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1.  Genital Tract HIV RNA Levels and Their Associations with Human Papillomavirus Infection and Risk of Cervical Pre-Cancer 
Plasma HIV RNA levels have been associated with risk of human papillomavirus (HPV) and cervical neoplasia in HIV-seropositive women. However, little is known regarding local genital tract HIV RNA levels and their relation with cervical HPV and neoplasia.
In an HIV-seropositive women’s cohort with semi-annual follow-up, we conducted a nested case-control study of genital tract HIV RNA levels and their relation with incident high-grade squamous intraepithelial lesions sub-classified as severe (severe HSIL), as provided for under the Bethesda 2001 classification system. Specifically, 66 incident severe HSIL were matched to 130 controls by age, CD4+ count, HAART use, and other factors. We also studied HPV prevalence, incident detection, and persistence in a random sample of 250 subjects.
Risk of severe HSIL was associated with genital tract HIV RNA levels (odds ratio comparing HIV RNA ≥ the median among women with detectable levels versus undetectable [ORVL] 2.96; 95% CI: 0.99–8.84; Ptrend=0.03). However, this association became non-significant (Ptrend=0.51) following adjustment for plasma HIV RNA levels. There was also no association between genital tract HIV RNA levels and the prevalence of any HPV or oncogenic HPV. However, the incident detection of any HPV (Ptrend=0.02) and persistence of oncogenic HPV (Ptrend=0.04) were associated with genital tract HIV RNA levels, after controlling plasma HIV RNA levels.
These prospective data suggest that genital tract HIV RNA levels are not a significant independent risk factor for cervical pre-cancer in HIV-seropositive women, but leave open the possibility that they may modestly influence HPV infection, an early stage of cervical tumoriogenesis.
PMCID: PMC4267467  PMID: 24694931
Genital tract HIV viral load; cervical neoplasia; HPV natural history
2.  Constructing a modern cytology laboratory: A toolkit for planning and design 
CytoJournal  2013;10:3.
Constructing or renovating a laboratory can be both challenging and rewarding. UAB Cytology (UAB CY) recently undertook a project to relocate from a building constructed in 1928 to new space. UAB CY is part of an academic center that provides service to a large set of patients, support training of one cytotechnology program and one cytopathology fellowship training program and involve actively in research and scholarly activity. Our objectives were to provide a safe, aesthetically pleasing space and gain efficiencies through lean processes.
The phases of any laboratory design project are Planning, Schematic Design (SD), Design Development (DD), Construction Documents (CD) and Construction. Lab personnel are most critical in the Planning phase. During this time stakeholders, relationships, budget, square footage and equipment were identified. Equipment lists, including what would be relocated, purchased new and projected for future growth ensure that utilities were matched to expected need. A chemical inventory was prepared and adequate storage space was planned. Regulatory and safety requirements were discussed. Tours and high level process flow diagrams helped architects and engineers understand the laboratory daily work. Future needs were addressed through a questionnaire which identified potential areas of growth and technological change. Throughout the project, decisions were driven by data from the planning phase. During the SD phase, objective information from the first phase was used by architects and planners to create a general floor plan. This was the basis of a series of meetings to brainstorm and suggest modifications. DD brings more detail to the plans with engineering, casework, equipment specifics, finishes. Design changes should be completed at this phase. The next phase, CD took the project from the lab purview into purely technical mode. Construction documents were used by the contractor for the bidding process and ultimately the Construction phase.
The project fitted out a total of 9,000 square feet; 4,000 laboratory and 5,000 office/support. Lab space includes areas for Prep, CT screening, sign out and Imaging. Adjacent space houses faculty offices and conferencing facilities. Transportation time was reduced (waste removal) by a Pneumatic Tube System, specimen drop window to Prep Lab and a pass thru window to the screening area. Open screening and prep areas allow visual management control. Efficiencies were gained by ergonomically placing CT Manual and Imaging microscopes and computers in close proximity, also facilitating a paperless workflow for additional savings. Logistically, closer proximity to Surgical Pathology maximized the natural synergies between the areas.
Lab construction should be a systematic process based on sound principles for safety, high quality testing, and finance. Our detailed planning and design process can be a model for others undertaking similar projects
PMCID: PMC3623545  PMID: 23599722
Cytolaboratory design; laboratory design; lean methods; quality control; laboratory construction; cytopathology equipments; cytopathology procedures
3.  A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53 
Oncogene  2011;31(3):322-332.
Human tumors are heterogeneous and evolve through a dynamic process of genetic mutation and selection. During this process, the effects of a specific mutation on the incipient cancer cell may dictate the nature of subsequent mutations that can be tolerated or selected for, affecting the rate at which subsequent mutations occur. Here we have used a new mouse model of prostate cancer that recapitulates several salient features of the human disease to examine the relative rates in which the remaining wild type alleles of Pten and p53 tumor suppressor genes are lost. In this model, focal overexpression of c-MYC in a few prostate luminal epithelial cells provokes a mild proliferative response. In the context of compound Pten/p53 heterozygosity, c-MYC-initiated cells progress to prostatic intraepithelial neoplasia (mPIN) and adenocarcinoma lesions with marked heterogeneity within the same prostate glands. Using Laser Capture Microdissection and gene copy number analyses, we found that the frequency of Pten loss was significantly higher than that of p53 loss in mPIN but not invasive carcinoma lesions. c-MYC overexpression, unlike Pten loss, did not activate the p53 pathway in transgenic mouse prostate cells, explaining the lack of selective pressure to lose p53 in the c-MYC-overexpressing cells. This model of heterogeneous prostate cancer based on alterations in genes relevant to the human disease may be useful for understanding pathogenesis of the disease and testing new therapeutic agents.
PMCID: PMC3179816  PMID: 21685943
c-MYC; Pten; p53; prostate cancer; rate of mutations
4.  Elevated levels of NO are localized to distal airways in asthma 
Free radical biology & medicine  2011;50(11):1679-1688.
The contribution of nitric oxide (NO) to the pathophysiology of asthma remains incompletely defined despite its established pro- and anti-inflammatory effects. Induction of the inducible nitric oxide synthase (iNOS), arginase and superoxide pathways is correlated with increased airway hyperresponsiveness (AHR) in asthmatic subjects. To determine the contributions of these pathways in proximal and distal airways, we compared bronchial wash (BW) to traditional bronchoalveolar lavage (BAL) for measurements of reactive nitrogen/oxygen species, arginase activation, and cytokine/chemokine levels in asthmatic and normal subjects. Levels of NO were preferentially elevated in the BAL, demonstrating higher-level NOS activation in the distal airway compartment of asthmatic subjects. In contrast, DHE+ cells which have the potential to generate reactive oxygen species were found to be increased in both proximal and distal airway compartments of asthmatics compared to controls. Different patterns of cytokines and chemokines were observed, with a predominance of epithelial cell-associated mediators in the BW as compared to macrophage/monocyte-derived mediators in the BAL of asthmatic subjects. Our study demonstrates differential production of reactive species and soluble mediators within the distal airways as compared to the proximal airways in asthma. These results indicate that cellular mechanisms are activated in the distal airways of asthmatics and must be considered in the development of therapeutic strategies for this chronic inflammatory disorder.
PMCID: PMC3124865  PMID: 21419218
Nitric oxide; superoxide; arginase; bronchoalveolar lavage; bronchial wash; distal airway
5.  Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis 
The Journal of Clinical Investigation  2012;122(5):1907-1919.
Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets of the tumor suppressor Nkx3.1. Further analysis indicated that a substantial fraction of Nkx3.1 target genes are also direct targets of the oncoprotein Myc. We also showed that Nkx3.1 and Myc bound to and crossregulated shared target genes in mouse and human prostate epithelial cells and that Nkx3.1 could oppose the transcriptional activity of Myc. Furthermore, loss of Nkx3.1 cooperated with concurrent overexpression of Myc to promote prostate cancer in transgenic mice. In human prostate cancer patients, dysregulation of shared NKX3.1/MYC target genes was associated with disease relapse. Our results indicate that NKX3.1 and MYC coregulate prostate tumorigenesis by converging on, and crossregulating, a common set of target genes. We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis.
PMCID: PMC3336973  PMID: 22484818
6.  Combined use of EUS-guided FNA and immunocytochemical stains discloses metastatic and unusual diseases in the evaluation of mediastinal lymphadenopathy of unknown etiology 
Annals of Thoracic Medicine  2012;7(2):84-91.
Mediastinal lymphadenopathy (ML) is a cause for concern, especially in patients with previous malignancy. We report our experience with the use of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with immunocytochemical stains in patients being evaluated for ML.
Retrospective analysis of patients with ML of unknown origin who underwent EUS-FNA. On-site evaluation was performed by experienced cytologist, and special immunocytochemical stains were requested as indicated.
A total of 116 patients were included, and a total of 136 mediastinal LN were sampled. Prior malignancy was present in 45%. The most common site of examined lymph node (LN) were subcarinal (76%, 103 LN). The median long and short axis diameters were 28 mm and 13 mm, respectively. FNA was read on-site as malignant, 21 (16%); benign, 100 (76.9%); suspicious, six (4%); atypical, 3 (2%); and inadequate sample, six (4%). Sixty-four LN were deferred for additional studies; 22 for immunocytochemical and 26 for Gimesa (GMS) stain and 21 for flow cytometry. Final FNA read was malignant in 28 (21%), benign in 103 (76%), suspicious in three (2%), and atypical in two (1%). Metastatic malignancies disclosed included Hodgkin's and Non-Hodgkin's lymphoma, melanoma, hepatoma, breast, lung, colon, renal, endometrial, Fallopian tube, and unknown carcinoma. The sensitivity, specificity, and accuracy of the final FNA read to predict malignancy were 100%.
EUS-guided FNA with additional ancillary studies is useful in disclosing metastatic ML from a variety of neoplasms. Due to its safety and accuracy profile, it should be considered the test of choice in evaluating abnormal ML in appropriately selected patients.
PMCID: PMC3339209  PMID: 22558013
Endoscopic ultrasound; fine needle aspiration; immunostains; lung cancer; metastatic disease
7.  Chronic Oral Exposure to Bisphenol A Results in a Nonmonotonic Dose Response in Mammary Carcinogenesis and Metastasis in MMTV-erbB2 Mice 
Environmental Health Perspectives  2011;119(11):1604-1609.
Background: Bisphenol A (BPA) is a synthetic compound used to produce plastics and epoxy resins. BPA can leach from these products in appreciable amounts, resulting in nearly ubiquitous daily exposure to humans. Whether BPA is harmful to humans, especially when administered orally in concentrations relevant to humans, is a topic of debate.
Objectives: In this study, we investigated the role of chronic oral exposure to BPA during adulthood on mammary carcinogenesis by using a transgenic mouse model that spontaneously develops tumors through overexpression of wild-type erbB2 [mouse mammary tumor virus (MMTV)-erbB2].
Methods: MMTV-erbB2 mice were exposed to 0, 2.5, 25, 250, or 2,500 µg BPA/L drinking water from 56 until 112 days of age (for mechanism of action) or 252 days of age (for tumorigenesis). Cellular and molecular mechanisms of BPA action in the mammary gland were investigated via immunohistochemistry and immunoblotting.
Results: Only low doses of BPA significantly decreased tumor latency and increased tumor multiplicity, tumor burden, and the incidence of metastasis. All BPA doses significantly increased the cell proliferation index, but only the higher doses also increased the apoptotic index in the mammary gland. At the molecular level, 25 µg BPA/L, but not 2,500 µg BPA/L, increased phosphorylation of erbB2, erbB3, insulin-like growth factor 1 receptor, and Akt in the mammary gland.
Discussion: Low, but not high, BPA doses significantly accelerated mammary tumorigenesis and metastasis in MMTV-erbB2 mice. The combined ratio of cell proliferation and apoptosis indices and alterations in protein expression best predicted the ability of each dose of BPA to alter tumorigenesis in this model.
PMCID: PMC3226508  PMID: 21988766
apoptosis; bisphenol A; BPA; mammary gland; MMTV-erbB2 mice; oral exposure; tumorigenesis
8.  Merkel Cell Carcinoma: Correlation of KIT Expression with Survival and Evaluation of KIT Gene Mutational Status 
Human pathology  2010;41(10):1405-1412.
Merkel cell carcinoma is one of the most aggressive primary cutaneous malignancies. Since some Merkel cell carcinomas express the receptor tyrosine kinase KIT, we aimed to evaluate the correlation of KIT expression with outcome and the presence of activating mutations in the KIT gene in Merkel cell carcinoma.
A total of 49 tumors from 40 patients with a diagnosis of Merkel cell carcinoma were identified of which 30 cases from 21 patients were used in the study. KIT expression was assessed by immunohistochemistry on formalin-fixed, paraffin embedded material. Cases were divided into low expressors (0-1+ staining intensity) and high expressors (2-3+ staining intensity). Direct sequencing of exons 9, 11, 13, 17, and 18 of the KIT gene spanning the extra-cellular, juxtamembrane and tyrosine kinase domains was performed from cases with high KIT expression.
Thirty tumors from 21 patients were analyzed for KIT expression. High KIT expression was seen in 67% of the patients. Five-year survival rates in tumors expressing high versus low levels of KIT were 0% versus 57.8% respectively however, this dramatic difference did not reach statistical significance (p=0.07). A total of 4 point mutations were identified in 18 tumors analyzed. Two of these were silent mutations involving exons 17 and 18, and 2 involved intron 16-17. Two of the identified mutations may represent novel polymorphisms.
Our work suggests a correlation between KIT expression and a worse prognosis in Merkel cell carcinoma patients, raising the possibility of an active role of this receptor in tumor progression and metastasis. We did not identify however, KIT activating mutations in any of the tumors analyzed.
PMCID: PMC3164849  PMID: 20594584
9.  Evaluation of lymph node numbers for adequate staging of Stage II and III colon cancer 
Although evaluation of at least 12 lymph nodes (LNs) is recommended as the minimum number of nodes required for accurate staging of colon cancer patients, there is disagreement on what constitutes an adequate identification of such LNs.
To evaluate the minimum number of LNs for adequate staging of Stage II and III colon cancer, 490 patients were categorized into groups based on 1-6, 7-11, 12-19, and ≥ 20 LNs collected.
For patients with Stage II or III disease, examination of 12 LNs was not significantly associated with recurrence or mortality. For Stage II (HR = 0.33; 95% CI, 0.12-0.91), but not for Stage III patients (HR = 1.59; 95% CI, 0.54-4.64), examination of ≥20 LNs was associated with a reduced risk of recurrence within 2 years. However, examination of ≥20 LNs had a 55% (Stage II, HR = 0.45; 95% CI, 0.23-0.87) and a 31% (Stage III, HR = 0.69; 95% CI, 0.38-1.26) decreased risk of mortality, respectively. For each six additional LNs examined from Stage III patients, there was a 19% increased probability of finding a positive LN (parameter estimate = 0.18510, p < 0.0001). For Stage II and III colon cancers, there was improved survival and a decreased risk of recurrence with an increased number of LNs examined, regardless of the cutoff-points. Examination of ≥7 or ≥12 LNs had similar outcomes, but there were significant outcome benefits at the ≥20 cutoff-point only for Stage II patients. For Stage III patients, examination of 6 additional LNs detected one additional positive LN.
Thus, the 12 LN cut-off point cannot be supported as requisite in determining adequate staging of colon cancer based on current data. However, a minimum of 6 LNs should be examined for adequate staging of Stage II and III colon cancer patients.
PMCID: PMC3124418  PMID: 21619690
Colon cancer; Clinical outcomes; Lymph nodes; Stage II; Stage III
10.  Genistein and Resveratrol, Alone and in Combination, Suppress Prostate Cancer in SV-40 Tag Rats 
The Prostate  2009;69(15):1668-1682.
Chemoprevention utilizing dietary agents is an effective means to slow the development of prostate cancer. We evaluated the potential additive and synergistic effects of genistein and resveratrol for suppressing prostate cancer in the Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model, a transgenic model of spontaneously developing prostate cancer.
Rats were fed genistein or resveratrol (250 mg/kg AIN-76A diet) alone and in combination, and a low dose combination (83 mg genistein + 83 mg resveratrol/kg diet). Histopathology and mechanisms of action studies were conducted at 30 and 12 weeks of age, respectively.
Genistein, resveratrol, and the high dose combination treatments suppressed prostate cancer. The low dose combination did not elicit protection against prostate cancer and was most likely below the effective dose for causing significant histopathological changes. Total genistein and resveratrol concentrations in the blood reached 2160 and 211 nM, respectively in rats exposed to the single treatments. Polyphenol treatments decreased cell proliferation and insulin-like growth factor-1 (IGF-1) protein expression in the prostate. In addition, genistein as a single agent induced apoptosis and decreased steroid receptor coactivator-3 (SRC-3) in the ventral prostate (VP).
Genistein and resveratrol, alone and in combination, suppress prostate cancer development in the SV-40 Tag model. Regulation of SRC-3 and growth factor signaling proteins are consistent with these nutritional polyphenols reducing cell proliferation and increasing apoptosis in the prostate.
PMCID: PMC2758814  PMID: 19670229
Genistein; Resveratrol; Prostate Cancer; Chemoprevention; SV-40 Tag Rat
11.  In Utero Exposure to Bisphenol A Shifts the Window of Susceptibility for Mammary Carcinogenesis in the Rat 
Environmental Health Perspectives  2010;118(11):1614-1619.
Bisphenol A (BPA) is a ubiquitous environmental chemical with reported endocrine-disrupting properties.
Our goal in this study was to determine whether prenatal exposure to BPA predisposes the adult rat mammary gland to carcinogenesis.
Pregnant rats were treated orally with 0, 25, or 250 μg BPA/kg body weight (BW) from gestation day (GD) 10 to GD21. For tumorigenesis experiments, prenatally exposed female offspring received a single gavage of 7,12-dimethylbenz(a)anthracene (DMBA; 30 mg/kg BW) on postnatal day (PND) 50, or PND100.
Prenatal exposure of the dam to 250 μg BPA/kg BW combined with a single exposure of female offspring to DMBA on PND100, but not on PND50, significantly increased tumor incidence while decreasing tumor latency compared with the control group. Prenatal exposure of the dam to 250 μg BPA/kg BW, in the absence of DMBA to the female offspring, increased cell proliferation and elicited differential effects at the protein level at PND100 compared with PND50. Differentially regulated proteins in the mammary gland included estrogen receptor-α, progesterone receptor-A, Bcl-2, steroid receptor coactivators, epidermal growth factor receptor, phospho-insulin-like growth factor 1 receptor, and phospho-Raf.
Our study demonstrates that oral prenatal exposure to BPA increases mammary cancer susceptibility in offspring and shifts the window of susceptibility for DMBA-induced tumorigenesis in the rat mammary gland from PND50 to PND100. These changes are accompanied by differential effects of prenatal BPA exposure on the expression of key proteins involved in cell proliferation.
PMCID: PMC2974702  PMID: 20675265
bisphenol A; cell proliferation; endocrine disruptors; mammary cancer; susceptibility
12.  Interactions between Cells with Distinct Mutations in c-MYC and Pten in Prostate Cancer 
PLoS Genetics  2009;5(7):e1000542.
In human somatic tumorigenesis, mutations are thought to arise sporadically in individual cells surrounded by unaffected cells. This contrasts with most current transgenic models where mutations are induced synchronously in entire cell populations. Here we have modeled sporadic oncogene activation using a transgenic mouse in which c-MYC is focally activated in prostate luminal epithelial cells. Focal c-MYC expression resulted in mild pathology, but prostate-specific deletion of a single allele of the Pten tumor suppressor gene cooperated with c-MYC to induce high grade prostatic intraepithelial neoplasia (HGPIN)/cancer lesions. These lesions were in all cases associated with loss of Pten protein expression from the wild type allele. In the prostates of mice with concurrent homozygous deletion of Pten and focal c-MYC activation, double mutant (i.e. c-MYC+;Pten-null) cells were of higher grade and proliferated faster than single mutant (Pten-null) cells within the same glands. Consequently, double mutant cells outcompeted single mutant cells despite the presence of increased rates of apoptosis in the former. The p53 pathway was activated in Pten-deficient prostate cells and tissues, but c-MYC expression shifted the p53 response from senescence to apoptosis by repressing the p53 target gene p21Cip1. We conclude that c-MYC overexpression and Pten deficiency cooperate to promote prostate tumorigenesis, but a p53-dependent apoptotic response may present a barrier to further progression. Our results highlight the utility of inducing mutations focally to model the competitive interactions between cell populations with distinct genetic alterations during tumorigenesis.
Author Summary
In most human cancers, mutations are thought to arise in a single cell or few cells surrounded by their unaffected neighbors. Expansion of mutant cells can then allow the accumulation of additional mutations. The cell–cell interactions that may occur between mutant and unaffected cells or between cells with distinct mutations during tumorigenesis have not been well studied due to the lack of suitable in vivo models. To help fill this gap, we generated and characterized transgenic mice in which the oncogene c-MYC is activated focally in prostate epithelial cells. We have also analyzed mice in which prostate epithelial cells with two mutations (c-MYC overexpression and loss of Pten tumor suppressor) are found next to cells with a single mutation (loss of Pten). Although loss of Pten in the prostate is tumorigenic, it also activates a cellular senescence response which restrains further tumor progression. We found that concurrent c-MYC expression suppressed the senescence response in Pten-null cells in favor of apoptosis. c-MYC+;Pten-null cells proliferated faster than Pten-null cells in the same glands, with the net result that c-MYC+;Pten-null cells outcompete Pten-null cells. Our results demonstrate the utility of accurate models to mimic the heterogeneous and incremental nature of human prostate carcinogenesis.
PMCID: PMC2697385  PMID: 19578399
13.  Oral Exposure to Bisphenol A Increases Dimethylbenzanthracene-Induced Mammary Cancer in Rats 
Environmental Health Perspectives  2009;117(6):910-915.
Bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles.
Based on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer.
We exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 μg BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age.
The combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days postpartum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1–3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age.
The data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1–3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure.
PMCID: PMC2702405  PMID: 19590682
apoptosis; bisphenol A; mammary cancer; proliferation; steroid receptor coactivators
14.  Characterization of SV-40 Tag rats as a model to study prostate cancer 
BMC Cancer  2009;9:30.
Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1) signaling proteins in the novel SV-40 Tag rat.
The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA) kits.
Prostatic intraepithelial neoplasia (PIN) and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP) followed by in the dorsolateral (DLP). At 8 weeks of age, testosterone and dihydrotestosterone (DHT) concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats.
The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of opportunity for preclinical trials and aids in the rational design of chemoprevention, intervention, regression, and therapeutic studies using prostate cancer rodent models.
PMCID: PMC2639608  PMID: 19171036
15.  Barriers to adoption of recent technology in cervical screening 
CytoJournal  2007;4:16.
The Pap smear is one of the modern success stories in the field of preventive medicine. Since its introduction as a screening test, there has been a dramatic reduction in the incidence of cervical cancer. However, the search for a better screening test continues. The new technologies, including liquid-based cytology (LBC), Human Papilloma Virus (HPV) testing and automated or machine-assisted screening have been introduced. However, there is continuous debate about whether society's limited resources are better spent on reaching the underserved rather than on these technologies. Another question is whether these technologies create yet another kind of disparity in delivering preventive care. For example, despite the wide use of LBC (99% of tests submitted to our laboratory are LBC), conventional Pap smears are still used to screen/follow up some women. It is not clear why some providers continue to prefer conventional smear over LBC and what are the barriers for adopting LBC in cervical cancer screening. We hypothesize the lower cost of conventional compared to LBC Pap testing, patient's lower socio-economic indices, a patient's medical history and provider's subspecialty/training all appear to play a role in the choice of using conventional Pap testing rather than LBC. Unintentionally, this choice results in repeat testing, delayed treatment and potentially higher costs than intended. The ultimate goal of this review article is to understand and explore possible barriers and disparities to adopting new technology in cancer screening.
PMCID: PMC1988799  PMID: 17705820
16.  Genistein chemoprevention of prostate cancer in TRAMP mice 
Epidemiological studies suggest an inverse association between soy intake and prostate cancer risk. Genistein, the predominant phytoestrogen in soy food, has been proposed as a potential chemopreventive agent due to its anti-estrogen and tyrosine kinase inhibitory effects. To determine the most effective period for genistein chemoprevention, the Transgenic adenocarcinoma mouse prostate (TRAMP) model was used. The treatments were 250 mg genistein/kg AIN-76A diet 1) prepubertally only, 2) in adulthood only or 3) through out life. Controls received AIN-76A diet. By 28 weeks of age, 100% TRAMP mice fed control diet developed prostatic intraepithelial neoplasia (PIN) or adenocarcinomas with 6%, 16%, 44% and 34% developing high grade PIN, well differentiated, moderately differentiated and poorly differentiated prostatic adenocarcinomas, respectively. Prepubertal only (1–35 days postpartum) and adult only genistein treatments (12 – 28 weeks) resulted in 6% and 29% decreases in poorly-differentiated cancerous lesions compared with controls, respectively. The most significant effect was seen in the TRAMP mice exposed to genistein throughout life (1–28 weeks) with a 50% decrease in poorly-differentiated cancerous lesions. In a separate experiment in castrated TRAMP mice, dietary genistein suppressed the development of advanced prostate cancer by 35% compared with controls. Of the tumors that developed in castrated TRAMP mice, 100% were poorly-differentiated in contrast to the 37% of noncastrated TRAMP mice that developed poorly-differentiated tumors. ICI 182,780 (ICI), genistein and estrogen down-regulated androgen receptor (AR), estrogen receptor alpha (ER-α) and progesterone receptor (PR) in the prostates of C57BL/6 mice, and act independently of ER. Our data obtained in intact and castrated transgenic mice suggest that genistein may be a promising chemopreventive agent against androgen-dependent and independent prostate cancers.
PMCID: PMC1832183  PMID: 17367528
17.  Dynamic telecytopathology of on site rapid cytology diagnoses for pancreatic carcinoma 
CytoJournal  2006;3:27.
Diagnosis of pancreatic lesions can be accurately performed by endoscopic ultrasound guided fine needle aspiration (EUS-FNA) with onsite cytopathologists to assess specimen adequacy and to determine a preliminary diagnosis. Considerable time is needed to perform on-site assessments. This takes away work time of cytopathologists and prohibits them from serving remote locations. It is therefore logical to ask if real-time telecytopathology could be used to assess specimen adequacy and if telecytopathology diagnosis has the same level of agreement to the final diagnosis as that of onsite evaluation. In this study, we compare agreement between cytodiagnoses rendered using telecytopathology with onsite and final interpretations.
40 Diff-Quik-stained EUS-FNA were re-evaluated retrospectively (patient ages 31–62, 19:21 male:female, 15 non-malignant lesions, 25 malignant lesions as classified by final diagnosis). Each previously assessed by a cytopathologist and finally reviewed by the same or different cytopathologist. Blinded to the final diagnosis, a resident pathologist re-screened all slides for each case, selected a slide and marked the diagnostic cells most representative of the lesion. Blinded to the diagnosis, one cytopathologist assessed the marked cells through a real time remotely operated telecytopathology system (MedMicroscopy). Diagnosis and time spent were recorded. Kappa statistic was used to compare agreements between telecytopathology vs. original onsite vs. final diagnoses.
Time spent for prescreening ranged from 1 to 5 minutes (mean 2.6 +/- 1.3 minutes) and time spent for telecytopathology diagnosis ranged from 2–20 minutes (mean 7.5 +/- 4.5 minutes). Kappa statistics, K, was as follows: telecytopathology versus onsite diagnosis K, 95% CI = 0.65, 0.41–0.88, for telecytopathology versus final K, 95% CI = 0.61, 0.37–0.85 and for onsite diagnosis versus final K, 95% CI = 0.79, 0.61–0.98. There is no significant difference in agreement between onsite and telecytopathology diagnoses. Kappa values for telecytopathology were less than onsite evaluation when compared to the final diagnosis; however, the difference was not statistically significant.
This retrospective study demonstrates the potential use of telecytopathology as a valid substitute for onsite evaluation of pancreatic carcinoma by EUS-FNA.
PMCID: PMC1713251  PMID: 17156485
19.  Preoperative diagnosis of a mediastinal granular cell tumor by EUS-FNA: a case report and review of the literature 
CytoJournal  2005;2:8.
We report the first case of a posterior mediastinal granular cell tumor initially diagnosed on cytologic material obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in a 51-year-old male with a prior history of colon cancer. Aspirates obtained were cellular and composed of polygonal cells with abundant granular cytoplasm and small, round dark nuclei. An immunoperoxidase stain performed on the cell block for antibodies to S-100 protein showed strong, diffuse staining of the cytoplasmic granules. Electron microscopy performed on the cell block revealed numerous cytoplasmic lysosomes. This is the first case report in the English literature of a definitive preoperative diagnosis of a mediastinal granular cell tumor utilizing material obtained via EUS-FNA.
PMCID: PMC1184093  PMID: 15943858
granular cell tumor; EUS-FNA; cytology; mediastinum
20.  Novel approaches to smoothing and comparing SELDI TOF spectra 
Cancer Informatics  2007;1(1):78-85.
Most published literature using SELDI-TOF has used traditional techniques in Spectral Analysis such as Fourier transforms and wavelets for denoising. Most of these publications also compare spectra using their most prominent feature, i.e, peaks or local maximums.
The maximum intensity value within each window of differentiable m/z values was used to represent the intensity level in that window. We also calculated the ‘Area under the Curve’ (AUC) spanned by each window.
Keeping everything else constant, such as pre-processing of the data and the classifier used, the AUC performed much better as a metric of comparison than the peaks in two out of three data sets. In the third data set both metrics performed equivalently.
This study shows that the feature used to compare spectra can have an impact on the results of a study attempting to identify biomarkers using SELDI TOF data.
PMCID: PMC2657649  PMID: 19305633
SELDI; biomarkers; denoising; peaks; AUC
21.  Randomized Trial Comparing the Flexible 19G and 25G Needles for Endoscopic Ultrasound-Guided Fine Needle Aspiration of Solid Pancreatic Mass Lesions 
Pancreas  2014;44(1):128-133.
Supplemental digital content is available in the text.
Although a large gauge needle can procure more tissue at endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), its advantage over smaller needles is unclear. This study compared flexible 19G and 25G needles for EUS-FNA of solid pancreatic masses.
This was a randomized trial of patients undergoing EUS-FNA of pancreatic masses using flexible 19G or 25G needle. Main outcome measure was to compare median number of passes for on-site diagnosis. Secondary measures were to compare specimen bloodiness, complications, technical failures, and histological core tissue procurement.
One hundred patients were randomized to EUS-FNA using flexible 19G or 25G needle. Median of 1 pass was required to achieve on-site diagnosis of 96% and 92% (P = 0.68) in 19G and 25G cohorts. There was no significant difference in technical failure (0% vs 2%, P = 0.99) or adverse events (2% vs 0%, P = 0.99) between 19G and 25G cohorts. Although histological core tissue procurement was significantly better with flexible 19G needle (88% vs 44%, P < 0.001), specimens were bloodier (severe bloodiness, 36% vs 4%; P < 0.001).
As there is no significant difference in the performance of flexible 19G and 25G needles, needle choice for sampling pancreatic masses should be based on endoscopist preference and need for histology.
PMCID: PMC4272223  PMID: 25232713
EUS-FNA; solid pancreatic mass; pancreatic cancer; pancreatic biopsy; flexible 19G needle; randomized trial

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