bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving self-management of cancer risk factors, underscreening for cancer and depression among general practice patients: study protocol of a randomised controlled trial
Authors: Carey Mariko , Sanson-Fisher Rob , Oldmeadow Christopher , Mansfield Elise , Walsh Justin 
Published: November 2016

IntroductionGeneral practitioners have a key role in reducing cancer risk factors, screening for cancer and managing depression. Given the time-limited nature of consultations, a new and more time-efficient approach is needed which addresses multiple health needs simultaneously, and encourages patient self-management to address health risks. The aim of this cluster randomised controlled trial is to test the effectiveness of a patient feedback intervention in improving patient self-management of health needs related to smoking, risky alcohol consumption and underscreening for cancers at 1 month follow-up.Methods and analysisAdult general practice patients will be invited to participate in a baseline survey to assess cancer risk factors, screening needs and depression. A total of 360 participants identified by the baseline survey as having at least one health need (a self-reported cancer risk factor, underscreening for cancer, or an elevated depression score) will be randomised to an intervention or control group. Participants in the intervention group will receive tailored printed feedback summarising their identified health needs and recommended self-management actions to address these. All participants will be invited to complete a telephone interview 1 month following recruitment to assess self-management actions taken in relation to health needs identified in the baseline survey. Control group participants will receive tailored printed feedback on their identified health needs after their follow-up interview. A logistic regression model, with group allocation as the main predictor, will be used to assess the impact of the intervention on self-management actions.Ethical considerations and disseminationParticipants identified as being at risk of depression will be advised to speak with their doctor. Results will be disseminated via publication in peer-reviewed journals. The study has been approved by the University of Newcastle Human Research Ethics Committee.Trial registration numberACTRN12616001443482.
MAGE-A family expression is correlated with poor survival of patients with lung adenocarcinoma: a retrospective clinical study based on tissue microarray
Authors: Sang Meixiang , Gu Lina , Yin Danjing , Liu Fei , Lian Yishui , Zhang Xiaochong , Liu Shina , Huang Weina , Wu Yunyan , Shan Baoen 
Published: November 2016

ObjectivesAs the best characterised cancer/testis antigen family members, melanoma-associated antigens (MAGE) have been reported to be expressed in various malignant tumours. However, the expression pattern of MAGE-A family in lung adenocarcinoma (LAC) specimens and their prognostic and therapeutic significance for patients with LAC is still unclear.Materials and methodsTissue microarray-based immunohistochemistry analysis was used to examine the expression of MAGE-A family members (including MAGE-A1, A2, A3, A4, A6, A10, A11 and A12) in 105 paired LAC specimens and the corresponding pericarcinoma specimens. The association between MAGE-A expression and the clinicopathological parameters, and the 10-year overall survival of patients with LAC were analysed. In addition, the association between MAGE-A expression and the epithelial growth factor receptor (EGFR) amplification and ALK-EML4 rearrangements of patients with LAC were also analysed.ResultsThe immunohistochemical evaluation revealed that MAGE-A family was expressed in 46.66% of LAC specimens, but not in the corresponding pericarcinoma specimens. MAGE-A expression was not associated with the clinicopathological factors but with worse 10-year survival, and was a poor prognostic marker for patients with LAC. MAGE-A expression was not correlated with EGFR amplification and ALK rearrangements. Interestingly, MAGE-A expression can affect the overall survival of patients with LAC without EGFR amplification or ALK rearrangements, but not affect the overall survival of patients with LAC and EGFR amplification or ALK rearrangements.ConclusionsMolecular assessment of MAGE-A family members could be considered to improve the prognostic evaluation and to provide a new potential therapeutic strategy for patients with LAC.
Reacquisition of E-cadherin expression in metastatic deposits of signet-ring cell carcinoma of the upper gastrointestinal system: a potential anchor for metastatic deposition
Authors: Ma Yihong R , Siegal Gene P , Wei Shi 
Published: November 2016

AimsTo examine the expression of E-cadherin in paired primary and metastatic signet-ring cell carcinomas (SRCC) of various organ systems in order to explore the potential role of the molecule in metastatic dissemination of this unique tumour type.MethodsThirty-seven consecutive cases of SRCC from various organs with paired primary and metastatic tumorous tissue available were retrieved. The intensity of membranous E-cadherin expression was semiquantitatively scored on a scale of 0–3+.ResultsReduced E-cadherin expression was a distinct feature of primary SRCC and was observed in 78% of primary tumours. Interestingly, the E-cadherin reduction was less frequently seen in metastatic SRCC when compared with their primary counterparts, and was only found in 57% of tumours in lymph node metastases or at distant sites of relapse. Furthermore, the mean score of E-cadherin expression of primary SRCC was significantly lower than that of their metastatic counterparts (2.3 vs 1.8; p=0.008). When divided by organ systems, the reacquisition of E-cadherin expression in the metastatic deposits was most remarkable in the SRCC of upper gastrointestinal tract origin (2.3 vs 1.4; p=0.003), whereas no significant difference was observed in other organ systems.ConclusionsWhile the reduction of E-cadherin in primary SRCC supports its pivotal role in epithelial-mesenchymal transition, a process crucial in tumour progression and metastatic dissemination, the re-expression of this molecule in metastatic SRCC cells implies a reversal to their epithelial phenotype (thus mesenchymal-epithelial transition) which, in turn, theoretically helps tumour cells to anchor and form cohesive metastatic deposits.
What are the critical steps in processing blood cultures? A prospective audit evaluating current practice of reporting blood cultures in a centralised laboratory serving secondary care hospitals
Authors: Meda Manjula , Clayton James , Varghese Reela , Rangaiah Jayakeerthi , Grundy Clive , Dashti Farnaz , Garner David , Groves Katherine , Fitzmaurice Karen , Hutley E 
Published: November 2016

AimsTo assess current procedures of processing positive blood cultures against national standards with an aim to evaluate its clinical impact and to determine the utility of currently available rapid identification and susceptibility tests in processing of blood cultures.MethodsBlood cultures from three secondary care hospitals, processed at a centralised laboratory, were prospectively audited. Data regarding processing times, communication with prescribers, changes to patient management and mortality within 30 days of a significant blood culture were collected in a preplanned pro forma for a 4-week period.ResultsOf 2206 blood cultures, 211 positive blood cultures flagged positive. Sixty-nine (3.1%) of all cultures were considered to be contaminated. Fifty per cent of blood cultures that flagged positive had a Gram stain reported within 2 hours. Two (0.99%) patients with a significant bacteraemia had escalation of antimicrobial treatment at the point of reporting the Gram stain that was subsequently deemed necessary once sensitivity results were known. Most common intervention was de-escalation of therapy for Gram-positive organisms at the point of availability of pathogen identification (25.6% in Gram positive vs 10% in Gram negative; p=0.012). For Gram-negative organisms, the most common intervention was de-escalation of therapy at the point of availability of sensitivity results (43% in Gram negatives vs 17.9% in Gram positive; p=0.0097). Overall mortality within 30 days of a positive blood culture was 10.9% (23/211). Antibiotic resistance may have contributed to mortality in four of these patients (three Gram negative and one Gram positive).ConclusionGram stain result had the least impact on antibiotic treatment interventions (escalation or de-escalation). Tests that improve identification time for Gram-positive pathogens and sensitivity time for Gram-negative pathogens had the greatest impact in making significant changes to antimicrobial treatment.
Grit and burnout in UK doctors: a cross-sectional study across specialties and stages of training
Authors: Halliday Laura , Walker Abigail , Vig Stella , Hines John , Brecknell John 
Published: November 2016

ABSTRACTPurpose of the studyGrit is characterised by the ability to persevere during difficulties and maintain a sustained effort over an extended period of time. Throughout their careers, doctors will experience many periods of stress and difficulty. This may result in burnout, defined by the presence of exhaustion and disengagement from work. This study aims to characterise the relationship between grit and burnout in doctors and to establish whether there are differences between specialties and levels of training.Study designA multicentre cross-sectional survey by questionnaire was used. Participants were recruited from training days and an online medical forum. The survey consisted of the Short Grit Scale and the Oldenburg Burnout Inventory, which examine levels of grit and burnout, respectively.Results548 responses were collected. We found a weak negative correlation between grit and burnout in UK doctors (r=−0.243, p&lt;0.001). Hospital consultants had significantly higher grit scores than trainees. The highest level of burnout was found among general practitioners (GPs). When GPs were analysed separately, the correlation between grit and resilience was not seen.ConclusionsAn understanding of an individual’s level of grit may be used to identify doctors at a greater risk of burnout. As a high level of grit is associated with less burnout, interventions to improve grit through resilience training should be examined. Further research is needed to understand how grit levels change during a doctor’s career and why GPs experience higher levels of burnout.
L5-LDL from ST-elevation myocardial infarction patients induces IL-1β production via LOX-1 and NLRP3 inflammasome activation in macrophages
Authors: Yang Tzu-Ching , Chang Po-Yuan , Lu Shao-Chun 
Published: November 2016

L5-LDL, the most electronegative LDL associated with major cardiovascular risks, significantly rises in patients with ST-segment elevation myocardial infarction (STEMI). The inflammatory nature of atherosclerotic vascular diseases has prompted us to investigate whether L5-LDL induces the production of inflammatory cytokines, especially vascular ischemia-related interleukin (IL)-1β, in the pathogenesis of STEMI. Clinical data showed that plasma levels of L5-LDL and IL-1β were higher in the STEMI patients than in the controls ( P < 0.05). In THP-1-derived human macrophages, L5-LDL significantly increased the levels of both IL-1β and cleaved caspase-1, indicating the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes by L5-LDL. Knockdown of NLRP3 and its adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) resulted in decreased L5-LDL-induced IL-1β. Furthermore, knock down of the lectin-type oxidized LDL receptor (LOX-1) in THP-1 cells attenuated L5-LDL-induced activation of NF-κB and caspase-1, leading to subsequent inhibition of IL-1β in macrophages. Furthermore, blockade LOX-1 with neutralizing antibody also inhibited L5-LDL-induced IL-1β in human peripheral blood mononuclear cell-derived macrophages. In conclusion, L5-LDL induces IL-1β production in macrophages by activation of NF-κB and caspase-1 through the LOX-1-dependent pathway. This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1β in STEMI, and identifies L5-LDL as a novel therapeutic target in acute myocardial infarction.NEW & NOTEWORTHY This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1β in ST-segment elevation myocardial infarction (STEMI). We elucidate the molecular mechanism underlying L5-LDL-induced production of IL-1β in macrophages. The results showed that L5-LDL induced activation of caspase-1 and NF-κB through the lectin-type oxidized LDL receptor (LOX-1)-dependent pathway, leading to the production of IL-1β.
PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1
Authors: Lacey Alexandra , Rodrigues-Hoffman Aline , Safe Stephen 
Published: November 2016

Abstract
Alveolar rhabdomyosarcoma (ARMS) is a devastating pediatric disease driven by expression of the oncogenic fusion gene PAX3-FOXO1A. In this study, we report overexpression of the nuclear receptor NR4A1 in rhabdomyosarcomas that is sufficient to drive high expression of PAX3-FOXO1A there. RNAi-mediated silencing of NR4A1 decreased expression of PAX3-FOXO1A and its downstream effector genes. Similarly, cell treatment with the NR4A1 small-molecule antagonists 1,1-bis(3-indolyl)-1-(p-hydroxy or p-carbomethoxyphenyl)methane (C-DIM) decreased PAX3-FOXO1A. Mechanistic investigations revealed a requirement for the NR4A1/Sp4 complex to bind GC-rich promoter regions to elevate transcription of the PAX3-FOXO1A gene. In parallel, NR4A1 also regulated expression of β1-integrin, which with PAX3-FOXO1A, contributed to tumor cell migration that was blocked by C-DIM/NR4A1 antagonists. Taken together, our results provide a preclinical rationale for the use of NR4A1 small-molecule antagonists to treat ARMS and other rhabdomyosarcomas driven by PAX3-FOXO1A. Cancer Res; 77(3); 732–41. ©2016 AACR.
Systems Approaches to Cancer Biology
Authors: Archer Tenley C. , Fertig Elana J. , Gosline Sara J.C. , Hafner Marc , Hughes Shannon K. , Joughin Brian A. , Meyer Aaron S. , Piccolo Stephen R. , Shajahan-Haq Ayesha N. 
Published: November 2016

Abstract
Cancer systems biology aims to understand cancer as an integrated system of genes, proteins, networks, and interactions rather than an entity of isolated molecular and cellular components. The inaugural Systems Approaches to Cancer Biology Conference, cosponsored by the Association of Early Career Cancer Systems Biologists and the National Cancer Institute of the NIH, focused on the interdisciplinary field of cancer systems biology and the challenging cancer questions that are best addressed through the combination of experimental and computational analyses. Attendees found that elucidating the many molecular features of cancer inevitably reveals new forms of complexity and concluded that ensuring the reproducibility and impact of cancer systems biology studies will require widespread method and data sharing and, ultimately, the translation of important findings to the clinic. Cancer Res; 76(23); 6774–7. ©2016 AACR.
Systemic Levels of Estrogens and PGE2 Synthesis in Relation to Postmenopausal Breast Cancer Risk
Authors: Kim Sangmi , Campbell Jeff , Yoo Wonsuk , Taylor Jack A. , Sandler Dale P. 
Published: November 2016

AbstractBackground:Prostaglandin E2 (PGE2) induces aromatase expression in adipose tissue, leading to increased estrogen production that may promote the development and progression of breast cancer. However, few studies have simultaneously investigated systemic levels of PGE2 and estrogen in relation to postmenopausal breast cancer risk.Methods:Here, we determined urinary estrogen metabolites (EM) using mass spectrometry in a case–cohort study (295 incident breast cancer cases and 294 subcohort members), and using linear regression estimated the effect of urinary levels of a major PGE2 metabolite (PGE-M) on EMs. HRs for the risk of developing breast cancer in relation to PGE-M and EMs were compared between Cox regression models with and without mutual adjustment.Results:PGE-M was a significant predictor of estrone (E1), but not estradiol (E2) levels in multivariable analysis. Elevated E2 levels were associated with an increased risk of developing breast cancer [HRQ5vs.Q1, 1.54; 95% confidence interval (CI), 1.01–2.35], and this association remained unchanged after adjustment for PGE-M (HRQ5vs.Q1, 1.52; 95% CI, 0.99–2.33). Similarly, elevated levels of PGE-M were associated with increased risk of developing breast cancer (HRQ4vs.Q1, 2.01; 95% CI, 1.01–4.29), and this association was only nominally changed after consideration of E1 or E2 levels.Conclusions:Urinary levels of PGE-M and estrogens were independently associated with future risk of developing breast cancer among these postmenopausal women.Impact:Increased breast cancer risk associated with PGE-M might not be fully explained by the estrogens–breast cancer association alone but also by additional effects related to inflammation. Cancer Epidemiol Biomarkers Prev; 26(3); 383–8. ©2016 AACR.
How Subclonal Modeling Is Changing the Metastatic Paradigm
Authors: Macintyre Geoff , Van Loo Peter , Corcoran Niall M. , Wedge David C. , Markowetz Florian , Hovens Christopher M. 
Published: November 2016

Abstract
A concerted effort to sequence matched primary and metastatic tumors is vastly improving our ability to understand metastasis in humans. Compelling evidence has emerged that supports the existence of diverse and surprising metastatic patterns. Enhancing these efforts is a new class of algorithms that facilitate high-resolution subclonal modeling of metastatic spread. Here we summarize how subclonal models of metastasis are influencing the metastatic paradigm. Clin Cancer Res; 23(3); 630–5. ©2016 AACR.
The Landscape of Viral Expression Reveals Clinically Relevant Viruses with Potential Capability of Promoting Malignancy in Lower-Grade Glioma
Authors: Wang Zheng , Hao Yajing , Zhang Chuanbao , Wang Zhiliang , Liu Xing , Li Guanzhang , Sun Lihua , Liang Jingshan , Luo Jianjun , Zhou Dabiao , Chen Runsheng , Jiang Tao 
Published: November 2016

Abstract
Purpose: RNA sequencing (RNA-seq) has recently proved to be effective for revealing novel virus–tumor associations. To get a thorough investigation of virus–glioma associations, we screened viruses in gliomas with RNA-seq data from the Chinese Glioma Genome Atlas project.
Experimental Design: In total, 325 samples were enrolled into this study. Reads that failed to map to the human genome were aligned to viral genomes and screened for potential virus-derived transcripts. For quantification, VPKM was calculated according to mapped reads weighted by genome sizes and sequencing depth.
Results: We observed that viruses tended to concertedly express in a certain subgroup of patients. Survival analysis revealed that individuals who were infected with Simian virus 40 (SV40) or woolly monkey sarcoma virus (WMSV) had a significantly shorter overall survival than those uninfected. A multivariate Cox proportional hazards model, taking clinical and molecular factors into account, was applied to assess the prognostic value of SV40 and WMSV. Both SV40 and WMSV were independent prognostic factors for predicting patient's survival in lower-grade gliomas. Subsequent gene analysis demonstrated that SV40 was correlated with regulation of transcription, whereas WMSV was correlated with cell-cycle phase, which indicated frequent proliferation of tumor cells.
Conclusions: RNA-seq was sufficient to identify virus infection in glioma samples. SV40 and WMSV were identified to be prognostic markers for patients with lower-grade gliomas and showed potential values for targeting therapy. Clin Cancer Res; 23(9); 2177–85. ©2016 AACR.
AMPK–ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells
Authors: Jang Ji Eun , Eom Ju-In , Jeung Hoi-Kyung , Cheong June-Won , Lee Jung Yeon , Kim Jin Seok , Min Yoo Hong 
Published: November 2016

Abstract
Purpose: Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSC) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1.
Experimental Design: We evaluated the levels of apoptosis and autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34+CD38− leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations.
Results: JQ1 effectively induced apoptosis in a concentration-dependent manner in JQ1-sensitive AML cells. However, in JQ1-resistant AML LSCs, JQ1 induced little apoptosis and led to upregulation of beclin-1, increased LC3-II lipidation, formation of autophagosomes, and downregulation of p62/SQSTM1. Inhibition of autophagy by pharmacologic inhibitors or knockdown of beclin-1 using specific siRNA enhanced JQ1-induced apoptosis in resistant cells, indicating that prosurvival autophagy occurred in these cells. Independent of mTOR signaling, activation of the AMPK (pThr172)/ULK1 (pSer555) pathway was found to be associated with JQ1-induced autophagy in resistant cells. AMPK inhibition using the pharmacologic inhibitor compound C or by knockdown of AMPKα suppressed autophagy and promoted JQ1-induced apoptosis in AML LSCs.
Conclusions: These findings revealed that prosurvival autophagy was one of the mechanisms involved in the resistance AML LSCs to JQ1. Targeting the AMPK/ULK1 pathway or inhibition of autophagy could be an effective therapeutic strategy for combating resistance to BET inhibitors in AML and other types of cancer. Clin Cancer Res; 23(11); 2781–94. ©2016 AACR.