Search

Objective: Despite alarming obesity levels in the Arabian Peninsula, its population lacks convincingly identified genetic determinants of obesity. A genome-wide association study was performed for obesity-related anthropometric traits in Arabs and to decipher mechanisms by which the variants mediate traits.Methods: The Illumina HumanOmniExpress BeadChip was used to genotype 1,353 Arab individuals (largely with Class I obesity) from Kuwait. Genome-wide association tests for obesity-related anthropometric traits were performed. Top associations were tested for replication in an independent cohort (1,176 unrelated Arabs). Resultant variants were investigated for interactions with obesity-related plasma biomarkers. Pathway analysis was performed on genes harboring markers in linkage disequilibrium (LD) with identified variants.Results: The rs9606756[c.67A>G,p.Ile23Val] variant from TCN2 was associated with waist circumference (WC) at nearly genome-wide significance (P = 8.92E-08). WC was inversely related with Apo-A1 or high-density lipoprotein levels; individuals with the AG genotype exhibited stronger relationship than those with the reference AA genotype. Interaction involving the AG genotype (effect allele = G) significantly contributed to an increase in anthropometric traits (particularly WC). Genes harboring single-nucleotide polymorphisms in LD with rs9606756 mapped onto an interaction network (with TP53 as central element) of established obesity/diabetes-related protein components.Conclusions: The TCN2 variant acts as a risk factor for WC in the Arab population. The variant mediates obesity-related anthropometric traits via interactions with Apo-A1/high-density lipoprotein or TP53. [ABSTRACT FROM AUTHOR]

Background: Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (Tregs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ Tregs as a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated in vitro and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease. Methods: Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease. Results: A co-existence of B7-H1+ T lymphocytes and FOXP3+ Tregs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3+ Tregs, B7-H1+ and PD-1+ TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022). Conclusion: Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting Tregs and B7-H1/PD-1 molecules. [ABSTRACT FROM AUTHOR]

Background: Breast cancer in young Saudi women is a crucial problem. According to the 2002 annual report of Saudi National Cancer Registry, breast cancers that developed before the age of 40 comprise 26.4% of all female breast cancers comparing to 6.5% in the USA. Breast cancer in young patients is often associated with a poorer prognosis, but there has been a scarcity of published data in the Middle East population. Methods: Total of 867 breast cancer patients seen at King Faisal Specialist Hospital & Research Centre (KFSH&RC) between 1986 and 2002 were reviewed. Patients were divided in two age groups: ≤ 40 years and above 40 years. The clinicopathological characteristics and treatment outcomes were compared between younger and older age groups. Results: Median age at presentation was 45 years. A total of 288 (33.2%) patients were aged ≤ 40 years. Hormone receptors were positive in 69% of patients 40 and 78.2% of patients above 40 (p = 0.009). There was a significantly higher incidence of grade III tumor in younger patients compared to older patients (p = 0.0006). Stage, tumor size, lymphatic/vascular invasion, number of nodes and axillary lymph node status, did not differ significantly between the two age groups. Younger patients had a greater probability of recurrence at all time periods (p = 0.035). Young age had a negative impact on survival of patients with positive axillary lymph nodes (p = 0.030) but not on survival of patients with negative lymph nodes (p = 0.695). Stage, tumor size, nodal status and hormonal receptors had negative impact on survival. Adjuvant chemotherapy was administered to 87.9% of younger and 65.6% of older patients (p < 0.0001). In terms of hormone therapy, the proportion of tamoxifen treated patients was significantly lower in young age group (p < 0.0001). No significant difference in radiation therapy between the two groups. Conclusion: Young age (≤ 40) is an independent risk factor for relapse in operable Saudi breast cancer patients. The fundamental biology of young age breast cancer patients needs to be elucidated. [ABSTRACT FROM AUTHOR]

Bioequivalence studies, required by law whenever a new formulation of an existing; drug product is introduced to the market, are designed to test whether the bioavailability, defined as the rate and extent to which a substance reaches systemic circulation, is equivalent for each of two or more formulations. Detection and treatment of outlying data in bioequivalence studies are practically important, because inclusion or deletion of potential outlying data may lead to a different conclusion concerning bioequivalence. A review of the literature reveals that four different methods have been proposed for detecting outliers in bioavailability/bioequivalence studies. We present the results of an extensive computer simulation testing the small sample performance of these four testing methods, the results of which indicate that one of these, the estimates distance test, is substantially more powerful than the alternatives. [ABSTRACT FROM AUTHOR]

Background: Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (Tregs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ Tregs as a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated in vitro and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease.Methods: Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease.Results: A co-existence of B7-H1+ T lymphocytes and FOXP3+ Tregs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3+ Tregs, B7-H1+ and PD-1+ TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022).Conclusion: Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting Tregs and B7-H1/PD-1 molecules. [ABSTRACT FROM AUTHOR]

Breast cancer has a major impact on the health of women worldwide. In the Kingdom of Saudi Arabia (KSA), breast cancer incidence is on the increase and is characterized by early onset and aggressiveness. Owing to the importance of the TP53 gene in breast carcinogenesis, we analyzed the possible link between TP53 single nucleotide polymorphisms (SNPs) and the risk of breast cancer in Saudi women by direct sequencing of the TP53 gene exon 4 from 100 breast cancer tissues. The proportion of the polymorphic forms of SNP72 in the Saudi breast cancer patients were: Arg/Arg (RR), 39%; Pro/Pro (PP), 36%; and Arg/Pro (RP), 25%. The frequencies of these forms in disease-free Saudi women were 7.59, 22.22 and 60.19%, respectively. This indicates that the RR form of the codon 72 polymorphism is a potential risk factor, whereas the RP form is a protection factor against breast cancer among Saudi women (p=0.0001). Moreover, the results have shown that the p53 R72P SNP is significantly associated with the early onset of breast cancer in the Saudi population (p=0.0138). However, the codon 47 polymorphism appears to have no role in this disease among Saudi women. These results indicate that the TP53 gene could play a major role in breast carcinogenesis and the early onset of the disease among Saudi women.

Aim of the Study: To evaluate different prognostic factors that may affect disease-specific survival in patients with bladder cancer following radical cystectomy., Methods: Between July 1975 and December 2000, 229 patients underwent radical cystectomy and urinary diversion for bladder cancer in King Faisal Specialist Hospital and Research Center (KFSH & RC), Riyadh, Saudi Arabia. 175 patients had available records for review. Retrospective chart review was done. Demographic, clinical and pathological variables which may affect disease specific survival in bladder cancer patients were pooled. Univariate and multivariate analyses were done with disease specific survival as an end point., Results: Our patients were 140 males (80%) and 35 females (20%). Their mean age was 54 years (range: 21-90 years). The median follow-up period was 1.5 years (range: one month-19 years). Five-year disease specific survival was 44%. On univariate analysis, patients' age, lymph node status, pathological staging and presence of hydronephrosis were significant predictors of disease specific survival. However, only lymph node status (p<0.0001), pathological staging (p=0.0411) & presence of hydronephrosis (p=0.0264) were significant predictors of disease specific survival in multivariate analysis., Conclusion: Pathological stage, lymph node status and upper obstructive uropathy are significant prognostic factors in bladder cancer patients after radical cystectomy. These factors may help to define bladder cancer patient groups who require further therapy or enrollment in controlled trials to investigate additional therapy.