Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

Obtained from Haematologica/the Hematology Journal website http://www.haematologica.orgPeripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy. New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol- 3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol- 3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas. Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T-cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot. The PIK3CD gene, which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3b and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC-0941-treated T-cell lymphoma cell lines, suggesting the presence of a combination of phosphatidylinositol-3-kinase and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T-cell lymphoma cell lines, and reducing cell viability in primary tumor T cells ex vivo. These results suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T-cell lymphomas.This work was supported by grants from the Asociación Española Contra el Cáncer, Fondo de Investigaciones Sanitarias (PI051623, PI052800 and PI080856), RTICC (RD06/0020/0107) and Ministerio de Ciencia e Innovación (SAF2008-0387-1). EMS is supported by a grant from the Department of Education, Universities and Research of the Basque Government (BFI08.207). MSB is supported by a Contract Miguel Servet from Fondo de Investigaciones Sanitarias (CP11/00018

Solitary caecal diverticulitis as an unusual cause of a right iliac fossa mass: a case report

Inflammation of a solitary caecal diverticulum is an uncommon pathological condition. Preoperatively the condition is almost indistinguishable from appendicitis, and is often confused with carcinoma of the caecum during operation. The typical patient with this condition is male, Asian, and in the fourth decade of life. This case is unusual in that the patient was a 26-year-old Caucasian man

Effect of solution treatment on spinodal decomposition during aging of an Fe-46.5 at.% Cr alloy

Spinodal decomposition is a key phase transition in advanced materials and a significant effort is paid to the quantitative modeling of the phenomenon. The initial materials condition is often assumed to be random during modeling, but this may be an oversimplification. In this work, the effect of solution treatment above the miscibility gap, on spinodal decomposition during subsequent aging, has been investigated for an Fe-46.5 at.% Cr alloy. By atom probe tomography (APT), it is found that different extents of quenched-in Cr clustering exist after solution treatments at different temperatures. The clustering is pronounced at 800 A degrees C but decreases significantly with increasing temperature to 900 A degrees C. Thermodynamic Monte Carlo simulations show that there is a difference in atomic short range order between the different solution treatment temperatures. By APT, it is, furthermore, found that the kinetics of spinodal decomposition at 500 A degrees C, i.e., within the miscibility gap, is enhanced in the initial alloy condition, where Cr was less randomly distributed. These observations are supported by kinetic Monte Carlo simulations, predicting a similar but less pronounced qualitative effect on spinodal decomposition kinetics. Other possible reasons for the enhanced kinetics could be related to clustering of interstitial elements and/or sigma phase, but neither was found in the experiments. Nonetheless, the observations in this work suggest that it is necessary to implement a modeling strategy, where the initial structure is properly accounted for when simulating spinodal decomposition

Effect of solution treatment on spinodal decomposition during aging of an Fe-46.5 at.% Cr alloy

Spinodal decomposition is a key phase transition in advanced materials and a significant effort is paid to the quantitative modeling of the phenomenon. The initial materials condition is often assumed to be random during modeling, but this may be an oversimplification. In this work, the effect of solution treatment above the miscibility gap, on spinodal decomposition during subsequent aging, has been investigated for an Fe-46.5 at.% Cr alloy. By atom probe tomography (APT), it is found that different extents of quenched-in Cr clustering exist after solution treatments at different temperatures. The clustering is pronounced at 800 A degrees C but decreases significantly with increasing temperature to 900 A degrees C. Thermodynamic Monte Carlo simulations show that there is a difference in atomic short range order between the different solution treatment temperatures. By APT, it is, furthermore, found that the kinetics of spinodal decomposition at 500 A degrees C, i.e., within the miscibility gap, is enhanced in the initial alloy condition, where Cr was less randomly distributed. These observations are supported by kinetic Monte Carlo simulations, predicting a similar but less pronounced qualitative effect on spinodal decomposition kinetics. Other possible reasons for the enhanced kinetics could be related to clustering of interstitial elements and/or sigma phase, but neither was found in the experiments. Nonetheless, the observations in this work suggest that it is necessary to implement a modeling strategy, where the initial structure is properly accounted for when simulating spinodal decomposition

Direct atom probe tomography observations of concentration fluctuations in Fe-Cr solid solution

The local concentration of atoms in an Fe-46.5 at.% Cr alloy, solution treated at four different temperatures above the miscibility gap, has been investigated using atom probe tomography. It is experimentally found that Cr atoms cluster in the solid solution and that the clustering tendency decreases with increasing temperature above the miscibility gap. These findings are corroborated by Monte Carlo simulations of the atomic short-range order, which show that clustering markedly decrease with increasing temperature from 800 to 1200 degrees C