Faculty Bibliography

BACKGROUND: Agents of opportunity (AO) are potentially harmful biological, chemical, radiological, and pharmaceutical substances commonly used for health care delivery and research. AOs are present in all academic medical centers (AMC), creating vulnerability in the health care sector; AO attributes and dissemination methods likely predict risk; and AMCs are inadequately secured against a purposeful AO dissemination, with limited budgets and competing priorities. We explored health care workers' perceptions of AMC security and the impact of those perceptions on AO risk. METHODS: Qualitative methods (survey, interviews, and workshops) were used to collect opinions from staff working in a medical school and 4 AMC-affiliated hospitals concerning AOs and the risk to hospital infrastructure associated with their uncontrolled presence. Secondary to this goal, staff perception concerning security, or opinions about security behaviors of others, were extracted, analyzed, and grouped into themes. RESULTS: We provide a framework for depicting the interaction of staff behavior and access control engineering, including the tendency of staff to 'defeat' inconvenient access controls. In addition, 8 security themes emerged: staff security behavior is a significant source of AO risk; the wide range of opinions about 'open' front-door policies among AMC staff illustrates a disparity of perceptions about the need for security; interviewees expressed profound skepticism concerning the effectiveness of front-door access controls; an AO risk assessment requires reconsideration of the security levels historically assigned to areas such as the loading dock and central distribution sites, where many AOs are delivered and may remain unattended for substantial periods of time; researchers' view of AMC security is influenced by the ongoing debate within the scientific community about the wisdom of engaging in bioterrorism research; there was no agreement about which areas of the AMC should be subject to stronger access controls; security personnel play dual roles of security and customer service, creating the negative perception that neither role is done well; and budget was described as an important factor in explaining the state of security controls. CONCLUSIONS: We determined that AMCs seeking to reduce AO risk should assess their institutionally unique AO risks, understand staff security perceptions, and install access controls that are responsive to the staff's tendency to defeat them. The development of AO attribute fact sheets is desirable for AO risk assessment; new funding and administrative or legislative tools to improve AMC security are required; and security practices and methods that are convenient and effective should be engineered

Agents of opportunity (AO) in academic medical centers (AMC) are defined as unregulated or lightly regulated substances used for medical research or patient care that can be used as 'dual purpose' substances by terrorists to inflict damage upon populations. Most of these agents are used routinely throughout AMC either during research or for general clinical practice. To date, the lack of careful regulations for AOs creates uncertain security conditions and increased malicious potential. Using a consensus-based approach, we collected information and opinions from staff working in an AMC and 4 AMC-affiliated hospitals concerning identification of AO, AO attributes, and AMC risk and preparedness, focusing on AO security and dissemination mechanisms and likely hospital response. The goal was to develop a risk profile and framework for AO in the institution. Agents of opportunity in 4 classes were identified and an AO profile was developed, comprising 16 attributes denoting information critical to preparedness for AO misuse. Agents of opportunity found in AMC present a unique and vital gap in public health preparedness. Findings of this project may provide a foundation for a discussion and consensus efforts to determine a nationally accepted risk profile framework for AO. This foundation may further lead to the implementation of appropriate regulatory policies to improve public health preparedness. Agents of opportunity modeling of dissemination properties should be developed to better predict AO risk

p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients

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.