Publications by authors named "Mahdi Montazer Haghighi"

30 Publications

  • Page 1 of 1

Whole-Genome Study of a Multigenerational Family with Essential Tremor.

Can J Neurol Sci 2021 May 5:1-6. Epub 2021 May 5.

Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada.

Background: Essential tremor (ET) is a common movement disorder with ˜5% prevalence in individuals above the age of 65, but in rare cases, it arises during childhood. Growing evidence suggests the role of cerebellum in the disease mechanism. ET is highly heritable, however, poor replication of risk loci point to its significant heterogeneity. Thus, it is important to genetically investigate kindreds with a strong aggregation of ET.

Methods: We conducted a clinical and whole-genome investigation of a large Caucasian Canadian family, in which six out of eight patients are affected by childhood-onset ET in four consecutive generations. Eight family members were available for study, including three patients affected by ET. Whole-genome sequencing (WGS) was conducted for the four most informative individuals, followed by Sanger sequencing in the entire kindred.

Results: We searched for rare variants absent in the eldest unaffected individual, but present in the patients (two siblings and their third-degree relative). Our stringent whole-genome filtering approach revealed a rare heterozygous p. Arg90Gln substitution in TCP10L (rs151233771) in all three investigated patients. Sanger sequencing confirmed the p. Arg90Gln variant and revealed its absence in the rest of the family members.

Conclusions: Whole-genome data of the family with ET resulted in a single candidate gene mapped to 21q22.11 locus (TCP10L) with the highest brain expression in cerebellum. Our study encourages future replication studies to validate the genetic link between TCP10L and ET, and suggests the p. Arg90Gln variant for functional investigation.
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http://dx.doi.org/10.1017/cjn.2021.104DOI Listing
May 2021

Combined epigenetic/genetic study identified an ALS age of onset modifier.

Acta Neuropathol Commun 2021 04 23;9(1):75. Epub 2021 Apr 23.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave., Toronto, ON, M5T 0S8, Canada.

Age at onset of amyotrophic lateral sclerosis (ALS) is highly variable (eg, 27-74 years in carriers of the GC-expansion in C9orf72). It might be influenced by environmental and genetic factors via the modulation of DNA methylation (DNAm) at CpG-sites. Hence, we combined an epigenetic and genetic approach to test the hypothesis that some common single nucleotide polymorphisms (SNPs) at CpG-sites (CpG-SNPs) could modify ALS age of onset. Our genome-wide DNAm analysis suggested three CpG-SNPs whose DNAm levels are significantly associated with age of onset in 249 ALS patients (q < 0.05). Next, genetic analysis validated the association of rs4970944 with age of onset in the discovery (n = 469; P = 0.025) and replication (n = 4160; P = 0.007) ALS cohorts. A meta-analysis of the cohorts combined showed that the median onset in AA-carriers is two years later than in GG-carriers (n = 4629; P = 0.0012). A similar association was observed with its tagging SNPs, implicating a 16 Kb region at the 1q21.3 locus as a modifier of ALS age of onset. Notably, rs4970944 genotypes are also associated with age of onset in C9orf72-carriers (n = 333; P = 0.025), suggesting that each A-allele delays onset by 1.6 years. Analysis of Genotype-Tissue Expression data revealed that the protective A-allele is linked with the reduced expression of CTSS in cerebellum (P = 0.00018), which is a critical brain region in the distributed neural circuits subserving motor control. CTSS encodes cathepsin S protein playing a key role in antigen presentation. In conclusion, we identified a 16 Kb locus tagged by rs4970944 as a modifier of ALS age of onset. Our findings support the role of antigen presenting processes in modulating age of onset of ALS and suggest potential drug targets (eg, CTSS). Future replication studies are encouraged to validate the link between the locus tagged by rs4970944 and age of onset in independent ALS cohorts, including different ethnic groups.
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http://dx.doi.org/10.1186/s40478-021-01183-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066440PMC
April 2021

The Intersection between COVID-19, the Gene Family of ACE2 and Alzheimer's Disease.

Neurosci Insights 2020 22;15:2633105520975743. Epub 2020 Nov 22.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.

We reviewed factors that might influence COVID-19 outcomes (eg, neurological symptoms), including the link to Alzheimer's disease. Since the virus triggers COVID-19 infection through binding to ACE2, we focused on the gene family, including . Both ACE2 and ACE are involved in the renin-angiotensin system (RAS). In general, ACE causes inflammation and vasoconstriction, while ACE2 leads to anti-inflammation activity and vasodilation. The disturbed balance between these counter-regulatory pathways could influence susceptibility to COVID-19. Notably, dysregulation of the RAS-equilibrium contributes to Alzheimer's disease. Differences in the incidence and symptoms of COVID-19 in diverse populations could be attributed to variability in the human genome. For example, and variations could modify the outcome of COVID-19 in different populations. It would be important to conduct genome-wide studies to detect variants influencing COVID-19 presentation, with a special focus on variants affecting immune-related pathways and expression of RAS-related genes.
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http://dx.doi.org/10.1177/2633105520975743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686598PMC
November 2020

The association between SMAD7 polymorphisms and colorectal cancer susceptibility as well as clinicopathological features in the Iranian population.

Gastroenterol Hepatol Bed Bench 2020 ;13(1):23-30

Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Aim: Our aim was to investigate the association between two single nucleotide polymorphisms (SNPs) of SMAD7 and the risk of CRC among Iranian individuals.

Background: Genome-wide association studies (GWAS) have identified 18q21 as a risk locus for colorectal cancer (CRC), which maps to the SMAD7 gene.

Methods: This case-control study was conducted on 109 CRC cases and 109 controls in the Iranian population to evaluate the influence of two SNPs of SMAD7, rs2337106 and rs6507874, on the risk of CRC as well as on clinicopathological features. Genotype determination was performed by TaqMan assay via an ABI 7500 Real Time PCR System (Applied Biosystems) for the DNA of peripheral blood. Descriptive analysis and logistic regression model were used for statistical analyses.

Results: Genotyping of the SNPs in the SMAD7 gene revealed that the frequency of G allele of rs2337106 was 53.7% in controls and 56.4% in cases (p-value=0.564) while the frequency of C allele of rs6507874 was 55.5% in controls and 56.3% in cases (p-value=0.772). Further, there were no significant differences in genotype frequencies of these SNPs between CRC patients and controls. The SMAD7 genotypes were not associated with the risk of CRC or with any clinicopathological characteristics such as tumor site, tumor grade, and stage TNM in CRC patients (p-value>0.05), even after adjustment for sex, age, and smoking status.

Conclusion: Our results provided the first evidence that SMAD7 genotypes, rs2337106 and rs6507874, could not be predisposing markers in genetic susceptibility to CRC in an Iranian population, at least in the studied population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069530PMC
January 2020

miR-130b is a potent stimulator of hepatic very-low-density lipoprotein assembly and secretion via marked induction of microsomal triglyceride transfer protein.

Am J Physiol Endocrinol Metab 2020 02 10;318(2):E262-E275. Epub 2019 Dec 10.

Molecular Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

miR-130b is a microRNA whose expression is particularly elevated within adipose tissue and in the circulation in diabetic states. Hepatic miR-130b expression has been linked to hepatocellular carcinoma and changes in lipid metabolism. Here, we investigated the role of miR-130b in hepatic lipid homeostasis and lipoprotein export. We observed that overexpression of miR-130b-3p or -5p in HepG2 cells markedly enhanced the secretion of very-low-density lipoprotein (VLDL) particles, enhanced the secretion of [H]glycerol metabolically labeled triglyceride (TG), and significantly increased the number or the average size of lipid droplets (LDs), respectively. Overexpression of miR-130b also altered the expression of key genes involved in lipid metabolism and in particular markedly increased both mRNA and protein expression levels of microsomal triglyceride transfer protein (MTP). Conversely, the miR-130b inhibitor decreased mRNA levels of and fatty acid synthase () in HepG2 cells. However, dual-luciferase reporter assays indicated that is not a direct target of miR-130b-3p. miR-130b overexpression did not alter de novo synthesized TG or the stability and secretion of apolipoprotein B 100. Interestingly, knockdown of phosphatase and tensin homolog () blocked the upregulation of mRNA induced by miR-130b. Finally, miR-130b-induced stimulation of VLDL secretion was also observed in a second hepatocyte cell culture model, immortalized human hepatocytes, confirming the effects observed in HepG2 cells. Overall, these data suggest a potential role for miR-130b in promoting hepatic VLDL assembly and secretion mediated by marked stimulation of MTP expression and TG mobilization. Thus miR-130b overexpression corrects the defect in VLDL production in HepG2 cells.
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http://dx.doi.org/10.1152/ajpendo.00276.2019DOI Listing
February 2020

Single Nucleotide Polymorphism (A870G) of the  gene: association with colorectal cancer susceptibility.

Gastroenterol Hepatol Bed Bench 2017 ;10(Suppl1):S48-S53

Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Aim: The aim of this study is to demonstrate the role of gene polymorphism, A870G, in susceptibility to sporadic colorectal cancer in Iranian population.

Background: It has been distinguished that gene is one of the main genes in Wnt signaling pathway which involves in generating colorectal cancer. Nonetheless, there is no consistent result in terms of association between the genetic variations of this gene and colorectal cancer risk.

Methods: We designed a case-control study consisting of 100 subjects with colorectal cancer (CRC) and 100 healthy controls to investigate the effect of A870G polymorphism on CRC susceptibility in an Iranian population. Genotype determination was performed by PCR-RFLP method.

Results: The frequency of GG, AG and AA genotypes for cases were 24%, 51% and 25% respectively, while the genotype frequency for controls were 21%, 50% and 29% respectively. It was identified that there is no significant association between A870G polymorphism and risk of CRC, even after adjusting sex, age and smoking status variables ( = 0.777; OR=1.32 95% CI: 0.6-2.93)..

Conclusion: Despite the well-known role of gene in cell cycle regulation, our results revealed that A870G polymorphism could not be a potential predisposing risk factor in genetic susceptibility to CRC, at least in the studied population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838181PMC
January 2017

Novel Missense Mutation at Codon 2774 (C.8321 G>A) p.S2774N of APC Gene in a Denovo Case of Familial Adenomatous Polyposis.

Arch Iran Med 2015 Jul;18(7):446-9

Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease caused by germline mutation in Adenomatous Polyposis Coli (APC) gene. FAP accounts less than 1% of all colorectal cancers incidence. Patients generally present hundreds to thousands of adenomas in colon and rectum and develop colorectal cancer by age 35 - 40 if left untreated. A milder form of FAP with fewer numbers of polyps (< 100) is Attenuated FAP (AFAP) and in comparison with classical FAP, it usually diagnosed at an older age. Approximately 15% - 20% of FAP patients are ''de novo'' cases without any family history of the disease and novel APC mutations account for approximately 25% of FAP cases. In our study, we reported a novel missense mutation at the APC gene in a denovo patient with AFAP like phenotype.
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http://dx.doi.org/0151807/AIM.0010DOI Listing
July 2015

Lack of influence of the SMAD7 gene rs2337107 polymorphism on risk of colorectal cancer in an Iranian population.

Asian Pac J Cancer Prev 2014 ;15(11):4437-41

Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, E-mail :

SMAD7 has been identified as a functional candidate gene for colorectal cancer (CRC). SMAD7 protein is a known antagonist of the transforming growth factor beta (TGF-β) signaling pathway which is involved in tumorigenesis. Polymorphisms in SMAD7 may thus alter cancer risk. The aim of this study was to investigate the influence of a SMAD7 gene polymorphism (rs2337107) on risk of CRC and clinicopathological features in an Iranian population. In total, 210 subjects including 105 patients with colorectal cancer and 105 healthy controls were recruited in our study. All samples were genotyped by TaqMan assay via an ABI 7500 Real Time PCR System (Applied Biosystems) with DNA from peripheral blood. The polymorphism was statistically analyzed to investigate the relationship with the risk of colorectal cancer and clinicopathological properties. Logistic regression analysis revealed that there was no significant association between rs2337107 and the risk of colorectal cancer. In addition, no significant association between genotypes and clinicopathological features was observed (p value>0.05). Although there was not any association between genotypes and disorder, CT was the most common genotype in this population. This genotype prevalence was also higher in the patients with well grade (54.9%) and colon (72.0%) tumors. Our results provide the first evidence that this polymorphism is not a potential contributor to the risk of colorectal cancer and clinicopathological features in an Iranian population, and suggests the need of a large-scale case-control study to validate our results.
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http://dx.doi.org/10.7314/apjcp.2014.15.11.4437DOI Listing
March 2015

The prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/ COX2) rs5277 polymorphism does not influence risk of colorectal cancer in an Iranian population.

Asian Pac J Cancer Prev 2014 ;15(8):3507-11

Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran E-mail :

Background: The prostaglandin-endoperoxide synthase 2 [PTGS2, commonly known as cyclooxygenase-2 (COX-2)] is an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue and involved in the synthesis of prostaglandins and thromboxanes, regulators of processes such as inflammation, cell proliferation, and angiogenesis, all relevant for cancer development. We investigated whether a functional genetic polymorphism, rs5277, in COX-2 may have a risk-modifying effect on sporadic colorectal cancer in an Iranian population.

Materials And Methods: We conducted a case-control study on 167 patients with colorectal cancer and 197 cancer-free controls in Taleghani Hospital in Tehran, Iran, between 2007 and 2011. Peripheral blood samples of both groups were processed for DNA extraction and genotyping of the COX-2 gene polymorphism (rs5277) using PCR-RFLP. RFLP results were confirmed by direct sequencing. Logistic regression analysis was performed to calculate the adjusted odds ratio (OR) and 95% confidence interval (95% CI).

Results: There was no significant difference in the distribution of COX-2 gene rs5277 polymorphism genotype and the allelic form, among CRC patients compared with the healthy control group (p: 0.867).

Conclusions: Our results suggest that rs5277 polymorphism in COX2 could not be a good prognostic indicator for patients with CRC.
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http://dx.doi.org/10.7314/apjcp.2014.15.8.3507DOI Listing
January 2015

The effect of 5'untranslated region polymorphism in EGF gene, rs4444903, on colorectal cancer.

Gastroenterol Hepatol Bed Bench 2013 ;6(3):129-35

Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran.

Aim: The purpose of this study was to determine the relationship of rs4444903 (EGF+61A/G) SNP genotype with colorectal cancer and tumor stage in an Iranian population.

Background: Epidermal growth factor (EGF) is one of the important proteins that determine survival of cells. EGF binds to its receptor on the cell surface and then activates some of the cell signaling pathway networks within cells that lead to activation or deactivation of factors which are responsible for growth and apoptosis of cells. In this study we assessed the association in EGF polymorphism rs4444903 with colorectal cancer (CRC) in Iranian population.

Patients And Methods: We conducted case-control study to investigate the association of polymorphism rs4444903 in EGF, with colorectal cancer risk in Iranian population. Analyzed Polymorphism of EGF rs4444903 with restriction fragment length polymorphisms (RFLP) among two groups of subjects consisting of including 220 cases with colorectal cancer and 220 healthy individuals as controls. Mutations were confirmed in 10% of the samples by direct sequencing.

Results: The frequencies of AA, AG and GG genotypes among cases with colorectal cancer were 28.2, 46.8, and 25.0 % respectively and in controls genotype frequencies were 23.2, 56.4, and 20.5 %, respectively. Frequency of A allele among case group was 51.6% and for control group was 51.4%. The frequency of G allele in case and control was, respectively 48.4% and 48.6% (OR= 1.009, 95% CI= 0.775-1.315; P= 0.946). The percentage of Stage 0, I, II, III, IV were 5%, 9.35%, 38.84%, 30.21% and 16.54%, respectively, among the cases. However, no significant association between this polymorphism and CRC stage was observed (p=0.626).

Conclusion: Our data suggest a SNP rs4444903 may not represent a risk factor in the development and progression of CRC among Iranian population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017510PMC
May 2014

XPD gene polymorphism and colorectal cancer risk.

Gastroenterol Hepatol Bed Bench 2013 ;6(2):110-1

Department of Biology, Faculty of science, East Tehran Branch, Islamic Azad University, Tehran, Iran.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017505PMC
May 2014

Telomere shortening: a biological marker of sporadic colorectal cancer with normal expression of p53 and mismatch repair proteins.

Genet Test Mol Biomarkers 2014 Apr 4;18(4):236-44. Epub 2014 Feb 4.

1 Department of Biology, Science Faculty, Islamic Azad University , East Tehran Branch, Tehran, Iran .

Uncontrolled growth of cells, a main criterion of cancer, is merged with pathologic telomere length alteration. Thereby, measurement of telomere length could provide important information on cell proliferation and senescence in cancer tissues. Telomere shortening and its potential correlation with clinicopathological predictive markers in sporadic colorectal cancer (CRC) with normal expression of mismatch repair (MMR) proteins (including Mlh1, Msh2, Pms2, and Msh6) and normal p53 expression was completely explored. Relative telomere length (RTL) was quantitatively measured in a cohort of 164 samples (68 patients with sporadic CRC and 96 healthy unrelated controls). Our results demonstrated a significant shortening of RTL in the tumor-derived tissue of patients compared with the control group (p<0.001). Interestingly, significant telomere shortening was observed in tumors from an ascending and sigmoid colon in comparison with tumors located in a descending colon. Additionally, the telomere length was significantly shorter in those with lymph node metastasis (p<0.05). The results suggest that pathological telomere shortening, leading to genome instability and lymphatic transformation, could serve as a potential sensitive detection and also as a classification marker for facilitating diagnosis and management of CRC.
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http://dx.doi.org/10.1089/gtmb.2013.0436DOI Listing
April 2014

Correlation between the EGF gene intronic polymorphism, rs2298979, and colorectal cancer.

Oncol Lett 2013 Oct 22;6(4):1079-1083. Epub 2013 Jul 22.

Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Colorectal cancer (CRC) is an important disorder that results from genetic and epigenetic alterations in one colonic epithelial cell. Epidermal growth factor (EGF) is critical in the development of tumors in epithelial tissues. Variations in the DNA sequence of the gene may be particularly significant with regard to susceptibility to CRC. The present study aimed to investigate the effect of the gene single nucleotide polymorphism (SNP), rs2298979, on CRC. In this prospective study, 220 samples were collected from patients with CRC and compared with 220 matched healthy controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and the result was validated by direct sequencing. A significant correlation was observed between the rs2298979 variant in the gene and CRC. The frequency of the A/G genotype in the control group was higher than in the patients with sporadic CRC [odds ratio (OR), 0.488; 95% confidence interval (CI), 0.307-0.774; P=0.002]. In this study there were no individuals with a G/G genotype. Although the frequency of the G and A alleles was similar in the healthy control and CRC patient groups, individuals with the A/G genotype were less susceptible to CRC compared with those with the A/A genotype.
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http://dx.doi.org/10.3892/ol.2013.1481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796412PMC
October 2013

Different frequency of epidermal growth factor rs76189946 polymorphism genotype in an Iranian colorectal cancer.

Gastroenterol Hepatol Bed Bench 2013 ;6(Suppl 1):S32-8

Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Aim: This study aimed to determinant association between rs76189946 polymorphism of EGF gene and risk of colorectal cancer in an Iranian population.

Background: Colorectal cancer (CRC) is the third most prevalent cancer in both genders worldwide. The determination of genetic variation becomes a new way to etiology of colorectal cancer. Epidermal growth factor (EGF) is a mitogen that plays an important role in cell growth and tumourigenesis, this protein acts by binding its receptor, EGFR.

Patients And Methods: DNA samples taken from totally 125 CRC patients and healthy controls were amplified by polymerase chain reaction (PCR) for the rs76189946 polymorphism. Genotypes were analyzed using restriction fragment length polymorphism (RFLP). Finally to confirm the RFLP procedure, 20 of the PCR products were sequenced using the ABI PRISM 3130xl Genetic Analyzer and chain termination method (Applied Biosystems, Carlsbad, CA).

Results: Genotype distribution and allele frequency was similar in CRC patients and controls individuals. We expect observe C and G allele in both groups but only was found C allele.

Conclusion: In this study for first time we identified genetic distribution of exonic rs76189946 polymorphism in EGF gene both CRC patients and healthy controls. These results suggest there wasn't association between EGF polymorphism rs76189946 and risk of colorectal cancer in an Iranian population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017547PMC
May 2014

Clinical implications of BRAF mutation test in colorectal cancer.

Gastroenterol Hepatol Bed Bench 2013 ;6(1):6-13

Gastroenterology and Liver Disease Research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Knowledge about the clinical significance of V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) mutations in colorectal cancer (CRC) is growing. BRAF encodes a protein kinase involved with intracellular signaling and cell division. The gene product is a downstream effector of Kirsten Ras 1(KRAS) within the RAS/RAF/MAPK cellular signaling pathway. Evidence suggests that BRAF mutations, like KRAS mutations, result in uncontrolled, non-growth factor-dependent cellular proliferation. Similar to the rationale that KRAS mutation precludes effective treatment with anti-EGFR drugs. Recently, BRAF mutation testing has been introduced into routine clinical laboratories because its significance has become clearer in terms of effect on pathogenesis of CRC, utility in differentiating sporadic CRC from Lynch syndrome (LS), prognosis, and potential for predicting patient outcome in response to targeted drug therapy. In this review we describe the impact of BRAF mutations for these aspects.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017487PMC
June 2014

Molecular analysis of imperative polymorphisms of MLH1 gene in sporadic colorectal cancer.

Cancer Biomark 2013 Jan;13(6):427-32

Gastroenterology and Liver Disease Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran.

Background: Single nucleotide polymorphisms in mismatch repair genes may be associated with different protein expression, production, and efficiency according to allele status and influence the risk of developing colorectal cancer.

Objective: This research aimed at analyzing two important polymorphisms in MLH1 gene and their association in colorectal cancer susceptibility.

Methods: In total, 219 CRC patients and 248 healthy controls were genotyped with PCR/RFLP for I219V and IVS12-169 C>T polymorphisms in MLH1 gene. Sequencing performed to ensure work flow and results. We used unconditional logistic regression after adjusting for age and sex to evaluate the association between each polymorphism and colorectal cancer.

Results: The MLH1 I219V polymorphism was associated with colorectal cancer susceptibility (P=0.01). Stratified data analysis for gender demonstrated association of AG (P=0.009) and GG (P=0.021) genotypes with risk of colorectal cancer in women. In contrast there is no association with IVS 12-169 C>T polymorphism and colorectal cancer risk.

Conclusions: I219V SNP might be a susceptibility factor for CRC and gender is a factor that must be considered when it is analyzing. Further tests need to be done to define it as a dependable prognosis factor.
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http://dx.doi.org/10.3233/CBM-140391DOI Listing
January 2013

Prevalence of ATP7B Gene Mutations in Iranian Patients With Wilson Disease.

Hepat Mon 2011 Nov 30;11(11):890-4. Epub 2011 Nov 30.

Research Centre for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Wilson disease (WD) is an autosomal recessive disorder. The WD gene, ATP7B, encodes a copper-transporting ATPase involved in the transport of copper into the plasma protein ceruloplasmin and in excretion of copper from the liver. ATP7B mutations cause copper to accumulate in the liver and brain.

Objectives: We examined the ATP7B mutation spectrum in Wilson disease patients in Iran.

Patients And Methods: Genomic DNA was extracted from patients with Wilson disease. The entire coding region of the ATP7B gene was amplified using PCR and analyzed using direct sequencing.

Results: We identified five novel mutations in 5 Iranian patients with Wilson disease. The first was a transversion, c.2363C > T, which led to an amino acid change from threonine to isoleucine. The second mutation was a deletion, c.2532delA (Val845Ser), which occurred in exon 10. The third mutation was a transition mutation, c.2311C > G (Leu770Leu), which occurred in the TM4 domain of the ATP7B protein. The fourth mutation was a transversion, (c.3061G > A) (Lys1020Lys), in exon 14. Lastly, we identified a transversion, c.3206C > A (His1069Asn) in exon 14 which led to a change in function of the ATP loop domain of the ATP7B protein. The H1069Q mutation was identified as the most common mutation in our study population.

Conclusions: Based on our findings, the H1069Q may be a biomarker that can be used in a rapid detection assay for diagnosing WD patients.
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http://dx.doi.org/10.5812/kowsar.1735143X.762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269057PMC
November 2011

Simplified MSI marker panel for diagnosis of colorectal cancer.

Asian Pac J Cancer Prev 2011 ;12(8):2101-4

Research Center for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Colorectal cancers (CRCs) tumors are diagnosed by microsatellite instability (MSI) due to accumulation of insertion/deletion mutations in tandem repeats of short DNA motifs (1-6 bp) called microsatellites. Microsatellite instability (MSI) is not only a hallmark marker for screening of hereditary nonpolyposis colorectal cancer (HNPCC), but also a prognostic and predictive marker for sporadic colorectal cancer. Our objective was to determine and study of five mononucleotide microsatellite markers status among Iranian patients with HNPCC and sporadic colorectal cancer.

Materials And Methods: In the current investigation 80 sporadic CRC and 80 HNPCC patients were evaluated for MSI. The pentaplex panel including 5 quasimonomorphic mononucleotide repeats (NR-21, BAT-26, BAT-25, NR-27 and NR-24) was used.

Results: Our findings showed that the NR-21 was the most frequent instable marker among the other markers. 53% and 25.6% specimens had instability in sporadic CRC and HNPCC, respectively. Furthermore, the frequencies of instability BAT-25 was determined in 20% sporadic CRC and 23% HNPCC samples. Interestingly our results demonstrated that the frequency of instability NR-24 was similar 20% sporadic CRC and 20.5% HNPCC. Moreover, percentage of NR-27 in HNPCC was 19.2 and 0% in sporadic CRC. Finally, BAT-26 was instable in 21.8% HNPCC patients while we could find 6.6% instability for BAT-26 in sporadic cases.

Conclusion: It seems that among 5 mononucleotides markers NR-21 was the most useful marker for diagnosis HNPCC and sporadic cancer. Following NR-21, BAT-25 and NR-24 are the most reliable markers. Therefore using a triplex panel including 3 aforementioned MSI markers should be more promising markers for identifying MSI status in both patients with HNPCC and/or sporadic colorectal cancer.
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August 2012

The role of kras mutations and MSI status in diagnosis of colorectal cancer.

Gastroenterol Hepatol Bed Bench 2011 ;4(2):70-5

Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Aim: The aim of the current investigation was to examine the profile of Kras mutations accompanied with MSI (microsattelite instability) status in polyps and colorectal carcinoma tissues in an Iranian population.

Background: Kras mutations in colorectal cancer cause resistance to anti-Epidermal Growth Factor Receptor (EGFR). So it can be considered as a true indicator of EGFR pathway activation status. Kras mutations can be detected in approximately 30% to 40% of all patients with colorectal cancer. The most hot spot of the gene is located in exons 2 and 3.

Patients And Methods: In this study we examined exons 2 and 3 Kras gene using polymerase chain reactions and subsequent sequencing of the exons in 95 patients with sporadic colorectal cancer including 48 tumors and 47 polyps. This study was performed using biopsy samples from the patients. We sequenced the Kras gene in a panel of human colorectal tumors and polyps in addition to detecting MSI status using fluorescent technique.

Results: We could detect 6 mutations in tumors including 5 mutations in codon 12 and one mutation in codon 13. Moreover, in polyps 2 mutations were determined in codon 13 and one in codon 12. Microsatellite instability assay revealed the presence of 5 and 6 MSI in tumors and polyps, respectively. Among the MSI mononucleotide markers, NR-21 marker demonstrated the most frequency (60%) in the both groups.

Conclusion: Our findings showed that probably the profile of mutations in tumors is not entirely compatible with the pattern of mutations in polyps. However, just one of the mutations, Gly12Asp, was similar in both groups.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017411PMC
May 2014

Frequent MSI mononucleotide markers for diagnosis of hereditary nonpolyposis colorectal cancer.

Asian Pac J Cancer Prev 2010 ;11(4):1033-5

Science and Research Branch, Islamic Azad University (IAU), and Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Tehran, Iran.

Background: Failure in the DNA mismatch repair system is commonly accompanied by microsatellite instability and leads to colorectal cancer. The aim of this study was to find the most frequent of five mononucleotide markers in order to devise the simplest diagnostic strategy for identification of patients with hereditary nonpolyposis colorectal cancer (HNPCC) who were defined by defects in mismatch repair system.

Materials And Methods: 78 patients with colorectal cancer were recruited for this investigation. Five mononucleotide markers, NR-27, NR-21, NR-24, BAT-25 and BAT-26, were used as a pentaplex panel to determine MSI status.

Results: Two out of five mononucleotide markers, NR-21 (25.6%) and BAT-25 (23.1%) showed more instability than the others.

Conclusion: In defining individuals with colorectal cancer, BAT25 and NR-21 may provide diagnostic assistance.
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April 2011

Impact of EXO1 polymorphism in susceptibility to colorectal cancer.

Genet Test Mol Biomarkers 2010 Oct 20;14(5):649-52. Epub 2010 Sep 20.

Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti Medical University, Tehran, Iran.

Background And Aim: One candidate gene for colorectal cancer (CRC) susceptibility is exonuclease 1 (EXO1). It is a member of RAD2 nuclease family, which plays a major role in mismatch repair, DNA replication, and recombination. Single-nucleotide polymorphisms are shown to be related with cancer incidence. The aim of the present study was to examine the association between the L757P polymorphism at exon 13 of the EXO1 gene and the risk of CRC in Iranian patients.

Methods: In this case-control study, 90 cases and 98 healthy control samples were analyzed genetically. The EXO1 polymorphism, P757L, was analyzed by polymerase chain reaction-restriction fragment length polymorphism. The obtained polymorphisms were examined for the relationship with CRC risk and also clinicopathological characteristics.

Results: Our findings showed that patients with the Leu/Leu genotype have a reduced risk of CRC (adjusted odds ratio [OR] = 0.192, 95% confidence interval [CI]: 0.040-0.921) when the Pro/Leu and Pro/Pro genotypes were blended and they were considered as the reference. The Leu/Leu genotype also showed a reduced risk (adjusted OR = 0.168, 95% CI: 0.034-0.816) when the Pro/Pro genotype was a reference; nevertheless, the Pro/Leu genotype did not reveal a significant association with CRC at the same status (adjusted OR = 0.686, 95% CI: 0.367-1.284).

Conclusions: Our results provide evidence diagnosing that the Leu/Leu genotype of EXO1 showed an inverse association with CRC. In addition, despite other investigations, we could define a significant association between the Leu allele and CRC (p = 0.001).
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http://dx.doi.org/10.1089/gtmb.2010.0034DOI Listing
October 2010

Correlation of telomere length shortening with promoter methylation profile of p16/Rb and p53/p21 pathways in breast cancer.

Mod Pathol 2010 May 15;23(5):763-72. Epub 2010 Jan 15.

Laboratory for Prenatal Medicine and Gynecologic Oncology, Women's Hospital/Department of Biomedicine, University of Basel, Basel, Switzerland.

Unregulated cell growth, a major hallmark of cancer, is coupled with telomere shortening. Measurement of telomere length could provide important information on cell replication and proliferation state in cancer tissues. Telomere shortening and its potential correlation with downregulation of cell-cycle regulatory elements were studied by the examination of relative telomere length and methylation status of the TP53, P21 and P16 promoters in tissues from breast cancer patients. Telomere length was measured in 104 samples (52 tumors and paired adjacent normal breast tissues) by quantitative PCR. Methylation profile of selected genes was analyzed in all samples using a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Our results demonstrated a significant shortening of tumor telomere regions compared with paired adjacent normal tissues (P<0.001). Similarly, telomere lengths were significantly shorter in advanced stage cases and in those with higher histological grades (P<0.05). Telomere shortening in cancer tissues was correlated with a different level of hypermethylation in the TP53, P21 and P16 promoters (r=-0.33, P=0.001; r=-0.70, P<0.0001 and r=-0.71, P<0.0001, respectively). The results suggested that inactivation of p16/Rb and/or p53/p21 pathways by hypermethylation may be linked to critical telomere shortening, leading to genome instability and ultimately to malignant transformation. Thus, telomere shortening and promoter hypermethylation of related genes both might serve as breast cancer biomarkers.
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http://dx.doi.org/10.1038/modpathol.2009.195DOI Listing
May 2010

Association between MTHFR polymorphism (C677T) with nonfamilial colorectal cancer.

Oncol Res 2009 ;18(2-3):57-63

Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti Medical University, Tehran, Iran.

The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) is linked to DNA methylation, synthesis, and repair. C677T is one of the most important polymorphisms in the MTHFR gene. The single nucleotide polymorphism C677T has been found to be associated with decreased enzyme activity and plasma folate, and thus may play a crucial role in the etiology of colorectal cancer. This decrease was observable in people with either high or low folate status. We aimed to test the hypothesis that the C677T genotype is involved in colorectal cancer. Using pyrosequencing, we analyzed the MTHFR genotypes in 234 colorectal cancer patients and 257 matched controls. We examined the polymorphisms in MTHFR and folate intake in relation to risk of colon cancer in an Iranian population-based case-control study. Our finding revealed that the CC, CT, and TT genotypes of MTHFR among the colorectal cancer patients were 50%, 29.1%, and 20.9%, respectively. On the other hand, we could find 29.5% of 677CC, 46% of 677CT and 24.5% of 677TT in the controls. A decreased risk of colon cancer for participants with wild-type genotype was observed. Interestingly, this association was stronger at higher levels of folate intake. Our study corroborates previous findings of an inverse association of the MTHFR 677TT genotype with colorectal cancer, in particular at high levels of folate.
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http://dx.doi.org/10.3727/096504009789954636DOI Listing
January 2010

Comparison of survival between patients with hereditary non polyposis colorectal cancer (HNPCC) and sporadic colorectal cancer.

Asian Pac J Cancer Prev 2009 Jul-Sep;10(3):497-500

Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti Medical University, Tehran, Iran.

Background: Hereditary non polyposis colorectal cancer (HNPCC) appears to have a better prognosis than sporadic cancer. In the present study we evaluated the clinical outcomes of HNPCC patients with their sporadic colorectal cancer counterparts arising from the general population recorded in a population-based cancer registry in Iran.

Patients And Methods: The population studied consisted of 121 individuals including 61 patients with sporadic colorectal cancer and 60 with HNPCC who were followed-up between 2003 and 2008 in Taleghani Hospital Tehran. The subjects with HNPCC were screened according to Amsterdam criteria II and Bethesda Guidelines. Subjects with sporadic cancer had no familial history of colorectal cancer. Observed survival was estimated using the Kaplan-Meier method and compared with the log rank test. Multivariate analysis was performed using Cox' regression analysis.

Results: In the HNPCC group, 85.0% showed tumors in the colon, vs. 68.9% in the sporadic cancer group. The 5-year survival was 82.5% in the HNPCC study group compared with only 56.4% in the sporadic colorectal cancer group (P= 0.044). The age distribution at diagnosis of sporadic patients was significantly higher than HNPCC patients (mean 50.1 years vs 44.3 years P= 0.008). The hazard ratio for sporadic cases was 2.93 (95% CI 1.06-8.11) compared with the HNPCC group (P= 0.038).

Conclusion: Our findings corroborate the results of previous studies which showed overall survival of colorectal cancer in patients with HNPCC is better than with sporadic CRC patients.
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November 2009

Comparison of survival between patients with hereditary non polyposis colorectal cancer (HNPCC) and sporadic colorectal cancer.

Asian Pac J Cancer Prev 2009 Apr-Jun;10(2):209-12

Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti University, (MC), Tehran, Iran.

Background: Hereditary non polyposis colorectal cancer (HNPCC) appears to have a better prognosis than sporadic cancer. In the present study we evaluated the clinical outcome of HNPCC patients with respect to that of patients with colorectal cancer recorded in a population-based cancer registry. Aim of our study was to examine survival rates in Iranian HNPCC patients with colorectal cancer and compare them with survival rates of sporadic cases arising from the general population.

Patients And Methods: The population studied consists of 121 individuals including 61 patients with sporadic colorectal cancer and 60 patients with HNPCC who were followed-up between 2003 and 2008 in Taleghani hospital Tehran. The subjects with HNPCC were screened according to Amsterdam criteria II and Bethesda Guidelines. All those with sporadic cancer had no familial history of colorectal cancer. Observed survival was estimated using the Kaplan-Meier method and compared with log rank test. Multivariate analysis was performed using the Cox regression analysis.

Results: In the HNPCC group, 85.0% showed tumors in colon, vs. 68.9% in the sporadic cancer group. The 5-year survival was 82.5% in the HNPCC study group compared with only 56.4% in the general population group (P= 0.044). The age distribution at diagnosis of sporadic patients was significantly higher than HNPCC patients (mean 50.1 years vs 44.3 years P= 0.008). The hazard ratio for sporadic for tumor location was 3.233 (95% CI 1.123-9.307) compared with the HNPCC group (P= 0.030).

Conclusion: Our findings corroborate the results of previous study which showed overall survival of colorectal cancer in patients with HNPCC is better than sporadic CRC patients.
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September 2009

Four novel germline mutations in the MLH1 and PMS2 mismatch repair genes in patients with hereditary nonpolyposis colorectal cancer.

Int J Colorectal Dis 2009 Aug 29;24(8):885-93. Epub 2009 May 29.

Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti Medical University, Tehran, Iran.

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common cause of early onset hereditary colorectal cancer. In the majority of HNPCC families, microsatellite instability (MSI) and germline mutation in one of the DNA mismatch repair (MMR) genes are found.

Materials And Methods: The entire coding sequence of MMR genes (MLH1, MLH2, MLH6, and PMS2) was analyzed using direct sequencing. Also, tumor tests were done as MSI and immunohistochemistry testing.

Results: We were able to find three novel MLH1 and one novel PMS2 germline mutations in three Iranian HNPCC patients. The first was a transversion mutation c.346A>C (T116P) and happened in the highly conserved HATPase-c region of MLH1 protein. The second was a transversion mutation c.736A>T (I246L), which caused an amino acid change of isoleucine to leucine. The third mutation (c.2145,6 delTG) was frameshift and resulted in an immature stop codon in five codons downstream. All of these three mutations were detected in the MLH1 gene. The other mutation was a transition mutation, c.676G>A (G207E), which has been found in exon six of the PMS2 gene and caused an amino acid change of glycine to glutamic acid. MSI assay revealed high instability in microsatellite for two patients and microsatellite stable for one patient.

Conclusion: In all patients, an abnormal expression of the MMR proteins in HNPCC was related to the above novel mutations.
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http://dx.doi.org/10.1007/s00384-009-0731-1DOI Listing
August 2009

Association between the 1793G> A MTHFR polymorphism and sporadic colorectal cancer in Iran.

Asian Pac J Cancer Prev 2008 Oct-Dec;9(4):659-62

Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti Medical University, Tehran, Iran.

Background: It has been proposed that folate and polymorphisms of the enzyme methylenetetrahydrofolate reductase (MTHFR), which regulates influx of folate for methylation reactions for DNA synthesis and repair, are involved in colorectal cancer. This study was designed to determine the influence of a genetic variant (MTHFR G1793A) and folate on colon cancer in Iran.

Materials And Methods: We analyzed 227 cases and 239 normal unmatched controls using pyrosequencing. Odds ratios and 95% confidence intervals (95% CI) were calculated to evaluate associations of the MTHFR gene polymorphism with colorectal cancer risk.

Results: A significantly reduced risk of recurrence was observed in patients heterozygous for the MTHFR G1793A polymorphism (OR: 0.17; 95% CI, 0.05-0.52). The frequency of GG, GA and AA genotypes of MTHFR among the colorectal cancer patients were 98%, 2% and 0% respectively, while the frequencies among controls were 90%, 10% and 0%, respectively. Furthermore, a significant reduction in recurrence risk was seen in MTHFR G1793A heterozygotes limited to those who received folate supplements.

Conclusion: Our study is compatible with previous findings concerning a reverse association between the MTHFR 1793G> A genotype with cancers in different populations.
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May 2009

Mitochondrial DNA content in paired normal and cancerous breast tissue samples from patients with breast cancer.

J Cancer Res Clin Oncol 2009 Aug 6;135(8):983-9. Epub 2009 Jan 6.

Laboratory for Prenatal Medicine and Gynecologic Oncology, Department of Biomedicine, Women's Hospital, University of Basel, Hebelstrasse 20, Room Nr. 416, 4031 Basel, Switzerland.

Introduction: We develop a multiplex quantitative real-time PCR for synchronized analysis of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) to investigate relative mtDNA abundance in paired normal and cancerous breast tissues.

Materials And Methods: The amounts of nDNA and mtDNA in 102 tissue samples were quantified for both glyceraldehype-3-phosphodehydrogenase (GAPDH) gene and mtDNA encoded ATPase (MTATP) 8 gene. The average threshold cycle (Ct) number values of the nDNA and mtDNA were used to calculate relative mtDNA content in breast tissues.

Results: The median delta Ct (DeltaCt) and the median mtDNA content for normal and cancerous breast tissues were 6.73 and 2.54, as well as 106.50 and 5.80 (P = 0.000, respectively). The mtDNA content was decreased in 82% of cancerous breast tissues compared with the normal ones. The changes were associated with hormone receptor status.

Conclusion: Our finding suggests that decreased mtDNA content in breast cancer may have diagnostic and prognostic value for the disease.
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http://dx.doi.org/10.1007/s00432-008-0533-9DOI Listing
August 2009

High-throughput hacking of the methylation patterns in breast cancer by in vitro transcription and thymidine-specific cleavage mass array on MALDI-TOF silico-chip.

Mol Cancer Res 2008 Nov;6(11):1702-9

Laboratory for Prenatal Medicine and Gynecologic Oncology, Women's Hospital/Department of Biomedicine, University of Basel, Basel, Switzerland.

Over the last decade, the rapidly expanding interest in the involvement of DNA methylation in developmental mechanisms, human diseases, and malignancies has highlighted the need for an accurate, quantitative, and high-throughput assay. Existing methods are limited and are often too laborious for high-throughput analysis or inadequate for quantitative analysis of methylation. Recently, a MassCLEAVE assay has been developed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to analyze base-specific methylation patterns after bisulfite conversion. To find an efficient and more cost-effective high-throughput method for analyzing the methylation profile in breast cancer, we developed a method that allows for the simultaneous detection of multiple target CpG residues by using thymidine-specific cleavage mass array on matrix-assisted laser desorption/ionization time-of-flight silicon chips. We used this novel quantitative approach for the analysis of DNA methylation patterns of four tumor suppressor genes in 96 breast tissue samples from 48 patients with breast cancer. Each individual contributed a breast cancer specimen and corresponding adjacent normal tissue. We evaluated the accuracy of the approach and implemented critical improvements in experimental design.
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http://dx.doi.org/10.1158/1541-7786.MCR-08-0262DOI Listing
November 2008

Neural differentiation from human embryonic stem cells in a defined adherent culture condition.

Int J Dev Biol 2007 ;51(5):371-8

Department of Stem Cells, Royan Institute, Tehran, Iran.

Understanding how to direct human embryonic stem cells (hESCs) toward a specific lineage pathway and generate appropriate cell types robustly is very important, not only for the study of developmental biology but also for potentially using these cells to treat human diseases. In this study, hESCs were differentiated to the neural lineage in defined adherent culture by retinoic acid and basic fibroblast growth factor. Our protocol seems to recapitulate the early steps of nervous system development in vivo in that undifferentiated hESCs organized into rosettes and then neural tube-like structures are formed. Differentiating cells expressed neuroectodermal and mature neuron markers during neural plate and tube formation and maturation, as shown by reverse transcriptase-PCR. More than 90% of differentiated cells expressed additional neuron-specific antigens (i.e., tubulin-III, MAP-2, synaptophysin and neurofilament protein). Ultrastructural analysis of differentiating neural tube-like structures in three dimensional collagen scaffolds showed an ependymal-like layer and neural structure with typical synapses. These results provide a simple and relatively defined system for differentiation of hESCs to neural lineages, particularly neurons with typical cellular, molecular and ultrastuctureal markers. The culture of neural precursor cells in a collagen scaffold may provide a new approach for the repair of spinal cord injury.
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http://dx.doi.org/10.1387/ijdb.72280hbDOI Listing
October 2007