tbuckley/cabot-search huggingface dataset:
A Decade of JAK Inhibitors: What Have We Learned and What May Be the Future?
Authors: Christine Liu, Jacqueline Kieltyka, Roy Fleischmann, Massimo Gadina, John J. O’Shea
Journal: Arthritis & Rheumatology (2021)

The discovery of cytokines and their role in immune and inflammatory disease led to the development of a plethora of targeted biologic therapies. Later, efforts to understand mechanisms of cytokine signal transduction led to the discovery of JAKs, which themselves were quickly identified as therapeutic targets. It has been a decade since the first JAK inhibitors (jakinibs) were approved, and there are now 9 jakinibs approved for the treatment of rheumatic, dermatologic, hematologic, and gastrointestinal indications, along with emergency authorization for COVID‐19. In this review, we will summarize relevant discoveries that led to first‐generation jakinibs and review their efficacy and safety as demonstrated in pivotal clinical studies. We will discuss the next generation of more selective jakinibs, along with agents that target kinase families beyond JAKs. Finally, we will reflect on both the opportunities and challenges ahead as we enter the second decade of the clinical use of jakinibs.
TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease
Authors: Adrian Cordido, Laura Nuñez-Gonzalez, Julio M. Martinez-Moreno, Olaya Lamas-Gonzalez, Laura Rodriguez-Osorio, Maria Vanessa Perez-Gomez, Diego Martin-Sanchez, Patricia Outeda, Marco Chiaravalli, Terry Watnick, Alessandra Boletta, Candido Diaz, Angel Carracedo, Ana B. Sanz, Alberto Ortiz, Miguel A. Garcia-Gonzalez
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement In autosomal dominant polycystic kidney disease (ADPKD), interstitial inflammation promotes cyst progression. TWEAK is a TNF superfamily cytokine that regulates inflammatory responses, and its receptor, Fn14, is expressed in nephron epithelium. This paper describes TWEAK’s role in ADPKD and its potential as a therapeutic target. The Fn14/TWEAK axis is upregulated in human and mouse polycystic kidneys, and TWEAK administration in mice accelerates cyst progression, whereas anti-TWEAK treatment slows cyst growth, improving kidney function and survival. Anti-TWEAK antibodies restore several ADPKD-related pathways, such as proliferation and NF- κ B; slightly reduces fibrosis and apoptosis; and indirectly decreases macrophage recruitment. These findings identify the TWEAK signaling pathway as a new disease mechanism in ADPKD and a new possible therapeutic approach. Background In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. Methods To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. Results Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation–related MAPK signaling, decreased NF- κ B pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. Conclusions This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.
Abstract 128: Impaired Beta Adrenergic Receptor Resensitization Contributes to Human Heart Failture
Authors: Elizabeth E Martelli, Arunachal Chatterjee, Maradumane M Mohan, John George, Randall Starling, Christine Moravec, Sathyamangla V Naga Prasad
Journal: Circulation Research (2016)

Beta adrenergic receptors (βARs) are one of the most powerful regulators of cardiac function, and βAR downregulation and desensitization are hallmarks of heart failure. Agonist occupied βARs undergo desensitization by G-protein coupled receptor kinase phosphorylation leading to βAR internalization. Desensitized βARs are resensitized by dephosphorylation in the endosomes by PP2A; however, less is known about role of resensitization in heart failure. Although we have previously shown that resensitization is regulated by inhibition of PP2A by I2PP2A via PI3Kγ (Vasudevan et. al., 2011), the underlying mechanisms of I2PP2A binding to PP2A are not well understood. We used PyMOL software to find the binding interaction between PP2A and I2PP2A. Based on in silico predictions, we generated a mutant PP2A that when expressed would compete out I2PP2A and inhibit I2PP2A from binding to endogenous PP2A. Expression of PP2A mutant in β2AR expressing cells showed preservation of β2AR function following stimulation as measured by reduced β2AR phosphorylation, increased cAMP generation and increased phosphatase function. We also tested whether resensitization as a mechanism is altered in endstage human heart failure samples. Since resensitization occurs in endosomes, plasma membranes and endosomes were isolated from human heart samples and assessed for PI3K activity, PP2A activity, β2AR phosphorylation and adenylyl cyclase (AC) activity as a measure of βAR function. Significant PI3Kγ activity was observed to increase in heart failure samples while AC activity was reduced in plasma membranes. Consistent with the reduced recovery in βAR function in heart failure samples, significant β2AR phosphorylation was observed in the endosomes and plasma membranes of human heart failure samples compared to non-failing. Correspondingly, we observed significant reduction in endosomal PP2A activity in heart failure samples versus controls suggesting inhibited resensitization occurs in human heart failure. Together our studies suggest that resensitization is inhibited in human heart failure and targeting I2PP2A may provide preservation of receptor function and beneficial cardiac remodeling.
Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis‐associated cancer
Authors: Shirong Yang, Xianli He, Jing Zhao, Dalin Wang, Shanshan Guo, Tian Gao, Gang Wang, Chao Jin, Zeyu Yan, Nan Wang, Yongxing Wang, Yilin Zhao, Jinliang Xing, Qichao Huang
Journal: Cancer Communications (2021)

Mitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis-associated cancer (CAC).TFAM expression was examined in tissue samples of inflammatory bowel diseases (IBD) and CAC by immunohistochemistry. Intestinal epithelial cell (IEC)-specific TFAM-knockout mice (TFAM△IEC ) and colorectal cancer (CRC) cells with TFAM knockdown or overexpression were used to evaluate the role of TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial respiration function and biogenesis.The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity. The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3 (STAT3)/miR-23b-dependent manner. In addition, TFAM knockout impaired IEC turnover to promote dextran sulfate sodium (DSS)-induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS-induced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis. By contrast, TFAM expression was upregulated in CAC tissues and contributed to cell growth. Furthermore, it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells. Mechanistically, TFAM promoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.TFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis.
The dynamics of N6-methyladenine RNA modification in interactions between rice and plant viruses
Authors: Kun Zhang, Xinjian Zhuang, Zhuozhuo Dong, Kai Xu, Xijun Chen, Fang Liu, Zhen He
Journal: Genome biology (2021)

N6-methyladenosine (m6A) is the most common RNA modification in eukaryotes and has been implicated as a novel epigenetic marker that is involved in various biological processes. The pattern and functional dissection of m6A in the regulation of several major human viral diseases have already been reported. However, the patterns and functions of m6A distribution in plant disease bursting remain largely unknown.We analyse the high-quality m6A methylomes in rice plants infected with two devastating viruses. We find that the m6A methylation is mainly associated with genes that are not actively expressed in virus-infected rice plants. We also detect different m6A peak distributions on the same gene, which may contribute to different antiviral modes between rice stripe virus or rice black-stripe dwarf virus infection. Interestingly, we observe increased levels of m6A methylation in rice plant response to virus infection. Several antiviral pathway-related genes, such as RNA silencing-, resistance-, and fundamental antiviral phytohormone metabolic-related genes, are also m6A methylated. The level of m6A methylation is tightly associated with its relative expression levels.We revealed the dynamics of m6A modification during the interaction between rice and viruses, which may act as a main regulatory strategy in gene expression. Our investigations highlight the significance of m6A modifications in interactions between plant and viruses, especially in regulating the expression of genes involved in key pathways.
Adipocyte iron levels impinge on a fat-gut crosstalk to regulate intestinal lipid absorption and mediate protection from obesity
Authors: Zhuzhen Zhang, Jan-Bernd Funcke, Zhenzhen Zi, Shangang Zhao, Leon G. Straub, Yi Zhu, Qingzhang Zhu, Clair Crewe, Yu A. An, Shiuhwei Chen, Na Li, May-yun Wang, Alexandra L. Ghaben, Charlotte Lee, Laurent Gautron, Luke J. Engelking, Prithvi Raj, Yingfeng Deng, Ruth Gordillo, Christine M. Kusminski, Philipp E. Scherer
Journal: Cell Metabolism (2021)
Applications and developments of gene therapy drug delivery systems for genetic diseases
Authors: Xiuhua Pan, Hanitrarimalala Veroniaina, Nan Su, Kang Sha, Fenglin Jiang, Zhenghong Wu, Xiaole Qi
Journal: Asian Journal of Pharmaceutical Sciences (2021)

Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity. Currently, gene therapy drugs such as siRNA, shRNA, antisense oligonucleotide, CRISPR/Cas9 system, plasmid DNA and miRNA have shown great potential in biomedical applications. To avoid the degradation of gene therapy drugs in the body and effectively deliver them to target tissues, cells and organelles, the development of excellent drug delivery vehicles is of utmost importance. Viral vectors are the most widely used delivery vehicles for gene therapy in vivo and in vitro due to their high transfection efficiency and stable transgene expression. With the development of nanotechnology, novel nanocarriers are gradually replacing viral vectors, emerging superior performance. This review mainly illuminates the current widely used gene therapy drugs, summarizes the viral vectors and non-viral vectors that deliver gene therapy drugs, and sums up the application of gene therapy to treat genetic diseases. Additionally, the challenges and opportunities of the field are discussed from the perspective of developing an effective nano-delivery system.
Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes
Authors: Zaipul I. Md Dom, Eiichiro Satake, Jan Skupien, Bozena Krolewski, Kristina O’Neil, Jill A. Willency, Simon T. Dillon, Jonathan M. Wilson, Hiroki Kobayashi, Katsuhito Ihara, Towia A. Libermann, Marlon Pragnell, Kevin L. Duffin, Andrzej S. Krolewski
Journal: Science Translational Medicine (2021)

Global proteomics profiling identified FGF20, TNFSF12, and ANGPT1 as protective against progression of renal function decline in those with diabetes.
Long-term protection from HIV infection with oral HIV pre-exposure prophylaxis in gay and bisexual men: findings from the expanded and extended EPIC-NSW prospective implementation study
Authors: Andrew E Grulich, Fengyi Jin, Benjamin R Bavinton, Barbara Yeung, Mohamed A Hammoud, Janaki Amin, Gesalit Cabrera, Shawn Clackett, Erin Ogilvie, Stefanie Vaccher, Tobias Vickers, Anna McNulty, David J Smith, Nila J Dharan, Christine Selvey, Cherie Power, Karen Price, Iryna Zablotska, David A Baker, Mark Bloch, Katherine Brown, Christopher J Carmody, Andrew Carr, Daniel Chanisheff, Nicholas Doong, Robert Finlayson, David A Lewis, Josephine Lusk, Sarah Martin, Catriona Ooi, Phillip Read, Nathan Ryder, Don Smith, Clara Tuck Meng Soo, David J Templeton, Emmanuel Vlahakis, Rebecca Guy
Journal: The Lancet HIV (2021)
T-Cell Receptor Gene Rearrangement Clonality, Flow Cytometry Status, and Associated Outcomes in Early-Stage Cutaneous T-Cell Lymphoma
Authors: Jennifer A. Marks, Jeffrey M. Switchenko, Dylan J. Martini, Erica S. Tarabadkar, Mohammad K. Khan, Mary Jo Lechowicz, Pamela B. Allen
Journal: JAMA Dermatology (2021)

The prognostic significance of clonal T-cell receptor (TCR) rearrangement or low-level blood involvement as assessed by flow cytometry for patients with early-stage cutaneous T-cell lymphoma (CTCL) is not clear.To assess the association of low-level blood involvement by TCR clonality and flow cytometry with outcomes for patients with early-stage CTCL.A retrospective cohort analysis was conducted from September 1, 2019, to February 29, 2020, of 322 patients with early-stage (I-IIA) CTCL seen at the Winship Cancer Institute of Emory University and Grady Memorial Hospital. T-cell receptor gene rearrangement and flow cytometry records from the peripheral blood were documented at initial assessment.T-cell receptor clonality and peripheral blood flow cytometry.Univariate and multivariable models and Kaplan-Meier assessments were analyzed for overall survival (OS) and time to next treatment. The primary outcome was OS from diagnosis and time to next treatment, and the hypotheses were formulated prior to data collection.A total of 322 patients (166 female patients [51.6%]; median age at diagnosis, 53.8 years [range, 8.6-87.4 years]) with early-stage CTCL diagnosed from 1990 to 2018 were identified; of these, 258 had data available for both flow cytometry and TCR. Positive results for both TCR clonality and flow cytometry were associated with inferior OS in early-stage CTCL compared with both having negative results (hazard ratio [HR], 2.86; 95% CI, 1.02-8.06; P = .046). Positive results for only TCR clonality or only flow cytometry were not associated with OS (TCR clonality: HR, 1.31; 95% CI, 0.70-2.47; P = .40; flow cytometry: HR, 1.21; 95% CI, 0.58-2.52; P = .61) or time to next treatment (TCR clonality: HR, 1.05; 95% CI, 0.77-1.43; P = .76; flow cytometry: HR, 0.74; 95% CI, 0.47-1.16; P = .12). However, positive flow cytometry results were associated with reduced OS in the stage IIA subgroup (n = 94; HR, 1.17; 95% CI, 1.18-8.74; P = .02). Covariates associated with reduced survival included advanced age at diagnosis, male sex, and higher disease stage.This cohort study of patients with early-stage CTCL suggests that low-level blood involvement as indicated by positive results for both TCR gene rearrangement and flow cytometry was associated with inferior OS, whereas positive results for either flow cytometry or TCR clonality was not. More precise measurements of blood involvement in CTCL and larger multi-institutional cohorts are needed to validate the prognostic significance of low-level blood involvement in early-stage CTCL.
Sequential Lymphoma between Classical Hodgkin Lymphoma and Diffuse Large B Cell Lymphoma: Clinicopathological Characteristics and Outcome of 18 Patients from Lysa Center
Authors: Guillaume Aussedat, Hervé Ghesquières, Aspasia Stamatoullas, Pierre Hirsch, Emmanuelle Nicolas-Virelizier, Guillaume Cartron, Caroline Regny, Lionel Karlin, Catherine Chassagne-Clément, Violaine Safar, Nicolas Albin, Antoine Deleuze, Alexis Lambour, Nicolas Daguindau, Christiane Copie, Richard Lemal, Gilles Salles, Alexandra traverse-Glehen, Clementine Sarkozy
Journal: Blood (2017)
神経精神疾患治療のための末梢免疫系の天然産物に基づく多薬理学的調節【JST・京大機械翻訳】
Authors: Mok Simon Wing-Fai, Wong Vincent Kam-Wai, Lo Hang-Hong, de Seabra Rodrigues Dias Ivo Ricardo, Leung Elaine Lai-Han, Law Betty Yuen-Kwan, Liu Liang
Journal: Pharmacology & Therapeutics (2020)
右室梗塞を合併した急性大動脈解離に対しBentall手術,弓部置換術,冠動脈バイパス術を施行した1例
Authors: Yonezawa Kazuma, Ishitoya Hiroshi, Kurobe Hiroshi, Hori Takashige, Isshiki Shingo, Takano Shinji, Hiraya Katsuhiko, Nagashima Mitsuki
Journal: Circulation (2008)
Functional Calsequestrin-1 Is Expressed in the Heart and Its Deficiency Is Causally Related to Malignant Hyperthermia-Like Arrhythmia
Authors: Zhipeng Sun, Luqi Wang, Lu Han, Yue Wang, Yuan Zhou, Qiang Li, Yongquan Wu, Shaletanati Talabieke, Yunlong Hou, Lulin Wu, Ronghua Liu, Zhiping Fu, Hongjie You, Bai-Yan Li, Yuanyuan Zheng, Dali Luo
Journal: Circulation (2021)

Calsequestrins (Casqs), comprising the Casq1 and Casq2 isoforms, buffer Ca2+ and regulate its release in the sarcoplasmic reticulum of skeletal and cardiac muscle, respectively. Human inherited diseases associated with mutations in CASQ1 or CASQ2 include malignant hyperthermia/environmental heat stroke (MH/EHS) and catecholaminergic polymorphic ventricular tachycardia. However, patients with an MH/EHS event often experience arrhythmia for which the underlying mechanism remains unknown.Working hearts from conventional (Casq1-KO) and cardiac-specific (Casq1-CKO) Casq1 knockout mice were monitored in vivo and ex vivo by ECG and electric mapping, respectively. MH was induced by 2% isoflurane and treated intraperitoneally with dantrolene. Time-lapse imaging was used to monitor intracellular Ca2+ activity in isolated mouse cardiomyocytes or neonatal rat ventricular myocytes with knockdown, overexpression, or truncation of the Casq1 gene. Conformational change in both Casqs was determined by cross-linking Western blot analysis.Like patients with MH/EHS, Casq1-KO and Casq1-CKO mice had faster basal heart rate and ventricular tachycardia on exposure to 2% isoflurane, which could be relieved by dantrolene. Basal sinus tachycardia and ventricular ectopic electric triggering also occurred in Casq1-KO hearts ex vivo. Accordingly, the ventricular cardiomyocytes from Casq1-CKO mice displayed dantrolene-sensitive increased Ca2+ waves and diastole premature Ca2+ transients/oscillations on isoflurane. Neonatal rat ventricular myocytes with Casq1-knockdown had enhanced spontaneous Ca2+ sparks/transients on isoflurane, whereas cells overexpressing Casq1 exhibited decreased Ca2+ sparks/transients that were absent in cells with truncation of 9 amino acids at the C terminus of Casq1. Structural evaluation showed that most of the Casq1 protein was present as a polymer and physically interacted with ryanodine receptor-2 in the ventricular sarcoplasmic reticulum. The Casq1 isoform was also expressed in human myocardium. Mechanistically, exposure to 2% isoflurane or heating at 41 °C induced Casq1 oligomerization in mouse ventricular and skeletal muscle tissues, leading to a reduced Casq1/ryanodine receptor-2 interaction and increased ryanodine receptor-2 activity in the ventricle.Casq1 is expressed in the heart, where it regulates sarcoplasmic reticulum Ca2+ release and heart rate. Casq1 deficiency independently causes MH/EHS-like ventricular arrhythmia by trigger-induced Casq1 oligomerization and a relief of its inhibitory effect on ryanodine receptor-2-mediated Ca2+ release, thus revealing a new inherited arrhythmia and a novel mechanism for MH/EHS arrhythmogenesis.
Abstract 2256: Increased Monocyte Activation Detected By Serum Neopterin and Long-Term Risk in Patients with Acute Coronary Syndromes: Analysis From PROVE IT-TIMI 22
Authors: Kausik K Ray, David A Morrow, Christopher P Cannon, Marc S Sabatine, Amy Shui, Nader Rifai, Carolyn H McCabe, Eugene Braunwald
Journal: Circulation (2006)

Background: Increased monocyte activation is implicated in the pathogenesis of acute coronary syndromes (ACS). We assessed the prognostic value of neopterin (a marker of monocyte activation) in pat...
Characterizing the Clinical Implications of Histologic Regression in Melanoma Requires Clear Diagnostic Criteria That Are Consistently Applied
Authors: Mark C. Mochel, David E. Elder
Journal: JAMA Dermatology (2021)

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