tbuckley/cabot-search huggingface dataset:
Growth Hormone Replacement Therapy in Heart Failure With Reduced Ejection Fraction
Authors: Alberto Maria Marra, Roberta D'Assante, Mariarosaria De Luca, Michele Arcopinto, Paola Gargiulo, Valeria Valente, Giulia Crisci, Carmen Rainone, Michele Modestino, Federica Giardino, Stefania Paolillo, Francesco Cacciatore, Lavinia Saldamarco, Dario Bruzzese, Donatella Scarpa, Pasquale Perrone Filardi, Giovanni Esposito, Luigi Saccà, Eduardo Bossone, Andrea Salzano, Antonio Cittadini
Journal: JACC Heart Failure (2025)

Growing evidence suggests that reduced activity of the growth hormone (GH)/insulin-like growth factor (IGF)-1 axis is common and associated with poor clinical status and outcome in heart failure (HF). In addition, preliminary results of growth hormone deficiency (GHD) correction in HF showed an improvement in quality of life, cardiac structure and function, and cardiovascular performance. The aim of the present double-blind, randomized, placebo-controlled trial was to evaluate the cardiovascular effects of 1 year of GH replacement therapy in a cohort of patients with heart failure and reduced ejection fraction (HFrEF). Consecutive patients with HFrEF in NYHA functional class I/II/III and concomitant GHD were recruited. GHD patients were randomized to receive GH (0.012 mg/kg every second day ∼2.5 IU), or placebo, on top of background therapy. The primary endpoint was peak oxygen consumption (VO2). Secondary endpoints included hospitalizations, end-systolic left ventricular volumes, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, health-related quality of life score, and muscle strength (handgrip). A total of 318 consecutive patients were screened, with 86 (27%) fulfilling the criteria for GHD. Of these, 22 subjects refused to participate in the study. The final study groups consisted of 64 patients, 30 randomized in the active treatment group and 34 in the control group. After 1 year, 45 patients completed the study (21 in the control group and 24 in the active group). A statistically significant improvement of peak VO2 was reached in the active group (from 12.8 ± 3.4 mL/kg/min to 15.5 ± 3.15 mL/kg/min; P < 0.01; delta peak VO2 between groups: +3.1 vs -1.8; P < 0.01). Other cardiopulmonary exercise test parameters (ie, peak workload, VO2 at the aerobic threshold, O2 pulse and VE/VCO2 slope; P < 0.05) also improved, paralleled by an increase in 6-minute walking test distance (P < 0.05) and handgrip strength (P < 0.01). GH improved right ventricular function (ie, TAPSE and TAPSE/pulmonary artery systolic pressure ratio; P < 0.01), leading to an amelioration of clinical status (NYHA functional class; P < 0.05) and health-related quality of life (Minnesota Living With Heart Failure Questionnaire; P < 0.05). A significant decrease of NT-proBNP was also found (P < 0.05). This randomized, double-blind, placebo-controlled trial demonstrates that GH replacement therapy in HFrEF patients with GHD improves exercise performance, and left ventricular and right ventricular structure and function, leading to an amelioration of clinical status and health-related quality of life. (Treatment of GHD Associated With CHF; NCT03775993).
Severe Heart Failure and Treatment With Dapagliflozin Across the Ejection Fraction Spectrum
Authors: Riccardo M Inciardi, Henri Lu, Brian L Claggett, Akshay S Desai, Pardeep S Jhund, Carolyn S P Lam, Mikhail N Kosiborod, Silvio E Inzucchi, Felipe A Martinez, Rudolf A de Boer, Adrian F Hernandez, Sanjiv J Shah, Lars Køber, Piotr Ponikowski, Marc S Sabatine, Magnus Petersson, Anna Maria Langkilde, John J V McMurray, Muthiah Vaduganathan, Scott D Solomon
Journal: JACC Heart Failure (2025)
Early Detection of Cardiorespiratory Diseases at Everton BEAT-Breathlessness Community Hub
Authors: Rajiv Sankaranarayanan, Nick Hartshorne-Evans, Lucy Mclean, Jonathan Jones, Michael Salla, Biswajit Chakrabarti, Justine Hadcroft, Christopher Pritchard, Andy Smith, Carolyn S P Lam
Journal: JACC Heart Failure (2025)
Pembrolizumab Plus Docetaxel Versus Docetaxel for Previously Treated Metastatic Castration-Resistant Prostate Cancer: The Randomized, Double-Blind, Phase III KEYNOTE-921 Trial
Authors: Daniel P. Petrylak, Raffaele Ratta, Nobuaki Matsubara, Ernesto Korbenfeld, Rustem Gafanov, Loic Mourey, Tilman Todenhöfer, Howard Gurney, Gero Kramer, Andries M. Bergman, Pawel Zalewski, Maria De Santis, Andrew J. Armstrong, Winald Gerritsen, Russell Pachynski, Seok Soo Byun, Margitta Retz, Eric Levesque, Ray McDermott, Sergio Bracarda, Ray Manneh, Meital Levartovsky, Xin Tong Li, Charles Schloss, Christian H. Poehlein, Karim Fizazi
Journal: Journal of Clinical Oncology (2025)

The standard of care for metastatic castration-resistant prostate cancer (mCRPC) after second-generation androgen receptor pathway inhibitor (ARPI) therapy is still docetaxel. The randomized, double-blind, phase III KEYNOTE-921 trial (Clinicaltrials.gov identifier: NCT03834506) evaluated the efficacy and safety of pembrolizumab or placebo plus docetaxel for previously treated mCRPC. Adults with mCRPC who progressed after androgen-deprivation therapy and one ARPI were randomly assigned 1:1 to pembrolizumab or placebo plus docetaxel with concomitant prednisone. Dual primary end points were radiographic progression-free survival (rPFS) by blinded independent central review per Prostate Cancer Working Group 3-modified RECIST 1.1 and overall survival (OS). Safety was a secondary end point. Between May 30, 2019, and June 17, 2021, 515 participants were randomly assigned to pembrolizumab plus docetaxel and 515 to placebo plus docetaxel. Median time from random assignment to data cutoff date (June 20, 2022) at final analysis (FA) was 22.7 months (range, 12.1-36.7). At first interim analysis (data cutoff date: September 27, 2021), median rPFS was 8.6 months (95% CI, 8.3 to 10.2) with pembrolizumab plus docetaxel versus 8.3 months (95% CI, 8.2 to 8.5) with placebo plus docetaxel (hazard ratio [HR], 0.85 [95% CI, 0.71 to 1.01]; P = .03). At FA, median OS was 19.6 months (95% CI, 18.2 to 20.9) versus 19.0 months (95% CI, 17.9 to 20.9), respectively (HR, 0.92 [95% CI, 0.78 to 1.09]; P = .17). Grade ≥3 treatment-related adverse events occurred in 43.2% of participants who received pembrolizumab plus docetaxel and 36.6% of participants who received placebo plus docetaxel. Two and seven participants, respectively, died due to a treatment-related adverse event. Pneumonitis was the most common immune-mediated adverse event (7.0% v 3.1%). The addition of pembrolizumab to docetaxel did not significantly improve efficacy outcomes for participants with previously treated mCRPC. The current standard of care remains unchanged.
Fine particulate matter (PM <sub>2.5</sub> ) and the blood-testis-barrier: an <i>in vivo</i> and <i>in vitro</i> mechanistic study
Authors: Shaokai Zheng, Nannan Zhao, Xiaojun Lin, Lianlian Jiang, Chong Qiu, Jinchen Jiang, Zhenhao Shu, Yingyun Qian, Bo Liang, Lianglin Qiu
Journal: Environmental Health Perspectives (2025)

Fine particulate matter (PM2.5) is considered a major component of ambient particulate matter (PM). Exposure to PM2.5 was shown to be related to male reproductive system injury. Ferroptosis is regarded as an iron-dependent programmed cell death, that is associated with the pathological process. It has been reported that SIRT1 has protective effects on the male reproductive system. However, the underlying mechanisms of exposure to PM2.5 induced-testicular injury are still unexplored. In this study, we investigated the relationship between ferroptosis and male reproductive injury, after exposure to PM2.5 and the role of SIRT1/HIF-1α signaling pathway in this process. We established PM2.5 exposure model in vivo and in vitro using Sertoli cell Sirt1 conditional knockout C57BL/6 (cKO) mice testes and primary Sertoli cells. Hematoxylin and eosin (H&E) staining were conducted to examine the histology of the mice testes. Sperm parameters and biotin tracer assay were conducted to evaluate the effects of exposure to PM2.5 on the mice testes. Related markers and genes related to the blood-testis barrier (BTB) and ferroptosis were measured by real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and immunofluorescence assay. siRNA transfection was used to evaluate the potential mechanism. Significant pathological damage and lower sperm quality were detected in mice testes exposed to PM2.5. We found that exposure to PM2.5 damaged the blood-testis barrier (BTB) and inhibited the expression level of the BTB-related proteins (including Connexin 43, Occludin, Claudin 11, N-Cadherin and ZO-1). According to the enrichment analysis results, ferroptosis and HIF-1α signaling pathway were significantly enriched in mice testes and primary Sertoli cells exposed to PM2.5. Subsequent experiments were conducted to verify the results of enrichment analysis and revealed differences in the expression levels of HIF-1α, ferroptosis-related genes (including GPX4, SLC7A11, ACSL4 and HO-1) and ferroptosis-related markers (including MDA, GSH and Fe2+), associated with lower expression of SIRT1 after exposure to PM2.5. These results suggest that PM2.5 exposure may be associated with ferroptosis and HIF-1α signaling pathway in male reproductive dysfunction. Taken together, in vivo and in vitro experiments verified that PM2.5 exposure in mice may lead to testicular dysfunction through new pathways. https://doi.org/10.1289/EHP14447.
Explaining the Relationships Between Age, Endocrine Therapy Persistence, and Risk of Recurrence in Hormone Receptor–Positive Early Breast Cancer: A Nationwide Cohort Study
Authors: Elise Dumas, Floriane Jochum, Florence Coussy, Anne-Sophie Hamy, Alena Majdling, Sophie Houzard, Christine Le Bihan-Benjamin, Fabien Reyal, Paul Gougis, Mats Julius Stensrud
Journal: Journal of Clinical Oncology (2025)

Young age is associated with increased risk of recurrence in hormone receptor (HR)-positive early-stage breast cancer (eBC). Lack of adherence to endocrine therapy (ET) is a potential reason for the lower survival proportions observed in younger patients, but the survival benefits of improving adherence to ET in young patients remain unknown. Using data from the French National Health Data System and target trial emulation methods, we considered three sustained ET persistence strategies (allowing treatment gaps of no more than 30, 90, or 180 continuous days) and estimated the 5-year disease-free survival (DFS) benefit of sustained ET persistence compared with observed ET persistence. A total of 121,601 patients with HR-positive eBC were included in the analyses, of whom 29.8% was younger than 50 years at diagnosis. Younger patients had lower DFS and were more likely to discontinue ET than older patients. In patients 34 years and younger, strict ET persistence (≤30-day gaps) improved 5-year DFS proportions from 74.5% to 78.8% (4.3 percentage points [95% CI, 2.6 to 7.2]) compared with observed persistence. ET persistence strategies allowing for ≤90-day and ≤180-day gaps reduced the 5-year DFS benefit in patients 34 years and younger to 1.3 (95% CI, 0.2 to 3.7) and 1.0 (95% CI, -0.2 to 3.4) percentage points, respectively. By contrast, DFS benefits of improved ET persistence in patients after 50 years old did not exceed 1.9 percentage points, compared with observed persistence, regardless of the persistence definition. The survival benefit that could be achieved with strict ET persistence in women 34 years and younger with HR-positive eBC highlights the need for tailored strategies to improve ET persistence in this population.
Combining Apatinib and Oxaliplatin Remodels the Immunosuppressive Tumor Microenvironment and Sensitizes Desert-Type Gastric Cancer to Immunotherapy
Authors: Guang-Tan Lin, Cheng Yan, Lu-Jie Li, Xiao-Wen Qiu, Yu-Xuan Zhao, Ju-Li Lin, Yu-Jing Chen, Chuan Feng, Shao-Qiong Chen, Jian-Wei Xie, Chao-Hui Zheng, Sachiyo Nomura, Chang-Ming Huang, Ping Li, Long-Long Cao
Journal: Cancer Research (2025)

Immune checkpoint blockade (ICB) therapies have achieved significant breakthroughs in cancer treatment over the past decade. However, ICB is largely ineffective in desert-type gastric cancer (GC) due to intrinsic tumor heterogeneity and a highly immunosuppressive tumor microenvironment (TME). Transforming tumors from immunosuppressive to immunostimulatory is a potential approach to enhance ICB response. Here, we developed a chromosomal instability (CIN) subtype GC mouse model with an immunoactive TME and a stem cell-originated mouse-derived allograft (MDA) model with an immunosuppressed TME to investigate mechanisms regulating the tumor immunophenotype and uncover therapeutic strategies to remodel the TME. Blocking β-catenin signaling attenuated the immunochemotherapeutic resistance of MDA tumors. The tyrosine kinase inhibitor apatinib reprogrammed the TME by increasing CD8+ T cells and IGHA+ plasma cells infiltration and decreasing M2 macrophages, but apatinib also induced PD-L1 and CD80 expression in both human and mouse desert-type tumors. Oxaliplatin decreased the apatinib-induced expression of immune checkpoints and enhanced the antitumor efficacy of immunotherapy. A prospective clinical trial (NCT04195828) demonstrated that a neoadjuvant regimen of apatinib plus ICB and chemotherapy was effective in patients with desert-type GC. Collectively, these findings identify potential drug targets for immune desert-type GC driven by β-catenin signaling.
Targeting the SP/KLF Transcriptional Regulatory Network Synergizes with HDAC Inhibition to Impede Progression of H3K27M Diffuse Intrinsic Pontine Glioma
Authors: Yu Kong, Fan Wang, Renwei Jing, Qian Zhao, Xuejiao Lv, Yingying Zhao, Ye Yuan, Xianyou Xia, Yu Sun, Yujie Tong, Han Yan, Qian Li, Ting Li, Lei Cao, Deng Liu, Dawei Huo, Shao-Kai Sun, Francisco Morís, Yujie Tang, Xudong Wu
Journal: Cancer Research (2025)

Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors that frequently harbor H3K27M mutations and lack effective treatments. Here, our epigenomic analyses uncovered an enrichment of SP/KLF transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared to normal pontine neural progenitor cells. SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized mithramycin analog, significantly suppressed the proliferation and invasiveness of H3K27M-DIPG cells. A screen of epigenetic drugs showed that histone deacetylase inhibitors (HDACi) synergized with EC-8042 to suppress H3K27M-DIPG cell growth. Unexpectedly, HDACi activated transcriptional programs that enhanced tumor adaptability and invasiveness, an effect counteracted by EC-8042. Mechanistically, HDACi treatment enhanced chromatin accessibility to SP/KLF factors, while EC-8042 disrupted both the primary SP/KLF transcription regulatory network and the HDACi-induced secondary network. Consequently, the combination treatment significantly impeded tumor progression in orthotopic xenograft models. Transcriptomic profiling indicated that this combinatorial strategy induced transcriptional changes associated with improved prognosis in DIPG patients. Thus, this study identifies a therapeutic approach for H3K27M-mutated DIPGs and sheds light on the limitations of HDACi in treating solid tumors.
SpinFlowSim: A blood flow simulation framework for histology-informed diffusion MRI microvasculature mapping in cancer
Authors: Anna Kira Voronova, Athanasios Grigoriou, Kinga Bernatowicz, Sara Simonetti, Garazi Serna, Núria Roson, Manuel Escobar, Maria Vieito, Paolo Nuciforo, Rodrigo Toledo, Elena Garralda, Els Fieremans, Dmitry S Novikov, Marco Palombo, Raquel Perez-Lopez, Francesco Grussu
Journal: Medical Image Analysis (2025)

Diffusion Magnetic Resonance Imaging (dMRI) sensitises the MRI signal to spin motion. This includes Brownian diffusion, but also flow across intricate networks of capillaries. This effect, the intra-voxel incoherent motion (IVIM), enables microvasculature characterisation with dMRI, through metrics such as the vascular signal fraction fV or the vascular Apparent Diffusion Coefficient (ADC) D∗. The IVIM metrics, while sensitive to perfusion, are protocol-dependent, and their interpretation can change depending on the flow regime spins experience during the dMRI measurements (e.g., diffusive vs ballistic), which is in general not known for a given voxel. These facts hamper their practical clinical utility, and innovative vascular dMRI models are needed to enable the in vivo calculation of biologically meaningful markers of capillary flow. These could have relevant applications in cancer, as in the assessment of the response to anti-angiogenic therapies targeting tumour vessels. This paper tackles this need by introducing SpinFlowSim, an open-source simulator of dMRI signals arising from blood flow within pipe networks. SpinFlowSim, tailored for the laminar flow patterns within capillaries, enables the synthesis of highly-realistic microvascular dMRI signals, given networks reconstructed from histology. We showcase the simulator by generating synthetic signals for 15 networks, reconstructed from liver biopsies, and containing cancerous and non-cancerous tissue. Signals exhibit complex, non-mono-exponential behaviours, consistent with in vivo signal patterns, and pointing towards the co-existence of different flow regimes within the same network, as well as diffusion time dependence. We also demonstrate the potential utility of SpinFlowSim by devising a strategy for microvascular property mapping informed by the synthetic signals, and focussing on the quantification of blood velocity distribution moments and of an apparent network branching index. These were estimated in silico and in vivo, in healthy volunteers scanned at 1.5T and 3T and in 13 cancer patients, scanned at 1.5T. In conclusion, realistic flow simulations, as those enabled by SpinFlowSim, may play a key role in the development of the next-generation of dMRI methods for microvascular mapping, with immediate applications in oncology.
Red teaming ChatGPT in medicine to yield real-world insights on model behavior
Authors: Crystal T Chang, Hodan Farah, Haiwen Gui, Shawheen Justin Rezaei, Charbel Bou-Khalil, Ye-Jean Park, Akshay Swaminathan, Jesutofunmi A Omiye, Akaash Kolluri, Akash Chaurasia, Alejandro Lozano, Alice Heiman, Allison Sihan Jia, Amit Kaushal, Angela Jia, Angelica Iacovelli, Archer Yang, Arghavan Salles, Arpita Singhal, Balasubramanian Narasimhan, Benjamin Belai, Benjamin H Jacobson, Binglan Li, Celeste H Poe, Chandan Sanghera, Chenming Zheng, Conor Messer, Damien Varid Kettud, Deven Pandya, Dhamanpreet Kaur, Diana Hla, Diba Dindoust, Dominik Moehrle, Duncan Ross, Ellaine Chou, Eric Lin, Fateme Nateghi Haredasht, Ge Cheng, Irena Gao, Jacob Chang, Jake Silberg, Jason A Fries, Jiapeng Xu, Joe Jamison, John S Tamaresis, Jonathan H Chen, Joshua Lazaro, Juan M Banda, Julie J Lee, Karen Ebert Matthys, Kirsten R Steffner, Lu Tian, Luca Pegolotti, Malathi Srinivasan, Maniragav Manimaran, Matthew Schwede, Minghe Zhang, Minh Nguyen, Mohsen Fathzadeh, Qian Zhao, Rika Bajra, Rohit Khurana, Ruhana Azam, Rush Bartlett, Sang T Truong, Scott L Fleming, Shriti Raj, Solveig Behr, Sonia Onyeka, Sri Muppidi, Tarek Bandali, Tiffany Y Eulalio, Wenyuan Chen, Xuanyu Zhou, Yanan Ding, Ying Cui, Yuqi Tan, Yutong Liu, Nigam Shah, Roxana Daneshjou
Journal: npj Digital Medicine (2025)

Red teaming, the practice of adversarially exposing unexpected or undesired model behaviors, is critical towards improving equity and accuracy of large language models, but non-model creator-affiliated red teaming is scant in healthcare. We convened teams of clinicians, medical and engineering students, and technical professionals (80 participants total) to stress-test models with real-world clinical cases and categorize inappropriate responses along axes of safety, privacy, hallucinations/accuracy, and bias. Six medically-trained reviewers re-analyzed prompt-response pairs and added qualitative annotations. Of 376 unique prompts (1504 responses), 20.1% were inappropriate (GPT-3.5: 25.8%; GPT-4.0: 16%; GPT-4.0 with Internet: 17.8%). Subsequently, we show the utility of our benchmark by testing GPT-4o, a model released after our event (20.4% inappropriate). 21.5% of responses appropriate with GPT-3.5 were inappropriate in updated models. We share insights for constructing red teaming prompts, and present our benchmark for iterative model assessments.
Condensates as a culprit in RAS activation and inhibitor resistance
Authors: Hannah C. Bergo, Logan B. Leak, Trever G. Bivona
Journal: Cancer Research (2025)

Therapy resistance is a significant cause of death in patients treated with targeted cancer therapy in diverse oncogene-driven cancers. A better understanding of resistance mechanisms can lay the foundation for improving existing and developing new therapies. A recent elegant study published in Nature Chemical Biology sheds light on a new resistance mechanism. The authors define a novel role for ARAF, a member of the RAF protein family (A-, B-, C-RAF), that is distinct from its previously understood role as a RAS effector and MEK protein kinase in the MAPK pathway. They describe how ARAF sequesters active RAS at the plasma membrane in phase-separated condensates to sustain signaling and prevent inactivation by the RAS GTPase activating protein (GAP) neurofibromin 1 (NF1). This study underscores emerging roles for biomolecular condensates in cancer and highlights important implications for disrupting protein condensates to address treatment resistance to RAS (and RAS pathway) targeted therapies. The study also illuminates evolutionary functional distinction between the RAF proteins and indicates unique biology for ARAF in normal physiology and disease.
US Government Sues Pharmacy Chains CVS and Walgreens for Their Alleged Role in the Opioid Epidemic
Authors: Eli Cahan
Journal: JAMA (2025)

This Medical News article discusses lawsuits filed by the US Department of Justice against CVS and Walgreens, two of the nation’s largest pharmacies, for their alleged role in exacerbating the opioid crisis by dispensing “massive quantities” of the drugs.