Expression of osteoprotegerin from a replicating adenovirus inhibits the progression of prostate cancer bone metastases in a murine model.

Metastatic involvement of the skeleton is a frequent consequence of advanced prostate cancer. These skeletal metastases cause a number of debilitating complications and are refractory to current treatments. New therapeutic options are being explored, including conditionally replicating adenoviruses (CRAds). CRAds are engineered to selectively replicate in and destroy tumor cells and can be 'armed' with exogenous transgenes for enhanced potency. We hypothesized that a CRAd armed with osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, would inhibit the progression of prostate cancer bone metastases by directly lysing tumor cells and by reducing osteoclast activity. Although prostate cancer bone metastases are predominantly osteoblastic in nature, increased osteoclast activity is critical for the growth of these lesions. Ad5-Δ24-sOPG-Fc-RGD is a CRAd that carries a fusion of the ligand-binding domains of OPG and the Fc region of human IgG1 in place of the viral E3B genes. To circumvent low tumor cell expression of the native adenoviral receptor, an arginine-glycine-aspartic acid (RGD) peptide insertion within the viral fiber knob allows infection of cells expressing α(v) integrins. A 24-base pair deletion (Δ24) within viral E1A limits replication to cells with aberrant retinoblastoma cell cycle regulator/tumor suppressor expression. We have confirmed that Ad5-Δ24-sOPG-Fc-RGD replicates within and destroys prostate cancer cells and, in both murine and human coculture models, that infection of prostate cancer cells inhibits osteoclastogenesis in vitro. In a murine model, progression of advanced prostate cancer bone metastases was inhibited by treatment with Ad5-Δ24-sOPG-Fc-RGD but not by an unarmed control CRAd.

Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial.

CONTEXT: Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d). OBJECTIVE: To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions. INTERVENTIONS: One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks. MAIN OUTCOME MEASURES: Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, postvoid residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms. RESULTS: Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -1.36) [corrected]with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P = .91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified. CONCLUSION: Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00603304.

Performance of the American Urological Association Symptom Index with and without an additional urge incontinence item.

OBJECTIVE: To examine the value of adding an urge incontinence question to the American Urological Association Symptom Index (AUASI) among men in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) trial. METHODS: The CAMUS study was a randomized trial of Saw palmetto fruit extract versus placebo among men aged ≥45 years with an AUASI score of ≥8 and ≤24. The baseline measurements included the AUASI, a question about urge incontinence (UI), the International Prostate Symptom Score quality of life question, and the Benign Prostatic Hyperplasia Impact Index. We correlated the items and scales and examined whether adding the UI question resulted in better prediction of disease-specific health status. RESULTS: The mean age of the 369 men in the CAMUS trial was 61 years, and mean baseline AUASI score was 14.6. UI was reported infrequently; about 82% of the respondents answered the question "not at all" or "<1 time in 5." UI correlated significantly with all other AUASI items, except for weak stream; the strongest correlation was to urgency (R=0.51, P<.0001). The correlation between the AUASI score and the AUASI+UI score was 0.98 (P<.0001). In a logistic regression analysis predicting the International Prostate Symptom Score quality of life score, adding UI to the AUASI slightly increased the discriminating ability (c statistic increased from 0.77 to 0.78, P<.0001). Similarly, in a linear regression analysis predicting the Benign Prostatic Hyperplasia Impact Index score, adding UI to the AUASI slightly increased the predictive ability (R2 statistic increased from 0.22 to 0.26, P<.0001). CONCLUSION: According to our analysis in the CAMUS trial population, the value of adding a UI question to the AUASI in terms of predicting bother seemed small at best.

Recruitment of participants to a clinical trial of botanical therapy for benign prostatic hyperplasia.

OBJECTIVES: The timely recruitment of study participants is a critical component of successful trials. Benign prostatic hyperplasia (BPH), a common nonmalignant urologic condition among older men, is characterized by lower urinary tract symptoms (LUTS). Successful recruitment methods for a trial of medical therapy for BPH, Medical Therapy of Prostate Symptoms (MTOPS), were mass mailing and advertising. The Complementary and Alternative Medicines Trial for Urological Symptoms (CAMUS) was designed to evaluate a botanical therapy, saw palmetto, for the treatment of BPH. The objective of this study was to evaluate recruitment strategies for CAMUS and to contrast the baseline characteristics of CAMUS participants with those recruited to a similar trial using conventional medical therapy. DESIGN: CAMUS is a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of saw palmetto given at escalating doses over an 18-month period on relief from LUTS. SUBJECTS: The target enrollment goal was 350 men with LUTS from 11 clinical centers over a 12-month period. The recruitment techniques used and participants contacted, screened, and randomized through each technique were obtained from the clinical centers. Baseline characteristics of the CAMUS participants were compared with participants in the MTOPS trial who met the CAMUS eligibility criteria for LUTS. RESULTS: The target enrollment goal was achieved in 11 months. The overall monthly recruitment rate per site was 3.7 and ranged from 2.4 to 8.0. The most successful recruitment methods were mass mailing and advertising, which accounted for 39% and 35% of the study participants, respectively. In comparison to MTOPS participants, CAMUS participants were younger, more highly educated, more diverse, and had less severe urinary symptoms. CONCLUSIONS: Successful recruitment methods for CAMUS were similar to those in MTOPS. The use of botanical therapy attracted a less symptomatic and more educated study population.

The relationship between lower urinary tract symptom severity and sleep disturbance in the CAMUS trial.

PURPOSE: Bothersome lower urinary tract symptoms, including nocturia, significantly impact general health related quality of life in men, as does sleep disturbance. However, few groups have examined the relationship between urinary symptom severity and sleep disturbance. MATERIALS AND METHODS: Men enrolled in a clinical trial of saw palmetto (Serenoa repens) were studied at baseline. Lower urinary tract symptom severity, as determined by the American Urological Association symptom index and quality of life scores, and the degree of sleep disturbance were determined by the Jenkins sleep scale. Analysis was done, adjusting for baseline characteristics, to identify predictors of severe sleep disturbance. RESULTS: A total of 366 men with a mean ± SD age of 60.9 ± 8.3 years who had moderate-severe lower urinary tract symptoms (mean American Urological Association symptom index score 14.58 ± 4.6 points) and a mean Jenkins sleep score of 7.3 ± 4.7 points were included in analysis. Overall there were significant associations between the American Urological Association symptom index score and sleep disturbance severity. Multivariate analysis revealed that obstructive and irritative symptoms were significantly associated with severe sleep disturbance. Further analysis showed that lower serum prostate specific antigen and post-void residual urine volume were also significantly associated with the degree of sleep disturbance. CONCLUSIONS: Lower urinary tract symptom severity is a risk factor for severe sleep disturbance in men. While nocturia was significantly associated with sleep disturbance, other lower urinary tract symptoms were also independent predictors of sleep dysfunction.

Dietary iron intake in the first 4 months of infancy and the development of type 1 diabetes: a pilot study.

AIMS: To investigate the impact of iron intake on the development of type 1 diabetes (T1DM). METHODS: Case-control study with self-administered questionnaire among families of children with T1DM who were less than 10 years old at the time of the survey and developed diabetes between age 1 and 6 years. Data on the types of infant feeding in the first 4 months of life was collected from parents of children with T1DM (n = 128) and controls (n = 67) <10 years old. Because some cases had sibling controls, we used conditional logistic regression models to analyze the data in two ways. First we performed a case-control analysis of all 128 cases and 67 controls. Next, we performed a case-control analysis restricted to cases (n = 59) that had a sibling without diabetes (n = 59). Total iron intake was modeled as one standard deviation (SD) increase in iron intake. The SD for iron intake was 540 mg in the total sample and 539 mg in the restricted sample as defined above. RESULTS: The median (min, max) total iron intake in the first 4 months of life was 1159 (50, 2399) mg in T1DM cases and 466 (50, 1224) mg among controls (P < 0.001). For each one standard deviation increase in iron intake, the odds ratio (95% confidence interval) for type 1 diabetes was 2.01 (1.183, 3.41) among all participants (128 cases and 67 controls) while it was 2.26 (1.27, 4.03) in a restricted sample of T1 D cases with a control sibling (59 cases and 59 controls) in models adjusted for birth weight, age at the time of the survey, and birth order. CONCLUSION: In this pilot study, high iron intake in the first 4 months of infancy is associated with T1DM. Whether iron intake is causal or a marker of another risk factor warrants further investigation.

Prognostic value of mucin 4 expression in colorectal adenocarcinomas.

BACKGROUND: Mucin 4 (MUC4) is aberrantly expressed in colorectal adenocarcinomas (CRCs) but its prognostic value is unknown. METHODS: Archival tissue specimens collected from 132 CRC patients who underwent surgical resection without presurgery or postsurgery therapy were evaluated for expression of MUC4 by using a mouse monoclonal antibody and horseradish peroxidase. MUC4 expression levels were correlated with clinicopathologic features and patient survival. Survival was estimated by both univariate Kaplan-Meier and multivariate Cox regression methods. RESULTS: In both normal colonic epithelium and CRCs, MUC4 staining was localized primarily in the cytoplasm. The optimal immunostaining cutoff value (>or=75% positive cells and an immunostaining score>or=2.0), which was derived by using the bootstrap method, was used to categorize CRCs into groups of high expression (33 of 132 patients; 25%) or low expression (99 of 132 patients; 75%). Patients who had early stage tumors (stages I and II) with high MUC4 expression had a shorter disease-specific survival (log-rank; P=.007) than patients who had with low expression. Patients who had advanced-stage CRCs (stages III and IV) did not demonstrate such a difference (log-rank; P=.108). Multivariate regression models that were generated separately for patients with early stage and advanced-stage CRC confirmed that increased expression of MUC4 was an independent indicator of a poor prognosis only for patients who had early stage CRCs (hazard ratio, 3.77; 95% confidence interval, 1.46-9.73). CONCLUSIONS: The current results indicated that increased MUC4 expression is a predictor of poor survival in CRC, specifically for patients who have early stage tumors.

Comparison of the predictive qualities of three prognostic models of colorectal cancer.

Most discoveries of cancer biomarkers involve construction of a single model to determine predictions of survival.. 'Data-mining' techniques, such as artificial neural networks (ANNs), perform better than traditional methods, such as logistic regression. In this study, the quality of multiple predictive models built on a molecular data set for colorectal cancer (CRC) was evaluated. Predictive models (logistic regressions, ANNs, and decision trees) were compared, and the effect of techniques for variable selection on the predictive quality of these models was investigated. The Kolmogorov-Smirnoff (KS) statistic was used to compare the models. Overall, the logistic regression and ANN methods outperformed use of a decision tree. In some instances (e.g., for a model that included 'all variables without tumor stage' and use of a decision tree for variable selection), the ANN marginally outperformed logistic regression, although the difference between the accuracy of the KS statistic was minimal (0.80 versus 0.82). Regardless of the variable(s) and the methods for variable selection, all three predictive models identified survivors and non-survivors with the same level of statistical accuracy.

A phase 1 trial of ABT-510 concurrent with standard chemoradiation for patients with newly diagnosed glioblastoma.

OBJECTIVE: To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. DESIGN: Phase 1 dose-escalation clinical trial. SETTING: Comprehensive Cancer Center, University of Alabama at Birmingham. Patients A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007. INTERVENTIONS: Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide. MAIN OUTCOME MEASURES: Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene expression arrays were analyzed. RESULTS: There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injection-site reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low-density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes. CONCLUSIONS: ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles.

Bax expression is a candidate prognostic and predictive marker of colorectal cancer.

OBJECTIVE: Since the anti-tumor activity of 5-fluorouracil (5-FU) is due to induction of apoptosis, we assessed the value of expression of key apoptotic molecules (Bax, Bcl-2 and p53) in predicting the efficacy of 5-FU therapy for colorectal adenocarcinomas (CRCs). METHODS: Archival tissues of CRCs from 56 patients who received a complete regimen of 5-FU-based chemotherapy after surgery, and 56 patients matched for age, gender, ethnicity, tumor stage, tumor location, and tumor differentiation who had undergone only surgery (without any pre- or post-surgery therapy), were evaluated for immunophenotypic expression of Bax, Bcl-2, and p53. Also, these CRCs were evaluated for Bax mutations. The predictive capacity or prognostic value of these markers was assessed by estimating overall survival. RESULTS: The majority of low Bax expressing CRCs have exhibited mutations at the G (8) tract. There was no significant difference in overall survival rates between the categories of surgery alone and 5-FU-treated patients. However, a better survival was observed for patients who received chemotherapy when their CRCs had low Bax/Bcl2 ratio (HR, 1.55; 95% CI: 1.46-31.00). Patients who received surgery alone and whose CRCs lacked Bax expression had 5.33 times higher mortality than those with high Bax expression (95% CI: 1.78-15.94), when controlled for tumor stage and other confounders. Bcl-2 and nuclear p53 accumulation had no predictive value in either patient group. CONCLUSION: These findings are the first to demonstrate that high Bax expression is a good prognosticator for patients who underwent surgery alone, and that patient with low Bax/Bcl-2 expression ratio benefit from 5-FU-based adjuvant therapies.

Redesigning a large-scale clinical trial in response to negative external trial results: the CAMUS study of phytotherapy for benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH), a common condition among older men, confers its morbidity through potentially bothersome lower urinary tract symptoms. Treatments for BPH include drugs such as alpha-adrenergic receptor blockers and 5-alpha reductase inhibitors, minimally invasive therapies that use heat to damage or destroy prostate tissue, and surgery including transurethral resection of the prostate. Complementary and alternative medicines are gaining popularity in the US. Two phytotherapies commonly used for BPH are extracts of the fruit of Serenoa repens, the Saw palmetto dwarf palm that grows in the Southeastern US, and extracts of the bark of Pygeum africanum, the African plum tree. PURPOSE: The objective of the Complementary and Alternative Medicines for Urological Symptoms (CAMUS) clinical trial is to determine if phytotherapy is superior to placebo in the treatment of BPH. METHODS: CAMUS was originally designed as a 3300-participant, four-arm trial of S. repens, P. africanum, an alpha-adrenergic blocking drug, and placebo with time to clinical progression of BPH, a measure of long-term efficacy, as the primary endpoint. Before enrollment started, a randomized, double-blind, placebo-controlled, single institution clinical trial showed that S. repens at the usual dose did not demonstrate any benefit over placebo with respect to symptom relief at 1 year. Consequently, the focus of CAMUS shifted from evaluating long-term efficacy to determining if any short-term (6-18 months) symptom relief could be achieved with increasing doses of S. repens, the phytotherapy most commonly used in the US for BPH. RESULTS: Results are anticipated in 2011. CONCLUSIONS: Trial design occurs in an environment of continually evolving information. In this case, emerging results from another trial suggested that a study of long-term efficacy was premature, and that an effective dose and preparation of S. repens had to be established before proceeding to a long-term clinical trial.

Anosmin-1 involved in neuronal cell migration is hypoxia inducible and cancer regulated.

Functional expression of KAL1 gene is critical in the migration of GnRH neurons from the olfactory placode to the hypothalamus in embryogenesis. This gene thus far has not been shown to play a functional role in any other physiological or pathological process either in the developed brain or in peripheral tissues. We show here that KAL1 gene expression is decreased in early stage and increased in later stages of cancers. Screening of colon, lung and ovarian cancer cDNA panels indicated significant decrease in KAL1 expression in comparison to corresponding uninvolved tissues. However, KAL1 expression increased with the progression of cancer from early (I and II) stages to later (III and IV) stages of the cancer. There was a direct correlation between the TGFbeta and KAL1 expression in colon cancer cDNA. Using colon cancer cell lines, we showed that TGFbeta induces KAL1 gene expression and secretion of anosmin-1 protein (KAL1 coded protein). We further report that hypoxia induces anosmin-1 expression; anosmin-1 protects cancer cells from apoptosis activated by hypoxia and increases cancer cell mobility. Using siRNA technique we found that KAL1 expression following hypoxia is hypoxia-inducible factor (HIF-1)alpha dependent. Our results suggest that KAL1 gene expression plays an important role in cancer metastasis and protection from apoptosis.

Inclusion of complementary and alternative medicine in US state comprehensive cancer control plans: baseline data.

BACKGROUND: The use of complementary and alternative medicine (CAM) among cancer patients has increased substantially during the last decade. The purpose of this investigation is to summarize CAM content of comprehensive cancer control (CCC) plans in the United States, territories, and tribes. METHODS: Sixty-six CCC plans, including all the states, most of the territories, and nearly all the Native American tribes were analyzed for content of CAM, and predominant thematic areas were summarized. RESULTS: Thirty-nine plans (59.1%) included CAM content. The predominant themes identified included increased education of CAM practices (46.2%), followed by utilization of existing CAM providers (28.2%), increasing CAM research efforts (18%), encouraging patient and provider communication about CAM use (18%), establishment of CAM baseline data (10.3%), and CAM as a barrier to treatment (10.3%). CONCLUSION: CAM is an emerging area in cancer care. The increasing inclusion of various themes of CAM into CCC plans indicate that many US cancer coalitions are taking steps to include the education and promotion of safe and efficacious CAM therapies for cancer patients.

Prognostic significance of p53 codon 72 polymorphism differs with race in colorectal adenocarcinoma.

PURPOSE: Several studies have examined the prognostic value of the codon 72 polymorphism of the p53 gene in colorectal adenocarcinoma, but none have addressed patient race/ethnicity. Therefore, this study assessed the prognostic value of this polymorphism in African American and Caucasian colorectal adenocarcinoma patients separately. EXPERIMENTAL DESIGN: Colorectal adenocarcinomas from 137 African Americans and 236 non-Hispanic Caucasians were assessed for p53 mutations and genotyped for the codon 72 polymorphism. The phenotypes were correlated with p53 mutational status, clinicopathologic features, and patient survival using the chi(2) test and Kaplan-Meier and Cox regression models. RESULTS: The incidence of p53 mutations was similar in African American and Caucasian patients (50% versus 54%, respectively); however, the homozygous Pro72 allele frequency was higher in African Americans (17%) as compared with Caucasians (7%). In contrast, the homozygous Arg72 allele frequency was higher in Caucasians (36%) than in African Americans (19%). In African Americans but not Caucasians, the Pro/Pro phenotype significantly correlated with a higher incidence of missense p53 mutations and with nodal metastasis. African Americans, but not Caucasians, with the Pro/Pro phenotype had significantly higher mortality (log-rank P = 0.005 versus. P = 0.886) and risk of death due to colorectal adenocarcinoma (hazard ratio, 2.15; 95% confidence interval, 1.02-4.53 versus hazard ratio, 1.60; 95% confidence interval, 0.69-3.18) than those with the phenotype Arg/Arg or Arg/Pro. CONCLUSIONS: The higher frequency of the Pro/Pro phenotype of p53 in African American patients with colorectal adenocarcinoma is associated with an increased incidence of p53 mutations, with advanced tumor stage, and with short survival.

Characterization and immunotherapeutic potential of gammadelta T-cells in patients with glioblastoma.

Classical immunotherapeutic approaches to glioblastoma multiforme (GBM) have shown mixed results, and therapies focused on innate lymphocyte activity against GBM have not been rigorously evaluated. We examined peripheral blood lymphocyte phenotype, gammadelta T-cell number, mitogenic response, and cytotoxicity against GBM cell lines and primary tumor explants from GBM patients at selected time points prior to and during GBM therapy. Healthy volunteers served as controls and were grouped by age. T-cell infiltration of tumors from these patients was assessed by staining for CD3 and T-cell receptor gammadelta. Our findings revealed no differences in counts of mean absolute T-cells, T-cell subsets CD3+CD4+ and CD3+CD8+, and natural killer cells from healthy volunteers and patients prior to and immediately after GBM resection. In contrast, gammadelta T-cell counts and mitogen-stimulated proliferative response of gammadelta T-cells were markedly decreased prior to GBM resection and throughout therapy. Expanded/activated gammadelta T-cells from both patients and healthy volunteers kill GBM cell lines D54, U373, and U251, as well as primary GBM, without cytotoxicity to primary astrocyte cultures. Perivascular T-cell accumulation was noted in paraffin sections, but no organized T-cell invasion of the tumor parenchyma was seen. Taken together, these data suggest that gammadelta T-cell depletion and impaired function occur prior to or concurrent with the growth of the tumor. The significant cytotoxicity of expanded/activated gammadelta T-cells from both healthy controls and selected patients against primary GBM explants may open a previously unexplored approach to cellular immunotherapy of GBM.

Resveratrol enhances cell-mediated immune response to DMBA through TLR4 and prevents DMBA induced cutaneous carcinogenesis.

Toll-like receptors (TLRs) activate signals that are critically involved in innate immune responses and that contribute to the initiation of adaptive immune responses. Resveratrol (trans-3,5,4-trihydroxystilbene), a polyphenol found in red grapes and in several other plant sources, is an effective chemopreventive agent in cutaneous chemical carcinogenesis. In this study, we investigated whether TLR4 was required for the chemopreventive action of resveratrol in DMBA skin carcinogenesis. For this purpose, mice with normal and deficient TLR4 function were compared when pretreated with resveratrol and then subjected to a DMBA-induced skin carcinogenesis protocol. There were fewer tumors/group (P < 0.001) in resveratrol treated TLR4 competent C3H/HeN mice than in TLR4 deficient C3H/HeJ mice. In addition, the size of tumors in C3H/HeN mice was reduced in vivo and their survival in vitro was inhibited by resveratrol to a significantly greater extent than in C3H/HeJ mice. Resveratrol inhibited angiogenesis to a much greater extent in the TLR4 competent mice than in TLR4 deficient mice. IFN-gamma and IL-12 levels were also increased in TLR4 competent mice compared to TLR4 deficient mice, and TLR4 competent C3H/HeN mice exhibited a greater increase in the cell-mediated immune response to DMBA. The results of this study indicate that TLR4 is an important mediator of resveratrol chemoprevention in DMBA skin tumorigenesis.

Comparison of predicted probabilities of proportional hazards regression and linear discriminant analysis methods using a colorectal cancer molecular biomarker database.

BACKGROUND: Although a majority of studies in cancer biomarker discovery claim to use proportional hazards regression (PHREG) to the study the ability of a biomarker to predict survival, few studies use the predicted probabilities obtained from the model to test the quality of the model. In this paper, we compared the quality of predictions by a PHREG model to that of a linear discriminant analysis (LDA) in both training and test set settings. METHODS: The PHREG and LDA models were built on a 491 colorectal cancer (CRC) patient dataset comprised of demographic and clinicopathologic variables, and phenotypic expression of p53 and Bcl-2. Two variable selection methods, stepwise discriminant analysis and the backward selection, were used to identify the final models. The endpoint of prediction in these models was five-year post-surgery survival. We also used linear regression model to examine the effect of bin size in the training set on the accuracy of prediction in the test set. RESULTS: The two variable selection techniques resulted in different models when stage was included in the list of variables available for selection. However, the proportion of survivors and non-survivors correctly identified was identical in both of these models. When stage was excluded from the variable list, the error rate for the LDA model was 42% as compared to an error rate of 34% for the PHREG model. CONCLUSIONS: This study suggests that a PHREG model can perform as well or better than a traditional classifier such as LDA to classify patients into prognostic classes. Also, this study suggests that in the absence of the tumor stage as a variable, Bcl-2 expression is a strong prognostic molecular marker of CRC.

Plasma protein profiles differ between women diagnosed with cervical intraepithelial neoplasia (cin) 1 and 3.

Early detection of precancerous cells in the cervix and their clinical management is the main purpose of cervical cancer prevention and treatment programs. Cytological findings or testing for high risk (HR)-human papillomavirus (HPV) are inadequately sensitive for use in triage of women at high risk for cervical cancer. The current study is an exploratory study to identify candidate surface-enhanced laser desorption/ionization (SELDI) time of flight (TOF) mass spectrometry (MS) protein profiles in plasma that may distinguish cervical intraepithelial neoplasia (CIN 3) from CIN 1 among women infected with HR-HPV. We evaluated the SELDI-TOF-MS plasma protein profiles of HR-HPV positive 32 women with CIN 3 (cases) and 28 women with CIN1 (controls). Case-control status was kept blinded and triplicates of each sample and quality control plasma samples were randomized and after robotic sample preparations were run on WCX2 chips. After alignment of mass/charge (m-z values), an iterative method was used to develop a classifier on a training data set that had 28 cases and 22 controls. The classifier developed was used to classify the subjects in a test data set that has six cases and six controls. The classifier separated the cases from controls in the test set with 100% sensitivity and 100% specificity suggesting the possibility of using plasma SELDI protein profiles to identify women who are likely to have CIN 3 lesions.