bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Combined Association of Modifiable Risk Factors with Breast Cancer Risk in the Women's Health Initiative
Authors: Arthur Rhonda , Wassertheil-Smoller Sylvia , Manson JoAnn E. , Luo Juhua , Snetselaar Linda , Hastert Theresa , Caan Bette , Qi Lihong , Rohan Thomas 
Published: February 2018

Abstract
Although several modifiable risk factors have been independently associated with risk of breast cancer, few studies have investigated their joint association with breast cancer risk. Using a healthy lifestyle index (HLI) score, we assessed the association of a combination of selected modifiable risk factors (diet, alcohol, physical activity, BMI, and smoking) with risk of invasive breast cancer in the Women's Health Initiative (WHI). This study comprised 131,833 postmenopausal women, of whom 8,168 had breast cancer, who were enrolled in the WHI Observational Study or the WHI clinical trials. Cox proportional hazards regression was used to estimate the HRs and 95% confidence intervals (CI) for the association of the score with the risk of developing breast cancer overall and according to specific breast cancer clinicopathologic characteristics. There was a 4% reduction in the risk of breast cancer per unit increase in the HLI score. Compared with those with an HLI score in the lowest quintile level, those in the highest quintile level had 30%, 37%, and 30% lower risk for overall, ER+/PR+, and HER2+ breast cancer, respectively (HR = 0.70; 95% CI, 0.64–0.76; 0.63, 0.57–0.69; and 0.70; 0.55–0.90, respectively). We also observed inverse associations between the score and risk of breast cancer irrespective of nodal status, tumor grade, and stage of the disease. Most individual lifestyle factors were independently associated with the risk of breast cancer. Our findings support the view that promoting healthy lifestyle practices may be beneficial with respect to lowering risk of breast cancer among postmenopausal women. Cancer Prev Res; 11(6); 317–26. ©2018 AACR.
See related editorial by Friedenreich and McTiernan, p. 313
Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts
Authors: Drapkin Benjamin J. , George Julie , Christensen Camilla L. , Mino-Kenudson Mari , Dries Ruben , Sundaresan Tilak , Phat Sarah , Myers David T. , Zhong Jun , Igo Peter , Hazar-Rethinam Mehlika H. , Licausi Joseph A. , Gomez-Caraballo Maria , Kem Marina , Jani Kandarp N. , Azimi Roxana , Abedpour Nima , Menon Roopika , Lakis Sotirios , Heist Rebecca S. , Büttner Reinhard , Haas Stefan , Sequist Lecia V. , Shaw Alice T. , Wong Kwok-Kin , Hata Aaron N. , Toner Mehmet , Maheswaran Shyamala , Haber Daniel A. , Peifer Martin , Dyson Nicholas , Thomas Roman K. , Farago Anna F. 
Published: February 2018

Abstract
Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical–translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.
Significance: Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. Cancer Discov; 8(5); 600–15. ©2018 AACR.
This article is highlighted in the In This Issue feature, p. 517
Allele-Specific Mechanisms of Activation of MEK1 Mutants Determine Their Properties
Authors: Gao Yijun , Chang Matthew T. , McKay Daniel , Na Na , Zhou Bing , Yaeger Rona , Torres Neilawattie M. , Muniz Keven , Drosten Matthias , Barbacid Mariano , Caponigro Giordano , Stuart Darrin , Moebitz Henrik , Solit David B. , Abdel-Wahab Omar , Taylor Barry S. , Yao Zhan , Rosen Neal 
Published: February 2018

Abstract
Mutations at multiple sites in MEK1 occur in cancer, suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS/RAF-dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output, and often cooccur with RAS or RAF mutations. They act as amplifiers of RAF signaling. In contrast, another class of mutants deletes a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, is unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors, which preferentially bind to the inactivated form of MEK1. All the mutants are sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants.
Significance: Mutants with which MEK1 mutants coexist and their sensitivity to inhibitors are determined by allele-specific properties. This study shows the importance of functional characterization of mutant alleles in single oncogenes and identifies a new class of MEK1 mutants, insensitive to current MEK1 inhibitors but treatable with a new ATP-competitive inhibitor. Cancer Discov; 8(5); 648–61. ©2018 AACR.
See related commentary by Maust et al., p. 534.
This article is highlighted in the In This Issue feature, p. 517
Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement
Authors: Ljungberg Johan , Janiec Mikael , Bergdahl Ingvar A. , Holmgren Anders , Hultdin Johan , Johansson Bengt , Näslund Ulf , Siegbahn Agneta , Fall Tove , Söderberg Stefan 
Published: February 2018

Background:
Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights.

Methods:
Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study.

Results:
Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease.

Conclusions:
We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.
Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure
Authors: Morine Kevin J. , Qiao Xiaoying , York Sam , Natov Peter S. , Paruchuri Vikram , Zhang Yali , Aronovitz Mark J. , Karas Richard H. , Kapur Navin K. 
Published: February 2018

Background:
Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-β1) promotes cardiac fibrosis, but also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFβ coreceptor that promotes TGF-β1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3, and, furthermore, that neutralizing endoglin activity promotes BMP9 activity.

Methods:
We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We used the transverse aortic constriction–induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling.

Results:

BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and a small interfering RNA approach. In BMP9
–/–
mice subjected to transverse aortic constriction, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to transverse aortic constriction with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 in comparison with vehicle-treated controls. Because endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to transverse aortic constriction–induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3.

Conclusions:
Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis attributable to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure.
Characterisation of biological and biocontrol traits of entomopathogenic nematodes promising for control of striped flea beetle (Phyllotreta striolata)
Authors: Yan Xun , Lin Yinying , Huang Zhenmao , Han Richou 
Published: February 2018

SummaryThe biological and biocontrol traits of two entomopathogenic nematode isolates,Steinernema pakistanense94-1 (Sp94-1) andHeterorhabditis indica212-2 (Hi212-2), were evaluated. The highest yield of infective juveniles (IJ) in monoxenic sponge culture system for Sp94-1 and Hi212-2 was 3.52 (± 0.45) × 105and 7.08 (± 0.11) × 105 IJ g−1, respectively. The optimum storage temperature was 25°C for Sp94-1 and 14°C for Hi212-2. Sp94-1 showed greater tolerance to heat exposure and UV radiation, whileS. carpocapsaeAll, a commercial strain, was more resistant to osmotic pressure, desiccation, cold treatment and hypoxia than the other tested isolates. Hi212-2 suppressed thePhyllotreta striolatalarvae when applied at 1.5 × 109 IJ ha−1or higher concentrations, while Sp94-1 suppressed theP. striolatalarvae only when applied at 4.5 × 109 IJ ha−1. Our study indicates the possibility of commercialisation of the EPN isolates, and further confirms their efficacy against theP. striolatalarvae in the field.
Measuring occupational balance and its relationship to perceived stress and health
Authors: Yu Yu , Manku Mandeep , Backman Catherine L. 
Published: February 2018

Background. There is an assumption that occupational balance is integrally related to health and well-being. Purpose. This study aimed to investigate test-retest reliability of the English-translated Occupational Balance Questionnaire (OBQ), its relationship to measures of health (Short Form Health Survey–36 Version 2.0 [SF-36v2]) and stress (Perceived Stress Scale–10; PSS-10), and demographic differences in OBQ scores in Canadian adults. Method. Test-retest reliability (2 weeks) was assessed using intraclass correlation (ICC) coefficients. Online surveys from 86 adults were analyzed using descriptive, correlational, and t test statistics. Findings. OBQ test-retest reliability was ICC = 0.74 (95% CI [0.34, 0.90]; p = .003) when excluding an influential case ( n = 20). OBQ correlations with PSS-10 were r = –.72; with SF-36v2 Mental Component Score, r = .65; and with Physical Component Score, r = .31; all p < .001. Age and gender had no impact on OBQ scores. Implications. Findings help elucidate relationships among health, stress, and occupational balance; however, further psychometric testing is warranted before using OBQ for clinical purposes.
Learning as a Process of Selection and Amplification
Authors: Young J Z 
Published: February 2018

These are only a few examples of how learning occurs during development by a process of sculpturing, selecting among the possible variations, combinations and sequences of actions. This is how we build up what may be called programs in the brain (Young 1978). The physiologist will say that these are only, as it were, metaphorical statements, not detailed descriptions of known brain actions. ‘The programmes of elaborate sequences of movement, built up over the course of many years, are not yet on the agenda of practical neurophysiology’ (Phillips & Porter 1978, p 333). Perhaps this statement may prove to be over-pessimistic, as I am sure the authors would hope. Studies of learning, of which I have tried to give a small sample, do begin to show us how programs are assembled by selecting from the vast number of possibilities that are available and then increasing the reliability of the chosen actions. It is particularly pleasing to find that we can begin to understand the various principles that are involved. In Aplysia we see something of them due to the cellular changes. In Octopus we see how learning involves different pieces of neuronal machinery. One serves to distribute signals to allow access to the full repertoire of possibilities. Another part distributes and balances rewards and penalties. In a third the actual learning change occurs and the many minute cells suggest that we may look for the origin of learning among reciprocal reflexes. In the vertebrate brain we see the multiplication of neuronal patterns and centres greatly increased. We get glimpses of how various parts of the brain cooperate in building and executing the programs. Learning involves many parts of the brain, each contributing in a different way. The cerebellum perhaps provides the repertoire of small variations in muscular contraction out of which those are selected that perform the acts that prove necessary. Perhaps the motivations to do these correctly come partly from the aminergic pathways such as those of the locus ceruleus, while the hippocampus provides the power to seek to make new ones. And of course the cerebral cortex and its attendant input and output centres provides the biggest repertoire of all, selection among whose modules has allowed us to build and use a program that studies itself. Surely John Hughlings Jackson would have rejoiced that there has been some advance in understanding of the ‘Relations of Different Divisions of the Central Nervous System to One Another and to Parts of the Body’, which was the title of the first Hughlings Jackson lecture, which he himself gave in 1897.
Management of Malignant Dysphagia by Intubation at Endoscopy
Authors: Atkinson Michael , Ferguson Roger , Ogilvie A L 
Published: February 2018

A method of relieving dysphagia in inoperable oesophagogastric neoplasms by per oral intubation using the Nottingham tube introducer was attempted in 63 patients with 3 failures. Twelve patients died within 10days of intubation, including 4 from a perforation of the growth sustained during the procedure, and 51 patients left hospital swallowing satisfactorily. The average period of survival was 3 months and 10patients survived for a year or more, including 2 in whom the tube was removed after regression of a squamous carcinoma following radiotherapy. Endoscopic per oral intubation is a simple and relatively safe procedure which when used in patients with oesophagogastric neoplasms gives adequate symptomatic relief and allows home management in the terminal stages of the illness.
A Multidisciplinary Approach to a Pediatric Difficult Airway Simulation Course
Authors: Lind Meredith Merz , Corridore Marco , Sheehan Cameron , Moore‐Clingenpeel Melissa , Maa Tensing 
Published: February 2018

ObjectiveTo design and assess an advanced pediatric airway management course, through simulation‐based team training and with multiple disciplines, to emphasize communication and cooperation across subspecialties and to provide a common skill set and knowledge base.MethodsTrainees from anesthesiology, emergency medicine, critical care, pediatric surgery, and otolaryngology at a tertiary children's hospital participated in a 1‐day workshop emphasizing airway skills and complex airway simulations. Small groups were multidisciplinary to promote teamwork. Participants completed pre‐ and postworkshop questionnaires.ResultsThirty‐nine trainees participated over the 3‐year study period. Compared with their precourse responses, participants’ postcourse responses indicated either agreement or strong agreement that the multidisciplinary format (1) helped in the development of team communication skills and (2) was preferred over single‐discipline training. Improvement in confidence in managing critical airway situations and in advanced airway management skills was significant (P <. 05). Eighty‐one percent of participants had improved confidence in following the hospital's critical airway protocol, and 64% were better able to locate advanced airway management equipment.DiscussionMultiple subspecialists manage pediatric respiratory failure, where successful care requires complex handoffs and teamwork. Multidisciplinary education to teach advanced airway management, teamwork, and communication skills is practical and preferred by learners and is possible to achieve despite differences in experience. Future study is required to better understand the impact of this course on patient care outcomes.Implications for PracticeImplementation of a pediatric difficult airway course through simulation‐based team training is feasible and preferred by learners among multiple disciplines. A multidisciplinary approach exposes previously unrecognized knowledge gaps and allows for better communication and collaboration among the fields.
Brain susceptibility changes in neurologically asymptomatic pediatric patients with Wilson’s disease: evaluation with quantitative susceptibility mapping
Authors: Saracoglu Sibel , Gumus Kazim , Doganay Selim , Koc Gonca , Kacar Bayram Ayse , Arslan Duran , Gumus Hakan 
Published: February 2018

Background Wilson’s disease (WD) is a copper metabolism disorder that causes hepatolenticular degeneration. It is important to diagnose WD before central nervous system involvement. Purpose To demonstrate the early susceptibility changes associated with the copper accumulation in the brain of neurologically asymptomatic pediatric patients with WD using quantitative susceptibility mapping (QSM). Material and Methods Twelve patients with neurologically asymptomatic WD (mean age = 13.7 ± 3.3 years) and 14 age-matched controls were prospectively examined using a 1.5-T clinical scanner. Routine magnetic resonance (MR) sequences and a three-dimensional multi-echo spoiled gradient echo (GRE) sequence were used and QSM maps were reproduced. The quantitative susceptibility of corpus striatum, thalamus, substantia nigra, and pons were analyzed with the region of interest analysis on QSM maps. The susceptibility values of two groups were statistically compared using a two-sample t-test. Results Conventional MR images of the patients and control group were similar. However increased magnetic susceptibility in the thalamus, pons and left posterior putamen were observed in the patients compared to the control group ( p < 0.05). Conclusion We observed statistically increased susceptibility values in the brains of neurologically asymptomatic patients with WD although the conventional MR images were normal. This might be compatible with early brain impairment, before neurological symptoms occur.
Risk Factors for Bladder Cancer
Authors: Janković Slavenka , Radosavljević Vladan 
Published: February 2018

Aims and background To summarize risk factors for bladder cancer, emphasizing the role of recently established associations and to present some ongoing debates on the issue. Methods A systematic literature search was performed using MEDLINE database on bladder cancer risk factors between January 1985 and June 2006 and by detailed examination of the references of original articles, reviews and monographs retrieved. Results Cigarette smoking is recognized as the main cause of bladder cancer and accounts for about 50% of cases in developed countries. A strong link exists between the amount and duration of cigarette smoking. A high risk of bladder carcinoma has been observed in workers exposed to some aromatic amines. Based on these and other occupational risks, it has been estimated that 5-10% of bladder carcinomas in industrialized countries were due to exposures of occupational origin. Infectious agents have a major influence on bladder cancer risks in the areas of the world where Schistosoma haematobium infestation is endemic. Other potential risk factors for bladder cancer are other urinary tract infections and drinking tap water with chlorination by-products or arsenic. Exposure to certain drugs, like cyclophosphamide used in chemotherapy and heavy consumption of phenacetin-containing analgesics, has been shown to cause bladder cancer in humans. Total fluid intake and high consumption of fruits and vegetables are probably associated with a small decrease in risk. Conclusions Avoidance of tobacco smoking and incriminated occupational exposures, habitual intake of fresh fruits and vegetables, and prevention and control of urinary tract infections should be recommended for bladder cancer prevention. Further studies are required to assess the role of genetic polymorphisms and their modifying effect of lifestyle risk factors for bladder cancer occurrence and to evaluate the benefit of bladder cancer screening, particularly in those at high risk.