bluuebunny/crossref_metadata_2025_split huggingface dataset:
Renal and Cardiovascular Effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF): protocol for a randomised controlled double-blind cross-over trial
Authors: Mordi Natalie A , Mordi Ify R , Singh Jagdeep S , Baig Fatima , Choy Anna-Maria , McCrimmon Rory J , Struthers Allan D , Lang Chim C 
Published: October 2017

IntroductionType 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium–glucose cotransporter 2 (SGLT2) inhibitors and their use in patients with HF. Data on the effect of SGLT2 inhibitor use with diuretics are limited. We hypothesise that SGLT2 inhibition may augment the effects of loop diuretics and the benefits of SGLT2 inhibitors may extend beyond those of their metabolic (glycaemic parameters and weight loss) and haemodynamic parameters. The effects of SGLT2 inhibitors as an osmotic diuretic and on natriuresis may underlie the cardiovascular and renal benefits demonstrated in the recent EMPA-REG study.Methods and analysisTo assess the effect of SGLT2 inhibitors when used in combination with a loop diuretic, the RECEDE-CHF (Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure) trial is a single-centre, randomised, double-blind, placebo-controlled, cross-over trial conducted in a secondary care setting within NHS Tayside, Scotland. 34 eligible participants, aged between 18 and 80 years, with stable T2D and CHF will be recruited. Renal physiological testing will be performed at two points (week 1 and week 6) on each arm to assess the effect of 25 mg empagliflozin, on the primary and secondary outcomes. Participants will be enrolled in the trial for a total period between 14 and 16 weeks. The primary outcome will assess the effect of empagliflozin versus placebo on urine output. The secondary outcomes are to assess the effect of empagliflozin on glomerular filtration rate, cystatin C, urinary sodium excretion, urinary protein/creatinine ratio and urinary albumin/creatinine ratio when compared with placebo.Ethics and disseminationEthics approval was obtained by the East of Scotland Research Ethics Service. Results of the trial will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT03226457; Pre-results.
Effects of polyethylene glycol 2 L alone or with ascorbic acid compared with polyethylene glycol 4 L alone for bowel preparation before colonoscopy: protocol for a systematic review and network meta-analysis
Authors: Tian Xu , Chen Wei-Qing , Huang Jie-Li , He Lan-Ying , Liu Bang-Lun , Liu Xi , Zhou Hang , Liu Bing-Rong 
Published: October 2017

IntroductionColonoscopy has been regarded as a standard method of detecting and removing gastrointestinal lesions early, while adequate bowel preparation is the prerequisite of determining the diagnostic accuracy and treatment safety of this process. Polyethylene glycol (PEG) based bowel preparation regimens remain the first recommendation, but the optimal option is still uncertain. The aim of this systematic review and network meta-analysis of randomised controlled trials (RCTs) is to determine the optimal PEG based bowel preparation regimen before colonoscopy.Methods and analysisWe will assign two investigators to independently search all potential citations, screen records, abstract essential information and appraise the risk of bias accordingly. Then, random effects pairwise and network meta-analyses of RCTs comparing PEG 2 L alone or with ascorbic acid with PEG 4 L alone will be performed using RevMan 5.3 (Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2013), Stata 14 (StataCorp, Texas, USA) and WinBUGS 1.4 (Imperial College School of Medicine, St Mary’s, London, UK) from January 2000 to April 2017. The surface under the cumulative ranking curve will also be calculated in order to rank the regimens.Ethics and disseminationEthics approval and patient written informed consent will not be required because all of the analyses in the present study will be performed based on data from published studies. We will submit our systematic review and network meta-analysis to a peer reviewed scientific journal for publication.Systematic review registrationPROSPERO: CRD42017068957.
An Akt3 Splice Variant Lacking the Serine 472 Phosphorylation Site Promotes Apoptosis and Suppresses Mammary Tumorigenesis
Authors: Suyama Kimita , Yao Jiahong , Liang Huizhi , Benard Outhiriaradjou , Loudig Olivier D. , Amgalan Dulguun , McKimpson Wendy M. , Phillips Greg R. , Segall Jeffrey , Wang Yihong , Fineberg Susan , Norton Larry , Kitsis Richard N. , Hazan Rachel B. 
Published: October 2017

Abstract
The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/−S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple-negative breast cancer cells, specific ablation of Akt3/−S472 enhanced, whereas overexpression, suppressed mammary tumor growth, consistent with a significant association with patient survival duration relative to Akt3/+S472. These effects were due to striking induction of apoptosis, which was mediated by Bim upregulation, leading to conformational activation of Bax and caspase-3 processing. Bim accumulation was caused by marked endocytosis of EGF receptors with concomitant ERK attenuation, which stabilizes BIM. These findings demonstrate an unexpected function of an endogenously expressed Akt isoform in promoting, as opposed to suppressing, apoptosis, underscoring that Akt isoforms may exert dissonant functions in malignancy.
Significance: These results illuminate an unexpected function for an endogenously expressed Akt isoform in promoting apoptosis, underscoring the likelihood that different Akt isoforms exert distinct functions in human cancer. Cancer Res; 78(1); 103–14. ©2017 AACR.
Administering xCT Inhibitors Based on Circadian Clock Improves Antitumor Effects
Authors: Okazaki Fumiyasu , Matsunaga Naoya , Hamamura Kengo , Suzuki Kayoko , Nakao Takaharu , Okazaki Hiroyuki , Kutsukake Masahiko , Fukumori Shiro , Tsuji Yasuhiro , To Hideto 
Published: October 2017

Abstract
Clock genes encoding transcription factors that regulate circadian rhythms may inform chronomodulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here, we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects and that the Clock gene itself induces xCT expression and regulates its circadian rhythm. Our findings highlight the clinical potential of chronomodulated chemotherapy and the importance of xCT-mediated transcriptional regulation in the utility of such strategies. Cancer Res; 77(23); 6603–13. ©2017 AACR.
Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression
Authors: Kim Sungjin , Alsaidan Omar Awad , Goodwin Octavia , Li Qianjin , Sulejmani Essilvo , Han Zhen , Bai Aiping , Albers Thomas , Beharry Zanna , Zheng Y. George , Norris James S. , Szulc Zdzislaw M. , Bielawska Alicja , Lebedyeva Iryna , Pegan Scott D. , Cai Houjian 
Published: October 2017

Abstract
Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or posttranslational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacologic evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell-cycle progression, proliferation, and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analogue B13 as a small-molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localization to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its anti-invasive and antitumor effects against prostate cancer cells, with minimal toxic side-effects in vivo. Structural optimization based on structure–activity relationships enabled the chemical synthesis of LCL204, with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclinical proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression. Cancer Res; 77(24); 6950–62. ©2017 AACR.
Tissue Force Programs Cell Fate and Tumor Aggression
Authors: Northey Jason J. , Przybyla Laralynne , Weaver Valerie M. 
Published: October 2017

Abstract
Biomechanical and biochemical cues within a tissue collaborate across length scales to direct cell fate during development and are critical for the maintenance of tissue homeostasis. Loss of tensional homeostasis in a tissue not only accompanies malignancy but may also contribute to oncogenic transformation. High mechanical stress in solid tumors can impede drug delivery and may additionally drive tumor progression and promote metastasis. Mechanistically, biomechanical forces can drive tumor aggression by inducing a mesenchymal-like switch in transformed cells so that they attain tumor-initiating or stem-like cell properties. Given that cancer stem cells have been linked to metastasis and treatment resistance, this raises the intriguing possibility that the elevated tissue mechanics in tumors could promote their aggression by programming their phenotype toward that exhibited by a stem-like cell.
Significance: Recent findings argue that mechanical stress and elevated mechanosignaling foster malignant transformation and metastasis. Prolonged corruption of tissue tension may drive tumor aggression by altering cell fate specification. Thus, strategies that could reduce tumor mechanics might comprise effective approaches to prevent the emergence of treatment-resilient metastatic cancers. Cancer Discov; 7(11); 1224–37. ©2017 AACR.
A Blueprint to Advance Colorectal Cancer Immunotherapies
Authors: Le Dung T. , Hubbard-Lucey Vanessa M. , Morse Michael A. , Heery Christopher R. , Dwyer Andrea , Marsilje Thomas H. , Brodsky Arthur N. , Chan Emily , Deming Dustin A. , Diaz Luis A. , Fridman Wolf H. , Goldberg Richard M. , Hamilton Stanley R. , Housseau Franck , Jaffee Elizabeth M. , Kang S. Peter , Krishnamurthi Smitha S. , Lieu Christopher H. , Messersmith Wells , Sears Cynthia L. , Segal Neil H. , Yang Arvin , Moss Rebecca A. , Cha Edward , O'Donnell-Tormey Jill , Roach Nancy , Davis Anjelica Q. , McAbee Keavy , Worrall Sharyn , Benson Al B. 
Published: October 2017

AbstractImmunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability–high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942–9. ©2017 AACR.
Precision Medicine for Cardiac Resynchronization
Authors: Nassif Michael E. , Tang Yuanyuan , Cleland John G. , Abraham William T. , Linde Cecilia , Gold Michael R. , Young James B. , Daubert J. Claude , Sherfesee Lou , Schaber Dan , Tang Anthony S.L. , Jones Philip G. , Arnold Suzanne V. , Spertus John A. 
Published: October 2017

Background:
Clinical trials have established the average benefit of cardiac resynchronization therapy (CRT), but estimating benefit for individual patients remains difficult because of the heterogeneity in treatment response. Accordingly, we created a multivariable model to predict changes in quality of life (QoL) with and without CRT.

Methods and Results:

Patient-level data from 5 randomized trials comparing CRT with no CRT were used to create a prediction model of change in QoL at 3 months using a partial proportional odds model for no change, small, moderate, and large improvement, or deterioration of any magnitude. The C statistics for not worsening or obtaining at least a small, moderate, and large improvement were calculated. Among the 3614 patients, regardless of assigned treatment, 33.3% had a deterioration in QoL, 9.2% had no change, 9.2% had a small improvement, 13.5% had a moderate improvement, and the remaining 34.9% had a large improvement. Patients undergoing CRT were less likely to have a decrement in their QoL (28.2% versus 38.9%;
P
<0.001) and more likely to have a large QoL improvement (38.7% versus 30.6%;
P
<0.001). A partial proportional odds model identified baseline QoL, age, and an interaction of CRT with QRS duration as predictors of QoL benefits 3 months after randomization. C statistics of 0.65 for not worsening, 0.68 for at least a small improvement, 0.69 for at least a moderate improvement, and 0.73 for predicting a large improvement were observed.

Conclusions:
There is marked heterogeneity of treatment benefit of CRT that can be predicted based on baseline QoL, age, and QRS duration.
Effect of Elective Percutaneous Coronary Intervention on Hyperemic Absolute Coronary Blood Flow Volume and Microvascular Resistance
Authors: Kanaji Yoshihisa , Murai Tadashi , Yonetsu Taishi , Usui Eisuke , Araki Makoto , Matsuda Junji , Hoshino Masahiro , Yamaguchi Masao , Niida Takayuki , Hada Masahiro , Ichijyo Sadamitsu , Hamaya Rikuta , Kanno Yoshinori , Isobe Mitsuaki , Kakuta Tsunekazu 
Published: October 2017

Background—
The hemodynamics involved in the relationship between absolute coronary blood flow (ABF) volume and myocardial resistance (MR) are complex, and the effect of percutaneous coronary intervention (PCI) on their changes remains unclear. The aim of this study was to investigate the differences in hyperemic ABF and MR before and after elective PCI using a thermodilution method.

Methods and Results—

We investigated 28 vessels (right coronary artery, 9; left anterior descending coronary artery, 18; left circumflex coronary artery, 1) from 28 patients with stable angina pectoris undergoing elective PCI. ABF was measured pre- and post-PCI using a pressure–temperature sensor-equipped wire, based on a thermodilution method with a continuous saline infusion of 20 mL/min through a proximally located microcatheter with an end-hole in the target vessel. MR equals distal coronary perfusion pressure divided by ABF at maximal hyperemia. Conventional fractional flow reserve was also measured pre- and post-PCI. Fractional flow reserve increased significantly after PCI (from 0.70 [0.65–0.75] to 0.88 [0.85–0.95]) in all examined territories. ABF also increased significantly (from 137.8 mL/min [86.3–180.8 mL/min] to 173.3 mL/min [137.9–234.3 mL/min] ; increase: 52.8 mL/min [9.7–80.8 mL/min]) while MR decreased in 11 vessels and increased in 17. No significant relationship was detected between these increases in fractional flow reserve and ABF. Both pre- and post-PCI MR distributed in a wide range, and there was a significant relationship between pre-PCI MR and the increase in ABF (
r
=0.44;
P
=0.02) although no significant change in MR was observed between pre- and post-PCI (
P
=0.37).

Conclusions—
Direct measurement of ABF and MR using thermodilution method offers a feasible approach that could shed a light on previously unclear aspects of coronary hemodynamics.
Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts
Authors: Magnussen Christina , Niiranen Teemu J. , Ojeda Francisco M. , Gianfagna Francesco , Blankenberg Stefan , Njølstad Inger , Vartiainen Erkki , Sans Susana , Pasterkamp Gerard , Hughes Maria , Costanzo Simona , Donati Maria Benedetta , Jousilahti Pekka , Linneberg Allan , Palosaari Tarja , de Gaetano Giovanni , Bobak Martin , den Ruijter Hester M. , Mathiesen Ellisiv , Jørgensen Torben , Söderberg Stefan , Kuulasmaa Kari , Zeller Tanja , Iacoviello Licia , Salomaa Veikko , Schnabel Renate B. 
Published: October 2017

Background:
Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood.

Methods:
In N=79 793 individuals without AF diagnosis at baseline (median age, 49.6 years; age range, 24.1–97.6 years; 51.7% women) from 4 community-based European studies (FINRISK, DanMONICA, Moli-sani Northern Sweden) of the BiomarCaRE consortium (Biomarker for Cardiovascular Risk Assessment in Europe), we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years.

Results:

Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men. Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18; 95% confidence interval [CI], 1.12–1.23 in women versus 1.31; 95% CI 1.25–1.38 in men; interaction
P
value of 0.001). Total cholesterol was inversely associated with incident AF with a greater risk reduction in women (hazard ratio per SD, 0.86; 95% CI, 0.81–0.90 versus 0.92; 95% CI, 0.88–0.97 in men; interaction
P
value of 0.023). No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index.

Conclusions:
Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies.
Coastal Wind and Turbulence Observations during the Morning and Evening Transitions over Tropical Terrain
Authors: Jensen Derek D. , Price Timothy A. , Nadeau Daniel F. , Kingston Jacob , Pardyjak Eric R. 
Published: October 2017

AbstractData collected during a multiyear, wind-resource assessment over a multi-land-use coastal environment in Belize are used to study the development and decay of wind and turbulence through the morning and evening transitions. Observations were made on three tall masts, forming an inland transect of approximately 5 km. The wind distribution is found to be bimodal and governed by synoptic scales, with onshore and offshore flow regimes. The behavior between the coastal and inland sites is found to be very similar when the flow is directed offshore; for onshore flow, stark differences occur. The mean wind speed at the coastal site is approximately 20% greater than the most inland site and is nearly constant throughout the diurnal cycle. For both flow regimes, the influence of the land–sea breeze circulation is inconsequential relative to the large-scale synoptic forcing. Composite time series are used to study the evolution of sensible heat flux and turbulence kinetic energy (TKE) throughout the morning and evening transitions. The TKE budget reveals that at the coastal site mechanical production of TKE is much more important than buoyant production. This allows for the unexpected case in which TKE increases through the ET despite the decrease of buoyant TKE production. Multiresolution flux decomposition is used to further study this phenomenon as well as the evolution of the sensible heat flux at differing time scales. An idealized schematic is presented to illustrate the timing and structure of the morning and evening transitions for an inland site and a coastal site that are subjected to similar synoptic forcing.
Turbulent Flow over Steep Steady and Unsteady Waves under Strong Wind Forcing
Authors: Sullivan Peter P. , Banner Michael L. , Morison Russel P. , Peirson William L. 
Published: October 2017

AbstractTurbulent flow over strongly forced steep steady and unsteady waves is simulated using large-eddy simulation (LES) with timetand spacexvarying wave heighth(x,t) imposed as a lower boundary condition. With steady waves,h(x,t) is based on measurements of incipient and active breaking waves collected in a wind-wave flume, while a numerical wave code is used to generate an unsteady evolving wave packet (group). Highly intermittent airflow separation is found in the simulations, and the results suggest separation near a wave crest occurs prior to the onset of wave breaking. The form (pressure) drag is most sensitive to the wave slope, and the form drag can contribute as much as 74% to the total stress. Wind and scalar profiles from the LES display log-linear variations above the wave surface; the LES wind profiles are in good agreement with the measurements. The momentum roughness increases as the water surface changes from wind ripples to incipient breaking to active breaking. However, the scalar roughness decreases as the wave surface becomes rougher. This highlights major differences in momentum and scalar transport over a rough wavy surface. For a rapidly evolving, strongly forced wave group, the form drag is highly correlated with the wave slope, and intermittent separation is found early in the packet evolution when the local wave slope −∂h/∂x(x,t) ≥ 0.22. The packet root-mean-square wave slope is 0.084, but the form drag fraction is 2.4 times larger than a comparably forced steady wave. Thus, a passing wave group can induce unsteadiness in the wind stress.