Publications by authors named "Javad Tavakkoly Bazzaz"

89 Publications

Bi-functionalized aminoguanidine-PEGylated periodic mesoporous organosilica nanoparticles: a promising nanocarrier for delivery of Cas9-sgRNA ribonucleoproteine.

J Nanobiotechnology 2021 Mar 31;19(1):95. Epub 2021 Mar 31.

Department of Systems and Synthetic Biology, Agricultural Biotechnology Research Institute of Iran (ABRII), Agricultural Research Education and Extension Organization (AREEO), Karaj, Iran.

Background: There is a great interest in the efficient intracellular delivery of Cas9-sgRNA ribonucleoprotein complex (RNP) and its possible applications for in vivo CRISPR-based gene editing. In this study, a nanoporous mediated gene-editing approach has been successfully performed using a bi-functionalized aminoguanidine-PEGylated periodic mesoporous organosilica (PMO) nanoparticles (RNP@AGu@PEG-PMO) as a potent and biocompatible nanocarrier for RNP delivery.

Results: The bi-functionalized MSN-based nanomaterials have been fully characterized using electron microscopy (TEM and SEM), nitrogen adsorption measurements, thermogravimetric analysis (TGA), X-ray powder diffraction (XRD), Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy (ATR-FTIR), and dynamic light scattering (DLS). The results confirm that AGu@PEG-PMO can be applied for gene-editing with an efficiency of about 40% as measured by GFP gene knockdown of HT1080-GFP cells with no notable change in the morphology of the cells.

Conclusions: Due to the high stability and biocompatibility, simple synthesis, and cost-effectiveness, the developed bi-functionalized PMO-based nano-network introduces a tailored nanocarrier that has remarkable potential as a promising trajectory for biomedical and RNP delivery applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12951-021-00838-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011395PMC
March 2021

A methylation signature at the CpG island promoter of estrogen receptor beta (ER-β) in breasts of women may be an early footmark of lack of breastfeeding and nulliparity.

Pathol Res Pract 2021 Feb 28;218:153328. Epub 2020 Dec 28.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Although little is known regarding the mechanisms behind the onset of breast cancer (BC) through reproductive risk factors, new researches have highlighted some early tumor-related methylation footmarks in the breast tissue of apparently clinically healthy women as their potential epigenetic mechanism. Previous evidence supports that the estrogen receptor beta (ER-β), whose anti-cancer roles had already been revealed in BC, is downregulated in the breasts of healthy nulliparous women. Nevertheless, data on such a link about its methylation alterations have not been reported. The goal of current study was to determine possible methylation alterations at CpG island promoter of the ER-β gene, including promoter 0 N and exon 0 N, in relation to aspects of reproductive history in the healthy breasts. The DNA was extracted from the breasts of 120 subjects undergoing cosmetic mammoplasty. Thereafter, the methylation levels of targeted regions in ER-β gene were determined by using MeDIP-qPCR assay. The results revealed that ER-β exon 0 N had no methylation in 84.2 % of the women, whereas the rest, comprising 2.5 % and 13.3 % of the samples, showed a lower and higher of its methylation, respectively. Interestingly, nulliparous women were found to have an elevated methylation level of the ER-β exon 0 N than parous women (P = 0.036). Moreover, we observed a high methylation of the ER-β exon 0 N in the breasts of non-breastfeeding women compared to breastfeeding subgroup (P = 0.048). Likewise, the non-breastfeeding subgroup showed exon 0N high methylation in comparison to women with breastfeeding >24 months (P = 0.023). Finally, although we found that 6.67 % of the samples had a high methylation level at the promoter 0N, no any relationship was found between its methylation and reproductive history. These results may provide key clues to revealing the epigenetic mechanism through which the nulliparity and lack of breastfeeding influencing the risk factor of BC as well as introducing the potential new early prediction and prevention strategies. Although further investigations need to be done in order to gain a better understanding the roles of these epigenetic signatures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2020.153328DOI Listing
February 2021

Evaluation of the potential role of long non-coding RNA LINC00961 in luminal breast cancer: a case-control and systems biology study.

Cancer Cell Int 2020 2;20:478. Epub 2020 Oct 2.

Medical Genetic Ward, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.

Background: Luminal subtype is the most common subgroup of breast cancer (BC), accounting for more than 70% of this cancer. Long non-coding RNAs (lncRNAs) are a group of RNAs which play critical roles in diverse cellular processes. It is proved that dysregulation of them can contribute to the development of various cancers, including BC. LINC00961 was reported to be downregulated in several cancers, however, its expression level in BC remains largely unknown. The purpose of the present study was to investigate the possible role of LINC00961 in luminal A and B subtypes of BC.

Methods: To obtain novel lncRNAs associated with different cancers and differentially expressed lncRNAs (DElncRNAs) between BC tumor and normal tissues, Lnc2Cancer and GDC databases were used, respectively. After performing literature review, the expression level of the selected lncRNA (LINC00961) was evaluated in 79 luminal A and B BC specimens and adjacent non-cancerous tissues by Quantitative Reverse Transcription PCR (qRT-PCR). LINC00961 expression was also evaluated in two luminal A BC cell lines, compared to a normal breast cell line. The comparison of the differences between tumor and adjacent non-tumor samples was performed by paired sample t-test. Moreover, correlation analysis between LINC00961 expression and clinicopathological features was performed using the chi-square, fisher exact, and independent t-test. In order to investigate the possible roles of LINC00961 in luminal A and B BC, different bioinformatics analyses such as functional annotation of the LINC00961 co-expressed genes and protein-protein interaction (PPI) networks construction were also performed.

Results: LINC00961 was selected as a significant DElncRNA which had not been studied in BC. According to q-RT PCR assay, LINC00961 was downregulated in luminal BC tissues and cell lines. Its expression was correlated with smoking status and the age of menarche in luminal BC patients. Also, the results of the bioinformatics analysis were consistent with the data obtained from q-RT PCR assay. The final results indicated that LINC00961 might be involved in multiple cancer-associated pathways such as chemokine, Ras and PI3K-Akt signaling pathways, GPCR ligand binding, and signal transduction in luminal subtypes of BC. CDH5, GNG11, GNG8, SELL, S1PR1, CCL19, FYN, ACAN, CD3E, ACVRL1, CAV1, and PPARGC1A were identified as the top hub genes of the PPI networks across luminal subgroup.

Conclusion: Our findings suggested that LINC00961 was significantly downregulated in luminal A and B subtypes of BC. Moreover, bioinformatics analysis provided a basis for better identification of the potential role of LINC00961 in luminal subtype of BC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12935-020-01569-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531117PMC
October 2020

Dysregulated Expression of miR-146a and Its Associated Immune Effectors in Peripheral Blood Mononuclear Cells of Esophageal Carcinoma Patients.

Immunol Invest 2020 Oct 2:1-11. Epub 2020 Oct 2.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences , Tabriz, Iran.

Esophageal cancer is one of the least studied aggressive tumors, with the squamous cell carcinoma (ESCC) being the most frequent histological type around the world. Growing evidence has shown that the abnormal expression of microRNAs (miRNAs) in peripheral blood mononuclear cells (PBMCs) is closely related to the pathogenesis of cancers. MiR-146a is a crucial regulator of inflammatory cascades. There is currently no data available regarding the possible role of miR-146a in PBMCs of ESCC patients. We evaluated the expression of miR-146a, as well as its target genes (IRAK1 and TRAF6) and its associated immune effectors (NF-κB1, IL1B, and IL6) in PBMCs of 40 ESCC patients and 50 control subjects. The geometric mean expression of five transcripts was used for normalizing expressions. The PBMC level of miR-146a, as measured by RT-qPCR, was upregulated, whereas levels of its target genes, IRAK1 and TRAF6, were downregulated in ESCC patients. NF-κB1 and IL6 was downregulated in PBMCs of ESCC patients. There was no difference in terms of the IL1B level between patients and the control group. Logistic regression and receiver operating characteristic curve analysis suggested that a model with PBMC levels of either NF-κB1+ IL6 or NF-κB1+ miR-146a as predictors may discriminate ESCC patients from subjects of the control group. Our findings, in the context of the current literature, may suggest a possible downregulatory mechanism of immune responses in PBMCs of ESCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08820139.2020.1828454DOI Listing
October 2020

Identification of dysregulated miRNAs-genes network in ovarian cancer: An integrative approach to uncover the molecular interactions and oncomechanisms.

Cancer Rep (Hoboken) 2020 Dec 4;3(6):e1286. Epub 2020 Sep 4.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Ovarian (OV) cancer is considered as one of the most deadly malignancies in women, since it is unfortunately diagnosed in advanced stages. Nowadays, the importance of bioinformatics tools and their frequent usage in tracking dysregulated cancer-related genes and pathways have been highlighted in researches.

Aim: The aim of this study is to investigate dysregulated miRNAs-genes network and its function in OV tumors based on the integration of microarray data through a system biology approach.

Methods: Two microarray data (GSE119056 and GSE4122) were analyzed to explore the differentially expressed miRNAs (DEmiRs) and genes among OV tumors and normal tissues. Then, through the help of TargetScan, miRmap, and miRTarBase databases, the dysregulated miRNA-gene network in OV tumors was constructed by Cytoscape. In the next step, co-expression and protein-protein interaction networks were made using GEPIA and STRING databases. Moreover, the functional analysis of the hub genes was done by DAVID, KEGG, and Enrichr databases. Eventually, the regulatory network of TF-miRNA-gene was constructed.

Results: The potential dysregulated miRNAs-genes network in OV tumors has been constructed, including 109 differentially expressed genes (DEGs), 25 DEmiRs, and 213 interactions. Two down-regulated microRNAs, miR-660-3p and hsa-miR-4510, have the most interactions with up-expressed oncogenic DEGs. CDK1, PLK1, CCNB1, CCNA2, and EZH2 are involved in protein module, which show significant overexpression in OV tumors according to The Cancer Genome Atlas (TCGA) data. EZH2 shows amplification in OV tumors with remarkable percentage. The transcription factors TFAP2C and GATA4 have the pivotal regulatory functions in oncotranscriptomic profile of OV tumors.

Conclusion: In current study, we have collected and integrated different data to uncover the complex molecular interactions and oncomechanisms in OV tumors. The DEmiRs-DEGs and TF-miRNA-gene networks reveal the potential interactions that could be a significant piece of the OV onco-puzzle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cnr2.1286DOI Listing
December 2020

Expression and clinicopathological significance of AOC4P, PRNCR1, and PCAT1 lncRNAs in breast cancer.

Pathol Res Pract 2020 Oct 21;216(10):153131. Epub 2020 Jul 21.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Long none coding RNAs (lncRNAs) AOC4P, PRNCR1, and PCAT-1 are dysregulated in various types of malignancies. However, their expression and clinicopathological significances are uncertain in breast cancer (BC). Quantitative real-time polymerase chain reaction (RT- qPCR) was used to measure the expression levels of the selected lncRNAs in tumor tissues obtained from 50 BC patients compared to the normal adjacent tissues (NATs) and 50 clinically healthy normal tissues. Our results revealed a significant downregulation of AOC4P, however, upregulated PRNCR1 and PCAT1 were found in tumor tissues compared to NATs and clinically healthy normal tissues (P < 0.05). Interestingly, remarkable decreased expression of AOC4P was observed in NATs than clinically healthy normal tissues. Dysregulation of the lncRNAs was correlated with worse outcomes of patients. Furthermore, our data showed that the altered expression levels of lncRNAs AOC4P, PRNCR1, and PCAT1 might be occurred through the function of demographic and reproductive variables. Taken together, the altered regulation of AOC4P, PRNCR1, and PCAT1 may highlight their crucial roles in BC development and pathogenesis. Our findings also proposed demographic and reproductive variables as risk factors in BC through the possible influence on the expression of the studied lncRNAs. Nevertheless, further explorations are required to elucidate the more detailed functions of these lncRNAs in BC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2020.153131DOI Listing
October 2020

Utilization of Whole Exome Sequencing in Lethal Form of Multiple Pterygium Syndrome: Identification of Mutations in Embryonal Subunit of Acetylcholine Receptor.

Int J Mol Cell Med 2019 ;8(4):258-269

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

The acetylcholine receptor (AChR) is a member of the superfamily of transmitter-gated ion channels having a critical role in controlling electrical signals between nerves and muscle cells. Disruptive mutations in genes encoding different subunits of AChR result in multiple pterygium syndrome (MPS), which can be associated with a severe prenatally lethal presentation. This study aimed to investigate the etiology of lethal MPS (LMPS) in two consanguineous families with a history of miscarriages. DNA was extracted from a tissue sample of two aborted fetuses (probands) from two different families with a history of spontaneous miscarriages. Parental peripheral blood samples were collected for confirmatory analysis and follow-up testing. Whole-exome sequencing (WES) was performed on DNA from the probands. The results were confirmed and segregated by Sanger sequencing. Moreover, protein structure evaluations were accomplished. We identified a homozygous frameshift mutation of c.753_754delCT (p.V253fs*44) and a homozygous missense mutation of c.715C>T (p.Arg239Cys) in the gene. Both aborted fetuses had pterygium, severe arthrogryposis, and fetal hydrops with cystic hygroma, being compatible with LMPS. The heterozygous state was confirmed in parents for both variants. Likewise, mutation was predicted to display the damaging effects by lowering the number of helixes and modifying the surface electrostatic potential. The present study identified rare sequence variants in the gene in aborted fetuses from consanguineous couples with recurrent miscarriage history. WES is a comprehensive and cost-effective approach to study heterogeneous diseases including MPS. Such findings can improve our knowledge of MPS databases, particularly for genetic counseling of high-risk families and preimplantation genetic diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22088/IJMCM.BUMS.8.4.258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305466PMC
January 2019

Expression Analysis of and in Head and Neck Squamous Cell Carcinoma.

Cancer Manag Res 2020 2;12:4085-4096. Epub 2020 Jun 2.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Head and neck squamous cell carcinoma (HNSCC) includes a group of heterogeneous tumors with generally invasive behavior. The PI3K/AKT pathway plays an important role in the pathogenesis of HNSCC.

Methods: In the current study, we investigated the expression of two negative feedback regulators of the PI3K pathway, namely and , in 45 paired samples of HNSCC and adjacent non-cancerous tissues (ANCTs).

Results: While expression of was down-regulated in tumoral tissues compared with ANCTs by the factor 4.21, expression levels were up-regulated by 5.99-times. Gender-based analysis revealed a significant down-regulation of gene expression level in male patients compared with the control samples and significant up-regulation of gene expression level in both sexes compared with the control samples. Differences in the expressions of both genes were significant in patients aged more than 60 years, but not in the younger patients. Expression of was only down-regulated in patients with positive smoking history. Expression of was decreased in grades 2 and 3 samples compared with controls. There was a significant increase in transcript levels of in stages II and III HNSCC samples compared with the controls group. ROC curve analysis indicated that the expression level of could be a promising marker for the diagnosis of HNSCC patients with a sensitivity and specificity of 0.666 and 0.688, respectively. In addition, sensitivity and specificity of were 0.755 and 0.577, respectively.

Discussion: The current study indicates dysregulation of regulators of PI3K pathway in HNSCC and their potential application as putative biomarkers for this cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CMAR.S252962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276198PMC
June 2020

The effect of cryopreservation on DNA methylation patterns of the chromosome 15q11-q13 region in human spermatozoa.

Cell Tissue Bank 2020 Sep 6;21(3):433-445. Epub 2020 Apr 6.

Faculty of Anatomy, School of Medicine, Tehran University of Medical Science, 16 Azar Avenue, Poor Sina Street, Tehran, Iran.

Human sperm cryopreservation is a common technique which is used in assisted reproductive technologies. Despite the existence of evidence supporting the production of ROS and DNA fragmentation during sperm cryopreservation, there is little and equivocal information about the cryopreservation effects on methylation of imprinted genes and imprinting control regions. In this study, we have investigated the effects of cryopreservation on DNA methylation in promoter regions of SNURF-SNRPN and UBE3A imprinted genes, PWS-ICR and AS-ICR in the chromosome 15q11-q13 region. Semen samples from 10 healthy normozoospermic men were collected and each sample was divided into four equal aliquots: fresh, cryoprotectant, cryopreservation, and HO. We measured the ROS levels and DNA fragmentation using DCFH-DA and TUNEL assay respectively by flow cytometry. DNA methylation in promoter regions of SNURF-SNRPN and UBE3A imprinted genes, PWS-ICR and AS-ICR in the chromosome 15q11-q13 region were evaluated by quantitative methylation-specific PCR technique. Intracellular levels of ROS and percentage of TUNEL-positive spermatozoa significantly increased in cryopreservation group compared to fresh group. Exposure to cryoprotectant had no significant effect on ROS levels and DNA fragmentation. Neither cryopreservation nor exposure to cryoprotectant significantly affected DNA methylation of the selected gene regions. However, DNA fragmentation had positive correlation with DNA methylation of AS-ICR. In conclusion, based on our study, clinical use of sperm cryopreservation for fertility treatments appear to be safe in regard to DNA methylation in the chromosome 15q11-q13 region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10561-020-09828-1DOI Listing
September 2020

Anti-tumor activity of neratinib, a pan-HER inhibitor, in gastric adenocarcinoma cells.

Eur J Pharmacol 2019 Nov 28;863:172705. Epub 2019 Sep 28.

Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Gastric adenocarcinoma (GAC), the most common malignancy of the stomach, is the fourth most common and the second cause of cancer-related death worldwide. Although HER family plays a cardinal role in tumorigenesis of GAC, trastuzumab is the only approved anti-HER drug for this malignancy and development of resistance to trastuzumab is inevitable. Additionally, single-targeted HER inhibitors have demonstrated limited activity in GAC. Hence, there is a pressing need to devise more efficacious anti-HER therapeutic strategies. Here, we examined the anti-tumor activity of neratinb, a pan-HER inhibitor, on GAC cells. Anti-proliferative effects of neratinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and anoikis resistance and wound healing assays were carried out to examine the effects of neratinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) analyses were applied to further investigate the anti-tumor activity of neratinib. We found that neratinib sensitized GAC cells to 5FU, carboplatin and oxaliplatin. Moreover, we found that neratinib was synergistic with trametinib (an approved MEK inhibitor) and foretinib (a c-MET inhibitor) and potentiated radio-sensitivity of GAC cells. Furthermore, we found that neratinib diminished GAC cell proliferation along with downregulation of FOXM1 and its targets. Additionally, neratinib induced apoptosis along with upregulation of pro-apoptotic and downregulation of anti-apoptotic genes. Treatment with neratinib attenuated invasive ability of GAC cells as shown by reduced anoikis resistance, downregulation of EMT markers, and reduced width in scratch assay. Our findings indicate that neratinib provides the therapeutic potential in the treatment of GAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2019.172705DOI Listing
November 2019

Anti-tumor activity of cediranib, a pan-vascular endothelial growth factor receptor inhibitor, in pancreatic ductal adenocarcinoma cells.

Cell Oncol (Dordr) 2020 Feb 6;43(1):81-93. Epub 2019 Sep 6.

Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal subtype of pancreatic cancer, with a 5-year survival rate of < 3%. Early tumor dissemination, late diagnosis and insensitivity to conventional treatment are the major reasons for its high mortality rate. Members of the vascular endothelial growth factor (VEGF) family are overexpressed in PDAC and play important roles in its malignant progression, suggesting that VEGF-targeted therapies may interrupt the proliferation and motility of PDAC cells. Here, we evaluated the anti-tumor activity of cediranib, a pan-VEGF receptor inhibitor, on PDAC cells.

Methods: Anti-proliferative effects of cediranib were determined using cell proliferation and crystal violet staining assays. Annexin V/PI staining, radiation therapy, and cell migration and invasion assays were carried out to examine the effects of cediranib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of cediranib.

Results: We found that cediranib decreased PDAC cell proliferation and clonogenic survival and induced apoptotic cell death through inhibition of the anti-apoptotic proteins cIAP1, XIAP, MCL-1 and survivin. Combination with cediranib synergistically increased the sensitivity of PDAC cells to chemotherapeutic agents such as gemcitabine and paclitaxel, and potentiated the effects of radiation therapy on PDAC cell growth inhibition and apoptosis induction. Furthermore, we found that treatment with cediranib impaired PDAC cell migration and invasion via expression reduction of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, N-cadherin and Snail.

Conclusions: Our data indicate that cediranib may exhibit anti-tumor activity in PDAC cells and provide a rationale for further investigation of the potential of VEGF receptor-targeted therapies for the treatment of PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13402-019-00473-9DOI Listing
February 2020

Integrative analyses of triple negative dysregulated transcripts compared with non-triple negative tumors and their functional and molecular interactions.

J Cell Physiol 2019 12 12;234(12):22386-22399. Epub 2019 May 12.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Triple-negative (TN) tumors are a subtype of breast cancer with aggressive behaviors and limited targeted therapies. Microarray studies were not concerned with interactions and functional relations of dysregulated transcripts. Here, we aimed to conduct integrative strategy to analyze gene and miRNA available microarray data as well as bioinformatic analyses to catch a more inclusive picture of pivotal dysregulated transcripts and their interactions in TN tumors. Several online datasets and offline bioinformatic tools were used to detect differentially expressed (DE) transcripts, both protein and nonprotein coding, in TN compared with non-TN tumors and their functional and molecular interactions. Sixteen upregulated and 58 downregulated genes with a log fold change higher or equal to | 2 | were identified, including nine transcription factors. Coexpression network revealed EN1 as a hub gene, moreover Kaplan-Meier plotter survival analysis indicated that it was an appropriate prognostic marker for TN patients with breast cancer. Functional annotation analysis of protein-protein interaction network showed FOXM1 as an upexpressed and ESR1 as a downexpressed hub genes are suitable targets as far as antitumor protein therapy is concerned in TN breast cancers. The consensus analysis of two microRNA datasets revealed seven DE miRNAs. The gene-transcriptional factor (TF)-miRNA network revealed mir-135b and mir-29b are the hub nodes and involved in feedback loops with GATA3. This study suggests that dysregulated TFs and miRNAs have pivotal roles in regulation of TN oncotranscriptomic profile and might become both biomarkers and therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.28804DOI Listing
December 2019

The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells.

Cell Oncol (Dordr) 2019 Aug 25;42(4):491-504. Epub 2019 Apr 25.

Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Purpose: Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells.

Methods: Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib.

Results: We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal.

Conclusions: Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13402-019-00448-wDOI Listing
August 2019

Methylation of progesterone receptor isoform A promoter in normal breast tissue: An epigenetic link between early age at menarche and risk of breast cancer?

J Cell Biochem 2019 08 28;120(8):12393-12401. Epub 2019 Feb 28.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Emerging evidence indicates that some altered patterns of methylation that occur in breast tumors may also be found in breast tissue of healthy women in relation to the breast cancer (BC) risk factors. Progesterone receptor (PR) isoform α is a crucial regulator of breast hormone responsiveness and its hypermethylation plays an important role in the initiation and development of breast tumors. However, such a methylation change in healthy women and its link with the different risk factors has not yet been investigated. In the present study, we aimed to examine the relationship of possible methylation changes within a critical region in the promoter CpG island of PGR-α (progesterone receptor α) gene in the healthy women with a set of reproductive and nonreproductive BC risk factors. The breast tissues were collected from 120 cancer-free women who had undergone cosmetic mammoplasty. The genomic DNA was extracted from the breast tissues and the methylation level of PGR-α promoter CpG island was determined by using MeDIP-qPCR assay. Using regression analysis, we found that increasing menarche age is inversely associated with the high methylation of PGR-α promoter ( β = -0.790, SE = 0.362; P = 0.031). Although lactating women had more methylation than nonlactating women (P = 0.026, the t test), this result was not confirmed by regression models. Such an observation may be helpful in better understanding of the underlying mechanisms by which early age at menarche increases the risk of BC. However, this perspective requires further validations in larger studies of more subjects as well as the inclusion of other related genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcb.28505DOI Listing
August 2019

Molecular investigation of mutations in androgen receptor and 5-alpha-reductase-2 genes in 46,XY Disorders of Sex Development with normal testicular development.

Andrologia 2019 Jun 27;51(5):e13250. Epub 2019 Feb 27.

Medical Genetics Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

In this study, we aimed to determine androgen receptor (AR) and SRD5A2 gene mutations in 45 patients characterised by 46,XY Disorders of Sex Differentiation (DSD) signs with normal testicular development referred to the Children's Medical Center from February 2015 to September 2017. Karyotype and sex hormone analyses were performed. Cytogenetic investigation showed that seven patients were 46,XX DSD, six patients were chromosomal DSD and 32 patients were 46,XY DSD. Eight exons of the AR gene and five exons of the SRD5A2 gene were amplified. Two cases were affected with androgen insensitivity syndrome (AIS) (missense mutation on exon 7, position c.3637 G>A: p.R841H and position c.3610 G>A: p.R832Q), one case was affected with 5-alpha-reductase deficiency type 2 (missense mutation at c.578A>G: p.N193S on exon 4), and 22 cases (88%) did not demonstrate AIS or 5α-RD2 gene abnormality. Due to the great impact of these disorders on human lifestyle, evaluation of genes involved can improve genetic counselling and therapeutic management. We focused on the AR and SRD5A2 genes in patients with 46,XY DSDs with normal testicular development referred to the Children's Medical Center from all over the country to eventually culminate in a reliable prenatal diagnosis protocol at this major referral centre giving service to a great number of families with consanguineous marriages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/and.13250DOI Listing
June 2019

An Association and Meta-Analysis of Esophageal Squamous Cell Carcinoma Risk Associated with PLCE1 rs2274223, C20orf54 rs13042395 and RUNX1 rs2014300 Polymorphisms.

Pathol Oncol Res 2020 Apr 21;26(2):681-692. Epub 2019 Jan 21.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

One of the highest risk of esophageal squamous cell carcinoma (ESCC) in the world has been reported in Iran, which is located in the Asian esophageal cancer belt. ESCC constitutes 90% of the esophageal cancer cases in Iran. Genome wide association studies (GWASs) in Chinese have identified a number of candidate variants, of which PLCE1rs2274223, C20orf54rs13042395 and RUNX1rs2014300 are studied in high risk populations including Chinese, Caucasians and Africans. However, results are inconsistent and it is unknown whether similar associations exist in Iranian population. We evaluated association of three GWAS identified variants with risk of ESCC in an Iranian cohort consisted of 200 ESCC patients and 300 healthy controls and conducted meta-analysis of ESCC risk associated with rs2274223 (involving 9810 cases and 13,128 controls) and rs13042395 (involving 2363 cases and 5329 controls). Logistic regression analysis showed that rs2274223 was associated with ESCC under codominant [GG/AA, 2.47(1.17-5.23), P:0.021], dominant [AG + GG/AA, 1.57(1.09-2.27), P:0.016], recessive [GG/AA+AG, 2.18(1.04-4.56), P:0.036] and log-additive models [1.51(1.12-2.02), P:0.006]. C20orf54 rs13042395 was not associated with ESCC under any genetic model. RUNX1 rs2014300 was associated with risk of ESCC assuming codominant [AG/GG, 0.63(0.41-0.97), P:0.018], dominant [AG + AA/GG, 0.59 (0.39-0.89), P:0.010] and log-additive models [0.61 (0.42-0.87), P: 0.005]. Meta-analysis found significant associations between rs2274223 and ESCC under all analyzed genetic models. However, meta-analysis stratified by ethnicity showed a significant association in Asians but not non-Asian populations. No significant association was found for rs13042395 in meta-analysis. This study provided first evidence for association of GWAS-identified variants with risk of ESCC in an Iranian cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12253-019-00579-3DOI Listing
April 2020

Breast cancer-linked lncRNA u-Eleanor is upregulated in breast of healthy women with lack or short duration of breastfeeding.

J Cell Biochem 2019 06 11;120(6):9869-9876. Epub 2018 Dec 11.

Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.

Recently, it has been revealed that estrogen-related reproductive factors are linked with some early gene expression lesions associated with malignancy in clinically healthy breasts. Accordingly, the aim of the current study was to evaluate the association of expression levels of estrogen-related long noncoding RNAs (lncRNAs) upstream Eleanor (u-Eleanor) and HOX antisense intergenic RNA (HOTAIR) with the different patterns of reproductive factors in breast tissue of healthy women. The subjects of this study were 98 cancer-free women who had undergone cosmetic mammoplasty. The expression levels of u-Eleanor and HOTAIR were measured using quantitative real-time polymerase chain reaction. The results of the current study showed that the women without a history of breastfeeding had a high-level expression of u-Eleanor compared with the women with a breastfeeding duration greater than 6 to 24 months (P = 0.03) as well as the women with a breastfeeding duration of more than 24 months (P = 0.005). Furthermore, a higher expression of u-Eleanor was found in the women with a short breastfeeding duration for 1 to 6 months than that in the women with a breastfeeding duration of greater than 24 months (P = 0.02). In the same way, the results of correlation test (r = -0.258; P = 0.036) and multivariate regression model (β = -0.321; P = 0.023) are indicative of a significant relationship of elevated expression of u-Eleanor with decreasing breastfeeding duration in the women. These findings could be important to identify the molecular mechanisms behind the relationship between a lack or short duration of the breastfeeding and the risk of breast cancer, which has previously been reported by epidemiological studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcb.28269DOI Listing
June 2019

Radioprotective effect of melatonin on expression of and genes in rat peripheral blood.

J Cancer Res Ther 2018 Dec;14(Supplement):S1070-S1075

Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Objective: Ionizing radiation is a critical threat to biomolecules, especially DNA. Various combinatorial compounds have been studied to protect this biomolecule. Melatonin has been reported as a direct and indirect free radical scavenger, but in this study, we explored the effect of melatonin on assisting in DNA repair by expression of Cdkn1a and Rad50; both of these genes are involved in DNA repair signaling, induced by radiation in rat peripheral blood.

Materials And Methods: Rats were irradiated with single whole-body linear accelerator X-ray radiation doses of 2 and 8 Gy with or without melatonin (100 mg/kg body weight) pretreatments. The rats were randomly divided into nine groups and given an intraperitoneal injection of melatonin or the same volume of vehicle alone 1 h before radiation. Blood samples were taken 8, 24, and 48 h postradiation to measure gene expression of Cdkn1a and Rad50 using quantitative reverse transcription polymerase chain reaction technique.

Results: Melatonin pretreatment increased the expression of Cdkn1a and Rad50 in 8 and 24 h postradiations (2 and 8 Gy) (P < 0.05), and there was no significant difference in 48 h postradiation compared to the radiation-only and vehicle plus radiation (2 and 8 Gy) groups.

Conclusions: Based on our results, pretreatment with melatonin (100 mg/kg) may ameliorates injurious effects of 2 and 8 Gy ionization radiation by increasing the expression level of Cdkn1a and Rad50 in rat peripheral blood and assist in DNA double-strand breaks repair, especially during the early postradiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0973-1482.196758DOI Listing
December 2018

Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer.

J Cell Physiol 2019 07 10;234(7):10080-10100. Epub 2018 Dec 10.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Breast cancer (BC) is the most frequently occurring malignancy in women worldwide. Despite the substantial advancement in understanding the molecular mechanisms and management of BC, it remains the leading cause of cancer death in women. One of the main reasons for this obstacle is that we have not been able to find the Achilles heel for the BC as a highly heterogeneous disease. Accumulating evidence has revealed that noncoding RNAs (ncRNAs), play key roles in the development of BC; however, the involving of complex regulatory interactions between the different varieties of ncRNAs in the development of this cancer has been poorly understood. In the recent years, the newly discovered mechanism in the RNA world is "competing endogenous RNA (ceRNA)" which proposes regulatory dialogues between different RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), transcribed pseudogenes, and circular RNAs (circRNAs). In the latest BC research, various studies have revealed that dysregulation of several ceRNA networks (ceRNETs) between these ncRNAs has fundamental roles in establishing the hallmarks of BC development. And it is thought that such a discovery could open a new window for a better understanding of the hidden aspects of breast tumors. Besides, it probably can provide new biomarkers and potential efficient therapeutic targets for BC. This review will discuss the existing body of knowledge regarding the key functions of ceRNETs and then highlights the emerging roles of some recently discovered ceRNETs in several hallmarks of BC. Moreover, we propose for the first time the "ceRnome" as a new term in the present article for RNA research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.27941DOI Listing
July 2019

TCF4 and GRM8 gene polymorphisms and risk of schizophrenia in an Iranian population: a case-control study.

Mol Biol Rep 2018 Dec 4;45(6):2403-2409. Epub 2018 Oct 4.

Department of Genomic Psychiatry and Behavioral Genomics (DGPBG), Roozbeh Hospital, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.

TCF4 and GRM8, two significant genes involved in the normal nervous development and glutamate pathway, are thought to be involved in the pathogenesis of schizophrenia (SCZ). We aimed to explore the association of TCF4 and GRM8 gene polymorphisms with risk of SCZ. The rs8766 in TCF4 and rs712723 in GRM8 were selected for genotyping in a set of Iranian case-control samples including 215 patients and 220 matched healthy controls using polymerase chain reaction-restriction fragment length polymorphism. Although rs8766 increased the OR, we found that rs8766 allele and genotype frequencies were not significantly different between case and control groups and a significant association cannot be suggested for the selected SNP. However, allele C and genotype CC (allele C: OR 1.48, 95% CI 1.13-1.94; genotype CC: OR 1.71, 95% CI 1.09-2.68) of rs712723 polymorphism was found to have a significant association with risk of SCZ. Frequency of allele C (P = 0.003) and genotype CC (P = 0.017) was higher in the schizophrenic patients, while allele T (P = 0.003) and genotype TT (P = 0.028) frequencies were found lower in patients. Our findings indicate that rs712723 in GRM8 may play an important role in the pathogenesis of SCZ. However, our conclusion needs to be confirmed in other population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11033-018-4406-2DOI Listing
December 2018

Molecular genetic study of glutaric aciduria, type I: Identification of a novel mutation.

J Cell Biochem 2019 03 11;120(3):3367-3372. Epub 2018 Sep 11.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Glutaric acidemia type I (GA-1) is an inborn error of metabolism due to deficiency of glutaryl-CoA dehydrogenase (GCDH), which catalyzes the conversion of glutaryl-CoA to crotonyl-CoA. GA-1 occurs in about 1 in 100 000 infants worldwide. The GCDH gene is on human chromosome 19p13.2, spans about 7 kb and comprises 11 exons and 10 introns. Tandem mass spectrometry (MS/MS) was used for clinical diagnosis in a proband from Iran with GA-1. Sanger sequencing was performed using primers specific for coding exons and exon-intron flanking regions of the GCDH gene in the proband. Cosegregation analysis and in silico assessment were performed to confirm the pathogenicity of the candidate variant. A novel homozygous missense variant c.1147C > A (p.Arg383Ser) in exon 11 of GCDH was identified. Examination of variant through in silico software tools determines its deleterious effect on protein in terms of function and stability. The variant cosegregates with the disease in family. In this study, the clinical and molecular aspects of GA-1 were investigated, which showed one novel mutation in the GCDH gene in an Iranian patient. The variant is categorized as pathogenic according to the the guideline of the American College of Medical Genetics and Genomics (ACMG) for variant interpretation. This mutation c.1147C > A (p.Arg383Ser) may also be prevalent among Iranian populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcb.27607DOI Listing
March 2019

Re: Genetic Polymorphism on Susceptibility to Nephrotoxic Properties of BTEXs Compounds.

J Occup Environ Med 2018 10;60(10):e560-e561

Research Center for Health Sciences, Institute of Health, Department of Occupational Health Engineering, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran Department of Occupational Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran Department of Occupational Health Engineering, School of Public Health, Institute for Environmental Research, Tehran University of Medical Sciences, Tehran, Iran Non-Communicable Diseases Research Center, Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran Department of Epidemiology and Biostatistics, School of Public Health, Knowledge Utilization Research Center (KURC), Tehran University of Medical Sciences Tehran, Iran.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001406DOI Listing
October 2018

Early Parity Epigenetic Footprint of FOXA1 Gene Body in Normal Breast Tissue of Iranian Women

Iran Biomed J 2019 03 28;23(2):99-106. Epub 2018 Jul 28.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Young age at first full-term pregnancy (FFTP) is an important factor in breast cancer risk reduction. It is postulated that this protective effect is the result of stable molecular signatures imprinted by physiological process of pregnancy, but the molecular mechanism of this protective role is unclear. The aim of the current study was to identify the effect of early FFTP on methylation status of FOXA1 gene body. FOXA1 is an essential transcription factor for mammary gland development and estrogen responsiveness of breast tissue.

Methods: Fresh frozen normal breast tissues (n = 51) were collected from Iranian women who underwent cosmetic mammoplasty (27 nulliparous women and 24 parous women who have experienced first pregnancy before the age of 25). DNA was extracted and then methylated DNA immunoprecipitation (MeDIP) real-time PCR was used to assess FOXA1 gene body methylation.

Results: Our results revealed that FOXA1 methylation level is significantly higher in early parous compared with nulliparous group (p = 0.041).

Conclusion: Our study provides new hint about the association between early FFTP and epigenetic modifications within gene body of FOXA1 in normal breast tissue. More investigation is required for clarifying molecular mechanisms underlying this association in order to develop breast cancer prevention strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707108PMC
March 2019

IL-6/IL-6R pathway is a therapeutic target in chemoresistant ovarian cancer.

Tumori 2019 Feb 19;105(1):84-91. Epub 2018 Jul 19.

1 Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Introduction:: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide and despite an initial response to therapeutic agents, the majority of patients have chemoresistant disease. There is no treatment strategy with proven efficacy against chemoresistant EOC and in this setting, overcoming therapy resistance is the key to successful treatment.

Methods:: This study aimed to investigate expression of interleukin-6 (IL-6) (IL-6) and IL-6 receptor (IL-6R) in a panel of the EOC cell lines. To achieve this, the expression of IL-6 and its receptor were compared in the EOC cells using quantitative reverse transcription polymerase chain reaction. MTT assay was performed to obtain chemosensitivity of the EOC cells.

Results:: In this report, we show that expressions of IL6 and IL6R are higher in therapy-resistant EOC cells compared to sensitive ones. Higher expression of IL6 and its receptor correlated with resistance to certain chemotherapeutic agents. Moreover, our findings showed that combination of tocilizumab (Actemra; Roche), an anti-IL-6R monoclonal antibody, with carboplatin synergistically inhibited growth and proliferation of the EOC cells and the most direct axis for IL-6 gene expression was NF-κB pathway.

Conclusion:: Collectively, our findings suggest that blockade of the IL-6 signaling pathway with anti-IL-6 receptor antibody tocilizumab might resensitize the chemoresistant cells to the current chemotherapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0300891618784790DOI Listing
February 2019

Dysregulated Expression of Long Intergenic Non-coding RNAs (LincRNAs) in Urothelial Bladder Carcinoma.

Int J Mol Cell Med 2017 12;6(4):212-221. Epub 2017 Nov 12.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Long intergenic non-coding RNA (lincRNA) has been introduced as key regulators of diverse biological processes, including transcription, chromatin organization, cell growth and tumorigenesis. With regard to the potential role of lincRNAs in cancer development, one may postulate that differential expression of lincRNAs could be employed as a tool in cancer diagnosis, prognosis, and targeted therapy. In this study, we aimed to explore the putative correlation between the expression levels of two lincRNAs: and in the bladder cancer (BC), in comparison with its adjacent non-cancerous tissue. Fifty Iranian subjects diagnosed with BC, representing in different stages and grades participated in this study The mRNA expression levels of the abovementioned lincRNAs were comparatively analyzed in cancerous and their adjacent non-cancerous counterpart tissues, of each subject by Real-Time PCR. The expression levels of , and were significantly lower in tumor tissues in comparison with their adjacent normal tissues (P<0.001). More notably, in the case of the reduced expression was differentiated by the muscle invasiveness pattern of the tumor (P= 0.05). Our study presents a new finding about the tumor suppressor potentiality of these lincRNAs in BC development that in turn may suggest them as candidate biomarkers. Replicating this study in higher number of BC subjects, coupled with functional analysis, is necessary to investigate interconnections between these RNAs and cancer development, leading to better understanding of cancer biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22088/BUMS.6.4.212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004296PMC
November 2017

Effects of Genetic Polymorphism on Susceptibility to Nephrotoxic Properties of BTEXs Compounds.

J Occup Environ Med 2018 08;60(8):e377-e382

Research Center for Health Sciences, Institute of Health, Department of Occupational Health Engineering, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran (Dr Neghab); Department of Occupational Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran (Dr Nourozi); Department of Occupational Health Engineering, School of Public Health, Institute for Environmental Research, Tehran University of Medical Sciences, Tehran, Iran (Dr Shahtaheri); Non-communicable Diseases Research Center, Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran (Dr Mansoori); Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran (Dr Bazzaz); and Department of Epidemiology and Biostatistics, School of Public Health, Knowledge Utilization Research Center (KURC), Tehran University of Medical Sciences, Tehran, Iran (Dr Nedjat).

Objective: The aim of this study was to ascertain whether genetic polymorphism affects susceptibility of individuals to nephrotoxic potentials of benzene, toluene, ethyl-benzene, and xylenes (BTEXs).

Methods: Fifty BTEXs exposed workers with one or more abnormal parameter of kidney function and 232 referent subjects, with similar exposure history, free from any abnormal kidney parameters were investigated. Atmospheric concentrations of BTEXs were measured. In addition, genetic polymorphisms were determined by multiplex polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP).

Results: The frequencies of GSTP1 Ile-Val/Val-Val, null GSTT1, and null GSTT1/GSTM1 genotypes and mean values of blood urea nitrogen and plasma creatinine were significantly higher, while average glomerular filtration rate was significantly lower in cases than in referent subjects.

Conclusion: These findings indicate that individuals carrying null GSTT1 or null GSTT1/GSTM1 are more susceptible to nephrotoxic properties of BTEXs compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001364DOI Listing
August 2018

PARP-1 Overexpression as an Independent Prognostic Factor in Adult Non-M3 Acute Myeloid Leukemia.

Genet Test Mol Biomarkers 2018 Jun 29;22(6):343-349. Epub 2018 May 29.

1 Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences , Tehran, Iran .

Aims: Poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in the repair of damaged DNA and has prognostic significance in a variety of human malignancies. However, little is known about its expression levels and clinical implication in patients with acute myeloid leukemia (AML).

Materials And Methods: Quantitative reverse transcription-polymerase chain reaction was done to evaluate PARP-1 expression levels in the bone marrow of 65 patients with non-M3 AML and 54 healthy counterparts. The correlation of PARP-1 expression with clinicopathological features of non-M3 AML patients was also analyzed.

Results: Non-M3 AML patients have higher PARP-1 expression than the healthy controls (p < 0.01). Patients with adverse cytogenetic risk have higher PARP-1 expression than other cytogenetic risk groups (p = 0.004). The PARP-1 median expression level divided AML patients into PARP-1 low-expressed and PARP-1 high-expressed groups. High expression levels of PARP-1 were associated with worse overall survival (OS) (p = 0.01) and relapse-free survival (RFS) (p = 0.005). Moreover, multivariate analysis revealed that high PARP-1 expression was an independent risk factor for both OS and RFS.

Conclusions: Our results suggest that PARP-1 overexpression may define an important risk factor in non-M3 AML patients and PARP-1 is a potential therapeutic target for AML treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/gtmb.2018.0085DOI Listing
June 2018

Expression levels of breast cancer-related GAS5 and LSINCT5 lncRNAs in cancer-free breast tissue: Molecular associations with age at menarche and obesity.

Breast J 2018 11 21;24(6):876-882. Epub 2018 May 21.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Long noncoding RNAs (lncRNAs) constitute a major class of the human transcriptome which play crucial roles in the key biological processes of both normal and malignant breast cells. Although the aberrant expression of lncRNAs has been well-documented in breast cancer (BC), little is currently known about the association between their expression levels in the breast tissue of healthy women and BC risk factors, especially the reproductive or demographic characteristics that are among the most well-known BC risk modifiers. This study was an attempt to investigate the correlation between the expression levels of 2 breast cancer-related lncRNAs, including GAS5 and LSINCT5, and reproductive and demographic characteristics in 145 normal breast tissues that were obtained from women without breast cancer undergoing cosmetic surgery. Total RNA was extracted from fresh normal breast tissues, and the expression level of target lncRNAs was quantified using real-time qPCR. Differences in the mean normalized gene expression among the subgroups of different variables were analyzed. The expression levels of both genes was lower in the overweight-obese (BMI ≥ 25) subgroup than that in the normal BMI (BMI < 25) subgroup (GAS5 P = .019, LSINCT5 P = .036). Moreover, the expression level of GAS5 was negatively correlated with BMI (r: -.170, P: .041). The expression level of GAS5 was higher in women with late menarche (>13 years) than that with early menarche (≤13 years; P = .017). These findings may assist to obtain insights into the molecular mechanisms through which the reproductive or obesity-related estrogen changes contribute to the breast carcinogenesis. In conclusion, this study presents the first evidence for the presence of a link between the lncRNA expression and the reproductive or obesity related factors in the breast tissue of healthy women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tbj.13067DOI Listing
November 2018

Cinemedicine: Using movies to improve students' understanding of psychosocial aspects of medicine.

Ann Med Surg (Lond) 2018 Apr 21;28:23-27. Epub 2018 Feb 21.

Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: There are rising concerns about how to teach psychosocial aspects of medicine to students. The aim of the study was the use of "cinemedicine" as a tool and technique in teaching psychosocial aspects of medicine to medical students at Tehran University of Medical Sciences (TUMS).

Methods: This was an educational study with quantitative and qualitative data analysis. Two hundred seventy medical students participated in this study. Nine sessions were held to teach psychosocial subjects in medicine using movies. Each session began with an initial explanation of the program objectives. After the show, medicine related points of the movie were discussed and analyzed by experts and students. In the end, questionnaires were distributed to assess the students' perceptions.

Results: The results of our study show that most of the students (84%) stated that teaching these subjects through movies was a nice event comparing to usual lectures. 56.5% of the students agreed with the application of points learned in the events in professional performance. The majority of the students (72.8%) agreed that participating in those events was useful for them as a physician and they would advise other students to attend to later sessions. Content analysis of the students' notes uncovered three categories of cinemedicine: "learning by observation", "creation of a supportive and tangible learning" and "motivation for learning".

Conclusion: Cinemedicine provides the opportunity for medical students to learn psychosocial subjects related to medicine through observing and reflecting on movies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amsu.2018.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938242PMC
April 2018

A link between expression level of long-non-coding RNA in breast tissue of healthy women and obesity.

Int J Biol Markers 2018 Nov 24;33(4):500-506. Epub 2018 Apr 24.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Epidemiological and experimental literature indicates that the risk of breast cancer incidence is strongly linked to hormone-dependent factors, including reproductive history and obesity. However, the molecular mechanisms underlying the association between these factors and breast cancer risk are poorly understood. The aim of this study, therefore, was to determine whether obesity and reproductive history are associated with expression levels of two breast cancer-related long non-coding RNAs (lncRNAs), namely and in cancer-free breast tissues of women.

Methods: In the current research, 145 healthy women were recruited, and the quantitative expression levels of the two lncRNAs were determined through qPCR assay after gathering the mammoplasty breast tissue samples.

Results: It was found that women with body mass index (BMI)≥30 kg/m and BMI 25-29 kg/m show a low expression of compared to the BMI<25 kg/m (=0.031 and =0.027, respectively). Then, the correlation analysis disclosed a negative correlation of low expression with increasing BMI (r=-0.194, =0.019). Interestingly, this analysis demonstrated a negative correlation between low expression of the and high BMI in women with menarche age below 14 (r=-221; =0.028). Lastly, it was also revealed that there was a negative association of the low expression level of with increasing BMI in women through regression models (B=-0.048, =0.019).

Conclusions: These findings suggest interesting clues about the links between high BMI and the expression levels of in non-diseased breasts that may help us better understand the underlying mechanisms through which obesity contributes to breast carcinogenesis. However, such results need more validations in future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1724600818762258DOI Listing
November 2018