bluuebunny/crossref_metadata_2025_split huggingface dataset:
Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Authors: Li Minghui , Kales Stephen C. , Ma Ke , Shoemaker Benjamin A. , Crespo-Barreto Juan , Cangelosi Andrew L. , Lipkowitz Stanley , Panchenko Anna R. 
Published: December 2015

Abstract
Oncogenic mutations in the monomeric Casitas B-lineage lymphoma (Cbl) gene have been found in many tumors, but their significance remains largely unknown. Several human c-Cbl (CBL) structures have recently been solved, depicting the protein at different stages of its activation cycle and thus providing mechanistic insight underlying how stability—activity tradeoffs in cancer-related proteins—may influence disease onset and progression. In this study, we computationally modeled the effects of missense cancer mutations on structures representing four stages of the CBL activation cycle to identify driver mutations that affect CBL stability, binding, and activity. We found that recurrent, homozygous, and leukemia-specific mutations had greater destabilizing effects on CBL states than random noncancer mutations. We further tested the ability of these computational models, assessing the changes in CBL stability and its binding to ubiquitin-conjugating enzyme E2, by performing blind CBL-mediated EGFR ubiquitination assays in cells. Experimental CBL ubiquitin ligase activity was in agreement with the predicted changes in CBL stability and, to a lesser extent, with CBL-E2 binding affinity. Two thirds of all experimentally tested mutations affected the ubiquitin ligase activity by either destabilizing CBL or disrupting CBL-E2 binding, whereas about one-third of tested mutations were found to be neutral. Collectively, our findings demonstrate that computational methods incorporating multiple protein conformations and stability and binding affinity evaluations can successfully predict the functional consequences of cancer mutations on protein activity, and provide a proof of concept for mutations in CBL. Cancer Res; 76(3); 561–71. ©2015 AACR.
Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression
Authors: Mittapalli Venugopal R. , Madl Josef , Löffek Stefanie , Kiritsi Dimitra , Kern Johannes S. , Römer Winfried , Nyström Alexander , Bruckner-Tuderman Leena 
Published: December 2015

Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin fragility disorder characterized by injury-driven blister formation, progressive soft-tissue fibrosis, and a highly elevated risk of early-onset aggressive cutaneous squamous cell carcinoma (cSCC). However, the mechanisms underlying the unusually rapid progression of RDEB to cSCC are unknown. In this study, we investigated the contribution of injury-induced skin alterations to cSCC development by using a genetic model of RDEB and organotypic skin cultures. Analysis of RDEB patient samples suggested that premalignant changes to the dermal microenvironment drive tumor progression, which led us to subject a collagen VII hypomorphic mouse model of RDEB to chemical carcinogenesis. Carcinogen-treated RDEB mice developed invasive tumors phenocopying human RDEB-cSCC, whereas wild-type mice formed papillomas, indicating that the aggressiveness of RDEB-cSCC is mutation-independent. The inherent structural instability of the RDEB dermis, combined with repeated injury, increased the bioavailability of TGFβ, which promoted extracellular matrix production, cross-linking, thickening of dermal fibrils, and tissue stiffening. The biophysically altered dermis increased myofibroblast activity and integrin β1/pFAK/pAKT mechanosignaling in tumor cells, further demonstrating that cSCC progression is governed by pre-existing injury-driven changes in the RDEB tissue microenvironment. Treatment of three-dimensional organotypic RDEB skin cultures with inhibitors of TGFβ signaling, lysyl oxidase, or integrin β1–mediated mechanosignaling reduced or bypassed tissue stiffness and limited tumor cell invasion. Collectively, these findings provide a new mechanism by which RDEB tissue becomes malignant and offer new druggable therapeutic targets to prevent cSCC onset. Cancer Res; 76(4); 940–51. ©2015 AACR.
SSBP1 Suppresses TGFβ-Driven Epithelial-to-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer by Regulating Mitochondrial Retrograde Signaling
Authors: Jiang Hong-Lin , Sun He-Fen , Gao Shui-Ping , Li Liang-Dong , Huang Sheng , Hu Xin , Liu Sheng , Wu Jiong , Shao Zhi-Ming , Jin Wei 
Published: December 2015

Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype lacking effective prognostic indicators or therapeutic targets. Mitochondrial function is dysregulated frequently in cancer cells to allow for adaptation to a harsh tumor microenvironment. Targeting mitochondrial biogenesis and bioenergetics is, therefore, an attractive therapeutic strategy. In this study, we performed quantitative proteomic analyses in human parental and metastatic breast cancer cell lines to identify mitochondrial proteins involved in TNBC metastasis. We found that single-strand DNA-binding protein 1 (SSBP1) was downregulated in highly metastatic breast cancer cells. Moreover, SSBP1 downregulation promoted TNBC cell metastasis in vitro and in vivo. Mechanistically, SSBP1 loss decreased mitochondrial DNA copy number, thereby potentiating calcineurin-mediated mitochondrial retrograde signaling that induced c-Rel/p50 nuclear localization, activated TGFβ promoter activity, and TGFβ-driven epithelial-to-mesenchymal transition. Low SSBP1 expression correlated with tumor progression and poor prognosis in patients. Collectively, our findings identified SSBP1 as a novel metastasis suppressor and elucidated the mechanisms by which dysregulated mitochondrial signaling contributes to metastatic potential, providing potential new prognostic indicators for patients with TNBC. Cancer Res; 76(4); 952–64. ©2015 AACR.
Variants in 6q25.1 Are Associated with Mammographic Density in Malaysian Chinese Women
Authors: Mariapun Shivaani , Ho Weang Kee , Kang Peter Choon Eng , Li Jingmei , Lindström Sara , Yip Cheng Har , Teo Soo Hwang 
Published: December 2015

Abstract
Background: Mammographic density is an established risk factor for breast cancer and has a strong heritable component. Genome-wide association studies (GWAS) for mammographic density conducted in women of European descent have identified several genetic associations, but none of the studies have been tested in Asians. We sought to investigate whether these genetic loci, and loci associated with breast cancer risk and breast size, are associated with mammographic density in an Asian cohort.
Methods: We conducted genotyping by mass spectrometry in 1,189 women (865 Chinese, 187 Indian, and 137 Malay). Quantitative measurements of mammographic density were performed using ImageJ, a fully automated thresholding technique. The associations of SNPs to densities were analyzed using linear regression models.
Results: We successfully evaluated the associations of 36 SNPs with mammographic densities. After adjusting for age, body mass index, parity, and menopausal status, we found that in our cohort of 865 Malaysian Chinese, three SNPs in the 6q25.1 region near ESR1 (rs2046210, rs12173570, and rs10484919) that were associated with mammographic density, breast cancer risk, or breast size in previous GWAS were significantly associated with both percentage density and absolute dense area. We could not replicate the most significant association found previously in European women (rs10995190, ZNF365 gene) because the minor allele was absent for Asian women.
Conclusion: We found that the directions of genetic associations were similar to those reported in Caucasian women.
Impact: Our results show that even in Asian women with lower population risk to breast cancer, there is shared heritability between mammographic density and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 25(2); 327–33. ©2015 AACR.
High-density lipoprotein therapy inhibits Porphyromonas gingivalis-induced abdominal aortic aneurysm progression
Authors: Rouer Martin , Alsac Jean-Marc , Louedec Liliane , Shoukr Faisal Al , Rouzet Francois , Michel Jean-Baptiste , Meilhac Olivier , Delbosc Sandrine 
Published: December 2015

SummaryClinical and experimental studies have highlighted the potential implication of periondontal bacteria contamination in the pathogenesis of abdominal aortic aneurysms (AAA). In addition to their role in reverse cholesterol transport, high-density lipoproteins (HDLs) display multiple functions, including anti-inflammatory and lipopolysaccharide scavenging properties. Low plasma levels of HDL-cholesterol have been reported in AAA patients. We tested the effect of a HDL therapy in Sprague-Dawley rat model of AAA, obtained by intraluminal elastase infusion followed by repeated injections of Porphyromonas gingivalis (Pg). HDLs, isolated by ultracentrifugation of plasma from healthy human volunteers, were co-injected intravenously (10 mg/kg) with Pg (1.107 Colony Forming Unit) one, eight and 15 days after elastase perfusion. Rats were sacrificed one week after the last injection. Our results show that Pg injections promote the formation of a persistent neutrophil-rich thrombus associated with increased aortic diameter in this AAA model. HDLs significantly reduced the increased AAA diameter induced by Pg. Histology showed the onset of a healing process in the Pg/HDL group. HDL injections also reduced neutrophil activation in Pg-injected rats associated with decreased cytokine levels in conditioned media and plasma. Scintigraphic analysis showed an intense uptake of 99mTc-HDL by the AAA suggesting that HDLs could exert their beneficial effect by acting directly on the thrombus components. HDL supplementation may therefore constitute a new therapeutic tool for AAA treatment.Supplementary Material to this article is available online at www.thrombosis-online.com.
Antithrombin: anti-inflammatory properties and clinical applications
Authors: Sniecinski Roman M. , Welsby Ian J. , Levi Marcel , Levy Jerrold H. 
Published: December 2015

SummaryMany humoral and cellular components participate in bidirectional communication between the coagulation and inflammation pathways. Natural anticoagulant proteins, including antithrombin (AT), tissue factor pathway inhibitor, and protein C, suppress proinflammatory mediators. Conversely, inflammation blunts anticoagulant activity and, when uncontrolled, promotes systemic inflammation-induced coagulation, such as those that occur in disseminated intravascular coagulation and severe sepsis. This review discusses the mechanisms of action and clinical use of AT concentrate in critically ill patients and in the settings of perioperative anticoagulation management for surgery and obstetrics. AT is a serine protease inhibitor with broad anticoagulant activity and potent anti-inflammatory properties. In clinical conditions associated with hereditary or acquired AT deficiency, administration of AT concentrate has been shown to restore proper haemostasis and attenuate inflammation. Of note, AT modulates inflammatory responses not only by inhibiting thrombin and other clotting factors that induce cytokine activity and leukocyte-endothelial cell interaction, but also by coagulation-independent effects, including direct interaction with cellular mediators of inflammation. An increasing body of evidence suggests that AT concentrate may be a potential therapeutic agent in certain clinical settings associated with inflammation. In addition to the well-known anticoagulation properties of AT for the treatment of hereditary AT deficiency, AT also possesses noteworthy anti-inflammatory properties that could be valuable in treating acquired AT deficiency, which often result in thrombotic states associated with an inflammatory component.
Novel Biomarker of Oxidative Stress Is Associated With Risk of Death in Patients With Coronary Artery Disease
Authors: Patel Riyaz S. , Ghasemzadeh Nima , Eapen Danny J. , Sher Salman , Arshad Shawn , Ko Yi-an , Veledar Emir , Samady Habib , Zafari A. Maziar , Sperling Laurence , Vaccarino Viola , Jones Dean P. , Quyyumi Arshed A. 
Published: December 2015

Background—

Free radical scavengers have failed to improve patient outcomes, promoting the concept that clinically important oxidative stress may be mediated by alternative mechanisms. We sought to examine the association of emerging aminothiol markers of nonf
ree radical
mediated oxidative stress with clinical outcomes.

Methods and Results—

Plasma levels of reduced (cyst
ei
ne and glutathione) and oxidized (cyst
i
ne and glutathione disulphide) aminothiols were quantified by high performance liquid chromatography in 1411 patients undergoing coronary angiography (mean age 63 years, male 66%). All patients were followed for a mean of 4.7±2.1 years for the primary outcome of all-cause death (n=247). Levels of cystine (oxidized) and glutathione (reduced) were associated with risk of death (
P
<0.001 both) before and after adjustment for covariates. High cystine and low glutathione levels (>+1 SD and <−1 SD, respectively) were associated with higher mortality (adjusted hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.19–2.21; HR, 2.19; 95% CI, 1.50–3.19; respectively) compared with those outside these thresholds. Furthermore, the ratio of cystine/glutathione was also significantly associated with mortality (adjusted HR, 1.92; 95% CI, 1.39–2.64) and was independent of and additive to high-sensitivity C-reactive protein level. Similar associations were found for other outcomes of cardiovascular death and combined death and myocardial infarction.

Conclusions—
A high burden of oxidative stress, quantified by the plasma aminothiols, cystine, glutathione, and their ratio, is associated with mortality in patients with coronary artery disease, a finding that is independent of and additive to the inflammatory burden. Importantly, these data support the emerging role of nonfree radical biology in driving clinically important oxidative stress.
Democratic Consolidation in Southeast Europe – A Step Forward?
Authors: Slavov Atanas 
Published: December 2015

Strengthening the rule of law and consolidating democracy is still a challenge facing countries in Southeastern Europe (see). Despite the prospective for eu accession for the Western Balkan states and full eu membership for others, issues regarding the quality of democratic institutions and the efficiency of legal procedures are still at stake. There are multiple factors that contribute to the weakened state of constitutional democracy in see countries while also blocking their political and social development.
This article offers a sober view on the democratic consolidation process, emphasizing that a decline from democratic politics may happen at any moment. For one, defective democracies in Southeastern Europe are exposed to nationalism and populism, suffering from weak institutional performance and a burdensome communist legacy. Furthermore, negative stereotypes and practices of exercising political power in see countries hamper the development of the rule of law, efficient democratic systems, and accountable governments. Corruption and clientelism likewise seem embedded in the social structures. Thus, in the absence or inefficiency of the rule of law, the political situation in see countries is often described in terms of a ‘state capture’, not democratic consolidation.
However, according to a mid-term perspective, positive change is still possible, but it requires active civil society participation as well as eu institutional commitment to the rule of law and democracy building in the region. In some cases, moreover, coordinated endeavors between active civil society groups and eu institutions could exercise effective pressure on the national political elites to introduce necessary institutional reforms.
Interannual Variability of the Mindanao Current/Undercurrent in Direct Observations and Numerical Simulations
Authors: Hu Shijian , Hu Dunxin , Guan Cong , Wang Fan , Zhang Linlin , Wang Fujun , Wang Qingye 
Published: December 2015

AbstractThe interannual variability of the boundary currents east of the Mindanao Island, including the Mindanao Current/Undercurrent (MC/MUC), is investigated using moored acoustic Doppler current profiler (ADCP) measurements combined with a series of numerical experiments. The ADCP mooring system was deployed east of the Mindanao Island at 7°59′N, 127°3′E during December 2010–August 2014. Depth-dependent interannual variability is detected in the two western boundary currents: strong and lower-frequency variability dominates the upper-layer MC, while weaker and higher-frequency fluctuation controls the subsurface MUC. Throughout the duration of mooring measurements, the weakest MC was observed in June 2012, in contrast to the maximum peaks in December 2010 and June 2014, while in the deeper layer the MUC shows speed peaks circa December 2010, January 2011, April 2013, and July 2014 and valleys circa June 2011, August 2012, and November 2013. Diagnostic analysis and numerical sensitivity experiments using a 2.5-layer reduced-gravity model indicate that wind forcing in the western Pacific Ocean is a driving agent in conditioning the interannual variability of MC and MUC. Results suggest that westward-propagating Rossby waves that generate in the western Pacific Ocean (roughly 150°–180°E) are of much significance in the interannual variability of the two boundary currents. Fluctuation of Ekman pumping due to local wind stress curl anomaly in the far western Pacific Ocean (roughly 120°–150°E) also plays a role in the interannual variability of the MC. The relationship between the MC/MUC and El Niño is discussed.
Modifications to the Rapid Update Cycle Land Surface Model (RUC LSM) Available in the Weather Research and Forecasting (WRF) Model
Authors: Smirnova Tatiana G. , Brown John M. , Benjamin Stanley G. , Kenyon Jaymes S. 
Published: December 2015

The land surface model (LSM) described in this manuscript was originally developed as part of the NOAA Rapid Update Cycle (RUC) model development effort; with ongoing modifications, it is now used as an option for the WRF community model. The RUC model and its WRF-based NOAA successor, the Rapid Refresh (RAP), are hourly updated and have an emphasis on short-range, near-surface forecasts including aviation-impact variables and preconvective environment. Therefore, coupling to this LSM (hereafter the RUC LSM) has been critical to provide more accurate lower boundary conditions. This paper describes changes made to the RUC LSM since earlier descriptions, including extension from six to nine levels, improved snow treatment, and new land-use data from MODIS.The RUC LSM became operational at the NOAA/National Centers for Environmental Prediction (NCEP) as part of the RUC from 1998–2012 and as part of the RAP from 2012 through the present. The simple treatments of basic land surface processes in the RUC LSM have proven to be physically robust and capable of realistically representing the evolution of soil moisture, soil temperature, and snow in cycled models. Extension of the RAP domain to encompass all of North America and adjacent high-latitude ocean areas necessitated further development of the RUC LSM for application in the tundra permafrost regions and over Arctic sea ice. Other modifications include refinements in the snow model and a more accurate specification of albedo, roughness length, and other surface properties. These recent modifications in the RUC LSM are described and evaluated in this paper.
Improving quality of diabetes care by integrating psychological and social care for poorly controlled diabetes
Authors: Doherty Anne M , Gayle Carol , Morgan-Jones Ruth , Archer Nicola , Laura-Lee  , Ismail Khalida , Werner Anne 
Published: December 2015

Objective Many people with persistent suboptimal diabetes control also have psychiatric morbidity and social problems which interfere with their ability to self-manage their diabetes. Current models of care in the UK do not integrate these different dimensions of care or address inequalities between physical and mental health. 3DFD (3 Dimensions of Care For Diabetes) integrated medical, psychological, and social care in diabetes for patients with persistent suboptimal glycemic control (HbA1c > 75 mmol/mol) despite guideline-based routine diabetes care, to improve glycemic control, reduce psychological distress, and improve social functioning. Methods The service delivered interventions including brief psychological therapies, mental health assessments, psychotropic medications, and social support, enhanced by patient-led case conferences aiming to optimize diabetes care. 3DFD measured changes in HbA1c, psychological functioning, quality of life, rates of unscheduled care, and levels of engagement with routine diabetes care at baseline and at 12 months. Conclusion At 12-month follow-up, 3DFD patients achieved significant reductions in HbA1c of 15 mmol/mol, International Federation of Clinical Chemistry (1.4% Diabetes Control and Complications Trial) and improvements in depression scores and patient satisfaction. This model of care demonstrates that integrated care can improve diabetes outcomes in people with psychological and social comorbidities.
Is serum 25-hydroxyvitamin D associated with depressive symptoms and suicidal ideation in Korean adults?
Authors: Park Jong-Il , Yang Jong-Chul , Won Park Tae , Chung Sang-Keun 
Published: December 2015

Objective Mixed results exist regarding the role of vitamin D deficiency in depression and suicidal ideation. The present study investigated the relationships among vitamin D, depressive symptoms, and suicidal ideation in a large representative of the general population of Korea. Method The data from the fifth Korea National Health and Nutrition Examination Surveys conducted by the Division of Chronic Disease Surveillance, Korea Centers for Disease Control and Prevention, from 2010 to 2012 were investigated. A total of 15,695 subjects aged 20 and older were included in analysis. Depressive symptoms and suicidal ideation were evaluated based on self-report information. The serum 25-hydroxyvitamin D concentrations were measured by radioimmunoassay. The associations among vitamin D, depressive symptoms, and suicidal ideation were explored using multivariate logistic regression analysis adjusting for various confounding variables including sociodemographic and health-related variables. Results Serum 25-hydroxyvitamin D concentrations were not significantly different depending on the depressive symptoms (participant with depressive symptom, n = 2085, 17.10 ng/ml; without depressive symptom, n = 13,610, 17.36 ng/ml; p = 0.142) and suicidal ideation (participant with suicidal ideation, n = 2319, 17.31 ng/ml; without suicidal ideation, n = 13,374, 17.33 ng/ml; p = 0.926). After adjustment for sociodemographic and health-related factors, this lack of relationship was held consistent in the multivariate logistic regression. Conclusions Significant associations were not observed among vitamin D, depressive symptoms, and suicidal ideation in Korean adults. Further studies are warranted to gain a better understanding of the association among vitamin D, depressive symptoms, and suicidal ideation.