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Patel V.N.,Case Western Reserve University | Gokulrangan G.,Case Western Reserve University | Chowdhury S.A.,Carnegie Mellon University | Chen Y.,Case Western Reserve University | And 4 more authors.
PLoS Computational Biology | Year: 2013

To determine a molecular basis for prognostic differences in glioblastoma multiforme (GBM), we employed a combinatorial network analysis framework to exhaustively search for molecular patterns in protein-protein interaction (PPI) networks. We identified a dysregulated molecular signature distinguishing short-term (survival<225 days) from long-term (survival>635 days) survivors of GBM using whole genome expression data from The Cancer Genome Atlas (TCGA). A 50-gene subnetwork signature achieved 80% prediction accuracy when tested against an independent gene expression dataset. Functional annotations for the subnetwork signature included "protein kinase cascade," "IκB kinase/NFκB cascade," and "regulation of programmed cell death" - all of which were not significant in signatures of existing subtypes. Finally, we used label-free proteomics to examine how our subnetwork signature predicted protein level expression differences in an independent GBM cohort of 16 patients. We found that the genes discovered using network biology had a higher probability of dysregulated protein expression than either genes exhibiting individual differential expression or genes derived from known GBM subtypes. In particular, the long-term survivor subtype was characterized by increased protein expression of DNM1 and MAPK1 and decreased expression of HSPA9, PSMD3, and CANX. Overall, we demonstrate that the combinatorial analysis of gene expression data constrained by PPIs outlines an approach for the discovery of robust and translatable molecular signatures in GBM. © 2013 Patel et al.

Hecht C.R.,MetroHealth Medical Center | Smith M.D.,MetroHealth Medical Center | Radonich K.,Cleveland State University | Kozlovskaya O.,John Carroll University | Totten V.Y.,University Hospital Case Medical Center
Annals of Emergency Medicine | Year: 2011

Objective: This study compares and contrasts emergency department (ED) patient and staff attitudes towards ED-based HIV testing in 2 major hospitals in a single city, with an attempt to answer the following: Should routine ED-based HIV testing be offered? If so, who should be responsible for disclosing HIV test results? And what barriers might prevent ED-based HIV testing? Methods: Paper-based surveys were presented to a convenience sample of ED patients and staff at 2 urban, academic, tertiary care hospitals between December 2007 and June 2009. Descriptive statistics were derived with SAS and MicroSoft Excel. Data are reported in percentages, fractions, and graphs. Results: A total of 457 patients and 85 staff completed the surveys. The majority of patients favor ED-based HIV testing. Only a minority of ED staff support ED-based HIV testing. In both hospitals, patients prefer to have HIV test results delivered by a physician. This was true for both positive and negative results. However, only about one third of attending physicians feel comfortable disclosing a positive HIV test result. Patients and staff both view privacy and confidentiality as significant barriers to ED-based HIV testing. Conclusion: Although ED patients are overwhelmingly in favor of ED-based HIV testing, the staff is not. Patients and staff agree that physicians should deliver HIV test results to patients, but a significant number of physicians are not comfortable doing so. Historical barriers continue to hinder ED-based HIV testing programs. Copyright © 2011 by the American College of Emergency Physicians.

Li C.,Case Western Reserve University | Xin W.,University Hospital Case Medical Center | Sy M.-S.,Case Western Reserve University
Oncogene | Year: 2010

Over the last decades, cancer research has focused on tumor suppressor genes and oncogenes. Genes in other cellular pathways has received less attention. Between 0.5% to 1% of the mammalian genome encodes for proteins that are tethered on the cell membrane via a glycosylphosphatidylinositol (GPI)-anchor. The GPI modification pathway is complex and not completely understood. Prion (PrP), a GPI-anchored protein, is infamous for being the only normal protein that when misfolded can cause and transmit a deadly disease. Though widely expressed and highly conserved, little is known about the functions of PrP. Pancreatic cancer and melanoma cell lines express PrP. However, in these cell lines the PrP exists as a pro-PrP as defined by retaining its GPI anchor peptide signal sequence (GPI-PSS). Unexpectedly, the GPI-PSS of PrP has a filamin A (FLNA) binding motif and binds FLNA. FLNA is a cytolinker protein, and an integrator of cell mechanics and signaling. Binding of pro-PrP to FLNA disrupts the normal FLNA functions. Although normal pancreatic ductal cells lack PrP, about 40% of patients with pancreatic ductal cell adenocarcinoma express PrP in their cancers. These patients have significantly shorter survival time compared with patients whose cancers lack PrP. Pro-PrP is also detected in melanoma in situ but is undetectable in normal melanocyte, and invasive melanoma expresses more pro-PrP. In this review, we will discuss the underlying mechanisms by which binding of pro-PrP to FLNA disrupts normal cellular physiology and contributes to tumorigenesis, and the potential mechanisms that cause the accumulation of pro-PrP in cancer cells. © 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10.

Hajar T.,Oregon Health And Science University | Leshem Y.A.,Oregon Health And Science University | Hanifin J.M.,Oregon Health And Science University | Nedorost S.T.,University Hospital Case Medical Center | And 3 more authors.
Journal of the American Academy of Dermatology | Year: 2015

Background The National Eczema Association has received increasing numbers of patient inquiries regarding "steroid addiction syndrome," coinciding with the growing presence of social media dedicated to this topic. Although many of the side effects of topical corticosteroids (TCS) are addressed in guidelines, TCS addiction is not. Objective We sought to assess the current evidence regarding addiction/withdrawal. Methods We performed a systematic review of the current literature. Results Our initial search yielded 294 results with 34 studies meeting inclusion criteria. TCS withdrawal was reported mostly on the face and genital area (99.3%) of women (81.0%) primarily in the setting of long-term inappropriate use of potent TCS. Burning and stinging were the most frequently reported symptoms (65.5%) with erythema being the most common sign (92.3%). TCS withdrawal syndrome can be divided into papulopustular and erythematoedematous subtypes, with the latter presenting with more burning and edema. Limitations Low quality of evidence, variability in the extent of data, and the lack of studies with rigorous steroid addiction methodology are limitations. Conclusions TCS withdrawal is likely a distinct clinical adverse effect of TCS misuse. Patients and providers should be aware of its clinical presentation and risk factors. © 2014 American Academy of Dermatology, Inc.

Armstrong A.,University Hospital Case Medical Center | Otvos B.,Case Western Reserve University | Singh S.,University Hospital Case Medical Center | Debernardo R.,University Hospital Case Medical Center
Gynecologic Oncology | Year: 2013

Objective Ovarian cancer accounts for 50% of deaths from gynecologic malignancies. We sought to determine the cost of common methods of surveillance of women with ovarian cancer in first clinical remission. The current standard for post treatment surveillance is the National Comprehensive Cancer Network (NCCN) guidelines. Methods We retrospectively determined how recurrence was initially detected at our institution and a cost model was created and applied to the United States population to calculate surveillance costs using the Surveillance Epidemiology & End Results (SEER) database. Results 57% (n = 60) of first recurrences were identified by increasing CA 125 level. Routine office visit identified 27% (n = 29) of recurrences, and 15% (n = 16) were diagnosed initially with CT scan. In 5% (5/105), CT abnormality was the only finding. 95% (100/105) of patients had either elevated CA 125 or office visit findings at time of recurrence. Of the 22,000 women diagnosed with ovarian cancer yearly, 60% (n = 13,266) will have advanced disease and are likely to recur. The surveillance cost for this population for 2 years using our model is $32,500,000 using NCCN guidelines and $58,000,000 if one CT scan is obtained. Conclusions Our data suggests that following NCCN guidelines will detect 95% of recurrences. An additional $26 million will be needed to identify the 5% of women with recurrence seen on CT only. Post treatment surveillance of ovarian cancer patients contributes significantly to health care costs. Use of CT scan to follow these patients largely increases cost with only a small increase in recurrence detection. © 2013 Elsevier Inc.

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