42 research outputs found
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
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
Molecular basis of targeted therapy in T/NKcell lymphoma/leukemia: A comprehensive genomic and immunohistochemical analysis of a panel of 33 cell lines
T and NK-cell lymphoma is a collection of aggressive disorders with unfavorable outcome, in which targeted treatments are still at a preliminary phase. To gain deeper insights into the deregulated mechanisms promoting this disease, we searched a panel of 31 representative T-cell and 2 NK-cell lymphoma/leukemia cell lines for predictive markers of response to targeted therapy. To this end, targeted sequencing was performed alongside the expression of specific biomarkers corresponding to potentially activated survival pathways. The study identified TP53, NOTCH1 and DNMT3A as the most frequently mutated genes. We also found common alterations in JAK/STAT and epigenetic pathways. Immunohistochemical analysis showed nuclear accumulation of MYC (in 85% of the cases), NFKB (62%), p-STAT (44%) and p-MAPK (30%). This panel of cell lines captures the complexity of T/NK-cell lymphoproliferative processes samples, with the partial exception of AITL cases. Integrated mutational and immunohistochemical analysis shows that mutational changes cannot fully explain the activation of key survival pathways and the resulting phenotypes. The combined integration of mutational/expression changes forms a useful tool with which new compounds may be assayed
Salivary pellets induce a pro-inflammatory response involving the TLR4–NF-kB pathway in gingival fibroblasts
Effect of solution treatment on spinodal decomposition during aging of an Fe-46.5 at.% Cr alloy
A roadmap of constitutive NF-κB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses
Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma
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