tbuckley/cabot-search huggingface dataset:
Clopidogrel and Percutaneous Coronary Interventions—Reply
Authors: Steven R. Steinhubl, Peter B. Berger, J. Tift Mann, Edward T. A. Fry, Augustin DeLago, Charles Wilmer, Eric J. Topol
Journal: JAMA (2003)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Association between change in cardiorespiratory fitness and prostate cancer incidence and mortality in 57 652 Swedish men
Authors: Kate A Bolam, Emil Bojsen-Møller, Peter Wallin, Sofia Paulsson, Magnus Lindwall, Helene Rundqvist, Elin Ekblom-Bak
Journal: British Journal of Sports Medicine (2024)

To examine the associations between changes in cardiorespiratory fitness (CRF) in adulthood and prostate cancer incidence and mortality.
APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model
Authors: Shihe Jiang, Xindi Li, Yan Li, Zhilin Chang, Meng Yuan, Ying Zhang, Huimin Zhu, Yuwen Xiu, Hengri Cong, Linlin Yin, Zhen-Wei Yu, Junwan Fan, Wenyan He, Kaibin Shi, De-Cai Tian, Jing Zhang, Alexei Verkhratsky, Wei-Na Jin, Fu-Dong Shi
Journal: Science Translational Medicine (2024)

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)–rich ADEVs in patients with AQP4-Abs–positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE 130–149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor–related protein 1 (LRP1) could block the restorative effects of APOE 130–149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE −/− mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.
TGFβ-specific T cells induced by a TGFβ-derived immune modulatory vaccine both directly and indirectly modulate the phenotype of tumor-associated macrophages and fibroblasts
Authors: Maria Perez-Penco, Lucia Lara de la Torre, Inés Lecoq, Evelina Martinenaite, Mads Hald Andersen
Journal: Journal for ImmunoTherapy of Cancer (2024)

The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive. We recently developed a transforming growth factor (TGF)β-based immune modulatory vaccine that controlled tumor growth in a murine model of pancreatic cancer by targeting immunosuppression and desmoplasia in the TME. We found that treatment with the TGFβ vaccine not only reduced the percentage of M2-like tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor but polarized CAFs away from the myofibroblast-like phenotype. However, whether the immune modulatory properties of the TGFβ vaccine on TAM and CAF phenotypes are a direct consequence of the recognition and subsequent targeting of these subsets by TGFβ-specific T cells or an indirect consequence of the overall modulation induced within the TME remains unknown. Recognition of M2 macrophages and fibroblast by TGFβ-specific T cells was assessed by ELISpot and flow cytometry. The indirect and direct effects of the TGFβ vaccine on these cell subsets were evaluated by culturing M2 macrophages or fibroblasts with tumor-conditioned media or with T cells isolated from the spleen of mice treated with the TGFβ vaccine or a control vaccine, respectively. Changes in phenotype were assessed by flow cytometry and Bio-Plex multiplex system (Luminex). We found that TGFβ-specific T cells induced by the TGFβ vaccine can recognize M2 macrophages and fibroblasts. Furthermore, we demonstrated that the phenotype of M2 macrophages and CAFs can be directly modulated by TGFβ-specific T cells induced by the TGFβ vaccine, as well as indirectly modulated as a result of the immune-modulatory effects of the vaccine within the TME. TAMs tend to have tumor-promoting functions, harbor an immunosuppressive phenotype and are linked to decreased overall survival in pancreatic cancer when they harbor an M2-like phenotype. In addition, myofibroblast-like CAFs create a stiff extracellular matrix that restricts T cell infiltration, impeding the effectiveness of immune therapies in desmoplastic tumors, such as pancreatic ductal adenocarcinoma. Reducing immunosuppression and immune exclusion in pancreatic tumors by targeting TAMs and CAFs with the TGFβ-based immune modulatory vaccine emerges as an innovative strategy for the generation of a more favorable environment for immune-based therapies, such as immune checkpoint inhibitors.
Remote haemodynamic monitoring in patients with heart failure – Authors' reply
Authors: Jasper J Brugts, Dilan Aydin, Pascal R D Clephas, Rudolf A de Boer
Journal: The Lancet (2024)

We thank Kazuo Komamra and Mitsunori Iwase, and John Kikoïne and colleagues for their interest in our Article. We are happy to clarify the trial safety endpoints of the device implantation that specifically refer to device-related or system-related complications (DSRCs). The safety endpoints of the three trials (CHAMPION, GUIDE-HF, and MONITOR-HF) are similar and use the same device and implantation technique.1–3 DSRCs were defined as an adverse event that was definitely or possibly related to the wireless pressure sensor or external electronics and was either treated with invasive means, resulted in the death of the patient, or resulted in the explant of the device.
Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial
Authors: Joël Guigay, Cécile Ortholan, Damien Vansteene, Didier Cupissol, Caroline Even, Marie-Christine Kaminsky, Christian Sire, Emmanuel Blot, Philippe Debourdeau, Laurence Bozec, Esma Saada-Bouzid, Jérôme Fayette, Pierre Dalloz, Yoann Pointreau, Hervé Le Caer, Claire Falandry, Laurence Digue, Antoine Braccini, Stéphane Lopez, Pierre Guillet, Cécile Michel, Nadir Cheurfa, Dominique Schwob, Jean Bourhis, Cécile Mertens, Anne Aupérin
Journal: The Lancet Healthy Longevity (2024)

At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population.
Machine Learning of Plasma Proteomics Classifies Diagnosis of Interstitial Lung Disease
Authors: Yong Huang, Shwu-Fan Ma, Justin M. Oldham, Ayodeji Adegunsoye, Daisy Zhu, Susan Murray, John S. Kim, Catherine Bonham, Emma Strickland, Angela L Linderholm, Cathryn T. Lee, Tessy Paul, Hannah Mannem, Toby M Maher, Philip L Molyneaux, Mary E. Strek, Fernando J. Martinez, Imre Noth
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Distinguishing connective tissue disease-associated interstitial lung disease (CTD-ILD) from idiopathic pulmonary fibrosis (IPF) can be clinically challenging.
Epigenome-Wide Association Studies of Chronic Obstructive Pulmonary Disease and Lung Function: A Systematic Review
Authors: Sandra Casas-Recasens, Raisa Cassim, Núria Mendoza, Alvar Agusti, Caroline Lodge, Shuai Li, Dinh Bui, David Martino, Shyamali C. Dharmage, Rosa Faner
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Chronic obstructive pulmonary disease (COPD) results from gene-environment interactions over the lifetime. These interactions are captured by epigenetic changes, such as DNA methylation.
Chronicity Counts: The Impact of <i>Pseudomonas aeruginosa</i>, <i>Staphylococcus aureus</i>, and Coinfection in Cystic Fibrosis
Authors: Micaela Mossop, Jonathan Ish-Horowicz, Dominic Hughes, Rebecca Dobra, Alessandra G. Cunanan, Mark Rosenthal, Siobhán B Carr, Newara Ramadan, Laura M Nolan, Jane C. Davies
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Chronicity Counts: The Impact of P. aeruginosa, S. aureus, and Co-Infection in Cystic Fibrosis." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
The impact of housing instability on health and other research
Authors: Tom Nolan
Journal: BMJ (2024)

Prescribe comes before a fallDoes prescribing opioids in older people increase their risk of having a serious fall?A cohort study set in New South Wales, Australia, examined the medical records of over three million people to see if they were more likely to subsequently visit the emergency department.The risk of falls was greater in all age groups (over 18 years of age) within 28 days of opioid exposure, compared with the risk beyond 29 days of exposure.In older people the risk was over six times greater (95% confidence interval of the adjusted incident rate ratio 6.20 to 6.51).However, researchers weren't able to adjust for the indication for opioid prescribing, meaning it's not clear how much the increase in falls risk is due to the opioid prescription and how much to the pain or injury that prompted it.
Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis
Authors: Nidhi S. Dey, Sujai Senaratne, Vijani Somaratne, Nayani P. Madarasinghe, Bimalka Seneviratne, Sarah Forrester, Marcela Montes de Oca, Luiza Campos Reis, Srija Moulik, Pegine B. Walrad, Mitali Chatterjee, Hiro Goto, Renu Wickremasinghe, Dimitris Lagos, Paul M. Kaye, Shalindra Ranasinghe
Journal: Journal of Clinical Investigation (2024)
NETs unleashed: neutrophil extracellular traps boost chemotherapy against colorectal cancer
Authors: Alexandra Mousset, Jean Albrengues
Journal: Journal of Clinical Investigation (2024)

Chemotherapy, which primarily acts on cancer cells, can influence the tumor microenvironment and the recruitment and behavior of stromal cells. In this issue of the JCI, Li et al. explored the potent anticancer effect of the combination of a glutaminase inhibitor (CB-839) and 5-FU against PIK3CA-mutant colorectal cancer tumors. This chemotherapy treatment strongly induced the recruitment of neutrophils that formed neutrophil extracellular traps in cancer, which actively killed cancer cells by inducing apoptosis. This study substantially advances our understanding of the multifaceted role of neutrophils and NETs in the outcome of anticancer treatment.
The etiologies of Kawasaki disease
Authors: Jane C. Burns
Journal: Journal of Clinical Investigation (2024)

Kawasaki disease (KD) is a systemic vasculitis that affects young children and can result in coronary artery aneurysms. The etiology is currently unknown, but new clues from the epidemiology of KD in Japan, the country of highest incidence, are beginning to shed light on what may trigger this acute inflammatory condition. Additional clues from the global changes in KD incidence during the COVID-19 pandemic, coupled with a new birth cohort study from Japan, point to the potential role of person-to-person transmission of an infectious agent. However, the rising incidence of KD in Japan, with coherent waves across the entire country, points to an increasing intensity of exposure that cannot be explained by person-to-person spread. This Review discusses new and historical observations that guide us toward a better understanding of KD etiology and explores hypotheses and interpretations that can provide direction for future investigations. Once the etiology of KD is determined, accurate diagnostic tests will become available, and new, less expensive, and more effective targeted therapies will likely be possible. Clearly, solving the mystery of the etiologies of KD remains a priority for pediatric research.
Cancer neoepitopes viewed through negative selection and peripheral tolerance: a new path to cancer vaccines
Authors: Pramod K. Srivastava
Journal: Journal of Clinical Investigation (2024)

A proportion of somatic mutations in tumors create neoepitopes that can prime T cell responses that target the MHC I-neoepitope complexes on tumor cells, mediating tumor control or rejection. Despite the compelling centrality of neoepitopes to cancer immunity, we know remarkably little about what constitutes a neoepitope that can mediate tumor control in vivo and what distinguishes such a neoepitope from the vast majority of similar candidate neoepitopes that are inefficacious in vivo. Studies in mice as well as clinical trials have begun to reveal the unexpected paradoxes in this area. Because cancer neoepitopes straddle that ambiguous ground between self and non-self, some rules that are fundamental to immunology of frankly non-self antigens, such as viral or model antigens, do not appear to apply to neoepitopes. Because neoepitopes are so similar to self-epitopes, with only small changes that render them non-self, immune response to them is regulated at least partially the way immune response to self is regulated. Therefore, neoepitopes are viewed and understood here through the clarifying lens of negative thymic selection. Here, the emergent questions in the biology and clinical applications of neoepitopes are discussed critically and a mechanistic and testable framework that explains the complexity and translational potential of these wonderful antigens is proposed.
The multivisceral landscape of colorectal cancer metastasis: implications for targeted therapies
Authors: Dominik Wolf, Stefan Salcher, Andreas Pircher
Journal: Journal of Clinical Investigation (2024)

Colorectal cancer (CRC) is among the most common cancer types and the second deadliest malignancy for both sexes. Metastatic disease poses substantial therapeutic challenges, and peritoneal spread, in particular, reduces quality of life and has a dismal outcome. In this issue of the JCI, Berlin and authors have made considerable advancements in understanding the cellular and molecular composition of multivisceral CRC metastasis in a sophisticated murine orthotopic organoid model and in humans. The study provides unprecedented insights into the complex biology of the disease and points toward the development of compartmentalized immune-therapeutic strategies.
Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways
Authors: Adelina Curaj, Raymond Vanholder, Joseph Loscalzo, Kaiseng Quach, Zhuojun Wu, Vera Jankowski, Joachim Jankowski
Journal: Circulation Research (2024)

The crosstalk of the heart with distant organs such as the lung, liver, gut, and kidney has been intensively approached lately. The kidney is involved in (1) the production of systemic relevant products, such as renin, as part of the most essential vasoregulatory system of the human body, and (2) in the clearance of metabolites with systemic and organ effects. Metabolic residue accumulation during kidney dysfunction is known to determine cardiovascular pathologies such as endothelial activation/dysfunction, atherosclerosis, cardiomyocyte apoptosis, cardiac fibrosis, and vascular and valvular calcification, leading to hypertension, arrhythmias, myocardial infarction, and cardiomyopathies. However, this review offers an overview of the uremic metabolites and details their signaling pathways involved in cardiorenal syndrome and the development of heart failure. A holistic view of the metabolites, but more importantly, an exhaustive crosstalk of their known signaling pathways, is important for depicting new therapeutic strategies in the cardiovascular field.
Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5
Authors: Meiling Li, Yu-Mi Kim, Jung Hee Koh, Jihyun Park, H Moo Kwon, Jong-Hwan Park, Jingchun Jin, Youngjae Park, Donghyun Kim, Wan-Uk Kim
Journal: Journal of Clinical Investigation (2024)

Nuclear factor of activated T-cells 5 (NFAT5), an osmo-sensitive transcription factor, can be activated by isotonic stimuli, such as infection. It remains unclear, however, whether NFAT5 is required for damage-associated molecular pattern-triggered (DAMP-triggered) inflammation and immunity. Here, we found that several DAMPs increased NFAT5 expression in macrophages. In particular, serum amyloid A (SAA), primarily generated by the liver, substantially upregulated NFAT5 expression and activity through TLR2/4-JNK signalling pathway. Moreover, the SAA-TLR2/4-NFAT5 axis promoted migration and chemotaxis of macrophages in an IL-6- and chemokine ligand 2-dependent (CCL2-dependent) manner in vitro. Intraarticular injection of SAA markedly accelerated macrophage infiltration and arthritis progression in mice. By contrast, genetic ablation of NFAT5 or TLR2/4 rescued the pathology induced by SAA, confirming the SAA-TLR2/4-NFAT5 axis in vivo. Myeloid-specific depletion of NFAT5 also attenuated SAA-accelerated arthritis. Of note, inflammatory arthritis in mice strikingly induced SAA overexpression in the liver. Conversely, forced overexpression of the SAA gene in the liver accelerated joint damage, indicating that the liver contributes to bolstering chronic inflammation at remote sites by secreting SAA. Collectively, this study underscores the importance of the SAA-TLR2/4-NFAT5 axis in innate immunity, suggesting that acute phase reactant SAA mediates mutual interactions between liver and joints and ultimately aggravates chronic arthritis by enhancing macrophage activation.
A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical models
Authors: Orhan Efe, Rodrigo B Gassen, Leela Morena, Yoshikazu Ganchiku, Ayman Al Jurdi, Isadora T Lape, Pedro Ventura-Aguiar, Christian LeGuern, Joren C Madsen, Zachary Shriver, Gregory J Babcock, Thiago J Borges, Leonardo V Riella
Journal: Journal of Clinical Investigation (2024)

Long-term organ transplant survival remains suboptimal, and life-long immunosuppression predisposes transplant recipients to an increased risk of infection, malignancy, and kidney toxicity. Promoting the regulatory arm of the immune system by expanding Tregs may allow immunosuppression minimization and improve long-term graft outcomes. While low-dose IL-2 treatment can expand Tregs, it has a short half-life and off-target expansion of NK and effector T cells, limiting its clinical applicability. Here, we designed a humanized mutein IL-2 with high Treg selectivity and a prolonged half-life due to the fusion of an Fc domain, which we termed mIL-2. We showed selective and sustainable Treg expansion by mIL-2 in 2 murine models of skin transplantation. This expansion led to donor-specific tolerance through robust increases in polyclonal and antigen-specific Tregs, along with enhanced Treg-suppressive function. We also showed that Treg expansion by mIL-2 could overcome the failure of calcineurin inhibitors or costimulation blockade to prolong the survival of major-mismatched skin grafts. Validating its translational potential, mIL-2 induced a selective and sustainable in vivo Treg expansion in cynomolgus monkeys and showed selectivity for human Tregs in vitro and in a humanized mouse model. This work demonstrated that mIL-2 can enhance immune regulation and promote long-term allograft survival, potentially minimizing immunosuppression.
Challenges in developing therapies in fragile X syndrome: how the FXLEARN trial can guide research
Authors: Jeffrey L. Neul
Journal: Journal of Clinical Investigation (2024)

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and the single-gene cause of autism, is caused by decreased expression of the fragile X messenger ribonucleoprotein protein (FMRP), a ribosomal-associated RNA-binding protein involved in translational repression. Extensive preclinical work in several FXS animal models supported the therapeutic potential of decreasing metabotropic glutamate receptor (mGluR) signaling to correct translation of proteins related to synaptic plasticity; however, multiple clinical trials failed to show conclusive evidence of efficacy. In this issue of the JCI, Berry-Kravis and colleagues conducted the FXLEARN clinical trial to address experimental design concerns from previous trials. Unfortunately, despite treatment of young children with combined pharmacological and learning interventions for a prolonged period, no efficacy of blocking mGluR activity was observed. Future systematic evaluation of potential therapeutic approaches should evaluate consistency between human and animal pathophysiological mechanisms, utilize innovative clinical trial design from FXLEARN, and incorporate translatable biomarkers.
Autophagy differentially regulates tissue tolerance of distinct target organs in graft-versus-host disease models
Authors: Katherine Oravecz-Wilson, Emma Lauder, Austin Taylor, Laure Maneix, Jeanine L Van Nostrand, Yaping Sun, Lu Li, Dongchang Zhao, Chen Liu, Pavan Reddy
Journal: Journal of Clinical Investigation (2024)

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.