Biomedical subjects

Renee A Desmond

Publications and source records attributed to Renee A Desmond.

At least 19 recordsLinked to original sources

PubMed2007

Chlorpromazine and apigenin reduce adenovirus replication and decrease replication associated toxicity.

BACKGROUND: Adenoviruses can cause severe toxicity in immunocompromised individuals. Although clinical trials have confirmed the potency and safety of selectively oncolytic adenoviruses for treatment of advanced cancers, increasingly effective agents could result in more toxicity and therefore it would be useful if replication could be abrogated if necessary. METHODS: We analyzed the effect of chlorpromazine, an inhibitor of clathrin-dependent endocytosis and apigenin, a cell cycle regulator, on adenovirus replication and toxicity. First, we evaluated the in vitro replication of a tumor targeted Rb-p16 pathway selective oncolytic adenovirus (Ad5/3-Delta24) and a wild-type adenovirus in normal cells, fresh liver samples and in ovarian cancer cell lines. Further, we analyzed the in vitro cell killing efficacy of adenoviruses in the presence and absence of the substances. Moreover, the effect on in vivo efficacy, replication and liver toxicity of the adenoviruses was evaluated. RESULTS: We demonstrate in vitro and in vivo reduction of adenovirus replication and associated toxicity with chlorpromazine and apigenin. Effective doses were well within what would be predicted safe in humans. CONCLUSIONS: Chlorpromazine and apigenin might reduce the replication of adenovirus, which could provide a safety switch in case replication-associated side effects are encountered in patients. In addition, these substances could be useful for the treatment of systemic adenoviral infections in immunosuppressed patients.

Adenocarcinoma↗

PubMed2006

The impact of cost on the availability of fruits and vegetables in the homes of schoolchildren in Birmingham, Alabama.

OBJECTIVES: Fruit and vegetable cost is a presumed barrier to intake. We sought to determine whether fruit and vegetable cost and consumers' race and income would predict availability of fruits and vegetables in homes of schoolchildren in the Birmingham, Ala, area. METHODS: Data on availability of 27 fruit and vegetable items were obtained from homes of 1355 children (32% African American) in the Birmingham area. Fruit and vegetable costs were obtained from the US Department of Agriculture. We used discrete choice analysis with the dependent variable represented as presence or absence of the fruit or vegetable item. Explanatory variables included fruit and vegetable price per serving; child's gender, race, and age; and parent's body mass index and income. RESULTS: Higher cost was inversely related to fruit and vegetable availability. Higher income, African American race, and female gender were positively related to availability. Cost per serving was stratified into 3 categories-low, medium, and high. Relative to low-cost items, only high-cost items decreased the odds of availability significantly. CONCLUSIONS: Fruit and vegetable cost does impact availability and has the greatest impact for high-cost items. Although cost was inversely related to availability, African Americans reported higher fruit and vegetable availability than Whites. Additional studies are needed to determine whether food items of lower nutritive value and comparable cost impact availability.

Black or African American↗

PubMed2006

Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians.

PURPOSE: African-American patients with colorectal cancer were observed to have increased 5-fluorouracil (5-FU)-associated toxicity (leukopenia and anemia) and decreased overall survival compared with Caucasian patients. One potential source for this disparity may be differences in 5-FU metabolism. Dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting enzyme of 5-FU catabolism, has previously been shown to have significant interpatient variability in activity. Several studies have linked reduced DPD activity to the development of 5-FU toxicity. Although the distribution of DPD enzyme activity and the frequency of DPD deficiency have been well characterized in the Caucasian population, the distribution of DPD enzyme activity and the frequency of DPD deficiency in the African-American population are unknown. EXPERIMENTAL DESIGN: Healthy African-American (n=149) and Caucasian (n=109) volunteers were evaluated for DPD deficiency using both the [2-(13)C]uracil breath test and peripheral blood mononuclear cell DPD radioassay. RESULTS: African-Americans showed significantly reduced peripheral blood mononuclear cell DPD enzyme activity compared with Caucasians (0.26+/-0.07 and 0.29+/-0.07 nmol/min/mg, respectively; P=0.002). The prevalence of DPD deficiency was 3-fold higher in African-Americans compared with Caucasians (8.0% and 2.8%, respectively; P=0.07). African-American women showed the highest prevalence of DPD deficiency compared with African-American men, Caucasian women, and Caucasian men (12.3%, 4.0%, 3.5%, and 1.9%, respectively). CONCLUSION: These results indicate that African-Americans, particularly African-American women, have significantly reduced DPD enzyme activity compared with Caucasians, which may predispose this population to more 5-FU toxicity.

Adult↗

PubMed2006

IFTA-2 is a conserved cilia protein involved in pathways regulating longevity and dauer formation in Caenorhabditis elegans.

Defects in cilia are associated with diseases and developmental abnormalities. Proper cilia function is required for sonic hedgehog and PDGFRalpha signaling in mammals and for insulin-like growth factor (IGF) signaling in Caenorhabditis elegans. However, the role of cilia in these pathways remains unknown. To begin addressing this issue, we are characterizing putative cilia proteins in C. elegans that are predicted to have regulatory rather than structural functions. In this report, we characterized the novel cilia protein T28F3.6 (IFTA-2, intraflagellar transport associated protein 2), which is homologous to the mammalian Rab-like 5 protein. We found that, unlike the intraflagellar transport (IFT) genes, disruption of ifta-2 does not result in overt cilia assembly abnormalities, nor did it cause chemotaxis or osmotic avoidance defects typical of cilia mutants. Rather, ifta-2 null mutants have an extended lifespan phenotype and are defective in dauer formation. Our analysis indicates that these phenotypes result from defects in the DAF-2 (insulin-IGF-1-like) receptor signaling pathway in ciliated sensory neurons. We conclude that IFTA-2 is not a ciliogenic protein but rather is a regulator of specific cilia signaling activities. Interestingly, a mammalian IFTA-2 homolog is also found in cilia, raising the possibility that its function has been conserved during evolution.

Amino Acid Sequence↗

PubMed2006

Triple-targeted oncolytic adenoviruses featuring the cox2 promoter, E1A transcomplementation, and serotype chimerism for enhanced selectivity for ovarian cancer cells.

Conditionally replicating adenoviruses (CRAd's) feature selective replication in and killing of tumor cells. Initial clinical studies with relatively attenuated early generation agents have resulted in promising safety and efficacy data. Nevertheless, increased specificity may be advantageous for an emerging generation of infectivity-enhanced CRAd's. Further, increased specificity could translate into a larger tolerated dose. An approach for increasing specificity is dual control of E1A expression. We constructed six CRAd's featuring two variants of the cyclo-oxygenase 2 (cox2) promoter, combined with three versions of E1A. Transcriptional targeting was supplemented with transductional targeting utilizing the serotype 3 knob. In vivo and in vitro results suggest that cox2 can be utilized for enhancing the specificity of E1A deletion mutants and that combination with the Delta24 mutation increases specificity without reducing potency. Combination with Delta2-Delta24 was specific but somewhat attenuated. The promoter variants behaved similarly, although the longer 1,554-bp version displayed a trend for improved specificity. Transcriptional modifications were compatible with transductional targeting and resulted in up to 100,000-fold increase in the therapeutic window for Ad5/3cox2Ld24 vs wild-type adenovirus. Thus, the proposed triple-targeting strategy may be useful for increasing the safety and efficacy of adenoviral gene therapy for ovarian cancer.

Adenoviridae↗

PubMed2006

Local and systemic cytokine levels in relation to changes in vaginal flora.

BACKGROUND: Bacterial vaginosis (BV) is associated with increased risk of obstetrical and gynecologic complications and acquisition of sexually transmitted diseases. Despite this, very little is known about the pathogenesis of this disease. METHODS: Interleukin (IL)-1 beta , tumor necrosis factor- alpha , IL-6, and IL-8 concentrations in vaginal wash and serum samples from women with normal flora, intermediate flora, and BV (determined by Nugent criteria) were measured by enzyme-linked immunosorbent assay. RESULTS: Cytokine levels were not different between women with intermediate flora and women with BV. Women with either intermediate flora or BV had significantly higher concentrations of IL-1 beta in vaginal wash samples than did women with normal flora. The presence of IL-1 beta in vaginal wash samples was associated with >30 Gardnerella or Prevotella morphotypes per high-power field, as detected by Gram staining of vaginal swab specimens. Variation in the numbers of Lactobacillus and Mobiluncus species did not influence local cytokine levels. Serum cytokine levels were not influenced by any changes in vaginal flora. CONCLUSIONS: Women with intermediate flora generate significant cytokine responses. It is possible that the risks associated with BV may also affect women with intermediate flora and that appropriate treatment may reduce such risk.

Adult↗

PubMed2006

The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity: pharmacokinetic relationship between expired 13CO2 and plasma [2-13C]dihydrouracil.

PURPOSE: Dihydropyrimidine dehydrogenase (DPD) deficiency is critical in the predisposition to 5-fluorouracil dose-related toxicity. We recently characterized the phenotypic [2-(13)C]uracil breath test (UraBT) with 96% specificity and 100% sensitivity for identification of DPD deficiency. In the present study, we characterize the relationships among UraBT-associated breath (13)CO(2) metabolite formation, plasma [2-(13)C]dihydrouracil formation, [2-(13)C]uracil clearance, and DPD activity. EXPERIMENTAL DESIGN: An aqueous solution of [2-(13)C]uracil (6 mg/kg) was orally administered to 23 healthy volunteers and 8 cancer patients. Subsequently, breath (13)CO(2) concentrations and plasma [2-(13)C]dihydrouracil and [2-(13)C]uracil concentrations were determined over 180 minutes using IR spectroscopy and liquid chromatography-tandem mass spectrometry, respectively. Pharmacokinetic variables were determined using noncompartmental methods. Peripheral blood mononuclear cell (PBMC) DPD activity was measured using the DPD radioassay. RESULTS: The UraBT identified 19 subjects with normal activity, 11 subjects with partial DPD deficiency, and 1 subject with profound DPD deficiency with PBMC DPD activity within the corresponding previously established ranges. UraBT breath (13)CO(2) DOB(50) significantly correlated with PBMC DPD activity (r(p) = 0.78), plasma [2-(13)C]uracil area under the curve (r(p) = -0.73), [2-(13)C]dihydrouracil appearance rate (r(p) = 0.76), and proportion of [2-(13)C]uracil metabolized to [2-(13)C]dihydrouracil (r(p) = 0.77; all Ps < 0.05). CONCLUSIONS: UraBT breath (13)CO(2) pharmacokinetics parallel plasma [2-(13)C]uracil and [2-(13)C]dihydrouracil pharmacokinetics and are an accurate measure of interindividual variation in DPD activity. These pharmacokinetic data further support the future use of the UraBT as a screening test to identify DPD deficiency before 5-fluorouracil-based therapy.

Administration, Oral↗

PubMed2006

Prognostic factors for survival in pancreatic cancer: a population-based study.

BACKGROUND: We performed a population-based study of patients from the deep South of the United States (with >25% black residents) to evaluate the survival rate of patients with pancreatic cancer. Our aims were to analyze prognostic factors influencing pancreatic cancer survival using the population-based Alabama Statewide Cancer Registry and to determine whether race/ethnicity is an independent determinant of outcomes in patients with pancreatic cancer. METHODS: Eligible participants included all persons diagnosed with pancreatic cancer from 1996 to 2000 and reported to the Alabama Statewide Cancer Registry. Survival time was calculated from time of diagnosis to death for pancreatic cancer deaths or to date of last contact or death from other causes for censored participants. Risk factors associated with survival were assessed with the Kaplan-Meier survival method and the log-rank test. Demographic, tumor, and treatment variables were assessed using the Cox proportional hazards model. RESULTS: Of 2230 patients, the median age at diagnosis was 71 years and the male to female ratio was approximately 1:1. Seventy-three percent of patients were white, and 27% of patients were black. The distribution by stage was 12.5% localized disease, 29.6% regional, 35.3% distant, and 22.6% unstaged. The median survival time for all patients was .39+/-.01 years. Patients who underwent surgical treatment were less likely to die of pancreatic cancer (hazard ratio, .48; 95% confidence interval, .41-.56). Similarly, patients who underwent either chemotherapy or radiation therapy had improved survival rates (hazard ratio, .62; 95% confidence interval, .53-.73). Across all stages, black patients were significantly less likely to receive chemotherapy compared with white patients (26.7% vs 32.3%, P=.02), and were less likely to receive surgical intervention (14.02% vs 17.0%, P=.09). When examining patients who were offered their therapy of choice but refused, we found across all stages that a greater proportion of black patients refused therapies versus whites: 5.6% versus 2.9% (P=.02) for chemotherapy, 3.8% versus 1.6% (P=.04) for radiation, and 9.0% versus 3.3% (P=.001 for surgery). The Cox proportional hazard model showed no effect of race on overall survival time while controlling for stage at presentation, type of therapy received, age at diagnosis, and site of primary tumor. CONCLUSIONS: Survival in patients with pancreatic cancer remains dismal. Tumor characteristics and treatment factors are related directly to survival time in patients with pancreatic cancer. Black patients were less likely to receive therapy but also were more likely to refuse the indicated therapy. Factors leading to racial disparity in the treatment of pancreatic cancer warrant further investigation.

Adult↗

PubMed2006

Alefacept in the treatment of psoriatic nail disease: a proof of concept study.

Nail psoriasis can be debilitating and as therapeutic options are limited, it can be notoriously difficult to treat. As there are many new medications currently undergoing clinical trials in psoriasis, questions have arisen concerning the effectiveness of these new therapies with regard to psoriatic nail disease. We present the results of a prospective, open-label, proof of concept study to determine the efficacy and safety of alefacept in subjects with moderate to severe nail psoriasis.

Adult↗

PubMed2005

Clinical significance of occult metastatic melanoma in sentinel lymph nodes and other high-risk factors based on long-term follow-up.

Selective sentinel lymphadenectomy (SSL) following preoperative lymphoscintigraphy is the most significant recent advance in the management of patients with primary melanoma. This study evaluates the prognostic value of sentinel lymph node (SLN) status and other risk factors in predicting survival and recurrence in patients with primary cutaneous melanoma. From October 1993 to July 1998 a series of 412 patients with primary invasive melanoma underwent SSL at the UCSF/ Mt. Zion Melanoma Center. The outcome of 363 evaluable patients is summarized in this study. The factors related to survival and disease recurrence were analyzed by Cox proportional hazard regression models. The overall incidence of patients with positive SLNs was 18%. Over a median follow-up of 4.8 years, the overall mortality rate in patients with primary cutaneous melanoma was 18.7%, and 74 recurrences occurred (20.4%). Mortality was significantly related to SLN status [HR = 2.06; 95% Confidence interval (CI) 1.18, 3.58], angiolymphatic invasion (HR = 2.21; 95% CI 1.08, 4.55), ulceration (HR = 1.79; 95% CI 1.02, 3.15), mitotic index (HR =1.38; 95% CI 1.01, 1.90), and tumor thickness (HR = 2.20, 95% CI 1.21, 3.99). Factors significantly related to disease-free survival included SLN status (HR = 2.09; 95% CI 1.31, 3.34), tumor thickness (HR = 1.89; 95%. CI 1.20,2.98), and age (HR= 1.26 95% CI 1.08, 1.47). SLN status was the most significant factor for melanoma recurrence and death. Other important predictors include tumor thickness, ulceration, lymphatic invasion, and mitotic index.

Adult↗

PubMed2004

A novel time-course cDNA microarray analysis method identifies genes associated with the development of cisplatin resistance.

In recent years, most cDNA microarray studies of chemotherapeutic drug resistance have not considered the temporal pattern of gene expression. The objective of this study was to examine systematically changes in gene expression of NCI-H226 and NCI-H2170 lung cancer cells treated weekly with IC10 doses of cisplatin. NCI-H226 lung cancer cells were treated weekly with an IC10 dose of cisplatin. Candidate genes with a fold change of 2.0 or more were identified from this study. A second experiment was conducted by exposing NCI-H2170 cells to cisplatin doses that were increased in week 4 and decreased in week 5. Overall, 44 genes were differentially expressed in both the NCI-H226 and NCI-H2170 cell lines. In the NCI-H2170 cell line, 24 genes had a twofold gene expression change from weeks 3 to 4. Real-time PCR found a significant correlation of the gene expression changes for seven genes of interest. This small time-ordered series identified novel genes associated with cisplatin resistance. This kind of analysis should be viewed as a first step towards building gene-regulatory networks.

Antineoplastic Agents↗

PubMed2004

Overestimation of HDL-cholesterol using a homogeneous "direct" assay.

Direct HDL-cholesterol (HDLc) assays have several advantages over other assays that are more laborious and time-consuming. A recent College of American Pathologists (CAP) report indicates that at least 385 Beckman LX-20 analyzers use the selective detergent (homogeneous or direct) method for analyzing HDLc. There is no published evaluation of direct HDLc assays on the Beckman platform. Here we report our evaluation of a direct HDLc assay marketed by Beckman for the Beckman LX-20 analyzers. In general, the assay performed well; however, the total error was not within National Cholesterol Education Program (NCEP) guidelines. This was largely because of a significant positive bias that appeared to be due, at least in part, to triglycerides. This bias was worse at HDLc concentrations <40 mg/dL, which may make it difficult to identify a low HDLc concentration and consequently an increased risk for cardiovascular disease (CVD).

Autoanalysis↗

PubMed2004

Effect of folic acid fortification of foods on folate intake in female smokers with cervical dysplasia.

OBJECTIVE: We investigated the effect of folic acid fortification of enriched cereal grains on folate intake in women of predominantly childbearing age at high risk for cervical cancer. METHODS: Subjects in this cross-sectional study were 77 women randomized between November 1999 and December 2000 in the Women's Intervention to Stay Healthy (WISH), a clinical trial evaluating the effect of a tobacco control intervention on the progression of cervical dysplasia. All subjects were cigarette smokers, had a previously abnormal Papanicolaou test, and were positive for high-risk human papillomavirus at entry. Dietary intake was assessed with food-frequency questionnaires completed at the baseline visit for WISH. The effect of folic acid fortification on folate intake was assessed by using pre- and postfortification folate databases to estimate folate intake. RESULTS: Mean folate intake assessed with the postfortification database was 63% higher than intake assessed with the prefortification database: 417 versus 256 microg/d of dietary folate equivalents (P < 0.0001). The proportion of subjects below the estimated average requirement for folate was smaller after fortification than before fortification: 40.3% versus 75.3% (P < 0.0001). Several foods, including white bread, cheese dishes, spaghetti, and rice, became major sources of folate as a result of fortification. CONCLUSIONS: Folic acid fortification resulted in an increased intake of folate in these subjects. However, even with fortification, folate intake in a large proportion of these women remained below recommended levels. These results should be considered before decisions regarding future levels of folic acid fortification are made.

Adolescent↗

PubMed2004

Incidence and risk factors for sexually transmitted infections among women in an Alabama HIV clinic.

The objectives of this study were to assess the prevalence and incidence of curable sexually transmitted infections (STI), i.e., gonorrhea, chlamydial infection, or trichomoniasis, in a cohort of HIV-infected women. The study population was derived from women seeking primary care at an outpatient university HIV clinic who were participants in a women's natural history study. Enrollees (n = 225) were predominantly African-American, heterosexually infected, with mean age 35 years. Mean entry CD4+ T cell count was 405 cells/mm3. Over 6% were STI positive at initial screening. Subsequently, the combined curable STI incidence was 4.82/1000 woman-months over a median of 33 months of observation. Of 36 incident STIs, trichomoniasis was most common (n = 32). Predictors for acquisition of a curable STI included absenteeism at scheduled clinic appointments, RR = 1.99 (1.28, 3.08), and a higher CD4+ T cell count, RR = 1.15 (1.0028, 1.3115) for 100 cells. Interventions to prevent curable STI in HIV-infected women are warranted in primary care settings.

Absenteeism↗

PubMed2004

Predictors of bacterial vaginosis in adolescent women who douche.

OBJECTIVE: Risk factors for bacterial vaginosis (BV) include douching and sexual activity, although the exact cause of BV is unknown. GOAL: The goal of this study was to determine the relative significance of douching as a risk factor for BV. STUDY DESIGN: Two hundred fifty adolescent women who regularly douched were enrolled into a randomized douching intervention trial. Behavioral questionnaires and testing for sexually transmitted diseases and BV were performed. Associations between baseline characteristics and behaviors were compared for teens who were BV-positive and BV-negative at baseline. RESULTS: Positive correlates of BV included multiple partners, recent sexual intercourse, douching after menses, recent douching, and gonorrhea. Of these, douching after menses showed the strongest association (odds ratio, 5.11; 95% confidence interval, 1.99-13.15) in a multivariate analysis. CONCLUSIONS: Douching after menses was strongly correlated with BV; however, difficulty remains in trying to evaluate douching and sexual behavior independently.

Adolescent↗

PubMed2003

Epidemiology of malignant melanoma.

Trends in melanoma incidence have shown an increase in thinner, less lethal tumors in recent years. The overall increases in melanoma incidence have begun to slow in Western Europe and North America. Environmental risk factors are important in the development of melanomas in individuals with high-risk phenotypes, and these people should modify their recreational and overall UV exposure. Primary prevention of melanoma and early detection are essential to reduce melanoma mortality in future years. The complex relationships between genetic factors and patterns of sun exposure, especially in childhood, are the focus of continued research.

Female↗

PubMed2003

A canine conditionally replicating adenovirus for evaluating oncolytic virotherapy in a syngeneic animal model.

Oncolytic adenoviruses, which selectively replicate in and subsequently kill cancer cells, have emerged as a promising approach for treatment of tumors resistant to other modalities. Although preclinical results have been exciting, single-agent clinical efficacy has been less impressive heretofore. The immunogenicity of adenoviruses, and consequent premature abrogation of replication, may have been a partial reason. Improving the oncolytic potency of agents has been hampered by the inability to study host-vector interactions in immune-competent systems, since human serotype adenoviruses do not productively replicate in animal tissues. Therefore, approaches such as immunomodulation, which could result in sustained replication and subsequently increased oncolysis, have not been studied. Utilizing the osteocalcin promoter for restricting the replication of a canine adenovirus to dog osteosarcoma cells, we generated and tested the first nonhuman oncolytic adenovirus. This virus effectively killed canine osteosarcoma cells in vitro and yielded a therapeutic benefit in vivo. Canine osteosarcoma is the most frequent malignant disease in large dogs, with over 8000 cases in the United States annually, and there is no curative treatment. Therefore, immunomodulation for increased oncolytic potency could be studied with clinical trials in this population. This could eventually translate into human trials.

Adenoviridae↗

PubMed2003

Production of an EGFR targeting molecule from a conditionally replicating adenovirus impairs its oncolytic potential.

Oncolytic virotherapy with conditionally replicating viruses is a promising approach for treating advanced cancers. Promiscuous tropism and low tumor transduction have represented limiting issues, which targeting approaches seek to overcome. An approach utilizing a secretory targeting molecule for the epidermal growth factor pathway (sCAR-EGF) has previously been shown to be compatible with replicating adenoviruses, when an E1-deleted vector was used in a dual-virus system in conjunction with a replication-competent agent. Here, we constructed a virus that replicates in cancer cells and codes for sCAR-EGF. Interestingly, the oncolytic potency of the novel agent was not improved over nontargeted controls in vitro or in vivo. These results suggest that the expression of biologically active proteins can be counterproductive to virus replication.

Adenoviridae↗