The metastasis-associated protein-1 gene encodes a host permissive factor for schistosomiasis, a leading global cause of inflammation and cancer

Schistosoma haematobium is responsible for two-thirds of the world's 200 million to 400 million cases of human schistosomiasis. It is a group 1 carcinogen and a leading cause of bladder cancer that occurs after years of chronic inflammation, fibrosis, and hyperproliferation in the host liver. The coevolution of blood flukes of the genus Schistosoma and their human hosts is paradigmatic of long-term parasite development, survival, and maintenance in mammals. However, the contribution of host genes, especially those discrete from the immune system, necessary for parasite establishment and development remains poorly understood. This study investigated the role of metastasis-associated protein-1 gene (Mta1) product in the survival of S. haematobium and productive infection in the host. Using a Mta-1 null mouse model, here we provide genetic evidence to suggest that MTA1 expression positively influences survival and/or maturation of schistosomes in the host to patency, as we reproducibly recovered significantly fewer S. haematobium worms and eggs from Mta1-/- mice than wild-type mice. In addition, we found a distinct loss of cytokine interdependence and aberrant Th1 and Th2 cytokine responses in the Mta1-/- mice compared to age-matched wild-type mice. Thus, utilizing this Mta1-null mouse model, we identified a distinct contribution of the mammalian MTA1 in establishing a productive host-parasite interaction and thus revealed a host factor critical for the optimal survival of schistosomes and successful parasitism. Moreover, MTA1 appears to play a significant role in driving inflammatory responses to schistosome egg-induced hepatic granulomata reactions, and thus offers a survival cue for parasitism as well as an obligatory contribution of liver in schistosomiasis. CONCLUSION: These findings raise the possibility to develop intervention strategies targeting MTA1 to reduce the global burden of schistosomiasis, inflammation, and neoplasia.     

Distribution of HPV16 and 18 intratypic variants in normal cytology, intraepithelial lesions, and cervical cancer in a Mexican population

OBJECTIVE: Several intratype variants of HPV16 and 18 have been identified. These variants are associated with populations from different geographic regions, and show a differential distribution among the severity of the cervical lesion, most likely due to different pathogenic potential. The objective of this study was to investigate the variant distribution of HPV16 and 18 in a Mexican population and its association with the severity of the cervical lesion and the histological lineage of cervical cancer. METHODS: HPV types 16 and 18 detection was performed in 412 samples of preinvasive and invasive specimens from patients attending a Primary Health-Care Center, an Early Cervical Lesion Clinic, or a Cancer Center. Distribution of HPV variants was correlated with the cytological findings and tumor cell types using contingency tables. Statistical difference was tested with the Fisher's Exact Test or its Fisher-Freeman-Halton extension for RXC tables. Alpha value was set at the P < 0.05. RESULTS: Among the 277 women included in this study without cancer, 63.5% (176 cases) had a normal cytology; from the remaining 101 women, 53.5% were LSIL (54 cases), and 46.5% HSIL (47 cases). From a total of 135 invasive carcinomas, 78.5% were squamous (106 cases); 6.6% adenocarcinoma (9 cases); 9.6% adenosquamous (ADSC) (13 cases); and 5.1% were undifferentiated carcinoma (7 cases). HPV16 E and AA-a were evenly distributed among preinvasive and invasive lesions. However, the isolate AA-c was exclusively found in cervical cancer. HPV18 Var-1(E) was almost exclusively found in invasive lesions, while the HPV18 Var-2(Af) predominated in normal or preinvasive lesions. In invasive cancer, this variant was found only in squamous tumors. CONCLUSIONS: The differential distribution of HPV16 and 18 variants in cervical lesions we found further supports experimental data on the different pathogenic potential of HPV16 and 18 variants for cervical cancer development.     

The mathematical model of insulin desorption from the bioactive, fibrous artificial store

The aim of this study was to study insulin desorption from fibrous insulin artificial store in vitro as well as in vivo, with the intention to define a mathematical model that would describe this process. Release profile of cylindrical fibrous matrixes for various insulin concentrations, desorption temperatures, time periods, and pH were presented. Change of insulin concentration in the fibers and the effect of insulin release were discussed. This model was also used to predict the optimal conditions of the release process. Possibility of predicting the effect of the fibrous store design parameters (fibre radius, amount of bonded insulin, fiber type) on the resulting insulin release rate was the major advantage of this mathematical model. Also, taking all the relevant conditions regarding these experiments into consideration, by the application of mathematical model, the diffusion coefficient during insulin release was determined.     

Cytotoxic, mutagenic and genotoxic effects of new anti-T. cruzi 5-phenylethenylbenzofuroxans. Contribution of phase I metabolites on the mutagenicity induction

5-Phenylethenylbenzofuroxans have displayed in vitro and in vivo activity against Trypanosoma cruzi, the etiologic agent of American Trypanosomiasis. On the basis of benzofuroxans pre-clinical studies we evaluated the potential of six 5-phenylethenyl derivatives to induce cytotoxicity, mutagenicity and genotoxicity using different in vitro models. Cytotoxic effects were evaluated using a set of cells, mammal pre-monocytic macrophages, V-79 lung fibroblast from Chinese hamster, and colorectal adenocarcinoma Caco-2 cells, in the MTT viability assay. Mutagenicity was tested in the Ames assay using Salmonella typhimurium TA98 strain with and without metabolic activation by S9-rat liver homogenate. The genotoxic potentials were evaluated with the alkaline single cell gel electrophoresis (comet assay) in V-79 cells. In view of the Ames test results we study whether the main mammals’ phase I metabolites, the corresponding o-nitroanilines, are involved in the mechanism of mutagenicity. These metabolites are produced by NADPH-dependent enzymes in cytosol and by xanthine oxidase and cytochrome P450 in microsomes from rat liver. Among them, the electronic property of phenyl substituent seems to be responsible for this effect. It could be pointed out that the equimolecular mixture of compounds 1 and 2 (5E- and 5Z-(2-phenylethenyl)benzofuroxan, respectively) could be used in further clinical studies as anti-T. cruzi drug.     

Antibacterial activity of the enniatin B, produced by Fusarium tricinctum in liquid culture, and cytotoxic effects on Caco-2 cells

The enniatins (ENs) are bioactive compounds of hexadepsipeptidic structure produced by several strains of Fusarium sp. The EN B was purified from extracts of Fusarium tricinctum growth on liquid culture of potato dextrose broth (PDB), using a semipreparative liquid chromatography (LC) followed by an analytical LC. The purity and the structure of the isolated compound were confirmed by the determination of the extinction coefficient and with electrospray ionization-mass spectrometry (ESI-MS) study. The pure fraction of EN B was utilized to determine the antibiotic effects on several bacterial strains that are considered normally pathogens of the intestinal tract: Escherichia coli, Enterococcus faecium, Salmonella enterica, Shigella dysenteriae, Listeria monocytogenes, Yersinia enterocolitica, Clostridium perfringens, Pseudomonas aeruginosa, and Staphylococcus aureus, and to study the cytotoxic effects on Caco-2 differentiated and undifferentiated cells. The results obtained demonstrated that in several antibiograms, EN B induced the inhibition of the grown microorganisms tested and no significant differences over control were detected when Caco-2 cells were exposed to EN B, at any of the concentrations used.     

Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of posttransplant proteinuria and stabilization of glomerular filtration rate. The number of SMPDL-3b(+) podocytes in postreperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase down-regulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner.