Onder Bozdogan

A Mouse Skin Multistage Carcinogenesis Model Reflects the Aberrant DNA Methylation Patterns of Human Tumors

Whereas accepted models of tumorigenesis exist for genetic lesions, the timing of epigenetic alterations in cancer is not clearly understood. We have analyzed the profile of aberrations in DNA methylation occurring in cells lines and primary tumors of one of the best-characterized mouse carcinogenesis systems, the multistage skin cancer progression model. Initial analysis using high-performance capillary electrophoresis and immunolocalization revealed a loss of genomic 5-methylcytosine associated with the degree of tumor aggressiveness. Paradoxically, this occurs in the context of a growing number of hypermethylated CpG islands of tumor suppressor genes at the most malignant stages of carcinogenesis. We have observed this last phenomenon using two approaches, a candidate gene approach, studying genes with well-known methylation-associated silencing in human tumors, and a mouse cDNA microarray expression analysis after treatment with DNA demethylating drugs. The transition from epithelial to spindle cell morphology is particularly associated with major epigenetic alterations, such as E-cadherin methylation, demethylation of the Snail promoter, and a decrease of the global DNA methylation. Analysis of data obtained from the cDNA microarray strategy led to the identification of new genes that undergo methylation-associated silencing and have growth-inhibitory effects, such as the insulin-like growth factor binding protein-3. Most importantly, all of the above genes were also hypermethylated in human cancer cell lines and primary tumors, underlining the value of the mouse skin carcinogenesis model for the study of aberrant DNA methylation events in cancer cells.

Examination of Bcl-2, Bcl-X and bax protein expression in psoriasis

Background  Psoriasis is an inflammatory skin disease characterized by epidermal hyperplasia and greatly accelerated epidermal turnover. The blockage of normal apoptotic process in the epidermis is one of the factors implicated in the pathogenesis of psoriasis.

Apoptosis-related proteins and steroid hormone receptors in normal, hyperplastic, and neoplastic endometrium.

The purpose of this study was to evaluate the distribution and frequency of apoptosis-related proteins and their correlation with estrogen, progesterone, and androgen receptors in endometrial tissues. Immunohistochemical analyses of bcl-2, bax, bcl-x, and steroid receptors were performed in 22 endometrial carcinomas, 26 endometrial hyperplasias, and 19 cases of normal cyclical endometrium. Bcl-2 was expressed in 45.4% of carcinomas and 92.3% of hyperplasias. Bax immunostaining was found in 90.9% of carcinomas and 76.9% of hyperplasias. Bcl-x positivity was similar in carcinomas (68.1%) and endometrial hyperplasias (76.9%). In normal cyclical endometria, bcl-2 staining was intense and diffuse in the proliferative phase, but decreased dramatically in the early and mid-secretory phase to reappear in the late secretory phase. Bax was expressed throughout the menstrual cycle but more strongly in the secretory phase. Bcl-x displayed a similar degree of expression in proliferative and secretory endometria. Nineteen carcinomas (86.3%), 25 hyperplasias (96.1%), and 18 normal cyclical endometria (94.7%) were positive for estrogen receptor (ER). Progesterone receptor (PR) was observed in 20 carcinomas (90.9%), all hyperplasias (100%), and 18 normal cyclical endometria (94.7%). Androgen receptor (AR) positivity was seen in 7 carcinomas (31.8%), 6 hyperplasias (23.0%), and 3 normal cyclical endometria (15.7%). There was a statistically positive correlation between bcl-x and ER and a tendency toward significant correlation between bcl-x and PR and between ER and PR in carcinomas. In hyperplasias, there was a significant positive correlation between bcl-2 and PR and between bcl-2 and bax and a negative correlation between ER and bax. There was a statistically significant difference for bcl-2 (p=0.001) and bax (p=0.001) between the hyperplasia and carcinoma groups. There was increased expression of bax, decreased expression of bcl-2, and persistence of bcl-x protein in advanced endometrial carcinomas. Our findings show that ovarian hormones have a regulatory role on bcl-2 protein and that there is a correlation between other members of the bcl-2 family (bcl-x and bax) and steroid hormone receptors. Bax/bcl-x may be the major control mechanisms of apoptosis in advanced carcinomas; other members of the bcl-2 family may also be under hormonal control.

Tularemia presenting as tonsillopharyngitis and cervical lymphadenitis: a case report and review of the literature

In this report, we describe a 57-year-old woman with oropharyngeal tularemia who presented with tonsillopharyngitis and cervical lymphadenitis. Clinical and radiological manifestations and histopathological characteristics of this disease are discussed with a review of the world literature. The oropharyngeal form of tularemia should be considered in the differential diagnosis of cases involving tonsillopharyngitis and cervical lymphadenitis, particularly in those not responding to penicillin treatment.

Fas-mediated pathway and apoptosis in normal, hyperplastic, and neoplastic endometrium

OBJECTIVES Abnormalities in the control of cell proliferation and apoptosis have been suggested to contribute to the development and progression of neoplasia. There are at least two pathways that activate apoptosis. The first is a mitochondria-dependent route governed by bcl-2 family proteins. The second is a parallel mechanism which involves the activation of a group of tumor necrosis factor (TNF) receptors, such as Fas. METHODS The aim of this study was to examine the distribution and interrelation between the expression patterns of apoptosis-related proteins such as Fas, caspase-3 (CPP32), and M30, and to investigate the role of Fas-mediated apoptosis in the pathogenesis and progression of endometrial neoplasms. RESULTS Using specific antibodies for Fas, caspase-3, and M30, we examined protein expressions in 29 endometrial carcinomas, 30 endometrial hyperplasias, and 21 normal cyclic endometria. The results of immunostaining for Fas and caspase-3 were analyzed semiquantitatively by using an immunohistochemical scoring system (HSCORE) that incorporated both the intensity and the distribution of specific staining. For M30, positive staining cells and extracellular particles were analyzed semiquantitatively per 10 high-power fields.HSCOREs of Fas and caspase-3 were slightly higher in the secretory endometria than in the proliferative endometria. Similarly, M30 reactivity seemed to increase in the late secretory phase of the cycle. HSCOREs of Fas and caspase-3 and the reactivity of M30 were significantly higher in the carcinoma group than in the simple hyperplasia group (P < 0.05). Complex hyperplasias, however, expressed quite similar HSCOREs of Fas and caspase-3 as carcinomas. M30 reactivity was also significantly higher in complex hyperplasias than in simple hyperplasias, and in carcinomas positivity increased significantly (P < 0.05) as the grade progressed. CONCLUSIONS The significant increase observed in Fas, caspase-3, and M30 expression in carcinomas as compared with simple hyperplasias may suggest that the Fas-related apoptotic pathway is also involved in the regulation of apoptosis in the endometrial tissue and promotes the development and progression of endometrial neoplasia.

Focal acral hyperkeratosis: A rare cutaneous disorder within the spectrum of costa acrokeratoelastoidosis

Abstract:  Acrokeratoelastoidosis and focal acral hyperkeratosis share similar clinical features and identical histologic epidermal alterations. These disorders are distinguished solely on the basis of the absence of elastorrhexis in the latter. We present a case of focal acral hyperkeratosis in a 9‐year‐old girl. The lesions consisted of translucent polygonal papules clustered on the thenar regions of the palms and over the metacarpophalangeal and interphalangeal joints. Histopathologic examination revealed orthohyperkeratosis within focal clavus‐like depressions of the epidermis and prominent hypergranulosis. There was no evidence of alterations in elastic tissue. The clinicopathologic distinction between focal acral hyperkeratosis and acrokeratoelastoidosis is blurred. There is enough evidence to consider the former as a histologic variant of Costa acrokeratoelastoidosis syndrome, and a better nomenclature for this disorder would be “acrokeratoelastoidosis without elastorrhexis.”

Effect of slow-release 5-Fluorouracil on capsule formation around silicone breast implants: an experimental study with mice.

BackgroundCapsule formation around breast implants, development of tendon adhesions after tendon repair, intestinal brits after laparatomies, hypertrophic scars in skin incisions all are the results of excessive collagen synthesis to the extracellular matrix by fibroblasts. Any intervention that leads to cessation of collagen synthesis in these clinical situations may help to prevent these untoward results of wound healing. Although 5-fluorouracil (5-FU) is used mainly as a cytotoxic drug in chemotherapy protocols, it decreases cellular metabolism and blocks protein synthesis only at lower concentrations. Findings have shown that 5-FU downregulates fibroblast proliferation and differentiation in vitro. It has been used to treat fibroproliferative disorders of the eye and skin and is thought to inhibit thymidylate synthetase, blocking DNA replication.MethodsThis study used five treatment groups: (1) gelatin only, (2) silicone only, (3) silicone + gelatin, (4) silicone + gelatin containing 1 mg of 5-FU, and (5) silicone + gelatin containing 5 mg of 5-FU. The release kinetics of 5-FU from gelatin have been investigated by means of ultraviolet spectrophotometric analysis. Specimens were obtained on postoperative day 30. Gross evaluation and histopathologic examination were conducted for capsule formation and the development of inflammation.ResultsThe silicone group had the most prominent capsule formation among all the groups. The gelatin group was second, and the silicone + gelatin group was third. As compared with the other groups, the 5-FU–containing groups had the least capsule formation. The 5-mg 5-FU–containing group had the most inflammation. The silicone + gelatin group was second in inflammation. Although the silicone, gelatin, and 1-mg 5-FU–containing groups had the same means, the results of the silicone group showed the most divergent data within the group.ConclusionsBecause 5-FU loaded to a gelatin carrier for its slow release seems to prevent capsule formation around silicone blocks, it may be used to prevent capsule formation around silicone breast implants.

Significance of p57(Kip2) down-regulation in oncogenesis of bladder carcinoma: an immunohistochemical study.

Aims and Background Cyclin-dependent kinase inhibitors have important roles in the oncogenesis of various tumors including urothelial cancer. The aim of this study was to establish the importance of p57Kip2, a unique cyclin-dependent kinase inhibitor, in the oncogenesis of bladder carcinoma. This article also focused on another cyclin-dependent kinase inhibitor, p27Kip1, and telomerase enzyme and examined the relationship between these proteins. Material and Methods Thirty-one patients with urothelial carcinomas of the bladder and 7 cases with normal urinary bladder mucosa were included in the study. Immunohistochemical study was performed by monoclonal antibodies of p27Kip1, p57Kip2, and the telomerase subunit (hTERT). All immunohistochemical preparations were evaluated by an immunohistochemical histological score. Results p57Kip2 and p27Kip1 expression were seen in all of the cases of normal mucosa. In carcinoma cases, 8 of 31 (25.8%) showed p57Kip2 nuclear positivity and 20 of 31 (64.5%) expressed nuclear p27Kip1. HSCOREs of carcinoma cases showed lower scores of nuclear p57Kip2 and p27Kip1 than normal mucosa, but only HSCOREs of nuclear p57Kip2 (P = 0 001) showed statistical significance. Despite unknown significance, cytoplasmic p57Kip2 and p27Kip1 were also evaluated. Immunohistochemical analysis showed that carcinomas expressed higher HSCOREs of hTERT than normal mucosa, and there was a significant difference (P = 0.026) between muscle invasive carcinomas and normal mucosa. Conclusions The data showed that p57Kip2 down-regulation along with p27Kip1 is a well-established feature of urothelial carcinoma. Probably, this down-regulation of cyclin-dependent kinase inhibitors supports the proliferation phase of oncogenesis. In the study, we also showed that hTERT expression was up-regulated in higher stages of urothelial carcinoma.

BCL2 expression and its correlation with neuroendocrine differentiation in colon carcinomas

Aims and background In this study we investigated the association between BCL2 expression and neuroendocrine differentiation in tubular adenomas and colon carcinomas. We also evaluated the prognostic significance of BCL2 expression and neuroendocrine differentiation in the carcinoma group. Methods Forty-eight colon carcinomas and twelve tubular adenomas were stained immunohistochemically with BCL2 and chromogranin A (CgA). Staining patterns were scored semiquantitatively and correlated with tumor type, tumor grade, Dukes stage, and survival time. Results BCL2 expression was detected in 7 of 12 (58.3%) adenomas and 37 of 48 (77.0%) carcinomas. In normal mucosa we observed positive staining only in the basal portions of the crypts. However, diffuse positivity was observed in the adenomas and carcinomas. Carcinomas had significantly higher BCL2 scores than the normal group, but we did not observe any significant differences either between the adenoma and carcinoma group or between the adenoma and normal group. BCL2 scores were higher in stage B than in stage C tumors, and in adenocarcinomas than in mucinous carcinomas. CgA positivity was observed in 24 of 48 (50%) carcinomas. It was not detected in adenomas. We did not find a significant correlation between CgA expression and any of the clinicopathological parameters. Conclusion On consecutive sections BCL2 and CgA positivity closely paralleled each other and a significant positive correlation was observed between CgA and BCL2 expression. These findings suggest a close association between BCL2 expression and neuroendocrine differentiation and indicate that BCL2 may be involved in neuroendocrine differentiation in addition to its role in protecting cells from apoptosis.

Juvenile Subcorneal Pustular Dermatosis: A Case Report

Abstract: Subcorneal pustular dermatosis is a chronic, relapsing, pustular dermatosis that usually develops in elderly women. It is rarely seen in childhood and adolescence. The hallmark of the disease is formation of a subcorneal pustule detected on histopathologic examination. Herein we present a 13‐year‐old girl diagnosed with subcorneal pustular dermatosis based on the typical clinical and histologic findings. Direct and indirect immunofluorescence and serum protein electrophoresis had negative results. The patient partially recovered after 5 weeks of treatment consisting of oral dapsone and a topical steroid ointment.