MedComm最新文献

{"title":"Liver Metastases from Colorectal Cancer: From Pathogenesis to Current Treatment.","authors":"Jialiang Fan, Huiru Zhang, Deyang Kong, Yu Sun, Shuaibing Lu, Wenjing Yang, Renshen Xiang, Qi Zhang, Wei Pei, Haizeng Zhang, Lin Feng","doi":"10.1002/mco2.71044","DOIUrl":"https://doi.org/10.1002/mco2.71044","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains one of the most frequently diagnosed malignancies worldwide, and colorectal cancer liver metastasis (CRLM) represents a major cause of CRC-related mortality. The liver provides a highly specialized environment that can be remodeled into a metastatic niche, where anatomical structure, metabolic properties, and immunological landscape collectively influence tumor cell survival, colonization, and outgrowth. Increasing evidence indicates that CRLM development is driven by dynamic interactions between tumor intrinsic programs and the hepatic tumor microenvironment(TME), involving epithelial plasticity, intercellular communication, stromal remodeling, and immune regulation. However, an integrated understanding that links metastatic initiation, hepatic niche formation, immune escape, and therapeutic intervention remain lacking. This review examines recent advances in the multistage progression of CRLM and discusses how immune tolerance, lymphocyte dysfunction, and suppressive cellular networks contribute to the establishment and maintenance of the CRLM. Finally, we review current clinical management strategies and emerging approaches, immunotherapy, and biomarker-guided precision treatment. By integrating mechanistic insights with clinical perspectives, this review aims to provide a conceptual framework for understanding CRLM progression and to identify potential directions for improving individualized therapeutic strategies.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71044"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121013","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":"Integrative Multiomics Profiling Reveals Immune Determinants of Response to Disitamab Vedotin Plus Penpulimab in HER2-Low Breast Cancer.","authors":"Xiaoxiao Liu, Yuting Song, Lei Liu, Aaron Qi Zhang, Xin Xie, Bing Wei, Ping He, Chunying Zhuang, Juanjuan Li, Xi Yan, Tinglun Tian, Xiaorong Zhong, Jie Chen, Yan Cheng, Dan Zheng, Shibao Li, Hao Wang, Ting Luo","doi":"10.1002/mco2.70988","DOIUrl":"https://doi.org/10.1002/mco2.70988","url":null,"abstract":"<p><p>This prospective single-arm study evaluated neoadjuvant disitamab vedotin plus penpulimab in Stage II-III HER2-low breast cancer (immunohistochemistry 1+ or 2+, fluorescence in situ hybridization-negative), a population lacking targeted neoadjuvant options. Twenty patients received the combination every 3 weeks for six cycles before surgery. In the intention-to-treat population, the pathologic complete response (pCR) was 20.0% (four out of 20; 95% CI, 5.7-43.7%), and the objective response rate (ORR) was 45.0% (nine out of 20; 95% CI, 23.1-68.5%). Among 16 patients who completed protocol-defined treatment and surgery, pCR was 25.0% (four out of 16; 95% CI, 7.3-52.4%), ORR was 56.3% (nine out of 16; 95% CI, 29.9-80.2%), and 31.3% achieved residual cancer burden Class 0-1. Grade ≥3 adverse events occurred in 25.0%; no treatment-related deaths occurred. pCR-associated tumors had a pretreatment immune-active microenvironment enriched in inflammatory proteins, transcripts, and tumor-infiltrating lymphocytes, whereas nonresponders displayed a higher M2/M1 macrophage ratio. An exploratory baseline score combining CCL19 and the M2/M1 ratio showed pCR/non-pCR separation (AUC = 0.8889) but attenuated on internal validation (LOOCV AUC = 0.6667, optimism-corrected bootstrap AUC = 0.8375). This combination showed preliminary antitumor activity with manageable safety; however, given the small sample size and wide confidence intervals, these findings preclude definitive conclusions about efficacy and warrant validation in larger randomized controlled trials.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e70988"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120984","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":"A State-Resolved Single-Cell and Spatial Atlas Reveals <i>IDH</i>-Associated Differences in Malignant and Immune Architecture in Diffuse Glioma.","authors":"Ashraf Zaman, Emily Holton, Madhavi Pandya, Genevieve Shillington, Cecile Escher, Kavitha Krishna Sudhakar, Agota Tuzesi, Ashish Mehta, Eric Lam, Rachael Zekanovic, Michael Sughrue, Charlie Teo, Jacky Yeung, Walter Muskovic, Joseph E Powell","doi":"10.1002/mco2.71022","DOIUrl":"https://doi.org/10.1002/mco2.71022","url":null,"abstract":"<p><p>Adult-type diffuse gliomas are defined by the isocitrate-dehydrogenase (IDH) axis, yet how this biology constrains malignant cell-state repertoires and their immune-modulatory potential remains unclear. We profiled 69 tumors using single-cell RNA sequencing (scRNA-seq), single-nucleus RNA sequencing (snRNA-seq), and spatial transcriptomics, and resolved seven recurrent malignant cell states: astrocyte-like progenitor cells (ALPC), hypoxia, cycling G1/S, cycling G2/M, oligo-lineage, neuro-oligo-lineage, and neuro-lineage. The <i>IDH</i> axis strongly biased state occupancy and malignant-immune composition, with <i>IDH</i>-mutant tumors dominated by differentiated lineage-like states and reduced immune infiltration, whereas glioblastoma (GBM) showed expansion of ALPC and hypoxia states alongside increased myeloid and lymphoid infiltration. Orthogonal analyses supported that ALPC-associated markers are expressed in situ and in patient-derived stem cell-permissive cultures, consistent with a stem-like, differentiation-competent malignant phenotype. State-resolved pathway analysis identified mitochondrial oxidative phosphorylation programs enriched in GBM ALPC and extracellular matrix remodeling, and chemotaxis-associated programs enriched in GBM hypoxia. Composition-controlled, patient-level interaction modeling identified a greater malignant-myeloid signaling interface in GBM, driven by SPP1-CD44/integrin signaling and confirmed by differential expression; GBM networks also featured TGFB and NECTIN modules, whereas <i>IDH</i>-mutant networks were dominated by APP/APOE-TREM2/TYROBP and MIF modules. These data suggest that the IDH axis shapes glioma behavior by constraining malignant state repertoires and biasing the deployment of state-specific metabolic and immunomodulatory programs.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71022"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120936","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":"Immune-Cell Dynamics in the Tumor Microenvironment: Implications for Cancer Therapy.","authors":"Pin Guo, Yizhao Xie, Rui Song, Mengdi Yang, Zhen Lin, Chao Guan, Zechen Wang, Jin Wen, Guang-Liang Chen","doi":"10.1002/mco2.71040","DOIUrl":"https://doi.org/10.1002/mco2.71040","url":null,"abstract":"<p><p>Immune-cell dynamics within the tumor microenvironment (TME) determine whether immune cells can reach, recognize, and sustain antitumor function against malignant cells under suppressive pressure. These dynamics are shaped by hypoxia, nutrient stress, cytokine and chemokine signaling, stromal architecture, vascular access, and multicellular crosstalk, and are further regulated by transcriptional and epigenetic programs. In this review, we organize TME immunity around four major barriers to effective therapy: failed immune access, defective antigen visibility and priming, failure to sustain effector function, and suppressive tissue remodeling. We use FOSL2/Fra-2, a component of activator protein-1 (AP-1) transcription factor complexes, as an example of how local signals can produce distinct regulatory effects in malignant, immune, and stromal compartments. FOSL2-associated programs have been linked to differentiation, plasticity, myeloid and stromal remodeling, stress adaptation, and selected immune-regulatory processes; however, the strength and direction of these associations vary by lineage, tumor type, model system, and level of functional evidence. We distinguish perturbation-supported mechanisms from correlative state signatures and identify the need for spatial validation, functional perturbation, and biomarker validation. This perspective supports biomarker-guided TME-directed therapy matched to the dominant immune barrier.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71040"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120939","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":"All-Oral PI3Kδ and HDAC Inhibition with Parsaclisib Plus Chidamide and Step-Down Maintenance in Relapsed or Refractory Peripheral T-Cell Lymphoma: A Phase Ib Trial.","authors":"Xufeng Luo, Zheng Yan, Wei Fang, Hanchi Duan, Qiuyu Zhang, Haiying Wang, Shuna Yao, Jiuyang Zhang, Yiping Jin, Wenyong Li, Xiaolu Teng, Lina Zhang, Lijie Liang, Quande Lin, Ping Wang, Haoran Si, Jinxin Miao, Wenping Zhou, Zhihua Yao, You-Wen He, Qingxin Xia, Yanyan Liu","doi":"10.1002/mco2.70993","DOIUrl":"https://doi.org/10.1002/mco2.70993","url":null,"abstract":"<p><p>Single-agent targeted therapies for relapsed or refractory peripheral T-cell lymphoma (R/R peripheral T-cell lymphoma [PTCL]) produce modest, short-lived responses, underscoring the need for tolerable, chemotherapy-free combinations. In an open-label, single-arm Phase Ib trial at two tertiary hospitals, we evaluated parsaclisib plus chidamide with step-down maintenance. Adults with R/R PTCL received parsaclisib 10-20 mg once daily plus chidamide 20 mg twice weekly for 8 weeks using 3+3 escalation; patients without progression or unacceptable toxicity continued parsaclisib 2.5 mg once daily plus chidamide 20 mg twice weekly. Primary endpoints were Cycle 1 dose-limiting toxicities (DLTs), treatment-related adverse events, and recommended Phase II dose; antitumor activity and biomarker correlates were exploratory. Twelve screened patients were enrolled and treated. One Grade 3 hepatotoxicity DLT occurred; no maximum tolerated dose was reached; parsaclisib 20 mg once daily plus chidamide 20 mg twice weekly was selected for Phase II. No Grade 4 treatment-related events or treatment-related deaths occurred. Objective and complete response rates were 58% (95% CI, 28-85) and 42% (95% CI, 15-72). With 26.8 months' median follow-up, 2-year progression-free and overall survival rates were 33.3 and 66.7%. Exploratory analyses suggested TET2 alterations and natural killer-cell expansion as correlates of durable remission. This regimen warrants prospective validation (ClinicalTrials.gov: NCT05083208).</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e70993"},"PeriodicalIF":14.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121007","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":"Colorectal Cancer: Epidemiology, Risk Factors, Signaling Pathways, Clinical Features, Screening, Diagnosis, and Management.","authors":"Kairui Wan, Ke Tang, Linglong Wang, Qin Tian, Mingwei Zheng, Cheng Qian, Limei Liu","doi":"10.1002/mco2.71028","DOIUrl":"https://doi.org/10.1002/mco2.71028","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a leading cause of cancer incidence and mortality worldwide and is increasingly characterized by two converging realities: a substantial global burden and a rising incidence of early-onset CRC. This review synthesizes current advances in CRC epidemiology, risk factors, signaling biology, clinical presentation, screening, diagnosis, and management across the care continuum. We frame CRC as a systems-level disease in which genomic instability, epigenetic dysregulation, metabolic remodeling, tumor microenvironmental evolution, and gut microbiota interactions converge on interconnected pathways, including Wnt/β-catenin, MAPK, PI3K/AKT/mTOR, TGF-β, and immune-regulatory networks. We distinguish established standards of care from recent practice-changing developments and investigational strategies. Within this framework, we discuss blood-based screening, AI-assisted endoscopy, ctDNA-informed residual disease assessment, biomarker-defined molecular workup, immunotherapy strategies for dMMR disease, and targeted approaches for KRAS G12C-mutated, BRAF V600E-mutated, and HER2-positive metastatic CRC. Despite substantial progress, major challenges remain, including limited immunotherapy benefit in microsatellite-stable CRC, unequal access to high-quality screening and molecular testing, and uncertainty regarding implementation of newer biomarkers across diverse populations. An integrated framework linking population risk, tumor ecology, evidence-based biomarker use, and equitable precision care is essential for the next phase of CRC prevention and management.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71028"},"PeriodicalIF":14.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120918","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":"Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases.","authors":"Miao Sun, Dengju Li, Jia Wei","doi":"10.1002/mco2.71029","DOIUrl":"https://doi.org/10.1002/mco2.71029","url":null,"abstract":"<p><p>Bruton's tyrosine kinase (BTK) is a nonreceptor tyrosine kinase that couples B-cell receptor (BCR) signaling to broader immune-cell activation. By integrating signals from BCR, Toll-like receptors, chemokine receptors, Fc receptors, and BAFF receptors, BTK governs B-cell development, immune-cell migration, innate immunity, and inflammation. Inhibition of BTK has transformed the treatment landscape of B-cell malignancies, while the development of covalent, noncovalent, dual-target inhibitors, and BTK degraders has expanded therapeutic opportunities. However, the mechanisms of action, resistance patterns, and expanding therapeutic applications of BTK inhibitors (BTKis) across malignant and nonmalignant diseases have yet to be comprehensively integrated. This review outlines BTK structure and signaling pathways, BTKi classification, resistance mechanisms, and emerging therapeutic strategies with emphasis on monotherapy in B-cell malignancies and combination strategies involving CAR-T therapy, immune checkpoint inhibitors, CD20-targeted antibodies, BCL2 inhibitors, and hematopoietic stem cell transplantation. Mechanistically, these combinations enhance T-cell function, attenuate immune checkpoint signaling, and remodel the tumor microenvironment (TME). We further discuss BTKis in solid tumors, autoimmune diseases, and chronic inflammatory disorders. Collectively, this review integrates current advances in BTK-targeted therapy and highlights opportunities for precision treatment across oncology and immune-mediated diseases.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71029"},"PeriodicalIF":14.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120966","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":"Cancer Cell Metastasis: From Molecular Mechanisms to Therapeutic Strategies.","authors":"Yupeng Zhao, Wenchao Xu, Yibo Wang, Haoran Huang, Yu Su, Li Zhou, Jianzhou Liu, Junchao Guo","doi":"10.1002/mco2.71026","DOIUrl":"https://doi.org/10.1002/mco2.71026","url":null,"abstract":"<p><p>Cancer metastasis is a spatiotemporal dynamic process jointly driven by the intrinsic evolution of cancer cells and continuous microenvironmental selection, rather than a simple linear accumulation of genetic alterations. The metastatic diversity of cancers is driven by heterogeneity in physicochemical properties, cellular composition, and signaling networks among primary tumors, dissemination routes, and target organs. Currently, the stage-dependent and route-dependent molecular mechanisms underlying metastasis and potential pan-cancer therapeutic targets remain incompletely defined. Here, we systematically discuss the genomic, chromosomal, and epigenetic evolution of metastatic tumor cells (MTCs) following their spatiotemporal trajectory from in situ evolution to metastatic colonization. We describe their migration behaviors and interaction patterns within the migratory tumor microenvironment across hematogenous, lymphatic, and perineural routes, and the establishment and remodeling of organ-specific metastatic niches. We also review the progress and limitations of metastasis-oriented diagnostic stratification and therapeutic interventions. We argue for the shift of antimetastatic strategies from target-centric approaches to precise interventions that match timing, routes, biomarkers, and endpoints. By integrating the molecular mechanisms underlying spatiotemporal changes during cancer metastasis, this review delineates the spatiotemporal evolutionary landscape of metastasis and the MTC-microenvironment interaction patterns, thereby offering insights for future clinical translation of metastasis‑targeted therapies.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71026"},"PeriodicalIF":14.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120978","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":"Iron and Other Metal Ions in Human Health and Disease.","authors":"Xiaofeng Dai, Jitian Li","doi":"10.1002/mco2.71021","DOIUrl":"https://doi.org/10.1002/mco2.71021","url":null,"abstract":"<p><p>Iron is the most abundant trace element, driving both the commonest deficiency and ferroptosis. This review takes iron as the central theme and extends to copper, zinc, and calcium, spanning physiological functions, pathological mechanisms, risk factors, diagnostics, and therapeutics. We classify these ions into redox-active (iron, copper), which engage in catalytic electron transfer, and redox-inert (zinc, calcium), which serve structural and signaling roles without redox cycling. Iron deficiency remains the global leading micronutrient deficit, whereas iron overload triggers ferroptosis-mediated organ damage. Copper deficiency manifests as hematological and neurological syndromes, while copper excess induces cuproptosis. Zinc deficiency impairs growth and immunity, yet chronic zinc toxicity primarily causes secondary copper deficiency. Calcium dysregulation underpins hypoparathyroidism, osteoporosis, cardiovascular diseases, and crystal deposition disorders. Diagnosis integrates clinical assessment, biochemical profiling, imaging, and genetic analysis; risk factors encompass dietary insufficiency, environmental exposure, genetic variants, and demographic variables. Given the narrow therapeutic window between deficiency and toxicity, vigilant monitoring is mandatory. Treatment strategies are metal-specific and include chelation, hormone replacement, source removal, and channel modulation. Future directions emphasize validated biomarkers, tissue-targeted delivery, and metallo-genomics to enable precision medicine, with iron metabolism as a pivotal entry point for understanding and managing systemic metal homeostasis.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71021"},"PeriodicalIF":14.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120959","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":"Presenilin 1 Mutations Converge on Aβ42/Aβ40 Elevation via Distinct Mechanisms.","authors":"Isabel Bestard-Lorigados, Keenan Sterling, Liwei Li, Zhehao Lin, Zhanghui Wu, Qinxin Zhu, Wenhao Pan, Fang Cai, Weihong Song","doi":"10.1002/mco2.70978","DOIUrl":"https://doi.org/10.1002/mco2.70978","url":null,"abstract":"<p><p>Mutations in Presenilin 1 (PS1) are the most common genetic cause of familial Alzheimer's disease (AD). However, the exact mechanisms by which these mutations alter amyloid precursor protein (APP) processing and drive amyloid β (Aβ) production remain unclear. In this study, five PS1 mutations (M146V, G384A, C410Y, Y115H, and the Notch-sparing mutation ΔS169) were transfected into neuroblastoma cells lacking endogenous PS1/PS2 expression and human embryonic kidney cells stably overexpressing either wild-type APP or the APP Swedish mutation. We investigated the effects of these mutations on APP processing, Aβ42/Aβ40 ratio, cytotoxicity, BACE1 expression, and PS1 endoproteolysis. Our results demonstrate that PS1 mutations differentially modulate APP processing, producing distinct Aβ profiles independent of their effects on Notch signaling. All mutations increased the Aβ42/Aβ40 ratio, while BACE1 levels were unchanged and no direct PS1-BACE1 interactions were found. All mutations increased cytotoxicity, whereas only the Notch-impairing mutations reduced cell viability, suggesting impaired Notch signaling may contribute to this effect. Lastly, the mutations exhibited distinct endoproteolytic rates that correlated only with APP-C83 levels. These findings provide novel insights into how distinct PS1 mutations impact amyloid pathology.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e70978"},"PeriodicalIF":14.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120944","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}