bluuebunny/crossref_metadata_2025_split huggingface dataset:
From cradle to grave: tracking socioeconomic inequalities in mortality in a cohort of 11 868 men and women born in Uppsala, Sweden, 1915–1929
Authors: Juárez Sol P , Goodman Anna , Koupil Ilona 
Published: February 2016

BackgroundAmple evidence has shown that early-life social conditions are associated with mortality later in life. However, little attention has been given to the strength of these effects across specific age intervals from birth to old age. In this paper, we study the effect of the family's socioeconomic position and mother's marital status at birth on all-cause mortality at different age intervals in a Swedish cohort of 11 868 individuals followed across their lifespan.MethodsUsing the Uppsala Birth Cohort Multigenerational Study, we fitted Cox regression models to estimate age-varying HRs of all-cause mortality according to mother's marital status and family's socioeconomic position.ResultsMother's marital status and family's socioeconomic position at birth were associated with higher mortality rates throughout life (HR 1.18 (95% CI 1.12 to 1.26) for unmarried mothers; 1.19 (95% CI 1.12 to 1.25) for low socioeconomic position). While the effect of family's socioeconomic position showed little variation across different age groups, the effect of marital status was stronger for infant mortality (HR 1.47 (95% CI 1.23 to 1.76); p=0.04 for heterogeneity). The results remained robust when early life and adult mediator variables were included.ConclusionsFamily's socioeconomic position and mother's marital status involve different dimensions of social stratification with independent effects on mortality throughout life. Our findings support the importance of improving early-life conditions in order to enhance healthy ageing.
The impact of SASA!, a community mobilisation intervention, on women's experiences of intimate partner violence: secondary findings from a cluster randomised trial in Kampala, Uganda
Authors: Abramsky Tanya , Devries Karen M , Michau Lori , Nakuti Janet , Musuya Tina , Kyegombe Nambusi , Watts Charlotte 
Published: February 2016

BackgroundIntimate partner violence (IPV) is a global public health and human rights concern, though there is limited evidence on how to prevent it. This secondary analysis of data from the SASA! Study assesses the potential of a community mobilisation IPV prevention intervention to reduce overall prevalence of IPV, new onset of abuse (primary prevention) and continuation of prior abuse (secondary prevention).MethodsA pair-matched cluster randomised controlled trial was conducted in 8 communities (4 intervention, 4 control) in Kampala, Uganda (2007–2012). Cross-sectional surveys of community members, 18–49 years old, were undertaken at baseline (n=1583) and 4 years postintervention implementation (n=2532). Outcomes relate to women's past year experiences of physical and sexual IPV, emotional aggression, controlling behaviours and fear of partner. An adjusted cluster-level intention-to-treat analysis compared outcomes in intervention and control communities at follow-up.ResultsAt follow-up, all types of IPV (including severe forms of each) were lower in intervention communities compared with control communities. SASA! was associated with lower onset of abuse and lower continuation of prior abuse. Statistically significant effects were observed for continued physical IPV (adjusted risk ratio 0.42, 95% CI 0.18 to 0.96); continued sexual IPV (0.68, 0.53 to 0.87); continued emotional aggression (0.68, 0.52 to 0.89); continued fear of partner (0.67, 0.51 to 0.89); and new onset of controlling behaviours (0.38, 0.23 to 0.62).ConclusionsCommunity mobilisation is an effective means for both primary and secondary prevention of IPV. Further support should be given to the replication and scale up of SASA! and other similar interventions.Trial registration numberNCT00790959
Challenges in reproducing results from publicly available data: an example of sexual orientation and cardiovascular disease risk
Authors: Austin Nichole , Harper Sam , Kaufman Jay S , Hamra Ghassan B 
Published: February 2016

BackgroundReplication is a vital part of the research process and has recently received considerable attention. Analyses using publicly available data should, if adequately described, be reproducible without assistance from the original investigators. Using data from the US National Health and Nutrition Examination Survey (NHANES), a recent study reported a statistically significant difference in cardiovascular disease risk comparing subgroups of sexual minority men. We attempted to reproduce these findings and assessed whether the results were robust to alternative analytic strategies and assumptions.MethodsWe used the exclusion criteria and coding strategy described in the original paper to construct our analytical data set. Sampling weights were constructed in accordance with NHANES analytical guidelines. We estimated crude and covariate-adjusted associations between sexual orientation and vascular age using the regression models specified in the original report. We also conducted a series of sensitivity analyses to improve on the original findings.ResultsOur replication attempt was partially successful: we replicated the general trends reported in the original analysis, but not identical effect estimates. Importantly, we identified a potential misapplication of the Framingham Risk Score; correcting for this increased the probability that the reported null hypothesis test was a type I error.ConclusionsThis paper supports the recent calls for greater transparency and improved reporting in research. Even with a publicly available and well-documented data source, we were unable to exactly replicate another study's original findings. Our sensitivity analyses revealed key issues in the original analysis and demonstrate the scientific importance of research replication.
A time-series study of percutaneous closure of patent foramen ovale: premature adoption?
Authors: Lew Kian Nian , Angelini Gianni D , Hollingworth William 
Published: February 2016

ObjectivesTo evaluate the impact of National Institute for Health and Care Excellence (NICE) guidance in January 2005 and subsequent trial evidence on the adoption of percutaneous closure of patent foramen ovale (PCPFO).MethodsA retrospective time series study was conducted using the Inpatient Hospital Episode Statistics (HES) England. A total of 3801 patients, aged ≥18 and ≤60 years, who had PCPFO from 1 April 2006 to 31 March 2012 in England. Percentage change annualised (PCA) in PCPFO procedure rates between initial NICE guidance and publication of trial results was analysed.ResultsBetween Quarter 2, 2006 and Quarter 4, 2009, 2163 PCPFO procedures were performed, with an increasing PCA of 48.4%. The procedure rate peaked before the presentation of equivocal results from the first randomised controlled trial (RCT) in late 2010, and declined between Quarter 4, 2009 and Quarter 4, 2011 (PCA=−15.3%). Of more than 2300 patients recruited to three RCTs, only 71 were recruited in English hospitals.ConclusionsPCPFO was rapidly adopted after the publication of initial NICE guidance despite the absence of RCT evidence of efficacy. Very few English patients participated in international RCTs of PCPFO, suggesting that NICE recommendations also failed to encourage the generation of RCT evidence.
Association of ambulatory heart rate and atherosclerosis risk factors with blood pressure in young non-hypertensive adults
Authors: Cheng Cynthia , Daskalakis Constantine 
Published: February 2016

ObjectiveThe study objective was to assess the association between 24 h ambulatory heart rate (HR), atherosclerosis risk factors and blood pressure (BP) in young non-hypertensive patients.MethodsWe recruited 186 participants aged 18–45 years from a large urban academic Family Medicine outpatient practice, serving 40 000 individuals for this observational study. The main analyses were based on multiple linear regression, with mean 24 h BP (systolic BP (SBP) or diastolic BP (DBP)) as the outcomes, mean 24 h HR as the main predictor of interest, and controlling for age, gender, race, insulin sensitivity/resistance and endothelial function measured by strain gauge venous occlusion plethysmography.ResultsHR was independently associated with mean 24 h SBP and DBP (SBP and DBP: p=0.042 and 0.001, respectively). In our analyses, associations were markedly stronger for ambulatory compared with office BP measurements. Endothelial dysfunction was associated with higher SBP (p=0.013); plasminogen activator inhibitor-1 was significantly associated with both SBP and DBP (p=0.041 and 0.015, respectively), while insulin resistance was not associated with either SBP or DBP. Insulin resistance and C reactive protein were significant predictors of HR (p=0.013 and 0.007, respectively).ConclusionsThese findings suggest that HR may be a potential marker of elevated cardiovascular risk in young asymptomatic individuals, prior to the development of clinical hypertension or cardiovascular disease.
Basophil Recruitment into Tumor-Draining Lymph Nodes Correlates with Th2 Inflammation and Reduced Survival in Pancreatic Cancer Patients
Authors: De Monte Lucia , Wörmann Sonja , Brunetto Emanuela , Heltai Silvia , Magliacane Gilda , Reni Michele , Paganoni Anna Maria , Recalde Helios , Mondino Anna , Falconi Massimo , Aleotti Francesca , Balzano Gianpaolo , Algül Hana , Doglioni Claudio , Protti Maria Pia 
Published: February 2016

Abstract
In pancreatic ductal adenocarcinomas (PDAC), lymphoid infiltrates, comprised mainly of Th2 cells, predict a poor survival outcome in patients. IL4 signaling has been suggested to stabilize the Th2 phenotype in this setting, but the cellular source of IL4 in PDAC is unclear. Here, we show that basophils expressing IL4 are enriched in tumor-draining lymph nodes (TDLN) of PDAC patients. Basophils present in TDLNs correlated significantly with the Th2/Th1 cell ratio in tumors, where they served as an independent prognostic biomarker of patient survival after surgery. Investigations in mouse models of pancreatic cancer confirmed a functional role for basophils during tumor progression. The recruitment of basophils into TDLN relied partly upon the release of chemokine CCL7/MCP3 by "alternatively activated" monocytes, whereas basophil activation was induced by T-cell–derived IL3. Our results show how basophils recruited and activated in TDLNs under the influence of the tumor microenvironment regulate tumor-promoting Th2 inflammation in PDAC, helping in illuminating a key element of the immune milieu of pancreatic cancer. Cancer Res; 76(7); 1792–803. ©2016 AACR.
Dual Targeting of CDK4 and ARK5 Using a Novel Kinase Inhibitor ON123300 Exerts Potent Anticancer Activity against Multiple Myeloma
Authors: Perumal Deepak , Kuo Pei-Yu , Leshchenko Violetta V. , Jiang Zewei , Divakar Sai Krishna Athaluri , Cho Hearn Jay , Chari Ajai , Brody Joshua , Reddy M.V. Ramana , Zhang Weijia , Reddy E. Premkumar , Jagannath Sundar , Parekh Samir 
Published: February 2016

AbstractMultiple myeloma is a fatal plasma cell neoplasm accounting for over 10,000 deaths in the United States each year. Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, potentially because of incomplete targeting of other critical myeloma oncogenic kinases. As a substantial number of multiple myeloma cell lines and primary samples were found to express AMPK-related protein kinase 5(ARK5), a member of the AMPK family associated with tumor growth and invasion, we examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 results in a better therapeutic outcome. Treatment of multiple myeloma cell lines and primary samples with ON123300 in vitro resulted in rapid induction of cell-cycle arrest followed by apoptosis. ON123300-mediated ARK5 inhibition or ARK5-specific siRNAs resulted in the inhibition of the mTOR/S6K pathway and upregulation of the AMPK kinase cascade. AMPK upregulation resulted in increased SIRT1 levels and destabilization of steady-state MYC protein. Furthermore, ON123300 was very effective in inhibiting tumor growth in mouse xenograft assays. In addition, multiple myeloma cells sensitive to ON123300 were found to have a unique genomic signature that can guide the clinical development of ON123300. Our study provides preclinical evidence that ON123300 is unique in simultaneously inhibiting key oncogenic pathways in multiple myeloma and supports further development of ARK5 inhibition as a therapeutic approach in multiple myeloma. Cancer Res; 76(5); 1225–36. ©2016 AACR.
Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma
Authors: Curry William T. , Gorrepati Ramana , Piesche Matthias , Sasada Tetsuro , Agarwalla Pankaj , Jones Pamela S. , Gerstner Elizabeth R. , Golby Alexandra J. , Batchelor Tracy T. , Wen Patrick Y. , Mihm Martin C. , Dranoff Glenn 
Published: February 2016

Abstract
Purpose: Recurrent malignant glioma carries a dismal prognosis, and novel therapies are needed. We examined the feasibility and safety of vaccination with irradiated autologous glioma cells mixed with irradiated GM-K562 cells in patients undergoing craniotomy for recurrent malignant glioma.
Experimental Design: We initiated a phase I study examining the safety of 2 doses of GM-K562 cells mixed with autologous cells. Primary endpoints were feasibility and safety. Feasibility was defined as the ability for 60% of enrolled subjects to initiate vaccination. Dose-limiting toxicity was assessed via a 3+3 dose-escalation format, examining irradiated tumor cells mixed with 5 × 106 GM-K562 cells or 1 × 107 GM-K562 cells. Eligibility required a priori indication for resection of a recurrent high-grade glioma. We measured biological activity by measuring delayed type hypersensitivity (DTH) responses, humoral immunity against tumor-associated antigens, and T-lymphocyte activation.
Results: Eleven patients were enrolled. Sufficient numbers of autologous tumor cells were harvested in 10 patients, all of whom went on to receive vaccine. There were no dose-limiting toxicities. Vaccination strengthened DTH responses to irradiated autologous tumor cells in most patients, and vigorous humoral responses to tumor-associated angiogenic cytokines were seen as well. T-lymphocyte activation was seen with significantly increased expression of CTLA-4, PD-1, 4-1BB, and OX40 by CD4+ cells and PD-1 and 4-1BB by CD8+ cells. Activation was coupled with vaccine-associated increase in the frequency of regulatory CD4+ T lymphocytes.
Conclusions: Vaccination with irradiated autologous tumor cells mixed with GM-K562 cells is feasible, well tolerated, and active in patients with recurrent malignant glioma. Clin Cancer Res; 22(12); 2885–96. ©2016 AACR.
Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies
Authors: Waters Alicia M. , Stewart Jerry E. , Atigadda Venkatram R. , Mroczek-Musulman Elizabeth , Muccio Donald D. , Grubbs Clinton J. , Beierle Elizabeth A. 
Published: February 2016

Abstract
Rare tumors of solid organs remain some of the most difficult pediatric cancers to cure. These difficult tumors include rare pediatric renal malignancies, such as malignant rhabdoid kidney tumors (MRKT) and non-osseous renal Ewing sarcoma, and hepatoblastoma, a pediatric liver tumor that arises from immature liver cells. There are data in adult renal and hepatic malignancies demonstrating the efficacy of retinoid therapy. The investigation of retinoic acid therapy in cancer is not a new strategy, but the widespread adoption of this therapy has been hindered by toxicities. Our laboratory has been investigating a novel synthetic rexinoid, UAB30, which exhibits a more favorable side-effect profile. In this study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo. We successfully demonstrated decreased cellular proliferation, invasion and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment. UAB30 should be further investigated as a developing therapeutic in these rare and difficult-to-treat pediatric solid organ tumors. Mol Cancer Ther; 15(5); 911–21. ©2016 AACR.
3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors
Authors: Onion David , Argent Richard H. , Reece-Smith Alexander M. , Craze Madeleine L. , Pineda Robert G. , Clarke Philip A. , Ratan Hari L. , Parsons Simon L. , Lobo Dileep N. , Duffy John P. , Atherton John C. , McKenzie Andrew J. , Kumari Rajendra , King Peter , Hall Brett M. , Grabowska Anna M. 
Published: February 2016

Abstract
There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor–derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non–small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753–63. ©2016 AACR.
STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion
Authors: Gotthardt Dagmar , Putz Eva M. , Grundschober Eva , Prchal-Murphy Michaela , Straka Elisabeth , Kudweis Petra , Heller Gerwin , Bago-Horvath Zsuzsanna , Witalisz-Siepracka Agnieszka , Cumaraswamy Abbarna A. , Gunning Patrick T. , Strobl Birgit , Müller Mathias , Moriggl Richard , Stockmann Christian , Sexl Veronika 
Published: February 2016

Abstract
Natural killer (NK) cells are tightly regulated by the JAK–STAT signaling pathway and cannot survive in the absence of STAT5. We now report that STAT5-deficient NK cells can be rescued by overexpression of BCL2. Our experiments define STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-deficient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The importance of VEGFA produced by NK cells was verified by experiments with a conditional knockout of VEGFA in NK cells. We show that STAT5 normally represses the transcription of VEGFA in NK cells, in both mice and humans. These findings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell–mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis.
Significance: The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK–STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK–STAT5 has the potential to promote tumor growth by enhancing NK-cell–mediated angiogenesis. Cancer Discov; 6(4); 414–29. ©2016 AACR.
See related commentary by Ni and Cerwenka, p. 347.
This article is highlighted in the In This Issue feature, p. 331
Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab
Authors: Weber Jeffrey , Gibney Geoffrey , Kudchadkar Ragini , Yu Bin , Cheng Pingyan , Martinez Alberto J. , Kroeger Jodie , Richards Allison , McCormick Lori , Moberg Valerie , Cronin Heather , Zhao Xiuhua , Schell Michael , Chen Yian Ann 
Published: February 2016

Abstract
The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3–4 drug-related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for ipilimumab-refractory patients was 30% (95% CI, 21%–41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naïve and ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3–4 toxicity to ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%–82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3–4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab. Cancer Immunol Res; 4(4); 345–53. ©2016 AACR.