bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trace element–enriched mid-Visean dikes in the New Carlisle area of Quebec, Canada: Unusual products of a tholeiitic melt sourced from metasomatized mantle rocks and fractionated in a brine-rich upper-crustal environment
Authors: Jutras Pierre , Dostal Jaroslav , Kamo Sandra 
Published: June 2019

Abstract
Early Carboniferous tholeiitic dikes in the New Carlisle area of Quebec, Canada, are abnormally enriched in high field strength elements (HFSEs), including rare earth elements. The enrichment is systematic and was apparently caused by an enhanced incompatibility of HFSEs during a prolonged episode of crystal fractionation. As a result, HFSE concentrations are up to one order of magnitude higher than those of typical mafic rocks. Very high F and Cl contents suggest that halogen complexing was largely responsible for the trace-element enrichment. The high halogen contents are in part accounted for by a subcontinental lithospheric mantle source that had previously been enriched in these elements by prolonged subduction. Additional Cl enrichment is interpreted to have occurred in a magma chamber that developed within porous and brine-rich country rocks of the upper crust. This conclusion is supported by the observation that HFSE-enriched mafic plutons in the same magmatic province occur in nonmetamorphosed upper-crustal rocks, suggesting high buoyancy and therefore high temperatures. Such evidence for high heat in the late Paleozoic magmatic system of eastern Canada corroborates previous studies suggesting that the transtensional basin in which it evolved was overriding a mantle plume at the time. In the case of the New Carlisle dikes, which are more than twice as enriched in incompatible trace elements as slightly older mafic rocks of the same magmatic system, the regional paleoenvironmental setting suggests that the associated upper-crustal magma chamber may have evolved in rocks with saltier pore water due to long-lasting evaporitic conditions at the surface.
Effects of a training programme of functional electrical stimulation (FES) powered cycling, recreational cycling and goal-directed exercise training on children with cerebral palsy: a randomised controlled trial protocol
Authors: Armstrong Ellen L , Boyd Roslyn N , Kentish Megan J , Carty Christopher P , Horan Sean A 
Published: June 2019

IntroductionChildren with cerebral palsy (CP) experience declines in gross motor ability as they transition from childhood to adolescence, which can result in the loss of ability to perform sit-to-stand transfers, ambulate or participate in leisure activities such as cycling. Functional electrical stimulation (FES) cycling is a novel technology that may provide opportunities for children with CP to strengthen their lower limbs, improve functional independence and increase physical activity participation. The proposed randomised controlled trial will test the efficacy of a training package of FES cycling, adapted cycling and goal-directed functional training to usual care in children with CP who are susceptible to functional declines.Methods and analysisForty children with CP (20 per group), aged 6–8 years and classified as Gross Motor Function Classification System (GMFCS) levels II–IV will be recruited across South East Queensland. Participants will be randomised to either an immediate intervention group, who will undertake 8 weeks of training, or a waitlist control group. The training group will attend two 1 hour sessions per week with a physiotherapist, consisting of FES cycling and goal-directed, functional exercises and a 1 hour home exercise programme per week, consisting of recreational cycling. Primary outcomes will be the gross motor function measure and Canadian occupational performance measure, and secondary outcomes will include the five times sit-to-stand test, habitual physical activity (accelerometry), power output during cycling and Participation and Environment Measure-Children and Youth. Outcomes will be assessed at baseline, postintervention (8 weeks) and 8 weeks following the intervention (retention).Ethics and disseminationEthical approval has been obtained from Griffith University (2018/037) and the Children’s Health Queensland Hospital and Health Service (CHQHHS) Human Research Ethics Committee (HREC/17/QRCH/88). Site-specific approval was obtained from CHQHHS research governance (SSA/17/QRCH/145). Results from this trial will be disseminated via publication in relevant peer-reviewed journals.Trial registration numberACTRN12617000644369p.
Individualised screening for diabetic retinopathy: the ISDR study—rationale, design and methodology for a randomised controlled trial comparing annual and individualised risk-based variable-interval screening
Authors: Broadbent Deborah M , Sampson Christopher J , Wang Amu , Howard Lola , Williams Abigail E , Howlin Susan U , Appelbe Duncan , Moitt Tracy , Cheyne Christopher P , Rahni Mehrdad Mobayen , Kelly John , Collins John , García-Fiñana Marta , Stratton Irene M , James Marilyn , Harding Simon P 
Published: June 2019

IntroductionCurrently, all people with diabetes (PWD) aged 12 years and over in the UK are invited for screening for diabetic retinopathy (DR) annually. Resources are not increasing despite a 5% increase in the numbers of PWD nationwide each year. We describe the rationale, design and methodology for a randomised controlled trial (RCT) evaluating the safety, acceptability and cost-effectiveness of personalised variable-interval risk-based screening for DR. This is the first randomised trial of personalised screening for DR and the largest ophthalmic RCT in the UK.Methods and analysisPWD attending seven screening clinics in the Liverpool Diabetic Eye Screening Programme were recruited into a single site RCT with a 1:1 allocation to individualised risk-based variable-interval or annual screening intervals. A risk calculation engine developed for the trial estimates the probability that an individual will develop referable disease (screen positive DR) within the next 6, 12 or 24 months using demographic, retinopathy and systemic risk factor data from primary care and screening programme records. Dynamic, secure, real-time data connections have been developed. The primary outcome is attendance for follow-up screening. We will test for equivalence in attendance rates between the two arms. Secondary outcomes are rates and severity of DR, visual outcomes, cost-effectiveness and health-related quality of life. The required sample size was 4460 PWD. Recruitment is complete, and the trial is in follow-up.Ethics and disseminationEthical approval was obtained from National Research Ethics Service Committee North West – Preston, reference 14/NW/0034. Results will be presented at international meetings and published in peer-reviewed journals. This pragmatic RCT will inform screening policy in the UK and elsewhere.Trial registration numberISRCTN87561257; Pre-results.
The acceptability of addressing alcohol consumption as a modifiable risk factor for breast cancer: a mixed method study within breast screening services and symptomatic breast clinics
Authors: Sinclair Julia , McCann Mark , Sheldon Ellena , Gordon Isabel , Brierley-Jones Lyn , Copson Ellen 
Published: June 2019

ObjectivesPotentially modifiable risk factors account for approximately 23% of breast cancers, with obesity and alcohol being the two greatest. Breast screening and symptomatic clinical attendances provide opportunities (‘teachable moments’) to link health promotion and breast cancer-prevention advice within established clinical pathways. This study explored knowledge and attitudes towards alcohol as a risk factor for breast cancer, and potential challenges inherent in incorporating advice about alcohol health risks into breast clinics and screening appointments.DesignA mixed-method study including a survey on risk factors for breast cancer and understanding of alcohol content. Survey results were explored in a series of five focus groups with women and eight semi-structured interviews with health professionals.SettingWomen attending NHS Breast Screening Programme (NHSBSP) mammograms, symptomatic breast clinics and healthcare professionals in those settings.Participants205 women were recruited (102 NHSBSP attenders and 103 symptomatic breast clinic attenders) and 33 NHS Staff.ResultsAlcohol was identified as a breast cancer risk factor by 40/205 (19.5%) of attenders and 16/33 (48.5%) of staff. Overall 66.5% of attenders drank alcohol, and 56.6% could not estimate correctly the alcohol content of any of four commonly consumed alcoholic drinks. All women agreed that including a prevention-focussed intervention would not reduce the likelihood of their attendance at screening mammograms or breast clinics. Qualitative data highlighted concerns in both women and staff of how to talk about alcohol and risk factors for breast cancer in a non-stigmatising way, as well as ambivalence from specialist staff as to their role in health promotion.ConclusionsLevels of alcohol health literacy and numeracy were low. Adding prevention interventions to screening and/or symptomatic clinics appears acceptable to attendees, highlighting the potential for using these opportunities as ‘teachable moments’. However, there are substantial cultural and systemic challenges to overcome if this is to be implemented successfully.
The specification, acceptability and effectiveness of respite care and short breaks for young adults with complex healthcare needs: protocol for a mixed-methods systematic review
Authors: Pilkington Gerlinde , Knighting Katherine , Bray Lucy , Downing Julia , Jack Barbara A , Maden Michelle , Mateus Ceu , Noyes Jane , O’Brien Mary R , Roe Brenda , Tsang Anthony , Spencer Sally 
Published: June 2019

IntroductionThe number of young adults with complex healthcare needs due to life-limiting conditions/complex physical disability has risen significantly as children with complex conditions survive into adulthood. Respite care and short breaks are an essential service, however, needs often go unmet after the transition to adult services, leading to a significant impact on the life expectancy and quality of life for this population. We aim to identify, appraise and synthesise relevant evidence to explore respite care and short breaks provision for this population, and to develop a conceptual framework for understanding service models.Methods and analysisA mixed-methods systematic review conducted in two stages: (1) knowledge map and (2) evidence review. We will comprehensively search multiple electronic databases; use the Citations, Lead authors, Unpublished materials, Google Scholar, Theories, Early examples, and Related projects (CLUSTER) approach, search relevant websites and circulate a ‘call for evidence’. Using the setting, perspective, intervention/phenomenon of interest, comparison and evaluation framework, two reviewers will independently select evidence for inclusion into a knowledge map and subsequent evidence review, extract data relating to study and population characteristics, methods and outcomes; and assess the quality of evidence. A third reviewer will arbitrate where necessary.Evidence will be synthesised using the following approaches: quantitative (narratively/conducting meta-analyses where appropriate); qualitative (framework approach); policy and guidelines (documentary analysis informed approach). An overall, integrated synthesis will be created using a modified framework approach. We will use Grading of Recommendations Assessment, Development and Evaluation (GRADE)/GRADE-Confidence in the Evidence from Reviews of Qualitative Research to assess the strength and confidence of the synthesised evidence. Throughout, we will develop a conceptual framework to articulate how service models work in relation to context and setting.Ethics and disseminationEthical approval is not required as this is a systematic review. We will present our work in academic journals, at appropriate conferences; we will disseminate findings across networks using a range of media. Steering and advisory groups were established to ensure findings are shared widely and in accessible formats.PROSPERO registration numberCRD42018088780.
Coordinated CTA Combination and Bandwidth Partitioning for GPU Concurrent Kernel Execution
Authors: Lin Zhen , Dai Hongwen , Mantor Michael , Zhou Huiyang 
Published: June 2019

Contemporary GPUs support multiple kernels to run concurrently on the same streaming multiprocessors (SMs). Recent studies have demonstrated that such concurrent kernel execution (CKE) improves both resource utilization and computational throughput. Most of the prior works focus on partitioning the GPU resources at the cooperative thread array (CTA) level or the warp scheduler level to improve CKE. However, significant performance slowdown and unfairness are observed when latency-sensitive kernels co-run with bandwidth-intensive ones. The reason is that bandwidth over-subscription from bandwidth-intensive kernels leads to much aggravated memory access latency, which is highly detrimental to latency-sensitive kernels. Even among bandwidth-intensive kernels, more intensive kernels may unfairly consume much higher bandwidth than less-intensive ones.
In this article, we first make a case that such problems cannot be sufficiently solved by managing CTA combinations alone and reveal the fundamental reasons. Then, we propose a coordinated approach for CTA combination and bandwidth partitioning. Our approach dynamically detects co-running kernels as latency sensitive or bandwidth intensive. As both the DRAM bandwidth and L2-to-L1 Network-on-Chip (NoC) bandwidth can be the critical resource, our approach partitions both bandwidth resources coordinately along with selecting proper CTA combinations. The key objective is to allocate more CTA resources for latency-sensitive kernels and more NoC/DRAM bandwidth resources to NoC-/DRAM-intensive kernels. We achieve it using a variation of dominant resource fairness (DRF). Compared with two state-of-the-art CKE optimization schemes, SMK [52] and WS [55], our approach improves the average harmonic speedup by 78% and 39%, respectively. Even compared to the best possible CTA combinations, which are obtained from an exhaustive search among all possible CTA combinations, our approach improves the harmonic speedup by up to 51% and 11% on average.
Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression
Authors: Bowen Cai , Ostrowski Michael C. , Leone Gustavo , Gelmann Edward P. 
Published: June 2019

Abstract

NKX3.1 is the most commonly deleted gene in prostate cancer and a gatekeeper suppressor. NKX3.1 is a growth suppressor, mediator of apoptosis, inducer of antioxidants, and enhancer of DNA repair. PTEN is a ubiquitous tumor suppressor that is often decreased in prostate cancer during tumor progression. Steady-state turnover of NKX3.1 is mediated by DYRK1B phosphorylation at NKX3.1 serine 185 that leads to polyubiquitination and proteasomal degradation. In this study, we show PTEN is an NKX3.1 phosphatase that protects NKX3.1 from degradation. PTEN specifically opposed phosphorylation at NKX3.1(S185) and prolonged NKX3.1 half-life. PTEN and NKX3.1 interacted primarily in the nucleus as loss of PTEN nuclear localization abrogated its ability to bind to and protect NKX3.1 from degradation. The effect of PTEN on NKX3.1 was mediated via rapid enzyme–substrate interaction. An effect of PTEN on Nkx3.1 gene transcription was seen in vitro, but not in vivo. In gene-targeted mice, Nkx3.1 expression significantly diminished shortly after loss of Pten expression in the prostate. Nkx3.1 loss primarily increased prostate epithelial cell proliferation in vivo. In these mice, Nkx3.1 mRNA was not affected by Pten expression. Thus, the prostate cancer suppressors PTEN and NKX3.1 interact and loss of PTEN is responsible, at least in part, for progressive loss of NKX3.1 that occurs during tumor progression.

Significance:
PTEN functions as a phosphatase of NKX3.1, a gatekeeper suppressor of prostate cancer.
A Tribute to John Mendelsohn: A Pioneer in Targeted Cancer Therapy
Authors: Kumar Rakesh , de Vijver Marc Van , Tortora Giampaolo , Ciardiello Fortunato , Goldkorn Tzipora , Miller Wilson H. , Norton Larry 
Published: June 2019

AbstractCancer scientists and clinicians are mourning the death of one of the most accomplished members of their community: Dr. John Mendelsohn. He was a pioneer in targeted cancer therapy and was instrumental for the discovery and deployment of the first antagonist epidermal growth factor receptor (EGFR) therapeutic antibodies, broadening the concept of targeted EGFR therapy to encompass other receptor tyrosine kinases, such as HER2, and developing blocking antibody-combination therapy with chemotherapies or radiotherapy. Dr. Mendelsohn, who died on January 7, 2019, always led by the strength of his accomplishments and the humility of his character. Above all, he was a well-revered mentor and clinician, who extended compassion and the gift of his time to patients, colleagues, and mentees alike. In tribute to Dr. Mendelsohn, Cancer Research has invited his former mentees and colleagues who were associated with Dr. Mendelsohn for over three decades to reflect on the broad impact of his work. Here, we discuss Dr. Mendelsohn's illustrious career at three elite academic cancer institutions and hospitals in the United States, his acumen to build, grow, and uplift institutions, and train a generation of medical oncologists, physician scientists, and cancer biologists. His profound legacy on targeted therapy and cancer research and treatment continue to prolong and save the lives of cancer patients globally.
Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation
Authors: Jaeger Alex M. , Stopfer Lauren , Lee Sunmin , Gaglia Giorgio , Sandel Demi , Santagata Sandro , Lin Nancy U. , Trepel Jane B. , White Forest , Jacks Tyler , Lindquist Susan , Whitesell Luke 
Published: June 2019

Abstract

Purpose:
Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as “foreign” and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options.
Experimental Design: We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacologic tools. Profiling of treatment-associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry.

Results:
We show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells on MHC-I molecules through an IFNγ-independent mechanism. In stark contrast, we find that acute, high-dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in patients with cancer. In mice, chronic non-heat shock–inducing HSP90 inhibition slowed progression of colon cancer implants, but only in syngeneic animals with intact immune function. Addition of a single dose of nonspecific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy.

Conclusions:
These highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.
See related commentary by Srivastava and Callahan, p. 6277
Association of Human Papillomavirus Genotype 16 Viral Variant and Viral Load with Cervical High-grade Intraepithelial Lesions
Authors: Álvarez-Paredes Ledicia , Santibañez Miguel , Galiana Antonio , Rodríguez Díaz Juan Carlos , Parás-Bravo Paula , Andrada-Becerra Mª Encarnación , Ruiz García María Montserrat , Rodríguez-Ingelmo José María , Portilla-Sogorb Joaquín , Paz-Zulueta María 
Published: June 2019

Abstract
Human papillomavirus genotype 16 (HPV16) is by far the genotype most strongly associated with cervical cancer; viral variant and/or viral load of HPV16 could modulate this association. The objective was to determine the association between the viral variant and viral load of HPV16 and the presence of cervical high-grade lesions. This cross-sectional study included all women in whom HPV infection was found by cervical smear during routine gynecologic health checks. Women with single or multiple HPV16 infections (n = 176) were selected for viral variant and viral load analysis. Smear results were classified using the Bethesda system. HPV types were classified according to the International Agency for Research on Cancer. Odds ratios (OR) with their 95% confidence intervals (CI) were estimated by logistic regression, adjusted for age, immigrant status, and coinfection with other high-risk genotypes. No statistically significant associations were found regarding the detected viral variants. A viral load above the median (&gt;1,367.79 copies/cell) was associated with a significant risk of high-grade epithelial lesion or carcinoma, after adjusting for age, immigrant status, coinfections, and viral variant: (adjusted OR 7.89; 95% CI: 2.75–22.68). This relationship showed a statistically significant dose–response pattern after categorizing by viral load tertiles: adjusted OR for a viral load greater than the third tertile was 17.23 (95% CI: 4.20–70.65), with adjusted linear Ptrend = 0.001. In patients infected with HPV16, viral load is associated with high-grade intraepithelial lesions or cervical carcinoma. This could be useful as prognostic biomarker of neoplastic progression and as screening for cervical cancer.
Prostate Stem Cell Antigen Gene Polymorphism Is Associated with H. pylori–related Promoter DNA Methylation in Nonneoplastic Gastric Epithelium
Authors: Tahara Tomomitsu , Tahara Sayumi , Horiguchi Noriyuki , Kato Takema , Shinkai Yasuko , Okubo Masaaki , Terada Tsuyoshi , Yoshida Dai , Funasaka Kohei , Nagasaka Mitsuo , Nakagawa Yoshihito , Kurahashi Hiroki , Shibata Tomoyuki , Tsukamoto Tetsuya , Ohmiya Naoki 
Published: June 2019

Abstract
Genome-wide association study identified two functional SNPs associated with gastric cancer especially the diffuse type. The first was a polymorphism (rs2294008) in prostate stem cell antigen (PSCA), and the other was a polymorphism (rs4072037) in mucin 1 (MUC1). DNA methylation is associated with gastric cancer and Helicobacter pylori (H. pylori)-induced gastritis, while hypermethylation of promoter CpG island (CGI) is a common characteristic of enlarged-fold gastritis induced by H. pylori, a risk factor of diffuse-type gastric cancer. We evaluated the association between PSCA and MUC1 polymorphisms with H. pylori--related promoter CGI methylation in the nonneoplastic gastric mucosa. PSCA rs2294008 C/T and MUC1 rs4072037 A/G polymorphisms were genotyped in 410 cancer-free subjects in relation to promoter CGI methylation status of three candidate genes, of which the methylation status is associated with H. pylori infection (IGF2, MYOD1, and SLC16A12). Methylation levels of all three genes were significantly higher in subjects with PSCA rs2294008 T/T compared with the PSCA rs2294008 C/C (all P &lt; 0.05). Such associations were more enhanced in H. pylori–positive subjects (all P &lt; 0.01). The multivariate analysis demonstrated that PSCA C/T [OR, 2.37; 95% CI (confidence interval), 1.06–5.29; P = 0.035] and T/T genotypes (OR, 3.2; 95% CI, 1.41–7.25; P = 0.005) were significantly associated with methylation-high gastric mucosa as independent factors. MUC1 rs4072037 A/G polymorphism was not associated with methylation status of all three genes. PSCA C/T and T/T genotypes are associated with H. pylori–related promoter DNA methylation in the gastric mucosa.
Impact: Our observations provided the evidence that PSCA polymorphism influence the susceptibility to gastric cancer through DNA methylation induction.