tbuckley/cabot-search huggingface dataset:
Rheb1 promotes glucose-stimulated insulin secretion in human and mouse β-cells by upregulating GLUT expression
Authors: Yan Yang, Zixin Cai, Zhenhong Pan, Fen Liu, Dandan Li, Yujiao Ji, Jiaxin Zhong, Hairong Luo, Shanbiao Hu, Lei Song, Shaojie Yu, Ting Li, Jiequn Li, Xianhua Ma, Weiping Zhang, Zhiguang Zhou, Feng Liu, Jingjing Zhang
Journal: Metabolism (2021)

Reduced β-cell mass and impaired β-cell function are primary causes of all types of diabetes. However, the intrinsic molecular mechanism that regulates β-cell growth and function remains elusive. Here, we demonstrate that the small GTPase Rheb1 is a critical regulator of glucose-stimulated insulin secretion (GSIS) in β-cells. Rheb1 was highly expressed in mouse and human islets. In addition, β-cell-specific knockout of Rheb1 reduced the β-cell size and mass by suppressing β-cell proliferation and increasing β-cell apoptosis. However, tamoxifen-induced deletion of Rheb1 in β-cells had no significant effect on β-cell mass and size but significantly impaired GSIS. Rheb1 facilitates GSIS in human or mouse islets by upregulating GLUT1 or GLUT2 expression, respectively, in a mTORC1 signaling pathway-dependent manner. Our findings reveal a critical role of Rheb1 in regulating GSIS in β-cells and identified a new target for the therapeutic treatment of diabetes mellitus.
An AIEgen as an Intrinsic Antibacterial Agent for Light‐Up Detection and Inactivation of Intracellular Gram‐Positive Bacteria
Authors: Tianjiao Dai, Bingpeng Guo, Guobin Qi, Shidang Xu, Cheng Zhou, Guillermo C. Bazan, Bin Liu
Journal: Advanced Healthcare Materials (2021)

Abstract Infections caused by Gram‐positive bacteria, especially those able to invade and survive in host cells, threaten human health severely. It is therefore highly desirable to develop therapeutics that can selectively target and kill intracellular Gram‐positive pathogens with minimal toxicity to host cells. Herein, it is described that the aggregation‐induced emission luminogen (AIEgen) TPEPy‐Et, containing a positively charged pyridinium group and a hydrophobic tetraphenylethylene fragment, is effective for Gram‐positive bacteria detection and elimination. The fluorescence of TPEPy‐Et is greatly enhanced after incubation with Gram‐positive bacteria, which can be used to detect and trace the bacteria in cells. TPEPy‐Et also shows excellent killing effects against both extracellular and intracellular Gram‐positive bacteria through a membrane depolarization mechanism. The luminescent antibacterial agent TPEPy‐Et is thus promising for diagnosis and therapy against intracellular bacterial infection.
RENAL FUNCTION DETERIORATES AFTER LIVING DONOR LIVER TRANSPLANTATION; HOW TO PREDICT CHRONIC DYSFUNCTION?
Authors: Ku Y, Urade T, Chuma M, Fukushima K, Tsugawa D, Tanaka M, Takahashi M, Kido M, Tuchida S, Fukumoto T, Kuramitsu K
Journal: Hepatology (2011)
Intubation Practices and Adverse Peri-intubation Events in Critically Ill Patients—Reply
Authors: John Laffey, Giacomo Bellani, Vincenzo Russotto
Journal: JAMA (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 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
Response to a Randomized Trial on Mannitol Use During Partial Nephrectomy
Authors: Patrick Lewicki, Spyridon P. Basourakos, Yuqing Qiu, Camilo Arenas-Gallo, Douglas S. Scherr, Lee E. Ponsky, Jonathan E. Shoag
Journal: JAMA Surgery (2021)

undocumented immigrant patients with end-stage kidney disease should not be precluded from consideration for kidney transplant based on immigration status alone.Additional studies are necessary to identify those at risk of dropout during follow-up and whether specialized protocols would benefit this unique population to further optimize posttransplant care and outcomes.
28484 A U.S. population–based epidemiologic analysis of head and neck and genital mucosal melanoma from the Surveillance, Epidemiology and End Results (SEER) database
Authors: Danyal Tahseen, Ghazal Ghafari, Walter J. Liszewski, Dennis P. West, Beatrice Nardone
Journal: Journal of the American Academy of Dermatology (2021)
マトリックスは不死化仲介幹細胞運命決定を逆転する【JST・京大機械翻訳】
Authors: Wang Yiming, Hu Gangqing, C Hill Ryan, Dzieciatkowska Monika, C Hansen Kirk, Zhang Xiao-Bing, Yan Zuoqin, Pei Ming
Journal: Biomaterials (2021)
An antisense circular RNA circSCRIB enhances cancer progression by suppressing parental gene splicing and translation
Authors: Jian Ma, William W. Du, Kaixuan Zeng, Nan Wu, Ling Fang, Juanjuan Lyu, Albert J. Yee, Burton B. Yang
Journal: Molecular Therapy (2021)

Circular RNAs (circRNAs) represent a large group of non-coding RNAs that are widely detected in mammalian cells. Although most circRNAs are generated in a sense orientation, there is a group of circRNAs that are synthesized in an antisense orientation. High-throughput analysis of breast cancer specimens revealed a significant enrichment of 209 antisense circRNAs. The tumor suppressor SCRIB was shown to potentially produce thirteen circRNAs, three of which are in an antisense orientation. Among these three circRNAs, circSCRIB (hsa_circ_0001831) was the most enriched in the breast cancer panel. This antisense SCRIB circRNA was shown to span one intron and two exons. We hypothesized that this circRNA could decrease pre-mRNA splicing and mRNA translation. To test this, we generated a hsa_circ_0001831 expression construct. We found that there was decreased SCRIB mRNA production but increased cancer cell proliferation, migration, and invasion. In comparison, an exonic sequence construct did not affect mRNA splicing but decreased protein translation, leading to increased E-cadherin expression and decreased expression of N-cadherin and vimentin. Thus, there was increased cell migration, invasion, proliferation, colony formation, and tumorigenesis. Our study suggests a novel modulatory role of antisense circRNAs on their parental transcripts. This may represent a promising approach for developing circRNA-directed therapy.
The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium
Authors: Weikang Ma, Marcus Henze, Robert L. Anderson, Henry Gong, Fiona L. Wong, Carlos L. del Rio, Thomas Irving
Journal: Circulation Research (2021)

Rationale: Myofilament length-dependent activation (LDA) is the key underlying mechanism of cardiac heterometric autoregulation, commonly referred as the Frank-Starling Law of the heart. Although alterations in LDA are common in cardiomyopathic states, the precise structural and biochemical mechanisms underlying LDA remain unknown. Objective: Here, we examine the role of structural changes in the thick filament during diastole, in particular changes in the availability of myosin heads, in determining both calcium sensitivity and maximum contractile force during systole in permeabilized porcine cardiac fibers. Methods and Results: Permeabilized porcine fibers from ventricular myocardium were studied under relaxing conditions at short and long sarcomere length using muscle mechanics, biochemical measurements, and X-ray diffraction. Upon stretch, the porcine myocardium showed the increased calcium sensitivity and maximum calcium-activated force characteristic of LDA. Stretch increased diastolic ATP turnover, recruiting reserve myosin heads from the super-relaxed state at longer sarcomere length. Structurally, X-ray diffraction studies in the relaxed-muscle confirmed a departure from the helical ordering of the thick filament upon stretch which occurred concomitantly with a displacement of myosin heads towards actin, facilitating cross-bridge formation upon systolic activation. Mavacamten, a selective myosin-motor inhibitor known to weaken the transition to actin-bound power-generating states and to enrich the ordered super-relaxed state myosin population, reversed the structural effects of stretch on the thick filament, blunting the mechanical consequences of stretch; mavacamten did not, however, prevent other structural changes associated with LDA in the sarcomere, such as decreased lattice spacing or troponin-displacement. Conclusions: Our findings strongly indicate that in ventricular muscle, LDA and its systolic consequences are dependent on the population of myosin heads competent to form cross bridges and involves the recruitment of myosin heads from the reserve super-relaxed state pool during diastole.
P-261 Phase I study of multiple kinase inhibitor, TT-00420, in advanced, refractory cholangiocarcinoma
Authors: S. Piha-Paul, A. Tsimberidou, F. Janku, K. Raghav, R. Wolff, R. Huey, P. Peng, W. Levin, B. Ngo, H. Wang, C. Sun, Q. Ru, F. Wu, M. Javle
Journal: Annals of Oncology (2021)
25805 Ixekizumab provides more durable improvements in skin clearance, itch, and quality of life than guselkumab in patients with moderate-to-severe psoriasis: 24-week results from IXORA-R
Authors: Abel Jarell, Stacy Smith, Gaia Gallo, Lisa Renda, Russel Burge, Baojin Zhu, Jiaying Guo, Emily K. Blue, David Rosmarin
Journal: Journal of the American Academy of Dermatology (2021)
P-214 Should patients with active gastrointestinal tumors receive thromboprophylaxis to avoid the negative clinical consequences of CAT? Sub-analysis of ACT4CAT study
Authors: N. Tsoukalas, A. Christopoulou, G. Anastopoulou, C. Papandreou, E. Timotheadou, I. Athanasiadis, A. Koumarianou, S. Peroukidis, G. Samelis, A. Psyrri, N. Kapodistrias, A. Nikolakopoulos, C. Andreadis, A. Ardavanis, E. Samantas, A. Bokas, V. Barbounis, N. Kentepozidis, D. Mavroudis, A. Athanasiadis, P. Papakotoulas, I. Boukovinas
Journal: Annals of Oncology (2021)
Slit2-Robo Signaling Promotes Glomerular Vascularization and Nephron Development
Authors: Jinyu Li, Luiz Henrique Geraldo, Alexandre Dubrac, Georgia Zarkada, Anne Eichmann
Journal: Journal of the American Society of Nephrology (2021)

Kidney function requires continuous blood filtration by glomerular capillaries. Disruption of glomerular vascular development or maintenance contributes to the pathogenesis of kidney diseases, but the signaling events regulating renal endothelium development remain incompletely understood. Here, we discovered a novel role of Slit2-Robo signaling in glomerular vascularization. Slit2 is a secreted polypeptide that binds to transmembrane Robo receptors and regulates axon guidance as well as ureteric bud branching and angiogenesis.
Towards a European strategy to address the COVID-19 pandemic
Authors: Viola Priesemann, Rudi Balling, Simon Bauer, Philippe Beutels, André Calero Valdez, Sarah Cuschieri, Thomas Czypionka, Uga Dumpis, Enrico Glaab, Eva Grill, Pirta Hotulainen, Emil N Iftekhar, Jenny Krutzinna, Christos Lionis, Helena Machado, Carlos Martins, Martin McKee, George N Pavlakis, Matjaž Perc, Elena Petelos, Martyn Pickersgill, Barbara Prainsack, Joacim Rocklöv, Eva Schernhammer, Ewa Szczurek, Sotirios Tsiodras, Steven Van Gucht, Peter Willeit
Journal: The Lancet (2021)
Pain/Sedation
Authors: K. Kralinský, M. Pisarčíková, Z. Drobová, J. Tuhársky, K. Miškovová, M. Zibolen, P. Gašparec, K. Kafková, Eva Nemeth, P. S. L. Silva, M. C. M. Fonseca, C. S. T. Paulo, L. A. Belli, W. B. Carvalho
Journal: Intensive Care Medicine (1996)
Arsenic
Authors: H. Frumkin, M. J. Thun
Journal: CA A Cancer Journal for Clinicians (2001)

The toxicity and carcinogenicity of arsenic are well known, but vexing questions remain. The current controversy over the appropriate Federal limit for arsenic in drinking water highlights some of the difficult scientific, ethical, economic, and political issues that complicate standard-setting in occupational and environmental health. These include limitations in the scientific evidence concerning the risk at low doses, uncertainty about the appropriate mathematical models for estimating the risk at low-level exposures based on data from higher-level exposures, and controversies concerning the appropriate safety margin, level of evidence required for standard-setting, and costs of remediation.
Genetic predisposition (HLA-SE) is associated with ACPA-IgG variable domain glycosylation in the predisease phase of RA
Authors: Theresa Kissel, Tineke J van Wesemael, Anders Lundquist, Heidi Kokkonen, Atsushi Kawakami, Mami Tamai, Dirkjan van Schaardenburg, Manfred Wuhrer, Tom WJ Huizinga, Hans Ulrich Scherer, Diane van der Woude, Solbritt Rantapää-Dahlqvist, René E M Toes
Journal: Annals of the Rheumatic Diseases (2021)

In addition to Fc glycans, IgG can carry N -linked glycans in the variable domain. The abundant presence of disialylated variable domain glycans (VDGs) is a special feature of anti-citrullinated protein antibody (ACPA)-IgG and possibly other autoantibodies. The introduction of glycosylation sites is mediated by somatic hypermutation (SHM), a T-cell dependent process.1 The high frequency of glycosylation sites does not correlate with the number of SHM, pointing towards a selective advantage of B cells expressing variable domain glycosylated ACPA.2 Previously, we observed that ACPA-IgG VDGs are already present in the phase preceding rheumatoid arthritis (RA) onset and predictive for disease development.3 In addition, we provided first evidence that the human leucocyte antigen (HLA) ‘shared epitope’ (SE) alleles, the most prominent genetic risk factor for ACPA-positive RA, are associated with the presence of VDG on ACPA-IgG predisease.4 Hence, VDG could possibly explain the contribution of HLA-SE restricted T cells in the maturation of the ACPA response. Building on these results, we now hypothesised that HLA-SE alleles may not be associated with ACPA positivity as such, but with the specific presence of variable domain glycosylated ACPA-IgG, a favourable factor for the development of this multifactorial disease.

To substantiate our hypothesis, we expanded the set of presymptomatic individuals (n=228) and RA-patients (n=126) from Sweden and analysed two additional cohorts comprising ACPA-positive Dutch subjects with arthralgia (n=239) and ACPA-positive healthy Japanese individuals (n=58) (online supplemental table S1). We determined the presence/percentage of ACPA-IgG VDG using liquid chromatography5 and assessed associations with HLA-SE (online supplemental materials and methods). In particular, we focused on the most prominent glycan peak (GP24) found on top of the variable domain,1 which carries a bisecting N -acetylglucosamine and two terminal sialic acids (G2FBS2) (figure 1A). ACPA-IgG VDG were, with a median of 58%, already …
Response to: Correspondence on “Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: results from the COVID-19 Global Rheumatology Alliance physician registry” by Sparks<i>et al</i>
Authors: Zachary S Wallace, Jeffrey A Sparks, Philip C Robinson, Pedro M Machado, Jinoos Yazdany
Journal: Annals of the Rheumatic Diseases (2021)

<h3>Abstract</h3> Mutations in the <i>dystrophin</i> gene cause the most common and currently incurable Duchenne muscular dystrophy (DMD) characterized by progressive muscle wasting. Although abnormal Ca<sup>2+</sup> handling is a pathological feature of DMD, mechanisms underlying defective Ca<sup>2+</sup> homeostasis remain unclear. Here we generate a novel DMD patient-derived pluripotent stem cell (PSC) model of skeletal muscle with an isogenic control using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated precise gene correction. Transcriptome analysis identifies dysregulated gene sets in the absence of dystrophin, including genes involved in Ca<sup>2+</sup> handling, excitation-contraction coupling and muscle contraction. Specifically, analysis of intracellular Ca<sup>2+</sup> transients and mathematical modeling of Ca<sup>2+</sup> dynamics reveal significantly reduced cytosolic Ca<sup>2+</sup> clearance rates in DMD-PSC derived myotubes. Pharmacological assays demonstrate Ca<sup>2+</sup> flux in myotubes is determined by both intracellular and extracellular sources. DMD-PSC derived myotubes display significantly reduced velocity of contractility. Compared with a non-isogenic wild type PSC line, these pathophysiological defects could be rescued by CRISPR-mediated precise gene correction. Our study provides new insights into abnormal Ca<sup>2+</sup> homeostasis in DMD and suggests that Ca<sup>2+</sup> signaling pathways amenable to pharmacological modulation are potential therapeutic targets. Importantly, we have established a human physiology-relevant <i>in vitro</i> model enabling rapid pre-clinical testing of potential therapies for DMD.
Chronic Kidney Disease Testing Among At-Risk Adults in the U.S. Remains Low: Real-World Evidence From a National Laboratory Database
Authors: David Alfego, Jennifer Ennis, Barbara Gillespie, Mary Jane Lewis, Elizabeth Montgomery, Silvia Ferrè, Joseph A. Vassalotti, Stanley Letovsky
Journal: Diabetes Care (2021)

An estimated 37 million Americans have chronic kidney disease (CKD). Nearly 90% do not know about their condition because of low awareness about the importance of CKD testing and diagnosis among practitioners and people at risk for CKD. This study uses data from a national clinical laboratory to identify guideline-recommended CKD testing rates across the U.S.
Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition
Authors: Lisa M. Butler, Chui Yan Mah, Jelle Machiels, Andrew D. Vincent, Swati Irani, Shadrack M. Mutuku, Xander Spotbeen, Muralidhararao Bagadi, David Waltregny, Max Moldovan, Jonas Dehairs, Frank Vanderhoydonc, Katarzyna Bloch, Rajdeep Das, Jurgen Stahl, James G. Kench, Thomas Gevaert, Rita Derua, Etienne Waelkens, Zeyad D. Nassar, Luke A. Selth, Paul J. Trim, Marten F. Snel, David J. Lynn, Wayne D. Tilley, Lisa G. Horvath, Margaret M. Centenera, Johannes V. Swinnen
Journal: Cancer Research (2021)

Abstract Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the “lipidome” in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. Significance: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.
Single-Agent Ibrutinib for Rituximab-Refractory Waldenström Macroglobulinemia: Final Analysis of the Substudy of the Phase III InnovateTM Trial
Authors: Judith Trotman, Christian Buske, Alessandra Tedeschi, Jeffrey V. Matous, David MacDonald, Constantine S. Tam, Olivier Tournilhac, Shuo Ma, Steven P. Treon, Albert Oriol, Jerry Ping, Eva M. Briso, Israel Arango-Hisijara, Meletios A. Dimopoulos
Journal: Clinical Cancer Research (2021)

The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia. Results from the final analysis are now reported.Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed.After a median follow-up of 58 months (range: 9-61), median PFS was 39 months [95% confidence interval (CI): 25-not evaluable]; 60-month PFS rate was 40%. In MYD88L265P/CXCR4WHIM and MYD88L265P/CXCR4WT subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (≥ partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin ≤11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of -37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation.In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia.