An immunohistochemical study on the expression of sex steroid receptors, Ki-67 and cytokeratins 7 and 20 in feline endometrial adenocarcinomas.

BACKGROUND: Endometrial adenocarcinomas are a rare type of tumour in cats. Though different morphologies have been reported, the most frequent histological type of feline endometrial adenocarcinoma (FEA) is the papillary serous. Characterization of molecular markers expression in FEA may contribute to clarify the pathogenesis of these tumours and to assess the differences between normal endometrium and FEA regarding the expression pattern of several proteins. Therefore, this study aimed to evaluate the immunohistochemical profile of a wide panel of antibodies (specific for ER-α, PR, Ki-67, CK7 and CK20) in twenty-four cases of FEA. Comparisons were made between FEA and feline normal cyclic endometrium in follicular (n = 13) and luteal (n = 10) stages. Except for Ki-67, all other molecular markers were assessed independently for the intensity of immunolabeling and for the percentage of cells expressing the protein. RESULTS: This study showed that in FEA a loss of expression occurs for ER-α (P ≤ 0.0001) and less markedly also for PR. The lost in sex steroid receptors concerns a decrease in both the proportion of labelled cells and the intensity of immunolabelling (P = 0.002 and P = 0.024, respectively). Proliferative activity, estimated via Ki-67 immunoreaction, significantly increased in FEA as compared to normal endometrium (P ≤ 0.0001). Feline endometrial adenocarcinomas maintained the CK7+/CK20+ status of normal endometrium. However, FEA showed decreased CK7 intensity of labelling compared to normal endometria (P ≤ 0.0001) and loss of CK20 expression, both in intensity (P ≤ 0.0001) and in percentage of positive cells (P = 0.01), compared to normal tissues. CONCLUSIONS: Data gathered in this study suggest that proliferation in FEA accompanies ER-α down-regulation, possibly following activation of pathways mediated by local growth factors. Moreover, FEA retains combined expression of CK7 and CK20, as evidenced in normal endometrial epithelia, although a decrease in CK7 expression was observed.

TLR2 deficiency by compromising p19 (IL-23) expression limits Th 17 cell responses to Mycobacterium tuberculosis.

CD4(+) T(h)1 cells producing IFN-γ are of extreme importance in controlling infections by Mycobacterium tuberculosis both in mice and in men. In addition to IFN-γ-producing T cells, IL-17-producing T cells (T(h)17) have been observed during mycobacterial infections. Nevertheless, their contribution for the host immune response to mycobacteria as well as the signals triggering M. tuberculosis -specific T(h)17 cell differentiation and maintenance are not fully understood. We show that signaling via Toll-like receptor (TLR) 2 has a major impact on the regulation of p19 (IL-23) expression in response to M. tuberculosis and therefore on the establishment of T(h)17 cell responses to M. tuberculosis infection. Diminished T(h)17 responses in the lung of M. tuberculosis -infected TLR2-deficient animals were not caused by defective cell differentiation in the draining lymph node (LN) but rather by reduced maintenance at the site of infection. Consistent with the decreased numbers of T(h)17 cells in the lungs of infected TLR2-deficient animals, we observed reduced expression of CXCL9, CXCL10 and CXCL11, chemokines involved in recall responses to M. tuberculosis. Our data provides insights into the TLR2 role in infection with M. tuberculosis, with implications in pathophysiology of the disease and vaccine design.

New Insights Into the Role of Tissue Eosinophils in the Progression of Colorectal Cancer: A Literature Review.

INTRODUCTION: Amongst the inflammatory cells implicated in the immune surveillance of colorectal cancer, a growing body of evidence suggests a role for eosinophils in carcinogenesis. We aimed to review the value of tumour-associated tissue eosinophilia (TATE) in the prognosis of colorectal cancer emphasizing the identification and measurement of tissue-infiltrating eosinophils and their association with the clinicopathological features of the disease. MATERIAL AND METHODS: We used PubMed and Web of Science search engines to retrieve studies that looked at the association between tissue eosinophils and colorectal cancer prognosis. RESULTS: We selected 15 studies for our review. In the majority of the studies, eosinophils were identified in hematoxylin-eosin stained sections and scores were generated for analysis. Most of the studies pointed to tumour-associated tissue eosinophilia as a favourable prognostic marker in colorectal cancer and found an inverse association between eosinophil count and the metastatic potential of these neoplasms. The association between tumour-associated tissue eosinophilia and established prognostic markers of colorectal cancer was assessed in some studies, with inconsistent results. Additionally, tumour-associated tissue eosinophilia decreased with the adenoma-carcinoma progression of colorectal lesions. DISCUSSION: Several mechanisms have been proposed regarding eosinophil chemoatraction to tumour tissues and eosinophil-cancer cell cross-talk, suggesting that eosinophils are actively involved in colorectal cancer progression. Although a scoring system is still lacking, tumour-associated tissue eosinophilia meets the criteria of a convenient histopathological prognosticator in colorectal cancer. CONCLUSION: Collectively, current evidence associates the presence of eosinophils in the colorectal cancer microenvironment with the modulation of tumour progression. The clinical impact of this finding deserves future research.

Introdução: O papel dos eosinófilos na carcinogénese colorretal tem sido discutido em várias publicações científicas. O objetivo deste estudo foi o de rever o valor dos eosinófilos tecidulares no prognóstico do cancro colorretal, enfatizando a sua identificação, mensuração e associação com as características clinicopatológicas da doença. Material e Métodos: Utilizámos os motores de busca PubMed e Web of Science para pesquisar estudos que associassem os eosinófilos tecidulares com o prognóstico do cancro colorretal. Resultados: Selecionámos 15 estudos para a nossa revisão. Maioritariamente, a análise do infiltrado foi realizada através da coloração de hematoxilina-eosina, com criação de scores. A maioria dos trabalhos descreveu a eosinofilia tecidular como um fator de prognóstico favorável no cancro colorretal e estabeleceu uma associação inversa entre ela e o comportamento metastático dos tumores. A associação com outros fatores de prognóstico foi por vezes abordada, com resultados inconsistentes. A eosinofilia tecidular diminuiu na progressão adenoma-carcinoma. Discussão: Vários mecanismos têm sido propostos para explicar a quimiotaxia de eosinófilos para os tecidos tumorais e a sua interação com as células neoplásicas, sugerindo o envolvimento dos eosinófilos na progressão do cancro colorretal. Apesar de não existir um sistema de avaliação validado, a eosinofilia tecidular associada a tumores pode constituir um parâmetro histopatológico de prognóstico no cancro colorretal. Conclusão: As evidências disponíveis associam a presença de eosinófilos no microambiente do cancro colorretal com a modulação da sua progressão. O impacto clínico deste achado deve ser estudado no futuro.

Presence and significance of Helicobacter spp. in the gastric mucosa of Portuguese dogs.

BACKGROUND: Non-Helicobacter pylori Helicobacters (NHPH) are also able to cause disease in humans. Dogs are a natural reservoir for many of these species. Close and intense human contact with animals has been identified as a risk factor and therefore, an important zoonotic significance has been attributed to NHPH. METHODS: To determine the prevalence of Helicobacter species and the gastric histopathological changes associated, gastric mucosa samples of 69 dogs were evaluated. RESULTS: Only one dog presented a normal histopathological mucosa with absence of spiral-shaped organisms. A normal gastric mucosa and the presence of spiral-shaped bacteria was observed in two dogs. All remaining animals presented histopathological changes representative of gastritis. Helicobacter species were detected in 60 dogs (87.0%) by at least one detection method. Histological, histochemical and immunohistochemical evaluations revealed that Helicobacter spp. were present in 45 (65.2%), 52 (75.4%) and 57 (82.6%) dogs, respectively. Spiral-shaped bacteria were detected by qPCR analysis in 33 (47.8%) dogs. H. heilmannii-like organisms were identified in 22 animals (66.7%) and predominantly in the antral gastric region. H. salomonis was the second most prevalent species (51.5%) although it was mainly found in association with other Helicobacter spp. and in the body gastric region. H. bizzozeronii and H. felis were less frequently detected. CONCLUSIONS: It was concluded that, despite the high incidence and worldwide distribution of gastric NHPH in dogs, the presence of specific Helicobacter species may vary between geographic regions. NHPH infections were significantly accompanied by mild to moderate intraepithelial lymphocyte infiltration and mild to moderate gastric epithelial injury, but a clear relationship between gastritis and Helicobacter infection could not be established.

TLR9 activation dampens the early inflammatory response to Paracoccidioides brasiliensis, impacting host survival.

BACKGROUND: Paracoccidioides brasiliensis causes paracoccidioidomycosis, one of the most prevalent systemic mycosis in Latin America. Thus, understanding the characteristics of the protective immune response to P. brasiliensis is of interest, as it may reveal targets for disease control. The initiation of the immune response relies on the activation of pattern recognition receptors, among which are TLRs. Both TLR2 and TLR4 have been implicated in the recognition of P. brasiliensis and regulation of the immune response. However, the role of TLR9 during the infection by this fungus remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: We used in vitro and in vivo models of infection by P. brasiliensis, comparing wild type and TLR9 deficient ((-/-)) mice, to assess the contribution of TLR9 on cytokine induction, phagocytosis and outcome of infection. We show that TLR9 recognizes either the yeast form or DNA from P. brasiliensis by stimulating the expression/production of pro-inflammatory cytokines by bone marrow derived macrophages, also increasing their phagocytic ability. We further show that TLR9 plays a protective role early after intravenous infection with P. brasiliensis, as infected TLR9(-/-) mice died at higher rate during the first 48 hours post infection than wild type mice. Moreover, TLR9(-/-) mice presented tissue damage and increased expression of several cytokines, such as TNF-α and IL-6. The increased pattern of cytokine expression was also observed during intraperitoneal infection of TLR9(-/-) mice, with enhanced recruitment of neutrophils. The phenotype of TLR9(-/-) hosts observed during the early stages of P. brasiliensis infection was reverted upon a transient, 48 hours post-infection, neutrophil depletion. CONCLUSIONS/SIGNIFICANCE: Our results suggest that TLR9 activation plays an early protective role against P. brasiliensis, by avoiding a deregulated type of inflammatory response associated to neutrophils that may lead to tissue damage. Thus modulation of TLR9 may be of interest to potentiate the host response against this pathogen.