bluuebunny/crossref_metadata_2025 huggingface dataset:
Pancreatic Lipase Immunoreactivity in Serum of Dogs with Diabetic Ketoacidosis
Authors: Bolton T.A. , Cook A. , Steiner J.M. , Fosgate G.T.
Published: May 2016

Background

Diabetic ketoacidosis (DKA) is a relatively common endocrine disorder in dogs and is routinely associated with concurrent pancreatic injury.

Objectives

The aims of this study were to determine the prevalence of pancreatic injury in dogs withDKAbased on measurement of pancreatic lipase immunoreactivity in serum (PLI); compare demographic, clinicopathologic, and ultrasonographic findings in dogs with and without evidence of concurrent pancreatic injury; determine the impact of pancreatic injury on duration of hospitalization and short‐term outcome.

Animals

One hundred and nineteen dogs with DKA with or without concurrent pancreatic injury.

Methods

Retrospective study. Dogs withDKAwere divided into three groups on the basis ofPLIresults: positive for pancreatic injury (PLIpos), negative for pancreatic injury (PLIneg), and not tested (PLIna). Demographics, clinicopathologic test results, findings on abdominal ultrasonography (AUS), duration of hospitalization, and short‐term outcome were compared between the three groups.

Results

Based on serumPLIactivity, 45 dogs (73%) withDKAhad evidence of concurrent pancreatic injury. Median total carbon dioxide was significantly lower in thePLIposdogs compared to thePLInegdogs. There was fair agreement (κ= 0.26) between serumPLIactivity andAUS. Evidence of pancreatic injury was not associated with significantly longer periods of hospitalization (PLIposmedian 6 days, range 4–7 days,PLInegmedian 4 days, range 3–6 days) and did not influence short‐term outcome (PLIposfailure to survive to discharge 11/45, 24%,PLInegfailure to survive to discharge 2/17, 12%).

Clinical Importance

Concurrent pancreatic injury is common in dogs withDKA, but did not affect prognosis in this population of dogs.
The Effects of Cyclosporine and Aspirin on Platelet Function in Normal Dogs
Authors: Thomason J. , Archer T. , Wills R. , Press S. , Mackin A.
Published: May 2016

Background

Cyclosporine increases thromboxane synthesis in dogs, potentially increasing the thrombogenic properties of platelets.

Hypothesis/Objectives

Our hypothesis was that the concurrent administration of low‐dose aspirin and cyclosporine would inhibit cyclosporine‐associated thromboxane synthesis without altering the antiplatelet effects of aspirin. The objective was to determine the effects of cyclosporine and aspirin on primary hemostasis.

Animals

Seven healthy dogs.

Methods

A randomized, crossover study utilized turbidimetric aggregometry and a platelet function analyzer to evaluate platelet function during the administration of low‐dose aspirin (1 mg/kg PO q24h), high‐dose aspirin (10 mg/kg PO q12h), cyclosporine (10 mg/kg PO q12h), and combined low‐dose aspirin and cyclosporine. The urine 11‐dehydro‐thromboxane‐B2 (11‐dTXB2)‐to‐creatinine ratio also was determined.

Results

On days 3 and 7 of administration, there was no difference in the aggregometry amplitude or the platelet function analyzer closure time between the low‐dose aspirin group and the combined low‐dose aspirin and cyclosporine group. On day 7, there was a significant difference in amplitude and closure time between the cyclosporine group and the combined low‐dose aspirin and cyclosporine group. High‐dose aspirin consistently inhibited platelet function. On both days, there was a significant difference in the urinary 11‐dTXB2‐to‐creatinine ratio between the cyclosporine group and the combined low‐dose aspirin and cyclosporine group. There was no difference in the urinary 11‐dTXB2‐to‐creatinine ratio among the low‐dose aspirin, high‐dose aspirin, and combined low‐dose aspirin and cyclosporine groups.

Conclusions and Clinical Importance

Low‐dose aspirin inhibits cyclosporine‐induced thromboxane synthesis, and concurrent use of these medications does not alter the antiplatelet effects of aspirin.
Dynamic metabolic and transcriptomic profiling of methyl jasmonate‐treated hairy roots reveals synthetic characters and regulators of lignan biosynthesis in Isatis indigotica Fort
Authors: Zhang Lei , Chen Junfeng , Zhou Xun , Chen Xiaofei , Li Qing , Tan Hexin , Dong Xin , Xiao Ying , Chen Langdong , Chen Wansheng
Published: May 2016

A molecular description of lignan biosynthesis in Isatis indigotica displaying its synthetic characteristics and regulatory mechanism is of great importance for the improvement of the production of this class of active compounds. To discover the potential key catalytic steps and regulatory genes, I. indigotica hairy roots elicited by methyl jasmonate (MeJA) were used as a source of systematic variation for exploring the metabolic/transcriptional changes and candidate genes that might play key roles in lignan biosynthesis. The reprogramming modulated by MeJA was classified into three distinct phases, referred to as signal responding, transcriptional activation of metabolic pathways and accumulation of metabolites. Candidate genes were pooled according to the three phases and applied to co‐expression network analysis. In total, 17 genes were identified as hub genes. 4CL3 was selected to validate its impact on lignan biosynthesis. RNAi of 4CL3 resulted in a significant reduction in lignan production. Taken together with its catalytic property, a major route of lignan biosynthesis in I. indigotica was highlighted, which was catalysed by 4CL3 via the esterization of caffeic acid. In conclusion, this study provides new insights into lignan biosynthesis as well as potential targets for metabolic engineering in I. indigotica.
Computational identification of genes modulating stem height–diameter allometry
Authors: Jiang Libo , Ye Meixia , Zhu Sheng , Zhai Yi , Xu Meng , Huang Minren , Wu Rongling
Published: May 2016

The developmental variation in stem height with respect to stem diameter is related to a broad range of ecological and evolutionary phenomena in trees, but the underlying genetic basis of this variation remains elusive. We implement a dynamic statistical model, functional mapping, to formulate a general procedure for the computational identification of quantitative trait loci (QTLs) that control stem height–diameter allometry during development. Functional mapping integrates the biological principles underlying trait formation and development into the association analysis of DNA genotype and endpoint phenotype, thus providing an incentive for understanding the mechanistic interplay between genes and development. Built on the basic tenet of functional mapping, we explore two core ecological scenarios of how stem height and stem diameter covary in response to environmental stimuli: (i) trees pioneer sunlit space by allocating more growth to stem height than diameter and (ii) trees maintain their competitive advantage through an inverse pattern. The model is equipped to characterize ‘pioneering’ QTLs (piQTLs) and ‘maintaining’ QTLs (miQTLs) which modulate these two ecological scenarios, respectively. In a practical application to a mapping population of full‐sib hybrids derived from two Populus species, the model has well proven its versatility by identifying several piQTLs that promote height growth at a cost of diameter growth and several miQTLs that benefit radial growth at a cost of height growth. Judicious application of functional mapping may lead to improved strategies for studying the genetic control of the formation mechanisms underlying trade‐offs among quantities of assimilates allocated to different growth parts.
Early Secreted Antigenic Target of 6 kDa of Mycobacterium tuberculosis Stimulates Macrophage Chemoattractant Protein‐1 Production by Macrophages and Its Regulation by p38 Mitogen‐Activated Protein Kinases and Interleukin‐4
Authors: Ma J. , Jung B‐G. , Yi N. , Samten B.
Published: May 2016

Early secreted antigenic target of 6 kDa (ESAT‐6), the major virulence factor of Mycobacterium tuberculosis, affects host immunity and the formation of granulomas likely through inflammatory cytokines. To understand its role in this regard further, we investigated the effect of ESAT‐6 on macrophages by determining the production of macrophage chemoattractant protein (MCP)‐1, a major chemokine associated with tuberculosis pathogenesis, by murine bone marrow‐derived macrophages (BMDMs) and its regulation by protein kinases and cytokines. The results revealed that ESAT‐6, but not Ag85A and culture filtrate protein 10 kDa (CFP10), induced MCP‐1 production by BMDMs dose and time dependently. Inhibition of p38 but not other mitogen‐activated protein kinases (MAPK) and PI3K further enhanced ESAT‐6‐induced MCP‐1 production by BMDMs. Inhibition of p38 MAPK enhanced ESAT‐6‐induced MCP‐1 mRNA accumulation without affecting mRNA stability. ESAT‐6 also induced TNF‐α from BMDMs and MCP‐1 from mouse lung epithelial cells, and these were suppressed by p38 MAPK inhibition, implying cytokine‐ and cell‐specific effect of p38 MAPK inhibition on ESAT‐6‐induced MCP‐1 by macrophages. Pretreatment of BMDMs with IL‐4, but not other cytokines (IL‐2, IL‐10, TNF‐α, IFN‐γ and IL‐1α) further elevated ESAT‐6‐stimulated MCP‐1 production although IL‐4 did not induce MCP‐1 without ESAT‐6. Both p38 MAPK inhibitor and IL‐4 did not show additive effect on ESAT‐6‐induced MCP‐1 protein level despite such effect on MCP‐1 mRNA level was evident. In conclusion, these results indicate a specific role for both p38 MAPK and IL‐4 in ESAT‐6‐induced MCP‐1 production by macrophages and suggest a pathway with significance in tuberculosis pathogenesis.
The earliest herbivorous marine reptile and its remarkable jaw apparatus
Authors: Chun Li , Rieppel Olivier , Long Cheng , Fraser Nicholas C.
Published: May 2016

The earliest known herbivorous marine reptile is described from the Middle Triassic of southern China.
Fermented Milk Containing Lactobacillus casei Strain Shirota Preserves the Diversity of the Gut Microbiota and Relieves Abdominal Dysfunction in Healthy Medical Students Exposed to Academic Stress
Authors: Kato-Kataoka Akito , Nishida Kensei , Takada Mai , Kawai Mitsuhisa , Kikuchi-Hayakawa Hiroko , Suda Kazunori , Ishikawa Hiroshi , Gondo Yusuke , Shimizu Kensuke , Matsuki Takahiro , Kushiro Akira , Hoshi Ryoutaro , Watanabe Osamu , Igarashi Tomoki , Miyazaki Kouji , Kuwano Yuki , Rokutan Kazuhito
Published: May 2016

Stress-induced abdominal dysfunction is an attractive target for probiotics. To investigate the effects of the probiotic
Lactobacillus casei
strain Shirota on abdominal dysfunction, a double-blind, placebo-controlled trial was conducted with healthy medical students undertaking an authorized nationwide examination for academic advancement. For 8 weeks, until the day before the examination, 23 and 24 subjects consumed an
L. casei
strain Shirota-fermented milk and a placebo milk daily, respectively. In addition to assessments of abdominal symptoms, psychophysical state, and salivary stress markers, gene expression changes in peripheral blood leukocytes and composition of the gut microbiota were analyzed using DNA microarray analysis and 16S rRNA gene amplicon sequence analysis, respectively, before and after the intervention. Stress-induced increases in a visual analog scale measuring feelings of stress, the total score of abdominal dysfunction, and the number of genes with changes in expression of more than 2-fold in leukocytes were significantly suppressed in the
L. casei
strain Shirota group compared with those in the placebo group. A significant increase in salivary cortisol levels before the examination was observed only in the placebo group. The administration of
L. casei
strain Shirota, but not placebo, significantly reduced gastrointestinal symptoms. Moreover, 16S rRNA gene amplicon sequencing demonstrated that the
L. casei
strain Shirota group had significantly higher numbers of species, a marker of the alpha-diversity index, in their gut microbiota and a significantly lower percentage of
Bacteroidaceae
than the placebo group. Our findings indicate that the daily consumption of probiotics, such as
L. casei
strain Shirota, preserves the diversity of the gut microbiota and may relieve stress-associated responses of abdominal dysfunction in healthy subjects exposed to stressful situations.

IMPORTANCE
A novel clinical trial was conducted with healthy medical students under examination stress conditions. It was demonstrated that the daily consumption of lactic acid bacteria provided health benefits to prevent the onset of stress-associated abdominal symptoms and a good change of gut microbiota in healthy medical students.
Visual dysfunction and its correlation with retinal changes in patients with Parkinson's disease: an observational cross-sectional study
Authors: Polo V , Satue M , Rodrigo M J , Otin S , Alarcia R , Bambo M P , Fuertes M I , Larrosa J M , Pablo L E , Garcia-Martin E
Published: May 2016

Objectives

To evaluate visual dysfunction and its correlation with structural changes in the retina in patients with Parkinson's disease (PD).

Methods

Patients with PD (n=37) and controls (n=37) were included in an observational cross-sectional study, and underwent visual acuity (VA), colour vision (using the Farnsworth and Lanthony desaturated D15 colour tests) and contrast sensitivity vision (CSV; using the Pelli-Robson chart and CSV 1000E test) evaluation to measure visual dysfunction. Structural measurements of the retinal nerve fibre layer (RNFL), and macular and ganglion cell layer (GCL) thicknesses, were obtained using spectral domain optical coherence tomography (SD-OCT). Comparison of obtained data, and correlation analysis between functional and structural results were performed.

Results

VA (in all different contrast levels) and all CSV spatial frequencies were significantly worse in patients with PD than in controls. Colour vision was significantly affected based on the Lanthony colour test. Significant GCL loss was observed in the minimum GCL+inner plexiform layer. A clear tendency towards a reduction in several macular sectors (central, outer inferior, outer temporal and superior (inner and outer)) and in the temporal quadrant of the RNFL thickness was observed, although the difference was not significant. CSV was the functional parameter most strongly correlated with structural measurements in PD. Colour vision was associated with most GCL measurements. Macular thickness was strongly correlated with macular volume and functional parameters (r>0.70, p<0.05).

Conclusions

Patients with PD had visual dysfunction that correlated with structural changes evaluated by SD-OCT. GCL measurements may be reliable indicators of visual impairment in patients with PD.
Examining the quality of evidence to support the effectiveness of interventions: an analysis of systematic reviews
Authors: Kane Robert L , Butler Mary , Ng Weiwen
Published: May 2016

Objective

This analysis examines the quality of evidence (QOE) for 1472 outcomes linked to interventions where the QOE was rated in 42 systematic reviews of randomised clinical trials and/or observational studies across different topics.

Setting

Not applicable.

Participants

76 systematic reviews.

Primary and secondary outcome measures

Strength of evidence ratings by initial reviewers.

Results

Among 76 systematic reviews, QOE ratings were available for only 42, netting 1472 comparisons. Of these, 57% included observational studies; 4% were rated as high and 12% as moderate; the rest were low or insufficient. The ratings varied by topic: 74% of the surgical study pairs were rated as low or insufficient, compared with 82% of pharmaceuticals and 86% of device studies, 88% of organisational, 91% of lifestyle studies, and 94% of psychosocial interventions.

Conclusions

We are some distance from being able to claim evidence-based practice. The press for individual-level data will make this challenge even harder.
Systematic review of prognostic models for recurrent venous thromboembolism (VTE) post-treatment of first unprovoked VTE
Authors: Ensor Joie , Riley Richard D , Moore David , Snell Kym I E , Bayliss Susan , Fitzmaurice David
Published: May 2016

Objectives

To review studies developing or validating a prognostic model for individual venous thromboembolism (VTE) recurrence risk following cessation of therapy for a first unprovoked VTE. Prediction of recurrence risk is crucial to informing patient prognosis and treatment decisions. The review aims to determine whether reliable prognostic models exist and, if not, what further research is needed within the field.

Design

Bibliographic databases (including MEDLINE, EMBASE and the Cochrane Library) were searched using index terms relating to the clinical field and prognosis. Screening of titles, abstracts and subsequently full texts was conducted by 2 reviewers independently using predefined criteria. Quality assessment and critical appraisal of included full texts was based on an early version of the PROBAST (Prediction study Risk Of Bias Assessment Tool) for risk of bias and applicability in prognostic model studies.

Setting

Studies in any setting were included.

Primary and secondary outcome measures

The primary outcome for the review was the predictive accuracy of identified prognostic models in relation to VTE recurrence risk.

Results

3 unique prognostic models were identified including the HERDOO2 score, Vienna prediction model and DASH score. Quality assessment highlighted the Vienna, and DASH models were developed with generally strong methodology, but the HERDOO2 model had many methodological concerns. Further, all models were considered at least at moderate risk of bias, primarily due to the need for further external validation before use in practice.

Conclusions

Although the Vienna model shows the most promise (based on strong development methodology, applicability and having some external validation), none of the models can be considered ready for use until further, external and robust validation is performed in new data. Any new models should consider the inclusion of predictors found to be consistently important in existing models (sex, site of index event, D-dimer), and take heed of several methodological issues identified through this review.

PROSPERO registration number

CRD42013003494.
Management of problematic behaviours among individuals on long-term opioid therapy: protocol for a Delphi study
Authors: Merlin Jessica S , Young Sarah R , Azari Soraya , Becker William C , Liebschutz Jane M , Pomeranz Jamie , Roy Payel , Saini Shalini , Starrels Joanna L , Edelman E Jennifer
Published: May 2016

Introduction

Given the sharp rise in opioid prescribing and heightened recognition of opioid addiction and overdose, opioid safety has become a priority. Clinical guidelines on long-term opioid therapy (LTOT) for chronic pain consistently recommend routine monitoring and screening for problematic behaviours. Yet, there is no consensus definition regarding what constitutes a problematic behaviour, and recommendations for appropriate management to inform front-line providers, researchers and policymakers are lacking. This creates a barrier to effective guideline implementation. Thus, our objective is to present the protocol for a Delphi study designed to: (1) elicit expert opinion to identify the most important problematic behaviours seen in clinical practice and (2) develop consensus on how these behaviours should be managed in the context of routine clinical care.

Methods/analysis

We will include clinical experts, defined as individuals who provide direct patient care to adults with chronic pain who are on LTOT in an ambulatory setting, and for whom opioid prescribing for chronic non-malignant pain is an area of expertise. The Delphi study will be conducted online in 4 consecutive rounds. Participants will be asked to list problematic behaviours and identify which behaviours are most common and challenging. They will then describe how they would manage the most frequently occurring common and challenging behaviours, rating the importance of each management strategy. Qualitative analysis will be used to categorise behaviours and management strategies, and consensus will be based on a definition established a priori.

Ethics/dissemination

This study has been approved by the Institutional Review Board (IRB) of the University of Alabama at Birmingham (UAB). This study will generate Delphi-based expert consensus on the management of problematic behaviours that arise in individuals on LTOT, which we will publish and disseminate to appropriate professional societies. Ultimately, our findings will provide guidance to front-line providers, researchers and policymakers.
Are self-reported neighbourhood characteristics associated with onset of functional limitations in older adults with or without memory impairment?
Authors: Nguyen Thu T , Rist Pamela M , Glymour M Maria
Published: May 2016

Background

Neighbourhood resources may preserve functional independence in older adults, but little is known about whether benefits differ for individuals with normal and impaired memory. We evaluated the extent to which neighbourhood context was related to onset of instrumental and basic activities of daily living (I/ADL) limitations and whether relationships were modified by memory impairment.

Methods

Health and Retirement Study participants 50+ years of age without baseline I/ADL limitations (n=8726 for IADL and n=8345 for ADL models) were interviewed biennially for up to 8 years. Self-reported neighbourhood characteristics were scaled from 0 (worst) to 1 (best). Memory, assessed by direct and proxy cognitive assessments, was dichotomised at the 20th centile. We used pooled logistic regression models, adjusted for demographics and individual characteristics.

Results

Low neighbourhood physical disorder (OR=0.51 (95% CI: 0.37 to 0.69)), high social cohesion (OR=0.46 (0.34 to 0.62)), and high safety (OR=0.59 (0.46 to 0.76)) were associated with reduced incidence of IADL limitations. These neighbourhood characteristics were also associated with lower incidence of ADL limitations (disorder OR=0.59 (0.43 to 0.81)); social cohesion OR=0.60 (0.45 to 0.81)); safety OR=0.74 (0.58 to 0.93)). High social ties were not related to ADLs (OR=1.01(0.80 to 1.28)) or IADLs (OR=0.93(0.74 to 1.17)). The benefits of these neighbourhood characteristics for ADLs were similar among those with and without memory impairment but primarily observed among those without memory impairment for IADLs.

Conclusions

Older adults living in neighbourhoods with low physical disorder, high social cohesion and high safety experience lower incidence of IADL and ADL limitations. Memory status modified the estimated effects of neighbourhood characteristics on IADL but not ADL limitations.
Communication in palliative care: talking about the end of life, before the end of life
Authors: Brighton Lisa Jane , Bristowe Katherine
Published: May 2016

Increasing evidence demonstrates the benefits of early end-of-life care discussions with patients with life-threatening illness and their families. However, these conversations often do not occur. This review explores some of the many barriers faced by clinicians in relation to end-of-life care discussions, including prognostic uncertainty, fear of causing distress, navigating patient readiness and feeling unprepared for these conversations. The value of core clinical communication skills, potential strategies for improvement and areas for future research are also discussed. It is essential that clinicians offer patients facing life-threatening illness, and those close to them, the opportunity to discuss end-of-life issues in line with their information and decision-making preferences. With a growing and ageing global population, supporting both generalist and specialist providers of palliative care in this task is key. With careful preparation, fears of undertaking these discussions should not be a barrier to initiating them.
The endothelial glycocalyx promotes homogenous blood flow distribution within the microvasculature
Authors: McClatchey P. Mason , Schafer Michal , Hunter Kendall S. , Reusch Jane E. B.
Published: May 2016

Many common diseases involve impaired tissue perfusion, and heterogeneous distribution of blood flow in the microvasculature contributes to this pathology. The physiological mechanisms regulating homogeneity/heterogeneity of microvascular perfusion are presently unknown. Using established empirical formulations for blood viscosity modeling in vivo (blood vessels) and in vitro (glass tubes), we showed that the in vivo formulation predicts more homogenous perfusion of microvascular networks at the arteriolar and capillary levels. Next, we showed that the more homogeneous blood flow under simulated in vivo conditions can be explained by changes in red blood cell interactions with the vessel wall. Finally, we demonstrated that the presence of a space-filling, semipermeable layer (such as the endothelial glycocalyx) at the vessel wall can account for the changes of red blood cell interactions with the vessel wall that promote homogenous microvascular perfusion. Collectively, our results indicate that the mechanical properties of the endothelial glycocalyx promote homogeneous microvascular perfusion. Preservation or restoration of normal glycocalyx properties may be a viable strategy for improving tissue perfusion in a variety of diseases.
Sex dimorphisms of crossbridge cycling kinetics in transgenic hypertrophic cardiomyopathy mice
Authors: Birch Camille L. , Behunin Samantha M. , Lopez-Pier Marissa A. , Danilo Christiane , Lipovka Yulia , Saripalli Chandra , Granzier Henk , Konhilas John P.
Published: May 2016

Familial hypertrophic cardiomyopathy (HCM) is a disease of the sarcomere and may lead to hypertrophic, dilated, restrictive, and/or arrhythmogenic cardiomyopathy, congestive heart failure, or sudden cardiac death. We hypothesized that hearts from transgenic HCM mice harboring a mutant myosin heavy chain increase the energetic cost of contraction in a sex-specific manner. To do this, we assessed Ca2+sensitivity of tension and crossbridge kinetics in demembranated cardiac trabeculas from male and female wild-type (WT) and HCM hearts at an early time point (2 mo of age). We found a significant effect of sex on Ca2+sensitivity such that male, but not female, HCM mice displayed a decrease in Ca2+sensitivity compared with WT counterparts. The HCM transgene and sex significantly impacted the rate of force redevelopment by a rapid release-restretch protocol and tension cost by the ATPase-tension relationship. In each of these measures, HCM male trabeculas displayed a gain-of-function when compared with WT counterparts. In addition, cardiac remodeling measured by echocardiography, histology, morphometry, and posttranslational modifications demonstrated sex- and HCM-specific effects. In conclusion, female and male HCM mice display sex dimorphic crossbridge kinetics accompanied by sex- and HCM-dependent cardiac remodeling at the morphometric, histological, and cellular level.
Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation
Authors: Emelyanova Larisa , Ashary Zain , Cosic Milanka , Negmadjanov Ulugbek , Ross Gracious , Rizvi Farhan , Olet Susan , Kress David , Sra Jasbir , Tajik A. Jamil , Holmuhamedov Ekhson L. , Shi Yang , Jahangir Arshad
Published: May 2016

Mitochondria are critical for maintaining normal cardiac function, and a deficit in mitochondrial energetics can lead to the development of the substrate that promotes atrial fibrillation (AF) and its progression. However, the link between mitochondrial dysfunction and AF in humans is still not fully defined. The aim of this study was to elucidate differences in the functional activity of mitochondrial oxidative phosphorylation (OXPHOS) complexes and oxidative stress in right atrial tissue from patients without (non-AF) and with AF (AF) who were undergoing open-heart surgery and were not significantly different for age, sex, major comorbidities, and medications. The overall functional activity of the electron transport chain (ETC), NADH:O2 oxidoreductase activity, was reduced by 30% in atrial tissue from AF compared with non-AF patients. This was predominantly due to a selective reduction in complex I (0.06 ± 0.007 vs. 0.09 ± 0.006 nmol·min−1·citrate synthase activity−1, P = 0.02) and II (0.11 ± 0.012 vs. 0.16 ± 0.012 nmol·min−1·citrate synthase activity−1, P = 0.003) functional activity in AF patients. Conversely, complex V activity was significantly increased in AF patients (0.21 ± 0.027 vs. 0.12 ± 0.01 nmol·min−1·citrate synthase activity−1, P = 0.005). In addition, AF patients exhibited a higher oxidative stress with increased production of mitochondrial superoxide (73 ± 17 vs. 11 ± 2 arbitrary units, P = 0.03) and 4-hydroxynonenal level (77.64 ± 30.2 vs. 9.83 ± 2.83 ng·mg−1 protein, P = 0.048). Our findings suggest that AF is associated with selective downregulation of ETC activity and increased oxidative stress that can contribute to the progression of the substrate for AF.
Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease
Authors: Siddesha Jalahalli M. , Nakada Emily M. , Mihavics Bethany R. , Hoffman Sidra M. , Rattu Gurkiranjit K. , Chamberlain Nicolas , Cahoon Jonathon M. , Lahue Karolyn G. , Daphtary Nirav , Aliyeva Minara , Chapman David G. , Desai Dhimant H. , Poynter Matthew E. , Anathy Vikas
Published: May 2016

Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases.
High-throughput sequencing reveals differential expression of miRNAs in prehierarchal follicles of laying and brooding geese
Authors: Yu Jing , He Ke , Ren Ting , Lou Yaping , Zhao Ayong
Published: May 2016

Broodiness is the primary factor influencing egg production in geese, in which several genes and miRNAs participate. Detailed spatiotemporal profiles of miRNAs encompassing follicle development levels, however, are lacking. In this study, we collected preovulatory follicles (classified as small white follicles, large white follicles, and small yellow follicles) from brooding and laying geese and aimed to analyze microRNA (miRNA or miR) during folliculogenesis. High-throughput sequencing and bioinformatics analysis were used to identify the miRNAs involved in follicle development. The let7 family, miR-10 family, and miR-143 family were abundant in these libraries, and they have been suggested to play a housekeeping role during folliculogenesis. Joint comparisons revealed 23 upregulated and 21 downregulated miRNAs (in at least two comparisons of follicles during brooding and laying, P < 0.1) in the laying stage. Unlike reproduction pathways reported for ovaries, GO and KEGG analysis suggested pathways for cell apoptosis and proliferation, such as the regulation of actin cytoskeleton, endocytosis, axon guidance, pathways in cancer, tight junctions, focal adhesion, the MAPK signaling pathway, cytokine-cytokine receptor interactions, and the Wnt signaling pathway in folliculogenesis. This study revealed the miRNAs that were directly involved in follicular atresia, and our results added to the understanding of the functional involvement of miRNAs during specific stages of follicle development.
Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas
Authors: Droog Marjolein , Nevedomskaya Ekaterina , Kim Yongsoo , Severson Tesa , Flach Koen D. , Opdam Mark , Schuurman Karianne , Gradowska Patrycja , Hauptmann Michael , Dackus Gwen , Hollema Harry , Mourits Marian J. , Nederlof Petra , van Boven Hester , Linn Sabine C. , Wessels Lodewyk , van Leeuwen Flora E. , Zwart Wilbert
Published: May 2016

Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERα binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERα binding sites proximal to genes involved in classical ERα target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERα and FOXA1 together with the enhancer-enriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERα expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERα are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773–84. ©2016 AACR.
Cell Cycle–Dependent Mechanisms Underlie Vincristine-Induced Death of Primary Acute Lymphoblastic Leukemia Cells
Authors: Kothari Anisha , Hittelman Walter N. , Chambers Timothy C.
Published: May 2016

Microtubule-targeting agents (MTA), such as the taxanes and vinca alkaloids, are used to treat a variety of cancers due to their ability to perturb microtubule dynamics. In cell culture, MTAs exert their anticancer effects primarily by causing mitotic arrest and cell death. However, accumulating indirect evidence suggests that MTAs may exert their cytotoxicity in human tumors by interfering with interphase microtubules. In this study, we sought to develop and characterize an experimental system in which to test the hypothesis that MTAs induce cell death during interphase. Primary adult acute lymphoblastic leukemia (ALL) cells treated with vincristine only weakly exhibited colocalization between mitotic and apoptotic markers and major characteristics of mitotic death, such as an increase in cells with 4N DNA content before the appearance of cells with <2N DNA content, suggesting a mixed response. Therefore, we separated ALL cells into distinct phases of the cell cycle by centrifugal elutriation, labeled cells with 5-ethynyl-2′-deoxyuridine (EdU), and then treated each population with vincristine. Cells isolated during G1 underwent cell death without evidence of EdU uptake, indicating that the cytotoxic effects of vincristine took place during G1. Conversely, cells isolated during S or G2–M phases underwent death following mitotic arrest. Thus, vincristine induces distinct death programs in primary ALL cells depending on cell-cycle phase, and cells in G1 are particularly susceptible to perturbation of interphase microtubules. Primary ALL cells may therefore provide a powerful model system in which to study the multimodal mechanisms underlying MTA-induced cell death. Cancer Res; 76(12); 3553–61. ©2016 AACR.
Selenium- or Vitamin E–Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT
Authors: Chan June M. , Darke Amy K. , Penney Kathryn L. , Tangen Catherine M. , Goodman Phyllis J. , Lee Gwo-Shu Mary , Sun Tong , Peisch Sam , Tinianow Alex M. , Rae James M. , Klein Eric A. , Thompson Ian M. , Kantoff Philip W. , Mucci Lorelei A.
Published: May 2016

Background: Epidemiologic studies and secondary analyses of randomized trials supported the hypothesis that selenium and vitamin E lower prostate cancer risk. However, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no benefit of either supplement. Genetic variants involved in selenium or vitamin E metabolism or transport may underlie the complex associations of selenium and vitamin E.

Methods: We undertook a case–cohort study of SELECT participants randomized to placebo, selenium, or vitamin E. The subcohort included 1,434 men; our primary outcome was high-grade prostate cancer (N = 278 cases, Gleason 7 or higher cancer). We used weighted Cox regression to examine the association between SNPs and high-grade prostate cancer risk. To assess effect modification, we created interaction terms between randomization arm and genotype and calculated log likelihood statistics.

Results: We noted statistically significant (P < 0.05) interactions between selenium assignment, SNPs in CAT, SOD2, PRDX6, SOD3, and TXNRD2, and high-grade prostate cancer risk. Statistically significant SNPs that modified the association of vitamin E assignment and high-grade prostate cancer included SEC14L2, SOD1, and TTPA. In the placebo arm, several SNPs, hypothesized to interact with supplement assignment and risk of high-grade prostate cancer, were also directly associated with outcome.

Conclusion: Variants in selenium and vitamin E metabolism/transport genes may influence risk of overall and high-grade prostate cancer, and may modify an individual man's response to vitamin E or selenium supplementation with regards to these risks.

Impact: The effect of selenium or vitamin E supplementation on high-grade prostate cancer risk may vary by genotype. Cancer Epidemiol Biomarkers Prev; 25(7); 1050–8. ©2016 AACR.
UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer
Authors: Gilani Rabia A. , Phadke Sameer , Bao Li Wei , Lachacz Eric J. , Dziubinski Michele L. , Brandvold Kristoffer R. , Steffey Michael E. , Kwarcinski Frank E. , Graveel Carrie R. , Kidwell Kelley M. , Merajver Sofia D. , Soellner Matthew B.
Published: May 2016

Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.

Experimental Design: We have analyzed the anti–triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts.

Results: We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.

Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC. Clin Cancer Res; 22(20); 5087–96. ©2016 AACR.
Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma
Authors: Ogura Michinori , Tobinai Kensei , Hatake Kiyohiko , Davies Andrew , Crump Michael , Ananthakrishnan Revathi , Ishibashi Taro , Paccagnella M. Luisa , Boni Joseph , Vandendries Erik , MacDonald David
Published: May 2016

Purpose: To evaluate the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immunochemotherapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL).

Experimental Design: In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin. Part 2 (n = 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose-limiting toxicity rate of <33% in cycle 1 and <33% of patients discontinuing before cycle 3 due to treatment-related adverse events (AEs). Part 3 (n = 22) evaluated the preliminary efficacy of inotuzumab ozogamicin plus R-CVP.

Results: The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m2. The most common treatment-related grade ≥3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10). Overall, 13 patients died, including one death due to treatment-related pneumonia secondary to neutropenia. Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84% (n = 32), including 24% (n = 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n = 27) and 57% for those with aggressive histology lymphoma (n = 21).

Conclusions: Inotuzumab ozogamicin at 0.8 mg/m2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22+ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 22(19); 4807–16. ©2016 AACR.
Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E–Deficient Mice
Authors: Higashi Yusuke , Sukhanov Sergiy , Shai Shaw-Yung , Danchuk Svitlana , Tang Richard , Snarski Patricia , Li Zhaohui , Lobelle-Rich Patricia , Wang Meifang , Wang Derek , Yu Hong , Korthuis Ronald , Delafontaine Patrice
Published: May 2016

Background—

We have previously shown that systemic infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and antioxidant effects and reduces atherosclerotic burden in apolipoprotein E (Apoe)–deficient mice. Monocytes/macrophages express high levels of IGF-1 receptor (IGF1R) and play a pivotal role in atherogenesis, but the potential effects of IGF-1 on their function are unknown.

Methods and Results—

To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/macrophage–specific IGF1R knockout (MΦ-IGF1R-KO) mice on an Apoe
−/−
background. We assessed atherosclerotic burden, plaque features of stability, and monocyte recruitment to atherosclerotic lesions. Phenotypic changes of IGF1R-deficient macrophages were investigated in culture. MΦ-IGF1R-KO significantly increased atherosclerotic lesion formation, as assessed by Oil Red O staining of en face aortas and aortic root cross-sections, and changed plaque composition to a less stable phenotype, characterized by increased macrophage and decreased α-smooth muscle actin–positive cell population, fibrous cap thinning, and decreased collagen content. Brachiocephalic artery lesions of MΦ-IGF1R-KO mice had histological features implying plaque vulnerability. Macrophages isolated from MΦ-IGF1R-KO mice showed enhanced proinflammatory responses on stimulation by interferon-γ and oxidized low-density lipoprotein and elevated antioxidant gene expression levels. Moreover, IGF1R-deficient macrophages had decreased expression of ABCA1 and ABCG1 and reduced lipid efflux.

Conclusions—

Our data indicate that macrophage IGF1R signaling suppresses macrophage and foam cell accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts antiatherogenic effects.
The Unknown Exorcist in Mark 9:38–40: A Study of Diversity and Inclusiveness in Early Christianity
Authors: Lee Sang Mok
Published: May 2016

This article discusses diversity and inclusiveness in the early church in terms of Mark’s attitudes towards the unknown exorcist in Mark 9:38–40. Exorcisms are well-documented phenomena in early Christianity. Mark’s episode of the unknown exorcist reflects such a historical situation. Through the episode, Mark explains that God’s kingdom expands not merely through certain well-known authoritative figures, but also anonymous, minor figures such as the unknown exorcist. The evangelist explains the diversity and inclusive characteristic of God’s kingdom to the reader. While many studies on the given Marcan passage understand the exorcist as an outsider of God’s kingdom, this research suggests that the evangelist regards the exorcist as an authentic member of God’s kingdom and his exorcism as a mystical way of the growth of the kingdom. The twelve disciples fail to recognize such a secret expansion of the kingdom. They define the boundary of the kingdom rather narrowly. Mark reveals the disciples’ narrow view and engages the reader in reflections on the true characteristic of God’s kingdom. He invites the reader to understand the mysterious expansion and the inclusiveness of the kingdom and participate in that expansion.