bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Infiltrating Immune Cells and Outcome of Merkel Cell Carcinoma: A Population-Based Study
Authors: Sihto Harri , Böhling Tom , Kavola Heli , Koljonen Virve , Salmi Marko , Jalkanen Sirpa , Joensuu Heikki 
Published: March 2012

Abstract
Purpose: Merkel cell carcinoma (MCC) is a rare skin cancer that often harbors Merkel cell polyomavirus (MCPyV) DNA. The clinical importance of intratumoral immune cells and their associations with MCPyV infection are poorly understood.
Experimental Design: We identified T lymphocytes (CD3-positive cells), T-cell subsets (CD4, CD8, and FoxP3-positive cells), natural killer cells (small CD16-positive cells), and macrophages (CD68 and CD163-positive cells) in tumors of 116 individuals diagnosed with MCC in Finland from 1979 to 2004 using immunohistochemistry and detected MCPyV DNA with quantitative PCR. The associations between immune cell counts, MCPyV DNA, patient and tumor characteristics, and patient outcome were examined.
Results: MCPyV DNA-positive cancers contained higher numbers of CD3+, CD8+, CD16+, FoxP3+, and CD68+ cells as compared with MCPyV DNA-negative carcinomas (all P values &lt; 0.05). High intratumoral numbers of CD3+, CD8+, or FoxP3+ cells, and high CD8+/CD4+ or FoxP3+/CD4+ ratios, were significantly associated with favorable overall survival. Individuals with a high tumor CD3+ count had metastases less often and survived longer, irrespective of the tumor MCPyV status. Tumor CD3+ count and MCPyV DNA status had independent influence on survival in a Cox multivariable model that also included presence of locoregional metastases at diagnosis and gender as covariates.
Conclusions: High intratumoral T-lymphocyte counts are associated with favorable survival in MCC. Although the numbers of T cells are generally higher in MCPyV-positive than in MCPyV-negative MCC, high intratumoral T-cell counts are also associated with favorable survival in MCPyV-negative MCC. Clin Cancer Res; 18(10); 2872–81. ©2012 AACR.
Reversing Resistance to Vascular-Disrupting Agents by Blocking Late Mobilization of Circulating Endothelial Progenitor Cells
Authors: Taylor Melissa , Billiot Fanny , Marty Virginie , Rouffiac Valérie , Cohen Patrick , Tournay Elodie , Opolon Paule , Louache Fawzia , Vassal Gilles , Laplace-Builhé Corinne , Vielh Philippe , Soria Jean-Charles , Farace Françoise 
Published: March 2012

Abstract
The prevailing concept is that immediate mobilization of bone marrow–derived circulating endothelial progenitor cells (CEP) is a key mechanism mediating tumor resistance to vascular-disrupting agents (VDA). Here, we show that administration of VDA to tumor-bearing mice induces 2 distinct peaks in CEPs: an early, unspecific CEP efflux followed by a late yet more dramatic tumor-specific CEP burst that infiltrates tumors and is recruited to vessels. Combination with antiangiogenic drugs could not disrupt the early peak but completely abrogated the late VDA-induced CEP burst, blunted bone marrow–derived cell recruitment to tumors, and resulted in striking antitumor efficacy, indicating that the late CEP burst might be crucial to tumor recovery after VDA therapy. CEP and circulating endothelial cell kinetics in VDA-treated patients with cancer were remarkably consistent with our preclinical data. These findings expand the current understanding of vasculogenic “rebounds” that may be targeted to improve VDA-based strategies.
Significance: Our findings suggest that resistance to VDA therapy may be strongly mediated by late, rather than early, tumor-specific recruitment of CEPs, the suppression of which resulted in increased VDA-mediated antitumor efficacy. VDA-based therapy might thus be significantly enhanced by combination strategies targeting late CEP mobilization. Cancer Discov; 2(5); 434–49. ©2012 AACR.
Read the Commentary on this article by De Palma and Nucera, p. 395.
This article is highlighted in the In This Issue feature, p. 377.
A Randomized Double‐Blind Crossover Study of Phase‐Shift Sound Therapy for Tinnitus
Authors: Heijneman Karin M. , de Kleine Emile , van Dijk Pim 
Published: March 2012

ObjectiveThe purpose of this study was to compare the efficacy of the treatment of tinnitus with a phase‐shifting pure tone to that of the same tone treatment without phase shifting.Study DesignA double‐blind crossover randomized controlled trial.SettingThis study was conducted at the University Medical Center Groningen.Subjects and MethodsTwenty‐two patients with predominantly tonal tinnitus underwent both intervention and control treatments. Each treatment consisted of three 30‐minute sessions in 1 week. The control treatment was identical to the intervention treatment, except that the stimulus was a pure tone without phase shifting. Questionnaires, tinnitus loudness match, and annoyance and loudness ratings were used to measure treatment effects.ResultsPure‐tone treatment and phase‐shift treatment had no significant effect on tinnitus according to questionnaires (Tinnitus Handicap Index, Tinnitus Reaction Questionnaire, Hospital Anxiety and Depression Scale, and Maastricht Questionnaire), audiological matching procedures, and loudness and annoyance ratings of tinnitus. Furthermore, phase‐shift treatment showed no additional significant improvement in comparison with pure‐tone treatment. Changes in questionnaire scores due to pure‐tone and the phase‐shift treatment were correlated.ConclusionOn average across the group, both treatments failed to demonstrate a significant effect. Both treatments were beneficial for some patients. However, a positive effect was not demonstrated that could be attributed to the periodic shifting of the phase of the stimulus tone.
Anatomic Variants on Computed Tomography in Congenital Aural Atresia
Authors: Dedhia Kavita , Yellon Robert F. , Branstetter Barton F. , Egloff Ann Marie 
Published: March 2012

ObjectiveTo report the prevalence of anatomic variants on computed tomography (CT) in congenital aural atresia (CAA) and external auditory canal stenosis (EACS). Anatomic variants included inferiorly displaced/obstructing tegmen mastoideum, malleus‐incus complex (MIC) directly lateral to stapes, facial nerve obstruction of oval window (OW) or middle ear, and incudostapedial joint (ISJ) angle.Study DesignCross‐sectional study.SettingTertiary care children’s hospital.Subjects and MethodsAn anatomic analysis of 130 CT scans (98 children, 32 bilateral) of CAA/EACS, performed by a blinded neuroradiologist. Both Jahrsdoerfer’s and new/modified anatomic considerations were graded in 32 atresiaplasty and 66 nonsurgical patients. Surgical data were analyzed for anatomic correlations related to surgical findings.ResultsPrevalence of anatomic variants was as follows: 13% of the ears had mild inferior displacement of tegmen, 4% had a significantly obstructing tegmen, and 24% had MIC directly lateral to stapes. The facial nerve obstructed access to OW in 41% and middle ear in 21%. Six atresiaplasty patients were reported to have a large MIC obstructing stapes access with increased intraoperative difficulty in viewing and assessing the integrity and mobility of the ISJ and stapes. Five of these 6 (83%) were noted on CT scan. The mean ISJ angle was 101° (range, 51°‐155°).ConclusionA large obstructing MIC increases difficulty of atresiaplasty. Awareness of the presence of these anatomic variants is an aid in teaching temporal bone anatomy and may possibly influence the decision regarding atresiaplasty.
Walking on thin ice: the use of triple antidepressant combinations in refractory melancholic depression
Authors: Restifo Sam 
Published: March 2012

Objective: To report on the outcome of cases of refractory depression treated with a combination of three antidepressant agents. Method: Retrospective case series. Results: Three of the four patients made a good recovery. One patient developed transient increased agitation and exacerbation of pre-existing confusion. Conclusion: The use of a triple antidepressant combination may be a treatment option, albeit unorthodox and inelegant, in very specific circumstances such as for patients with refractory melancholic depression who have only partially responded to vigorous pharmacological treatment with combined antidepressants and are unwilling to use, or are unsuitable for, established treatments, such as lithium augmentation or electro-convulsive therapy (ECT).
It’s raining mental health commissions: prospects and pitfalls in driving mental health reform
Authors: Rosenberg Sebastian , Rosen Alan 
Published: March 2012

Objective: Partly in response to ongoing concerns about the state of mental health care, several jurisdictions across Australia, including the federal government, are hoping to drive change via the establishment of a mental health commission. This is the first of two articles in a series which aims to describe the background to this new trend. The commissions are being established with different powers and structures. This variety is explored and considered against a typology of commissions. Some consistent themes and goals emerge. The paper then provides a contemporary assessment of the ‘state of play’ of the nascent commissions and describes important emerging issues and differences between the models. Conclusion: There are significant differences not only in the construct of the respective commissions but also in the political circumstances in which each must work. At the same time, the problems facing mental health in Australia are ubiquitous and profound. For commissions to be successful they will require not only astute leadership but also durable, bipartisan political support and an enduring capacity to generate new resources for the mental health sector.
A framework for exploring the potential of routine outcome measurement to improve mental health care
Authors: McKay Rod , Coombs Tim , Pirkis Jane 
Published: March 2012

Objective: To present a framework for exploring the potential applications of routine outcome measurement (ROM) to improve clinical practice. Conclusions: ROM is now commonplace in Australian mental health services, but it is fair to say that it has not yet achieved its potential in guiding service quality improvements. The framework described in this paper articulates the key components of ROM, noting that data from standardized outcome measures must be augmented by contextual information from other datasets. It considers the key users of ROM, and suggests the kind of questions that ROM might answer for each user group. It presents the use of ROM as a cycle of understanding the context, prioritization, brainstorming and planning, action and review. It is hoped that this framework might help to maximize the clinical utility of ROM at a number of levels.
Applying Motivational Interviewing to the initiation of long-acting injectable atypical antipsychotics
Authors: Kisely Steve , Ligate Loys , Roy Marc-André , Lavery Terri 
Published: March 2012

Objective: Non-concordance with pharmacotherapy is common in psychiatric patients. Long-acting injectable atypical antipsychotic (LAI AA) medication may improve adherence but patients and clinicians may be reluctant to consider this alternative. This paper describes the application of Motivational Interviewing (MI) to the commencement of LAI AA. Method: We developed a workshop applying the principles of MI to address medication adherence through the use of LAIs. This includes a training video to illustrate the following motivational techniques, as summarised by the acronym OARS: (a) Open questions; (b) Affirmation of patients’ self-efficacy and support; (c) Reflections of patients’ thoughts, desires, abilities, reasons, needs, and commitments; (d) Summaries of the patient’s history to promote consideration of change. Results: We delivered four workshops across Canada. Results of feedback ( n=25) were encouraging. Conclusions: Motivational Interviewing has many applications in psychiatric care for engagement in treatment, reduction in alcohol or substance misuse, and improving medication acceptance and adherence. Further research is required to assess whether changes in physicians’ views are reflected in improved adherence.
3D GRASE arterial spin labelling reveals an inverse correlation of cortical perfusion with the white matter lesion volume in MS
Authors: Amann Michael , Achtnichts Lutz , Hirsch Jochen G , Naegelin Yvonne , Gregori Johannes , Weier Katrin , Thöni Alain , Mueller-Lenke Nicole , Radue Ernst-Wilhelm , Günther Matthias , Kappos Ludwig , Gass Achim 
Published: March 2012

Background: We hypothesized that in multiple sclerosis (MS) patients, reduced cortical perfusion is associated with chronic white matter injury. Objective: To investigate the influence of different clinical and magnetic resonance imaging characteristics on cortical perfusion. Methods: Cerebral blood flow (CBF) was assessed by applying a pulsed arterial spin labelling (ASL) technique combined with single-shot 3D-GRASE (gradient-spin echo) in a cohort of 165 MS patients with a relapsing–remitting ( n=123) or secondary progressive disease course ( n=42). Mean age was 45.4 years (20–68 years), mean disease duration was 14.2 years (1–48 years). Results: Mean cortical CBF was 45.6 ml/100g per min (SD: 7.8 ml/100g per min). Stepwise multiple linear regression models were calculated to investigate the relationship between different factor sets and mean CBF. The model with the highest adjusted coefficient of determination included T2 lesion load, age, gender and disease duration as significant factors. Post-hoc Spearman rank correlation revealed significant correlation of adjusted CBF with T2 lesion load (t=−0.35, p=1*10–6), with age (t =−0.34, p=4*10–6), and with disease duration (t=0.16, p=0.03), while Expanded Disability Status Scale (EDSS) did not reach significance in either model. Conclusion: This study suggests that the amount of white matter lesions indicates a reduced metabolic demand and reduced perfusion at a cortical level.
Deterioration of endothelial function and carotid intima-media thickness in Tibetan male adolescents exposed to second-hand smoke
Authors: Yang Bo , Li Min , Chen Bin , Xu Yong , Li Tian-De 
Published: March 2012

Introduction: It has been commonly accepted that second-hand smoke (SHS) is associated with atherosclerosis and endothelial dysfunction. There is growing evidence that the changes might begin in childhood. Unfortunately, no study has focused on the early atherosclerosis of Tibetan adolescents exposed to SHS. Aims: We aimed to investigate the endothelial function and carotid atherosclerosis in healthy school-aged Tibetan male adolescents. Materials and methods: All passive smoking participants (SHS) were students were 16 years old and male, and were recruited through middle schools in Lhasa city. In total 624 subjects were accepted after excluding subjects who actively smoked. The adolescents were divided into three groups according to serum cotinine level: high cotinine group (High Group) with 205 boys, intermediate cotinine group (Intermediate Group) with 210 boys, and low cotinine group (Low Group) with 209 boys. Venous blood was sampled for the measurement of cotinine concentration, lipid profile and endothelin-1 (ET-1) quantitation. High-resolution B-mode ultrasonography was performed to evaluate carotid intima-media thickness (cIMT) and intima smoothness. The invasive vascular endothelial function was evaluated through the measurement of flow-mediated dilation (FMD) with B-mode ultrasound and ankle-brachial index (ABI) by using a blood pressure cuff and a Doppler instrument. Results: No statistical significance was found between groups in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, ApoA-I, systolic blood pressure, diastolic blood pressure, and heart rate ( p>0.05). In the lipid profile, only apolipoprotein B (ApoB) values were different between groups: ApoB in the High Group was higher than in the Low Group ( p=0.0164). Plasma ET-1 concentrations in the High Group were also much higher than in the Intermediate and Low Groups ( p=0.0112, p<0.001). The cIMT and intima smoothness had deteriorated in the High Group compared with the Low Group ( p<0.001 and p<0.05 respectively). FMD and ABI, which indicate vascular endothelial function, was decreased in the High Group compared with the Intermediate and Low Groups (FMD, p<0.001; ABI, p<0.001). Conclusions: SHS was associated with sub-clinical carotid atherosclerosis and endothelial dysfunction in Tibetan school-aged male adolescents. Considering the widespread exposure to SHS and the clinical relevance of early atherosclerosis, this result is of public health importance in Tibet, where health education is not satisfactory. Data from our study emphasize the importance of endorsing smoke-free environments for adolescents.
Categorization of 77 dystrophinexons into 5 groups by a decision tree using indexes of splicing regulatory factors as decision markers
Authors: Malueka Rusdy Ghazali , Takaoka Yutaka , Yagi Mariko , Awano Hiroyuki , Lee Tomoko , Dwianingsih Ery Kus , Nishida Atsushi , Takeshima Yasuhiro , Matsuo Masafumi 
Published: March 2012

Abstract

Background
Duchenne muscular dystrophy, a fatal muscle-wasting disease, is characterized by dystrophin deficiency caused by mutations in the dystrophin gene. Skipping of a target dystrophin exon during splicing with antisense oligonucleotides is attracting much attention as the most plausible way to express dystrophin in DMD. Antisense oligonucleotides have been designed against splicing regulatory sequences such as splicing enhancer sequences of target exons. Recently, we reported that a chemical kinase inhibitor specifically enhances the skipping of mutated dystrophin exon 31, indicating the existence of exon-specific splicing regulatory systems. However, the basis for such individual regulatory systems is largely unknown. Here, we categorized the dystrophin exons in terms of their splicing regulatory factors.

Results
Using a computer-based machine learning system, we first constructed a decision tree separating 77 authentic from 14 known cryptic exons using 25 indexes of splicing regulatory factors as decision markers. We evaluated the classification accuracy of a novel cryptic exon (exon 11a) identified in this study. However, the tree mislabeled exon 11a as a true exon. Therefore, we re-constructed the decision tree to separate all 15 cryptic exons. The revised decision tree categorized the 77 authentic exons into five groups. Furthermore, all nine disease-associated novel exons were successfully categorized as exons, validating the decision tree. One group, consisting of 30 exons, was characterized by a high density of exonic splicing enhancer sequences. This suggests that AOs targeting splicing enhancer sequences would efficiently induce skipping of exons belonging to this group.

Conclusions
The decision tree categorized the 77 authentic exons into five groups. Our classification may help to establish the strategy for exon skipping therapy for Duchenne muscular dystrophy.
De novo sequencing and characterization of Picrorhiza kurrooa transcriptome at two temperatures showed major transcriptome adjustments
Authors: Gahlan Parul , Singh Heikham Russiachand , Shankar Ravi , Sharma Niharika , Kumari Anita , Chawla Vandna , Ahuja Paramvir Singh , Kumar Sanjay 
Published: March 2012

Abstract

Background

Picrorhiza kurrooa Royle ex Benth. is an endangered plant species of medicinal importance. The medicinal property is attributed to monoterpenoids picroside I and II, which are modulated by temperature. The transcriptome information of this species is limited with the availability of few hundreds of expressed sequence tags (ESTs) in the public databases. In order to gain insight into temperature mediated molecular changes, high throughput de novo transcriptome sequencing and analyses were carried out at 15°C and 25°C, the temperatures known to modulate picrosides content.

Results
Using paired-end (PE) Illumina sequencing technology, a total of 20,593,412 and 44,229,272 PE reads were obtained after quality filtering for 15°C and 25°C, respectively. Available (e.g., De-Bruijn/Eulerian graph) and in-house developed bioinformatics tools were used for assembly and annotation of transcriptome. A total of 74,336 assembled transcript sequences were obtained, with an average coverage of 76.6 and average length of 439.5. Guanine-cytosine (GC) content was observed to be 44.6%, while the transcriptome exhibited abundance of trinucleotide simple sequence repeat (SSR; 45.63%) markers.
Large scale expression profiling through "read per exon kilobase per million (RPKM)", showed changes in several biological processes and metabolic pathways including cytochrome P450s (CYPs), UDP-glycosyltransferases (UGTs) and those associated with picrosides biosynthesis. RPKM data were validated by reverse transcriptase-polymerase chain reaction using a set of 19 genes, wherein 11 genes behaved in accordance with the two expression methods.

Conclusions
Study generated transcriptome of P. kurrooa at two different temperatures. Large scale expression profiling through RPKM showed major transcriptome changes in response to temperature reflecting alterations in major biological processes and metabolic pathways, and provided insight of GC content and SSR markers. Analysis also identified putative CYPs and UGTs that could help in discovering the hitherto unknown genes associated with picrosides biosynthesis.
Computational models for in-vitro anti-tubercular activity of molecules based on high-throughput chemical biology screening datasets
Authors: Periwal Vinita , Kishtapuram Shireesha ,   Open Source Drug Discovery Consortium, Scaria Vinod 
Published: March 2012

Abstract

Background
The emergence of Multi-drug resistant tuberculosis in pandemic proportions throughout the world and the paucity of novel therapeutics for tuberculosis have re-iterated the need to accelerate the discovery of novel molecules with anti-tubercular activity. Though high-throughput screens for anti-tubercular activity are available, they are expensive, tedious and time-consuming to be performed on large scales. Thus, there remains an unmet need to prioritize the molecules that are taken up for biological screens to save on cost and time. Computational methods including Machine Learning have been widely employed to build classifiers for high-throughput virtual screens to prioritize molecules for further analysis. The availability of datasets based on high-throughput biological screens or assays in public domain makes computational methods a plausible proposition for building predictive models. In addition, this approach would save significantly on the cost, effort and time required to run high throughput screens.

Results
We show that by using four supervised state-of-the-art classifiers (SMO, Random Forest, Naive Bayes and J48) we are able to generate in-silico predictive models on an extremely imbalanced (minority class ratio: 0.6%) large dataset of anti-tubercular molecules with reasonable AROC (0.6-0.75) and BCR (60-66%) values. Moreover, these models are able to provide 3-4 fold enrichment over random selection.

Conclusions
In the present study, we have used the data from in-vitro screens for anti-tubercular activity from a high-throughput screen available in public domain to build highly accurate classifiers based on molecular descriptors of the molecules. We show that Machine Learning tools can be used to build highly effective predictive models for virtual high-throughput screens to prioritize molecules from large molecular libraries.