tbuckley/cabot-search huggingface dataset:
Abstract P179: Comparison of Earlier versus Later Orthostatic Hypotension Assessment Times in Middle-Age Adults of the Atherosclerosis Risk in Communities Study (ARIC)
Authors: Stephen P Juraschek, Natalie Daya, Andreea M Rawlings, Lawrence J Appel, Edgar R Miller, B G Windham, Michael E Griswold, Elizabeth Selvin
Journal: Circulation (2017)

Background: Guidelines recommend assessing orthostatic hypotension (OH) 3 minutes after rising from supine to standing positions. Hypothesis: Measurements performed immediately after standing will be as informative as measurements performed closer to 3 minutes after standing with regards to symptoms of dizziness or risk of adverse outcomes. Methods: OH, defined as a drop in blood pressure (systolic ≥20 mm Hg or diastolic ≥10 mm Hg) from the supine to standing position, was measured up to five times at 25 seconds intervals in middle-aged (range 44 to 66 years) ARIC participants (1987-1989). Associations between each measurement and history of dizziness upon standing were examined via logistic regression. We used Cox models to examine the association between each of five measurements with risk of fall, fracture, syncope, and all-cause mortality over a median follow-up of 23 years. Results: In 11,449 participants (mean age 54 years, 54% women, 26% black) 10% reported a history of dizziness upon standing. OH assessed at measurement 1 (performed at a mean of 28 seconds after standing) was associated with risk of fall ( P = 0.03), fracture ( P = 0.05), syncope ( P &lt;0.001), and mortality ( P &lt; 0.001) ( Table ). Furthermore, measurement 1 was the only measurement associated with higher odds of dizziness upon standing (OR: 1.5; P = 0.001). Measurement 2 (performed on average 53 seconds after standing) was associated with all long-term outcomes. Measurements 4 and 5 (mean 100 and 116 seconds after standing) were generally less informative with regards to prospective outcomes than earlier measurements and were not statistically associated with history of dizziness. Conclusions: OH measurements obtained, on average, within the first 30 seconds of standing were predictive of long-term adverse health outcomes and were the most strongly related to symptoms of dizziness compared to later measurements. These findings suggest that BP measurements for determining orthostatic hypotension should be performed immediately after standing.
Anticarin-β shows a promising anti-osteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis
Authors: Gan Wang, Min Zhang, Ping Meng, Chengbo Long, Xiaodong Luo, Xingwei Yang, Yunfei Wang, Zhiye Zhang, James Mwangi, Peter Muiruri Kamau, Zhi Dai, Zunfu Ke, Yi Zhang, Wenlin Chen, Xudong Zhao, Fei Ge, Qiumin Lv, Mingqiang Rong, Dongsheng Li, Yang Jin, Xia Sheng, Ren Lai
Journal: Acta Pharmaceutica Sinica B (2022)

Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex (TRiC) contains eight paralogous subunits (CCT1-8), and assists the folding of as many as 10% of cytosolic proteome. TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma, and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma. Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.
In persons at intermediate risk for CVD, polypills reduce a composite of CV events at 5 y
Authors: Krysta Brown, Anthony A. Donato
Journal: Annals of Internal Medicine (2022)

Source Citation Joseph P, Roshandel G, Gao P, et al. Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis. Lancet. 2021;398:1133-46. 34469765
Plasma concentrations of fibrinolytic factors in the subacute phase of acute myocardial infarction predict recurrence of myocardial infarction Takeshi Soeki, Yoshiyuki Tamura, Hisanori Shinohara, Yuki Sawada, Nobuo Fukuda. Zentsuji National Hospital, Zentsuji, Japan
Journal: Journal of the American College of Cardiology (2001)
Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation
Authors: Hideyuki Hakui, Hidetaka Kioka, Yohei Miyashita, Shunsuke Nishimura, Ken Matsuoka, Hisakazu Kato, Osamu Tsukamoto, Yuki Kuramoto, Ayako Takuwa, Yusuke Takahashi, Shigeyoshi Saito, Kunio Ohta, Hiroshi Asanuma, Hai Ying Fu, Haruki Shinomiya, Noriaki Yamada, Tomohito Ohtani, Yoshiki Sawa, Masafumi Kitakaze, Seiji Takashima, Yasushi Sakata, Yoshihiro Asano
Journal: Science Translational Medicine (2022)

Dilated cardiomyopathy (DCM) is a major cause of heart failure, characterized by ventricular dilatation and systolic dysfunction. Familial DCM is reportedly caused by mutations in more than 50 genes, requiring precise disease stratification based on genetic information. However, the underlying genetic causes of 60 to 80% of familial DCM cases remain unknown. Here, we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance. BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding. Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes. Immunocytochemical analysis revealed that BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling. Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities. We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis. Our study suggests that loss-of-function mutations in BAG5 can cause DCM, that BAG5 may be a target for genetic testing in cases of DCM, and that gene therapy may potentially be a treatment for this disease.
Disease-associated mutations in topoisomerase IIβ result in defective NK cells
Authors: Lori Broderick, Gwendolyn M. Clay, Robert H. Blum, Yang Liu, Rachael McVicar, Fabio Papes, Laela M. Booshehri, Ian G. Cowell, Caroline A. Austin, Christopher D. Putnam, Dan S. Kaufman
Journal: Journal of Allergy and Clinical Immunology (2022)

BackgroundHoffman syndrome is a syndromic, inborn error of immunity due to autosomal-dominant mutations in TOP2B, an essential gene required to alleviate topological stress during DNA replication and gene transcription. Although mutations identified in patients lead to a block in B-cell development and the absence of circulating B cells, an effect on natural killer (NK) cells was not previously examined.ObjectiveWe sought to determine whether disease-associated mutations in TOP2B impact NK-cell development and function.MethodsUsing a knockin murine model and patient-derived induced pluripotent stem cells (iPSCs), we investigated NK-cell development in mouse bone marrow and spleen, and performed immunophenotyping by flow cytometry, gene expression, and functional assessment of cytotoxic activity in murine NK cells, and human IPSC-derived NK cells.ResultsMature NK cells were reduced in the periphery of TOP2B knockin mice consistent with patient reports, with reduced cytotoxicity toward target cell lines. IPSCs were successfully derived from patients with Hoffman syndrome, but under optimal conditions showed reduced cytotoxicity compared with iPSC-derived NK cells from healthy controls.ConclusionsHoffman syndrome–associated mutations in TOP2B impact NK-cell development and function in murine and human models. Hoffman syndrome is a syndromic, inborn error of immunity due to autosomal-dominant mutations in TOP2B, an essential gene required to alleviate topological stress during DNA replication and gene transcription. Although mutations identified in patients lead to a block in B-cell development and the absence of circulating B cells, an effect on natural killer (NK) cells was not previously examined. We sought to determine whether disease-associated mutations in TOP2B impact NK-cell development and function. Using a knockin murine model and patient-derived induced pluripotent stem cells (iPSCs), we investigated NK-cell development in mouse bone marrow and spleen, and performed immunophenotyping by flow cytometry, gene expression, and functional assessment of cytotoxic activity in murine NK cells, and human IPSC-derived NK cells. Mature NK cells were reduced in the periphery of TOP2B knockin mice consistent with patient reports, with reduced cytotoxicity toward target cell lines. IPSCs were successfully derived from patients with Hoffman syndrome, but under optimal conditions showed reduced cytotoxicity compared with iPSC-derived NK cells from healthy controls. Hoffman syndrome–associated mutations in TOP2B impact NK-cell development and function in murine and human models.
Percutaneous mitral valvuloplasty with inoue balloon versus metallic commissurotome: A prospective randomized study Enio E. Guerios, Ronaldo R. L. Bueno, Jose C. E. Tarastchuk, Deborah C. Nercolini, Paulo M. P. Andrade, Alvaro L. A. Pacheco, Sonia Perreto. Hospital Evangelico, Curitiba, Brazil
Journal: Journal of the American College of Cardiology (2001)
Low Glucose–Induced Overexpression of <i>HOXC-AS3</i> Promotes Metabolic Reprogramming of Breast Cancer
Authors: Wenjie Zhu, Xu Chen, Xiangyu Guo, Haiting Liu, Ranran Ma, Yawen Wang, Yahang Liang, Ying Sun, Mengqi Wang, Ruinan Zhao, Peng Gao
Journal: Cancer Research (2022)

Abstract Breast cancer is the most common malignancy in women worldwide. However, the mechanisms underlying breast cancer energy metabolism and progression remain obscure. Cancer cells rapidly adapt to microenvironments with fluctuating nutrient levels. Here, we characterized a long noncoding RNA (lncRNA), HOXC-AS3, which is activated upon glucose deprivation to trigger a nutrient-stress response and a switch in glucose metabolism. Upregulation of HOXC-AS3 in breast cancer was identified by in published microarray and RNA-sequencing datasets, and then confirmed by qRT-PCR in fresh breast cancer tissues. Glucose deprivation induced HOXC-AS3 overexpression in a dose- and time-dependent manner in breast cancer cells. Gain- and loss-of-function experiments in vitro and in vivo showed that HOXC-AS3 triggers energy metabolism reprogramming. ChIRP-mass spectrometry and unique molecular identifier RNA immunoprecipitation and high-throughput sequencing (UMI RIP-seq) identified binding motifs of HOXC-AS3 with SIRT6. HOXC-AS3 selectively antagonized SIRT6-mediated H3K9ac deacetylation of glycolysis-related genes. Moreover, HOXC-AS3 binding to SIRT6 prevented contact inhibition of HIF1α, leading to reprogramming of metabolic pathways. In addition, HOXC-AS3, SP1, and miR-1224–5p formed a positive feedback loop to maintain cancer-promoting signals. Furthermore, administration of anti-HOXC-AS3-motif-RNAs effectively blocked the function of HOXC-AS3, ultimately suppressing breast cancer progression. These results reveal a critical role for HOXC-AS3 in regulating the metabolic reprogramming of breast cancer cells under metabolic stress. Use of an anti-HOXC-AS3-motif RNA mixture may be a promising strategy to suppress breast cancer progression. Significance: HOXC-AS3 is a low glucose–activated long noncoding RNA that triggers metabolic reprogramming in breast cancer cells to adapt to nutrient stress, identifying HOXC-AS3 as a potential therapeutic target for breast cancer treatment.
The enhanced PR logicTM dual chamber tachyarrhythmia detection algorithm: Retrospective analysis of supraventricular tachycardia with long PR intervals Bruce L. Wilkoff, Jeffrey M. Gillberg, Cynthia M. DeSouza. The Cleveland Clinic Foundation, Cleveland, OH, Medtronic Inc., Minneapolis, MN
Journal: Journal of the American College of Cardiology (2001)
Effect of primary tumor location on second- or later-line treatment with anti-epidermal growth factor receptor antibodies in patients with metastatic colorectal cancer: A retrospective multicenter study.
Authors: Krittiya Korphaisarn, Anita Archwamety, Nattaya Sintawichai, Teerada Siripoon, Naravat Poungvarin, Suebpong Tanasanvimon, Ekaphop Sirachainan, Charuwan Akewanlop
Journal: Journal of Clinical Oncology (2022)

195 Background: Currently, there are no guideline recommendations of anti-EGFR Ab specific to tumor sidedness in subsequent-line treatment in patients with metastatic colorectal cancer (mCRC). We previously reported the effect of primary tumor location on subsequent-line treatment with anti-EGFR Ab from a single center. Here we presented the outcome from a multi-center study. Methods: Medical records of patients diagnosed with mCRC at 3 academic centers in Thailand (Siriraj, Chulalongkorn, and Ramathibodi hospital) between 2008 and 2019 were retrospectively reviewed. Patients with KRASwt mCRC who received anti-EGFR Ab in second- or later-line treatment were included. The impact of tumor sidedness on progression-free survival (PFS) was determined using Kaplan-Meier method, and those results were compared using log-rank test. Results: Among the 2,102 patients who had KRAS analysis data, 1,130 (54%) patients had KRASwt. Of those, 413 patients received anti-EGFR Ab in second- or later-line treatment. One hundred and sixty-two of 413 (39%) patients had extended RAS analysis. Seventy (17%) patients had right-sided tumors. Two hundred and thirty-eight (58%) patients received anti-EGFR Ab in the third line, and 132 (32%) patients and 43 (10%) patients were treated in the second and more than third line, respectively. Single-agent irinotecan was the most commonly used backbone chemotherapy (303/413, 73%). Patients with right-sided tumors had non-significantly inferior PFS compared to patients with left-sided tumors (median PFS: 5.7 months (mo), 95% confidence interval [CI]: 3.9-7.5 vs. 7.5 mo, 95% CI 6.5-8.5; p =0.17). Subgroup analysis showed no difference in PFS when stratified by treatment lines. Patient with right-sided tumors had significantly inferior OS compared to patients with left-sided tumors (median OS: 23.3 mo vs. 29.9 mo; p =0.005). Conclusions: To date, this is the largest real world data of the effect of primary tumor location on anti-EGFR Ab which demonstrated that tumor sidedness has no significant impact on treatment outcomes in KRASwt mCRC patients receiving second- or later-line therapy. Our findings do not support the utility of tumor sidedness for treatment selection in these settings. We confirmed that patients with right-sided tumors had significantly worse survival.
Effectiveness of Screening in Early Intervention Settings to Improve Diagnosis of Autism and Reduce Health Disparities
Authors: R. Christopher Sheldrick, Alice S. Carter, Abbey Eisenhower, Thomas I. Mackie, Megan B. Cole, Noah Hoch, Sophie Brunt, Frances Martinez Pedraza
Journal: JAMA Pediatrics (2022)

<h3>Importance</h3> The American Academy of Pediatrics recommends referring children at elevated risk of autism spectrum disorder (ASD) for Part C early intervention (EI) services, but notes that EI services often fail to provide ASD screening. <h3>Objective</h3> To evaluate the hypothesis that a multistage screening protocol for ASD implemented in 3 EI settings will increase autism detection, especially among Spanish-speaking families. <h3>Design, Setting, and Participants</h3> Difference-in-differences analyses with propensity score weighting of a quasi-experimental design using administrative data on 3 implementation EI agencies and 9 comparison EI agencies from 2012 to 2018 provided by the Massachusetts Department of Public Health. Eligible children were aged 14 to 36 months, enrolled in EI, had no prior ASD diagnosis or medical condition precluding participation, and had parents who spoke English or Spanish. The final analytic sample included 33 326 unique patients assessed across 150 200 person-quarters. <h3>Exposures</h3> Multistage ASD assessment protocol including ASD screening questionnaires, observational screener, and diagnostic evaluation. <h3>Main Outcomes and Measures</h3> Increased incidence of ASD diagnoses as documented in Department of Public Health records and reductions in language-associated health care disparities. <h3>Results</h3> Implementation of screening at 3 EI sites was associated with a significant increase in the rate of ASD diagnoses (incidence rate ratios [IRR], 1.6; 95% CI, 1.3-2.1;<i>P</i> &lt; .001), representing an additional 8.1 diagnoses per 1000 children per quarter. Among Spanish-speaking families, screening was also associated with a significant increase in the rate of ASD diagnoses (IRR, 2.6; 95% CI, 1.6-4.3;<i>P</i> &lt; .001), representing 15.4 additional diagnoses per 1000 children per quarter—a larger increase than for non–Spanish-speaking families (interaction IRR, 1.8; 95% CI, 1.0-3.1;<i>P</i> = .005). Exploratory analyses revealed that screening was associated with a larger increase in the rate of ASD diagnoses among boys (IRR, 1.8; 95% CI, 1.4-2.3;<i>P</i> &lt; .001) than among girls (IRR, 1.1; 95% CI, 0.6-1.7;<i>P</i> = .84). <h3>Conclusions and Relevance</h3> In this study, associations between increased rates of ASD diagnoses and reductions in disparities for Spanish-speaking households support the effectiveness of multistage screening in EI. This study provides a comprehensive evaluation of ASD screening in EI settings as well as a rigorous evaluation of ASD screening in any setting with a no-screening comparison condition. Given that the intervention included multiple components, mechanisms of action warrant further research, as do disparities by child sex.
Effect of <i>Lactobacillus rhamnosus</i> GG on Incident Pneumonia in Critically Ill Patients—Reply
Authors: Jennie Johnstone, Diane Heels-Ansdell, Deborah Cook
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
Just Words
Authors: Alexander Gode
Journal: JAMA (1963)

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
Survival in total preoperative verus perioperative chemotherapy for patients with metastatic high-grade appendiceal adenocarcinoma undergoing CRS/HIPEC.
Authors: Ryan B. Morgan, Allie Yan, Ankit Dhiman, Divya Sood, Cecilia T. Ong, Xiaoyang Wu, Ardaman Shergill, Blase N. Polite, Kiran Turaga, Oliver Eng
Journal: Journal of Clinical Oncology (2022)

90 Background: Due to the relative infrequency of high grade appendiceal adenocarcinoma with peritoneal metastases, there is limited data to guide treatment strategies. Current practices for this disease are largely extrapolated from colon cancer patients with peritoneal metastases, who typically undergo six months of systemic chemotherapy in conjunction with cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). The optimal timing of chemotherapy in relation to CRS/HIPEC remains unknown. In this study, we compare the efficacy of peri-operative chemotherapy to pre-operative chemotherapy alone. Methods: This is a retrospective review of patients who underwent CRS/HIPEC for high grade appendiceal cancers from a tertiary referral center from 2014-2020. Outcomes were compared between patients who underwent planned 6 months of chemotherapy followed by CRS/HIPEC (pre-operative group) versus planned 3 months of chemotherapy both pre- and post-operatively (peri-operative group). Results: 85 patients were treated for metastatic high-grade appendiceal cancers during the study period, of whom24 were eligible for inclusion. Of those included, 16 were in the peri-operative group and 8 in the pre-operative group. Most patients were white (75%), non-Hispanic (96%) and female (54%). Patients in the pre-operative group tended to be older (65 vs. 56 years, p = 0.02). For patients with specified histologic grading, poorly differentiated tumors were common (50%). Signet ring cell histology (42%) and mucinous features (67%) were frequent as well. Median overall survival was similar between the pre-operative and peri-operative groups (32.3 vs. 31.6 months, p = 0.97), although patients undergoing peri-operative treatment received fewer total cycles of chemotherapy on average (14.1 vs. 9.5 cycles, p &lt; 0.01). Half of the patients in the peri-operative group (8/16) did not complete their chemotherapy regimen, with 75% discontinuing therapy due to chemotherapy-related toxicities. Within the peri-operative group, a non-significant decrease in median survival was observed for those who did not complete chemotherapy (27.8 vs &gt; 53.6 months, p = 0.22). Conclusions: Peri-operative and total pre-operative chemotherapy strategies are associated with similar survival in patients with high grade appendiceal cancers undergoing CRS/HIPEC. Peri-operative administration may be limited by chemotherapy-related toxicities.