bluuebunny/crossref_metadata_2025 huggingface dataset:
141: THE IMPACT OF THE EFFECTIVENESS OF THE METHODS OF DISTRACTION IN THE MANAGEMENT OF PAIN AND ANXIETY OF VENIPUNCTURE IN CHILDREN
Authors: Keyhaniazar Elham , Seyyedrasooly Alehe , Vahedi Pedram , Rooeintan Nahid
Published: August 2017

Background and aims:

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage occurs and the most common venous catheter placement procedure is painful in the area of ​​children. Children's pain relief is a priority for nursing care. Distraction can lead to various ways to manage pain and anxiety in children.

Methods:

The review of the literature between 2000 and 2016 with a focus on distraction, pain management – anxiety and intravenous injections databases scholar Google, PubMed, ISI, Cochrane, Sid and conflicting results in this regard, there magiran.

Results:

The study findings. kaperlii (2007) to “determine the effect of music on children's distress and pain during blood” showed that pain intensity was significantly reduced in the intervention group . In the study Hassan pour (2006) with the aim of “comparison of distraction and cryotherapy” showed that both methods are effective in reducing pain caused by injection. In the press (2003) Listen to the song as one of the conductors of distraction techniques, the pain of venipuncture in children 16–6 years old children to the emergency department reduced But significant differences between the intervention and control groups for pain levels were reported.

Conclusion:

Given the importance of pain control in children and the effects of drug treatments with regard to this matter that the use of non-pharmacological approaches to manage pain and anxiety can be useful and The basic role of nurses in pain management for children during painful procedures such as venipuncture, using distraction methods in different ways can be induced by intravenous administration of pain and anxiety in children is effective.
Analysis of the potential for point-of-care test to enable individualised treatment of infections caused by antimicrobial-resistant and susceptible strains ofNeisseria gonorrhoeae: a modelling study
Authors: Turner Katy ME , Christensen Hannah , Adams Elisabeth J , McAdams David , Fifer Helen , McDonnell Anthony , Woodford Neil
Published: August 2017

Objective

To create a mathematical model to investigate the treatment impact and economic implications of introducing an antimicrobial resistance point-of-care test (AMR POCT) for gonorrhoea as a way of extending the life of current last-line treatments.

Design

Modelling study.

Setting

England.

Population

Patients accessing sexual health services.

Interventions

Incremental impact of introducing a hypothetical AMR POCT that could detect susceptibility to previous first-line antibiotics, for example, ciprofloxacin or penicillin, so that patients are given more tailored treatment, compared with the current situation where all patients are given therapy with ceftriaxone and azithromycin. The hypothetical intervention was assessed using a mathematical model developed in Excel. The model included initial and follow-up attendances, loss to follow-up, use of standard or tailored treatment, time taken to treatment and the costs of testing and treatment.

Main outcome measures

Number of doses of ceftriaxone saved, mean time to most appropriate treatment, mean number of visits per (infected) patient, number of patients lost to follow-up and total cost of testing.

Results

In the current situation, an estimated 33 431 ceftriaxone treatments are administered annually and 792 gonococcal infections remain untreated due to loss to follow-up. The use of an AMR POCT for ciprofloxacin could reduce these ceftriaxone treatments by 66%, and for an AMR POCT for penicillin by 79%. The mean time for patients receiving an antibiotic treatment is reduced by 2 days in scenarios including POCT and no positive patients remain untreated through eliminating loss to follow-up. Such POCTs are estimated to add £34 million to testing costs, but this does not take into account reductions in costs of repeat attendances and the reuse of older, cheaper antimicrobials.

Conclusions

The introduction of AMR POCT could allow clinicians to discern between the majority of gonorrhoea-positive patients with strains that could be treated with older, previously abandoned first-line treatments, and those requiring our current last-line dual therapy. Such tests could extend the useful life of dual ceftriaxone and azithromycin therapy, thus pushing back the time when gonorrhoea may become untreatable.
Rural emergency care 360°: mobilising healthcare professionals, decision-makers, patients and citizens to improve rural emergency care in the province of Quebec, Canada: a qualitative study protocol
Authors: Fleet Richard , Dupuis Gilles , Fortin Jean-Paul , Gravel Jocelyn , Ouimet Mathieu , Poitras Julien , Légaré France
Published: August 2017

Introduction

Emergency departments (EDs) are an important safety net for rural populations. Results of our earlier studies suggest that rural Canadian hospitals have limited access to advanced imaging services and intensive care units and that patients are transferred over large distances. They also revealed significant geographical variations in rural services. In the absence of national standards, our studies raise questions about inequities in rural access to emergency services and the risks for citizens. Our goal is to build recommendations for improving services by mobilising stakeholders interested in rural emergency care. With help and full engagement of stakeholders, we will (1) identify solutions for improving quality and performance in rural EDs; (2) formulate and prioritise recommendations; (3) transfer knowledge of the recommendations to rural EDs and support operationalisation and (4) assess knowledge transfer and explore further impacts of this participatory action research project.

Methodology

We will use a participatory action research approach. We will plan for a governance structure that includes all stakeholdersâ€™ representatives, so throughout this project, stakeholders are fully engaged at every step. Our sample will be 26 EDs in rural Quebec. We will conduct semistructured individual and focus group interviews with relevant and representative participants, including patients and citizens (estimated n=200). Interviews will be thematically analysed to extract potential solutions and other qualitative information.

An expert panel (Â±15) will use an analysis grid to develop consensus recommendations from solutions suggested and will evaluate feasibility, impacts, costs, conditions for implementation and establish monitoring indicators. Recommendations will be transferred to stakeholders using tailored knowledge translation strategies (web platform, meetings and so on).

Discussion and expected results

This study will result in a comprehensive consensus list of feasible and high-priority recommendations enabling decision-makers in emergency care to implement improvements in rural emergency care in Quebec.

Ethics and dissemination

This protocol has been approved by the CSSS Alphonse-Desjardins research ethics committee (Project number: MP 2017-009). The qualitative material will be kept confidential and the data will be presented in a way that respects confidentiality. The dissemination plan for the study includes publications in scientific and professional journals. We will also use social media to disseminate our findings and activities such as communications in public conferences.
Individual, social and environmental determinants of sleep among women: protocol for a systematic review and meta-analysis
Authors: Vézina-Im Lydi-Anne , Moreno Jennette P , Thompson Debbe , Nicklas Theresa A , Baranowski Tom
Published: August 2017

Introduction

Sleep is important to promote optimal health and avoid negative health outcomes. Short-duration and low-quality sleep may be more common and more detrimental among women compared with men. Identifying the determinants of behaviour is one of the first steps in designing effective interventions. To our knowledge, no systematic review has identified the individual, social and environmental determinants of sleep among adult women.

Methods and analysis

Studies reporting data on adult women from 18 to 64 years of age will be included. On the basis of ecological models of health behaviour and sleep, the types of determinants that will be included in the review are individual (eg, demographic, psychological and behavioural), social (eg, family) and environmental (eg, physical environment and policies) determinants. Observational (cross-sectional and longitudinal) and experimental studies will be included. MEDLINE/PubMed, PsycINFO, CINAHL, EMBASE and Proquest Dissertations and Theses will be investigated. Data will be extracted independently by two reviewers using a standardised data extraction form. The quality of observational studies will be assessed using the National Institute of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies and the quality of experimental studies will be assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Study. If there is a sufficient number of studies reporting data on a similar determinant among a similar population (k>5), a meta-analysis of the results will be performed with a random-effects model. If between-study heterogeneity is high (I2≥75%), it will be investigated through sensitivity analyses and meta-regression.

Ethics and dissemination

Formal ethical approval is not required as no primary data will be collected. The results will be published in a peer-reviewed journal. This review will provide valuable information to those interested in developing empirically based sleep interventions among women.

PROSPERO registration number

CRD42017056894.
Factors influencing career intentions on completion of general practice vocational training in England: a cross-sectional study
Authors: Dale Jeremy , Russell Rachel , Scott Emma , Owen Katherine
Published: August 2017

Objectives

General practice is experiencing a growing crisis with the numbers of doctors who are training and then entering the profession in the UK failing to keep pace with workforce needs. This study investigated the immediate to medium term career intentions of those who are about to become general practitioners (GPs) and the factors that are influencing career plans.

Design

Online questionnaire survey, with quantitative answers analysed using descriptive statistics and free text data analysed using a thematic framework approach.

Setting and participants

Doctors approaching the end of 3-year GP vocational training in the West Midlands, England.

Results

178 (57.2%) doctors completed the survey. Most participants planned to work as salaried GPs or locums rather than entering a general practice partnership for at least the first 5 years post-completion of training; others failed to express a career plan or planned to leave general practice completely or work overseas. Many were interested in developing portfolio careers.

The quality of general practice experience across undergraduate, foundation and vocational training were reported as influencing personal career plans, and in particular perceptions about workload pressure and morale within the training practices in which they had been placed. Experience of a poor work–life balance as a trainee had a negative effect on career intentions, as did negative perceptions about how general practice is portrayed by politicians and the media.

Conclusion

This study describes a number of potentially modifiable factors related to training programmes that are detrimentally influencing the career plans of newly trained GPs. In addition, there are sociodemographic factors, such as age, gender and having children, which are also influencing career plans and so need to be accommodated. With ever-increasing workload in general practice, there is an urgent need to understand and where possible address these issues at national and local level.
Vibrotactile feedback as a tool to improve motor learning and sports performance: a systematic review
Authors: van Breda Eric , Verwulgen Stijn , Saeys Wim , Wuyts Katja , Peeters Thomas , Truijen Steven
Published: August 2017

Background

Evidence concerning the use of vibrotactile feedback for acquiring and learning new motor skills is limited. Although various concepts and applications for tactile feedback have been proposed, little is known about the suitability of this feedback mechanism in sports training.

Aim

The goal of this systematic review was to gather knowledge on the efficacy of the use of vibrotactile feedback in improving sports performance skills.

Design

Systematic review.

Methods

Comprehensively searched databases were: PubMed, Cochrane and Web of Science. Studies investigating the effects of using vibrotactile feedback in sports training in healthy subjects were included in this review.

Results

No consensus was found regarding the positive effectiveness on performance using vibrotactile feedback in a sports context. No evidence was found that the addition of tactile feedback is effective for acquiring new motor skills. None of the studies show a significant learning effect.
O13 ‘I was struggling to feel intimate, the drugs just helped’. chemsex and HIV-risk among men who have sex with men (MSM) in the uk: syndemics of stigma, minority-stress, maladaptive coping and risk environments
Authors: Pollard Alex , Nadarzynski Tom , Llewellyn Carrie
Published: August 2017

Introduction

There has been a steep rise in the use of drugs during sex by some men who have sex with men (MSM), with associated increases in sexual risk for HIV and other STIs. This ‘Chemsex’ has been described, but there is a lack of theoretical perspectives applied to this particular phenomenon.

We aimed to assess participants’ reasoning and conceptualisation of Chemsex and situate this within theoretical frameworks.

Methods

This study presents data from telephone interviews with 15 MSM attending sexual health clinics following a risk of HIV and accessing post-exposure prophylaxis (PEP). Interviews were conducted as part of a larger interventional study, which used an adapted version of Motivational Interviewing to explore risk behaviour and support change. We used Framework analysis on interview transcripts in order to understand participants’ perspectives on the use of chemsex.

Results

Participants conceptualised their chemsex and HIV risks in their psycho-social context, highlighting the influence of the psycho-socio-cultural challenges of homophobic marginalisation and the ‘gay scene’ on their behaviour. Narratives of loneliness and difficulties in forming satisfying social and sexual relationships were repeatedly identified.

Discussion

Multiple influences of stigma, minority stress and maladaptive coping (including drug-use) are seen to contribute to syndemic ‘risk-environments’ in which chemsex and risk behaviours are played out. Interventions to address the harms of chemsex must recognise the complex psychosocial context of risk, and shift the responsibility for change from vulnerable individuals to a shared responsibility distributed across social, political and institutional contexts.
O14 Chemsex, consent and the rise in sexual assault
Authors: Ward Chris , McQuillan Orla , Evans Rebecca
Published: August 2017

Introduction

Within the chemsex population reports of sexual assault, non-consensual sex and coercion are rising. We looked at consent among our chemsex clinic users.

Methods

Retrospective data review of patients from April 2015 to March 2017. Data was collected on sexual assault, coercion, exploitation, risk taking, sexually transmitted infections and drug use.

Results

72 men were seen with a median age of 32. 41 (56.9%) were HIV positive, and 11 (15.3%) had Hepatitis C. 53 (73.6%) patients used Mephedrone, 40 (55.6%) GHB and 22 (30.6%) Crystal Meth. 13 (18.1%) patients reported self-harm. In total 23 (31.9%) patients reported non-consensual sex. A minority 5/30 (16.7%) were identified from April 2015 to Jan 2016 when using the terminology ‘forced into sex’. After realising that addressing consent is more complex in this cohort, we prioritised consent discussions around unwanted sexual attention and from Jan 2016 to March 2017 18/42 (42.9%) reported non-consensual sex (Table 1).

Abstract O14 Table 1

Chemsex

Assault/coercionN/42 (%)Non-consensual sex18 (42.9%)Reported as sexual assault6 (14.3%)Coercive sex4 (9.5%)Sex while unconscious3 (7.1%)Assaulted > once2 (4.8%)Allegations of organised assault2 (4.8%)Injected/filmed while unconscious1 (2.4%)

Discussion

Our data shows rates of non-consensual sex among chemsex users of up to 42.9%. There is a lack of patient understanding around what sexual assault and consent are and exploring this in a sensitive manner is paramount. Sexual assault discussions must be reviewed in both standard sexual health and chemsex clinics.
Comparison of veterinary drugs and veterinary homeopathy: part 2
Authors: Lees P. , Pelligand L. , Whiting M. , Chambers D. , Toutain P‐L. , Whitehead M. L.
Published: August 2017

Part 2 of this narrative review outlines the theoretical and practical bases for assessing the efficacy and effectiveness of conventional medicines and homeopathic products. Known and postulated mechanisms of action are critically reviewed. The evidence for clinical efficacy of products in both categories, in the form of practitioner experience, meta‐analysis and systematic reviews of clinical trial results, is discussed. The review also addresses problems and pitfalls in assessing data, and the ethical and negative aspects of pharmacology and homeopathy in veterinary medicine.
Cartesian Kerr–Schild variation on the Newman–Janis trick
Authors: Rajan Del , Visser Matt
Published: August 2017

The Newman–Janis trick is a procedure, (not even really an ansatz), for obtaining the Kerr spacetime from the Schwarzschild spacetime. This 50 years old trick continues to generate heated discussion and debate even to this day. Most of the debate focusses on whether the Newman–Janis procedure can be upgraded to the status of an algorithm, or even an inspired ansatz, or is it just a random trick of no deep physical significance. (That the Newman–Janis procedure very quickly led to the discovery of the Kerr–Newman spacetime is a point very much in its favor.) In the current paper, we will not answer these deeper questions, we shall instead present a much simpler alternative variation on the theme of the Newman–Janis trick that might be easier to work with. We shall present a 2-step version of the Newman–Janis trick that works directly with the Kerr–Schild “Cartesian” metric presentation of the Kerr spacetime. That is, we show how the original 4-step Newman–Janis procedure can, (using the interplay between oblate spheroidal and Cartesian coordinates), be reduced to a considerably cleaner 2-step process.
The geodesics structure of Schwarzschild black hole immersed in an electromagnetic universe
Authors: Al-Badawi A. , Owaidat M. Q. , Tarawneh S.
Published: August 2017

The geodesic equations are considered in a spacetime that represents a Schwarzschild metric coupled to a uniform external electromagnetic (em) field. Due to the em field horizon shrinks and geodesics are modified. By analyzing the behavior of the effective potentials for the massless and massive particle we study the radial and circular trajectories. Radial geodesics for both photons and particles are solved exactly. It is shown that a particle that falls toward the horizon in a finite proper time slows down so that the particle reaches the singularity slower than Schwarzschild case. Timelike and null circular geodesics are investigated. We have shown that, there are no stable circular orbits for photons, however stable and unstable second-kind orbits exist for the massive particle. An exact analytical solution for the innermost stable circular orbits (ISCO) has been obtained. It has been shown that the radius of the ISCO shrinks due to the presence of the em field.
Discotic liquid crystals of transition metal complexes, 54: Rapid microwave-assisted synthesis and homeotropic alignment of phthalocyanine-based liquid crystals
Authors: Akabane Toshiyuki , Ohta Kazuchika , Takizawa Tokihiro , Matsuse Takehiro , Kimura Mutsumi
Published: August 2017

The most difficult problem on syntheses of the phthalocyanine-based liquid crystals is the long reaction time. In order to shorten the reaction time, we have developed novel Methods A, B and D, for the syntheses of phthalocyanine-based liquid crystals by using microwave heating and/or adding a phase transfer catalysis of Aliquat 336. A series of phthalocyanine derivatives C[Formula: see text]PcZn(1) ([Formula: see text] 10, 12, 14, 16 and 18: a, b, c and e) could be successfully synthesized in a dramatically short reaction time of 30–60 min using Methods A and B by microwave heating. On the other hand, anothor series of the derivatives C[Formula: see text](OH)PcZn (2a–2e) could not be synthesized by microwave heating. Therefore, all these derivatives were synthesized using conventional Method C by oil bath heating, but the reaction took a very long time (22.5–88 h). To shorten the reaction time, we have developed Method D by oil bath heating with adding a phase transfer catalyst of Aliquat 336. In this method, we successfully shortened the reaction time from 88 h to 3 h for the synthesis of the derivative 2a. Thus, the reaction time for oil bath heating can be also greatly shortened by adding the phase transfer catalyst of Aliquat 336. Furthermore, we have established from POM, DSC and temperature-dependent X-ray diffraction measurements that the derivative C[Formula: see text]PcZn (1a) shows a very rare pseudohexagonal columnar (Col[Formula: see text] phase, and that the derivatives C[Formula: see text]PcZn (1b–1e) and C[Formula: see text](OH)PcZn (2b–2e) exhibit spontaneous perfect homeotropic alignment in a large area between two glass plates in their Col[Formula: see text] phases.
Fra-2 negatively regulates postnatal alveolar septation by modulating myofibroblast function
Authors: Tsujino Kazuyuki , Li John T. , Tsukui Tatsuya , Ren Xin , Bakiri Latifa , Wagner Erwin , Sheppard Dean
Published: August 2017

Mice that globally overexpress the transcription factor Fos-related antigen-2 (Fra-2) develop extensive pulmonary fibrosis and pulmonary vascular remodeling. To determine if these phenotypes are a consequence of ectopic Fra-2 expression in vascular smooth muscle cells and myofibroblasts, we generated mice that overexpress Fra-2 specifically in these cell types (α-SMA-rtTA;tetO-Fra-2). Surprisingly, these mice did not develop vascular remodeling or pulmonary fibrosis but did develop a spontaneous emphysema-like phenotype characterized by alveolar enlargement. Secondary septa formation is an important step in the normal development of lung alveoli, and α-smooth muscle actin (SMA)-expressing fibroblasts (myofibroblasts) play a crucial role in this process. The mutant mice showed reduced numbers of secondary septa at postnatal day 7 and enlarged alveolae starting at postnatal day 12, suggesting impairment of secondary septa formation. Lineage tracing using α-SMA-rtTA mice crossed to a floxed TdTomato reporter revealed that embryonic expression of α-SMA Cre marked a population of cells that gave rise to nearly all alveolar myofibroblasts. Comprehensive transcriptome analyses (RNA sequencing) demonstrated that the overwhelming majority of genes whose expression was significantly altered by overexpression of Fra-2 in myofibroblasts encoded secreted proteins, components of the extracellular matrix (ECM), and cell adhesion-associated genes, including coordinate upregulation of pairs of integrins and their principal ECM ligands. In addition, primary myofibroblasts isolated from the mutant mice showed reduced migration capacity. These findings suggest that Fra-2 overexpression might impair myofibroblast functions crucial for secondary septation, such as myofibroblast migration across alveoli, by perturbing interactions between integrins and locally produced components of the ECM.
Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells
Authors: Gall Victor A. , Philips Anne V. , Qiao Na , Clise-Dwyer Karen , Perakis Alexander A. , Zhang Mao , Clifton Guy T. , Sukhumalchandra Pariya , Ma Qing , Reddy Sangeetha M. , Yu Dihua , Molldrem Jeffrey J. , Peoples George E. , Alatrash Gheath , Mittendorf Elizabeth A.
Published: August 2017

Early-phase clinical trials evaluating CD8+ T cell–eliciting, HER2-derived peptide vaccines administered to HER2+ breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein, an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. On the basis of these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy. Cancer Res; 77(19); 5374–83. ©2017 AACR.
PADI2-Mediated Citrullination Promotes Prostate Cancer Progression
Authors: Wang Lin , Song Guanhua , Zhang Xiang , Feng Tingting , Pan Jihong , Chen Weiwen , Yang Muyi , Bai Xinnuo , Pang Yu , Yu Jindan , Han Jinxiang , Han Bo
Published: August 2017

Onset of castration-resistance prostate cancer (CRPC) after long-term androgen deprivation therapy remains a major obstacle in the treatment of prostate cancer. The peptidylarginine deiminase PADI2 has been implicated in chronic inflammatory diseases and cancer. Here we show that PADI2 is an androgen-repressed gene and is upregulated in CRPC. PADI2 expression was required for survival and cell-cycle progression of prostate cancer cells, and PADI2 promoted proliferation of prostate cancer cells under androgen-deprived or castration conditions in vitro and in vivo. Cytoplasmic PADI2 protected the androgen receptor (AR) against proteasome-mediated degradation and facilitated AR binding to its target genes after nuclear translocation and citrullination of histone H3 amino acid residue R26. In contrast, mutant PADI2 D180A failed to affect AR stability, nuclear translocation, or transcriptional activity. PADI2 mediated AR control in a manner dependent on its enzymatic activity and nuclear localization, as correlated with increased histone H3 citrullination. Notably, coadministration of the PADI inhibitor Cl-Amidine and the AR signaling inhibitor enzalutamide synergized in inhibiting CRPC cell proliferation in vitro and tumor growth in vivo. Overall, our results establish PADI2 as a key mediator for AR in prostate cancer progression, especially CRPC, and they suggest PADI as novel therapeutic targets in this disease setting. Cancer Res; 77(21); 5755–68. ©2017 AACR.
β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy
Authors: Bucsek Mark J. , Qiao Guanxi , MacDonald Cameron R. , Giridharan Thejaswini , Evans Lauren , Niedzwecki Brian , Liu Haichao , Kokolus Kathleen M. , Eng Jason W.-L. , Messmer Michelle N. , Attwood Kristopher , Abrams Scott I. , Hylander Bonnie L. , Repasky Elizabeth A.
Published: August 2017

The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T-cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies—physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intratumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of programmed death receptor-1 (PD-1), in addition to an elevated effector CD8+ T-cell to CD4+ regulatory T-cell ratio (IFNγ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy. Cancer Res; 77(20); 5639–51. ©2017 AACR.
Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells
Authors: Daniloski Zharko , Smith Susan
Published: August 2017

Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. STAG2 silencing in normal human cells that lack telomerase led to increased recombination at telomeres, delayed telomere shortening, and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of STAG2 could promote tumorigenesis by extending the period during which tumor-driving mutations occur. Cancer Res; 77(20); 5530–42. ©2017 AACR.
Phenotypic Heterogeneity of Circulating Tumor Cells Informs Clinical Decisions between AR Signaling Inhibitors and Taxanes in Metastatic Prostate Cancer
Authors: Scher Howard I. , Graf Ryon P. , Schreiber Nicole A. , McLaughlin Brigit , Jendrisak Adam , Wang Yipeng , Lee Jerry , Greene Stephanie , Krupa Rachel , Lu David , Bamford Pascal , Louw Jessica E. , Dugan Lyndsey , Vargas Hebert A. , Fleisher Martin , Landers Mark , Heller Glenn , Dittamore Ryan
Published: August 2017

The heterogeneity of an individual patient's tumor has been linked to treatment resistance, but quantitative biomarkers to rapidly and reproducibly evaluate heterogeneity in a clinical setting are currently lacking. Using established tools available in a College of American Pathologists–accredited and Clinical Laboratory Improvement Amendments–certified clinical laboratory, we quantified digital pathology features on 9,225 individual circulating tumor cells (CTC) from 179 unique metastatic castration-resistant prostate cancer (mCRPC) patients to define phenotypically distinct cell types. Heterogeneity was quantified on the basis of the diversity of cell types in individual patient samples using the Shannon index and associated with overall survival (OS) in the 145 specimens collected prior to initiation of the second or later lines of therapy. Low CTC phenotypic heterogeneity was associated with better OS in patients treated with androgen receptor signaling inhibitors (ARSI), whereas high heterogeneity was associated with better OS in patients treated with taxane chemotherapy. Overall, the results show that quantifying CTC phenotypic heterogeneity can help inform the choice between ARSI and taxanes in mCRPC patients. Cancer Res; 77(20); 5687–98. ©2017 AACR.
MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress
Authors: Spehalski Elizabeth , Capper Kayla M. , Smith Cheryl J. , Morgan Mary J. , Dinkelmann Maria , Buis Jeffrey , Sekiguchi JoAnn M. , Ferguson David O.
Published: August 2017

Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double-strand breaks, where it functions in repair and triggers cell-cycle checkpoints via activation of the ataxia-telangiectasia mutated kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus. These preneoplastic B lymphocytes did not progress to detectable B lineage lymphoma, even in the absence of p53. Moreover, Mre11 deficiencies prevented tumorigenesis in a mouse model strongly predisposed to spontaneous B-cell lymphomas. Our findings indicate that MRN cannot be considered a standard tumor suppressor and instead imply that nuclease activities of MRE11 are required for oncogenesis. Inhibition of MRE11 nuclease activity increased DNA damage and selectively induced apoptosis in cells overexpressing oncogenes, suggesting MRE11 serves an important role in countering oncogene-induced replication stress. Thus, MRE11 may offer a target for cancer therapeutic development. More broadly, our work supports the idea that subtle enhancements of endogenous genome instability can exceed the tolerance of cancer cells and be exploited for therapeutic ends. Cancer Res; 77(19); 5327–38. ©2017 AACR.
New Horizons for Precision Medicine in Biliary Tract Cancers
Authors: Valle Juan W. , Lamarca Angela , Goyal Lipika , Barriuso Jorge , Zhu Andrew X.
Published: August 2017

Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.

Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943–62. ©2017 AACR.
The Tumor Microenvironment Regulates Sensitivity of Murine Lung Tumors to PD-1/PD-L1 Antibody Blockade
Authors: Li Howard Y. , McSharry Maria , Bullock Bonnie , Nguyen Teresa T. , Kwak Jeff , Poczobutt Joanna M. , Sippel Trisha R. , Heasley Lynn E. , Weiser-Evans Mary C. , Clambey Eric T. , Nemenoff Raphael A.
Published: August 2017

Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 induce tumor regression in a subset of non–small cell lung cancer patients. However, clinical response rates are less than 25%. Evaluation of combinations of immunotherapy with existing therapies requires appropriate preclinical animal models. In this study, murine lung cancer cells (CMT167 and LLC) were implanted either orthotopically in the lung or subcutaneously in syngeneic mice, and response to anti–PD-1/PD-L1 therapy was determined. Anti–PD-1/PD-L1 therapy inhibited CMT167 orthotopic lung tumors by 95%. The same treatments inhibited CMT167 subcutaneous tumors by only 30% and LLC orthotopic lung tumors by 35%. CMT167 subcutaneous tumors had more Foxp3+ CD4+ T cells and fewer PD-1+ CD4+ T cells compared with CMT167 orthotopic tumors. Flow cytometric analysis also demonstrated increased abundance of PD-L1high cells in the tumor microenvironment in CMT167 tumor–bearing lungs compared with CMT167 subcutaneous tumors or LLC tumor–bearing lungs. Silencing PD-L1 expression in CMT167 cells resulted in smaller orthotopic tumors that remained sensitive to anti–PD-L1 therapy, whereas implantation of CMT167 cells into PD-L1− mice blocked orthotopic tumor growth, indicating a role for PD-L1 in both the cancer cell and the microenvironment. These findings indicate that the response of cancer cells to immunotherapy will be determined by both intrinsic properties of the cancer cells and specific interactions with the microenvironment. Experimental models that accurately recapitulate the lung tumor microenvironment are useful for evaluation of immunotherapeutic agents. Cancer Immunol Res; 5(9); 767–77. ©2017 AACR.
Heterologous Expression of Spinosyn Biosynthetic Gene Cluster in Streptomyces Species Is Dependent on the Expression of Rhamnose Biosynthesis Genes
Authors: Zhao Chen , Huang Ying , Guo Chao , Yang Bolei , Zhang Yan , Lan Zhou , Guan Xiong , Song Yuan , Zhang Xiaolin
Published: August 2017

Spinosyns are a group of macrolide insecticides produced by Saccharopolyspora spinosa. Although S. spinosa can be used for industrial-scale production of spinosyns, this might suffer from several limitations, mainly related to its long growth cycle, low fermentation biomass, and inefficient utilization of starch. It is crucial to generate a robust strain for further spinosyn production and the development of spinosyn derivatives. A BAC vector, containing the whole biosynthetic gene cluster for spinosyn (74 kb) and the elements required for conjugal transfer and site-specific integration, was introduced into different Streptomyces hosts in order to obtain heterologous spinosyn-producing strains. The exconjugants of different Streptomyces strains did not show spinosyn production unless the rhamnose biosynthesis genes from S. spinosa genomic DNA were present and expressed under the control of a strong constitutive ermE*p promoter. Using this heterologous expression system resulted in yields of 1 μg/mL and 1.5 μg/mL spinosyns in Streptomyces coelicolor and Streptomyces lividans, respectively. This report demonstrates spinosyn production in 2 Streptomyces strains and stresses the essential role of rhamnose in this process. This work also provides a potential alternative route for producing spinosyn analogs by means of genetic manipulation in the heterologous hosts.
Prognostic Impact of Adjuvant Chemotherapy after Hepatic Resection for Synchronous and Early Metachronous Colorectal Liver Metastases
Authors: Nishioka Yujiro , Moriyama Jin , Matoba Shuichiro , Kuroyanagi Hiroya , Hashimoto Masaji , Shindoh Junichi
Published: August 2017

Background: Although the usefulness of adjuvant chemotherapy has been established in the treatment for stages II/III colorectal cancer, its prognostic advantage for colorectal liver metastases (CLM) remains controversial. Methods: Two hundred and nine patients who underwent curative resection for CLM were reviewed. The potential advantage of adjuvant chemotherapy was investigated in 3 groups stratified by disease-free interval (DFI): synchronous CLM (S-CLM), early metachronous CLM (EM-CLM, DFI ≤1 year), and late metachronous CLM (LM-CLM, DFI >1 year). Results: Of the 105 patients who underwent adjuvant chemotherapy after surgery, 47 received uracil-tegafur and leucovorin (UFT/LV) while 58 received the oxaliplatin-based regimen. Five-year recurrence-free survival (RFS) rates in patients with/without adjuvant chemotherapy were 32.8/11.2% in S-CLM (p = 0.002), 43.7/15.2% in EM-CLM (p = 0.002), 44.1/29.6% in LM-CLM (p = 0.163), respectively. Five-year overall survival (OS) rates were 77.9/44.5% in S-CLM (p = 0.021), 81.5/39.5% in EM-CLM (p = 0.015), 76.1/65.4% in LM-CLM (p = 0.411), respectively. Multivariate analyses in S-CLM and EM-CLM indicated that adjuvant chemotherapy is correlated with better RFS and OS irrespective of the regimens, while the incidence of severe adverse event was significantly different between UFT/LV and oxaliplatin (6.8 vs. 50.9%, p < 0.0001). Conclusion: Adjuvant chemotherapy might improve the clinical outcomes in S-CLM and EM-CLM. UFT/LV might be a choice for CLM in adjuvant settings in selected patients.
Reliability of Entire Corneal Thickness Mapping in Normal Post-Laser in situ Keratomileusis and Keratoconus Eyes Using Long Scan Depth Spectral Domain Optical Coherence Tomography
Authors: Xu Zhe , Chen Sisi , Yang Chun , Huang Shenghai , Shen Meixiao , Wang Yuanyuan
Published: August 2017

Purpose: To investigate the repeatability and reproducibility of mapping the entire corneal thickness using spectral domain optical coherence tomography (SD-OCT). Methods: Thirty normal eyes, 30 post-laser in situ keratomileusis (LASIK) surgery eyes, and 30 keratoconus eyes were analyzed. A custom-built long scan depth SD-OCT device was used to obtain entire corneal images. Ten-millimeter-diameter corneal thickness maps were generated by an automated segmentation algorithm. Intraclass correlation coefficients of repeatability (ICC1) and reproducibility (ICC2), and coefficients of repeatability (CoR1) and reproducibility (CoR2), were calculated to quantify the precision and accuracy of corneal pachymetry measurements using the Bland-Altman method. Results: For SD-OCT measurements in healthy subjects, CoR1 and CoR2 were less than 5.00 and 5.53 μm. ICC1 and ICC2 were more than 0.997 and 0.996. For SD-OCT measurements in LASIK patients, CoR1 and CoR2 were less than 5.09 and 5.34 μm. ICC1 and ICC2 were more than 0.997 and 0.996. For SD-OCT measurements in keratoconus patients, CoR1 and CoR2 were less than 11.57 and 10.92 μm. ICC1 and ICC2 were more than 0.995 and 0.996. Conclusions: The measurements of corneal pachymetric mapping by long scan depth SD-OCT can be assessed over the entire corneal area with good repeatability and reproducibility.
Epidemiology of Multiple Sclerosis in Austria
Authors: Salhofer-Polanyi Sabine , Cetin Hakan , Leutmezer Fritz , Baumgartner Anna , Blechinger Stephan , Dal-Bianco Assunta , Altmann Patrick , Bajer-Kornek Barbara , Rommer Paulus , Guger Michael , Leitner-Bohn Doris , Reichardt Berthold , Alasti Farideh , Temsch Wilhelm , Stamm Tanja
Published: August 2017

Background: To assess the incidence rate and prevalence ratio of multiple sclerosis (MS) in Austria. Methods: Hospital discharge diagnosis and MS-specific immunomodulatory treatment prescriptions from public health insurances, covering 98% of Austrian citizens with health insurance were used to extrapolate incidence and prevalence numbers based on the capture-recapture method. Results: A total of 1,392,629 medication prescriptions and 40,956 hospitalizations were extracted from 2 data sources, leading to a total of 13,205 patients. The incidence rate and prevalence ratio of MS in Austria based on the capture-recapture method were 19.5/100,000 person-years (95% CI 14.3-24.7) and 158.9/100,000 (95% CI 141.2-175.9), respectively. Female to male ratio was 1.6 for incidence and 2.2 for prevalence. Conclusions: Incidence rates and prevalence ratios of MS in our study are within the upper range of comparable studies across many European countries as well as the United States.
Multimorbidities Are Associated to Lower Survival in Ischaemic Stroke: Results from a Brazilian Stroke Cohort (EMMA Study)
Authors: Castro Herbert H.G. , Alencar Airlane Pereira , Benseñor Isabela M. , Lotufo Paulo A. , Goulart Alessandra C.
Published: August 2017

Background: Stroke prognosis is related to the multimorbidity profile. Moreover, performing an individual evaluation of most common cerebrovascular risk factors (CVRF) not always identifies patients with poor prognosis. Thus, we decided to evaluate multimorbidity profile, focusing on the Charlson Comorbidity Index (CCI) validated by Goldstein for ischaemic stroke (IS) patients, a score that measures a burden of comorbidities and its related mortality in the long-term survival of the EMMA Study (Study of Stroke Mortality and Morbidity). Methods: Nine hundred fifty-nine individuals (median age 70 years) had validated data on the diagnosis of IS, main CVRF and clinical comorbidities pre index event such as atrial fibrillation (AF), stroke recurrence, diabetes, hypertension, heart failure and cancer. CCI modified by Goldstein was calculated, which includes 17 clinical conditions with scores ranging from 1 to 6 (0-31 points). Survival analyses were performed by Kaplan-Meier curves and Cox logistic regression models (cumulative hazard ratio [HR] with [95% CI]) for all-cause mortality at 180 days, and every 3 years up to 9-year follow-up. Mortality analyzes were performed by CCI categorized according to weight added to comorbidities (Reference group: zero, moderate: 1, severe: 2 and very severe: ≥3 points). We also tested the modification effect of AF and stroke recurrence including these conditions in the CCI. Results: The overall survival rate was 47% (508 deaths/959). The worst survival (577, 95% CI 381-773 days) and the highest risk of death after stroke were observed in the very severe CCI group (HR 3.18; 95% CI 2.16-4.69) up to 9 years. The inclusion of previous AF and stroke in the CCI slightly increased the risk of death for very severe CCI (HR 3.27; 95% CI 2.07-5.18). Conclusions: A high burden of comorbidities represented an independent predictor of poor prognosis increasing the risk of dying by 2 to 3 times among IS up to 9 years in the EMMA study. The inclusion of other CVRF such as AF and stroke recurrence slightly modified all-cause mortality risk.