Human Vault Nanoparticle Targeted Delivery of Antiretroviral Drugs to Inhibit Human Immunodeficiency Virus Type 1 Infection.

"Vaults" are ubiquitously expressed endogenous ribonucleoprotein nanoparticles with potential utility for targeted drug delivery. Here, we show that recombinant human vault nanoparticles are readily engulfed by certain key human peripheral blood mononuclear cells (PBMC), predominately dendritic cells, monocytes/macrophages, and activated T cells. As these cell types are the primary targets for human immunodeficiency virus type 1 (HIV-1) infection, we examined the utility of recombinant human vaults for targeted delivery of antiretroviral drugs. We chemically modified three different antiretroviral drugs, zidovudine, tenofovir, and elvitegravir, for direct conjugation to vaults. Tested in infection assays, drug-conjugated vaults inhibited HIV-1 infection of PBMC with equivalent activity to free drugs, indicating vault delivery and drug release in the cytoplasm of HIV-1-susceptible cells. The ability to deliver functional drugs via vault nanoparticle conjugates suggests their potential utility for targeted drug delivery against HIV-1

Coding of Barrett's oesophagus with high-grade dysplasia in national administrative databases: a population-based cohort study.

OBJECTIVES: The International Classification of Diseases 10th Revision (ICD-10) system used in the English hospital administrative database (Hospital Episode Statistics (HES)) does not contain a specific code for oesophageal high-grade dysplasia (HGD). The aim of this paper was to examine how patients with HGD were coded in HES and whether it was done consistently. SETTING: National population-based cohort study of patients with newly diagnosed with HGD in England. The study used data collected prospectively as part of the National Oesophago-Gastric Cancer Audit (NOGCA). These records were linked to HES to investigate the pattern of ICD-10 codes recorded for these patients at the time of diagnosis. PARTICIPANTS: All patients with a new diagnosis of HGD between 1 April 2013 and 31 March 2014 in England, who had data submitted to the NOGCA. OUTCOMES MEASURED: The main outcome assessed was the pattern of primary and secondary ICD-10 diagnostic codes recorded in the HES records at endoscopy at the time of diagnosis of HGD. RESULTS: Among 452 patients with a new diagnosis of HGD between 1 April 2013 and 31 March 2014, Barrett's oesophagus was the only condition coded in 200 (44.2%) HES records. Records for 59 patients (13.1%) contained no oesophageal conditions. The remaining 193 patients had various diagnostic codes recorded, 93 included a diagnosis of Barrett's oesophagus and 57 included a diagnosis of oesophageal/gastric cardia cancer. CONCLUSIONS: HES is not suitable to support national studies looking at the management of HGD. This is one reason for the UK to adopt an extended ICD system (akin to ICD-10-CM)

Effects of an educational program and a standardized insulin order form on glycemic outcomes in non-critically ill hospitalized patients

BACKGROUND: The optimal approach to managing hyperglycemia in noncritically ill hospital patients is unclear. OBJECTIVE: To investigate the effects of targeted quality improvement interventions on insulin prescribing and glycemic control. DESIGN: A cohort study comparing an intervention group (IG) to a concurrent control group (CCG) and an historic control group (HCG). SETTING: University of Michigan Hospital. PATIENTS: Hyperglycemic, noncritically ill hospital patients treated with insulin. INTERVENTION: Physician and nurse education and a standardized insulin order form based on the principles of physiologic insulin use. MEASUREMENTS: Glycemic control and insulin prescribing patterns. RESULTS: Patients in the IG were more likely to be treated with a combination of scheduled basal and nutritional insulin than in the other groups. In the final adjusted regression model, patients in the IG were more likely to be in the target glucose range (odds ratio [OR], 1.72; P = 0.01) and less likely to be severely hyperglycemic (OR, 0.65; P < 0.01) when compared to those in the CCG. Patients in the IG were also less likely to experience hypoglycemia than those in the CCG ( P = 0.06) or the HCG ( P = 0.01). Over 80% of all patient-days for all groups contained glucose readings outside of the target range. CONCLUSIONS: Standardized interventions encouraging the physiologic use of subcutaneous insulin can lead to significant improvements in glycemic control and patient safety in hospitalized patients. However, the observed improvements are modest, and poor metabolic control remains common, despite these interventions. Additional research is needed to determine the best strategy for safely achieving metabolic control in these patients. Journal of Hospital Medicine 2010. © 2010 Society of Hospital Medicine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78247/1/780_ftp.pd

Adenoma development in familial adenomatous polyposis andMUTYH-associated polyposis: somatic landscape and driver genes

Familial adenomatous polyposis (FAP) and MUTYH‐associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss‐of‐function mutations in WTX (9%; p < 9.99e‐06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab

Background Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesized that common germline variants within these pathways may also play similar roles. Methods We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy +cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%. Results We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab - in patients with KRAS wild type CRCs, 36.4% of patients with one allele encoding proline responded, as compared to 71.2% of patients homozygous for alleles encoding serine (OR 0.23, 95% CI 0.09-0.56, P=0.0014) and this association was predictive for cetuximab (Pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated. Conclusions Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity

Brief of Tax Law Professors as \u3ci\u3eAmici Curiae\u3c/i\u3e in Support of Petitioner in \u3ci\u3eLoudoun County, Virginia v. Dulles Duty Free, LLC\u3c/i\u3e

Amici are professors of tax law at universities across the United States. As scholars and teachers, they have considered the doctrinal roots and practical consequences of judicial limits on state and local taxation. Amici join this brief solely on their own behalf and not as representatives of their universities. A full list of amici appears in the Appendix to this brief

Individual, behavioural and home environmental factors associated with eating behaviours in young adolescents

This study aimed to examine individual, behavioural and home environmental factors associated with frequency of consumption of fruit, vegetables and energy-dense snacks among adolescents. Adolescents aged 11-12 years (n = 521, 48% boys) completed a paper-based questionnaire during class-time which included a Food Frequency Questionnaire assessing their consumption of fruit, vegetables, and energy dense (ED) snacks, and items assessing habits, self-efficacy, eating at the television (TV), eating with parents, parenting practices, and home availability and accessibility of foods. Multiple linear regression analyses showed that eating fruit and vegetables while watching TV and home availability and accessibility of fruit and vegetables were positively associated with frequency of fruit consumption and vegetable consumption, while home accessibility of ED snack foods was negatively associated with frequency of fruit consumption. Habit for eating ED snack foods in front the TV, eating ED snack foods while watching TV, and home availability of ED snacks were positively associated with frequency of ED snack consumption. This study has highlighted the importance of a healthy home environment for promoting fruit and vegetable intake in early adolescents and also suggests that, if snacking while TV viewing occurs, this could be a good opportunity for promoting fruit and vegetable intake. These findings are likely to be useful for supporting the development of multi-faceted interventions and aid us in knowing what advice to give to parents to help them to help their young adolescents to develop and maintain healthy eating habits

Pharmacogenetic analyses of 2,183 patients with advanced colorectal cancer; Potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy.

BACKGROUND: Inherited genetic variants may influence response to, and side-effects from, chemotherapy. We sought to generate a comprehensive inherited pharmacogenetic profile for oxaliplatin and 5FU/capecitabine therapy in advanced colorectal cancer (aCRC). METHODS: We analysed more than 200 potentially functional, common, inherited variants in genes within the 5FU, capecitabine, oxaliplatin and DNA repair pathways, together with four rare dihydropyrimidine dehydrogenase (DPYD) variants, in 2183 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy with, or without, cetuximab (from MRC COIN and COIN-B trials). Primary end-points were response, any toxicity and peripheral neuropathy. We had >85% power to detect odds ratios (ORs) = 1.3 for variants with minor allele frequencies >20%. RESULTS: Variants in DNA repair genes (Asn279Ser in EXO1 and Arg399Gln in XRCC1) were most associated with response (OR 1.9, 95% confidence interval [CI] 1.2-2.9, P = 0.004, and OR 0.7, 95% CI 0.5-0.9, P = 0.003, respectively). Common variants in DPYD (Cys29Arg and Val732Ile) were most associated with toxicity (OR 0.8, 95% CI 0.7-1.0, P = 0.008, and OR 1.6, 95% CI 1.1-2.1, P = 0.006, respectively). Two rare DPYD variants were associated with increased toxicity (Asp949Val with neutropenia, nausea and vomiting, diarrhoea and infection; IVS14+1G>A with lethargy, diarrhoea, stomatitis, hand-foot syndrome and infection; all ORs > 3). Asp317His in DCLRE1A was most associated with peripheral neuropathy (OR 1.3, 95% CI 1.1-1.6, P = 0.003). No common variant associations remained significant after Bonferroni correction. CONCLUSIONS: DNA repair genes may play a significant role in the pharmacogenetics of aCRC. Our data suggest that both common and rare DPYD variants may be associated with toxicity to fluoropyrimidine-based chemotherapy