Keratinocytes Determine Th1 Immunity during Early Experimental Leishmaniasis

Experimental leishmaniasis is an excellent model system for analyzing Th1/Th2 differentiation. Resistance to Leishmania (L.) major depends on the development of a L. major specific Th1 response, while Th2 differentiation results in susceptibility. There is growing evidence that the microenvironment of the early affected tissue delivers the initial triggers for Th-cell differentiation. To analyze this we studied differential gene expression in infected skin of resistant and susceptible mice 16h after parasite inoculation. Employing microarray technology, bioinformatics, laser-microdissection and in-situ-hybridization we found that the epidermis was the major source of immunomodulatory mediat…

Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia : results from a randomized, placebo-controlled trial

Purpose The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML. Patients and Methods All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary ob…

Sorafenib In Combination with Standard Induction and Consolidation Therapy In Elderly AML Patients: Results From a Randomized, Placebo-Controlled Phase II Trial

Abstract Abstract 333 Background: Standard chemotherapy for elderly AML patients results in a median overall survival of only about one year. Case reports and early phase I/II data have shown that the kinase inhibitor Sorafenib might show clinical benefit for Flt3-ITD-positive AML patients (Metzelder S Blood 2009; 113:6567) and that its addition to standard chemotherapy is feasible (Ravandi F JCO 2010; 28:1856). Sorafenib is a potent Raf, c-Kit and FLT3 inhibitor that may also affect AML blasts and bone marrow (BM) stroma cells via VEGFR and PDGFR-β inhibition. Therefore, we performed a multicenter, randomized, placebo-controlled, double-blind phase II trial in elderly (>60 y) AML pa…

Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors

Unfavorable patient survival coincides with lineage plasticity observed in human acute leukemias. These cases are assumed to arise from hematopoietic stem cells, which have stable multipotent differentiation potential. However, here we report that plasticity in leukemia can result from instable lineage identity states inherited from differentiating progenitor cells. Using mice with enhanced c-Myc expression, we show, at the single-cell level, that T-lymphoid progenitors retain broad malignant lineage potential with a high capacity to differentiate into myeloid leukemia. These T-cell-derived myeloid blasts retain expression of a defined set of T-cell transcription factors, creating a lymphoi…

The prognostic and predictive value of IKZF1 and IKZF3 expression in T-cells in patients with multiple myeloma

Purpose: While recent studies described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells. In this study we examine the prognostic and predictive value of IKZF1/3 expression in T-cells in patients with MM stage III. Experimental design: We analysed the IKZF1/3 expression levels in T-cells from 45 MM stage I (MMI) and 50 newly diagnosed MM stage III (MMIII) patients, according to Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value. We also combined in vivo observations with in vitro assays to determine the effect of IKZF1/3 expression on the T-cell immunophenotype and…

Prognostic Stratification For Curatively Resected NSCLC Patients By Apoptosis Panel

Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction

AbstractAltered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3-D) DNA topology is unknown. Here we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML, Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. These analyses allow the identification of long-range cis-regulatory circuits, including a novel super-enhancer of the Hoxa locus, as well as larger and more …

The prognostic impact of PD1 and PDL1 expression in non-small cell lung cancer

Introduction: To improve the prognosis of lung cancer patients, immunotherapy is expected to become a powerful therapeutic option. Several clinical studies demonstrate a positive prognostic effect of a targeted therapy against the programmed cell death receptor PD1 and its ligand PDL1 in solid tumors. For non-small lung cancer (NSCLC) however, the diagnostic, prognostic and predictive impact of these factors needs to be clarified. Materials and Methods: Immunohistochemistry was performed to evaluate the expression profile of PD1 and PDL1 in 398 NSCLC patients (median age: 66 years, 78% male sex, 45% squamous cell carcinoma (SCC) histology). Statistical analysis included Fisher9s Exact test,…

Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells

PLoS one 7(7), e40853 (2012). doi:10.1371/journal.pone.0040853

AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations

Activating mutations of Flt3 are found in approximately one third of patients with acute myeloid leukemia (AML) and are an attractive drug target. Two classes of Flt3 mutations occur: internal tandem duplications (ITDs) in the juxtamembrane and point mutations in the tyrosine kinase domain (TKD). We and others have shown that Flt3-ITD induced aberrant signaling including strong activation of signal transducer and activator of transcription 5 (STAT5) and repression of CCAAT/estradiol-binding protein α (c/EBPα) and Pu.1. Here, we compared the signaling properties of Flt3-ITD versus Flt3-TKD in myeloid progenitor cells. We demonstrate that Flt3-TKD mutations induced autonomous growth of 32D ce…