tbuckley/cabot-search huggingface dataset:
Germline-Somatic Interactions in BRCA-Associated Cancers: Unique Molecular Profiles and Clinical Outcomes Linking ATM to TP53 Synthetic Essentiality
Authors: Ali T. Arafa, Siddhartha Yadav, Catherine H. Marshall, Elizabeth Mauer, Minxuan Huang, Binyam Yilma, Ymke van der Pol, Stamatina Fragkogianni, Emily A. Teslow, Samuel Kellen, Ella Boytim, Christine Luo, Megan Ludwig, Weijie Zhang, Arockia Jayaraj, Deborah K. Armstrong, William B. Isaacs, Justin M. Drake, Hai Dang Nguyen, R. Stephanie Huang, Calvin Y. Chao, Emil Lou, Scott M. Dehm, Fergus J. Couch, Justin H. Hwang, Emmanuel S. Antonarakis
Journal: Clinical Cancer Research (2025)

Abstract Background: Germline alterations in homologous recombination repair (gHRR) genes impact the pathogenesis, treatment options, and survival of cancer patients. However, distinct gHRR gene alterations may differentially impact treatment response and oncogenic signaling. Here we interrogated genomic and transcriptomic data and assessed clinical outcomes of patients with gHRR mutations across four BRCA-associated cancers (breast, ovarian, pancreatic, and prostate cancers) to identify therapeutic vulnerabilities. Methods: We assessed 24,309 patients undergoing matched tumor/normal next-generation DNA and RNA sequencing. Annotated gHRR gene variants (gBRCA1, gBRCA2, gPALB2, gATM, gCHEK2) were analyzed. Hazard ratios were used to assess survival outcomes comparing germline versus sporadic groups. Somatic alterations and their frequencies were compared across gHRR-altered groups. Differential gene expression and gene set enrichment analysis was used to compare transcriptomic profiles. Results: Somatic TP53 mutations were depleted in gATM carriers (p&amp;lt;0.05) across all four BRCA-associated cancers by up to 2.5-fold. Tumors with gBRCA1/2 mutations were associated with improved survival in ovarian cancer patients, and had consistent enrichment of TP53 mutations in all four cancers. gATM mutations displayed elevated p53 transcriptional activity in all four cancers, with significance reached in breast and prostate cancers (p&amp;lt;0.01). In breast, ovarian, and prostate cancers, gATM tumors demonstrated significantly increased inflammatory pathways (p&amp;lt;0.001). Finally, using gene-dependency data, we found that cell lines that were highly dependent on ATM were co-dependent on canonical p53 function. Conclusion: gATM-associated cancers appear to require intact p53 activity and this synthetic essentiality may be used to guide targeted therapies that perturb canonical TP53 function.
Phase II trial of atezolizumab and bevacizumab for treatment of HPV-positive unresectable or metastatic squamous cell carcinoma of the anal canal
Authors: Van K. Morris, Suyu Liu, Kangyu Lin, Haifeng Zhu, Seema Prasad, Armeen Mahvash, Priya Bhosale, Baohua Sun, Edwin R. Parra, Ignacio Wistuba, Arjun Peddireddy, James Yao, Julia Mendoza-Perez, Mark Knafl, Scott E. Woodman, Cathy Eng, Daniel Halperin
Journal: Clinical Cancer Research (2025)

Abstract Background: Anti-PD-(L)1 antibodies are associated with responses in &amp;lt;25% of patients with metastatic human papillomavirus (HPV)-associated malignancies. VEGF signaling causes intratumoral immune evasion and immune suppression. We evaluated the anti-PD-L1 antibody atezolizumab and anti-VEGF antibody bevacizumab for patients with unresectable, advanced anal cancer. Patients and methods: For this phase II study, participants with previously treated, immunotherapy-naïve anal cancer received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST v1.1). The primary endpoint was best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pretreatment/on-treatment biopsies) using a log-rank test. Results: Among 20 participants, the overall response rate was 11% (95% confidence interval (CI): 1.2-32). Median PFS and OS were 4.1 months (95% CI: 2.6-not assessable) and 11.6 months (95% CI, 9.5-20), respectively. One grade 5 bevacizumab-related bowel perforation occurred. Analyses of 16 paired biopsies linked increases in interferon gamma (P=.03) and inflammatory response (P =.02) gene expression signatures with prolonged PFS, as did rises in CD3+CD8+PD1+ (P=.02) cells and decreases in CD3+FoxP3+ cells (P=.04) from 10 paired biopsies with multiplex immunoflorescence. A subgroup of anal cancers characterized by the SBS31 “prior-platinum” signature demonstrated shorter OS (HR 6.3, 95% CI 1.2-32; P=.01). Conclusions: Atezolizumab and bevacizumab demonstrate activity similar to anti-PD-1 monotherapy for unresectable anal cancer. Our translational data identify undescribed chromosomal and transcriptomic biomarkers associated with survival. These correlative findings warrant confirmation and further validation in larger, prospective immunotherapy trials for advanced anal cancer.
Effects of Meditation and Yoga on Anxiety, Depression and Chronic Inflammation in Patients with Parkinson’s Disease: A Randomized Clinical Trial
Authors: Jojo Yan Yan Kwok, Lily Man Lee Chan, Charis Ann Lai, Philip Wing Lok Ho, Zoe Yuen-Kiu Choi, Man Auyeung, Shirley Yin Yu Pang, Edmond Pui Hang Choi, Daniel Yee Tak Fong, Doris Sau Fung Yu, Chia-Chin Lin, Richard Walker, Samuel Yeung Shan Wong, Rainbow Tin Hung Ho
Journal: Psychotherapy and Psychosomatics (2025)

Introduction: Clinical guidelines recommend a holistic approach to Parkinson’s disease (PD) care, yet randomized trials examining mindfulness-based interventions in this context are scarce. This study investigated the effects of two mindfulness practices – meditation and yoga – on biopsychosocial outcomes in PD patients, including anxiety symptoms, depressive symptoms, motor/nonmotor symptoms, health-related quality-of-life (HRQOL), mindfulness, and stress and inflammation biomarkers, compared to usual care. Methods: 159 participants with a clinical diagnosis of idiopathic PD and a Hoehn and Yahr stage of 1, 2, and 3, were randomized into meditation (n = 53), yoga (n = 52), and control (n = 54). Meditation and yoga were delivered in 90-min groups for 8 weeks. Primary outcomes included anxiety symptoms and depressive symptoms. Secondary outcomes included motor and nonmotor symptoms, HRQOL, mindfulness, and serum levels of interleukin-6, cortisol and TNF-alpha. Assessments were done at baseline (T0), 2 months (T1), and 6 months (T2). Linear mixed models were conducted following intention-to-treat principle. Results: Compared to control, both meditation, and yoga groups had significant improvements in anxiety symptoms (meditation: mean difference [MD] = −1.36, 95% CI: −2.46 to−0.26; yoga: MD = −1.61, CI: −2.70 to −0.52), motor symptoms (meditation: MD = −5.35, CI: −8.61 to−2.09; yoga: MD = −6.59, CI: −9.82 to−3.36), HRQOL (meditation: MD = −2.01, CI: −3.41 to−0.62; yoga: MD = −1.45, CI: −2.83 to−0.08), and describing skills (meditation: MD = 0.97, CI: 0.04–1.89; yoga: MD = 0.92, CI: 0.01–1.84) at T1, and significant reductions in serum interleukin-6 levels (meditation: MD = −1.14, CI: −2.18 to−0.10; yoga: MD = −1.11, CI: −2.09 to−0.13) at T2. Only meditation significantly reduced depression (MD = −1.44, CI: −2.57 to−0.30) at T1 and sustained the motor and HRQOL improvements at T2. Conclusion: Meditation and yoga significantly improved anxiety symptoms, chronic inflammation, motor symptoms, mindfulness-describing facet, and HRQOL in PD patients. Meditation provided additional benefits in reducing depressive symptoms and sustaining motor and HRQOL improvements.
Interleukin-5 enhances human mast cell survival and interferon responses to viral infection.
Authors: Jasmine Barra, Christopher R Liwski, Phoebe Phonchareon, Liliana Portales-Cervantes, Daniel Gaston, Tobias K Karakach, Ian D Haidl, Jean S Marshall
Journal: Journal of Allergy and Clinical Immunology (2025)
Rac1 Suppression by the Focal Adhesion Protein GIT2 and Podocyte Protection
Authors: Naoyuki Shimada, Jun Matsuda, Kana Asano-Matsuda, Maho Tokuchi, Lamine Aoudjit, Agnieszka Masztalerz, Serge Lemay, Tomoko Takano, Yoshitaka Isaka
Journal: Journal of the American Society of Nephrology (2025)

Background: Podocytes have an intricate structure featured by numerous actin-based projections called foot processes. Rho-family of small GTPases, including Ras-related C3 botulinum toxin substrate 1 (Rac1), play important roles in actin cytoskeletal remodeling required for cell morphology and adhesion. We previously showed that Rac1 activation in podocytes causes foot process effacement and proteinuria, but the upstream and spatiotemporal regulatory mechanism directing Rac1 is largely unknown. Recently we identified the focal adhesion protein, GIT ArfGAP2 (GIT2) as one of the Rac1 interactors in human podocytes by proximity-dependent biotin identification (BioID) and proteomics. Methods: Systemic and podocyte-specific GIT2 knockout mice were generated and assessed for kidney phenotypes. Human podocytes with GIT2 knockdown and overexpression were established using lentiviral transduction and characterized. Results: GIT2 was enriched in glomeruli including podocytes in the mouse kidney. Gene deletion of Git2 in podocytes caused exacerbated proteinuria and foot process effacement when subjected to the minimal change disease model and the salt-sensitive hypertension model, which were improved by pharmacological inhibition of Rac1. In cultured podocytes, GIT2 knockdown resulted in Rac1-dependent cell spreading with marked lamellipodial protrusions, accelerated focal adhesion disassembly, and a shorter focal adhesion lifetime. In GIT2 knockdown podocytes, tyrosine phosphorylation of the focal adhesion protein, p130 Crk-associated substrate (Cas), was significantly increased, accompanied by impaired localization of the tyrosine phosphatase, PTP1B, to focal adhesions. These phenotypes observed in GIT2 knockdown podocytes were reversed by GIT2 overexpression. Conclusions: The results indicate that GIT2 facilitates translocation of PTP1B to focal adhesions where it dephosphorylates p130Cas, thereby suppressing local Rac1 activity and protecting against podocyte injury and proteinuria.
Mechanisms of Cyst Expansion in Polycystic Kidney Disease
Authors: Kai M. Schmidt-Ott
Journal: Journal of the American Society of Nephrology (2025)

Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany Correspondence: Prof. Dr. med. Kai M. Schmidt-Ott, email: [email protected] See related article, "Adamts1 and Cyst Expansion in Polycystic Kidney Disease," on pages XXX–XXX.
p21-Activated Kinase 4 and Ischemic Acute Kidney Injury in Mice and Humans
Authors: Hwang Chan Yu, Byeoung Hoon Chung, Yoejin Kim, Yoonji Lee, Hyunchae Sim, Sangkyu Lee, Hong Pil Hwang, Hee Chul Yu, Seunggyu Jeon, Han-Joo Maeng, Dongyun Shin, Kyung Pyo Kang, Seung-Yong Seo, Eun Ju Bae, Byung-Hyun Park
Journal: Journal of the American Society of Nephrology (2025)

Background Acute kidney injury following ischemia−reperfusion remains a substantial perioperative challenge lacking effective treatment. p21-activated kinase 4 (PAK4), a downstream effector of Rho GTPase, has been explored in hepatic ischemia−reperfusion injury, but its role in renal ischemia−reperfusion is unknown. Methods Wild-type and proximal tubule-specific Pak4 knockout mice underwent 25 min of ischemia followed by 24 h of reperfusion injury. Primary tubular cells and HK-2 cells were exposed to hypoxia−reoxygenation injury to investigate the in vitro impact of PAK4. Selective degradation of PAK4 was employed using proteolysis-targeting chimeras (PROTAC) to ameliorate acute kidney injury. Results Post-ischemia−reperfusion, the expression of PAK4 was upregulated through hypoxia-inducible factor 1 alpha in mouse kidneys. Deletion of PAK4 in proximal tubule cells, but not in myeloid cells, significantly mitigated ischemia−reperfusion-induced acute kidney injury, as evidenced by decreased levels of blood urea nitrogen, creatinine, tubular necrosis, apoptosis, macrophage infiltration, and lipid accumulation compared to control mice. Further investigation revealed that PAK4 phosphorylated glutathione peroxidase 3 at T47, leading to its proteasomal degradation. Additionally, pretreatment of mice with the PAK4 PROTAC preserved glutathione peroxidase 3 and enhanced fatty acid β-oxidation, thereby protecting against acute kidney injury. In kidney tissues from people with a kidney transplant, elevated levels of PAK4 protein and phosphorylation of glutathione peroxidase 3 at T47 were observed. Conclusions Renal tubular PAK4 contributes to tissue damage during ischemia−reperfusion injury, while PAK4 PROTAC mitigates ischemia−reperfusion injury by reducing oxidative stress and promoting fatty acid β-oxidation.
Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer’s disease
Authors: Zhipei Sang, Shuheng Huang, Wanying Tan, Yujuan Ban, Keren Wang, Yufan Fan, Hongsong Chen, Qiyao Zhang, Chanchan Liang, Jing Mi, Yunqi Gao, Ya Zhang, Wenmin Liu, Jianta Wang, Wu Dong, Zhenghuai Tan, Lei Tang, Haibin Luo
Journal: Acta Pharmaceutica Sinica B (2025)
Adeno-associated viral delivery of Env-specific antibodies prevents SIV rebound after discontinuing antiretroviral therapy
Authors: Vadim A. Klenchin, Natasha M. Clark, Nida K. Keles, Saverio Capuano, Rosemarie Mason, Guangping Gao, Aimee Broman, Emek Kose, Taina T. Immonen, Christine M. Fennessey, Brandon F. Keele, Jeffrey D. Lifson, Mario Roederer, Matthew R. Gardner, David T. Evans
Journal: Science Immunology (2025)

An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here, we show that adeno-associated virus (AAV) delivery of two rhesus macaque antibodies to the simian immunodeficiency virus (SIV) envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIV mac 239M after discontinuing suppressive ART. After AAV administration, sustained antibody expression with minimal antidrug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within 2 weeks in all control animals but remained &lt;15 copies per milliliter in plasma for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals that rebounded with delayed kinetics exhibited restricted clonal diversity and antibody escape mutations in Env. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.
Reply to Sohal: Vascular Pruning in Smokers, Patients with Small Airway Disease and Early COPD
Authors: Sylvia Verbanck, Pieter Boonen, Jef Vandemeulebroucke, Wilfried Cools, Raúl San José Estépar, Eef Vanderhelst
Journal: American Journal of Respiratory and Critical Care Medicine (2025)

"Reply to Sohal: Vascular Pruning in Smokers, Patients with Small Airway Disease and Early COPD." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Engineering Mice to Study Human Immunity
Authors: Esen Sefik, Tianli Xiao, Michael Chiorazzi, Ian Odell, Fengrui Zhang, Kriti Agrawal, Goran Micevic, Richard A. Flavell
Journal: Annual Review of Immunology (2025)

Humanized mice, which carry a human hematopoietic and immune system, have greatly advanced our understanding of human immune responses and immunological diseases. These mice are created via the transplantation of human hematopoietic stem and progenitor cells into immunocompromised murine hosts further engineered to support human hematopoiesis and immune cell growth. This article explores genetic modifications in mice that enhance xeno-tolerance, promote human hematopoiesis and immunity, and enable xenotransplantation of human tissues with resident immune cells. We also discuss genetic editing of the human immune system, provide examples of how humanized mice with humanized organs model diseases for mechanistic studies, and highlight the roles of these models in advancing knowledge of organ biology, immune responses to pathogens, and preclinical drugs tested for cancer treatment. The integration of multi-omics and state-of-the art approaches with humanized mouse models is crucial for bridging existing human data with causality and promises to significantly advance mechanistic studies.
Effectiveness of home-based cardiac rehabilitation interventions delivered via mHealth technologies: a systematic review and meta-analysis
Authors: Leah Li, Mickaël Ringeval, Gerit Wagner, Guy Paré, Cemal Ozemek, Spyros Kitsiou
Journal: The Lancet Digital Health (2025)

Centre-based cardiac rehabilitation (CBCR) is underused due to low referral rates, accessibility barriers, and socioeconomic constraints. mHealth technologies have the potential to address some of these challenges through remote delivery of home-based cardiac rehabilitation (HBCR). This study aims to assess the effects of mHealth HBCR interventions compared with usual care and CBCR in patients with heart disease. We conducted a systematic review and meta-analysis of randomised controlled trials of mHealth HBCR interventions. Four electronic databases (MEDLINE, CENTRAL, CINAHL, and Embase) were searched from inception to March 31, 2023, with no restrictions on language or publication type. Eligible studies were randomised controlled trials of adult patients (age ≥18 years) with heart disease, comparing mHealth interventions with usual care or CBCR. The primary outcome of interest was aerobic exercise capacity, assessed with VO2 peak or 6-min walk test (6MWT). Quality of evidence was assessed using the GRADE system. This review was registered with PROSPERO, CRD42024544087. Our search yielded 9164 references, of which 135 were retained for full-text review. 13 randomised controlled trials met eligibility criteria and were included in the systematic review, involving 1508 adults with myocardial infarction, angina pectoris, or heart failure, or who had undergone revascularisation. Intervention duration ranged from 6 weeks to 24 weeks. Random-effects meta-analysis showed that, compared with usual care, mHealth HBCR significantly improved 6MWT (mean difference 24·74, 95% CI 9·88-39·60; 532 patients) and VO2 peak (1·77, 1·19-2·35; 359 patients). No significant differences were found between mHealth HBCR and CBCR. Quality of evidence ranged from low to very low across outcomes due to risk of bias and imprecision (small sample size). mHealth HBCR could improve access and health outcomes in patients who are unable to attend CBCR. Further research is needed to build a robust evidence base on the clinical effectiveness and cost-effectiveness of mHealth HBCR, particularly in comparison with CBCR, to inform clinical practice and policy. None.
Rebuilding trust and equity in Syria's health system: a governance-driven transition
Authors: Munzer Alkhalil, Aula Abbara, Mayssoon Dashash, Richard Sullivan, Maher Aboumayaleh, Abdulkarim Ekzayez, Zuhair Kharrat, Reem Hasan Obaydo, Zeidoun Alzoubi, Majd Alghatrif, Fouad M Fouad
Journal: The Lancet (2025)
Artificial intelligence in public health: promises, challenges, and an agenda for policy makers and public health institutions
Authors: Dimitra Panteli, Keyrellous Adib, Stefan Buttigieg, Francisco Goiana-da-Silva, Katharina Ladewig, Natasha Azzopardi-Muscat, Josep Figueras, David Novillo-Ortiz, Martin McKee
Journal: The Lancet Public Health (2025)

Artificial intelligence (AI) can rapidly analyse large and complex datasets, extract tailored recommendations, support decision making, and improve the efficiency of many tasks that involve the processing of data, text, or images. As such, AI has the potential to revolutionise public health practice and research, but accompanying challenges need to be addressed. AI can be used to support public health surveillance, epidemiological research, communication, the allocation of resources, and other forms of decision making. It can also improve productivity in daily public health work. Core challenges to its widespread adoption span equity, accountability, data privacy, the need for robust digital infrastructures, and workforce skills. Policy makers must acknowledge that robust regulatory frameworks covering the lifecycle of relevant technologies are needed, alongside sustained investment in infrastructure and workforce development. Public health institutions can play a key part in advancing the meaningful use of AI in public health by ensuring their staff are up to date regarding existing regulatory provisions and ethical principles for the development and use of AI technologies, thinking about how to prioritise equity in AI design and implementation, investing in systems that can securely process the large volumes of data needed for AI applications and in data governance and cybersecurity, promoting the ethical use of AI through clear guidelines that align with human rights and the public good, and considering AI's environmental impact.
Efficacy and safety of once-weekly tirzepatide in Japanese patients with obesity disease (SURMOUNT-J): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial
Authors: Takashi Kadowaki, Arihiro Kiyosue, Tomotaka Shingaki, Tomonori Oura, Koutaro Yokote
Journal: The Lancet Diabetes & Endocrinology (2025)
Correction: Leaving colorectal polyps in situ with endocytoscopy assisted by computer-aided diagnosis: a cost-effectiveness study
Authors: Natalie Halvorsen, Ishita Barua, Michael Bretthauer, Yuichi Mori, Shin-ei Kudo, Shraddha Gulati, Masashi Misawa, Kensaku Mori, Bu'Hussain Hayee, Olaolu Olabintan, Jens Aksel Nilsen, Svein Oskar Frigstad, James E. East, Amit Rastogi, Cesare Hassan, Mette Kalager, Magnus Løberg, Øyvind Holme, Amyn Haji
Journal: Endoscopy (2025)

Correction to: Leaving colorectal polyps in situ with endocytoscopy assisted by computer-aided diagnosis: a cost-effectiveness studyEndoscopy eFirstDOI: 10.1055/a-2532-9282
Admixture as a source for HLA variation in Neolithic European farming communities
Authors: Nicolas Antonio da Silva, Onur Özer, Magdalena Haller-Caskie, Yan-Rong Chen, Daniel Kolbe, Sabine Schade-Lindig, Joachim Wahl, Carola Berszin, Michael Francken, Irina Görner, Kerstin Schierhold, Joachim Pechtl, Gisela Grupe, Christoph Rinne, Johannes Müller, Tobias L. Lenz, Almut Nebel, Ben Krause-Kyora
Journal: Genome biology (2025)

Abstract Background The northern European Neolithic is characterized by two major demographic events: immigration of early farmers from Anatolia at 7500 years before present, and their admixture with local western hunter-gatherers forming late farmers, from around 6200 years before present. The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is understudied. Results We analyzed genome-wide data of 125 individuals from seven archeological early farmer and late farmer sites located in present-day Germany. The late farmer group studied here is associated with the Wartberg culture, from around 5500–4800 years before present. We note that late farmers resulted from sex-biased admixture from male western hunter-gatherers. In addition, we observe Y-chromosome haplogroup I as the dominant lineage in late farmers, with site-specific sub-lineages. We analyze true HLA genotypes from 135 Neolithic individuals, the majority of which were produced in this study. We observe significant shifts in HLA allele frequencies from early farmers to late farmers, likely due to admixture with western hunter-gatherers. Especially for the haplotype DQB1*04:01-DRB1*08:01, there is evidence for a western hunter-gatherer origin. The HLA diversity increased from early farmers to late farmers. However, it is considerably lower than in modern populations. Conclusions Both early farmers and late farmers exhibit a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time.