tbuckley/cabot-search huggingface dataset:
Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation
Authors: Christian T Ruff, Siddharth M Patel, Robert P Giugliano, David A Morrow, Bruce Hug, Julia F Kuder, Erica L Goodrich, Shih-Ann Chen, Shaun G Goodman, Boyoung Joung, Robert G Kiss, Jindrich Spinar, Wojciech Wojakowski, Jeffrey I Weitz, Sabina A Murphy, Stephen D Wiviott, Sanobar Parkar, Daniel Bloomfield, Marc S Sabatine
Journal: New England Journal of Medicine (2025)

BackgroundAbelacimab is a fully human monoclonal antibody that binds to the inactive form of factor XI and blocks its activation. The safety of abelacimab as compared with a direct oral anticoagulant in patients with atrial fibrillation is unknown.MethodsPatients with atrial fibrillation and a moderate-to-high risk of stroke were randomly assigned, in a 1:1:1 ratio, to receive subcutaneous injection of abelacimab (150 mg or 90 mg once monthly) administered in a blinded fashion or oral rivaroxaban (20 mg once daily) administered in an open-label fashion. The primary end point was major or clinically relevant nonmajor bleeding.Download a PDF of the Plain Language Summary.ResultsA total of 1287 patients underwent randomization; the median age was 74 years, and 44% were women. At 3 months, the median reduction in free factor XI levels with abelacimab at a dose of 150 mg was 99% (interquartile range, 98 to 99) and with abelacimab at a dose of 90 mg was 97% (interquartile range, 51 to 99). The trial was stopped early on the recommendation of the independent data monitoring committee because of a greater-than-anticipated reduction in bleeding events with abelacimab. The incidence rate of major or clinically relevant nonmajor bleeding was 3.2 events per 100 person-years with 150-mg abelacimab and 2.6 events per 100 person-years with 90-mg abelacimab, as compared with 8.4 events per 100 person-years with rivaroxaban (hazard ratio for 150-mg abelacimab vs. rivaroxaban, 0.38 [95% confidence interval {CI}, 0.24 to 0.60]; hazard ratio for 90-mg abelacimab vs. rivaroxaban, 0.31 [95% CI, 0.19 to 0.51]; P<0.001 for both comparisons). The incidence and severity of adverse events appeared to be similar in the three groups.ConclusionsAmong patients with atrial fibrillation who were at moderate-to-high risk for stroke, treatment with abelacimab resulted in markedly lower levels of free factor XI and fewer bleeding events than treatment with rivaroxaban. (Funded by Anthos Therapeutics; AZALEA–TIMI 71 ClinicalTrials.gov number, NCT04755283.) Quick Take Abelacimab versus Rivaroxaban in Atrial Fibrillation 1m 53s
Case 3-2025: A 54-Year-Old Man with Exertional Dyspnea and Chest Pain
Authors: Clyde W Yancy, J Sawalla Guseh, Brian G Ghoshhajra, Rodney H Falk, Andrew J Yee, Bailey M Hutchison
Journal: New England Journal of Medicine (2025)

A 54-year-old male athlete was evaluated at this hospital because of exertional dyspnea and chest pain. Physical examination revealed jugular venous distention and Kussmaul's sign. A diagnosis was made.
Intravesical Instillation of Chemotherapy Before Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: The REBACARE Trial
Authors: Thomas van Doeveren, Sebastiaan Remmers, Egbert R Boevé, Erik B Cornel, Antoine G van der Heijden, Kees Hendricksen, Evelyne C C Cauberg, Rens Jacobs, Bin K Kroon, Annemarie M Leliveld, Richard P Meijer, Harm van Melick, Bob Merks, Jorg R Oddens, Benjamin Pradere, Luc A J Roelofs, Diederik M Somford, Peter de Vries, Bart Wijsman, Willemijn A K M Windt, Marit Yska, Peter J Zwaan, Katja K H Aben, Pim J van Leeuwen, Joost L Boormans
Journal: European Urology (2025)
Stevioside mitigates metabolic dysregulation in offspring induced by maternal high-fat diet: the role of gut microbiota-driven thermogenesis
Authors: Jin Ye, Renjie Shi, Xiaoning Wu, Hua Fan, Yapei Zhao, Xinyun Hu, Lulu Wang, Xiaowei Bo, Dongning Li, Yunshu Ge, Danna Wang, Bing Xia, Zhenting Zhao, Chunxia Xiao, Beita Zhao, Yutang Wang, Xuebo Liu
Journal: Gut Microbes (2025)

Maternal obesity poses a significant threat to the metabolic profiles of offspring. Microorganisms acquired from the mother early in life critically affect the host's metabolic functions. Natural non-nutritive sweeteners, particularly stevioside (STV), play a crucial role in reducing obesity and affecting gut microbiota composition. Based on this, we hypothesized that maternal STV supplementation could improve the health of mothers and offspring by altering their gut microbiota. Our study found that maternal STV supplementation reduced obesity during pregnancy, decreased abnormal lipid accumulation in offspring mice caused by maternal obesity, and modified the gut microbiota of both dams and offspring, notably increasing the abundance of Lactobacillus apodemi (L. apodemi). Co-housing and fecal microbiota transplant experiments confirmed that gut microbiota mediated the effects of STV on metabolic disorders. Furthermore, treatment with L. apodemi alone replicated the beneficial effects of STV, which were associated with increased thermogenesis. In summary, maternal STV supplementation could alleviate lipid metabolic disorders in offspring by enhancing L. apodemi levels and promoting thermogenic activity, potentially involving changes in bile acid metabolism pathways.
Lessons Learned From Epidemiology of Type 2 Diabetes in South Asians: Kelly West Award Lecture 2024
Authors: Viswanathan Mohan
Journal: Diabetes Care (2025)

South Asia has high prevalence rates of type 2 diabetes (T2D). Until the 1990s, the prevalence of T2D within South Asia was low but much higher in the South Asian diaspora living abroad. Today, high prevalence rates of T2D are reported among those living in South Asia. T2D in South Asians presents with unique clinical features described as the “South Asian phenotype” that include younger age at onset of diabetes than in White Europeans, much lower BMI, hyperinsulinemia and greater insulin resistance, rapid decline in β-cell function resulting in low insulin reserve, low muscle mass, and greater ectopic fat deposition, especially in the liver. Also, prevalence of impaired fasting glucose is higher among South Asians than prevalence of impaired glucose tolerance. Genetic predisposition combined with intrauterine fetal programming (low vitamin B12 intake and high folate intake) increases susceptibility to T2D, from birth. In later life, overnutrition, especially a high carbohydrate intake with refined grains of higher glycemic index, coupled with low physical activity likely triggers the T2D epidemic in South Asians. Additionally, there are emerging risk factors like air pollution. Preventing T2D in South Asians requires a multifactorial approach, including improvements in maternal and fetal nutrition with special reference to vitamin B12 and folate intake, decreasing refined carbohydrate and increasing protein and fiber intake in the diet, increasing physical activity, and control of air pollution. Lessons learned from epidemiology of T2D in South Asians could be useful to other developing countries that are in earlier stages of epidemiological transition.
Efficacy of GLP-1 Receptor Agonists on Weight Loss, BMI, and Waist Circumference for Patients With Obesity or Overweight: A Systematic Review, Meta-analysis, and Meta-regression of 47 Randomized Controlled Trials
Authors: Hon Jen Wong, Bryan Sim, Yao Hao Teo, Yao Neng Teo, Mark Y. Chan, Leonard L.L. Yeo, Pei Chia Eng, Benjamin Y.Q. Tan, Naveed Sattar, Mayank Dalakoti, Ching-Hui Sia
Journal: Diabetes Care (2025)

OBJECTIVE To provide an updated synthesis on effects of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on weight, BMI, and waist circumference incorporating newer randomized controlled trials (RCTs), particularly in individuals with overweight or obesity. RESEARCH DESIGN AND METHODS We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) for RCTs published from inception to 4 October 2024. The search was limited to RCTs evaluating the use of GLP-1 RAs for mean differences from baseline in weight, BMI, and waist circumference in adults with obesity or overweight with or without diabetes. Two independent reviewers performed the literature search and data extraction, resolving disagreements via consensus or third-reviewer consultation. RESULTS Forty-seven RCTs were included, with a combined cohort of 23,244 patients. GLP-1 RAs demonstrated a mean weight reduction of −4.57 kg (95% CI −5.35 to −3.78), mean BMI reduction of −2.07 kg/m2 (95% CI −2.53 to −1.62), and mean waist circumference reduction of −4.55 cm (95% CI −5.72 to −3.38) compared with placebo. This effect was consistent across diabetes status, GLP-1 RA used, and route of administration. The greatest treatment benefit appeared to favor patients who were younger, female, without diabetes, with higher baseline weight and BMI but lower baseline HbA1c, and treated over a longer duration. Limitations include substantial statistical heterogeneity, in part due to broad inclusion criteria. However, this heterogeneity may improve generalizability by reflecting a wide range of study designs and patient populations. CONCLUSIONS GLP-1 RAs demonstrated significant weight, BMI, and waist circumference reduction benefits in this meta-analysis.
Additive Value of Polygenic Risk Score to Family History for Type 2 Diabetes Prediction: Results From the All of Us Research Database
Authors: Emily Drzymalla, Laura Raffield, Katherine Kolor, Alain Koyama, Ramal Moonesinghe, Meda E. Pavkov, Cassandra N. Spracklen, Muin J. Khoury
Journal: Diabetes Care (2025)

OBJECTIVE The goal of this study was to assess the additive value of considering type 2 diabetes (T2D) polygenic risk score (PRS) in addition to family history for T2D prediction. RESEARCH DESIGN AND METHODS Data were obtained from the All of Us (AoU) research database. First-degree T2D family history was self-reported on the personal family history health questionnaire. A PRS was constructed from 1,289 variants identified from a large multiancestry genome-wide association study meta-analysis for T2D. Logistic regression models were run to generate odds ratios (ORs) and 95% CIs for T2D. All models were adjusted for age, sex, and BMI. RESULTS A total of 109,958 AoU research participants were included in the analysis. The odds of T2D increased with 1 SD PRS (OR 1.75; 95% CI 1.71–1.79) and positive T2D family history (OR 2.32; 95% CI 2.20–2.43). In the joint model, both 1 SD PRS (OR 1.69; 95% CI 1.65–1.72) and family history (OR 2.06; 95% CI 1.98–2.15) were significantly associated with T2D, although the ORs were slightly attenuated. Predictive models that included both the PRS and family history (area under the curve [AUC] 0.794) performed better than models including only family history (AUC 0.763) or the PRS (AUC 0.785). CONCLUSIONS In predicting T2D, inclusion of a T2D PRS in addition to family history of T2D (first-degree relatives) added statistical value. Further study is needed to determine whether consideration of both family history and a PRS would be useful for clinical T2D prediction.
Human Epidermal Growth Factor Receptor 2 Loss Following Treatment with Trastuzumab Deruxtecan in Patients with Metastatic Breast Cancer
Authors: Mohamed A. Gouda, Amrit Gonugunta, Ecaterina E. Dumbrava, Timothy A. Yap, Jordi Rodon, Sarina A. Piha-Paul, Paula R. Pohlmann, Senthil Damodaran, Rashmi Murthy, Vicente Valero, Jason Mouabbi, Debu Tripathy, Aysegul A. Sahin, Hui Chen, Funda Meric-Bernstam
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Trastuzumab deruxtecan (T-DXd) is currently approved for treating metastatic breast cancer (MBC) which is HER2-positive (immunohistochemistry [IHC] score of 3+ or ISH positivity) or HER2-low (IHC score of 1+ or IHC 2+/ISH negative), as well as for HER2-positive gastric cancer, HER2-mutant lung cancer, and HER2 overexpressing solid tumors. Given the increasing utilization of T-DXd, we sought to determine how HER2 receptor status might change following T-DXd therapy. Design: We retrospectively reviewed patients with MBC who received T-DXd at The University of Texas MD Anderson Cancer Center. We included patients with paired pre- and post-treatment biopsies assessed for HER2 status using IHC. Results: We included 41 patients with MBC who received treatment with T-DXd, and had paired pre- and post-treatment biopsies assessed for HER2 status using IHC. HER2 loss was observed in 11 patients (32.4% of 34 patients with pre-treatment HER2 expression (1+, 2+, or 3+)) following treatment with T-DXd. In addition to the 11 patients with HER2 loss, another 10 patients (29.4%) had a decrease in HER2 score after treatment with T-DXd. Conclusions: HER2 loss and decrease in HER2 expression are common in patients with MBC receiving treatment with T-DXd. Re-evaluation of HER2 status post-T-DXd should be considered prior to certain alternate HER2-targeted therapies which require HER2 overexpression for efficacy.
Pretargeted Trop-2 immunoPET for rapid, selective detection of pancreatic tumors
Authors: Edwin C. Pratt, Komal Mandleywala, David Bauer, Alexander Bolaender, Grace Chao, Mark A. Castanares, Emily C. Collins, Jason S. Lewis
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Recent clinical advances with the approval of antibody-drug conjugates targeting Trop-2 such as sacituzumab-govitecan and datopotomab-deruxtecan have garnered tremendous interest for their therapeutic efficacy in numerous tumor types including breast and lung cancers. ImmunoPET can stratify tumor avidity, clarifying patient eligibility for ADC therapy as well as a diagnostic companion during therapy. Slow antibody circulation requires days to reach optimal imaging timepoints. To overcome this shortfall, bioorthogonal click chemistry for pretargeting can be employed, decoupling antibody circulation time and the delivery of the radionuclide. Experimental Design: Here we report the characterization of a new full-length Trop-2.2 antibody showing high affinity for Trop-2 positive cancers and leverage different site selective labeling and pretargeting radionuclide combinations to yield rapid imaging with minimal radionuclide footprint after imaging. Three pretargeting strategies for Fluorine-18, Copper-64, and Zirconium-89 were explored in addition to site specific bioconjugation. Results: We found pretargeting with [64Cu]Cu-Sar-Tz to yield the best images identifying Trop-2 positive tumors with optimal tumor-to-background ratios. Intriguingly we found the full-length antibody when directly conjugated, yielded rapid accumulation starting at 3 hours post injection and leading to over 50% injected activity per gram in the tumor before 24 hours. Conclusions: [89Zr]Zr-DFO-Trop-2 as well as pretargeting with [64Cu]Cu-Sar-Tz are viable imaging strategies to quickly identify Trop-2 positive tumors for subsequent Trop-2 therapies.
Effects of Acute Phase Intensive Exercise Training in Patients With Acute Decompensated Heart Failure
Authors: Kentaro Kamiya, Shinya Tanaka, Hiroshi Saito, Masashi Yamashita, Ryusuke Yonezawa, Nobuaki Hamazaki, Ryota Matsuzawa, Kohei Nozaki, Yoshiko Endo, Kazuki Wakaume, Shota Uchida, Emi Maekawa, Yuya Matsue, Makoto Suzuki, Takayuki Inomata, Junya Ako
Journal: JACC Heart Failure (2025)
Elevated Neutrophil-to-Lymphocyte Ratio Predicts Prognosis in Acute Myocarditis
Authors: Antonio Cannata, Amitai Segev, Cristina Madaudo, Emanuele Bobbio, Chiara Baggio, Jonathan Schütze, Piero Gentile, Marta Sanguineti, Luca Monzo, Matteo Schettino, Emma Ferone, Ahmed Elshanoury, Anan Younis, Matteo Palazzini, Adriana Ferroni, Valentina Giani, Matthew Sadler, Daniela Di Lisi, Mohammad Albarjas, Leonardo Calò, Daniel Sado, Christian Lars Polte, Andrea Garascia, Paul A. Scott, Ajay M. Shah, Mauro Giacca, Gianfranco Sinagra, Entela Bollano, Theresa McDonagh, Carsten Tschöpe, Giuseppina Novo, Enrico Ammirati, Roy Beigel, Christoph Gräni, Marco Merlo, Pietro Ameri, Daniel I. Bromage
Journal: JACC Heart Failure (2025)
Hypoxia as a medicine
Authors: Robert S. Rogers, Vamsi K. Mootha
Journal: Science Translational Medicine (2025)

Oxygen is essential for human life, yet a growing body of preclinical research is demonstrating that chronic continuous hypoxia can be beneficial in models of mitochondrial disease, autoimmunity, ischemia, and aging. This research is revealing exciting new and unexpected facets of oxygen biology, but translating these findings to patients poses major challenges, because hypoxia can be dangerous. Overcoming these barriers will require integrating insights from basic science, high-altitude physiology, clinical medicine, and sports technology. Here, we explore the foundations of this nascent field and outline a path to determine how chronic continuous hypoxia can be safely, effectively, and practically delivered to patients.
Cardiac allograft tolerance can be achieved in nonhuman primates by donor bone marrow and kidney cotransplantation
Authors: Makoto Tonsho, Jane M. O, Kaitlan Ahrens, Kortney Robinson, Wiebke Sommer, Svjetlan Boskovic, Parth M. Patel, David C. Becerra, Kyu Ha Huh, Cynthia L. Miller, Abbas Dehnadi, Isabel Hanekamp, Ivy A. Rosales, Robert B. Colvin, David H. Sachs, Alessandro Alessandrini, A. Cosimi, Robert L. Fairchild, Paolo Cravedi, Sofia Bin, Peter S. Heeger, James S. Allan, Tatsuo Kawai, Gilles Benichou, Joren C. Madsen
Journal: Science Translational Medicine (2025)

Long-term, immunosuppression-free allograft survival has been induced in human and nonhuman primate (NHP) kidney recipients after nonmyeloablative conditioning and donor bone marrow transplantation (DBMT), resulting in transient mixed hematopoietic chimerism. However, the same strategy has consistently failed in NHP heart transplant recipients. Here, we investigated whether long-term heart allograft survival could be achieved by cotransplanting kidneys from the same donor. Cynomolgus monkeys were transplanted with heart allografts alone or heart and kidney allografts from the same major histocompatibility complex (MHC)–mismatched donors. All animals except one received DBMT, either at the same time or after a 2- to 4-month delay, plus short-term costimulation blockade and calcineurin inhibitor treatment. Long-term, immunosuppression-free heart allograft survival was consistently achieved in heart/kidney, but not heart-alone, recipients. This was not associated with greater donor/recipient histocompatibility or altered lymphoid cell reconstitution after conditioning. The maintenance of tolerance after heart/kidney transplantation was associated with the presence of forkhead box P3 (Foxp3 + ) regulatory T cell (T reg )–rich organized lymphoid structures in kidneys but not hearts. Substituting high-dose erythropoietin treatment for kidney transplantation was unsuccessful, suggesting that it was not the sole mechanism of action. RNA sequencing analysis revealed that gene expression in hearts from tolerant recipients closely resembled that in hearts from chronically immunosuppressed recipients but differed markedly from rejecting allografts and naïve hearts. A version of this protocol may be able to induce tolerance in patients with end-stage heart and kidney failure who require combined heart and kidney transplantation.
Triple knockdown of <i>CD11a</i> , <i>CD49d</i> , and <i>PSGL1</i> in T cells reduces CAR-T cell toxicity but preserves activity against solid tumors in mice
Authors: Hongye Wang, Zhaorong Wu, Dan Cui, Linke Bian, Zhigang Zheng, Jiufei Zhu, Haigang Geng, Zhen Sun, Yixiao Pan, Yaoping Shi, Qiaoyong Yi, Zhenyu Song, Yantao Li, Kangjie Shen, Yuan Li, Weiming Shen, Hexin Yan, Ruidong Hao, Minmin Sun, Shuangshung Zhang, Chuanjie Zhang, Haojie Jin, Bo Zhai
Journal: Science Translational Medicine (2025)

Chimeric antigen receptor (CAR)–T cell therapies have revolutionized the landscape of cancer treatment, in particular in the context of hematologic malignancies. However, for solid tumors that lack tumor-specific antigens, CAR-T cells can infiltrate and attack nonmalignant tissues expressing the CAR target antigen, leading to on-target, off-tumor toxicity. Severe on-target, off-tumor toxicities have been observed in clinical trials of CAR-T therapy for solid tumors, highlighting the need to address this issue. Here, we demonstrated that targeting the cell adhesion and migration molecules lymphocyte function–associated antigen 1 (LFA-1; CD11a/CD18) and very late activation antigen 4 (VLA-4; CD49d/CD29) with blocking antibodies reduced the on-target, off-tumor toxicity of CAR-T cells in mice. To translate this observation into improved CAR-T cell therapy, we either knocked out both CD11a and CD49d or knocked down CD11a and CD49d along with PSGL1 , another cell adhesion molecule, in CAR-T cells. We found that these modified CAR-T cells exhibited reduced on-target, off-tumor toxicity in vivo without affecting CAR-T cell efficacy. Furthermore, we showed that this approach promoted T cell memory formation and decreased tonic signaling. On the basis of these data, we engineered a human version of these low-toxicity CAR-T cells and further validated the feasibility of this approach in vitro and in vivo. Together, these results provide a potential solution to address the clinical challenge of on-target, off-tumor toxicity in CAR-T therapy.
Perinatal dysfunction of innate immunity in cystic fibrosis
Authors: Florian Jaudas, Florian Bartenschlager, Bachuki Shashikadze, Gianluca Santamaria, Daniel Reichart, Alexander Schnell, Jan Bernd Stöckl, Roxane L. Degroote, Josep M. Cambra, Simon Y. Graeber, Andrea Bähr, Heike Kartmann, Monika Stefanska, Huan Liu, Nora Naumann-Bartsch, Heiko Bruns, Johannes Berges, Lea Hanselmann, Michael Stirm, Stefan Krebs, Cornelia A. Deeg, Helmut Blum, Christian Schulz, Dorota Zawada, Melanie Janda, Ignacio Caballero-Posadas, Karl Kunzelmann, Alessandra Moretti, Karl-Ludwig Laugwitz, Christian Kupatt, Armin Saalmüller, Thomas Fröhlich, Eckhard Wolf, Marcus A. Mall, Lars Mundhenk, Wilhelm Gerner, Nikolai Klymiuk
Journal: Science Translational Medicine (2025)

In patients with cystic fibrosis (CF), repeated cycles of infection and inflammation eventually lead to fatal lung damage. Although diminished mucus clearance can be restored by highly effective CFTR modulator therapy, inflammation and infection often persist. To elucidate the role of the innate immune system in CF etiology, we investigated a CF pig model and compared these results with those for preschool children with CF. In newborn CF pigs, we observed changes in lung immune cell composition before the onset of infection that were dominated by increased monocyte infiltration, whereas neutrophil numbers remained constant. Flow cytometric and transcriptomic profiling revealed that the infiltrating myeloid cells displayed a more immature status. Cells with comparably immature transcriptomic profiles were enriched in the blood of CF pigs at birth as well as in preschool children with CF. This pattern coincided with decreased CD16 expression in the myeloid cells of both pigs and humans, which translated into lower phagocytic activity and reduced production of reactive oxygen species in both species. These results were indicative of a congenital, translationally conserved, and functionally relevant aberration of the immune system in CF. In newborn wild-type pigs, CFTR transcription in immune cells, including lung-derived and circulating monocytes, isolated from the bone marrow, thymus, spleen, and blood was below the detection limits of highly sensitive assays, suggesting an indirect etiology of the observed effects. Our findings highlight the need for additional immunological treatments to target innate immune deficits in patients with CF.