Med最新文献

{"title":"Ultra-rapid droplet digital PCR enables intraoperative tumor quantification.","authors":"Zachary R Murphy, Emilia C Bianchini, Andrew Smith, Lisa I Körner, Teresa Russell, David Reinecke, Nader Maarouf, Yuxiu Wang, John G Golfinos, Alexandra M Miller, Matija Snuderl, Daniel A Orringer, Gilad D Evrony","doi":"10.1016/j.medj.2025.100604","DOIUrl":"10.1016/j.medj.2025.100604","url":null,"abstract":"<p><strong>Background: </strong>The diagnosis and treatment of tumors often depend on molecular-genetic data. However, rapid and iterative access to molecular data is not currently feasible during surgery, complicating intraoperative diagnosis and precluding measurement of tumor cell burdens at surgical margins to guide resections.</p><p><strong>Methods: </strong>Here, we introduce Ultra-Rapid droplet digital PCR (UR-ddPCR), a technology that achieves the fastest measurement, to date, of mutation burdens in tissue samples, from tissue to result in 15 min. Our workflow substantially reduces the time from tissue biopsy to molecular diagnosis and provides a highly accurate means of quantifying residual tumor infiltration at surgical margins.</p><p><strong>Findings: </strong>We demonstrate UR-ddPCR assays for the IDH1 R132H and BRAF V600E clonal mutations that are present in many low-grade gliomas and melanomas, respectively, and whose intraoperative detection would shape surgical decision-making. We illustrate the clinical feasibility of UR-ddPCR by performing it intraoperatively for 22 brain tumor cases, and we further combine UR-ddPCR tumor cell percentage measurements with UR-stimulated Raman histology intraoperatively to estimate tumor cell densities ranging from >1,300 tumor cells/mm² within a tumor core to <5 tumor cells/mm² at tumor margins. UR-ddPCR measurements were virtually identical to standard ddPCR measurements performed on the same samples (R² = 0.995).</p><p><strong>Conclusions: </strong>The technology and workflow developed here enable intraoperative molecular-genetic assays with unprecedented speed and sensitivity. We anticipate that our method will facilitate novel point-of-care diagnostics and molecularly guided surgeries that improve clinical outcomes.</p><p><strong>Funding: </strong>This study was funded by the National Institutes of Health and NYU Grossman School of Medicine institutional funds. Reagents and instruments were provided in kind by Bio-Rad.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100604"},"PeriodicalIF":12.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516869","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":"Humoral signatures of Caspr2-antibody spectrum disorder track with clinical phenotypes and outcomes.","authors":"Paula Terroba-Navajas, Marianna Spatola, Omar Chuquisana, Bastien Joubert, Juna M de Vries, Andre Dik, Laura Marmolejo, Friederike Jönsson, Gordan Lauc, Stjepana Kovac, Harald Prüss, Heinz Wiendl, Maarten J Titulaer, Jérôme Honnorat, Jan D Lünemann","doi":"10.1016/j.medj.2024.09.004","DOIUrl":"10.1016/j.medj.2024.09.004","url":null,"abstract":"<p><strong>Background: </strong>Immunoglobulin (Ig) G4 auto-antibodies (Abs) against contactin-associated protein-like 2 (Caspr2), a transmembrane cell adhesion protein expressed in the central and peripheral nervous system, are found in patients with a broad spectrum of neurological symptoms. While the adoptive transfer of Caspr2-specific IgG induces brain pathology in susceptible rodents, the mechanisms by which Caspr2-Abs mediate neuronal dysfunction and translate into clinical syndromes are incompletely understood.</p><p><strong>Methods: </strong>We use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral biosignatures in patients with Caspr2-Ab-associated neurological syndromes.</p><p><strong>Findings: </strong>We identify two signatures strongly associated with two major clinical phenotypes, limbic encephalitis (LE) and predominant peripheral nerve hyperexcitability without LE (non-LE). Caspr2-IgG Fc-driven pro-inflammatory features, characterized by increased binding affinities for activating Fcγ receptors (FcγRs) and C1q, along with a higher prevalence of IgG1-class Abs, in addition to IgG4, are strongly associated with LE. Both the occurrence of Caspr2-specific IgG1 and higher serum levels of interleukin (IL)-6 and IL-15, along with increased concentrations of biomarkers reflecting neuronal damage and glial cell activation, are associated with poorer clinical outcomes at 1-year follow-up.</p><p><strong>Conclusions: </strong>The presence of IgG1 isotypes and Fc-mediated effector functions control the pathogenicity of Caspr2-specific Abs to induce LE. Biologics targeting FcR function might potentially restrain Caspr2-Ab-induced pathology and improve clinical outcomes.</p><p><strong>Funding: </strong>This study was funded by a German-French joint research program supported by the German Research Foundation (DFG) and the Agence Nationale de la Recherche (ANR) and by the Interdisciplinary Centre for Clinical Research (IZKF) Münster.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100515"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406970","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":"Oral SERDs: Transforming the treatment of advanced breast cancer-Insights from EMBER-3.","authors":"Manuel Alva-Bianchi, Rodrigo Sánchez-Bayona, Eva Ciruelos","doi":"10.1016/j.medj.2025.100602","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100602","url":null,"abstract":"<p><p>The phase 3 EMBER-3 trial¹ demonstrated that when compared to standard therapy, imlunestrant improved progression-free survival (PFS) in advanced ER+/HER2- breast cancer with ESR1 mutations. When combined with abemaciclib, it significantly improved PFS for the entire population. However, the absence of a biomarker-based control group limits broader conclusions, highlighting the need for trials incorporating specific standards in ER+/HER2- breast cancer.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 2","pages":"100602"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426320","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":"On-treatment PSA kinetics as a potential biomarker: Guiding personalized treatment in metastatic hormone-sensitive prostate cancer.","authors":"Zeynep Irem Ozay, Chadi Hage Chehade, Neeraj Agarwal","doi":"10.1016/j.medj.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.011","url":null,"abstract":"<p><p>In this issue of Med, Bian et al. present a post-hoc analysis of the phase 3 CHART trial investigating rezvilutamide in the metastatic hormone-sensitive prostate cancer setting.¹ They show that patients achieving a deep PSA response at six months had significantly improved outcomes. These findings could impact patient counseling and support the potential role of on-treatment PSA kinetics in personalizing therapy.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 2","pages":"100534"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426316","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":"Targeting HLA-E-overexpressing cancers with a NKG2A/C switch receptor.","authors":"Michelle Sætersmoen, Ivan S Kotchetkov, Lamberto Torralba-Raga, Jorge Mansilla-Soto, Ebba Sohlberg, Silje Zandstra Krokeide, Quirin Hammer, Michel Sadelain, Karl-Johan Malmberg","doi":"10.1016/j.medj.2024.09.010","DOIUrl":"10.1016/j.medj.2024.09.010","url":null,"abstract":"<p><strong>Background: </strong>Human leukocyte antigen (HLA)-E is overexpressed by a large proportion of solid tumors, including malignant glioblastoma, and acts as a major checkpoint for NKG2A⁺ CD8⁺ T cells and natural killer (NK) cells in the tumor microenvironment and circulation. This axis operates alongside PD-L1 to inhibit effector responses by T and NK cells.</p><p><strong>Methods: </strong>We engineered a chimeric A/C switch receptor, combining the high HLA-E binding affinity of the NKG2A receptor ectodomain with the activating signaling of the NKG2C receptor endodomain. The cytotoxic function of A/C switch-transduced NK and T cells was evaluated against tumor cells with varying levels of HLA-E expression. In vivo efficacy was assessed using a xenograft model of glioblastoma.</p><p><strong>Findings: </strong>A/C switch-transduced NK and T cells exhibited superior and specific cytotoxicity against tumor cells with medium to high HLA-E expression. A/C switch-expressing human T cells demonstrated enhanced anti-tumor function in a glioblastoma xenograft model. The activity of the modified T cells was governed by an equilibrium between A/C switch levels and HLA-E expression, creating a therapeutic window to minimize on-target, off-tumor toxicities. Normal cells remained insensitive to A/C switch T cells, even after interferon (IFN)-γ pretreatment to induce HLA-E expression.</p><p><strong>Conclusions: </strong>The A/C switch receptor effectively targets tumor cells expressing high levels of HLA-E, either alone or in combination with other engineered specificities, to overcome the suppressive NKG2A/HLA-E checkpoint. This approach offers a promising therapeutic strategy with a favorable safety profile for targeting HLA-E-overexpressing tumors.</p><p><strong>Funding: </strong>This work was funded by The Research Council of Norway, the Norwegian Cancer Society, and the National Cancer Institute.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100521"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476308","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 VIVID-1 study: A novel methodological approach provides further evidence of efficacy of selective IL-23 inhibition in Crohn's disease.","authors":"Maria Cappello, Ciro Celsa","doi":"10.1016/j.medj.2024.100572","DOIUrl":"https://doi.org/10.1016/j.medj.2024.100572","url":null,"abstract":"<p><p>The VIVID-1 study is a phase 3 randomized controlled trial assessing the efficacy and safety of mirikizumab in moderate-to-severe active Crohn's disease.¹ The study confirms the advantage of selective IL-23 inhibition, while the treat-through design and the choice of composite coprimary endpoints represent an innovative strategy in conducting clinical trials in Crohn's disease.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 2","pages":"100572"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426332","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":"Maternal exercise during pregnancy is associated with reduced risk of asthma in the child: A prospective birth cohort study.","authors":"Emma-Reetta Musakka, Maija Paula Tuulia Ylilauri, Jonna Jalanka, Anne Maarit Karvonen, Martin Täubel, Sari Hantunen, Soili Marianne Lehto, Juha Pekkanen, Katri Backman, Leea Keski-Nisula, Pirkka Viljami Kirjavainen","doi":"10.1016/j.medj.2024.09.003","DOIUrl":"10.1016/j.medj.2024.09.003","url":null,"abstract":"<p><strong>Background: </strong>The means of primary prevention of asthma are limited. Maternal physical activity during pregnancy promotes fetal lung development and the newborn's lung function; thus, it could lower asthma risk and aid in asthma prevention. The objective of this study is to determine whether maternal physical activity during pregnancy is associated with asthma development in the child.</p><p><strong>Methods: </strong>The study population included 963 mother-infant pairs from the prospective Kuopio Birth Cohort study. Data on maternal physical activity during pregnancy, confounding factors, and children's asthma at 5 to 7 years of age were obtained from the Kuopio University Hospital birth registry and questionnaires.</p><p><strong>Findings: </strong>Maternal physical activity during pregnancy, when practiced three or more times per week, was associated with a reduced risk of asthma in the child, with an adjusted odds ratio of 0.54 (95% confidence interval 0.33-0.89; p = 0.02). The association was stable across a comprehensive set of adjustments, including length of gestation, mode of delivery, and maternal health indicators (e.g., asthma, smoking, pre-pregnancy body mass index and weight gain during pregnancy, infections, medication, healthy diet, stress), as well as various family environment variables.</p><p><strong>Conclusions: </strong>Maternal physical activity during pregnancy may be associated with marked protection of asthma in childhood and should be studied further as an applicable measure for asthma prevention.</p><p><strong>Funding: </strong>The study has been financially supported by grants from the Academy of Finland (no. 349427), the Emil Aaltonen Foundation, the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, the Juho Vainio Foundation (no. 202200461), the Kuopio Area Respiratory Foundation, and the Ida Montini Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100514"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401505","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":"Always more immunotherapy in the management of B-lineage acute lymphoblastic leukemia.","authors":"Robin Foà","doi":"10.1016/j.medj.2025.100603","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100603","url":null,"abstract":"<p><p>In the FELIX study,¹ the CAR-T product obecabtagene autoleucel (obe-cel) was investigated in relapsed/refractory adult B-cell lymphoblastic leukemia (B-ALL). The high responses associated with the low incidence of grade ≥3 side effects make obe-cel an attractive candidate for a broader use of CAR-T cells in B-ALL. Its impact will have to be weighed with the monoclonal antibody blinatumomab in the frontline treatment of B-ALL.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 2","pages":"100603"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426310","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 tumor cornification and immune-infiltration-based scheme for anti-PD-1 plus chemotherapy response in advanced squamous cell lung carcinoma.","authors":"Minlin Jiang, Jiya Sun, Congli Hu, Lin Wu, Yun Fan, Zhehai Wang, Lianke Liu, Chunyan Wu, Fengying Wu, Guanghui Gao, Fei Li, Lei Wang, Xuefei Li, Lei Cheng, Bo Peng, Hui Zhou, Caicun Zhou","doi":"10.1016/j.medj.2024.09.005","DOIUrl":"10.1016/j.medj.2024.09.005","url":null,"abstract":"<p><strong>Background: </strong>Anti-PD-1 immunotherapy plus chemotherapy (combo) exhibits significantly prolonged survival for squamous cell lung cancer (LUSC). An exploration of predictive biomarkers is still needed.</p><p><strong>Methods: </strong>High-throughput RNA sequencing (RNA-seq) of 349 LUSC samples from the randomized, multi-center, phase 3 trial ORIENT-12 (ClinicalTrials.gov: NCT03629925) was conducted for biomarker discovery, followed by flow cytometry and multiplex immunohistochemistry (mIHC) in additional clinical cohorts, and in vitro experiments were performed for verification.</p><p><strong>Results: </strong>A high abundance of activated CD8⁺ T and CD56^bright natural killer (NK) cells benefited patients' outcomes (progression-free survival [PFS]; overall survival [OS]) with combo treatment. Tumor cornification level remarkably affected the infiltration of the two crucial immune cells. Thus, a novel scheme of LUSC immune infiltration and cornification characterization-based classification (LICC) was established for combo efficacy prediction. Patients who received combo treatment achieved significant PFS improvements in LICC1 (hazard ratio [HR] = 0.43, 95% confidence interval [CI]: 0.25-0.75, p = 0.0029) and LICC2 (HR = 0.32, 95% CI: 0.17-0.58, p = 0.0002) subtypes but not in the LICC3 subtype (HR = 0.86, 95% CI: 0.60-1.23, p = 0.4053). Via single-cell RNA-seq analysis, the tumor cornification signal was mainly mapped to SPRR3⁺ tumor cells, whose relationships with activated CD8⁺ T or CD56^bright NK cells were verified using flow cytometry and mIHC. Our data suggest that SPRR3⁺ tumor cells might evade immune surveillance via the CD24-SIGLEC10 (M2 macrophage) axis to maintain a suppressive tumor microenvironment.</p><p><strong>Conclusions: </strong>Tumor cornification greatly impacts immune infiltration, and the LICC scheme may guide clinical medication of anti-PD-1+chemo treatment in patients with LUSC.</p><p><strong>Funding: </strong>The study was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, Shanghia Multidisplinary Cooperation Building Project for Diagnosis and Treatment of Major Disease, and Innovent Biologics, Inc.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100516"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476404","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":"Molecular insights into trauma: A framework of epigenetic pathways to resilience through intervention.","authors":"Sarah M Merrill, Chaini Konwar, Zaid Fraihat, Justin Parent, Rana Dajani","doi":"10.1016/j.medj.2024.11.013","DOIUrl":"10.1016/j.medj.2024.11.013","url":null,"abstract":"<p><p>Experiences of complex trauma and adversity, especially for children, are ongoing global crises necessitating adaptation. Bioadaptability to adversity and its health consequences emphasizes the dynamism of adaptation to trauma and the potential for research to inform intervention strategies. Epigenetic variability, particularly DNA methylation, associates with chronic adversity while allowing for resilience and adaptability. Epigenetics, including age- and site-specific changes in DNA methylation, gene-environment interactions, pharmacological responses, and biomarker characterization and evaluation, may aid in understanding trauma responses and promoting well-being by facilitating psychological and biological adaptation. Understanding these molecular processes provides a foundation for a biologically adaptive framework to shift public health strategies from restorative to long-term adaptation and resilience. Psychological, cultural, and biological trauma must be addressed in innovative interventions for vulnerable populations, particularly children and adolescents. Understanding molecular changes may provide a biopsychosocial perspective for culturally sensitive, evidence-based interventions that promote resilience and thriving in new settings.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100560"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872832","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}