bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Expression of Vitamin D Receptor and Breast Cancer Histopathological Characteristics and Prognosis
Authors: Al-Azhri Jamila , Zhang Yali , Bshara Wiam , Zirpoli Gary , McCann Susan E. , Khoury Thaer , Morrison Carl D. , Edge Stephen B. , Ambrosone Christine B. , Yao Song 
Published: July 2016

Abstract
Purpose: Our previous work has shown low serum 25-hydroxyvitamin D concentrations in association with aggressive breast cancer subtypes. Vitamin D receptor (VDR) is central for vitamin D–mediated transcription regulation. Few studies have examined breast VDR expression with tumor characteristics or patient survival.
Experimental Design: VDR expression in breast tumor tissue microarrays was determined by immunohistochemistry in 1,114 female patients as low, moderate, and strong expression based on an immunoreactive score, and examined with histopathologic tumor characteristics and survival outcomes including progression-free survival, breast cancer–specific survival, and overall survival.
Results: A majority (58%) of breast tumors showed moderate or strong VDR expression. VDR expression was inversely related to aggressive tumor characteristics, including large tumor size, hormonal receptor (HR) negativity, and triple-negative subtype (P &lt; 0.05). In addition, VDR expression was also inversely related to Ki-67 expression among patients older than 50 years. Nevertheless, VDR expression was not associated with any patient survival outcomes examined.
Conclusions: In a large patient population, VDR expression is inversely associated with more aggressive breast cancer, but not with breast cancer survival outcomes. The present findings of VDR expression are consistent with our previous results of circulating vitamin D biomarkers, which provide two converging lines of evidence supporting the putative benefits of vitamin D against aggressive breast cancer. Because of the observational nature of our analyses, future studies are warranted to establish the causality of the reported associations. Clin Cancer Res; 23(1); 97–103. ©2016 AACR.
Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials
Authors: Yuan Ying , Hess Kenneth R. , Hilsenbeck Susan G. , Gilbert Mark R. 
Published: July 2016

Abstract
Despite more than two decades of publications that offer more innovative model-based designs, the classical 3 + 3 design remains the most dominant phase I trial design in practice. In this article, we introduce a new trial design, the Bayesian optimal interval (BOIN) design. The BOIN design is easy to implement in a way similar to the 3 + 3 design, but is more flexible for choosing the target toxicity rate and cohort size and yields a substantially better performance that is comparable with that of more complex model-based designs. The BOIN design contains the 3 + 3 design and the accelerated titration design as special cases, thus linking it to established phase I approaches. A numerical study shows that the BOIN design generally outperforms the 3 + 3 design and the modified toxicity probability interval (mTPI) design. The BOIN design is more likely than the 3 + 3 design to correctly select the MTD and allocate more patients to the MTD. Compared with the mTPI design, the BOIN design has a substantially lower risk of overdosing patients and generally a higher probability of correctly selecting the MTD. User-friendly software is freely available to facilitate the application of the BOIN design. Clin Cancer Res; 22(17); 4291–301. ©2016 AACR.
EPIC Early Detection of Ovarian Cancer
Authors: Skates Steven J. 
Published: July 2016

Abstract
CA125 dominated performance for ovarian cancer early detection among four serum biomarkers evaluated in EPIC study prediagnostic serum, rising on average 3 years prior to detection. Adding HE4 provided only marginal improvement. This natural history supports annual testing for early detection and highlights the importance of biomarker discovery complementing CA125. Clin Cancer Res; 22(18); 4542–4. ©2016 AACR.
See related article by Terry et al., p. 4664
BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members
Authors: Hogg Simon J. , Newbold Andrea , Vervoort Stephin J. , Cluse Leonie A. , Martin Benjamin P. , Gregory Gareth P. , Lefebure Marcus , Vidacs Eva , Tothill Richard W. , Bradner James E. , Shortt Jake , Johnstone Ricky W. 
Published: July 2016

Abstract
Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Eμ-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of proapoptotic (Bim) and antiapoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1 resistance phenotype. These studies provide important information on mechanisms of apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. Mol Cancer Ther; 15(9); 2030–41. ©2016 AACR.
ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma
Authors: Ryan Meagan B. , Finn Alexander J. , Pedone Katherine H. , Thomas Nancy E. , Der Channing J. , Cox Adrienne D. 
Published: July 2016

Abstract
Recently, we identified that PREX1 overexpression is critical for metastatic but not tumorigenic growth in a mouse model of NRAS-driven melanoma. In addition, a PREX1 gene signature correlated with and was dependent on ERK MAPK activation in human melanoma cell lines. In the current study, the underlying mechanism of PREX1 overexpression in human melanoma was assessed. PREX1 protein levels were increased in melanoma tumor tissues and cell lines compared with benign nevi and normal melanocytes, respectively. Suppression of PREX1 by siRNA impaired invasion but not proliferation in vitro. PREX1-dependent invasion was attributable to PREX1-mediated activation of the small GTPase RAC1 but not the related small GTPase CDC42. Pharmacologic inhibition of ERK signaling reduced PREX1 gene transcription and additionally regulated PREX1 protein stability. This ERK-dependent upregulation of PREX1 in melanoma, due to both increased gene transcription and protein stability, contrasts with the mechanisms identified in breast and prostate cancers, in which PREX1 overexpression was driven by gene amplification and HDAC-mediated gene transcription, respectively. Thus, although PREX1 expression is aberrantly upregulated and regulates RAC1 activity and invasion in these three different tumor types, the mechanisms of its upregulation are distinct and context dependent.
Implications: This study identifies an ERK-dependent mechanism that drives PREX1 upregulation and subsequent RAC1-dependent invasion in BRAF- and NRAS-mutant melanoma. Mol Cancer Res; 14(10); 1009–18. ©2016 AACR.
Il Cibo Nella Letteratura di Primo Levi e nel Cinema di Roberto Benigni
Authors: Zuccarello Maria Franca 
Published: July 2016

La cucina italiana è il risultato di tradizioni, molte delle quali risalgono a tempi molto antichi ed ai molti popoli stranieri che hanno dominatole regioni italiane, apportandovi cultura ed innumerevoli ricette chene fanno, nelle sue diversità, il prodotto Made in Italy, conosciuto in tutto il mondo. Molti autori hanno parlato del cibo in momenti di azione dei personaggi, attorno ad imbandite tavole di gente ricca e potente, o del campo, senza risorse per fare delle buone ricette. Però non parleremo qui dei piaceri del buon cibo italiano, ma della necessità del cibo come alimento che dà la forza per continuare a vivere. Ed allora, così come Primo Levi in Se questo è un uomo, ci domandiamo: è uomo chi mangia un cibo senza sapore, senza colore, senza odore e quindi senza piacere, che gli serve solo per sopravvivere? E vedremo anche la maniera giocherellona ed allegra, cheall’inizio del film La vita è bella Benigni usa per parlare del cibo, mentre nella seconda parte, quando la sua vita non è più un gioco - malgrado lui la conduca come tale affinché il figlio non capisca dove sono stati portati, fadi tutto affinché non manchi al piccolo Giosuè.
L´italiano parlato a San Paolo da madrelingua colti. Primi sondaggi e ipotesi di lavoro
Authors: Raso Tommaso 
Published: July 2016

A partir da análise de 13 entrevistas com italianos cultos residentes na cidade de São Paulo, há pelo menos 20 anos, apontam-se numerosos aspectos linguisticos que são afetados pela interferência e pela erosão no contato com o português brasileiro. Além do léxico e dos mecanismos do code-switching e do code-mixing, a erosão é apontada em vários aspectos morfossintáticos, tais como o uso do artigo para indicar a referência, a redução das formas pronominais do verbo, os usos do gerúndio, a ordem das palavras e as formas para expressar a estrutura informativa do enunciado.
p38δ MAPK
Authors: Rajamäki Kristiina , Mäyränpää Mikko I. , Risco Ana , Tuimala Jarno , Nurmi Katariina , Cuenda Ana , Eklund Kari K. , Öörni Katariina , Kovanen Petri T. 
Published: July 2016

Objective—
Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinflammatory and proatherogenic cytokines, interleukin (IL)-1β, and IL-18. Atherosclerotic lesions are characterized by the presence of various endogenous activators of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, including cholesterol crystals and extracellular ATP. The aim of this study was to comprehensively characterize the expression of inflammasome pathway components and regulators in human atherosclerotic lesions.

Approach and Results—
Twenty human coronary artery RNA samples from 10 explanted hearts were analyzed using an inflammasome pathway–focused quantitative polymerase chain reaction array. Advanced atherosclerotic plaques, when compared with early-to-intermediate lesions from the same coronary trees, displayed significant upregulation of 12 target genes, including the key inflammasome components apoptosis-associated speck-like protein containing a CARD domain, caspase-1, and IL-18. Immunohistochemical stainings of the advanced plaques revealed macrophage foam cells positive for NLRP3 inflammasome components around the necrotic lipid cores. The polymerase chain reaction array target p38δ mitogen-activated protein kinase was upregulated in advanced plaques and strongly expressed by lesional macrophage foam cells. In cultured human monocyte–derived macrophages, the p38δ mitogen-activated protein kinase was activated by intracellular stress signals triggered during ATP- and cholesterol crystal–induced NLRP3 inflammasome activation and was required for NLRP3-mediated IL-1β secretion.

Conclusions—
Increased expression of the key inflammasome components in advanced coronary lesions implies enhanced activity of the inflammasome pathway in progression of coronary atherosclerosis. The p38δ mitogen-activated protein kinase was identified as a novel regulator of NLRP3 inflammasome activation in primary human macrophages, and thus, represents a potential target for modulation of atherosclerotic inflammation.
Utilization of Whole Exome Sequencing to Identify Causative Mutations in Familial Congenital Heart Disease
Authors: LaHaye Stephanie , Corsmeier Don , Basu Madhumita , Bowman Jessica L. , Fitzgerald-Butt Sara , Zender Gloria , Bosse Kevin , McBride Kim L. , White Peter , Garg Vidu 
Published: July 2016

Background—
Congenital heart disease (CHD) is the most common type of birth defect with family- and population-based studies supporting a strong genetic cause for CHD. The goal of this study was to determine whether a whole exome sequencing (WES) approach could identify pathogenic-segregating variants in multiplex CHD families.

Methods and Results—

WES was performed on 9 kindreds with familial CHD, 4 with atrial septal defects, 2 with patent ductus arteriosus, 2 with tetralogy of Fallot, and 1 with pulmonary valve dysplasia. Rare variants (<1% minor allele frequency) that segregated with disease were identified by WES, and variants in 69 CHD candidate genes were further analyzed. These selected variants were subjected to in silico analysis to predict pathogenicity and resulted in the discovery of likely pathogenic mutations in 3 of 9 (33%) families. A
GATA4
mutation in the transactivation domain, p.G115W, was identified in familial atrial septal defects and demonstrated decreased transactivation ability in vitro. A p.I263V mutation in
TLL1
was identified in an atrial septal defects kindred and is predicted to affect the enzymatic functionality of TLL1. A disease-segregating splice donor site mutation in
MYH11
(c.4599+1delG) was identified in familial patent ductus arteriosus and found to disrupt normal splicing of
MYH11
mRNA in the affected individual.

Conclusions—
Our findings demonstrate the clinical utility of WES to identify causative mutations in familial CHD and demonstrate the successful use of a CHD candidate gene list to allow for a more streamlined approach enabling rapid prioritization and identification of likely pathogenic variants from large WES data sets.

Clinical Trial Registration—

URL:
https://clinicaltrials.gov
; Unique Identifier: NCT0112048.
Predictors and Prognostic Impact of Progressive Ischemic Mitral Regurgitation in Patients With Advanced Ischemic Cardiomyopathy
Authors: Kwon Deborah H. , Kusunose Kenya , Obuchowski Nancy A. , Cavalcante João L. , Popovic Zoran B. , Thomas James D. , Desai Milind Y. , Flamm Scott D. , Griffin Brian P. 
Published: July 2016

Background—
Ischemic mitral regurgitation (IMR) is associated with poor outcomes. It is unknown what factors contribute to progression of IMR and how progressive IMR affects outcomes. We sought to determine imaging predictors of IMR progression and to determine if progressive IMR is an independent predictor of survival in patients with advanced ischemic cardiomyopathy.

Methods and Results—

Consecutive advanced ischemic cardiomyopathy patients who underwent cardiac magnetic resonance and echocardiograms at baseline with echocardiographic follow-up were studied. Cardiac magnetic resonance was used to assess left ventricular volumes, infarct size, and mitral valve geometry. The effective regurgitant orifice area (EROA) was calculated from the proximal isovelocity surface area by echocardiography. Repeated measures mixed effects and Cox proportional hazards regression models were built to identify predictors of IMR progression and survival. We evaluated 336 patients (age, 62±11 years) over a median follow-up time of 54 months: 154 patients were subsequently revascularized, and 182 patients were medically treated. Ninety-eight patients (29%) demonstrated an increase in EROA values of ≥0.1 cm
2
. There were 87 adverse events (death or transplant). On multivariable analysis, infarct size (
P
<0.001), progression in IMR (
P
=0.008), age (
P
=0.003), and baseline EROA (
P
=0.010) were independently associated with adverse events. Independent predictors of IMR progression were as follows: baseline EROA (
P
<0.001), left ventricular end–systolic volume index (
P
=0.014), and total scar (
P
=0.036).

Conclusions—
IMR frequently increases in severity, and progression is independently associated with adverse left ventricular remodeling and infarct size, as assessed by cardiac magnetic resonance. Furthermore, IMR progression is a powerful independent predictor of adverse events, even after controlling for the severity of IMR at baseline.
Recanalization of Chronic Total Occlusions in Patients With Previous Coronary Bypass Surgery and Consideration of Retrograde Access via Saphenous Vein Grafts
Authors: Dautov Rustem , Manh Nguyen Can , Altisent Omar , Gibrat Claire , Rinfret Stéphane 
Published: July 2016

Background—
The prevalence of native coronary chronic total occlusions (CTOs) after coronary artery bypass grafts (CABGs) is higher than in non-CABG population. We examined outcomes of CTO percutaneous coronary intervention (PCI) post-CABG versus without CABG. Then, we looked at feasibility and outcomes of retrograde CTO PCI via patent or occluded saphenous vein graft.

Methods and Results—

We compared patient and procedural characteristics of 470 CTO cases treated from January 2010 to December 2015 depending on history of CABG. We assessed major adverse cardiac events, including cardiac death, myocardial infarction, ischemia-driven target-vessel revascularization, or reocclusion 1 year after successful CTO PCI in patients treated before February 2015. Post-CABG patients (175 cases) had a higher J-CTO score (2.5 versus 2.1;
P
=0.002). In-hospital complications were similar, although the incidence of contrast-induced nephropathy was higher in post-CABG patients (4.6% versus 1%;
P
=0.01). With multivariable analysis, post-CABG status was associated with higher incidence of 1-year major adverse cardiac event (hazards ratio=2.2;
P
=0.02). As a second level analysis, we looked at the feasibility and safety of CTO PCI via saphenous vein grafts (19% of post-CABG cases) versus collateral channels (36%) versus with an antegrade-only approach (45%), and assessed short-term outcomes and complications. High success was achieved in the saphenous vein graft group. In-hospital events were similar in the 3 groups.

Conclusions—
Post-CABG CTO PCI is associated with similar high success and low complications compared with CTO PCI in patients who never had CABG. However, it is associated with higher recurrent events at 1 year. To achieve high success rate, use of saphenous vein grafts as retrograde conduits seems to be safe and effective.
Long-Term Outcomes From Acute Rheumatic Fever and Rheumatic Heart Disease
Authors: He Vincent Y.F. , Condon John R. , Ralph Anna P. , Zhao Yuejen , Roberts Kathryn , de Dassel Jessica L. , Currie Bart J. , Fittock Marea , Edwards Keith N. , Carapetis Jonathan R. 
Published: July 2016

Background:
We investigated adverse outcomes for people with acute rheumatic fever (ARF) and rheumatic heart disease (RHD) and the effect of comorbidities and demographic factors on these outcomes.

Methods:
Using linked data (RHD register, hospital, and mortality data) for residents of the Northern Territory of Australia, we calculated ARF recurrence rates, rates of progression from ARF to RHD to severe RHD, RHD complication rates (heart failure, endocarditis, stroke, and atrial fibrillation), and mortality rates for 572 individuals diagnosed with ARF and 1248 with RHD in 1997 to 2013 (94.9% Indigenous).

Results:
ARF recurrence was highest (incidence, 3.7 per 100 person-years) in the first year after the initial ARF episode, but low-level risk persisted for >10 years. Progression to RHD was also highest (incidence, 35.9) in the first year, almost 10 times higher than ARF recurrence. The median age at RHD diagnosis in Indigenous people was young, especially among males (17 years). The development of complications was highest in the first year after RHD diagnosis: heart failure incidence rate per 100 person-years, 9.09; atrial fibrillation, 4.70; endocarditis, 1.00; and stroke, 0.58. Mortality was higher among Indigenous than non-Indigenous RHD patients (hazard ratio, 6.55; 95% confidence interval, 2.45–17.51), of which 28% was explained by comorbid renal failure and hazardous alcohol use. RHD complications and mortality rates were higher for urban than for remote residents.

Conclusions:
This study provides important new prognostic information for ARF/RHD. The residual Indigenous survival disparity in RHD patients, which persisted after accounting for comorbidities, suggests that other factors contribute to mortality, warranting further research.
Do Convection-Permitting Regional Climate Models Improve Projections of Future Precipitation Change?
Authors: Kendon Elizabeth J. , Ban Nikolina , Roberts Nigel M. , Fowler Hayley J. , Roberts Malcolm J. , Chan Steven C. , Evans Jason P. , Fosser Giorgia , Wilkinson Jonathan M. 
Published: July 2016

Abstract
Regional climate projections are used in a wide range of impact studies, from assessing future flood risk to climate change impacts on food and energy production. These model projections are typically at 12–50-km resolution, providing valuable regional detail but with inherent limitations, in part because of the need to parameterize convection. The first climate change experiments at convection-permitting resolution (kilometer-scale grid spacing) are now available for the United Kingdom; the Alps; Germany; Sydney, Australia; and the western United States. These models give a more realistic representation of convection and are better able to simulate hourly precipitation characteristics that are poorly represented in coarser-resolution climate models. Here we examine these new experiments to determine whether future midlatitude precipitation projections are robust from coarse to higher resolutions, with implications also for the tropics. We find that the explicit representation of the convective storms themselves, only possible in convection-permitting models, is necessary for capturing changes in the intensity and duration of summertime rain on daily and shorter time scales. Other aspects of rainfall change, including changes in seasonal mean precipitation and event occurrence, appear robust across resolutions, and therefore coarse-resolution regional climate models are likely to provide reliable future projections, provided that large-scale changes from the global climate model are reliable. The improved representation of convective storms also has implications for projections of wind, hail, fog, and lightning. We identify a number of impact areas, especially flooding, but also transport and wind energy, for which very high-resolution models may be needed for reliable future assessments.
Secondary Eyewall Formation in an Idealized Tropical Cyclone Simulation: Balanced and Unbalanced Dynamics
Authors: Wang Hui , Wu Chun-Chieh , Wang Yuqing 
Published: July 2016

Abstract
The secondary eyewall formation (SEF) in an idealized simulation of a tropical cyclone (TC) is examined from the perspective of both the balanced and unbalanced dynamics and through the tangential wind (Vt) budget analysis. It is found that the expansion of the azimuthal-mean Vt above the boundary layer occurs prior to the development of radial moisture convergence in the boundary layer. The Vt expansion results primarily from the inward angular momentum transport by the mid- to lower-tropospheric inflow induced by both convective and stratiform heating in the spiral rainbands. In response to the Vt broadening is the development of radial inflow convergence and the supergradient flow near the top of the inflow boundary layer. Results from the Vt budget analysis show that the combined effect of the mean advection and the surface friction is to spin down Vt in the boundary layer, while the eddy processes (eddy radial and vertical advection) contribute positively to the spinup of Vt in the SEF region in the boundary layer. Therefore, eddies play an important role in the spinup of Vt in the boundary layer during SEF. The balanced Sawyer–Eliassen solution can well capture the secondary circulation in the full-physics model simulation. The radial inflow diagnosed from the Sawyer–Eliassen equation is shown to spin up Vt and maintain the vortex above the boundary layer. However, the axisymmetric balanced dynamics cannot explain the spinup of Vt in the boundary layer, which results mainly from the eddy processes.