tbuckley/cabot-search huggingface dataset:
Phase 2 randomized study of a walking intervention for radiation-related fatigue among older breast cancer patients receiving radiation.
Authors: Noam Avraham VanderWalde, Michelle Y. Martin, Mehmet Kocak, Catherine Morningstar, Allison Mary Deal, Kirsten A Nyrop, Michael Farmer, Matthew T. Ballo, David L. Schwartz, Hyman B. Muss
Journal: Journal of Clinical Oncology (2018)

10037 Background: This study's purpose is to determine if an exercise intervention can decrease fatigue in older women receiving radiotherapy (RT) for breast cancer. Methods: A phase 2 randomized study was conducted in women age ≥ 65 years with breast cancer receiving adjuvant RT. After informed consent, women were randomized to the intervention arm; the Walk with Ease (WWE) pamphlet, or the usual care arm (UC); a document describing the benefit of moderate exercise. Prior to RT patients completed an objective assessment of physical function using the Short Physical Performance Battery (SPPB), and questionnaires to assess fatigue, physical function, and other fatigue-related symptoms. All assessments were repeated at last week of radiotherapy and 1 month follow up. The primary outcome was change in fatigue as measured by the Total Disruption Index (TDI) of the Fatigue Symptom Index (FSI) over time. Secondary outcomes include change in level of activity (based on self-reported walking log), change in physical function as measured by the SPPB, and change in fatigue related symptoms. A Repeated Measures Mixed Linear Model was used to describe the change in outcomes over time. Results: Of the 54 patients accrued, 50 had complete data. Median age was 69 years (range 65-84). With the exception of hormone status, the baseline criteria were similar between study arms. Longitudinal modeling revealed no significant change over time in TDI between the two arms (p-value = 0.79). However, these models revealed that increasing walking over time was associated with lower levels of fatigue (p = 0.04). Number of minutes walking per week increased in both arms (45 min/wk baseline to 432 min/wk end of RT, p < 0.01) and physical function improved statistically over time in both arms (p < 0.01) and both remained improved at follow up (p-value = 0.01 and < 0.01 respectively). Conclusions: This study demonstrated no benefit in fatigue with the WWE program. However, women in both arms increased their walking and had improved physical function during and following RT. Increased walking was statistically associated with lower fatigue scores during and after radiotherapy in this older group of women with breast cancer. Clinical trial information: NCT02434367.
The Course of Lung Function in Middle-aged Heavy Smokers: Incidence and Time to Early Onset of Chronic Obstructive Pulmonary Disease
Authors: Hans Petersen, Akshay Sood, Francesca Polverino, Caroline A. Owen, Victor Pinto-Plata, Bartolomé R. Celli, Yohannes Tesfaigzi
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Liver Transplant Listing in Pediatric Acute Liver Failure: Practices and Participant Characteristics
Authors: James E. Squires, David A. Rudnick, Regina M. Hardison, Simon Horslen, Vicky L. Ng, Estella M. Alonso, Steven H. Belle, Robert H. Squires
Journal: Hepatology (2018)

Liver transplant (LT) decisions in pediatric acute liver failure (PALF) are complex. Three phases of the PALF registry, containing data on 1,144 participants over 15 years, were interrogated to characterize clinical features associated with listing status. A decrease in the cumulative incidence of listing (P < 0.005) and receiving (P < 0.05) LT occurred without an increase in the cumulative incidence of death (P = 0.67). Time to listing was constant and early (1 day; quartiles 1-3 = 0-2; P = 0.88). The most frequent reasons for not listing were "not sick enough" and "medically unsuitable." Participants listed for LT were more likely male, with coma grade scores >0; had higher international normalized ratio, bilirubin, lactate, and venous ammonia; and had lower peripheral lymphocytes and transaminase levels compared to those deemed "not sick enough." Participants listed versus those deemed "medically unsuitable" were older; had higher serum aminotransferase levels, bilirubin, platelets, and albumin; and had lower lactate, venous ammonia, and lymphocyte count. An indeterminate diagnosis was more prevalent in listed participants. Ventilator (23.8%) and vasopressor (9.2%) support occurred in a significant portion of listed participants but less frequently than in those who were not "medically suitable." Removal from the LT list was a rare event. Conclusion: The cumulative incidence of listing for and receiving LT decreased throughout the PALF study without an increase in the cumulative incidence of death. While all participants fulfilled entry criteria for PALF, significant differences were noted between participants listed for LT and those deemed "not sick enough" as well as those who were "medically unsuitable." Having an indeterminate diagnosis and a requirement for cardiopulmonary support appeared to influence decisions toward listing; optimizing listing decisions in PALF may reduce the frequency of LT without increasing the frequency of death.
Angiotensin II–Induced Ca2+ Influx in Renal Afferent and Efferent Arterioles
Authors: KathyLoutzenhiser, RodgerLoutzenhiser
Journal: Circulation Research (2000)

Abstract—Angiotensin II (Ang II)–induced Ca2+ signaling was studied in isolated rat renal arterioles using fura-2. Ang II (10 nmol/L) caused a sustained elevation in [Ca2+]i, which was dependent on [Ca2+]o in both vessel types. This response was blocked by nifedipine in only the afferent arteriole. Using the Mn2+ quench technique, we found that Ang II stimulates Ca2+ influx in both vessels. Nifedipine blocked the Ang II–induced Ca2+ influx in afferent arterioles but not in efferent arterioles. In contrast to Ang II, KCl-induced depolarization stimulated Ca2+ influx in only the afferent arteriole. Cyclopiazonic acid (CPA, 30 μmol/L) was used to examine the presence of store-operated Ca2+ entry in myocytes isolated from each arteriole. In efferent myocytes, CPA induced a sustained Ca2+ increase that was dependent on [Ca2+]o and insensitive to nifedipine. This mechanism was absent in afferent myocytes. SKF 96365 inhibited Ang II–induced Ca2+ entry in efferent arterioles and CPA-induced Ca2+ entry in efferent...
Abstract 17970: Cardiac Specific Overexpression of Histone Deacetylase 4 Aggravates High Fat Diet-Induced Cardiac Dysfunction and Metabolic Disorders
Authors: Jianfeng Du, Ling Zhang, Hao Wang, Yu T Zhao, Naohiro Yano, Ting C Zhao
Journal: Circulation (2016)

Introduction: Histone deacetylase are recently identified as key regulators for cardiac pathophysiology and metabolic disorders. However, the function of this specific HDAC isoform in the heart con...
Response to Letter Regarding Article, “Left Ventricular Versus Simultaneous Biventricular Pacing in Patients With Heart Failure and a QRS Complex >120 Milliseconds”
Authors: BernardThibault, AniqueDucharme, FrançoisHarel, MichelWhite, EileenO'Meara, JoelLavoie, MarcDubuc, PeterGuerra, LaurentMacle, LénaRivard, DenisRoy, MarioTalajic, PaulKhairy, Marie-ClaudeGuertin, NancyFrasure-Smith
Journal: Circulation (2012)
Abstract 14862: Gender Differences in Impact of CYP2C19 Polymorphism and Low Grade Inflammation on Coronary Microvascular Disease
Authors: TomonoriAkasaka, SeijiHokimoto, NoriakiTabata, KenjiSakamoto, KenichiTsujita, SunaoKojima, KoichiKaikita, HisaoOgawa
Journal: Circulation (2014)

Background: Specific CYPs localized in vascular smooth muscle and endothelium contribute to the regulation of vascular tone and homeostasis. CYP2C19 two loss-of-function alleles (PM) were found to be an independent risk factor for diabetic retinopathy, and PM is associated with the coronary spasm especially in female. However, it is unknown whether CYP2C19 genotype is associated with the coronary microvascular disease. The aim was to evaluate the impact of CYP2C19 genotype on coronary microvascular disease. Methods: We examined CYP2C19 genotype in patients with microvascular disease (n=40) who were diagnosed by intra-coronary acetylcholine infusion test and healthy subjects (n=455) as control group. We defined the coronary microvascular disease that have no epicardial spasm and have angina, ischemic ECG changes, reduced coronary blood flow, or inversion of lactic acid level between intra-coronary and coronary sinus. CYP2C19 genotypes were divided into 3 groups; (1) CYP2C19*1/*1: EM, (2) one loss-of-functi...
Abstract 4591: Integration of genomic analysis and assessment of pre-analytic variables in the HD-SCA workflow: A technical validation study
Authors: Stephanie Nicole Shishido, Mariam Rodriguez_Lee, Anand Kolatkar, Liya Xu, Sara Restrepo-Vassalli, Lisa Welter, Anders Carlsson, Emily Greenspan, Shelley Hwang, Kathryn Waitman, Jorge Nieva, Kelley Bethel, James Hicks, Peter Kuhn
Journal: Cancer Research (2018)

Abstract The liquid biopsy allows assessment of multiple biological analytes over time to provide dynamic temporal information with the potential for improving clinical management and guiding treatment decisions. While the promise of liquid biopsies for prediction and response monitoring are intensely investigated, the pre-analytic variables are of primary concern for its implementation in diagnostic clinical medicine, including such categories as collection method, shipping conditions, and sample storage. Here we utilize an integrated high-definition single cell analysis (HD-SCA) workflow for genomic analysis of rare cells and cfDNA from the liquid biopsy to characterize the effects of pre-analytical variation and reproducibility of data analysis from the same cohort of patients. The results presented here confirm consistent rare cell enumeration and morphometric characterization between 24h and 48h time to assay (TTA), with a high efficiency and capacity for both copy number variation (CNV) and single nucleotide variation (SNV) analysis at the single cell level. Additionally, the freezing process neither diminishes or increases the DNA quantity, nor does it affect the DNA quality for CNV or SNV analysis. The integration of genomic information is imperative to reveal essential disease-implicated mutational profiles, but effective molecular diagnostic tests require reproducible coverage over a broad dynamic range. The performance of the HD-SCA platform quantified here may be utilized as a guide for implementation into patient care and/or research biorepository processes. Citation Format: Stephanie Nicole Shishido, Mariam Rodriguez_Lee, Anand Kolatkar, Liya Xu, Sara Restrepo-Vassalli, Lisa Welter, Anders Carlsson, Emily Greenspan, Shelley Hwang, Kathryn Waitman, Jorge Nieva, Kelley Bethel, James Hicks, Peter Kuhn. Integration of genomic analysis and assessment of pre-analytic variables in the HD-SCA workflow: A technical validation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4591.
Abstract 5802: Efficacy of PI3Kβ inhibitor AZD8186 in PTEN-deficient triple-negative breast cancer
Authors: Nicci Owusu-Brackett, Ming Zhao, Argun Akcakanat, Kurt W. Evans, Erkan Yuca, Funda Meric-Bernstam
Journal: Cancer Research (2018)

Abstract Background: Phosphatase and tensin homologue (PTEN) loss is a frequently disrupted tumor suppressor in cancer. PTEN serves as a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to promote balanced cell proliferation, survival and differentiation. Consequently, loss of PTEN function increases cell proliferation, decreases cell death and contributes to tumor initiation. PTEN loss occurs across a variety of cancer subtypes, and these PTEN deficient tumors are dependent on PI3Kβ activity. As a result, therapeutic approaches that focus on the inhibition of PI3Kβ isoform in PTEN-null cells are of interest. We evaluate the efficacy of PI3Kβ inhibitors focused on triple negative breast cancers with loss of PTEN function. Methods: We studied the effects of p110β inhibitor AZD8186 in a panel of ten TNBC cell lines, which included four PTEN-mutant cell lines. Three of four cell lines were confirmed to have PTEN loss on western blot. In vitro, cell proliferation assays were performed to determine the half maximal inhibitory concentration (IC50) after 3 days of treatment and to test the effects in combination with chemotherapy. We confirmed the sensitivity of the PTEN-null cell lines to AZD8186 with colony formation assays. Western blot analysis was performed to assess PTEN expression and PI3K pathway activation in MDA-MB-436 and MDA-MB-468 cell lines, and to evaluate effects of AZD8186 on PI3K signaling. Results: Cell lines with PTEN loss were significantly more sensitive to AZD8186 in vitro (p= 0.008). AZD8186 inhibited PI3K signaling. Western blot revealed decreased activation of pAKT, pGSK3β, pPRAS40 and pS6. Activation of other pathways were evaluated with no activation of the MAPK/ERK or MEK pathways appreciated. AZD8186 treatment resulted in increased apoptosis but did not have a significant effect on cell-cycle progression in PTEN-deficient cell lines. AZD8186 was not synergistic with eribulin, paclitaxel or carboplatin; combinations with novel targeted therapies in vitro and in vivo are ongoing. Conclusion: AZD8186 had single agent efficacy in PTEN-deficient triple negative breast cancer cell lines in vitro. Further study is needed to identify rationale combinations and in vivo efficacy. Citation Format: Nicci Owusu-Brackett, Ming Zhao, Argun Akcakanat, Kurt W. Evans, Erkan Yuca, Funda Meric-Bernstam. Efficacy of PI3Kβ inhibitor AZD8186 in PTEN-deficient triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5802.
Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice
Authors: JunichiOmura, KimioSatoh, NobuhiroKikuchi, TaijyuSatoh, RyoKurosawa, MasamichiNogi, TomohiroOtsuki, KatsuyaKozu, KazuhikoNumano, KotaSuzuki, ShinichiroSunamura, ShunsukeTatebe, TatsuoAoki, KoichiroSugimura, SatoshiMiyata, YasushiHoshikawa, YoshinoriOkada, HiroakiShimokawa
Journal: Circulation Research (2016)

Rationale:Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated. Objective:To determine the role of endothelial AMPK in the development of PAH. Methods and Results:Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK-knockout mice (eAMPK–/–), which were exposed to hypoxia. Under normoxic condition, eAMPK–/– mice showed the normal morphology of pulmonary arteries compared with littermate controls (eAMPKflox/flox). In contrast, development of hypoxia-induced PH was accelerated in eAMPK–/– mice compared with controls. Furthermore, the exacerbation of PH in eAMPK–/– mice was accompanied by reduced endoth...
Abstract 1086: Phosphoproteomic analysis of signaling pathways driving bone metastasis in prostate cancer
Authors: Benjamin Abbott, Andrew Pierce, Anthony D. Whetton, Paul A. Townsend
Journal: Cancer Research (2018)

Abstract Osteoblasts play a fundamental role in prostate cancer bone metastasis, whereby dysregulated bone remodelling results in bone pain, fractures and increased mortality. Although it remains unclear how early on in the disease pathway prostate cancer cells populate the endosteal niche, osteoblasts almost certainly play a role in the homing of tumor cells to this microenvironment. In support of this, prostate cancer cells have been shown to home to osteoblast-rich areas in animal models of bone metastasis and human prostate cancer bone metastases are typically osteoblastic on radiography. We have shown that conditioned medium from mature, mineralising human hFOB1.19 osteoblasts (hFOB-CM) is rich in pro-inflammatory cytokines including IL-6, IL-8 and various chemokine ligands. hFOB-CM promotes a strong migratory and invasive phenotype in a panel of prostate cancer cell lines (including androgen-sensitive and -insensitive lines), with invading cells displaying increased actomyosin contractility and amoeboid-like traits, namely a rounded cell morphology, cytoskeletal reorganization and phosphorylation of myosin light chain. We now aim to comprehensively interrogate the intracellular signaling pathways driving endosteal homing in prostate cancer cells by systems-wide ITRAQ mass spectrometry-based phosphoproteomic analysis of prostate cancer cells treated with hFOB-CM. This approach will identify individual signaling pathways or combinations of pathways to target with existing kinase inhibitors to inhibit osteoblast-driven invasion and endosteal homing during prostate cancer metastasis. Ultimately, targeting tumor cell responses to stromal signals may prove critical in the search for better therapies to treat this frequently lethal disease. Citation Format: Benjamin Abbott, Andrew Pierce, Anthony D. Whetton, Paul A. Townsend. Phosphoproteomic analysis of signaling pathways driving bone metastasis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1086.
Evidence for cAMP-Independent Mechanisms Mediating the Effects of Adrenomedullin, a New Inotropic Peptide
Authors: IstvánSzokodi, PietariKinnunen, PasiTavi, MattiWeckström, MiklósTóth, HeikkiRuskoaho
Journal: Circulation (1998)

Background—Adrenomedullin (ADM), a new vasorelaxing and natriuretic peptide, may function as an endogenous regulator of cardiac function, because ADM and its binding sites have been found in the heart. We characterize herein the cardiac effects of ADM as well as the underlying signaling pathways in vitro. Methods and Results—In isolated perfused, paced rat heart preparation, infusion of ADM at concentrations of 0.1 to 1 nmol/L for 30 minutes induced a dose-dependent, gradual increase in developed tension, whereas proadrenomedullin N-20 (PAMP; 10 to 100 nmol/L), a peptide derived from the same gene as ADM, had no effect. The ADM-induced positive inotropic effect was not altered by a calcitonin gene–related peptide (CGRP) receptor antagonist, CGRP8–37, or H-89, a cAMP-dependent protein kinase inhibitor. ADM also failed to stimulate ventricular cAMP content of the perfused hearts. Ryanodine (3 nmol/L), a sarcoplasmic reticulum Ca2+ release channel opener, suppressed the overall ADM-induced positive inotropic...
Endothelial Estrogen Receptor-α Plays a Crucial Role in the Atheroprotective Action of 17β-Estradiol in Low-Density Lipoprotein Receptor–Deficient Mice
Authors: AudreyBillon-Galés, CoralieFontaine, VictorineDouin-Echinard, LaurentDelpy, HortenseBerges, BertrandCalippe, FrançoiseLenfant, HenrikLaurell, Jean-CharlesGuéry, PierreGourdy, Jean-FrançoisArnal
Journal: Circulation (2009)

Background— The prevention of early atheroma by estrogens has been clearly demonstrated in all animal models and appears to be mediated through a direct action on the arterial wall rather than through an effect on the lipoprotein profile. The goal of the present study was to evaluate which cellular target is crucial in this beneficial action of estradiol. Methods and Results— We first confirmed the key role of estrogen receptor-α (ERα) in the atheroprotective effect of estradiol, because this action was completely abolished in mice deficient in both the low-density lipoprotein receptor (LDLr) and ERα. Second, using chimeric mice with an ERα deficiency in the hematopoietic lineage, we showed the persistence of the protective action of estradiol, which suggests the involvement of extrahematopoietic ERα. Third, we showed that loxP-flanked ERα mice (ERαflox/flox) bred with Tie2-Cre+ mice on an LDLr−/− background had complete inactivation of ERα in most hematopoietic and all endothelial cells. Remarkably, in t...
Changes in Connexin Expression and the Atrial Fibrillation Substrate in Congestive Heart Failure
Authors: BrettBurstein, PhilippeComtois, GeorghiaMichael, KunihiroNishida, LouisVilleneuve, Yung-HsinYeh, StanleyNattel
Journal: Circulation Research (2009)

Rationale: Although connexin changes are important for the ventricular arrhythmic substrate in congestive heart failure (CHF), connexin alterations during CHF-related atrial arrhythmogenic remodeling have received limited attention. Objective: To analyze connexin changes and their potential contribution to the atrial fibrillation (AF) substrate during the development and reversal of CHF. Methods and Results: Three groups of dogs were studied: CHF induced by 2-week ventricular tachypacing (240 bpm, n=15); CHF dogs allowed a 4-week nonpaced recovery interval after 2-week tachypacing (n=16); and nonpaced sham controls (n=19). Left ventricular (LV) end-diastolic pressure and atrial refractory periods increased with CHF and normalized on CHF recovery. CHF caused abnormalities in atrial conduction indexes and increased the duration of burst pacing-induced AF (DAF, from 22±7 seconds in control to 1100±171 seconds, P<0.001). CHF did not significantly alter overall atrial connexin (Cx)40 and Cx43 mRNA and protein ...
Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication
Authors: Junjie Zhang, Jun Zhao, Simin Xu, Junhua Li, Shanping He, Yi Zeng, Linshen Xie, Na Xie, Ting Liu, Katie Lee, Gil Ju Seo, Lin Chen, Alex C. Stabell, Zanxian Xia, Sara L. Sawyer, Jae Jung, Canhua Huang, Pinghui Feng
Journal: Cell Host & Microbe (2018)
Abstract 13891: Prognostic Value of Simple Risk Index at Discharge in Patients Admitted for Acute Decompensated Heart Failure With Reduced or Preserved Left Ventricular Ejection Fraction
Authors: TakahisaYamada, TakashiMorita, YoshioFurukawa, ShunsukeTamaki, YusukeIwasaki, MasatoKawasaki, AtsushiKikuchi, TakumiKondo, TatsuhisaOzaki, MasahiroSeo, YoshihiroSato, IyoIkeda, EijiFukuhara, MakotoAbe, JunNakamura, MasatakeFukunami
Journal: Circulation (2016)

Backgrounds: Increased heart rate (HR) and low systolic blood pressure (SBP) are associated with adverse clinical outcomes in patients (pts) admitted for acute decompensated heart failure (ADHF). It has been reported that simple risk index (SRI) based on easily assessed clinical characteristics (age, HR, and SBP) is useful for the prediction of short-term mortality in pts with acute myocardial infarction. However, there is no information available on the prognostic significance of pre-discharge SRI in pts admitted for ADHF relating to reduce or preserved left ventricular ejection fraction (HFrEF or HFpEF). Methods and Results: We studied 303 consecutive ADHF pts discharged with survival (HFrEF(LVEF<50%);n=163, HFpEF(LVEF≥50%);n=140), and obtained clinical characteristics, conventional hemodynamic parameters and laboratory data. SRI was calculated as (HRх[age/10]2)/SBP. During a follow up period of 4.2±3.3 yrs, 96 pts had all-cause death. In HFrEF group, at multivariate Cox analysis, SRI at the discharge (...