Publications by authors named "Ayman M Ibrahim"

10 Publications

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Clinical, cellular, and molecular characterisation of cardiac rhabdomyoma in tuberous sclerosis.

Cardiol Young 2021 Feb 19:1-9. Epub 2021 Feb 19.

Aswan Heart Center, Aswan, Egypt.

Background: Rhabdomyoma is the most common cardiac tumour in children. It is usually associated with tuberous sclerosis complex caused by mutations in TSC-1 or TSC-2 genes. This tumour typically regresses by unknown mechanisms; however, it may cause inflow or outflow obstruction that necessitates urgent surgery. Here we investigate the clinical features and the genetic analysis of patients with tuberous sclerosis complex presenting with large rhabdomyoma tumours. We also investigate the potential role of autophagy and apoptosis in the pathogenesis of this tumour.

Methods: All the patients with cardiac rhabdomyoma referred to Aswan Heart Centre from 2010 to 2018 were included in this study. Sanger sequencing was performed for coding exons and the flanking intronic regions of TSC1 and TSC2 genes. Histopathological evaluation, immunohistochemistry, and western blotting were performed with P62, LC3b, caspase3, and caspase7, to evaluate autophagic and apoptotic signaling.

Results: Five patients were included and had the clinical features of tuberous sclerosis complex. Three patients, who were having obstructive tumours, were found to have pathogenic mutations in TSC-2. The expression of two autophagic markers, P62 and LC3b, and two apoptotic markers, caspase3 and caspase7, were increased in the tumour cells compared to normal surrounding myocardial tissue.

Conclusion: All the patients with rhabdomyoma were diagnosed to have tuberous sclerosis complex. The patients who had pathogenic mutations in the TSC-2 gene had a severe disease form necessitating urgent intervention. We also demonstrate the potential role of autophagy and apoptosis as a possible mechanism for tumourigenesis and regression. Future studies will help in designing personalised treatment for cardiac rhabdomyoma.
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http://dx.doi.org/10.1017/S1047951121000172DOI Listing
February 2021

Diverse Macrophage Populations Contribute to the Inflammatory Microenvironment in Premalignant Lesions During Localized Invasion.

Front Oncol 2020 24;10:569985. Epub 2020 Sep 24.

Department of Biochemistry and Molecular Biology, Tulane School of Medicine, New Orleans, LA, United States.

Myeloid cell heterogeneity remains poorly studied in breast cancer, and particularly in premalignancy. Here, we used single cell RNA sequencing to characterize macrophage diversity in mouse pre-invasive lesions as compared to lesions undergoing localized invasion. Several subpopulations of macrophages with transcriptionally distinct profiles were identified, two of which resembled macrophages in the steady state. While all subpopulations expressed tumor-promoting genes, many of the populations expressed pro-inflammatory genes, differing from reports in tumor-associated macrophages. Gene profiles of the myeloid cells were similar between early and late stages of premalignancy, although expansion of some subpopulations occurred. These results unravel macrophage heterogeneity in early progression and may provide insight into early intervention strategies that target macrophages.
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http://dx.doi.org/10.3389/fonc.2020.569985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541939PMC
September 2020

An Investigation of Fibulin-2 in Hypertrophic Cardiomyopathy.

Int J Mol Sci 2020 Sep 29;21(19). Epub 2020 Sep 29.

Aswan Heart Center, Aswan 200, Egypt.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart muscle disease, with a prevalence of at least 1 in 500 in the general population. The disease is pleiotropic and is characterized by an increased stiffness of the myocardium, partly due to changes in the extracellular matrix (ECM), with elevated levels of interstitial fibrosis. Myocardial fibrosis is linked to impaired diastolic function and possibly phenotypic heterogeneity of HCM. The ECM consists of a very large number of proteins, which actively interact with each other as well as with myocardial cells. The role of other multiple components of the ECM in HCM has not been defined. Fibulin-2 is a glycoprotein component of the ECM, which plays an important role during embryogenesis of the heart; however, its role in adult myocardium has not been adequately studied. We here describe, for the first time, abnormal expression of fibulin-2 in the myocardium in patients with HCM as compared to normal controls. This abnormal expression was localized in the cytoplasm of myocardial cells and in the interstitial fibroblasts. In addition, fibulin-2 levels, measured by ELISA, were significantly elevated in the serum of patients with HCM as compared to normal controls.
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http://dx.doi.org/10.3390/ijms21197176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583916PMC
September 2020

Inflammatory Breast Carcinoma: Elevated microRNA miR-181b-5p and Reduced miR-200b-3p, miR-200c-3p, and miR-203a-3p Expression as Potential Biomarkers with Diagnostic Value.

Biomolecules 2020 07 16;10(7). Epub 2020 Jul 16.

Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt.

Inflammatory breast cancer (IBC) is a rare yet aggressive breast cancer variant, associated with a poor prognosis. The major challenge for IBC is misdiagnosis due to the lack of molecular biomarkers. We profiled dysregulated expression of microRNAs (miRNAs) in primary samples of IBC and non-IBC tumors using human breast cancer miRNA PCR array. We discovered that 28 miRNAs were dysregulated (10 were upregulated, while 18 were underexpressed) in IBC vs. non-IBC tumors. We identified 128 hub genes, which are putative targets of the differentially expressed miRNAs and modulate important cancer biological processes. Furthermore, our qPCR analysis independently verified a significantly upregulated expression of miR-181b-5p, whereas a significant downregulation of miR-200b-3p, miR-200c-3p, and miR-203a-3p was detected in IBC tumors. Receiver operating characteristic (ROC) curves implied that the four miRNAs individually had a diagnostic accuracy in discriminating patients with IBC from non-IBC and that miR-203a-3p had the highest diagnostic value with an AUC of 0.821. Interestingly, a combination of miR-181b-5p, miR-200b-3p, and miR-200c-3p robustly improved the diagnostic accuracy, with an area under the curve (AUC) of 0.897. Intriguingly, qPCR revealed that the expression of zinc finger E box-binding homeobox 2 () mRNA, the putative target of miR-200b-3p, miR-200c-3p, and miR-203a-3p, was upregulated in IBC tumors. Overall, this study identified a set of miRNAs serving as potential biomarkers with diagnostic relevance for IBC.
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http://dx.doi.org/10.3390/biom10071059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407124PMC
July 2020

Tissue-resident macrophages promote extracellular matrix homeostasis in the mammary gland stroma of nulliparous mice.

Elife 2020 06 1;9. Epub 2020 Jun 1.

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States.

Tissue-resident macrophages in the mammary gland are found in close association with epithelial structures and within the adipose stroma, and are important for mammary gland development and tissue homeostasis. Macrophages have been linked to ductal development in the virgin mammary gland, but less is known regarding the effects of macrophages on the adipose stroma. Using transcriptional profiling and single-cell RNA sequencing approaches, we identify a distinct resident stromal macrophage subpopulation within the mouse nulliparous mammary gland that is characterized by the expression of Lyve-1, a receptor for the extracellular matrix (ECM) component hyaluronan. This subpopulation is enriched in genes associated with ECM remodeling and is specifically associated with hyaluronan-rich regions within the adipose stroma and fibrous capsule of the virgin mammary gland. Furthermore, macrophage depletion leads to enhanced accumulation of hyaluronan-associated ECM in the adipose-associated stroma, indicating that resident macrophages are important for maintaining homeostasis within the nulliparous mammary gland stroma.
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http://dx.doi.org/10.7554/eLife.57438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297528PMC
June 2020

Gas6 expression is reduced in advanced breast cancers.

NPJ Precis Oncol 2020 24;4. Epub 2020 Apr 24.

1Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane School of Medicine, New Orleans, LA USA.

Growth arrest-specific gene 6 (Gas6) is a cytokine that binds to receptor tyrosine kinases Tyro3, Axl, and Mer. Numerous studies have suggested that macrophage-derived Gas6 interacts with Axl to promote cancer progression, and Axl has been associated with poor clinical outcome. However, the expression and relevance of Gas6 in human breast cancer patients has not been studied. Analysis of tissue microarrays showed that Gas6 was highly expressed in ductal carcinoma in situ (DCIS) but markedly decreased in invasive breast cancer. Gas6 and Axl were weakly correlated, suggesting that their functions may not exclusively rely on each other. Analyses of publicly available databases showed significantly improved overall and relapse-free survival in patients with high Gas6 mRNA, particularly in luminal A breast cancers. These findings indicate that tumor-derived Gas6 is not overexpressed in invasive breast cancer, and may not be a negative prognostic factor in human breast cancer.
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http://dx.doi.org/10.1038/s41698-020-0116-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181799PMC
April 2020

Cor Triatriatum Sinister (Divided Left Atrium): Histopathologic Features and Clinical Management.

Ann Thorac Surg 2020 10 28;110(4):1380-1386. Epub 2020 Feb 28.

Aswan Heart Center, Aswan Governate, Egypt; Department of Cardiac Surgery, Royal Brompton and Harefield National Health Service Trust, London, United Kingdom. Electronic address:

Background: Cor triatriatum sinister (CTS), or divided left atrium, is a rare congenital cardiac disease in which the left atrium is divided into 2 chambers by a fibromuscular diaphragm that will cause blood flow obstruction to the left ventricle. Recent animal studies suggested the role of hyaluronidase-2 (HYAL-2) deficiency as a risk factor for developing CTS. The histopathologic features of this diaphragm and our surgical experience with the management of this disease are reviewed.

Methods: Ten patients underwent surgical correction of CTS between 2010 and 2018. All patients had complete clinical and imaging evaluation. The fibromuscular diaphragms were histologically evaluated with myosin, troponin, vimentin, smooth muscle actin, and HYAL-2 to characterize the structure of the CTS diaphragm.

Results: All patients underwent excision of CTS diaphragm using cardiopulmonary bypass with no early mortality. Most patients had the classic form of CTS in which the diaphragm separates the pulmonary and the vestibular chambers with no atrial septal defect. The histologic studies demonstrated the presence of fibrous, mesenchymal cells, along with cardiac muscle cells, at the site of membrane attachments. HYAL-2 enzyme was expressed in the CTS diaphragm.

Conclusions: Surgical repair of CTS provides satisfactory results with low risk of death. Our histologic studies revealed the cellular composition of the CTS diaphragm. HYAL-2 deficiency may not explain the pathogenesis of CTS, and further studies are needed to evaluate the complex mechanisms involved in the development of this disease.
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http://dx.doi.org/10.1016/j.athoracsur.2020.01.025DOI Listing
October 2020

Prognostic Value of Serum Antiphospholipid Antibodies in Patients with ST-Segment Elevation Myocardial Infarction.

Egypt J Immunol 2018 Jan;25(1):143-151

Department of Zoology, Faculty of Science, Aswan University, Aswan, Egypt.

Hypercoagulability in patients with primary Antiphospholipid syndrome (APS) predisposes to high rates of thromboembolic events and restenosis of the coronaries causing significant morbidity and mortality. Although the association between the APS and Acute Myocardial infraction (AMI) is very rare about 4%. Treatment of patients with APS represent a clinical challenge. Current study was designed to investigate the correlation between antiphospholipid antibodies (aPL) in prediction of the complication-associated AMI in Aswan governorate. Fifty AMI patients were compared to thirty controls. Serum aPLs was assessed using commercial ELISA kits. In patients; data revealed that mean Lupus anticoagulant was 59.2 U/mL, IgM and IgG anticardiolipin was 1.14 U/mL and 1.26 U/mL respectively. In addition the mean of antiphosphatidyl inositol (aPI) was 11.68 U/mL. On follow-up; Lupus and aCA IgM showed weak correlation with cases that showed further complications, while aCA-IgG showed protective effects (P=0.001/ r=-0.463) and aPI-IgM moderate correlation with the complications (P=0.048/ r=0.281). It's concluded that aCAs play distinct roles in the pathogenesis of AMI reduced levels of aCA-IgG has protective effects while the aCA-IgM indicate a poor prognosis, and that aPI is a good marker for prediction of recurrence of cardiovascular events among patients.
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January 2018

Fibulin-2 is required for basement membrane integrity of mammary epithelium.

Sci Rep 2018 09 20;8(1):14139. Epub 2018 Sep 20.

Institute of Cancer Sciences, College of MVLS, University of Glasgow, Glasgow, G12 8QQ, UK.

Fibulin-2 (FBLN2) is a secreted extracellular matrix glycoprotein which has been associated with tissue development and remodelling. In the mouse mammary gland, FBLN2 can be detected during ductal morphogenesis in cap cells and myoepithelial cells at puberty and early pregnancy, respectively. In an attempt to assign its function, we knocked down Fbln2 in the mouse mammary epithelial cell line EpH4. FBLN2 reduction led to an increase in the size of spheroidal structures when compared to scrambled control shRNA-transduced cells plated on Matrigel matrix. This phenotype was associated with a disruption of the collagen IV sheath around the epithelial spheroids and downregulation of integrin β1, suggesting a role for FBLN2 in stabilizing the basement membrane (BM). In contrast to mice, in normal adult human breast tissue, FBLN2 was detected in ductal stroma, and in the interlobular stroma, but was not detectable within the lobular regions. In tissue sections of 65 breast cancers FBLN2 staining was lost around malignant cells with retained staining in the neighbouring histologically normal tissue margins. These results are consistent with a role of FBLN2 in mammary epithelial BM stability, and that its down-regulation in breast cancer is associated with loss of the BM and early invasion.
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http://dx.doi.org/10.1038/s41598-018-32507-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148073PMC
September 2018

RNA Profiling of Non-cultured Fibroblasts Isolated from Pubertal Mouse Mammary Gland Sections.

Methods Mol Biol 2017 ;1501:149-164

Institute of Cancer Sciences, College of MVLS, University of Glasgow, Glasgow, G12 8QQ, UK.

The epithelium of the pubertal mouse mammary gland grows and invades the mammary fat pad to form a primary ductal network. This outgrowth is tightly controlled by epithelial and stromal factors that are present in the environment around the terminal end buds (TEB) at the growth front and the newly formed ducts. Identifying the contribution that each cell type makes to this regulation is a major challenge. To identify the role that fibroblasts play during this process we have optimised a fibroblast isolation procedure, followed by cell cleanup, RNA extraction, and amplification from non-cultured, freshly isolated fibroblasts from around the TEB as well as the subtending ducts. This was facilitated by the use of mice that constitutively expressed EGFP, which allowed the visualization of the growth front of the pubertal mammary tree under UV light. The isolated RNA is of sufficiently high quality, giving reproducible qRT-PCR results, for transcriptome analysis after RNA amplification.
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http://dx.doi.org/10.1007/978-1-4939-6475-8_6DOI Listing
January 2018