tbuckley/cabot-search huggingface dataset:
Randomized controlled study of a digital data driven intervention for depressive and generalized anxiety symptoms
Authors: Panagiotis Fatouros, Charalampos Tsirmpas, Dimitrios Andrikopoulos, Sharon Kaplow, Konstantinos Kontoangelos, Charalabos Papageorgiou
Journal: npj Digital Medicine (2025)

As mental health disorders like Major Depressive Disorder and Generalized Anxiety Disorder rise globally, effective, scalable, and personalized treatments are urgently needed. This 16-week prospective, decentralized, randomized, waitlist-controlled study investigated the effectiveness of a digital data-driven therapeutic integrating wearable sensor data with a mobile app to deliver personalized CBT-based interventions for individuals with depressive and generalized anxiety symptoms. 200 adults were randomized to intervention or control groups, with 164 completing the study. The intervention group demonstrated significant reductions in depressive (mean change = −5.61, CI = −7.14, −4.08) and anxiety symptoms (mean change = −5.21, CI = −6.66, −3.76), compared to the control group, with medium-to-large effect sizes (r = 0.64 and r = 0.62, P < 0.001). Notably, these improvements were also observed in participants with clinically significant depression and anxiety, further reinforcing the potential of digital therapeutics in targeting more severe cases. These findings, combined with high engagement levels, suggest that data-driven digital health interventions could complement traditional treatments, though further research is needed to assess their long-term impact.
A Hitchhiker’s Guide to Antibody-Mediated Rejection
Authors: Parmjeet Randhawa
Journal: New England Journal of Medicine (2025)

Antibody-mediated rejection is an important determinant of allograft survival. Our understanding of antibody-mediated rejection has increased dramatically since the era when only hyperacute antibody-mediated rejection was known. Subacute, acute, and slowly progressive antibody-mediated rejection were subsequently recognized. Many aspects regarding the diagnosis and grading of allograft rejection have been developed through the Banff Classification of Allograft Pathology, an international consensus classification system for the reporting of biopsy specimens obtained from patients with solid-organ transplants. Since its 1991 inception, the Banff Classification of Renal Allograft Pathology has undergone review every 2 years. The diagnosis of antibody-mediated kidney allograft rejection is based . . .
Catheter Ablation for Ventricular Tachycardia — The Case for Earlier Intervention
Authors: Timothy M Markman
Journal: New England Journal of Medicine (2025)

Catheter ablation as a treatment for ventricular tachycardia has lagged behind ablation procedures for atrial arrhythmias in becoming an established first-line therapy. Barriers to the study of catheter ablation for ventricular tachycardia are substantial and include technical and procedural challenges, which have contributed to disappointing results and difficulties in evaluating the efficacy of this rapidly evolving procedure. Nevertheless, ablation is an increasingly effective treatment for ventricular tachycardia, and it is a highly attractive option, given the limited efficacy and frequent adverse effects of antiarrhythmic drug therapy.1-4 The Ventricular Tachycardia Ablation versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease (VANISH) . . .
Reduced‐volume radiotherapy versus conventional‐volume radiotherapy after induction chemotherapy in nasopharyngeal carcinoma: An open‐label, noninferiority, multicenter, randomized phase 3 trial
Authors: Ling‐Long Tang, Lin Chen, Gui‐Qiong Xu, Ning Zhang, Cheng‐Long Huang, Wen‐Fei Li, Yan‐Ping Mao, Guan‐Qun Zhou, Feng Lei, Lu‐Si Chen, Shao Hui Huang, Lei Chen, Yu‐Pei Chen, Yuan Zhang, Xu Liu, Cheng Xu, Yin Zhao, Ji‐Bin Li, Na Liu, Fang‐Yun Xie, Rui Guo, Ying Sun, Jun Ma
Journal: CA A Cancer Journal for Clinicians (2025)

Abstract Background Nearly 90% locoregionally advanced nasopharyngeal carcinoma (LANPC) responds to induction chemotherapy (IC) with significant tumor volume shrinkage. Radiotherapy always follows IC, and reduced volume has been proposed. However, the efficacy and safety of reduced‐volume radiotherapy is uncertain. Methods In this multi‐center, noninferiority, randomized, controlled trial, patients with LANPC who completed IC were randomly assigned (1:1) to receive reduced‐volume radiotherapy based on post‐IC tumor volume (Post‐IC group) or conventional volume radiotherapy based on pre‐IC tumor volume (Pre‐IC group). The primary endpoint was locoregional relapse‐free survival, with a noninferiority margin of 8%. Secondary endpoints comprised adverse events, and quality of life (QoL). Results Between August 7, 2020, and May 27, 2022, 445 patients were randomly assigned to Post‐IC ( n = 225) or Pre‐IC ( n = 220) groups. The average volume receiving radical dose was 66.6 cm 3 in Post‐IC group versus 80.9 cm 3 . After a median follow‐up of 40.4 months, the 3‐year locoregional relapse‐free survival was 91.5% in the Post‐IC group versus 91.2%, with a difference of 0.3% (95% confidence interval −4.9% to 5.5%). The incidence of grade 3‐4 radiation‐related toxicity was lower in the Post‐IC group including: acute mucositis (19.8% vs 34.1%), late otitis media (9.5% vs 20.9%) and late dry month (3.6% vs 9.5%). The Post‐IC group had better QoL for global health status, physical functioning, emotional functioning, dry mouth and sticky saliva. Conclusions In this trial, reduced‐volume radiotherapy was noninferior to conventional volume radiotherapy in locoregional relapse‐free survival, and was associated with lower toxicities and improved QoL. (ClinicalTrials.gov identifier NCT04384627).
Case 6-2025: A 62-Year-Old Man with Abdominal Pain
Authors: Gabrielle K Bromberg, Robert G Rasmussen, Kenneth E Sherman, Sanjeeva P Kalva, Katayoon Goodarzi, Jonathan N Glickman
Journal: New England Journal of Medicine (2025)

A 62-year-old man was admitted because of postprandial abdominal pain and weight loss. Cirrhosis had reportedly been diagnosed 1 year earlier; imaging showed portal vein thrombosis. A diagnosis was made.
Another Win for SGLT2 Inhibitors in Chronic Kidney Disease
Authors: David E Leaf, Nisha Bansal
Journal: New England Journal of Medicine (2025)

Chronic kidney disease affects 14% of the U.S. population1 and is associated with an extraordinarily high risk of poor outcomes, including progression to end-stage kidney disease, cardiovascular events, and death.2 Finally, after decades of therapeutic stagnation, a recent explosion of new therapies has revolutionized treatment options in this vulnerable patient population. Prominent among these therapies are the sodium–glucose cotransporter 2 (SGLT2) inhibitors, as described in landmark trials, including the EMPA-KIDNEY trial of empagliflozin in 2023.3 In this issue of the Journal,4 Herrington et al. report the long-term results of the EMPA-KIDNEY follow-up trial involving patients with chronic kidney disease who . . .
Risdiplam for Prenatal Therapy of Spinal Muscular Atrophy
Authors: Richard S Finkel, Samuel H Hughes, JulieAnn Parker, Matthew Civitello, Alfonso Lavado, Heather C Mefford, Lutz Mueller, Heidemarie Kletzl
Journal: New England Journal of Medicine (2025)

The alternate splicing small molecule risdiplam, administered to a fetus with spinal muscular atrophy, had an apparent ameliorating effect on the disorder through 30 months.
Mechanical Ventilation in Patients with Acute Brain Injuries – A Pathophysiology-based Approach
Authors: Dimitrios Georgopoulos, Shaurya Taran, Maria Bolaki, Evangelia Akoumianaki
Journal: American Journal of Respiratory and Critical Care Medicine (2025)

Applying mechanical ventilation and selecting ventilatory strategies in patients with acute brain injuries, especially those with lung damage, is challenging. Static (positive-end-expiratory-pressure) and dynamic (intra-tidal) changes in ventilator pressure, via complex pathways, influence cerebral arterial inflow and cerebral venous pressure and thus, cerebral blood volume and intracranial pressure. In this process, the relationship between airway pressure and pleural and trans-alveolar pressures, heavily affected by elastance of chest wall and lung, respectively, plays a central role. This relationship determines the extent to which a static and dynamic increase in airway pressure affect the cardiac function and venous return curves, which govern the static and dynamic arterial and central venous pressures. The integrity of cerebral autoregulation determines whether static changes in arterial pressure alter cerebral arterial inflow. Conversely, dynamic changes in arterial pressure during the breath are followed by corresponding changes in cerebral arterial inflow, due to inability of autoregulation to control rapid arterial pressure fluctuations. The flow dynamics in the jugular veins and the relationship between intracranial and sagittal sinus pressures determine whether static and dynamic changes in central venous pressure alter cerebral venous pressure. Setting the ventilator and planning strategies should be individualized and guided by the complex, interactive effects among central nervous, respiratory and cardiovascular systems on cerebral blood volume and cerebral perfusion and intracranial pressures. Following a logical framework, the clinician may anticipate the likely effects of ventilator settings and strategies on cerebral hemodynamics, enabling a more individualized approach in setting the ventilator and planning ventilatory strategies.
Effectiveness and safety of the recombinant zoster vaccine in individuals ≥50 years of age with rheumatoid arthritis: a matched cohort and self-controlled case series study
Authors: Emily Rayens, Lina S Sy, Lei Qian, Jun Wu, Bradley K Ackerson, Yi Luo, Yanjun Cheng, Antony T Lin, Zendi Solano, Justine De Jesus, Britta Amundsen, Ana Florea, Jennifer H Ku, Elizabeth Chmielewski-Yee, Driss Oraichi, Harry Seifert, Huifeng Yun, Hung Fu Tseng
Journal: Annals of the Rheumatic Diseases (2025)

In an interim analysis, we evaluated vaccine effectiveness (VE) against herpes zoster (HZ) and postherpetic neuralgia (PHN) and safety of recombinant zoster vaccine (RZV) in adults aged ≥50 years with rheumatoid arthritis (RA). VE was assessed using a retrospective matched cohort analysis of Kaiser Permanente Southern California members aged ≥50 years with RA receiving 2 RZV doses (≥4 weeks apart) and matched up to 1:3 to RZV-unvaccinated individuals. Stratified Cox proportional hazards regression was used to estimate adjusted hazard ratios and VE against HZ and PHN. Safety was assessed using a self-controlled case series analysis of chart-confirmed RA flare within 30 days after any RZV vaccination versus comparison periods. The relative risk (RR) was estimated using conditional Poisson regression. In adults ≥50 years with RA (2-dose vaccinated: 1926; unvaccinated: 5746), the adjusted VE of 2 RZV doses against HZ was 60.7% (95% CI, 41.0%-73.8%); in a subgroup analysis among those who received 2 doses 4 weeks to 6 months apart, VE against HZ was 57.9% (95% CI, 34.4%-73.0%). Adjusted VE of 2 RZV doses against PHN was 88.7% (95% CI, 12.1%-98.5%). Among 2606 adults with RA who received ≥1 RZV dose, no increased risk of RA flares within 30 days after RZV vaccination was observed (RR, 1.02; 95% CI, 0.75-1.37). Among adults ≥50 years with RA, 2 RZV doses provided protection against HZ and PHN. The study did not observe an increased risk of RA flares within 30 days following RZV vaccination.
Targeting PRC2 Enhances the Cytotoxic Capacity of Anti-CD19 CAR-T Cells Against Hematological Malignancies
Authors: Maria Leticia R. Carvalho, Clara O. Andrade, Mariela P. Cabral-Piccin, Gabriela S. Kinker, Glauco A. F. Vitiello, Raylane A. G. Cambui, Luiza Abdo, Eduardo Mannarino, Bruno D. S. Elias, Emmanuel Vinicius O. Araujo, Alexandre S. Chaves, Pedro Henrique B. Pereira, Karina Hajdu, Amanda Rondinelli, Arianne Gusmao, Maria Luisa M. Pierre, Igor Brasil-Costa, Caroline P. Zanella, Marta Maria M. Lemos, Marjorie V. Batista, Jayr S. Filho, Cheryl Arrowsmith, Vladmir Cordeiro de Lima, Martin Bonamino, Tiago da Silva Medina
Journal: Cancer Research (2025)

Abstract Chimeric antigen receptor (CAR) T cell therapy is increasingly being adopted as a clinical modality for patients with relapsed/refractory hematological malignancies. Despite the clinical efficacy of CAR-T cell therapy, a considerable fraction of patients still relapses during the first months following CAR-T cell infusion. The limited CAR-T cell efficiency is thought to relate to epigenetic mechanisms involved in T cell suppression and dysfunction. Here, screening of multiple epigenetic inhibitors revealed that targeting PRC2 consistently induced the development of granzyme B+ effector memory CD8+ T cells. Notably, PRC2 inhibition also promoted the long-term persistence of granzyme B+ effector memory 19BBζ CAR-T cells and sustainably enhanced their antitumor activity both in vitro and in vivo. Consistent with their long-lasting antitumor activity, PRC2-inhibited 19BBζ CAR-T cells did not exhibit signs of exhaustion over time. Furthermore, TCR restimulation along with PRC2 inhibition promoted the differentiation of patient-derived anti-CD19 CAR-T cells to a granzyme B+ effector memory phenotype with enhanced cytotoxic features that elicited potent antitumor responses. A gene signature derived from in-house PRC2-inhibited 19BBζ CAR-T cells was enriched in tisagenlecleucel (tisa-cel) BBζ CAR-T cell therapy responders with large B-cell lymphoma. Collectively, these results demonstrate that targeting PRC2 may be a promising approach to enhance a functional effector program in CAR-T cells to improve the efficacy in treating hematological malignancies.
Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling
Authors: Nicholas C. DeVito, Y-Van Nguyen, Michael Sturdivant, Michael P. Plebanek, Kaylee A. Villarreal, Nagendra Yarla, Vaibhav Jain, Michael Aksu, Georgia M. Beasley, Balamayooran Theivanthiran, Brent A. Hanks
Journal: Cancer Research (2025)

Abstract Therapeutic resistance to immune checkpoint blockade has been commonly linked to the process of mesenchymal transformation (MT) and remains a prevalent obstacle across many cancer types. An improved mechanistic understanding for MT-mediated immune evasion promises to lead to more effective combination therapeutic regimens. Herein, we identified the Hedgehog transcription factor, GLI2, as a key node of tumor-mediated immune evasion and immunotherapy resistance during MT. GLI2 generated an immunotolerant tumor microenvironment through the upregulation of WNT ligand production and increased prostaglandin synthesis. This pathway drove the recruitment, viability, and function of granulocytic myeloid-derived suppressor cells while also impairing type I conventional dendritic cell, CD8+ T cell, and natural killer cell functionality. Pharmacologic inhibition of EP2/EP4 prostaglandin receptor signaling or WNT ligand secretion each reversed a subset of the immunomodulatory effects of GLI2 and prevented primary and adaptive resistance to anti-PD-1 immunotherapy, respectively. A transcriptional GLI2 signature correlated with resistance to anti-PD-1 immunotherapy in stage IV melanoma patients. Together, these findings provide a translational roadmap to direct combination immunotherapies in the clinic.
Dysfunctional CD11c <sup>−</sup> CD21 <sup>−</sup> extrafollicular memory B cells are enriched in the periphery and tumors of patients with cancer
Authors: Ayana T. Ruffin, Allison N. Casey, Sheryl R. Kunning, Ian P. MacFawn, Zhentao Liu, Charu Arora, Anjali Rohatgi, Felicia Kemp, Caleb Lampenfeld, Ashwin Somasundaram, Giovanna Rappocciolo, John M. Kirkwood, Umamaheswar Duvvuri, Raja Seethala, Riyue Bao, Yufei Huang, Anthony R. Cillo, Robert L. Ferris, Tullia C. Bruno
Journal: Science Translational Medicine (2025)

Many patients with recurrent and metastatic cancer fail to produce a durable response to immunotherapy, highlighting the need for additional therapeutic targets to improve the immune landscape in tumors. Recent studies have highlighted the importance of B cells in the antitumor response, with memory B cells (MBCs) being prognostic in a variety of solid tumors. MBCs are a heterogenous B cell subset and can be generated through both germinal center reactions and extrafollicular (EF) responses. EF-derived MBCs have been recently linked to poor prognosis and treatment resistance in solid tumors and thus may represent candidate biomarkers or immunotherapy targets. EF-derived MBCs, termed “double-negative” (DN) MBCs may be further classified on the basis of surface expression of CD11c and CD21 into DN1, DN2, and DN3 MBCs. CD11c − CD21 + DN1 MBCs and CD11c + CD21 − DN2 MBCs have been well studied across inflammatory diseases; however, the biology and clinical relevance of CD11c − CD21 − DN3 MBCs remain unknown. Here, we report an accumulation of DN3 MBCs in the blood and tumors of patients with head and neck squamous cell carcinoma (HNSCC) and an increase in DN3 MBCs in locally advanced HNSCC tumors. Circulating and intratumoral DN3 MBCs were hyporesponsive to antigen stimulation, had low antibody production, and failed to differentiate into antibody-secreting cells. Moreover, DN3 MBCs accumulated selectively outside of tertiary lymphoid structures. Last, circulating DN3 MBCs correlated with poor therapeutic response, advanced disease, and worse outcomes in patients with HNSCC and melanoma, supporting further assessment of EF-derived MBCs as potential biomarkers and therapeutic targets.
Inhibiting mechanotransduction prevents scarring and yields regeneration in a large animal model
Authors: Shamik Mascharak, Michelle Griffin, Heather E. Talbott, Jason L. Guo, Jennifer Parker, Annah Grace Morgan, Caleb Valencia, Maxwell Michael Kuhnert, Dayan J. Li, Norah E. Liang, Rachel M. Kratofil, Joseph A. Daccache, Ikjot Sidhu, Michael F. Davitt, Nicholas Guardino, John M. Lu, Darren B. Abbas, Nestor M. D. Deleon, Christopher V. Lavin, Sandeep Adem, Anum Khan, Kellen Chen, Dominic Henn, Amanda Spielman, Asha Cotterell, Deena Akras, Mauricio Downer, Ruth Tevlin, H. Peter Lorenz, Geoffrey C. Gurtner, Michael Januszyk, Shruti Naik, Derrick C. Wan, Michael T. Longaker
Journal: Science Translational Medicine (2025)

Modulating mechanotransduction by inhibiting yes-associated protein (YAP) in mice yields wound regeneration without scarring. However, rodents are loose-skinned and fail to recapitulate key aspects of human wound repair. We sought to elucidate the effects of YAP inhibition in red Duroc pig wounds, the most human-like model of scarring. We show that one-time treatment with verteporfin, a YAP inhibitor, immediately after wounding is sufficient to prevent scarring and to drive wound regeneration in pigs. By performing single-cell RNA sequencing (scRNA-seq) on porcine wounds in conjunction with spatial proteomic analysis, we found perturbations in fibroblast dynamics with verteporfin treatment and the presence of putative pro-regenerative/profibrotic fibroblasts enriched in regenerating/scarring pig wounds, respectively. We also identified differences in enriched myeloid cell subpopulations after treatment and linked this observation to increased elaboration of interleukin-33 (IL-33) in regenerating wounds. Finally, we validated our findings in a xenograft wound model containing human neonatal foreskin engrafted onto nude mice and used scRNA-seq of human wound cells to draw parallels with fibroblast subpopulation dynamics in porcine wounds. Collectively, our findings provide support for the clinical translation of local mechanotransduction inhibitors to prevent human skin scarring, and they clarify a YAP/IL-33 signaling axis in large animal wound regeneration.
A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma
Authors: Veronica Rendo, Eudocia Q. Lee, Connor Bossi, Nicholas Khuu, Michelle A. Rudek, Sangita Pal, Narmen Azazmeh, Rumana Rashid, Jia-Ren Lin, Margaret Cusick, Abigail R. N. Reynolds, Auriole C. R. Fassinou, Georges Ayoub, Seth Malinowski, Emily Lapinskas, William Pisano, John Jeang, Sylwia A. Stopka, Michael S. Regan, Johan Spetz, Arati Desai, Frank Lieberman, Kamalakannan Palanichamy, Joy D. Fisher, Kristine Pelton, Raymond Y. Huang, Kristopher A. Sarosiek, Louis B. Nabors, Matthias Holdhoff, Neeraja Danda, Roy Strowd, Serena Desideri, Tobias Walbert, Xiaobu Ye, Arnab Chakravarti, Peter K. Sorger, Sandro Santagata, Nathalie Y. R. Agar, Stuart A. Grossman, Brian M. Alexander, Patrick Y. Wen, Keith L. Ligon, Rameen Beroukhim
Journal: Science Translational Medicine (2025)

Inhibitors of murine double minute homolog 2 (MDM2) represent a promising therapeutic approach for the treatment of TP53 wild-type glioblastomas (GBMs), reactivating p53 signaling to induce cancer cell death. We conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) in 21 patients with TP53 wild-type recurrent GBM to determine achievable drug concentrations within tumor tissues and biological mechanisms of response and resistance. Participants received navtemadlin at 120 mg ( n = 10) or 240 mg ( n = 11) for 2 days before surgical resection and after surgery until progression or unacceptable toxicity. Both 120 and 240 mg daily dosing achieved a pharmacodynamic impact, but median progression-free survival was 3.1 months. DNA sequencing of three recurrent tumors revealed an absence of TP53 -inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived GBM neurosphere models. Navtemadlin induced partial tumor cell death as monotherapy, and combination with temozolomide enhanced apoptosis in GBM neurospheres while sparing normal bone marrow cells in vitro. We also observed up-regulation of oligodendrocyte differentiation genes with navtemadlin treatment and enrichment of oligodendrocyte transcription factor 2 (OLIG2)–positive cells at relapse, suggesting an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicated that clinically achievable doses of navtemadlin exert pharmacodynamic effects on GBM and suggest that combined treatment with temozolomide may be a route to more durable survival benefits.