bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness analysis of arthroscopic surgery compared with non-operative management for osteoarthritis of the knee
Authors: Marsh Jacquelyn D , Birmingham Trevor B , Giffin J Robert , Isaranuwatchai Wanrudee , Hoch Jeffrey S , Feagan Brian G , Litchfield Robert , Willits Kevin , Fowler Peter 
Published: January 2016

ObjectiveTo determine the cost-effectiveness of arthroscopic surgery in addition to non-operative treatments compared with non-operative treatments alone in patients with knee osteoarthritis (OA).Design, setting and participantsWe conducted an economic evaluation alongside a single-centre, randomised trial among patients with symptomatic, radiographic knee OA (KL grade ≥2).InterventionsPatients received arthroscopic debridement and partial resection of degenerative knee tissues in addition to optimised non-operative therapy, or optimised non-operative therapy only.Main outcome measuresDirect and indirect costs were collected prospectively over the 2-year study period. The effectiveness outcomes were the Western Ontario McMaster Osteoarthritis Index (WOMAC) and quality-adjusted life years (QALYs). Cost-effectiveness was estimated using the net benefit regression framework considering a range of willingness-to-pay values from the Canadian public payer and societal perspectives. We calculated incremental cost-effectiveness ratios and conducted sensitivity analyses using the extremes of the 95% CIs surrounding mean differences in effect between groups.Results168 patients were included. Patients allocated to arthroscopy received partial resection and debridement of degenerative meniscal tears (81%) and/or articular cartilage (97%). There were no significant differences between groups in use of non-operative treatments. The incremental net benefit was negative for all willingness-to-pay values. Uncertainty estimates suggest that even if willing to pay $400 000 to achieve a clinically important improvement in WOMAC score, or ≥$50 000 for an additional QALY, there is <20% probability that the addition of arthroscopy is cost-effective compared with non-operative therapies only. Our sensitivity analysis suggests that even when assuming the largest treatment effect, the addition of arthroscopic surgery is not economically attractive compared with non-operative treatments only.ConclusionsArthroscopic debridement of degenerative articular cartilage and resection of degenerative meniscal tears in addition to non-operative treatments for knee OA is not an economically attractive treatment option compared with non-operative treatment only, regardless of willingness-to-pay value.Trial registration numberNCT00158431.
Comparison of informal caregiver and named nurse assessment of symptoms in elderly patients dying in hospital using the palliative outcome scale
Authors: Dawber Rebecca , Armour Kathy , Ferry Peter , Mukherjee Bhaskar , Carter Christopher , Meystre Chantal 
Published: January 2016

ObjectivesA prospective study of symptom assessments made by a healthcare professional (HCP; named nurse) and an informal caregiver (ICG) compared with that of the patient with a terminal diagnosis. To look at the validity of HCP and ICG as proxies, which symptoms they can reliably assess, and to determine who is the better proxy between HCP and ICG.MethodsA total of 50 triads of patient (>65 years) in the terminal phase, ICG and named nurse on medical wards of an acute general hospital. Assessments were made using the patient and caregiver versions of the palliative outcome scale (POS), all taken within a 24 h period. Agreement between patient-rated, ICG-rated and HCP-rated POS and POS for symptoms (POS-S) was measured using weighted-κ statistics. Demographic and clinical data on each group of participants were collected.ResultsICG assessments have higher agreement with those of the patient than HCP. Better agreement in both groups was found for physical symptoms, and best agreement was for pain. The worst agreements were for psychological symptoms, such as anxiety and depression, and for satisfaction with information given. Psychological symptoms are overestimated by both ICG and HCP.ConclusionsICGs are more reliable proxies than HCPs. A trend for overestimation of symptoms was found in both groups which may lead to undervaluation of the quality of life by proxy and overtreatment of symptoms. This highlights the need to always use the patient report when possible, and to be aware of the potential flaws in proxy assessment. Reasons for overestimation by proxies deserve further research.
Experience of providing palliative care in critical care settings
Authors: Davies James , Vora Vandana 
Published: January 2016

BackgroundChanging demographics and medical advances have led to an increased demand for beds in critical care units. Patients in critical care are at risk of physical and psychosocial suffering. The goal of palliative care is to achieve the best quality of life for patients and families irrespective of diagnosis or location of care. The delivery of high-quality end-of-life care in critical care units can be challenging.ObjectivesOur aim was to (1) identify patient characteristics and timing of referral to Hospital Palliative Care Team (HPCT) since admission to critical care unit; (2) assess the impact of HPCT on patient care and location of death; (3) describe challenges of providing input in this setting by HPCT.MethodsWe retrospectively reviewed all referrals to HPCT from critical care units of a large teaching hospital over a 6-year period. Data were extracted from an electronic database storing details of all patient referrals and contacts.ResultsAs a proportion of all referrals to HPCT, those from critical care rose from 1.7% to 3.17%. The proportion of patients with non-malignant diagnoses referred has risen from 29% to 39%. Of total referrals, 96/144 (66.6%) patients died within the same episode of care. 65% of these died within 1 week. 51% of patients died on critical care. We also describe challenges encountered and impact of the HPCT on patient care.ConclusionsThe HPCT provide an important contribution to patients in critical care, through symptom control, family support, continuity of care and in end-of-life care. On the basis of our review, the challenge is to move from a sequential model of care to a more integrated approach.
Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results
Authors: Yelnik Cecile M , Laskin Carl A , Porter T Flint , Branch D Ware , Buyon Jill P , Guerra Marta M , Lockshin Michael D , Petri Michelle , Merrill Joan T , Sammaritano Lisa R , Kim Mimi Y , Salmon Jane E 
Published: January 2016

ObjectiveWe previously reported that lupus anticoagulant (LAC) is the main predictor of poor pregnancy outcome in antiphospholipid antibody (aPL)-positive patients. We sought to confirm this finding in an independent group of patients who were subsequently recruited into the PROMISSE study.MethodsThe PROMISSE study is a multicentre, prospective, observational study of pregnancy outcomes in women with aPL and/or systemic lupus erythematosus (SLE) that enrolled patients from 2003 to 2015. All consecutive, aPL-positive patients from the PROMISSE study who completed their pregnancy between April 2011 and January 2015 (after the previous PROMISSE report) are included in the current report. Patients were followed monthly until delivery, and aPL was tested at first, second and third trimesters of pregnancy and at 12 weeks post partum. Adverse pregnancy outcomes (APOs) were defined as fetal death after 12 weeks of gestation, neonatal death, delivery prior to 36 weeks of gestation due to pre-eclampsia or placental insufficiency or small-for-gestational age (birth weight <5th percentile).ResultsForty-four aPL-positive patients are included in this paper. Thirteen patients had APOs, which occurred in 80% of cases during the second trimester of pregnancy. LAC was present in 69% of patients with APOs compared with 27% of patients without APOs (p=0.01). No association was found between anticardiolipin antibodies (aCL) or anti-β2 glycoprotein I antibodies (aβ2GPI) IgG or IgM positivity and APOs. Definite antiphospholipid syndrome (history of thrombosis and/or pregnancy morbidity and aPL) was found in 92% of patients with any APOs compared with 45% of patients without APOs (p=0.004). Conversely, the frequency of SLE was not statistically different between those with and without APOs (30% vs 39%).ConclusionsOur findings, in an independent group of aPL-positive patients from the PROMISSE study, confirm that LAC, but not aCL and aβ2GPI, is predictive of poor pregnancy outcomes after 12 weeks of pregnancy.Trial registration numberNCT00198068.
RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway
Authors: Dubois Fatéméh , Keller Maureen , Calvayrac Olivier , Soncin Fabrice , Hoa Lily , Hergovich Alexander , Parrini Maria-Carla , Mazières Julien , Vaisse-Lesteven Mélissa , Camonis Jacques , Levallet Guénaëlle , Zalcman Gérard 
Published: January 2016

Abstract
Inactivation of the tumor suppressor gene RASSF1A by promoter hypermethylation represents a key event underlying the initiation and progression of lung cancer. RASSF1A inactivation is also associated with poor prognosis and may promote metastatic spread. In this study, we investigated how RASSF1A inactivation conferred invasive phenotypes to human bronchial cells. RNAi-mediated silencing of RASSF1A induced epithelial-to-mesenchymal transition (EMT), fomenting a motile and invasive cellular phenotype in vitro and increased metastatic prowess in vivo. Mechanistic investigations revealed that RASSF1A blocked tumor growth by stimulating cofilin/PP2A–mediated dephosphorylation of the guanine nucleotide exchange factor GEF-H1, thereby stimulating its ability to activate the antimetastatic small GTPase RhoB. Furthermore, RASSF1A reduced nuclear accumulation of the Hippo pathway transcriptional cofactor Yes-associated protein (YAP), which was reinforced by RhoB activation. Collectively, our results indicated that RASSF1 acts to restrict EMT and invasion by indirectly controlling YAP nuclear shuttling and activation through a RhoB-regulated cytoskeletal remodeling process, with potential implications to delay the progression of RASSF1-hypermethylated lung tumors. Cancer Res; 76(6); 1627–40. ©2016 AACR.
Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation
Authors: Marmary Yitzhak , Adar Revital , Gaska Svetlana , Wygoda Annette , Maly Alexander , Cohen Jonathan , Eliashar Ron , Mizrachi Lina , Orfaig-Geva Carmit , Baum Bruce J. , Rose-John Stefan , Galun Eithan , Axelrod Jonathan H. 
Published: January 2016

AbstractHead and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiation-induced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (γH2AX and 53BP1) and the expression of senescence-associated markers (SA-βgal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation-induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy. Cancer Res; 76(5); 1170–80. ©2016 AACR.
AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation
Authors: Li Chia-Wei , Xia Weiya , Lim Seung-Oe , Hsu Jennifer L. , Huo Longfei , Wu Yun , Li Long-Yuan , Lai Chien-Chen , Chang Shih-Shin , Hsu Yi-Hsin , Sun Hui-Lung , Kim Jongchan , Yamaguchi Hirohito , Lee Dung-Fang , Wang Hongmei , Wang Yan , Chou Chao-Kai , Hsu Jung-Mao , Lai Yun-Ju , LaBaff Adam M. , Ding Qingqing , Ko How-Wen , Tsai Fuu-Jen , Tsai Chang-Hai , Hortobagyi Gabriel N. , Hung Mien-Chie 
Published: January 2016

Abstract
Epithelial-to-mesenchymal transition (EMT) is an essential physiologic process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKBα, but not AKT2 or AKT3, serves as a negative regulator of EMT and breast cancer metastasis. However, the underlying mechanism by which AKT1 suppresses EMT remains poorly defined. Here, we demonstrate that phosphorylation of Twist1 by AKT1 is required for β-TrCP–mediated Twist1 ubiquitination and degradation. The clinically used AKT inhibitor MK-2206, which possesses higher specificity toward AKT1, stabilized Twist1 and enhanced EMT in breast cancer cells. However, we discovered that resveratrol, a naturally occurring compound, induced β-TrCP–mediated Twist1 degradation to attenuate MK-2206–induced EMT in breast cancer cells. Taken together, our findings demonstrate that resveratrol counteracts the unexpected metastatic potential induced by anti-AKT therapy and therefore suggest that the addition of resveratrol to an anti-AKT therapeutic regimen may provide extra support for limiting EMT. Cancer Res; 76(6); 1451–62. ©2016 AACR.
Cdx2 Expression and Intestinal Metaplasia Induced by H. pylori Infection of Gastric Cells Is Regulated by NOD1-Mediated Innate Immune Responses
Authors: Asano Naoki , Imatani Akira , Watanabe Tomohiro , Fushiya Jun , Kondo Yutaka , Jin Xiaoyi , Ara Nobuyuki , Uno Kaname , Iijima Katsunori , Koike Tomoyuki , Strober Warren , Shimosegawa Tooru 
Published: January 2016

Abstract
Chronic infection with the bacterial Helicobacter pylori is a major cause of gastric and duodenal ulcer disease, gastric mucosal atrophy, and cancer. H. pylori–induced expression of the intestinal epithelial–specific transcription factor caudal-related homeobox 2 (Cdx2) contributes to intestinal metaplasia, a precursor event to gastric cancer. Given a role for the bacterial pattern recognition molecule nucleotide-binding oligomerization domain 1 (NOD1) in the innate immune response to bacterial infection, we investigated mechanisms used by NOD1 to regulate H. pylori infection and its propensity towards the development of intestinal metaplasia. We found that Cdx2 was induced by H. pylori infection in both normal and neoplastic gastric epithelial cells in a manner that was inversely related to NOD1 signaling. Mechanistic investigations revealed that Cdx2 induction relied upon activation of NF-κB but was suppressed by NOD1-mediated activation of TRAF3, a negative regulator of NF-κB. In vivo, prolonged infection of NOD1-deficient mice with H. pylori led to increased Cdx2 expression and intestinal metaplasia. Furthermore, gastric epithelial cells from these mice exhibited increased nuclear expression of the NF-κB p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pylori–induced Cdx2 expression in gastric epithelial cells, suggesting a rationale to augment NOD1 signaling in H. pylori–infected patients to limit their risks of accumulating precancerous gastric lesions. Cancer Res; 76(5); 1135–45. ©2016 AACR.
EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape
Authors: Lim Seung-Oe , Li Chia-Wei , Xia Weiya , Lee Heng-Huan , Chang Shih-Shin , Shen Jia , Hsu Jennifer L. , Raftery Daniel , Djukovic Danijel , Gu Haiwei , Chang Wei-Chao , Wang Hung-Ling , Chen Mong-Liang , Huo Longfei , Chen Chung-Hsuan , Wu Yun , Sahin Aysegul , Hanash Samir M. , Hortobagyi Gabriel N. , Hung Mien-Chie 
Published: January 2016

Abstract
Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. EGF signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGFR, thereby increasing lactate excretion, which leads to inhibition of local cytotoxic T-cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-d-glucose with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC. Cancer Res; 76(5); 1284–96. ©2016 AACR.
Identification of DNA Methylation–Independent Epigenetic Events Underlying Clear Cell Renal Cell Carcinoma
Authors: Becket Elinne , Chopra Sameer , Duymich Christopher E. , Lin Justin J. , You Jueng Soo , Pandiyan Kurinji , Nichols Peter W. , Siegmund Kimberly D. , Charlet Jessica , Weisenberger Daniel J. , Jones Peter A. , Liang Gangning 
Published: January 2016

Abstract
Alterations in chromatin accessibility independent of DNA methylation can affect cancer-related gene expression, but are often overlooked in conventional epigenomic profiling approaches. In this study, we describe a cost-effective and computationally simple assay called AcceSssIble to simultaneously interrogate DNA methylation and chromatin accessibility alterations in primary human clear cell renal cell carcinomas (ccRCC). Our study revealed significant perturbations to the ccRCC epigenome and identified gene expression changes that were specifically attributed to the chromatin accessibility status whether or not DNA methylation was involved. Compared with commonly mutated genes in ccRCC, such as the von Hippel-Lindau (VHL) tumor suppressor, the genes identified by AcceSssIble comprised distinct pathways and more frequently underwent epigenetic changes, suggesting that genetic and epigenetic alterations could be independent events in ccRCC. Specifically, we found unique DNA methylation–independent promoter accessibility alterations in pathways mimicking VHL deficiency. Overall, this study provides a novel approach for identifying new epigenetic-based therapeutic targets, previously undetectable by DNA methylation studies alone, that may complement current genetic-based treatment strategies. Cancer Res; 76(7); 1954–64. ©2016 AACR.
Statin Use and Breast Cancer Risk in the Nurses' Health Study
Authors: Borgquist Signe , Tamimi Rulla M. , Chen Wendy Y. , Garber Judy E. , Eliassen A. Heather , Ahern Thomas P. 
Published: January 2016

Abstract
Preclinical studies support an anticancer effect of statin drugs, yet epidemiologic evidence remains inconsistent regarding their role in breast cancer primary prevention. Here, we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses' Health Study (NHS) cohort. Postmenopausal NHS participants without a cancer history were followed from 2000 until 2012 (n = 79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence [former users: HRadj, 0.96; 95% confidence interval (CI), 0.82–1.1; current users: HRadj, 1.1; 95% CI, 0.92–1.3]. Associations did not differ by estrogen receptor (ER) status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histologic subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. Cancer Epidemiol Biomarkers Prev; 25(1); 201–6. ©2016 AACR.
Comparative Effectiveness of Implantable Cardioverter Defibrillators for Primary Prevention in Women
Authors: Zeitler Emily P. , Hellkamp Anne S. , Schulte Phillip J. , Fonarow Gregg C. , Hernandez Adrian F. , Peterson Eric D. , Sanders Gillian D. , Yancy Clyde W. , Al-Khatib Sana M. 
Published: January 2016

Background—
Clinical trials of implantable cardioverter defibrillators (ICDs) for primary prevention enrolled a limited number of women. We sought to examine clinical practice data to compare survival rates among women with heart failure with or without a primary prevention ICD.

Methods and Results—

We linked data from 264 US hospitals included in the Get With The Guidelines for Heart Failure registry with data from the Centers for Medicare and Medicaid Services. From these sources, we propensity score matched 430 women with heart failure who received a primary prevention ICD to 430 women who did not; we further adjusted using a Cox proportional hazards model. Median follow-up was 3.4 and 3.0 years. For comparison, we matched 859 men receiving an ICD with 859 who did not; median follow-up was 3.9 versus 2.9 years. In the matched cohorts, an ICD was associated with similarly better survival in women (hazard ratio, 0.78; 95% confidence interval, 0.66–0.92;
P
=0.003) and men (hazard ratio, 0.76; 95% confidence interval, 0.67–0.87
P
<0.001). There was no interaction between sex and presence of an ICD with respect to survival (
P
=0.79).

Conclusions—
Among patients with heart failure with reduced left ventricular ejection fraction, a primary prevention ICD was associated with a significant survival advantage among women and among men. These findings support guideline-directed use of primary prevention ICDs in eligible patients.