tbuckley/cabot-search huggingface dataset:
“Unfinished Business” Brings Robert Califf, MD, Back for a Second Stint as FDA Commissioner
Authors: Rita Rubin
Journal: JAMA (2022)

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 Publications 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 2023 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
JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA
Authors: Zegui Ni, Pengli Sun, Jin Zheng, Mingqing Wu, Congcong Yang, Maosheng Cheng, Mingwei Yin, Chengying Cui, Guangxian Wang, Lin Yuan, Qian Gao, Yang Li
Journal: Cancer Research (2022)

The RNA N6-methyladenosine (m6A) writer methyltransferase-like 3 (METTL3) is upregulated in many types of cancer and promotes cancer progression by increasing expression of several oncogenes. Therefore, a better understanding of the mechanisms regulating METTL3 expression and the key targets of METTL3 in cancer cells could provide new therapeutic targets. In this study, we found that activated JNK signaling is associated with increased METTL3 expression in bladder cancer. Knockdown of JNK1 or administration of a JNK inhibitor impaired the binding of c-Jun with the METTL3 promoter, thereby decreasing the expression of METTL3 and global RNA m6A levels. Moreover, RNA m6A sequencing indicated enrichment of m6A in the 3'-UTR of immune checkpoint PD-L1 mRNA, which could be recognized by the m6A reader IGF2BP1 to mediate RNA stability and expression levels of PD-L1. Inhibition of JNK signaling suppressed m6A abundance in PD-L1 mRNA, leading to decreased PD-L1 expression. Functionally, METTL3 was essential for bladder cancer cells to resist the cytotoxicity of CD8+ T cells by regulating PD-L1 expression. Additionally, JNK signaling contributed to tumor immune escape in a METTL3-dependent manner both in vitro and in vivo. These data reveal the JNK/METTL3 axis as a mechanism of aberrant m6A modification and immune regulation in bladder cancer.The identification of a novel m6A-dependent mechanism underlying immune system evasion by bladder cancer cells reveals JNK signaling as a potential target for bladder cancer immunotherapy.
Immunogenicity and Safety of Standard and <scp>Third‐Dose SARS</scp>–<scp>CoV</scp>‐2 Vaccination in Patients Receiving Immunosuppressive Therapy
Authors: Silje W. Syversen, Ingrid Jyssum, Anne T. Tveter, Trung T. Tran, Joseph Sexton, Sella A. Provan, Siri Mjaaland, David J. Warren, Tore K. Kvien, Gunnveig Grødeland, Lise S. H. Nissen‐Meyer, Petr Ricanek, Adity Chopra, Ane M. Andersson, Grete B. Kro, Jørgen Jahnsen, Ludvig A. Munthe, Espen A. Haavardsholm, John T. Vaage, Fridtjof Lund‐Johansen, Kristin K. Jørgensen, Guro L. Goll
Journal: Arthritis & Rheumatology (2022)

Objective Immunogenicity and safety following receipt of the standard SARS–CoV‐2 vaccination regimen in patients with immune‐mediated inflammatory diseases (IMIDs) are poorly characterized, and data after receipt of the third vaccine dose are lacking. The aim of the study was to evaluate serologic responses and adverse events following the standard 2‐dose regimen and a third dose of SARS–CoV‐2 vaccine in IMID patients receiving immunosuppressive therapy. Methods Adult patients receiving immunosuppressive therapy for rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis, as well as healthy adult controls, who received the standard 2‐dose SARS–CoV‐2 vaccination regimen were included in this prospective observational study. Analyses of antibodies to the receptor‐binding domain (RBD) of the SARS–CoV‐2 spike protein were performed prior to and 2–4 weeks after vaccination. Patients with a weak serologic response, defined as an IgG antibody titer of ≤100 arbitrary units per milliliter (AU/ml) against the receptor‐binding domain of the full‐length SARS–Cov‐2 spike protein, were allotted a third vaccine dose. Results A total of 1,505 patients (91%) and 1,096 healthy controls (98%) had a serologic response to the standard regimen ( P &lt; 0.001). Anti‐RBD antibody levels were lower in patients (median 619 AU/ml interquartile range [IQR] 192–4,191) than in controls (median 3,355 AU/ml [IQR 896–7,849]) ( P &lt; 0.001). The proportion of responders was lowest among patients receiving tumor necrosis factor inhibitor combination therapy, JAK inhibitors, or abatacept. Younger age and receipt of messenger RNA–1273 vaccine were predictors of serologic response. Of 153 patients who had a weak response to the standard regimen and received a third dose, 129 (84%) became responders. The vaccine safety profile among patients and controls was comparable. Conclusion IMID patients had an attenuated response to the standard vaccination regimen as compared to healthy controls. A third vaccine dose was safe and resulted in serologic response in most patients. These data facilitate identification of patient groups at risk of an attenuated vaccine response, and they support administering a third vaccine dose to IMID patients with a weak serologic response to the standard regimen.
An Atlas of Genetic Correlations and Genetically Informed Associations Linking Psychiatric and Immune-Related Phenotypes
Authors: Daniel S. Tylee, Yu Kyung Lee, Frank R. Wendt, Gita A. Pathak, Daniel F. Levey, Flavio De Angelis, Joel Gelernter, Renato Polimanti
Journal: JAMA Psychiatry (2022)

Certain psychiatric and immune-related disorders are reciprocal risk factors. However, the nature of these associations is unclear.
Combination of oxaliplatin and POM-1 by nanoliposomes to reprogram the tumor immune microenvironment
Authors: Xianglei Fu, Yanbin Shi, Hengchang Zang, Qingjie Wang, Yongjun Wang, Hang Wu, Shengnan Qiu, Hua Shen, Fanyang Mo, Yankun Zhang, Guimei Lin
Journal: Journal of Controlled Release (2022)
Metabolomics and Type 2 Diabetes Risk: An Updated Systematic Review and Meta-analysis of Prospective Cohort Studies
Authors: Jakub Morze, Clemens Wittenbecher, Lukas Schwingshackl, Anna Danielewicz, Andrzej Rynkiewicz, Frank B. Hu, Marta Guasch-Ferré
Journal: Diabetes Care (2022)

Due to the rapidly increasing availability of metabolomics data in prospective studies, an update of the meta evidence on metabolomics and type 2 diabetes risk is warranted.
Normothermic Machine Perfusion Increases Donor Liver Use
Authors: Joan Miguel Romero, Nikita Kalashnikov
Journal: JAMA Surgery (2022)

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 Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications 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) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 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 Surgery journal
Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma
Authors: Miles Piper, Benjamin Van Court, Adam Mueller, Shuichi Watanabe, Thomas Bickett, Shilpa Bhatia, Laurel B. Darragh, Max Mayeda, Diemmy Nguyen, Jacob Gadwa, Michael Knitz, Sophia Corbo, Rustain Morgan, Jung-Jae Lee, Alexander Dent, Karyn Goodman, Wells Messersmith, Richard Schulick, Marco Del Chiaro, Yuwen Zhu, Ross M. Kedl, Laurel Lenz, Sana D. Karam
Journal: Clinical Cancer Research (2021)

Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden.PDAC patient tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following radiotherapy. Genetically engineered mouse strains in combination with orthotopic tumor models of PDAC were used to characterize disease progression. Flow cytometry was used to analyze tumor infiltrating, circulating, and nodal immune populations.We demonstrate that although radiotherapy increases the infiltration and activation of dendritic cells (DC), it also increases the infiltration of regulatory T cells (Treg) while failing to recruit natural killer (NK) and CD8 T cells in PDAC patient tissue samples. In murine orthotopic tumor models, we show that genetic and pharmacologic depletion of Tregs and NK cells enhances and attenuates response to radiotherapy, respectively. We further demonstrate that targeted inhibition of STAT3 on Tregs results in improved control of local and distant disease progression and enhanced NK-mediated immunosurveillance of metastasis. Moreover, combination treatment of STAT3 antisense oligonucleotide (ASO) and radiotherapy invigorated systemic immune activation and conferred a survival advantage in orthotopic and metastatic tumor models. Finally, we show the response to STAT3 ASO + radiotherapy treatment is dependent on NK and DC subsets.Our results suggest targeting Treg-mediated immunosuppression is a critical step in mediating a response to treatment, and identifying NK cells as not only a prognostic marker of improved survival, but also as an effector population that functions to combat metastasis.
Evaluation of the Dermatology Physician Assistant Workforce in the US
Authors: Justin D. Arnold, Kasey Puckett, Colette Jeffery, Andrzej Kozikowski
Journal: JAMA Dermatology (2022)

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 Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications 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) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 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 Dermatology journal
Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m6A Methyltransferase METTL3
Authors: Long Liao, Yan He, Shu-Jun Li, Guo-Geng Zhang, Wei Yu, Jing Yang, Zi-Jia Huang, Can-Can Zheng, Qing-Yu He, Yan Li, Bin Li
Journal: Cancer Research (2022)

Abstract N6-methyladenosine (m6A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A methylation in various aspects of cancer biology. In this study, we aimed to explore the biological role of RNA m6A modification in tumor metastasis and to identify novel therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Integration of genome-wide CRISPR/Cas9 functional screening with highly invasive and metastatic ESCC subline models led to the identification of METTL3, the catalytic subunit of the N6-adenosine-methyltransferase complex, as a promoter of cancer metastasis. METTL3 expression was upregulated in ESCC tumors and metastatic tissues. In vitro and in vivo experiments indicated that METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into the regulation of METTL3 expression found that KAT2A increased H3K27 acetylation levels in the METTL3 promoter region and activated transcription of METTL3, whereas SIRT2 exerted the opposite effects. Molecular docking and computational screening in a Food and Drug Administration–approved compound library consisting of 1,443 small molecules identified compounds targeting METTL3 to suppress cancer metastasis. Elvitegravir, originally developed to treat human immunodeficiency virus (HIV) infection, suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation. Overall, RNA m6A modifications are important in cancer metastasis, and targeting METTL3 with elvitegravir has therapeutic potential for treating ESCC. Significance: This study finds that METTL3 promotes cancer metastasis by activating EGR1/Snail signaling in an m6A-dependent manner, revealing vulnerability to METTL3 blockade in esophageal squamous cell carcinoma.
Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma
Authors: Nicholas D. Klemen, Sinchun Hwang, Martina Bradic, Evan Rosenbaum, Mark A. Dickson, Mrinal M. Gounder, Ciara M. Kelly, Mary L. Keohan, Sujana Movva, Katherine A. Thornton, Ping Chi, Benjamin A. Nacev, Jason E. Chan, Edmund K. Bartlett, Allison L. Richards, Samuel Singer, Mark T.A. Donoghue, William D. Tap, Sandra P. D'Angelo
Journal: Clinical Cancer Research (2021)

Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors.
Uniaxial and Coaxial Vertical Embedded Extrusion Bioprinting (Adv. Healthcare Mater. 9/2022)
Authors: Liming Lian, Cuiping Zhou, Guosheng Tang, Maobin Xie, Zixuan Wang, Zeyu Luo, Julia Japo, Di Wang, Jianhua Zhou, Mian Wang, Wanlu Li, Sushila Maharjan, Marina Ruelas, Jie Guo, Xunwei Wu, Yu Shrike Zhang
Journal: Advanced Healthcare Materials (2022)

Coaxial Extrusion In article number 2102411 by Xunwei Wu, Yu Shrike Zhang, and co-workers, an enabling vertical-embedded extrusion bioprinting strategy is reported by using uniaxial or coaxial nozzles, which allows formation of vertical tissue structures of homogeneous or heterogeneous properties in nature. This technique will likely bring further improvements in the reconstruction of certain human tissue types, especially those with a linear structure, leading to wide utilities in tissue engineering and drug discovery.
Cerebral Autoregulation during Orthostatic Challenge in Congenital Central Hypoventilation Syndrome
Authors: Eric L. Vu, Emma C. Dunne, Allison Bradley, Amy Zhou, Michael S. Carroll, Casey M. Rand, Kenneth M. Brady, Tracey M. Stewart, Debra E. Weese-Mayer
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Congenital central hypoventilation syndrome (CCHS) is a rare autonomic disorder with altered regulation of breathing, heart rate (HR), and blood pressure (BP). Aberrant cerebral oxygenation in response to hypercapnia/hypoxia in CCHS raises the concern that altered cerebral autoregulation may contribute to CCHS-related, variably impaired neurodevelopment. Objectives: To evaluate cerebral autoregulation in response to orthostatic challenge in CCHS cases versus controls. Methods: CCHS and age- and sex-matched control subjects were studied with head-up tilt (HUT) testing to induce orthostatic stress. Fifty CCHS and 100 control HUT recordings were included. HR, BP, and cerebral oxygen saturation (regional oxygen saturation) were continuously monitored. The cerebral oximetry index (COx), a real-time measure of cerebral autoregulation based on these measures, was calculated. Measurements and Main Results: HUT resulted in a greater mean BP decrease from baseline in CCHS versus controls (11% vs. 6%; P < 0.05) and a diminished increase in HR in CCHS versus controls (11% vs. 18%; P < 0.01) in the 5 minutes after tilt-up. Despite a similar COx at baseline, orthostatic provocation within 5 minutes of tilt-up caused a 50% greater increase in COx (P < 0.01) and a 29% increase in minutes of impaired autoregulation (P < 0.02) in CCHS versus controls (4.0 vs. 3.1 min). Conclusions: Cerebral autoregulatory mechanisms appear to be intact in CCHS, but the greater hypotension observed in CCHS consequent to orthostatic provocation is associated with greater values of COx/impaired autoregulation when BP is below the lower limits of autoregulation. Effects of repeated orthostatic challenges in everyday living in CCHS necessitate further study to determine their influence on neurodevelopmental disease burden.
Persistent Socioeconomic Disparities in Insulin Pump Uptake Despite Universal Health Coverage—Nonmonetary Drivers in Insulin Pump Use
Authors: Elise S. Tremblay
Journal: JAMA Network Open (2022)

Jennifer M. Ladd, MD; Atul Sharma, MD, MSc; Elham Rahme, PhD; Kristine Kroeker, MSc; Marjolaine Dubé, BSc; Marc Simard, MSc; Céline Plante, MSc; Claudia Blais, PhD; Marni Brownell, PhD; Celia Rodd, MD, MSc; Meranda Nakhla, MD, MSc
Comprehensive Analysis of Metabolic Isozyme Targets in Cancer
Authors: Michal Marczyk, Vignesh Gunasekharan, David Casadevall, Tao Qing, Julia Foldi, Raghav Sehgal, Naing Lin Shan, Kim R.M. Blenman, Tess A. O'Meara, Sheila Umlauf, Yulia V. Surovtseva, Viswanathan Muthusamy, Jesse Rinehart, Rachel J. Perry, Richard Kibbey, Christos Hatzis, Lajos Pusztai
Journal: Cancer Research (2022)

Abstract Metabolic reprogramming is a hallmark of malignant transformation, and loss of isozyme diversity (LID) contributes to this process. Isozymes are distinct proteins that catalyze the same enzymatic reaction but can have different kinetic characteristics, subcellular localization, and tissue specificity. Cancer-dominant isozymes that catalyze rate-limiting reactions in critical metabolic processes represent potential therapeutic targets. Here, we examined the isozyme expression patterns of 1,319 enzymatic reactions in 14 cancer types and their matching normal tissues using The Cancer Genome Atlas mRNA expression data to identify isozymes that become cancer-dominant. Of the reactions analyzed, 357 demonstrated LID in at least one cancer type. Assessment of the expression patterns in over 600 cell lines in the Cancer Cell Line Encyclopedia showed that these reactions reflect cellular changes instead of differences in tissue composition; 50% of the LID-affected isozymes showed cancer-dominant expression in the corresponding cell lines. The functional importance of the cancer-dominant isozymes was assessed in genome-wide CRISPR and RNAi loss-of-function screens: 17% were critical for cell proliferation, indicating their potential as therapeutic targets. Lists of prioritized novel metabolic targets were developed for 14 cancer types; the most broadly shared and functionally validated target was acetyl-CoA carboxylase 1 (ACC1). Small molecule inhibition of ACC reduced breast cancer viability in vitro and suppressed tumor growth in cell line– and patient-derived xenografts in vivo. Evaluation of the effects of drug treatment revealed significant metabolic and transcriptional perturbations. Overall, this systematic analysis of isozyme expression patterns elucidates an important aspect of cancer metabolic plasticity and reveals putative metabolic vulnerabilities. Significance: This study exploits the loss of metabolic isozyme diversity common in cancer and reveals a rich pool of potential therapeutic targets that will allow the repurposing of existing inhibitors for anticancer therapy. See related commentary by Kehinde and Parker, p. 1695
Tumor Expression Quantitative Trait Methylation Screening Reveals Distinct CpG Panels for Deconvolving Cancer Immune Signatures
Authors: Xiaoqing Yu, Ling Cen, Y. Ann Chen, Joseph Markowitz, Timothy I. Shaw, Kenneth Y. Tsai, Jose R. Conejo-Garcia, Xuefeng Wang
Journal: Cancer Research (2022)

Abstract DNA methylation signatures in tumors could serve as reliable biomarkers that are accessible in archival tissues for tracking the epigenetic dynamics shaped by both cancer cells and the tumor microenvironment. However, given the ultrahigh dimensionality and noncollapsible nature of the data, it remains challenging to screen all CpG sites to identify the most promising marker panels. In this article, we introduce the concept of tumor-based expression quantitative trait methylation (eQTM) for the prioritization and systematic mining of predictive biomarkers. In melanoma as a disease model, eQTM CpGs and genes represent new and efficient candidate targets to be investigated for both prognostic and immune status monitoring purposes. Three cis-eQTM CpGs (cg07786657, cg12446199, and cg00027570) were strongly associated with and can serve as surrogate biomarkers for the tumor immune cytolytic activity score (CYT). In addition, multiple eQTM genes could be further exploited for predicting immunoregulatory phenotypes. A targeted gene panel analysis identified one eQTM in TCF7 (cg25947408) as a novel candidate biomarker for uncoupling overall T-cell differentiation and exhaustion status in a tumor. The prognostic significance of this eQTM as an independent signature to CYT was validated by both The Cancer Genome Atlas and Moffitt melanoma cohort data. Overall, eQTMs represent a mechanistically distinct class of potential biomarkers that can be used to predict patient prognosis and immune status. Significance: This study provides a novel and promising approach to identify targeted epigenetic biomarkers in cancer and will spur further analysis in tumor immune phenotyping.
Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity
Authors: Raja Chakraborty, Allison C. Ostriker, Yi Xie, Jui M. Dave, Ana Gamez-Mendez, Payel Chatterjee, Yaw Abu, Jake Valentine, Kimberly Lezon-Geyda, Daniel M. Greif, Vincent P. Schulz, Patrick G. Gallagher, William C. Sessa, John Hwa, Kathleen A. Martin
Journal: Circulation (2022)

Vascular smooth muscle cell (VSMC) phenotypic switching contributes to cardiovascular diseases. Epigenetic regulation is emerging as a key regulatory mechanism, with the methylcytosine dioxygenase TET2 acting as a master regulator of smooth muscle cell phenotype. The histone acetyl-transferases p300 and CREB-binding protein (CBP) are highly homologous and often considered to be interchangeable, and their roles in smooth muscle cell phenotypic regulation are not known.