Cyclin D1 gene polymorphism as a risk factor for squamous cell carcinoma of the upper aerodigestive system in non-alcoholics

Squamous cell carcinoma of the upper aerodigestive tract (UADT) is associated with environmental factors, especially tobacco and alcohol consumption. Genetic factors, including cyclin D1 (CCND1) polymorphism have been suggested to play an important rote in tumorigenesis and progression of UADT cancer. To investigate the relationship between CCND1 polymorphism on susceptibility for UADT cancers, 147 cancer and 135 non-cancer subjects were included in this study. CCND1 genotype at codon 242(G870A) in exon 4 was undertaken using denaturing high performance liquid chromatography (DHPLC) and DNA sequencing. Significant odds ratio (OR) of the AA + GA genotypes [OR = 7.5 (95% Cl: 1.4-39.7)] was observed in non-drinkers but for non-smokers a non-significant [OR = 5.4 (95% Cl: 0.9-31.4)] was found in the adjusted model. These results suggest that allele A may be a risk factor for UADT cancer, especially in non-alcoholics. However, further epidemiological studies are needed to establish the exact role of CCND1 polymorphism and the development of UADT cancers. (C) 2004 Elsevier Ltd. All rights reserved.

CYP1A2*1C, CYP2E1*5B, and GSTM1 polymorphisms are predictors of risk and poor outcome in head and neck squamous cell carcinoma patients

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Gene expression profiling reveals molecular marker candidates of laryngeal squamous cell carcinoma

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Genomic imbalances in esophageal squamous cell carcinoma identified by molecular cytogenetic techniques

This review summarizes the chromosomal changes detected by molecular cytogenetic approaches in esophageal squamous cell carcinoma (ESCC), the ninth most common malignancy in the world. Whole genome analyses of ESCC cell lines and tumors indicated that the most frequent genomic gains occurred at 1, 2q, 3q, 5p, 6p, 7, 8q, 9q, 11q, 12p, 14q, 15q, 16, 17, 18p, 19q, 20q, 22q and X, with focal amplifications at 1q32, 2p16-22, 3q25-28, 5p13-15.3, 7p12-22, 7q21-22, 8q23-24.2, 9q34, 10q21, 11p11.2, 11q13, 13q32, 14q13-14, 14q21, 14q31-32, 15q22-26, 17p11.2, 18p11.2-11.3 and 20p11.2. Recurrent losses involved 3p, 4, 5q, 6q, 7q, 8p, 9, 10p, 12p, 13, 14p, 15p, 18, 19p, 20, 22, Xp and Y. Gains at 5p and 7q, and deletions at 4p, 9p, and 11q were significant prognostic factors for patients with ESCC. Gains at 6p and 20p, and losses at 10p and 10q were the most significant imbalances, both in primary carcinoma and in metastases, which suggested that these regions may harbor oncogenes and tumor suppressor genes. Gains at 12p and losses at 3p may be associated with poor relapse-free survival. The clinical applicability of these changes as markers for the diagnosis and prognosis of ESCC, or as molecular targets for personalized therapy should be evaluated.

Carcinoma basalóide escamoso: uma forma rara e agressiva de câncer do esôfago e revisão da literatura

RACIONAL: O carcinoma basalóide escamoso ocorre com maior freqüência no trato aerodigestivo superior e raramente acomete o esôfago. OBJETIVO: Apresentar os aspectos clínico-patológicos e os atributos imunoistoquímicos de um paciente com carcinoma basalóide escamoso do esôfago. RELATO do CASO: Dos 134 pacientes com câncer do esôfago atendidos no Hospital Universitário de Botucatu-Unesp, São Paulo, de 1990 a 1999, somente um paciente (0,74%) apresentou carcinoma basalóide escamoso do esôfago. Tratava-se de paciente masculino, 41 anos, branco, lavrador com disfagia, regurgitação e emagrecimento há três meses. Referia tabagismo e etilismo há muitos anos. O esofagograma e o exame endoscópico revelaram lesão vegetante no terço distal do esôfago. A biópsia demonstrou neoplasia intraepitelial de alto grau associada a blocos de células basalóides que infiltravam o cório da mucosa, caracterizando o carcinoma basalóide escamoso. Os marcadores imunoistoquímicos foram positivos para o antígeno carcinoembriônico e para citoceratinas de alto peso molecular. A tomografia computadorizada revelou múltiplas metástases nos pulmões, fígado, e nódulos linfáticos regionais, documentando a fase avançada de evolução da doença. O tratamento consistiu apenas na realização de gastrostomia. O paciente apresentou queda acentuada do estado geral e evoluiu para óbito com quadro de melena quatro meses após o diagnóstico. CONCLUSÃO: O carcinoma basalóide escamoso é uma forma rara e agressiva de câncer do esôfago e o prognóstico depende do estadiamento da lesão e das condições clínicas do paciente no momento do diagnóstico.

Paracoccidioidomicose em paciente com carcinoma do colo uterino

Os autores relatam caso de paciente do sexo feminino com paracoccidioidomicose, associada a carcinoma do colo uterino estádio IIIB. Paracoccidioidomicose, associada à neoplasia, ocorre entre 0,16% a 14,1% segundo diferentes séries de casos. em casos com neoplasia disseminada a infecção fúngicas pode apresentar comportamento oportunístico

Opposite effects of bFGF and TGF-beta on collagen metabolism by human periodontal ligament fibroblasts

This study evaluated the effects of bFGF and TGF-beta, individually and combined, on cell proliferation and collagen metabolism. Primary human periodontal ligament cells were stimulated with two concentrations (I and 10 ng/ml) of each growth factor, both individually and combined. Proliferation was determined by a commercial biochemical assay. Real time RT-PCR determined gene expression of NMP-1 and -2, collagen types I and III, TIMP-1, -2 and -3. Autocrine effects on synthesis of bFGF and TGF-beta were evaluated by ELISA. Only TGF-beta, either isolated or associated with bFGF, significantly increased cell proliferation. TGF-beta had anabolic effects, increasing expression of type I and III collagen as well as of TIMPs, whereas bFGF had opposite effects. When bFGF and TGF-beta were associated, the anabolic effects prevailed. Synthesis of TGF-beta was induced only by the association of lower concentrations of the growth factors, whereas there was a dose-dependent production of bFGF. It is concluded that bFGF had a predominantly catabolic effect, and TGF-beta exerted an anabolic effect on hPDL cells. (c) 2007 Elsevier Ltd. All rights reserved.

Common bile duct obstruction associated with platinosoma concinum in cat

Extrahepatic obstruction in cat,can be caused by cholelithiasis, inspissated bile, pancreatic inflammation or fibrosis, duodenal inflammation, bile duct carcinoma or liver fluke infection (Amphimerus pseudofelineus e Platynosomurn concinum). A three-year-old, female neutered siames cat was present with a two-month history of progressive letargy, anorexia and emaciation. She had severe icterus of the mucous membranes, skin, and sclerae. A diagnosis of extrahepataic biliary obstruction was made based on the increased levels of conjugated bilirubin in the serum and the ultrasonography. Hepatic fluke eggs were not diagnosed in the feces because the fibrotic bile ducts were occluded and no eggs were shed into the intestine. Cholecystoduodenostomy was done to relieve posthepatic-biliary obstruction.

Abnormal expression of bcl-2 and bax in rat tongue mucosa during the development of squamous cell carcinoma induced by 4-nitroquinoline 1-oxide

4-Nitroquinoline 1-oxide (4NQO)-induced rat tongue carcinogenesis is a useful model for studying oral squamous cell carcinoma. The aim of this study was to investigate the expression of bcl-2 and bax during tongue carcinogenesis induced by 4NQO. Male Wistar rats were distributed into three groups of 10 animals each and treated with 50 ppm 4NQO solution through their drinking water for 4, 12 or 20 weeks. Ten animals were used as negative control. Although no histological changes were induced in the epithelium after 4 weeks of carcinogen exposure, bcl-2 and bax were over-expressed (P < 0.01) in all layers of the 'normal' epithelium. The expression levels were the same in all layers of epithelium for both the antibodies used (bcl-2 or bax). In dysplastic lesions at 12 weeks following carcinogen administration, the levels of bcl-2 and bax expression did not increase when compared to negative control with the immunoreactivity for bcl-2 being restricted to the superficial layer of epithelium. In well-differentiated squamous cell carcinoma induced after 20 weeks of treatment with 4NQO, bcl-2 was expressed in some cells of tumour islands. on the other hand, immunostaining for bax was widely observed at the tumour nests. The labelling index for bcl-2 and bax showed an increase (P < 0.05) after only 4 weeks of 4NQO administration. In conclusion, our results suggest that abnormalities in the apoptosis pathways are associated with the development of persistent clones of mutated-epithelial cells in the oral mucosa. Bcl-2 and bax expression appears to be associated with a risk factor in the progression of oral cancer.

Aromatic compounds produced by Periconia atropurpurea, an endophytic fungus associated with Xylopia aromatica

6,8-Dimethoxy-3-(2'-oxo-propyl)-coumarin (1) and 2,4-dihydroxy-6-[(1'E,3'E)-penta-1', 3'-dienyl]-benzaldehyde (2), in addition to the known compound periconicin B (3), were isolated from the ethyl acetate extract of Periconia atropurpurea, an endophytic fungus obtained from the leaves of Xylopia aromatica, a native plant of the Brazilian Cerrado. Their chemical structures were assigned based on analyses of MS, 1D and 2D-NMR spectroscopic experiments. Biological analyses were performed using two mammalian cell lines, human cervix carcinoma (HeLa) and Chinese hamster ovary (CHO). The results showed that compound I had no effect when compared to the control group, which was treated with the vehicle (DMSO). Compound 2 was able to induce a slight increase in cell proliferation of HeLa (37% of increase) and CHO (38% of increase) cell lines. Analysis of compound 3 showed that it has potent cytotoxic activity against both cell lines, with an IC50 of 8.0 mu M. Biological analyses using the phytopathogenic fungi Cladosporium sphaerospermum and C. cladosporioides revealed that also 2 showed potent antifungal activity compared to nystatin. (c) 2006 Elsevier Ltd. All rights reserved.

Clinicopathological features influencing pelvic lymph node metastasis and vaginal and parametrial involvement in patients with carcinoma of the cervix

Purpose: This study was undertaken to evaluate clinical and pathologic findings that predicted pelvic lymph node metastasis and parametrial and vaginal involvement in patients with stage IB carcinoma of the cervix. Methods: 71 patients with diagnosis of stage IB (FIGO) cervical cancer were prospectively studied from December 1997 to August 2002. The patient's age, clinical stage (IB1 or IB2), histological classification, grade of differentiation, tumor volume, and lymphatic vascular space invasion (LVSI) were evaluated. Statistical methods included chi(2) test and Fisher's exact test to evaluate significant differences between the groups. The level of significance was set at p < 0.05. Results: the clinical stage was IB1 in 51 patients (71.8%) and IB2 in 20 patients (28.2%). The histological classification identified squamous cell carcinoma in 60 patients (84.5%) and adenocarcinoma in 11 patients (15.5%). The average tumoral volume was 22.8 &PLUSMN; 8 24.3 cm(3) (0.3-140.0 cm(3)). The tumor was well differentiated (G1) in 8 (11.3%), moderately differentiated (G2) in 40 (56.3%) and poorly differentiated in 23 (32.4%) of the cases. The presence of LVSI was detected in 14 patients (19.7%) and was associated with pelvic lymph node metastasis and vaginal and parametrial involvement (p = 0.002, p = 0.001 and p < 0.001; respectively). The average number of positive pelvic lymph nodes was significantly higher in the patients with LVSI compared with patients without LVSI (2.47 +/- 2.8 vs. 0.33 +/- 0.74; p = 0.001). There was no association of age, clinical stage, histological classification, grade of differentiation or tumor volume with pelvic lymph node metastasis and vaginal and parametrial involvement. Conclusion: the presence of LVSI is significantly associated with pelvic lymph node metastasis and vaginal and parametrial involvement in patients with stage IB cervical carcinoma. Copyright (C) 2005 S. Karger AG, Basel.

MKK3/6-p38 MAPK negatively regulates murine MMP-13 gene expression induced by IL-1 beta and TNF-alpha in immortalized periodontal ligament fibroblasts

Matrix metalloprotease-13 (MMP-13) or collagenase-3 is involved in a number of pathologic processes such as tumor metastasis and angiogenesis, osteoarthritis, rheumatoid arthritis and periodontal diseases. These conditions are associated with extensive degradation of both connective tissue and bone. This report examines gene regulation mechanisms and signal transduction pathways involved in Mmp-13 expression induced by proinflammatory cytokines in periodontal ligament (PDL) fibroblasts. Mmp-13 mRNA expression was increased 10.7 and 9.5 fold after stimulation with IL-1 beta (5 ng/mL) and TNF-alpha (10 ng/mL), respectively. However, inhibition of p38 MAPKinase with SB203580 resulted in significant (p < 0.001) induction (23.2 and 18.1 fold, respectively) of Mmp-13 mRNA as assessed by real time PCR. Negative regulation of IL-1 induced Mmp-13 expression was confirmed by inhibiting p38 MAPK gene expression with siRNA. Transient transfection of dominant negative forms of MKK3 and MKK6 also resulted in increased levels of Mmp-13 mRNA after IL-1 beta stimulation. Mmp-13 mRNA expression induced by TNF-alpha was decreased by JNK and ERK inhibition. Western blot and zymogram analysis indicated that Mmp-13 protein expression induced by the proinflammatory cytokines were also upregulated by inhibition of p38 MAPK. Reporter gene experiments using stable cell lines harboring 660-bp sequence of the murine Mmp-13 proximal promoter indicated that transcriptional mechanisms were at least partially involved in this negative regulation of Mmp-13 expression by p38 MAPK and upstream MKK3/6. These results suggest a negative transcriptional regulatory mechanism mediated by p38 MAPK and upstream MKK3/6 on Mmp-13 expression induced by proinflammatory cytokines in PDL fibroblasts. (c) 2005 Elsevier B.V./International Society of Matrix Biology. All rights reserved.

Spectrum of carcinoembryonic antigen immunoreactivity from isolated ductal hyperplasias to atypical hyperplasias associated with infiltrating ductal breast cancer

Aims - To study the immunohistochemical expression of carcinoembryonic antigen (CEA) in ductal hyperplasia of the breast and to investigate its putative relation with atypia and co-existing infiltrating ductal carcinoma.Methods - Paraffin wax embedded tissue from 37 cases of isolated ductal hyperplasia (five with atypia and 32 without atypia) and 25 cases of ductal hyperplasia associated infiltrating ductal carcinoma (IDC) (seven with atypia and 18 without atypia) was stained with a monoclonal anti-CEA antibody using a standard avidin biotin immunoperoxidase method.Results - CEA immunoreactivity was observed in eight (12.8%) ductal hyperplasia cases. The percentage of CEA positivity in ductal hyperplasia cases with atypia (33.3%) was substantially higher than that observed in cases of ductal hyperplasia without atypia (8.0%). Six cases of ductal hyperplasia associated IDC reacted with CEA; in these six cases the neoplastic cells of the co-existing carcinoma were also CEA positive. The percentage of CEA immunoreactivity in ductal hyperplasia associated IDC was higher than that observed in isolated ductal hyperplasia (24.0 v 5.4%). The percentage of CEA immunoreactivity in atypical ductal hyperplasia associated IDC was similar to that observed in IDC alone (42.9 v 40.0%).Conclusions-The presence of CEA immunoreactivity has been confirmed in benign proliferative breast lesions. The prevalence of such immunoreactivity increases from 3.1% in isolated, nonatypical ductal hyperplasia to 42.9% in atypical ductal hyperplasia associated IDC. This finding and the similarity of the frequency of CEA positivity in atypical ductal hyperplasia associated IDC and in IDC alone suggests that there is a pathogenetic link between ductal hyperplasia and some types of breast cancer.

Epstein-Barr virus (EBV) nuclear antigen (EBNA)-4 mutation in EBV-associated malignancies in three different populations

Different ethnic groups with a high human leukocyte antigen (HLA)-A11 prevalence have been shown to experience a high rate of Epstein-Barr virus (EBV) infection, EBV-associated malignancies, and Epstein-Barr nuclear antigen (EBNA)-4 mutations. The epitopes 393-408 and 416-424 of EBNA-4 are major antigenic epitopes that elicit an HLA-A11 cytotoxic T lymphocyte (CTL) response to EBV infection. Mutations selectively involving one or more nucleotide residues in these epitopes affect the antigenicity of EBNA-4, because the mutant EBV strains are not recognized by the HLA-A11-restricted CTLs. To investigate these mutations in common EBV-associated malignancies occurring in different populations, we studied the mutation rate of epitopes 393-408 and 416-424 of EBNA-4 in 25 cases of EBV-associated Hodgkin's disease (HD), nine cases of AIDS-related non-Hodgkin's lymphoma, and 37 cases of EBV-associated gastric carcinoma (GC) from the United States, Brazil, and Japan. We found one or more mutations in these two epitopes in 50% (6/12) of United States HD, 15% (2/13) of Brazilian HD, 50% (6/12) United States GC and 28% (7/25) Japanese GC, and 22% (2/9) of United States AIDS-lymphoma. Similar mutations were found in 30% (3/10) of United States reactive, 0% (0/6) of Brazilian reactive, and 25% (2/8) Japanese reactive tissues. The most frequent amino acid substitutions were virtually identical to those seen in previously reported isolates from EBV-associated nasopharyngeal carcinomas and Burkitt's lymphomas occurring in high prevalence HLA-A11 regions. However, only 2/28 (7%) mutations occurred in HLA-A11-positive patients. Our studies suggest that: 1) EBNA-4 mutations are a common phenomenon in EBV-associated HD, GC, and AIDS-lymphoma; 2) the mutation rate does not vary in these geographic areas and ethnic groups; 3) EBNA-4 mutations in EBV-associated United States and Brazilian HD, United States and Japanese GC, and United States AIDS lymphomas are not related to patients' HLA-A11 status.

Chromosome aberrations as a predictor of clinical outcome for smoking associated lung cancer

The ability to identify individuals at greatest risk of developing lung cancer can significantly enhance the efficacy of intervention modalities. One strategy for identifying these individuals is through biomarkers that reflect the severity of their cancer. In the present study, we evaluated 22 lung cancer patients and 35 controls to determine whether the frequency of chromosome aberrations was significantly associated with specific clinical variables such as the histological type, grade and stage of the turners. Chromosome aberrations (expressed as total breaks) were investigated on chromosome 1 in interphase nuclei obtained from blood Lymphocytes of the study participants using the fluorescence in situ hybridization (FISH) chromosome aberration assay. Our results indicate a significant linear increase (P = 0.01) in the level of breaks with respect to the grade of the carcinoma. The poorly differentiated tumors had a significantly higher level of chromosome breaks mean +/- SD (1.7 +/- 0.46) as compared to the well differentiated tumors (0.98 +/- 0,23, P < 0,05). These results indicate that chromosome aberrations, as determined by the FISH assay, can be used as a biomarker for identifying individuals with aggressive types of lung cancer and potentially, as a predictor for prognostic outcome of the disease. (C) 2000 Elsevier B.V. Ireland Ltd. All rights reserved.