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Biomedical subjects

M R Hussein

Publications and source records attributed to M R Hussein.

At least 19 recordsLinked to original sources
PubMed2006

Retinoic acid can induce markers of endocrine transdifferentiation in pancreatic ductal adenocarcinoma: preliminary observations from an in vitro cell line model.

BACKGROUND AND HYPOTHESIS: The pancreatic ductal adenocarcinoma (HPAF) cells have a multipotent stem cell potential. It was hypothesised that all-trans-retinoic acid (atRA) can induce transdifferentiation of these cells into cells with an endocrine phenotype. MATERIAL AND METHODS: To explore this hypothesis, an in vitro system of cells was established. Some cells were treated with atRA at concentrations of 100 nmol/l (non-apoptosis-inducing) and 5 micromol/l (apoptosis-inducing) and harvested. Cells were examined for cell cycle kinetics, apoptosis (terminal deoxynucleotidyl transferase assay and p53 protein expression) and immunomorphological features of redifferentiation (MUC1 and DUPAN-2) and endocrine transdifferentiation (insulin, somatostatin, glucagon, neurone-specific enolase) by using immunoperoxidase staining methods. Levels of insulin, transforming growth factor (TGF) beta2, TGFalpha and epidermal growth factor receptor (EGFR) were measured by enzyme-linked immunosorbent assay (ELISA). The vehicle-treated cells served as a control group. RESULTS: When compared with untreated cells, cells treated with 100 nmol/l and 5 micromol/l atRA were observed to show (1) decreased proliferative activity (cpm) as indicated by decreased incorporation of thymidine labelled with hydrogen-3; (2) cell cycle arrest; (3) increased apoptotic activity associated with p53 protein overexpression; (4) upregulated expression of the transdifferentiation and redifferentiation markers; (5) morphological changes indicative of transdifferentiation (increased cell size and appearance of dendrites); (6) decreased production of EGFR; (7) upregulation of TGFalpha and TGFbeta2; and (8) increase in basal and glucose-induced insulin secretion. CONCLUSIONS: Functional endocrine transdifferentiation can be induced in HPAF lines by atRA. Further investigations are mandated to explore the underlying mechanisms of this transdifferentiation and to explore its in vivo extrapolation.

Antineoplastic Agents↗
PubMed2006

Age-associated decrease of CD1d protein production in normal human skin.

BACKGROUND: CD1d belongs to a family of antigen-presenting molecules structurally related to the classical major histocompatibility complex class I proteins. OBJECTIVES: To examine the expression pattern of CD1d protein in normal human skin with ageing. METHODS: Twenty normal human skin biopsy specimens were obtained from 20 healthy individuals. The latter were divided into three age groups: children (5-20 years), adults (21-50 years) and the elderly (51-81 years). The intensity of CD1d protein production was examined in human skin using immunofluorescent and immunoalkalinephosphatase staining methods. RESULTS: In the epidermis, CD1d protein production was strong in the skin of the children and declined gradually with age, being moderate in adults and weak in the elderly. As compared with values in children, there was a statistically significant decrease (P<0.05) in CD1d protein production in the elderly. In the dermis, CD1d protein production was strong in the fibroblasts, sweat glands, sebaceous glands, blood vessels and hair follicles regardless of age. CONCLUSIONS: Our study reports a decreased CD1d protein production in normal human skin with ageing. The clinical ramifications of these observations mandate further investigations.

Adolescent↗
PubMed2006

Glomerular expression and elevated serum Bcl-2 and Fas proteins in lupus nephritis: preliminary findings.

Programmed cell death (apoptosis) is involved in glomerular injuries leading to glomerulonephritis. Bcl-2 and Fas are proteins that promote cell survival and death, respectively. This study tests the hypothesis that lupus nephritis is associated with alterations of Bcl-2 and Fas protein expression. Thirty-six patients with lupus nephritis and 10 controls (normal individuals) were included in this study. Bcl-2 and Fas positive cells were examined in kidney biopsies by immunohistochemistry. Bcl-2 and Fas serum levels were evaluated by enzyme-linked immunosorbent assay (ELISA). In the glomeruli of normal kidneys, Bcl-2 and Fas proteins were completely absent. In lupus nephritis patients, glomerular expression of Bcl-2 and Fas was seen in mesangial cells (1.3 +/- 0.1 and 2.0 +/- 0.1 for Bcl-2 and Fas, respectively). Similarly, a statistically significantly higher Bcl-2 (217.1 +/- 85.9) and Fas (767.9 +/- 271) serum levels were found in lupus patients compared to controls (148.6 +/- 87, 550.3 +/- 91 for Bcl-2 and Fas, P < 0.05). A direct correlation between serum Bcl-2 and Fas and chronicity index was also found. Compared to normal controls, lupus nephritis is associated with glomerular expression and elevated serum levels of Bcl-2 and Fas proteins. These findings suggest possible roles for Bcl-2 and Fas in glomerular injury during evolution of lupus nephritis. The diagnostic, prognostic and therapeutic ramifications of our findings are open to further investigation.

Adult↗
PubMed2006

Immunohistological characterisation of tumour infiltrating lymphocytes in melanocytic skin lesions.

BACKGROUND: Although the presence of tumour infiltrating lymphocytes (TIL) is a constant feature in melanomas, their immunophenotypic characterisation is still incomplete. We hypothesise that the transition from normal skin to benign naevi (BN) to melanocytic dysplastic naevi (MDN) to radial growth phase cutaneous malignant melanoma (RGP-CMM) to vertical growth phase cutaneous malignant melanoma (VGP-CMM) is associated with alterations in TIL. This study attempted to test this hypothesis and to characterise TIL in the melanocytic skin lesions. METHODS: In total, 74 lesions (12 BN, 12 MDN, 13 RGP-CMM, 26 VGP-CMM, and 11 metastatic melanomas) were examined using immunoperoxidase staining methods and antibodies targeting leukocyte common antigen (LCA+), T (CD3+) and B (CD20+) lymphocytes, and resting cytotoxic T cells (TIA-1+). RESULTS: Histologically, the transitions from normal skin to BN to MDN to RGP-CMM to VGP-CMM was associated with a gradual increase in the numbers of TIL (total, parenchymal, stromal, perivascular, and epidermal TIL, as well as TIL at the base of the lesions). The numbers of TIL were higher at the stroma than at the parenchyma. Similarly, immunostaining revealed that these transitions were associated with a gradual increase in the staining values (staining intensity, percentage of positive cells, and immunoreactivity score) for LCA+, CD20+, CD3+, and TIA-1+cells. The number of CD3+ cells was higher than that of CD20+ cells. All these differences between the normal skin and the lesional ones reached statistical significance (p<0.01). The majority of CD3+ cells were TIA-1+ T cells with cytotoxic potential. Compared with primary melanomas, there was a decrease in TIL in metastatic melanomas. CONCLUSIONS: The gradual increase in TIL during melanoma tumorigenesis may reflect increased antigenicity of the tumour cells. Although both humoral and cell mediated immunity are involved in melanomagenesis, the latter seems to have the major role. The immune profile of MDN suggests their intermediacy between BN and CMM.

Analysis of Variance↗
PubMed2006

Analysis of the mononuclear inflammatory cell infiltrate in the normal breast, benign proliferative breast disease, in situ and infiltrating ductal breast carcinomas: preliminary observations.

BACKGROUND: Mammary carcinogenesis is a multistep process entailing the transition from normal breast to benign proliferative breast disease (ductal hyperplasia) to ductal carcinoma in situ to infiltrating ductal carcinoma. HYPOTHESIS: These transitions are associated with changes in the mononuclear inflammatory cell infiltrate. MATERIALS AND METHODS: A total of 53 mastectomy specimens of normal breast, benign proliferative breast disease, ductal carcinoma in situ and infiltrating ductal carcinoma were evaluated for mononuclear inflammatory cell infiltrate by using immunohistological methods and monoclonal antibodies including CD20, CD68, CD3 and granzyme B, histiocytes, T cells and cytotoxic T cells. RESULTS: Transitions from normal breast to the subsequent tissue with lesions (normal skin v benign proliferative breast disease v ductal carcinoma in situ v infiltrating ductal carcinoma) were associated with significantly (p<0.01) increased mean (SD) density of mononuclear inflammatory cell infiltrate at the parenchyma (3.2 (1.0) v 26.4 (7.8) v 33.6 (7.9) v 39.1 (4.7) for CD20+ B cells; 2.8 (1.0) v 81.5 (14.0) v 84.0 (14.9) v103.7 (3.9) for CD3; 1.3 (2.0) v 3.8 (4.0) v 12.7 (23) v 22.1 (25.0) for CD68+ macrophages; 2.0 (1.0) v 58.3 (5.0) v 60.0 (10.0) v 74.1 (28.0) for granzyme B+ cytotoxic T cells) and at the stroma (0.7 (1.0) v 3.0 (5.0) v 13.3 (20) v 16.7 (30.0) for CD20+ B cells; 1.0 (2.06) v 4.0 (2.5) v 16.7 (5.0) v 21.7 (15) for CD68+ macrophages; 1.4 (0.6) v 4.2 (1.2) v 46.6 (16.7) v 77.0 (5.0) for CD3+ cells and 0 (0) v 0.5 (1.0) v 0.7 (1.0) v 0.7 (1.0) for granzyme B+ cytotoxic T cells). CONCLUSIONS: The increased mononuclear inflammatory cell infiltrate during mammary carcinogenesis may reflect non-specific or specific immunological processes.

B-Lymphocyte Subsets↗
PubMed2005

Analysis of fibronectin expression in the bilharzial granulomas and of laminin in the transformed urothelium in schistosoma haematobium infested patients.

UNLABELLED: The bilharzial granulomas and urothelial transformation are common findings in Schistosoma haematobium infested patients. We hypothesize that the distribution of extrinsic (fibronectin, FN) and intrinsic basement membrane (BM) proteins (laminin, LN) is altered during the evolution of these lesions. METHODS: To test this hypothesis, 70 cystectomy specimens, entailing variable associations of normal and dysplastic urothelium (all cases), and bilharzial granulomas were examined for FN and LN protein expression. RESULTS: The biharzial granulomas were formed of admixture of CD3+T cells, CD68+histiocytes and CD220B cells. The CD3+T cells and and CD68+histiocytes were the predominant cell populations. Increased deposition of FN occurred with the evolution from cellular (loose fibrillary network, 20 cases) to fibrocellualr (dense fibrillary network, 30 cases) to fibrotic (tight conglomerates, 20 cases) granulomas. Alternatively, BM staining for LN was linear and continuous underlying normal and metaplastic urothelium. In dysplastic urothelium (20 cases), it showed breaks in continuity. CONCLUSIONS: Alterations of FN and LN occur during the development of the bilharzial granuloma and urothelial transformation.

Animals↗
PubMed2005

Tumour-infiltrating lymphocytes and melanoma tumorigenesis: an insight.

The presence of tumour-infiltrating lymphocytes (TILs) amid the tumour cells in the stroma and overlying epidermis is a constant feature of melanoma, the deadliest skin cancer. These lymphocytes are mostly cytotoxic T cells (CTLs) that can be propagated in vitro by specific cytokines. Also, they can kill melanoma cells. This specific killing can be abrogated by monoclonal antibodies against CD3, CD8, T-cell receptors (TCRs) and against class I human leucocyte antigens (HLAs). This indicates that these CTLs can recognize the melanoma cells through the TCRs, in an HLA class I-restricted manner. Therefore, these cells and their products both are critical players in T cell-induced melanoma regression and are powerful predictors of survival. This review seeks to examine the characteristics, activation and role of TILs and their associated molecules in melanomas.

Antigens, Neoplasm↗
PubMed2005

Alterations of mononuclear inflammatory cells, CD4/CD8+ T cells, interleukin 1beta, and tumour necrosis factor alpha in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a multisystem disease with underlying immune mechanisms. AIMS: To investigate the clinicopathological characteristics of the lesions; immunological alterations in the bronchoalveolar lavage fluid (BALF), peripheral blood, and skin; and correlations between the clinicopathological characteristics and immunological alterations in SSc. MATERIALS/METHODS: Skin biopsies, BALF, and peripheral blood samples were obtained from 19 patients (18 women, one man) with SSc and six age and sex matched healthy controls (HCs). Mononuclear inflammatory cells (MICs), CD4/CD8 cells, tumour necrosis factor alpha (TNFalpha), and interleukin 1beta (IL1-1beta) concentrations were examined in all samples using histological methods, enzyme linked immunosorbent assay, and immunoperoxidase staining. RESULTS: The mean (SD) age of the patients with SSc was 34.8 (2.6) years. Proteinuria, positive rheumatoid factor, and C reactive protein were seen in 15.8%, 26.3%, and 26.3% of patients, respectively. Compared with HCs, there were significantly higher: total MICs (macrophages, lymphocytes), neutrophils, and eosinophils in BALF, blood, and skin (all p<0.05); cytokine concentrations in BALF (TNFalpha, p<0.001; IL-1, p<0.01) and peripheral blood (p<0.01 and p<0.05); and CD8/CD4+ T cells in peripheral blood (p<0.05). Compared with HCs, lesional skin had significantly higher histiocyte cell counts (p<0.05), lower lymphocyte counts (p<0.05), and higher CD4/CD8 ratios (p<0.001). There were significant correlations between cytokine concentrations and CD8+ T cells and forced vital capacity (p<0.001 and p<0.01, respectively). CONCLUSIONS: MICs, CD4/CD8+ cells, and cytokines are altered in SSc. These alterations correlated with the underlying disease process and therefore may have pathogenic, modulatory, and potential prognostic roles in SSc.

Adult↗
PubMed2005

Melanocytic dysplastic naevi occupy the middle ground between benign melanocytic naevi and cutaneous malignant melanomas: emerging clues.

Although several studies have confirmed the aetiological importance of melanocytic dysplastic naevi (MDN) in the development of cutaneous malignant melanoma (CMM), the analysis of these lesions was directed mostly towards the study of melanomas. The underlying reasons include the relatively large size of CMMs, their direct lethal outcome, and the feasibility of establishing melanoma cell lines. In contrast, because of their relatively small size, questionable malignant potential, and the difficulty in establishing in vitro cultures, MDN have been studied less extensively. Hypothetically, transformed melanocytes can give rise to any lesion in the hierarchy of melanocytic tumours. Based on this hypothetical perspective, and on the epidemiological, morphological, immunohistochemical, and genetic characteristics of MDN, it is not surprising that these lesions occupy an intermediate position in the hierarchy of melanocytic lesions, and may be precursors of CMM. Although this argument appears to be straightforward, it is still controversial. This review explores the components of this argument and provides supporting evidence for this hypothesis.

Cell Transformation, Neoplastic↗
PubMed2005

Genomic instability in radial growth phase melanoma cell lines after ultraviolet irradiation.

BACKGROUND/AIMS: Although ultraviolet (UV) irradiation, apoptosis, and genomic instability are all potentially involved in the pathogenesis of melanoma, in vitro studies investigating these changes in the radial growth phase of this neoplasm are still lacking; therefore, this study was designed to investigate these changes. METHOD: An in vitro system consisting of three radial growth phase Wistar melanoma cell lines (WM35, WM3211, and WM1650) was established. Cells were UV irradiated (10 mJ/cm2 for UVB and 6 J/cm2 for UVA), harvested after UV exposure, and evaluated for viability and apoptosis using Trypan blue and terminal deoxynucleotidyl transferase mediated dUTP digoxigenin nick end labelling assays, respectively. Polymerase chain reaction based microsatellite assays were used to examine the cell lines for the presence of microsatellite instability (MSI) using 21 markers at the 1p, 2p, 3p, 4q, 9p, and 17p regions. RESULTS: Exposure to UV initiated progressive cell death associated with pronounced apoptosis, with UVA having a greater effect than UVB. MSI was found in UVB (WM35 and WM3211) and UVA (WM35) irradiated cell lines at 1p, 9p, and 17p, but not in non-irradiated cells. The prevalence of MSI was higher after UVB irradiation (14%) than UVA irradiation (4.7%), and was most frequently found at D1S233. CONCLUSIONS: The ability of erythemogenic UV irradiation to induce both apoptosis and MSI in radial growth phase melanoma cells is suggestive of its role in melanoma pathogenesis. This instability may reflect a hypermutability state, oxidative stress induced DNA damage, replication infidelity, or a combination of these factors.

Apoptosis↗
PubMed2005

Analysis of Bcl-2 protein expression in choroidal melanomas.

BACKGROUND: Bcl-2 protooncogene alterations are involved in tumorigenesis and may have prognostic ramifications. AIMS: To investigate normal ocular structures and choroidal melanoma for: (1) Bcl-2 protein expression (semiquantitative staining values: SI, staining intensity; PP, percentage of positive cells; and IRS, immunoreactivity score) and (2) any associations between the staining values and clinicopathological features in these lesions. MATERIALS/METHODS: Bcl-2 protein expression was analysed in 24 choroidal melanomas using immunoperoxidase staining methods. RESULTS: Bcl-2 protein expression was seen in corneal epithelium, lens epithelium, the ciliary body, and retinal cells. In these structures, the mean (SEM) values were: 1.1 (0.1), 1.6 (0.3), 1.1 (0.1), and 2.3 (0.3), respectively, for SI; 1.6 (0.2), 1.7 (0.1), 1.7 (0.2), and 1.7 (0.2) for PP, respectively; and 1.9 (0.4), 2.7 (0.5), 1.9 (0.1), and 4.0 (0.8), respectively, for IRS. Based on Bcl-2 immunoreactivity, the lesions were divided into two groups. The first group comprised 12 tumours with Bcl-2 expression. Bcl-2 expression was significantly higher in this group compared with normal ocular structures (1.5 (0.1) v 2.8 (0.2), 1.7 (0.1) v 3.5 (0.1), and 2.6 (0.3) v 9.3 (0.9) for mean (SEM) SI, PP, and IRS scores, respectively; p = 0.00). The second group comprised 12 tumours lacking Bcl-2 protein expression. There was no significant correlation between Bcl-2 protein expression and most of the clinicopathological features of these lesions. CONCLUSIONS: Bcl-2 protein expression is altered in choroidal melanomas.

Adult↗
PubMed2004

Genetic pathways to melanoma tumorigenesis.

The incidence of cutaneous malignant melanomas is growing faster than that of any other cancer and therefore posing a major heath threat worldwide. In melanocytic skin tumours, the feasibility of correlating a specific pathological stage with a corresponding genetic alteration provides a remarkable opportunity to study the multistep tumorigenesis model. This multistep melanoma tumorigenesis is best described as a continuum of transformation of the melanocytes, melanocytic dysplasia, and melanoma formation. These steps involve genotypic alterations including loss of tumour suppressor genes, microsatellite instability, and alterations of the mismatch repair system. This review seeks to examine melanoma tumorigenesis based on these genetic changes.

Chromosome Fragility↗
PubMed2003

p53-related pathways and the molecular pathogenesis of melanoma.

Cutaneous malignant melanoma (CMM) is a life-threatening cancer that can have a poor prognosis with high metastatic potential. Its incidence is rapidly increasing worldwide. Its molecular alterations involve multiple pathways, including those related to p53. Since 1981, more than 380 papers containing the terms 'p53 and melanoma' as key words in the Abstract have been published in the literature. However, in spite of these extensive investigations, a review of p53 and associated genes in CMM is still lacking. To remedy this issue, this review seeks to provide a brief overview of p53 and discuss the genes targeted along its related pathways.

Animals↗
PubMed2001

Comprehensive analysis of 112 melanocytic skin lesions demonstrates microsatellite instability in melanomas and dysplastic nevi, but not in benign nevi.

INTRODUCTION: the length of DNA repetitive sequences (microsatellite instability (MSI)) represent distinct tumorigenic pathways associated with several familial and sporadic tumors. MATERIAL AND METHODS: To investigate the prevalence and frequency of MSI in melanocytic lesions, the polymerase chain reaction (PCR)-based microsatellite assay was used to examine formalin-fixed, paraffin-embedded tissues of 30 benign melanocytic nevi, 60 melanocytic dysplastic nevi (MDN), and 22 primary vertical growth phase cutaneous malignant melanomas (CMM). Twenty-four microsatellite markers at the 1p, 2p, 3p, 4q and 9p chromosomal regions were used. RESULTS: MSI was found at 1p and 9p in MDN and CMM but not in benign melanocytic nevi. The overall prevalence of MSI was 17/60 (28%) in MDN and 7/22 (31%) in CMM. The frequency of MSI ranged from 2/24 (9%) to 4/24 (17%) and was most commonly found at D9S162. There was a statistically significant correlation between degree of atypia and frequency of MSI (p<0.001) in MDN. There were two MSI banding patterns: band shifts and additional bands. CONCLUSIONS: The data presented revealed the presence of low-frequency MSI (MSI-L) at the 1p and 9p regions in both MDN and CMM. Whether the MSI-L pattern reflects a defect in mismatch repair genes is still to be determined.

Chromosome Mapping↗
PubMed2001

An early lesion in hepatic carcinogenesis: loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region.

Loss of heterozygosity (LOH) of chromosome 1 has been suggested, by karyotyping, to be an initial episode in human hepatocarcinogenesis. However, this alteration has not yet been investigated in cirrhotic nodules (CNs) or dysplastic nodules (DNs). In an initial study from explanted or resected cirrhotic livers, LOH in 1p36-p32 was examined in 31 hepatocellular carcinomas (HCCs), 25 low-grade dysplastic nodules (LGDNs), and 24 high-grade dysplastic nodules (HGDNs). In HCCs, LOH was detected most frequently at loci D1S2843 (1p36.1) (28.6%), D1S513 (1p34.3) (29.2%), and MYCL1 (1p34.1) (28.6%). In HGDN and LGDN, LOH incidences at D1S513 were 11.1% and 13.6%, respectively. To further refine those results and to determine sequential relationships among CN, DN, and HCC, LOH was next studied in an additional 53 HCCs, 56 HGDNs, 30 LGDNs, and 215 CNs from 11 explanted human cirrhotic livers, including 30 "nodule-in-nodule" lesions. Seven markers between D1S2843 (1p36.12) and MYCL1 (1p34.1), and 1 each at D1S484 (1q24.1), IGF2R-3 (6q26), and TP53 (17p13.1) were used. LOH at D1S2843 and D1S513 was detected in HCCs (20.4% and 23.5%, respectively), HGDNs (7.7% and 18.5%), LGDNs (13.6% and 6.9%), and CNs surrounding either HCCs or DNs (7.4% and 8.3%). These results demonstrate that LOH at D1S2843 and D1S513 are early events in human liver carcinogenesis. Data from CN surrounding either HCCs or DN, and also nodule-in-nodule lesions, provide evidence supporting a CN-->DN-->HCC progression. Different deletion patterns from multiple HCCs and DNs suggest independent origins for carcinogenesis in the same individual.

Chromosomes, Human, Pair 1↗