bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA Methylation Signature Reveals Cell Ontogeny of Renal Cell Carcinomas
Authors: Malouf Gabriel G. , Su Xiaoping , Zhang Jianping , Creighton Chad J. , Ho Thai H. , Lu Yue , Raynal Noël J.-M. , Karam Jose A. , Tamboli Pheroze , Allanick Frederick , Mouawad Roger , Spano Jean-Philippe , Khayat David , Wood Christopher G. , Jelinek Jaroslav , Tannir Nizar M. 
Published: June 2016

AbstractPurpose: DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype–phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here, we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron.Experimental Designs: We performed deep profiling of DNA methylation and transcriptome in diverse histopathological RCC subtypes and validated DNA methylation in an independent dataset as well as in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets.Results: Our data provide the first mapping of methylome epi-signature and indicate that RCC subtypes can be grouped into two major epi-clusters: C1, which encompasses clear-cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2, which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed 3-fold more hypermethylation as compared with C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC.Conclusions: Our data define the epi-clusters that can discriminate between distinct RCC subtypes and for the first time define the epigenetic basis for proximal versus distal tubule derived kidney tumors. Clin Cancer Res; 22(24); 6236–46. ©2016 AACR.
Bruton's Tyrosine Kinase Inhibitors Prevent Therapeutic Escape in Breast Cancer Cells
Authors: Wang Xianhui , Wong Jason , Sevinsky Christopher J. , Kokabee Leila , Khan Faiza , Sun Yan , Conklin Douglas S. 
Published: June 2016

Abstract
We have reported that a novel isoform of BTK (BTK-C) expressed in breast cancer protects these cells from apoptosis. In this study, we show that recently developed inhibitors of BTK, such as ibrutinib (PCI-32765), AVL-292, and CGI-1746, reduce breast cancer cell survival and prevent drug-resistant clones from arising. Ibrutinib treatment impacts HER2+ breast cancer cell viability at lower concentrations than the established breast cancer therapeutic lapatinib. In addition to inhibiting BTK, ibrutinib, but not AVL-292 and CGI-1746, efficiently blocks the activation of EGFR, HER2, ErbB3, and ErbB4. Consequently, the activation of AKT and ERK signaling pathways are also blocked leading to a G1–S cell-cycle delay and increased apoptosis. Importantly, inhibition of BTK prevents activation of the AKT signaling pathway by NRG or EGF that has been shown to promote growth factor–driven lapatinib resistance in HER2+ breast cancer cells. HER2+ breast cancer cell proliferation is blocked by ibrutinib even in the presence of these factors. AVL-292, which has no effect on EGFR family activation, prevents NRG- and EGF-dependent growth factor–driven resistance to lapatinib in HER2+ breast cancer cells. In vivo, ibrutinib inhibits HER2+ xenograft tumor growth. Consistent with this, immunofluorescence analysis of xenograft tumors shows that ibrutinib reduces the phosphorylation of HER2, BTK, Akt, and Erk and histone H3 and increases cleaved caspase-3 signals. As BTK-C and HER2 are often coexpressed in human breast cancers, these observations indicate that BTK-C is a potential therapeutic target and that ibrutinib could be an effective drug especially for HER2+ breast cancer. Mol Cancer Ther; 15(9); 2198–208. ©2016 AACR.
Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss
Authors: Stacchiotti Silvia , Astolfi Annalisa , Gronchi Alessandro , Fontana Andrea , Pantaleo Maria A. , Negri Tiziana , Brenca Monica , Tazzari Marcella , Urbini Milena , Indio Valentina , Colombo Chiara , Radaelli Stefano , Brich Silvia , Dei Tos Angelo P. , Casali Paolo G. , Castelli Chiara , Dagrada Gian Paolo , Pilotti Silvana , Maestro Roberta 
Published: June 2016

Abstract
Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases.
Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target. Mol Cancer Res; 14(9); 820–9. ©2016 AACR.
Gene Methylation and Cytological Atypia in Random Fine-Needle Aspirates for Assessment of Breast Cancer Risk
Authors: Stearns Vered , Fackler Mary Jo , Hafeez Sidra , Bujanda Zoila Lopez , Chatterton Robert T. , Jacobs Lisa K. , Khouri Nagi F. , Ivancic David , Kenney Kara , Shehata Christina , Jeter Stacie C. , Wolfman Judith A. , Zalles Carola M. , Huang Peng , Khan Seema A. , Sukumar Saraswati 
Published: June 2016

AbstractMethods to determine individualized breast cancer risk lack sufficient sensitivity to select women most likely to benefit from preventive strategies. Alterations in DNA methylation occur early in breast cancer. We hypothesized that cancer-specific methylation markers could enhance breast cancer risk assessment. We evaluated 380 women without a history of breast cancer. We determined their menopausal status or menstrual cycle phase, risk of developing breast cancer (Gail model), and breast density and obtained random fine-needle aspiration (rFNA) samples for assessment of cytopathology and cumulative methylation index (CMI). Eight methylated gene markers were identified through whole-genome methylation analysis and included novel and previously established breast cancer detection genes. We performed correlative and multivariate linear regression analyses to evaluate DNA methylation of a gene panel as a function of clinical factors associated with breast cancer risk. CMI and individual gene methylation were independent of age, menopausal status or menstrual phase, lifetime Gail risk score, and breast density. CMI and individual gene methylation for the eight genes increased significantly (P &lt; 0.001) with increasing cytological atypia. The findings were verified with multivariate analyses correcting for age, log (Gail), log (percent density), rFNA cell number, and body mass index. Our results demonstrate a significant association between cytological atypia and high CMI, which does not vary with menstrual phase or menopause and is independent of Gail risk and mammographic density. Thus, CMI is an excellent candidate breast cancer risk biomarker, warranting larger prospective studies to establish its utility for cancer risk assessment. Cancer Prev Res; 9(8); 673–82. ©2016 AACR.
Forecasting Cytokine Storms with New Predictive Biomarkers
Authors: Rouce Rayne H. , Heslop Helen E. 
Published: June 2016

Abstract
Summary: T cells genetically modified with CD19 chimeric antigen receptors have produced impressive clinical responses in patients with refractory B-cell malignancies, but therapeutic responses are often accompanied by cytokine release syndrome (CRS), which can cause significant morbidity and mortality. Teachey and colleagues have identified predictive biomarkers for this complication that may allow testing of earlier intervention with agents such as the IL6 receptor blocker tocilizumab to evaluate whether CRS can be ameliorated without jeopardizing clinical responses. Cancer Discov; 6(6); 579–80. ©2016 AACR.
See related article by Teachey et al., p. 664.
Where to Focus Efforts to Reduce the Black–White Disparity in Stroke Mortality
Authors: Howard George , Moy Claudia S. , Howard Virginia J. , McClure Leslie A. , Kleindorfer Dawn O. , Kissela Brett M. , Judd Suzanne E. , Unverzagt Fredrick W. , Soliman Elsayed Z. , Safford Monika M. , Cushman Mary , Flaherty Matthew L. , Wadley Virginia G. 
Published: June 2016

Background and Purpose—
At age 45 years, blacks have a stroke mortality ≈3× greater than their white counterparts, with a declining disparity at older ages. We assess whether this black–white disparity in stroke mortality is attributable to a black–white disparity in stroke incidence versus a disparity in case fatality.

Methods—
We first assess if black–white differences in stroke mortality within 29 681 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort reflect national black–white differences in stroke mortality and then assess the degree to which black–white differences in stroke incidence or 30-day case fatality after stroke contribute to the disparities in stroke mortality.

Results—
The pattern of stroke mortality within the study mirrors the national pattern, with the black-to-white hazard ratio of ≈4.0 at age 45 years decreasing to ≈1.0 at age 85 years. The pattern of black-to-white disparities in stroke incidence shows a similar pattern but no evidence of a corresponding disparity in stroke case fatality.

Conclusions—
These findings show that the black–white differences in stroke mortality are largely driven by differences in stroke incidence, with case fatality playing at most a minor role. Therefore, to reduce the black–white disparity in stroke mortality, interventions need to focus on prevention of stroke in blacks.
Postmenopausal Hormone Therapy and Risk of Stroke
Authors: Canonico Marianne , Carcaillon Laure , Plu-Bureau Geneviève , Oger Emmanuel , Singh-Manoux Archana , Tubert-Bitter Pascale , Elbaz Alexis , Scarabin Pierre-Yves 
Published: June 2016

Background and Purpose—
The benefit/risk analysis of hormone therapy in postmenopausal women is not straightforward and depends on cardiovascular disease. Evidence supports the safety of transdermal estrogens and the importance of progestogens for thrombotic risk. However, the differential association of oral and transdermal estrogens with stroke remains poorly investigated. Furthermore, there are no data regarding the impact of progestogens.

Methods—
We set up a nested case–control study of ischemic stroke (IS) within all French women aged 51 to 62 years between 2009 and 2011 without personal history of cardiovascular disease or contraindication to hormone therapy. Participants were identified using the French National Health Insurance database, which includes complete drug claims for the past 3 years and French National hospital data. We identified 3144 hospitalized IS cases who were matched for age and zip code to 12 158 controls. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI).

Results—

Compared with nonusers, the adjusted ORs of IS were1.58 (95% CI, 1.01–2.49) in oral estrogen users and 0.83 (0.56–1.24) in transdermal estrogens users (
P
<0.01). There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49–1.26), pregnanes (OR, 1.00; 95% CI, 0.60–1.67), and nortestosterones (OR, 1.26; 95% CI, 0.62–2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05–4.81).

Conclusions—
Both route of estrogen administration and progestogens were important determinants of IS. Our findings suggest that transdermal estrogens might be the safest option for short-term hormone therapy use.
A Hidden Markov Model Approach to the Problem of Heuristic Selection in
Hyper-Heuristics with a Case Study in High School Timetabling Problems
Authors: Kheiri Ahmed , Keedwell Ed 
Published: June 2016

Abstract
Operations research is a well-established field that uses computational systems to support decisions in business and public life. Good solutions to operations research problems can make a large difference to the efficient running of businesses and organisations and so the field often searches for new methods to improve these solutions. The high school timetabling problem is an example of an operations research problem and is a challenging task which requires assigning events and resources to time slots subject to a set of constraints. In this article, a new sequence-based selection hyper-heuristic is presented that produces excellent results on a suite of high school timetabling problems. In this study, we present an easy-to-implement, easy-to-maintain, and effective sequence-based selection hyper-heuristic to solve high school timetabling problems using a benchmark of unified real-world instances collected from different countries. We show that with sequence-based methods, it is possible to discover new best known solutions for a number of the problems in the timetabling domain. Through this investigation, the usefulness of sequence-based selection hyper-heuristics has been demonstrated and the capability of these methods has been shown to exceed the state of the art.
The Rain Is Askew: Two Idealized Models Relating Vertical Velocity and Precipitation Distributions in a Warming World
Authors: Pendergrass Angeline G. , Gerber Edwin P. 
Published: June 2016

AbstractAs the planet warms, climate models predict that rain will become heavier but less frequent and that the circulation will weaken. Here, two heuristic models relating moisture, vertical velocity, and rainfall distributions are developed—one in which the distribution of vertical velocity is prescribed and another in which it is predicted. These models are used to explore the response to warming and moistening as well as changes in circulation, atmospheric energy budget, and stability. Some key assumptions of the models include that relative humidity is fixed within and between climate states and that stability is constant within each climate state. The first model shows that an increase in skewness of the vertical velocity distribution is crucial for capturing salient characteristics of the changing distribution of rain, including the muted rate of mean precipitation increase relative to extremes and the decrease in the total number or area of rain events. The second model suggests that this increase in the skewness of the vertical velocity arises from the asymmetric impact of latent heating on vertical motion.
Assessment of the Timing of Daily Peak Streamflow during the Melt Season in a Snow-Dominated Watershed
Authors: Chen Xing , Kumar Mukesh , Wang Rui , Winstral Adam , Marks Danny 
Published: June 2016

AbstractPrevious studies have shown that gauge-observed daily streamflow peak times (DPTs) during spring snowmelt can exhibit distinct temporal shifts through the season. These shifts have been attributed to three processes: 1) melt flux translation through the snowpack or percolation, 2) surface and subsurface flow of melt from the base of snowpacks to streams, and 3) translation of water flux in the streams to stream gauging stations. The goal of this study is to evaluate and quantify how these processes affect observed DPTs variations at the Reynolds Mountain East (RME) research catchment in southwest Idaho, United States. To accomplish this goal, DPTs were simulated for the RME catchment over a period of 25 water years using a modified snowmelt model, iSnobal, and a hydrology model, the Penn State Integrated Hydrologic Model (PIHM). The influence of each controlling process was then evaluated by simulating the DPT with and without the process under consideration. Both intra- and interseasonal variability in DPTs were evaluated. Results indicate that the magnitude of DPTs is dominantly influenced by subsurface flow, whereas the temporal shifts within a season are primarily controlled by percolation through snow. In addition to the three processes previously identified in the literature, processes governing the snowpack ripening time are identified as additionally influencing DPT variability. Results also indicate that the relative dominance of each control varies through the melt season and between wet and dry years. The results could be used for supporting DPTs prediction efforts and for prioritization of observables for DPT determination.
Evaluating the performance of elevator group control algorithms using a three-element new paradigm
Authors: Al-Sharif Lutfi , Jaber Zaid , Hamdan Jamal , Riyal Anas 
Published: June 2016

This paper presents a new paradigm for assessing the effectiveness of up-peak elevator group control algorithms. The new paradigm can be very effective in providing a mechanism for objectively assessing and comparing elevator group control algorithms. It is built around three essential components: idealised optimal benchmarks; random scenario testing; and progressive introduction of reality. An idealised optimal benchmark is the starting point for calculating an analytical upper bound for the performance of any algorithm. It provides a reference for comparing the performance of all algorithms. Random scenario testing is used to subject the elevator group controller to a randomly generated scenario (usually of passenger origin-destination pairs). The response of the group controller to a randomly generated scenario is recorded, and more scenarios are generated and added. The overall response (e.g., average of all responses) of the group control algorithm to the large number of scenarios represents an objective measure of its efficacy. The random scenario testing is first carried out under idealised or partially idealised conditions. Under the third component of the new paradigm, the conditions are gradually made more realistic and better reflective of reality. This third element is called the progressive introduction of reality. Practical application: This paper presents to the designer of the elevator group controller a new paradigm for assessing the benchmark against which he/she is working. The designer can be confident that whatever up-peak group control algorithm he/she develops, it cannot exceed this upper benchmark. This has important practical applications in benchmarking the performance of up-peak group controllers. It can also be used by consultants and clients to mediate elevator group controller performance claims presented by elevator manufacturers.
Cryptococcal meningitis in a tertiary hospital in Pretoria, mortality and risk factors – A retrospective cohort study
Authors: Hiesgen J , Schutte C , Olorunju S , Retief J 
Published: June 2016

Aim This retrospective cohort study analyzes the impact of possible risk factors on the survival chance of patients with cryptococcal meningitis. These factors include the patient’s socio-economic background, age, gender, presenting symptoms, comorbidities, laboratory findings and, in particular, non-adherence versus adherence to therapy. Methods Data were collected from all adult patients admitted to Kalafong Hospital with laboratory confirmed cryptococcal meningitis over a period of 24 months. We analyzed the data by the presentation of descriptive summary statistics, logistic regression was used to assess factors which showed association between outcome of measure and factor. Furthermore, multivariable logistic regression analysis using all the factors that showed significant association in the cross tabulation was applied to determine which factors had an impact on the patients’ mortality risk. Results A total of 87 patients were identified. All except one were HIV-positive, of which 55.2% were antiretroviral therapy naïve. A history of previous tuberculosis was given by 25 patients (28.7%) and 49 (56.3%) were on tuberculosis treatment at admission or started during their hospital stay. In-hospital mortality was 31%. Statistical analysis showed that antiretroviral therapy naïve patients had 9.9 (CI 95% 1.2–81.2, p < 0.0032) times greater odds of dying compared to those on antiretroviral therapy, with 17 from 48 patients (35.4%) dying compared with 1 out of 21 patients (4.8%) on treatment. Defaulters had 14.7 (CI 95% 1.6–131.6, p < 0.016) times greater odds of dying, with 9 from 18 patients dying (50%), compared to the non-defaulters. In addition, patients who presented with nausea and vomiting had a 6.3 (95% CI 1.7–23.1, p < 0.005) times greater odds of dying (18/47, 38.3%); this remained significant when adjusted for antiretroviral therapy naïve patients and defaulters. Conclusion Cryptococcal meningitis is still a common opportunistic infection in people living with HIV/AIDS resulting in hospitalization and a high mortality. Defaulting antiretroviral therapy and presentation with nausea and vomiting were associated with a significantly increased mortality risk.
Gallstone Disease and the Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Observational Studies
Authors: Upala S. , Sanguankeo A. , Jaruvongvanich V. 
Published: June 2016

Objectives: Gallstone disease shares certain risk factors with cardiovascular disease, particularly metabolic risk factors. Patients with gallstone disease may be at increased risk of cardiovascular disease. Several recent studies exploring the effect of gallstone disease on cardiovascular disease outcomes demonstrated inconsistent results. Design: We conducted a systematic review and meta-analysis of cohort, case–control, and cross-sectional studies that compared the risk of developing cardiovascular disease events in patients with gallstone disease versus non-gallstone disease controls. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate the pooled hazard ratio, odd ratio, and 95% confidence interval. Results: Data were extracted from six studies involving 176,734 cases and 803,714 controls. The pooled hazard ratio of cardiovascular events in patients with gallstone disease was 1.28 (95% confidence interval: 1.23–1.33, I2 = 42%). The pooled odd ratio of cardiovascular events in patients with gallstone disease was 1.82 (95% confidence interval: 1.47–2.24, I2 = 68%). Conclusions: Our study demonstrated a statistically significant increase in the risk of cardiovascular disease among patients with gallstone disease.