tbuckley/cabot-search huggingface dataset:
Combination of a Novel Gene Expression Signature with a Clinical Nomogram Improves the Prediction of Survival in High-Risk Bladder Cancer
Authors: Markus Riester, Jennifer M. Taylor, Andrew Feifer, Theresa Koppie, Jonathan E. Rosenberg, Robert J. Downey, Bernard H. Bochner, Franziska Michor
Journal: Clinical Cancer Research (2012)

Abstract Purpose: We aimed to validate and improve prognostic signatures for high-risk urothelial carcinoma of the bladder. Experimental Design: We evaluated microarray data from 93 patients with bladder cancer managed by radical cystectomy to determine gene expression patterns associated with clinical and prognostic variables. We compared our results with published bladder cancer microarray data sets comprising 578 additional patients and with 49 published gene signatures from multiple cancer types. Hierarchical clustering was utilized to identify subtypes associated with differences in survival. We then investigated whether the addition of survival-associated gene expression information to a validated postcystectomy nomogram utilizing clinical and pathologic variables improves prediction of recurrence. Results: Multiple markers for muscle invasive disease with highly significant expression differences in multiple data sets were identified, such as fibronectin 1 (FN1), NNMT, POSTN, and SMAD6. We identified signatures associated with pathologic stage and the likelihood of developing metastasis and death from bladder cancer, as well as with two distinct clustering subtypes of bladder cancer. Our novel signature correlated with overall survival in multiple independent data sets, significantly improving the prediction concordance of standard staging in all data sets [mean ΔC-statistic: 0.14; 95% confidence interval (CI), 0.01–0.27; P &amp;lt; 0.001]. Tested in our patient cohort, it significantly enhanced the performance of a postoperative survival nomogram (ΔC-statistic: 0.08, 95% CI, −0.04–0.20; P &amp;lt; 0.005). Conclusions: Prognostic information obtained from gene expression data can aid in posttreatment prediction of bladder cancer recurrence. Our findings require further validation in external cohorts and prospectively in a clinical trial setting. Clin Cancer Res; 18(5); 1323–33. ©2012 AACR.
Potentiation of Taxol Efficacy by Discodermolide in Ovarian Carcinoma Xenograft-Bearing Mice
Authors: Gloria S. Huang, Lluis Lopez-Barcons, B. Scott Freeze, Amos B. Smith, Gary L. Goldberg, Susan Band Horwitz, Hayley M. McDaid
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To evaluate the drug combination of discodermolide and Taxol in human ovarian cancer cells and in an in vivo model of ovarian carcinoma. Experimental Design: The combination index method was used to evaluate the interaction of Taxol and discodermolide in human ovarian SKOV-3 carcinoma cells. Data were correlated with alterations in cell cycle distribution and caspase activation. In addition, SKOV-3 xenograft-bearing mice were treated with either Taxol, discodermolide, or a combination of both drugs given concurrently to evaluate the antitumor efficacy and toxicity of this combination. The Matrigel plug assay and CD31 immunohistochemistry were done to assess antiangiogenic effects. Results: Taxol and discodermolide interact synergistically over a range of concentrations and molar ratios that cause drug-induced aneuploidy in ovarian carcinoma cells. In SKOV-3 xenograft-bearing mice, the combination is significantly superior to either single agent, and induces tumor regressions without notable toxicities. Immunohistochemical analysis of CD31 and Matrigel plug analysis show decreased vessel formation in mice treated with the combination relative to either drug alone. Conclusions: The synergistic activity of Taxol and discodermolide in cells is most potent at drug concentrations that result in drug-induced aneuploidy rather than mitotic arrest. Moreover, in an animal model of ovarian carcinoma, this is a well-tolerated combination that induces tumor regressions and suppresses angiogenesis. These data confirm the potency of this combination and support the use of concurrent low doses of Taxol and discodermolide for potential use in cancer therapeutics.
Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation
Authors: Bermans J. Iskandar, Elias Rizk, Brenton Meier, Nithya Hariharan, Teodoro Bottiglieri, Richard H. Finnell, David F. Jarrard, Ruma V. Banerjee, J.H. Pate Skene, Aaron Nelson, Nirav Patel, Carmen Gherasim, Kathleen Simon, Thomas D. Cook, Kirk J. Hogan
Journal: Journal of Clinical Investigation (2010)

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.
NHS is on track to meet 65% of efficiency target by April, officials say
Authors: A. O'Dowd
Journal: BMJ (2013)

<h3>Abstract</h3> Parkinson’s disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (α-syn) into Lewy body aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests α-syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes a potential trigger initiating the misfolding of α-syn. However, changes in the gut virome in response to α-syn alterations have not been investigated. In this study, we show longitudinal changes in the faecal virome of rats administered either monomeric or preformed fibrils (PFF) of α-syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF α-syn. The virome β-diversity changes after α-syn treatment were compounded by the addition of LPS as an adjunct. Changes in the diversity of rat faecal viromes were observed after one month and did not resolve within the study’s five month observational period. Overall, these results suggest that microbiome alterations associated with PD may, partially, be reactive to host α-syn associated changes.
Chronic platelet-activating factor induces a decrease in pulmonary vascular compliance, hydroxyproline, and loss of vascular matrix.
Authors: J A Ohar, K S Waller, J Pantano, D E Demello, T E Dahms
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

We have previously demonstrated that chronic intravenous platelet-activating factor (PAF) induces morphologic remodeling of pulmonary arteries characterized by a decrease in internal and external elastic lamina circumference, pulmonary arterial contracture, and internal elastic lamina duplication. The mechanism of PAF-induced arterial contracture is unknown. In this study we determined whether PAF caused arterial contracture through cell loss by calculating the number of cell nuclei/total cross-sectional area of arteries. The nuclear ratio was increased in intra- and preacinar pulmonary arteries of PAF-treated rabbits. Hydroxyproline content of lungs stratified by anatomic region was significantly reduced in intra-acinar tissue of PAF-treated rabbits, indicating that PAF-induced vascular contracture was associated with loss of interstitial collagen. We next tested whether these morphologic alterations were associated with decreased pulmonary vascular compliance and increased resistance. Compliance and resistance were determined in isolated, perfused lungs from rabbits chronically treated with PAF. Compliance was calculated: (1) from the slope of the venous occlusion trace (CVO), (2) by increasing left atrial pressure (CLA), (3) by increasing flow (CHF), and (4) by the classic static technique (CAV) of adding volume (2 ml) to a passively drained lung. Vascular compliance was significantly reduced in PAF-treated lungs when measured by all four methods; however, pulmonary vascular resistance was unchanged. We conclude that structural changes that result from chronic intravenous PAF infusion affect the elastic modulus to a greater extent than factors that influence pulmonary vascular resistance.
Treatment With Growth Hormone Enhances Contractile Reserve and Intracellular Calcium Transients in Myocytes From Rats With Postinfarction Heart Failure
Authors: Minori Tajima, Ellen O. Weinberg, Jozef Bartunek, Hongkui Jin, Renhui Yang, Nicholas F. Paoni, Beverly H. Lorell
Journal: Circulation (1999)

Background —Recombinant human growth hormone (GH) improves in vivo cardiac function in rats with postinfarction heart failure (MI). We examined the effects of growth hormone (14 days of 3.5 mg · kg −1 · d −1 begun 4 weeks after MI) on contractile reserve in left ventricular myocytes from rats with chronic postinfarction heart failure. Methods and Results —Cell shortening and [Ca 2+ ] i were measured with the indicator fluo 3 in myocytes from MI, MI+GH, control, and normal animals treated with GH (C+GH) under stimulation at 0.5 Hz at 37°C. Cell length was similar in MI and MI+GH rats (150±5 and 157±5 μm) and was greater in these groups than in the control and C+GH groups (140±4 and 139±4 μm, P &lt;0.05). At baseline perfusate calcium of 1.2 mmol/L, myocyte fractional shortening and [Ca 2+ ] i transients were similar among the 4 groups. We then assessed contractile reserve by measuring the increase in myocyte fractional shortening in the presence of high-perfusate calcium of 3.5 mmol/L. In the control and C+GH groups, myocyte fractional shortening and peak systolic [Ca 2+ ] i were similarly increased in the presence of high-perfusate calcium. In the presence of high-perfusate calcium, both myocyte fractional shortening and peak systolic [Ca 2+ ] i were depressed in the MI compared with the control groups. In contrast, myocyte fractional shortening (14.1±.9% versus 11.1±.9%, P &lt;0.05) and peak systolic [Ca 2+ ] i (647±43 versus 509±37 nmol/L, P &lt;0.05) were significantly higher in MI+GH than in MI rats and were comparable to controls. Left ventricular myocyte expression of sarcoplasmic reticulum Ca 2+ ATPase 2 (SERCA-2) and left ventricular SERCA-2 protein levels were increased in MI+GH compared with MI rats. Conclusions —Calcium-dependent contractile reserve is depressed in myocytes from rats with postinfarction heart failure. Long-term growth hormone therapy increases contractile reserve by restoring normal augmentation of systolic [Ca 2+ ] i in myocytes from rats with postinfarction heart failure.
Electrocardiographic Changes Produced by Potassium and Other Ions Injected into the Coronary Arteries of Intact Dogs
Authors: LOUIS A. SOLOFF, GUIDO ASCANIO DE LOS SANTOS, M. J. OPPENHEIMER
Journal: Circulation Research (1960)

Ions injected into the circumflex branch of the left coronary artery of the intact dog produce sequential electrocardiographic changes different from those produced by exposure of the entire heart to these ions. Of all substances tested, the contour of the surface electrocardiogram is most sensitive to potassium. The electrocardiographic sequence of alterations produced by potassium so injected are characteristic and similar to those produced by subtotal and total occlusion of a coronary artery.
Outcomes of the Largest Series of Transcatheter Aortic Valve Implantation with the CoreValve in Turkey: First Experiences in High Implantation Strategy
Authors: Mehmet Bilge, Recai Alemdar, Sina Ali, Ayse Saatci Yasar, Özgür Kırba, Turgay Aslan, Cemal Köseoglu, Bilge Karaduman Duran, Özge Kurmus, Mehmet Erdogan, Mustafa Duran, Serkan Sivri, Zeynep Seyma Turinay
Journal: Journal of the American College of Cardiology (2013)
Life Course Influences on Insulin Resistance
Authors: Debbie A. Lawlor, George Davey Smith, Shah Ebrahim
Journal: Diabetes Care (2003)

OBJECTIVE—To assess the independent associations of a broad range of early life risk factors and adult obesity with adult insulin resistance. RESEARCH DESIGN AND METHODS—This was a cross-sectional study of 1,394 women, aged 60–79 years, from 23 British towns. RESULTS—There was a strong (independent of confounding factors, other early life factors, and adult waist-to-hip ratio) inverse association between birth weight and insulin resistance in women in the highest third of BMI (&amp;gt;28.77 kg/m2): −0.12 (95% CI −0.19 to −0.04) log homeostasis model assessment (HOMA) score per 1 SD birth weight, but no association between birth weight and insulin resistance in women in the two lowest thirds of BMI (P for interaction = 0.04). Offspring birth weight, own leg length, and childhood manual social class did not interact with adult obesity and were all independently inversely associated with insulin resistance: −0.05 (−0.09 to −0.01) log HOMA score per 1 SD offspring birth weight, −0.09 (−0.12 to −0.06) log HOMA score per 1 SD leg length, and a −0.07 (−0.14 to 0.00) difference in log HOMA score between manual and nonmanual childhood social class. Childhood manual social class and shorter leg length were both independently associated with adverse lipid profiles. BMI and waist-to-hip ratio were independently positively associated with insulin resistance and with all other components of the insulin resistance syndrome. CONCLUSIONS—Insulin resistance is an important risk factor for type 2 diabetes and coronary heart disease. Our results suggest that genetic factors, intrauterine environment, early childhood, and adult environmental factors are all relevant in determining adult insulin resistance.
Regression and inhibition of sarcoma growth by interference with a radiosensitive T-cell population.
Authors: K E Hellström, I Hellström, J A Kant, J D Tamerius
Journal: The Journal of Experimental Medicine (1978)

BALB/c mice were inoculated subcutaneously with 10(6) cells from either of two syngeneic sarcomas 1315 and 1425. 6--8 days later, the mice were randomized into groups which were left untreated or given 400 rads of whole body irradiation. Irradiation significantly retarded the growth of both sarcomas, and complete regressions were seen of approximately equal to 30% of the small, established 1315 tumors. The anti-tumor effect of irradiation was abolished if the irradiated mice were inoculated with a T-cell-enriched (but not with a T-cell deprived) suspension of syngeneic spleen cells, suggesting that the irradiation inhibited tumor growth by affecting a radiosensitive population of host suppressor T cells.
Nonmetastatic Ewing family tumors: high-dose chemotherapy with stem cell rescue in poor responder patients. Results of the Italian Sarcoma Group/Scandinavian Sarcoma Group III protocol
Authors: S Ferrari, K Sundby Hall, R Luksch, A Tienghi, T Wiebe, F Fagioli, T A Alvegard, A Brach Del Prever, A Tamburini, M Alberghini, L Gandola, M Mercuri, R Capanna, S Mapelli, A Prete, M Carli, P Picci, E Barbieri, G Bacci, S Smeland
Journal: Annals of Oncology (2010)
Totally implantable venous access devices in cystic fibrosis: complications and patients' opinions
Authors: HC Rodgers, K Liddle, SJ Nixon, JA Innes, AP Greening
Journal: European Respiratory Journal (1998)

The introduction of totally implantable venous access devices (TIVAD) has provided a solution to difficult venous access in patients with cystic fibrosis. Early reports have, however, recognized a number of complications with their use. We report our experience with five devices used over 8 yrs with regard to complications and patient attitudes. Patients' notes were reviewed to record the details of TIVAD insertion, duration of function, and complications. In January 1996 the surviving 30 patients were surveyed on their attitudes to TIVAD and complications by written questionnaire. Sixty one ports were implanted in 42 patients (aged 16-47 yrs) between June 1988 and January 1996, giving a total of 1,510 patient-months' experience. The duration of function ranged from 2 weeks to 6 yrs. Survival analysis showed that the median survival of ports was 53 months, 42 out of 61 (69%) had not failed in service at the end of follow-up or patient death. Twenty-three complications occurred in 19 patients. These included: line occlusion (10 patients), venous thrombosis (4), difficult access (3), infection (2), cellulitis (1), inversion of port chamber (2) and pneumothorax (1). The questionnaire showed that patients had strong views on the positioning of their port. Lifestyle issues included interference with seatbelts (8 patients), sport (4), clothing (2), sexual relations (2) and cosmetic appearance (15). Complication rates were similar to those in other studies, although infection rates and salvage of an occluded port were lower. The survey highlighted a number of lifestyle issues, with cosmetic appearance deemed unsatisfactory by half of the patients. However, the majority (28 out of 30) believed their totally implantable venous access devices to be a better alternative to cannulae or long lines.
Superoxide Signaling Mediates <i>N</i>-acetyl-<scp>l</scp>-cysteine–Induced G1 Arrest: Regulatory Role of Cyclin D1 and Manganese Superoxide Dismutase
Authors: Sarita G. Menon, Ehab H. Sarsour, Amanda L. Kalen, Sujatha Venkataraman, Michael J. Hitchler, Frederick E. Domann, Larry W. Oberley, Prabhat C. Goswami
Journal: Cancer Research (2007)

Abstract Thiol antioxidants, including N-acetyl-l-cysteine (NAC), are widely used as modulators of the intracellular redox state. We investigated the hypothesis that NAC-induced reactive oxygen species (ROS) signaling perturbs cellular proliferation by regulating the cell cycle regulatory protein cyclin D1 and the ROS scavenging enzyme Mn–superoxide dismutase (MnSOD). When cultured in media containing NAC, mouse fibroblasts showed G1 arrest with decreased cyclin D1 protein levels. The absence of a NAC-induced G1 arrest in fibroblasts overexpressing cyclin D1 (or a nondegradable mutant of cyclin D1-T286A) indicates that cyclin D1 regulates this G1 arrest. A delayed response to NAC exposure was an increase in both MnSOD protein and activity. NAC-induced G1 arrest is exacerbated in MnSOD heterozygous fibroblasts. Results from electron spin resonance spectroscopy and flow cytometry measurements of dihydroethidine fluorescence showed an approximately 2-fold to 3-fold increase in the steady-state levels of superoxide (O2•−) in NAC-treated cells compared with control. Scavenging of O2•− with Tiron reversed the NAC-induced G1 arrest. These results show that an O2•− signaling pathway regulates NAC-induced G1 arrest by decreasing cyclin D1 protein levels and increasing MnSOD activity. [Cancer Res 2007;67(13):6392–9]
Should chronic obstructive pulmonary disease patients must be vaccinated
Authors: Pinar Cimen, Fatma Ucsular, Cenk Kirakli, Nuran Katgi, Salih Guclu
Journal: European Respiratory Journal (2013)

Chronic obstructive pulmonary disease (COPD) patients have 2 or 4 exacerbations in a year, especially during the winter months. Tracheobronchial infections are responsible from the 50% to 70% of acute exacerbations. Exacerbations of COPD cause frequent emergency and hospital admissions, influence health-related quality of life and increase mortality. In this study we aimed to determine the level of knowledge and rates of influenza and pneumococcal vaccination in COPD patients, we investigated the effect of the vaccine about the emergency department and hospital admission rate. 88 COPD patients admitted to our outpatient clinic between September-October 2012 were included. Educational levels of patients, history of vaccination, emergency and hospital admission in one year were questioned. 70% of patients went to the primary school, 24% of middle school / high school, %1 of university graduates, and 5% of the patients were illliterate. 51% of the patients have been vaccinated and 49% of them not vaccinated. There was no relationship between educational level and the rate of vaccine administration. Emergency and hospital admissions were significantly decreased in vaccinated COPD patients (respectively p
P-Selectin or Intercellular Adhesion Molecule (Icam)-1 Deficiency Substantially Protects against Atherosclerosis in <b>Apolipoprotein E</b>–Deficient Mice
Authors: Robert G. Collins, Rizwan Velji, Natalia V. Guevara, M. John Hicks, Lawrence Chan, Arthur L. Beaudet
Journal: The Journal of Experimental Medicine (2000)

The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory response. The importance of the inflammatory response in the development of atherosclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone areas and by protection in mice deficient in various aspects of the inflammatory response. We have quantitated the effect of deficiency for intercellular adhesion molecule (ICAM)-1, P-selectin, or E-selectin on atherosclerotic lesion formation at 20 wk of age in apolipoprotein (apo) E−/− (deficient) mice fed a normal chow diet. All mice were apo E−/− and CAM+/+ or CAM−/− littermates, and no differences were found in body weight or cholesterol levels among the various genotypes during the study. ICAM-1−/− mice had significantly less lesion area than their ICAM-1+/+ littermates: 4.08 ± 0.70 mm2 for −/− males vs. 5.87 ± 0.66 mm2 for +/+ males, and 3.95 ± 0.65 mm2 for −/− females vs. 5.59 ± 1.131 mm2 for +/+ females, combined P &amp;lt; 0.0001. An even greater reduction in lesion area was observed in P-selectin−/− mice: 3.06 ± 1.04 mm2 for −/− males vs. 5.09 ± 1.22 mm2 for +/+ males, and 2.85 ± 1.26 mm2 for −/− females compared with 5.60 ± 1.19 mm2 for +/+ females, combined P &amp;lt; 0.001. The reduction in lesion area for the E-selectin null mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 ± 2.14 mm2 for −/− males vs. 5.92 ± 0.63 mm2 for +/+ males, and 4.38 ± 0.85 mm2 for −/− females compared with 5.94 ± 1.44 mm2 for +/+ females, combined P &amp;lt; 0.01). These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.