bluuebunny/crossref_metadata_2025 huggingface dataset:
Draft Genome Sequence of Paenarthrobacter nicotinovorans Hce-1
Authors: Meng Jing , Sun Xiaomeng , Li Shuaishuai , Liang Hao
Published: July 2017

Paenarthrobacter nicotinovorans
Hce-1 is a Gram-positive obligate aerobe actinomycete. We report here the complete genome sequence of this organism. The genome has a length of 4,174,362 bp and contains 4,568 protein-coding genes, 64 tRNA operons, and 22 rRNA operons. Its GC content in the gene region is 63.4%.
Ploidy Variation in Fungi: Polyploidy, Aneuploidy, and Genome Evolution
Authors: Todd Robert T. , Forche Anja , Selmecki Anna
Published: July 2017

The ability of an organism to replicate and segregate its genome with high fidelity is vital to its survival and for the production of future generations. Errors in either of these steps (replication or segregation) can lead to a change in ploidy or chromosome number. While these drastic genome changes can be detrimental to the organism, resulting in decreased fitness, they can also provide increased fitness during periods of stress. A change in ploidy or chromosome number can fundamentally change how a cell senses and responds to its environment. Here, we discuss current ideas in fungal biology that illuminate how eukaryotic genome size variation can impact the organism at a cellular and evolutionary level. One of the most fascinating observations from the past 2 decades of research is that some fungi have evolved the ability to tolerate large genome size changes and generate vast genomic heterogeneity without undergoing canonical meiosis.
Cerebral haemorrhage as a clinical manifestation of human ehrlichiosis
Authors: Garc­Ía-Baena Catalina , Cárdenas MarÍa Fernanda , Ramón Juan Fernando
Published: July 2017

A 16-year-old young man presented to the emergency room with new-onset generalised tonic-clonic seizures. Examination showed a Glasgow score of 13 and predominantly crural left hemiparesis. Imaging demonstrated a right frontoparietal haemorrhage of non-vascular origin with perilesional oedema. Surgical drainage was carried out, but rebleeding occurred within 24 hours following surgery, and again 1 week after discharge. On reinterrogation and examination,Ehrlichia canisinfection was suspected and empirical management with doxycycline was begun. Improvement was evident 72 hours after antibiotic initiation, and PCR confirmed the diagnosis; thus, doxycycline was continued for 6 months. After 2 years, seizures recurred and treatment was reinstated with good clinical response. However, seizures reappeared whenever treatment discontinuation was attempted. Lacking alternatives, doxycycline was maintained up to the third year following the initial episode. Subsequently, the patient showed complete resolution without neurological sequelae up to his last follow-up visit, 12 months following treatment cessation.
Between fire and ice: refractory hypothermia and warmth-induced pain in inherited erythromelalgia
Authors: Tham See Wan , Li Li , Effraim Philip , Waxman Stephen
Published: July 2017

Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Nav1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise. Pain is not adequately treated by existing pharmacological agents. Individuals with IEM classically cool their limbs for relief, in some cases resulting in tissue injury. We describe a patient from a family with IEM due to the L858F mutation of Nav1.7 who presented with refractory hypothermia due to overcooling. This presentation of refractory hypothermia necessitating warming strategies, complicated by severe warmth-induced pain, posed a substantial therapeutic challenge. We report our experience in overcoming hypothermia lasting 3 weeks in a child with IEM, discuss possible pathophysiological mechanisms underlying this unusual complication and suggest potential therapeutic interventions.
Profiles of children's social–emotional health at school entry and associated income, gender and language inequalities: a cross-sectional population-based study in British Columbia, Canada
Authors: Thomson Kimberly C , Guhn Martin , Richardson Chris G , Ark Tavinder K , Shoveller Jean
Published: July 2017

Objectives

Early identification of distinct patterns of child social–emotional strengths and vulnerabilities has the potential to improve our understanding of child mental health and well-being; however, few studies have explored natural groupings of indicators of child vulnerability and strengths at a population level. The purpose of this study was to examine heterogeneity in the patterns of young children's social and emotional health and investigate the extent to which sociodemographic characteristics were associated.

Design

Cross-sectional study based on a population-level cohort.

Setting

All kindergarten children attending public schools between 2004 and 2007 in British Columbia (BC), Canada.

Participants

35 818 kindergarten children (age of 5 years) with available linked data from the Early Development Instrument (EDI), BC Ministry of Health and BC Ministry of Education.

Outcome measure

We used latent profile analysis (LPA) to identify distinct profiles of social–emotional health according to children's mean scores across eight social–emotional subscales on the EDI, a teacher-rated measure of children's early development. Subscales measured children's overall social competence, responsibility and respect, approaches to learning, readiness to explore, prosocial behaviour, anxiety, aggression and hyperactivity.

Results

Six social–emotional profiles were identified: (1) overall high social–emotional functioning, (2) inhibited-adaptive (3) uninhibited-adaptive, (4) inhibited-disengaged, (5) uninhibited-aggressive/hyperactive and (6) overall low social–emotional functioning. Boys, children with English as a second language (ESL) status and children with lower household income had higher odds of membership to the lower social–emotional functioning groups; however, this association was less negative among boys with ESL status.

Conclusions

Over 40% of children exhibited some vulnerability in early social–emotional health, and profiles were associated with sociodemographic factors. Approximately 9% of children exhibited multiple co-occurring vulnerabilities. This study adds to our understanding of population-level distributions of children's early social–emotional health and identifies profiles of strengths and vulnerabilities that can inform future intervention efforts.
Common attributes in retired professional cricketers that may enhance or hinder quality of life after retirement: a qualitative study
Authors: Filbay Stephanie R , Bishop Felicity , Peirce Nicholas , Jones Mary E , Arden Nigel K
Published: July 2017

Objectives

Retired professional cricketers shared unique experiences and may possess specific psychological attributes with potential to influence quality of life (QOL). Additionally, pain and osteoarthritis can be common in retired athletes which may negatively impact QOL. However, QOL in retired athletes is poorly understood. This study explores the following questions from the personal perspective of retired cricketers: How do retired cricketers perceive and experience musculoskeletal pain and function in daily life? Are there any psychological attributes that might enhance or hinder retired cricketers’ QOL?

Design

A qualitative study using semistructured interviews, which were subject to inductive, thematic analysis. A data-driven, iterative approach to data coding was employed.

Setting

All participants had lived and played professional cricket in the UK and were living in the UK or abroad at the time of interview.

Participants

Eighteen male participants, aged a mean 57±11 (range 34–77) years had played professional cricket for a mean 12±7 seasons and had been retired from professional cricket on average 23±9 years.

Results

Fifteen participants reported pain or joint difficulties and all but one was satisfied with their QOL. Most retired cricketers reflected on experiences during their cricket career that may be associated with the psychological attributes that these individuals shared, including resilience and a positive attitude. Additional attributes included a high sense of body awareness, an ability to self-manage pain and adapt lifestyle choices to accommodate physical limitations. Participants felt fortunate and proud to have played professional cricket, which may have further contributed to the high QOL in this group of retired cricketers.

Conclusions

Most retired cricketers in this study were living with pain or joint difficulties. Despite this, all but one was satisfied or very satisfied with their QOL. This may be partly explained by the positive psychological attributes that these retired cricketers shared.
Five-level emergency triage systems: variation in assessment of validity
Authors: Kuriyama Akira , Urushidani Seigo , Nakayama Takeo
Published: July 2017

Introduction

Triage systems are scales developed to rate the degree of urgency among patients who arrive at EDs. A number of different scales are in use; however, the way in which they have been validated is inconsistent. Also, it is difficult to define a surrogate that accurately predicts urgency. This systematic review described reference standards and measures used in previous validation studies of five-level triage systems.

Methods

We searched PubMed, EMBASE and CINAHL to identify studies that had assessed the validity of five-level triage systems and described the reference standards and measures applied in these studies. Studies were divided into those using criterion validity (reference standards developed by expert panels or triage systems already in use) and those using construct validity (prognosis, costs and resource use).

Results

A total of 57 studies examined criterion and construct validity of 14 five-level triage systems. Criterion validity was examined by evaluating (1) agreement between the assigned degree of urgency with objective standard criteria (12 studies), (2) overtriage and undertriage (9 studies) and (3) sensitivity and specificity of triage systems (7 studies). Construct validity was examined by looking at (4) the associations between the assigned degree of urgency and measures gauged in EDs (48 studies) and (5) the associations between the assigned degree of urgency and measures gauged after hospitalisation (13 studies). Particularly, among 46 validation studies of the most commonly used triages (Canadian Triage and Acuity Scale, Emergency Severity Index and Manchester Triage System), 13 and 39 studies examined criterion and construct validity, respectively.

Conclusion

Previous studies applied various reference standards and measures to validate five-level triage systems. They either created their own reference standard or used a combination of severity/resource measures.
Validation of the Singapore nomogram for outcome prediction in breast phyllodes tumours in a large patient cohort
Authors: Chng Tze Wei , Gudi Mihir , Lim Swee Ho , Li HuiHua , Tan Puay Hoon
Published: July 2017

Aims

To validate the Singapore nomogram for outcome prediction in breast phyllodes tumours in a large cohort of Singaporean patients, as previous validation studies were conducted on small numbers of patients. We also investigate the association of fibroadenomas and phyllodes tumours within a subset of our cohort.

Methods

Histological parameters, surgical margin status and clinical follow-up data of 259 women diagnosed with phyllodes tumours were analysed. Patients with concurrent malignant or premalignant disease were excluded from the validation to minimise confounding influences. Biostatistics modelling was performed, and the concordance between predicted and observed survivals was calculated. The association between fibroadenomas and phyllodes tumours was quantified in a subset of the women.

Results

Phyllodes tumours with higher number of mitoses, stromal overgrowth and positive surgical margins were found to be associated with greater risk of clinical recurrence. Patients with a higher nomogram score had a significantly higher risk of developing relapse. Forty out of 78 (51.3%) of the subset of phyllodes cases reviewed showed either fibroadenoma-like areas within the phyllodes tumours or concurrent fibroadenomas in the ipsilateral or contralateral breast.

Conclusions

The Singapore nomogram is useful in predicting outcome in breast phyllodes tumours when applied to a large cohort of Singaporean women.
Attention and Memory Impairments in Pediatric Patients with Cystic Fibrosis and Inflammatory Bowel Disease in Comparison to Healthy Controls
Authors: Piasecki Bartosz , Stanisławska-Kubiak Maia , Strzelecki Wojciech , Mojs Ewa
Published: July 2017

The main aim of the study was to analyze and compare attention and memory performance in pediatric patients with cystic fibrosis (CF), inflammatory bowel disease (IBD) and in healthy controls. 28 patients with CF, 30 patients with IBD and 30 healthy subjects took part in the study (all in age range of 7–17). All subjects were in intellectual norm. To analyze the functioning of attention, the d2 Test of Attention by Brickenkamp (d2 test) was applied. Memory performance was assessed using the Benton Visual Retention Test (BVRT) and the Trial of 10 words. The CF and IBD groups committed significantly more errors in the d2 test than the healthy controls. The CF group also had significantly higher fluctuation rates and received significantly lower scores in overall concentration performance than the control group. Patients with CF made more mistakes and had fewer correct memory projections in BVRT than the healthy controls. Patients with IBD committed significantly more errors in BVRT than the control group. Patients with CF and IBD also got significantly lower scores in the Trial of 10 words than the control group. Pediatric patients with CF and IBD performed more poorly than the healthy controls on attention and memory tests. More distinct cognitive impairments were observed in the CF group. Further research is needed to find the underlying mechanisms and clinical and/or functional significance of observed cognitive deficits.
A simplified method to estimate curvatures of continuous pipelines induced by normal fault movement
Authors: Shi Jiangwei , Wang Yu , Chen Yonghui
Published: July 2017

Significant permanent fault rupture may occur during earthquakes and induce adverse effects on pipelines when they are located within a fault zone. Although fault movement–pipeline interaction has attracted increasing research attention recently, a simplified method that can be used to directly estimate curvatures of continuous pipelines due to normal fault movement has not been developed. In this study, a systematic finite element (FE) parametric study with 950 FE runs is conducted to investigate normal fault movement–induced bending behavior in continuous pipelines. Centrifuge test results are adopted to verify the numerical model. It is found that ground settlement due to normal fault movement is well captured by an error function. A dimensionless plot is developed between relative pipe–soil stiffness and ratio of maximum pipe curvature to maximum ground curvature. The maximum curvatures of pipelines due to normal fault movement can be estimated directly from the developed dimensionless plot. As the relative pipe–soil stiffness increases from 1.0 × 10–4to 1.0 × 103, the curvature ratio decreases from 1 to 0. When the relative pipe–soil stiffness is less than 1.0 × 10–3, the curvature ratio is close to 1. In contrast, the curvature ratio is close to zero when the relative pipe–soil stiffness is larger than 102.
Contribution of monoamine oxidases to vascular oxidative stress in patients with end-stage renal disease requiring hemodialysis
Authors: Uțu Diana , Pantea Stelian , Duicu Oana M. , Muntean Danina M. , Sturza Adrian
Published: July 2017

Arteriovenous fistula (AVF) is the “lifeline” for patients with end-stage renal disease (ESRD) undergoing hemodialysis. AVF maturation failure is a poorly understood process, one of the contributors being endothelial dysfunction due to oxidative stress. Monoamine oxidases (MAOs) A and B were recently identified as novel sources of vascular oxidative stress. The aim of the present study was to assess the contribution of MAOs to the endothelial dysfunction in patients with ESDR with indication of hemodialysis. Fragments of brachial artery collaterals were harvested from ESRD patients during the surgical procedure aimed at creating the vascular access in the cubital fossa. The effect of increasing concentrations (10, 30, 100 μmol/L) of the irreversible MAO-A inhibitor, clorgyline, and MAO-B inhibitor, selegiline, on endothelial-dependent relaxation (EDR) in response to cumulative doses of acetylcholine was studied in isolated phenylephrine-preconstricted vascular rings. Hydrogen peroxide (H2O2) production was assessed using ferrous oxidation xylenol orange assay. We showed that incubation of brachial rings with MAO inhibitors significantly improved EDR and attenuated H2O2 generation in patients with ESRD. MAO-related oxidative stress might contribute to the primary dysfunction/non-maturation of the AVF and MAO inhibitors could improve maturation and long-term patency of the vascular access in dialysis patients.
Analytic torsion of half spheres
Authors: Hartmann Luiz , Spreafico Mauro
Published: July 2017

In this paper, we present explicit formulas for the analytic torsion of an half sphere.
An application of N-Bishop frame to spherical images for direction curves
Authors: Keskin Ozgur , Yayli Yusuf
Published: July 2017

In this paper, we first introduce [Formula: see text]-Bishop frame for a normal direction curve which is defined as an integral curve of the principal normal of a curve. We express this new frame and its properties. Afterwards, we obtain new spherical images by translating [Formula: see text]-Bishop frame vectors to the center of unit sphere [Formula: see text] in [Formula: see text]. Then, these new spherical images are called [Formula: see text]-Bishop spherical images. Additionally, we compute the Frénet–Serret equations of these new spherical images. Moreover, we show that integral curves of [Formula: see text]-Bishop spherical images of slant helices are also slant helices. Finally, we present some illustrated examples.
Data-Driven Techniques in Computing System Management
Authors: Li Tao , Zeng Chunqiu , Jiang Yexi , Zhou Wubai , Tang Liang , Liu Zheng , Huang Yue
Published: July 2017

Modern forms of computing systems are becoming progressively more complex, with an increasing number of heterogeneous hardware and software components. As a result, it is quite challenging to manage these complex systems and meet the requirements in manageability, dependability, and performance that are demanded by enterprise customers. This survey presents a variety of data-driven techniques and applications with a focus on computing system management. In particular, the survey introduces intelligent methods for event generation that can transform diverse log data sources into structured events, reviews different types of event patterns and the corresponding event-mining techniques, and summarizes various event summarization methods and data-driven approaches for problem diagnosis in system management. We hope this survey will provide a good overview for data-driven techniques in computing system management.
Hollow Heaps
Authors: Hansen Thomas Dueholm , Kaplan Haim , Tarjan Robert E. , Zwick Uri
Published: July 2017

We introduce the
hollow heap
, a very simple data structure with the same amortized efficiency as the classical Fibonacci heap. All heap operations except
delete
and
delete
-
min
take
O
(1) time, worst case as well as amortized;
delete
and
delete
-
min
take
O
(log
n
) amortized time on a heap of
n
items. Hollow heaps are the simplest structure to achieve these bounds. Hollow heaps combine two novel ideas: the use of lazy deletion and re-insertion to do
decrease
-
key
operations and the use of a dag (directed acyclic graph) instead of a tree or set of trees to represent a heap. Lazy deletion produces hollow nodes (nodes without items), giving the data structure its name.
Perceived Space in the HTC Vive
Authors: Kelly Jonathan W. , Cherep Lucia A. , Siegel Zachary D.
Published: July 2017

Underperception of egocentric distance in virtual reality has been a persistent concern for almost 20 years. Modern head-mounted displays (HMDs) appear to have begun to ameliorate underperception. The current study examined several aspects of perceived space in the HTC Vive. Blind-walking distance judgments, verbal distance judgments, and size judgments were measured in two distinct virtual environments (VEs)—a high-quality replica of a real classroom and an empty grass field—as well as the real classroom upon which the classroom VE was modeled. A brief walking interaction was also examined as an intervention for improving anticipated underperception in the VEs. Results from the Vive were compared to existing data using two older HMDs (nVisor SX111 and ST50). Blind-walking judgments were more accurate in the Vive compared to the older displays, and did not differ substantially from the real world nor across VEs. Size judgments were more accurate in the classroom VE than the grass VE and in the Vive compared to the older displays. Verbal judgments were significantly smaller in the classroom VE compared to the real classroom and did not significantly differ across VEs. Blind-walking and size judgments were more accurate after walking interaction, but verbal judgments were unaffected. The results indicate that underperception of distance in the HTC Vive is less than in older displays but has not yet been completely resolved. With more accurate space perception afforded by modern HMDs, alternative methods for improving judgments of perceived space—such as walking interaction—may no longer be necessary.
A Bundle of Relations: Collections, Collecting, and Communities
Authors: Bell Joshua A.
Published: July 2017

Anthropology has always involved collections and collecting. Collections helped give rise to the discipline's formation and were integral to theoretical perspectives rooted in hierarchies of race and technology in the nineteenth century. With the disavowal of these perspectives, collecting, and its resulting collections, remained an ongoing but unacknowledged activity. The material (re)turn in the 1980s brought anthropology's material legacies under renewed scrutiny by repositioning objects as having histories and agency. Ethnographies of collecting have helped reveal the often obscured collaborations that were, and are, critical to anthropological knowledge. Collaborations with indigenous communities involving collections are helping to address the discipline's asymmetry by challenging anthropological categories and authority. In the process, experimental ethnographies through digital and nondigital means are demonstrating that collections are profoundly relational. This relational perspective is helping to chart new directions for work in museums and the wider discipline.
An innovative intermittent hypoxia model for cell cultures allowing fast Po2 oscillations with minimal gas consumption
Authors: Minoves Mélanie , Morand Jessica , Perriot Frédéric , Chatard Morgane , Gonthier Brigitte , Lemarié Emeline , Menut Jean-Baptiste , Polak Jan , Pépin Jean-Louis , Godin-Ribuot Diane , Briançon-Marjollet Anne
Published: July 2017

Performing hypoxia-reoxygenation cycles in cell culture with a cycle duration accurately reflecting what occurs in obstructive sleep apnea (OSA) patients is a difficult but crucial technical challenge. Our goal was to develop a novel device to expose multiple cell culture dishes to intermittent hypoxia (IH) cycles relevant to OSA with limited gas consumption. With gas flows as low as 200 ml/min, our combination of plate holders with gas-permeable cultureware generates rapid normoxia-hypoxia cycles. Cycles alternating 1 min at 20% O2 followed by 1 min at 2% O2 resulted in Po2 values ranging from 124 to 44 mmHg. Extending hypoxic and normoxic phases to 10 min allowed Po2 variations from 120 to 25 mmHg. The volume of culture medium or the presence of cells only modestly affected the Po2 variations. In contrast, the nadir of the hypoxia phase increased when measured at different heights above the membrane. We validated the physiological relevance of this model by showing that hypoxia inducible factor-1α expression was significantly increased by IH exposure in human aortic endothelial cells, murine breast carcinoma (4T1) cells as well as in a blood-brain barrier model (2.5-, 1.5-, and 6-fold increases, respectively). In conclusion, we have established a new device to perform rapid intermittent hypoxia cycles in cell cultures, with minimal gas consumption and the possibility to expose several culture dishes simultaneously. This device will allow functional studies of the consequences of IH and deciphering of the molecular biology of IH at the cellular level using oxygen cycles that are clinically relevant to OSA.
Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats
Authors: McMillin Matthew , DeMorrow Sharon , Glaser Shannon , Venter Julie , Kyritsi Konstantina , Zhou Tianhao , Grant Stephanie , Giang Thao , Greene John F. , Wu Nan , Jefferson Brandi , Meng Fanyin , Alpini Gianfranco
Published: July 2017

Melatonin is a hormone produced by the pineal gland with increased circulating levels shown to inhibit biliary hyperplasia and fibrosis during cholestatic liver injury. Melatonin also has the capability to suppress the release of hypothalamic gonadotropin-releasing hormone (GnRH), a hormone that promotes cholangiocyte proliferation when serum levels are elevated. However, the interplay and contribution of neural melatonin and GnRH to cholangiocyte proliferation and fibrosis in bile duct-ligated (BDL) rats have not been investigated. To test this, cranial levels of melatonin were increased by implanting osmotic minipumps that performed an intracerebroventricular (ICV) infusion of melatonin or saline for 7 days starting at the time of BDL. Hypothalamic GnRH mRNA and cholangiocyte secretion of GnRH and melatonin were assessed. Cholangiocyte proliferation and fibrosis were measured. Primary human hepatic stellate cells (HSCs) were treated with cholangiocyte supernatants, GnRH, or the GnRH receptor antagonist cetrorelix acetate, and cell proliferation and fibrosis gene expression were assessed. Melatonin infusion reduced hypothalamic GnRH mRNA expression and led to decreased GnRH and increased melatonin secretion from cholangiocytes. Infusion of melatonin was found to reduce hepatic injury, cholangiocyte proliferation, and fibrosis during BDL-induced liver injury. HSCs supplemented with BDL cholangiocyte supernatant had increased proliferation, and this increase was reversed when HSCs were supplemented with supernatants from melatonin-infused rats. GnRH stimulated fibrosis gene expression in HSCs, and this was reversed by cetrorelix acetate cotreatment. Increasing bioavailability of melatonin in the brain may improve outcomes during cholestatic liver disease.

NEW & NOTEWORTHY We have previously demonstrated that GnRH is expressed in cholangiocytes and promotes their proliferation during cholestasis. In addition, dark therapy, which increases melatonin, reduced cholangiocyte proliferation and fibrosis during cholestasis. This study expands these findings by investigating neural GnRH regulation by melatonin during BDL-induced cholestasis by infusing melatonin into the brain. Melatonin infusion reduced cholangiocyte proliferation and fibrosis, and these effects are due to GNRH receptor 1-dependent paracrine signaling between cholangiocytes and hepatic stellate cells.
PARP2 deficiency affects invariant-NKT-cell maturation and protects mice from concanavalin A-induced liver injury
Authors: Filliol Aveline , Piquet-Pellorce Claire , Dion Sarah , Genet Valentine , Lucas-Clerc Catherine , Dantzer Françoise , Samson Michel
Published: July 2017

Excessive or persistent inflammation and hepatocyte death are the key triggers of liver diseases. The poly(ADP-ribose) polymerase (PARP) proteins induce cell death and inflammation. Chemical inhibition of PARP activity protects against liver injury during concanavalin A (ConA)-induced hepatitis. In this mice model, ConA activates immune cells, which promote inflammation and induce hepatocyte death, mediated by the activated invariant natural killer T (iNKT) lymphocyte population. We analyzed immune cell populations in the liver and several lymphoid organs, such as the spleen, thymus, and bone marrow in Parp2-deficient mice to better define the role of PARP proteins in liver immunity and inflammation at steady state and during ConA-induced hepatitis. We show that 1) the genetic inactivation of Parp2, but not Parp1, protected mice from ConA hepatitis without deregulating cytokine expression and leucocyte recruitment; 2) cellularity was lower in the thymus, but not in spleen, liver, or bone marrow of Parp2−/−mice; 3) spleen and liver iNKT lymphocytes, as well as thymic T and NKT lymphocytes were reduced in Parp2 knockout mice. In conclusion, our results suggest that the defect of T-lymphocyte maturation in Parp2 knockout mice leads to a systemic reduction of iNKT cells, reducing hepatocyte death during ConA-mediated liver damage, thus protecting the mice from hepatitis.

NEW & NOTEWORTHY The genetic inactivation of Parp2, but not Parp1, protects mice from concanavalin A hepatitis. Immune cell populations are lower in the thymus, but not in the spleen, liver, or bone marrow of Parp2-deficient mice compared with wild-type mice. Spleen and liver invariant natural killer T (NKT) lymphocytes, as well as thymic T and NKT lymphocytes, are reduced in Parp2-deficient mice.
Nebivolol Attenuates Neutrophil Lymphocyte Ratio: A Marker of Subclinical Inflammation in Hypertensive Patients
Authors: Hussain Mazhar , Saeed Muhammad , Babar Muhammad Zafar Majeed , Atif Moazzam Ali , Akhtar Lubna
Published: July 2017

Background. High value of neutrophil lymphocyte ratio (NLR) is a strong independent predictor and biomarker of ongoing vascular inflammation in various cardiovascular disorders. Objective. The main focus of the study is to investigate the effect of nebivolol on NLR in mild to moderate hypertensive patients in comparison with metoprolol. In addition, BMI, blood pressure, TLC count, blood sugar, and lipid profile were also assayed before and after treatment. Materials and Methods. In this 12-week prospective double-blinded randomized study, 120 patients with mild to moderate hypertension were randomly divided into two groups to prescribed daily dose of tab nebivolol 5–10 mg and metoprolol 50–100 mg, respectively, for 12 weeks. The data were analyzed using SPSS 16 software. Results. A total of 100 patients completed the study. Both drugs lowered blood pressure significantly, nebivolol 20.5/10.5 and metoprolol 22.5/11.2 (p<0.001) from baseline. Regarding inflammation, nebivolol reduced total leukocyte count (p=0.005) and neutrophil count (p=0.003) and increased lymphocyte count (p=0.004) as compared to metoprolol. Similarly, nebivolol but not metoprolol significantly reduced NLR ratio (p=0.07). Nebivolol improved lipid profile and blood sugar compared to metoprolol, but values were nonsignificant. Conclusion. Nebivolol has a strong impact on reducing NLR, a marker of subclinical inflammation in hypertensive patients. Moreover NLR can be used as a disease and drug monitoring tool in these patients.
Dynamic Investigation of the Hunting Motion of a Railway Bogie in a Curved Track via Bifurcation Analysis
Authors: Uyulan Caglar , Gokasan Metin , Bogosyan Seta
Published: July 2017

The main purpose of this paper is to analyze and compare the Hopf bifurcation behavior of a two‐axle railway bogie and a dual wheelset in the presence of nonlinearities, which are yaw damping forces in the longitudinal suspension system and heuristic creep model of the wheel‐rail contact including dead‐zone clearance, while running on a curved track. Two‐axle railway bogie and dual wheelset were modeled using 12‐DOF and 8‐DOF system with considering lateral, vertical, roll, and yaw motions. By utilizing Lyapunov’s indirect method, the critical hunting speeds related to these models are evaluated as track radius changes. Hunting defined as the lateral vibration of the wheelset with a large domain was characterized by a limit cycle‐type oscillation behavior. Influence of the curved track radius on the lateral displacement of the leading wheelset was also investigated through 2D bifurcation diagram, which is employed in the design of a stable model. Frequency power spectra at critical speeds, which are related to the subcritical and supercritical bifurcations, were represented by comparing the two‐axle bogie and dual wheelset model. The evaluated accuracy to predict the critical hunting speed is higher and the hunting frequency in unstable region is lower compared to the dual wheelset model.
Associations of Coffee Drinking and Cancer Mortality in the Cancer Prevention Study-II
Authors: Gapstur Susan M. , Anderson Rebecca L. , Campbell Peter T. , Jacobs Eric J. , Hartman Terryl J. , Hildebrand Janet S. , Wang Ying , McCullough Marjorie L.
Published: July 2017

Background: Associations of coffee consumption with cancer mortality are inconsistent for many types of cancer, and confounding by smoking is an important concern.

Methods: Cox proportional hazards regression was used to estimate multivariable-adjusted HRs for coffee consumption associated with death from all cancers combined and from specific cancer types among 922,896 Cancer Prevention Study-II participants ages 28–94 years who completed a four-page questionnaire and were cancer free at baseline in 1982.

Results: During follow-up through 2012, there were 118,738 cancer-related deaths. There was a nonlinear association between coffee consumption and all-cancer death among current smokers and former smokers and no association among never smokers. Among nonsmokers, a 2 cup/day increase in coffee consumption was inversely associated with death from colorectal [HR = 0.97; 95% confidence interval (CI) 0.95–0.99], liver [HR = 0.92; 95% CI, 0.88–0.96], and female breast (HR = 0.97; 95% CI, 0.94–0.99) cancers, and positively associated with esophageal cancer–related death (HR = 1.07; 95% CI, 1.02–1.12). For head and neck cancer, a nonlinear inverse association was observed starting at 2–3 cups per day (HR = 0.72; 95% CI, 0.55–0.95), with similar associations observed at higher levels of consumption.

Conclusions: These findings are consistent with many other studies that suggest coffee drinking is associated with a lower risk of colorectal, liver, female breast, and head and neck cancer. The association of coffee consumption with higher risk of esophageal cancer among nonsmokers in our study should be confirmed.

Impact: These results underscore the importance of assessing associations between coffee consumption and cancer mortality by smoking status. Cancer Epidemiol Biomarkers Prev; 26(10); 1477–86. ©2017 AACR.
miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/β-catenin Complex in Lung Adenocarcinoma
Authors: Fu Qiaofen , Song Xin , Liu Zhen , Deng Xiaojie , Luo Rongcheng , Ge Chunlei , Li Ruilei , Li Zhen , Zhao Mengyang , Chen Yiyu , Lin Xian , Zhang Qianbing , Fang Weiyi
Published: July 2017

Purpose: This study was performed to identify the detailed mechanisms by which miR-296-3p functions as a tumor suppressor to prevent lung adenocarcinoma (LADC) cell growth, metastasis, and chemoresistance.

Experimental Design: The miR-296-3p expression was examined by real-time PCR and in situ hybridization. MTT, EdU incorporation, Transwell assays, and MTT cytotoxicity were respectively performed for cell proliferation, metastasis, and chemoresistance; Western blotting was performed to analyze the pathways by miR-296-3p and HDGF/DDX5 complex. The miRNA microarray and luciferase reporter assays were respectively used for the HDGF-mediated miRNAs and target genes of miR-296-3p. The ChIP, EMSA assays, and coimmunoprecipitation combined with mass spectrometry and GST pull-down were respectively designed to analyze the DNA–protein complex and HDGF/DDX5/β-catenin complex.

Results: We observed that miR-296-3p not only controls cell proliferation and metastasis, but also sensitizes LADC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that miR-296-3p directly targets PRKCA to suppress FAK–Ras-c–Myc signaling, thus stimulating its own expression in a feedback loop that blocks cell cycle and epithelial–mesenchymal transition (EMT) signal. Furthermore, we observed that suppression of HDGF–β-catenin–c-Myc signaling activates miR-296-3p, ultimately inhibiting the PRKCA–FAK–Ras pathway. Finally, we found that DDX5 directly interacts with HDGF and induces β-catenin–c-Myc, which suppresses miR-296-3p and further activates PRKCA–FAK–Ras, cell cycle, and EMT signaling. In clinical samples, reduced miR-296-3p is an unfavorable factor that inversely correlates with HDGF/DDX5, but not PRKCA.

Conclusions: Our study provides a novel mechanism that the miR-296-3p–PRKCA–FAK–Ras–c-Myc feedback loop modulated by HDGF/DDX5/β-catenin complex attenuates cell growth, metastasis, and chemoresistance in LADC. Clin Cancer Res; 23(20); 6336–50. ©2017 AACR.
Exposure–Response of Veliparib to Inform Phase II Trial Design in Refractory or Relapsed Patients with Hematological Malignancies
Authors: Mehrotra Shailly , Gopalakrishnan Mathangi , Gobburu Jogarao , Ji Jiuping , Greer Jacqueline M. , Piekarz Richard , Karp Judith E. , Pratz Keith W. , Rudek Michelle A.
Published: July 2017

Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated a 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure–response analysis to inform the phase II trial design.

Experimental Design: Pharmacokinetic, efficacy, and safety data from 95 patients, who were administered 10 to 100 mg b.i.d. doses of veliparib for either 8, 14, or 21 days with T+C, were utilized for exposure–efficacy (objective response and overall survival) and exposure–safety (≥grade 3 mucositis) analysis. Multivariate cox proportional hazards and logistic regression analyses were conducted. The covariates evaluated were disease status, duration of treatment, and number of prior therapies.

Results: The odds of having objective response were 1.08-fold with 1,000 ng/hr/mL increase in AUC, 1.8-fold with >8 days treatment, 2.8-fold in patients with myeloproliferative neoplasms (MPN), and 0.5-fold with ≥2 prior therapies. Based on analysis of overall survival, hazard of death decreased by 1.5% for 1,000 ng/hr/mL increase in AUC, 39% with >8 days treatment, 44% in patients with MPN, while increased by 19% with ≥2 prior therapies. The odds of having ≥grade 3 mucositis increased by 29% with 1,000 ng.h/mL increase in AUC.

Conclusions: Despite shallow exposure–efficacy relationship, doses lower than 80 mg do not exceed veliparib single agent preclinical IC50. Shallow exposure–mucositis relationship also supports the 80-mg dose. Based on benefit/risk assessment, veliparib at a dose of 80 mg b.i.d. for at least 14 days in combination with T+C is recommended to be studied in MPN patients. Clin Cancer Res; 23(21); 6421–9. ©2017 AACR.
T2–FLAIR Mismatch, an Imaging Biomarker for IDH and 1p/19q Status in Lower-grade Gliomas: A TCGA/TCIA Project
Authors: Patel Sohil H. , Poisson Laila M. , Brat Daniel J. , Zhou Yueren , Cooper Lee , Snuderl Matija , Thomas Cheddhi , Franceschi Ana M. , Griffith Brent , Flanders Adam E. , Golfinos John G. , Chi Andrew S. , Jain Rajan
Published: July 2017

Purpose: Lower-grade gliomas (WHO grade II/III) have been classified into clinically relevant molecular subtypes based on IDH and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower-grade glioma molecular subtypes.

Experimental Design: MRI scans from the TCGA/TCIA lower grade glioma database (n = 125) were evaluated by two independent neuroradiologists to assess (i) presence/absence of homogenous signal on T2WI; (ii) presence/absence of “T2–FLAIR mismatch” sign; (iii) sharp or indistinct lesion margins; and (iv) presence/absence of peritumoral edema. Metrics with moderate–substantial agreement underwent consensus review and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower-grade glioma database were analyzed for molecular–radiographic associations. A separate institutional cohort (n = 82) was analyzed to validate the T2–FLAIR mismatch sign.

Results: Among TCGA/TCIA cases, interreader agreement was calculated for lesion homogeneity [κ = 0.234 (0.111–0.358)], T2–FLAIR mismatch sign [κ = 0.728 (0.538–0.918)], lesion margins [κ = 0.292 (0.135–0.449)], and peritumoral edema [κ = 0.173 (0.096–0.250)]. All 15 cases that were positive for the T2–FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (P < 0.0001; PPV = 100%, NPV = 54%). Analysis of the validation cohort demonstrated substantial interreader agreement for the T2–FLAIR mismatch sign [κ = 0.747 (0.536–0.958)]; all 10 cases positive for the T2–FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (P < 0.00001; PPV = 100%, NPV = 76%).

Conclusions: Among lower-grade gliomas, T2–FLAIR mismatch sign represents a highly specific imaging biomarker for the IDH-mutant, 1p/19q non-codeleted molecular subtype. Clin Cancer Res; 23(20); 6078–85. ©2017 AACR.
Altered Global 5-Hydroxymethylation Status in Hidradenitis Suppurativa: Support for an Epigenetic Background
Authors: Hessam Schapoor , Sand Michael , Lang Kerstin , Käfferlein Heiko U. , Scholl Lisa , Gambichler Thilo , Skrygan Marina , Brüning Thomas , Stockfleth Eggert , Bechara Falk G.
Published: July 2017

Background: The pathogenesis of hidradenitis suppurativa (HS), with its complex inflammatory network, is still elusive. Imbalances in DNA methylation can lead to genome destabilization and have been assumed to play a role in inflammatory diseases. Global DNA methylation and hydroxymethylation have not been studied in HS yet. Objective: We conducted this study to investigate the global DNA methylation and hydroxymethylation status in lesional and perilesional HS skin compared to healthy controls. Methods: Immunohistochemical analysis was performed for 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in 30 lesional and 30 corresponding healthy-appearing perilesional HS tissue samples. We included 30 healthy subjects as an interindividual control group. Results: 5-hmC levels were significantly lower in healthy-appearing perilesional (p < 0.0001) and lesional HS skin (p < 0.0001) when compared to healthy controls. There was no significant difference between lesional HS skin and perilesional HS skin regarding 5-hmC levels (p = 0.6654). In contrast to 5-hmC, 5-mC staining showed no significant changes between the 3 groups. Univariate analysis revealed no significant association between patients' characteristics, disease severity, and the levels of 5-mC and 5-hmC. Conclusion: Our findings indicate that imbalances in DNA hydroxymethylation may play a role in the pathogenesis of HS rather than DNA methylation. Further studies are warranted to investigate the significance of DNA hydroxymethylation and the regulating enzymes in HS in order to advance our knowledge of the inflammatory network in this disease.
Communication Skills Trainings: Subjective Appraisal of Physicians from Five Cancer Centres in North Rhine, Germany
Authors: Karger Andre , Geiser Franziska , Vitinius Frank , Sonntag Bernd , Schultheis Ulrike , Hey Beate , Radbruch Lukas , Ernstmann Nicole , Petermann-Meyer Andrea
Published: July 2017

Background: Physician-patient communication is an essential component of high-quality health care provision for cancer patients. To date, communication skills training programmes have not been systematically implemented in oncology and have low physician participation rates. Methods: As a part of a needs assessment a written questionnaire was used to explore needs and preferences (structural conditions and content) regarding communication skills training programmes for physicians working in oncology settings in 5 university hospitals in North Rhine, Germany. Results: 207 physicians took part in the survey. Analyses revealed positive attitudes and high willingness to attend such training programmes, with a preference for short trainings that are compatible with clinical practice. Suggested topics included breaking bad news, conversations about death and dying and dealing with difficult emotions. Conclusion: Communication skills training approaches should not only pay attention to evidence regarding their efficacy, but also take into consideration physicians' needs and preferences. Further research is required on the subject of barriers to participation in such training programmes.
Challenges Associated with Managing End-Stage Renal Disease in Extremely Morbid Obese Patients: Case Series and Literature Review
Authors: Turgut Faruk , Abdel-Rahman Emaad M.
Published: July 2017

Obesity has grown into an epidemic across the globe. Mirroring this growth in the number of obese individuals in the general population, the prevalence of obesity and extremely morbid obesity (body mass index >50 kg/m2) is similarly rising in patients with end-stage renal disease (ESRD). Obesity, and more so, extremely morbid obesity, creates additional challenges for clinicians aiming at providing the best treatment options to patients with ESRD. Although literature is available regarding renal replacement therapy (RRT) for obese patients, literature about challenges facing clinicians managing ESRD in the extremely obese patients is lacking. Furthermore, the optimal strategies and goals for managing these patients with ESRD are not well defined. To our knowledge, no study has been done evaluating RRT options available to extremely morbid obese patients and the challenges associated with these options. Here, we report a case series and discuss the potential challenges faced by extremely obese patients with ESRD requiring RRT.