Publications by authors named "Hooman Mosannen Mozaffari"

9 Publications

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Diagnosis of an occult gastric adenocarcinoma by oral manifestations (acanthosis nigricans): A case report.

Caspian J Intern Med 2021 ;12(Suppl 2):S383-S387

Department of Oral Medicine, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran.

Background: Acanthosis nigricans (AN) is a condition with an important characteristics of symmetrical areas of thickened skin with grayish brown hyperpigmentation. The mucosa may show a papillomatous surface, with or without hyperpigmentation. Lips and sites at risk of trauma may be affected and palmoplantar keratosis might also be present. In some rare cases, acanthosis nigricans presents as a sign of internal neoplasia, mostly a gastrointestinal cancer, and is called malignant acanthosis nigricans (MAN).

Case Presentation: In this study, a 55-year-old female Iranian patient with malignant acanthosis nigricans (MAN) is reported. She was seeking esthetic treatment for her oral and perioral regions. The peculiarity of this case is simultaneous skin manifestation consistent with MAN, "tripe palms" (TP) and Leser-Trélat (LT) sign and mucosal changes in the oral cavity such as papillomatosis and roughened surfaces of the lips, hard palate and buccal mucosa. These changes harbored gastric adenocarcinoma stage T3 N3, but the patient was asymptomatic except for pruritis.

Conclusion: There is an urgent need to suspect a correlation between oral and skin changes and the possibility of an internal neoplasia, therefore it is of utmost importance to refer these patients for early diagnosis of the underlying disease. This would improve the prognosis and lessen the consequences to a great extent.
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January 2021

Characteristics of gastric precancerous conditions and Helicobacter pylori infection among dyspeptic patients in north-eastern Iran: is endoscopic biopsy and histopathological assessment necessary?

BMC Cancer 2021 Oct 26;21(1):1143. Epub 2021 Oct 26.

Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Early detection and appropriate treatment of precancerous, mucosal changes could significantly decrease the prevalence of life-threatening gastric cancer. Biopsy of the normal-appearing mucosa to detect Helicobacter pylori and these conditions is not routinely obtained. This study assesses the prevalence and characteristics of H. pylori infection and precancerous conditions in a group of patients suffering from chronic dyspepsia who were subjected to gastric endoscopy and biopsy mapping.

Methods: This cross-sectional study included dyspeptic patients, not previously treated for H. pylori, undergoing esophagogastroduodenoscopy (EGD) with their gastric endoscopic biopsies obtained for examination for evidence of H. pylori infection and precancerous conditions. Demographic and clinical data on the gender, smoking, opium addiction, alcohol consumption, medication with aspirin, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) and family history of cancer were collected by interviewing the patients and evaluating their health records. The cohort examined consisted of 585 patients with a mean (SD) age of 48.0 (14.46) years, 397 (67.9%) of whom were women.

Results: H. pylori infection was identified in 469 patients (80.2%) with the highest prevalence (84.2%) in those aged 40-60 years. Opium addiction correlated with a higher a H. pylori infection rate, while alcohol consumption was associated with a lower rate by Odds Ratio 1.98 (95% CI 1.11-3.52) and 0.49 (95% CI 0.26-0.92), respectively. The prevalence of intestinal metaplasia, gastric atrophy and gastric dysplasia was 15.2, 12.6 and 7.9%, respectively. Increased age, positive H. pylori infection, endoscopic abnormal findings and opium addiction showed a statistically significant association with all precancerous conditions, while NSAID consumption was negatively associated with precancerous conditions. For 121 patients (20.7% of all), the EGD examination revealed normal gastric mucosa, however, for more than half (68/121, 56.2%) of these patients, the histological evaluation showed H. pylori infection, and also signs of atrophic mucosa, intestinal metaplasia and dysplasia in 1.7, 4.1 and 1.7%, respectively.

Conclusion: EGD with gastric biopsy mapping should be performed even in the presence of normal-appearing mucosa, especially in dyspeptic patients older than 40 years with opium addiction in north-eastern Iran. Owing to the high prevalence of precancerous conditions and H. pylori infection among patients with dyspepsia in parts of Iran, large-scale national screening in this country should be beneficial.
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October 2021

Promoter methylation, transcription, and retrotransposition of LINE-1 in colorectal adenomas and adenocarcinomas.

Cancer Cell Int 2020 1;20:426. Epub 2020 Sep 1.

Stem Cell Biology and Regenerative Medicine Research Group, Research Institute of Biotechnology, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 91779-48974 Iran.

Background: The methylation of the CpG islands of the LINE-1 promoter is a tight control mechanism on the function of mobile elements. However, simultaneous quantification of promoter methylation and transcription of LINE-1 has not been performed in progressive stages of colorectal cancer. In addition, the insertion of mobile elements in the genome of advanced adenoma stage, a precancerous stage before colorectal carcinoma has not been emphasized. In this study, we quantify promoter methylation and transcripts of LINE-1 in three stages of colorectal non-advanced adenoma, advanced adenoma, and adenocarcinoma. In addition, we analyze the insertion of LINE-1, Alu, and SVA elements in the genome of patient tumors with colorectal advanced adenomas.

Methods: LINE-1 hypomethylation status was evaluated by absolute quantitative analysis of methylated alleles (AQAMA) assay. To quantify the level of transcripts for LINE-1, quantitative RT-PCR was performed. To find mobile element insertions, the advanced adenoma tissue samples were subjected to whole genome sequencing and MELT analysis.

Results: We found that the LINE-1 promoter methylation in advanced adenoma and adenocarcinoma was significantly lower than that in non-advanced adenomas. Accordingly, the copy number of LINE-1 transcripts in advanced adenoma was significantly higher than that in non-advanced adenomas, and in adenocarcinomas was significantly higher than that in the advanced adenomas. Whole-genome sequencing analysis of colorectal advanced adenomas revealed that at this stage polymorphic insertions of LINE-1, Alu, and SVA comprise approximately 16%, 51%, and 74% of total insertions, respectively.

Conclusions: Our correlative analysis showing a decreased methylation of LINE-1 promoter accompanied by the higher level of LINE-1 transcription, and polymorphic genomic insertions in advanced adenoma, suggests that the early and advanced polyp stages may host very important pathogenic processes concluding to cancer.
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September 2020

Expression profile analysis of two antisense lncRNAs to improve prognosis prediction of colorectal adenocarcinoma.

Cancer Cell Int 2019 6;19:278. Epub 2019 Nov 6.

1Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 9177948974 Iran.

Background: Long noncoding RNAs (lncRNAs) are involved in different pathogenesis pathways including cancer pathogenesis. The adenoma-carcinoma pathway in colorectal cancer may involve the aberrant and variable gene expression of regulatory RNAs. This study was conducted to analyse the expression and prognosis prediction ability of two natural antisense transcripts, protein kinase C theta antisense RNA 1 (PRKCQ-AS1), and special AT-rich sequence binding protein 1 antisense RNA 1 (SATB1-AS1) in colorectal low-grade adenoma, advanced adenoma, and adenocarcinomas.

Methods: In this study, from two RNA-seq analyses of CCAT1-ko cells and colorectal carcinoma biopsies having diminished and increased levels of CCAT1 transcription, respectively, we nominated two antisense lncRNAs of PRKCQ-AS1 and SATB1-AS1. Samples from colorectal low-grade adenomas, advanced adenomas, adenocarcinomas, and adjacent tissue were subjected to RT-qPCR to determine the expression of PRKCQ-AS1, SATB1-AS1 along with colon cancer-associated transcript 1 (CCAT1) and cMYC. In addition, we used different bioinformatics analyses and webservers (including GEPIA 2, TCGA, and CancerMine) to elucidate the prognosis prediction value, the expression correlation of sense-antisense pair of genes, and the expression profile of these antisense transcripts at the presence or absence of mutations in the driver genes, or the corresponding sense genes.

Results: PRKCQ-AS1 showed a wide range of expression levels in colorectal adenoma, advanced adenoma, and adenocarcinoma. Upregulation of PRKCQ-AS1 was related to a significant decrease in survival of colorectal cancer (CRC) patients. The expression levels of PRKCQ-AS1 and PRKCQ were strong and significantly concordant in normal and cancerous colorectal tissues. While SATB1-AS1 showed a wide range of expression in colorectal adenoma, advanced adenoma, and adenocarcinoma as well, its expression was not related to a decrease in survival of CRC patients. The expression levels of SATB1-AS1 and SATB1 (the sense gene) were not strong in normal colorectal tissues. In addition, where SATB1 gene was mutated, the expression of SATB1-AS1 was significantly downregulated.

Conclusions: We found the expression of PRKCQ-AS1 and SATB1-AS1 at a given stage of CRC very variable, and not all biopsy samples showed the increased expression of these antisense transcripts. PRKCQ-AS1 in contrast to SATB1-AS1 showed a significant prognostic value. Since a significantly concordant expression was observed for SATB1-AS1 and SATB1 in only cancerous, and for PRKCQ-AS1 and PRKCQ in both normal and cancerous colorectal tissues, it can be concluded that common mechanisms may regulate the expression of these sense and antisense genes.
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November 2019

Role of MAML1 in targeted therapy against the esophageal cancer stem cells.

J Transl Med 2019 04 16;17(1):126. Epub 2019 Apr 16.

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

Background: Esophageal cancer is the sixth-leading cause of cancer-related deaths worldwide. Cancer stem cells (CSCs) are the main reason for tumor relapse in esophageal squamous cell carcinoma (ESCC). The NOTCH pathway is important in preservation of CSCs, therefore it is possible to target such cells by targeting MAML1 as the main component of the NOTCH transcription machinery.

Methods: In present study we isolated the CD44+ ESCC CSCs and designed a MAML1-targeted therapy to inhibit the NOTCH signaling pathway. CSCs were isolated using magnetic cell sorting utilizing the CD44 cell surface marker. Several stem cell markers were analyzed in the levels of protein and mRNA expression. The isolated CSCs were characterized in vivo in NUDE mice. Biological role of MAML1 was assessed in isolated CD44+ CSCs. A drug resistance assay was also performed to assess the role of MAML1 in CD44+ CSCs with 5FU resistance.

Results: The CD44+ CSCs had ability to form tumors in NUDE mice. MAML1 silencing caused a significant decrease (p = 0.019) and ectopic expression caused a significant increase in migration of CD44+ CSCs (p = 0.012). Moreover, MAML1 silencing and ectopic expression significantly increased and decreased 5FU resistance, respectively (p < 0.05). MAML1 silencing significantly increased the number of cells in G1 phase (p = 0.008), and its ectopic expression significantly increased the number of CD44+ CSCS in S phase (p = 0.037).

Conclusions: MAML1 may be utilized for targeted therapy with a low side effect to eliminate the CD44+ CSCs through inhibition of canonical NOTCH pathway in ESCC patients.
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April 2019

Prevalence and clinicopathological characteristics of mismatch repair-deficient colorectal carcinoma in early onset cases as compared with late-onset cases: a retrospective cross-sectional study in Northeastern Iran.

BMJ Open 2018 08 30;8(8):e023102. Epub 2018 Aug 30.

Department of Health Information Technology, Neyshabur University of Medical Sciences, Neyshabur, Iran.

Objectives: Lynch syndrome (LS), a genetically inherited autosomal disorder, increases the incidence of colorectal carcinoma (CRC). We aimed to perform a universal strategy to assess the prevalence and clinicopathological characteristics of early onset CRCs at high risk of LS versus late-onset ones in the Iranian population.

Setting: A local population-based study from Northeastern Iran.

Participants: 321 consecutive CRCs and pathology specimen screened between 2013 and 2016.

Primary And Secondary Outcome Measures: Retrospectively, information regarding the clinical criteria was obtained by interviewing the patients with CRC or, their families. Pathologists tested tumours with immunohistochemistry (IHC) staining of four mismatch repair (MMR) proteins ( and ). Tumours with absent IHC staining of were tested for BRAF mutations to exclude sporadic CRCs. Prevalence of early onset CRCs at high risk of LS and familial CRC type X were assessed as primary and secondary outcome measures, respectively.

Results: Of 321 CRCs (13/123 (10.57%), early onset vs 21/198 (10.6%) late-onset) were detected to be MMR-deficient (dMMR). Nine early onset cases and 14 late-onset ones with a loss of underwent testing for the BRAF mutation, none of the early onset and four (2.02%) late-onset were recognised as sporadic. The difference in the outcome of IHC-analysis between early and late-onset CRCs at high risk of LS was not statistically significant (p=0.34). Majority of the suspected LS tumours from early onset patients had arisen in distal part (8/11 (72.72%) vs 8/14 (57.14%)), all of which were occurred in the rectum or sigmoid.

Conclusion: Clinically, these findings suggest that in case of limitation for BRAF testing, the practitioner in Iran may consider managing early onset dMMR cases like LS until access to BRAF testing becomes available to them, before germline testing to accurately diagnose LS.
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August 2018

Screening for Lynch Syndrome in Cases with Colorectal Carcinoma from Mashhad.

Arch Iran Med 2017 Jun;20(6):332-337

Anatomical and Clinical Pathologist, Moayyed Medical Laboratory, Mashhad, Iran.

Introduction: Lynch Syndrome (LS) is a genetically inherited autosomal disorder that increases the risk of many types of cancer, especially colorectal cancer (CRC). Identifying these subjects improves morbidity and mortality. We aimed to assess the prevalence of LS with both clinical criteria and universal strategy in Mashhad, Iran.

Methods: In this retrospective study, we screened 322 patients with CRC between 2013 and 2016 in Mashhad, Iran. CRCs were screened based on Amsterdam II criteria, revised Bethesda guideline, and universal strategy. Information regarding the clinical criteria was obtained by interviewing the patients or, their families. Tumors were screened by pathologists with IHC staining of four Mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2). Tumors with absent IHC staining of MLH1 were tested for BRAF mutations to exclude sporadic CRCs.

Results: Of 322 CRCs, 33 cases were found to be deficient-MMR; 22 of these had concurrent loss of MLH1 and PMS2, followed by concurrent loss of MSH2 and MSH6 in 8 CRCs. Twenty-two cases with a loss of MLH1 underwent testing for the BRAF mutation, 4 of which were recognized as a positive BRAF mutation. Finally, 29 CRCs were found as being positive screen for LS. Poor sensitivity (21.74%) was found for the Amsterdam II criteria and a poor positive predictive value (15.39%) for the revised Bethesda.

Conclusion: Application of clinical criteria may not be effective enough to identify LS and at least 2-antibody panel (PMS2, MSH6) should be conducted for newly diagnosed CRCs.
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June 2017

Role of Msi1 and PYGO2 in esophageal squamous cell carcinoma depth of invasion.

J Cell Commun Signal 2016 Mar 7;10(1):49-53. Epub 2015 Dec 7.

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Deregulation of developmental signaling pathways such as Wnt/b-catenin and NOTCH are commonly observed in different cancers. A normal wnt pathway is essential for development and tissue homeostasis to preserve a normal balance between the differentiation and proliferation. PYGO2 is the main transcription factor of wnt pathway, while Msi1 is one of the wnt inhibitors. In this study we assessed the correlation between Msi1 and PYGO2 mRNA expression using Real time polymerase chain reaction in 48 esophageal squamous cell carcinoma (ESCC) patients. Although, there was not any significant correlation between the levels of Msi1 and PYGO2 mRNA expression, we observed a significant correlation between the Msi1 and PYGO2 overexpressed cases and depth of tumor invasion (p = 0.05). In conclusion, despite the role of these markers in tumor depth of invasion there is not any feedback between Msi1 and PYGO2 gene expression in ESCC.
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March 2016

Role of Msi1 and MAML1 in Regulation of Notch Signaling Pathway in Patients with Esophageal Squamous Cell Carcinoma.

J Gastrointest Cancer 2015 Dec;46(4):365-9

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Purpose: Developmental pathways such as Wnt and Notch are involved in different cellular functions from the cell cycle regulation to self-renewal. Therefore, aberrations in these pathways may cause tumorigenesis. Msi1 has a critical regulatory role for the Wnt and Notch pathways. In the present study, we have assessed the probable correlation between the Msi1 and MAML1 in esophageal squamous cell carcinoma (ESCC) progression and metastasis.

Methods: Levels of Msi1 and MAML1 mRNA expression in 51 ESCC patients were compared to the normal tissues using real-time polymerase chain reaction (PCR).

Results: Nine out of 51 (17.6 %) cases had Msi1/MAML1 overexpression, and there was a significant correlation between such overexpressed cases and tumor location (p = 0.013).

Conclusions: We showed that there is not any direct correlation and feedback between the Msi1 and MAML1 in ESCC patients.
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December 2015