Carlos Resende

Genetic and epigenetic alteration in gastric carcinogenesis.

Gastric cancer (GC) is an important cause of morbidity and mortality worldwide. In addition to environmental factors, genetic factors also play an important role in GC etiology, as demonstrated by the fact that only a small proportion of individuals exposed to the known environmental risk factors develop GC. Molecular studies have provided evidence that GC arises not only from the combined effects of environmental factors and susceptible genetic variants but also from the accumulation of genetic and epigenetic alterations that play crucial roles in the process of cellular immortalization and tumorigenesis. This review is intended to focus on the recently described basic aspects that play key roles in the process of gastric carcinogenesis. Genetic variation in the genes DNMT3A, PSCA, VEGF, and XRCC1 has been reported to modify the risk of developing gastric carcinoma. Several genes have been newly associated with gastric carcinogenesis, both through oncogenic activation (MYC, SEMA5A, BCL2L12, RBP2 and BUBR1) and tumor suppressor gene inactivation mechanisms (KLF6, RELN, PTCH1A, CLDN11, and SFRP5). At the level of gastric carcinoma treatment, the HER‐2 tyrosine kinase receptor has been demonstrated to be a molecular target of therapy.

Gastric Cancer: Basic Aspects: Gastric Cancer: Basics

Gastric cancer (GC) is a world health burden, ranging as the second cause of cancer death worldwide. Etiologically, GC arises not only from the combined effects of environmental factors and susceptible genetic variants but also from the accumulation of genetic and epigenetic alterations. In the last years, molecular oncobiology studies brought to light a number of genes that are implicated in gastric carcinogenesis. This review is intended to focus on the recently described basic aspects that play key roles in the process of gastric carcinogenesis. Genetic variants of the genes IL‐10, IL‐17, MUC1, MUC6, DNMT3B, SMAD4, and SERPINE1 have been reported to modify the risk of developing GC. Several genes have been newly associated with gastric carcinogenesis, both through oncogenic activation (GSK3β, CD133, DSC2, P‐Cadherin, CDH17, CD168, CD44, metalloproteinases MMP7 and MMP11, and a subset of miRNAs) and through tumor suppressor gene inactivation mechanisms (TFF1, PDX1, BCL2L10, XRCC, psiTPTE‐HERV, HAI‐2, GRIK2, and RUNX3). It also addressed the role of the inflammatory mediator cyclooxygenase‐2 (COX‐2) in the process of gastric carcinogenesis and its importance as a potential molecular target for therapy.

Infectious balanoposthitis: management, clinical and laboratory features

Background  Balanitis is defined as inflammation of the glans penis, often involving the prepuce (balanoposthitis). It is a common condition due to a wide variety of causes with infection being the most frequent and several microorganisms reported. The clinical aspect is often non specific. The management of balanoposthitis remains a clinical challenge.

C/EBPbeta is over‐expressed in gastric carcinogenesis and is associated with COX‐2 expression

The CCAAT/enhancer‐binding protein beta (C/EBPbeta) transcription factor has been associated with several cancer models. In this study, the expression of C/EBPbeta was analysed in a series of 90 gastric carcinomas (GCs). We also assessed the effect of C/EBPbeta on COX‐2 expression. In normal gastric mucosa, C/EBPbeta expression was restricted to cells in the proliferative zone. In intestinal metaplasia, dysplasia, and GC of the intestinal and atypical subtypes, C/EBPbeta was over‐expressed (p < 0.0001, for the association with histological type). C/EBPbeta and Ki67, a marker of cell proliferation, were also co‐expressed in primary GC. We also observed an overlap between C/EBPbeta and COX‐2 expression in GC. Using GC cell lines we show that C/EBPbeta can regulate the expression of endogenous COX‐2 and transactivate the promoter of the COX‐2 gene, depending on its methylation status. These results suggest that C/EBPbeta may be a marker of neoplastic transformation and also play an active role in gastric tumourigenesis by regulating COX‐2 expression. Copyright

C/EBPα expression is associated with homeostasis of the gastric epithelium and with gastric carcinogenesis

Transcription factors from the CCAAT/enhancer-binding protein (C/EBP) family are fundamental for the control of differentiation and proliferation of many adult tissues. C/EBPα has a crucial role in inducing terminal differentiation and is an established tumor suppressor gene in several cancer models. The objective of this study was to analyze the putative role of C/EBPα in gastric carcinoma (GC). We analyzed the expression of C/EBPα in normal and neoplastic gastric tissues, and assessed the role of C/EBPα on proliferation and differentiation of GC cells. In normal gastric mucosa, C/EBPα is expressed in the foveolar epithelium and co-localizes with the gastric differentiation marker trefoil factor 1 (TFF1). The expression of C/EBPα was found to be lost in 30% of GC cases. To evaluate the role of C/EBPα in cell proliferation and differentiation, we transfected GC cells with a full-length C/EBPα protein. We observed a significant decrease in proliferation in C/EBPα-transfected cells. This was accompanied by a decrease in Cyclin D1, an increase in P27 expression, and an increased expression of TFF1. Finally, we showed that inhibition of the Ras/MAPK pathway leads to increased C/EBPα and TFF1 expression, and decreased cell proliferation and cyclin D1 expression in GC cells. Our results suggest that C/EBPα (together with other members of the C/EBP family) has an active role in the control of differentiation and proliferation in normal gastric mucosa. In GC, loss of C/EBPα may be associated with the switch from a cellular differentiation to a cellular proliferation program, presumably as a consequence of Ras/MAPK pathway activation.

Severe acute form of adult dermatomyositis treated with cyclosporine.

The classical treatment of severe forms of dermatomyositis includes high doses of steroids and/or cytotoxic agents. Acute forms are frequently life threatening. Because cyclosporine is a fast‐acting immunosuppressive drug, it appears to be a good candidate for the treatment of refractory forms of acute dermatomyositis. We report a dramatic improvement of a severe, acute, steroid‐resistent adult form after cyclosporine administration. A rapid clinical and biochemical improvement is reported, and the reversibility of immunologic abnormalities is emphasized.

CCAAT/Enhancer Binding Protein β (C/EBPβ) Isoforms as Transcriptional Regulators of the Pro-Invasive CDH3/P-Cadherin Gene in Human Breast Cancer Cells

P-cadherin is a cell-cell adhesion molecule codified by the CDH3 gene, which expression is highly associated with undifferentiated cells in normal adult epithelial tissues, as well as with poorly differentiated carcinomas. In breast cancer, P-cadherin is frequently overexpressed in high-grade tumours and is a well-established indicator of aggressive tumour behaviour and poor patient prognosis. However, till now, the mechanisms controlling CDH3 gene activation have been poorly explored. Since we recently described the existence of several CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor binding sites at the CDH3 promoter, the aim of this study was to assess if the distinct C/EBPβ isoforms were directly involved in the transcriptional activation of the CDH3 gene in breast cancer cells. DNA-protein interactions, mutation analysis and luciferase reporter assay studies have been performed. We demonstrated that C/EBPβ is co-expressed with P-cadherin in breast cancer cells and all the three isoforms function as transcriptional regulators of the CDH3 gene, directly interacting with specific regions of its promoter. Interestingly, this transcriptional activation was only reflected at the P-cadherin protein level concerning the LIP isoform. Taken together, our data show that CDH3 is a newly defined transcriptional target gene of C/EBPβ isoforms in breast cancer, and we also identified the binding sites that are relevant for this activation.

Tuberculosis in a child presenting as asymptomatic oropharyngeal and laryngeal lesions.

Abstract: We describe an 11‐year‐old boy who had several, asymptomatic, erythematous papules in the oropharynx and larynx with recent onset, two cervical lymphadenopathies, and a painless, erythematous plaque on the right wrist with a 2.5‐year history of slow growth. Histologic examination of the mucocutaneous lesions revealed a submucous infiltrate of lymphocytes and Langhans giant cells in the papules and granulomatous dermatitis in the plaque. The cervical lymph node was biopsied and on the surgical scar, an erythematous, nodular lesion developed. A biopsy specimen of this lesion showed tuberculoid granulomas with prominent caseation necrosis, and culture was positive for Mycobacterium tuberculosis. The Mantoux test was strongly positive with a vesicular response. A diagnosis of mucocutaneous lupus vulgaris and scrofuloderma secondary to cervical tuberculous lymphadenitis was made. Two months after initiation of antituberculosis therapy there was a complete resolution of mucous lesions and healing with atrophic scars on the neck and wrist. This is a rare presentation in the literature and reminds clinicians that tuberculosis should be kept in mind in the differential diagnosis of oral cavity lesions.

Oral and Gastric Helicobacter Pylori: Effects and Associations

Introduction This study consisted in the comparison of the prevalence of Helicobacter pylori (H. pylori) present in the stomach and in saliva of a sample of Portuguese adolescents and the assessment of the association between H. pylori infection with socio-demographic variables and prevalence of dental caries. Materials and Methods A cross-sectional study was designed including a sample of 447 adolescents aged 12 to 19 years old, attending a public school in Sátão, Portugal. A questionnaire about socio-demographic variables and oral health behaviors was applied. Gastric H. pylori infection was determined using the urease breath test (UBT). Saliva collection was obtained and DNA was extracted by Polymerase Chain Reaction (PCR) in order to detect the presence of oral H. pylori. Results The prevalence of gastric H. pylori detected by UBT was 35.9%. Within the adolescents with a gastric UBT positive, only 1.9% were positive for oral H. pylori. The presence of gastric H. pylori was found to be associated with age (>15years, Odds ratio (OR)=1.64,95%CI=1.08-2.52), residence area (urban,OR=1.48,95%CI=1.03-2.29) and parents´ professional situation (unemployed,OR=1.22,95%CI=1.02-1.23). Among those with detected dental caries during the intra-oral observation, 37.4% were positive for gastric H. pylori and 40.2% negative for the same bacterial strain (p=0.3). Conclusions The oral cavity cannot be considered a reservoir for infection of H. pylori. Gastric H. pylori infection was found to be associated with socio-demographic variables such as age, residence area and socioeconomic status.

Noninfectious balanitis in patients attending a sexually transmitted diseases clinic.

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