Citations

Abstract High-throughput and high-content databases are increasingly important resources in molecular medicine, systems biology, and pharmacology. However, the information usually resides in unwieldy databases, limiting ready data analysis and integration. One resource that offers substantial potential for improvement in this regard is the NCI-60 cell line database compiled by the U.S. National Cancer Institute, which has been extensively characterized across numerous genomic and pharmacologic response platforms. In this report, we introduce a CellMiner (http://discover.nci.nih.gov/cellminer/) web application designed to improve the use of this extensive database. CellMiner tools allowed rapid data retrieval of transcripts for 22,379 genes and 360 microRNAs along with activity reports for 20,503 chemical compounds including 102 drugs approved by the U.S. Food and Drug Administration. Converting these differential levels into quantitative patterns across the NCI-60 clarified data organization and cross-comparisons using a novel pattern match tool. Data queries for potential relationships among parameters can be conducted in an iterative manner specific to user interests and expertise. Examples of the in silico discovery process afforded by CellMiner were provided for multidrug resistance analyses and doxorubicin activity; identification of colon-specific genes, microRNAs, and drugs; microRNAs related to the miR-17-92 cluster; and drug identification patterns matched to erlotinib, gefitinib, afatinib, and lapatinib. CellMiner greatly broadens applications of the extensive NCI-60 database for discovery by creating web-based processes that are rapid, flexible, and readily applied by users without bioinformatics expertise. Cancer Res; 72(14); 3499–511. ©2012 AACR.

Prostate cancer is the most common solid tumor in American men and is screened for using prostate-specific antigen (PSA) tests. We report on a nonstationary partially observable Markov decision process (POMDP) for prostate biopsy referral decisions. The core states are the patients' prostate cancer related health states, and PSA test results are the observations. Transition probabilities and rewards are inferred from the Mayo Clinic Radical Prostatectomy Registry and the medical literature. The objective of our model is to maximize expected quality-adjusted life years. We solve the POMDP model to obtain an age and belief (probability of having prostate cancer) dependent optimal biopsy referral policy. We also prove a number of structural properties including the existence of a control-limit type policy for the biopsy referral decision. Our empirical results demonstrate a nondecreasing belief threshold in age, and we provide sufficient conditions under which PSA screening should be discontinued for older patients. Finally, the benefits of screening under the optimal biopsy referral policy are estimated, and sensitivity analysis is used to prioritize the model parameters that would benefit from additional data collection.

Abstract Chronic nasal and skin colonization with superantigen (SAg)-producing Staphylococcus aureus is well documented in humans. Given that trans-mucosal and trans-cutaneous absorption of SAgs can occur, we determined whether chronic exposure to small amounts of SAg per se could activate autoreactive CD4+ and CD8+ T cells and precipitate any autoimmune disease without further external autoantigenic stimulation. Because HLA class II molecules present SAg more efficiently than do mouse MHC class II molecules, HLA-DQ8 transgenic mice were implanted s.c. with mini-osmotic pumps capable of continuously delivering the SAg, staphylococcal enterotoxin B (total of 10 μg/mouse), or PBS over 4 wk. Chronic exposure to staphylococcal enterotoxin B resulted in a multisystem autoimmune inflammatory disease with features similar to systemic lupus erythematosus. The disease was characterized by mononuclear cell infiltration of lungs, liver, and kidneys, accompanied by the production of anti-nuclear Abs and deposition of immune complexes in the renal glomeruli. The inflammatory infiltrates in various organs predominantly consisted of CD4+ T cells bearing TCR Vβ8. The extent of immunopathology was markedly reduced in mice lacking CD4+ T cells and CD28, indicating that the disease is CD4+ T cell mediated and CD28 dependent. The absence of disease in STAT4-deficient, as well as IFN-γ–deficient, HLA-DQ8 mice suggested the pathogenic role of Th1-type cytokines, IL-12 and IFN-γ. In conclusion, our study suggests that chronic exposure to extremely small amounts of bacterial SAg could be an etiological factor for systemic lupus erythematosus.

This review provides an update on the treatment of benign prostatic hyperplasia and the pharmacologic considerations for perioperative care. By age 85 years, approximately 90% of men have prostate histologic characteristics consistent with benign prostatic hyperplasia. Pharmacologic treatment with an alpha 1 receptor antagonist may reduce symptoms and, when given in combination with a 5-alpha-reductase inhibitor, may decrease the risk of urinary retention and the need for surgical intervention. Transurethral resection of the prostate has been the historical standard when surgical intervention is indicated. However, recent evidence suggests that Holmium laser enucleation of the prostate may have similar efficacy with less risk of complications and with decreased catheterization time. Prostatic urological operations may have perioperative complications, including urethral bleeding, acute urinary retention, urinary tract infection, urge incontinence, and venous thromboembolism. Pharmacist recommendations for the appropriate use of laxatives, antibiotics, anticoagulation, and urinary antispasmodics are key components of perioperative management. Surgical interventions improve symptoms but may have complications, providing the pharmacist an opportunity to improve perioperative care.

Abstract Purpose: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept. Experimental Design: Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose. Results: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P < 0.05) and increase in placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2. Conclusions: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting. Clin Cancer Res; 18(18); 5081–9. ©2012 AACR.

As retail clinics provide a less costly alternative for health care, it would be reasonable to expect an increase in multiple (repeat) retail visits by those patients who may have expenses for receiving primary care. If costs were not a significant factor, then repeat visits should not be significantly different between these patients and those with coverage for primary care visits. The hypothesis for this study was that patients with the potential for out-of-pocket expenses would have a higher frequency of repeat retail clinic visits within 180 days compared to those with primary care coverage. A retrospective chart review was conducted of 5703 patients utilizing a retail clinic in Rochester, Minnesota from January 1, 2009 through June 30, 2009. The first visit to the retail clinic was considered the index visit and the chart was reviewed for repeat retail clinic visits within the next 180 days. Using a multiple logistic regression model, the odds of a pediatric patient ( N =2344) having a repeat retail visit within 180 days of the index visit were not significantly impacted by insurance coverage ( P =0.4209). Of the 3359 adult patients, those with unknown coverage had a 25.6% higher odds ratio of repeat retail clinic visits than those with insurance coverage (odds ratio 1.2557, confidence interval 1.0421–1.5131). This study suggested that when cost is an issue, the adult patient may favor retail clinics for episodic, low-acuity health care. In contrast, the pediatric population did not, suggesting that other factors, such as convenience, may play more of a role in the choice of episodic health care for this age group. ( Population Health Management 2012;15:358–361)

Background— Treatment options for patients with recurrent ventricular arrhythmias refractory to pharmacotherapy and ablation are minimal. Although left cardiac sympathetic denervation (LCSD) is well established in long-QT syndrome, its role in non–long-QT syndrome arrhythmogenic channelopathies and cardiomyopathies is less clear. Here, we report our single-center experience in performing LCSD in this setting. Methods and Results— In this institutional review board–approved study, we retrospectively reviewed the electronic medical records of all patients (N=91) who had videoscopic LCSD at our institution from 2005 to 2011. Data were analyzed for the subset (n=27) who were denervated for an underlying diagnosis other than autosomal dominant or sporadic long-QT syndrome. The spectrum of arrhythmogenic disease included catecholaminergic polymorphic ventricular tachycardia (n=13), Jervell and Lange-Nielsen syndrome (n=5), idiopathic ventricular fibrillation (n=4), left ventricular noncompaction (n=2), hypertrophic cardiomyopathy (n=1), ischemic cardiomyopathy (n=1), and arrhythmogenic right ventricular cardiomyopathy (n=1). Five patients had LCSD because of high-risk assessment and β-blocker intolerance, none of whom had a sentinel breakthrough cardiac event at early follow-up. Among the remaining 22 previously symptomatic patients who had LCSD as secondary prevention, all had an attenuation in cardiac events, with 18 having no breakthrough cardiac events so far and 4 having experienced ≥1 post-LCSD breakthrough cardiac event. Conclusions— LCSD may represent a substrate-independent antifibrillatory treatment option for patients with life-threatening ventricular arrhythmia syndromes other than long-QT syndrome. The early follow-up seems promising, with a marked reduction in the frequency of cardiac events postdenervation.

Rac1b mediates the matrix metalloproteinase–induced epithelial-mesenchymal transition in lung adenocarcinoma and is a potential therapeutic target in early-stage lung cancer.