tbuckley/cabot-search huggingface dataset:
Downregulation of BK channel function and protein expression in coronary arteriolar smooth muscle cells of type 2 diabetic patients
Authors: Tong Lu, Qiang Chai, Guoqing Jiao, Xiao-Li Wang, Xiaojing Sun, Jonathan D Furuseth, John M Stulak, Richard C Daly, Kevin L Greason, Yong-Mei Cha, Hon-Chi Lee
Journal: Cardiovascular Research (2018)

Type 2 diabetes (T2D) is strongly associated with cardiovascular morbidity and mortality in patients. Vascular large conductance Ca2+-activated potassium (BK) channels, composed of four pore-forming α subunits (BK-α), and four regulatory β1 subunits (BK-β1), are densely expressed in coronary arterial smooth muscle cells (SMCs) and play an important role in regulating vascular tone and myocardial perfusion. However, the role of BK channels in coronary microvascular dysfunction of human subjects with diabetes is unclear. In this study, we examined BK channel function and protein expression, and BK channel-mediated vasodilation in freshly isolated coronary arterioles from T2D patients.Atrial tissues were obtained from 16 patients with T2D and 25 matched non-diabetic subjects during cardiopulmonary bypass procedure. Microvessel videomicroscopy and immunoblot analysis were performed in freshly dissected coronary arterioles and inside-out single BK channel currents was recorded in enzymatically isolated coronary arteriolar SMCs. We found that BK channel sensitivity to physiological Ca2+ concentration and voltage was downregulated in the coronary arteriolar SMCs of diabetic patients, compared with non-diabetic controls. BK channel kinetics analysis revealed that there was significant shortening of the mean open time and prolongation of the mean closed time in diabetic patients, resulting in a remarkable reduction of the channel open probability. Functional studies showed that BK channel activation by dehydrosoyasaponin-1 was diminished and that BK channel-mediated vasodilation in response to shear stress was impaired in diabetic coronary arterioles. Immunoblot experiments confirmed that the protein expressions of BK-α and BK-β1 subunits were significantly downregulated, but the ratio of BK-α/BK-β1 was unchanged in the coronary arterioles of T2D patients.Our results demonstrated for the first time that BK channel function and BK channel-mediated vasodilation were abnormal in the coronary microvasculature of diabetic patients, due to decreased protein expression and altered intrinsic properties of BK channels.
Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve
Authors: Norihito Uemura, Hisashi Yagi, Maiko T. Uemura, Yusuke Hatanaka, Hodaka Yamakado, Ryosuke Takahashi
Journal: Molecular Neurodegeneration (2018)

Intraneuronal α-synuclein (α-Syn) aggregates known as Lewy bodies (LBs) and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the pathological hallmarks of Parkinson's disease (PD). Braak's hypothesis based on autopsy studies suggests that Lewy pathology initially occurs in the enteric nervous system (ENS) and then travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX), proceeding from there in a caudo-rostral direction. Recent evidence that α-Syn aggregates propagate between interconnected neurons supports this hypothesis. However, there is no direct evidence demonstrating this transmission from the ENS to the dmX and then to the SNpc. We inoculated α-Syn preformed fibrils (PFFs) or phosphate-buffered saline (PBS) into the mouse gastric wall and analyzed the progression of the pathology. The mice inoculated with α-Syn PFFs, but not with PBS, developed phosphorylated α-Syn (p-α-Syn)–positive LB-like aggregates in the dmX at 45 days postinoculation. This aggregate formation was completely abolished when vagotomy was performed prior to inoculation of α-Syn PFFs, suggesting that the aggregates in the dmX were retrogradely induced via the vagus nerve. Unexpectedly, the number of neurons containing p-α-Syn–positive aggregates in the dmX decreased over time, and no further caudo-rostral propagation beyond the dmX was observed up to 12 months postinoculation. P-α-Syn–positive aggregates were also present in the myenteric plexus at 12 months postinoculation. However, unlike in patients with PD, there was no cell-type specificity in neurons containing those aggregates in this model. Conclusions: These results indicate that α-Syn PFF inoculation into the mouse gastrointestinal tract can induce α-Syn pathology resembling that of very early PD, but other factors are apparently required if further progression of PD pathology is to be replicated in this animal model.
Increased access for and enhancement of cancer (ca) patients (pts) participation (par) in clinical trials (cts) by alleviation of financial toxicity.
Authors: Edith P. Mitchell, Dana Dornsife
Journal: Journal of Clinical Oncology (2018)

24 Background: Prognosis for pts is increasing as a result of advances in cts. However, the degree to which cancer caused financial problems may influence ca pts par in cts and negatively impact quality of life. Excess financial burden of cts par, may include finding an appropriate trial, traveling to the trial site, travel costs, lodging and medical expenses. The Lazarex Cancer Foundation (LCF) was founded in 2006 with mission to improve care, giving hope, dignity, and life to advanced ca pts by providing assistance with options and costs to cts par, community outreach, and education. LCF developed processes to removing the barriers to cts par by improving equitable access to cancer care, increasing cts enrollment, retention and minority par, and increasing cts referrals. Methods: To determine the extent of benefit of LCF, we conducted a retrospective analysis of LCF beneficiaries participating in cts by reviewing and summarizing the number of pts, states and countries of residence, age, type of cancer, location and distance to cts site, type of assistance, and number of advocacy/outreach. Results: From 1/01/2010 – 12/31/2016 2179 pts were assisted financially; age range 1-102 yrs, median 50-60; (43%) male, (53%) female, (3.4%) undeclared. (6.4%) were African American, 10.3% Hispanic, 3.6 Asian Pacific Islander, other minority 2.1, and Caucasian 72.7%;total minority 22.5%. Pts resided in 50 states with largest CA , TX , MA , and FL. Cts were at 199 sites – 43 NCI CCC, 7 NCI DCC and 149 other cancer centers. Most common diagnoses were breast, leukemia, colorectal cancers. type tumors. Median household income was $75,000. Financial assistance to travel to and living expenses at the cts site was the most frequently identified need. Conclusions: Relieving pts of financial burden allows greater access to and participation in cancer clinical trials. Further research and greater resources are needed to define patient needs and determine methods to eliminate barriers to enrollment and retention investigate coverage thresholds that minimize adverse financial outcomes and identify ca pts at greatest risk for financial toxicity to increase par in cts.
Questioning the Associations of ω-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks
Authors: Savina Nodari, Javed Butler, Pier Luigi Temporelli
Journal: JAMA Cardiology (2018)

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
Pilot study of gemcitabine, nab-paclitaxel, PEGPH20, and rivaroxaban for advanced pancreatic adenocarcinoma: An interim analysis.
Authors: Kenneth H. Yu, Simon Mantha, Catherine Tjan, Erica S. Kaufmann, Robin Brenner, Maeve Aine Lowery, Geoffrey Yuyat Ku, Nitya Prabhakar Raj, Marina Shcherba, Zoe Goldberg, Jia Li, Alice Zervoudakis, Audrey M. Hamilton, Elizabeth Won, Antonio Ucar, Richard K. G. Do, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2018)

405 Background: PEGPH20 (P) degrades hyaluronan (HA), a key component of pancreatic adenocarcinoma (PDAC) tumor microenvironment, leading to reduction of tumor interstitial pressure, decompression of tumor blood vessels and improvement in delivery of chemotherapeutics. A prior study of P with chemotherapy in PDAC (HALO-202) found an increased risk of thromboembolic (TE) events, 43%, effectively reduced with subcutaneous enoxaparin treatment. Rivaroxaban (R) is a safe and effective oral anticoagulant for treating cancer-related TE. Methods: 28 patients with advanced PDAC, KPS ≥ 70 and without prior TE were enrolled from January to June 2017. Patients received treatment with PAG (P; 3 µg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus AG) every 28 days, with R (15 mg twice daily for 21 days, followed by 20 mg once daily). Primary endpoint is symptomatic TE event rate; secondary endpoints include PFS, OS, major bleeding rate and RR. Results: All 28 patients are evaluable for efficacy and safety. Key patient characteristics: age = 62 (range 45-76), M/F = 15/13, stage III/IV = 4/24, KPS 70/80/90 = 1/13/14. Median follow-up is 5.4 mo. No symptomatic and one grade 2, asymptomatic TE event (DVT) occurred (1/28 = 3.6%). Two grade 3 GI hemorrhages occurred. Best responses: partial response 11 (39%), stable disease 13 (46%), progressive disease 4 (14%), and overall disease control rate of 86%. Median PFS and OS have not been reached. Conclusions: Interim analysis shows R is safe and effectively prevents TE events in patients receiving PAG. Responses and disease control rate are encouraging in this tumor HA-level unselected patient population. Updated safety and efficacy data will be reported. Clinical trial information: NCT02921022.
Women's Health Policy in the United States: An American College of Physicians Position Paper
Authors: Hilary Daniel, Shari M. Erickson, Sue S. Bornstein
Journal: Annals of Internal Medicine (2018)

In this position paper, the American College of Physicians (ACP) examines the challenges women face in the U.S. health care system across their lifespans, including access to care; sex- and gender-specific health issues; variation in health outcomes compared with men; underrepresentation in research studies; and public policies that affect women, their families, and society. ACP puts forward several recommendations focused on policies that will improve the health outcomes of women and ensure a health care system that supports the needs of women and their families over the course of their lifespans.
Abstract 17284: Metabolomic Effects of Statin Therapy, Ezetimibe and PCSK9-Inhibition: Comparison by Genetic Evidence
Authors: Peter Wurtz, Qin Wang, Eeva Sliz, Johannes Kettunen, George Davey Smith, Mika Ala-Korpela
Journal: Circulation (2016)

Aim:  LDL cholesterol is the primary target for cardiovascular prevention. Statins are first-line therapy, but also other LDL lowering drugs are approved: ezetimibe and PCSK9-inhibitors. We aimed to compare the metabolomic profiles of these 3 drug targets via genetic proxies in  HMGCR ,  NPC1L1 , and  PCSK9 . We have recently shown that metabolomics of statin therapy provides insights into the drug mechanisms and potential side-effects ( J Am Coll Cardiol  2016;67:1200).   Hypothesis:  We hypothesized that  NPC1L1  and  PCSK9  give rise to similar lipoprotein subclass and fatty acid effects as  HMGCR  for a similar lowering in LDL-C. We also assessed how  NPC1L1  and  PCSK9  affect VLDL-cholesterol and many novel biomarkers for type 2 diabetes.   Methods:  123 metabolic measures quantified by nuclear magnetic resonance metabolomics were assessed for n~20,000 individuals with genotype data ( Nat Commun  2016;7:11122). The effects of genetic variants in  HMGCR ,  NPC1L1 , and  PCSK9  were compared to statin effects on lipoprotein subclasses, fatty acids and small molecules including amino acids and glycolysis biomarkers.   Results:  Ezetimibe mimicking genotypes caused similar lipoprotein subclass effects as statin therapy, including substantial lowering of VLDL and remnant cholesterol. In contrast, the effects of PCSK9 genotypes were more specific to LDL lipids. Substantial differences in the 3 drug targets were observed for omega-3 and omega-6 fatty acid effects. No robust side-effects on amino acids or glycemic precursors were observed. The 3 drugs had similar modest effects on inflammation.   Conclusions:  Based on genetic evidence, lowering of LDL cholesterol by ezetimibe and PCSK9-inhibition results in broadly similar metabolic effects as statin therapy; however, PCSK9-inhibition appears to be less efficacious for lowering triglyceride-rich lipoproteins. Metabolomic characterization of genetic proxies for drug targets can inform pharmacological mechanisms and side-effects.
Wait Time for Hip Fracture Surgery and Mortality
Authors: Skerdi Haviari
Journal: JAMA (2018)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Detection, dynamic monitoring, and resistance mechanism exploration of genomic alterations in circulating cell free tumor DNA (ctDNA) in Chinese metastatic breast cancer (mBC).
Authors: Huiping Li, Jianjun Yu, Xiao-Ran Liu, Amy Wang, Zhixin Zhao, Tak Cheung, Wei-Jie Shi, Yue Zhang, Phoebe Zhang, Meng-Yao Tan, Peter Du, Wei-yao Kong, Ya-Xin Liu, Jia-yang Zhang, Ying Yan, Shidong Jia
Journal: Journal of Clinical Oncology (2018)

1080 Background: Circulating DNA fragments (ctDNA) are using to longitudinal non-invasive molecular monitoring and resistance mechanism interrogation of the disease by detecting genomic alteration change and clonal evolution including somatic mutation and copy number alteration. Methods: We performed a retrospective analysis of blood samples from mBC patients (pts) collected at pre-treatment, on-treatment, and disease progression. A highly sensitive, plasma-derived ctDNA-based NGS assay was conducted to detect somatic mutations and copy number variations using pre-specified algorithms. Descriptive statistics and hypothesis tests were performed in R. Results: Total 350 blood samples were collected from 160 mBC pts who undertook therapy at Beijing cancer hospital after approved by Research Ethics Committee. Among these pts, the percent of HR+, HER2+ and triple-negative pts is 45%, 27% and 28% respectively. FFPE tissue slides at initial diagnosis were also available for a subset of pts. The most frequent mutations detected are TP53 (40%), PIK3CA (30%), and CDKN2A (12.5%). 24% showed mutations in DNA damage repair such as BRCA1, BRCA2 and ATM. HER2 copy number amplifications was detected amplification events in all IHC-based HER2 positive cases, resulted in 100% specificity and overall 91% accuracy in predicting HER2 amplification status for pre-treatment baseline samples, only a few on-treatment/disease progression samples detected HER2 amplifications. The result is further confirmed and validated by ddPCR assay. The study also identified additional genomic alterations that change dynamically along with the course of treatment or associate with drug response and/or resistance. Conclusions: This study showed ctDNA-based genomic analysis was highly sensitive, and consistent with sequencing data generated from matched tissues. it provides comprehensive mutation information of individual pts, enables molecular monitoring of disease and targeted therapy, suggesting that HER2 copy number variations could serve as a value tool for monitoring of treatment effect and disease progression.
Abstract 12861: Assessment of Both Coronary Microvascular Damage and Epicardial Flow Velocity Measurement Immediately After Successful Percutaneous Coronary Intervention Predicts In-Hospital Complications and Survival in ST-Segment Elevation Myocardial Infarction
Authors: Atsushi Yamamuro, Koichi Tamita, Junichi Yoshikawa, Kaji Shuichiro, Yutaka Furukawa
Journal: Circulation (2016)

Background: Quantitative measurement of post-reperfusion epicardial flow velocity by a Doppler guidewire can predict clinical cardiac events in ST-segment elevation myocardial infarction (STEMI). It has also been reported that the coronary flow velocity pattern in patients with microvascular obstruction is characterized by the presence of early systolic retrograde flow and a rapid diastolic deceleration time (DDT). The purpose of this study was to examine the role of assessing both epicardial flow velocity and microvascular damage in the prediction of in-hospital complications and survival after percutaneous coronary intervention (PCI). Methods: Two hundred and fifty-one consecutive patients with first anterior STEMI who underwent successful PCI were subjected to coronary flow measurement with a Doppler guidewire. The coronary flow velocity spectrum provided the following parameters: time-averaged peak velocity (cm/s, APV), systolic peak velocity (cm/s) and DDT (ms). We defined the presence of microvascular obstruction as DDT ≤600 ms and the presence of systolic flow reversal, and slow epicardial flow as resting APV ≤10cm/s. We classified the patients into three categories: without microvascular obstruction (group 1, n=140), with microvascular obstruction and normal epicardial flow (group 2, n= 51, with microvascular obstruction and slow epicardial flow (group 3, n=60). The clinical event rate was compared among the 3 groups. Results: The in-hospital event rates for congestive heart failure (15/140 [11%], 15/51 [29%] and 34/60 [57%], respectively; P &lt; 0.01), left ventricular thrombus (3/140 [2%], 9/51 [18%] and 14/60 [23%], respectively; P &lt; 0.01), and cardiac rupture (0/140 [0%], 5/51 [10%], and 16/60 [27%]; P &lt; 0.01) were highest in group 3 and lowest in group 1. Group 3 was at the highest risk of cardiac death, while group 1 was at the lowest (0/140 [0%], 3/51 [6%], and 12/60 [20%]; P &lt; 0.01). Conclusions: Assessment of both coronary microvascular damage and epicardial flow velocity can accurately predict in-hospital complications and survival in STEMI patients who underwent successful reperfusion of the infarct-related coronary artery, identifying a subset of high risk patients.
Efficacy and safety of rovalpituzumab tesirine in patients With DLL3-expressing, ≥ 3<sup>rd</sup> line small cell lung cancer: Results from the phase 2 TRINITY study.
Authors: David Paul Carbone, Daniel Morgensztern, Sylvestre Le Moulec, Rafael Santana-Davila, Neal Ready, Christine L. Hann, Bonnie S. Glisson, Afshin Dowlati, Charles M. Rudin, Satwant Lally, Sreeni Yalamanchili, Juergen Wolf, Ramaswamy Govindan, Benjamin Besse
Journal: Journal of Clinical Oncology (2018)

8507 Background: Small cell lung cancer (SCLC) accounts for ~15% of lung cancer with no approved therapies in ≥ 3rd line (3L) patients (pts). In 3L pts, historical data demonstrate a median overall survival (mOS) of 4.7 mo and a best overall response of 18%; no historical data exist for objective response rate (ORR). Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting Delta-like 3 protein (DLL3), an atypical Notch ligand that is highly expressed in SCLC but not normal tissue. A Ph1 study showed that Rova-T has antitumor activity in pts with recurrent SCLC and high DLL3 expression, and a manageable safety profile. Methods: TRINITY was an open-label, single-arm, Ph2 study of Rova-T in adult pts with DLL3-expressing SCLC (NCT02674568). Eligibility: ≥ 2 prior systemic regimens including ≥ 1 platinum-based regimen; ECOG 0-1; stable CNS disease. Pts received 0.3 mg/kg Rova-T intravenously on Day 1 of a 6-week cycle for 2 cycles. DLL3-high (hi) pts had ≥ 75% tumor cells positive by immunohistochemistry; DLL3-positive (pos) pts had ≥ 25%. Primary endpoints: confirmed ORR, overall survival (OS). Results: Interim analysis (6 Oct 17) included 199 pts, of which 64% were 3L. Common drug-related adverse events (AEs) were fatigue (32%), photosensitivity (31%), pleural effusion (26%), peripheral edema (26%), thrombocytopenia (23%). Drug-related Grade 3/4 AEs were thrombocytopenia (15%), photosensitivity (7%), pleural effusion (7%), fatigue (5%). In DLL3-hi 3L pts, median progression-free survival (mPFS) = 4.1 mo, mOS = 6.7 mo. Conclusions: Rova-T demonstrated antitumor activity and a favorable benefit:risk profile in ≥ 3L SCLC pts, with clinically meaningful mOS and mPFS. Updated analysis will be shown at presentation. Clinical trial information: NCT02674568.n (%) DLL3-hi DLL3-pos 3L N = 85 ≥ 3L N = 140 3L N = 103 ≥ 3L N = 165 Best Overall Response IA 27 (32) 39 (28) 31 (30) 45 (27) IRC 24 (28) 32 (23) 27 (26) 36 (22) ORR IA 20 (24) 30 (21) 23 (22) 35 (21) IRC 15 (18) 20 (14) 17 (17) 23 (14) Clinical Benefit Rate* IA 59 (69) 100 (71) 67 (65) 111 (67) IRC 60 (71) 105 (75) 67 (65) 117 (71) IA, investigator assessment; IRC, independent radiology committee*complete response + partial response + stable disease