Faculty Bibliography

Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination.

AIM: To evaluate circulating endothelial lineage cells (ELCs) as biomarkers of tumor neovascularization in patients with pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: ELCs were isolated from the peripheral blood of patients with PDAC (n=14) or controls (n=17) before and after tumor resection/surgery and quantified using flow cytometry. Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were detected in tumor using immunohistochemistry and in plasma using an ELISA technique. RESULTS: Circulating ELC levels were increased in patients with PDAC compared to controls. After PDAC resection, ELC levels declined. ELC level increases were associated with cancer recurrence. VEGF and PlGF were identified in cancer cells and exocrine pancreas cells. Only PlGF was detected in tumor-associated inflammatory cells. Plasma levels of PlGF were higher in patients with PDAC compared to controls. CONCLUSION: Circulating ELCs are a potential biomarker of PDAC neovascularization, and PlGF may be an important target in treatment of PDAC

BACKGROUND: Sera from lung cancer patients contain autoantibodies that react with tumor associated antigens (TAAs) that reflect genetic over-expression, mutation, or other anomalies of cell cycle, growth, signaling, and metabolism pathways. METHODS: We performed immunoassays to detect autoantibodies to ten tumor associated antigens (TAAs) selected on the basis of previous studies showing that they had preferential specificity for certain cancers. Sera examined were from lung cancer patients (22); smokers with ground-glass opacities (GGOs) (46), benign solid nodules (55), or normal CTs (35); and normal non-smokers (36). Logistic regression models based on the antibody biomarker levels among the high risk and lung cancer groups were developed to identify the combinations of biomarkers that predict lung cancer in these cohorts. RESULTS: Statistically significant differences in the distributions of each of the biomarkers were identified among all five groups. Using Receiver Operating Characteristic (ROC) curves based on age, c-myc, Cyclin A, Cyclin B1, Cyclin D1, CDK2, and survivin, we obtained a sensitivity = 81% and specificity = 97% for the classification of cancer vs smokers(no nodules, solid nodules, or GGO) and correctly predicted 31/36 healthy controls as noncancer. CONCLUSION: A pattern of autoantibody reactivity to TAAs may distinguish patients with lung cancer versus smokers with normal CTs, stable solid nodules, ground glass opacities, or normal healthy never smokers

BACKGROUND: This article introduces a comprehensive health and wellness program that serves young women, ages 14 to 21, with physical disabilities. The program is a component of the Initiative for Women with Disabilities (IWD), a hospital-based center serving women with physical disabilities/conditions that offers accessible gynecology, primary care, physical therapy, nutrition consultations, exercise and fitness classes, and wellness and social work services. Recent literature has shown that young women with physical disabilities often face physical and emotional barriers to their own health and wellness. This group of adolescents often has difficulty developing a healthy image of their bodies, especially compared with their able-bodied peers. Unhealthy attitudes regarding the body image and sexuality of those with physical differences are often perpetuated by the media, peers, and parents. People with disabilities have become increasingly able to live fulfilling lives in recent decades. This is due largely to studies that have confirmed that once barriers are addressed and minimized, young women with physical disabilities lead active and productive lives and have much to contribute to society. METHODS: The goal of the Young Women's Program (YWP), established in 2006, is to help young women adopt healthy lifestyles by exposing them to a carefully planned curriculum. The program provides a variety of classes and workshops, expert instruction, and access to resources and a network of peers and mentors. The ultimate goal is for the participants to apply the concepts learned in the group sessions to identify and evaluate their personal goals and develop health and wellness plans for achieving these goals. RESULTS: Data were obtained from several sources: a self-administered program evaluation, program recruitment and retention statistics, and an assessment of whether individual health and wellness goals were achieved. All of these measures indicate a favorable response to the program structure and content. Participants are able to integrate and apply the learned concepts to alter aspects of their daily lifestyles and improve their self-confidence, self-worth, and self-competence. CONCLUSIONS: The results to date suggest that the YWP addresses the transitional challenges cited in the literature that young women with physical disabilities face from adolescence to adulthood. The structure of the program, which combines individual and group sessions, and the focused content appear to have a positive impact on the participants' lives by exposing them to experiences that promote self-determination and self-competence. By providing opportunities for socialization with peers and mentors and exposure to community resources, and by helping participants to develop self-care skills and to set goals for a healthy lifestyle, the program facilitates leading an independent life. The efficacy of the YWP will be determined by annual follow-up studies as participants enter adulthood.

Background: Most skin cancer-related deaths are due to malignant melanoma. Risk assessment criteria for melanoma currently include skin phenotype, family and sun exposure history, factors that are subject to observer and recall bias. Genetic markers of susceptibility have been identified in association studies; however little progress has been made in developing them to improve screening and identification of individuals at risk of melanoma. Tyrosinase (TYR), a known susceptibility gene and a determinant of skin pigmentation, was thus investigated further to characterize its association with melanoma susceptibility and to identify markers which can be used in a risk assessment model. Methods: The cohort consisted of 326 individuals diagnosed with melanoma and 400 control subjects. TYR was interrogated using fifteen tag single nucleotide polymorphisms (SNPs) spanning the gene and statistical association tests performed. Additionally, ancestry informative markers were utilized to correct for population genetic sub-structure. Haplotype analysis was performed to determine if specific regions of the gene contributed more significantly to susceptibility. Coding regions of the gene are currently being sequenced and identified variants will be tested for impact on enzymatic function. Results: Of the 15 SNPs, 8 were associated with melanoma; 4 with decreased risk (Odds ratios 0.41-0.71) and 4 with increased risk (Odds ratios 1.43-1.96). SNPs localized to 2 regions of the gene (spanning exon 1 to intron 2 and intron 3 to 4) with markers of increased as well as decreased susceptibility present in both areas. With the exception of one coding region variant, SNPs were localized to introns. Conclusions: SNPs localized to TYR may serve as useful biomarkers for determining susceptibility to melanoma. We are currently sequencing the gene in our population in order to identify additional and potentially more potent markers of melanoma susceptibility. Coding region variants are being characterized for their effect on protein stability and enzyme activity such that functional active variants (most likely to affect susceptibility to melanoma) can be identified and assessed for their utility in melanoma risk assessment

Background/Aims: Patients with myelofibrosis have increased risk of bleeding and thrombosis. Increased numbers of platelet microparticles (PMP) and/or pathological platelet-neutrophil interactions has been suggested to underlie this trait. Megakaryocytes from patients, as well as from mice expressing low levels of Gata1(the Gata1low model of myelofibrosis) is characterized by an abnormal localization of P-selectin (P-sel). Whether these mice also develop thrombosis is not known. Aims: The aim of this study was to determine whether Gata1low mice develop thrombosis with age and, in this case, the role played by P-sel. Materials and methods: Gata1low mice were crossed with P-selnull mice according to standard protocols and Gata1lowP-selWT, Gata1lowP-selnull and Gata1WTPselnull or Gata1WTP-selWT littermates obtained. Blood platelet counts (ptl) and PMP counts were compared among the four experimental groups (Table). The presence of thrombosis was determined according to standard histological criteria. Results: Gata1WT mice had significantly greater platelet levels than Gata1low mice regardless of P-sel (Wilcoxon rank test, p <=0.0001). PMP were found to be reduced in Gata1low mice compared to Gata1WT littermates (Table I). Gata1WTP-selnull and Gata1low/P-selnull littermates had also reduced numbers of PMP. P-sel was only expressed by PMP from Gata1WTP-selWT mice. Thrombosis was only found in adult (5-9 months) and old (10-16 months) Gata1lowP-selWT mice. The majority of the thrombi were found in adult mice (67% vs 33% of organs affected). Conclusions: The maturation defect induced in megakaryocytes by the Gata1low mutation leads to a pro-thrombotic state detectable from 5 months of age. The presence of the P-selnull mutation rescues the thrombotic phenotype but not the ptl or PMP deficiency induced by the Gata1low mutation. Thus, abnormal P-sel localization, rather than altered PMP numbers, appears to be responsible for the thrombogenicity induced by the Gata1low mutation. These results suggest P-sel as possible target for therapeutic prevention of thrombosis in PMF