bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo roles for myosin phosphatase targeting subunit‐1 phosphorylation sites T694 and T852 in bladder smooth muscle contraction
Authors: Chen Cai‐Ping , Chen Xin , Qiao Yan‐Ning , Wang Pei , He Wei‐Qi , Zhang Cheng‐Hai , Zhao Wei , Gao Yun‐Qian , Chen Chen , Tao Tao , Sun Jie , Wang Ye , Gao Ning , Kamm Kristine E. , Stull James T. , Zhu Min‐Sheng 
Published: November 2014

Key points
Force production and maintenance in smooth muscle is largely controlled by myosin regulatory light chain (RLC) phosphorylation, which relies on a balance between Ca2+/calmodulin‐dependent myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activities.
MYPT1 is the regulatory subunit of MLCP that biochemically inhibits MLCP activity via T694 or T852 phosphorylation in vitro.
Here we separately investigated the contribution of these two phosphorylation sites in bladder smooth muscles by establishing two single point mutation mouse lines, T694A and T852A, and found that phosphorylation of MYPT1 T694, but not T852, mediates force maintenance via inhibition of MLCP activity and enhancement of RLC phosphorylation in vivo.
Our findings reveal the role of MYPT1 T694/T852 phosphorylation in vivo in regulation of smooth muscle contraction.
AbstractForce production and maintenance in smooth muscle is largely controlled by different signalling modules that fine tune myosin regulatory light chain (RLC) phosphorylation, which relies on a balance between Ca2+/calmodulin‐dependent myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activities. To investigate the regulation of MLCP activity in vivo, we analysed the role of two phosphorylation sites on MYPT1 (regulatory subunit of MLCP) that biochemically inhibit MLCP activity in vitro. MYPT1 is constitutively phosphorylated at T694 by unidentified kinases in vivo, whereas the T852 site is phosphorylated by RhoA‐associated protein kinase (ROCK). We established two mouse lines with alanine substitution of T694 or T852. Isolated bladder smooth muscle from T852A mice displayed no significant changes in RLC phosphorylation or force responses, but force was inhibited with a ROCK inhibitor. In contrast, smooth muscles containing the T694A mutation showed a significant reduction of force along with reduced RLC phosphorylation. The contractile responses of T694A mutant smooth muscle were also independent of ROCK activation. Thus, phosphorylation of MYPT1 T694, but not T852, is a primary mechanism contributing to inhibition of MLCP activity and enhancement of RLC phosphorylation in vivo. The constitutive phosphorylation of MYPT1 T694 may provide a mechanism for regulating force maintenance of smooth muscle.
In the beginning: a personal reminiscence on the origin and legacy of ClC‐0, the ‘Torpedo Cl− channel’
Authors: Miller Christopher 
Published: November 2014

AbstractThis unapologetically subjective essay recalls the Torpedo Cl– channel in the years when it had neither a molecular identity nor proper name (ClC‐0), and membership in a large superfamily. I discuss the circumstances surrounding its discovery and subsequent research through the 1980s that revealed its unusual molecular architecture and other strange mechanistic characteristics.
Are interventions for low-income groups effective in changing healthy eating, physical activity and smoking behaviours? A systematic review and meta-analysis
Authors: Bull Eleanor R , Dombrowski Stephan U , McCleary Nicola , Johnston Marie 
Published: November 2014

ObjectiveTo conduct a systematic review and meta-analysis examining the effectiveness of behavioural interventions targeting diet, physical activity or smoking in low-income adults.DesignSystematic review with random effects meta-analyses. Studies before 2006 were identified from a previously published systematic review (searching 1995–2006) with similar but broader inclusion criteria (including non-randomised controlled trials (RCTs)). Studies from 2006 to 2014 were identified from eight electronic databases using a similar search strategy.Data sourcesMEDLINE, EMBASE, PsycINFO, ASSIA, CINAHL, Cochrane Controlled Trials, Cochrane Systematic Review and DARE.Eligibility criteria for selecting studiesRCTs and cluster RCTs published from 1995 to 2014; interventions targeting dietary, physical activity and smoking; low-income adults; reporting of behavioural outcomes.Main outcome measuresDietary, physical activity and smoking cessation behaviours.Results35 studies containing 45 interventions with 17 000 participants met inclusion criteria. At postintervention, effects were positive but small for diet (standardised mean difference (SMD) 0.22, 95% CI 0.14 to 0.29), physical activity (SMD 0.21, 95% CI 0.06 to 0.36) and smoking (relative risk (RR) of 1.59, 95% CI 1.34 to 1.89). Studies reporting follow-up results suggested that effects were maintained over time for diet (SMD 0.16, 95% CI 0.08 to 0.25) but not physical activity (SMD 0.17, 95% CI −0.02 to 0.37) or smoking (RR 1.11, 95% CI 0.93 to 1.34).ConclusionsBehaviour change interventions for low-income groups had small positive effects on healthy eating, physical activity and smoking. Further work is needed to improve the effectiveness of behaviour change interventions for deprived populations.
The Safety Tips for ATV Riders (STARs) programme: short-term impact of a school-based educational intervention
Authors: Jennissen Charles A , Peck Jeffrey , Wetjen Kristel , Hoogerwerf Pam , Harland Karisa K , Denning Gerene M 
Published: November 2014

BackgroundSince 1985, one-third of all US all-terrain vehicle (ATV)-related injuries and one-quarter of deaths involved victims <16 years of age. ATV safety education of youth could help reduce these tragedies.ObjectivesTo assess the efficacy of theSafetyTips forATVRiders(STARs) school-based programme targeting adolescents.MethodsA survey was anonymously administered before and after the programme to determine demographics, knowledge and reported likelihood of using the information learned.ResultsOver 4600 students in 30 Iowa schools participated from November 2010 to April 2013. Initially, 52% knew most ATVs are designed for one rider, 25% knew the recommended vehicle size for their age range and 42% knew riding on Iowa's roads was legal only for agricultural purposes. After the programme, this increased to 92%, 82% and 76%, respectively (p<0.0001 in each case), with 61% of students correct on all three. Better preintervention scores were associated with being males, higher riding frequency and being from isolated rural communities. After the programme, 48% and 32% said they were likely/very likely versus unlikely/very unlikely to use the safety information learned, respectively; younger students, females and infrequent riders reported higher likelihoods.ConclusionsSTARs increased short-term ATV safety knowledge and almost half the participants reported they would use the safety information presented. Males and frequent riders seemed more resistant, but some groups that may be more vulnerable to potential ATV crash and injury appeared amenable to the training with higher increases in postprogramme scores and greater intention of improving safety behaviours.
“There are bugs in condoms”: Tanzanian close-to-community providers' ability to offer effective adolescent reproductive health services
Authors: Dusabe John , Mchome Zaina , Nnko Soori , Changalucha John , Obasi Angela 
Published: November 2014

ObjectivesYoung people in Tanzania are known to access reproductive health services from a range of close-to-community providers outside formal health settings such as drug stores, village AIDS committees, traditional healers and traditional birth attendants (TBAs). However, questions remain about the quality of services such agents provide. This study investigated their capacity to provide adolescent reproductive health (ARH) services and explored their readiness and ability to integrate with the mainstream health sector through community referral interventions.MethodsThirty-five focus group discussions exploring close-to-community provider experiences and attitudes to ARH service provision were carried out in two districts in Northern Tanzania. Discussions were conducted in Kiswahili, digitally recorded, verbatim-transcribed, translated and back-translated from Swahili to English. A thematic analysis was conducted using NVivo 9.ResultsThe major close-to-community cadres providing reproductive health services were drug stores, traditional healers, TBAs and village health workers. They reported being the first port of call for adolescents seeking reproductive health services, but their knowledge of ARH needs was poor. They had negative attitudes to, and lacked the necessary resources for, the provision of such services for adolescents. Some were particularly unwilling to provide condom services and were prejudiced against adolescents using them. There was poor integration between the close-to-community providers and the formal health sector, further limiting their ability to provide adequate services.ConclusionsAlthough close-to-community providers are considered a key resource in the community, most have limited capacity to provide ARH services. Without capacity-building investments such as training and cooperation with the mainstream health sector, their contribution to positive reproductive health outcomes is limited, or could indeed lead to adverse outcomes.
A meta-analysis of prospective randomized controlled trials evaluating endovascular therapies for acute ischemic stroke
Authors: Fargen Kyle M , Neal Dan , Fiorella David J , Turk Aquilla S , Froehler Michael , Mocco J 
Published: November 2014

IntroductionA recent randomized controlled trial (RCT), the Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN), demonstrated better outcomes with endovascular treatment compared with medical therapy for acute ischemic stroke (AIS). However, previous trials have provided mixed results regarding the efficacy of endovascular treatment for AIS. A meta-analysis of all available trial data was performed to summarize the available evidence.MethodsA literature search was performed to identify all prospective RCTs comparing endovascular therapies with medical management for AIS. Two datasets were created: (1) all patients randomized after confirmation of large vessel occlusion (LVO) (consistent with the contemporary standard of practice at the majority of centers); and (2) all patients with outcome data who underwent randomization regardless of qualifying vascular imaging. The pre-specified primary outcome measure was modified Rankin Scale score of 0–2 at 90 days. A fixed-effect model was used to determine significance.ResultsFive prospective RCTs comparing endovascular therapies with medical management were included in dataset 1 (1183 patients) and six were included in dataset 2 (1903 total patients). Endovascular therapies were associated with significantly improved outcomes compared with medical management (OR 1.67, 95% CI 1.29 to 1.16, p=0.0001) for patients with LVO (dataset 1). This benefit persisted when patients from all six RCTs were included, even in the absence of confirmation of LVO (OR 1.27, 95% CI 1.05 to 1.54, p=0.019; dataset 2).ConclusionsA meta-analysis of prospective RCTs comparing endovascular therapies with medical management demonstrates superior outcomes in patients randomized to endovascular therapy.
Comparative efficacy and safety of mavacoxib and carprofen in the treatment of canine osteoarthritis
Authors: Payne‐Johnson M , Becskei C , Chaudhry Y , Stegemann M R 
Published: November 2014

A multi‐site, masked, randomised parallel group study employing a double dummy treatment design was performed in canine veterinary patients to determine the comparative efficacy and safety of mavacoxib and carprofen in the treatment of pain and inflammation associated with osteoarthritis for a period of 134 days. Treatments were administered according to their respective summaries of product characteristics. Of 139 dogs screened, 124 were suitable for study participation: 62 of which were dosed with mavacoxib and 62 with carprofen. Both treatments resulted in a very similar pattern of considerable improvement as indicated in all parameters assessed by both owner and veterinarian. The primary efficacy endpoint ‘overall improvement’ was a composite score of owner assessments after approximately six weeks of treatment. Both drugs were remarkably effective, with 57/61 (93.4 per cent) of mavacoxib‐treated dogs and 49/55 (89.1 per cent) of carprofen‐treated dogs demonstrating overall improvement and with mavacoxib's efficacy being non‐inferior to carprofen. The treatments had a similar safety profile as evidenced by documented adverse events and summaries of clinical pathology parameters. The positive clinical response to treatment along with the safety and dosing regimen of mavacoxib makes it an attractive therapy for canine osteoarthritis.
Intramuscular administration of alfaxalone for sedation in rabbits
Authors: Huynh Minh , Poumeyrol Séverine , Pignon Charly , Le Teuff Gwenaël , Zilberstein Luca 
Published: November 2014

Alfaxalone is a neuroactive steroid derivative of pregnanedione that was recently reintroduced to the market for use as an induction agent in small animal anaesthesia. The aim of this study was to determine an intramuscular alfaxalone dose for safe immobilisation. Ten healthy New Zealand white rabbits were used to evaluate a single intramuscular injection of alfaxalone. The design of the study was a three‐way, complete block, cross‐over trial to compare the effect of alfaxalone at three doses (4, 6 and 8 mg). The mean duration of the effect for the 4, 6 and 8 mg/kg doses was, respectively, 36.9 (95% CI (31.6 to 42.3)), 51.8 (46.4 to 57.2) and 58.4 (52.8 to 63.9) minutes. The loss of the righting reflex was achieved after 3.1 (2.5 to 3.8), 2.4 (1.7 to 3.1) and 2.3 (1.6 to 2.9) minutes, respectively. The mean duration of the effect for the 6 and 8 mg doses was significantly higher than for the 4 mg dose (with estimated differences of 14.8 95% CI (8.8 to 20.8) minutes and 21.4 (15.3 to 27.6) minutes, respectively). No significant dose effect was observed before the loss of the righting reflex (P=0.14). Ear pinching and limb withdrawal were elicited in all groups at every dose. Doses of 4 or 6 mg/kg could be recommended; higher doses do not provide clinical benefits and can be associated with anaesthetic complication.
Activin Upregulation by NF-κB Is Required to Maintain Mesenchymal Features of Cancer Stem–like Cells in Non–Small Cell Lung Cancer
Authors: Wamsley J. Jacob , Kumar Manish , Allison David F. , Clift Sheena H. , Holzknecht Caitlyn M. , Szymura Szymon J. , Hoang Stephen A. , Xu Xiaojiang , Moskaluk Christopher A. , Jones David R. , Bekiranov Stefan , Mayo Marty W. 
Published: November 2014

Abstract
Soluble growth factors and cytokines within the tumor microenvironment aid in the induction of the epithelial-to-mesenchymal transition (EMT). Although EMT promotes the development of cancer-initiating cells (CIC), cellular mechanisms by which cancer cells maintain mesenchymal phenotypes remain poorly understood. Work presented here indicates that induction of EMT stimulates non–small cell lung cancer (NSCLC) to secrete soluble factors that function in an autocrine fashion. Using gene expression profiling of all annotated and predicted secreted gene products, we find that NF-κB activity is required to upregulate INHBA/Activin, a morphogen in the TGFβ superfamily. INHBA is capable of inducing and maintaining mesenchymal phenotypes, including the expression of EMT master-switch regulators and self-renewal factors that sustain CIC phenotypes and promote lung metastasis. Our work demonstrates that INHBA mRNA and protein expression are commonly elevated in primary human NSCLC and provide evidence that INHBA is a critical autocrine factor that maintains mesenchymal properties of CICs to promote metastasis in NSCLC. Cancer Res; 75(2); 426–35. ©2014 AACR.
A Urokinase Receptor–Bim Signaling Axis Emerges during EGFR Inhibitor Resistance in Mutant EGFR Glioblastoma
Authors: Wykosky Jill , Hu Jingjing , Gomez German G. , Taylor Tiffany , Villa Genaro R. , Pizzo Donald , VandenBerg Scott R. , Thorne Amy Haseley , Chen Clark C. , Mischel Paul S. , Gonias Steven L. , Cavenee Webster K. , Furnari Frank B. 
Published: November 2014

Abstract
EGFR is the most common genetically altered oncogene in glioblastoma (GBM), but small-molecule EGFR tyrosine kinase inhibitors (TKI) have failed to yield durable clinical benefit. Here, we show that in two novel model systems of acquired resistance to EGFR TKIs, elevated expression of urokinase plasminogen activator (uPA) drives signaling through the MAPK pathway, which results in suppression of the proapoptotic BCL2-family member protein BIM (BCL2L11). In patient-derived GBM cells and genetic GBM models, uPA is shown to suppress BIM levels through ERK1/2 phosphorylation, which can be reversed by siRNA-mediated knockdown of uPA. TKI-resistant GBMs are resensitized to EGFR TKIs by pharmacologic inhibition of MEK or a BH3 mimetic drug to replace BIM function. A link between the uPA–uPAR–ERK1/2 pathway and BIM has not been previously demonstrated in GBM, and involvement of this signaling axis in resistance provides rationale for a new strategy to target EGFR TKI-resistant GBM. Cancer Res; 75(2); 394–404. ©2014 AACR.
Akt Inhibition Enhances Expansion of Potent Tumor-Specific Lymphocytes with Memory Cell Characteristics
Authors: Crompton Joseph G. , Sukumar Madhusudhanan , Roychoudhuri Rahul , Clever David , Gros Alena , Eil Robert L. , Tran Eric , Hanada Ken-ichi , Yu Zhiya , Palmer Douglas C. , Kerkar Sid P. , Michalek Ryan D. , Upham Trevor , Leonardi Anthony , Acquavella Nicolas , Wang Ena , Marincola Francesco M. , Gattinoni Luca , Muranski Pawel , Sundrud Mark S. , Klebanoff Christopher A. , Rosenberg Steven A. , Fearon Douglas T. , Restifo Nicholas P. 
Published: November 2014

Abstract
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. Cancer Res; 75(2); 296–305. ©2014 AACR.
Effects of Tailored Risk Communications for Skin Cancer Prevention and Detection: The PennSCAPE Randomized Trial
Authors: Glanz Karen , Volpicelli Kathryn , Jepson Christopher , Ming Michael E. , Schuchter Lynn M. , Armstrong Katrina 
Published: November 2014

Abstract
Background: Prevention and early detection measures for melanoma, such as sun avoidance and skin examinations, are important, but are practiced inconsistently. In this replication of the Project SCAPE trial, we sought to determine whether tailored print materials were more effective at improving adherence than generic print materials for patients at increased risk of skin cancer.
Methods: Participants were randomized to receive personalized mailed communications about their skin cancer risk and recommended sun protection, or generic mailings. Participants were Caucasian adults, at moderate or high risk for skin cancer, recruited in outpatient primary care. The main outcomes were overall sun protection behaviors and specific protective behaviors including use of sunscreen, shirt, hat, sunglasses, shade, and sun avoidance; recent sunburns; and skin self-examination and provider skin examination.
Results: One hundred ninety-two (93.2%) subjects completed the study. Six outcome variables showed significant intervention condition effects in mixed effects models: overall sun protection behavior (P = 0.025); sunscreen use (P = 0.026); use of sunglasses (P = 0.011); sunburns in the past three months (P = 0.033); recency of last skin self-exam (P = 0.017); and frequency of skin exams by health care provider (P = 0.016).
Conclusions: Relative to generic communications, tailored risk communications resulted in improved adherence to six skin cancer protective behaviors, including a composite sun protection behavior measure, sunburns, and health care provider skin examinations.
Impact: Tailored interventions can be more effective in improving patient prevention behaviors than nontailored, generic information for patients at moderate to high risk of skin cancer. Cancer Epidemiol Biomarkers Prev; 24(2); 415–21. ©2014 AACR.
Offering Self-Sampling to Non-Attendees of Organized Primary HPV Screening: When Do Harms Outweigh the Benefits?
Authors: Rozemeijer Kirsten , de Kok Inge M.C.M , Naber Steffie K. , van Kemenade Folkert J. , Penning Corine , van Rosmalen Joost , van Ballegooijen Marjolein 
Published: November 2014

Abstract
Background: Human papillomavirus (HPV) self-sampling might be a promising tool to increase effectiveness of primary HPV screening programs when offered to non-attendees. However, effectiveness could decrease if regular attendees “switch” to self-sampling, because self-sampling test characteristics may be inferior. We examined under which conditions the harms would outweigh the benefits.
Methods: The MISCAN-cervix model was used to estimate quality-adjusted life years (QALY) gained and costs of offering HPV self-sampling to non-attendees. We varied the relative CIN2+ sensitivity and specificity (self-sampling vs. regular sampling), extra attendance, risk of extra attendees, and the switching percentage.
Results: Without switching, offering self-sampling is (cost-)effective under every studied condition. If the attendance due to self-sampling increases by ≥6 percentage points, higher primary background risk women (unscreened women who will never attend regular screening) attend and the relative CIN2+ sensitivity and specificity are ≥0.95; it is (cost-)effective to offer self-sampling to non-attendees, even if all regular attendees switch. If the relative sensitivity decreases to 0.90 combined with either a 3 percentage points extra attendance or the absence of higher primary background risk women, QALYs are lost when more than 30% to 20% of the regular attendees switch.
Conclusions: Offering self-sampling will gain health effects if the relative CIN2+ sensitivity is ≥0.95, unscreened attendees are recruited, and the total attendance increases by ≥6 percentage points. Otherwise, switching of regular attendees may decrease the total effectiveness of the program.
Impact: Self-sampling needs to be implemented with great care and advantages of office-based sampling need to be emphasized to prevent switching. Cancer Epidemiol Biomarkers Prev; 24(5); 773–82. ©2014 AACR.
See related commentary by Arbyn and Castle, p. 769
Steroid Sidestep: Evading Androgen Ablation by Abiraterone
Authors: Sharifi Nima 
Published: November 2014

Abstract
Tumor mechanisms of abiraterone resistance in clinical prostate cancer are not well defined. Chen and colleagues report that a T878A androgen receptor mutation occurs in a subset of patients progressing while receiving abiraterone, suggesting that this may be a therapeutically exploitable mechanism of abiraterone resistance in castration-resistant prostate cancer. Clin Cancer Res; 21(6); 1240–2. ©2014 AACR.
See related article by Chen et al., p. 1273