tbuckley/cabot-search huggingface dataset:
The Mineralocorticoid Receptor in Salt-Sensitive Hypertension and Renal Injury
Authors: Nobuhiro Ayuzawa, Toshiro Fujita
Journal: Journal of the American Society of Nephrology (2021)

Hypertension and its comorbidities pose a major public health problem associated with disease-associated factors related to a modern lifestyle, such high salt intake or obesity. Accumulating evidence has demonstrated that aldosterone and its receptor, the mineralocorticoid receptor (MR), have crucial roles in the development of salt-sensitive hypertension and coexisting cardiovascular and renal injuries. Accordingly, clinical trials have repetitively shown the promising effects of MR blockers in these diseases. We and other researchers have identified novel mechanisms of MR activation involved in salt-sensitive hypertension and renal injury, including the obesity-derived overproduction of aldosterone and ligand-independent signaling. Moreover, recent advances in the analysis of cell-specific and context-dependent mechanisms of MR activation in various tissues-including a classic target of aldosterone, aldosterone-sensitive distal nephrons-are now providing new insights. In this review, we summarize recent updates to our understanding of aldosterone-MR signaling, focusing on its role in salt-sensitive hypertension and renal injury.
Reappraising Medical Syntax—Does Race Belong in the First Line of the Patient History?
Authors: Jesse C. Ikeme, James W. Salazar, Richard W. Grant
Journal: JAMA Internal Medicine (2021)

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 Internal Medicine 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 Internal Medicine journal
A bifunctional molecule-based strategy for the development of theranostic antibody-drug conjugate
Authors: Dian Xiao, Lei Zhao, Fei Xie, Shiyong Fan, Lianqi Liu, Wei Li, Ruiyuan Cao, Song Li, Wu Zhong, Xinbo Zhou
Journal: Theranostics (2021)

Antibody-drug conjugates (ADCs) are being developed worldwide with the potential to revolutionize current cancer treatment strategies. Developing novel theranostic ADCs with therapeutic utility and imaging capability is an attractive and challenging subject that promises advances in the field of personalized medicine. In this work, we propose a bifunctional molecule-based strategy for the development of theranostic ADCs. Methods: We developed a theranostic ADC consisting of the anti-Her2 antibody Mil40, monomethyl auristatin E (MMAE) as the active payload, and a 7-amino-3-hydroxyethyl-coumarin (7-AHC)-based dipeptide linker, which functions as a novel bifunctional fluorescence probe that allows self-elimination cleavage in the presence of cathepsin B for payload release and fluorophore activation. The on-off fluorescence properties and the antitumor effect in vitro and in vivo were investigated. Results: A 48-fold fluorescence enhancement was observed within 1 h when the 7-AHC-based linker was exposed to cathepsin B. Cleavage upon exposure to cathepsin B allows MMAE and fluorophore intracellular release and the monitoring of MMAE distribution using confocal microscopy. Additionally, the newly developed ADC retains the advantages of traditional p-aminobenzyloxycarbonyl-containing ADCs, such as good stability (t1/2 > 7 days) and high activity in vitro (IC50 = 0.09-3.74 nM). Importantly, the theranostic ADC exhibited the equivalent antitumor efficacy to the marketed ADC T-DM1 in the classic breast cancer model. Conclusion: We suggest that the present strategy can be universally applied in all p-aminobenzyloxycarbonyl-containing ADCs. Overall, theranostic ADCs may play a role in developing new theranostic systems and promoting personalized medicine research.
Nearly two thirds of doctors have anxiety or depression, BMA survey finds
Authors: Abi Rimmer
Journal: BMJ (2021)

A survey of over 7000 doctors conducted by the BMA in December found that, while many thought that their colleagues were coping with work during the covid-19 pandemic, most had concerns about the standard of patient care being delivered.

Of 7067 doctors in England, Wales, and Northern Ireland who answered a question on their mental health,1 58% (4067) said that they had symptoms of depression, anxiety, stress, burnout, emotional distress, or another mental health condition related to or …
Protein-induced metamorphosis of unilamellar lipid vesicles to multilamellar hybrid vesicles
Authors: Bon Il Koo, Inhye Kim, Moon Young Yang, Sung Duk Jo, Kunmo Koo, Seo Yeon Shin, Kyung Mok Park, Jong Min Yuk, Eunji Lee, Yoon Sung Nam
Journal: Journal of Controlled Release (2021)
SARS-CoV-2–specific CD8+ T cell responses in convalescent COVID-19 individuals
Authors: Hassen Kared, Andrew D. Redd, Evan M. Bloch, Tania S. Bonny, Hermi Sumatoh, Faris Kairi, Daniel Carbajo, Brian Abel, Evan W. Newell, Maria P. Bettinotti, Sarah E. Benner, Eshan U. Patel, Kirsten Littlefield, Oliver Laeyendecker, Shmuel Shoham, David Sullivan, Arturo Casadevall, Andrew Pekosz, Alessandra Nardin, Michael Fehlings, Aaron A.R. Tobian, Thomas C. Quinn
Journal: Journal of Clinical Investigation (2021)

Characterization of the T cell response in individuals who recover from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical to understanding its contribution to protective immunity. A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 coronavirus disease 2019 convalescent individuals. T cells were evaluated using a 28-marker phenotypic panel, and findings were modelled against time from diagnosis and from humoral and inflammatory responses. There were 132 SARS-CoV-2-specific CD8+ T cell responses detected across 6 different HLAs, corresponding to 52 unique epitope reactivities. CD8+ T cell responses were detected in almost all convalescent individuals and were directed against several structural and nonstructural target epitopes from the entire SARS-CoV-2 proteome. A unique phenotype for SARS-CoV-2-specific T cells was observed that was distinct from other common virus-specific T cells detected in the same cross-sectional sample and characterized by early differentiation kinetics. Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem cell and transitional memory states (subsets), which may be key to developing durable protection.
Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer
Authors: Zheng Zhang, Menglan Lu, Cailong Chen, Xing Tong, Yunhong Li, Kai Yang, Haitao Lv, Jiaying Xu, Liqiang Qin
Journal: Theranostics (2021)

Rationale: Iron-saturated Lf (Holo-Lactoferrin, Holo-Lf) exhibits a superior anticancer property than low iron-saturated Lf (Apo-Lf). Ferroptosis is an iron-dependent cell death characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). Radiotherapy also exerts its therapeutic effect through ROS. Methods: The effect of different iron-saturated Lf on ferroptosis and radiotherapy were tested on triple-negative breast cancer (TNBC) cell line MDA-MB-231 and non-TNBC cell line MCF-7. Results: Holo-Lf significantly increased the total iron content, promoted ROS generation, increased lipid peroxidation end product, malondialdehyde (MDA), and enhanced ferroptosis of MDA-MB-231 cells. By contrast, Apo-Lf upregulated SLC7a11 expression, increased GSH generation and inhibited ferroptosis of MDA-MB-231 cells. However, non-TNBC MCF-7 cells were resistant to Holo-Lf-induced ferroptosis because MCF-7 cells have a higher redox balance capacity than MDA-MB-231 cells. More importantly, Holo-Lf downregulated HIF-1α expression, ameliorated the hypoxia microenvironment in subcutaneous MDA-MB-231 tumors, and promoted radiation-induced DNA damage to hypoxic MDA-MB-231 cells. Finally, the efficacy of radiotherapy to MDA-MB-231 tumors was enhanced by Holo-Lf. Conclusion: Holo-Lf could induce ferroptosis in MDA-MB-231 cells and sensitize MDA-MB-231 tumors to radiotherapy.
The endangered physician-scientist and COVID-19
Authors: Rajesh C. Rao, Brian J. Dlouhy, Brian C. Capell, Oluwaseun Akeju
Journal: Cell Reports Medicine (2021)

The COVID-19 pandemic has affected almost every stakeholder in healthcare, including the vulnerable population of clinician investigators known as physician-scientists. In this commentary, Rao et al. highlight the underappreciated challenges and opportunities, and present solutions, for physician-scientists vis-à-vis the uniquely disruptive event of the pandemic.
MO01.47 Tepotinib Exposure-Response Analyses of Safety and Efficacy in Patients with Solid Tumors
Authors: W. Xiong, S. Hietala, J. Nyberg, O. Papasouliotis, R. Anziano, K. Berghoff, A. Johne, P. Girard, R. Strotmann, P. Paik
Journal: Journal of Thoracic Oncology (2021)
British Society of Gastroenterology Inflammatory Bowel Disease Section and IBD Clinical Research Group position statement on SARS-CoV-2 Vaccination
Authors: JL Alexander, G Moran, Gaya, T Raine, A Hart, NA Kennedy, JO Lindsay, J MacDonald, JP Segal, S Sebastian, S Selinger, M Parkes, PJ Smith, A Dhar, S Subramanian, R Arasaradnam, CA Lamb, T Ahmad, C Lees, L Dobson, R Wakeman, I Arnott, N Powell
Journal: The Lancet. Gastroenterology & hepatology (2021)
Chlorthalidone with potassium citrate decreases calcium oxalate stones and increases bone quality in genetic hypercalciuric stone-forming rats
Authors: Nancy S. Krieger, John Asplin, Ignacio Granja, Luojing Chen, Daiana Spataru, Tong Tong Wu, Marc Grynpas, David A. Bushinsky
Journal: Kidney International (2021)
A genome-wide CRISPR-based screen identifies <i>KAT7</i> as a driver of cellular senescence
Authors: Wei Wang, Yuxuan Zheng, Shuhui Sun, Wei Li, Moshi Song, Qianzhao Ji, Zeming Wu, Zunpeng Liu, Yanling Fan, Feifei Liu, Jingyi Li, Concepcion Rodriguez Esteban, Si Wang, Qi Zhou, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Fuchou Tang, Guang-Hui Liu
Journal: Science Translational Medicine (2021)

Inactivation of the histone acetyltransferase gene KAT7 prolongs survival in naturally aged mice and progeroid mice that age prematurely.
Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia–like IBMFS <i>ADH5/ALDH2</i> deficiency
Authors: Anfeng Mu, Asuka Hira, Akira Niwa, Mitsujiro Osawa, Kenichi Yoshida, Minako Mori, Yusuke Okamoto, Kazuko Inoue, Keita Kondo, Masato T. Kanemaki, Tomonari Matsuda, Etsuro Ito, Seiji Kojima, Tatsutoshi Nakahata, Seishi Ogawa, Keigo Tanaka, Keitaro Matsuo, Megumu K. Saito, Minoru Takata
Journal: Blood (2021)
Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma: Final Overall Survival Analysis of the Phase 3 PROTECT Trial
Authors: Robert J. Motzer, Paul Russo, Naomi Haas, Christian Doehn, Frede Donskov, Marine Gross-Goupil, Sergei Varlamov, Evgeny Kopyltsov, Jae Lyun Lee, Ho Yeong Lim, Bohuslav Melichar, Milada Zemanova, Brian Rini, Toni K. Choueiri, Lori Wood, M. Neil Reaume, Arnulf Stenzl, Simon Chowdhury, Ray McDermott, Agnieszka Michael, Miguel Izquierdo, Paola Aimone, Hong Zhang, Cora N. Sternberg
Journal: European Urology (2021)
Abstract 17345: Dysregulated Phenylalanine Catabolism is a Key Determinant of Cardiac Aging
Authors: Gabor Czibik
Journal: Circulation (2020)

Introduction: Cardiac aging is characterized by cardiomyocyte hypertrophy and myocardial interstitial fibrosis with impaired contractility and relaxation. Recent metabolomics studies revealed an age-dependent increase in the plasma levels of essential amino acid phenylalanine (Phe), which is predictive of heart failure hospitalization. The present study aimed to dissect 1) the basis for increased Phe levels with age and 2) how Phe may promote age-related cardiac dysfunction. Methods: To establish a role for Phe in driving cardiac aging, wild-type (WT) male mice were treated twice a day with Phe (200 mg/kg) for a month. The impact of Phe on cellular senescence, redox biology and epigenetics were explored in cultured cardiomyocytes (primary adult rat and AC-16 human cardiomyocytes) treated with Phe. In vivo cardiac structure and function, together with Phe catabolism were monitored in WT and in p21 -/- mice (in pursuit of p21 induction with Phe and age) up to 24 months of age. Finally, we treated aged WT mice with tetrahydrobiopterin (BH4; 10 mg/kg), the essential cofactor for Phe-degrading enzyme phenylalanine hydroxylase (Pah). The effect of aging and Phe treatment on hepatic Phe catabolism was explored in vivo and vitro in AML-12 hepatocytes. Results: Natural aging induced a progressive increase in plasma Phe levels concomitant with cardiac dysfunction, whilst p21 deficiency prevented these changes. Phe treatment triggered cellular senescence, along with complex redox and epigenetic changes in vitro and induced an age-mimicking cardiac deterioration in young WT mice in vivo . Pharmacological restoration of Phe catabolism with BH4 reversed the rise in plasma Phe and senescent cardiac alterations in aged WT mice without affecting myocardial NOS activity. Key observations were reproduced in corresponding human samples and collectively they pointed to hepatic Phe catabolic decline with ensuing elevated plasma Phe levels compromising cardiac integrity. Conclusions: Our findings established a pathogenic role for increased Phe levels in cardiac aging, highlighting modulation of Phe catabolism as a potential therapeutic target for age-associated cardiac impairment.
Pre-Treatment Myocardial 18FDG Uptake Predicts Response to Immunosuppression in Patients With Cardiac Sarcoidosis
Authors: Muthiah Subramanian, Nalla Swapna, Abubacker Zakir Ali, Daljeet Kaur Saggu, Sachin Yalagudri, Jugal Kishore, L.T. Narasimha Swamy, C. Narasimhan
Journal: JACC. Cardiovascular imaging (2021)
Racial Justice Requires Ending the War on Drugs
Authors: Brian D. Earp, Jonathan Lewis, Carl L. Hart
Journal: The American Journal of Bioethics (2021)

Historically, laws and policies to criminalize drug use or possession were rooted in explicit racism, and they continue to wreak havoc on certain racialized communities. We are a group of bioethicists, drug experts, legal scholars, criminal justice researchers, sociologists, psychologists, and other allied professionals who have come together in support of a policy proposal that is evidence-based and ethically recommended. We call for the immediate decriminalization of all so-called recreational drugs and, ultimately, for their timely and appropriate legal regulation. We also call for criminal convictions for nonviolent offenses pertaining to the use or possession of small quantities of such drugs to be expunged, and for those currently serving time for these offenses to be released. In effect, we call for an end to the "war on drugs."
Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial
Authors: Stephan Kadauke, Regina M. Myers, Yimei Li, Richard Aplenc, Diane Baniewicz, David M. Barrett, Allison Barz Leahy, Colleen Callahan, Joseph G. Dolan, Julie C. Fitzgerald, Whitney Gladney, Simon F. Lacey, Hongyan Liu, Shannon L. Maude, Regina McGuire, Laura S. Motley, David T. Teachey, Gerald B. Wertheim, Lisa Wray, Amanda M. DiNofia, Stephan A. Grupp
Journal: Journal of Clinical Oncology (2021)

PURPOSE To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy. METHODS Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial. RESULTS The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (P < .001), but persistence was not different (P = .73). Event-free and overall survival were worse in the HTBC (P = .004, P < .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (P = .18). CONCLUSION Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.
MO01.22 Canakinumab as Adjuvant Therapy in Patients with Completely Resected Non-Small Cell Lung Cancer (NSCLC): CANOPY-A Trial
Authors: A.I. Spira, A. Ardizzoni, F. Barlesi, B.C. Cho, P. De Marchi, Y. Goto, D. Kowalski, S. Lu, L. Paz-Ares, D.R. Spigel, M. Thomas, M. Leung, J. Baum, W. Zhou, S. Portella, J. Chih-Hsin Yang, E.B. Garon
Journal: Journal of Thoracic Oncology (2021)
COVID‐19‐associated cutaneous manifestations: does human herpesvirus 6 play an aetiological role?
Authors: I. Abadías‐Granado, A. Navarro‐Bielsa, A.M. Morales‐Callaghan, L. Roc, C.C. Suso‐Estívalez, M. Povar‐Echeverría, Y. Gilaberte
Journal: British Journal of Dermatology (2021)

Treatment of MKL-1 cells with selinexor resulted in a dosedependent reduction of both LTA and STA protein expression.Furthermore, a reduction in XPO1 protein expression was detected even at the lowest selinexor dose, although this downregulation did not demonstrate a dose response in the MKL-1 cells (Figure 1a).Treatment of MS-1 cells resulted in similar results, with nearly complete ablation of viral protein production at the higher selinexor doses tested.Furthermore, a reduction in XPO1 protein expression was detected, but this was dose-dependent in MS-1 cells (Figure 1b).The IC 50 values determined by cell proliferation assay were 7Á85 nmol L -1 for MKL-1 cells and 85Á72 nmol L -1 for MS-1 cells.XPO1 inhibitors demonstrate antiviral activity against an array of viruses, including influenza A, influenza B and severe acute respiratory syndrome coronavirus. 5,6While our study was conducted in vitro, the results demonstrate that XPO1 inhibitor treatment can efficiently downregulate MCPyV viral oncoprotein expression in MCC cell lines.This illustrates that there is promise in using XPO1 inhibitors for MCPyV-associated MCC management.The downregulation of STA expression is particularly striking because STA is capable of inducing oncogenesis alone. 1Differences in the dose of selinexor needed to achieve LTA and STA protein ablation between the MCPyV-positive cell lines tested suggest some MCCs may be more vulnerable to this treatment than others.In addition, the decrease in XPO1 expression after selinexor treatment may represent a therapeutic advantage independent of LTA and STA expression inhibition.XPO1 is frequently overexpressed or mutated in a variety of viral and nonviral-associated malignancies, and XPO1 expression is often associated with poor prognosis in these cancers, although the association with MCC has not been established. 7 Tumour-targeted therapies such as selinexor represent a growing treatment modality for MCC.A previous study by Akaike et al. examining the use of somatostatin analogues to treat metastatic MCC with high somatostatin receptor expression found that these receptor analogues led to clinically significant disease control. 8Taken together, our results demonstrate that evaluating MCC tumour-targeted therapies must continue.Such agents may be used in combination with the standard of care (e.g.immunotherapies) and may have more favourable side-effect profiles than traditional chemotherapies. 8Future studies are warranted in exploring the importance of XPO1 in MCC and investigating the use of XPO1 inhibitors in vivo and in combination with other therapies.
Association of novel rare coding variants with juvenile idiopathic arthritis
Authors: Xinyi Meng, Xiaoyuan Hou, Ping Wang, Joseph T Glessner, Hui-Qi Qu, Michael E March, Sipeng Zhang, Xiaohui Qi, Chonggui Zhu, Kenny Nguyen, Xinyi Gao, Xiaoge Li, Yichuan Liu, Wentao Zhou, Shuyue Zhang, Junyi Li, Yan Sun, Jie Yang, Patrick M A Sleiman, Qianghua Xia, Hakon Hakonarson, Jin Li
Journal: Annals of the Rheumatic Diseases (2021)

Objective Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children, but a few studies have investigated the contribution of rare variants to JIA. In this study, we aimed to identify rare coding variants associated with JIA for the genome-wide landscape. Methods We established a rare variant calling and filtering pipeline and performed rare coding variant and gene-based association analyses on three RNA-seq datasets composed of 228 JIA patients in the Gene Expression Omnibus against different sets of controls, and further conducted replication in our whole-exome sequencing (WES) data of 56 JIA patients. Then we conducted differential gene expression analysis and assessed the impact of recurrent functional coding variants on gene expression and signalling pathway. Results By the RNA-seq data, we identified variants in two genes reported in literature as JIA causal variants, as well as additional 63 recurrent rare coding variants seen only in JIA patients. Among the 44 recurrent rare variants found in polyarticular patients, 10 were replicated by our WES of patients with the same JIA subtype. Several genes with recurrent functional rare coding variants have also common variants associated with autoimmune diseases. We observed immune pathways enriched for the genes with rare coding variants and differentially expressed genes. Conclusion This study elucidated a novel landscape of recurrent rare coding variants in JIA patients and uncovered significant associations with JIA at the gene pathway level. The convergence of common variants and rare variants for autoimmune diseases is also highlighted in this study.