tbuckley/cabot-search huggingface dataset:
Spatial heterogeneity, stromal phenotypes, and therapeutic vulnerabilities in colorectal cancer peritoneal metastasis
Authors: Johnny Chin-Ann. Ong, Joseph J. Zhao, Ying Liu, Supriya Srivastava, Daryl K. A. Chia, Ying En Quek, Xiaonan Fan, Haoran Ma, Kie Kyon Huang, Taotao Sheng, Qiu Xuan Tan, Gillian Ng, Joey W. S. Tan, Jia-Ying Joey. Lee, Lit-Hsin Loo, Li Yen Chong, Xue Wen. Ong, Su Ting Tay, Takeshi Hagihara, Angie Tan, Craig Ryan Cecil Joseph, Melissa C. C. Teo, Josephine Hendrikson, Clara Y. L. Chong, Wanyu Guo, Claramae S. Chia, Jolene S.M. Wong, Chin Jin Seo, Mingzhe Cai, Yvonne Tay, Kevin M. S. Sim, Ryan Y. K. Tay, Robert Walsh, Marcello Guaglio, Federica Morano, Ming Teh, Huey Yew Jeffrey Lum, Tony K. H. Lim, Louis Vermeulen, Maarten F. Bijlsma, Kristiaan Lenos, Samuel J. Klempner, Joe P. S. Yeong, Wei Peng Yong, Filippo Pietrantonio, Patrick Tan, Raghav Sundar
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Peritoneal metastases (PM) in colorectal cancer (CRC) portend a poor prognosis. We sought to elucidate molecular features differentiating primary tumors (PTs) from PMs and actionable targets facilitating transcoelomic dissemination and progression. Experimental Design: We performed multi-omic profiling of 227 samples from 136 patients, including 56 primary tumor (PT) and 120 synchronous PMs comprising 34 matched PT-PM pairs. Whole exome, and bulk RNA-seq analysis was conducted to identify underlying genomic aberrations and transcriptomic differences between primary and peritoneal lesions. We spatially characterized the microenvironment of tumor-stroma compartments and studied the roles of stromal phenotypes in promulgating tumorigenesis. Results: Whole exome sequencing found genomic alterations and clonality patterns between PTs and PMs remain broadly similar. Transcriptomic profiles however, suggest a transition as tumors reach the peritoneum towards a more mesenchymal tumor profile and fibrotic tumor microenvironment. Applying spatial profiling, we identify a fibro-collagenous and immune-infiltrated stromal phenotype (stromal cluster [SC] 2) characterized by increased cancer-associated fibroblasts, memory B cells, M2 macrophages and T-cell exhaustion. These findings were orthogonally validated by multiplex immunohistochemistry. Patients with SC2 stroma had poorer survival and were characterized by high SERPINE-1 (PAI-1) expression. PM in patients with SC2 stroma were associated with enriched oncogenic pathways such as TGF-β. PAI-1 inhibition of CRC PM cell-lines with a novel biologic demonstrated reduced IL2-STAT5 and TGF-β pathways and cell death. Conclusions: Our findings unveil distinctive and actionable molecular signatures, offering deeper insights into the intricate crosstalk between tumor cells and stromal microenvironments enabling PM in CRC.
A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in PDAC
Authors: Caroline Broderick, Riccardo Mezzadra, Exequiel M. Sisso, Felix Mbuga, Rashi Raghulan, Almudena Chaves Perez, Amanda Kulick, Lingyan Jiang, Jingjing Jiang, Yu-Jui Ho, Janelle Simon, Eric Rosiek, Eric Chan, Aveline Filliol, Ronan Chaligne, Elisa de Stanchina, Ximo Pechuan-Jorge, Andrea Schietinger, Mallika Singh, Scott W. Lowe
Journal: Cancer Discovery (2025)

Abstract Pharmacological inhibition of oncogenic RAS represents an attractive strategy to target pancreatic ductal adenocarcinoma (PDAC), an almost ubiquitously RAS-driven disease. However, initial responses to targeted monotherapy inhibition of active RAS can be followed by relapses, potentially driven by the persistence of drug-tolerant tumor cells. To target these ‘persister’ cells, we investigated strategies to increase their immune visibility in mouse models of PDAC. We show that combining a RAS(ON) multi-selective inhibitor with the CDK4/6 inhibitor palbociclib drives persister cells into a senescent-like state, which coincides with improved tumor control and substantial remodeling of the tumor microenvironment. Combining RAS(ON) and CDK4/6 inhibition with a CD40 agonist results in durable regressions and CD4 T cell-dependent tumor-immune equilibrium. Our studies reveal a combinatorial approach that circumvents resistance to RAS(ON) inhibitor monotherapy in preclinical models and demonstrate a mechanism by which therapy-induced senescence can be reinforced by the immune system, resulting in durable tumor control.
Widespread distribution of transcriptionally active, clonally expanded, HIV-1 proviruses despite suppressive antiretroviral therapy
Authors: Hiromi Imamichi, Ven Natarajan, Francesca Scrimieri, Mindy Smith, Yunden Badralmaa, Marjorie Bosche, Jack M Hensien, Thomas Buerkert, Weizhong Chang, Brad T Sherman, Kanal Singh, H Clifford Lane
Journal: Journal of Clinical Investigation (2025)

The rapid viral rebound observed following treatment interruption, despite prolonged time on antiretroviral therapy with plasma HIV-RNA levels <40 copies/mL, suggests persistent HIV-1 reservoir(s) outside of the blood. Studies of HIV-1 proviruses in autopsy tissue samples have hinted at their persistence. However, their distribution across different anatomical compartments and their transcriptional activity within tissues remains unclear. The present study has examined molecular DNA and RNA reservoirs of HIV-1 in autopsy samples from 13 individuals with HIV-1 infection. Of the 13, 5 had detectable levels of HIV-1 RNA in plasma while 8 did not. Cell associated HIV-RNA was detected in 12 out of 13 donors and in 27 of the 30 different tissues examined. HIV-specific DNA and RNA were widely distributed and predominantly associated with clonal expansions. No significant differences were noted between the groups and no tissues were preferentially affected. These data imply that a substantial seeding of tissues with cells harboring transcriptionally active proviral DNA can be seen in the setting of HIV-1 infection despite ART and highlight one of the challenges in achieving an HIV-1 cure.
Hybrid membrane-coated Cyclosporine A nanocrystals preventing secondary brain injury via alleviating neuroinflammatory and oxidative stress
Authors: Yifan Zhou, Sai Qiao, Luoqi Zhang, Miao Liu, Qifeng Ji, Bangle Zhang, Huile Gao, Siyuan Zhou, Daozhou Liu
Journal: Journal of Controlled Release (2025)
Fes-Deficient Macrophages Prime CD8+ T Cells to Stimulate Anti-tumor Immunity and Improve Immunotherapy Efficacy
Authors: Brian J. Laight, Danielle Harper, Natasha Dmytryk, Connie S. Zhang, Changnian Shi, Andrew Garven, Richard W. Nauman, Jacob Kment, Faizah Alotaibi, Ivan Shapovalov, Victoria Hoskin, Yan Gao, Jeffery Mewburn, Caitlyn Vlasschaert, Ami Wang, Julian Simonetti, David LeBrun, Kathrin Tyryshkin, David M. Berman, Amber L. Simpson, Charles H. Graham, Andrew W. Craig, Sameh Basta, Madhuri Koti, Peter A. Greer
Journal: Cancer Research (2025)

Abstract Homeostatic immunoregulatory mechanisms that prevent adverse effects of immune overaction can serve as barriers to successful anti-cancer immunity, representing attractive targets to improve cancer immunotherapy. Here, we demonstrated the role of the non-receptor tyrosine kinase Fes, abundantly expressed in immune cells, as an innate intracellular immune checkpoint. Host Fes-deficiency delayed tumor onset in a gene dose-dependent manner and improved tumor control, survival, doxorubicin efficacy, and anti-PD-1 therapy sensitization in murine triple-negative breast cancer and melanoma models. These effects were associated with a shift to an anti-tumorigenic immune microenvironment. Fes-deficient macrophages displayed increased Toll-like receptor signaling, proinflammatory cytokine production, antigen presentation to and activation of T cells, leading to increased cancer cell killing in vitro and tumor control in vivo. This study highlights Fes as an innate immune checkpoint with potential as a therapeutic target and a predictive biomarker to guide immune checkpoint inhibitor treatment.
Current perspectives on perioperative combination therapy for hepatocellular carcinoma
Authors: Takahiro Nishio, Tomoaki Yoh, Hiroto Nishino, Satoshi Ogiso, Yoichiro Uchida, Takamichi Ishii, Etsuro Hatano
Journal: Liver Cancer (2025)

Background: Multidisciplinary treatment of hepatocellular carcinoma (HCC) has made notable advancements with the emergence of novel agents for systemic therapies, including receptor tyrosine kinase inhibitors (TKIs) and cancer immuno-oncology therapy (IO) utilizing immune checkpoint inhibitors. Although each of these regimens is effective as monotherapy for advanced HCCs, combining them with local treatments (LRT), such as transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and radiotherapy (RT), provides an additional antitumor effect. The emergence of novel systemic therapies has given rise to anticipation for the development of multidisciplinary treatments with a combination of systemic therapy and LRT, which aim to achieve curative-intent resection and improve long-term prognosis after resection. Summary: Perioperative combination therapy, a combination of multiple treatment modalities including systemic therapy (TKI and/or IO) and LRT (TACE, HAIC, or RT), is attracting attention as a potentially useful approach for multidisciplinary curative-intent surgical resection or ablation. Currently, there is no evidence-based guidance regarding selection criteria and optimal regimens for perioperative combination therapy. The definition of oncological resectability for HCC is being pursued to establish the indication and protocol for perioperative combination therapy, which broadly encompasses conversion as well as neoadjuvant and adjuvant therapy for intermediate-to-advanced HCC. Key Messages: Perioperative combination therapy, which positions curative-intent surgical resection or ablation within the combination of multiple modalities including systemic therapy and LRT, provides perspectives for improving the long-term prognosis of patients with initially unresectable HCC and borderline resectable HCC with a high risk of recurrence.
Menstrual Cycle Length Changes Following Vaccination Against Influenza Alone or With COVID-19
Authors: Emily R. Boniface, Blair G. Darney, Agathe van Lamsweerde, Eleonora Benhar, Alexandra Alvergne, Alison Edelman
Journal: JAMA Network Open (2025)

Multiple studies have identified an association between COVID-19 vaccination and menstrual disturbances. Data on whether menstrual health is impacted by other vaccines are needed to counsel individuals about what to expect and to address vaccine hesitancy. To assess the association of changes in length of the menstrual cycle with influenza vaccination, with or without concurrent receipt of a COVID-19 vaccine. This global retrospective cohort study prospectively collected menstrual cycle data from April 25, 2023, to February 27, 2024 (4-5 cycles per individual), among international English-speaking users of a digital birth control application. Participants included individuals aged 18 to 45 years, not using hormonal contraception, and with average cycle lengths of 24 to 38 days in 3 consecutive cycles before receipt of vaccines. Seasonal influenza vaccination with or without concurrent receipt of COVID-19 vaccine. The primary outcome consisted of adjusted mean within-individual changes of menstrual cycle length assessed by vaccination group. Secondary analysis evaluated the phase of menstrual cycle at time of vaccination. A total of 1501 individuals met the inclusion criteria, of whom 791 were vaccinated for influenza only and 710 were concurrently vaccinated for influenza and COVID-19. By race and ethnicity, 1 participant (0.1%) was American Indian or Alaska Native; 10 (0.7%), Asian; 3 (0.2%), Black; 15 (1.0%), Hispanic or Latina; 1 (0.1%), Middle Eastern or North African; 368 (24.5%), White; and 19 (1.3%), other; and 1084 (72.2%), missing. Most of the cohort was younger than 35 years (1230 [82.0%]), had at least a college degree (1122 [74.8%]), and was located in the US or Canada (938 [62.5%]). Individuals vaccinated for influenza alone experienced an adjusted mean increase of 0.40 (95% CI, 0.08-0.72) days, while those vaccinated concurrently for influenza and COVID-19 experienced a mean increase of 0.49 (95% CI, 0.16-0.83) days (P = .69 for difference between vaccine groups). A total of 37 individuals (4.7%) experienced a change in cycle length of at least 8 days with influenza vaccine only and 42 (5.9%) with concurrent receipt of both vaccines (P = .28). In the postvaccination cycle, both vaccination groups returned to their prevaccination cycle lengths. Menstrual cycle changes occurred with vaccination in the follicular phase but not the luteal phase. In this cohort study of individuals with regular menstrual cycles, influenza vaccine given alone or in combination with a COVID-19 vaccine was associated with a small but temporary change in menstrual cycle length. These findings may help clinicians confirm the utility of vaccination for patients with concerns about menstrual adverse effects of vaccination.
Uptake of and Disparities in Semaglutide and Tirzepatide Prescribing for Obesity in the US
Authors: Chungsoo Kim, Joseph S. Ross, Ania M. Jastreboff, Daniella Meeker, Harry Freedman, Harlan M. Krumholz, Yuan Lu
Journal: JAMA (2025)

This study uses data from the US nationwide electronic health record–based Epic Cosmos Dataset to examine prescriptions for semaglutide and tirzepatide, focusing on differences across race, ethnicity, social vulnerability, and urbanicity and assess the need for strategies to promote equitable access to these therapies.
Consensus on Adolescent and Young Adult HIV Research Consent in Low- and Middle-Income Countries
Authors: Suzanne Day, Sonam J. Shah, Ujunwa F. Onyeama, Lauren Fidelak, Ucheoma Nwaozuru, Stuart Rennie, Abdulhammed Opeyemi Babatunde, Weiming Tang, Elzette Rousseau, Chisom Obiezu-Umeh, Kelechi Prince Chima, Nadia A. Sam-Agudu, Erin C. Wilson, Seema K. Shah, Susan Nkengasong, Titilola Gbaja-Biamila, Bill G. Kapogiannis, Linda-Gail Bekker, Juliet Iwelunmor, Oliver Ezechi, Joseph D. Tucker
Journal: JAMA Network Open (2025)

Importance Many adolescents and young adults (AYAs) in low- and middle-income countries (LMICs) are excluded from HIV research because of challenges with informed consent for study participation, which makes it difficult to understand and improve the lives of AYAs living with HIV and AIDS in a wide variety of settings. Objective To help increase the inclusion of AYAs in HIV research, we developed a consensus statement on practical strategies for improving AYA consent in HIV research in LMICs. Evidence Review The VOICE (HIV Youth Informed Consent &amp;amp;amp; Ethics in Research) Working Group included AYAs, researchers, community organizers, advocates, research ethics committee members, parents of AYAs, and bioethicists who drafted initial statement items using data from a global open call and scoping review. An adapted Delphi process was then used to develop consensus statement items. The process involved 3 rounds of online Likert-scale questionnaires and a hybrid (online and in-person) consensus summit in Lagos, Nigeria, in 2022, with the total study period lasting from August 23, 2021, to February 10, 2023. Findings Thirty-five people participated in the final round of the Delphi process, including 14 individuals younger than 35 years (40.0%), 25 HIV researchers (71.4%), and 32 people who worked in an LMIC (91.4%). Twenty-five items reached a predefined threshold for consensus (≥80% agreement). Strong consensus emerged for formal mechanisms (eg, cocreation, crowdsourcing, or youth advisory boards) for AYA engagement in and education about research as well as for strategies to enhance parental and guardian involvement in HIV research when safe and appropriate. Capacity strengthening can allow AYAs to review research protocols, join ethical review committees, and advocate for regulatory change. Two items in the statement (alternatives to parental consent and raising awareness among research ethics committees about AYA-independent consent) required further refinement to reach the agreement threshold for inclusion. Conclusions and Relevance Greater engagement of both AYAs and parents may help to enhance consent processes and increase the inclusion of AYAs in LMIC HIV research studies. The resulting consensus statement provides practical strategies for implementing improved consent processes for AYA research participation at the organizational, community, and policy levels, which may help foster greater inclusion of AYAs in HIV research and address existing data gaps.
Maternal Hypertension and Adverse Neurodevelopment in a Cohort of Preterm Infants
Authors: Shipra Jain, Ting Ting Fu, Maria E. Barnes-Davis, Rashmi D. Sahay, Shelley R. Ehrlich, Chunyan Liu, Mounira Habli, Nehal A. Parikh, Priyanka VSP Illapani, Karen Harpster, Beth Kline-Fath, Hailong Li, Lili He, Stephanie Merhar, Jean Tkach, Hui Wang
Journal: JAMA Network Open (2025)

Importance Whether maternal hypertensive disorders of pregnancy (HDP) confer independent neurodevelopmental deficit risks in premature infants is controversial. Previous studies are limited by inadequate confounding variable control and other biases. Objective To evaluate the associations between maternal HDP, especially preeclampsia, and neurodevelopmental outcomes of preterm infants at 2 years’ corrected age. Design, Setting, and Participants Regional prospective cohort study of 395 preterm infants (≤32 weeks’ gestation) from 5 level III and IV southeast Ohio neonatal intensive care units from September 2016 to November 2019. Data analysis was conducted in August 2022. Exposure HDP, defined by maternal diagnosis of chronic or gestational hypertension or preeclampsia during pregnancy. Main Outcomes and Measures Structural brain magnetic resonance imaging was performed at term-equivalent age. Neurodevelopment was assessed by Bayley Scales of Infant and Toddler Development (BSID), Third Edition, between 22 and 26 months’ corrected age. Multivariable regression was used to identify the independent association of HDP and preeclampsia on cognitive (primary outcome), language, and motor development, controlling for several confounders. Mediation analyses were performed to understand if the association with HDP was mediated by its association with birth weight or brain abnormalities. Results In a cohort of 395 infants, the median (IQR) gestational age was 29.6 (27.6-31.4) weeks, birth weight was 1230 (950-1628) g, and 210 (53.2%) were male. Of these, 170 (43%) were HDP-exposed, of which 104 of 170 (61%) were exposed to preeclampsia. A total of 341 children (87%) completed the BSID. In adjusted analyses, HDP exposure was negatively associated with BSID cognitive scores (−3.69; 95% CI, −6.69 to −0.68; P = .02) and language scores (−4.07; 95% CI, −8.03 to −0.11; P = .04). Preeclampsia exposure showed similarly negative but greater associations for BSID scores (−4.85; 95% CI, −8.63 to −1.07; P = .01 for cognitive and −6.30; 95% CI, −11.49 to −1.09; P = .02 for language scores). Mediation analysis revealed that the association between HDP and cognitive scores was partially mediated by its adverse association with brain abnormalities at term-equivalent age (24% of the total effect; −0.82; 95% CI, −1.72 to −0.13; P = .02). Conclusions and Relevance In this preterm cohort study, maternal HDP was independently associated with adverse cognitive and language development, with accentuated associations observed in preeclampsia-exposed preterm infants, emphasizing the clinical importance of recognizing HDP as a risk, enabling targeted risk management strategies for closer monitoring and aggressive early intervention in affected populations.
Linkage of Clinical Trial Data to Routinely Collected Data Sources
Authors: Mehdi NajafZadeh, Ana Fernández Oromendia, Mehmet Burcu, Ben Mcconnochie, Ella Kim, Thomas Vaccaro, Elisabetta Patorno
Journal: JAMA Network Open (2025)

Importance Patients who participate in clinical trials generate valuable routinely collected data (eg, medical records, electronic health records, claims databases, disease registries, or vital statistics) through their routine interactions with the health care system before, during, and after the trial. When this routinely collected data is linked at the participant level, it can supplement active data collection in the trial and provide deeper insights into the benefits, risks, and costs of treatments. Objective To review clinical trials linked to routinely collected data in various countries, identifying the use cases and designs of these linkage studies. Evidence Review Research articles that reported the linkage of clinical trials to medical records, electronic health records, claims databases, disease registries, or vital statistics in their title or abstract were searched for in PubMed and MEDLINE. The search covered the period from January 1, 2016, through December 30, 2023. Opinion pieces, study protocols, or studies that involved interventions other than medications, dietary supplements, vaccines, devices, procedures, or diagnostics (eg, behavioral interventions) were excluded. Study eligibility and data extraction were performed independently by 2 reviewers to ensure the accuracy of findings. Findings Of the 990 abstracts initially screened, a full text review was conducted for 147 articles. In total, 71 studies were included in the results, including 42 medication, vaccine, and dietary supplement trials (59.2%) and 29 device, procedure, or diagnostic trials (40.8%). Of these 71 studies, 24 (32.4%) were conducted in the US. In 32 studies (45.1%), consent for linkage was obtained prospectively as part of the main trial, while 33 studies (46.5%) received a waiver of authorization from the respective ethical review boards. The most frequent use cases of linkage to were posttrial long-term follow-up (22 studies [31.0%]), capturing primary or secondary outcomes of trials (19 studies [26.8%]), validation of routinely collected data outcomes (17 studies [23.9%]), and measuring health care resource utilization and cost in trials (12 studies [16.9%]). Conclusions and Relevance This study found that the linkage of patients’ clinical trial data to routinely collected data has been implemented in several trials for various use cases and that most studies obtained consent for linkage prospectively as part of the main trial or received a waiver of authorization from ethical review boards. These findings demonstrate the feasibility and provide an overview of the use cases for linking trials to routinely collected data.
Core GRADE 2: choosing the target of certainty rating and assessing imprecision
Authors: Gordon Guyatt, Linan Zeng, Romina Brignardello-Petersen, Manya Prasad, Hans De Beer, M Hassan Murad, Alfonso Iorio, Arnav Agarwal, Liang Yao, Thomas Agoritsas, Jamie Rylance, Reem A Mustafa, Per Olav Vandvik, Prashanti Eachempati, Chunjuan Zhai, Lingli Zhang, Victor M Montori, Monica Hultcrantz
Journal: BMJ (2025)
Angiotensinogen inhibition concurrently mitigates alcohol-associated hepatic and muscle injury
Authors: Zhaodi Che, Mingxiang Cai, Xiaowu Dong, Yuan Yuan, Yaodong Wang, Lu Xiao, Yali Song, Jiajun Zhong, Pingping Luo, Hao Wang, Guotao Lu, Yao Sun, Jia Xiao
Journal: Metabolism (2025)