bluuebunny/crossref_metadata_2025 huggingface dataset:
Murine Gammaherpesvirus 68 LANA and SOX Homologs Counteract ATM-Driven p53 Activity during Lytic Viral Replication
Authors: Sifford Jeffrey M. , Stahl James A. , Salinas Eduardo , Forrest J. Craig
Published: December 2015

Tumor suppressor p53 is activated in response to numerous cellular stresses, including viral infection. However, whether murine gammaherpesvirus 68 (MHV68) provokes p53 during the lytic replication cycle has not been extensively evaluated. Here, we demonstrate that MHV68 lytic infection induces p53 phosphorylation and stabilization in a manner that is dependent on the DNA damage response (DDR) kinase ataxia telangiectasia mutated (ATM). The induction of p53 during MHV68 infection occurred in multiple cell types, including splenocytes of infected mice. ATM and p53 activation required early viral gene expression but occurred independently of viral DNA replication. At early time points during infection, p53-responsive cellular genes were induced, coinciding with p53 stabilization and phosphorylation. However, p53-related gene expression subsided as infection progressed, even though p53 remained stable and phosphorylated. Infected cells also failed to initiate p53-dependent gene expression and undergo apoptosis in response to treatment with exogenous p53 agonists. The inhibition of p53 responses during infection required the expression of the MHV68 homologs of the shutoff and exonuclease protein (muSOX) and latency-associated nuclear antigen (mLANA). Interestingly, mLANA, but not muSOX, was necessary to prevent p53-mediated death in MHV68-infected cells under the conditions tested. This suggests that muSOX and mLANA are differentially required for inhibiting p53 in specific settings. These data reveal that DDR responses triggered by MHV68 infection promote p53 activation. However, MHV68 encodes at least two proteins capable of limiting the potential consequences of p53 function.

IMPORTANCE
Gammaherpesviruses are oncogenic herpesviruses that establish lifelong chronic infections. Defining how gammaherpesviruses overcome host responses to infection is important for understanding how these viruses infect and cause disease. Here, we establish that murine gammaherpesvirus 68 induces the activation of tumor suppressor p53. p53 activation was dependent on the DNA damage response kinase ataxia telangiectasia mutated. Although active early after infection, p53 became dominantly inhibited as the infection cycle progressed. Viral inhibition of p53 was mediated by the murine gammaherpesvirus 68 homologs of muSOX and mLANA. The inhibition of the p53 pathway enabled infected cells to evade p53-mediated cell death responses. These data demonstrate that a gammaherpesvirus encodes multiple proteins to limit p53-mediated responses to productive viral infection, which likely benefits acute viral replication and the establishment of chronic infection.
Nipah Virus Matrix Protein Influences Fusogenicity and Is Essential for Particle Infectivity and Stability
Authors: Dietzel Erik , Kolesnikova Larissa , Sawatsky Bevan , Heiner Anja , Weis Michael , Kobinger Gary P. , Becker Stephan , von Messling Veronika , Maisner Andrea
Published: December 2015

Nipah virus (NiV) causes fatal encephalitic infections in humans. To characterize the role of the matrix (M) protein in the viral life cycle, we generated a reverse genetics system based on NiV strain Malaysia. Using an enhanced green fluorescent protein (eGFP)-expressing M protein-deleted NiV, we observed a slightly increased cell-cell fusion, slow replication kinetics, and significantly reduced peak titers compared to the parental virus. While increased amounts of viral proteins were found in the supernatant of cells infected with M-deleted NiV, the infectivity-to-particle ratio was more than 100-fold reduced, and the particles were less thermostable and of more irregular morphology. Taken together, our data demonstrate that the M protein is not absolutely required for the production of cell-free NiV but is necessary for proper assembly and release of stable infectious NiV particles.

IMPORTANCE
Henipaviruses cause a severe disease with high mortality in human patients. Therefore, these viruses can be studied only in biosafety level 4 (BSL-4) laboratories, making it more challenging to characterize their life cycle. Here we investigated the role of the Nipah virus matrix protein in virus-mediated cell-cell fusion and in the formation and release of newly produced particles. We found that even though low levels of infectious viruses are produced in the absence of the matrix protein, it is required for the release of highly infectious and stable particles. Fusogenicity of matrixless viruses was slightly enhanced, further demonstrating the critical role of this protein in different steps of Nipah virus spread.
Endobronchial actinomycosis: successful treatment with oral antibiotics
Authors: Skehan Nicole , Naeem Muhammad , Reddy Raja Vongala
Published: December 2015

This is a case report of an 84-year-old lady who presented with haemoptysis, weight loss and a right hilar mass on chest radiograph. CT scan of the chest revealed complete proximal occlusion of the right upper lobe from an endobronchial lesion consistent with a tumour. The patient was initially reluctant to undergo fibreoptic bronchoscopy as she was deemed to be unsuitable for any curative treatment of lung carcinoma. Bronchoscopy showed an exophytic necrotic tumour within the right upper lobe. Biopsies showed many bacterial colonies consistent with actinomyces and a diagnosis of endobronchial actinomycosis was made. Owing to multiple antibiotic allergies and patient refusal to have intravenous antibiotics, she was started on a course of doxycycline 200 mg once daily. There was near complete improvement in symptoms and radiographic appearances by the end of 4 months. This case highlights the importance of confirmatory diagnosis in the elderly as curable conditions are otherwise missed.
Higher body mass index is associated with plantar fasciopathy/‘plantar fasciitis’: systematic review and meta-analysis of various clinical and imaging risk factors
Authors: van Leeuwen K D B , Rogers J , Winzenberg T , van Middelkoop M
Published: December 2015

Question

What (risk) factors are associated with plantar fasciopathy (PF)?

Design

Systematic review with meta-analyses.

Participants

Patients with PF.

Factors

All factors described in prospective, case–control or cross-sectional observational studies.

Results

51 included studies (1 prospective, 46 case–control and 4 cross-sectional studies) evaluated a total of 104 variables. Pooling was possible for 12 variables. Higher body mass index (BMI) (BMI>27, OR 3.7 (95% CI 2.93 to 5.62)) in patients with PF was the only significant clinical association, and its effect was the strongest in the non-athletic subgroup. In people with PF compared to controls, pooled imaging data demonstrated a significantly thicker, hypoechogenic plantar fascia with increased vascular signal and perifascial fluid collection. In addition, people with PF were more likely to have a thicker loaded and unloaded heel fat pat, and bone findings, including a subcalcaneal spur and increased Tc-99 uptake. No significant difference was found in the extension of the first metatarsophalangeal joint.

Conclusions

We found a consistent clinical association between higher BMI and plantar fasciopathy. This association may differ between athletic and non-athletic subgroups. While consistent evidence supports a range of bone and soft tissue abnormalities, there is lack of evidence for the dogma of clinical and mechanical measures of foot and ankle function. Clinicians can use this information in shared decision-making.
Information resources to aid parental decision-making on when to seek medical care for their acutely sick child: a narrative systematic review
Authors: Neill Sarah , Roland Damian , Jones Caroline HD , Thompson Matthew , Lakhanpaul Monica
Published: December 2015

Objective

To identify the effectiveness of information resources to help parents decide when to seek medical care for an acutely sick child under 5 years of age, including the identification of factors influencing effectiveness, by systematically reviewing the literature.

Methods

5 databases and 5 websites were systematically searched using a combination of terms on children, parents, education, acute childhood illness. A narrative approach, assessing quality via the Mixed Methods Appraisal Tool, was used due to non-comparable research designs.

Results

22 studies met the inclusion criteria: 9 randomised control trials, 8 non-randomised intervention studies, 2 qualitative descriptive studies, 2 qualitative studies and 1 mixed method study. Consultation frequency (15 studies), knowledge (9 studies), anxiety/reassurance (7 studies), confidence (4 studies) satisfaction (4 studies) and antibiotic prescription (4 studies) were used as measures of effectiveness. Quality of the studies was variable but themes supported information needing to be relevant and comprehensive to enable parents to manage an episode of minor illness Interventions addressing a range of symptoms along with assessment and management of childhood illness, appeared to have the greatest impact on the reported measures. The majority of interventions had limited impact on consultation frequencies, No conclusive evidence can be drawn from studies measuring other outcomes.

Conclusions

Findings confirm that information needs to be relevant and comprehensive to enable parents to manage an episode of minor illness. Incomplete information leaves parents still needing to seek help and irrelevant information appears to reduce parents’ trust in the intervention. Interventions are more likely to be effective if they are also delivered in non-stressful environments such as the home and are coproduced with parents.
Impact of geography on the control of type 2 diabetes mellitus: a review of geocoded clinical data from general practice
Authors: Jiwa Moyez , Gudes Ori , Varhol Richard , Mullan Narelle
Published: December 2015

Objective

To review the clinical data for people with diabetes mellitus with reference to their location and clinical care in a general practice in Australia.

Materials and methods

Patient data were extracted from a general practice in Western Australia. Iterative data-cleansing steps were taken. Data were grouped into Statistical Area level 1 (SA1), designated as the smallest geographical area associated with the Census of Population and Housing. The data were analysed to identify if SA1s with people aged 70 years and older, and with relatively high glycosylated haemoglobin (HbA1c) were significantly clustered, and whether this was associated with their medical consultation rate and treatment. The analysis included Cluster and Outlier Analysis using Moran's I test.

Results

The overall median age of the population was 70 years with more males than females, 53% and 47%, respectively. Older people (>70 years) with relatively high HbA1c comprised 9.3% of all people with diabetes in the sample, and were clustered around two ‘hotspot’ locations. These 111 patients do not attend the practice more or less often than people with diabetes living elsewhere in the practice (p=0.098). There was some evidence that they were more likely to be recorded as having consulted with regard to other chronic diseases. The average number of prescribed medicines over a 13-month time period, per person in the hotspots, was 4.6 compared with 5.1 in other locations (p=0.26). Their prescribed therapy was deemed to be consistent with the management of people with diabetes in other locations with reference to the relevant diabetes guidelines.

Conclusions

Older patients with relatively high HbA1c are clustered in two locations within the practice area. Their hyperglycaemia and ongoing cardiovascular risk indicates causes other than therapeutic inertia. The causes may be related to the social determinants of health, which are influenced by geography.
Protocol for a mixed-methods longitudinal study to identify factors influencing return to work in the over 50s participating in the UK Work Programme: Supporting Older People into Employment (SOPIE)
Authors: Brown Judith , Neary Joanne , Katikireddi Srinivasa Vittal , Thomson Hilary , McQuaid Ronald W , Leyland Alastair H , Frank John , Jeavons Luke , de Pellette Paul , Kiran Sibel , Macdonald Ewan B
Published: December 2015

Introduction

Increasing employment among older workers is a policy priority given the increase in life expectancy and the drop in labour force participation after the age of 50. Reasons for this drop are complex but include poor health, age discrimination, inadequate skills/qualifications and caring roles; however, limited evidence exists on how best to support this group back to work. The Work Programme is the UK Government's flagship policy to facilitate return to work (RTW) among those at risk of long-term unemployment. ‘Supporting Older People Into Employment’ (SOPIE) is a mixed-methods longitudinal study involving a collaboration between academics and a major Work Programme provider (Ingeus). The study will investigate the relationship between health, worklessness and the RTW process for the over 50s.

Methods and analysis

There are three main study components. Embedded fieldwork will document the data routinely collected by Ingeus and the key interventions/activities delivered. The quantitative study investigates approximately 14 000 individuals (aged 16–64 years, with 20% aged over 50) who entered the Ingeus Work Programme (referred to as ‘clients’) in a 16-month period in Scotland and were followed up for 2 years. Employment outcomes (including progression towards work) and how they differ by client characteristics (including health), intervention components received and external factors will be investigated. The qualitative component will explore the experiences of clients and Ingeus staff, to better understand the interactions between health and (un)employment, Work Programme delivery, and how employment services can be better tailored to the needs of the over 50s.

Ethics and dissemination

Ethical approval was received from the University of Glasgow College of Social Sciences Research Ethics Committee (application number 400140186).

Results

Results will be disseminated through journal articles, national and international conferences. Findings will inform current and future welfare-to-work and job retention initiatives to extend healthy working lives.
Adenoma detection with Endocuff colonoscopy versus conventional colonoscopy: a multicentre randomised controlled trial
Authors: van Doorn SC , van der Vlugt M , Depla ACTM , Wientjes CA , Mallant-Hent RC , Siersema PD , Tytgat KMAJ , Tuynman H , Kuiken SD , Houben GMP , Stokkers PCF , Moons LMG , Bossuyt PMM , Fockens P , Mundt MW , Dekker E
Published: December 2015

Background and aims

Colonoscopy is the current reference standard for the detection of colorectal neoplasia, but nevertheless adenomas remain undetected. The Endocuff, an endoscopic cap with plastic projections, may improve colonic visualisation and adenoma detection. The aim of this study was to compare the mean number of adenomas per patient (MAP) and the adenoma detection rate (ADR) between Endocuff-assisted colonoscopy (EAC) and conventional colonoscopy (CC).

Methods

We performed a multicentre, randomised controlled trial in five hospitals and included fecal immonochemical test (FIT)-positive screening participants as well as symptomatic patients (>45 years). Consenting patients were randomised 1:1 to EAC or CC. All colonoscopies were performed by experienced colonoscopists (≥500 colonoscopies) who were trained in EAC. All colonoscopy quality indicators were prospectively recorded.

Findings

Of the 1063 included patients (52% male, median age 65 years), 530 were allocated to EAC and 533 to CC. More adenomas were detected with EAC, 722 vs 621, but the gain in MAP was not significant: on average 1.36 per patient in the EAC group versus 1.17 in the CC group (p=0.08). In a per-protocol analysis, the gain was 1.44 vs 1.19 (p=0.02), respectively. In the EAC group, 275 patients (52%) had one or more adenomas detected versus 278 in the CC group (52%; p=0.92). For advanced adenomas these numbers were 109 (21%) vs 117 (22%). The adjusted caecal intubation rate was lower with EAC (94% vs 99%; p<0.001), however when allowing crossover from EAC to CC, they were similar in both groups (98% vs 99%; p value=0.25).

Interpretation

Though more adenomas are detected with EAC, the routine use of Endocuff does not translate in a higher number of patients with one or more adenomas detected. Whether increased detection ultimately results in a lower rate of interval carcinomas is not yet known.

Trial registration number

http://www.trialregister.nlDutch Trial Register: NTR3962.
The physical activity profiles of South Asian ethnic groups in England
Authors: Bhatnagar Prachi , Townsend Nick , Shaw Alison , Foster Charlie
Published: December 2015

Background

To identify what types of activity contribute to overall physical activity in South Asian ethnic groups and how these vary according to sex and age. We used the White British ethnic group as a comparison.

Methods

Self-reported physical activity was measured in the Health Survey for England 1999 and 2004, a nationally representative, cross-sectional survey that boosted ethnic minority samples in these years. We merged the two survey years and analysed data from 19 476 adults. The proportions of total physical activity achieved through walking, housework, sports and DIY activity were calculated. We stratified by sex and age group and used analysis of variances to examine differences between ethnic groups, adjusted for the socioeconomic status.

Results

There was a significant difference between ethnic groups for the contributions of all physical activity domains for those aged below 55 years, with the exception of walking. In women aged 16–34 years, there was no significant difference in the contribution of walking to total physical activity (p=0.38). In the 35–54 age group, Bangladeshi males have the highest proportion of total activity from walking (30%). In those aged over 55 years, the proportion of activity from sports was the lowest in all South Asian ethnic groups for both sexes.

Conclusions

UK South Asians are more active in some ways that differ, by age and sex, from White British, but are similarly active in other ways. These results can be used to develop targeted population level interventions for increasing physical activity levels in adult UK South Asian populations.
International Committee on Mental Health in Cystic Fibrosis: Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus statements for screening and treating depression and anxiety
Authors: Quittner Alexandra L , Abbott Janice , Georgiopoulos Anna M , Goldbeck Lutz , Smith Beth , Hempstead Sarah E , Marshall Bruce , Sabadosa Kathryn A , Elborn Stuart
Published: December 2015

Studies measuring psychological distress in individuals with cystic fibrosis (CF) have found high rates of both depression and anxiety. Psychological symptoms in both individuals with CF and parent caregivers have been associated with decreased lung function, lower body mass index, worse adherence, worse health-related quality of life, more frequent hospitalisations and increased healthcare costs. To identify and treat depression and anxiety in CF, the CF Foundation and the European CF Society invited a panel of experts, including physicians, psychologists, psychiatrists, nurses, social workers, a pharmacist, parents and an individual with CF, to develop consensus recommendations for clinical care. Over 18 months, this 22-member committee was divided into four workgroups: Screening; Psychological Interventions; Pharmacological Treatments and Implementation and Future Research, and used the Population, Intervention, Comparison, Outcome methodology to develop questions for literature search and review. Searches were conducted in PubMed, PsychINFO, ScienceDirect, Google Scholar, Psychiatry online and ABDATA by a methodologist at Dartmouth. The committee reviewed 344 articles, drafted statements and set an 80% acceptance for each recommendation statement as a consensus threshold prior to an anonymous voting process. Fifteen guideline recommendation statements for screening and treatment of depression and anxiety in individuals with CF and parent caregivers were finalised by vote. As these recommendations are implemented in CF centres internationally, the process of dissemination, implementation and resource provision should be closely monitored to assess barriers and concerns, validity and use.
Urinary excretion of calcium and phosphate in dogs with pituitary‐dependent hypercortisolism: case control study in 499 dogs
Authors: Fracassi F. , Malerba E. , Furlanello T. , Caldin M.
Published: December 2015

Pituitary‐dependent hypercortisolism (PDH) in dogs is frequently associated with high serum phosphate and parathormone concentrations which are in turn associated with prognosis and clinical presentation. The pathogenesis of such abnormalities remains unknown. The aim of the present study was to evaluate the serum and urinary concentrations and the urinary fractional excretion of phosphate and calcium in dogs with PDH. Medical records of newly diagnosed PDH dogs before treatment from one referral centre were retrospectively evaluated. One clinically normal and one sick dog for each dog with PDH were included as controls. One hundred and sixty‐seven dogs with PDH were included. The serum phosphate concentration in PDH dogs was significantly (P<0.0001) higher compared with clinically normal control dogs (CNDs) and sick control dogs (SCDs). The serum calcium concentration in PDH dogs was significantly higher compared with SCDs but not different compared with CNDs. Urinary fractional excretion of phosphate in PDH dogs was significantly lower compared with CNDs and SCDs. Urinary fractional excretion of calcium in PDH dogs was significantly higher compared with CNDs and SCDs. In conclusion, PDH dogs have lower phosphaturia and higher calciuria compared with control dogs. These findings suggest that, at least in part, high serum phosphate concentrations are related to the renal retention of phosphate.
Affine connection form of Regge calculus
Authors: Khatsymovsky V. M.
Published: December 2015

Regge action is represented analogously to how the Palatini action for general relativity (GR) as some functional of the metric and a general connection as independent variables represents the Einstein–Hilbert action.

The piecewise flat (or simplicial) spacetime of Regge calculus is equipped with some world coordinates and some piecewise affine metric which is completely defined by the set of edge lengths and the world coordinates of the vertices. The conjugate variables are the general nondegenerate matrices on the three-simplices which play the role of a general discrete connection. Our previous result on some representation of the Regge calculus action in terms of the local Euclidean (Minkowsky) frame vectors and orthogonal connection matrices as independent variables is somewhat modified for the considered case of the general linear group GL(4, R) of the connection matrices.

As a result, we have some action invariant w.r.t. arbitrary change of coordinates of the vertices (and related GL(4, R) transformations in the four-simplices). Excluding GL(4, R) connection from this action via the equations of motion we have exactly the Regge action for the considered spacetime.
Do atomic electrons fall to the center of multi-electron atoms?
Authors: Manoukian E. B.
Published: December 2015

This communication is involved in providing, via a modern approach, a direct derivation that, with 100% probability, none of the atomic electrons falls to the center of multi-electron atoms — a problem which has been around historically in the quantum mechanics of atoms since the birth of the former and has, undoubtedly, come across every learner of the subject since then. No need arises for explicit eigenfunctions.
Developing digital fieldwork technologies at the British Geological Survey
Authors: Jordan Colm J. , Napier Bruce
Published: December 2015

Geological Surveys are faced with budget constraints and calls for efficiency gains; the effective application of digital techniques is often seen as a route to meeting these demands while increasing the value of outcrop studies and reducing the inherent subsurface uncertainty. The British Geological Survey may be the oldest national Survey in the world (established in 1835); however, developing and implementing new, innovative and efficient technologies for fieldwork is a high priority. Efficient tools for capturing, integrating, manipulating and disseminating outcrop data and information are imperative to enable geoscientists to increase their understanding of geological processes and therefore to reduce subsurface uncertainty and risk. Systems for capturing structured digital field data and for visualizing and interacting with large datasets are increasingly being utilized by geoscientists in the UK and internationally. Augmented reality and unmanned aerial vehicles are amongst the developing technologies being explored for future operational implementation. This paper describes the digital field mapping (BGS·SIGMAmobile) and visualization (GeoVisionary) systems and refers to a case study outlining their contribution to reducing uncertainty and risk in hydrocarbon exploration.
Absence of Dystrophin Disrupts Skeletal Muscle Signaling: Roles of Ca2+, Reactive Oxygen Species, and Nitric Oxide in the Development of Muscular Dystrophy
Authors: Allen David G. , Whitehead Nicholas P. , Froehner Stanley C.
Published: December 2015

Dystrophin is a long rod-shaped protein that connects the subsarcolemmal cytoskeleton to a complex of proteins in the surface membrane (dystrophin protein complex, DPC), with further connections via laminin to other extracellular matrix proteins. Initially considered a structural complex that protected the sarcolemma from mechanical damage, the DPC is now known to serve as a scaffold for numerous signaling proteins. Absence or reduced expression of dystrophin or many of the DPC components cause the muscular dystrophies, a group of inherited diseases in which repeated bouts of muscle damage lead to atrophy and fibrosis, and eventually muscle degeneration. The normal function of dystrophin is poorly defined. In its absence a complex series of changes occur with multiple muscle proteins showing reduced or increased expression or being modified in various ways. In this review, we will consider the various proteins whose expression and function is changed in muscular dystrophies, focusing on Ca2+-permeable channels, nitric oxide synthase, NADPH oxidase, and caveolins. Excessive Ca2+entry, increased membrane permeability, disordered caveolar function, and increased levels of reactive oxygen species are early changes in the disease, and the hypotheses for these phenomena will be critically considered. The aim of the review is to define the early damage pathways in muscular dystrophy which might be appropriate targets for therapy designed to minimize the muscle degeneration and slow the progression of the disease.
General Anaesthesia and Emergency Surgery in Heart Transplant Recipient
Authors: Ejtehadi Farshid , Carter Sharon , Evans Lucy , Zia Mubashar , Bradpiece Howard
Published: December 2015

The number of patients who undergo heart transplant is increasing. Due to surgical emergencies, many of those may require general anesthesia in hospitals where subspecialized anesthetists may not be available. We present a case of a male patient who had heart transplant and required general anesthesia for emergency appendicectomy. Physiology of the heart after transplant, preoperative considerations, and postoperative monitoring has been discussed in our report.
The Role of Descending Modulation in Manual Therapy and Its Analgesic Implications: A Narrative Review
Authors: Vigotsky Andrew D. , Bruhns Ryan P.
Published: December 2015

Manual therapy has long been a component of physical rehabilitation programs, especially to treat those in pain. The mechanisms of manual therapy, however, are not fully understood, and it has been suggested that its pain modulatory effects are of neurophysiological origin and may be mediated by the descending modulatory circuit. Therefore, the purpose of this review is to examine the neurophysiological response to different types of manual therapy, in order to better understand the neurophysiological mechanisms behind each therapy’s analgesic effects. It is concluded that different forms of manual therapy elicit analgesic effects via different mechanisms, and nearly all therapies appear to be at least partially mediated by descending modulation. Additionally, future avenues of mechanistic research pertaining to manual therapy are discussed.
Interstitial Lung Disease in Werner Syndrome: A Case Report of a 55-Year-Old Male Patient
Authors: Goletto Tiphaine , Crockett Flora , Aractingi Selim , Toper Cecile , Senet Patricia , Cadranel Jacques , Naccache Jean-Marc
Published: December 2015

Werner syndrome (WS) is a progeroid or premature aging syndrome characterized by early onset of age-related pathologies and cancer. The average life expectancy of affected people is 52.8 years and tends to increase. The major causes of death are malignancy and myocardial infarction. Increased telomere attrition and decay are thought to play a causative role in the clinical and pathological manifestations of the disease. Although telomere length, with or without germline mutation, is known to be associated with interstitial lung disease, the latter is not associated with WS. To the best of our knowledge, we report the first case describing a WS patient with fatal ILD. This case suggests that older patients with WS could develop ILD. Clinical outcome of WS patients may thus be improved by counselling them regarding smoking cessation or other exposure and by proposing antifibrotic therapy.
Reverse Skyline Computation over Sliding Windows
Authors: Xin Junchang , Wang Zhiqiong , Bai Mei , Wang Guoren
Published: December 2015

Reverse skyline queries have been used in many real-world applications such as business planning, market analysis, and environmental monitoring. In this paper, we investigated how to efficiently evaluate continuous reverse skyline queries over sliding windows. We first theoretically analyzed the inherent properties of reverse skyline on data streams and proposed a novel pruning technique to reduce the number of data points preserved for processing continuous reverse skyline queries. Then, an efficient approach, called Semidominance Based Reverse Skyline (SDRS), was proposed to process continuous reverse skyline queries. Moreover, an extension was also proposed to handlen-of-Nand(n1,n2)-of-Nreverse skyline queries. Our extensive experimental studies have demonstrated the efficiency as well as effectiveness of the proposed approach with various experimental settings.
Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma
Authors: Liao Chen-Yi , Lee Ching-Chang , Tsai Chi-chang , Hsueh Chao-Wen , Wang Chih-Chiang , Chen I-Hung , Tsai Ming-Kai , Liu Mei-Yu , Hsieh An-Tie , Su Kuan-Jen , Wu Hau-Ming , Huang Shih-Chung , Wang Yi-Chen , Wang Chien-Yao , Huang Shu-Fang , Yeh Yen-Cheng , Ben Ren-Jy , Chien Shang-Tao , Hsu Chin-Wen , Kuo Wu-Hsien
Published: December 2015

We would like to highlight the application of natural products to hepatocellular carcinoma (HCC). We will focus on the natural products known as flavonoids, which target this disease at different stages of hepatocarcinogenesis. In spite of the use of chemotherapy and radiotherapy in treating HCC, patients with HCC still face poor prognosis because of the nature of multidrug resistance and toxicity derived from chemotherapy and radiotherapy. Flavonoids can be found in many vegetables, fruits, and herbal medicines that exert their different anticancer effects via different intracellular signaling pathways and serve as antioxidants. In this review, we will discuss seven common flavonoids that exert different biological effects against HCC via different pathways.
Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis
Authors: Guo Yabin , Updegraff Barrett L. , Park Sunho , Durakoglugil Deniz , Cruz Victoria H. , Maddux Sarah , Hwang Tae Hyun , O'Donnell Kathryn A.
Published: December 2015

Aberrant signaling through cytokine receptors and their downstream signaling pathways is a major oncogenic mechanism underlying hematopoietic malignancies. To better understand how these pathways become pathologically activated and to potentially identify new drivers of hematopoietic cancers, we developed a high-throughput functional screening approach using ex vivo mutagenesis with the Sleeping Beauty transposon. We analyzed over 1,100 transposon-mutagenized pools of Ba/F3 cells, an IL3-dependent pro-B-cell line, which acquired cytokine independence and tumor-forming ability. Recurrent transposon insertions could be mapped to genes in the JAK/STAT and MAPK pathways, confirming the ability of this strategy to identify known oncogenic components of cytokine signaling pathways. In addition, recurrent insertions were identified in a large set of genes that have been found to be mutated in leukemia or associated with survival, but were not previously linked to the JAK/STAT or MAPK pathways nor shown to functionally contribute to leukemogenesis. Forced expression of these novel genes resulted in IL3-independent growth in vitro and tumorigenesis in vivo, validating this mutagenesis-based approach for identifying new genes that promote cytokine signaling and leukemogenesis. Therefore, our findings provide a broadly applicable approach for classifying functionally relevant genes in diverse malignancies and offer new insights into the impact of cytokine signaling on leukemia development. Cancer Res; 76(4); 773–86. ©2015 AACR.
Integrated Genomic Analysis of Pancreatic Ductal Adenocarcinomas Reveals Genomic Rearrangement Events as Significant Drivers of Disease
Authors: Murphy Stephen J. , Hart Steven N. , Halling Geoffrey C. , Johnson Sarah H. , Smadbeck James B. , Drucker Travis , Lima Joema Felipe , Rohakhtar Fariborz Rakhshan , Harris Faye R. , Kosari Farhad , Subramanian Subbaya , Petersen Gloria M. , Wiltshire Timothy D. , Kipp Benjamin R. , Truty Mark J. , McWilliams Robert R. , Couch Fergus J. , Vasmatzis George
Published: December 2015

Many somatic mutations have been detected in pancreatic ductal adenocarcinoma (PDAC), leading to the identification of some key drivers of disease progression, but the involvement of large genomic rearrangements has often been overlooked. In this study, we performed mate pair sequencing (MPseq) on genomic DNA from 24 PDAC tumors, including 15 laser-captured microdissected PDAC and 9 patient-derived xenografts, to identify genome-wide rearrangements. Large genomic rearrangements with intragenic breakpoints altering key regulatory genes involved in PDAC progression were detected in all tumors. SMAD4, ZNF521, and FHIT were among the most frequently hit genes. Conversely, commonly reported genes with copy number gains, including MYC and GATA6, were frequently observed in the absence of direct intragenic breakpoints, suggesting a requirement for sustaining oncogenic function during PDAC progression. Integration of data from MPseq, exome sequencing, and transcriptome analysis of primary PDAC cases identified limited overlap in genes affected by both rearrangements and point mutations. However, significant overlap was observed in major PDAC-associated signaling pathways, with all PDAC exhibiting reduced SMAD4 expression, reduced SMAD-dependent TGFβ signaling, and increased WNT and Hedgehog signaling. The frequent loss of SMAD4 and FHIT due to genomic rearrangements strongly implicates these genes as key drivers of PDAC, thus highlighting the strengths of an integrated genomic and transcriptomic approach for identifying mechanisms underlying disease initiation and progression. Cancer Res; 76(3); 749–61. ©2015 AACR.
GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells
Authors: Li Chong , Du Ying , Yang Zhao , He Luyun , Wang Yanying , Hao Lu , Ding Mingxia , Yan Ruping , Wang Jiansong , Fan Zusen
Published: December 2015

The existence of bladder cancer stem cells (BCSC) has been suggested to underlie bladder tumor initiation and recurrence. Sonic Hedgehog (SHH) signaling has been implicated in promoting cancer stem cell (CSC) self-renewal and is activated in bladder cancer, but its impact on BCSC maintenance is unclear. In this study, we generated a mAb (BCMab1) against CD44+ human bladder cancer cells that recognizes aberrantly glycosylated integrin α3β1. The combination of BCMab1 with an anti-CD44 antibody identified a BCMab1+CD44+ cell subpopulation as BCSCs with stem cell–like properties. Gene expression analysis revealed that the hedgehog pathway was activated in the BCMab1+CD44+ subpopulation and was required for BCSC self-renewal. Furthermore, the glycotransferase GALNT1 was highly expressed in BCMab1+CD44+ cells and correlated with clinicopathologic features of bladder cancers. Mechanistically, GALNT1 mediated O-linked glycosylation of SHH to promote its activation, which was essential for the self-renewal maintenance of BCSCs and bladder tumorigenesis. Finally, intravesical instillation of GALNT1 siRNA and the SHH inhibitor cyclopamine exerted potent antitumor activity against bladder tumor growth. Taken together, our findings identify a BCSC subpopulation in human bladder tumors that appears to be responsive to the inhibition of GALNT1 and SHH signaling, and thus highlight a potential strategy for preventing the rapid recurrence typical in patients with bladder cancer. Cancer Res; 76(5); 1273–83. ©2015 AACR.
miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer
Authors: Adams Brian D. , Wali Vikram B. , Cheng Christopher J. , Inukai Sachi , Booth Carmen J. , Agarwal Seema , Rimm David L. , Győrffy Balázs , Santarpia Libero , Pusztai Lajos , Saltzman W. Mark , Slack Frank J.
Published: December 2015

Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency driver mutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell–like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR-34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c-SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC. Cancer Res; 76(4); 927–39. ©2015 AACR.
The Influence of Exercise on the Insulin-like Growth Factor Axis in Oncology: Physiological Basis, Current, and Future Perspectives
Authors: Devin James L. , Bolam Kate A. , Jenkins David G. , Skinner Tina L.
Published: December 2015

Exercise and physical activity have been shown to reduce the risk of many common cancers and strongly influence tumor biology. A cause–effect mechanism explaining this relationship is dependent on cellular pathways that can influence tumor growth and are exercise responsive. The insulin-like growth factor (IGF) axis is reported to promote the development and progression of carcinomas through cellular signaling in cancerous tissues. This review summarizes the physiologic basis of the role of the IGF axis in oncology and the influence of exercise on this process. We examined the effects of exercise prescription on the IGF axis in cancer survivors by evaluating the current scope of the literature. The current research demonstrates a remarkable heterogeneity and inconsistency in the responses of the IGF axis to exercise in breast, prostate, and colorectal cancer survivors. Finally, this review presents an in-depth exploration of the physiologic basis and mechanistic underpinnings of the seemingly disparate relationship between exercise and the IGF axis in oncology. Although there is currently insufficient evidence to categorize the effects of exercise prescription on the IGF axis in cancer survivors, the inconsistency of results suggests a multifaceted relationship, the complexities of which are considered in this review. Cancer Epidemiol Biomarkers Prev; 25(2); 239–49. ©2015 AACR.
Circulating Biomarkers of Gut Barrier Function: Correlates and Nonresponse to Calcium Supplementation among Colon Adenoma Patients
Authors: Yang Baiyu , Bostick Roberd M. , Tran Hao Quang , Gewirtz Andrew T. , Campbell Peter T. , Fedirko Veronika
Published: December 2015

Background: Gut barrier dysfunction contributes to several gastrointestinal disorders, including colorectal cancer, but factors associated with intestinal hyperpermeability have been minimally studied in humans.

Methods: We tested the effects of two doses of calcium (1.0 or 2.0 g/d) on circulating biomarkers of gut permeability [anti-flagellin and anti-lipopolysaccharide (LPS) Ig, measured via ELISA] over a 4-month treatment period among colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193), and evaluated the factors associated with baseline levels of these biomarkers.

Results: Baseline concentrations of anti-flagellin IgA and anti-LPS IgA were, respectively, statistically significantly proportionately higher by 11.8% and 14.1% among men, 31.3% and 39.8% among those with a body mass index ≥ 35 kg/m2, and 19.9% and 22.0% among those in the upper relative to the lowest sex-specific tertile of waist circumference. A combined permeability score (the summed optical densities of all four biomarkers) was 24.3% higher among women in the upper tertile of plasma C–reactive protein (Ptrend < 0.01). We found no appreciable effects of supplemental calcium on anti-flagellin or anti-LPS Igs.

Conclusions: Our results suggest that (i) men and those with higher adiposity may have greater gut permeability, (ii) gut permeability and systemic inflammation may be directly associated with one another, and (iii) supplemental calcium may not modify circulating levels of gut permeability biomarkers within 4 months.

Impact: Our findings may improve the understanding of the factors that influence gut permeability to inform development of treatable biomarkers of risk for colorectal cancer and other health outcomes. Cancer Epidemiol Biomarkers Prev; 25(2); 318–26. ©2015 AACR.
Summer Peaks in Uptake of Human Papillomavirus and Other Adolescent Vaccines in the United States
Authors: Moss Jennifer L. , Reiter Paul L. , Rimer Barbara K. , Ribisl Kurt M. , Brewer Noel T.
Published: December 2015

Background: Seasonality in human papillomavirus (HPV) vaccination could have a large impact on national cancer prevention efforts. We hypothesized that uptake of HPV vaccine and other adolescent vaccines in the United States would be highest in the summer.

Methods: Data came from health care provider–verified vaccination records for 70,144 adolescents (ages 13–17 years) from the 2008 to 2012 versions of the National Immunization Survey-Teen. Using the Edwards method for testing annual trends, we examined seasonal patterns in the uptake of HPV and other recommended adolescent vaccines [tetanus, diphtheria, and pertussis (Tdap) booster and meningococcal vaccine]. HPV vaccine initiation (receipt of the first of the three-dose series) data were for female adolescents.

Results: Uptake for HPV and other adolescent vaccines peaked in the summer across years and states (all P < 0.001). Uptake was five times as frequent at the peak as at the trough for HPV vaccine, and HPV vaccine initiation was highest in June, July, and August (percent of doses delivered in these months: 38.7%). The same pattern existed for Tdap booster and meningococcal vaccine. Concomitant (same-day) vaccination of HPV vaccine with other adolescent vaccines also demonstrated summer peaks each year nationally (all P < 0.001).

Conclusion: Uptake of adolescent vaccines increased dramatically in summer months. These summer peaks are an important opportunity for interventions focused on concomitant vaccination.

Impact: The potential cancer prevention impact of HPV vaccination programs could be increased, for example, by delivering messages about concomitant vaccination during the summer, when adolescents and their parents might be most open to them. Cancer Epidemiol Biomarkers Prev; 25(2); 274–81. ©2015 AACR.
The Prognostic and Predictive Value of Soluble Type IV Collagen in Colorectal Cancer: A Retrospective Multicenter Study
Authors: Rolff Hans Christian , Christensen Ib Jarle , Vainer Ben , Svendsen Lars Bo , Eefsen Rikke Løvendahl , Wilhelmsen Michael , Lund Ida Katrine , Høyer-Hansen Gunilla , Nielsen Hans Jørgen , Illemann Martin
Published: December 2015

Purpose: To investigate the prognostic and predictive biomarker value of type IV collagen in colorectal cancer.

Experimental Design: Retrospective evaluation of two independent cohorts of patients with colorectal cancer included prospectively in 2004–2005 (training set) and 2006–2008 (validation set). Plasma samples were available from 297 (training set) and 482 (validation set) patients. Type IV collagen determinations were performed using an ELISA. From the training set, 222 tumors were available for IHC. Clinical and follow-up data were retrieved from patient files and national registries.

Results: High levels of type IV collagen showed independent prognostic significance in both cohorts with hazard ratios (HRs; for a one-unit change on the log base 2 scale) of 2.25 [95% confidence intervals (CIs), 1.78–2.84; P < 0.0001] and 2.24 (95% CI, 1.75–2.86; P < 0.0001) for the training and validation set, respectively. The prognostic impact was present both in patients with metastatic and nonmetastatic disease. The predictive value of the marker was investigated in stage II and III patients. In the training set, type IV collagen was prognostic both in the subsets of patients receiving and not receiving adjuvant antineoplastic therapy. However, in the validation set, the prognostic effect of the marker vanished when looking at patients who received adjuvant antineoplatic therapy (HR 0.90; 95% CI, 0.42–1.93) but was still present in the group not receiving adjuvant chemotherapy (HR 2.88; 95% CI, 1.98–4.21).

Conclusions: The results indicate clinical validity of type IV collagen as a prognostic biomarker in colorectal cancer, although the suggested predictive role of the marker should be validated. Clin Cancer Res; 22(10); 2427–34. ©2015 AACR.