Brent J. Shelton

Distribution of Chemokine Receptor CCR2 and CCR5 Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

ABSTRACT At the CC (β) chemokine receptor 2 (CCR2) and CCR5 loci, combinations of common single-nucleotide polymorphisms (SNPs) and a 32-bp deletion (Δ32) form nine stable haplotypes (designated A through G*2). The distribution of these CCR2-CCR5 haplotypes was examined among 703 participants in the Multicenter AIDS Cohort Study (MACS), the District of Columbia Gay (DCG) Study, and the San Francisco Men’s Health Study (SFMHS). Highly exposed and persistently seronegative (HEPS; n = 90) Caucasian men from MACS more frequently carried heterozygous G*2 (Δ32) genotypes (especially A/G*2) and less frequently carried the homozygous E/E genotype compared with 469 Caucasian seroconverters (SCs) from the same cohort (P = 0.004 to 0.042). Among 341 MACS Caucasian SCs with 6- to 12-month human immunodeficiency virus type 1 (HIV-1) seroconversion intervals and no potent antiretroviral therapy, mean plasma HIV-1 RNA level during the initial 42 months after seroconversion was higher in carriers of the E/E genotype and lower in those with the 64I-bearing haplotype F*2 or the Δ32-bearing haplotype G*2 (and especially genotypes A/G*2 and F*2/G*2). A multivariable model containing these CCR markers showed significant composite effects on HIV-1 RNA at each of four postconversion intervals (P = 0.0004 to 0.050). In other models using time to AIDS as the endpoint, the same markers showed more modest contributions (P = 0.08 to 0.24) to differential outcome during 11.5 years of follow-up. Broadly consistent findings in the larger MACS Caucasian SCs and the smaller groups of MACS African-American SCs and the DCG and SFMHS Caucasian SCs indicate that specific CCR2-CCR5 haplotypes or genotypes mediate initial acquisition of HIV-1 infection, early host-virus equilibration, and subsequent pathogenesis.

Reciprocal age related change in natural killer cell receptors for MHC class I

Natural killer (NK) cells are essential for healthy aging. NK cell activation is controlled by MHC class I-specific CD94/NKG2 receptors and killer immunoglobulin-like receptors (KIR). To assess NK cytotoxic function in isolation from MHC receptor engagement, we measured the ability of purified NK cells to kill mouse P815 target cells in the presence of anti-CD16 mAb. CD16-mediated cytotoxicity did not change with age, indicating that NK activation and cytotoxic granule release remained functional. We then investigated MHC class I receptor expression on NK cells. There was an age related decrease in CD94 and NKG2A expression and a reciprocal age related increase in KIR expression. NKG2A expression also declined with age on CD56(+) T cells. CD94/NKG2A receptor function was proportional to expression, indicating that NK cell inhibitory signaling pathways were intact. NKG2A and KIR expression were complementary, suggesting that CD94/NKG2A function could substitute for inhibitory KIR function during polyclonal NK cell development in both young and elderly adults. The distinct roles of CD94/NKG2A and KIR receptors suggest that shifting MHC class I receptor expression patterns reflect age related changes in NK cell and CD56(+) T cell turnover and function in vivo.

Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway

Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealed that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of β-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of β-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited β-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggests that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/β-catenin signaling pathway.

Incidence of Tooth Loss and Prosthodontic Dental Care: Effect on Chewing Difficulty Onset, a Component of Oral Health–Related Quality of Life

Objectives: To quantify incidence of tooth loss, prosthodontic dental restoration, and chewing difficulty onset and the effect of tooth loss and prosthodontic restoration on chewing difficulty onset.

Stereotactic Body Radiation Therapy Can Be Used Safely to Boost Residual Disease in Locally Advanced Non-Small Cell Lung Cancer: A Prospective Study

PURPOSE To report the results of a prospective, single-institution study evaluating the feasibility of conventional chemoradiation (CRT) followed by stereotactic body radiation therapy (SBRT) as a means of dose escalation for patients with stage II-III non-small cell lung cancer (NSCLC) with residual disease. METHODS AND MATERIALS Patients without metastatic disease and with radiologic evidence of limited residual disease (≤5 cm) within the site of the primary tumor and good or complete nodal responses after standard CRT to a target dose of 60 Gy were considered eligible. The SBRT boost was done to achieve a total combined dose biological equivalent dose >100 Gy to the residual primary tumor, consisting of 10 Gy × 2 fractions (20 Gy total) for peripheral tumors, and 6.5 Gy × 3 fractions (19.5 Gy total) for medial tumors using the Radiation Therapy Oncology Group protocol 0813 definitions. The primary endpoint was the development of grade ≥3 radiation pneumonitis (RP). RESULTS After a median follow-up of 13 months, 4 patients developed acute grade 3 RP, and 1 (2.9%) developed late and persistent grade 3 RP. No patients developed grade 4 or 5 RP. Mean lung dose, V2.5, V5, V10, and V20 values were calculated for the SBRT boost, and none were found to significantly predict for RP. Only advancing age (P=.0147), previous smoking status (P=.0505), and high CRT mean lung dose (P=.0295) were significantly associated with RP development. At the time of analysis, the actuarial local control rate at the primary tumor site was 82.9%, with only 6 patients demonstrating recurrence. CONCLUSIONS Linear accelerator-based SBRT for dose escalation of limited residual NSCLC after definitive CRT was feasible and did not increase the risk for toxicity above that for standard radiation therapy.

Racial Differences in Predictors of Dental Care Use

OBJECTIVE To test five hypotheses that non-Hispanic African Americans (AAs) and non-Hispanic whites (NHWs) differ in responsiveness to new dental symptoms by seeking dental care, and differ in certain predictors of dental care utilization. DATA SOURCES/STUDY SETTING Florida Dental Care Study, comprising AAs and NHWs 45 years old or older, who had at least one tooth, and who lived in north Florida. STUDY DESIGN We used a prospective cohort design. The key outcome of interest was whether dental care was received in a given six-month period, after adjusting for the presence of certain time-varying and fixed characteristics. DATA COLLECTION/EXTRACTION METHODS In-person interviews were conducted at baseline and 24 months after baseline, with six-monthly telephone interviews in between. PRINCIPAL FINDINGS African Americans were less likely to seek dental care during follow-up, with or without adjusting for key predisposing, enabling, and oral health need characteristics. African Americans were more likely to be problem-oriented dental attenders, to be unable to pay an unexpected

Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/β-catenin pathway in human colorectal adenocarcinoma DLD1 cells

500 dental bill, and to report postbaseline dental problems. However, the effect of certain postbaseline dental signs and symptoms on postbaseline dental care use differed between AAs and NHWs. Although financial circumstance was predictive for both groups, it was more salient for NHWs in separate NHW and AA regressions. Frustration with past dental care, propensity to use a homemade remedy, and dental insurance were significant predictors among AAs, but not among NHWs. The NHWs were much more likely to have sought care for preventive reasons. CONCLUSIONS Racial differences in responsiveness to new dental symptoms by seeking dental care were evident, as were differences in other predictors of dental care utilization. These differences may contribute to racial disparities in oral health.

Human NK Cells Proliferate and Die In Vivo More Rapidly than T Cells in Healthy Young and Elderly Adults

Long term exposure to arsenic can increase incidence of human cancers, such as skin, lung, and colon rectum. The mechanism of arsenic induced carcinogenesis is still unclear. It is generally believed that reactive oxygen species (ROS) may play an important role in this process. In the present study, we investigate the possible linkage between ROS, β-catenin and arsenic induced transformation and tumorigenesis in human colorectal adenocarcinoma cell line, DLD1 cells. Our results show that arsenic was able to activate p47(phox) and p67(phox), two key proteins for activation of NADPH oxidase. Arsenic was also able to generate ROS in DLD1 cells. Arsenic increased β-catenin expression level and its promoter activity. ROS played a major role in arsenic-induced β-catenin activation. Treatment of DLD1 cells by arsenic enhanced both transformation and tumorigenesis of these cells. The tumor volumes of arsenic treated group were much larger than those without arsenic treatment. Addition of either superoxide dismutase (SOD) or catalase reduced arsenic induced cell transformation and tumor formation. The results indicate that ROS are involved in arsenic induced cell transformation and tumor formation possible through Wnt/β-catenin pathway in human colorectal adenocarcinoma cell line DLD1 cells.

Adverse impact of a history of violence for women with breast, cervical, endometrial, or ovarian cancer.

NK cells are essential for health, yet little is known about human NK turnover in vivo. In both young and elderly women, all NK subsets proliferated and died more rapidly than T cells. CD56bright NK cells proliferated rapidly but died relatively slowly, suggesting that proliferating CD56bright cells differentiate into CD56dim NK cells in vivo. The relationship between CD56dim and CD56bright proliferating cells indicates that proliferating CD56dim cells both self-renew and are derived from proliferating CD56bright NK cells. Our data suggest that some dying CD56dim cells become CD16+CD56− NK cells and that CD16−CD56low NK cells respond rapidly to cellular and cytokine stimulation. We propose a model in which all NK cell subsets are in dynamic flux. About half of CD56dim NK cells expressed CD57, which was weakly associated with low proliferation. Surprisingly, CD57 expression was associated with higher proliferation rates in both CD8+ and CD8− T cells. Therefore, CD57 is not a reliable marker of senescent, nonproliferative T cells in vivo. NKG2A expression declined with age on both NK cells and T cells. Killer cell Ig-like receptor expression increased with age on T cells but not on NK cells. Although the percentage of CD56bright NK cells declined with age and the percentage of CD56dim NK cells increased with age, there were no significant age-related proliferation or apoptosis differences for these two populations or for total NK cells. In vivo human NK cell turnover is rapid in both young and elderly adults.

Congenic interval of CD45/Ly-5 congenic mice contains multiple genes that may influence hematopoietic stem cell engraftment.

OBJECTIVE: The experience of physical and sexual violence (victimization) is common among U.S. women and is associated with adverse health consequences. The study objectives were to estimate the prevalence of victimization in women with cancer and to examine associations with demographics, cancer screening, and cancer stage. METHODS: From 2004 to 2005, 101 women with breast, cervical, endometrial, or ovarian cancer were interviewed to collect demographics, cancer screening history, health care access/use, and violence history. Chi-square and Fisher exact tests were used test risk-factor associations. A multinomial logistic regression model was used for multivariable analysis. RESULTS: The prevalence of a history of violence was 48.5% (49/101 women), and within that group, 46.9% (23/49) had a positive childhood violence screen, 75.5% (37/49) had a positive adult screen, and 55% (27/49) reported sexual violence at any age. Women with a positive violence screen differed significantly from women with a negative screen in that they were younger (P = .031), more often divorced (P = .012), more likely to smoke (P = .010), more often lacked commercial insurance (P = .036), and had more advanced stage of disease (P = .013), but they did not differ with regard to race, cancer type, education level, alcohol or drug use, or cancer screening compliance. Multivariable analysis revealed that only stage remained significant; women with a history of violence had a 2.6-fold increased chance of diagnosis in later stages (odds ratio 2.61, 95% confidence interval 1.03–6.59). CONCLUSION: A history of violence in breast, ovarian, endometrial, and ovarian cancer patients was extremely common and correlated with advanced stage at diagnosis. LEVEL OF EVIDENCE: II-2