tbuckley/cabot-search huggingface dataset:
Cerebrovascular damage caused by the gut microbe/host co-metabolite <i>p</i> -cresol sulfate is prevented by blockade of the EGF receptor
Authors: Sita N. Shah, Tobias B-A. Knausenberger, Matthew G. Pontifex, Emily Connell, Gwénaëlle Le Gall, Tom A.J. Hardy, David W. Randall, Kieran McCafferty, Muhammad M. Yaqoob, Egle Solito, Michael Müller, Andrew V. Stachulski, Robert C. Glen, David Vauzour, Lesley Hoyles, Simon McArthur
Journal: Gut Microbes (2024)

The gut microbiota-brain axis has been associated with the pathogenesis of numerous disorders, but the mechanism(s) underlying these links are generally poorly understood. Accumulating evidence indicates the involvement of gut microbe-derived metabolites. Circulating levels of the gut microbe/host co-metabolite p-cresol sulfate (pCS) correlate with cerebrovascular event risk in individuals with chronic kidney disease (CKD), but whether this relationship is mechanistic is unclear. We hypothesized that pCS would impair the function of the blood–brain barrier (BBB), the primary brain vasculature interface. We report that pCS exposure impairs BBB integrity in human cells in vitro and both acutely (≤6 hours) and chronically (28 days) in mice, enhancing tracer extravasation, disrupting barrier-regulating tight junction components and ultimately exerting a suppressive effect upon whole-brain transcriptomic activity. In vitro and in vivo mechanistic studies showed that pCS activated epidermal growth factor receptor (EGFR) signaling, sequentially activating the intracellular signaling proteins annexin A1 and STAT3 to induce mobilization of matrix metalloproteinase MMP-2/9 and disruption to the integrity of the BBB. This effect was confirmed as specific to the EGFR through the use of both pharmacological and RNA interference approaches. Confirming the translational relevance of this work, exposure of the cerebromicrovascular endothelia to serum from hemodialysis patients in vitro led to a significant increase in paracellular permeability, with the magnitude of permeabilization closely correlating with serum pCS, but not most other uremic toxin, content. Notably, this damaging effect of hemodialysis patient serum was prevented by pharmacological blockade of the EGFR. Our results define a pathway linking the co-metabolite pCS with BBB damage and suggest that targeting the EGFR may mitigate against cerebrovascular damage in CKD. This work further provides mechanistic evidence indicating the role of gut microbe-derived metabolites in human disease.
Integrated single-cell transcriptome and TCR profiles of hepatocellular carcinoma highlight the convergence on interferon signaling during immunotherapy
Authors: Tianhao Li, Shengnan Guo, Chang Xu, Mingjie Zhang, Cheng Lyu, Huanhuan Xu, Zepeng Hou, Mingshuo Zhang, Xiaobo Li, Jing Ren, Changqing Liu, Dan Kong, Dapeng Hao, Guangyu Wang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Despite the success of immune checkpoint inhibitor (ICI)-based combination therapies in hepatocellular carcinoma (HCC), its effectiveness remains confined to a subset of patients. The development of reliable, predictive markers is important for accurate patient stratification and further mechanistic understanding of therapy response. Methods We comprehensively analyzed paired single-cell RNA transcriptome and T-cell repertoire profiles from 14 HCC ascites samples, collected from 7 patients before and after treatment with the combination of sintilimab (anti-PD-1) and bevacizumab (anti-VEGF). Results We identify a widespread convergence on interferon (IFN) signaling across various immune cell lineages in treatment-responsive patients with HCC, indicating a common transcriptional state transition in the immune microenvironment linked to immunotherapy response in HCC. Strong IFN signaling marks CD8 + T cells with larger clonal expansion and enhanced cytotoxicity, macrophages toward M1-like polarization and strong T-cell recruitment ability, dendritic cells with increased antigen presentation capacity, as well as highly cytotoxic natural killer cells and activated B cells. By translating our finding to cohorts of patients with HCC, we demonstrate the specificity of IFN-signaling in the prognosis of patients with HCC and its ability to predict immunotherapy response. Conclusions This study provides a unique single-cell resource with clonal and longitudinal resolution during ICI therapy and reveals IFN signaling as a biomarker of immunotherapy response in HCC, suggesting a beneficial effect by combining IFN inducers with ICIs for patients with HCC.
Propafenone facilitates mitochondrial-associated ferroptosis and synergizes with immunotherapy in melanoma
Authors: Qian Zhou, Yating Dian, Yi He, Lei Yao, Hui Su, Yu Meng, Yuming Sun, Daishi Li, Yixiao Xiong, Furong Zeng, Xiaowei Liang, Hong Liu, Xiang Chen, Guangtong Deng
Journal: Journal for ImmunoTherapy of Cancer (2024)

Despite the successful application of immunotherapy, both innate and acquired resistance are typical in melanoma. Ferroptosis induction appears to be a potential strategy to enhance the effectiveness of immunotherapy. However, the relationship between the status of ferroptosis and the effectiveness of immunotherapy, as well as viable strategies to augment ferroptosis, remains unclear. A screening of 200 cardiovascular drugs obtained from the Food and Drug Administration-approved drug library was conducted to identify the potential ferroptosis sensitizer. In vitro and in vivo experiments explored the effects of propafenone on ferroptosis in melanoma. Animal models and transcriptomic analyses evaluated the therapeutic effects and survival benefits of propafenone combined with immune checkpoint blockades (ICBs). The relationship between propafenone targets and the efficacy of ICBs was validated using the Xiangya melanoma data set and publicly available clinical data sets. Through large-scale drug screening of cardiovascular drugs, we identified propafenone, an anti-arrhythmia medication, as capable of synergizing with ferroptosis inducers in melanoma. Furthermore, we observed that propafenone, in combination with glutathione peroxidase 4 inhibitor RSL3, collaboratively induces mitochondrial-associated ferroptosis. Mechanistically, propafenone transcriptionally upregulates mitochondrial heme oxygenase 1 through the activation of the Jun N-terminal kinase (JNK)/JUN signaling pathway under RSL3 treatment, leading to overloaded ferrous iron and reactive oxygen species within the mitochondria. In xenograft models, the combination of propafenone and ferroptosis induction led to nearly complete tumor regression and prolonged survival. Consistently, propafenone enhances immunotherapy-induced tumorous ferroptosis and antitumor immunity in tumor-bearing mice. Significantly, patients exhibiting high levels of ferroptosis/JUN/HMOX1 exhibited improved efficacy of immunotherapy and prolonged progression-free survival. Taken together, our findings suggest that propafenone holds promise as a candidate drug for enhancing the efficacy of immunotherapy and other ferroptosis-targeted therapies in the treatment of melanoma.
PTPN9 regulates HER3 phosphorylation during trastuzumab treatment and loss of PTPN9 is a potential biomarker for trastuzumab resistance in HER2 positive breast cancer
Authors: Abul Azad, Maryam Arshad, Daniele Generali, Katharina Feldinger, Merel Gijsen, Carla Strina, Mariarosa Cappelletti, Daniele Andreis, Russell Leek, Syed Haider, Pirkko‐Liisa Kellokumpu‐Lehtinen, Ioannis Roxanis, Adrian Llewellyn Harris, Abeer Mahmoud Shaaban, Heikki Joensuu, Anthony Kong
Journal: Cancer Communications (2024)
Co-occurring mutations identify prognostic subgroups of microsatellite stable colorectal cancer
Authors: Luís Nunes, Jakob Mørkved Stenersen, Kushtrim Kryeziu, Tobias Sjöblom, Bengt Glimelius, Ragnhild A. Lothe, Anita Sveen
Journal: Molecular Cancer (2024)

Co-occurring mutations in pairs of genes can pinpoint clinically relevant subgroups of cancer. Most colorectal cancers (CRCs) are microsatellite stable (MSS) and have few frequent mutations. Large patient cohorts and broad genomic coverage are needed for comprehensive co-mutation profiling.
Photo-controlled multifunctional hydrogel for photothermal sterilization and microenvironment amelioration of infected diabetic wounds
Authors: Fan Yang, Dong Mo, Beibei Wu, Jiahao Chen, Qinhui Liu, Wenfei Chen, Juan Pang, Wenjing Wang, Xiandan Jing, Yimin Xiong, Na Yang, Yining Xu, Yanping Li, Yuan Huang, Li Mo, Jinhan He
Journal: Journal of Controlled Release (2024)
Macrophage membrane-encapsulated miRNA nanodelivery system for the treatment of hemophilic arthritis
Authors: Yufan Qian, Yetian Ma, Atanas Banchev, Weifeng Duan, Pingcheng Xu, Lingying Zhao, Miao Jiang, Ziqiang Yu, Feng Zhou, Jiong Jiong Guo
Journal: Journal of Controlled Release (2024)
Top-down infliximab plus azathioprine versus azathioprine alone in patients with acute severe ulcerative colitis responsive to intravenous steroids: a parallel, open-label randomised controlled trial, the ACTIVE trial
Authors: Aurelien Amiot, Philippe Seksik, Antoine Meyer, Carmen Stefanescu, Pauline Wils, Romain Altwegg, Lucine Vuitton, Laurianne Plastaras, Adrien Nicolau, Bruno Pereira, Nicoals Duveau, David Laharie, Bassirou Mboup, Medina Boualit, Matthieu Allez, Sylvie Rajca, Elise Chanteloup, Guillaume Bouguen, Thomas Bazin, Felix Goutorbe, Nicolas Richard, Driffa Moussata, Eric Vicaut, Laurent Peyrin-Biroulet
Journal: Gut (2024)

It is unknown which maintenance therapy is the most effective option for patients admitted for an acute severe ulcerative colitis (ASUC) episode responding to intravenous steroids.
A Randomized Phase III Study to Compare Efficacy and Safety of BAT2206 (Proposed Ustekinumab Biosimilar) with Reference Ustekinumab in Patients with Moderate to Severe Plaque Psoriasis
Authors: Xiaoyong Man, Katya Zaharieva, Grażyna Pulka, Agnieszka Zebrowska, Yunhua Deng, Lally Mekokishvili, Xiaolei Yang, Yunpeng Qi, Cailing Gu, Qingfeng Dong, Min Zheng
Journal: Journal of the American Academy of Dermatology (2024)
Neoadjuvant immunotherapy in the evolving landscape of sarcoma treatment
Authors: Qiyan Cai, Yi Que, Xing Zhang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Soft tissue sarcoma is characterized by its rarity and complexity, making it more difficult to conduct large clinical trials compared with other solid tumors. Also known as 'cold tumors,' sarcomas, especially advanced sarcomas, have poor responses to immunotherapy. Based on that, the results of two groundbreaking phase 2 clinical trials about neoadjuvant immunotherapy in patients with liposarcoma or undifferentiated pleomorphic sarcoma are encouraging. In this paper, we discuss the results of these clinical trials and the challenges we are facing to conduct neoadjuvant immunotherapy in sarcomas and call for further research to promote the development of it.
Breathing down resistance: Tackling hypoxia to overcome immunotherapy barriers in lung cancer
Authors: Huanhuan Joyce Chen
Journal: The Journal of Experimental Medicine (2024)

In this issue of JEM, Robles-Oteiza et al. (https://doi.org/10.1084/jem.20231106) present compelling evidence linking tumor hypoxia to acquired resistance mechanisms in non-small cell lung cancer (NSCLC) treatments involving immune checkpoint inhibitors (ICIs). Their research advocates targeting these hypoxic tumor regions with hypoxia-activated pro-drugs like TH-302, which may substantially delay the onset of resistance and herald a significant advancement in cancer therapy.
Anti-tumor activity and biomarker analysis for TROP2-antibody drug conjugate Datopotamab deruxtecan in patient-derived breast cancer xenograft models
Authors: Funda Meric-Bernstam, Erkan Yuca, Kurt W. Evans, Ming Zhao, Takanori Maejima, Tsuyoshi Karibe, Maria Gabriela Raso, Ximing Tang, Xiaofeng Zheng, Yasmeen Qamar Rizvi, Argun Akcakanat, Stephen M. Scott, Bailiang Wang, Lauren A. Byers, Debu Tripathy, Daisuke Okajima, Senthil Damodaran
Journal: Clinical Cancer Research (2024)

Datopotamab deruxtecan (Dato-DXd) is a humanized anti-trophoblast cell-surface antigen-2 (TROP2) IgG1 mAb linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCX) varying in TROP2 expression. The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors postneoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines. Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival in 8 (73%) models, whereas IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged event-free survival in 3 (27%) models. TROP2 RNA and protein were significantly higher in Dato-DXd-sensitive models. In isogenic cell lines derived from Dato-DXd-resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the two Dato-DXd-sensitive BCXs but not in a Dato-DXd-resistant BCX. In Dato-DXd-sensitive models, antitumor activity was enhanced in combination with a PARP inhibitor, olaparib. Dato-DXd is active in breast cancer models. Dato-DXd has TROP2-dependent and -independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.
Response-Adaptive Surgical Timing in neoadjuvant immunotherapy demonstrates enhanced pathologic treatment response in Head and Neck Squamous Cell Carcinoma
Authors: Eric V. Mastrolonardo, Kathryn L. Nunes, Pablo Llerena, Anastasia Nikitina, Anastasia Sobol, E. Reilly Scott, Madalina Tuluc, Christopher J.H. Davitt, Jessica Scher, Sruti Tekumalla, Derek Mann, Camilo Henao, Victor Jegede, Stacey Gargano, Larry A. Harshyne, Angela Alnemri, Andrey Tyshevich, Vladimir Kushnarev, Madison Chasse, Danielle Sookiasian, Rita Axelrod, Tingting Zhan, Benjamin E. Leiby, Matthew Old, Nolan Seim, My G. Mahoney, Ubaldo Martinez-Outschoorn, David M. Cognetti, Joseph M. Curry, George Prendergast, Athanassios Argiris, Andrew P. South, Alban J. Linnenbach, Jennifer M. Johnson, Adam J. Luginbuhl
Journal: Clinical Cancer Research (2024)

Abstract Purpose: We evaluated whether IDO-inhibitor BMS986205 (IDOi) + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable HNSCC. We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response. Patients and Methods: Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 PO daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by HPV status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after nivolumab in both arms. Non-responders underwent surgical resection, while responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing. Results: Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (p=0.909). Treatment was well-tolerated with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDO-inhibitor augmented rates of pTR in patients with high baseline IDO RNA expression (p&amp;lt;0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus non-responders (p=0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-g expression in the HPV– cohort correlated with response. HPV+ cohort found B-cell and CAF signatures predictive of response/non-response. Conclusions: Response-adaptive surgical timing enhanced treatment response. IDO-inhibitor BMS986205 augmented pTR in patients with high IDO1-expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV-status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.
Psychological Resilience and Frailty Progression in Older Adults
Authors: Bo Ye, Yunxia Li, Zhijun Bao, Junling Gao
Journal: JAMA Network Open (2024)

Importance The association between psychological resilience (PR) and frailty progression in older adults is not fully understood. Objective To investigate the longitudinal associations between PR and its changes (ΔPR) with frailty progression among older adults. Design, Setting, and Participants Data were collected from a community-based prospective cohort study conducted in Shanghai from 2020 to 2023. Older adults aged 60 years and above were recruited at baseline and completed follow-up assessments. Statistical analysis was performed from May to July 2024. Exposures PR was assessed using the 25-item Connor-Davidson resilience scale (CD-RISC). ΔPR was calculated using the difference between 3-year follow-up and baseline CD-RISC scores. Multiple key covariates were included such as demographics, health behaviors, social participation, and chronic diseases. Main Outcomes and Measures Frailty was evaluated using the Chinese Frailty Screening Scale-10. Frailty progression was categorized into 3 groups (improvement, stability, and deterioration) by the difference assessment between 3-year follow-up and baseline. Results A total of 4033 participants were included in the study (mean [SD] age, 71.0 [6.1] years; 2257 [56.0%] women). Over a 3-year follow-up period, 1142 participants (28.3%) experienced an improvement in frailty, 1200 (29.8%) experienced stability, and 1691 (41.9%) exhibited deterioration. After controlling for confounding variables, a significant association was found between PR and future frailty, particularly when baseline frailty scores were at least 3 vs 2 or lower (β, −0.136 [95% CI, −0.214 to −0.057] vs −0.020 [-95% CI, −0.052 to 0.012]; P for interaction &amp;amp;lt; .001). A similar association was observed between PR and frailty improvement (adjusted odds ratio [OR], 1.28 [95% CI, 1.05 to 1.57]). Furthermore, ΔPR displayed a significant association with frailty, exhibiting a nonlinear association that was stronger when ΔPR was less than 0 vs when ΔPR was greater than 0 (β,−0.186 [95% CI, −0.228 to −0.145] vs −0.068 [95% CI, −0.107 to −0.029]; P for nonlinear &amp;amp;lt; .001). Similarly, ΔPR was significantly associated with frailty progression, indicating both improvement (adjusted OR, 1.30 [95% CI, 1.19 to 1.42]) and deterioration (adjusted OR, 0.74 [95% CI, 0.69 to 0.80]). These associations were more pronounced among older adults with higher levels of baseline frailty. Conclusions and relevance In this cohort study of community-dwelling older adults, a longitudinal association between PR and frailty progression was found. The results suggest that monitoring changes in PR can help forecast future frailty trajectories, particularly highlighting the need to support individuals facing declines in resilience. Targeted interventions that prioritize enhancing PR have potential to prevent and ameliorate frailty.
A New Clue on Diffuse Brain Swelling After Pediatric TBI
Authors: Patrick M. Kochanek, Dennis W. Simon, Robert S. B. Clark
Journal: JAMA Network Open (2024)

Josie L. Fullerton, PhD; Jennifer Hay, PhD; Charlotte Bryant-Craig, BDS; Josephine Atkinson, MSci; Douglas H. Smith, MD; William Stewart, MBChB, PhD
Antihypertensive Deprescribing and Cardiovascular Events Among Long-Term Care Residents
Authors: Michelle C. Odden, Laura A. Graham, Xiaojuan Liu, Chintan V. Dave, Sei J. Lee, Yongmei Li, Bocheng Jing, Kathy Fung, Carmen A. Peralta, Michael A. Steinman
Journal: JAMA Network Open (2024)

Importance The practice of deprescribing antihypertensive medications is common among long-term care residents, yet the effect on cardiovascular outcomes is unclear. Objective To compare the incidence of hospitalization for myocardial infarction (MI) or stroke among long-term care residents who are deprescribed or continue antihypertensive therapy. Design, Setting, and Participants This comparative effectiveness research study used target trial emulation with observational electronic health record data from long-term care residents aged 65 years or older admitted to US Department of Veterans Affairs community living centers between October 1, 2006, and September 30, 2019, and taking at least 1 antihypertensive medication. Analyses were conducted between August 2023 and August 2024. Exposure A reduction in the number of antihypertensive medications or dose (by ≥30%), assessed using barcode medication administration data. Main Outcome and Measures Incidence of MI and stroke hospitalization up to 2 years was assessed using International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. A pooled logistic regression model with inverse probability of treatment weighting (IPTW) and inverse probability of censoring weighting (IPCW) was used to estimate per-protocol effects. Results Of 13 096 long-term care residents (97.4% men; median age, 77 years [IQR, 70-84 years]) taking antihypertensive medication, 17.8% were deprescribed antihypertensive medication over a period of 12 weeks. The estimated unadjusted cumulative incidence of stroke or MI hospitalization over 2 years was similar among residents who were and were not deprescribed antihypertensives in per-protocol analyses (11.2% vs 8.8%; difference, 2.4 percentage points [95% CI, −2.3 to 7.1 percentage points]). Participant characteristics were balanced after applying IPTW and IPCW; all standardized mean differences were less than 0.05. After full adjustment for confounding and informative censoring, the per-protocol analysis results showed no association of antihypertensive deprescribing with MI or stroke hospitalization (hazard ratio, 0.93; 95% CI, 0.70-1.26). Conclusions and Relevance In this comparative effectiveness research study, deprescribing antihypertensive medication was not associated with risk of hospitalization for MI or stroke in long-term care residents. These findings may be informative for long-term care residents and clinicians who are considering deprescribing antihypertensive medications.