tbuckley/cabot-search huggingface dataset:
Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women
Authors: Anita K. Dunbier, Helen Anderson, Zara Ghazoui, Elizabeth J. Folkerd, Roger A'Hern, Robert J. Crowder, Jeremy Hoog, Ian E. Smith, Peter Osin, Ashutosh Nerurkar, Joel S. Parker, Charles M. Perou, Matthew J. Ellis, Mitch Dowsett
Journal: Journal of Clinical Oncology (2010)

PURPOSE To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)-positive breast cancers in postmenopausal women. Materials and METHODS Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = -0.179; P = .05; and r = -0.389; P = .0005, respectively). CONCLUSION Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.
Efficient Sequencing of Anuran mtDNAs and a Mitogenomic Exploration of the Phylogeny and Evolution of Frogs
Authors: Peng Zhang, Dan Liang, Rong-Li Mao, David M. Hillis, David B. Wake, David C. Cannatella
Journal: Molecular Biology and Evolution (2013)

Anura (frogs and toads) constitute over 88% of living amphibian diversity but many important questions about their phylogeny and evolution remain unresolved.For this study, we developed an efficient method for sequencing anuran mitochondrial DNAs (mtDNAs) by amplifying the mitochondrial genome in 12 overlapping fragments using frog-specific universal primer sets.Based on this method, we generated 47 nearly complete, new anuran mitochondrial genomes and discovered nine novel gene arrangements.By combining the new data and published anuran mitochondrial genomes, we assembled a large mitogenomic data set (11,007 nt) including 90 frog species, representing 39 of 53 recognized anuran families, to investigate their phylogenetic relationships and evolutionary history.The resulting tree strongly supported a paraphyletic arrangement of archaeobatrachian (=nonneobatrachian) frogs, with Leiopelmatoidea branching first, followed by Discoglossoidea, Pipoidea, and Pelobatoidea.Within Neobatrachia, the South African Heleophrynidae is the sister-taxon to all other neobatrachian frogs and the Seychelles-endemic Sooglossidae is recovered as the sister-taxon to Ranoidea.These phylogenetic relationships agree with many nuclear gene studies.The chronogram derived from two Bayesian relaxed clock methods (MultiDivTime and BEAST) suggests that modern frogs (Anura) originated in the early Triassic about 244 Ma and the appearance of Neobatrachia took place in the late Jurassic about 163 Ma.The initial diversifications of two species-rich superfamilies Hyloidea and Ranoidea commenced 110 and 133 Ma, respectively.These times are older than some other estimates by approximately 30-40 My.Compared with nuclear data, mtDNA produces compatible time estimates for deep nodes (>150 Ma), but apparently older estimates for more shallow nodes.Our study shows that, although it evolves relatively rapidly and behaves much as a single locus, mtDNA performs well for both phylogenetic and divergence time inferences and will provide important reference hypotheses for the phylogeny and evolution of frogs.
Performance measures in three rounds of the English bowel cancer screening pilot
Authors: S M Moss, C Campbell, J Melia, D Coleman, S Smith, R Parker, P Ramsell, J Patnick, D P Weller
Journal: Gut (2011)

<h3>Objectives</h3> To compare performance measures across all three rounds of the English bowel cancer screening faecal occult blood test pilot and their relation to social deprivation and ethnicity. <h3>Methods</h3> In each round in three primary care trusts, data for a restricted population of over 48 500 aged 60–69 years were analysed. Individual-based data included postcode linked to area-based data on the Index of Multiple Deprivation (IMD) 2004, and ethnicity. Outcomes were the rates of screening and colonoscopy uptake, positivity and detection of neoplasia (adenomas or bowel cancer) and bowel cancer, and the positive predictive values (PPVs) of a positive test for neoplasia and bowel cancer. Sensitivity was calculated by the proportional incidence method using data on interval cancers identified from cancer registrations. <h3>Results</h3> The overall uptake rate was 61.8%, 57.0% and 58.7% in the first, second and third rounds, respectively. Although the PPV for cancer decreased over the course of the three rounds (10.9% in the 1st round, 6.5% in 3rd round), the PPV for all neoplasia remained relatively constant (42.6% in 1st round, 36.9% in 3rd round). Deprivation and non-white ethnic background (principally Indian subcontinent in the pilot region) were associated with low screening and colonoscopy uptake rates, and this changed little over the three screening rounds. Uptake was lower in men, although differences in uptake between men and women decreased over time. Non-participation in previous rounds was a strong predictor of low uptake. <h3>Conclusions</h3> Performance measures are commensurate with expectations in a screening programme reaching its third round of screening, but a substantial ongoing effort is needed, particularly to address the effects of deprivation and ethnicity in relation to uptake.
Ulcerative Pretibial Lesions in the Setting of Multifactorial Immunosuppression
Authors: Patricia M. Richey, Arash Radfar, Ali A. Damavandy
Journal: JAMA Dermatology (2015)

A man in his 50s with a kidney transplant was admitted for a 1-month history of an enlarging left lower extremity mass that ulcerated, was occasionally painful, and drained small amounts of sanguinopurulent fluid. What is your diagnosis?
LOXL2 Is Highly Expressed in Cancer-Associated Fibroblasts and Associates to Poor Colon Cancer Survival
Authors: Sofía Torres, Irene Garcia-Palmero, Mercedes Herrera, Rubén A. Bartolomé, Cristina Peña, M. Jesús Fernandez-Aceñero, Guillermo Padilla, Alberto Peláez-García, María Lopez-Lucendo, Rufo Rodriguez-Merlo, Antonio García de Herreros, Félix Bonilla, J. Ignacio Casal
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Cancer-associated fibroblasts (CAF) are major mediators in tumor microenvironment. We investigated the changes in protein expression in colon cancer–associated fibroblasts compared with normal fibroblasts (NF) in the context of searching for prognostic biomarkers, particularly for stage II patients. Experimental Design: CAFs and NFs isolated from colon cancer patients were used to identify differentially expressed proteins using quantitative proteomics. Stromal expression of deregulated proteins was analyzed by IHC. Prognostic impact was studied using external gene-expression datasets for training, then quantitative PCR and IHC for validation in different cohorts of patients. Combined datasets were used for prediction of risk assessment at stages II and III. Results: A desmoplastic signature composed of 32 proteins, highly specific for stromal components in colon cancer, was identified. These proteins were enriched for extracellular matrix organization components, TGFβ signaling pathway, fibrosis, and wound-healing proteins. The expression in CAFs of 11 upregulated proteins and four downregulated proteins, selected for biomarker validation, was verified by orthogonal techniques. LOXL2 displayed a high prognostic impact by using external independent datasets and further validation in two different cohorts of patients. High expression of LOXL2 was associated with higher recurrence P = 0.001 HR, 5.38 [95% confidence interval (CI), 1.70–17.01] and overall survival P = 0.001 HR, 8.52 (95% CI, 1.90–38.29). IHC analysis revealed a prognostic value for LOXL2 in stage II patients. Conclusions: We identified LOXL2 to be associated with the outcome of colon cancer patients. Furthermore, it can be used to stratify patients at stages II and III for further therapeutic decisions. Clin Cancer Res; 21(21); 4892–902. ©2015 AACR.
Nucleotide precursors modify the effects of isoproterenol. Studies on heart function and cardiac adenine nucleotide content in intact rats.
Authors: H G Zimmer, A Schneider
Journal: Circulation Research (1991)

In closed-chest rats, isoproterenol (ISO, 25 mg/kg), 5 hours after subcutaneous administration, increased heart rate by 53%, left ventricular (LV) dP/dtmax by 80%, and cardiac output by 37%. LV systolic pressure (LVSP, -10%), mean arterial pressure (MAP, -12%), and total peripheral resistance (TPR, -36%) were diminished. In separate experiments, continuous intravenous infusion of adenine (50 mg/kg/hr) for 5 hours reduced heart rate (-11%), LVSP (-16%), MAP (-20%), TPR (-33%), and LV dP/dtmax (-20%). Cardiac output was increased (+20%). Inosine has been shown to have similar effects, except for a decline in cardiac output. Adenine (50 mg/kg/hr) attenuated the ISO-induced increase in heart rate and LV dP/dtmax and aggravated the decline in LVSP, MAP, and TPR. The increase in cardiac output was not changed. Inosine (200 mg/kg/hr) modified the ISO effects to a similar extent. Ribose (200 mg/kg/hr) added to the adenine infusion did not have functional effects. However, it aggravated the modifying influence of inosine on LVSP, LV dP/dtmax, and MAP. ISO reduced the cardiac ATP content (mumol/g) from a control value of 5.02 +/- 0.06 (n = 12) to 3.51 +/- 0.13 (n = 10). Adenine (3.56 +/- 0.21, n = 7) and ribose (3.64 +/- 0.11, n = 9) alone did not affect it, but inosine attenuated it (4.33 +/- 0.08, n = 8). Adenine and inosine in combination with ribose abolished the ISO-induced ATP decline (5.18 +/- 0.23, n = 7, and 4.76 +/- 0.10, n = 8, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Conservation of the cag pathogenicity island is associated with vacA alleles and gastroduodenal disease in South African Helicobacter pylori isolates
Authors: M Kidd
Journal: Gut (2001)

<h3>BACKGROUND</h3> The development of clinically significant disease in South Africa is associated with the vacuolating cytotoxin gene (<i>vacA</i>) s1 genotype but not with the presence of the cytotoxin associated gene <i>cagA. cagA</i> occurs in &gt;95% of South African isolates and is a variable marker for the entire<i>cag</i> pathogenicity island (PAI). <h3>AIM</h3> To characterise the <i>cag</i>PAI in South African isolates and to investigate if structural variants of this multigene locus were associated with variations in <i>vacA</i> status and clinical outcome. <h3>PATIENTS AND METHODS</h3> We studied 109<i>Helicobacter pylori</i> strains (36 from patients with peptic ulceration, 26 with gastric adenocarcinoma, and 47 with no pathology other than gastritis) for differences in selected genes of the <i>cag</i>PAI and alleles of<i>vacA</i> by polymerase chain reaction. <h3>RESULTS</h3> All strains were <i>cagA</i><sup><i>+</i></sup>. Sixty five (60%) strains had an intact contiguous <i>cag</i>PAI; 78% of peptic ulcer isolates, 73% of gastric adenocarcinoma isolates, but only 40% of gastritis alone isolates (p&lt; 0.01). The entire<i>cagII</i> region was undetectable in 23% of gastritis alone isolates but in only 8% of peptic ulceration isolates (p&lt;0.05). The <i>vacA</i> signal sequence and mid region demonstrated a strong relationship between the virulence associated <i>vacA</i> s1 (p&lt;0.005) and<i>vacA</i> m1 (p=0.05) alleles and an intact<i>cag</i>PAI. <h3>CONCLUSION</h3> Although a complete <i>cag</i>PAI was a feature of most infected individuals, deletions in the 5′ region of this genetic locus were associated with gastritis alone and with the non-cytotoxic s2/m2<i>vacA</i> genotype.
Pressure-flow characteristics of coronary stenoses in unsedated dogs at rest and during coronary vasodilation.
Authors: K L Gould
Journal: Circulation Research (1978)

The pressure-flow characteristics of 100 left circumflex stenoses in 10 chronically instrumented unsedated dogs were studied under resting conditions and during pharmacological coronary vasodilation. At rest, the pressure loss (deltaP) due to a stenosis and arterial flow velocity (V) were related by the equation, deltaP = FV + SV2, where F is the coefficient of pressure loss due to viscous friction in the stenotic segment and S is the coefficient of pressure loss due to flow separation at the diverging end of the stenosis. The linear term due to viscous friction accounted for 65% and the nonlinear term due to flow separation accounted for 35% of the total pressure loss at resting coronary flow. At peak coronary flow after coronary vasodilation, the pressure loss due to viscous friction accounted for 33% and pressure loss due to flow separation accounted for 67% of the total pressure loss. The pressure gradient-velocity relationship at high flows was characterized by the same general equation but with proportionately larger values of the coefficient S and therefore greater pressure loss associated with flow separation than predicted by the resting gradient-velocity relationship. The pressure loss predicted for high coronary flow velocities on the basis of the gradient-velocity equation at rest was only 64% of the actual experimentally observed pressure gradient at peak coronary flow. The augmented separation loss following coronary vasodilation probably was due to dilation of the epicardial artery adjacent to the fixed stenotic segment which caused more severe relative percent narrowing and a larger divergence angle at the distal end of the stenosis, the primary geometric determinants of separation losses.
Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart
Authors: E. E. Creemers, Y. M. Pinto
Journal: Cardiovascular Research (2010)

When considering the pathological steps in the progression from cardiac overload towards the full clinical syndrome of heart failure, it is becoming increasingly clear that the extracellular matrix (ECM) is an important determinant in this process. Chronic pressure overload induces a number of structural alterations, not only hypertrophy of cardiomyocytes but also an increase in ECM proteins in the interstitium and perivascular regions of the myocardium. When this culminates in excessive fibrosis, myocardial compliance decreases and electrical conduction is affected. Altogether, fibrosis is associated with an increased risk of ventricular dysfunction and arrhythmias. Consequently, anti-fibrotic strategies are increasingly recognized as a promising approach in the prevention and treatment of heart failure. Thus, dissecting the molecular mechanisms underlying the development of cardiac fibrosis is of great scientific and therapeutic interest. In this review, we provide an overview of the available evidence supporting the general idea that fibrosis plays a causal role in deteriorating cardiac function. Next, we will delineate the signalling pathways importantly governed by transforming growth factor β (TGFβ) in the control of cardiac fibrosis. Finally, we will discuss the recent discovery that miRNAs importantly regulate cardiac fibrosis.
Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in out-patients with COPD
Authors: MP Engelen, AM Schols, WC Baken, GJ Wesseling, EF Wouters
Journal: European Respiratory Journal (1994)

Although increasing attention has been paid to nutritional aspects in chronic obstructive pulmonary disease (COPD), limited information is available regarding the prevalence and consequences of nutritional depletion in a random out-patient COPD population. We studied body composition in relation to respiratory and peripheral skeletal muscle function in 72 COPD patients (mean (SD) forced expiratory volume in one second (FEV1) 53 (15) % predicted), who came to the lung function laboratory for routine lung function measurements. Patients were characterized by the degree of body weight loss and fat-free mass depletion. According to this definition, 14% of the group suffered from both loss of body weight and depletion of fat-free mass, whereas 7% had one of these conditions. We found that tissue depletion was concomitant with lower values for respiratory and peripheral skeletal muscle strength (46.0 (27.2) vs 77.1 (29.8) kg), and a significantly lower transfer coefficient for carbon monoxide (KCO 64.9 (16.2) vs 81.9 (24.5) % pred). Stratification by KCO (< 60% vs > 80%) also revealed significantly lower values for fat-free mass and higher values for intrathoracic gas volumes, total lung capacity (TLC) and residual volume (RV) in the group with a KCO < 60% pred. Analysis of covariance, taking fat-free mass as covariate, indicated an independent contribution of KCO on maximal inspiratory mouth pressure (PImax) but not on peripheral skeletal muscle strength. It is concluded that a substantial number of COPD out-patients suffer from nutritional depletion, preferentially affecting peripheral skeletal muscle function.
Human Cytomegalovirus Causes Endothelial Injury Through the Ataxia Telangiectasia Mutant and p53 DNA Damage Signaling Pathways
Authors: Y.H. Shen, B. Utama, J. Wang, M. Raveendran, D. Senthil, W.J. Waldman, J.D. Belcher, G. Vercellotti, D. Martin, B.M. Mitchelle, X.L. Wang
Journal: Circulation Research (2004)

Atherosclerosis is the leading cause of death in the United States, and human cytomegalovirus (HCMV), a member of the herpes virus family, may play a role in the development of the disease. We previously showed that HCMV regulated endothelial apoptosis. In this study, we investigated the induction of apoptosis and signal transduction pathways regulating this process in HCMV-infected endothelial cells. As observed previously, HCMV induced a typical cytopathic effect in human aortic endothelial cells (HAECs), ie, the formation of single nucleated or multinucleated giant cells. Although infected HAECs were resistant to apoptosis at earlier stages of infection, they became apoptotic with prolonged infection as demonstrated by positive staining using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). This apoptotic process was mediated by the caspase-dependent mitochondrial apoptotic pathway as indicated by increased expression and cleavage of caspases 3 and 9 as well as increased expressions of pro-apoptotic molecules Bax and Bak. Blocking caspases 3 or 9 significantly inhibited the HCMV-induced apoptosis. Further exploration of the upstream pathway demonstrated upregulation of the tumor suppressor p53 gene and activation of the ataxia telangiectasia mutant (ATM) pathway in the infected cells. Blocking p53 inhibited HCMV-stimulated Bax and Bak expression as well as caspase-3 activation and blocking the ATM pathway inhibited HCMV-stimulated p53 activation. Although early infection may render cells antiapoptotic, prolonged infection, however, induced endothelial apoptosis through ATM and p53-dependent activation of the mitochondrial death pathway. This proapoptotic effect may be relevant to endothelial dysfunction and HCMV-associated vascular diseases.
P78 Long-term antibiotic prescription in patients relisted for late hepatic artery thrombosis is associated with greater waiting list mortality independent of meld
Authors: M. Smith, J. Leithead, L. Materacki, V. Sagar, B. Gunson, S. Bramhall, D. Mutimer, T. Shah
Journal: Gut (2011)

<h3>Introduction</h3> Optimal prioritisation and medical management of patients with late hepatic artery thrombosis (HAT) awaiting liver transplantation remains unclear. <h3>Aim</h3> To examine the association of complications of late HAT and their interventions with liver transplant waiting list mortality. <h3>Method</h3> Single centre study of 49 patients listed for late HAT 01/1995–06/2010. Late HAT was defined as occurrence &gt;4 weeks following liver transplantation. Cox regression was adjusted for listing MELD score at all times. Despite increasing waiting time statistical analyses did not demonstrate any influence of listing time period. <h3>Results</h3> Mean listing MELD score was 16 (SD 7). 29% of patients demonstrated biliary stricture/s, 20% cholangitis and 63% biloma/abscess/s. The estimated 3- and 12-month transplant-free survival following listing was 85% and 53%, respectively. 36 patients were regrafted, with a median time from listing to transplantation of 45 (IQR 13–167) days. No relationship was demonstrated between the presence of biliary stricture/s (p=0.984), cholangitis (p=0.770) or biloma/abscess/s (p=0.143), and wait-list mortality. Instead, an increasing number of biloma/abscess drain insertions (p=0.038) and long-term (LT) prescription of antibiotics (p=0.029) were linked with an increased risk of death. Multi-drug resistant bacteria (MDRB) were cultured in bile/blood more frequently in those receiving LT antibiotics (44% vs 8%, p=0.004), and MDRB positivity was also a risk factor for waiting list mortality (p=0.033). On multivariate analysis the only predictor of death was LT antibiotics (MELD, HR 1.23; 95% CI 1.04 to 1.44, p=0.013: antibiotics, HR 24.20; 95% CI 1.28 to 455.88, p=0.033). Following regraft, LT antibiotics (p=0.025) and MDRB positivity while listed (p=0.002) remained predictors of patient mortality independent of the preoperative MELD score. The estimated 3- and 12-month post transplant survival of patients with MDRB positivity was 63% and 25%, respectively, and for those without 89% and 86% (log-rank p=0.001). <h3>Conclusion</h3> Patients listed for late HAT receiving LT antibiotics are a high risk group who require greater priority for liver transplantation. Our results raise the possibility that by increasing bacterial resistance LT antibiotics may have a detrimental effect on patient survival.
Comment on: Ramos-Zavala et al. Effect of Diacerein on Insulin Secretion and Metabolic Control in Drug-Naïve Patients With Type 2 Diabetes: A Randomized Clinical Trial. Diabetes Care 2011;34:1591–1594
Authors: Natália Tobar, Alexandre G. Oliveira, Dioze Guadagnini, Renata A. Bagarolli, Guilherme Z. Rocha, Tiago G. Araujo, Patrícia O. Prada, Mario J.A. Saad
Journal: Diabetes Care (2012)

Ramos-Zavala et al. (1) described in their report the effects of diacerein, an anti-inflammatory drug used in the treatment of rheumatic diseases, on insulin secretion in patients with type 2 diabetes. They showed that diacerein induced a significant decrease in fasting glucose levels, A1C levels, tumor necrosis factor-α levels, and interleukin (IL)-1β serum levels. By using the hyperinsulinemic-euglycemic clamp, they also showed that diacerein is able to improve insulin secretion but does not modify insulin sensitivity.

Our laboratory recently investigated the antihyperglycemic effect of diacerein and the mechanisms responsible for …