tbuckley/cabot-search huggingface dataset:
Guided by the Light—Transillumination of a Paravalvular Leak
Authors: Ilya Karagodin, Atman P. Shah, Roberto M. Lang
Journal: JAMA Cardiology (2020)

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 Cardiology 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 Cardiology journal
Abstract 5689: CH7233163, a mutant-selective EGFR inhibitor, overcomes osimertinib resistant EGFR-T790M/C797S
Authors: Kenji Kashima
Journal: Cancer Research (2020)

Abstract EGFR tyrosine kinase inhibitors (TKI) show dramatic improvement of treatment for EGFR-mutated lung cancer, but these clinical efficacy is limited by acquired drug resistance. Osimertinib is a clinically approved covalent EGFR-TKI and has been demonstrated to overcome the EGFR-T790M, the most relevant acquired resistance to first-generation EGFR-TKIs. However, the C797S mutation, which impairs the covalent binding between EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutics to inhibit EGFR triple-mutation (C797S/T790M/activating-mutation). In this study, we identified CH7233163, a novel EGFR TKI, capable of overcoming the EGFR triple-mutation. CH7233163 inhibited preferentially enzymatic activity of EGFR triple-mutation, and showed potent antitumor activity against the tumor with EGFR triple-mutation in vitro and in vivo. Crystal structure of EGFR triple mutant in complex with CH7233163 shows that this compound interacted with multiple amino acids located in the ATP pocket of EGFR. This binding mode suggests that CH7233163 non-covalently but potently competes ATP without steric hindrance with T790M. Consistent with this insight, CH7233163 also showed potent antitumor activity against the tumors harboring EGFR single activating-mutation (deletion 19 or L858R) and double-mutation (T790M/activating-mutation) in vitro and in vivo. These result suggested that CH723316 may become a potential therapeutics to overcome osimertinib resistance in EGFR-mutated NSCLC. Citation Format: Kenji Kashima. CH7233163, a mutant-selective EGFR inhibitor, overcomes osimertinib resistant EGFR-T790M/C797S [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5689.
ARC Is a Critical Protector against Inflammatory Bowel Disease (IBD) and IBD-Associated Colorectal Tumorigenesis
Authors: Qiushi Wang, Tianshun Zhang, Xiaoyu Chang, Do Young Lim, Keke Wang, Ruihua Bai, Ting Wang, Joohyun Ryu, Hanyong Chen, Ke Yao, Wei-Ya Ma, Lisa A. Boardman, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2020)

The key functional molecules involved in inflammatory bowel disease (IBD) and IBD-induced colorectal tumorigenesis remain unclear. In this study, we found that the apoptosis repressor with caspase recruitment domain (ARC) protein plays critical roles in IBD. ARC-deficient mice exhibited substantially higher susceptibility to dextran sulfate sodium (DSS)-induced IBD compared with wild-type mice. The inflammatory burden induced in ARC-deficient conditions was inversely correlated with CCL5 and CXCL5 levels in immune cells, especially CD4-positive T cells. Pathologically, ARC expression in immune cells was significantly decreased in clinical biopsy specimens from patients with IBD compared with normal subjects. In addition, ARC levels inversely correlated with CCL5 and CXCL5 levels in human biopsy specimens. ARC interacted with TNF receptor associated factor (TRAF) 6, regulating ubiquitination of TRAF6, which was associated with NF-κB signaling. Importantly, we identified a novel ubiquitination site at lysine 461, which was critical in the function of ARC in IBD. ARC played a critical role in IBD and IBD-associated colon cancer in a bone marrow transplantation model and azoxymethane/DSS-induced colitis cancer mouse models. Overall, these findings reveal that ARC is critically involved in the maintenance of intestinal homeostasis and protection against IBD through its ubiquitination of TRAF6 and subsequent modulation of NF-κB activation in T cells. SIGNIFICANCE: This study uncovers a crucial role of ARC in the immune system and IBD, giving rise to a novel strategy for IBD and IBD-associated colon cancer therapy.
Requirements for cDC2 positioning in blood-exposed regions of the neonatal and adult spleen
Authors: Dan Liu, Jiaxi Wu, Jinping An, Jason G. Cyster
Journal: The Journal of Experimental Medicine (2020)

The marginal zone (MZ) of the spleen contains multiple cell types that are involved in mounting rapid immune responses against blood-borne pathogens, including conventional dendritic cells (cDCs) and MZ B cells. MZ B cells develop later than other B cell types and are sparse in neonatal mice. Here, we show that cDC2s are abundant in the MZ of neonatal compared with adult mice. We find that conditions associated with reduced MZ B cell numbers in adult mice cause increased cDC2 occupancy of the MZ. Treatment with the S1PR1-modulating drug, FTY720, causes cDC2 movement into the MZ through the indirect mechanism of displacing MZ B cells into follicles. Splenic cDC2s express high amounts of α4β1 and αLβ2 integrins and depend on these integrins and the adaptor Talin for their retention in blood-exposed regions of the spleen. Splenic CD4 T cell activation by particulate antigens is increased in mice with higher cDC2 density in the MZ, including in neonatal mice. Our work establishes requirements for homeostatic cDC2 positioning in the spleen and provides evidence that localization in blood-exposed regions around the white pulp augments cDC2 capture of particulate antigens. We suggest that MZ positioning of cDC2s partially compensates for the lack of MZ B cells during the neonatal period.
Pathophysiological regulation of lung function by the free fatty acid receptor FFA4
Authors: Rudi Prihandoko, Davinder Kaur, Coen H. Wiegman, Elisa Alvarez-Curto, Chantal Donovan, Latifa Chachi, Trond Ulven, Martha R. Tyas, Eloise Euston, Zhaoyang Dong, Abdulrahman Ghali M. Alharbi, Richard Y. Kim, Jack G. Lowe, Philip M. Hansbro, Kian Fan Chung, Christopher E. Brightling, Graeme Milligan, Andrew B. Tobin
Journal: Science Translational Medicine (2020)

FFA4 receptor agonism corrects dysfunctional lung responses and inflammation in models and is a potential target for inflammatory lung disease.
Abstract 13403: Enhanced Expression of Hemoglobin Scavenger Receptor and Heme Oxygenase-1 is Associated With Aortic Valve Stenosis in Patients Undergoing Hemodialysis
Authors: Kazuki Mizutani, Kei Yunoki, Ryushi Komatsu, Kazuo Haze, Yasuyuki Kato, Toshiiko Shibata, Takahiko Naruko, Kenichi Sugioka, Mayumi Inaba, Minoru Yoshiyama, Makiko Ueda
Journal: Circulation (2013)

Background: A high prevalence and a rapid progression of aortic valve stenosis (AS) in patients undergoing hemodialysis (HD) has been reported. Under these conditions, intraleaflet hemorrhage of th...
The Biological Significance of Multi-copy Regions and Their Impact on Variant Discovery
Authors: Jing Sun, Yanfang Zhang, Minhui Wang, Qian Guan, Xiujia Yang, Jin Xia Ou, Mingchen Yan, Chengrui Wang, Yan Zhang, Zhi-Hao Li, Chunhong Lan, Chen Mao, Hong-Wei Zhou, Bingtao Hao, Zhenhai Zhang
Journal: Genomics Proteomics & Bioinformatics (2020)

Identification of genetic variants via high-throughput sequencing (HTS) technologies has been essential for both fundamental and clinical studies. However, to what extent the genome sequence composition affects variant calling remains unclear. In this study, we identified 63,897 multi-copy sequences (MCSs) with a minimum length of 300 bp, each of which occurs at least twice in the human genome. The 151,749 genomic loci (multi-copy regions, or MCRs) harboring these MCSs account for 1.98% of the genome and are distributed unevenly across chromosomes. MCRs containing the same MCS tend to be located on the same chromosome. Gene Ontology (GO) analyses revealed that 3800 genes whose UTRs or exons overlap with MCRs are enriched for Golgi-related cellular component terms and various enzymatic activities in the GO biological function category. MCRs are also enriched for loci that are sensitive to neocarzinostatin-induced double-strand breaks. Moreover, genetic variants discovered by genome-wide association studies and recorded in dbSNP are significantly underrepresented in MCRs. Using simulated HTS datasets, we show that false variant discovery rates are significantly higher in MCRs than in other genomic regions. These results suggest that extra caution must be taken when identifying genetic variants in the MCRs via HTS technologies.
Gene expression profile analysis of aromatase inhibitor-resistant MCF-7aro cells
Authors: Kimberly Karlsberg, Yate-Ching Yuan, David Smith, Sheryl Phung, Toru Itoh, Sharon Kwok, Ikuko Kijima, Shiuan Chen
Journal: Cancer Research (2005)

1275  While the new generation of aromatase inhibitors have shown to be useful in the treatment of hormonal responsive breast cancer for postmenopausal women, the emergence of drug cross resistance to such endocrine therapy needs to be overcame. To unravel the molecular mechanisms of aromatase inhibitor resistance and compare these to that of tamoxifen resistance, MCF-7aro cell lines that are resistant to anastrozole, letrozole or tamoxifen have been generated in our laboratory. The MCF-7aro breast cancer cell line is aromatase over-expressing and ER-positive. We have performed differential expression profile analysis using Affymetrix Human Genome U133A on inhibitor-resistant MCF-7aro cells. The intensities of the probe signals on the GeneChips were statistically normalized following a background noise subtraction, and were analyzed using algorithms in R/Bioconductor. We compared the more than 22,000 gene expressions using two-sample t-tests and applied the Benjamini-Yekutieli p-value correction to control the false discovery rate. Using a minimum fold change criteria of 2.0 and an adjusted p-value cutoff of 0.05, We then compared these results to our previous results with inhibitor-responsive cells, in order to find genes that behave differently between the two groups. The number of genes we found that were up-regulated (down-regulated) were 4 (5),10 (13), 8 (13), for androgen versus anastrozole, letrozole, and tamoxifen, respectively. The genes identified as statistically significant were classified based on their expression patterns and biological function/pathways. We believe that the results of this study serve as the first step in identifying unique expression patterns corresponding to drug resistance, and that this will ultimately be useful in predicting and overcoming drug resistance when treating breast cancer patients.
Cbls boost B cells
Authors: Michelle A. Linterman
Journal: The Journal of Experimental Medicine (2020)

T cell regulation of antibody-mediated immunity is critical for health. In this issue of JEM, Li et al. (https://doi.org/10.1084/jem.20191537) identify the Cbl family of E3 ubiquitin ligases as B cell–intrinsic gatekeepers of T cell–dependent humoral immunity.
Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function
Authors: Longhui Qiu, Xingqiang Lai, Jiao-jing Wang, Xin Yi Yeap, Shulin Han, Feibo Zheng, Charlie Lin, Zhuoli Zhang, Daniele Procissi, Deyu Fang, Lin Li, Edward B. Thorp, Michael M. Abecassis, Yashpal S. Kanwar, Zheng J. Zhang
Journal: Kidney International (2020)
Abstract 11858: Epigenetic Reversion of Metabolic Memory Alterations in Human Cardiac Stromal Cells Isolated from Type-2 Diabetic Patients
Authors: Matteo Vecellio, Giulio Pompilio, Francesco Spallotta, Claudia Colussi, Gianluca Sbardella, Sabrina Castellano, Antonello Mai, Maurizio C Capogrossi, Alessandra Rossini, Carlo Gaetano
Journal: Circulation (2011)

INTRODUCTION: Stem cells derived from diabetes patients often loose most of their regenerative potential. Aims of this study were: 1) investigate the epigenetic basis of diabetes-dependent alterati...
Prevalence of Flavored e-Cigarette Use Among Subpopulations of Adults in the United States
Authors: Adam M Leventhal, Hongying Dai
Journal: JNCI Journal of the National Cancer Institute (2020)

Evidence of US adult flavored e-cigarette use prevalence stratified by age, smoking status, and purpose for vaping (ie, quitting smoking, to use when or where smoking is not allowed) can inform policies that reduce the tobacco-related cancer burden.Current flavored e-cigarette use (use 1 or more nontobacco flavors) prevalence estimates were compared across subpopulation groups using 2-sided statistical significance tests in the July 2018 Current Population Survey Tobacco Use Supplement, a nationally representative cross-sectional adult survey (n = 46 759).Current flavored e-cigarette use was reported by 1.6% (95% confidence interval [CI] = 1.47% to 1.69%) of all respondents. Among current vapers, the percentage of those who used flavored e-cigarettes was higher for adults aged 18-24 years (89.6%), 25-34 years (86.7%), and 35-44 years (76.0%) than for adults aged 45 years and older (60.4%, Ps < .001); was higher in never smokers (89.8%) than current (72.9%), long-term former (73.9%), and recent former (80.4%) smokers (Ps ≤ .009); was higher in smokers who reportedly did (78.9%) vs did not (71.1%) use e-cigarettes to vape where or when smoking is not allowed (P = .005); and did not differ between smokers who reportedly did (75.0%) vs did not (73.9%) vape to quit smoking (P = .71). Individuals who vaped to quit smoking and currently used flavored e-cigarettes constituted 0.9% (95% CI = 0.82% to 0.99%) of all adults (weighted N = 2 251 000, 95% CI = 2 046 000 to 2 476 000) and 57.2% of current flavored e-cigarette users.Flavored e-cigarette use prevalence was low among US adults overall but common for current vapers. Flavored e-cigarette use was disproportionately prevalent among never smokers and other subpopulations that might experience harm from vaping.
Low lumbar bone mineral density in patients with major depression
Authors: Ulrich Schweiger, Michael Deuschle, Andreas Körner, Claas-Hinrich Lammers, Jurgen Schmider, Ulrike Gotthardt, Florian Holsboer, Isabella Heuser
Journal: American Journal of Psychiatry (1994)

Major depression is associated with hypercorticoidism, a risk factor for osteoporosis. However, it is unknown whether depressive disorders are associated with alterations in bone mineral density. The authors measured the density of trabecular bone from the first to the third lumbar vertebra by quantitative computerized tomography in 80 depressed inpatients older than 40 years and in 57 healthy comparison subjects. An analysis of covariance model with age as a covariate showed a significant effect of diagnosis on the dependent variable spinal bone mineral density: depressed patients had lower values. Other factors could not explain the finding. The authors conclude that major depression is a significant risk factor for osteoporosis.
Calcium Ionophore-Treated Myeloid Cells Acquire Many Dendritic Cell Characteristics Independent of Prior Differentiation State, Transformation Status, or Sensitivity to Biologic Agents
Authors: Gary K. Koski, Gretchen N. Schwartz, David E. Weng, Ronald E. Gress, Friederike H.C. Engels, Maria Tsokos, Brian J. Czerniecki, Peter A. Cohen
Journal: Blood (1999)
Single-cell DNA amplicon sequencing reveals clonal heterogeneity and evolution in T-cell acute lymphoblastic leukemia
Authors: Llucia Albertí-Servera, Sofie Demeyer, Inge Govaerts, Toon Swings, Jolien De Bie, Olga Gielen, Marco Brociner, Lucienne Michaux, Johan Maertens, Anne Uyttebroeck, Kim De Keersmaecker, Nancy Boeckx, Heidi Segers, Jan Cools
Journal: Blood (2020)
How to integrate recovery during heat acclimation
Authors: Mohammed Ihsan, Julien D. Périard, Sebastien Racinais
Journal: British Journal of Sports Medicine (2020)

The games of the XXXII Olympiad have been announced from 23 July to 8 August 2021, coinciding with the height of the Japanese summer. Heat acclimation/acclimatisation (HA) is the most important countermeasure athletes can adopt to safeguard their health and performance when competing in the heat. However, it is important for practitioners to recognise that repeated daily exposures to heat stress is a physiologically demanding endeavour. Prolonged heat exposure is characterised by increased thermal and cardiovascular strain, augmented glycogen utilisation and fluid losses, increased hormonal responses (ie, increased cortisol and catecholamine secretion), cytokinaemia and endotoxaemia, which may result in sleep and gastrointestinal disturbances, augmented lethargy and delayed physical recovery.1–3 For instance, consecutive days of training in the heat, particularly at high exercise intensities, can result in a state of over-reaching, despite signs of successful heat adaptation.4 It is therefore imperative to manage recovery when training in the heat, as accumulated fatigue may impact on the overall success of the HA programme, as well as interfere with the quality of other training sessions. This editorial aims to provide practitioners and coaches with an up-to-date synopsis of recovery strategies during HA (figure 1).



Figure 1 
Schematic illustration on the responses to repeated training in the heat and recovery strategies.



Pre-exercise nutritional strategies are crucial in limiting fluid and electrolyte imbalance during exertional heat stress, such that HA sessions can be optimally …
Rationing of sildenafil
Authors: S. Hayes, A. Green, None Anonymous
Journal: BMJ (1999)

# Nobody needs an erection at public expense {#article-title-2} EDITOR—I am a BMA member, but Drs John Chisholm and Ian Bogle do not speak for me on sildenafil (Viagra). 1 2 I understood that we had been asking successive governments for years to accept the need for explicit rationing decisions. As soon as this government makes one—a sensible one that the general public accepts—we kick it in the teeth. The grounds for differentiating between different causes of erectile dysfunction outlined by the health secretary, Frank Dobson, were imperfect but not unreasonable3; for the first time there was an overt admission that totally comprehensive demand-led care had to be limited. This was not the time to pick a fight. The media comment suggests that the public accepts that when resources are limited conditions such as cataract and stroke should be given higher priorities than erectile dysfunction. I have been telling my patients who request sildenafil that the NHS cannot afford it. I still take that view, but the BMA's reported comments will make my position harder to sustain. Sildenafil should be available at cost without prescription; it will cost about as much as an acceptable bottle of table wine. 1. ↵1. Chisholm J .Viagra: a botched case for rationing.BMJ1999; 318:273–274. (30 January.) [OpenUrl][1][FREE Full Text][2] 2. ↵1. British Medical Association .GPC Viagra statement.London:BMA,1999(Press release 21 January.) 3. ↵1. Department of Health .Viagra: NHS prescription proposals announced.London:DoH,1999(Press release 21 January.) # True debate is needed {#article-title-4} EDITOR—The proposals for rationing of sildenafil (Viagra) put forward by the secretary of state are unethical,1 and the General Practitioners Committee is correct to advise general practitioners to prescribe the drug on prescription to all patients who require it.2 Many doctors would welcome a mature debate regarding rationing in the NHS, recognising that in an underfunded service where rationing has always existed such a discussion should be held openly and honestly. Few, however, can have expected that the first politically … [1]: {openurl}?query=rft.jtitle%253DBMJ%26rft.stitle%253DBMJ%26rft.issn%253D0007-1447%26rft.aulast%253DChisholm%26rft.auinit1%253DJ.%26rft.volume%253D318%26rft.issue%253D7179%26rft.spage%253D273%26rft.epage%253D274%26rft.atitle%253DViagra%253A%2Ba%2Bbotched%2Btest%2Bcase%2Bfor%2Brationing%26rft_id%253Dinfo%253Apmid%252F9924034%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=FULL&journalCode=bmj&resid=318/7179/273&atom=%2Fbmj%2F318%2F7198%2F1620.atom
Elevated ACE-2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication
Authors: Mengfei Chen, Wenjuan Shen, Nicholas R. Rowan, Heather Kulaga, Alexander Hillel, Murugappan Ramanathan, Andrew P. Lane
Journal: European Respiratory Journal (2020)

<b>ACE2 protein is expressed at high levels in the human olfactory epithelium relative to upper airway epithelial cells. This may explain COVID-19-associated olfactory dysfunction, and suggests a SARS-CoV-2 reservoir site and potential intranasal therapy.</b>https://bit.ly/3hxT0qm