208 ","pages":"Article 111887"},"PeriodicalIF":0.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036237","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}