tbuckley/cabot-search huggingface dataset:
Germline <i>BRCA</i> Mutations Denote a Clinicopathologic Subset of Prostate Cancer
Authors: David J. Gallagher, Mia M. Gaudet, Prodipto Pal, Tomas Kirchhoff, Lisa Balistreri, Kinjal Vora, Jasmine Bhatia, Zsofia Stadler, Samson W. Fine, Victor Reuter, Michael Zelefsky, Michael J. Morris, Howard I. Scher, Robert J. Klein, Larry Norton, James A. Eastham, Peter T. Scardino, Mark E. Robson, Kenneth Offit
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined. Experimental Design: We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models. Results: BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score ≥7) tumors (85% versus 57%; P = 0.0002) compared with non–BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer–specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers. Conclusions: BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer. Clin Cancer Res; 16(7); 2115–21. ©2010 AACR.
Lactate and lactate clearance were associated with higher mortality in patients with septic shock
Authors: Prapun Kittivoravitkul, Anan Wattanathum, Adisorn Wongsa
Journal: European Respiratory Journal (2011)

Introduction: An elevated lactate level is associated with higher mortality in patients with severe sepsis. Also, lactate clearance is a surrogate for magnitude and duration of global tissue hypoxia. However, the utility of the lactate clearance after ICU admission as an indicator of outcome in patients with septic shock is still limited.

Objectives: The purpose of study is to evaluate the advantage of lactate level and clearance in predicting mortality of patients with septic shock.

Methods: We prospectively enrolled 38 patients with septic shock in ICU at Phramongkutklao hospital. Measurements of venous lactate and ScvO2 were obtained at 0, 2, 6, 24, 48, and 72 hours after ICU admission. Lactate clearance was defined as the percent change in lactate levels after 2 or 6 hours from the baseline value. The primary outcome was 28-day mortality rate.

Results: The 28-day mortality rate was 55.3%. There was no significant differences in 28-day mortality rate between normal ScvO2 (≥ 70%) group and low ScvO2 (< 70%) group at initial presentation. Using cut off value of 3 mmol/L, higher initial lactate level was significantly associated with higher 28-d mortality (p = 0.017). There was, also, significant association between lactate non-clearance (lactate clearance < 10%) at 2 and 6 hrs and higher 28-d mortality (p = 0.029 and 0.014).

Conclusions: Early lactate clearance may indicate a resolution of global tissue hypoxia and is associated with decreased mortality. Patients with higher lactate clearance after 2 and 6 hrs of ICU admission have improved outcome compared with those with lower lactate clearance. Also, initial lactate level was independently associated with 28-day mortality rate.
THE BIOLOGICAL IDENTITY OF THE FRIEDLÄNDER BACILLUS
Authors: Calvin B. Coulter
Journal: The Journal of Experimental Medicine (1917)

We conclude therefore that this series of eleven lactose-negative organisms of the Friedländer type, grouped together by Perkins on the basis of fermentation reactions represents a single biological group. It can be distinguished from Bacillus aerogenes and other similar bacilli by cultural, fermentative, and serological reactions. There appears to be a close analogy between this group and Pneumococcus mucosus in the possession of a fixed cultural type, and the behavior toward immune serum. Both represent apparently a single biological group. Unfortunately no immune sera have been developed against the two strains that grew in moist and dry phases; it is possible that with immune sera for these light could be thrown on the relation suggested by Fitzgerald that the capsulated bacilli represent a parasitic development of the Bacillus coli group.
Left Ventricular Assist Device as Destination for Patients Undergoing Intravenous Inotropic Therapy
Authors: Lynne Warner Stevenson, Leslie W. Miller, Patrice Desvigne-Nickens, Deborah D. Ascheim, Michael K. Parides, Dale G. Renlund, Ronald M. Oren, Steven K. Krueger, Maria Rosa Costanzo, L. Samuel Wann, Ronald G. Levitan, Donna Mancini
Journal: Circulation (2004)

Left ventricular assist devices (LVADs) have improved survival in patients with end-stage heart failure. Compared with previous trials, the Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure (REMATCH) trial enrolled patients with more advanced heart failure and high prevalence of intravenous inotropic therapy. This study analyzes, on a post hoc basis, outcomes in patients undergoing inotropic infusions at randomization.Of 129 patients randomized, 91 were receiving intravenous inotropic therapy at randomization to LVAD or optimal medical management (OMM). Mean systolic pressure was 100 versus 107 mm Hg in those not receiving inotropes, serum sodium was 134 versus 137 mEq/L, and left ventricular ejection fraction was 17% for both groups. LVADs improved survival throughout follow-up for patients undergoing baseline inotropic infusions (P=0.0014); for the LVAD group versus the OMM group, respectively, 6-month survival was 60% versus 39%, 1-year survival rates were 49% versus 24%, and 2-year survival rates were 28% versus 11%. For 38 patients not undergoing inotropic infusions, 6-month survival was 61% for those with LVADs and 67% for those with OMM, whereas 1-year rates were 57% and 40%, respectively (P=0.55). Quality-of-life scores for survivors improved. Median days out of hospital for patients on inotropic therapy at randomization were 255 with LVAD and 105 with OMM.Despite severe compromise, patients undergoing inotropic infusions at randomization derived major LVAD survival benefit with improved quality of life. Patients not undergoing inotropic infusions had higher survival rates both with and without LVAD, but differences did not reach significance. Future studies should prespecify analyses of inotropic and other therapies to determine how disease severity and parallel medical treatment influence the benefits offered by mechanical circulatory support.
Evaluation of Multiple Biomarkers of Cardiovascular Stress for Risk Prediction and Guiding Medical Therapy in Patients With Stable Coronary Disease
Authors: Marc S. Sabatine, David A. Morrow, James A. de Lemos, Torbjorn Omland, Sarah Sloan, Petr Jarolim, Scott D. Solomon, Marc A. Pfeffer, Eugene Braunwald
Journal: Circulation (2011)

Background— Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy. Methods and Results— We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P ≤0.002 for each biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36–0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74–1.59; P interaction =0.012). Conclusions— In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.
Expression of Activated Signal Transducer and Activator of Transcription 3 Predicts Expression of Vascular Endothelial Growth Factor in and Angiogenic Phenotype of Human Gastric Cancer
Authors: Weida Gong, Liwei Wang, James C. Yao, Jaffer A. Ajani, Daoyan Wei, Kenneth D. Aldape, Keping Xie, Raymond Sawaya, Suyun Huang
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Angiogenic behavior is a critical aspect of cancer biology and subject to regulation by multiple molecular pathways. Because the signal transducer and activator of transcription 3 (Stat3) transcription factor regulates multiple genes important to angiogenesis, we sought to determine whether Stat3 expression is related to vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in gastric cancer and whether these factors predict survival in gastric cancer patients. Experimental Design: The expression of Stat3 and VEGF was determined by immunohistochemistry using archival tissues from 86 cases of resected human gastric cancer and confirmed by Western blot analysis. Angiogenic phenotype was determined by CD34 staining and microvessel counting. Results: Stat3 expression correlated with VEGF expression and MVD. In univariate survival analyses, Stat3 expression (P = 0.013) and MVD (P = 0.036) were associated with inferior survival. However, when Stat3 expression, VEGF expression, MVD, stage, completeness of resection, Lauren's histologic classification, and age were entered into a Cox proportional hazards model, only strong Stat3 expression (P = 0.049) and advanced stage (P &amp;lt; 0.01) were independently prognostic of poor survival. Furthermore, genetically enforced alterations of activated Stat3 expression led to altered VEGF expression and angiogenic potential in human gastric cancer cells. Conclusion: Dysregulated Stat3 activation may play an important role in VEGF overexpression and elevated angiogenic phenotype in gastric cancer and contribute to gastric cancer development and progression.
The American Society of Clinical Oncology Recommended Breast Cancer Surveillance Guidelines Can Be Done in a Routine Office Visit
Authors: Thomas J. Smith
Journal: Journal of Clinical Oncology (2005)

REFERENCE 1. Fossa SD, Horwich A, Russell JM, et al: Optimal planning target volume for stage I testicular seminoma: A Medical Research Council Randomized Trial. J Clin Oncol 17:1146-1154, 1999 2. Jones WG, Fossa SD, Mead GM, et al: Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: A report on Medical Research Council Trial TE18, European Organisation for Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol 23:1200-1208, 2005
MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-κB signaling
Authors: Jian Liang, Yasser Saad, Tianhua Lei, Jing Wang, Dongfei Qi, Qinglin Yang, Pappachan E. Kolattukudy, Mingui Fu
Journal: The Journal of Experimental Medicine (2010)

The intensity and duration of macrophage-mediated inflammatory responses are controlled by proteins that modulate inflammatory signaling pathways. MCPIP1 (monocyte chemotactic protein–induced protein 1), a recently identified CCCH Zn finger–containing protein, plays an essential role in controlling macrophage-mediated inflammatory responses. However, its mechanism of action is poorly understood. In this study, we show that MCPIP1 negatively regulates c-Jun N-terminal kinase (JNK) and NF-κB activity by removing ubiquitin moieties from proteins, including TRAF2, TRAF3, and TRAF6. MCPIP1-deficient mice spontaneously developed fatal inflammatory syndrome. Macrophages and splenocytes from MCPIP1−/− mice showed elevated expression of inflammatory gene expression, increased JNK and IκB kinase activation, and increased polyubiquitination of TNF receptor–associated factors. In vitro assays directly demonstrated the deubiquitinating activity of purified MCPIP1. Sequence analysis together with serial mutagenesis defined a deubiquitinating enzyme domain and a ubiquitin association domain in MCPIP1. Our results indicate that MCPIP1 is a critical modulator of inflammatory signaling.
Phase III Trial of Bevacizumab Plus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma (AVOREN): Final Analysis of Overall Survival
Authors: Bernard Escudier, Joaquim Bellmunt, Sylvie Négrier, Emilio Bajetta, Bohuslav Melichar, Sergio Bracarda, Alain Ravaud, Sophie Golding, Sangeeta Jethwa, Vesna Sneller
Journal: Journal of Clinical Oncology (2010)

A phase III trial of bevacizumab combined with interferon alfa-2a (IFN) showed significant improvements in progression-free survival (PFS) in metastatic renal cell carcinoma (mRCC). Here, we report overall survival (OS) data.Six hundred forty-nine patients with previously untreated mRCC were randomly assigned to receive bevacizumab (10 mg/kg every 2 weeks) plus IFN (9 MIU subcutaneously three times a week; n = 327) or IFN plus placebo (n = 322) in a multicenter, randomized, double-blind, phase III trial. The primary end point was OS. Final analysis of the secondary end point (PFS) was reported earlier.Median OS was 23.3 months with bevacizumab plus IFN and 21.3 months with IFN plus placebo (unstratified hazard ratio [HR] = 0.91; 95% CI, 0.76 to 1.10; P = .3360; stratified HR = 0.86; 95% CI, 0.72 to 1.04; P = .1291). Patients (> 55%) in both arms received at least one postprotocol antineoplastic therapy, possibly confounding the OS analysis. Patients receiving postprotocol therapy including a tyrosine kinase inhibitor had longer median OS (bevacizumab plus IFN arm: 38.6 months; IFN plus placebo arm: 33.6 months; HR = 0.80; 95% CI, 0.56 to 1.13). Tolerability was similar to that reported previously.Bevacizumab plus IFN is active as first-line treatment in patients with mRCC. Most patients with mRCC receive multiple lines of therapy, so considering the overall sequence of therapy when selecting first-line therapy may optimize patient benefit.
Involvement of Tachykinin NK<sub>1</sub>Receptor in the Development of Allergen-induced Airway Hyperreactivity and Airway Inflammation in Conscious, Unrestrained Guinea Pigs
Authors: MARTIN SCHUILING, ANNET B. ZUIDHOF, JOHAN ZAAGSMA, HERMAN MEURS
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

It has been suggested that tachykinin NK1 receptor-mediated neurogenic inflammation, characterized by microvascular leakage, mucus secretion, and infiltration and activation of inflammatory cells in the airways, may be involved in allergic asthma. Therefore, in a guinea pig model of allergic asthma, we investigated the involvement of the NK1 receptor in allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions and airway inflammation, using the selective nonpeptide NK1 receptor antagonist SR140333. On two different occasions, separated by 1 wk interval, OA-sensitized guinea pigs inhaled either saline (3 min) or SR140333 (100 nM, 3 min) at 30 min before as well as at 5.5 h after OA provocation (between the EAR and LAR) in a random crossover design. A control group, receiving saline inhalations before and at 5.5 h after the two OA provocations, was included as well. SR140333 had no significant effect on either the EAR or the LAR compared with saline control inhalations. However, the NK1 receptor antagonist significantly reduced the OA-induced AHR to histamine, both after the EAR at 5 h after OA challenge (1.77 +/- 0.13-fold increase in histamine reactivity versus 2.50 +/- 0.25-fold increase in the control animals, p < 0.01) and after the LAR at 23 h after OA challenge (1.15 +/- 0.12-fold increase versus 1.98 +/- 0. 34-fold increase, respectively, p < 0.05). Moreover, bronchoalveolar lavage studies performed at 25 h after the second OA provocation indicated that SR140333 significantly inhibited the allergen-induced infiltration of eosinophils, neutrophils, and lymphocytes in the airways (p < 0.05 for all observations), whereas a tendency to reduced accumulation of ciliated epithelial cells in the airway lumen was observed (p = 0.10). These results indicate that the NK1 receptor is involved in the development of allergen-induced AHR to histamine, and that NK1 receptor-mediated infiltration of inflammatory cells in the airways may contribute to this AHR.
CD36 Deficiency Rescues Lipotoxic Cardiomyopathy
Authors: John Yang, Nandakumar Sambandam, Xianlin Han, Richard W. Gross, Michael Courtois, Attila Kovacs, Maria Febbraio, Brian N. Finck, Daniel P. Kelly
Journal: Circulation Research (2007)

Obesity-related diabetes mellitus leads to increased myocardial uptake of fatty acids (FAs), resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that chronic activation of the FA-activated nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), is sufficient to drive the metabolic and functional abnormalities of the diabetic heart. Mice with cardiac-restricted overexpression of PPARalpha (myosin heavy chain [MHC]-PPARalpha) exhibit myocyte lipid accumulation and cardiac dysfunction. We sought to define the role of the long-chain FA transporter CD36 in the pathophysiology of lipotoxic forms of cardiomyopathy. MHC-PPARalpha mice were crossed with CD36-deficient mice (MHC-PPARalpha/CD36-/- mice). The absence of CD36 prevented myocyte triacylglyceride accumulation and cardiac dysfunction in the MHC-PPARalpha mice under basal conditions and following administration of high-fat diet. Surprisingly, the rescue of the MHC-PPARalpha phenotype by CD36 deficiency was associated with increased glucose uptake and oxidation rather than changes in FA utilization. As predicted by the metabolic changes, the activation of PPARalpha target genes involved in myocardial FA-oxidation pathways in the hearts of the MHC-PPARalpha mice was unchanged in the CD36-deficient background. However, PPARalpha-mediated suppression of genes involved in glucose uptake and oxidation was reversed in the MHC-PPARalpha/ CD36-/- mice. We conclude that CD36 is necessary for the development of lipotoxic cardiomyopathy in MHC-PPARalpha mice and that novel therapeutic strategies aimed at reducing CD36-mediated FA uptake show promise for the prevention or treatment of cardiac dysfunction related to obesity and diabetes.
Mice With Cardiac Overexpression of Peroxisome Proliferator–Activated Receptor γ Have Impaired Repolarization and Spontaneous Fatal Ventricular Arrhythmias
Authors: John P. Morrow, Alexander Katchman, Ni-Huiping Son, Chad M. Trent, Raffay Khan, Takayuki Shiomi, Haiyan Huang, Vaibhav Amin, Joshua M. Lader, Carolina Vasquez, Gregory E. Morley, Jeanine D'Armiento, Shunichi Homma, Ira J. Goldberg, Steven O. Marx
Journal: Circulation (2011)

Diabetes mellitus and obesity, which confer an increased risk of sudden cardiac death, are associated with cardiomyocyte lipid accumulation and altered cardiac electric properties, manifested by prolongation of the QRS duration and QT interval. It is difficult to distinguish the contribution of cardiomyocyte lipid accumulation from the contribution of global metabolic defects to the increased incidence of sudden death and electric abnormalities.In order to study the effects of metabolic abnormalities on arrhythmias without the complex systemic effects of diabetes mellitus and obesity, we studied transgenic mice with cardiac-specific overexpression of peroxisome proliferator-activated receptor γ 1 (PPARγ1) via the cardiac α-myosin heavy-chain promoter. The PPARγ transgenic mice develop abnormal accumulation of intracellular lipids and die as young adults before any significant reduction in systolic function. Using implantable ECG telemeters, we found that these mice have prolongation of the QRS and QT intervals and spontaneous ventricular arrhythmias, including polymorphic ventricular tachycardia and ventricular fibrillation. Isolated cardiomyocytes demonstrated prolonged action potential duration caused by reduced expression and function of the potassium channels responsible for repolarization. Short-term exposure to pioglitazone, a PPARγ agonist, had no effect on mortality or rhythm in WT mice but further exacerbated the arrhythmic phenotype and increased the mortality in the PPARγ transgenic mice.Our findings support an important link between PPARγ activation, cardiomyocyte lipid accumulation, ion channel remodeling, and increased cardiac mortality.
Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10
Authors: Dominique Berrebi, Stefano Bruscoli, Nicolas Cohen, Arnaud Foussat, Graziella Migliorati, Laurence Bouchet-Delbos, Marie-Christine Maillot, Alain Portier, Jacques Couderc, Pierre Galanaud, Michel Peuchmaur, Carlo Riccardi, Dominique Emilie
Journal: Blood (2002)
Branching patterns in the porcine coronary arterial tree. Estimation of flow heterogeneity.
Authors: E VanBavel, J A Spaan
Journal: Circulation Research (1992)

The aim of this study is to quantify the porcine coronary arterial branching pattern and to use this quantification for the interpretation of flow heterogeneity. Two casts of the coronary arterial tree were made at diastolic arrest and maximal dilation. The relation between length and diameter of arterial segments was quantified, as well as the area expansion ratio and diameter symmetry of vascular nodes. These relations were used to construct computer models of the coronary arterial tree, covering diameters between 10 and 500 microns. Topology of these simulated trees was analyzed using Strahler ordering: Bifurcation ratio, diameter ratio, and length ratio were constant along orders 2-8 and equal to 3.30, 1.51, and 1.63, respectively. In each order, the number of segments per Strahler vessel was almost geometrically distributed. For the lowest orders, these predictions were confirmed by direct observations. From the network model, local pressure and flow were also predicted: Pressure fell from 90 to 32 mm Hg at the 10-microns level. The coefficient of variation (CV) of flow in individual segments was dependent on the number of perfused terminal segments (Nt) according to the fractal relation CV(Nt) approximately Nt(1-D), where D is the fractal dimension (1.20). CV of flow in 1-g tissue units was predicted to be 18%. This study shows that the structure of the coronary arterial bed is an important determinant of the fractal nature of local flow heterogeneity.