No abstract

Intestinal mucositis is a common side effect of irinotecan-based anticancer regimens. Mucositis causes cell damage, bacterial/endotoxin translocation and production of cytokines including IL–1 and IL–18. These molecules and toll-like receptors (TLRs) activate a common signaling pathway that involves the Myeloid Differentiation adaptor protein, MyD88, whose role in intestinal mucositis is unknown. Then, we evaluated the involvement of TLRs and MyD88 in the pathogenesis of irinotecan-induced intestinal mucositis. MyD88-, TLR2- or TLR9-knockout mice and C57BL/6 (WT) mice were given either saline or irinotecan (75 mg/kg, i.p. for 4 days). On day 7, animal survival, diarrhea and bacteremia were assessed, and following euthanasia, samples of the ileum were obtained for morphometric analysis, myeloperoxidase (MPO) assay and measurement of pro-inflammatory markers. Irinotecan reduced the animal survival (50%) and induced a pronounced diarrhea, increased bacteremia, neutrophil accumulation in the intestinal tissue, intestinal damage and more than twofold increased expression of MyD88 (200%), TLR9 (400%), TRAF6 (236%), IL–1β (405%), IL–18 (365%), COX–2 (2,777%) and NF-κB (245%) in the WT animals when compared with saline-injected group (P<0.05). Genetic deletion of MyD88, TLR2 or TLR9 effectively controlled the signs of intestinal injury when compared with irinotecan-administered WT controls (P<0.05). In contrast to the MyD88-/- and TLR2-/- mice, the irinotecan-injected TLR9-/- mice showed a reduced survival, a marked diarrhea and an enhanced expression of IL–18 versus irinotecan-injected WT controls. Additionally, the expression of MyD88 was reduced in the TLR2-/- or TLR9-/- mice. This study shows a critical role of the MyD88-mediated TLR2 and TLR9 signaling in the pathogenesis of irinotecan-induced intestinal mucositis.

Metalloproteinase-2 (MMP-2) and -14 (MMP-14) and the tissue inhibitor of metalloproteinases type 2 (TIMP-2) participate in epithelial-mesenchymal transition and tumor progression in many cancers. However, the correlation between these enzymes in gastric cancer and the metastatic potential to their respective lymph node needs to be determined. Here, we evaluated the expression of these enzymes in gastric carcinoma and lymph node metastases and their possible involvement in tumor progression. Histological samples from 83 patients with gastric cancer and their respective lymph nodes were used. MMP-2, MMP-14 and TIMP-2 immunoexpression was scored. TIMP-2 expression in tumor-associated macrophages occurred more frequently than in normal mucosa (P = 0.0128). Female tumor samples presented higher MMP-2 expression (P = 0.0248), while TIMP-2 occurred mainly in patients over 50 years old (P = 0.0034). MMP-2 was higher expressed in primary tumor macrophages than in neoplastic cells (P = 0.0118), and was also seen in macrophages from metastatic-affected lymph nodes of intestinal and diffuse histotypes (P = 0.0006). MMP-2, MMP-14 and TIMP-2 expression in mononuclear cells might be correlated with progression of gastric cancer. MMP-14 production by macrophages appears to be more involved in diffuse gastric cancer progression.

-ORIGINAL ARTICLEEXPERIMENTAL ABSTRACT PURPOSE:To determine the effects of green propolis extracted in L-lysine (WSDP) and of L-lysine for 40 weeks on induced rat bladder carcinogenesis. METHODS:The animals (groups I, II, III, IV, V and VI) received BBN during 14 weeks. Group I was treated with propolis 30 days prior received BBN, and then these animals were treated daily with propolis; Groups II and III was treated with subcutaneous and oral propolis (respectively) concurrently with BBN. The animals of Group IV were treated L-lysine; Group V received water subcutaneous;and Group VI received only to BBN. Among the animals not submitted to carcinogenesis induction, Group VII received propolis, Group VIII received L-lysine and Group IX received water. RESULTS:The carcinoma incidence in Group I was lower than that of control (Group VI). The carcinoma multiplicity in Group IV was greater than in Group VI. All animals treated with L-lysine developed carcinomas, and they were also more invasive in Group IV than in controls. On the other hand, Group VIII showed no bladder lesions. CONCLUSION:The WSDP is chemopreventive against rat bladder carcinogenesis, if administered 30 days prior to BBN , and that L-lysine causes promotion of bladder carcinogenesis.

Background and purpose Severe diarrhoea, a common gastrointestinal manifestation of anticancer treatment with irinotecan, might involve single nucleotide polymorphisms (SNPs) of toll‐like receptors (TLRs), described as critical bacterial sensors in the gut. Here, colorectal cancer patients carrying missense TLR4 A896G (rs4986790) or C1,196T (rs4986791) SNPs and Tlr4 knockout (Tlr4−/−) mice were given irinotecan to investigate the severity of the induced diarrhoea. Experimental approach Forty‐six patients treated with irinotecan‐based regimens had diarrhoea severity analysed according to TLR4 genotypes. In the experimental setting, wild‐type (WT) or Tlr4−/− mice were given irinotecan (45 or 75 mg·kg−1, i.p.) or saline (3 ml·kg−1). Diarrhoea severity was evaluated by measuring intestinal injury and inflammatory markers expression after animals were killed. Key results All patients with TLR4 SNPs chemotherapy‐treated presented diarrhoea, whereas gastrointestinal toxicity was observed in 50% of the wild homozygous individuals. Mice injected with irinotecan presented systemic bacterial translocation and increased TLR4 immunostaining in the intestine. In line with the clinical findings, Tlr4 gene deficiency enhanced irinotecan‐related diarrhoea and TLR9 expression in mice. An increased myeloperoxidase activity and Il‐18 expression along with IL‐10 decreased production in Tlr4−/− mice also indicated an intensified intestinal damage and inflammatory response. Conclusion and implications TLR4 deficiency upregulates TLR9 expression and enhances intestinal damage and the severity of late‐onset diarrhoea during irinotecan‐based treatment. Identifying patients genetically predisposed to chemotherapy‐associated diarrhoea is a strategy toward precision medicine.

OBJECTIVE:The aim of this study is to investigate the presence of human papillomavirus DNA and genotypes in breast cancer and normal breast tissue samples obtained from women from the northeast region of Brazil.METHOD:One hundred three breast cancer samples and 95 normal breast samples, as the non-malignant controls, were studied. DNA extraction was verified by human beta-globin gene amplification, and polymerase chain reaction was conducted based on HPV L1-specific consensus primers MY09/MY11 and GP5+/GP6+, followed by nested multiplex polymerase chain reaction with type-specific primers for the E6/E7 consensus region.RESULTS:Human papillomavirus DNA was detected in 51 (49.5%) breast carcinoma samples and 15 (15.8%) normal breast samples (p<0.0001). Human papillomavirus genotypes 6 and 11 were identified in 15.2% of all samples.CONCLUSIONS:The high frequency of human papillomavirus infection in breast cancer samples indicates a potential role of this virus in breast carcinogenesis in the studied participants.

This is the first report of a consistent model of IRI-induced NASH capable of mimicking clinical findings.

We developed a new experimental model of IM induced by combining irinotecan and 5-FU treatments, which will allow us to gain a better knowledge concerning the pathogenesis of this disease through the pharmacological modulation of key inflammatory mediators.