Shen J.,University of Maryland Baltimore County |
Barrios R.J.,Methodist Hospital |
Jaiswal A.K.,University of Maryland Baltimore County
Cancer Research | Year: 2010
The cytosolic quinone oxidoreductases NQO1 and NQO2 protect cells against oxidative stress by detoxifying quinones and preventing redox cycling. In this study, we used double knockout (DKO) mice deficient for NQO1 and NQO2 to investigate the role of these antioxidative enzymes in a two-stage model of inflammatory skin carcinogenesis. In this model, tumors are caused by exposure to topical carcinogen dimethylbenz(a)anthracene or benzo(a)pyrene (BP) followed by twice weekly application of proinflammatory phorbol 12-myristate 13-acetate. On this classic chemical carcinogenesis protocol, DKO mice showed a significantly higher skin tumor frequency and multiplicity compared with control wild-type or single knockout mice. Analysis of skin from wild-type and DKO mice exposed to BP for 6, 12, or 24 hours revealed a relative delay in the activation of p53, p63, p19ARF, and apoptosis in DKO mice, consistent with a negative modifier role for NQO1/NQO2 in carcinogenesis. Our findings offer genetic evidence of the significance of quinone oxidoreductases NQO1 and NQO2 in limiting chemical skin carcinogenesis. ©2010 AACR.
Cagle P.T.,Methodist Hospital |
Chirieac L.R.,Harvard University
Archives of Pathology and Laboratory Medicine | Year: 2012
Context.-Ongoing preclinical investigations and clinical trials involving new targeted therapies promise to improve survival for patients with lung cancer. Targeted therapeutic agents, based on genetic mutations and signaling pathways altered in lung cancer, have added significantly to our armamentarium for lung cancer treatment while minimizing drug toxicity. To date, 4 targeted therapies have been approved for treatment of lung cancer by the US Food and Drug Administration: gefitinib in 2002, erlotinib in 2003, bevacizumab in 2006, and crizotinib in 2011. Objective.-To review targeted therapies in lung cancer, the molecular biomarkers that identify patients likely to benefit from these targeted therapies, the basic molecular biology principles, selected molecular diagnostic techniques, and pathologic features correlated with molecular abnormalities in lung cancer. To review new molecular abnormalities described in lung cancer that are predictive for response to novel promising targeted agents in various phases of clinical trials. Data Sources.-Review of the literature covering the molecular abnormalities of lung cancer with a focus on the molecular diagnostics and targeted therapy. Special emphasis is placed on summarizing evolving technologies useful in the diagnosis and characterization of lung cancer. Conclusions.-Molecular testing of lung cancer expands the expertise of the pathologist, who will identify the tumor markers that are predictive of sensitivity or resistance to various targeted therapies and allow patients with cancer to be selected for highly effective and less toxic therapies.
Chandler W.L.,Methodist Hospital
Blood Coagulation and Fibrinolysis | Year: 2013
This study provides the first estimates of microparticle numbers in platelet-rich plasma (PRP) from normal individuals, closer to in-vivo levels, using higher-resolution flow cytometry. We measured platelet (CD41+) and annexin V+ microparticles in fresh and frozen aliquots of PRP, platelet-poor plasma, platelet-free plasma (PFP), and microparticles isolated by high-speed centrifugation. PRP from healthy individuals contained 730â€Š 000/μl total microparticles based on light-scattering measurements. A median of 27â€Š000/μl microparticles in PRP were of platelet origin and 120â€Š000/μl annexin V+, and of these, 24â€Š000/μl were dual-positive procoagulant platelet microparticles. Double centrifugation of PRP removed 99% of platelets, but also 80% of annexin V+ CD41+, 93% of annexin V+ CD41-, and 58% of annexin V- CD41+ microparticles. Loss of microparticles with centrifugation varied from individual to individual. Microparticle counts after isolation by centrifugation and double washing were not significantly different than counts in the original PFP sample, but lower than in PRP. Freeze-thawing of PFP had no effect on platelet microparticle counts, but slightly increased annexin V+, CD41- counts. Freeze-thawing of isolated washed microparticles resulted in a 30-50% increase in annexin V+ microparticles. PRP contains large numbers of cellular microparticles, including platelet and annexin V+ microparticles, which are lost to varying degrees when PRP is double centrifuged to remove platelets. Microparticles remaining in PFP can be recovered by high-speed centrifugation without loss compared to the original PFP sample. Freeze-thawing has variable effects on microparticle counts depending on the sample preparation used. © 2013 Wolters Kluwer Health Lippincott Williams & Wilkins.
Quigley E.M.M.,Methodist Hospital
American Journal of Gastroenterology | Year: 2013
Although the etiology of irritable bowel syndrome (IBS) remains unknown, clinical and laboratory observations suggest that within the broad and varying phenotype, that is, IBS, there may exist subgroups, which can be defined on the basis of a distinctive pathophysiological basis. Of these, postinfectious IBS is the best characterized; in IBS, in general, studies of inflammatory mediators and substances elaborated by cells involved in the intestinal immune response, such as proteases, suggest that some IBS sufferers can be differentiated on the basis of an aberrant immune response. Valdez-Morales and colleagues extend this concept by demonstrating the ability of supernatants of biopsy cultures from individuals with diarrhea-predominant IBS to enhance neuronal excitability - an effect that could well contribute to a clinical hallmark of IBS, namely, visceral hypersensitivity. © 2013 by the American College of Gastroenterology.
Olar A.,Methodist Hospital |
Aldape K.D.,University of Houston
Current Treatment Options in Oncology | Year: 2012
Diffuse gliomas are the most common primary brain tumors, with glioblastoma (GBM) encompassing more than 50 % of all cases. Despite aggressive therapy, patients nearly always succumb to their disease and the survival for patients with GBM is approximately 1 year. During past years, numerous scientific contributions have reshaped the field of neuro-oncology and neuropathology. A series of molecular discoveries have shed light on new pathogenic mechanisms, as well as new prognostic and predictive biomarkers with clinical relevance. The current World Health Organization (WHO) classification system is solely based on morphologic criteria; however, there is accumulated evidence that tumors with similar histology have distinct molecular signatures with a clinically significant impact on treatment response and survival. Molecular markers and signatures could be incorporated into the glioma classification and grading system to mirror the clinical outcomes. Additionally, molecular markers could lead to a redefinition of currently controversial entities, such as mixed oligoastrocytomas. Newly discovered molecular alterations also have the potential to become targets for future drug development. Despite tremendous progress in the past decade, therapeutic progress for diffuse gliomas has been slow. A further understanding of glioma biology, in concert with well-designed clinical trials, is necessary to identify more putative molecular biomarkers and unravel the mysteries in the pathogenic mechanisms that trigger this menacing disease. © Springer Science+Business Media, LLC 2012.