bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leisure-time aerobic physical activity, muscle-strengthening activity and mortality risks among US adults: the NHANES linked mortality study
Authors: Zhao Guixiang , Li Chaoyang , Ford Earl S , Fulton Janet E , Carlson Susan A , Okoro Catherine A , Wen Xiao Jun , Balluz Lina S 
Published: October 2013

BackgroundRegular physical activity elicits multiple health benefits in the prevention and management of chronic diseases. We examined the mortality risks associated with levels of leisure-time aerobic physical activity and muscle-strengthening activity based on the2008 Physical Activity Guidelines for Americansamong US adults.MethodsWe analysed data from the 1999 to 2004 National Health and Nutrition Examination Survey with linked mortality data obtained through 2006. Cox proportional HRs with 95% CIs were estimated to assess risks for all-causes and cardiovascular disease (CVD) mortality associated with aerobic physical activity and muscle-strengthening activity.ResultsOf 10 535 participants, 665 died (233 deaths from CVD) during an average of 4.8-year follow-up. Compared with participants who were physically inactive, the adjusted HR for all-cause mortality was 0.64 (95% CI 0.52 to 0.79) among those who were physically active (engaging in ≥150 min/week of the equivalent moderate-intensity physical activity) and 0.72 (95% CI 0.54 to 0.97) among those who were insufficiently active (engaging in >0 to <150 min/week of the equivalent moderate-intensity physical activity). The adjusted HR for CVD mortality was 0.57 (95% CI 0.34 to 0.97) among participants who were insufficiently active and 0.69 (95% CI 0.43 to 1.12) among those who were physically active. Among adults who were insufficiently active, the adjusted HR for all-cause mortality was 44% lower by engaging in muscle-strengthening activity ≥2 times/week.ConclusionsEngaging in aerobic physical activity ranging from insufficient activity to meeting the2008 Guidelinesreduces the risk of premature mortality among US adults. Engaging in muscle-strengthening activity ≥2 times/week may provide additional benefits among insufficiently active adults.
When can a professional athlete return to play following scapholunate ligament delayed reconstruction?
Authors: Williams Ashleigh , Ng Chye Yew , Hayton Michael J 
Published: October 2013

BackgroundThe aim of this study was to determine the outcomes in relation to return-to-play in professional athletes who had undergone a delayed scapholunate ligament reconstruction.MethodsWe searched our prospectively managed database and identified 15 professional athletes who had undergone the modified Brunelli procedure for scapholunate instability. They were contacted to complete a telephone interview. We established the duration between the operation and return-to-play, the level of competition before and after the procedure and if applicable, reasons for reduction in the level of competition.ResultsBetween 2008 and 2011, 15 professional male athletes underwent the modified Brunelli procedure. One was lost to follow-up and 14 athletes (11 rugby, 2 boxing and 1 golf) were contactable. The mean age of the patients was 30 years (range 18–42). The mean follow-up period was 25 months (range 3–43). Eleven of the 14 (79%) athletes returned to play within 4 months of surgery. By the final review, 9 of the 14 (64%) athletes had returned to play at their preinjury level of competition.ConclusionsA majority (approximately 80%) of professional athletes return to competitive playing within 4 months of undergoing a scapholunate ligament reconstruction. Approximately two-thirds return to play at their preinjury level of competition.
A 3-year survey quantifying the risk of dose escalation of benzodiazepines and congeners to identify risk factors to aid doctors to more rationale prescribing
Authors: Tvete Ingunn Fride , Bjørner Trine , Aursnes Ivar Andreas , Skomedal Tor 
Published: October 2013

ObjectivesThis study investigated and quantified risk factors of dose escalation, as an indication of drug misuse and dependency of benzodiazepines and congeners, among presumably drug naïve patients in the Norwegian drug prescription database, observed over 3 years.DesignObservational study.SettingPrescription database study.ParticipantsWe defined an excessive user as one redeeming more than two defined daily doses per day in 3 months.Primary and secondary outcome measuresWe examined the risk of excessive use over time and the effect of risk factors through multistate logistic regression and scenarios.ResultsMost of the 81 945 patients had zopiclone or zolpidem as the initial drug (63.8%), followed by diazepam (25.3%), oxazepam (6.1%), nitrazepam/flunitrazepam (2.9%), hydroxyzine/buspirone (1.6%) and alprazolam (0.3%). At any time 23% redeemed prescriptions, about 34% did not redeem any prescriptions beyond any 3-month period and 0.9% ended up as excessive users. Patients previously using drugs, such as opioids, antialcohol or smoke cessation treatment, had a higher risk to become excessive users compared to patients who had not. Patients whose first prescription was for oxazepam or nitrazepam/flunitrazepam had a higher risk of becoming an excessive user compared to those who started with diazepam. A specialist in general practice as the first-time prescriber was associated with a lower risk compared to doctors without specialty.ConclusionsMost benzodiazepine use occurred according to guidelines. Still, some experienced dose escalation over time, and risk factors were previous use of other psychotropic drugs, long time use, choice of first-time drug and prescriber's specialty. This could incite doctors to have a cessation plan when issuing first-time prescriptions.
Applying ethnography to the study of context in healthcare quality and safety
Authors: Leslie Myles , Paradis Elise , Gropper Michael A , Reeves Scott , Kitto Simon 
Published: October 2013

BackgroundTranslating and scaling healthcare quality improvement (QI) and patient safety interventions remains a significant challenge. Context has been identified as a major factor in this. QI and patient safety research have begun to focus on context, with ethnography seen as a promising methodology for understanding the professional, organisational and cultural aspects of context. While ethnography is used to investigate the context of a variety of QI and safety interventions, the challenges inherent in effectively importing a qualitative methodology and its social science practitioners into this work have been largely unexamined.Method and resultsWe explain ethnography as a research practice grounded in theory and dependent on observations gathered and interpreted in particular ways. We then review the approach of health services literature to evaluating this sort of qualitative research. Although the study of context is an interest shared by both social scientists and healthcare QI and safety researchers, we identify three key points at which those ‘exporting’ ethnography as a methodology and those ‘importing’ it to deal with QI and safety challenges may diverge. We describe perspectival divergences on the methodology's mission, form and scale. At the level of mission we demonstrate how ethnography has been adapted to a ‘describe and feed back’ role in the service of QI. At the level of form, we show how the long-term embedded observation at the heart of ethnography can be adapted only so far to accommodate QI interests if both data quality and ethical standards are to be upheld. Finally, at the level of scale, we demonstrate one ethnographic study design that balances breadth of exposure with depth of experience in its observations and so generates a particular type of scalable findings.SummaryThe effective export of ethnography into QI and safety research requires discussion and negotiation between social scientific and health services research perspectives, as well as creative approaches to producing self-reflexive data that will allow clinicians to understand their own context and so improve their own processes.
Socioeconomic determinants of haemoglobin levels of African women are less important in areas with more health facilities: a multilevel analysis
Authors: Haverkate Manon , Smits Jeroen , Meijerink Hinta , van der Ven André 
Published: October 2013

BackgroundThe prevalence of anaemia in Africa is the highest in the world. Especially women are at risk because of blood loss during menstruation and increased iron requirements during pregnancy. This study examined determinants of the haemoglobin (Hb) level of African women at individual/household, cluster, district, and national level. Special attention was paid to socioeconomic factors and the presence of health facilities.MethodsData were derived from Demographic and Health Surveys conducted between 2003 and 2010 in 21 African countries. We included all women aged 15–49 who participated in a women's survey and had a Hb measurement. Multilevel models were used to examine the influence of various factors at different hierarchical levels simultaneously.Results104 899 women were included in the study, of which 23.1% were anaemic (Hb<110 g/L). Socioeconomic factors were strongly related to the Hb level of women. Wealth, education, having a job, occupation of the partner, presence of a toilet facility, context educational level and preventive health measures were positively associated with the Hb level. Interaction analysis indicated that socioeconomic differences in the Hb level of women were reduced by the presence of health facilities.ConclusionsInterventions aimed at improving the Hb level of African women should take socioeconomic and contextual aspects into account. Increasing availability of health facilities might be a tool for reducing socioeconomic differences.
Novel Modeling of Cancer Cell Signaling Pathways Enables Systematic Drug Repositioning for Distinct Breast Cancer Metastases
Authors: Zhao Hong , Jin Guangxu , Cui Kemi , Ren Ding , Liu Timothy , Chen Peikai , Wong Solomon , Li Fuhai , Fan Yubo , Rodriguez Angel , Chang Jenny , Wong Stephen TC 
Published: October 2013

Abstract
A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target–disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease. Cancer Res; 73(20); 6149–63. ©2013 AACR.
Contribution of Bcl-2 Phosphorylation to Bak Binding and Drug Resistance
Authors: Dai Haiming , Ding Husheng , Meng X. Wei , Lee Sun-Hee , Schneider Paula A. , Kaufmann Scott H. 
Published: October 2013

Abstract
Bcl-2 is phosphorylated on Ser70 after treatment of cells with spindle poisons. On the basis of effects observed in cells overexpressing Bcl-2 S70E or S70A mutants, various studies have concluded that Ser70 phosphorylation either enhances or diminishes Bcl-2 function. In the present study, the ability of phosphorylated Bcl-2, as well as the S70E and S70A mutants, to bind and neutralize proapoptotic Bcl-2 family members under cell-free conditions and in intact cells was examined in an attempt to resolve this controversy. Surface plasmon resonance indicated that phosphorylated Bcl-2, Bcl-2 S70E, and Bcl-2 S70A exhibit enhanced binding to Bim and Bak compared with unmodified Bcl-2. This enhanced binding reflected a readily detectable conformation change in the loop domain of Bcl-2. Furthermore, Bcl-2 S70E and S70A bound more Bak and Bim than wild-type Bcl-2 in pull-downs and afforded greater protection against several chemotherapeutic agents. Importantly, binding of endogenous Bcl-2 to Bim also increased during mitosis, when Bcl-2 is endogenously phosphorylated, and disruption of this mitotic Bcl-2/Bim binding with navitoclax or ABT-199, like Bcl-2 downregulation, enhanced the cytotoxicity of paclitaxel. Collectively, these results provide not only a mechanistic basis for the enhanced antiapoptotic activity of phosphorylated Bcl-2, but also an explanation for the ability of BH3 mimetics to enhance taxane sensitivity. Cancer Res; 73(23); 6998–7008. ©2013 AACR.
RSK Isoforms in Cancer Cell Invasion and Metastasis
Authors: Sulzmaier Florian J. , Ramos Joe W. 
Published: October 2013

Abstract
Metastasis, the spreading of cancer cells from a primary tumor to secondary sites throughout the body, is the primary cause of death for patients with cancer. New therapies that prevent invasion and metastasis in combination with current treatments could therefore significantly reduce cancer recurrence and morbidity. Metastasis is driven by altered signaling pathways that induce changes in cell–cell adhesion, the cytoskeleton, integrin function, protease expression, epithelial-to-mesenchymal transition and cell survival. The ribosomal S6 kinase (RSK) family of kinases is a group of extracellular signal–regulated kinase/mitogen-activated protein kinase (ERK/MAPK) effectors that can regulate these steps of metastasis by phosphorylating both nuclear and cytoplasmic targets. However, our understanding of RSK function in metastasis remains incomplete and is complicated by the fact that the four RSK isoforms perform nonredundant, sometimes opposing functions. Although some isoforms promote cell motility and invasion by altering transcription and integrin activity, others impair cell motility and invasion through effects on the actin cytoskeleton. The mechanism of RSK action depends both on the isoform and the cancer type. However, despite the variance in RSK-mediated outcomes, chemical inhibition of this group of kinases has proven effective in blocking invasion and metastasis of several solid tumors in preclinical models. RSKs are therefore a promising drug target for antimetastatic cancer treatments that could supplement and improve current therapeutic approaches. This review highlights contradiction and agreement in the current data on the function of RSK isoforms in metastasis and suggests ways forward in developing RSK inhibitors as new antimetastasis drugs. Cancer Res; 73(20); 6099–105. ©2013 AACR.
Interleukin-6 Is Required for Pancreatic Cancer Progression by Promoting MAPK Signaling Activation and Oxidative Stress Resistance
Authors: Zhang Yaqing , Yan Wei , Collins Meredith A. , Bednar Filip , Rakshit Sabita , Zetter Bruce R. , Stanger Ben Z. , Chung Ivy , Rhim Andrew D. , di Magliano Marina Pasca 
Published: October 2013

Abstract
Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the stepwise progression of the human disease. The inflammatory cytokine interleukin (IL)-6 is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL-6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL-6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL-6 synergizes with oncogenic Kras to activate the reactive oxygen species detoxification program downstream of the mitogen-activated protein kinase/extracellular signal—regulated kinase (MAPK/ERK) signaling cascade. In addition, IL-6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL-6 emerges as a key player at all stages of pancreatic carcinogenesis and a potential therapeutic target. Cancer Res; 73(20); 6359–74. ©2013 AACR.
The Evolution of Melanoma Resistance Reveals Therapeutic Opportunities
Authors: Thakur Meghna Das , Stuart Darrin D. 
Published: October 2013

Abstract
The RAS–RAF–MEK–ERK pathway is a key driver of proliferation and survival signals in tumor cells and has been the focus of intense drug development efforts over the past 20 years. The recent regulatory approval of RAF inhibitors and a MAP–ERK kinase (MEK) inhibitor for metastatic melanoma provides clinical validation of tumor dependency on this pathway. Unfortunately, the therapeutic benefit of these agents is often short lived and resistance develops within a matter of months. Preclinical models of resistance to vemurafenib have provided critical insights into predicting, validating, and characterizing potential mechanisms. A key observation has been that vemurafenib-resistant tumor cells suffer a fitness deficit in the absence of drug treatment and this led to the predication that modulating the selective pressure of drug treatment through intermittent dosing could delay or prevent the emergence of resistant tumors. Most importantly, the preclinical data are supported by observations in vemurafenib-treated patients with melanoma providing a strong rationale for clinical testing of alternative dosing regimens. Cancer Res; 73(20); 6106–10. ©2013 AACR.
Twenty-fifth Annual Pezcoller Symposium: Metabolism and Tumorigenesis
Authors: Kaelin William , Livingston David , Loda Massimo , Vousden Karen , Mihich Enrico 
Published: October 2013

Abstract
Choking cancer via inhibition of metabolic enzymes essential for tumor but dispensable in normal tissues was discussed as was the altered metabolism in cancer cells related to: tumor suppressor protein (pVHL) function, the histone acetylation dependence upon glucose, the epigenomic reprogramming of acetyl CoA synthesis, the plasticity of aging mechanisms, and the metabolism orchestration in macrophage polarization. The p53 and p73 pathways role in metabolic adaptation, the effects on growth of AMP-dependent kinase, the growth regulation by the mTOR pathways, and the bioenergetics requirements of cancer cells were also discussed. A novel computational model of personalized metabolic changes in cancer was outlined with applications in patients with breast cancer. Imaging metabolic characteristics of tumors by MRI and 13C-nuclear magnetic resonance was described. The cancer metabolism regulation related to O-linked β-N-acetylglucosame was described. DNA hypermethylation and impaired hematopoietic differentiation in AML after isocitrate dehydrogenase 1/2 mutation and 2-hydroxyglutarate increases were outlined. Cancer Res; 73(20); 6124–7. ©2013 AACR.
Semaphorin 4F as a Critical Regulator of Neuroepithelial Interactions and a Biomarker of Aggressive Prostate Cancer
Authors: Ding Yi , He Dandan , Florentin Diego , Frolov Anna , Hilsenbeck Sue , Ittmann Michael , Kadmon Dov , Miles Brian , Rowley David , Ayala Gustavo 
Published: October 2013

Abstract
Background: Semaphorin 4F (S4F) has roles in embryologic axon guidance and is expressed in adults. S4F is involved in cancer-induced neurogenesis.
Methods: Prostate cells were transfected with S4F retrovirus. Cells and controls were used for a bromodeoxyuridine (BrdUrd) incorporation assay (proliferation) and in vitro scratch and Matrigel Transwell chamber invasion assay (migration). Monoclonal antibodies were developed using baculovirus-expressed recombinant GST-S4F and used to immunostain tissue microarrays. Slides were imaged using deconvolution and analyzed using tissue segmentation. Data were correlated with clinicopathologic parameters, other biomarkers and survival analysis conducted. Heterogeneity of S4F expression was analyzed with unsupervised clustering algorithms.
Results: Proliferation rates measured by BrdUrd incorporation were higher in all S4F-transfected cells. S4F overexpression was associated with increased motility of the cancer cells. S4F expression was overexpressed in high-grade prostatic intraepithelial neoplasia/prostate cancer than normal epithelium. S4F expression correlated with seminal vesicle invasion. Patients with high values of S4F in prostate cancer cytoplasm are at significantly higher risk of biochemical recurrence, by univariate and multivariate analyses. S4F cytoplasmic expression in prostate cancer cells also correlates with nerve density in prostate cancer and perineural invasion diameter. Correlations were identified with NF-κB and inversely with apoptosis in perineural invasion.
Conclusion: These data show that S4F is significantly involved in human prostate cancer progression. S4F is a key regulator of the interactions between nerves in the tumor microenvironment and cancer cells. Because of the importance of cancer nerve interaction in the biology of cancer and its clinical implication, S4F can be considered a major therapeutic target. Clin Cancer Res; 19(22); 6101–11. ©2013 AACR.
Ang-2-VEGF-A CrossMab, a Novel Bispecific Human IgG1 Antibody Blocking VEGF-A and Ang-2 Functions Simultaneously, Mediates Potent Antitumor, Antiangiogenic, and Antimetastatic Efficacy
Authors: Kienast Yvonne , Klein Christian , Scheuer Werner , Raemsch Romi , Lorenzon Erica , Bernicke Dirk , Herting Frank , Yu Sidney , The Huynh Hung , Martarello Laurent , Gassner Christian , Stubenrauch Kay-Gunnar , Munro Kate , Augustin Hellmut G. , Thomas Markus 
Published: October 2013

Abstract
Purpose: VEGF-A blockade has been clinically validated as a treatment for human cancers. Angiopoietin-2 (Ang-2) expression has been shown to function as a key regulator of tumor angiogenesis and metastasis.
Experimental Design: We have applied the recently developed CrossMab technology for the generation of a bispecific antibody recognizing VEGF-A with one arm based on bevacizumab (Avastin), and the other arm recognizing Ang-2 based on LC06, an Ang-2 selective human IgG1 antibody. The potency of Ang-2-VEGF CrossMab was evaluated alone and in combination with chemotherapy using orthotopic and subcutaneous xenotransplantations, along with metastasis analysis by quantitative real-time Alu-PCR and ex vivo evaluation of vessels, hypoxia, proliferation, and apoptosis. The mechanism of action was further elucidated using Western blotting and ELISA assays.
Results: Ang-2-VEGF-A CrossMab showed potent tumor growth inhibition in a panel of orthotopic and subcutaneous syngeneic mouse tumors and patient or cell line-derived human tumor xenografts, especially at later stages of tumor development. Ang-2-VEGF-A CrossMab treatment led to a strong inhibition of angiogenesis and an enhanced vessel maturation phenotype. Neoadjuvant combination with chemotherapy resulted in complete tumor regression in primary tumor-bearing Ang-2-VEGF-A CrossMab-treated mice. In contrast to Ang-1 inhibition, anti-Ang-2-VEGF-A treatment did not aggravate the adverse effect of anti-VEGF treatment on physiologic vessels. Moreover, treatment with Ang-2-VEGF-A CrossMab resulted in inhibition of hematogenous spread of tumor cells to other organs and reduced micrometastatic growth in the adjuvant setting.
Conclusion: These data establish Ang-2-VEGF-A CrossMab as a promising antitumor, antiangiogenic, and antimetastatic agent for the treatment of cancer. Clin Cancer Res; 19(24); 6730–40. ©2013 AACR.