Predictive models for nanotoxicology: current challenges and future opportunities.

Characterizing the risks posed by nanomaterials is extraordinarily complex because these materials can have a wide range of sizes, shapes, chemical compositions and surface modifications, all of which may affect toxicity. There is an urgent need for a testing strategy that can rapidly and efficiently provide a screening approach for evaluating the potential hazard of nanomaterials and inform the prioritization of additional toxicological testing where necessary. Predictive toxicity models could form an integral component of such an approach by predicting which nanomaterials, as a result of their physico-chemical characteristics, have potentially hazardous properties. Strategies for directing research towards predictive models and the ancillary benefits of such research are presented here

Extranuclear ERα is associated with regression of T47D PKCα-overexpressing, tamoxifen-resistant breast cancer

Background: Prior to the introduction of tamoxifen, high dose estradiol was used to treat breast cancer patients with similar efficacy as tamoxifen, albeit with some undesirable side effects. There is renewed interest to utilize estradiol to treat endocrine resistant breast cancers, especially since findings from several preclinical models and clinical trials indicate that estradiol may be a rational second-line therapy in patients exhibiting resistance to tamoxifen and/or aromatase inhibitors. We and others reported that breast cancer patients bearing protein kinase C alpha (PKCα)- expressing tumors exhibit endocrine resistance and tumor aggressiveness. Our T47D:A18/PKCα preclinical model is tamoxifen-resistant, hormone-independent, yet is inhibited by 17β-estradiol (E2) in vivo. We previously reported that E2-induced T47D:A18/PKCα tumor regression requires extranuclear ERα and interaction with the extracellular matrix. Methods: T47D:A18/PKCα cells were grown in vitro using two-dimensional (2D) cell culture, three-dimensional (3D) Matrigel and in vivo by establishing xenografts in athymic mice. Immunofluoresence confocal microscopy and co-localization were applied to determine estrogen receptor alpha (ERα) subcellular localization. Co-immunoprecipitation and western blot were used to examine interaction of ERα with caveolin-1. Results: We report that although T47D:A18/PKCα cells are cross-resistant to raloxifene in cell culture and in Matrigel, raloxifene induces regression of tamoxifen-resistant tumors. ERα rapidly translocates to extranuclear sites during T47D:A18/PKCα tumor regression in response to both raloxifene and E2, whereas ERα is primarily localized in the nucleus in proliferating tumors. E2 treatment induced complete tumor regression whereas cessation of raloxifene treatment resulted in tumor regrowth accompanied by re-localization of ERα to the nucleus. T47D:A18/neo tumors that do not overexpress PKCα maintain ERα in the nucleus during tamoxifen-mediated regression. An association between ERα and caveolin-1 increases in tumors regressing in response to E2. Conclusions: Extranuclear ERα plays a role in the regression of PKCα-overexpressing tamoxifen-resistant tumors. These studies underline the unique role of extranuclear ERα in E2- and raloxifene-induced tumor regression that may have implications for treatment of endocrine-resistant PKCα-expressing tumors encountered in the clinic

Cost-effectiveness of insulin pumps compared with multiple daily injections, both provided with structured education, for adults with type 1 diabetes:a health economic analysis of the Relative Effectiveness of Pumps over Structured Education (REPOSE) randomised controlled trial

Objectives To assess the long-term cost-effectiveness of insulin pumps and Dose Adjustment for Normal Eating (pumps+DAFNE) compared with multiple daily insulin injections and DAFNE (MDI+DAFNE) for adults with type 1 diabetes mellitus (T1DM) in the UK. Methods We undertook a cost–utility analysis using the Sheffield Type 1 Diabetes Policy Model and data from the Relative Effectiveness of Pumps over Structured Education (REPOSE) trial to estimate the lifetime incidence of diabetic complications, intervention-based resource use and associated effects on costs and quality-adjusted life years (QALYs). All economic analyses took a National Health Service and personal social services perspective and discounted costs and QALYs at 3.5% per annum. A probabilistic sensitivity analysis was performed on the base case. Further uncertainties in the cost of pumps and the evidence used to inform the model were explored using scenario analyses. Setting Eight diabetes centres in England and Scotland. Participants Adults with T1DM who were eligible to receive a structured education course and did not have a strong clinical indication or a preference for a pump. Intervention Pumps+DAFNE. Comparator MDI+DAFNE. Main outcome measures Incremental costs, incremental QALYs gained and incremental cost-effectiveness ratios (ICERs). Results Compared with MDI+DAFNE, pumps+DAFNE was associated with an incremental discounted lifetime cost of +£18 853 (95% CI £6175 to £31 645) and a gain in discounted lifetime QALYs of +0.13 (95% CI -0.70 to +0.96). The base case mean ICER was £142 195 per QALY gained. The probability of pump+DAFNE being cost-effective using a cost-effectiveness threshold of £20 000 per QALY gained was 14.0%. All scenario and subgroup analyses examined indicated that the ICER was unlikely to fall below £30 000 per QALY gained. Conclusions Our analysis of the REPOSE data suggests that routine use of pumps in adults without an immediate clinical need for a pump, as identified by National Institute for Health and Care Excellence, would not be cost-effective. Trial registration number ISRCTN61215213

Gender-specific 30-day outcomes after carotid endarterectomy and carotid artery stenting in the Society for Vascular Surgery Vascular Registry

ObjectiveAlthough the optimal treatment of carotid stenosis remains unclear, available data suggest that women have higher risk of adverse events after carotid revascularization. We used data from the Society for Vascular Surgery Vascular Registry to determine the effect of gender on outcomes after carotid endarterectomy (CEA) and carotid artery stenting (CAS).MethodsThere were 9865 patients (40.6% women) who underwent CEA (n = 6492) and CAS (n = 3373). The primary end point was a composite of death, stroke, and myocardial infarction at 30 days.ResultsThere was no difference in age and ethnicity between genders, but men were more likely to be symptomatic (41.6% vs 38.6%; P < .003). There was a higher prevalence of hypertension and chronic obstructive pulmonary disease in women, whereas men had a higher prevalence of coronary artery disease, history of myocardial infarction, and smoking history. For disease etiology in CAS, restenosis was more common in women (28.7% vs 19.7%; P < .0001), and radiation was higher in men (6.2% vs 2.6%; P < .0001). Comparing by gender, there were no statistically significant differences in the primary end point for CEA (women, 4.07%; men, 4.06%) or CAS (women, 6.69%; men, 6.80%). There remains no difference after stratification by symptomatology and multivariate risk adjustment.ConclusionsIn this large, real-world analysis, women and men demonstrated similar results after CEA or CAS. These data suggest that, contrary to previous reports, women do not have a higher risk of adverse events after carotid revascularization

The decline and rise of neighbourhoods: the importance of neighbourhood governance

There is a substantial literature on the explanation of neighbourhood change. Most of this literature concentrates on identifying factors and developments behind processes of decline. This paper reviews the literature, focusing on the identification of patterns of neighbourhood change, and argues that the concept of neighbourhood governance is a missing link in attempts to explain these patterns. Including neighbourhood governance in the explanations of neighbourhood change and decline will produce better explanatory models and, finally, a better view about what is actually steering neighbourhood change

The Grizzly, November 5, 1991

Red and Gold Day • Changes for Education Majors • Golf Cart Stolen • Unrest in the Quad • Alcohol Update • Fourth Annual Grizzly Network Career Day • U.S.G.A. Minutes • Chemical Awareness • Biology Department Update • Environmental Notes • Fraternities Experience Humanity of Habitat • The Winner Is: Mudslinger #1 • The Harm of Rumors • Priorities in College Athletics • Feed Your Mind • Halloween Flop • Soviet Art at Ursinus • The Quad Peacock • College Choir Performs Requiem • Senior Barn Bash • Goodfellas • Bears Rush by the Mules in 13-9 Upset • Volleyball Ends Season with a Loss • Field Hockey Passes by Princeton • Senior Runners Reflect on Seasonhttps://digitalcommons.ursinus.edu/grizzlynews/1282/thumbnail.jp

The Grizzly, November 19, 1991

Founders\u27 Day Excitement • Grizzly Network Career Day • Women\u27s Choices • Volksmarching • Louisiana Election • Service Opportunities for Students • The European Situation • Jonas Salk Addresses Founders Day Convocation • Dr. Takats Awarded the Clamer Chair • Wellness Services Proposal • U.S.G.A. Minutes • Ursinus Continues Helping Habitat • Turkey Drive Needs You • Zack: The Man, The Myth, The Statue • Hocus Pocus a Success • Ursinus Students in Community Production of Gypsy • Movie Review: Hamlet • Battle of the Bands • Rollins Rocks Lower Lounge • Branker Tours to St. Petersburg • CAB Trip to New York • Writing in Good Taste • Magic: One Trick Too Many • Letters: Faculty Members Speak Out; GALA Replies to Letter; Call for Diversity; Publishing the Truth?; Student Reaction to Ronning; Response to Black Hole ; Students React to Social Life • No More Crap! • Filling in the Black Hole • One Professor\u27s Awakening • Lady Bears End Season • Men\u27s Lacrosse Awaits Chance • Women Swimmers Wash Out Washington • Spinella Takes Over as Head Coach of Basketball Team • Dickinson Defeats the Bearshttps://digitalcommons.ursinus.edu/grizzlynews/1284/thumbnail.jp

Choosing to live with home dialysis-patients' experiences and potential for telemedicine support: a qualitative study

<p>Abstract</p> <p>Background</p> <p>This study examines the patients' need for information and guidance in the selection of dialysis modality, and in establishing and practicing home dialysis. The study focuses on patients' experiences living with home dialysis, how they master the treatment, and their views on how to optimize communication with health services and the potential of telemedicine.</p> <p>Methods</p> <p>We used an inductive research strategy and conducted semi-structured interviews with eleven patients established in home dialysis. Our focus was the patients' experiences with home dialysis, and our theoretical reference was patients' empowerment through telemedicine solutions. Three informants had home haemodialysis (HHD); eight had peritoneal dialysis (PD), of which three had automated peritoneal dialysis (APD); and five had continuous ambulatory peritoneal dialysis (CAPD). The material comprises all PD-patients in the catchment area capable of being interviewed, and all known HHD-users in Norway at that time.</p> <p>Results</p> <p>All of the interviewees were satisfied with their choice of home dialysis, and many experienced a normalization of daily life, less dominated by disease. They exhibited considerable self-management skills and did not perceive themselves as ill, but still required very close contact with the hospital staff for communication and follow-up. When choosing a dialysis modality, other patients' experiences were often more influential than advice from specialists. Information concerning the possibility of having HHD, including knowledge of how to access it, was not easily available. Especially those with dialysis machines, both APD and HHD, saw a potential for telemedicine solutions.</p> <p>Conclusions</p> <p>As home dialysis may contribute to a normalization of life less dominated by disease, the treatment should be organized so that the potential for home dialysis can be fully exploited. Pre-dialysis information should be unbiased and include access to other patients' experiences. Telemedicine may potentially facilitate a communication-based follow-up and improve safety within the home setting, making it easier to choose and live with home dialysis.</p

Risk of Ovarian Cancer and Inherited Variants in Relapse-Associated Genes

Background: We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk. Methods and Findings: Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95 % CI 0.66–0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p,0.05), and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95 % CI 1.02–1.91). Conclusions: Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasiv