Pharmacogenetic Study of Drugs Affecting Mycobacterium tuberculosis.

BACKGROUND: Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing challenge is the variable occurrence of adverse drug reactions in some TB patients. Previous studies have indicated that genetic variations in the N-acetyltransferase 2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) genes can impact the blood concentrations of the first-line anti-TB drugs isoniazid (INH) and rifampicin (RIF), respectively. This study aimed to investigate the influence of pharmacogenetic markers in the NAT2 and SLCO1B1 genes on TB treatment outcomes using whole-exome sequencing (WES) analysis. METHODS: DNA samples were collected from 30 healthy Iranian adults aged 18-40 years. The allelic frequencies of single-nucleotide polymorphisms (SNPs) in the NAT2 and SLCO1B1 genes were determined through WES. RESULTS: Seven frequent SNPs were identified in the NAT2 gene (rs1041983, rs1801280, rs1799929, rs1799930, rs1208, rs1799931, rs2552), along with 16 frequent SNPs in the SLCO1B1 gene (rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs2291075, rs201722521, rs11045852, rs11045854, rs756393362, rs11045859, rs74064211, rs201556175, rs34671512, rs71581985, rs4149085). CONCLUSION: Genetic variations in NAT2 and SLCO1B1 can affect the metabolism of INH and RIF, respectively. A better understanding of the pharmacogenetic profile in the study population may facilitate the design of more personalized and effective TB treatment strategies. Further research is needed to directly correlate these genetic markers with clinical outcomes in TB patients.

Clinical characteristics of breast cancer patients admitted to academic surgical wards in Tehran, Iran: an analytical cross-sectional study.

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women. Knowledge of the clinical characteristics of BC in a population may be informative for disease prediction or diagnosis and for developing screening and diagnostic guidelines. This study aimed to evaluate the clinical characteristics of female patients with BC who were admitted to academic surgical wards in Tehran, Iran. METHODS: In this cross-sectional study, demographic information and clinical characteristics of Iranian females with BC who had undergone breast surgery from 2017-2021 in four academic Breast Surgery Units were extracted from medical files and recorded via a pre-designed checklist. RESULTS: A total of 1476 patients with a mean age of 48.03 (± 11.46) years were enrolled. Among them, 10.4% were aged less than 35. In younger patients, Triple-negative and Her2-enriched subtypes of BC were significantly higher compared to older ones. Overall, 85.7% of tumors were invasive ductal carcinoma, 43.3% were grade 2, 41.4% were located in the UOQ, and 65.2% had presented with mass palpation. The mean pathologic tumor size was 28.94 mm, and the most common subtype was luminal B. CONCLUSIONS: Many characteristics of breast cancer in this study were similar to other countries and previous studies in Iran. However, a higher proportion of young BC compared with Western countries, and even with older studies in Iran, suggest a trend toward lower age for BC in recent years. These results indicate the need for preventive measures and screening in Iranian women at a younger age.

Novel EPG5 Mutation Associated with Vici Syndrome Gene.

Introduction: Vici syndrome (also known as immunodeficiency with cleft lip/palate, cataract, and hypopigmentation and absent corpus callosum) is considered as a progressive neurodevelopmental multisystem disorder. Till date, only 80 cases, including our patient, with this syndrome have been reported .This syndrome is characterized by agenesis of the corpus callosum, hypopigmentation of the eyes and hair, cataract, cardiomyopathy, combined immunodeficiency, hearing loss, seizures, and additional multisystem involvements which have been reported as case reports in the past. Clinical Manifestation. A 5-year-old girl, who is a product of consanguineous marriage, was referred to our center with developmental delay, optic atrophy, blindness, spasticity, seizure, movement disability, and spasticity. Her magnetic resonance imaging (MRI) test showed agenesis of the corpus callosum and her metabolic test reported normal. Materials and Methods: In our laboratory, blood sample was obtained from the patient. DNA was extracted from lymphocytes, and whole exome sequencing (WES) using next generation Illumina sequencing was performed. Result: A novel (private), homozygous, nonsynonymous mutation c.A3206G (p.Y1069C Het) in EPG5 gene was detected; in continuum, testing for this specific variant in her parents was carried out. DNA sequencing of the PCR-amplified product of the EPG5 exon 17 showed that her parents were heterozygote for this variant. These mutations have not been reported before and therefore classified as variation of unknown significance (VUS). Mutation in this gene is shown to cause autosomal recessive Vici syndrome. Conclusion: Since clinical features of Vici syndrome has overlap, its diagnosis is differential and developmental delay occurs in 98% of reported cases. Vici syndrome can be considered as one of the main causes of developmental delay, and this syndrome can be introduced as a novel group of inherited neurometabolic conditions and congenital disorders.

Multi-stage analysis of FOXM1, PYROXD1, hTERT, PPARA, PIM3, BMI1 and MCTP1 expression patterns in colorectal cancer.

Aim: To explore biomarkers with a tumor stage-dependent expression pattern in patients with colorectal cancer (CRC). Background: The fourth most common cancer in the world is colorectal cancer (CRC). A variation in the gene expression rate is a common change in cancers initiation and the accumulation of these variation changes the behavior of normal cells and turns them into cancer cells. Methods: Real-time RT-PCR was used to investigate the expression patterns of the FOXM1, PYROXD1, hTERT, BMI, PPARA, PIM3 and MCTP1 genes in 54 patients with stage I to IV CRC and their relation with clinicopathological features of CRC were analyzed. Results: FOXM1, hTERT and MCTP1 genes are overexpressed in CRC tumor tissues when compared to normal adjacent tissues in all the stages. Results: FOXM1, PYROXD1, hTERT, PIM3, BMI1, PPARA and MCTP1 had-stage dependent expression. Investigation of the association between clinicopathological features and expression pattern of the studied genes revealed; a) a significant relationship between FOXM1 gene expression level and tumor stage, tumor size and lymph node involvement, b) a considerable association between alterations in PPARA and PIM3 expression and lymph node involvement, c) a notable correlation between hTERT expression level and the tumor stage and d) a strong correlation between MCTP1 expression and patient's age only. Conclusion: Our study indicates that expression profiles of these genes either individually or together can be applied as potential biomarkers for prognosis of CRC.

Investigation of promoter methylation patterns association with genes expression profile of ISL1, MGMT and DMNT3b in tissue of breast cancer patients.

BACKGROUND AND OBJECTIVES: Cancer initiation and progression could influenced by both genetic and epigenetic events revealing of the overlap between epigenetic and genetic alteration can give important insights into cancer biology. METHODS AND RESULTS: In this experiment ISL1, MGMT, DMNT3b genes were candidate to investigate both methylation status and expression profile by using methylation-specific PCR and real time PCR in 40 breast cancer patients, respectively, also we have assessed relation of the promoter methylation status and expression variation of the target genes. The mean level of methylation of ISL1 and MGMT in tumor tissues were significantly greater than normal tissues. In Contrast, DMNT3b gene was showed lower mean level of methylation in tumor tissue compared to normal tissues, however, this was not statistically significant. Relative expression analysis was displayed a significant reduction in expression level of ISL1 and MGMT in tumor tissues. Furthermore, there was a meaningful association between down expression of ISL1 with histological grade, Her2 and ER status. Moreover, MGMT down expression was significantly associated with tumor sizes. Any remarkable relation was not observed between DMNT3b expression level and clinic pathological features. At the end, significant relation between methylation status and expression level has been revealed. CONCLUSIONS: In this study all observed results were exactly in line with the results were obtained from articles which were based on the methylation research and illustrate that the real-time PCR and methylation methods are in correlated with each other, furthermore, selected genes are capable to use as a potential biomarkers, however, more research on extended cases are needed.

Characterization of pathways involved in colorectal cancer using real-time RT-PCR gene expression data.

AIM: Efforts to explore biomarkers and biological pathways involved in the disease are needed to improve colorectal cancer (CRC) diagnosis and alternative treatments. BACKGROUND: The fourth common malignancy in the world is colorectal cancer. The over-all burden is predicted to rise by 2030. METHODS: In the current study, nine genes were selected. Previously, a panel of genes by Agendia, a classifier of robust gene expression (ColoPrint), was determined to significantly improve the prognostic accuracy of pathologic factors in stage II and III colorectal cancer patients. Five genes, including Ppara, Mctp1, Pyroxd1, Il2r, and Cyfip2, from this panel and four other genes which were not in this panel but were cited abundantly in the literature were selected. Then, expression levels of the selected genes in CRC tissue were compared with levels in adjacent normal tissue. To identify the pathways involved in CRC, gene set enrichment analysis was subsequently performed. Furthermore, to illustrate the relationship between genes in this disease, the cross-shaped co-expression pattern and gene regulatory network were determined using computational methods. RESULTS: This research found that the pairs of genes: {IL2R, CYFIP2}, {FOXM1, PPARA}, {MCTP1, CTSC}, and {PYROXD1, CYF1P2} are functionally related. Furthermore, two differentially expressed gene pairs ({FOXM1, PPARA} and {IL2R, CYFIP2}) are involved in the vascular endothelial growth factor receptor signaling pathway and the purine ribonucleoside diphosphate metabolic process, respectively. CONCLUSION: This research found that the combination of computational analysis and laboratory data provided the opportunity to better characterize the relation between central colorectal cancer genes as well as possible pathways involved in the colorectal cancer.

Pivotal cytokines and their transcription factors are the targets of guluronic acid (G2013) for inhibiting the immunopathogenesis process of multiple sclerosis.

The α-L-guluronic acid (G2013), is a novel immunosuppressive drug (PCT/EP2017/067920). One of the most popular ideas in designing drugs for multiple sclerosis (MS) is to restrict the main inflammation-related lymphocytes and cytokines. The foremost problems with conventional drugs are their side effects and low efficacy. In order to rectify these problems, we examined the effect of two doses of G2013 on the gene expression of IFN-γ, IL-17, IL-22, T-bet, RORC, and AHR, in MS patients PBMCs. RNA was extracted from peripheral blood mononuclear cell (PBMC) of 12 relapsing-remitting MS patients and 12 healthy volunteers and the effect of two doses of G2013 on the gene expression of IFN-γ, IL-17, IL-22, T-bet, RORC, and AHR, were assessed by real-time PCR. Overall, the results show that G2013 is able to significantly reduce the gene expression of IL-22, AHR, RORC, and T-bet. Collectively, G2013 might be considered and studied as a new drug of possible use to MS patients due to its immunosuppressive property on some of the main inflammatory cytokine and transcription factors.

A siRNA-based method for efficient silencing of PYROXD1 gene expression in the colon cancer cell line HCT116.

PURPOSE: The aim of this study was to determine the biological function of pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1), a recently discovered protein, in colon cancer cell line HCT116. METHODS: The small interfering RNA (siRNA) was designed rationally on the basis of the target sequence against PYROXD1. Relative PYROXD1 mRNA levels were measured by a quantitative real-time polymerase chain reaction. Flow cytometry was performed to monitor tumor cells proliferation and apoptosis after siRNA transfection. RESULTS: Knockdown of PYROXD1 arrested the cell cycle, and induced late apoptosis in colon cancer cell line HCT116 DISCUSSION: Taken together, these results revealed the critical roles of PYROXD1 in regulating cell cycle and apoptosis and possibly will signify its therapeutic potential for targeting colorectal cancer models.

Prognostic Value of FBXO39 and ETS-1 but not BMI-1 in Iranian Colorectal Cancer Patients

Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Despite recent progress in diagnosis and treatment, it remains a major health problem and further studies are needed. We here investigated expression profiles of the FBXO39, ETS-1 and BMI-1 genes in CRCs to validate any possible diagnostic/prognostic significance. Material and Methods: Thirty six patients with locally advanced CRC admitted to Hazrate-Rasoul Hospital-Tehran were enrolled. Initially the expression pattern of FBXO39, ETS-1 and BMI-1 genes were determined using RT-PCR in CRC tumor and adjacent normal tissues then real-time RT-PCR was employed to quantify BMI-1 gene expression. Results: FBXO39 expression was restricted to tumor tissues. Interestingly, expression of this gene was detected in all stage-0 tumor samples. There was a significant relation between FBXO39 gene expression and lymph node involvement. The ETS-1 gene was expressed in 66% of all tumor tissues with p-value=0.03 for increase as compared to the adjacent normal samples. In addition, there was a significant relation between ETS-1 gene expression and tumor size and lymph node involvement. RT-PCR demonstrated BMI-1 gene expression in both tumor and normal tissues and quantification by real-time RT-PCR showed no association between BMI-1 levels and CRC clinicopathological features. Conclusion: Expression of FBXO39 and ETS-1 with lymph node involvement may be considered as an alarm for the occurrence of CRC metastasis, and therfore have prognostic value while BMI-1 appears without importance.

AKAP4, SPAG9 and NY-ESO-1 in Iranian Colorectal Cancer Patients as Probable Diagnostic and Prognostic Biomarkers

Background and objectives: Colorectal cancer (CRC) is the most common gastrointestinal cancer and the second leading cause of cancer death in women in the world. Cancer-Testis Antigens (CTAs) are a group of tumor-associated proteins which typically are expressed in normal reproductive cells of men, but their expression in normal somatic cells is silenced. CTAs, due to their limited expression pattern, are considered as promising targets for cancer diagnosis and immuno-therapy. Methods: Expression of AKAP4, SPAG9 and CTAG1B genes from the CTAs family was studied in both tumor and normal tissues of 62 Iranian CRC patients by RT-PCR with the aim of finding biomarkers for early detection and anticipated progression. Statistical analysis was performed SPSS software V22.0 to assess the significance of any associations. Results: Elevated expression of SPAG9 and AKAP4 genes was observed in approximately 66% and 44% of tumours, respectively, as compared to adjacent non-cancerous tissues. While a significant association was found between AKAP4 gene expression and metastasis (P-value: 0.045), expression of the CTAG1B (NY-ESO-1) gene was not observed in our cases. Conclusion: AKAP4 and SPAG9 genes may find use as diagnostic biomarkers for CRC and AKAP4 may play an important role in progression to metastasis.