tbuckley/cabot-search huggingface dataset:
High <i>Skp2</i> Expression Characterizes High-Risk Neuroblastomas Independent of <i>MYCN</i> Status
Authors: Frank Westermann, Kai-Oliver Henrich, Jun S. Wei, Werner Lutz, Matthias Fischer, Rainer König, Ruprecht Wiedemeyer, Volker Ehemann, Benedikt Brors, Karen Ernestus, Ivo Leuschner, Axel Benner, Javed Khan, Manfred Schwab
Journal: Clinical Cancer Research (2007)

Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome. However, a substantial number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified neuroblastomas even in the absence of high MYCN mRNA and/or protein levels.To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN-amplified and single-copy high-risk neuroblastomas, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk neuroblastoma tumors (n = 49) using cDNA microarrays. Candidate gene expression was validated in a separate cohort of 117 patients using quantitative PCR, and protein expression was analyzed in neuroblastoma tumors by immunoblotting and immunohistochemistry.We identified a genetic signature characterized by a subset of MYCN/MYC and E2F targets, including Skp2, encoding the F-box protein of the SCF(Skp2) E3-ligase, to be highly expressed in high-risk neuroblastomas independent of amplified MYCN. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n = 117) using quantitative PCR. High Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54; 95% confidence interval, 1.56-8.00; P = 0.002). Skp2 protein expression was inversely correlated with expression of p27, the primary target of the SCF(Skp2) E3-ligase, in neuroblastoma tumors.Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.
Pregnancy in granulomatous vasculitis.
Authors: F Lima, N Buchanan, L Froes, S Kerslake, M A Khamashta, G R Hughes
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To study the fetal and maternal outcome of pregnancy in patients with granulomatous vasculitis. METHODS--Four pregnancies in two patients with Wegener9s granulomatosis (WG) and one patient with Churg-Strauss syndrome (CSS) were identified and followed in our specialised clinic for pregnancy and connective tissue diseases. RESULTS--Three pregnancies ended with live babies and one with intrauterine death at 25 weeks of gestation. One WG patient remained in remission throughout pregnancy and the other experienced severe activity at 12 weeks. The CSS patient was in remission during her first pregnancy, but the disease flared severely in the second. CONCLUSIONS--Pregnancy in patients with granulomatous vasculitis requires preconceptual planning, careful clinical management, and vigorous treatment of active disease.
Genetic analysis of low V beta 3 expression in humans.
Authors: J P Donahue, N S Ricalton, C E Behrendt, C Rittershaus, S Calaman, P Marrack, J W Kappler, B L Kotzin
Journal: The Journal of Experimental Medicine (1994)

While studying the T cell receptor (TCR) repertoire of normal individuals, we found that more than 20% of adults have low levels of circulating V beta 3.1+ T cells in both CD4 and CD8 populations. A similar frequency was found in fetal cord blood samples, suggesting that in most cases, the V beta 3.1low phenotype is inherited. In support of this conclusion, children expressing low levels were only found in families where one of the parents expressed this phenotype. In two large families, genetic studies showed that low expression was a recessive trait and dependent on inheritance of particular TCR VB gene complexes. Family members with the low phenotype, however, expressed VB3.1 genes with normal sequences and expressed normal levels of receptor per cell. Results from these families suggest that up to 50% of normal individuals may carry a VB3.1 allele that is defective in its ability to rearrange effectively. In another large family, low expression in one individual was shown not to be determined by genes within the TCR VB gene or major histocompatibility complexes, suggesting a different mechanism for low V beta 3.1+ T cells. Overall, our results describe novel mechanisms that result in low levels of V beta 3.1+ T cells in a relatively large subset of the normal human population.
Serum C-Reactive Protein as Independent Prognostic Variable in Patients with Ovarian Cancer
Authors: Lukas A. Hefler, Nicole Concin, Gerda Hofstetter, Christian Marth, Alexander Mustea, Jalid Sehouli, Robert Zeillinger, Heinz Leipold, Harald Lass, Christoph Grimm, Clemens B. Tempfer, Alexander Reinthaller
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To evaluate serum C-reactive protein (CRP) as prognostic variable in patients with epithelial ovarian cancer (EOC). Experimental Design: In a multicenter study, preoperative serum CRP was evaluated in 623 patients with EOC. Results were correlated with clinical data. Results: Mean (SD) preoperative serum CRP was 3.6 (4.8) mg/dL. Serum CRP was significantly associated with International Federation of Gynecologists and Obstetricians stage (P &amp;lt; 0.001) and postoperative residual tumor mass (P &amp;lt; 0.001) but not with histologic grade (P = 0.1) and type (P = 0.7), patients' age (Pearson's correlation coefficient = 0.05; P = 0.2), and serum CA 125 (Pearson's correlation coefficient = 0.02; P = 0.6). Patients with platinum-resistant EOC had significantly higher CRP serum levels compared with patients with platinum-sensitive EOC [6.0 (6.6) mg/dL versus 2.8 (3.8) mg/dL; P &amp;lt; 0.001]. Higher International Federation of Gynecologists and Obstetricians stage (P &amp;lt; 0.001), presence of postoperative residual tumor mass (P &amp;lt; 0.001), tumor grade (P = 0.001), serum CA 125 (P = 0.03), and serum CRP (P = 0.001) were independently associated with overall survival. Patients with serum CRP ≤1 mg/dL versus &amp;gt;1 mg/dL had an overall 5-year survival of 82% versus 58.5% (P &amp;lt; 0.001). Conclusion: Serum CRP can be seen as a novel, widely available independent prognostic variable of ovarian cancer.
Net Risk Reclassification P Values: Valid or Misleading?
Authors: Margaret S. Pepe, Holly Janes, Christopher I. Li
Journal: JNCI Journal of the National Cancer Institute (2014)

Background The Net Reclassification Index (NRI) and its P value are used to make conclusions about improvements in prediction performance gained by adding a set of biomarkers to an existing risk prediction model. Although proposed only 5 years ago, the NRI has gained enormous traction in the risk prediction literature. Concerns have recently been raised about the statistical validity of the NRI.
ANO1 expression and activity in cystic fibrosis
Authors: Manon Ruffin, Solenne Marie, Céline Charlier, Harriet Corvol, Annick Clement, Olivier Tabary
Journal: European Respiratory Journal (2012)

Defective CFTR function in the airway epithelium is responsible for cystic fibrosis (CF) patient lung disease. CFTR represents the most important pathway for apical chloride (Cl-) secretion in human bronchial epithelial cells. Calcium activated Cl- channels (CaCCs) are also an important pathway of Cl- secretion. In 2008, three independent teams suggest that ANO1 (Anoctamine 1) also called TMEM16a could be a CaCC candidate. Mice lacking ANO1 exhibit a defect in epithelial Cl- transport and pathology similar to CF.  The main aim of this study is to characterize ANO1 protein in CF vs non CF context.  For this study, we used different CF and non CF models whose cell lines, mice and lung explants from CF and non CF patients.  Our results show that ANO1 expression and activity are significantly decreased in CF compared to non CF models.  ANO1 is expressed at plasma membrane of bronchial epithelial cells and there is no difference in localization between CF and non CF cells. To understand the differential expression between CF and non-CF cells/tissus we will investigate miRNA expression that could modulate ANO1 protein.  We conclude that decreased ANO1 activity in CF cells could be explained by decreased ANO1 ARNm and protein expression and may contribute to the worsening of ionic imbalance and decrease lung function.  All of these results lead us to think that this Cl- channel could be a potential pharmacological target for the treatment of cystic fibrosis patients.
Interactions of Fc receptors with antibodies against Ia antigens and other cell surface components.
Authors: V Schirrmacher, P Halloran, C S David
Journal: The Journal of Experimental Medicine (1975)

Two Fc receptor-dependent tests were investigated to study the question of a relationship between Fc receptors and known cell surface antigens, in particular I region-associated (Ia) antigens: (a) a rosette assay with antibody-coated erythrocytes (EA) as indicator cells and normal mouse lymphoid cells as source of rosette-forming cells, and (b) a cytotoxicity test with antibody-coated erythrocytes as target cells and normal mouse spleen cells as a source of cytotoxic cells (K cells). EA rosettes were specifically inhibited by antibodies reacting with Ia antigens. Various other antisera reacting with antigens on B lymphocytes, like anti-Ly 4.2 (raised in H-2 identical mice), rabbit antimouse B-cell serum, or rabbit antimouse immunoglobulin, also specifically inhibited the rosettes. No inhibition occurred in the presence of allogeneic or xenogeneic antisera reacting with T lymphocytes. K-cell cytotoxicity was specifically inhibited by each of the antisera (reacting with either B cells or T cells). F(ab')2 fragments of anti-Ia antibodies could still specifically inhibit EA rosettes but they could not inhibit K-cell cytotoxicity. Similar results were obtained with F(ab')2 fragments of anti-immunoglobulin antibodies. These results indicate that the mechanism of inhibition of Fc receptors in the two tests was different. In neither of the tests could we find any evidence for a unique association between the Fc receptors and Ia antigens. The Fc receptors on K cells did not seem to be associated at all with Ia antigens.
Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on All-Cause Mortality, Cardiovascular Deaths, and Cardiovascular Events in Patients With Diabetes Mellitus
Authors: Jun Cheng, Wen Zhang, Xiaohui Zhang, Fei Han, Xiayu Li, Xuelin He, Qun Li, Jianghua Chen
Journal: JAMA Internal Medicine (2014)

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may have different effects on cardiovascular (CV) events in patients with diabetes mellitus (DM).To conduct a meta-analysis to separately evaluate the effects of ACEIs and ARBs on all-cause mortality, CV deaths, and major CV events in patients with DM. DATA SOURCES Data sources included MEDLINE (1966-2012), EMBASE (1988-2012), the Cochrane Central Register of Controlled Trials, conference proceedings, and article reference lists.We included randomized clinical trials reporting the effects of ACEI and ARB regimens for DM on all-cause mortality, CV deaths, and major CV events with an observation period of at least 12 months. Studies were excluded if they were crossover trials.Dichotomous outcome data from individual trials were analyzed using the risk ratio (RR) measure and its 95% CI with random-effects models. We estimated the difference between the estimates of the subgroups according to tests for interaction. We performed meta-regression analyses to identify sources of heterogeneity.Primary end points were all-cause mortality and death from CV causes. Secondary end points were the effects of ACEIs and ARBs on major CV events.Twenty-three of 35 identified trials compared ACEIs with placebo or active drugs (32,827 patients) and 13 compared ARBs with no therapy (controls) (23,867 patients). When compared with controls (placebo/active treatment), ACEIs significantly reduced the risk of all-cause mortality by 13% (RR, 0.87; 95% CI, 0.78-0.98), CV deaths by 17% (0.83; 0.70-0.99), and major CV events by 14% (0.86; 0.77-0.95), including myocardial infarction by 21% (0.79; 0.65-0.95) and heart failure by 19% (0.81; 0.71-0.93). Treatment with ARBs did not significantly affect all-cause mortality (RR, 0.94; 95% CI, 0.82-1.08), CV death rate (1.21; 0.81-1.80), and major CV events (0.94; 0.85-1.01) with the exception of heart failure (0.70; 0.59-0.82). Both ACEIs and ARBs were not associated with a decrease in the risk for stroke in patients with DM. Meta-regression analysis showed that the ACEI treatment effect on all-cause mortality and CV death did not vary significantly with the starting baseline blood pressure and proteinuria of the trial participants and the type of ACEI and DM.Angiotensin-converting enzyme inhibitors reduced all-cause mortality, CV mortality, and major CV events in patients with DM, whereas ARBs had no benefits on these outcomes. Thus, ACEIs should be considered as first-line therapy to limit excess mortality and morbidity in this population.
High PTP4A3 Phosphatase Expression Correlates with Metastatic Risk in Uveal Melanoma Patients
Authors: Cécile Laurent, Fabien Valet, Nathalie Planque, Licia Silveri, Selma Maacha, Océane Anezo, Philippe Hupe, Corine Plancher, Cécile Reyes, Benoit Albaud, Audrey Rapinat, David Gentien, Jérôme Couturier, Xavier Sastre-Garau, Laurence Desjardins, Jean-Paul Thiery, Sergio Roman-Roman, Bernard Asselain, Emmanuel Barillot, Sophie Piperno-Neumann, Simon Saule
Journal: Cancer Research (2010)

A high percentage of uveal melanoma patients develop metastatic tumors predominantly in the liver. We studied the molecular profiles derived from gene expression microarrays and comparative genomic hybridization microarrays, to identify genes associated with metastasis in this aggressive cancer. We compared 28 uveal melanomas from patients who developed liver metastases within three years of enucleation with 35 tumors from patients without metastases or who developed metastases more than 3 years after enucleation. Protein tyrosine phosphatase type IV A member 3 (PTP4A3/PRL3), was identified as a strong predictor of metastasis occurrence. We demonstrated that the differential expression of this gene, which maps to 8q24.3, was not merely a consequence of 8q chromosome overrepresentation. PTP4A3 overexpression in uveal melanoma cell lines significantly increased cell migration and invasiveness in vivo, suggesting a direct role for this protein in metastasis. Our findings suggest that PTP4A3 or its cellular substrates could constitute attractive therapeutic targets to treat metastatic uveal melanomas.
Radioiodine Treatment of Paroxysmal Supraventricular Tachycardia in the Euthyroid Patient
Authors: ELIOT CORDAY, HERBERT GOLD, HENRY L. JAFFE
Journal: Circulation (1958)

Twenty-five euthyroid patients subject to recurrent paroxysmal supraventricular tachycardias, which were resistant to usual prophylactic therapy, were treated with radioactive iodine. In many of the patients, with follow-up ranging up to 6 years, there were no recurrences of the tachycardia subsequent to the isotope therapy. Two patients were considered refractory to this therapy.
Surviving low oxygen
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Hypoxia-inducible factor–1α (HIF-1α) prolongs the life of oxygen-deprived neutrophils by inducing NF-κB–driven survival signals, according to a study by Walmsley et al. on page 105. HIF-1α, a transcription factor induced by low oxygen, is required for myeloid cell function but has never been linked to myeloid apoptosis. Walmsley et al. now show that cells lacking this protein are robbed of the ability to resist apoptosis in low-oxygen environments like those encountered in wounds and inflamed tissues.






Figure 

Neutrophils no longer survive hypoxia in the absence of HIF-1α.




Neutrophils must function in adverse environments where oxygen and nutrient supplies are low. To do this, they turn on HIF-1α, which drives the synthesis of enzymes that make ATP anaerobically. In mice whose myeloid cells lack HIF-1α, the cells quickly lose their ATP supplies and thus have no energy to migrate or function in response to inflammatory stimuli.

Neutrophils also delay apoptosis during hypoxia, and the authors now show HIF-1α is required for this delay. The accelerated death could be mimicked in HIF-1α–positive cells by blocking NF-κB, suggesting a key role for this transcription factor in prolonging survival. The authors speculate that the ability of HIF-1α to induce neutrophil survival might contribute to a delayed resolution of inflammation, making a bad situation even worse.
Association of pulmonary dysfunction with physical inactivity and loss of muscle mass in elderly COPD patients
Authors: Kazuya Yoshimura, Susumu Sato, Shigeo Muro, Minoru Yamada, Hirofumi Kiyokawa, Michiaki Mishima, Tomoki Aoyama
Journal: European Respiratory Journal (2013)

Sustaining muscle mass and physical activity are important in terms of physical functions and quality of life of COPD patients. However, it is still unclear as well as difficult to understand whether the relationship between muscle wasting and physical inactivity in COPD patients is disease specific or due to physiological aging. The present study aimed to determine the pulmonary factors associated with muscle mass and physical activity among elderly patients with COPD by analyzing specific respiratory functions, body composition, physical activity, and daily diet.

We enrolled outpatients with COPD who were aged ≥60 years. Pulmonary function tests (spirometry, residual volume, total lung capacity, and diffusing capacity) were performed. Skeletal muscle mass index (SMI) was measured using bioelectrical impedance, and then, daily physical activity and intake of energy or protein were recorded for 2 weeks using a pedometer and the food frequency questionnaire.

Thirty-eight patients (mean age and %FEV1; 74.8 y.o. and 49.5%) were investigated. SMI had a significant positive relationship with BMI (r = 0.63) and %DLCO (r = 0.47) after controlling for %FEV1. The number of daily steps showed a relationship with %FVC, %DLCO, SMI, and energy and protein intake. These measurements were significant after controlling for %FEV1. Multivariate analysis showed that %FVC (β = 0.40) and SMI (β = 0.44) were the determinants of number of daily steps.

Both muscle mass and physical activity were associated with %DLCO and %FVC, respectively, and were independent of %FEV1. These pulmonary factors may be used as markers to predict physical function among COPD patients.
Antitumor Action of cis-Dichlorobis(methylamine)platinum(II)2
Authors: Glen R. Gale, Michael G. Rosenblum, Loretta M. Atkins, Ernest M. Walker, Alayne B. Smith, Sandra J. Meischen
Journal: JNCI Journal of the National Cancer Institute (1973)

cis-Dichlorobis(methyla mine) platinum(II) (cis-DMAP) induced unbalanced growth in Escherichia coli and prolonged survival times of BALB/c mice bearing the Ehrlich ascites tumor as well as of (C57BL × DBA/2)F1 mice bearing the L1210 leukemia. In vitro, cis-DMAP inhibited the synthesis of DNA, RNA, and, to a lesser extent, protein in Ehrlich ascites tumor cells. Inhibition once conferred was irreversible when the cells were washed with fresh medium. Suspensions of tumor cells became approximately 95% nonviable after 7.5 hours of incubation with the compound at 10-4M. cis-DMAP-3H bound firmly to intact tumor cells in vitro, and the response of this interaction to various chemical and physical influences indicated that binding was not mediated enzymatically. cis-DMAP-3H, which was bound to cells, was not removed on precipitation and washing with trichloroacetic acid. cis-DMAP-3H did bind to isolated DNA and RNA but not to bovine serum albumin. Dialysis experiments with the polynucleotides of adenine (A), cytosine (C), guanine (G), and uridine (U) showed that the relative degree of binding occurred in the order poly-U> poly-G> poly-A>poly-C. About 50% of an injected dose of cis-DMAP-3H was excreted in urine by rats in 24 hours, and no appreciable amount was excreted in feces. Studies of distribution of radioactivity from cis-DMAP-3H in organs of rats showed an initially high value in kidneys and liver followed by a decline. The amount recovered in lungs was relatively constant over the 96-hour period of measurement. The relative rates of the hydrolytic aquation reactions in a series of organo-substituted square planar platinum (II) complexes may have some value in predicting the relative anti-tumor effectiveness within the series.
Effect of Various Diuretic Treatments on Rosiglitazone-Induced Fluid Retention
Authors: Janaka Karalliedde, Robin Buckingham, Margaret Starkie, Daniel Lorand, Murray Stewart, Giancarlo Viberti
Journal: Journal of the American Society of Nephrology (2006)

The efficacy of diuretics in the management of rosiglitazone (RSG)-induced fluid retention was evaluated in a multicenter, randomized, open-label, parallel-group, proof-of-concept study. Of 381 patients who had type 2 diabetes and were on treatment with sulfonylurea or sulfonylurea plus metformin, 260 (63% male, 37% female) showed evidence of volume expansion as defined by an absolute reduction in hematocrit (Hct) of > or =0.5% after 12 wk of rosiglitazone 4 mg twice daily. They were randomly assigned to five treatments for 7 d: (1) Continuation of RSG (RSG-C), (2) RSG + furosemide (RSG+FRUS), (3) RSG + hydrochlorothiazide (RSG+HCTZ), (4) RSG + spironolactone (RSG+SPIRO), and (5) discontinuation of RSG. The primary end point was change in Hct at day 7 of diuretic treatment phase, powered to compare each diuretic group and the RSG discontinuation with the control group of RSG-C, with adjustments for multiple testing. After 12 wk on RSG, Hct fell by mean of 2.92% (95% confidence interval [CI] -3.10 to -2.63%; P < 0.001) and extracellular fluid volume increased by 0.62 L/1.73 m(2) (95% CI 0.26 to 0.90 L/1.73 m(2); P < 0.001). After treatment, the RSG+SPIRO group only showed a mean increase in Hct of 0.24%. The estimated mean difference in Hct reduction was significant: 1.14% (95% CI 0.29 to 1.98%) for RSG+SPIRO (P = 0.004) and 0.87% (95% CI 0.03 to 1.71%) for RSG+HCTZ (P = 0.041) only. In additional analyses of between-diuretic treatment effects SPIRO induced a greater Hct rescue at 0.88% (95% CI -0.12 to 1.87%; P = 0.095) and extracellular fluid volume reduction of -0.75 L/1.73 m(2) (95% CI -1.52 to 0.03 L/1.73 m(2); P = 0.06) compared with FRUS, suggesting superiority in the management of RSG-associated fluid retention. There were no significant differences between SPIRO and HCTZ. These findings are consistent with peroxisome proliferator-activated receptor-gamma agonist activation of the epithelial sodium channel in the distal collecting duct, a site of action of SPIRO and a potential target for thiazide diuretics.