bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Burden of Rare and Common Variants on Tumor Characteristics, Survival, and Mode of Detection in Breast Cancer
Authors: Li Jingmei , Ugalde-Morales Emilio , Wen Wei Xiong , Decker Brennan , Eriksson Mikael , Torstensson Astrid , Christensen Helene Nordahl , Dunning Alison M. , Allen Jamie , Luccarini Craig , Pooley Karen A. , Simard Jacques , Dorling Leila , Easton Douglas F. , Teo Soo Hwang , Hall Per , Czene Kamila 
Published: November 2018

Abstract
Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes—or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer–specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers (n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16–2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21–2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (&lt;25%), non-BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12–3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64–0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection.
Significance: These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. Cancer Res; 78(21); 6329–38. ©2018 AACR.
Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib
Authors: Crona Daniel J. , Skol Andrew D. , Leppänen Veli-Matti , Glubb Dylan M. , Etheridge Amy S. , Hilliard Eleanor , Peña Carol E. , Peterson Yuri K. , Klauber-DeMore Nancy , Alitalo Kari K. , Innocenti Federico 
Published: November 2018

Abstract

Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC.

Significance:
Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.
MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53
Authors: Hines John , Lartigue Schan , Dong Hanqing , Qian Yimin , Crews Craig M. 
Published: November 2018

Abstract

Although the number of proteins effectively targeted for posttranslational degradation by PROTAC has grown steadily, the number of E3 ligases successfully exploited to accomplish this has been limited to the few for which small-molecule ligands have been discovered. Although the E3 ligase MDM2 is bound by the nutlin class of small-molecule ligands, there are few nutlin-based PROTAC. Because a nutlin-based PROTAC should both knockdown its target protein and upregulate the tumor suppressor p53, we examined the ability of such a PROTAC to decrease cancer cell viability. A nutlin-based, BRD4-degrading PROTAC, A1874, was able to degrade its target protein by 98% with nanomolar potency. Given the complementary ability of A1874 to stabilize p53, we discovered that the nutlin-based PROTAC was more effective in inhibiting proliferation of many cancer cell lines with wild-type p53 than was a corresponding VHL-utilizing PROTAC with similar potency and efficacy to degrade BRD4. This is the first report of a PROTAC in which the E3 ligase ligand and targeting warhead combine to exert a synergistic antiproliferative effect. Our study highlights the untapped potential that may be unlocked by expanding the repertoire of E3 ligases that can be recruited by PROTAC.

Significance:
These findings present the first BRD4-targeting MDM2-based PROTAC that possesses potent, distinct, and synergistic biological activities associated with both ends of this heterobifunctional molecule.
Клініко-морфологічні особливості багатоточкового та лінійного товстокишкового електрозварного анастомозу
Authors: Podpriatov S. S. , Podpryatov S. E. , Gichka S. G. , Makarov A. V. , Marinsky G. S. , Tkachenko V. A. , Tkachenko S. V. , Chernets O. V. , Tarnavsky D. V. 
Published: November 2018

Мета роботи: вплив на клінічні властивості герметичної міцності електрозварного товсто-товстокишкового анастомозу особливостей морфологічних перетворень в стінках кишки при застосуванні лінійного та точкового методів з’єднання та різних величин тиску в інструменті.
Матеріал і методи. На ділянках товстої кишки діаметром 31 см в умовах комплексного гострого експерименту на свинях наклали 2 дворядних скобкових анастомози степлером та по 48 електрозварювальних: точковим зварюванням (зубчастий пінцет з тиском на вістрі 1,8 Н/мм2) та лінійним циркулярним (у варіантах тиску на тканину 2,1 Н/мм2 та 3,0 Н/мм2), кінець-в-кінець. Використовували програму електрозварювального апарату «Патонмед» ЕКВЗ-300 (440 кГц). Випробовували анастомози повільним, до 15 мм рт. ст./хв введенням рідини. Сліпим методом обирали варіант дослідження на кожен з 3 типів електрозварного з’єднання: до настання розриву – або до рівня втрати герметичності скобкового анастомозу: 23,5 мм рт. ст. Після цього настомози спрямували на гістологічне дослідження.
Результати досліджень та їх обговорення. Всі електрозварні анастомози залишалися герметичними при тиску розпирання 23,5 мм рт. ст. і надалі втратили герметичність: точковий за тиску 37,2±5,2 мм рт. ст. лінійний (створений під тиском 2,1 Н/мм2 ) – (53,6±9,8) мм рт. ст. лінійний (створений під тиском 3,0 Н/мм2 ) – (62,8±6,2) мм рт. ст. З’єднання в лінійному анастомозі змінювалася в товщині від 0,1 до 0,3 мм, і відрізнялася за морфологічними характеристиками на сегменті 1/3 довжини кола по брижовому краю, де виявили більшу частку щілин та числа проміжків між коагульовано з’єднаними м’язовими оболонками, хоча загалом суцільність коагуляційних змін по колу зберігається. Розрив відбувався в цьому сегменті. Створений під тиском 3,0 Н/мм2 мав значно меншу кількість щілин та краще з’єднання шарів стінки в конгломераті. Товщина точкового анастомозу хвилеподібно змінювалася від 1,8 до 5 мм. В місцях зближення зубоподібних електродів формуються: з’єднання між м’язовими оболонками, просторова орієнтація клітинних фрагментів і волокон, електрозварний конгломерат. Перифокально м’язові шари не зливаються, але перебувають в складі коагуляційного конгломерату, яких охоплює переважно м’язовий та підслизовий шари. Серозні оболонки також з’єднані.
Діагностика та хірургічне лікування поєднаних форм туберкульозу і раку легень
Authors: Koshak Yu. F. , Savenkov Yu. F. 
Published: November 2018

The aim of the work: to raise efficiency of the surgical treatment of patients with combined forms of pulmonary tuberculosis and non-small cell lung cancer.
Materials and Methods. The retrospective analysis was conducted to 91 patient with combined forms of pulmonary tuberculosis and lung cancer, who were treated in TB hospitals, surgical departments of different regions of Ukraine.
Results and Discussion. The analysis of the morphological features of combined forms of pulmonary tuberculosis and non-small cell lung cancer was made in comparison groups , that were explored retrospectively.
Conclusion. The leading effect of pulmonary tuberculosis on the surgical treatment of patients with combined forms of tuberculosis and lung cancer was shown in groups of comparison. The increase of 3 years survival in patients of basic groups is set , demonstrating the advantage of active surgical tactics of sterno-mediastinal access and the appliance of more radical bilateral lymph node dissection.
Mechanisms for and Predictability of a Drastic Reduction in the Arctic Sea Ice: APPOSITE Data with Climate Model MIROC
Authors: Ono J. , Tatebe H. , Komuro Y. 
Published: November 2018

Abstract
The mechanisms for and predictability of a drastic reduction in the Arctic sea ice extent (SIE) are investigated using the Model for Interdisciplinary Research on Climate (MIROC) version 5.2. Here, a control (CTRL) with forcing fixed at year 2000 levels and perfect-model ensemble prediction (PRED) experiments are conducted. In CTRL, three (model years 51, 56, and 57) drastic SIE reductions occur during a 200-yr-long integration. In year 56, the sea ice moves offshore in association with a positive phase of the summer Arctic dipole anomaly (ADA) index and melts due to heat input through the increased open water area, and the SIE drastically decreases. This provides the preconditioning for the lowest SIE in year 57 when the Arctic Ocean interior is in a warm state and the spring sea ice volume has a large negative anomaly due to drastic ice reduction in the previous year. Although the ADA is one of the key mechanisms behind sea ice reduction, it does not always cause a drastic reduction. Our analysis suggests that wind direction favoring offshore ice motion is a more important factor for drastic ice reduction events. In years experiencing drastic ice reduction events, the September SIE can be skillfully predicted in PRED started from July, but not from April. This is because the forecast errors for the July sea level pressure and those for the sea ice concentration and sea ice thickness along the ice edge are large in PRED started from April.
Symmetric and Baroclinic Instability in Dense Shelf Overflows
Authors: Yankovsky Elizabeth , Legg Sonya 
Published: November 2018

AbstractIn this study, we revisit the problem of rotating dense overflow dynamics by performing nonhydrostatic numerical simulations, resolving submesoscale variability. Thermohaline stratification and buoyancy forcing are based on data from the Eurasian basin of the Arctic Ocean, where overflows are particularly crucial to the exchange of dense water between shelves and deep basins, yet have been studied relatively little. A nonlinear equation of state is used, allowing proper representation of thermohaline structure and mixing. We examine three increasingly complex scenarios: nonrotating 2D, rotating 2D, and rotating 3D. The nonrotating 2D case behaves according to known theory: the gravity current descends alongslope until reaching a relatively shallow neutral buoyancy level. However, in the rotating cases, we have identified novel dynamics: in both 2D and 3D, the submesoscale range is dominated by symmetric instability (SI). Rotation leads to geostrophic adjustment, causing dense water to be confined within the forcing region longer and attain a greater density anomaly. In the 2D case, Ekman drainage leads to descent of the geostrophic jet, forming a highly dense alongslope front. Beams of negative Ertel potential vorticity develop parallel to the slope, initiating SI and vigorous mixing in the overflow. In 3D, baroclinic eddies are responsible for cross-isobath dense water transport, but SI again develops along the slope and at eddy edges. Remarkably, through two different dynamics, the 2D SI-dominated case and 3D eddy-dominated case attain roughly the same final water mass distribution, highlighting the potential role of SI in driving mixing within certain regimes of dense overflows.
Conceptual Reasoning in Reading: A Complex Seriation of Meaning
Authors: Watson Alan J. , Sinclair Kenneth E. 
Published: November 2018

A cognitive developmental view of learning to read was tested with 100 Year 4 children by examining the relationship of conceptual reasoning (multiple seriation and perceptual regulations), oral language (vocabulary and grammatic prediction) and reading (word recognition and comprehension). Regression analysis showed that multiple seriation and perceptual regulations, though related, are distinct in their contributions to the variance in reading. Backward regression indicated that reasoning contributed to the variance in reading independently of the influence of oral language. Qualitative aspects of student responses suggest ways in which reading involves the reasoning tasks studied. The findings, by suggesting the importance of non-language mental structuring activity for children's reading, indicate that language learning explanations of reading may not be sufficient. The study calls for longitudinal follow-up to examine the dynamic of developmental change over the extended period needed for learning to read.
Standardized drug and alcohol questions at admission to an acute adult mental health unit: clarifying the burden of dual diagnoses across a five-year period
Authors: Reilly John , McDermott Brett , Dillon John 
Published: November 2018

Objectives: We aimed to report substance use across a five-year period in individuals admitted to an acute mental health unit, utilizing data from a routine clinical measure, diagnoses, and findings related to gender, ethnicity and the implementation of a new dual-diagnosis policy. Methods: Data was extracted from the electronic records of 2118 individuals who had consecutive admissions to the acute inpatient unit. Analysis focused on demographic and diagnosis variables and the drug and alcohol question in the Health of the Nations Outcome Scale. Results: Some 57.6% of the sample was in the at-risk drug and alcohol category. Male and indigenous inpatients were most at risk. More than 50% of patients with schizophrenia, anxiety and personality disorders were deemed at-risk. Following implementation of the dual-diagnosis policy, recorded primary and secondary substance use disorder (SUD) diagnoses significantly increased. Conclusions: The study replicated previous findings of a high proportion of patients with co-morbid drug and alcohol use. In this sample it seems likely that the dual-diagnosis policy and related activities increased the rate of SUD diagnoses recorded, although it is likely to still be under-reported.
Perceptions of pregnant women regarding antidepressant and anxiolytic medication use during pregnancy
Authors: Kothari Alka , de Laat John , Dulhunty Joel M , Bruxner George 
Published: November 2018

Objective: The objective of this study was to explore attitudes and decision-making by pregnant women regarding antidepressant and anxiolytic use during pregnancy. Method: An observational study at an outer metropolitan hospital in Brisbane, Queensland. Pregnant women presenting for their first antenatal clinic visit were invited to complete a questionnaire. Participants were asked about current or previous antidepressant/anxiolytic use, influences on drug decision-making and the adequacy of information received. Perceptions were measured on a 7-point Likert scale. Results: A total of 503 pregnant women were surveyed. The background prevalence of anxiety and depression was 30.0% (151), with 9.3% (47) respondents using antidepressant or anxiolytic medications during the current pregnancy. Of these 47 women, 68% ceased these medications during or while trying to become pregnant, most commonly due to potential side effects to the baby (16), health professional advice (8) and symptomatology that was under control (7). While the effect was modest, decision-making was most strongly influenced by general practitioners, family and the internet. Conclusions: Most women cease antidepressant/anxiolytic medication before and during pregnancy for reasons other than stability of condition. This study reveals an unmet need for accessible reliable information to guide pregnant women and their care providers.
International consensus on quality standards for brain health-focused care in multiple sclerosis
Authors: Hobart Jeremy , Bowen Amy , Pepper George , Crofts Harriet , Eberhard Lucy , Berger Thomas , Boyko Alexey , Boz Cavit , Butzkueven Helmut , Celius Elisabeth Gulowsen , Drulovic Jelena , Flores José , Horáková Dana , Lebrun-Frénay Christine , Marrie Ruth Ann , Overell James , Piehl Fredrik , Rasmussen Peter Vestergaard , Sá Maria José , Sîrbu Carmen-Adella , Skromne Eli , Torkildsen Øivind , van Pesch Vincent , Vollmer Timothy , Zakaria Magd , Ziemssen Tjalf , Giovannoni Gavin 
Published: November 2018

Background: Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS. Objectives: We sought to develop internationally applicable quality standards for timely, brain health–focused MS care. Methods: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define ‘core’, ‘achievable’ and ‘aspirational’ time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders. Results: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms. Conclusion: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.
Household Dietary Adequacy and Individual Nutrition Status: Relationships and Seasonal Effects in a Sahelian Community in Chad
Authors: Begin France , Alladoumgué Mariam , Nandjingar Korite , Delisle Helene 
Published: November 2018

A survey was conducted in a local area in the Sahelian zone of Chad to assess the relationship between household food consumption and individual nutrition status in two different seasons. Eighty households were surveyed during the non-harvest and harvest seasons. Household consumption was measured by weighing food items over two consecutive days. The intake of energy, protein, and iron was adequate. The median intake of vitamin A was low, particularly in the non-harvest season, 48% of FAO/WHO/UNU recommendations. Seasonal differences were detected only for vitamin A and iron. The mean child weight-for-height Z score and mean adult body mass index were lower at the harvest season (p< .05). Household vitamin A adequacy was a significant predictor of child weight for height and adult body mass index at the harvest season, even when energy adequacy was controlled for. This study shows that the weak relationship between household dietary intake and individual nutrition status changed with the seasons, and that both provided complementary information on household nutrition. It is suggested that where household energy supply is not limiting, monitoring the consumption of major sources of vitamin A may help to identify malnourished households.
The Impact of Non-Traditional Export Agriculture on Income and Food Availability in Guatemala: An Intra-Household Perspective
Authors: Katz Elizabeth 
Published: November 2018

This paper assesses the impact of non-traditional agriculture exports (NTAE) in highland Guatemala on the level and distribution of household income, and the financing and purchase of food items. Heckman's two-step procedure was used to control for self-selection of NTAE producers and potential correlation of preferences. Farmers with greater extension of land, as well as younger Catholic farmers with higher-quality land, are most likely to adopt the new crops (broccoli, snow peas (mange-tout!), and NTAE crops are highly profitable for those who adopt them. Despite the widespread use of female labour in the production of NTAE crops, the extent of adoption is not negatively associated with women's ability to generate independent income. Land devoted to the new crops also exhibits a strong positive relationship with subsistence production of corn and beans. Weak evidence supports the hypothesis that distinct intra-household income transfer patterns obtained in NTAE crop-adopting households compared with non-adopting households: in the former, the level of the weekly food allowance provided to women by their husbands is less responsive to changes in both household and female income, making women's earnings a more important overall determinant of food expenditure. A simulation exercise showed that households that have not adopted new crops would use increases in income to augment food expenditures to a much greater extent than adopting households. Within adopting households, the impact of increases in women's income on food expenditures is nearly double that of increases in men's income. Women's flexibility with regard to the allocation of their labour time and income plays an important role in the relative success of non-traditional agriculture as a means of improving household food availability. Improving the food consumption of poor households is often an important implicit or explicit goal of income-generating strategies such as the promotion of non-traditional agricultural export (NTAE) crops. However, a fair amount of controversy surrounds the strength of the relationship between increases in household income and greater access to and intake of nutritious foods. This is particularly the case when those increases in income are based on the displacement of subsistence crops and/or are biased in flavour of men, who may have less propensity than women to spend marginal income gains on food for the family. The nutritional impact of NTAE in highland Guatemala was assessed in a conceptual framework that accounts for the mediating influences of changes in household income, subsistence food production, and alterations in intra-household resource transfers. The data were drawn from a survey of over 300 rural households in five central highland communities between October 1990 and August 1991.