Med最新文献

{"title":"Antibody-drug conjugates: Current challenges and innovative solutions for precision cancer therapy.","authors":"Xingyu Zhou, Yanjie Han, Yuan Fang, Peiwen Ma, Jiawei Zhou, Yale Jiang, Shujun Xing, Qiyu Tang, Yiru Hou, Shuhang Wang, Ning Li","doi":"10.1016/j.medj.2025.100849","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100849","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) have advanced cancer therapy by combining antibody specificity with cytotoxic potency. However, clinical experience has revealed challenges limiting their efficacy and safety. This review addresses key questions in ADC development and corresponding optimization strategies. It discusses the relationship between target antigen expression and clinical response and the role of antibodies beyond targeting. Enhancing ADC distribution via bispecific targeting and probody masking is summarized. Traditional assumptions in linker design, such as favoring maximum stability, are re-evaluated to improve clinical outcomes. Innovations in linker chemistry encompass tumor microenvironment-responsive release mechanisms and bioorthogonal reactions. Emerging payload strategies like immune-stimulating ADCs (ISACs) and degrader-antibody conjugates (DACs) expand therapeutic possibilities but introduce new safety challenges. Ultimately, merely increasing ADC structural complexity is insufficient. Understanding tumor delivery barriers and bridging preclinical-clinical gaps will be vital to fully realize the potential of ADCs in precision oncology.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100849"},"PeriodicalIF":11.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial homeostasis and dysbiosis in physiological and pathological skin.","authors":"Yuyang Gan, Jiarui Zhang, Fangfang Qi, Elizabeth A Grice, Luis A Garza, Gaofeng Wang","doi":"10.1016/j.medj.2025.100847","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100847","url":null,"abstract":"<p><p>The human skin serves as a major reservoir of mutualists that penetrate skin appendages and contribute to skin development, barrier repair, appendage health, and wound healing. The skin microbiota exhibits significant shifts in community composition in response to pathological skin conditions, such as impaired barrier integrity, follicular-sebaceous-related diseases, and wound healing, which contribute to the progression of skin diseases. Crosstalk among bacteria, fungi, and viruses and their collective effects on the host are critical determinants of skin health and disease. This review discusses the changes in the skin microbiota under both physiological and pathological conditions, with a particular focus on bacterial strains, virulence factors, and pathogenic genes, and their impact on host outcomes. Additionally, we preview the emerging clinical applications of specific bacterial strains, microbial competition, fungal cooperation, phage therapy, and engineered microbial interventions.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100847"},"PeriodicalIF":11.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A case of H10N3 avian influenza in a young woman.","authors":"Jing Wei, Ping Cen, Dewu Bi","doi":"10.1016/j.medj.2025.100845","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100845","url":null,"abstract":"<p><strong>Background: </strong>Avian influenza viruses, frequently identified in wild waterfowl and poultry, have occasionally been transmitted to humans, causing severe respiratory diseases. This report covers the fourth case of a human contracting the H10N3 subtype of avian influenza virus.</p><p><strong>Methods: </strong>A case of novel avian influenza virus subtype H10N3 was detected in a female patient hospitalized in Nanning, China, in December 2024. Blood, feces, urine, and bronchoalveolar lavage fluid were collected from the patient for medical analysis during the hospitalization.</p><p><strong>Findings: </strong>A case of novel avian influenza virus subtype H10N3 was detected in a female patient hospitalized in Nanning, China, in December 2024. She also had a history of exposure to live poultry. This case represents the fourth documented instance of H10N3 infection in humans. She was treated with a combination of baloxavir marboxil and oseltamivir. She exhibited extensive lung lesions. Additionally, she presented complicating factors, including secondary infection, pneumothorax, and numbness in her feet. She recovered and was discharged on March 27, 2025, amid comprehensive supportive care, which included therapy with baloxavir marboxil, oseltamivir, fluconazole, tigecycline, amikacin, extracorporeal membrane oxygenation, and rehabilitation therapy.</p><p><strong>Conclusions: </strong>The virus was effectively cleared by the combination therapies. The internal genes of the H10N3 virus in this patient were highly homologous to the corresponding genes from the A/Yunnan/2024 virus (GenBank accession numbers, hemagglutinin [HA] [GenBank: PP555669] and PB-2 [GenBank: PP555666]).</p><p><strong>Funding: </strong>This work was funded by the Fourth People's Hospital of Nanning - Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) Clinical Treatment Center of Guangxi (Nanning).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100845"},"PeriodicalIF":11.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From poor prognosis to precision promise: Clinical trials targeting BRAF-mutant metastatic colorectal cancer.","authors":"Hironaga Satake, Hideaki Bando, Shin Kobayashi, Takayuki Yoshino","doi":"10.1016/j.medj.2025.100811","DOIUrl":"10.1016/j.medj.2025.100811","url":null,"abstract":"<p><p>BRAF V600E-mutant metastatic colorectal cancer, a rare subtype with poor prognosis, has historically carried limited treatment options. Evolving approaches, including targeted combinations and investigational immunotherapy-based strategies, offer potential to improve outcomes. We highlight the evolving treatment landscape and emerging strategies for this molecularly distinct subtype.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 9","pages":"100811"},"PeriodicalIF":11.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis uncovers pathways associated with mortality.","authors":"Thanh Hoang Nhat Le, Kirsten C J van Abeelen, Edwin Ardiansyah, Julian Avila-Pacheco, Sofiati Dian, Gesa Carstens, Lara Schramke, Hoang Thanh Hai, Tran Binh Minh Nguyen, Thai Minh Triet, Amy Deik, Jesse Krejci, Jeff Pruyne, Lucas Dailey, Bachti Alisjahbana, Mihai G Netea, Riwanti Estiasari, Trinh Thi Bich Tram, Joseph Donovan, Dorothee Heemskerk, Thi Hong Chau Tran, Nguyen Duc Bang, Ahmad Rizal Ganiem, Raph L Hamers, Rovina Ruslami, Darma Imran, Kartika Maharani, Vinod Kumar, Reinout van Crevel, Guy Thwaites, Clary B Clish, Nguyen Thuy Thuong Thuong, Arjan van Laarhoven","doi":"10.1016/j.medj.2025.100703","DOIUrl":"10.1016/j.medj.2025.100703","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of cerebrospinal fluid (CSF) tryptophan metabolism contributes to the high mortality of tuberculous meningitis (TBM). We aimed to identify novel metabolic pathways associated with TBM mortality through untargeted metabolome-wide analysis.</p><p><strong>Methods: </strong>We measured 619 metabolites using untargeted liquid chromatography-mass spectrometry in pre-treatment CSF from adults with TBM from Indonesia (n = 388, 34 HIV positive) and Vietnam (n = 679, 250 HIV positive). Sixty-day mortality was modeled using Cox regression, adjusting for age and HIV status. Metabolites were ranked in a screening subset (n = 194, Indonesia) and validated in the same cohort (n = 194) and externally (n = 679, Vietnam). Secondary analysis included variable selection, clustering to classify associated metabolites into subgroups, comparison with non-infectious controls, and correlation with patient characteristics, CSF cytokines, CSF protein, and serum metabolite concentrations.</p><p><strong>Findings: </strong>Sixty-day mortality was 21.6% and was associated with the concentration of 10 CSF metabolites, including tryptophan. The strongest association was with 3-hydroxyoctanoate (FA 8:0;3OH), part of a cluster of hydroxylated fatty acids also including hydroxy-isocaproate (FA 6:0;OH), hydroxyisobutyrate (FA 4:0;OH), and C4-OH-carnitine. These fatty acids correlated weakly with CSF tumor necrosis factor alpha, interleukin-6 (IL-6), leukocyte counts, bacterial load, and CSF protein. Mediation analysis showed that the variation in fatty acids was linked directly to mortality rather than through disease severity.</p><p><strong>Conclusion: </strong>We identified and validated nine new metabolites associated with TBM mortality, independent of HIV status, disease severity, and tryptophan. These metabolites suggest that altered fatty acid β-oxidation is linked to TBM-associated mortality. Interventions targeting cerebral fatty acid metabolism may improve survival of TBM.</p><p><strong>Funding: </strong>National Institute of Health; Wellcome Trust, UK.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100703"},"PeriodicalIF":11.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of low- versus high-dose-LSD-assisted therapy in patients with major depression: A randomized trial.","authors":"Felix Müller, Hannes Zaczek, Anna M Becker, Laura Ley, Stefan Borgwardt, Joyce Santos de Jesus, Nico Loh, Jan Kohut, Mathias Auernig, Christopher Boehlke, Matthias E Liechti","doi":"10.1016/j.medj.2025.100725","DOIUrl":"10.1016/j.medj.2025.100725","url":null,"abstract":"<p><strong>Background: </strong>This trial aimed to assess the efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with moderate-to-severe major depressive disorder.</p><p><strong>Methods: </strong>This was a randomized, parallel, double-blind, low-dose controlled trial (Clinicaltrials.gov: NCT03866252). Patients were randomly assigned in a 1:1 ratio to receive supportive psychotherapy and either 100 μg + 200 μg LSD or 25 μg + 25 μg LSD in two dosing sessions. The primary endpoints were the changes in scores on the Inventory of Depressive Symptomatology, in the Clinician-Rated (IDS-C) version (assessed by the treating therapist) and the Self-Rated (IDS-SR) version, from baseline to 2 weeks after the second administration. The IDS scores were also assessed 6 and 12 weeks after the second administration.</p><p><strong>Findings: </strong>Thirty-one patients were randomized to the low-dose group, and 30 were randomized to the high-dose group. At the primary endpoint, least-squares mean change (LSM) in IDS-SR scores was -3.9 in the low-dose and -11.8 in the high-dose group (difference: -7.9; 95% CI, -16.0 to 0.3; effect size: -0.5; p = 0.059). LSM in IDS-C scores was -3.6 in the low-dose and -12.9 in the high-dose group (difference: -9.2; CI, -17.1 to -1.3; effect size: -0.6; p = 0.023; corrected <0.05). However, significance was not reached after adjusting for baseline depression scores (p = 0.086). Both outcomes remained numerically consistent up to the final follow-up at 12 weeks. Adverse events were comparable between groups.</p><p><strong>Conclusions: </strong>The findings of this exploratory study support further investigation of LSD-assisted therapy in depression in a larger phase 3 trial.</p><p><strong>Funding: </strong>Gertrud Thalmann Fund for depression research.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100725"},"PeriodicalIF":11.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASPEN: Brensocatib's role in advancing bronchiectasis management in adults through neutrophil serine protease inhibition.","authors":"Hannah E O'Farrell, Anne B Chang","doi":"10.1016/j.medj.2025.100801","DOIUrl":"10.1016/j.medj.2025.100801","url":null,"abstract":"<p><p>ASPEN demonstrated that 52 weeks of once-daily brensocatib (10 mg or 25 mg), compared to placebo, significantly reduced pulmonary exacerbations among adults with bronchiectasis.¹ Additionally, time to the first exacerbation was significantly longer at the end of the 52-week treatment. Further, the decline in forced expiratory volume in 1 s was significantly lower in the 25-mg group, suggesting that brensocatib has a disease-modifying effect.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 9","pages":"100801"},"PeriodicalIF":11.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chimeric antigen receptor T cells in treatment-refractory DAGLA antibody-associated encephalitis.","authors":"Tobias Hegelmaier, Denise Wolleschak, Vaia Pappa, Jonathan Wickel, Christian Geis, Ramona Miske, Alexander Duscha, Christiane Desel, Martin Böttcher, Alexandra Neyazi, Simon Faissner, Jeremias Motte, Ralf Gold, Dominic Borie, Georg Schett, Dimitrios Mougiakakos, Aiden Haghikia","doi":"10.1016/j.medj.2025.100776","DOIUrl":"10.1016/j.medj.2025.100776","url":null,"abstract":"<p><strong>Background: </strong>Autoimmune encephalitides are a heterogeneous group of autoantibody-associated central nervous system disorders. The clinical course of autoimmune encephalitides can be life threatening, and treatment can be challenging.</p><p><strong>Objective: </strong>This report describes a case of treatment-refractory, anti-diacylglycerol lipase alpha (DAGLA) antibody-associated autoimmune encephalitis successfully treated with chimeric antigen receptor (CAR) T cells.</p><p><strong>Methods: </strong>Treatment was done by single intravenous infusion of fully human, second-generation CAR T cells (KYV-101) targeting CD19 and depleting B cells. Clinical response was measured by International Cooperative Ataxia Rating Scale and Clinical Assessment Scale in Autoimmune Encephalitis scores. Autoantibodies against DAGLA were measured by a recombinant cell-based indirect immunofluorescence assay in the serum and the cerebrospinal fluid and confirmed by staining of primary murine neurons and brain sections.</p><p><strong>Findings: </strong>A 36-year-old man developed rapidly progressing generalized myoclonus, cerebellar head tremor, vertical binocular nystagmus, and tetraparesis despite treatment with pulse glucocorticoid therapy, plasma exchange, and rituximab. Anti-DAGLA antibodies were positive in the indirect immunofluorescence assay, in serum and cerebrospinal fluid, and reacted with neurons and brain sections. Due to his severe clinical condition and treatment refractoriness, the patient received a single infusion of autologous anti-CD19 CAR T cells. Clinical scores improved significantly after treatment, and anti-DAGLA antibody levels in serum and cerebrospinal fluid diminished. Oligoclonal bands in the cerebrospinal fluid were initially positive and became negative after CAR T cell therapy.</p><p><strong>Conclusion: </strong>The report highlights the therapeutic potential of anti-CD19 CAR T cell therapy in severe, treatment-refractory autoimmune encephalitis.</p><p><strong>Funding: </strong>There was no external funding for the treatment or the data generated.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100776"},"PeriodicalIF":11.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144709204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Switching ahead of progression: Insights from the SERENA-6 trial on targeting emerging ESR1 mutations in advanced HR+/HER2- breast cancer.","authors":"Pablo Tolosa, Juan Montes, Eva Ciruelos","doi":"10.1016/j.medj.2025.100781","DOIUrl":"10.1016/j.medj.2025.100781","url":null,"abstract":"<p><p>The phase 3 SERENA-6 trial showed that, in ER+/HER2- advanced breast cancer patients with emerging ESR1 mutations in ctDNA during aromatase inhibitor (AI) plus CDK4/6 inhibitor therapy, switching the AI to camizestrant significantly improved progression-free survival and delayed quality-of-life (QoL) deterioration.¹ However, the clinical utility of early ctDNA-guided switching remains unconfirmed, as secondary endpoints (including PFS2 and overall survival) are still immature.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 9","pages":"100781"},"PeriodicalIF":11.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ENERGIZE trial: Is mitapivat ready to take center stage in NTDT management?","authors":"Mattia Algeri, Franco Locatelli","doi":"10.1016/j.medj.2025.100844","DOIUrl":"10.1016/j.medj.2025.100844","url":null,"abstract":"<p><p>The ENERGIZE trial¹ represents a step forward in managing non-transfusion-dependent thalassemia, demonstrating that mitapivat, a novel pyruvate kinase activator, may rapidly increase hemoglobin levels and reduce patient-reported fatigue. Efficacy was shown in both α- and β-thalassemia subtypes. Longer follow-up is required to document mitapivat-sustained effects and impact on disease-related complications.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 9","pages":"100844"},"PeriodicalIF":11.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}