HOXA1 is overexpressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis

<p>Abstract</p> <p>Background</p> <p>HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis. However, members of this family demonstrated oncogenic properties in some malignancies. The present study investigated whether genes of the HOXA cluster play a role in oral cancer.</p> <p>Methods</p> <p>In order to identify differentially expressed HOXA genes, duplex RT-PCR in oral samples from healthy mucosa and squamous cell carcinoma was used. The effects of HOXA1 on proliferation, apoptosis, adhesion, invasion, epithelial-mesenchymal transition (EMT) and anchorage-independent growth were assessed in cells with up- and down-regulation of HOXA1. Immunohistochemical analysis using a tissue microarray (TMA) containing 127 oral squamous cell carcinomas (OSCC) was performed to determine the prognostic role of HOXA1 expression.</p> <p>Results</p> <p>We showed that transcripts of HOXA genes are more abundant in OSCC than in healthy oral mucosa. In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas. Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it. Enforced HOXA1 expression in HaCAT cells was not capable of modulating other events related to tumorigenesis, including apoptosis, adhesion, invasion, EMT and anchorage-independent growth. A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival. In multivariate analysis, HOXA1 was an independent prognostic factor for OSCC patients (HR: 2.68; 95% CI: 1.59-2.97; p = 0.026).</p> <p>Conclusion</p> <p>Our findings indicate that HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with OSCC.</p

Genomics and epidemiology for gastric adenocarcinomas (GE4GAC): a Brazilian initiative to study gastric cancer

Abstract Gastric cancer (GC) is the fifth most common type of cancer worldwide with high incidences in Asia, Central, and South American countries. This patchy distribution means that GC studies are neglected by large research centers from developed countries. The need for further understanding of this complex disease, including the local importance of epidemiological factors and the rich ancestral admixture found in Brazil, stimulated the implementation of the GE4GAC project. GE4GAC aims to embrace epidemiological, clinical, molecular and microbiological data from Brazilian controls and patients with malignant and pre-malignant gastric disease. In this letter, we summarize the main goals of the project, including subject and sample accrual and current findings

Bone marrow transplantation in patients with storage diseases: a developing country experience

Bone marrow transplantation (BMT) is a therapeutic option for patients with genetic storage diseases. Between 1979 and 2002, eight patients, four females and four males (1 to 13 years old) were submitted to this procedure in our center. Six patients had mucopolysaccharidosis (MPS I in 3; MPS III in one and MPS VI in 2), one had adrenoleukodystrophy (ALD) and one had Gaucher disease. Five patients had related and three unrelated BMT donor. Three patients developed graft versus host disease (two MPS I and one MPS VI) and died between 37 and 151 days after transplantation. Five patients survived 4 to 16 years after transplantation. Three patients improved (one MPS I; one MPS VI and the Gaucher disease patient), one patient had no disease progression (ALD) and in one patient this procedure did not change the natural course of the disease (MPS III)

Therapy of chronic myeloid leukemia with imatinib mesylate in Brazil: a study of 98 cases Tratamento da leucemia mielóide crônica com imatinib mesilato no Brasil: estudo de 98 casos

Chronic Myeloid Leukemia (CML) is a clonal disease characterized by balanced translocation between chromosomes 9 and 22 (Philadelphia chromosome). The resulting BCR-ABL gene has tyrosine kinase activity which stimulates cellular growth. Imatinib mesylate is a potent and specific inhibitor of all ABL related kinases. Ninety-eight CML patients were treated with imatinib mesylate from October 2000 to January 2003. Disease stage was: late chronic phase resistant or intolerant to alpha-interferon (CP): 28; accelerated phase (AP): 55; blastic phase (BP): 15 patients. Dose: 400 mg for CP and 600 mg for AP or CB. The objectives were to evaluation the efficacy, safety and survival with imatinib mesylate therapy in all phases of CML. The median follow up time was 545 days (range: 7-862), complete hematologic response was 86% in CP, 47% in AP and 13% in BP. Complete cytogenetic response was 61%, 24% and 0% respectively. BCR-ABL was not detected by nested RT-PCR in 9% of patients. Grade 3-4 hematologic toxicity was seen in 21% of CP, 74% of AP and 87% of BP patients. Grade 3-4 non-hematologic toxicity was observed in 11% of CP, 51% of AP and 53% of BP patients. Two-year overall survival was 64% for all patients, 96% for CP and 36% for AP patients. All BP patients died within a median of 60 days. Imatinib mesylate induced cytogenetic responses in Brazilian patients with previously treated CML in chronic and accelerated phase. Adverse events are similar to those reported in the literature, except for lower rates of gastrointestinal symptoms and muscle cramps in our study group.INTRODUÇÃO: A Leucemia Mielóide Crônica (LMC) é uma doença clonal caracterizada pela presença da translocação entre os cromossomos 9 e 22 (cromossomo Philadelphia). O gene resultante BCR-ABL possui atividade de tirosino-quinase, que estimula o crescimento celular. O mesilato de imatinibe é um inibidor potente e específico de todas as quinases relacionadas ao ABL. PACIENTES E MÉTODOS: Noventa e oito pacientes com LMC foram tratados com mesilato de imatinibe de outubro de 2000 a janeiro de 2003: 28 em fase crônica (FC) resistente ou intolerante ao interferon alfa; 55 em fase acelerada (FA) e 55 em crise blástica (CB). Dose: 400 mg para CP e 600 mg para FA ou CB. OBJETIVOS: Avaliação da eficácia, segurança e sobrevida após tratamento da LMC com mesilato de imatinibe. RESULTADOS: Seguimento mediano: 545 dias (variação: 7-862). Resposta hematológica completa ocorreu em 86% dos pacientes em FC, 47% na FA e 13% na CB. Sessenta e um por cento, 24% e 0% dos pacientes em FC, FA e CB, atingiram resposta citogenética completa, respectivamente. Não foram detectados transcritos BCR-ABL por "nested RT-PCR" em 9% dos pacientes. Toxicidade hematológica grau 3-4: 21% na FC, 74% na FA e em 87% na CB. Toxicidade não hematológica grau 3-4: 11% na FC, 51% na FA e 53% na CB. A sobrevida global em dois anos foi de 64% para todos os pacientes, 96% na FC e 36% na FA. Todos os pacientes em CB faleceram numa mediana de 60 dias. CONCLUSÕES: O mesilato de imatinibe induziu respostas citogenéticas completas em pacientes brasileiros com LMC em fase crônica e acelerada. Os eventos adversos nos nossos pacientes foram semelhantes aos relatados em literatura, exceto pela menor incidência de sintomas gastro-intestinais e câimbras

Carcinoma de células escamosas em língua pós-transplante de medula óssea por Anemia de Fanconi

Anemia Fanconi (AF) é uma síndrome autossômica recessiva, caracterizada por pancitopenia progressiva com hipoplasia de MO, em associação com várias anormalidades constitucionais, tendo como único recurso terapêutico com possibilidade potencial de cura o transplante de medula óssea, e sendo tais pacientes propensos ao desenvolvimento de malignidades hematológicas e carcinoma de células escamosas (CEC) em diversos locais: reto, vagina, cérvice, esôfago, cavidade bucal, faringe ou pele, mas especialmente em cabeça e pescoço. Relatamos aqui três casos de pacientes portadores de AF, que após TMO desenvolveram CEC em língua. Além disso, mencionamos fatores de risco relatados para tal evento, como diagnóstico de AF, condicionamento pré-transplante (quimioterápicos e irradiação), terapia com drogas imunossupressoras para tratamento de doença enxerto contra hospedeiro (DECH) aguda ou crônica, sexo e idade avançada. Além do que, discorremos sobre a existência de três mecanismos postulados que predispõem indivíduos com AF ao desenvolvimento de neoplasia: (1) defeito na reparação do DNA; (2) defeito na detoxificação de radicais de oxigênio; e (3) imunodeficiência.<br>Fanconi's Anemia, first described in 1927, is a rare autonomic recessive disease characterized by progressive pancytopenia, congenital malformations, spontaneous or chemically induced chromosome breakage and increased incidence of leukemia and other cancers. The onset of bone marrow hypoplasia and its hematological manifestations is usually in the 3 - 7 year age range. The disease has traditionally been managed clinically through administration of blood products, treatment of infections and prolonged administration of androgens, growth factors and more recently with gene therapy. The value of bone marrow transplantation in correcting the hematological manifestations of Fanconi's anemia has been established. Alkilanting agents and radiation have been utilized as a conditioning regimen in bone marrow transplantation for Fanconi's anemia, but these patients are particularly hypersensitive to these agents and its toxicity is the main cause of mortality and morbidity. Bone marrow transplantation is at the moment the only therapeutic modality able to bring hematological cure. Fanconi's anemia patients are particularly susceptible to the development of hematological malignancies and squamous cell carcinoma in the epithelium of the rectum, vagina, cervix, esophagus, oral cavity, pharynx or skin in general but more frequently on the head and neck; probably not only because the basic cellular defect but also because of the conditioning regimen. We report on three cases of Fanconi's anemia patients developing squamous cell carcinoma of the tongue after bone marrow transplantation. Furthermore, there is mention of the risk factors linked in an event, such as the diagnosis of Fanconi's anemia, pre-transplant conditioning regimen that usually includes alkylating agents and irradiation; immunosuppressive prophylactic therapy for acute and chronic graft-versus-host-disease, gender and age. Additionally, we discussed the existence of three postulated mechanisms that make individuals with Fanconi's anemia susceptible to the development of neoplasias: (1) deficiency in the DNA repair system, (2) deficiency in oxygen radical detoxification; and (3) immunodeficiency

Estudo retrospectivo do tratamento de leucemia mielóide aguda com o transplante de medula óssea: a experiência brasileira Retrospective study of stem cell transplantation for acute myeloid leukemia (AML): the Brazilian experience

Dados do Registro Internacional de Transplante de Medula Óssea, International Bone Marrow Transplant Registry (IBMTR) contribuem para o progresso do transplante de medula óssea (TMO) em todo o mundo. Neste artigo relatamos a experiência brasileira em leucemia mielóide aguda e comparamos os resultados do TMO com os dados internacionais. Foi realizado um estudo retrospectivo com dados de tratamento de LMA com o TMO de 16 instituições brasileiras. A análise estatística dos transplantes da modalidade autogênica (TMO auto) e alogênica (TMO alo) foi realizada com o método de Kaplan-Meier e log-rank. Todos os valores de p foram bicaudados. Foram avaliados os dados de 731 pacientes (205 TMO auto e 526 TMO alo). A mediana de sobrevida global dos pacientes submetidos ao TMO auto foi superior à dos submetidos ao TMO alo (1.035 vs 466 dias, p=0,0012). A origem das células-tronco (OCT) no TMO alo em 73% dos pacientes foi de medula óssea (CTMO), em 23% de sangue periférico (CTSP) e em 4% de cordão umbilical. No TMO auto, a OCT foi 63% de CTSP, 22% CTMO e 15% de ambas as fontes. A OCT não teve impacto na sobrevida global (SG). Não houve diferença na SG também entre os pacientes segundo a classificação FAB no TMO alo, mas os pacientes com LMA M3 com o TMO auto tiveram SG longa. Como esperado, a principal causa de óbito entre os pacientes do TMO auto foi relacionada à recidiva de doença (60%), enquanto no TMO alo as principais causas foram a doença enxerto versus hospedeiro e infecções (38%). Em ambos os grupos foi observada SG mais longa nos pacientes tratados em primeira remissão completa (1RC) quando comparados aos de segunda remissão (2RC) e outras fases (p<0,0001), tendo sido observado SG mais longa nos pacientes com LMA de novo quando comparados aos de LMA secundária. No TMO alo a SG foi mais longa com doadores aparentados (538 versus 93 dias p=0,001). A SG foi mais curta nos pacientes que utilizaram irradiação corpórea total no regime de condicionamento (p=0,0001). No TMO alo foram observados mais pacientes com doença avançada (60%) enquanto no grupo de TMO auto 24% eram da morfologia M3, o que pode explicar a diferença de SG entre os grupos. O resultado do estudo está em concordância com os dados do IBMTR. Considerando a natureza do estudo, retrospectivo e multicêntrico, os resultados devem ser analisados com cautela.<br>Data from the International Bone Marrow Transplant Registry (IBMTR) contribute for the improvement of Bone Marrow Transplant (BMT) worldwide. We studied the Brazilian experience in BMT for AML to compare this with international data. We performed a retrospective study by sending questionnaires to 16 BMT centers regarding clinical and treatment variables. Statistical analyses concerning autologous BMT (autoBMT) and allogeneic BMT (alloBMT) were performed using the Kaplan-Meier method and the log-rank test. All p-values were two-tailed. We collected data from 731 patients (205 autoBMT and 526 alloBMT). Median overall survival (OS) for autoBMT patients was longer than alloBMT patients (1035 vs. 466 days, p=0.0012). AlloBMT stem cell source (SCS): 73% bone marrow stem cell (BMSC), 23% peripheral blood stem cells (PBSC) and 4% umbilical cord blood. Among the autoBMT patients, the SCS was 63% PBSC, 22% BMSC and 15% both. The SCS did not impact on OS. There was no difference in OS between different FAB classifications in the alloBMT group, but in the autoBMT the M3 patients had longer survival. As expected, the main cause of mortality among autoBMT patients was related to disease relapse (60%), while in the alloBMT, to infection (38%). In both groups we found longer OS in first complete remission (1CR) compared to second (2CR) and other (p<0.0001), and longer OS in de novo AML than in secondary. In the alloBMT group we found more patients with advanced disease (60%), while in the autoBMT group, we found more M3 patients (24%), which could explain the difference in OS. Most of our results are in accordance with IBMTR data. One should consider the fact that this is a retrospective study and our findings should be analysed with caution

Genome sequence of the gram-positive sugarcane pathogen Leifsonia xyli subsp. xyli

The genome sequence of Leifsonia xyli subsp. xyli, which causes ratoon stunting disease and affects sugarcane worldwide, was determined. The single circular chromosome of Leifsonia xyli subsp. xyli CTCB07 was 2.6 Mb in length with a GC content of 68% and 2,044 predicted open reading frames. The analysis also revealed 307 predicted pseudogenes, which is more than any bacterial plant pathogen sequenced to date. Many of these pseudogenes, if functional, would likely be involved in the degradation of plant heteropolysaccharides, uptake of free sugars, and synthesis of amino acids. Although L. xyli subsp. xyli has only been identified colonizing the xylem vessels of sugarcane, the numbers of predicted regulatory genes and sugar transporters are similar to those in free-living organisms. Some of the predicted pathogenicity genes appear to have been acquired by lateral transfer and include genes for cellulase, pectinase, wilt-inducing protein, lysozyme, and desaturase. The presence of the latter may contribute to stunting, since it is likely involved in the synthesis of abscisic acid, a hormone that arrests growth. Our findings are consistent with the nutritionally fastidious behavior exhibited by L. xyli subsp. xyli and suggest an ongoing adaptation to the restricted ecological niche it inhabits