Analysis of the immune response induced by a scorpion venom sub-fraction, a pure peptide and a recombinant peptide, against toxin Cn2 of Centruroides noxius Hoffmann.

Three different immunogens from the venom of the Mexican scorpion Centruroides noxius Hoffmann were used to study protective antibody response in mice and rabbits, challenged with toxin Cn2, one of the most abundant toxic peptide of this venom. The immunogens were: Cn5, a crustacean specific toxin; a recombinant protein containing the peptide Cn5 linked to the maltose transporter and a sub-fraction (F.II.5) containing 25 distinct peptides, among which is Cn5. Mice immunized with these three preparations, when directly challenged with Cn2 presented no apparent protection, whereas anti-sera produced in rabbits with these three immunogens were capable of partially neutralizing the effect of Cn2, when injected into naive mice. Cn5 rabbit anti-serum showed a better protective effect on mice, than the rabbit sera obtained against the two other antigens. The subcutaneous route of challenging mice was shown to be better than intraperitoneal injections. Comparative structural analysis of Cn5 with other toxins of this venom showed that our results are important to be taken into consideration, when choosing appropriate immunogens aimed at the production of better anti-venoms or for the rational design of possible vaccines.     

CD34+ cells from acute myeloid leukemia, myelodysplastic syndromes, and normal bone marrow display different apoptosis and drug resistance-associated phenotypes.

Myelodysplastic syndromes and acute myeloid leukemia (AML) are heterogeneous disorders in which conflicting results in apoptosis and multidrug resistance (MDR) have been reported. We have evaluated by multiparameter flow cytometry the expression of apoptosis- (APO2.7, bcl-2, and bax) and MDR-related proteins [P-glycoprotein (P-gp), multidrug resistance protein (MRP), and lung resistance protein (LRP)] specifically on bone marrow (BM) CD34+ cells, and their major CD32-/dim and CD32+ subsets, in de novo AML (n=90), high-risk myelodysplastic syndrome (n=9), and low-risk myelodysplastic syndrome (n=21) patients at diagnosis, and compared with normal BM CD34+ cells (n=6). CD34+ myeloid cells from AML and high-risk myelodysplastic syndrome patients displayed higher expression of bcl-2 (P <0.0001) and lower reactivity for APO2.7 (P=0.002) compared with low-risk myelodysplastic syndrome and normal controls. Similar results applied to the two predefined CD34+ myeloid cell subsets. No significant differences were found in the expression of P-gp, MRP, and LRP between low-risk myelodysplastic syndrome patients and normal BM, but decreased expression of MRP (P <0.03) in AML and high-risk myelodysplastic syndromes and P-gp (P=0.008) in high-risk myelodysplastic syndromes were detected. Hierarchical clustering analysis showed that low-risk myelodysplastic syndrome patients were clustered next to normal BM samples, whereas high-risk myelodysplastic syndromes were clustered together and mixed with the de novo AML patients. In summary, increased resistance to chemotherapy of CD34+ cells from both AML and high-risk myelodysplastic syndromes would be explained more appropriately in terms of an increased antiapoptotic phenotype rather than a MDR phenotype. In low-risk myelodysplastic syndromes abnormally high apoptotic rates would be restricted to the CD34- cell compartments.     

Riesgo de enfermar y morir por cáncer de mama en Castilla-La Mancha (1975–1998)

Background. To know the temporary tendency in the mortality due to breast cancer in Castilla-La Mancha (CLM, Spain) between 1975 and 1998. Patients and methods. The mortality data are from the Registry of Mortality of CLM. Crude and standardized mortality rates are calculated. In order to evaluate the tendency, we use the Poisson’s log- linear model. We have calculated the accumulated rate to die and the accumulated risks to die and to become ill. Results. Between 1975 and 1998, 2.44% of all deaths in CLM women were consequence of a breast cancer. The crude rate increased from the 14.55 by 100,000 in 1975 to 25.23 by 100,000 in 1998, with an annual average increase of 1.49%. The average age of death increased until the 67 years old in 1998 as opposed to the 59 years old of 1975. The risk of dying of a breast cancer increased in the period from 1.4% in 1975 to 2.34% in 1998. Conclusion. Mortality by breast cancer has raised until 1993, when it begun to decrease. In general, women with breast cancer die elderly, and young women have increased risk to fall ill.     

Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism.

Aplidine is a promising antitumor agent derived from the Mediterranean tunicate Aplidium albicans. We have found that Aplidine at nM concentrations (10-100 nM) induced apoptosis in human leukemic cell lines and primary leukemic cell cultures from leukemic patients. Inhibition of the Fas (CD95)/Fas ligand (CD95L) signaling pathway with an antagonistic anti-Fas antibody partially inhibited Aplidine-induced apoptosis. L929 cells were resistant to Aplidine action but underwent apoptosis after transfection with human Fas cDNA. Aplidine induced a rapid and sustained c-Jun NH(2)-terminal kinase activation, and pretreatment with curcumin or SP600125 inhibited Aplidine-induced c-Jun NH(2)-terminal kinase activation and apoptosis. However, inhibition of extracellular signal-regulated kinase and p38 kinase signaling pathways did not affect Aplidine-induced apoptosis. Aplidine induced caspase-3 activation, and caspase inhibition prevented Aplidine-induced apoptosis. Aplidine failed to induce apoptosis in MCF-7 breast cancer cells, defective in caspase-3, additionally implicating caspase-3 in its proapoptotic action. Aplidine also triggered an early release of cytochrome c from mitochondria, and overexpression of bcl-2 by gene transfer abrogated mitochondrial cytochrome c release and apoptosis. Aplidine rapidly induced cleavage of Bid, a mediator that connects the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. Primary cultures of normal human cells, including hepatocytes and resting peripheral blood lymphocytes, were spared or weakly affected after Aplidine treatment. Nevertheless, mitogen (phytohemagglutinin/interleukin-2)-activated T lymphocytes resulted sensitively to the apoptotic action of Aplidine. Thus, Aplidine is an extremely potent and rapid apoptotic inducer on leukemic cells that triggers Fas/CD95- and mitochondrial-mediated apoptotic signaling routes, and shows a rather selective apoptotic action on cancer cells and activated T cells.     

A comparative study of the utility of two superdisintegrants in microcrystalline cellulose pellets prepared by extrusion-spheronization.

This study evaluated the utility of including superdisintegrants (croscarmellose sodium or sodium starch glycolate) in microcrystalline cellulose extrusion-spheronization pellets as a means of increasing the dissolution rate of poorly water-soluble drugs. The model drug was hydrochlorothiazide, with water or water/ethanol as wetting agent for pellet preparation. Neither disintegrant had significant effects on pellet morphology, flow properties or mechanical resistance. Neither disintegrant caused disintegration of the pellet in drug dissolution medium. Nevertheless, the disintegrants afforded a modest increase in drug dissolution rate, attributable to the observed increase in pellet micropore volume. Drug dissolution rate was slightly higher in pellets prepared with sodium starch glycolate, probably because of this disintegrant's higher swelling capacity.     

The Astounding Breadth of Health Disparity: Phenome-Wide Effects of Race on Disease Risk

ObjectiveWe conducted a phenotype-wide association study (PheWAS) to compare diagnoses among Blacks with those of Whites in one health center in Tennessee using data from 1,883,369 patients.MethodsWe used our deidentified EHR, the Synthetic Derivative, to assess risk of diagnoses associated with Black as compared with White race using Firth logistic regression with covariates including age, sex, and density of clinical encounters.ResultsThere were anchoring associations in both directions, including the highest increased risk for Blacks of having sickle cell anemia, and strongest decreased risk of basal cell carcinoma. Results included established areas of disparity and many novel associations.ConclusionsPheWAS is a viable tool for calculating risk associated with any biomarker. The current analysis provide a new approach to generating hypotheses and understanding the breadth of health disparities. Future analyses will further explore causality, risk factors, and potential confounders not accounted for here.     

Elevated Plasma S100B,Psychotic Symptoms,and Cognition in Schizophrenia

S100B is a calcium binding protein mainly produced by glial cells. Previous studies have shown elevated levels of S100B in patients with schizophrenia. We measured S100B levels in fasting plasma of 39 patients with schizophrenia and 19 adult healthy controls. We used linear regression to compare S100B between patients and controls. In patients only, we also investigated the relationship between S100B levels and psychotic symptoms (assessed by the Positive and Negative Syndrome Scale), and cognitive function (assessed by the NIH Toolbox Cognition Battery), respectively by calculating Pearson’s correlation coefficients. Mean plasma S100B was significantly higher in the patient group than in the control group. There were no significant correlations between plasma S100B and psychotic symptoms or cognition.     

High rate of hematological responses to sorafenib in FLT3‐ITD acute myeloid leukemia relapsed after allogeneic hematopoietic stem cell transplantation

Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell transplantation (HSCT) for FLT3‐ITD‐positive acute myeloid leukemia (AML), and available therapies are largely unsatisfactory. In this study, we retrospectively collected data on the off‐label use of the tyrosine kinase inhibitor sorafenib, either alone or in association with hypomethylating agents and adoptive immunotherapy, in 13 patients with post‐transplantation FLT3‐ITD‐positive AML relapses. Hematological response was documented in 12 of 13 patients (92%), and five of 13 (38%) achieved complete bone marrow remission. Treatment was overall manageable in the outpatient setting, although all patients experienced significant adverse events, especially severe cytopenias (requiring a donor stem cell boost in five patients) and typical hand‐foot syndrome. None of the patients developed graft‐vs.‐host disease following sorafenib alone, whereas this was frequently observed when this was given in association with donor T‐cell infusions. Six patients are alive and in remission at the last follow‐up, and four could be bridged to a second allogeneic HSCT, configuring a 65 ± 14% overall survival at 100 d from relapse. Taken together, our data suggest that sorafenib might represent a valid treatment option for patients with FLT3‐ITD‐positive post‐transplantation relapses, manageable also in combination with other therapeutic strategies.