bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reactivation of cAMP Pathway by PDE4D Inhibition Represents a Novel Druggable Axis for Overcoming Tamoxifen Resistance in ER-positive Breast Cancer
Authors: Mishra Rasmi R. , Belder Nevin , Ansari Suhail A. , Kayhan Merve , Bal Hilal , Raza Umar , Ersan Pelin G. , Tokat Ünal M. , Eyüpoğlu Erol , Saatci Özge , Jandaghi Pouria , Wiemann Stefan , Üner Ayşegül , Cekic Caglar , Riazalhosseini Yasser , Şahin Özgür 
Published: January 2018

Abstract
Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance.
Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo. Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance.
Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo.
Conclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987–2001. ©2018 AACR.
YAP-Induced PD-L1 Expression Drives Immune Evasion in BRAFi-Resistant Melanoma
Authors: Kim Min Hwan , Kim Chang Gon , Kim Sang-Kyum , Shin Sang Joon , Choe Eun Ah , Park Su-Hyung , Shin Eui-Cheol , Kim Joon 
Published: January 2018

Abstract
Activation of YAP, a Hippo pathway effector, is an important resistance mechanism to BRAF inhibitor (BRAFi) in melanoma. Emerging evidence also suggests that YAP is involved in suppression of the antitumor immune response. However, the potential direct impact of YAP activity on cytotoxic T-cell immune responses has not been explored yet. Here, we show that BRAFi-resistant melanoma cells evade CD8+ T-cell immune responses in a PD-L1–dependent manner by activating YAP, which synchronously supports melanoma cell survival upon BRAF inhibition. PD-L1 expression is elevated in BRAFi-resistant melanoma cells, in which YAP is robustly activated, and YAP knockdown decreases PD-L1 expression. In addition, constitutively active YAP (YAP-5SA) increases PD-L1 expression by binding to an upstream enhancer of the PD-L1 gene and potentiating its transcription. Both BRAFi-resistant and YAP-5SA–expressing melanoma cells suppress the cytotoxic function and cytokine production of Melan-A–specific CD8+ T cells, whereas anti–PD-1 antibody reverses the YAP-mediated T-cell suppression. Moreover, nuclear enrichment of YAP in clinical melanoma samples correlates with increased PD-L1 expression. Our findings show that YAP directly mediates evasion of cytotoxic T-cell immune responses in BRAFi-resistant melanoma cells by upregulating PD-L1, and targeting of YAP-mediated immune evasion may improve prognosis of melanoma patients. Cancer Immunol Res; 6(3); 255–66. ©2018 AACR.
Definition of Iron Deficiency Based on the Gold Standard of Bone Marrow Iron Staining in Heart Failure Patients
Authors: Grote Beverborg Niels , Klip IJsbrand T. , Meijers Wouter C. , Voors Adriaan A. , Vegter Eline L. , van der Wal Haye H. , Swinkels Dorine W. , van Pelt Joost , Mulder Andre B. , Bulstra Sjoerd K. , Vellenga Edo , Mariani Massimo A. , de Boer Rudolf A. , van Veldhuisen Dirk J. , van der Meer Peter 
Published: January 2018

Background
The most commonly used definition of iron deficiency (ID; ferritin <100 ng/mL or ferritin 100–300 ng/mL and transferrin saturation [TSAT] <20%) has not been validated in patients with heart failure (HF). We aimed to define and validate the biomarker-based definition of ID in HF, using bone marrow iron staining as the gold standard. Second, we aimed to assess the prognostic value of the optimized definition.

Methods and Results

Bone marrow aspiration with iron staining was performed in 42 patients with HF and a reduced left ventricular ejection fraction (≤45%) undergoing median sternotomy for coronary artery bypass grafting. Patients were mostly male (76%) with mild-to-moderate HF and a mean age of 68±10 years. Bone marrow ID was found in 17 (40%) of the HF patients. The most commonly used definition of ID had a sensitivity of 82% and a specificity of 72%. A definition solely based on TSAT ≤19.8% or serum iron ≤13 µmol/L had a sensitivity of 94% and specificity of 84% and 88%, respectively (
P
<0.05 compared with the former definition). Subsequently, we assessed the incidence of all-cause mortality in 387 consecutive outpatient HF patients (left ventricular ejection fraction ≤45%). In these patients, TSAT ≤19.8% and serum iron ≤13 µmol/L, and not ferritin, were independently associated with mortality.

Conclusions
A TSAT ≤19.8% or a serum iron ≤13 µmol/L shows the best performance in selecting patients with ID and identifies HF patients at the highest risk of death. Our findings validate the currently used TSAT cutoff of <20% for the identification of ID in HF patients, but question the diagnostic value of ferritin.
Six-Year Changes in Physical Activity and the Risk of Incident Heart Failure
Authors: Florido Roberta , Kwak Lucia , Lazo Mariana , Nambi Vijay , Ahmed Haitham M. , Hegde Sheila M. , Gerstenblith Gary , Blumenthal Roger S. , Ballantyne Christie M. , Selvin Elizabeth , Folsom Aaron R. , Coresh Josef , Ndumele Chiadi E. 
Published: January 2018

Background:
Higher physical activity (PA) is associated with lower heart failure (HF) risk; however, the effect of changes in PA on HF risk is unknown.

Methods:
We evaluated 11 351 ARIC study (Atherosclerosis Risk in Communities) participants (mean age 60 years) who attended visit 3 (1993–1995) and did not have a history of cardiovascular disease. Exercise PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines as recommended, intermediate, or poor. We used Cox regression models to characterize the association of 6-year changes in PA between the first (1987–1989) and third ARIC visits and HF risk.

Results:
During a median of 19 years of follow-up, 1750 HF events occurred. Compared with those with poor activity at both visits, the lowest HF risk was seen for those with persistently recommended activity (hazard ratio, 0.69; 95% confidence interval, 0.60–0.80). However, those whose PA increased from poor to recommended also had reduced HF risk (hazard ratio, 0.77; 95% confidence interval 0.63–0.93). Among participants with poor baseline activity, each 1 SD higher PA at 6 years (512.5 METS*minutes/week, corresponding to ≈30 minutes of brisk walking 4 times per week) was associated with significantly lower future HF risk (hazard ratio, 0.89, 95% confidence interval, 0.82–0.96).

Conclusions:
Although maintaining recommended activity levels is associated with the lowest HF risk, initiating and increasing PA, even in late middle age, are also linked to lower HF risk. Augmenting PA may be an important component of strategies to prevent HF.
Hypertensive Disorders of Pregnancy and Offspring Cardiometabolic Health at Midchildhood: Project Viva Findings
Authors: Tripathi Ruby Reetika , Rifas‐Shiman Sheryl L. , Hawley Nicola , Hivert Marie‐France , Oken Emily 
Published: January 2018

Background

Exposure to preeclampsia or gestational hypertension is associated with higher offspring systolic blood pressure (
SBP
), but less is known about associations with other cardiometabolic risk markers.

Methods and Results

We studied 1097 children from the Project Viva cohort born 1999‐2002. Exposures were preeclampsia or gestational hypertension and mean maternal
SBP
in each trimester from prenatal records. Outcomes were research measures in midchildhood (mean 8.0 years) of
SBP
, overall adiposity, and a global cardiometabolic risk score comprising measures of
SBP
, waist circumference, glycemia, and lipids. We conducted linear regression analyses adjusted for maternal characteristics and offspring sex and age. In adjusted models, maternal preeclampsia or gestational hypertension (n=98, 9.1%) versus normal blood pressure was associated with slightly higher offspring
SBP
z‐score (0.15 units; 95% confidence interval [CI] −0.03, 0.32) but otherwise predicted better cardiometabolic health markers including metabolic risk z‐score (−0.23 units; −95%
CI
0.44, −0.03) and several of its components as well as lower body mass index z‐score (−0.27 units; 95%
CI
−0.48, −0.06) and lower fat mass index (−0.91 kg/m
2
; 95%
CI
−1.35, −0.47). Similarly, higher mean third‐trimester maternal
SBP
was associated with higher offspring
SBP
z‐score (0.09 units per 10 mm Hg; 95%
CI
0.02, 0.16) and lower overall and central adiposity but not with biomarkers of metabolic risk. Results for second‐trimester
SBP
were generally similar. First‐trimester blood pressure was associated with higher offspring blood pressure but not with other outcomes.

Conclusions

Higher maternal late‐pregnancy
SBP
and hypertensive disorders of pregnancy were associated with higher offspring
SBP
but otherwise better cardiometabolic health.
Using the Atmospheric Radiation Measurement (ARM) Datasets to Evaluate Climate Models in Simulating Diurnal and Seasonal Variations of Tropical Clouds
Authors: Wang Hailong , Burleyson Casey D. , Ma Po-Lun , Fast Jerome D. , Rasch Philip J. 
Published: January 2018

AbstractLong-term Atmospheric Radiation Measurement (ARM) datasets collected at the three tropical western Pacific (TWP) sites are used to evaluate the ability of the Community Atmosphere Model (CAM5) to simulate the various types of clouds, their seasonal and diurnal variations, and their impact on surface radiation. A number of CAM5 simulations are conducted at various horizontal grid spacing (around 2°, 1°, 0.5°, and 0.25°) with meteorological constraints from analysis or reanalysis. Model biases in the seasonal cycle of cloudiness are found to be weakly dependent on model resolution. Positive biases (up to 20%) in the annual mean total cloud fraction appear mostly in stratiform ice clouds. Higher-resolution simulations do reduce the positive bias in ice clouds, but they inadvertently increase the negative biases in convective clouds and low-level liquid clouds, leading to a positive bias in annual mean shortwave fluxes at the sites, as high as 65 W m−2 in the 0.25° simulation. Such resolution-dependent biases in clouds can adversely lead to biases in ambient thermodynamic properties and, in turn, produce feedback onto clouds. Both the model and observations show distinct diurnal cycles in total, stratiform, and convective cloud fractions; however, they are out of phase by 12 h and the biases vary by site. The results suggest that biases in deep convection affect the vertical distribution and diurnal cycle of stratiform clouds through the transport of vapor and/or the detrainment of liquid and ice. The approach used here can be easily adapted for the evaluation of new parameterizations being developed for CAM5 or other global or regional models.
Preoperative Tibial Subchondral Bone Marrow Lesion Patterns and Associations With Outcomes After Isolated Meniscus Allograft Transplantation
Authors: Saltzman Bryan M. , Cotter Eric J. , Stephens Jeffrey P. , Cvetanovich Gregory L. , Madden Brett , Wang Kevin , Yanke Adam B. , Cole Brian J. 
Published: January 2018

Background: The association between preoperative tibial subchondral bone marrow lesion (BML) patterns and outcomes after isolated meniscus allograft transplantation (MAT) are unknown. Purpose: To determine (1) if a superior classification means exists (ie, high interrater reliability [IRR]) for grading tibial subchondral BML before isolated MAT and (2) whether quality and/or severity of preoperative tibial subchondral BML patterns was associated with clinical outcomes and/or failure rates after isolated MAT. Study Design: Cohort study; Level of evidence, 3. Methods: All patients who underwent isolated MAT with a single surgeon between October 2006 and February 2017 were identified. Three means were evaluated to quantify the degree of subchondral BML in the affected tibial-sided compartment: Welsch et al, based on maximum diameter of the lesion; Costa-Paz et al, based on appearance and location of the lesion; and Filardo et al, based on severity of findings. IRR was generated and compared among the 3 classifications. The preoperative magnetic resonance imaging (MRI) subchondral BML grading scheme with the highest IRR was then used to assess for associations with postoperative outcomes for those patients with >2-year follow-up, per a Spearman correlation matrix with each reviewer’s grades. Results: In total, 60 MRI scans were available for subchondral BML grading. Grader 1 identified the presence of subchondral BML in the tibia of the affected compartment in 40 (66.7%) of the available MRI scans, as compared with 38 (63.3%) for grader 2. The calculated IRRs with the Welsch et al and Costa-Paz et al classifications were rated “strong/almost perfect” agreement. A significant correlation was demonstrated between grader 1 with the Welsch et al grading scheme and outcome measures of KOOS pain (Knee injury and Osteoarthritis Outcome Score; negative correlation, P = .05), WOMAC pain (Western Ontario and McMaster Universities Osteoarthritis Index; positive correlation, P = .026), and Marx Activity Rating Scale (negative correlation, P = .019). A significant correlation was demonstrated between grader 2 with the Costa-Paz et al grading scheme and postoperative satisfaction (positive correlation, P = .018). There were no significant differences in survivorship based on gradings. Conclusion: Nearly two-thirds of patients who undergo isolated MAT have subchondral BML on preoperative MRI. Our findings suggest that increasing BML size (Welsch et al) is correlated with worse postoperative pain measures (KOOS pain, WOMAC pain) and worse activity ratings (Marx Activity Rating Scale). Additionally, increasing disruption or depression of the normal contour of the cortical surface, with or without lesion contiguity with the subjacent articular surface (Costa-Paz et al), is correlated with greater postoperative satisfaction.
Depoliticising addiction
Authors: Bujalski Michał , Hellman Matilda , Moskalewicz Jacek , Beccaria Franca , Rolando Sara 
Published: January 2018

Aims: The article presents an analysis of sources of information employed in mainstream print media reporting on addiction problems in Finland, Italy and Poland in the 1990s and 2000s. Method: A quantitative content analysis of frequency of different sources employed in articles in daily newspapers from Finland ( N = 258), Italy ( N = 296), and Poland ( N = 212) from the years 1991, 1998 and 2011. Semantic units were coded in Atlas.ti. The societal spheres represented were identified using a common coding scheme broadly inspired by Boltanski and Thévenot’s typology of polities of worth. Transformations were identified in line with van Leeuwen’s framework for trends in discourse salience over time. Results: The study highlights different patterns of coverage of addictions in the three countries. Over time, increased salience is given to the individuals affected by addictions and experts who represent biomedical sciences. This process occurred with varying intensity and expressiveness in all countries under study. Conclusions: Social and political sources were employed to less extent over time. The media focus seemed to shift to the affected individuals and scientific expertise. This confirms results from previous studies on a general move towards individualisation and an increased focus on more personal and technical aspects of addiction problems in the mass media.
Evaluation of the oxidative stress–related genes ALOX5, ALOX5AP, GPX1, GPX3 and MPO for contribution to the risk of type 2 diabetes mellitus in the Han Chinese population
Authors: Liu Ding , Liu Lei , Hu Zhongyang , Song Zhi , Wang Yaqin , Chen Zhiheng 
Published: January 2018

Aim: Type 2 diabetes mellitus is a polygenic metabolic disorder resulting from oxidative stress, the root cause of insulin resistance, β-cell dysfunction and impaired glucose tolerance. The aim of this study was to investigate the role of oxidative stress–related genes ALOX5, ALOX5AP, GPX1, GPX3 and MPO in type 2 diabetes mellitus susceptibility in the Chinese Han population. Methods: A total of 396 type 2 diabetes mellitus patients and 678 controls were recruited. The ALOX5 rs10900213, ALOX5AP rs4293222, GPX1 rs1050450, GPX3 rs3828599 and MPO rs2107545 gene polymorphisms were genotyped. Results: We found one single-nucleotide polymorphism in the MPO gene was associated with type 2 diabetes mellitus susceptibility [rs2107545: odds ratio = 1.563 (1.166–2.096); p = 0.003], after adjusting for covariates. Furthermore, we also considered the likely complexity of effects of genetic and conventional risk factors in type 2 diabetes mellitus–related vascular complications, such as carotid plaques. Our analysis revealed that the GPX1 rs1050450 and MPO rs2107545 were significantly associated with increased risk of carotid plaques in type 2 diabetes mellitus patients. Conclusion: Our study presents novel evidence for main effects of MPO gene on type 2 diabetes mellitus susceptibility. Furthermore, our study supported the association between variants of oxidative stress–related genes ( GPX1 and MPO) and carotid plaques in type 2 diabetes mellitus patients, which indicated a modulation of type 2 diabetes mellitus–related vascular complication susceptibility by genetic predisposition.
Differences of energy expenditure while sitting versus standing: A systematic review and meta-analysis
Authors: Saeidifard Farzane , Medina-Inojosa Jose R , Supervia Marta , Olson Thomas P , Somers Virend K , Erwin Patricia J , Lopez-Jimenez Francisco 
Published: January 2018

Background Replacing sitting with standing is one of several recommendations to decrease sedentary time and increase the daily energy expenditure, but the difference in energy expenditure between standing versus sitting has been controversial. This systematic review and meta-analysis aimed to determine this difference. Designs and methods We searched Ovid MEDLINE, Ovid Embase Scopus, Web of Science and Google Scholar for observational and experimental studies that compared the energy expenditure of standing versus sitting. We calculated mean differences and 95% confidence intervals using a random effects model. We conducted different predefined subgroup analyses based on characteristics of participants and study design. Results We identified 658 studies and included 46 studies with 1184 participants for the final analysis. The mean difference in energy expenditure between sitting and standing was 0.15 kcal/min (95% confidence interval (CI) 0.12–0.17). The difference among women was 0.1 kcal/min (95% CI 0.0–0.21), and was 0.19 kcal/min (95% CI 0.05–0.33) in men. Observational studies had a lower difference in energy expenditure (0.11 kcal/min, 95% CI 0.08–0.14) compared to randomised trials (0.2 kcal/min, 95% CI 0.12–0.28). By substituting sitting with standing for 6 hours/day, a 65 kg person will expend an additional 54 kcal/day. Assuming no increase in energy intake, this difference in energy expenditure would be translated into the energy content of about 2.5 kg of body fat mass in 1 year. Conclusions The substitution of sitting with standing could be a potential solution for a sedentary lifestyle to prevent weight gain in the long term. Future studies should aim to assess the effectiveness and feasibility of this strategy.
Innovative Financing of Higher Education
Authors: Panigrahi Jinusha 
Published: January 2018

With the onset of new public management, there is a shift in the methods of financing of higher education institutions across the countries of the world, particularly emerging market economies, from public financing to private financing of higher education.1 Many countries adopted this shift very quickly while others have moved towards a gradual shift in adopting new systems to various extents. With the gradual decline in public financing of higher education institutions in developing countries like India, due to the competing demand for public funds and thereby privatization of public higher education institutions to share the cost of higher education to meet the growing demand for higher education, there are many new innovative methods that are adopted to finance higher education institutions. Further, the massification of higher education has encouraged the expansion of private higher education institutions to meet the sudden burst in the demand for higher education. The article discusses the issues and challenges in implementing the innovative methods of financing across the developed and developing countries with special regard to their implementation in a developing country like India.
Effect of nonpermissive HLA-DPB1 mismatches after unrelated allogeneic transplantation with in vivo T-cell depletion
Authors: Oran Betül , Saliba Rima M. , Carmazzi Yudith , de Lima Marcos , Rondon Gabriela , Ahmed Sairah , Alousi Amin , Andersson Borje S. , Anderlini Paolo , Alvarez Michelle , Bashir Qasier , Ciurea Stefan , Fernandez-Vina Marcelo , Hosing Chitra , Kebriaei Partow , Korbling Martin , Cano Pedro , Khouri Issa , Marin David , Nieto Yago , Olson Amanda , Popat Uday , Rezvani Katy , Qazilbash Muzaffar , Shpall Elizabeth J. , Champlin Richard E. , Cao Kai 
Published: January 2018

Key Points
After HSCT with in vivo T-cell depletion using ATG, HLA-DPB1 nonpermissive mismatches at the GVH direction increase the risk for aGVHD. HLA-DPB1–matched pairs have an increased risk for disease progression if intermediate risk by the Disease Risk Index.
Mitotic spindles revisited – new insights from 3D electron microscopy
Authors: Müller-Reichert Thomas , Kiewisz Robert , Redemann Stefanie 
Published: January 2018

ABSTRACT
The mitotic spindle is a complex three-dimensional (3D) apparatus that functions to ensure the faithful segregation of chromosomes during cell division. Our current understanding of spindle architecture is mainly based on a plethora of information derived from light microscopy with rather few insights about spindle ultrastructure obtained from electron microscopy. In this Review, we will provide insights into the history of imaging of mitotic spindles and highlight recent technological advances in electron tomography and data processing, which have delivered detailed 3D reconstructions of mitotic spindles in the early embryo of the nematode Caenorhabditis elegans. Tomographic reconstructions provide novel views on spindles and will enable us to revisit and address long-standing questions in the field of mitosis.