bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA-testing for BRCA1/2 prior to genetic counselling in patients with breast cancer: design of an intervention study, DNA-direct
Authors: Sie Aisha S , Spruijt Liesbeth , van Zelst-Stams Wendy AG , Mensenkamp Arjen R , Ligtenberg Marjolijn J , Brunner Han G , Prins Judith B , Hoogerbrugge Nicoline 
Published: May 2012

Abstract

Background
Current practice for patients with breast cancer referred for genetic counseling, includes face-to-face consultations with a genetic counselor prior to and following DNA-testing. This is based on guidelines regarding Huntington’s disease in anticipation of high psychosocial impact of DNA-testing for mutations in BRCA1/2 genes. The initial consultation covers generic information regarding hereditary breast cancer and the (im)possibilities of DNA-testing, prior to such testing. Patients with breast cancer may see this information as irrelevant or unnecessary because individual genetic advice depends on DNA-test results. Also, verbal information is not always remembered well by patients. A different format for this information prior to DNA-testing is possible: replacing initial face-to-face genetic counseling (DNA-intake procedure) by telephone, written and digital information sent to patients’ homes (DNA-direct procedure).

Methods/design
In this intervention study, 150 patients with breast cancer referred to the department of Clinical Genetics of the Radboud University Nijmegen Medical Centre are given the choice between two procedures, DNA-direct (intervention group) or DNA-intake (usual care, control group). During a triage telephone call, patients are excluded if they have problems with Dutch text, family communication, or of psychological or psychiatric nature. Primary outcome measures are satisfaction and psychological distress. Secondary outcome measures are determinants for the participant’s choice of procedure, waiting and processing times, and family characteristics. Data are collected by self-report questionnaires at baseline and following completion of genetic counseling. A minority of participants will receive an invitation for a 30 min semi-structured telephone interview, e.g. confirmed carriers of a BRCA1/2 mutation, and those who report problems with the procedure.

Discussion
This study compares current practice of an intake consultation (DNA-intake) to a home informational package of telephone, written and digital information (DNA-direct) prior to DNA-testing in patients with breast cancer. The aim is to determine whether DNA-direct is an acceptable procedure for BRCA1/2 testing, in order to provide customized care to patients with breast cancer, cutting down on the period of uncertainty during this diagnostic process.

Trial registration
The study is registered at the Dutch Trial Registry http://www.trialregister.nl (NTR3018).
Complete genome sequence of a highly divergent astrovirus isolated from a child with acute diarrhea
Authors: Finkbeiner Stacy R , Kirkwood Carl D , Wang David 
Published: May 2012

Abstract

Background
Astroviruses infect a variety of mammals and birds and are causative agents of diarrhea in humans and other animal hosts. We have previously described the identification of several sequence fragments with limited sequence identity to known astroviruses in a stool specimen obtained from a child with acute diarrhea, suggesting that a novel virus was present.

Results
In this study, the complete genome of this novel virus isolate was sequenced and analyzed. The overall genome organization of this virus paralleled that of known astroviruses, with 3 open reading frames identified. Phylogenetic analysis of the ORFs indicated that this virus is highly divergent from all previously described animal and human astroviruses. Molecular features that are highly conserved in human serotypes 1–8, such as a 3'NTR stem-loop structure and conserved nucleotide motifs present in the 5'NTR and ORF1b/2 junction, were either absent or only partially conserved in this novel virus.

Conclusion
Based on the analyses described herein, we propose that this newly discovered virus represents a novel species in the family Astroviridae. It has tentatively been named Astrovirus MLB1.
The Role of Cation-Dependent Chloride Transporters in Neuropathic Pain Following Spinal Cord Injury
Authors: Cramer Samuel W , Baggott Christopher , Cain John , Tilghman Jessica , Allcock Bradley , Miranpuri Gurwattan , Rajpal Sharad , Sun Dandan , Resnick Daniel 
Published: May 2012

Background: Altered Cl− homeostasis and GABAergic function are associated with nociceptive input hypersensitivity. This study investigated the role of two major intracellular Cl− regulatory proteins, Na+-K+-Cl− cotransporter 1 (NKCC1) and K+-Cl− cotransporter 2 (KCC2), in neuropathic pain following spinal cord injury (SCI). Results: Sprague-Dawley rats underwent a contusive SCI at T9 using the MASCIS impactor. The rats developed hyperalgesia between days 21 and 42 post-SCI. Thermal hyperalgesia (TH) was determined by a decrease in hindpaw thermal withdrawal latency time (WLT) between days 21 and 42 post-SCI. Rats with TH were then treated with either vehicle (saline containing 0.25% NaOH) or NKCC1 inhibitor bumetanide (BU, 30 mg/kg, i.p.) in vehicle. TH was then re-measured at 1 h post-injection. Administration of BU significantly increased the mean WLT in rats (p < 0.05). The group administered with the vehicle alone showed no anti-hyperalgesic effects. Moreover, an increase in NKCC1 protein expression occurred in the lesion epicenter of the spinal cord during day 2–14 post-SCI and peaked on day 14 post-SCI (p < 0.05). Concurrently, a down-regulation of KCC2 protein was detected during day 2–14 post-SCI. The rats with TH exhibited a sustained loss of KCC2 protein during post-SCI days 21–42. No significant changes of these proteins were detected in the rostral region of the spinal cord. Conclusion: Taken together, expression of NKCC1 and KCC2 proteins was differentially altered following SCI. The anti-hyperalgesic effect of NKCC1 inhibition suggests that normal or elevated NKCC1 function and loss of KCC2 function play a role in the development and maintenance of SCI-induced neuropathic pain.
Recombinant Ecto-5′-Nucleotidase (CD73) Has Long Lasting Antinociceptive Effects That are Dependent on Adenosine A1 Receptor Activation
Authors: Sowa Nathaniel A , Voss Meagen K , Zylka Mark J 
Published: May 2012

Background: Ecto-5-nucleotidase (NT5E, also known as CD73) hydrolyzes extracellular adenosine 5′-monophosphate (AMP) to adenosine in nociceptive circuits. Since adenosine has antinociceptive effects in rodents and humans, we hypothesized that NT5E, an enzyme that generates adenosine, might also have antinociceptive effects in vivo. Results: To test this hypothesis, we purified a soluble version of mouse NT5E (mNT5E) using the baculovirus expression system. Recombinant mNT5E hydrolyzed AMP in biochemical assays and was inhibited by α,β-methylene-adenosine 5′-diphosphate (α,β-me-ADP; IC50 = 0.43 μM), a selective inhibitor of NT5E. mNT5E exhibited a dose-dependent thermal antinociceptive effect that lasted for two days when injected intrathecally in wild-type mice. In addition, mNT5E had thermal antihyperalgesic and mechanical antiallodynic effects that lasted for two days in the complete Freund's adjuvant (CFA) model of inflammatory pain and the spared nerve injury (SNI) model of neuropathic pain. In contrast, mNT5E had no antinociceptive effects when injected intrathecally into adenosine A1 receptor ( A1 R, Adora1) knockout mice. Conclusion: Our data indicate that the long lasting antinociceptive effects of mNT5E are due to hydrolysis of AMP followed by activation of A1R. Moreover, our data suggest recombinant NT5E could be used to treat chronic pain and to study many other physiological processes that are regulated by NT5E.
On the complexity of miRNA-mediated regulation in plants: novel insights into the genomic organization of plant miRNAs
Authors: Colaiacovo Moreno , Lamontanara Antonella , Bernardo Letizia , Alberici Renzo , Crosatti Cristina , Giusti Lorenzo , Cattivelli Luigi , Faccioli Primetta 
Published: May 2012

Abstract
MicroRNAs (miRNAs) are endogenous small non-coding RNAs of about 20–24 nt, known to play key roles in post-transcriptional gene regulation, that can be coded either by intergenic or intragenic loci. Intragenic (exonic and intronic) miRNAs can exert a role in the transcriptional regulation and RNA processing of their host gene. Moreover, the possibility that the biogenesis of exonic miRNAs could destabilize the corresponding protein-coding transcript and reduce protein synthesis makes their characterization very intriguing and suggests a possible novel mechanism of post-transcriptional regulation of gene expression.
This work was designed to carry out the computational identification of putative exonic miRNAs in 30 plant species and the analysis of possible mechanisms involved in their regulation.
The results obtained represent a useful starting point for future studies on the complex networks involved in microRNA-mediated gene regulation in plants.
Bone to pick: the importance of evaluating reference genes for RT-qPCR quantification of gene expression in craniosynostosis and bone-related tissues and cells
Authors: Yang Xianxian , Hatfield Jodie T , Hinze Susan J , Mu Xiongzheng , Anderson Peter J , Powell Barry C 
Published: May 2012

Abstract

Background
RT-qPCR is a common tool for quantification of gene expression, but its accuracy is dependent on the choice and stability (steady state expression levels) of the reference gene/s used for normalization. To date, in the bone field, there have been few studies to determine the most stable reference genes and, usually, RT-qPCR data is normalised to non-validated reference genes, most commonly GAPDH, ACTB and 18 S rRNA. Here we draw attention to the potential deleterious impact of using classical reference genes to normalise expression data for bone studies without prior validation of their stability.

Results
Using the geNorm and Normfinder programs, panels of mouse and human genes were assessed for their stability under three different experimental conditions: 1) disease progression of Crouzon syndrome (craniosynostosis) in a mouse model, 2) proliferative culture of cranial suture cells isolated from craniosynostosis patients and 3) osteogenesis of a mouse bone marrow stromal cell line. We demonstrate that classical reference genes are not always the most ‘stable’ genes and that gene ‘stability’ is highly dependent on experimental conditions. Selected stable genes, individually or in combination, were then used to normalise osteocalcin and alkaline phosphatase gene expression data during cranial suture fusion in the craniosynostosis mouse model and strategies compared. Strikingly, the expression trends of alkaline phosphatase and osteocalcin varied significantly when normalised to the least stable, the most stable or the three most stable genes.

Conclusion
To minimise errors in evaluating gene expression levels, analysis of a reference panel and subsequent normalization to several stable genes is strongly recommended over normalization to a single gene. In particular, we conclude that use of single, non-validated “housekeeping” genes such as GAPDH, ACTB and 18 S rRNA, currently a widespread practice by researchers in the bone field, is likely to produce data of questionable reliability when changes are 2 fold or less, and such data should be interpreted with due caution.
Receptor cleavage and P-selectin-dependent reduction of leukocyte adhesion in the spontaneously hypertensive rat
Authors: Chen Angela Y , Ha Jessica N , DeLano Frank A , Schmid-Schönbein Geert W 
Published: May 2012

Abstract
Elevated matrix metalloproteinase activity in the plasma of the spontaneously hypertensive rat is associated with reduced mesenteric venular extracellular P-selectin density and impaired leukocyte adhesion.
The SHR, a genetic model for hypertension and the metabolic syndrome, has attenuated leukocyte adhesion to the postcapillary endothelium by an unknown mechanism. Based on recent evidence of elevated levels of MMPs in plasma and on microvascular endothelium of the SHR with cleavage of several receptor types, we hypothesize that the reduced leukocyte-endothelial interaction is a result of enhanced proteolytic cleavage of P-selectin on the postcapillary endothelium and PSGL-1 on leukocytes. The attenuated rolling interactions of SHR leukocytes with the endothelium were restored by chronic treatment with a broad-spectrum MMP inhibitor (CGS) for 24 weeks. The SHR MMP levels, in plasma and mesentery, as well as the systolic blood pressure, decreased significantly with treatment. In the SHR mesentery, labeling of P-selectin in the postcapillary venules by immunohistochemistry demonstrated, on average, a 31% lower extracellular P-selectin density compared with the normotensive WKY. A significantly lower extracellular PSGL-1 density on the membranes of SHR neutrophils compared with the WKY also supported our hypothesis. In vivo stimulation of the mesenteric postcapillary venules with histamine demonstrated that the SHR had an attenuated response, as measured by leukocyte rolling velocity on the endothelium. The reduced P-selectin and PSGL-1 density, on SHR postcapillary endothelium and on SHR leukocytes, respectively, was restored significantly by chronic MMP inhibition. The impaired ability of SHR leukocytes to reduce rolling velocity upon inflammatory stimulation led to fewer firmly adhered leukocytes to the endothelium as a contributor to immune suppression.
Neoadjuvant Chemotherapy With Methotrexate, Cisplatin, and Doxorubicin With or Without Ifosfamide in Nonmetastatic Osteosarcoma of the Extremity: An Italian Sarcoma Group Trial ISG/OS-1
Authors: Ferrari Stefano , Ruggieri Pietro , Cefalo Graziella , Tamburini Angela , Capanna Rodolfo , Fagioli Franca , Comandone Alessandro , Bertulli Rossella , Bisogno Gianni , Palmerini Emanuela , Alberghini Marco , Parafioriti Antonina , Linari Alessandra , Picci Piero , Bacci Gaetano 
Published: May 2012

Purpose We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity. Patients and Methods Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m2, MTX 120 g/m2, CDP 600 mg/m2, and IFO 30 g/m2) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS). Results From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B. Conclusion IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.
Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study
Authors: Bachelot Thomas , Bourgier Céline , Cropet Claire , Ray-Coquard Isabelle , Ferrero Jean-Marc , Freyer Gilles , Abadie-Lacourtoisie Sophie , Eymard Jean-Christophe , Debled Marc , Spaëth Dominique , Legouffe Eric , Allouache Djelila , El Kouri Claude , Pujade-Lauraine Eric 
Published: May 2012

Purpose Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs). Patients and Methods This open-label, phase II study randomly assigned postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned. Results The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%). Conclusion This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.
Sunitinib Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer: A Phase III Trial
Authors: Scagliotti Giorgio V. , Krzakowski Maciej , Szczesna Aleksandra , Strausz Janos , Makhson Anatoly , Reck Martin , Wierzbicki Rafal F. , Albert Istvan , Thomas Michael , Miziara Jose Elias Abrao , Papai Zsolt S. , Karaseva Nina , Thongprasert Sumitra , Portulas Elsa Dalmau , von Pawel Joachim , Zhang Ke , Selaru Paulina , Tye Lesley , Chao Richard C. , Govindan Ramaswamy 
Published: May 2012

Purpose Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non–small-cell lung cancer (NSCLC), based on the importance of the signaling pathways involved in tumor growth, angiogenesis, and metastasis. This phase III trial investigated overall survival (OS) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC. Patients and Methods Patients previously treated with one to two chemotherapy regimens (including one platinum-based regimen) for recurrent NSCLC, and for whom erlotinib was indicated, were randomly assigned (1:1) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d, stratified by prior bevacizumab use, smoking history, and epidermal growth factor receptor expression. The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Results In all, 960 patients were randomly assigned, and baseline characteristics were balanced. Median OS was 9.0 months for sunitinib plus erlotinib versus 8.5 months for erlotinib alone (hazard ratio [HR], 0.922; 95% CI, 0.797 to 1.067; one-sided stratified log-rank P = .1388). Median PFS was 3.6 months versus 2.0 months (HR, 0.807; 95% CI, 0.695 to 0.937; one-sided stratified log-rank P = .0023), and ORR was 10.6% versus 6.9% (two-sided stratified log-rank P = .0471), respectively. Treatment-related toxicities of grade 3 or higher, including rash/dermatitis, diarrhea, and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm. Conclusion In patients with refractory NSCLC, sunitinib plus erlotinib did not improve OS compared with erlotinib alone, but the combination was associated with a statistically significantly longer PFS and greater ORR. The incidence of grade 3 or higher toxicities was greater with combination therapy.
The use of anaesthetic for transrectal ultrasound-guided prostate biopsy
Authors: Jan K , Mak S M , Ley N , Naisby G , Chadwick D 
Published: May 2012

Background Transrectal ultrasound-guided prostate biopsy is the gold standard technique for detecting prostate cancer, undertaken routinely without the use of local anaesthetic (LA) in our institution. Current national guidelines provided by The NHS Prostate Cancer Risk Management Programme and the National Institute for Health and Clinical Excellence recommend and support the use of local anaesthetic injection as the most effective form of pain relief. Methods The primary aim of the study was to assess the impact of the introduction of national guidelines on the patient's pain perception of the procedure. Secondary aims were to compare the complication rates, i.e. bleeding, symptoms of infection and acceptance of a repeat procedure. A quantitative comparative study was performed. After the procedure, pain was evaluated using a questionnaire containing a visual analogue scale. A total of 75 consecutive patients’ prospective, anonymized questionnaire data, from those who were given LA, were compared with data from 75 patients who underwent prostate biopsy before the introduction of local anaesthetic. Data were analysed using two independent samples tests. Results The study findings supported the national clinical guidelines in the routine use of local anaesthetic during transrectal ultrasound-guided prostate biopsy: by demonstrating improvement in pain score, decreased reported discomfort and increased tolerability with no additional significant morbidity or complications. Conclusion The study has informed future policy and protocols by providing evidence based practice. Current working practice has changed to the routine offer of LA and is at present considered the gold standard.
Joint Partial Crosstalk Cancellation and Spectrum Management for xDSL Systems with Data Rate Constraints
Authors: Düngen Monique 
Published: May 2012

AbstractxDSL systems have to be able to support an always increasing amount of high-rate applications. To make the applications run stably, service providers need to be capable of guaranteeing these high data rates to their customers at a limited amount of available computational complexity usable for crosstalk cancellation.In order to be able to support high data rate targets with a low amount of computational complexity, partial crosstalk cancellation was combined with spectrum management techniques. A selection procedure was found, which jointly chooses the canceled crosstalkers and the transmit powers for each user on each tone by interlacing Iterative Water Filling (IWF) and a newly developed successive crosstalk selection algorithm for partial crosstalk cancellation, which takes into account the data rate requirements of the users. It distributes the available computational complexity in an intelligent way, so that data rate requirements are fulfilled. With the joint procedure savings in computational complexity are achieved.