Effects of a marine serine protease inhibitor on viability and morphology of Trypanosoma cruzi, the agent of Chagas disease

It has been reported that serine peptidase activities of Trypanosoma cruzi play crucial roles in parasite dissemination and host cell invasion and therefore their inhibition could affect the progress of Chagas disease. The present study investigates the interference of the Stichodactyla helianthus Kunitz-type serine protease inhibitor (ShPI-I), a 55-amino acid peptide, in T. cruzi serine peptidase activities, parasite viability, and parasite morphology. The effect of this peptide was also studied in Leishmania amazonensis promastigotes and it was proved to be a powerful inhibitor of serine proteases activities and the parasite viability. The ultrastructural alterations caused by ShPI-I included vesiculation of the flagellar pocket membrane and the appearance of a cytoplasmic vesicle that resembles an autophagic vacuole. ShPI-I, which showed itself to be an important T. cruzi serine peptidase inhibitor, reduced the parasite viability, in a dose and time dependent manner. The maximum effect of peptide on T. cruzi viability was observed when ShPI-I at 1 × 10⁻⁵ M was incubated for 24 and 48 h which killed completely both metacyclic trypomastigote and epimastigote forms. At 1 × 10⁻⁶ M ShPI-I, in the same periods of time, reduced parasite viability about 91–95% respectively. Ultrastructural analysis demonstrated the formation of concentric membranar structures especially in the cytosol, involving organelles and small vesicles. Profiles of endoplasmic reticulum were also detected, surrounding cytosolic vesicles that resembled autophagic vacuoles. These results suggest that serine peptidases are important in T. cruzi physiology since the inhibition of their activity killed parasites in vitro as well as inducing important morphological alterations. Protease inhibitors thus appear to have a potential role as anti-trypanosomatidal agents.     

Gougerot-Sjögren syndrome disclosed by MALT lymphoma of the salivary glands. Report of 3 cases

Sj?gren's syndrome is characterized by an increased risk of developing non-Hodgkin's lymphoma. The lymphoma is most frequently extra-nodal, preferentially affecting the salivary gland: low-grade MALT lymphoma. Conversely, underlying Sj?gren's syndrome has been recently identified by some authors in patients with non-Hodgkin's lymphoma. In the present report, we present three cases of Sj?gren's syndrome disclosed by low-grade salivary gland MALT lymphoma. The patients were all women aged 33, 38 and 52 years. Extension work-up revealed nodal and bone marrow involvement in one case and no evidence of disseminated disease in the two others. Using the European criteria, all of our patients had certain Sj?gren's syndrome. Labial salivary gland biopsy and immunopathological studies in newly diagnosed low-grade MALT lymphoma would be helpful in identifying the real frequency of this association.     

Adénocarcinome colique révélateur de tumeurs carcinoïdes multiples du grêle

Neuroendocrine tumors of the small intestine are often discovered by accident. This tumor can be multiple and can be associated with other tumors, particularly gastrointestinal malignancy. We present a rare case involving a 68-year-old man in whom we discovered multiple neuroendocrine tumors in the ileum, associated with colonic adenocarcinoma. Following this observation we wish to draw attention to the concept of multiple neuroendocrine tumors and the possibility of synchronous malignancy.     

Presence of simian virus 40 in diffuse large B-cell lymphomas in Tunisia correlates with germinal center B-cell immunophenotype, t(14;18) translocation, and P53 accumulation.

Previously we have reported the presence of simian virus 40 DNA in 56% of diffuse large B-cell lymphomas in Tunisia. Here, we investigated the relationship between the status of simian virus 40 and t(14;18) translocation, germinal center status, and P53 and BCL2 expression to assess the clinical and biological relevance of simian virus 40 presence in diffuse large B-cell lymphomas. Therefore, we evaluated by immunohistochemistry the expression patterns of CD10, BCL6, MUM1, BCL2, and P53 in 86 diffuse large B-cell lymphomas (48 simian virus 40-positive and 38 simian virus 40-negative cases). The t(14;18) translocation was investigated by polymerase chain reaction. Immunostaining patterns for CD10, BCL6, and MUM1 were used to subclassify diffuse large B-cell lymphoma cases as germinal center or non-germinal center phenotypes. Germinal center phenotype, t(14;18), P53, and BCL2 expression were found in 71, 30, 55, and 65% of cases, respectively. Interestingly, germinal center phenotype, t(14;18), and P53 accumulation were found to be more frequent in simian virus 40-positive cases than in simian virus 40-negative ones (81, 44, 69 vs 58, 13, 37%; P=0.018, 0.002, and 0.003, respectively). However, there were no correlations between the presence of simian virus 40 and the expression of CD10, BCL6, MUM1 and BCL2, patient's age and gender, clinical stage, or the International Prognosis Index. Multivariate logistic regression analyses revealed that the germinal center phenotype, P53 accumulation, and t(14;18) were independent factors for simian virus 40 association (P=0.029, 0.006, and 0.014, respectively). There were no significant differences in overall survival regarding P53, BCL2, or t(14;18) status. However, patients with germinal center phenotype or low International Prognosis Index scores displayed a significantly better survival than those with non-germinal center phenotype or high International Prognosis Index scores (P=0.003 and 0.0001, respectively). These two prognosis factors remain independent in multivariate analyses (P=0.001 and <0.0001, respectively). Interestingly, among patients with germinal center phenotype, simian virus 40-positive subgroup displayed a significantly shorter survival than simian virus 40-negative subgroup (P=0.034). In summary, these findings support a role of simian virus 40 in the pathogenesis of diffuse large B-cell lymphomas. On other hand, they suggest that a significant proportion of diffuse large B-cell lymphoma cases with germinal center phenotype may result from early transformation by simian virus 40, mainly those harboring the t(14;18).Modern Pathology (2008) 21, 282-296; doi:10.1038/modpathol.3800993; published online 28 December 2007.     

Modulation of cellular redox state underlies antagonism between oxaliplatin and cetuximab in human colorectal cancer cell lines

Background and purpose:

Oxaliplatin is the first platinum-based compound effective in the treatment of colorectal cancer. Oxaliplatin combined with cetuximab for metastatic colorectal cancer is under evaluation. The preliminary results seem controversial, particularly for the use of cetuximab in K-Ras mutated patients. K-Ras mutation is known to affect redox homeostasis. Here we evaluated how the efficacy of oxaliplatin alone or combined with cetuximab varied according to the Ras mutation and redox status in a panel of colorectal tumour cell lines.

Experimental approach:

Viability was evaluated by methylthiazoletetrazolium assay, reactive oxygen species production by DCFDA and lucigenin on HT29-D4, Caco-2, SW480 and SW620 cell lines.

Key results:

Combination of oxaliplatin and cetuximab was less cytotoxic than oxaliplatin alone in colorectal cells harbouring wild-type Ras and membrane expression of receptors for epidermal growth factor receptor (EGFR), such as HT29-D4 and Caco-2 cells. In contrast, cetuximab did not affect oxaliplatin efficiency in cells harbouring K-Ras^V12 mutation, irrespective of membrane EGFR expression (SW620 and SW480 cells). Transfection of HT29-D4 with K-Ras^V12 decreased oxaliplatin IC₅₀ and impaired cetuximab sensitivity, without affecting expression of membrane EGFR compared with HT29-D4 control. Oxaliplatin efficacy relies on endogenous production of H₂O₂. Cetuximab inhibits H₂O₂ production inhibiting the EGFR/Nox1 NADPH oxidase pathway. Oxaliplatin efficacy was impaired by short hairpin RNA for Nox1 and by catalase (H₂O₂ scavenger).

Conclusions and implications:

Cetuximab limited oxaliplatin efficiency by affecting the redox status of cancer cells through Nox1. Such combined therapy might be improved by controlling H₂O₂ elimination.     

Torsion annexielle révélatrice d’un carcinome papillaire séreux utérin

We report a case of uterine papillary serous carcinoma in a 50 years-old woman, after salpingo-oophorectomy performed for ovarian cyst. Uterine papillary serous carcinoma metastases in ovarian mature teratoma was diagnosed by pathology examination. Uterine primary neoplasm was suspected by magnetic resonance imaging and confirmed after uterine and cervix biopsy. Liver and pleural metastasis with a fatal issue occurred after six weeks.     

Anorectal malignant melanomas. Apropos of 2 new cases]

Clinical and therapeutic characteristics of anorectal melanoma have been studied about 2 new cases. The initial symptoms were often misdiagnosed with hemorrhoids disease. This cancer carries a bad prognosis but the best treatment seems to be abdominoperineal resection (APR) when the thickness of the melanoma is under 3 mm. Over this limit, APR alone will not cure this disease. Curative treatment will probably involve a combined therapy with local and systemic therapies.