tbuckley/cabot-search huggingface dataset:
PAI-1-driven SFRP2high cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy
Authors: Yan-Pei Zhang, Ze-Qin Guo, Xiao-Ting Cai, Zi-Xuan Rong, Yuan Fang, Jia-Qi Chen, Kui-Mao Zhuang, Min-Jie Ruan, Si-Cong Ma, Le-Yi Lin, Duan-Duan Han, Yang-Si Li, Yuan-Yuan Wang, Jian Wang, Chuan-Hui Cao, Xin-Ran Tang, Qian-Kun Xie, Yue Chen, Yan Lin, Jia-Le Tan, Zi-Hang Yu, Ze-Nan Wu, Wei Wei, Da-Yong Zheng, Yu-Jie Zeng, Ying-Chen Ruan, Zi-Peng Xu, Jun-Zi Gu, Lu-Shan Xiao, Li Liu, Jian Guan, Xue Bai, De-Hua Wu, Zhong-Yi Dong
Journal: Cancer Cell (2025)
Silencing PTPN2 with nanoparticle-delivered small interfering RNA remodels tumor microenvironment to sensitize immunotherapy in hepatocellular carcinoma
Authors: Fu Wang, Haoyu You, Huahua Liu, Zhuoran Qi, Xuan Shi, Zhiping Jin, Qingyang Zhong, Taotao Liu, Xizhong Shen, Sergii Rudiuk, Jimin Zhu, Tao Sun, Chen Jiang
Journal: Acta Pharmaceutica Sinica B (2025)
Sotorasib’s Accelerated Approval
Authors: Mark J. Ratain, Aaron S. Kesselheim
Journal: JAMA Oncology (2025)

This Viewpoint reviews the accelerated approval process and lack of postapproval studies to verify its benefit as it applied to sotorasib, a treatment for non–small cell lung cancer with the KRAS g12c mutation, and recommends measures to ensure confirmatory follow-up studies.
Health Care Contact Days for Older Adults Enrolled in Cancer Clinical Trials
Authors: Arjun Gupta, Cathee Till, Riha Vaidya, Dawn L. Hershman, Joseph M. Unger
Journal: JAMA Network Open (2025)

Importance Contact days—days with health care contact outside the home—are a measure of how much of a patient’s life is consumed by health care. Clinical trials, with a more uniform patient mix and protocolized care, provide a unique opportunity to assess whether burdens differ by individuals’ sociodemographic backgrounds. Objective To characterize patterns of contact days for older adults with cancer participating in clinical trials. Design, Setting, and Participants In this cohort study, data from 6 SWOG Cancer Research Network trials across prostate, lung, and pancreatic cancers that recruited patients aged 65 years or older from 1999 to 2014 were linked with Medicare claims data. Data were analyzed from December 14, 2023, to September 26, 2024. Exposures Demographic variables, including age, sex, self-reported race and ethnicity, and insurance status; clinical factors, such as cancer type and study-specific prognostic risk score; and social factors, such as neighborhood socioeconomic deprivation. Main Outcomes and Measures Number of contact days, defined as number of days with contact with the health care system, percentage of health care contact days (number of contact days divided by follow-up), and sources of contact days (eg, ambulatory or inpatient) in the first 12 months after trial enrollment. Sociodemographic and clinical factors associated with contact days were examined using negative binomial regression, including an offset variable for duration of observation. Results The study included 1429 patients (median age, 71 years [range, 65-91 years]; 1123 men [78.6%]; and 332 patients [23.5%] with rural residence). The median number of contact days was 48 (IQR, 26-71), of a median of 350 days (IQR, 178-365 days) of observation; the median percentage of contact days was 19% (IQR, 13%-29%). The most common sources of contact days were ambulatory clinician visits (median, 17 [IQR, 7-25]), tests (median, 12 [IQR, 3-24]), and treatments (median, 11 [IQR, 3-22]). A median of 70% (IQR, 50%-88%) of ambulatory contact days had only a single service performed on that day (eg, only tests). In multivariable regression, factors associated with increased contact days included age (relative risk [RR] per year, 1.02 [95% CI, 1.01-1.02]), insurance type (Medicare alone or with Medicaid or private insurance vs other: RR, 2.47 [95% CI, 2.16-2.83]), prognostic risk score (above the median vs at or below the median: RR, 1.14 [95% CI, 1.04-1.25]), and type of cancer (pancreatic vs prostate cancer: RR, 1.69 [95% CI, 1.51-1.89]; lung vs prostate cancer: RR, 1.69 [95% CI, 1.54-1.85]). Conclusions and Relevance In this cohort study of older adults with advanced stage cancer participating in phase 3 randomized clinical trials, patients spent nearly 1 in 5 days with health care contact. These findings highlight the need to simplify trial requirements to minimize participant burden.
Vulnerability Index Approach to Identify Pharmacy Deserts and Keystone Pharmacies
Authors: Walter S. Mathis, Lucas A. Berenbrok, Peter A. Kahn, Giovanni Appolon, Shangbin Tang, Inmaculada Hernandez
Journal: JAMA Network Open (2025)

Importance Community pharmacies are crucial for public health, providing essential services such as medication dispensing, vaccinations, and point-of-care testing. Addressing disparities in pharmacy access, particularly in underserved rural and low-income areas, is critical for health equity. Objective To identify areas in the US at risk of becoming pharmacy deserts through the development of a novel pharmacy vulnerability index. Design, Setting, and Participants This population-based cross-sectional study in the contiguous 48 states performed geographic information systems analysis of pharmacy data from the National Council for Prescription Drug Programs (NCPDP) dataQ. Participants included all open-door pharmacies (community or retail pharmacies open to the general public without restrictions on who can access its services) in the US as of February 2024. Statistical analysis was performed from July to August 2024. Exposure The primary exposure was travel time to pharmacies across the US. Main Outcomes and Measures A pharmacy desert was defined as a census tract where the travel time to the nearest pharmacy exceeds the supermarket access time for that region and urbanicity level. Building on this definition, a pharmacy vulnerability index was developed, which indicates the number of pharmacies that would need to close for a census tract to become a pharmacy desert. Tracts with a pharmacy vulnerability index of 1, depending solely on a single pharmacy for access, were identified as at risk of becoming deserts. Subpopulation totals and percentages living in pharmacy deserts or relying on keystone pharmacies were computed, and then stratified by urbanicity and race. Results Among 321.3 million individuals (39.7 million [12.3%] Black, 59.0 million [18.2%] Hispanic, 195.0 million [60.3%] White) in the contiguous US, 57.1 million (17.7%) were identified as living in pharmacy deserts, with 28.9 million (8.9%) additionally relying on a single pharmacy for access. Small rural areas were particularly affected, with a higher dependency on single pharmacies (4.1 million individuals [14.3%]). Conclusions and Relevance In this cross-sectional study of pharmacy access in the US, significant disparities in pharmacy access were identified, especially pronounced in small rural areas. Targeted policy interventions, such as incremental reimbursement rates or other monetary incentives, are needed to ensure the financial sustainability of pharmacies that serve as the sole source of pharmacy services in at-risk areas.
The immune response modulated by inoculation of commensal bacteria at birth impacts the gut microbiota and prevents <i>Salmonella</i> colonization
Authors: Florent Kempf, Rosanna Drumo, Anne Marie Chaussé, Pierrette Menanteau, Tereza Kubasova, Sylvie Roche, Anne Christine Lalmanach, Rodrigo Guabiraba, Thierry Chaumeil, Guillaume Larivière-Gauthier, Ignacio Caballero-Posadas, Béatrice Laroche, Ivan Rychlík, Isabelle Virlogeux-Payant, Philippe Velge
Journal: Gut Microbes (2025)

Super- and low-shedding phenomena have been observed in genetically homogeneous hosts infected by a single bacterial strain. To decipher the mechanisms underlying these phenotypes, we conducted an experiment with chicks infected with Salmonella Enteritidis in a non-sterile isolator, which prevents bacterial transmission between animals while allowing the development of the gut microbiota. We investigated the impact of four commensal bacteria called Mix4, inoculated at hatching, on chicken systemic immune response and intestinal microbiota composition and functions, before and after Salmonella infection. Our results revealed that these phenotypes were not linked to changes in cell invasion capacity of bacteria during infection. Mix4 inoculation had both short- and long-term effects on immune response and microbiota and promoted the low-shedder phenotype. Kinetic analysis revealed that Mix4 activated immune response from day 4, which modified the microbiota on day 6. This change promotes a more fermentative microbiota, using the aromatic compounds degradation pathway, which inhibited Salmonella colonization by day 11 and beyond. In contrast, control animals exhibited a delayed TNF-driven pro-inflammatory response and developed a microbiota using anaerobic respiration, which facilitates Salmonella colonization and growth. This strategy offers promising opportunities to strengthen the barrier effect against Salmonella and possibly other pathogens.
Health outcomes and their association with weight regain after substantial weight loss in Sweden: a prospective cohort study
Authors: Lena M S Carlsson, Ida Arnetorp, Johanna C Andersson-Assarsson, Peter Jacobson, Per-Arne Svensson, Magdalena Taube, Sofie Ahlin, Felipe M Kristensson, Kristjan Karason, Ingrid Larsson, Cecilia Karlsson, Kirsi H Pietiläinen, Ingmar Näslund, Björn Carlsson, Markku Peltonen, Kajsa Sjöholm
Journal: The Lancet Regional Health - Europe (2025)
Continuous time and dynamic suicide attempt risk prediction with neural ordinary differential equations
Authors: Yi-han Sheu, Jaak Simm, Bo Wang, Hyunjoon Lee, Jordan W. Smoller
Journal: npj Digital Medicine (2025)

Current clinician-based and automated risk assessment methods treat the risk of suicide-related behaviors (SRBs) as static, while in actual clinical practice, SRB risk fluctuates over time. Here, we develop two closely related model classes, Event-GRU-ODE and Event-GRU-Discretized, that can predict the dynamic risk of events as a continuous trajectory across future time points, even without new observations, while updating these estimates as new data become available. Models were trained and validated for SRB prediction using a large electronic health record database. Both models demonstrated high discrimination (e.g., Event-GRU-ODE AUROC = 0.93, AUPRC = 0.10, relative risk = 13.4 at 95% specificity in a low-prevalence [0.15%] general cohort with a 1.5-year prediction window). This work provides an initial step toward developing novel suicide prevention strategies based on dynamic changes in risk.
Potent and durable control of mesothelin-expressing tumors by a novel T cell-secreted bi-specific engager
Authors: Paris Kosti, Johan Abram-Saliba, Laetitia Pericou-Troquier, Sarah Pavelot, Tiphaine Ruggeri, Marc Laffaille, Melita Irving, George Coukos, Evripidis Lanitis, Steven M Dunn
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The glycosylphosphatidylinositol-anchored cell surface protein mesothelin (MSLN) shows elevated expression in many malignancies and is an established clinical-stage target for antibody-directed therapeutic strategies. Of these, the harnessing of autologous patient T cells via engineered anti-MSLN chimeric antigen receptors (CAR-T) is an approach garnering considerable interest. Although generally shown to target tumor MSLN safely, CAR-T trials have failed to deliver the impressive curative or response metrics achieved for hematological malignancies using the same technology. A need exists, therefore, for improved anti-MSLN molecules and/or more optimal ways to leverage immune effector cells. Methods We performed ELISA, label-free kinetic binding assays, FACS, Western blotting, and transient recombinant MSLN expression to characterize the recognition properties of a novel CAR-active human scFv clone, LABC-13F08. To investigate T cell redirection, we conducted kinetic IncuCyte co-culture killing assays using transduced primary T cells and MSLN + target cell lines and assessed levels of activation markers and effector cytokines. The antitumor potential of LABC-13F08 formatted as a bispecific engager (BiTE) was evaluated in vivo using transduced human primary T cells and immunocompromised NSG mice xenografted with ovarian, mesothelioma, and pancreatic MSLN + tumor cell lines. Results The LABC-13F08 scFv is highly unusual and distinct from existing (pre)clinical anti-MSLN antibody fragments, exhibiting an absolute requirement for divalent cations to drive MSLN recognition. As a monovalent BiTE, LABC-13F08 demonstrates robust in vitro potency. Additionally, primary human T cells engineered for constitutive secretion of the 13F08 BiTE exhibit strong antitumor activity toward in vivo ovarian and mesothelioma xenograft models and show encouraging levels of monotherapy control in a challenging pancreatic model. LABC-13F08 BiTE secreted from engineered T cells (BiTE-T) can both recruit non-engineered bystander T cells and also induce activation-dependent MSLN-independent bystander killing of cells lacking cognate antigen. To address safety concerns, 13F08 BiTE-T cells can be rapidly targeted for clearance via a molecular “off” switch. Conclusions The novel LABC-13F08 scFv exhibits a mode of binding to MSLN which is not observed in typical anti-MSLN antibodies. Efficacious targeting by a T cell secreted engager would represent a clinically differentiated approach for the treatment of MSLN + tumors.
Leveraging T cell co-stimulation for enhanced therapeutic efficacy of trispecific antibodies targeting prostate cancer
Authors: Yanping Sun, Linling Zhou, Xinyu Gu, Jiaqi Zhao, Jie Bi, Liqiang Pan
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Clinical trials have demonstrated the efficacy of bispecific antibodies in eliciting potent antitumor responses by redirecting T cells to target cancer cells, particularly for the treatment of hematologic malignancies. However, their efficacy against solid tumors is limited by intratumoral T-cell dysfunction and inadequate persistence. The co-stimulatory domains of 4-1BB, OX40, and CD28 are most widely used in engineering chimeric antigen receptor T-cells to augment T-cell responses. Methods In this study, we designed three co-stimulatory trispecific T cell-engaging antibodies (TriTCEs) that target Prostate-specific membrane antigen, CD3, and an additional co-stimulatory receptor(OX40, 4-1BB, or CD28). We conducted comparative profiling of the attributes of distinct co-stimulatory signals to T-cell functions in prostate cancer models. Results Co-stimulatory trispecific T-cell engagers enhance T-cell activation, proliferation, and display tumor cell-killing activity in vitro. These trispecific antibodies further boosted antitumor activity in humanized mouse xenograft models and increased the infiltration of CD45 + immune cells into solid tumors. Specifically, TriTCE-4-1BB and TriTCE-CD28 selectively promoted the expansion of effector memory T cells and increased the presence of CD4 + T cells more than TriTCE-OX40. T cells stimulated with TriTCE-4-1BB exhibited reduced exhaustion. Furthermore, T cells treated with co-stimulatory trispecific antibodies demonstrated enhanced metabolic activity characterized by increased oxidative phosphorylation and elevated glycolysis. Conclusions Collectively, incorporating co-stimulatory receptor targeting domains represents a potentially effective strategy to unlock the full therapeutic potential of T-cell-engaging antibodies for the treatment of solid tumors.
Myeloid targeting antibodies PY159 and PY314 for platinum-resistant ovarian cancer
Authors: Oladapo O Yeku, Minal Barve, Winston W Tan, Judy Wang, Amita Patnaik, Patricia LoRusso, Debra L Richardson, Abdul Rafeh Naqash, Sarah K Lynam, Siqing Fu, Michael Gordon, Joleen Hubbard, Shivaani Kummar, Christos Kyriakopoulos, Afshin Dowlati, Marc Chamberlain, Ira Winer
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Novel treatment options are required in patients with platinum-resistant ovarian cancer (PROC). Myeloid-derived suppressor cells promote a hostile tumor microenvironment and are associated with worse clinical outcomes in PROC. We evaluated the safety and preliminary efficacy of PY159, an agonist antibody to Triggering receptor expressed on myeloid cells-1 (TREM1) that reprograms immunosuppressive intratumoral myeloid cells, and PY314, an antagonist antibody to Triggering receptor expressed on myeloid cells-2 (TREM2) that depletes tumor-associated macrophages, as single agents and in combination with pembrolizumab in subjects with PROC. Methods PY159 and PY314 were individually evaluated in patients with PROC. Patients were treated with monotherapy (PY159 3 mg/kg or PY314 10 mg/kg), based on the recommended dose for expansion derived from the phase 1a studies. At the time of first progression, patients could continue study drug and crossover to combination therapy with pembrolizumab (200 mg) every 3 weeks at the discretion of the investigator. Disease assessment by Response Evaluation Criteria in Solid Tumor version 1.1 was performed every 6 weeks. Results 17 patients were enrolled in the PY159 study (median age 67, range 22–77; median prior therapies 6, range 2–18) and 16 patients in PY314 (median age 65.5, range 49–81; median prior therapies 4, range 2–10). 7 patients in PY159 and 8 patients in PY314 crossed over to combination therapy. Safety events included the following: treatment-related adverse events occurred in 15 patients (88.2%) in PY159 and 9 patients (56.3%) in PY314. Infusion-related reactions occurred in 6 patients (35.3%) in PY159 and 3 patients (18.8%) in PY314. Immune-related adverse events occurred in 13 patients (76.5%) in PY159 (arthralgias) and 1 patient (6.3%) in PY314 (diarrhea). Serious adverse events occurred in 6 patients (36.3%) in PY159 (1 related) and 12 patients (75%) in PY314 (all unrelated). The best radiographic response in PY159 was stable disease in 8/16 patients (50%; median 16 weeks, range 9–33), and in PY314, it was stable disease in 8/16 patients (50%; median 12 weeks, range 6–36). Median PFS was 2.76 months and 2.69 months in PY159 and PY314, respectively. There were no responses in the crossover arm. Conclusions Both PY159 and PY314 were well tolerated, with an acceptable safety profile, as both single agents and in combination with pembrolizumab. Both agents warrant further investigation in heavily pretreated PROC.
Pedestrian and Overall Road Traffic Crash Deaths — United States and 27 Other High-Income Countries, 2013–2022
Authors: Rebecca B. Naumann, Bethany A. West, Vaughn Barry, Sarah Matthews, Robin Lee
Journal: MMWR Morbidity and Mortality Weekly Report (2025)

Road traffic deaths are preventable but remain a major public health problem. Crashes cause more than 40,000 deaths annually in the United States, and traffic-related pedestrian deaths have increased rapidly. To examine change in pedestrian and overall traffic death rates (deaths per 100,000 population) within an international context, CDC analyzed 2013-2022 data from the United States and 27 other high-income countries in the International Road Traffic and Accident Database, as well as early 2023 U.S. estimates. Between 2013 and 2022, U.S. pedestrian death rates increased 50% (from 1.55 to 2.33 per 100,000 population), while other countries generally experienced decreases (median decrease = 24.7%). During this period, overall U.S. traffic death rates increased 22.5% (from 10.41 to 12.76), but decreased by a median of 19.4% in 27 other high-income countries. Among all countries examined, the United States had the highest pedestrian death rates overall and among persons aged 15-24 and 25-64 years. Projected 2023 U.S. estimates suggest a potential decline in pedestrian (2%) and overall traffic (4%) deaths, compared with those in 2022. Accelerated adoption of a Safe System approach, focused on creating safer roadways and vehicles, establishing safer speeds, supporting safer road users, and improving post-crash care, can help reduce U.S. pedestrian and overall traffic deaths.
Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy
Authors: Ziena Abdulrahman, Roderick C Slieker, Daniel McGuire, Marij J P Welters, Mariette I E van Poelgeest, Sjoerd H van der Burg
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The tumor microenvironment (TME) is a complex and dynamic ecosystem that is known to influence responses to immunotherapy. We leveraged single-cell spatial transcriptomics to systematically dissect the intricate complexity of the TME, in particular the cellular heterogeneity and spatial interactions. Their collective impact on immunotherapy efficacy was studied in the context of a homogeneous group of patients with vulvar high-grade squamous intraepithelial lesions (vHSIL) treated with an immunotherapeutic tumor-specific peptide vaccine. Methods We performed single-cell spatial transcriptomics on 20 pretreatment vHSIL lesions, stratified by clinical response to immunotherapeutic vaccination into complete responders (CR), partial responders (PR) and non-responders (NR). Using a 1,000-gene panel, we mapped over 274,000 single cells in situ, identifying 18 cell clusters and 99 distinct non-epithelial cell states. Findings were validated against public single-cell transcriptomic data sets to assess their broader relevance across tumor types. Results Profound heterogeneity within the TME was detected across the response groups. CR lesions exhibited a higher ratio of immune-supportive to immune-suppressive cells—a pattern mirrored in other solid tumors following neoadjuvant checkpoint blockade. Key immune populations enriched in CRs included CD4+CD161+ effector T cells and chemotactic CD4+ and CD8+ T cells. Conversely, PRs were characterized by increased proportions of T helper 2 cells and CCL18-expressing macrophages, which are associated with the recruitment of type 2 T cells and regulatory T cells. NRs displayed preferential infiltration with immunosuppressive fibroblasts. Distinct spatial immune ecosystems further defined response groups. Although a number of immune cells were detected in all patients, type 1 effector cells dominated interactions in CRs, type 2 cells were prominently interacting in PRs, while NRs lacked organized immune cell interactions. Conclusions This study underscores the dual importance of both cellular composition and spatial organization in steering clinical response to immunotherapy.