tbuckley/cabot-search huggingface dataset:
The costs of asthma
Authors: PJ Barnes, B Jonsson, JB Klim
Journal: European Respiratory Journal (1996)

At present, asthma represents a substantial burden on health care resources in all countries so far studied. The costs of asthma are largely due to uncontrolled disease, and are likely to rise as its prevalence and severity increase. Costs could be significantly reduced if disease control is improved. A large proportion of the total cost of illness is derived from treating the consequences of poor asthma control-direct costs, such as emergency room use and hospitalizations. Indirect costs, which include time off work or school and early retirement, are incurred when the disease is not fully controlled and becomes severe enough to have an effect on daily life. In addition, quality of life assessments show that asthma has a significant socioeconomic impact, not only on the patients themselves, but on the whole family. Underuse of prescribed therapy, which includes poor compliance, significantly contributes towards the poor control of asthma. The consequences of poor compliance in asthma include increased morbidity and sometimes mortality, and increased health care expenditure. To improve asthma management, international guidelines have been introduced which recommend an increase in the use of prophylactic therapy. The resulting improvements in the control of asthma will reduce the number of hospitalizations associated with asthma, and may ultimately produce a shift within direct costs, with subsequent reductions in indirect costs. In addition, costs may be reduced by improving therapeutic interventions and through effective patient education programmes. This paper reviews current literature on the costs of asthma to assess how effectively money is spent and, by estimating the proportion of the cost attributable to uncontrolled disease, will identify where financial savings might be made.
Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure
Authors: Anil-Martin Sinha, Erik C Skobel, Ole-Alexander Breithardt, Christine Norra, Kai U Markus, Christian Breuer, Peter Hanrath, Christoph Stellbrink
Journal: Journal of the American College of Cardiology (2004)
Nitric oxide release as an essential mitigating step in tubuloglomerular feedback
Authors: E Turkstra, B Braam, H A Koomans
Journal: Journal of the American Society of Nephrology (1998)

Nitric oxide synthase inhibition in the kidney enhances tubuloglomerular feedback (TGF) responsiveness. This may reflect either the effect of reduced basal nitric oxide (NO) availability or the effect of impaired NO release that is physiologically induced by TGF activation. However, it is unknown whether the latter actually takes place. In this study, it was hypothesized that NO is released (from macula densa cells or endothelium) as part of the normal TGF loop, and mitigates the TGF response. In Sprague Dawley rats, TGF responsiveness was assessed (fall in tubular stop flow pressure, deltaSFP, upon switching loop of Henle perfusion rates from 0 to 40 nl/min) during an intrarenal NO clamp (systemic infusion of nitro-L-arginine, 10 microg/kg per min, followed by intrarenal nitroprusside infusion adjusted to restore renal blood flow [RBF]). This maneuver was presumed to fix intrarenal NO impact at a physiologic level. To validate the approach, TGF responsiveness during an intrarenal angiotensin II (AngII) clamp (systemic infusion of enalaprilat 0.2 mg/kg per min, followed by intrarenal AngII infusion) was also studied. AngII is presumed to modulate but not mediate, TGF, thus not to increase as part of the TGF loop. In untreated animals, RBF was 7.4 +/- 0.4 ml/min, and deltaSFP was 5.7 +/- 1.6 mmHg. Nitro-L-arginine infusion alone reduced RBF to 5.3 +/- 0.5 ml/min (P < 0.05); with nitroprusside infusion, RBF was restored to 8.3 +/- 0.7 ml/min. In this condition (NO clamp), deltaSFP was markedly increased to 19.6 +/- 3.2 mmHg (P < 0.05). By contrast, deltaSFP, which was virtually abolished during enalaprilat alone (0.2 +/- 0.3 mmHg), was not significantly different from controls during AngII clamp (8.2 +/- 1.0 mmHg). These data suggest that NO may well be released upon TGF activation. By contrast, AngII is not dynamically involved in TGF activation, but may modulate the TGF response. Thus, dynamic release of NO during TGF activation mitigates the TGF response, so that it will offset the action of a primary, as yet undefined, vasoconstrictor mediator. The source of this NO, macula densa or endothelium, remains to be elucidated.
Induction of Apoptosis in Small-Cell Lung Cancer Cells by an Antisense Oligodeoxynucleotide Targeting the Bcl-2 Coding Sequence
Authors: A. Ziegler, G. H. Luedke, R. A. Stahel, U. Zangemeister-Wittke, D. Fabbro, K.-H. Altmann
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: The emergence of resistance to chemotherapy remains a major problem in the treatment of patients with small-cell lung cancer. Elevated expression of Bcl-2, a protein that inhibits programmed cell death or apoptosis, has been associated with radiation and drug resistance and has been observed in the majority of small-cell lung cancer specimens and cell lines. Purpose: To test the hypothesis that Bcl-2 expression levels are critical for inhibiting apoptosis in small-cell lung cancer cells, we used an antisense strategy to reduce Bcl-2 expression in these cells in an attempt to restore the natural occurrence of apoptosis. Methods: Thirteen antisense oligodeoxynucleotides (ODNs) targeting various regions of the bcl-2 messenger RNA and a control scrambledsequence ODN were tested to identify the most effective sequence(s) for reducing Bcl-2 protein levels. Northern and western blot analyses were used to examine basal bcl-2 messenger RNA and protein levels, respectively, in four human small-cell lung cancer cell lines (SW2, NCI-H69, NCI-H82, and NCI-N417). SW2 cells were treated with the antisense ODNs in the presence of cationic lipids (to facilitate uptake), and cytotoxic effects were measured by use of a cell viability assay. Flow cytometric analysis of DNA fragmentation and cell morphology was also performed. The cytotoxic effect of the most potent antisense ODN was also tested on the three other cell lines. Results: The viability of SW2 cells was effectively reduced by ODNs that targeted the translation initiation and termination sites of the bcl-2 messenger RNA, but ODN 2009 that targeted the coding region was the most cytotoxic. Treatment of SW2 cells with 0.15 µM ODN 2009 for 96 hours reduced their viability by 91% (95% confidence interval [CI] = 88%-94%) and caused a dose-dependent reduction in Bcl-2 levels that became detectable 24 hours after treatment and persisted up to 96 hours; analysis of cellular morphology demonstrated that viability was reduced through apoptosis. Moreover, ODN 2009 at 0.15 µM was cytotoxic to NCI-H69, NCI-H82, and NCI-N417 cells, resulting in decreases in cell viability of 82% (95% CI = 78%- 86%), 100%, and 100%, respectively, after 96 hours of treatment. The cytotoxic effects were inversely correlated with the basal Bcl-2 levels in the cell lines ( r = −.9964). A control scrambled-sequence oligodeoxynucleotide had no statistically significant effect on the cell lines ( P values ranging from .38 to .89). Conclusion: We have identified a novel antisense ODN sequence (ODN 2009) that effectively reduces the viability of small-cell lung cancer cells by reducing Bcl-2 levels and facilitating apoptosis.
Signalling by NO-induced protein S-nitrosylation and S-glutathionylation: Convergences and divergences
Authors: A MARTINEZRUIZ, S LAMAS
Journal: Cardiovascular Research (2007)

The role of nitric oxide in several signalling routes has been clearly established. In recent years increasing attention has been paid to its ability to produce covalent protein post-translational modifications in conjunction with other reactive oxygen and nitrogen species. Among these, the modification of cysteine residues has been shown to be of particular importance due to the functional relevance of many of them. In this review, we focus on the modification of the cysteine thiol by incorporation of a NO moiety (S-nitrosylation) or of a glutathione moiety (S-glutathionylation). Both modifications are produced by different reactions induced by nitric oxide-related species. We discuss the differences and similarities of both modifications, and their relationships, in regard to the biochemical mechanisms that produce them, including the enzymatic activities that may catalyze some of them and their subcellular compartmentalization. Even when biochemical knowledge is one step ahead of the demonstration of their pathophysiological relevance, we also describe the potential role of both modifications in several processes in which both post-translational modifications are involved.
Toward the Prognostic Significance and Therapeutic Potential of HER3 Receptor Tyrosine Kinase in Human Colon Cancer
Authors: Abdelhamid Beji, David Horst, Jutta Engel, Thomas Kirchner, Axel Ullrich
Journal: Clinical Cancer Research (2011)

Abnormal accumulation and dysregulation of the epidermal growth factor receptor family member HER3 is associated with the development of various human cancers including those of the breast, lung, and ovary. We have previously shown that in melanoma HER3 is frequently overexpressed and is associated with poor prognosis. However, the importance of HER3 in colon cancer and its putative prognostic significance is still unknown.HER3 expression was analyzed in primary colon tumors from 110 patients by immunohistochemistry and correlated with time of progression. Parallel to this, the influence of HER3 overexpression on cell proliferation, migration, invasion, and apoptosis was investigated in four different colon cancer cell lines including DLD-1, LoVo, CaCO2, and T-84.HER3 was detected at high frequency and exclusively at the membrane of the primary tumors. Elevated HER3 expression levels may serve as a putative prognostic marker because it associates with cell proliferation and decreased time to disease progression. High HER3 protein expression as well as phosphorylation levels were detected in tested cells. HER3 downregulation by RNA interference abrogated cell proliferation, migration, and invasion. In addition, suppression of HER3 resulted in a G(2)-M cell-cycle arrest, induced apoptosis, and led to morphologic changes in colon cancer cell lines. Furthermore, application of a monoclonal antibody specific to the extracellular portion of the receptor reduced heregulin-β1-induced migration and invasion and also induced apoptosis in colon cancer cell lines.We postulate that HER3 is critically involved in colon cancer progression and may serve as a novel target for therapeutic intervention.
Lynch Syndrome Caused by Germline <i>PMS2</i> Mutations: Delineating the Cancer Risk
Authors: Sanne W. ten Broeke, Richard M. Brohet, Carli M. Tops, Heleen M. van der Klift, Mary E. Velthuizen, Inge Bernstein, Gabriel Capellá Munar, Encarna Gomez Garcia, Nicoline Hoogerbrugge, Tom G.W. Letteboer, Fred H. Menko, Annika Lindblom, Arjen R. Mensenkamp, Pal Moller, Theo A. van Os, Nils Rahner, Bert J.W. Redeker, Rolf H. Sijmons, Liesbeth Spruijt, Manon Suerink, Yvonne J. Vos, Anja Wagner, Frederik J. Hes, Hans F. Vasen, Maartje Nielsen, Juul T. Wijnen
Journal: Journal of Clinical Oncology (2014)

Purpose The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. Methods Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome–associated cancers. Results The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P &lt; .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis. Conclusion CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.
Phase I Trial of Oral Fenretinide in Children With High-Risk Solid Tumors: A Report From the Children's Oncology Group (CCG 09709)
Authors: Judith G. Villablanca, Mark D. Krailo, Matthew M. Ames, Joel M. Reid, Gregory H. Reaman, C. Patrick Reynolds
Journal: Journal of Clinical Oncology (2006)

Purpose To determine the maximal tolerated dosage (MTD) of oral fenretinide given as intact capsules for 7 days, repeated every 21 days, in children with high-risk solid tumors. Methods Children 21 years of age or younger received daily doses from 350 mg/m 2 to 3,300 mg/m 2 (divided into two or three doses), with pharmacokinetics during course one. The MTD was defined as zero to one of six patients with dose-limiting toxicity (DLT), with at least two of three or two of six DLT at next higher dose. Results Fifty-four patients, age 2 years to 20 years (median, 9 years), were treated: neuroblastoma (n = 39), Ewing sarcoma (n = 5), and other (n = 10). Prior therapy included autologous stem cell transplantation (n = 42), 13-cis-RA (n = 35), and 9-cis-RA (n = 1). One of four patients at 1,050 mg/m 2 with prior liver transplant had grade 3 ALT/abdominal pain/nausea/dehydration and grade 4 AST/emesis. At 1,860 mg/m 2 , one of seven patients had grade 3 hypoalbuminemia/hypophosphatemia. At 2,475 mg/m 2 , one of eight patients had grade 3 alkaline phosphatase; three of five patients had DLT at 3,300 mg/m 2 : grade 3 AST/ALT (n = 1), grade 4 bilirubin/grade 3 AST/ALT (n = 1), pseudotumor cerebri (n = 1). Pseudotumor cerebri also occurred at 600 mg/m 2 and 800 mg/m 2 . There was one complete response and 13 patients with stable disease (SD) for 8 or more courses in 30 assessable neuroblastoma patients. SD for 8 or more courses was seen in one of five Ewing sarcoma patients and one melanoma patient. Mean N-4-hydroxyphenyl retinamide plasma level (day 7, steady-state concentration) was 9.9 μmol/L at MTD. Conclusion The pediatric MTD of oral capsular fenretinide was 2,475 mg/m 2 per day, which achieved levels active against neuroblastoma in vitro with minimal toxicity. Response data support a phase II trial in neuroblastoma.
Prognostic Factors in Patients with Advanced Renal Cell Carcinoma
Authors: Ronald M. Bukowski, Sylvie Negrier, Paul Elson
Journal: Clinical Cancer Research (2004)

Abstract The identification of prognostic factors in patients with metastatic renal cell carcinoma represents an area of increasing interest. Multiple publications identifying pertinent clinical and laboratory variables have appeared since 1986. The current study of 353 patients with advanced disease treated at The Cleveland Clinic from 1987 to 2002 was conducted to additionally assess and validate a model proposed recently by investigators from Memorial Sloan-Kettering Cancer Center. The data presented are similar to those reported previously, which demonstrated that patients with metastatic renal cell carcinoma can be categorized into good-, intermediate-, and poor-risk groups, using readily available clinical factors. Additionally, comparability of patients in this database to a group treated recently in France was assessed. These two groups appear similar in their distribution of various clinical factors and survival. Finally, a group of international investigators has been developed to provide a comprehensive database of &amp;gt;4,000 patients with metastatic renal cell carcinoma to provide and validate a single model that can be used to predict survival. This project is now under way.
Activation of NF-κB by TMPRSS2/ERG Fusion Isoforms through Toll-Like Receptor-4
Authors: Jianghua Wang, Yi Cai, Long-jiang Shao, Javed Siddiqui, Nallasivam Palanisamy, Rile Li, Chengxi Ren, Gustavo Ayala, Michael Ittmann
Journal: Cancer Research (2010)

The TMPRSS2/ERG (T/E) fusion gene is present and thought to be an oncogenic driver of approximately half of all prostate cancers. Fusion of the androgen-regulated TMPRSS2 promoter to the ERG oncogene results in constitutive high level expression of ERG which promotes prostate cancer invasion and proliferation. Here, we report the characterization of multiple alternatively spliced T/E fusion gene isoforms which have differential effects on invasion and proliferation. We found that T/E fusion gene isoforms differentially increase NF-κB-mediated transcription, which may explain in part the differences in biological activities of the T/E fusion isoforms. This increased activity is due to phosphorylation of NF-κB p65 on Ser536. Tissue microarray immunochemistry revealed that p65 phospho-Ser536 is present in the majority of prostate cancers where it is associated with ERG protein expression. The T/E fusion gene isoforms differentially increase expression of a number of NF-κB associated genes including PAR1, CCL2, FOS, TLR3, and TLR4 (Toll-like receptor). TLR4 activation is known to promote p65 Ser536 phosphorylation and knockdown of TLR4 with shRNA decreases Ser536 phosphorylation in T/E fusion gene expressing cells. TLR4 can be activated by proteins in the tumor microenvironment and lipopolysacharide from Gram (-) bacteria. Our findings suggest that bacterial infection of the prostate and/or endogenous microenvironment proteins may promote progression of high-grade prostatic intraepithelial neoplasia and/or prostate cancers that express the T/E fusion gene, where the NF-κB pathway might be targeted as a rational therapeutic approach.
Ageing and COPD affect different domains of nutritional status: the ECCE study
Authors: S. Battaglia, M. Spatafora, G. Paglino, C. Pedone, A. Corsonello, N. Scichilone, R. Antonelli-Incalzi, V. Bellia
Journal: European Respiratory Journal (2010)

Chronic obstructive pulmonary disease (COPD) and ageing may contribute to malnutrition. We aimed to explore whether COPD and ageing determine malnutrition in different manners. 460 stable COPD outpatients (376 males and 84 females) from the Extrapulmonary Consequences of COPD in the Elderly (ECCE) study database were investigated (age 75.0±5.9 yrs; forced expiratory volume in 1 s 54.7±18.3% predicted). Nutritional status was evaluated using the Mini Nutritional Assessment® (MNA) questionnaire. From the MNA, three scores exploring the domains of the nutritional status were calculated: body composition, energy intake and body functionality scores. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages were negatively correlated with five MNA items exploring mobility, patient ’ s perception of own nutrition and health status, and arm and calf circumferences (lowest Spearman’s rho (r s ) = -0.011; highest p = 0.039). GOLD stages were independently correlated with body composition and body functionality scores (model r 2 = 0.073). Age was negatively correlated with four MNA items exploring loss of appetite, fluid intake, mobility and autonomy in daily life (lowest r s = -0.013; highest p = 0.030). Age was independently correlated with body functionality score (model r 2 = 0.037). Severe COPD and ageing are independent and probably concurrent conditions leading to malnutrition. The MNA questionnaire allows a valuable insight into the complexity of components of nutritional status and may provide useful clues for treatment strategies.
Erythropoietin-induced hypertension in rat is not mediated by alterations of plasma endothelin, vasopressin, or atrial natriuretic peptide levels.
Authors: X J Zhou, D Pandian, X Q Wang, N D Vaziri
Journal: Journal of the American Society of Nephrology (1997)

Regular administration of recombinant erythropoietin (EPO) in patients with chronic renal failure (CRF) is frequently complicated by a rise in arterial blood pressure. Clinical studies intended to discern the possible role of endothelin (ET) in the pathogenesis of EPO-induced hypertension have produced contradictory results. Given the limitations of the clinical studies, this placebo-controlled study was carried out in CRF (5/6 nephrectomized) rats treated with either EPO, 150 U/kg intraperitoneally, or the vehicle alone twice weekly for 6 wk. Plasma ET was measured at baseline, and weeks 2, 4, and 6. In addition, plasma arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) were determined at the conclusion of the study period. As expected, blood pressure rose markedly after 1 wk of EPO therapy as compared with the placebo therapy. However, there was no significant difference in plasma ET levels between the EPO- and placebo-treated groups during the study period. Likewise, EPO therapy had no effect on plasma ANP level but depressed plasma AVP concentration. Thus, this placebo-controlled animal study revealed that EPO therapy markedly raised arterial blood pressure but had no effect on plasma ET in the CRF rats. This observation suggests that EPO-induced hypertension in this model is not mediated by an increased circulating ET level. However, the possible effect, if any, of EPO on local vascular tissue ET level is uncertain and awaits further investigation.
Truncating <b> <i>BRCA1</i> </b> Mutations Are Uncommon in a Cohort of Hereditary Prostate Cancer Families with Evidence of Linkage to 17q Markers
Authors: Kimberly A. Zuhlke, Jennifer J. Madeoy, Jennifer Beebe-Dimmer, Kirsten A. White, Angela Griffin, Ethan M. Lange, Stephen B. Gruber, Elaine A. Ostrander, Kathleen A. Cooney
Journal: Clinical Cancer Research (2004)

Abstract Purpose: A genome-wide scan of 175 hereditary prostate cancer families from the University of Michigan Prostate Cancer Genetics Project provided evidence of prostate cancer linkage to 17q markers near the BRCA1 gene. To examine the possibility that germ-line BRCA1 mutations were associated with hereditary prostate cancer, individuals from 93 families with evidence of linkage to chromosome 17q were screened for germ-line BRCA1 mutations. Experimental Design: One individual from each of the 93 families, the majority with three or more cases of prostate cancer, were screened for BRCA1 mutations with denaturing high-performance liquid chromatography (HPLC). Fragments exhibiting denaturing HPLC variant patterns were additionally analyzed by direct sequencing. Results: Sixty-five of the individuals selected for sequencing from 65 unrelated families were determined to have wild-type BRCA1 sequence by denaturing HPLC. One individual from a family with both prostate and ovarian cancer was found to have a truncating BRCA1 mutation (3829delT). An additional 27 germ-line variants were identified, including 15 missense variants. Conclusions: These sequencing results suggest that BRCA1 truncating mutations do not account for the linkage evidence on chromosome 17 observed in University of Michigan Prostate Cancer Genetics Project families. A recently completed combined genome scan has also detected linkage to 17q22, and studies are ongoing to identify the relevant prostate cancer susceptibility gene in this region.