Medical sciences (Basel, Switzerland)最新文献

{"title":"The PD Effluentome-A Multi-Omics Atlas Defining the Composition, Transport Dynamics, and Molecular Origin of Peritoneal Dialysis Effluent.","authors":"Rebecca Herzog, Fabian Eibensteiner, Florian M Wiesenhofer, Lisa Daniel-Fischer, Anja Wagner, Markus Unterwurzacher, Isabel J Sobieszek, Juan Manuel Sacnun, Michael Böhm, Andreas Vychytil, Christoph Aufricht, Klaus Kratochwill","doi":"10.3390/medsci14040496","DOIUrl":"10.3390/medsci14040496","url":null,"abstract":"<p><p><b>Background</b>: Peritoneal dialysis (PD) effluent of kidney failure patients represents an accessible liquid biopsy of the peritoneal cavity, yet the mechanisms determining its molecular composition remain poorly understood. We applied an integrative multi-omics approach to characterize the composition, transport dynamics, and molecular origin of the PD effluentome. <b>Methods</b>: Cell-free effluent, effluent cells, and plasma were collected from stable PD patients during standardized peritoneal equilibration tests in a randomized clinical trial. Targeted metabolomics, proteomics, and transcriptomic profiling were integrated with a reference human plasma proteome to investigate temporal molecular changes, peritoneal transport characteristics, and protein origin. <b>Results</b>: A total of 207 metabolites and 2970 proteins were identified in PD effluent. Metabolites exhibited distinct class-specific transport kinetics, with rapid equilibration of amino acids and biogenic amines, whereas lipids remained markedly underrepresented despite prolonged dwell times, indicating that transport is governed by physicochemical properties beyond molecular size alone. The effluent proteome underwent concordant alteration, with dwell time-dependent enrichment of pathways related to extracellular matrix organization, angiogenesis, coagulation, and tissue repair. Integrative analysis of the effluent proteome, effluent-cell transcriptome, and human plasma proteome resolved distinct plasma-associated, effluent cell-associated, resident peritoneal tissue-associated, and mixed-origin protein populations. <b>Conclusions</b>: This study establishes the first systems-level approach describing the composition, transport dynamics, and molecular origin of the PD effluentome. By transforming PD effluent into a biologically interpretable molecular readout of peritoneal membrane biology, this work provides a reference for the mechanistic interpretation of effluent-derived biomarkers and supports future therapeutic monitoring and precision medicine in PD.</p>","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreas Transplant Recipients with and Without Pretransplant Alcohol Use Disorder: A Real-World Cohort Study.","authors":"Arkadeep Dhali, Jyotirmoy Biswas, Sajjad Ahmed Khan, Fayaz Khan, Saikat Mandal, Ashish Sharma, Dushyant Singh Dahiya, Manideepa Maji","doi":"10.3390/medsci14040497","DOIUrl":"10.3390/medsci14040497","url":null,"abstract":"<p><p><b>Background:</b> Alcohol use disorder (AUD) is generally regarded as a relative contraindication to pancreas transplantation. Yet the effect of documented AUD before transplantation on long-term results after pancreas transplantation is still poorly understood. Therefore, we used a large real-world electronic health records database to compare the three-year outcomes among pancreas transplant recipients who had and who had not had documented AUD before transplantation. <b>Methods:</b> We carried out a retrospective cohort study involving propensity score matching using the TriNetX US Collaborative Network. Each adult patient who had a documented case of alcohol use disorder (ICD-10-CM codes F10.1/F10.2) before transplantation was paired one to one with a patient who did not have such a disorder, matching them on demographic characteristics, comorbidities, transplant-related factors, medications, body mass index, and glycated hemoglobin. The outcomes were evaluated from one day after transplantation up to three years later and comprised all-cause mortality, emergency visits, transplant complications, cachexia, severe protein-calorie malnutrition, pain, vitamin deficiencies, iron deficiency anaemia, diarrhea, and adult failure to thrive. <b>Results:</b> Out of 14,367 eligible recipients, propensity score matching resulted in 439 patients in each group. Pretransplant AUD was linked to a significantly higher rate of all-cause mortality (15.1% compared with 8.5%; risk ratio [RR] 1.78, 95% CI 1.22-2.60; hazard ratio [HR] 1.86, 95% CI 1.25-2.78; <i>p</i> = 0.002). Cachexia affected 5.2% rather than 2.5% (RR 2.09, 95% CI 1.03-4.24; HR 2.16, 95% CI 1.06-4.44; <i>p</i> = 0.036), while diarrhea occurred in 39.6% compared with 28.2% (RR 1.40, 95% CI 1.16-1.69; HR 1.54, 95% CI 1.22-1.94; <i>p</i> < 0.001). There were no significant differences in the case of emergency visits (49.0% versus 44.6%; <i>p</i> = 0.199), transplant complications (11.1% versus 14.4%; <i>p</i> = 0.163), severe protein-calorie malnutrition (12.1% versus 8.9%; <i>p</i> = 0.123), pain (59.0% versus 54.7%; <i>p</i> = 0.195), vitamin deficiencies (31.4% versus 29.4%; <i>p</i> = 0.509), iron deficiency anemia (21.2% versus 21.9%; <i>p</i> = 0.805), or adult failure to thrive (7.3% versus 4.3%; <i>p</i> = 0.061). <b>Conclusions:</b> The presence of a history of alcohol use disorder (AUD) before transplantation was found to be independently linked to a higher three-year mortality rate, as well as the occurrence of cachexia and diarrhea after pancreas transplantation, but it was not associated with an increased number of coded transplant complications or most of the other adverse outcomes following the procedure. These results indicate that pancreas transplant recipients with a history of AUD should have enhanced monitoring in the areas of nutrition, the gastrointestinal system, and addiction.</p>","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of Second Primary Cancers in Melanoma Survivors: A Retrospective Hospital-Based Cohort Study from Two Romanian Referral Centres.","authors":"Salomea-Ruth Halmágyi, Loredana Ungureanu, Alina Florentina Vasilovici, Mihail-Alexandru Badea, Ioana-Irina Trufin, Adina Patricia Apostu, Adrian Ilie Pascu, Simona Corina Şenila","doi":"10.3390/medsci14040494","DOIUrl":"10.3390/medsci14040494","url":null,"abstract":"<p><strong>Background and objectives: </strong>Melanoma survivors may develop additional primary malignancies, but data from Eastern European hospital cohorts are scarce. We aimed to estimate the observed incidence of second primary cancers (SPCs) within a Romanian referral-centre cohort, identify associated factors, and explore the association of SPC occurrence with overall survival.</p><p><strong>Methods: </strong>We conducted a retrospective, hospital-based cohort study of 394 patients with histopathologically confirmed cutaneous melanoma followed at two referral centres in Cluj-Napoca. Additional malignancies were counted as new primaries only when clinical and/or histopathological documentation distinguished them from recurrence or metastasis. Incidence density was expressed per 1000 person-years. Multivariable logistic regression assessed age, sex, residence, and Breslow thickness. Fixed-covariate Cox and Kaplan-Meier analyses were considered exploratory because of immortal-time and competing-risk limitations.</p><p><strong>Results: </strong>Over 1848 person-years, 79 patients (20.1%) developed at least one SPC (131 events; observed incidence 70.9/1000 person-years), most frequently cutaneous (53.6/1000 person-years). SPC occurrence increased with age (Cochran-Armitage Z = 5.63, <i>p</i> < 0.001); the Kaplan-Meier complement estimate reached 20.7% at five years. Age independently predicted SPC (OR 1.86 per decade, <i>p</i> < 0.001), whereas greater Breslow thickness was inversely associated (OR 0.86, <i>p</i> = 0.008). Actinic keratosis showed a strong unadjusted association (OR 6.64, <i>p</i> < 0.001) but was not included in the adjusted model. The fixed-status Cox model showed lower mortality among patients with an SPC (HR 0.36, <i>p</i> < 0.001), a finding vulnerable to detection and immortal-time bias.</p><p><strong>Conclusions: </strong>SPCs were frequent in this hospital cohort and predominantly cutaneous. Older age was an independent predictor, while actinic keratosis was a strong unadjusted marker. Prospective, population-based validation is needed before surveillance intensity is individualised.</p>","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporomandibular Joint Abnormalities in Hemodialysis Patients: A Cross-Sectional Ultrasonographic Study from a Single Center in Italy.","authors":"Beatrice Maranini, Andrea Brunati, Marcello Govoni, Stefano Mandrioli, Manlio Galiè, Fabio Fabbian","doi":"10.3390/medsci14040492","DOIUrl":"10.3390/medsci14040492","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Temporomandibular joint (TMJ) abnormalities are a common finding in the general adult population, but they have been rarely investigated in people receiving chronic dialysis. The TMJ is a unique synovial joint that can be altered by either inflammatory or degenerative processes, both of which are amenable to ultrasound (US) assessment. The aim of this study was to describe the pattern of TMJ involvement in a cohort of hemodialysis patients using TMJ ultrasound (TMJ US). <b>Methods:</b> This cross-sectional, single-center study evaluated the clinical utility of TMJ US to detect inflammatory and degenerative changes in patients undergoing chronic hemodialysis and was carried out between June and December 2025. Demographic data, dialysis vintage, the Controlling Nutritional Status (CONUT) score and the Charlson Comorbidity Index (CCI) were collected and related to TMJ US findings and to bone-metabolism biomarkers (calcium, phosphate, parathyroid hormone). <b>Results:</b> 100 hemodialysis patients were included (65 male, 65%; mean age 71.6 ± 13.1 years). Comorbidity and undernutrition were frequent findings (CCI ≥ 4 in 63%; CONUT ≥ 3 in 68%). TMJ US revealed that degenerative indicators were more common than inflammatory ones: calcifications (36%), condylar irregularities (33%) and enthesophytes (25%) were the most prevalent degenerative findings, whereas joint effusion (16%), synovial hypertrophy (15%) and cartilage changes (15%) were the leading inflammatory findings; a positive power Doppler signal was rare (1%). Cortical/condylar irregularity was significantly more prevalent in patients with a dialysis vintage of less than 30 months (43.8% vs. 23.1%, <i>p</i> = 0.034), who also had lower serum calcium levels. No other TMJ US finding showed a significant association with age, sex, comorbidity burden, nutritional status, or bone-metabolism parameters on univariate. <b>Conclusions:</b> TMJ US demonstrated a substantial burden of subclinical degenerative and, to a lesser extent, inflammatory TMJ findings in this cohort of hemodialysis patients; none of these abnormalities were spontaneously reported as symptomatic, and their prevalence was independent of age, dialysis vintage, comorbidity, nutritional status and classical bone-metabolism parameters. These findings cannot be directly attributed to the dialysis/uremic environment rather than to age-related degeneration; they support the concept that the TMJ warrants further investigation as a potentially under-recognized target within the broader systemic metabolic derangement of end-stage kidney disease, and suggest that TMJ US is a feasible, accessible technique for detecting subclinical TMJ involvement in this population, pending confirmation of clinical utility in controlled studies.</p>","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motion as Medicine: Physical Activity, Joint Sensitivity, and Pain Management-A Narrative Review.","authors":"Luminita Labusca, Bogdan Puha, Bianca-Ana Dmour, Ilie Onu, Mihaela Camelia Tirnovanu, Ștefan-Dragoș Tîrnovanu, Awad Dmour","doi":"10.3390/medsci14040495","DOIUrl":"10.3390/medsci14040495","url":null,"abstract":"<p><strong>Background: </strong>Physical activity is widely recommended for preserving musculoskeletal health and managing osteoarthritis-related pain, although its benefits are commonly framed in terms of muscle strengthening, weight control, and physical performance. This narrative review aimed to examine movement more broadly as a physiological regulator of synovial joint homeostasis, sensory calibration, and functional adaptation.</p><p><strong>Methods: </strong>A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science from database inception to 1 February 2026. Experimental studies, observational studies, clinical trials, systematic reviews, meta-analyses, and selected narrative reviews addressing movement-responsive joint biology or pain regulation were considered. Evidence was synthesized across four interrelated domains: mechanical, fluidic, immune-metabolic, and sensory regulation.</p><p><strong>Results: </strong>The narrative synthesis indicates that the concept of the synovial joint as a dynamic mechano-fluidic organ in which cartilage, synovium, synovial fluid, capsule, subchondral bone, periarticular tissues, and sensory pathways interact continuously. Repeated physiological movement may promote synovial fluid exchange, lubrication, cartilage nutrition, hyaluronic acid and lubricin function, matrix turnover, anti-inflammatory signaling, proprioceptive control, and exercise-induced hypoalgesia. In contrast, inactivity and unloading may impair fluid dynamics, promote muscle inhibition, stiffness, inflammatory persistence, sensory deconditioning, and loss of function. Excessive or poorly distributed loading may also disrupt homeostasis through matrix injury, inflammation, fatigue, and nociceptive sensitization. These findings informed the proposed adaptive loading window, a hypothesis-generating conceptual framework rather than a clinically validated threshold, describing the dynamic range of movement within which joint function and pain regulation may be supported without sustained tissue or symptom aggravation.</p><p><strong>Conclusions: </strong>Movement should be viewed not only as a therapeutic intervention, but also as a continuous regulator of joint biology and perception. Its clinical value may depend on identifying an individualized loading range that supports adaptation, function, and confidence in movement while avoiding both underloading and overload.</p>","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Transcriptional Programs Controlled by <i>NR5A1</i> and β-Catenin in Adrenocortical Carcinoma.","authors":"João Carlos Degraf Muzzi, Bonald Cavalcante Figueiredo, Jean Silva de Souza Resende, Igor Samesima Giner, Mauro Antônio Alves Castro, Enzo Lalli","doi":"10.3390/medsci14040493","DOIUrl":"10.3390/medsci14040493","url":null,"abstract":"<p><strong>Background/objectives: </strong>Adrenocortical carcinoma (ACC) is a rare malignancy in which overexpression of steroidogenic factor-1 (SF-1/<i>NR5A1</i>) and aberrant activation of canonical Wnt/β-catenin signaling are important oncogenic events. However, the extent to which these regulatory axes converge or interact at the transcriptional level remains unclear. We investigated their relationship using bulk transcriptomic and regulatory-network approaches.</p><p><strong>Methods: </strong>Regulatory network inference using RTN/ARACNe was applied to the TCGA-ACC cohort. <i>NR5A1</i> and β-catenin-associated TCF/LEF regulon activities were evaluated in perturbation datasets and tested for associations with CpG island methylator phenotype (CIMP), overall survival, and gene-level interaction effects. Candidate modulators of <i>NR5A1</i> activity were assessed using the MINDy algorithm. The effects of cBAF inhibition on <i>NR5A1</i> regulon activity were also evaluated in H295R and CU-ACC1 cells.</p><p><strong>Results: </strong><i>NR5A1</i> knockdown repressed steroidogenic pathways, whereas β-catenin knockdown predominantly suppressed Wnt/β-catenin signaling. In TCGA-ACC, <i>NR5A1</i> regulon activity was associated with CIMP-high status and overall survival. In contrast, β-catenin-related regulons were not significantly associated with CIMP-high status after adjustment for <i>NR5A1</i> activity, and no significant multiplicative interaction effects were identified. Fewer than 3% of protein-coding genes showed improved fit in models including <i>NR5A1</i> × TCF/LEF interaction terms, without enrichment for steroidogenic or Wnt/β-catenin-related pathways. <i>CTNNB1</i> was identified as a statistically significant but low-ranking positive modulator of <i>NR5A1</i> activity, whereas <i>CTNNBIP1</i> was a top-decile negative modulator. cBAF inhibition was associated with <i>NR5A1</i> regulon repression in both cell models.</p><p><strong>Conclusions: </strong>These findings indicate limited detectable global transcriptional convergence between <i>NR5A1</i> and canonical β-catenin-related regulons in the evaluated bulk transcriptomic frameworks. Potential relationships between these pathways may depend on more localized, chromatin-dependent, protein-level, or context-specific regulatory mechanisms. <i>NR5A1</i> regulon activity showed more consistent associations with CIMP-high status and clinical outcome than the β-catenin/TCF-LEF regulons in the evaluated TCGA-ACC models. The modulation patterns associated with <i>CTNNB1</i> and <i>CTNNBIP1</i>, together with the repression of NR5A1 regulon activity following cBAF inhibition, raise the possibility that NR5A1 acts as a context-dependent regulatory node connecting oncogenic signaling and chromatin-remodeling mechanisms in ACC. These findings support further investigation into the role of chromatin-remodeling complexes in sustaining NR5A1-driven transcriptional programs in ACC.</p>","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Porcine Model of Pulmonary Ischemia-Reperfusion Injury Relevant to Post-Esophagectomy Acute Respiratory Distress Syndrome.","authors":"Mohammadreza Hafezi, Arash Saffari, Elias Khajeh, Christa Flechtenmacher, Christoph Lichtenstern, Arianeb Mehrabi, Camelia Garoussi","doi":"10.3390/medsci14040490","DOIUrl":"10.3390/medsci14040490","url":null,"abstract":"<p><p><b>Background</b>: Acute respiratory distress syndrome (ARDS) occurs in 20-40% of patients following esophagectomy and is associated with substantial postoperative morbidity and mortality. A major contributor to postoperative ARDS is pulmonary ischemia-reperfusion injury (IRI); however, the role of IRI in ARDS following esophagectomy is not adequately addressed in current experimental models. In this study, we established a large animal model of pulmonary IRI that reproduces key physiological, inflammatory, and histopathological features of pulmonary ischemia-reperfusion-induced acute lung injury relevant to postoperative ARDS after esophagectomy. <b>Methods</b>: Sequential pulmonary ischemia-reperfusion injury was induced in ten anesthetized Landrace pigs using unilateral hilar inflow occlusion. Right lung ischemia was achieved by clamping the hilar inflow for three hours, followed by reperfusion. Subsequently, the left lung underwent two hours of ischemia. Hemodynamic, respiratory, and inflammatory parameters were continuously monitored throughout the experiment. Blood samples were collected to assess leukocyte counts and circulating inflammatory cytokines, including tumor necrosis factor-α and interleukin-6. Lung tissue samples were obtained for histopathological evaluation. <b>Results</b>: ARDS-like lung injury was successfully induced in all animals, with PaO₂/FiO₂ ratios falling below 200 mmHg during the predefined reperfusion observation period. Lung compliance decreased by approximately 50% after ischemia and further declined following reperfusion. Progressive leukocyte elevation and elevated tumor necrosis factor-α and interleukin-6 levels were observed, indicating a systemic inflammatory response. Hallmark features of ARDS were histologically confirmed, including intra-alveolar hemorrhage, interstitial and perivascular edema, and neutrophil infiltration. <b>Conclusions</b>: This porcine model reproduces key physiological, inflammatory, and histopathological features consistent with pulmonary ischemia-reperfusion-induced ARDS-like lung injury. Although it does not reproduce the complete clinical syndrome of post-esophagectomy ARDS, it provides a clinically relevant translational platform for investigating pulmonary ischemia-reperfusion injury and evaluating potential preventive and therapeutic strategies.</p>","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De Novo Actionable Genomic Alterations in High-Grade Pulmonary Neuroendocrine Carcinomas: Therapeutic Implications of Targeted Treatment.","authors":"Ari Raphael, Nir Peled, Roni Gillis, Hovav Nechushtan, Walid Shalata, Elizabeth Dudnik","doi":"10.3390/medsci14040491","DOIUrl":"10.3390/medsci14040491","url":null,"abstract":"<p><strong>Background/objectives: </strong>High-grade pulmonary neuroendocrine carcinoma (HGNEC-L), including SCLC and LCNEC, is aggressive and usually treated according to SCLC paradigms. The clinical relevance of de novo actionable genomic alterations (AGA) remains incompletely defined.</p><p><strong>Methods: </strong>We performed a retrospective multicenter analysis of advanced HGNEC-L with de novo AGA, assessing rwORR, rwDCR, rwPFS, and OS. Findings were contextualized by a structured literature review and exploratory pooled reconstructed-IPD Cox analysis, with targeted therapy modeled as a source-stratified time-dependent covariate.</p><p><strong>Results: </strong>Ten patients from four tertiary centers were included. Most were women (90.0%) and never-smokers (70.0%); histology was LCNEC in 60.0% and SCLC/mixed SCLC in 40.0%. AGA included <i>EGFR</i> mutations (<i>n</i> = 6), <i>EML4</i>-<i>ALK</i> fusions (<i>n</i> = 2), <i>KIF5B</i>-<i>RET</i> fusion (<i>n</i> = 1), and <i>KRAS</i> p.G12C (<i>n</i> = 1). Targeted-containing regimens achieved rwORR 77.8%, rwDCR 88.9%, and median rwPFS 9.0 months (95% CI, 2.0-18.7), as opposed to 3.7 months for ICI-containing regimens and 2.6 months for chemotherapy alone. Median OS for the entire cohort was 17.2 months (95% CI, 4.8-36.3); overall survival did not differ significantly between patients with and without targeted-containing exposure (19.0 vs. 17.2 months; log-rank <i>p</i> = 0.50). In pooled reconstructed-IPD time-dependent Cox analysis (72 patients, 39 deaths), targeted therapy showed a favorable but non-significant OS association (HR, 0.89; 95% CI, 0.31-2.56; <i>p</i> = 0.831), maintained directionally in the age/sex-adjusted subset (HR, 0.54; 95% CI, 0.16-1.77; <i>p</i> = 0.306).</p><p><strong>Conclusions: </strong>De novo AGA-positive HGNEC-L represents a clinically relevant subgroup with potential sensitivity to genotype-matched targeted therapy, supporting comprehensive molecular profiling and early targeted therapy consideration.</p>","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective Neuronal Vulnerability to Alpha-Synuclein Pathology in Parkinson's Disease: A Critical Review of Mechanistic Rationale and Biomarker Stratification.","authors":"Livia Livinț-Popa, Andreea Nicolaie, Alexandra Mastaleru, Ștefan Socolov, Mihaela Mitrea, Gabriela Popescu, Thomas Gabriel Schreiner, Roxana Covali, Laura-Elena Cucu, Lucia Corina Dima-Cozma, Romica Sebastian Cozma, Alin Ciubotaru, Raluca Olariu, Cosmin Mihai Ciurumelea, Liana Rada Borza, Albert Vamanu","doi":"10.3390/medsci14040489","DOIUrl":"10.3390/medsci14040489","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Parkinson's disease (PD) exhibits remarkable clinical heterogeneity, with substantial variability in motor progression, cognitive decline, and the development of non-motor manifestations. Although the propagation of pathological alpha-synuclein is considered a central mechanism of PD pathogenesis, it does not fully explain why specific neuronal populations demonstrate differential susceptibility to degeneration. Emerging evidence suggests that selective neuronal vulnerability is determined by the interaction of multiple biological domains, including calcium homeostasis, mitochondrial bioenergetic capacity, lysosomal function, axonal architecture, synaptic resilience, and neuroinflammatory responses. &lt;b&gt;Methods:&lt;/b&gt; A structured critical narrative review was performed using PubMed/MEDLINE, Scopus, and Web of Science databases from inception to March 2025. Only full-text articles published in English and peer-reviewed journals were included. Evidence from human post-mortem studies, genetic analyses, biomarker investigations, experimental models, induced pluripotent stem cell studies, and longitudinal clinical cohorts were systematically synthesised to identify the principal mechanisms underlying selective neuronal vulnerability and their potential translational application. To capture evidence published after this electronic cut-off, a supplementary manual review of reference lists of key systematic reviews and landmark publications was conducted up to the date of manuscript submission; references with 2025 or 2026 publication dates entered through this supplementary process. The supplementary manual review was conducted as a targeted scan of reference lists of key systematic reviews and high-impact publications identified during the primary search and did not constitute an independent updated systematic search. &lt;b&gt;Results:&lt;/b&gt; Five interconnected biological domains emerged as key determinants of neuronal susceptibility in PD: calcium-mediated metabolic stress associated with autonomous pacemaker activity, mitochondrial dysfunction and energetic failure, impaired lysosomal degradation and proteostasis (particularly involving the GBA1-glucocerebrosidase pathway), vulnerability related to extensive axonal and synaptic architecture, and neuroinflammatory mechanisms involving microglial and astrocytic activation. Among these domains, the lysosomal pathway currently provides the strongest translational link between molecular mechanisms and measurable clinical outcomes. Based on this integrated framework, we propose the Parkinson's Vulnerability Index (PVI), a hypothesis-generating multidimensional model combining genetic, enzymatic, alpha-synuclein seeding, cognitive, olfactory, and neuroimaging biomarkers to facilitate biological stratification and improve the design of mechanism-targeted clinical trials. &lt;b&gt;Conclusions:&lt;/b&gt; Selective neuronal vulnerability provides a complementary framework to alpha-synuclein propagation model","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"See the (In)Visible: Infrared Thermography for Characterizing Thermal Patterns Associated with Peripheral Arterial Disease and Diabetes Mellitus.","authors":"Slobodan Tanasković, Aleksandra Milačić, Nikola Ružić, Stefan Graovac, Jovan Petrović, Milovan Bojić, Bojan Božić","doi":"10.3390/medsci14040487","DOIUrl":"10.3390/medsci14040487","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Peripheral arterial disease (PAD) and diabetes mellitus (DM) may produce different and overlapping plantar thermal patterns. This study descriptively characterized whole-foot temperature-distribution patterns in clinically defined healthy, PAD, DM, and combined PAD_DM cohorts. <b>Methods</b>: This single-center, exploratory, cross-sectional observational study included 73 participants: healthy controls (<i>n</i> = 21), isolated PAD (<i>n</i> = 13), isolated DM (<i>n</i> = 19), and combined PAD_DM (<i>n</i> = 20). Right- and left-foot temperature distributions were processed separately for each participant and interpreted as one paired bilateral thermal footprint using patient-level histograms, representative bilateral kernel density estimation (KDE) profiles, and a cohort-derived deterministic rule-based model. The model was developed from the present cohort and was not evaluated as an independent diagnostic classifier. Results: Among healthy controls, 11 of 21 participants (52.4%) were assigned to healthy and 8 of 21 (38.1%) to borderline healthy categories. In the DM cohort, 7 of 19 participants (36.8%) were assigned to DM, 3 of 19 (15.8%) to borderline healthy/suspected DM or controlled DM, 3 of 19 (15.8%) to DM suspected PAD, and 5 of 19 (26.3%) to PAD_DM. In the combined PAD_DM cohort, 15 of 20 participants (75.0%) were assigned to PAD_DM. The isolated PAD cohort was the most heterogeneous: 6 of 13 participants (46.2%) were assigned to PAD_DM, while none were assigned to the isolated PAD output. <b>Conclusions</b>: This exploratory, cross-sectional study demonstrated that whole-foot plantar temperature distributions can descriptively characterize differences among healthy individuals, patients with isolated DM, and those with combined PAD and DM. While healthy controls generally demonstrated symmetric thermal footprints, the DM cohort frequently exhibited globally elevated and compact temperature-distribution profiles, while mixed asymmetric patterns were common in participants with combined PAD and DM. In contrast, the isolated PAD cohort was characterized by pronounced thermal heterogeneity.</p>","PeriodicalId":74152,"journal":{"name":"Medical sciences (Basel, Switzerland)","volume":"14 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13515561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}