bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atmospheric fine particulate matter and breast cancer mortality: a population-based cohort study
Authors: Tagliabue Giovanna , Borgini Alessandro , Tittarelli Andrea , van Donkelaar Aaron , Martin Randall V , Bertoldi Martina , Fabiano Sabrina , Maghini Anna , Codazzi Tiziana , Scaburri Alessandra , Favia Imma , Cau Alessandro , Barigelletti Giulio , Tessandori Roberto , Contiero Paolo 
Published: November 2016

ObjectivesAtmospheric fine particulate matter (PM2.5) has multiple adverse effects on human health. Global atmospheric levels of PM2.5increased by 0.55 μg/m3/year (2.1%/year) from 1998 through 2012. There is evidence of a causal relationship between atmospheric PM2.5and breast cancer (BC) incidence, but few studies have investigated BC mortality and atmospheric PM2.5. We investigated BC mortality in relation to atmospheric PM2.5levels among patients living in Varese Province, northern Italy.MethodsWe selected female BC cases, archived in the local population-based cancer registry, diagnosed at age 50–69 years, between 2003 and 2009. The geographic coordinates of each woman's place of residence were identified, and individual PM2.5exposures were assessed from satellite data. Grade, stage, age at diagnosis, period of diagnosis and participation in BC screening were potential confounders. Kaplan-Meir and Nelson-Aalen methods were used to test for mortality differences in relation to PM2.5quartiles. Multivariable Cox proportional hazards modelling estimated HRs and 95% CIs of BC death in relation to PM2.5exposure.ResultsOf 2021 BC cases, 325 died during follow-up to 31 December 2013, 246 for BC. Risk of BC death was significantly higher for all three upper quartiles of PM2.5exposure compared to the lowest, with HRs of death: 1.82 (95% CI 1.15 to 2.89), 1.73 (95% CI 1.12 to 2.67) and 1.72 (95% CI 1.08 to 2.75).ConclusionsOur study indicates that the risk of BC mortality increases with PM2.5exposure. Although additional research is required to confirm these findings, they are further evidence that PM2.5exposure is harmful and indicate an urgent need to improve global air quality.
Incentives and disincentives for treating of depression and anxiety in Ontario Family Health Teams: protocol for a grounded theory study
Authors: Ashcroft Rachelle , Menear Matthew , Silveira Jose , Dahrouge Simone , McKenzie Kwame 
Published: November 2016

IntroductionThere is strong consensus that prevention and management of common mental disorders (CMDs) should occur in primary care and evidence suggests that treatment of CMDs in these settings can be effective. New interprofessional team-based models of primary care have emerged that are intended to address problems of quality and access to mental health services, yet many people continue to struggle to access care for CMDs in these settings. Insufficient attention directed towards the incentives and disincentives that influence care for CMDs in primary care, and especially in interprofessional team-based settings, may have resulted in missed opportunities to improve care quality and control healthcare costs. Our research is driven by the hypothesis that a stronger understanding of the full range of incentives and disincentives at play and their relationships with performance and other contextual factors will help stakeholders identify the critical levers of change needed to enhance prevention and management of CMDs in interprofessional primary care contexts. Participant recruitment began in May 2016.Methods and analysisAn explanatory qualitative design, based on a constructivist grounded theory methodology, will be used. Our study will be conducted in the Canadian province of Ontario, a province that features a widely implemented interprofessional team-based model of primary care. Semistructured interviews will be conducted with a diverse range of healthcare professionals and stakeholders that can help us understand how various incentives and disincentives influence the provision of evidence-based collaborative care for CMDs. A final sample size of 100 is anticipated. The protocol was peer reviewed by experts who were nominated by the funding organisation.Ethics and disseminationThe model we generate will shed light on the incentives and disincentives that are and should be in place to support high-quality CMD care and help stimulate more targeted, coordinated stakeholder responses to improving primary mental healthcare quality.
Implementing mobile devices to reduce non-rostered workload for junior doctors
Authors: Plant Allan , Round Suzanne , Bourne Joe 
Published: November 2016

There is a large body of evidence demonstrating the detrimental effect of long work hours on the performance, mood, and job satisfaction of junior doctors. By extension these effects carry over into the realm of patient safety, compromising the quality of care provision.House officers in the general surgery department of Tauranga Hospital, New Zealand are often required to arrive at work well before their rostered start time of 7.30am to hand write the results of clinical investigations on their patient lists. Baseline measurement demonstrated that each house officer was spending an average of 28 minutes a day of non-rostered time completing this task, increasing to 33 minutes on post-acute days. This quality improvement project trialed the use of a mobile device for accessing clinical results in real-time on surgical ward rounds with the ultimate aim of reducing non-rostered workload by one hour per house officer, per week.A sustainable reduction to a median of 15 minutes non-rostered work per day for each house officer was achieved, translating into 75 minutes less non-rostered work for each house officer every week. Importantly, this result was sustained for more than seven working weeks and spanned a changeover in house officer rotation. Furthermore, the use of the devices was associated with a perceived improvement in the accuracy and timeliness of access to clinical results with no perceived detriment to the speed or flow of the ward round.
Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44
Authors: Huang Yinghui , Zhou Jie , Luo Shenglin , Wang Yang , He Jintao , Luo Peng , Chen Zelin , Liu Tao , Tan Xu , Ou Juanjuan , Miao Hongming , Liang Houjie , Shi Chunmeng 
Published: November 2016

ObjectiveAs the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated. However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues. This study aims to develop a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism.DesignA series of mitochondria-targeting near-infrared (NIR) fluorophores were synthesised, screened and identified for their autophagy-enhancing activity. The optical properties and biological effects were tested both in vitro and in vivo. The underlying mechanism was investigated using inhibitors, small interfering RNA (siRNA), RNA sequencing, mass spectrometry and human samples.ResultsWe have screened and identified a new NIR autophagy-enhancer, IR-58, which exhibits significant tumour-selective killing effects. IR-58 preferentially accumulates in the mitochondria of colorectal cancer (CRC) cells and xenografts, a process that is glycolysis-dependent and organic anion transporter polypeptide-dependent. IR-58 kills tumour cells and induces apoptosis via inducing excessive autophagy, which is mediated through the reactive oxygen species (ROS)-Akt-mammalian target of rapamycin (mTOR) pathway. RNA sequencing, mass spectrometry and siRNA interference studies demonstrate that translocase of inner mitochondrial membrane 44 (TIM44)-superoxide dismutase 2 (SOD2) pathway inhibition is responsible for the excessive ROS, autophagy and apoptosis induced by IR-58. TIM44 expression correlates positively with CRC development and poor prognosis in patients.ConclusionsA novel NIR small-molecule autophagy-enhancer, IR-58, with mitochondria-targeted imaging and therapy capabilities was developed for CRC treatment. Additionally, TIM44 was identified for the first time as a potential oncogene, which plays an important role in autophagy through the TIM44-SOD2-ROS-mTOR pathway.
Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma
Authors: Bollard Julien , Miguela Verónica , Ruiz de Galarreta Marina , Venkatesh Anu , Bian C Billie , Roberto Mark P , Tovar Victoria , Sia Daniela , Molina-Sánchez Pedro , Nguyen Christie B , Nakagawa Shigeki , Llovet Josep M , Hoshida Yujin , Lujambio Amaia 
Published: November 2016

ObjectiveAdvanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC.DesignThe effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses.ResultsPalbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of ‘RB1 loss of function’ was found in <30% of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival.ConclusionsPalbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70% of all patients with HCC.
CR1 exon variants are associated with lowered CR1 expression and increased susceptibility to SLE in aPlasmodium falciparumendemic population
Authors: Panda Aditya K , Ravindran Balachandran , Das Bidyut K 
Published: November 2016

BackgroundComplement receptor 1 (CR1) plays an important role in immune complex clearance by opsonisation and possibly protects subjects from development of autoantibodies. Lower CR1 expression has been associated with susceptibility to systemic lupus erythematosus (SLE). In contrast, subjects displaying lower CR1 expression are protected against severe manifestations of falciparum malaria. This study is the first of its kind to investigate the association of CR1 variants with development of SLE in aP. falciparumendemic population from Odisha, India.MethodsCR1 polymorphisms (intron 27 (A>T), exon 22 (A>G) and exon 33 (G>C)) were typed by PCR and restriction length polymorphism in 297 cases of female patients with SLE and 300 age-matched and sex-matched healthy controls from malaria endemic areas in Odisha, India. CR1 expression on monocytes was quantified by flow cytometry.ResultsThe homozygous mutants of CR1 exon 22 (GG) and exon 33 (GG) and their minor alleles were associated with susceptibility to SLE. Furthermore, patients with SLE who harboured the GG genotype of the exon 33 polymorphism had a 3.12-fold higher chance of developing lupus nephritis. CR1 exon (22 and 33) variants were associated with lowered CR1 expression on monocytes in patients with SLE and in healthy controls. Patients with lupus nephritis showed significantly diminished CR1 expression than those without renal involvement (p=0.01).ConclusionsThe results of the present study demonstrate that common CR1 exon variants are associated with diminished CR1 expression on monocytes and increased susceptibility to development of SLE and lupus nephritis in a malaria endemic area.
Quantitative assessment of device–clot interaction for stent retriever thrombectomy
Authors: van der Marel Kajo , Chueh Ju-Yu , Brooks Olivia W , King Robert M , Marosfoi Miklos G , Langan Erin T , Carniato Sarena L , Gounis Matthew J , Nogueira Raul G , Puri Ajit S 
Published: November 2016

PurposeRapid revascularization in emergent large vessel occlusion with endovascular embolectomy has proven clinical benefit. We sought to measure device–clot interaction as a potential mechanism for efficient embolectomy.MethodsTwo different radiopaque clot models were injected to create a middle cerebral artery occlusion in a patient-specific vascular phantom. A radiopaque stent retriever was deployed within the clot by unsheathing the device or a combination of unsheathing followed by pushing the device (n=8/group). High-resolution cone beam CT was performed immediately after device deployment and repeated after 5 min. An image processing pipeline was created to quantitatively evaluate the volume of clot that integrates with the stent, termed the clot integration factor (CIF).ResultsThe CIF was significantly different for the two deployment variations when the device engaged the hard clot (p=0.041), but not the soft clot (p=0.764). In the hard clot, CIF increased significantly between post-deployment and final imaging datasets when using the pushing technique (p=0.019), but not when using the unsheathing technique (p=0.067). When we investigated the effect of time on CIF in the different clot models disregarding the technique, the CIF was significantly increased in the final dataset relative to the post-deployment dataset in both clot models (p=0.004–0.007).ConclusionsThis study demonstrates in an in vitro system the benefit of pushing the Trevo stent during device delivery in hard clot to enhance integration. Regardless of delivery technique, clot–device integration increased in both clot models by waiting 5 min.
Perspective and future of evidence-based medicine
Authors: You Suning 
Published: November 2016

BackgroundEvidence-based medicine (EBM) has evolved over a century. EBM is now the guiding principle of medical practice. High-level EBM usually derives from a well-designed, randomised, double blind, placebo controlled trial of parallel groups and sufficient number of patients enrolled. However, in recent times, concerns of EBM misguiding clinical practice have been on the rise. This paper aims at exploring the root cause of why EBM is perhaps losing its touch as the measuring standard of clinical practice.MethodHistory of EBM and criteria of determining a well-designed and conducted trial were reviewed. The impact of pharmaceutical industry on EBM has been elucidated. The percentage of clinical trials that were sponsored by the pharmaceutical industry was calculated. Some of the wrong motives of conducting clinical research were identified.ResultTo some extent, EBM may have contributed to overdiagnose or overuse of medicine. Nearly 46% of clinical trials were financed by pharmaceutical companies. About 90% of manuscripts printed might not need to be published. Many trials contained at least one outcome that did not match its initial specification as registered.ConclusionsWhile EBM continues to be the guiding principle, clinicians should be aware of potential tainted results. In the future, big data is likely going to offer us a new aspect of EBM and arm us with more comprehensive data when we make our clinical decisions.
A test of local Lorentz invariance with Compton scattering asymmetry
Authors: Mohanmurthy Prajwal , Narayan Amrendra , Dutta Dipangkar 
Published: November 2016

We report on a measurement of the constancy and anisotropy of the speed of light relative to the electrons in photon–electron scattering. We used the Compton scattering asymmetry measured by the new Compton polarimeter in Hall C at Jefferson Lab (JLab) to test for deviations from unity of the vacuum refractive index (n). For photon energies in the range of 9–46 MeV, we obtain a new limit of 1 − n < 1.4 × 10[Formula: see text]. In addition, the absence of sidereal variation over the six-month period of the measurement constrains any anisotropies in the speed of light. These constitute the first study of Lorentz invariance (LI) using Compton asymmetry. Within the minimal Standard Model extension (MSME) framework, our result yield limits on the photon and electron coefficients [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text]. Although these limits are several orders of magnitude larger than the current best limits, they demonstrate the feasibility of using Compton asymmetry for tests of LI. Future parity-violating electron-scattering experiments at JLab will use higher energy electrons enabling better constraints.
Two-qubit separability probabilities as joint functions of the Bloch radii of the qubit subsystems
Authors: Slater Paul B. 
Published: November 2016

We detect a certain pattern of behavior of separability probabilities [Formula: see text] for two-qubit systems endowed with Hilbert–Schmidt (HS), and more generally, random induced measures, where [Formula: see text] and [Formula: see text] are the Bloch radii ([Formula: see text]) of the qubit reduced states ([Formula: see text]). We observe a relative repulsion of radii effect, that is [Formula: see text], except for rather narrow “crossover” intervals [Formula: see text]. Among the seven specific cases we study are, firstly, the “toy” seven-dimensional [Formula: see text]-states model and, then, the fifteen-dimensional two-qubit states obtained by tracing over the pure states in [Formula: see text]-dimensions, for [Formula: see text], with [Formula: see text] corresponding to HS (flat/Euclidean) measure. We also examine the real (two-rebit) [Formula: see text], the [Formula: see text]-states [Formula: see text], and Bures (minimal monotone)–for which no nontrivial crossover behavior is observed–instances. In the two [Formula: see text]-states cases, we derive analytical results; for [Formula: see text], we propose formulas that well-fit our numerical results; and for the other scenarios, rely presently upon large numerical analyses. The separability probability crossover regions found expand in length (lower [Formula: see text]) as [Formula: see text] increases. This report continues our efforts [P. B. Slater, arXiv:1506.08739] to extend the recent work of [S. Milz and W. T. Strunz, J. Phys. A 48 (2015) 035306.] from a univariate ([Formula: see text]) framework — in which they found separability probabilities to hold constant with [Formula: see text] — to a bivariate ([Formula: see text]) one. We also analyze the two-qutrit and qubit–qutrit counterparts reported in Quantum Inform. Process. 15 (2016) 3745 in this context, and study two-qubit separability probabilities of the form [Formula: see text]. A physics.stack.exchange link to a contribution by Mark Fischler addressing, in considerable detail, the construction of suitable bivariate distributions is indicated at the end of the paper.
Immune Therapies in Multiple Myeloma
Authors: Kumar Shaji K. , Anderson Kenneth C. 
Published: November 2016

Abstract
Treatment paradigms have changed rapidly for multiple myeloma, and immune therapies have taken center stage. Advances in therapies for myeloma have led to a dramatic improvement in the survival of patients with this incurable malignancy. The immune system is significantly impaired in patients with myeloma as a result of the disease leading to suppression of normal plasma cells as well the negative effects on cellular immunity. Given this scenario, immune approaches have not been successful until recently. Monoclonal antibodies directed against CD38 (daratumumab) and SLAMF7 (elotuzumab) are already in the clinic, and several other antibodies directed against different plasma cell antigens are under evaluation. Although immune checkpoint inhibition with PD-1 inhibitors had no clinical efficacy when the inhibitors were used as single agents, it has led to some dramatic results when the inhibitors are combined with immunomodulatory drugs such as lenalidomide and pomalidomide. Vaccination strategies have shown in vivo immune responses but no clear clinical efficacy. Newer approaches to vaccination with multiple antigens, used in combinations with immunomodulatory drugs and in the setting of minimal residual disease, have all increased possibility of this approach succeeding. Ex vivo effector cell expansion also appears to be promising and is in clinical trials. Finally, a chimeric antigen receptor T-cell approach appears to have some promise based on isolated reports of success and remains an area of intense investigation. Immune-based approaches can potentially augment or even supplant some of the current approaches and, given the low toxicity profile, may hold great potential in the early treatment of precursor-stage diseases. Clin Cancer Res; 22(22); 5453–60. ©2016 AACR.
See all articles in this CCR Focus section, “Multiple Myeloma: Multiplying Therapies.”
Cytotoxic T Cells in PD-L1–Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors
Authors: Awad Mark M. , Jones Robert E. , Liu Hongye , Lizotte Patrick H. , Ivanova Elena V. , Kulkarni Meghana , Herter-Sprie Grit S. , Liao Xiaoyun , Santos Abigail A. , Bittinger Mark A. , Keogh Lauren , Koyama Shohei , Almonte Christina , English Jessie M. , Barlow Julianne , Richards William G. , Barbie David A. , Bass Adam J. , Rodig Scott J. , Hodi F. Stephen , Wucherpfennig Kai W. , Jänne Pasi A. , Sholl Lynette M. , Hammerman Peter S. , Wong Kwok-Kin , Bueno Raphael 
Published: November 2016

Abstract
PD-L1 immunohistochemical staining does not always predict whether a cancer will respond to treatment with PD-1 inhibitors. We sought to characterize immune cell infiltrates and the expression of T-cell inhibitor markers in PD-L1–positive and PD-L1–negative malignant pleural mesothelioma samples. We developed a method for immune cell phenotyping using flow cytometry on solid tumors that have been dissociated into single-cell suspensions and applied this technique to analyze 43 resected malignant pleural mesothelioma specimens. Compared with PD-L1–negative tumors, PD-L1–positive tumors had significantly more infiltrating CD45+ immune cells, a significantly higher proportion of infiltrating CD3+ T cells, and a significantly higher percentage of CD3+ cells displaying the activated HLA-DR+/CD38+ phenotype. PD-L1–positive tumors also had a significantly higher proportion of proliferating CD8+ T cells, a higher fraction of FOXP3+/CD4+ Tregs, and increased expression of PD-1 and TIM-3 on CD4+ and CD8+ T cells. Double-positive PD-1+/TIM-3+ CD8+ T cells were more commonly found on PD-L1–positive tumors. Compared with epithelioid tumors, sarcomatoid and biphasic mesothelioma samples were significantly more likely to be PD-L1 positive and showed more infiltration with CD3+ T cells and PD-1+/TIM-3+ CD8+ T cells. Immunologic phenotypes in mesothelioma differ based on PD-L1 status and histologic subtype. Successful incorporation of comprehensive immune profiling by flow cytometry into prospective clinical trials could refine our ability to predict which patients will respond to specific immune checkpoint blockade strategies. Cancer Immunol Res; 4(12); 1038–48. ©2016 AACR.