Myelodysplastic Syndrome and Histone Deacetylase Inhibitors: “To Be or Not to Be Acetylated”?

Myelodysplastic syndrome (MDS) represents a heterogeneous group of diseases with clonal proliferation, bone marrow failure and increasing risk of transformation into an acute myeloid leukaemia. Structured guidelines are developed for selective therapy based on prognostic subgroups, age, and performance status. Although many driving forces of disease phenotype and biology are described, the complete and possibly interacting pathogenetic pathways still remain unclear. Epigenetic investigations of cancer and haematologic diseases like MDS give new insights into the pathogenesis of this complex disease. Modifications of DNA or histones via methylation or acetylation lead to gene silencing and altered physiology relevant for MDS. First clinical trials give evidence that patients with MDS could benefit from epigenetic treatment with, for example, DNA methyl transferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi). Nevertheless, many issues of HDACi remain incompletely understood and pose clinical and translational challenges. In this paper, major aspects of MDS, MDS-associated epigenetics and the potential use of HDACi are discussed

Combination of the Deacetylase Inhibitor Panobinostat and the Multi-Kinase Inhibitor Sorafenib for the Treatment of Metastatic Hepatocellular Carcinoma - Review of the Underlying Molecular Mechanisms and First Case Report

Advanced hepatocellular carcinoma still represents an unmet medical need that has only a limited overall survival despite the introduction of the multi-kinase inhibitor sorafenib. Recently, inhibitors of histone and other protein deacetylases have been established as novel therapeutic approaches to cancer diseases. We here review the molecular rationale for combining these two novel targeted therapies and report a patient with metastasized hepatocellular carcinoma who showed a partial remission of primary and metastatic lesions for five months after a combination therapy with sorafenib and the orally available pan-deacetylase inhibitor panobinostat

Epigenetic Regulation of p21cip1/waf1 in Human Cancer

p21cip1/waf1 is a central regulator of cell cycle control and survival. While mutations are rare, it is commonly dysregulated in several human cancers due to epigenetic mechanisms influencing its transcriptional control. These mechanisms include promoter hypermethylation as well as additional pathways such as histone acetylation or methylation. The epigenetic regulators include writers, such as DNA methyltransferases (DNMTs); histone acetyltransferases (HATs) and histone lysine methyltransferases; erasers, such as histone deacetylases (HDACs); histone lysine demethylases [e.g., the Lysine Demethylase (KDM) family]; DNA hydroxylases; readers, such as the methyl-CpG-binding proteins (MBPs); and bromodomain-containing proteins, including the bromo- and extraterminal domain (BET) family. We further discuss the roles that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play in the epigenetic control of p21cip1/waf1 expression and its function in human cancers

Differential diagnostic challenge of chronic neutrophilic leukemia in a patient with prolonged leukocytosis

Our interesting case deals with the clinical and morphological aspects of a chronic neutrophilic leukemia and the critical evaluation of differential diagnosis of leukemoid reaction in bone marrow biopsies

Phase 1 dose escalation study of the allosteric AKT inhibitor BAY 1125976 in advanced solid cancer-Lack of association between activating AKT mutation and AKT inhibition-derived efficacy

This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring th

Influence of Five Potential Anticancer Drugs on Wnt Pathway and Cell Survival in Human Biliary Tract Cancer Cells

Background: The role of Wnt signalling in carcinogenesis suggests compounds targeting this pathway as potential anti-cancer drugs. Several studies report activation of Wnt signalling in biliary tract cancer (BTC) thus rendering Wnt inhibitory drugs as potential candidates for targeted therapy of this highly chemoresistant disease

The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells

BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 μM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC

Reconfigurable Si Nanowire Nonvolatile Transistors

Reconfigurable transistors merge unipolar p- and n-type characteristics of field-effect transistors into a single programmable device. Combinational circuits have shown benefits in area and power consumption by fine-grain reconfiguration of complete logic blocks at runtime. To complement this volatile programming technology, a proof of concept for individually addressable reconfigurable nonvolatile transistors is presented. A charge-trapping stack is incorporated, and four distinct and stable states in a single device are demonstrated