Med最新文献

{"title":"Inactivation of TACC2 epigenetically represses CDKN1A and confers sensitivity to CDK inhibitors.","authors":"Zhi-Rui Lin, Tian-Liang Xia, Meng-Yao Wang, Lan-Jun Zhang, Yan-Min Liu, Bo-Yu Yuan, Ai-Jun Zhou, Li Yuan, Jian Zheng, Jin-Xin Bei, Dong-Xin Lin, Mu-Sheng Zeng, Qian Zhong","doi":"10.1016/j.medj.2024.12.002","DOIUrl":"10.1016/j.medj.2024.12.002","url":null,"abstract":"<p><strong>Background: </strong>The genomic landscape of esophageal squamous cell carcinoma (ESCC) has been characterized extensively, but there remains a significant need for actionable targets and effective therapies.</p><p><strong>Methods: </strong>Here, we perform integrative analysis of genome-wide loss of heterozygosity and expression to identify potential tumor suppressor genes. The functions and mechanisms of one of the candidates, TACC2, are then explored both in vitro and in vivo, leading to the proposal of a therapeutic strategy based on the concept of synthetic lethality.</p><p><strong>Findings: </strong>We reveal that the inactivation of TACC2, due to copy number loss and promoter hypermethylation, is associated with poor prognosis in ESCC patients. TACC2 depletion enhances ESCC tumorigenesis and progression, as demonstrated in Tacc2 knockout mouse models and by increased growth abilities of ESCC cells. Mechanistically, TACC2 interacts with components of the NuRD and CoREST co-repressor complexes, including MTA1, MBD3, and HMG20B, in the cytoplasm. TACC2 loss leads to the translocation of these proteins into the nucleus, facilitating the formation of functional NuRD and CoREST complexes and the epigenetic repression of CDKN1A. This repression results in elevated CDK1/2 activation. Furthermore, TACC2-deficient cells and ESCC patient-derived organoids with reduced TACC2 expression show increased sensitivity to CDK inhibitors, particularly dinaciclib, which is currently in a phase III trial. Notably, the combination of TACC2-specific RNAi and dinaciclib in subcutaneous ESCC models significantly impairs tumor growth.</p><p><strong>Conclusions: </strong>The findings suggest a strategy for cancer treatment based on synthetic lethality.</p><p><strong>Funding: </strong>Funded by NKRDP, NSFC, GDIIET, GDBABRF, GDECISTP, and SYSUTP.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100568"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967017","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":"Regulatory T cell therapy is associated with distinct immune regulatory lymphocytic infiltrates in kidney transplants.","authors":"Oliver McCallion, Amy R Cross, Matthew O Brook, Conor Hennessy, Ricardo Ferreira, Dominik Trzupek, William R Mulley, Sandeep Kumar, Maria Soares, Ian S Roberts, Peter J Friend, Giovanna Lombardi, Kathryn J Wood, Paul N Harden, Joanna Hester, Fadi Issa","doi":"10.1016/j.medj.2024.11.014","DOIUrl":"10.1016/j.medj.2024.11.014","url":null,"abstract":"<p><strong>Background: </strong>Adoptive transfer of autologous regulatory T cells (Tregs) is a promising therapeutic strategy aimed at enabling immunosuppression minimization following kidney transplantation. In our phase 1 clinical trial of Treg therapy in living donor renal transplantation, the ONE Study (ClinicalTrials.gov: NCT02129881), we observed focal lymphocytic infiltrates in protocol kidney transplant biopsies that are not regularly seen in biopsies of patients receiving standard immunosuppression.</p><p><strong>Methods: </strong>We present 7 years of follow-up data on patients treated with adoptive Treg therapy early post-transplantation who exhibited focal lymphocytic infiltrates on a 9-month protocol biopsy. We phenotyped their adoptively transferred and peripherally circulating Treg compartments using CITE-seq and investigated the focal lymphocytic infiltrates with spatial proteomic and transcriptomic technologies.</p><p><strong>Findings: </strong>Graft survival rates were not significantly different between Treg-treated patients and the control reference group. None of the Treg-treated patients experienced clinical rejection episodes or developed de novo donor-specific antibodies, and three of ten successfully reduced their immunosuppression to tacrolimus monotherapy. All Treg-treated patients who underwent a protocol biopsy 9 months post-transplantation exhibited focal lymphocytic infiltrates. Spatial profiling analysis revealed prominent CD20⁺ B cell and regulatory (IKZF2, IL10, PD-L1, TIGIT) signatures within cell-therapy-associated immune infiltrates, distinct from the pro-inflammatory myeloid signature associated with rejection biopsies.</p><p><strong>Conclusions: </strong>We demonstrate for the first time that immune cell infiltrates in transplanted kidneys can occur following adoptive Treg therapy in humans, potentially facilitating within-graft T:B cell interactions that promote local immune regulation.</p><p><strong>Funding: </strong>This work was funded by the 7^th EU Framework Programme, grant/award no. 260687, and the National Institute for Health Research (NIHR).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100561"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898728","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":"ElevateHER: Engineering a new era in women's health.","authors":"Erika Moore, Shreya A Raghavan","doi":"10.1016/j.medj.2025.100697","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100697","url":null,"abstract":"<p><p>Women's health operates in fragmented silos despite encompassing all unique biological and physiological factors affecting women across their lifespan. Consequently, healthcare decisions and technological advances take place under a universal approach, leading to data deficiency and lack of robust models to predict or tailor care for women's health. Engineering innovations hold immense potential to revolutionize health but require broader awareness of their relevance to the spectrum of challenges that fall under the umbrella of women's health. The ElevateHER (Engineering Innovations in Women's Health Discovery) conference convened scientists to identify critical areas for strategic research investment in women's health. Calls for action additionally focused on resource sharing and standardization, streamlining funding opportunities, science communication and outreach, and future workforce development. This perspective highlights these calls for action to engineer a new era in women's health with a cohesive approach that seamlessly integrates women's health into the fabric of overall health.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 5","pages":"100697"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064877","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 impact of real-world evidence in implementing and optimizing Alzheimer's disease care.","authors":"Harald Hampel, Gang Li, Michelle M Mielke, James E Galvin, Miia Kivipelto, Emiliano Santarnecchi, Claudio Babiloni, Viswanath Devanarayan, Rifky Tkatch, Yan Hu, Ricky Kurzman, Min Cho, Jo Vandercappellen, Yosuke Nakamura, Joanne Bell, Soeren Mattke, Nicola Toschi","doi":"10.1016/j.medj.2025.100695","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100695","url":null,"abstract":"<p><p>Real-world evidence (RWE) can complement clinical trials by addressing gaps in how approved anti-amyloid therapies for early Alzheimer's disease (AD) are used in everyday practice. This article outlines strategies to generate RWE that bridge three key challenges in AD care: low detection rates of mild cognitive impairment (MCI), limited data on long-term safety and effectiveness, and a lack of personalized treatment strategies. With MCI detection rates among primary care providers as low as 6%-15%, we propose cost-effective triage tools using electronic health records to enhance early diagnosis and intervention. We also highlight the importance of understanding anti-amyloid therapy outcomes in diverse, real-world populations. Supported by FDA initiatives, pragmatic trials and observational studies using real-world data (RWD) can help develop predictive models that incorporate biomarkers and support precision medicine. These approaches aim to move AD care beyond one-size-fits-all treatment, guiding more tailored, effective strategies for patients.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 5","pages":"100695"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045544","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":"Bioengineering solutions to improve women's health.","authors":"Catherine M Klapperich, Gordana Vunjak-Novakovic, Jenny Robinson, Renita Horton, Pamela K Kreeger, Morteza Mahmoudi, Samit Shah, Antonina Frolova","doi":"10.1016/j.medj.2025.100699","DOIUrl":"10.1016/j.medj.2025.100699","url":null,"abstract":"<p><p>In recognition of The International Day of Action for Women's Health on May 28^th, we bring together a collection of Voices highlighting the need for innovative solutions to tackle long-standing women's health challenges from a bioengineering perspective. Many common diseases manifest differently in women, and an insufficient understanding of the underlying mechanisms as well as a lack of tailored treatment strategies continue to impact health outcomes. Bioengineered organoids, organ-on-chip systems, and biomaterials hold promise as tools to dissect pathological mechanisms in reproductive health, cancer, autoimmune diseases, and musculoskeletal health, while tailored diagnostic and therapeutic strategies can enhance the efficacy of clinical interventions. An interdisciplinary approach uniting technological, translational, and clinical research is essential to realize the full potential of bioengineering solutions to improve women's health.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 5","pages":"100699"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001035","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":"Depemokimab in chronic rhinosinusitis with nasal polyps: A turning point or a missed opportunity?","authors":"Enrico Heffler, Giovanni Paoletti","doi":"10.1016/j.medj.2025.100674","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100674","url":null,"abstract":"<p><p>The ANCHOR-1 and ANCHOR-2 trials of the long-acting anti-interleukin (IL)-5 monoclonal antibody depemokibab in chronic rhinosinusitis with nasal polyposis demonstrated the safety and statistical efficacy of the drug compared to placebo.¹ However, its clinical benefits appear limited compared to other biologic therapies. The reduced dosing interval may improve adherence, but further research is needed to identify the most responsive patients.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 5","pages":"100674"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988116","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":"Navigating ethical challenges across professions: Insights from an Ethics Lab on patient-derived organoids.","authors":"Jeanette Bresson Ladegaard Knox, Mie Seest Dam, Sara Green, Daniel E Stange, Franziska Baenke, Bon-Kyoung Koo, Steffen Rulands, Tim Schmäche, Vivian Mittné, Ivan Terlizzi, Beatrix Jahnke, Mette N Svendsen","doi":"10.1016/j.medj.2025.100675","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100675","url":null,"abstract":"<p><p>In translational medicine, ethics is often treated as a question of approval and something to overcome to be allowed to do research. Given the many moral challenges related to developing biomedicine, we argue for the need to expand our understanding of ethics.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 5","pages":"100675"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040137","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":"Combination of autophagy inhibitors with high-dose CDK4/6 inhibitors offers new hope for advanced HR+/HER2- breast cancer.","authors":"Li-Ping Ge, Yi-Zhou Jiang","doi":"10.1016/j.medj.2024.100571","DOIUrl":"https://doi.org/10.1016/j.medj.2024.100571","url":null,"abstract":"<p><p>Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) with endocrine therapy are standard for advanced hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. However, treatment options following resistance to CDK4/6is remain poorly defined. Gong et al. conducted a phase 1b/2 trial, demonstrating that autophagy inhibitors combined with high-dose CDK4/6is are well tolerated and effective in patients with advanced HR+/HER2- breast cancer resistant to first-line CDK4/6i therapy.¹.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 5","pages":"100571"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989362","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":"Progress in reducing mortality from 10 major causes by county poverty level, from 1990-1994 to 2016-2020, in the US.","authors":"Daniel Wiese, Hyuna Sung, Ahmedin Jemal, Farhad Islami","doi":"10.1016/j.medj.2024.11.009","DOIUrl":"10.1016/j.medj.2024.11.009","url":null,"abstract":"<p><strong>Background: </strong>Overall death rates in the US have been declining in the past few decades. However, progress against mortality across counties with different socioeconomic profiles has not been well described. The objective of this study was to examine changes in death rates from leading causes of death by county poverty level in the contiguous US.</p><p><strong>Methods: </strong>Using county-level death (all causes, 10 leading causes in 2020, excluding COVID-19) and population data derived from the National Center for Health Statistics, we calculated absolute and relative changes in age-standardized death rates by county poverty level from 1990-1994 to 2016-2020.</p><p><strong>Findings: </strong>From 1990-1994 to 2016-2020, death rates from all causes, diseases of the heart, cancer, cerebrovascular disease, and pneumonia/influenza declined nationally, but rates increased for unintentional injury, chronic obstructive pulmonary disease, Alzheimer's disease, diabetes, suicide/self-inflicted injury, and kidney disease mortality. Counties with higher poverty levels (≥20%) had smaller declines or larger increases in death rates for each evaluated cause of death, exacerbating the disparities in mortality by county poverty level, except for unintentional injury and suicide/self-inflicted injury. Consequently, in 2016-2020, the death rates for leading causes of death were 12% (for Alzheimer's disease; suicide/self-inflicted injury) to 81% (for diabetes) higher in people residing in counties with the highest poverty level than in those residing in counties with the lowest poverty level.</p><p><strong>Conclusions: </strong>Disparities in mortality from most leading causes of death by county poverty level widened during the past three decades.</p><p><strong>Funding: </strong>There was no external funding for this study.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100556"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872837","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 autophagy plus high-dose CDK4/6 inhibitors in advanced HR+HER2- breast cancer: A phase 1b/2 trial.","authors":"Chang Gong, Qun Lin, Tao Qin, Yinduo Zeng, Fei Xu, Yaping Yang, Dong Yin, Zhuxi Duan, Chun-Long Chen, Louis Wing-Cheong Chow, Qiang Liu, Ahmed Hamaï, Maryam Mehrpour, Qianchong Lin, Jun Li, Erwei Song","doi":"10.1016/j.medj.2024.11.012","DOIUrl":"10.1016/j.medj.2024.11.012","url":null,"abstract":"<p><strong>Background: </strong>The unmet needs of managing patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer who progress after cyclin-dependent kinase (CDK)4/6 inhibitor (CDK4/6i) treatment remain unclarified.</p><p><strong>Methods: </strong>This was a phase 1b/2, single-arm, open-label study that enrolled 29 patients with HR+/HER2- breast cancer who experienced first-line palbociclib treatment failure. The primary endpoint was the incidence of dose-limiting toxicity (DLT). The secondary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The clinical trial registration number is ClinicalTrials.gov: NCT05953350.</p><p><strong>Findings: </strong>The phase 1b study demonstrated no DLT in patients treated with hydroxychloroquine (HCQ; 600 mg, bis in die [bid]) plus increasing doses of palbociclib (100, 150, or 200 mg, quaque die [qd]). The plasma pharmacokinetics of palbociclib were not significantly affected by HCQ. The recommended phase 2 dose (RP2D) was HCQ (600 mg, bid) plus palbociclib (200 mg, qd). The dose-expansion cohort demonstrated that HCQ plus palbociclib (200 mg, qd) treatment was tolerable. Grade 3 treatment-emergent adverse events (TEAEs) with an incidence higher than 15.0% included neutropenia (25.0%), leukopenia (25.0%), fatigue (20.0%), and back pain (15.0%). The ORR of all enrolled patients in our present trial was 41.4% (12/29). In the dose-expansion cohort, with the last enrolled patient having a follow-up duration of 32.3 weeks, the median PFS was not reached. The clinical benefit rate (CBR) at 6 months was 90.0% (95% confidence interval [CI]: 68.3%-98.8%). These findings were supported by preclinical data.</p><p><strong>Conclusions: </strong>Combined HCQ with high-dose CDK4/6i palbociclib (200 mg, qd) showed tolerable toxicity and promising efficacy for patients with advanced HR+/HER2- breast cancer after CDK4/6i failure.</p><p><strong>Funding: </strong>This work was funded by the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100559"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898733","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}