bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples
Authors: Scoles Haley A , Urraca Nora , Chadwick Samuel W , Reiter Lawrence T , LaSalle Janine M 
Published: December 2011

Abstract

Background
Duplication of chromosome 15q11-q13 (dup15q) accounts for approximately 3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (imprinting center of the Prader-Willi locus, PWS-IC). Maternal dup15q occurs as both interstitial duplications and isodicentric chromosome 15. Overexpression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two postmortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of the GABAA receptor genes, UBE3A and SNRPN in a manner not predicted by copy number or parental imprint.

Methods
Postmortem human brain tissue (Brodmann area 19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control tissue samples. Quantitative PCR was used to confirm duplication status. Quantitative RT-PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high-resolution melting-curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC.

Results
Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that dup15q was maternal in origin. UBE3A transcript and protein levels were significantly higher than control and autism in dup15q, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3 levels but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls.

Conclusions
Although these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain.
Quantification of atopy, lung function and airway hypersensitivity in adults
Authors: Marinho Susana , Simpson Angela , Marsden Paul , Smith Jacky A , Custovic Adnan 
Published: December 2011

AbstractBackgroundStudies in children have shown that concentration of specific serum IgE (sIgE) and size of skin tests to inhalant allergens better predict wheezing and reduced lung function than the information on presence or absence of atopy. However, very few studies in adults have investigated the relationship of quantitative atopy with lung function and airway hyperresponsiveness (AHR).ObjectiveTo determine the association between lung function and AHR and quantitative atopy in a large sample of adults from the UK.MethodsFEV1 and FVC (% predicted) were measured using spirometry and airway responsiveness by methacholine challenge (5‐breath dosimeter protocol) in 983 subjects (random sample of 800 parents of children enrolled in a population‐based birth cohort enriched with 183 patients with physician‐diagnosed asthma). Atopic status was assessed by skin prick tests (SPT) and measurement of sIgE (common inhalant allergens). We also measured indoor allergen exposure in subjects' homes.ResultsSpirometry was completed by 792 subjects and 626 underwent methacholine challenge, with 100 (16.0%) having AHR (dose‐response slope>25). Using sIgE as a continuous variable in a multiple linear regression analysis, we found that increasing levels of sIgE to mite, cat and dog were significantly associated with lower FEV1 (mite p = 0.001, cat p = 0.0001, dog p = 2.95 × 10‐8). Similar findings were observed when using the size of wheal on skin testing as a continuous variable, with significantly poorer lung function with increasing skin test size (mite p = 8.23 × 10‐8, cat p = 3.93 × 10‐10, dog p = 3.03 × 10‐15, grass p = 2.95 × 10‐9). The association between quantitative atopy with lung function and AHR remained unchanged when we repeated the analyses amongst subjects defined as sensitised using standard definitions (sIgE>0.35 kUa/l, SPT‐3 mm>negative control).ConclusionsIn the studied population, lung function decreased and AHR increased with increasing sIgE levels or SPT wheal diameter to inhalant allergens, suggesting that atopy may not be a dichotomous outcome influencing lung function and AHR.
Abatacept with methotrexate versus other biologic agents in treatment of patients with active rheumatoid arthritis despite methotrexate: a network meta-analysis
Authors: Guyot Patricia , Taylor Peter , Christensen Robin , Pericleous Louisa , Poncet Coralie , Lebmeier Maximilian , Drost Pieter , Bergman Gert 
Published: December 2011

Abstract

Introduction

The goal of this study was to compare the efficacy in terms of Health Assessment Questionnaire change from baseline (HAQ CFB), 50% improvement in American College of Rheumatology criterion (ACR-50) and Disease Activity Score in 28 joints (DAS28) defined remission (< 2.6) between abatacept and other biologic disease modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who have inadequate response to methotrexate (MTX-IR).

Methods

A systematic literature review identified controlled trials investigating the efficacy of abatacept (three studies), etanercept (two studies), infliximab (two), adalimumab (two), certolizumab pegol (two) ritixumab (three), and tocilizumab (two) in MTX-IR patients with RA. The clinical trials included in this analysis were similar with respect to trial design, baseline patient characteristics and background therapy (MTX). The key clinical endpoints of interest were HAQ CFB, ACR-50 and DAS28 < 2.6 measured at 24 and 52 weeks. The results were analysed using network meta-analysis methods that enabled calculation of an estimate for expected relative effect of comparative treatments. Analysis results were expressed as the difference in HAQ CFB score and odds ratio (OR) of achieving an ACR-50 and DAS28 response and associated 95% credible intervals (CrI).

Results

The analysis of HAQ CFB at 24 weeks and 52 weeks showed that abatacept in combination with MTX is expected to be more efficacious than MTX monotherapy and is expected to show a comparable efficacy relative to other biologic DMARDs in combination with MTX. Further, abatacept showed comparable ACR-50 and DAS28 < 2.6 response rates with other biologic DMARDs at 24 and 52 weeks, except for ACR-50 compared to certolizumab pegol at 52 weeks and for DAS28 < 2.6 compared to tocilizumab at 24 weeks. Sensitivity analyses confirmed the robustness of the findings.

Conclusions

Abatacept in combination with MTX is expected to result in a comparable change from baseline in HAQ score and comparable ACR-50 and DAS28 < 2.6 response rates in MTX-IR patients compared to other approved biologic agents.
Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients
Authors: Iirola Timo , Aantaa Riku , Laitio Ruut , Kentala Erkki , Lahtinen Maria , Wighton Andrew , Garratt Chris , Ahtola-Sätilä Tuula , Olkkola Klaus T 
Published: December 2011

Abstract
Introduction
Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.

Methods
Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.

Results
The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.

Conclusions
The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.

Trial Registration
ClinicalTrials.gov: NCT00747721
Long-term psychological effects of a no-sedation protocol in critically ill patients
Authors: Strøm Thomas , Stylsvig Mette , Toft Palle 
Published: December 2011

Abstract
Introduction
A protocol of no sedation has been shown to reduce the time patients receive mechanical ventilation and to reduce intensive care and total hospital length of stay. The long-term psychological effects of this strategy have not yet been described. The purpose of the study was to test whether a strategy of no sedation alters long-term psychological outcome compared with a standard strategy with sedation.

Methods
During intensive care stay, 140 patients requiring mechanical ventilation were randomized to either no sedation or sedation with daily interruption of sedation. This study was done as a single-blinded cohort study. After discharge, patients were interviewed by a neuropsychologist assessing quality of life, depression, anxiety, and posttraumatic stress disorder.

Results
Two years after randomization, 38 patients were eligible for interview, and 26 patients were interviewed (13 from each group). No difference was found with respect to quality of life (Medical Outcome Study, 36-item short-form health survey). Both mental and physical components were nonsignificant. The Beck depression index was low in both groups (one patient in intervention group versus three patients in the control group were depressed, p = 0.32). Evaluated with the Impact of Events Scale, both groups had low stress scores (one in the intervention group versus two in the control group had scores greater than 32; p = 0.50). State anxiety scores were also low (28 in the control group versus 30 in the intervention group, p = 0.58).

Conclusions
Our data suggest that a protocol of no sedation applied to critically ill patients undergoing mechanical ventilation does not increase the risk of long-term psychological sequelae after intensive care compared with standard treatment with sedation.
Phase I, Dose-Escalation Study of BKM120, an Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors
Authors: Bendell Johanna C. , Rodon Jordi , Burris Howard A. , de Jonge Maja , Verweij Jaap , Birle Diana , Demanse David , De Buck Stefan S. , Ru Qinhua C. , Peters Malte , Goldbrunner Michael , Baselga José 
Published: December 2011

Purpose This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), safety, preliminary activity, pharmacokinetics (PK), and pharmacodynamics of BKM120, a potent and highly specific oral pan-Class I PI3K inhibitor. Patients and Methods Thirty-five patients with advanced solid tumors received daily BKM120 12.5 to 150 mg. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Assessments included archival tumor molecular status, response by Response Evaluation Criteria in Solid Tumors (RECIST), positron emission tomography tracer uptake ([18F]fluorodeoxyglucose positron emission tomography [FDG-PET]), fasting plasma C-peptide, and phosphorylated ribosomal protein S6 (pS6) in skin biopsies. Results Overall, treatment was well tolerated. Dose-limiting toxicities were grade 2 mood alteration (80 mg), grade 3 epigastralgia, grade 3 rash, grade 2 and grade 3 mood alteration (100 mg), and two grade 4 hyperglycemia (150 mg). The MTD was 100 mg/d. Frequent treatment-related adverse events included rash, hyperglycemia, diarrhea, anorexia, and mood alteration (37% each); nausea (31%); fatigue (26%); pruritus (23%); and mucositis (23%). BKM120 demonstrated rapid absorption, half-life of ∼40 hours, ∼three-fold steady-state accumulation, dose-proportional exposure, and moderate interpatient variability. One patient demonstrated a confirmed partial response (triple-negative breast cancer); seven patients (20%) were on study for ≥ 8 months. BKM120 demonstrated dose-dependent pharmacodynamic effects on [18F]FDG-PET, fasting C-peptide, fasting blood glucose, and pS6. No significant trends were seen to correlate tumor molecular alterations with clinical activity. Conclusion This study demonstrates feasibility and proof-of-concept of class I PI3K inhibition in patients with advanced cancers. BKM120, at the MTD of 100 mg/d, is safe and well tolerated, with a favorable PK profile, clear evidence of target inhibition, and preliminary antitumor activity.
Insulin- and Obesity-Related Variables in Early-Stage Breast Cancer: Correlations and Time Course of Prognostic Associations
Authors: Goodwin Pamela J. , Ennis Marguerite , Pritchard Kathleen I. , Trudeau Maureen E. , Koo Jarley , Taylor Sara K. , Hood Nicky 
Published: December 2011

Purpose To investigate patterns of prognostic associations over time of insulin- and obesity-related variables measured at diagnosis of early breast cancer (BC), focusing on whether the prognostic associations with distant recurrence and death changed over time. Patients and Methods Five hundred thirty-five nondiabetic women with T1-3, N0-1, M0 invasive BC diagnosed from 1989 to 1996 were included in the study. Insulin-related variables included fasting insulin, Homeostasis Model Assessment, C-peptide, and glucose. Obesity-related variables included weight, body mass index (BMI), waist and hip circumference, and leptin. Correlations were examined using the Pearson correlation coefficient and prognostic associations using the Cox model. Results There was evidence that associations of baseline insulin-related variables with distant recurrence and death were not constant over time; univariable adverse prognostic associations were significant only during the first 5 years (eg, insulin quartile 4 v 1: hazard ratio [HR], 2.32; 95% CI, 1.39 to 3.86; P < .001 for distant disease-free survival [DDFS]; and HR, 2.85; 95% CI, 1.48 to 5.50; P = .002 for overall survival [OS], with little attenuation of this pattern in multivariable analyses). In contrast, obesity-related variables (BMI, weight, leptin) exerted significant adverse univariable associations that were constant over time (eg, BMI quartile 4 v 2: HR, 1.40; 95% CI, 1.07 to 1.82 for DDFS; P = .014; and HR, 1.50; 95% CI, 1.16 to 1.93; P < .001 for OS); prognostic associations of leptin remained significant in multivariable analyses. Conclusion Baseline insulin- and obesity-related variables exert different patterns of prognostic associations over time in early BC.
Treatment of Colorectal Peritoneal Carcinomatosis With Systemic Chemotherapy: A Pooled Analysis of North Central Cancer Treatment Group Phase III Trials N9741 and N9841
Authors: Franko Jan , Shi Qian , Goldman Charles D. , Pockaj Barbara A. , Nelson Garth D. , Goldberg Richard M. , Pitot Henry C. , Grothey Axel , Alberts Steven R. , Sargent Daniel J. 
Published: December 2011

Purpose Symptoms and complications of metastatic colorectal cancer (mCRC) differ by metastatic sites. There is a paucity of prospective survival data for patients with peritoneal carcinomatosis colorectal cancer (pcCRC). We characterized outcomes of patients with pcCRC enrolled onto two prospective randomized trials of chemotherapy and contrasted that with other manifestations of mCRC (non-pcCRC). Methods A total of 2,095 patients enrolled onto two prospective randomized trials were evaluated for overall survival (OS) and progression-free survival (PFS). A Cox proportional hazard model was used to assess the adjusted associations. Results The characteristics of the pcCRC group (n = 364) were similar to those of the non-pcCRC patients in median age (63 v 61 years, P = .23), sex (57% males v 61%, P = .23), and performance status (Eastern Cooperative Oncology Group performance status 0 or 1 94% v 96%, P = .06), but differed in frequency of liver (63% v 82%, P < .001) and lung metastases (27% v 34%, P = .01). Median OS (12.7 v 17.6 months, hazard ratio [HR] = 1.3; 95% CI, 1.2 to 1.5; P < .001) and PFS (5.8 v 7.2 months, HR = 1.2; 95% CI, 1.1 to 1.3; P = .001) were shorter for pcCRC versus non-pcCRC. The unfavorable prognostic influence of pcCRC remained after adjusting for age, PS, liver metastases, and other factors (OS: HR = 1.3, P < .001; PFS: HR = 1.1, P = .02). Infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, and fluorouracil as a first-line treatment among pcCRC (HR for OS = 0.62, P = .005) and non-pcCRC patients (HR = 0.66, P < .001). Conclusion pcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations of mCRC. Future trials for mCRC should consider stratifying on the basis of pcCRC status.
Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986
Authors: De Santis Maria , Bellmunt Joaquim , Mead Graham , Kerst J. Martijn , Leahy Michael , Maroto Pablo , Gil Thierry , Marreaud Sandrine , Daugaard Gedske , Skoneczna Iwona , Collette Sandra , Lorent Julie , de Wit Ronald , Sylvester Richard 
Published: December 2011

Purpose This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible (“unfit”) for cisplatin chemotherapy. Patients and Methods The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life. Results In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI. Conclusion There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI.
Interim [18F]Fluorodeoxyglucose Positron Emission Tomography Scan in Diffuse Large B-Cell Lymphoma Treated With Anthracycline-Based Chemotherapy Plus Rituximab
Authors: Safar Violaine , Dupuis Jehan , Itti Emmanuel , Jardin Fabrice , Fruchart Christophe , Bardet Stéphane , Véra Pierre , Copie-Bergman Christiane , Rahmouni Alain , Tilly Hervé , Meignan Michel , Haioun Corinne 
Published: December 2011

Purpose The prognostic value of [18F]fluorodeoxyglucose–positron emission tomography (PET), interpreted according to visual criteria, is a matter of debate for diffuse large B-cell lymphoma (DLBCL). Moreover, most published studies do not differentiate between patients treated with or without rituximab. We retrospectively investigated the prognostic value of PET performed in patients with DLBCL receiving chemotherapy plus rituximab. Images were interpreted both visually and by computing maximum standardized uptake value (SUVmax) between PET performed at baseline and after two cycles of chemotherapy. Patients and Methods One hundred twelve patients newly diagnosed with DLBCL were treated with an anthracycline-based regimen plus rituximab. A PET was performed after two cycles of treatment. PET positivity or negativity was related to progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier analysis. Results Visual analysis showed that 70 patients (62.5%) presented with a negative PET scan after two cycles of treatment. The 3-year PFS and OS rates were 84% and 88%, respectively, in patients with PET-negative results versus 47% and 62%, respectively, in patients with PET-positive results (P < .0001 and P < .003, respectively). A second analysis was performed on 85 patients by using interim PET in a quantitative approach on the basis of a ΔSUVmax evaluation of more than 66%. The 3-year PFS was 77% for patients with PET-negative results and 37.5% for patients with PET-positive results (P = .002). Conclusion An early PET scan after two cycles of treatment can effectively predict the outcome in patients with DLBCL treated with rituximab and anthracycline-based chemotherapy by using either a visual or quantitative approach.