bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy
Authors: Lindner Andreas U. , Concannon Caoimhín G. , Boukes Gerhardt J. , Cannon Mary D. , Llambi Fabien , Ryan Deborah , Boland Karen , Kehoe Joan , McNamara Deborah A. , Murray Frank , Kay Elaine W. , Hector Suzanne , Green Douglas R. , Huber Heinrich J. , Prehn Jochen H.M. 
Published: January 2013

Abstract
Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors. This counterintuitive finding suggested that sole inhibition of effector BAX and BAK could not be sufficient for systems stability in nonstressed cells. Assuming a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing dugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients. Cancer Res; 73(2); 519–28. ©2012 AACR.
YM-155 Potentiates the Effect of ABT-737 in Malignant Human Glioma Cells via Survivin and Mcl-1 Downregulation in an EGFR-Dependent Context
Authors: Jane Esther P. , Premkumar Daniel R. , DiDomenico Joseph D. , Hu Bo , Cheng Shi-Yuan , Pollack Ian F. 
Published: January 2013

Abstract
Antiapoptotic proteins are commonly overexpressed in gliomas, contributing to therapeutic resistance. We recently reported that clinically achievable concentrations of the Bcl-2/Bcl-xL inhibitor ABT-737 failed to induce apoptosis in glioma cells, with persistent expression of survivin and Mcl-1. To address the role of these mediators in glioma apoptosis resistance, we analyzed the effects of YM-155, a survivin suppressant, on survival on a panel of glioma cell lines. YM-155 inhibited cell growth and downregulated survivin and Mcl-1 in a dose- and cell line–dependent manner. While U373, LN18, LNZ428, T98G, LN229, and LNZ308 cells exhibited an IC50 of 10 to 75 nmol/L, A172 cells were resistant (IC50 ∼ 250 nmol/L). No correlation was found between sensitivity to YM-155 and baseline expression of survivin or cIAP-1/cIAP-2/XIAP. However, strong correlation was observed between EGF receptor (EGFR) activation levels and YM-155 response, which was confirmed using EGFR-transduced versus wild-type cells. Because we postulated that decreasing Mcl-1 expression may enhance glioma sensitivity to ABT-737, we examined whether cotreatment with YM-155 promoted ABT-737 efficacy. YM-155 synergistically enhanced ABT-737–induced cytotoxicity and caspase-dependent apoptosis. Downregulation of Mcl-1 using short hairpin RNA also enhanced ABT-737–inducing killing, confirming an important role for Mcl-1 in mediating synergism between ABT-737 and YM-155. As with YM-155 alone, sensitivity to YM-155 and ABT-737 inversely correlated with EGFR activation status. However, sensitivity could be restored in highly resistant U87-EGFRvIII cells by inhibition of EGFR or its downstream pathways, highlighting the impact of EGFR signaling on Mcl-1 expression and the relevance of combined targeted therapies to overcome the multiple resistance mechanisms of these aggressive tumors. Mol Cancer Ther; 12(3); 326–38. ©2013 AACR.
Blood Urea Nitrogen/Creatinine Ratio Identifies a High-Risk but Potentially Reversible Form of Renal Dysfunction in Patients With Decompensated Heart Failure
Authors: Brisco Meredith A. , Coca Steven G. , Chen Jennifer , Owens Anjali Tiku , McCauley Brian D. , Kimmel Stephen E. , Testani Jeffrey M. 
Published: January 2013

Background—
Identifying reversible renal dysfunction (RD) in the setting of heart failure is challenging. The goal of this study was to evaluate whether elevated admission blood urea nitrogen/creatinine ratio (BUN/Cr) could identify decompensated heart failure patients likely to experience improvement in renal function (IRF) with treatment.

Methods and Results—

Consecutive hospitalizations with a discharge diagnosis of heart failure were reviewed. IRF was defined as ≥20% increase and worsening renal function as ≥20% decrease in estimated glomerular filtration rate. IRF occurred in 31% of the 896 patients meeting eligibility criteria. Higher admission BUN/Cr was associated with in-hospital IRF (odds ratio, 1.5 per 10 increase; 95% confidence interval [CI], 1.3–1.8;
P
<0.001), an association persisting after adjustment for baseline characteristics (odds ratio, 1.4; 95% CI, 1.1–1.8;
P
=0.004). However, higher admission BUN/Cr was also associated with post-discharge worsening renal function (odds ratio, 1.4; 95% CI, 1.1–1.8;
P
=0.011). Notably, in patients with an elevated admission BUN/Cr, the risk of death associated with RD (estimated glomerular filtration rate <45) was substantial (hazard ratio, 2.2; 95% CI, 1.6–3.1;
P
<0.001). However, in patients with a normal admission BUN/Cr, RD was not associated with increased mortality (hazard ratio, 1.2; 95% CI, 0.67–2.0;
P
=0.59; p interaction=0.03).

Conclusions—
An elevated admission BUN/Cr identifies decompensated patients with heart failure likely to experience IRF with treatment, providing proof of concept that reversible RD may be a discernible entity. However, this improvement seems to be largely transient, and RD, in the setting of an elevated BUN/Cr, remains strongly associated with death. Further research is warranted to develop strategies for the optimal detection and treatment of these high-risk patients.
Percutaneous Left Atrial Appendage Closure for Stroke Prophylaxis in Patients With Atrial Fibrillation
Authors: Reddy Vivek Y. , Doshi Shephal K. , Sievert Horst , Buchbinder Maurice , Neuzil Petr , Huber Kenneth , Halperin Jonathan L. , Holmes David 
Published: January 2013

Background—
The multicenter PROTECT AF study (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) was conducted to determine whether percutaneous left atrial appendage closure with a filter device (Watchman) was noninferior to warfarin for stroke prevention in atrial fibrillation.

Methods and Results—
Patients (n=707) with nonvalvular atrial fibrillation and at least 1 risk factor (age >75 years, hypertension, heart failure, diabetes, or prior stroke/transient ischemic attack) were randomized to either the Watchman device (n=463) or continued warfarin (n=244) in a 2:1 ratio. After device implantation, warfarin was continued for ≈45 days, followed by clopidogrel for 4.5 months and lifelong aspirin. Study discontinuation rates were 15.3% (71/463) and 22.5% (55/244) for the Watchman and warfarin groups, respectively. The time in therapeutic range for the warfarin group was 66%. The composite primary efficacy end point included stroke, systemic embolism, and cardiovascular death, and the primary analysis was by intention to treat. After 1588 patient-years of follow-up (mean 2.3±1.1 years), the primary efficacy event rates were 3.0% and 4.3% (percent per 100 patient-years) in the Watchman and warfarin groups, respectively (relative risk, 0.71; 95% confidence interval, 0.44%–1.30% per year), which met the criteria for noninferiority (probability of noninferiority >0.999). There were more primary safety events in the Watchman group (5.5% per year; 95% confidence interval, 4.2%–7.1% per year) than in the control group (3.6% per year; 95% confidence interval, 2.2%–5.3% per year; relative risk, 1.53; 95% confidence interval, 0.95–2.70).

Conclusions—
The “local” strategy of left atrial appendage closure is noninferior to “systemic” anticoagulation with warfarin. PROTECT AF has, for the first time, implicated the left atrial appendage in the pathogenesis of stroke in atrial fibrillation.

Clinical Trial Registration:—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00129545.
Effects of Statins on Serum n-3 to n-6 Polyunsaturated Fatty Acid Ratios in Patients With Coronary Artery Disease
Authors: Nozue Tsuyoshi , Yamamoto Shingo , Tohyama Shinichi , Fukui Kazuki , Umezawa Shigeo , Onishi Yuko , Kunishima Tomoyuki , Sato Akira , Nozato Toshihiro , Miyake Shogo , Takeyama Youichi , Morino Yoshihiro , Yamauchi Takao , Muramatsu Toshiya , Hibi Kiyoshi , Michishita Ichiro 
Published: January 2013

Background: A low n-3 to n-6 polyunsaturated fatty acids (PUFAs) ratio is reported to be associated with cardiovascular events. However, the effects of statins on this ratio have not been fully examined. Methods: A total of 101 patients with coronary artery disease, who were not receiving lipid-lowering therapy were randomly assigned to receive either 4 mg/day of pitavastatin or 20 mg/day of pravastatin. Serum PUFA levels were measured at baseline and 8 months after treatment with statins. Results: Pitavastatin was used to treat 51 patients and the remaining 50 patients were treated using pravastatin. A significant positive correlation was observed between the percent change in low-density lipoprotein cholesterol and that in dihomogamma-linolenic acid ( r = .376, P = .007), arachidonic acid (AA; r = .316, P = .02), eicosapentaenoic acid (EPA; r = .408, P = .003), or docosahexaenoic acid (DHA; r = .270, P = .056) in the pitavastatin group. However, these correlations were not observed in the pravastatin group. The DHA/AA ratio decreased significantly in the pitavastatin group only (from 0.96 to 0.83, P = .0002) and the DHA/AA ratio was significantly lower in the pitavastatin group at 8 months (0.83 vs 0.96, P = .03). The EPA/AA ratio did not show significant changes in either group. Conclusions: Pitavastatin decreased the serum DHA/AA ratio, whereas pravastatin had no effect on this ratio. Neither pitavastatin nor pravastatin had an effect on the serum EPA/AA ratio in patients with coronary artery disease.
Fatigue-Related Gene Networks Identified in CD14+ Cells Isolated From HIV-Infected Patients—Part I
Authors: Voss Joachim G. , Dobra Adrian , Morse Caryn , Kovacs Joseph A. , Danner Robert L. , Munson Peter J. , Logan Carolea , Rangel Zoila , Adelsberger Joseph W. , McLaughlin Mary , Adams Larry D. , Raju Raghavan , Dalakas Marinos C. 
Published: January 2013

Purpose: Human immunodeficiency virus (HIV)–related fatigue (HRF) is multicausal and potentially related to mitochondrial dysfunction caused by antiretroviral therapy with nucleoside reverse transcriptase inhibitors (NRTIs). Methodology: The authors compared gene expression profiles of CD14+ cells of low versus high fatigued, NRTI-treated HIV patients to healthy controls ( n = 5/group). The authors identified 32 genes predictive of low versus high fatigue and 33 genes predictive of healthy versus HIV infection. The authors constructed genetic networks to further elucidate the possible biological pathways in which these genes are involved. Relevance for nursing practice: Genes including the actin cytoskeletal regulatory proteins Prokineticin 2 and Cofilin 2 along with mitochondrial inner membrane proteins are involved in multiple pathways and were predictors of fatigue status. Previously identified inflammatory and signaling genes were predictive of HIV status, clearly confirming our results and suggesting a possible further connection between mitochondrial function and HIV. Isolated CD14+ cells are easily accessible cells that could be used for further study of the connection between fatigue and mitochondrial function of HIV patients. Implication for Practice: The findings from this pilot study take us one step closer to identifying biomarker targets for fatigue status and mitochondrial dysfunction. Specific biomarkers will be pertinent to the development of methodologies to diagnosis, monitor, and treat fatigue and mitochondrial dysfunction.
Predictors for antibiotic prescribing in patients with exacerbations of COPD in general practice
Authors: Llor Carl , Bjerrum Lars , Munck Anders , Hansen Malene P. , Córdoba Gloria Cristina , Strandberg Eva Lena , Ovhed Ingvar , Radzeviciene Ruta , Cots Josep M. , Reutskiy Anatoliy , Caballero Lidia 
Published: January 2013

Background: The aim of this study was to describe the antibiotic prescribing rate in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), to analyse predictors for antibiotic prescribing and to explore the influence of the use C-reactive protein (CRP) rapid test. Methods: A cross-sectional study was carried out in January and February 2008 in primary care. General practitioners (GPs) from six countries (Denmark, Sweden, Lithuania, Russia, Spain and Argentina) registered all patients with AECOPD during a 3-week period. A multilevel logistic regression model was estimated using two hierarchical levels, (i) patients and (ii) physicians, and was used to analyse the association between antibiotic prescribing and potential predictors for antibiotic use: patients’ age and gender, duration and symptoms and signs of exacerbations (fever, cough, dyspnoea, sputum volume and purulence) and the results of the CRP test. Results: A total of 617 GPs registered 1233 patients with AECOPD. A total of 970 patients (79%) were prescribed antibiotics, varying from 49% (Denmark) to 93% (Russia). The presence of purulent sputum was the strongest predictor for antibiotic treatment (odds ratio [OR] 8.7; 95% confidence interval [CI] 5.9–12.8). CRP determination was carried out mainly in Denmark and Sweden and its use was the strongest protective factor for antibiotic therapy (OR 0.3; 95% CI 0.2-0.6). GPs that used CRP testing weighted purulent sputum lower than GPs who did not use CRP testing. CRP values had a strong influence on the antibiotic prescribing rate. Conclusions: Antibiotic treatment for AECOPD is very high. This study shows that GPs performing CRP rapid tests prescribe fewer antibiotics than those who do not.
Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients
Authors: Li Jian-Ming , Hossain Mohammad S. , Southerland Lauren , Waller Edmund K. 
Published: January 2013

Key PointsA small-molecule peptide inhibitor of VIP-signaling protected murine allo-BMT recipients from lethal mCMV infection without increasing GvHD. Treatment with the VIP inhibitor reduced viral loads, increased antigen-specific T-cells, and decreased PD-1 expression.
Comprehensive structural annotation of Pichia pastoris transcriptome and the response to various carbon sources using deep paired-end RNA sequencing
Authors: Liang Shuli , Wang Bin , Pan Li , Ye Yanrui , He Minghui , Han Shuangyan , Zheng Suiping , Wang Xiaoning , Lin Ying 
Published: January 2013

Abstract

Background
The methylotrophic yeast Pichia pastoris is widely used as a bioengineering platform for producing industrial and biopharmaceutical proteins, studying protein expression and secretion mechanisms, and analyzing metabolite synthesis and peroxisome biogenesis. With the development of DNA microarray and mRNA sequence technology, the P. pastoris transcriptome has become a research hotspot due to its powerful capability to identify the transcript structures and gain insights into the transcriptional regulation model of cells under protein production conditions. The study of the P. pastoris transcriptome helps to annotate the P. pastoris transcript structures and provide useful information for further improvement of the production of recombinant proteins.

Results
We used a massively parallel mRNA sequencing platform (RNA-Seq), based on next-generation sequencing technology, to map and quantify the dynamic transcriptome of P. pastoris at the genome scale under growth conditions with glycerol and methanol as substrates. The results describe the transcription landscape at the whole-genome level and provide annotated transcript structures, including untranslated regions (UTRs), alternative splicing (AS) events, novel transcripts, new exons, alternative upstream initiation codons (uATGs), and upstream open reading frames (uORFs). Internal ribosome entry sites (IRESes) were first identified within the UTRs of genes from P. pastoris, encoding kinases and the proteins involved in the control of growth. We also provide a transcriptional regulation model for P. pastoris grown on different carbon sources.

Conclusions
We suggest that the IRES-dependent translation initiation mechanism also exists in P. pastoris. Retained introns (RIs) are determined as the main AS event and are produced predominantly by an intron definition (ID) mechanism. Our results describe the metabolic characteristics of P. pastoris with heterologous protein production under methanol induction and provide rich information for further in-depth studies of P. pastoris protein expression and secretion mechanisms.
Hemiarthroplasties in young patients with osteonecrosis or a tumour of the proximal femur; an observational cohort study
Authors: van Egmond Pim W , Taminiau Antonie HM , van der Heide Huub JL 
Published: January 2013

Abstract

Background
The failure scenario in total hip arthroplasty (THA), in younger patients, is dependent on the fixation and wear of the acetabular component. In selected cases, where endoprosthetic replacement of the femoral head is unavoidable for limb salvage or functional recovery, hemiarthroplasty can be chosen as an alternative. The purpose of this study is to evaluate hemiarthroplasty as treatment strategy for young patients with osteonecrosis or a tumour of the proximal femur.

Methods
Between 1985 and 2008, 42 hemiarthroplasties (unipolar and bipolar) were performed in patients younger than 65 years with osteonecrosis (n=13) or a tumour of the proximal femur (n=29). All patients were seen at yearly follow-up examination and evaluated. Revision or conversion to a THA was regarded as a failure of the implant. A Kaplan Meier analysis was performed. To determine significant differences between categorical groups, the Pearson chi-square test was used. In numerical groups the independent T-test and One-way ANOVA were used.

Results
After a mean follow-up of 7.1 years, failure of the hemiarthroplasty occurred 6 times. The Kaplan Meier survival analysis with conversion to THA or revision as endpoint of the bipolar hemiarthroplasties (n=38) shows a 96% survival at 15, and 60% at 20 years. In the unipolar type (n=4) we found a conversion rate of 50% within 3 years.

Conclusions
Bipolar hemiarthroplasty is a reasonable alternative in a young patient with osteonecrosis or a tumour of the proximal femur as indication. Because of the high conversion rate after unipolar hemiarthroplasties, we would not recommend this type of prosthesis in the young patient.
Health service quality scale: Brazilian Portuguese translation, reliability and validity
Authors: Rocha Luiz Roberto Martins , Veiga Daniela Francescato , e Oliveira Paulo Rocha , Song Elaine Horibe , Ferreira Lydia Masako 
Published: January 2013

Abstract

Background
The Health Service Quality Scale is a multidimensional hierarchical scale that is based on interdisciplinary approach. This instrument was specifically created for measuring health service quality based on marketing and health care concepts. The aim of this study was to translate and culturally adapt the Health Service Quality Scale into Brazilian Portuguese and to assess the validity and reliability of the Brazilian Portuguese version of the instrument.

Methods
We conducted a cross-sectional, observational study, with public health system patients in a Brazilian university hospital. Validity was assessed using Pearson’s correlation coefficient to measure the strength of the association between the Brazilian Portuguese version of the instrument and the SERVQUAL scale. Internal consistency was evaluated using Cronbach’s alpha coefficient; the intraclass (ICC) and Pearson’s correlation coefficients were used for test-retest reliability.

Results
One hundred and sixteen consecutive postoperative patients completed the questionnaire. Pearson’s correlation coefficient for validity was 0.20. Cronbach's alpha for the first and second administrations of the final version of the instrument were 0.982 and 0.986, respectively. For test-retest reliability, Pearson’s correlation coefficient was 0.89 and ICC was 0.90.

Conclusions
The culturally adapted, Brazilian Portuguese version of the Health Service Quality Scale is a valid and reliable instrument to measure health service quality.