tbuckley/cabot-search huggingface dataset:
Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders
Authors: Yangliu Xia, Yang Zhang, Zhipeng Zhang, Nana Yan, Vorthon Sawaswong, Lulu Sun, Wanwan Guo, Ping Wang, Kristopher W Krausz, Oksana Gavrilova, James M Ntambi, Haiping Hao, Tingting Yan, Frank J Gonzalez
Journal: Acta Pharmaceutica Sinica B (2024)

Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies, the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, an SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.
“Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation
Authors: Jiayu Lu, Zhaomin Xia, Yongjing Zhang, He Wang, Wen Yang, Siqi Wang, Nan Wang, Yun Liu, Huaizhen He, Cheng Wang, Langchong He
Journal: Acta Pharmaceutica Sinica B (2024)

MRGPRX2 antagonists possess the potential for the treatment of allergic rhinitis, atopic dermatitis, and chronic urticaria. Previously, we identified a class of diaryl urea (DPU) MRGPRX2 antagonists with sub-micromolar IC50 values in vitro. However, the structure-activity relationship remains unclear. Herein, we adopted a "relative symmetry with electronegativity of different key-groups" strategy for further modification of DPUs to achieve a promising MRGPRX2 antagonist with higher activity and safety. Electrostatic potential energy analysis and biological evaluation revealed that B-1023 and B-5023, that possess relatively symmetric electron-withdrawing substituents, remarkable inhibited mast cell degranulation at a sub-micromolar IC50 in vitro and alleviated anaphylactic symptoms. Furthermore, B-1023, mitigated antigen-induced pulmonary inflammation (AIPI) in mice and competitively bonded to MRGPRX2. In summary, the "relative symmetry with electronegativity of different key-groups" strategy provided a drug design pattern for MRGPRX2 antagonists and identified promising antiallergic precursors for AIPI treatment.
The Mental Health of Sexual Minority Individuals: Five Explanatory Theories and Their Implications for Intervention and Future Research
Authors: John E. Pachankis, Kirsty A. Clark
Journal: Annual Review of Clinical Psychology (2024)

Research on the disparity in common mental health problems borne by sexual minority individuals has entered a stage of increasing theoretical complexity. Indeed, such a substantial disparity is likely not determined by a singular cause and therefore warrants diverse etiological perspectives tested with increasingly rigorous methodologies. The research landscape is made even more complex by the constant and rapid shift in the ways in which sexual minority people understand and characterize their own identities and experiences. This review introduces readers to this complexity by summarizing the historical legacy of research on the sexual orientation disparity in mental health, describing five contemporary theoretical explanations for this disparity and their supporting evidence, and suggesting theoretically informed interventions for reducing this disparity. Last, we offer an agenda for future research to accurately model the complexity of the pathways and solutions to the disproportionately poorer mental health of sexual minority populations.
Long-term clinical and safety outcomes from a single-site phase 1 study of neural stem cell transplantation for chronic thoracic spinal cord injury
Authors: Joel R. Martin, Daniel Cleary, Mickey E. Abraham, Michelle Mendoza, Betty Cabrera, Catriona Jamieson, Martin Marsala, Joseph D. Ciacci
Journal: Cell Reports Medicine (2024)

Highlights•NSI-566 transplanted in the spinal injury site of patients can be performed safely•NSI-566 transplantation was shown to decrease post-operative pain•NSI-566 transplantation was shown to improve motor and sensory function•NSI-566 transplantation resulted in electrophysiological defined improvementSummaryWe report the long-term results for a phase 1 study of neural stem cell transplantation for chronic spinal cord injury. The trial was registered on ClinicalTrials.gov as NCT01772810. The primary outcome of the trial was to test the feasibility and safety of human spinal cord-derived neural stem cell (NSI-566) transplantation for the treatment of chronic spinal cord injury in four subjects with thoracic two to thoracic twelve spinal cord injury. Here, we report that all four subjects tolerated the stem cell implantation procedure well, and two subjects had durable electromyography-quantifiable evidence of neurological improvement as well as increased neurological motor and sensory scores at five years post-transplantation.Graphical abstract
UBA1 inhibition sensitizes cancer cells to PARP inhibitors
Authors: Sharad Awasthi, Lacey E Dobrolecki, Christina Sallas, Xudong Zhang, Yang Li, Sima Khazaei, Sumanta Ghosh, Collene R Jeter, Jinsong Liu, Gordon B Mills, Shannon N Westin, Michael T Lewis, Weiyi Peng, Anil K Sood, Timothy A Yap, S Stephen Yi, Daniel J McGrail, Nidhi Sahni
Journal: Cell Reports Medicine (2024)
Age-related clonal hematopoiesis and HIV infection are associated with geriatric outcomes: The ARCHIVE study
Authors: Win Min Han, Hossain M S Sazzad, Mark Bloch, David A Baker, Norman Roth, Ellen Bowden-Reid, Don E Smith, Jennifer F Hoy, Ian Woolley, Robert Finlayson, David J Templeton, Gail V Matthews, Jane Costello, Mark A Dawson, Sarah-Jane Dawson, Mark N Polizzotto, Kathy Petoumenos, Paul Yeh, Nila J Dharan
Journal: Cell Reports Medicine (2024)
Wisdom, Resilience, and Well-Being in Later Life
Authors: Dilip V. Jeste, George S. Alexopoulos, Dan G. Blazer, Helen Lavretsky, Perminder S. Sachdev, Charles F. Reynolds
Journal: Annual Review of Clinical Psychology (2024)

As the numbers of older adults continue to increase globally, the need for facilitating healthy aging has become critical. While a physically healthy lifestyle, including exercise and diet, is important, recent research has highlighted a major impact of psychosocial determinants of health, such as resilience, wisdom, positive social connections, and mental well-being, on whole health. This article focuses on keeping the mind and brain healthy with psychosocially active aging. It has six sections: Philosophy Concepts of Wisdom, Resilience, and Well-Being; Wisdom: Clinical, Neurobiological, and Evolutionary Perspectives; Resilience, Adaptation, and Augmentation; Psychological Resilience, Brain Health, and Whole Person Health; Preventing Depression and Promoting Resilience and Well-Being in Old Age; and The Centenarian as a Model of Resilience and Well-Being. We discuss the biopsychosocial mechanisms and effectiveness of healthy lifestyle strategies and propose a framework for future research and its practical implications for promoting wisdom, resilience, and well-being at the individual, societal, and policy levels.
Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors
Authors: Esra Karakose, Xuedi Wang, Peng Wang, Saul Carcamo, Deniz Demircioglu, Luca Lambertini, Olivia Wood, Randy Kang, Geming Lu, Donald K Scott, Adolfo Garcia-Ocaña, Carmen Argmann, Robert P Sebra, Dan Hasson, Andrew F Stewart
Journal: Cell Reports Medicine (2024)
Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4+ T cell for inflammatory bowel diseases treatment
Authors: Jiangnan Zhang, Yunhan Jiang, Dongmei Fan, Zhiqiang Qiu, Xinlian He, Song Liu, Linjie Li, Zhengyi Dai, Lidan Zhang, Ziyi Shu, Lili Li, Hu Zhang, Tao Yang, Youfu Luo
Journal: Cell Reports Medicine (2024)
Campylobacter jejuni-derived cytolethal distending toxin promotes colorectal cancer metastasis
Authors: Zhen He, Jing Yu, Junli Gong, Jinjie Wu, Xuan Zong, Zhanhao Luo, Xiaowen He, Wai Ming Cheng, Yugeng Liu, Chen Liu, Qiang Zhang, Lei Dai, Tao Ding, Beile Gao, Raad Z Gharaibeh, Jinlin Huang, Christian Jobin, Ping Lan
Journal: Cell Host & Microbe (2024)

Various forms of solid tumors harbor intracellular bacteria, but the physiological consequences of these microorganisms are poorly understood. We show that Campylobacter is significantly enriched in primary colorectal cancer (CRC) lesions from patients with metastasis. Campylobacter jejuni-derived cytolethal distending toxin (CDT) promotes CRC metastasis through JAK2-STAT3-MMP9 signaling in liver or pulmonary metastatic mice models, as confirmed in C. jejuni-infected human colonic tissue and CDT-treated colonic tumoroids from patients. Genetic deletion of cdtB (ΔcdtB) or purified CdtB protein demonstrates that the genotoxin is essential for C. jejuni's pro-metastatic property. In C.-jejuni-colonized mice, increased translocation of CDT-producing C. jejuni to extraintestinal implanted tumors potentially leads to accelerated metastasis of these tumors. Overall, these findings demonstrate that an intratumor-bacteria-derived genotoxin accelerates tumor metastasis, potentially opening a new diagnostic and therapeutic avenue for cancer management.
An engineered α1β1 integrin-mediated FcγRI signaling component to control enhanced CAR macrophage activation and phagocytosis
Authors: Fuyu Du, Zixuan Ye, Anna He, Jingtong Yuan, Maozhi Su, Qingan Jia, Huaiyu Wang, Peng Yang, Zuo Yang, Pengbo Ning, Zhongliang Wang
Journal: Journal of Controlled Release (2024)
The Prostaglandin EP4 Antagonist Vorbipiprant Combined with PD-1 Blockade for Refractory Microsatellite Stable Metastatic Colorectal Cancer: A Phase 1b/2a Trial
Authors: Filippo Pietrantonio, Federica Morano, Monica Niger, Filippo Ghelardi, Claudia Chiodoni, Michele Palazzo, Federico Nichetti, Paolo Manca, Eleonora Cristarella, Valentina Doldi, Nadia Zaffaroni, Giovanna Sabella, Nadia Brambilla, Elena Benincasa, Giampaolo Giacovelli, Cristina Vitalini, Federica Girolami, Lucio C. Rovati
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Novel combinations are required to overcome resistance to immune checkpoint inhibitors (ICIs) in proficient mismatch repair (pMMR) or microsatellite stable (MSS) metastatic colorectal cancer (mCRC). We aimed to determine whether vorbipiprant, a prostaglandin EP4 receptor antagonist, can convert immune-resistant mCRC into a tumor responsive to anti-PD-1 inhibition. Patients and Methods: This phase 1b/2a prospective, open-label, single-arm trial followed a 3 + 3 dose escalation and dose optimization design. A total of 28 patients with chemorefractory pMMR/MSS mCRC were given dose-escalated oral vorbipiprant (30, 90, or 180 mg twice daily), along with biweekly intravenous balstilimab (3 mg/kg), an anti-PD-1 antibody. The primary endpoints included safety and the disease control rate (DCR). Secondary endpoints were the objective response rate (ORR), duration of response, progression-free survival (PFS) and overall survival (OS). Results: No dose-limiting toxicities were observed. Out of the 28 patients, seven (25%) experienced serious adverse events, but only one was attributed to vorbipiprant and one to balstilimab. The trial achieved a DCR of 50% observed across the entire cohort. In the subgroup of patients with liver metastases (n = 12) DCR was 25%. The ORR was 11%, with three patients showing a partial response (median duration of response: 7.4 months). Median PFS was 2.6 months and median OS was 14.2 months. Translational exploratory analyses suggested that vorbipiprant may boost response to anti-PD-1 in patients with immunogenic tumors. Conclusions: The combination of vorbipiprant and a PD-1 inhibitor (balstilimab) yielded sufficient activity in refractory pMMR/MSS mCRC, worth of confirmation in future clinical trials in biomarker-enriched populations.
Non-invasive multi-cancer detection using DNA hypomethylation of LINE-1 retrotransposons
Authors: Marc Michel, Maryam Heidary, Anissa Mechri, Kévin Da Silva, Marine Gorse, Victoria Dixon, Klaus von Grafenstein, Charline Bianchi, Caroline Hego, Aurore Rampanou, Constance Lamy, Maud Kamal, Christophe Le Tourneau, Mathieu Séné, Ivan Bièche, Cécile Reyes, David Gentien, Marc-Henri Stern, Olivier Lantz, Luc Cabel, Jean-Yves Pierga, François-Clément Bidard, Chloé-Agathe Azencott, Charlotte Proudhon
Journal: Clinical Cancer Research (2024)

Abstract Purpose: The detection of ctDNA, which allows noninvasive tumor molecular profiling and disease follow-up, promises optimal and individualized management of patients with cancer. However, detecting small fractions of tumor DNA released when the tumor burden is reduced remains a challenge. Experimental Design: We implemented a new, highly sensitive strategy to detect bp resolution methylation patterns from plasma DNA and assessed the potential of hypomethylation of long interspersed nuclear element-1 retrotransposons as a noninvasive multicancer detection biomarker. The Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA method targets 30 to 40,000 young long interspersed nuclear element-1 retrotransposons scattered throughout the genome, covering about 100,000 CpG sites and is based on a reference-free analysis pipeline. Results: Resulting machine learning–based classifiers showed powerful correct classification rates discriminating healthy and tumor plasmas from six types of cancers (colorectal, breast, lung, ovarian, and gastric cancers and uveal melanoma, including localized stages) in two independent cohorts (AUC = 88%–100%, N = 747). The Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA method can also be used to perform copy number alteration analysis that improves cancer detection. Conclusions: This should lead to the development of more efficient noninvasive diagnostic tests adapted to all patients with cancer, based on the universality of these factors.
Compounded GLP 1 and Dual GIP/GLP 1 Receptor Agonists: A Statement from the American Diabetes Association
Authors: Joshua J. Neumiller, Mandeep Bajaj, Raveendhara R. Bannuru, Rozalina G. McCoy, Elizabeth J. Pekas, Alissa R. Segal, Nuha A. ElSayed
Journal: Diabetes Care (2024)

The use of glucagon-like peptide 1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA (GIP/GLP-1 RA) classes has increased substantially over the past several years for treating type 2 diabetes and obesity. Increased demand for these pharmacotherapies has resulted in temporary product shortages for both GLP-1 RA and dual GIP/GLP-1 RA medications. These shortages, in part, have led to entities producing and marketing compounded formulations that bypass regulatory measures, raising safety, quality, and efficacy concerns. Even as shortages resolve, compounded GLP-1 RA and GIP/GLP-1 RA products continue to be heavily marketed to people with diabetes and obesity. The purpose of this statement by the American Diabetes Association is to guide health care professionals and people with diabetes and/or obesity in these circumstances of medication unavailability to promote optimal care and medication use safety.
Active surveillance in patients with extra-abdominal desmoid-type fibromatosis: a pooled analysis of three prospective observational studies
Authors: Chiara Colombo, Stefanie Hakkesteegt, Axel Le Cesne, Francesco Barretta, Jean-Yves Blay, Dirk J. Grünhagen, Nicolas Penel, Laurent Lam, Marco Fiore, Elena Palassini, Giovanni Grignani, Francesco Tolomeo, Paola Collini, Alessandra Merlini, Federica Perrone, Silvia Stacchiotti, Cornelis Verhoef, Sylvie Bonvalot, Alessandro Gronchi
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Three prospective observational studies (Italy, the Netherlands, France) on active surveillance (AS) in patients with extra-abdominal desmoid-type fibromatosis (DTF) support AS as a frontline approach. Identifying prognostic factors for the failure of AS will help determine the strategy. The aim of this study was to investigate the prognostic impact of clinical and molecular variables in a larger series. Experimental design: Data available as of January 31st, 2024, from the three studies, in which patients were followed for ≥3 years, were pooled. Patients ≥18 years old, with primary sporadic DTF and with CTNNB1 mutations available, were eligible. The primary study endpoint was treatment-free survival (TFS). Secondary endpoints included the incidence of RECIST progression, spontaneous RECIST regression and regression post-RECIST progression. Results: Two hundred and eighty-two patients (n = 282) with a median follow-up of 53 months (IQR, 39-63) were included. Three-year and five-year TFS were 67% and 66%, crude cumulative incidences (CCI) of RECIST progression were 33% and 34%, of RECIST regression 26% and 34% and of regression post-RECIST progression 33% and 38%. In multivariable analysis, larger tumour size, mutation type, tumor locations were associated to lower TFS. The specific mutation (S45F), larger tumor size, and extremity and trunk location were all associated with a lower probability of spontaneous RECIST regression. Conclusions: This study confirms that spontaneous regression occurs in a significant proportion of patients and that two-thirds are treatment-free at 5 years. Initial tumor size, CTNNB1 mutation, and location should be factored into the initial decision-making process.
Major Bleeding and Mortality After Revascularization of Left Main Disease
Authors: Gennaro Giustino, Joseph F Sabik, Patrick W Serruys, John D Puskas, Dimitri Karmpaliotis, David E Kandzari, Marie-Claude Morice, Michael Ragosta, Zixuan Zhang, Ovidiu Dressler, Bjorn Redfors, Ori Ben-Yehuda, Samin K Sharma, Arie Pieter Kappetein, Gregg W Stone
Journal: Journal of the American College of Cardiology (2024)
Reimbursement in the age of generalist radiology artificial intelligence
Authors: Siddhant Dogra, Ezequiel “Zeke” Silva, Pranav Rajpurkar
Journal: npj Digital Medicine (2024)

Abstract We argue that generalist radiology artificial intelligence (GRAI) challenges current healthcare reimbursement frameworks. Unlike narrow AI tools, GRAI’s multi-task capabilities render existing pathways inadequate. This perspective examines key questions surrounding GRAI reimbursement, including issues of coding, valuation, and coverage policies. We aim to catalyze dialogue among stakeholders about how reimbursement might evolve to accommodate GRAI, potentially influencing AI reimbursement strategies in radiology and beyond.
Pembrolizumab Versus chemotherapy in microsatellite instability–high or mismatch repair–deficient metastatic colorectal cancer: 5-year follow-up from the randomized phase 3 KEYNOTE-177 study
Authors: T André, K-K Shiu, T W Kim, B V Jensen, L H Jensen, C J A Punt, D Smith, R Garcia-Carbonero, J Alcaide-Garcia, P Gibbs, C de la Fouchardiere, F Rivera, E Elez, D T Le, T Yoshino, Y Zuo, D Fogelman, D Adelberg, L A Diaz
Journal: Annals of Oncology (2024)
Targeting RNA and Protein Turnover in Aneuploid Cancers
Authors: Samuel F. Bakhoum
Journal: Cancer Discovery (2024)

Summary: Aneuploidy, an imbalance in chromosome number, is a hallmark of human cancers with chromosomal instability, and it remains a major therapeutic challenge. In this issue, Ippolito and colleagues identify RNA and protein turnover as targetable therapeutic vulnerabilities in aneuploid cancers. See related article by Ippolito et al., p. 2532
Tales of Cancer-Induced Bone Disease from the Senescent Osteocyte Crypt
Authors: Jeremy S. Frieling, Conor C. Lynch
Journal: Cancer Research (2024)

Cancer-induced bone disease greatly diminishes the quality of life for patients with bone metastatic breast cancer, resulting in painful skeletal-related events including bone loss and fracture. Improved understanding of the roles of osteoblasts and osteoclasts, and how tumors alter their biology, has led to blockbuster therapies that significantly reduce skeletal-related events, but the disease remains incurable. However, emerging technologies and tools for studying the role of other stromal and immune components in controlling tumor–host interactions have begun to reveal new insights that may yield tractable therapeutic targets to further mitigate the painful effects of bone metastases. In this issue of Cancer Research, Kaur and colleagues study osteocytes, which are terminally differentiated osteoblasts and entombed within the bone matrix, from established bone metastatic breast cancer and report how the disease ages them as characterized by a senescence-associated secretory phenotype. This premature development of osteocyte senescence in turn enhances bone destruction and osteoclastogenic potential. Targeting senescent cells using senolytics suppressed bone resorption and preserved bone mass. Collectively, these findings underscore osteocyte involvement in the “vicious cycle” of bone metastasis, and targeting senescent osteocytes represents a new avenue for managing cancer-induced bone disease. See related article by Kaur et al., p. 3936
Paralog Co-Targeting Identifies Selective Genetic Redundancies across Cancer Types
Authors: Gregory Gauthier-Coles, Jason M. Sheltzer
Journal: Cancer Discovery (2024)

Summary: In this issue, Klingbeil and colleagues deploy a paralog co-targeting strategy to reveal microtubule affinity–regulating kinases 2 and 3 as redundant negative regulators of the Hippo pathway and potentially actionable targets in YAP/TAZ-addicted tumors. See related article by Klingbeil et.al., p. 2471
Characterization of Persister Cells Provides Insights into Mechanisms of Therapy Resistance in Neuroblastoma
Authors: Amber B. Wolf, C. Patrick Reynolds, Eveline Barbieri
Journal: Cancer Discovery (2024)

Summary: The study by Grossmann and colleagues uses single-nucleus RNA sequencing in a cohort of matched high-risk neuroblastoma primary tumor samples, obtained from the same patient at diagnosis and definitive surgery, to identify persister cells that survive induction chemotherapy. These persister cells utilize mechanisms of chemoresistance that are both tumor-intrinsic and tumor-extrinsic, are highly dependent on the original genetic profile of the tumor, and represent novel, patient-specific targets to precisely inhibit chemoresistance and disease recurrence. See related article by Grossmann et.al., p. 2387