tbuckley/cabot-search huggingface dataset:
Composite and component expression score correlations in ER-positive breast cancer.
Authors: A. M. Wang, C. Santini, U. Vogt, R. Lagier, D. Kemming, C. Rowland, S. Kwok, S. Broder, J. Sninsky, B. Brandt
Journal: Journal of Clinical Oncology (2010)

641 Background: The similarity of the prognostic performance of different gene expression sets is thought to result from the identification of common tumor phenotypes. Knowledge of the components of composite expression scores provides insight into the relative contributions of biological processes involved and may better inform therapeutic decisions. In this study, we assessed the correlation of a constructed composite Oncotype Dx Recurrence Score (cRS) using the published algorithm with a reported 14-gene Metastasis Score (MS), individual gene and group components of the cRS, as well as a composite score of MS and progesterone receptor (PGR). Methods: We examined the RNA expression profile of 114 formalin-fixed, paraffin-embedded sections from ER-positive breast cancer cases from University of Muenster. The individual genes of the signatures reported by Paik et al (21-gene recurrence score) and Tutt et al (14-gene metastasis score) were profiled using RT-PCR. The changes in gene expression relative to reference genes were calculated as described for each score. Correlations were estimated by Pearson's product-moment correlation coefficient. Results: Correlations of gene groups and individual genes with the cRS were determined (ER group [R2 = 0.80], proliferation group [R2 = 0.21], invasion group [R2 = 0.16], HER2 group [R2 = 0.15], CD68 [R2 = 0.02], GSTM1 [R2 = 0.23], and BAG1 [R2 = 0.21]). The ER group was the only component highly correlated to the overall cRS. Individual components of the ER group found to have good correlation to this group score were PGR (R2 = 0.63) and SCUBE2 (R2 = 0.63). Correlation of the MS with the proliferation group of the cRS (R2 = 0.73) was high but correlation with the composite cRS was fair (R2 = 0.27). A composite score including both MS and PGR showed good correlation with the cRS (R2 = 0.63). Conclusions: Progesterone receptor mRNA levels alone contribute significantly to the ER group and the overall constructed Oncotype Dx scores. The 14 gene metastasis score and the proliferation group of cRS are highly correlated. The constructed Oncotype Dx and a composite of the MS and progesterone receptor show good statistical correlation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celera, European Laboratory Association, Indivicon Diagnostics, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg Celera, Indivicon Diagnostics
60 Minutes of Cardiac Rescue and Stabilization with a Small Intravenous Bolus of Adenocaine Following 8 Minutes of Asphyxial Hypoxia in the Rat in Vivo: Effect of Therapeutic Hypothermia.
Authors: Yulia Y. Djabir, Geoffrey P. Dobson
Journal: Circulation (2011)

Sudden cardiac death claims more than 7,000,000 lives per year globally and a survival rate of 2 to 8% for out-of-hospital cardiac arrest (OHCA) victims has not improved in 30 years. Previously we reported that Adenocaine (adenosine and lidocaine) can arrest and reanimate the heart for use in cardiac surgery/transplantation, and that 7.5% NaCl/Adenocaine/Mg2+ can resuscitate the rat following severe hemorrhagic shock. Our aim was to examine Adenocaine's ability to rescue and stabilize the heart following 8 min of asphyxial hypoxia in the rat model of cardiac arrest at warm (37°C) and cold (rectal 32-33°C) temperatures.
Variants in the Itpa Gene Protect Against Early Ribavirin-Induced Hemolytic Anemia in Hiv/hcv Co-Infected Patients
Authors: Susanna Naggie, Norma I. Rallon, Jose M. Benito, Judith Morello, Sonia Rodriguez-Novoa, Paul J. Clark, Alexander J. Thompson, Kevin Shianna, Eugenia Vispo, John G. McHutchison, David B. Goldstein, Vincent Soriano
Journal: Hepatology (2010)
Therapy escape mechanisms in the malignant prostate
Authors: Frédéric R. Santer, Holger H.H. Erb, Rhiannon V. McNeill
Journal: Seminars in Cancer Biology (2015)

Androgen receptor (AR) is the main target for prostate cancer therapy. Clinical approaches for AR inactivation include chemical castration, inhibition of androgen synthesis and AR antagonists (anti-androgens). However, treatment resistance occurs for which an important number of therapy escape mechanisms have been identified. Herein, we summarise the current knowledge of molecular mechanisms underlying therapy resistance in prostate cancer. Moreover, the tumour escape mechanisms are arranged into the concepts of target modification, bypass signalling, histologic transformation, cancer stem cells and miscellaneous mechanisms. This may help researchers to compare and understand same or similar concepts of therapy resistance in prostate cancer and other cancer types.
Anti-CD20 Chimeric Antigen Receptor Transduced T Cells Can Recognize Very Low Antigen Expression: Determination Of The Lower Threshold Required To Activate The CAR-T Cells
Authors: Keisuke Watanabe, Seitaro Terakura, Tatsunori Goto, Ryo Hanajiri, Nobuhiko Imahashi, Kazuyuki Shimada, Tetsuya Nishida, Akihiro Tomita, Makoto Murata, Tomoki Naoe
Journal: Blood (2013)
Abstract 345: Effects Of Endothelial-targeted Overexpression Of Nox4 On Vascular Tone And Blood Pressure In Mice
Authors: Robin Ray, Min Zhang, Alison C Brewer, Ajay M Shah
Journal: Circulation (2007)

NADPH oxidases (Noxs) are major sources of reactive oxygen species (ROS) that are involved in the pathophysiology of several cardiovascular disorders. Of the 5 Nox isoforms identified to date, Nox2 and Nox4 are the main isoforms expressed in the endothelium. Whereas Nox2 has been implicated in the genesis of endothelial dysfunction, the role of Nox4 remains unclear. Interestingly, the activation mechanisms of Nox2 and Nox4 appear to be distinct. To specifically examine the function of endothelial Nox4 in vivo , we generated transgenic mice with endothelial-targeted overexpression of Nox4 using a Tie2 promoter construct. Nox4 transgenic mice (TG) backcrossed onto a C57BL/6J background had increased Nox4 mRNA in endothelial-rich tissues and in isolated coronary microvascular endothelial cells (CMEC) compared to wild-type littermates (WT) (2-fold increase in CMEC; p&lt;0.001). Aortic Nox4 protein levels were 3-fold higher in TG compared to WT. CMEC isolated from TG mice had increased NADPH-dependent superoxide production compared to WT (237.6 ± 2.7 vs. 186.5 ± 7.1 integrated RLU; n = 3, p&lt;0.01) as well as increased H 2 O 2 production (7.60 ± 0.70 vs. 3.22 ± 0.42 μM H 2 O 2 /105 cells; n=3, p&lt;0.01). No changes were detected in mRNA expression of SOD1, SOD2, SOD3, catalase or eNOS in aorta of TG compared to WT mice. Isolated aortic rings from TG mice exhibited enhanced endothelial-dependent vasorelaxation to cumulative addition of acetylcholine compared to WT (−log EC 50 7.76 ± 0.07 vs. 7.20 ± 0.05; n =12, p&lt;0.001), a difference that was abolished by catalase (1500 units/ml). There was no difference in endothelial-independent responses to sodium nitroprusside (−log EC 50 8.57 ± 0.11 vs. 8.54 ± 0.09; n = 12, p = NS). In vivo blood pressure measured both by tail-cuff plethysmography and ambulatory telemetry was significantly lower in TG compared to WT (systolic 117.4 ± 1.9 vs. 125.5 ± 2.1 mmHg and diastolic 90.1 ± 2.0 vs. 98.1 ± 2.1 mmHg by telemetry; n =5, p&lt;0.05). These results indicate that modest endothelium-targeted overexpression of Nox4 in vivo enhances endothelium-dependent relaxation and reduces blood pressure, probably through increased generation of H 2 O 2 . These in vivo effects are quite distinct from those that have been found with Nox2 overexpression.
Research on which to base guidelines is possible in primary care
Authors: P. Elliston
Journal: BMJ (1996)

EDITOR,—Paul Little and colleagues' study shows the difficulties encountered in applying evidence of effectiveness in general practice.1 The authors question the applicability to primary care of evidence derived from another setting. What struck me, however, was that one third of the respondents rated their satisfaction with their management of back pain as </=4 out of 10 (I had thought that …
Abstract 4017: Reduced Anti-Platelet Response to Clopidogrel in Diabetic Patients Undergoing Percutaneous Coronary Intervention
Authors: Jorge Saucedo, Anand Singla, Karin Mauer, Kevin P Bliden, Mark J Antonino, Sunny Yadav, Miruais Hamed, Thomas Hennebry, Paul A Gurbel
Journal: Circulation (2008)

Despite dual antiplatelet therapy with aspirin and clopidogrel, patients with diabetes mellitus (DM) suffer from frequent recurrent ischemic events. Previous studies have shown that DM patients have a higher prevalence of aspirin resistance than non-DM patients. The aim of this analysis was to determine if DM patients have a decreased antiplatelet response to either maintenance or high loading clopidogrel administration when compared to non-DM patients. One hundred and thirty eight patients that underwent percutaneous coronary intervention (PCI) in the Clear Platelets-2 Study were included in this analysis. Patients were grouped according to clopidogrel dose use and presence of DM. Subjects were either on maintenance therapy with 75mg of clopidogrel (C75 group; n=72) or received a loading dose of 600mg of clopidogrel immediately after PCI (C600 group; n=66). All patients received 325-mg aspirin. Platelet function was measured by Light Transmission Aggregometry using ADP (5 and 20μM), TRAP (15 μM), and collagen (2μg/ml). Overall, DM patients in the C75 group had higher platelet aggregation using 5 and 20μM ADP and 2μg/ml collagen. DM patients had lower relative platelet inhibition at 24hrs with 5 μM ADP and 2μg/ml collagen in the C600 group when compared to non-DM patients (Table ). DM patients undergoing PCI exhibit higher platelet aggregation when receiving standard clopidogrel maintenance dose and lower relative platelet inhibition with high clopidogrel loading dose. Higher doses of clopidogrel or more potent P2Y12 receptor antagonists may be needed in DM patients to obtain comparable platelet inhibition to non-DM patients.
Abstract 10384: Age at Menopause and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis
Authors: Imo A Ebong, Karol E Watson, David C Goff, David A Bluemke, Preethi Srikanthan, Tamara Horwich, Alain G Bertoni
Journal: Circulation (2013)

Objective: To evaluate associations of early menopause (menopause occurring before 45 years of age) and age at menopause with incident heart failure (HF) in post-menopausal women. We also explored ...
Abstract 2135: Correlation between Resting Heart Rate and Defibrillation Energy Threshold in Patients Undergoing Implantable Cardioverter Defibrillator Device Implantation
Authors: Ramtin Anousheh, David E Krummen, Navinder S Sawhney, Wei Chung Chen, Linda Tone, Gregory K Feld
Journal: Circulation (2008)

To investigate the association between resting heart rate (HR) and defibrillation threshold (DFT) in patients (pts) undergoing ICD implantation. DFT testing is usually considered standard of care during ICD implantation. However, the risk factors for high DFTs remain ill defined and the extent of testing required at implant has not been well defined. Baseline HR has been associated with higher DFTs in prior studies. We studied 128 pts undergoing ICD implantation. Baseline HR and DFTs were determined. HR was determined using ECGs obtained in the resting position on the day of ICD implantation. DFT testing was done during ICD implantation. We excluded 13 pts who were on amiodarone. The baseline characteristics of pts in the study are shown below in the table below (values in parenthesis represents standard error of the mean): First, a multivariate analysis of the association between baseline HR and DFT was performed, adjusting for left ventricular ejection fraction (LVEF), gender, body surface area (BSA) and beta blocker therapy. For every 10 beat increase in heart rate, DFT increased by 1 joule (p=0.02). Gender and beta blocker therapy did not effect this association. Second, pts were dichotomized based on DFTs to low (&lt;15 joules) and high (≥15 joules). Mean resting HR was significantly higher among pts with high DFT (79 bpm) compared to those with low DFT (70 bpm) after adjusting for LVEF and BSA (p=0.01). Baseline resting HR is a risk factor for high DFT and may help define a higher risk pt population undergoing DFT testing.
Abstract 972: Anchoring Of Thrombomodulin On Endothelium Protects Against Mouse Lung Ischemia-reperfusion Injury
Authors: Bi-Sen Ding, Nankang Hong, Claudia Gottstein, Steven M Albelda, Douglas B Cines, Aron B Fisher, Vladimir R Muzykantov
Journal: Circulation (2007)

The endothelial cell (EC) transmembrane protein thrombomodulin (TM) plays a key role in controlling the intertwined pathological processes of thrombosis and inflammation both through and independen...
Estrogen receptor positive primary breast tumors are more frequently associated with promoter hypermethylation
Authors: Eiji Sunami, Masaru Shinozaki, Armando Giuliano, Dave Hoon
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

258 

Introduction: 

Estrogen receptor (ER) status of breast cancers is an important feature for treatment and prognosis. Approximately 75% of breast cancers express ER and they are generally considered with more favorable prognosis than tumors ER(-). However ER(+) tumors can have variable prognosis. To evaluate the epigenetic differences of tumor-related genes between ER(+) and (-) tumors, we examined the difference in gene promoter methylation status of eight genes (RASSF1A, CCND2, GSPT1, TWIST, APC, NES1, RARβ2 and CDH1) suspected to be involved in breast cancer progression and metastasis by methylation specific PCR (MSP).

Material and Method: 

130 primary tumors, paired ER(+) (n=65) and ER(-) (n=65) were selected that were matched for age, tumor size (T stage) and nodal status [lymph node metastases (+) or (-)]. DNA was extracted from paraffin-embedded primary tumor specimen sections after microdissection and then (MSP) was performed. Post-MSP product was analyzed using capillary array electrophoresis. Chi-squared test and Fisher's exact test were used for comparing clinical factors between tumors demonstrating hypermethylation versus no methylation.

Results: 

First, we analyzed the difference of methylation status of 8 genes between ER(+) group and (-) group using univariate analysis. There were two groups concerning the differences about methylation status: For RASSF1A, CCND2, GSPT1, TWIST and APC, the proportion of methylated tumors was higher in ER(+) group than that in ER(-) group (p<0.05). Differences were not significant regarding methylation status of NES1, RAR-β2 and CDH1. Secondly, we compared differences among T and N status; T1c vs. T2 and N0 vs. N1/N2. For T1c and N0, RASSF1A and CCND2 remained significantly more frequently methylated in the ER(+) group than ER(-) group (p<0.05). No difference was observed between T1c vs. T2 and N0 vs. N1/N2 regarding methylation frequency ratio of ER(+) group and ER(-) group for all markers.

Conclusion: 

Significant hypermethylation in 5 of 8 genes in the ER(+) group were observed. RASSF1A and CCND2 methylation status differences between ER(+) group and ER(-) group can be recognized in early stage of breast cancer such as T1c stage or N0 stage. The differences of methylation patterns between ER(+) and ER(-) occur at early stage of development. These results suggest that the ER expression is correlated with methylation of RASSF1A and CCND2 arises in early stages of breast cancer.
TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow
Authors: Qi Yang, Fengyin Li, Christelle Harly, Shaojun Xing, Longyun Ye, Xuefeng Xia, Haikun Wang, Xinxin Wang, Shuyang Yu, Xinyuan Zhou, Maggie Cam, Hai-Hui Xue, Avinash Bhandoola
Journal: Nature Immunology (2015)
Abstract 1157: Coronary Endothelial Dysfunction In Mice With Conditional, Cardiomyocyte Specific Overexpression Of The Mineralocorticoid Receptor: Prevention By An Antioxidant Treatment
Authors: Julie Favre, Andi Zhang, Christian Thuillez, Frèdèric Jaisser, Vincent Richard
Journal: Circulation (2007)

Deleterious effects of aldosterone excess have been demonstrated in cardiovascular diseases, and they might be linked in part to coronary vascular dysfunction. However, whether such vascular dysfunction is a cause or a consequence of the changes occurring in the cardiomyocytes is unclear. Moreover, the possible link between aldosterone-mediated effects on the cardiomyocyte on one hand and the coronary arteries on the other hand are unknown. Thus, we used a mouse model of conditional, cardiomyocyte-specific overexpression of human mineralocorticoid receptor (MR) (Ouvrard-Pascaud et al., Circulation 2005) and observed its effects on coronary endothelial function. Three months old transgenic (TG) mice were obtained after removing doxycycline treatment used to inhibit lethal embryonic MR overexpression. TG mice and their matched controls (Cont) were either untreated or treated with MR antagonist canrenoate (40 mg/kg/day) or with an antioxidant treatment (vitamin E 1% in chow and vitamin C 0.05% in water) for 1 month. Segments of left coronary arteries (diameter 180 –220 μm) were isolated and mounted in a wire myograph. After pre-contraction with serotonin, we assessed endothelium-mediated (either NO-dependent or independent) relaxations in response to increasing concentrations of acetylcholine (Ach) before and after incubation with a NOSynthase inhibitor (LNNA). Compared to control mice, cardiac MR overexpression induced decreased relaxing responses to Ach either without (maximal relaxation: Cont: 95±4% n=7; TG: 68±8% n=7 p&lt;0.05) or with LNNA (Cont: 19±3% n=7; TG: 5±4% n=7 p&lt;0.05). A one month treatment by canrenoate totally prevented this coronary dysfunction which was also prevented by a one month treatment with vitamin E/vitamin C. The endothelium-independent relaxing responses to the NO-donor sodium nitroprusside were similar in all groups.We thus demonstrate that an increase in MR expression, restricted to cardiomyocytes is sufficient to induce a coronary endothelial dysfunction mostly through an increase in reactive oxygen species production. This suggests for the first time that the phenotypic changes induced by aldosterone within the cardiomyocyte are sufficient to induce per se a secondary coronary vascular dysfunction.
Ethnic origin is more important than social deprivation
Authors: M J Doherty, P D O Davies, M A Bellis, K Tocque
Journal: BMJ (1995)

EDITOR,--The papers by Punam Mangtani and colleagues1 and N Bhatti and colleagues2 highlight the importance of poverty and overcrowding in the recent increase in rates of tuberculosis in Britain. The study by Mangtani and colleagues shows that overcrowding and the proportion of migrants were related to the average rate of notification of tuberculosis in 1981 but that only changes in unemployment were related to the rate of change in tuberculosis between 1981 and 1991. This period might, however, be better regarded as two distinct periods, with a decline in the rate of tuberculosis between 1981 and 1986 followed …
Abstract 1046: The ApoA-I Mimetic Peptide, 4F, Inhibits LPS-induced Inflammatory Reactions Through Dysregulation Of The NFkB Activation Pathway.
Authors: Geeta Datta, C. R White, Manjula Chaddha, M. N Palgunachari, G. M Anantharamaiah, Lesley Smythies
Journal: Circulation (2007)

Background: The apoA-I mimetic peptide 4F possesses potent anti-inflammatory properties. We previously reported that 4F inhibits lipopolysaccharide (LPS)-induced cytokine, chemokine and adhesion molecule expression in vivo and in vitro . Other data show that 4F reduces macrophage content in atheroma in susceptible mice. Objective: In this study, we explored anti-inflammatory mechanisms of 4F action under basal conditions and in the presence of LPS using THP1 monocytes/macrophages and primary human blood monocytes. Methods and Results: Blood monocytes isolated by Ficoll and CD14+ MACS separation were analyzed by FACS for CD14, TLR-4 and p-NFκB expression. Cytokines, chemokines and adhesion molecules were measured by the Searchlight multi-analyte analysis (Pierce, MA, USA). 4F treatment (3 days) of both THP-1 and blood monocytes enhanced the secretion of GM-CSF (25-fold), a potent inducer of monocyte to dendritic cell differentiation. 4F also inhibited (by 80%) the PMA-induced phagocytosis of FITC-labeled beads by THP-1 cells. In subsequent studies, effects of 4F on LPS-induced inflammatory responses in monocytes were tested. Pre-treatment with 4F significantly inhibited LPS-induced MCP-1 expression (by 50%) in both THP-1 cells and blood monocytes. Under these conditions, the expression of the anti-inflammatory cytokine IL-10 was increased by 200%. The effects of 4F on the activation of NFκB, a downstream mediator of LPS action, were studied using flow cytometry. 4F pre-treatment significantly inhibited LPS-induced NFκB phosphorylation (NFκBp65) compared to vehicle treatment. Protective effects of 4F in LPS-treated monocytes were associated with a 50% reduction in the expression of TLR-4 and CD14, cell surface receptors for LPS. Conclusions: These data provide evidence that 4F modulates functional properties of monocytes and show for the first time that 4F inhibits LPS-induced inflammatory responses by inhibiting the expression of CD14, TLR-4 and phosphorylation of NFκB. Enhanced GM-CSF expression and inhibition of monocyte phagocytic activity also suggest that 4F may favor the differentiation of monocytes to a dendritic cell rather than a macrophage phenotype.
Book: The Giant, O'Brien
Authors: B. Cohen
Journal: BMJ (1998)

Hilary Mantel Fourth Estate, £14.99, pp 210 ISBN 1857028848 Rating: ![Graphic][1]</img> This book is beautifully produced with clear, well spaced print, but what at first sight seems an artistic and original cover is almost identical to that of The Irish Giant by Frankcom and Musgrave, published in 1976. The attempt to weave a historical novel around the life of John Hunter is, of course, not original, but Garet Rogers' Brother Surgeons , written in 1957, is in every way a more credible, more colourful, and much more readable account of life in those tumultuous times. In this book, with O'Brien as its central character, quasi-Irish storytelling occupies much of the chronicle, but Mantel fails dismally to match up to those traditional skills. … [1]: /embed/inline-graphic-1.gif
Determining the Value of Vitamin D Supplementation—Reply
Authors: JoAnn E. Manson, Shari S. Bassuk
Journal: JAMA (2015)

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