PD-L1 intrinsically promotes the proliferation of breast cancer cells through the SKP2-p27/p21 axis.

BACKGROUND: PD-L1 intrinsically promotes tumor progression through multiple mechanisms, which potentially leads to resistance to anti-PD-1/PD-L1 therapies. The intrinsic effect of PD-L1 on breast cancer (BC) cell proliferation has not been fully elucidated. METHODS: we used proteomics, gene expression knockdown (KD), quantitative immunofluorescence (qIF), western blots, functional assays including colony-forming assay (CFA) and real-time cell analyzer (RTCA), and in vivo data using immunohistochemistry in breast cancer patients. RESULTS: PD-L1 promoted BC cell proliferation by accelerating cell cycle entry at the G1-to-S phase transition. Global proteomic analysis of the differentially expressed nuclear proteins indicated the involvement of several proliferation-related molecules, including p21CIP1/WAF1. Western blotting and qIF demonstrated the higher expression of SKP2 and the lower expression of p21CIP1/WAF1 and p27Kip1 in PD-L1 expressing (PD-L1pos) cells as compared to PD-L1 KD (PD-L1KD) cells. Xenograft-derived cells and the TCGA BC dataset confirmed this relationship in vivo. Functionally, CFA and RTCA demonstrated the central role of SKP2 in promoting PD-L1-mediated proliferation. Finally, immunohistochemistry in 74 breast cancer patients confirmed PD-L1 and SKP-p21/p27 axis relationship, as it showed a highly statistically significant correlation between SKP2 and PD-L1 expression (p < 0.001), and both correlated significantly with the proliferation marker Ki-67 (p < 0.001). On the other hand, there was a statistically significant inverse relationship between PD-L1 and p21CIP1/WAF1 expression (p = 0.005). Importantly, double negativity for p21CIP1/WAF1 and p27Kip1 correlated significantly with PD-L1 (p < 0.001), SKP2 (p = 0.002), and Ki-67 (p = 0.002). CONCLUSIONS: we have demonstrated the role of the SKP2-p27/p21 axis in intrinsic PD-L1-enhanced cell cycle progression. Inhibitors of SKP2 expression can alleviate resistance to ICPIs.

Changes in the Fibrinolytic System of Patients Infected with Severe Acute Respiratory Syndrome Coronavirus 2.

INTRODUCTION: In this study, coagulation and fibrinolysis parameters and their association with disease severity were investigated in coronavirus disease (COVID-19) patients. MATERIALS AND METHODS: COVID-19 patients (n = 446) admitted to our institute between 21 February 2021 and 17 March 2022, were recruited. Clinical data and staging were collected from all patients. Blood samples were collected and analyzed for several parameters of fibrinolysis and coagulation, including alpha-2-antiplasmin(α2AP) and plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), D-dimer, and fibrinogen levels. RESULTS: The TAFI, fibrinogen, and tPA levels were significantly higher in participants who died compared to that of patients who recovered (p < 0.001). However, PAI-1, tPA, and TAFI were significantly higher in patients admitted to the ICU than those of the healthy controls (p < 0.001 for PAI-1 and tPA; p = 0.0331 for TAFI). Our results showed that stage C and D COVID-19 patients had significantly higher levels of PAI-1 (p = 0.003). Furthermore, stage D COVID-19 patients had significantly higher tPA and TAFI values (p = 0.003). CONCLUSIONS: Hypofibrinolysis was the most prevalent condition among patients with severe COVID-19. In this study, several coagulation markers were elevated, making them suitable prognostic markers for hypofibrinolysis.

In Silico Core Proteomics and Molecular Docking Approaches for the Identification of Novel Inhibitors against Streptococcus pyogenes.

Streptococcus pyogenes is a significant pathogen that causes skin and upper respiratory tract infections and non-suppurative complications, such as acute rheumatic fever and post-strep glomerulonephritis. Multidrug resistance has emerged in S. pyogenes strains, making them more dangerous and pathogenic. Hence, it is necessary to identify and develop therapeutic methods that would present novel approaches to S. pyogenes infections. In the current study, a subtractive proteomics approach was employed to core proteomes of four strains of S. pyogenes using several bioinformatic software tools and servers. The core proteome consists of 1324 proteins, and 302 essential proteins were predicted from them. These essential proteins were analyzed using BLASTp against human proteome, and the number of potential targets was reduced to 145. Based on subcellular localization prediction, 46 proteins with cytoplasmic localization were chosen for metabolic pathway analysis. Only two cytoplasmic proteins, i.e., chromosomal replication initiator protein DnaA and two-component response regulator (TCR), were discovered to have the potential to be novel drug target candidates. Three-dimensional (3D) structure prediction of target proteins was carried out via the Swiss Model server. Molecular docking approach was employed to screen the library of 1000 phytochemicals against the interacting residues of the target proteins through the MOE software. Further, the docking studies were validated by running molecular dynamics simulation and highly popular binding free energy approaches of MM-GBSA and MM-PBSA. The findings revealed a promising candidate as a novel target against S. pyogenes infections.

Biological control of yeast contamination of industrial foods by propolis.

Bee glue (Propolis, PR), mixture of beeswax and resin is collected from honeybee (Apis mellifera) of different plant parts. The antimicrobial potential of PR against food borne yeast was reported. The experiment was designed to examine the way of antimicrobial impact of PR on food borne yeasts (Cryptococcus laurentii and Candida famata) and its usage use as biological strategy for the preservation of soft foods against microbial spoilage. The study also highlights, the ability of ethanol and water- PR extracts, discouraged growth of tested yeast. Antifungal properties were also determined using electron microscope while biochemical analysis was determined using free and proteinic amino acid technique and oxidative enzymes were determined using HPLC analysis. Antioxidant enzymes were determined using ELISA assay. The highest effect was recorded on C. laurentii however, the lowest effect shows on C. famata. The electron microscopic studies clearly disclosed the effect of water PR distillate on the external shape and internal organs of some tested yeast e.g. C. laurentii and C. famata. The result indicated some differences on concentrations of bio-chemical analyses for these tested yeasts treated with 70% water- PR extracts of different food materials. Moreover, biochemical analysis results also reported that the treated yeast indicated natural preservative to food products and considered as best alternative to the (chemical) preservatives currently employed.

Epidemiological characterization of serotype group B Streptococci neonatal infections associated with interleukin-6 level as a sensitive parameter for the early diagnosis.

Group B streptococcal infection (Streptococcus agalactiae) is one of the leading causes of life-threatening disease in the early neonatal period, resulting in sepsis, pneumonia, and meningitis. During invasive infections, an excessive release of pro-inflammatory cytokine, such as interleukin-6 (IL-6), thus IL-6 gene is significant, as a diagnostic marker of systemic infection of the newborns. The present study aimed to describe the epidemiology diagnostic of GBS disease in neonatal by phenotypic and genotypic methods. Nine hundred and ninety-six samples were taken at Maternity and Children Hospital, Jeddah, Saudi Arabia for a period of one year (2011-2012). Results indicated that out of 217 infected samples, twenty (9.23.0%) were positive for group B Streptococci bacteria. This study also shows that female infants are more susceptible than males. The level of IL-6 was higher in mothers above 30 years. Twenty positive Streptococci group B isolates showed bands with the cylE gene primers in the border between 228 bp, 267 bp and 50 bp. Molecular detection by Real time polymerase chain reaction was also done to detect the target (Sip gene) encoding the Sip surface immunogenic protein. Specific primers and TaqMan probe were chosen for this purpose. A Real-time PCR method targeting the sip gene of GBS in neonates after delivery has been evaluated.

Lead removal by Spirulina platensis biomass.

In this investigation, we report on the biosorption of Pb (II) from aqueous solutions by the nonliving biomass of the micro-alga (cyanobacterium) Spirulina platensis. Propagation of the micro-alga was carried out in outside oblong raceway ponds. The biomass was cleaned, dried and used for the investigation. The effects of pH, adsorbent dose, temperature, initial concentration of Pb (II), and contact time on the adsorption of lead by the dry biomass were studied. The experiments were carried out in 250 ml conical flasks containing 100 ml of test solutions using an orbital incubator at 150 rpm. Concentrations of the metal before and after the experiments were measured using Atomic Absorption Spectrophotometer. Very high levels of Pb (II) removal (>91%) were obtained. The optimum conditions for maximal adsorption by S. platensis were found to be pH 3; 2 g of adsorbent dose; incubation at 26°C; 100 mg/l of lead initial concentration and 60 minutes of contact time. The experimental data fitted well with Freundlich isotherm equation with R(2) values greater than 0.97. Based on our results, we recommend the utilization of S. platensis biomass for heavy metal removal from aqueous solutions.

Adsorptive removal of cadmium ions by Spirulina platensis dry biomass.

Cadmium is one of the most toxic substances found in aquatic ecosystems. This metal tends to accumulate in photosynthetic plants and fish and is transferred to humans causing many diseases. It has to be removed from our environment to reduce any health risks. Dry biomass of the microalga (cyanobacterium) Spirulina platensis was used as biosorbent for the removal of cadmium ions (Cd(2+)) from aqueous solutions. The effects of different levels of pH (3-9), biomass concentration (0.25-2 g), temperature (18-46 °C), metal concentration (40-200 mg/l) and contact time (30-120 min) were tested. Batch cultures were carried out in triplicate in an orbital shaker at 150 rpm. After centrifuging the biomass, the remaining levels of cadmium ions were measured in the supernatant by Atomic Absorption Spectrometer. Very high levels of removal, reaching up to 87.69% were obtained. The highest percentage of removal was reached at pH 8, 2 g of biosorbent, 26 °C, and 60 mg/l of cadmium concentration after 90 min of contact time. Langmuir and Freundlich isotherm models were applied to describe the adsorption isotherm of the metal ions by S. platensis. Langmuir model was found to be in better correlation with experimental data (R (2) = 0.92). Results of this study indicated that S. platensis is a very good candidate for the removal of heavy metals from aquatic environments. The process is feasible, reliable and eco-friendly.

Genomics, phylogeny and in silico analysis of mitochondrial glutathione S-transferase-kappa from the camel Camelus dromedarius.

The domesticated one-humped camel, Camelus dromedarius, is one of the most important animals in the Arabian Peninsula. For most of its life, this species is exposed to both intrinsic and extrinsic genotoxic factors that cause gross DNA alterations in many organisms. GST enzymes constitute an important supergene family involved in protection against the deleterious effects of oxidative stress and xenobiotics. Cloning the camel mitochondrial GST kappa (GSTK) gene and comparing its structural similarities with different species may aid in understanding its evolutionary relics. We cloned the camel GSTK using RT-PCR. This yielded an open reading frame of 678 nucleotides, encoding a protein of 226 amino acid residues. In a comparative analysis, the cloned GSTK was used to screen orthologues from different organisms. Phylogenetic analysis demonstrated that the camel GSTK apparently evolved from an ancestral GSTK gene that predated the appearance of vertebrates, and it grouped with pig, cattle, dog, horse, human and monkey GSTKs. The calculated molecular weight of the translated ORF was 25.52 kDa and the isoelectric point was 8.4. The deduced cGSTK sequence exhibited high identity with many mammals, such as Bactrian camel (99.55%), pig, cattle and human (>74%), and lower identity with other unrelated organisms, such as frog (Xenopus tropicalis, 61%), chicken (Gallus gallus, 57%), salmon (Salmo salar, 49%), sponge (Amphimedon queenslandica, 46%), tick (Amblyomma maculatum, 45%) and roundworm (Caenorhabditis elegans, 33%). A 3D structure was built based on the crystal structure of the human and rat enzymes. The levels of cGSTK expression in five camel tissues were examined via real-time PCR. The highest level of cGSTK transcripts was found in the camel liver, followed by the testis, spleen, kidney and lung.

Human papillomaviruses in cervical specimens of women residing in Riyadh, Saudi Arabia: a hospital-based study.

INTRODUCTION: Certain genotypes of human papillomavirus (HPV) are linked to cervical abnormalities. HPV DNA and genotype prevalence among women residing in Riyadh, Saudi Arabia is investigated in this hospital-based study. METHODOLOGY: Cervical specimens were taken from 519 subjects along with consent and demographic data. DNA was extracted and PCR was performed on all specimens using general primers. Low- and high-risk HPV genotypes were determined by reverse blot hybridization assay using specific probes. SPSS version 17 was used for the data analysis. RESULTS: Of 519 cervical specimens, 164 (31.6%) were positive for HPV DNA. There was a significant association between HPV positivity and abnormal cytology (p < 0.00001). Even though the HPV positivity was relatively high, the squamous intraepithelial lesions were minimal, with one low grade and one high grade case among those HPV DNA-positive specimens. Regardless of single or multiple infections per specimen, HPV-16 was found in 87.8%, followed by HPV-18 in 86%, and HPV-11 in 78.3%. CONCLUSIONS: Amplification technology showed that HPV is common among women in Riyadh, Saudi Arabia, with a strong association between HPV infection and cytological changes. HPV-16 was the most frequent genotype but had a low prevalence of cervical cancer.

Renin-angiotensin system gene polymorphisms among Saudi patients with coronary artery disease.

BACKGROUND: The polymorphisms in the components of the renin-angiotensin system (RAS) are important in the development and progression of coronary artery disease (CAD) in some individuals. Our objectives in the present investigation were to determine whether three RAS polymorphisms, angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensin receptor II (Ang II AT2 - C3123A) and angiotensinogen (AGT-M235T), are associated with CAD in the Saudi population. We recruited 225 subjects with angiographically confirmed CAD who had identical ethnic backgrounds and 110 control subjects. The polymerase chain reaction-restriction fragment length polymorphisms (RFLP) technique was used to detect polymorphisms in the RAS gene. RESULTS: Within the CAD group, for the ACE I/D genotype, DD was found in 64.4%, 26.3% carried the ID genotype, and 9.3% carried the II genotype. Within the control group, the DD genotype was found in 56.4%, 23.6% carried the ID genotype, and 20% carried the II genotype. The odds ratio (OR) of the ACE DD vs II genotype with a 95% confidence interval (CI) was 2.45 (1.26-4.78), with p = 0.008. For the Ang II AT2 receptor C3123A genotype, within the CAD group, CC was found in 39.6%, 17.8% carried the CA genotype, and 42.6% carried the AA genotype. Within the control group, CC was found in 39.1%, 60.9% carried the CA genotype, and there was an absence of the AA genotype. The OR of the Ang II AT2 receptor C3123A CC vs AA genotypes (95% CI) was 0.01, with p = 0.0001. A significant association with CAD was shown. For the AGT-M235T genotype, within the CAD group, MM was found in 24.0%, 43.6% carried the MT genotype and 32.4% carried the TT genotype. Within the control group, MM was found in 26.4%, 45.5% carried the TT genotype and 28.2% carried the MT genotype. The OR of MM vs TT (95% CI) was 0.79 (0.43 to 1.46), which was insignificant. CONCLUSIONS: There is an association between the ACE I/D and Ang II AT2 receptor C3123A polymorphisms and CAD, however, no association was detected between the AGT M235T polymorphism and CAD in the Saudi population.

Aluminium oxide nanoparticles induce mitochondrial-mediated oxidative stress and alter the expression of antioxidant enzymes in human mesenchymal stem cells.

An urgent need for toxicological studies on aluminium oxide nanoparticles (Al(2) [Formula: see text]NPs) has arisen from their rapidly emerging range of applications in the food and agricultural sectors. Despite the widespread use of nanoscale aluminium and its composites in the food industry, there is a serious lack of information concerning the biological activities of Al(2) [Formula: see text]NPs (ANPs) and their impact on human health. In this preliminary study, the effects of ANPs on metabolic stress in human mesenchymal stem cells (hMSCs) were analysed. The results showed dose-dependent effects, including cellular toxicity. The mitochondrial membrane potential in the hMSCs decreased with increasing ANP concentrations after 24 h of exposure. The expression levels of oxidative stress-responsive enzymes were monitored by RT-PCR. The expression levels of CYP1A and POR were up-regulated in response to ANPs, and a significant down-regulation in the expression of the antioxidant enzyme SOD was observed. Further, dose-dependent changes in the mRNA levels of GSTM3, GPX and GSR were noted. These findings suggest that the toxicity of ANPs in hMSCs may be mediated through an increase in oxidative stress. The results of this study clearly demonstrate the nanotoxicological effects of ANPs on hMSCs, which will be useful for nanotoxicological indexing.

Association of COX-2 rs20417 with aspirin resistance.

Aspirin is the most commonly used antiplatelet drug for treatment of a serious vascular event, most notably stroke and myocardial infarction. However, despite the demonstrated benefit of aspirin, significant fraction of aspirin-treated patients may be resistant to the antiplatelet effects of the drug. The possible mechanisms of aspirin resistance (AR) are multifactorial. A genetic basis for AR has been suggested to exist. Therefore, the present study was taken up to investigate the role of -765G/C polymorphism (rs20417) in the cyclooxygenase-2 (COX-2) gene with AR in stroke patients. Four hundred and fifty stroke patients and four hundred and forty age and sex matched healthy controls were involved in the study. Baseline clinical data were collected and follow-up telephone interviews were conducted with patients at 3 months post event to determine stroke outcome using Modified Rankin Scale. Blood samples were collected and genotypes determined by polymerase chain reaction-restriction digestion technique. The association between the genotypes and outcome was evaluated by stepwise multiple logistic regression analysis. The COX-2 CC and GC genotype showed a significant association with bad outcome. Therefore, the carriers of C allele of COX-2 -765G/C polymorphism are more prone to AR in comparison with non-carriers. These results support a potential role of -765G/C COX-2 gene polymorphism with AR in ischemic stroke patients.

Al2O3 nanoparticles induce mitochondria-mediated cell death and upregulate the expression of signaling genes in human mesenchymal stem cells.

An increase in the broad usage of Al2O3 nanoparticles (ANPs) in the food and agricultural sectors may produce rare hazards for human health. The objective of this study was to assess the acute toxicity of ANPs in human mesenchymal stem cells (hMSCs) in vitro. Cell viability, cellular uptake, morphology, and gene expression using quantitative real-time polymerase chain reaction (qRT-PCR) were analyzed. The results indicate that ANPs have a significant and dose-dependent effect on cytotoxicity. Control cells showed a characteristic, homogeneous nuclear staining pattern, whereas ANP-exposed cells showed abnormal nuclear morphological changes such as condensation or fragmentation. An early characteristic of apoptosis was observed in ANP-treated cells. Further confirmation of cell death in hMSCs was observed through increased expression of chosen signaling genes and also decreased expression of Bcl-2 during mitochondria-mediated cell death. Although they provide great advantages in food and agricultural products, the chronic and acute toxicity of ANPs still needs to be assessed carefully.

Differential expression profile and genetic variants of microRNAs sequences in breast cancer patients.

The technology available for cancer diagnosis and prognosis is not yet satisfactory at the molecular level, and requires further improvements. Micro RNAs (miRNAs) have been recently reported as useful biomarkers in diseases including cancer. We performed a miRNA expression profiling study using peripheral blood from breast cancer patients to detect and identify characteristic patterns. A total of 100 breast cancer patients and 89 healthy patients were recruited for miRNA genotyping and expression profiling. We found that hs-miR-196a2 in premenopausal patients, and hs-miR-499, hs-miR-146a and hs-miR-196a2 in postmenopausal patients, may discriminate breast cancer patients from healthy individuals. In addition, we found a significant association between two microRNA polymorphisms (hs-miR-196a2 and hs-miR-499) and breast cancer risk. However, no significant association between the hs-miR-146a gene and breast cancer risk was found. In summary, the study demonstrates that peripheral blood miRNAs and their expression and genotypic profiles can be developed as biomarkers for early diagnosis and prognosis of breast cancer.

Artemisia absinthium (AA): a novel potential complementary and alternative medicine for breast cancer.

Natural products have become increasingly important in pharmaceutical discoveries, and traditional herbalism has been a pioneering specialty in biomedical science. The search for effective plant-derived anticancer agents has continued to gain momentum in recent years. The present study aimed to investigate the role of crude extracts of the aerial parts of Artemisia absinthium (AA) extract in modulating intracellular signaling mechanisms, in particular its ability to inhibit cell proliferation and promote apoptosis in a human breast carcinoma estrogenic-unresponsive cell line, MDA-MB-231, and an estrogenic-responsive cell line, MCF-7. Cells were incubated with various concentrations of AA, and anti-proliferative activity was assessed by MTT assays, fluorescence microscopy after propidium iodide staining, western blotting and cell cycle analysis. Cell survival assays indicated that AA was cytotoxic to both MDA-MB-231 and MCF-7 cells. The morphological features typical of nucleic staining and the accumulation of sub-G1 peak revealed that the extract triggered apoptosis. Treatment with 25 µg/mL AA resulted in activation of caspase-7 and upregulation of Bad in MCF-7 cells, while exposure to 20 µg/mL AA induced upregulation of Bcl-2 protein in a time-dependent response in MDA-MB-231 cells. Both MEK1/2 and ERK1/2 was inactivated in both cell lines after AA treatment in a time-dependent manner. These results suggest that AA-induced anti-proliferative effects on human breast cancer cells could possibly trigger apoptosis in both cell lines through the modulation of Bcl-2 family proteins and the MEK/ERK pathway. This might lead to its possible development as a therapeutic agent for breast cancer following further investigations.

Association of genetic variants of fibrinolytic system with stroke and stroke subtypes.

Genetic variants of tPA (PLAT) and PAI-1 genes have been suggested to be the risk factors for stroke. In the present case-control study we investigated the association of -7351C/T polymorphism (rs2020918) and I/D polymorphism of tPA gene and Insertion/deletion polymorphism (4G/5G) of PAI-1 gene with genetic predisposition to ischemic stroke. 516 stroke patients and 513, sex and age matched healthy controls were involved in the study. We did not find a significant association of tPA -7351C/T polymorphism and PAI-1 4G/5G polymorphism with stroke. However, in case of I/D polymorphism significant difference was observed in the genotypic distribution and allelic frequency between the stroke patients and healthy controls. DD genotype and D allele associated significantly with stroke (p=0.002 and <0.001 respectively). We also found significant association of I/D polymorphism with intracranial large artery atherosclerosis and stroke of undetermined etiology. Exploring the association between gene-gene interaction (26 combinations including the three variants) and stroke, we found that individuals with CC+4G4G+DD, CC+5G5G+ID, CT+4G5G+ID, CT+5G5G+II, CT+5G5G+ID and TT+4G5G+II had a significantly higher risk of stroke. The results of this study suggest that -7351C/T polymorphism of tPA and 4G/5G polymorphism of PAI-1 are not associated with stroke, while as DD genotype and D allele of tPA gene are important risk factors for ischemic stroke. Further we found that the subjects with different tPA and PAI genotype combinations displayed a significantly high risk for overall ischemic stroke suggesting that gene-gene interaction involving more variants may change the susceptibility of particular subjects to the disease.

Association of 1347 G/A cytochrome P450 4F2 (CYP4F2) gene variant with hypertension and stroke.

Genetic variants of cytochrome P450 4F2 (CYP4F2) gene have been suggested to be risk factors for hypertension, cardiovascular diseases and stroke. In the present case-control study we investigated the association of 1347 G/A polymorphism (rs2108622) in the 11th exon region of CYP4F2 gene with hypertension, ischemic stroke and stroke subtypes classified according to TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Five hundred and seven stroke patients (hypertensives: normotensives = 279:228) and four hundred and eighty seven, age and sex matched controls (males: females = 356:131) (hypertensives: normotensives = 148:339) were involved in the study. The genotypes were determined by PCR-RFLP technique. Genotypes were confirmed by subjecting the PCR products to sequencing. Significant difference was observed in the genotypic distribution and allelic frequency between the stroke patients and healthy controls. AA genotype and A allele associated significantly with stroke and hypertension [P = 0.009; OR = 1.59 (95% CI = 1.119-2.283) and P = 0.010; OR = 1.26 (95% CI = 1.056-1.502); P = 0.01; OR = 1.58 (95% CI = 1.11-2.272) and P = 0.010; OR = 1.25(95% CI = 1.054-1.504) respectively]. A stepwise logistic regression analysis confirmed these findings. To establish that this polymorphism is associated with stroke independent of hypertension; we compared stroke patients without hypertension with normotensive controls. Significant difference was observed in genotypic distribution and allelic frequency between the two groups (P = 0.001 and 0.002 respectively). Evaluating the association of this polymorphism with stroke subtypes we found significant associations with cardioembolic stroke (P < 0.001). In conclusion our study suggests that 1347A allele of CYP4F2 gene is an important risk factor for hypertension and ischemic stroke.

Association of C3435T multi drug resistance gene-1 polymorphism with aspirin resistance in ischemic stroke and its subtypes.

Aspirin is the most commonly used antiplatelet drug for treatment of a serious vascular event, most notably myocardial infarction and stroke. Significant fraction of aspirin treated patients is resistant to the antiplatelet effects of the drugs. Previous studies have suggested that a genetic basis for aspirin resistance exists. Therefore the present study was taken up to investigate the role of C3435T polymorphism (rs 1045642) of multiple drug resistance-1 (MDR-1) gene with aspirin resistance in stroke patients. Five hundred and sixty ischemic stroke patients and 560 age and sex matched healthy controls were involved in the study. Baseline clinical data were collected and follow-up telephone interviews were conducted with patients at 3, 6 and 12 months post event to determine stroke outcome. Blood samples were collected and genotypes determined. Significant difference was observed in the genotype distribution and allele frequency between patients and controls. The results were confirmed by a step wise multiple logistic regression analysis controlling all other confounding risk factors [adjusted Odds ratio=3.132 (95% CI; 2.043-4.800; p<0.001)]. There was a significant difference in genotype distribution between drug responders and non-responders. The risk of aspirin resistance was significantly high in patients with TT genotype in comparison to those with CC genotype [(TT vs. CC, χ(2)=6.268; p=0.012, Odds ratio=1.85) (95% CI; 1.142-3.017) (adjusted Odds ratio=2.465; 95% CI; 1.895-4.625 and p<0.001)]. As far as the stroke subtypes are concerned TT genotype associated significantly with aspirin resistance in intracranial large artery atherosclerosis. Our results indicate that the risk of aspirin resistance is more in patients with 3435TT genotype than in those with CC genotype. However, this is a preliminary study and a large study of replication is needed to confirm our results.

A single-nucleotide polymorphism in the TP53 and MDM-2 gene modifies breast cancer risk in an ethnic Arab population.

Breast cancer is the most common oncological disease in women worldwide. Genetic predisposition to breast cancer can be associated with single-nucleotide polymorphisms (SNPs), which are observed in many women. Such gene polymorphisms, in combination with nutritional and environmental factors, can affect breast cancer development. The tumor suppressor TP53 and its negative regulator MDM2 play crucial roles in carcinogenesis. Previous case-control studies have revealed that TP53 72Arg > Pro and MDM2 309T > G polymorphisms contribute to the risk of common cancers. However, the relationship between these two functional polymorphisms and breast cancer susceptibility in the Saudi population has not been explored. In this study, we performed a case-control study of patients with breast cancer and healthy controls in a Saudi population using TaqMan-based real-time PCR. We found an increased breast cancer risk associated with the MDM2 GG [odds ratio (OR) = 2.79, 95% confidence interval (CI) = 2.04-3.92] and TG [OR = 1.43, 95% CI = 1.12-2.02] genotypes. An increased risk was also associated with the TP53 Pro/Pro genotype (OR = 2.19, 95% CI = 1.54-3.06) compared with the Arg/Arg genotype. The gene-gene interaction of MDM2 and TP53 polymorphisms increased breast cancer risk in a multiplicative manner (OR for the presence of both MDM2 GG and TP53 Pro/Pro genotypes = 7.71, 95% CI = 3.49-17.54). These findings suggest that polymorphisms of MDM2 and TP53 genes may be a genetic modifier for developing breast cancer in this ethnic population in the Arab world.