Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect.

Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting toxicity. Carfilzomib (CFZ), a second-generation PI, induces a significantly less severe PN. We investigated possible BTZ and CFZ off-targets able to explain their different neurotoxicity profiles. In order to identify the possible PIs off-targets we used the SPILLO-PBSS software that performs a structure-based in silico screening on a proteome-wide scale. Among the top-ranked off-targets of BTZ identified by SPILLO-PBSS we focused on tubulin which, by contrast, did not turn out to be an off-target of CFZ. We tested the hypothesis that the direct interaction between BTZ and microtubules would inhibit the tubulin alfa GTPase activity, thus reducing the microtubule catastrophe and consequently furthering the microtubules polymerization. This hypothesis was validated in a cell-free model, since BTZ (but not CFZ) reduces the concentration of the free phosphate released during GTP hydrolysis. Moreover, NMR binding studies clearly demonstrated that BTZ, unlike CFZ, is able to interact with both tubulin dimers and polymerized form. Our data suggest that different BTZ and CFZ neurotoxicity profiles are independent from their proteasome inhibition, as demonstrated in adult mice dorsal root ganglia primary sensory neurons, and, first, we demonstrate, in a cell free model, that BTZ is able to directly bind and perturb microtubules.

Natural occurrence of aflatoxins, deoxynivalenol, fumonisins and zearalenone in maize from Entre Ríos Province, Argentina.

In Entre Ríos, Argentina, corn is one of the most important cereal grains produced, being an important income for the regional economy. The aim of this work was to assess aflatoxins, zearalenone, deoxynivalenol (DON) and fumonisins (FB) in corn harvest in 2003 and 2004 in the most contaminated departments found in previous studies in selected sampling places. At the harvest time, when the trucks arrived to store plants, samples of corn were taken from seven different positions of the trucks and from five in the trailer. Composite samples were randomised reduced to 10 kg. The samples were analysed by immunological tests, by thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and/or gas liquid chromatography-electron capture detector (GLC-ECD). In 2003 average contamination was 3.19 u.g/kg for aflatoxins, 118.5 µg/kg for deoxynivalenol, 230.8 µg/kg for zearalenone and 10200 µg/kg of total fumonisins (HPLC and ELISA quantification showed a linear correlation (r(2) =0.9618), but RIDASCREEN®FAST values were 1.7 higher than HPLC values); in 2004 deoxynivalenol and zearalenone were not detected and an average of 2.0 µg/kg for aflatoxins and 4700 µg/kg for total fumonisins was found.This province, with the earliest harvested corn in the country each summer, tends to display different contaminations from the rest of the provinces, probably due to climate characteristics, particularly hotter weather.

Distribution of fumonisins in dry-milled corn fractions in Argentina.

Corn samples and different dry-milled fractions collected from an industrial mill in Argentina were analysed. Average contaminations were FB(1) 1540 microg kg(-1), FB(2) 716 microg kg(-1) and FB(3) 152 microg kg(-1) in whole corn; FB(1) 135 microg kg(-1), FB(2) 39.1 microg kg(-1) and FB(3) 10.2 microg kg(-1) in corn grits; FB(1) 358 microg kg(-1), FB(2) 122 microg kg(-1) and FB(3) 45.9 microg kg(-1) in 'C' flour; FB(1) 148 microg kg(-1), FB(2) 52.5 microg kg(-1) and FB(3) 28.3 microg kg(-1) in corn meal; and FB(1) 4210 microg kg(-1), FB(2) 2010 microg kg(-1) and FB(3) 447 microg kg(-1) in germ and bran together. The fumonisin contamination level was approximately three times higher in germ and bran than in whole corn, 13 times higher than in 'C' flour and 29 times higher than in corn meal and corn grits. Taking into account the distribution of fumonisins in commercial dry-milled corn fractions and corn meal consumption in Argentina, a theoretical whole corn level of 6640 microg kg(-1) maximum of total fumonisins could be processed to obtain products considered safe for human health.

[Sequential scintigraphic evaluation in renal transplantation (author's transl)]. / Valutazione della scintigrafia sequenziale nel trapianto di rene: considerazioni in 57 pazienti.

In a series of 57 renal transplantation of a sequential scintigraphy was carried out within the tenth day from surgical operation. According to the various scintigraphic findings and on the basis of the possible acute renal failure, the patients were subdivided into 7 groups and the data were correlated with clinical and hystological findings.

Morphological, immunohistological and clinical findings in renal amyloidosis: correlations with prognosis in 16 patients.

Sixteen patients affected by renal amyloidosis (A.) and submitted to renal biopsy have been studied by light microscopy and immunofluorescence. Clinical manifestations at observation and follow up have been reviewed. Survival was 32% at ten years, lower than all other nephropathies except rapidly-progressive glomerulonephritis. Primary A. had a significantly worse survival rate than secondary A. An observation up to 6 years after biopsy allowed us to isolate a group of patients with a steady good renal function: this group is characterized by: a longer mean duration of nephropathy before observation, a lower incidence of nephrotic syndrome (NS), absence of renal failure at time of biopsy, a higher incidence of increased mesangial areas at light microscopy, a lower percentage of glomerular capillary walls thickening, a higher incidence of amyloid deposits on vessels but not on glomerular capillaries, a definite more elevated presence of Ig and C3 over mesangium and glomerular capillary walls. The possible role of the last findings is discussed.

[Treatment with antilymphocyte globulin (ALG) and evolution of renal transplant: observations of 42 cases]. / Trattamento con globulina antilinfocitaria (GAL) ed evoluzione del trapianto renale: osservazioni in 42 casi.

42 necrokidney transplants, performed in Renal Unit of "Niguarda - Ca' Granda" Hospital in Milan, since 1972, have been examined. Hystocompatibility score and previous transfusions and/or pregnancies apparently did not correlate with three months transplants survival. Our patients have been separated into two groups according to treatment with or without ALG: the group treated with ALG showed a better percentage survival of the kidney at three months a lower incidence of rejection episodes during the same period. The usefulness of ALG treatment is reaffirmed; we consider that a better prognosis at three months probably means a more favorable clinical course.