Trastuzumab and Doxorubicin Sequential Administration Increases Oxidative Stress and Phosphorylation of Connexin 43 on Ser368

Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancer cases, causing a more aggressive tumour growth and poor prognosis. Trastuzumab, the humanized antibody targeted to HER2, increased the life expectancy of patients, but severe cardiotoxicity emerged as a long-term adverse effect. Clinical evidence highlights that Trastuzumab-induced cardiotoxicity drastically increases in association with Doxorubicin; however, the exact mechanisms involved remain incompletely understood. In order to analyse the molecular mechanisms involved and the possible adaptative responses to Trastuzumab and Doxorubicin treatment, in this study, H9c2 cardiomyoblasts were used. Results showed that Trastuzumab and Doxorubicin sequential administration in cardiomyoblast increased cytosolic and mitochondrial ROS production, intracellular calcium dysregulation, mitochondrial membrane depolarization, and the consequent apoptosis, induced by both Trastuzumab and Doxorubicin alone. Furthermore, in these conditions, we observed increased levels of Connexin43 phosphorylated on Ser368 (pCx43). Since phosphorylation on Ser368 decreases gap junction intracellular communication, thus reducing the spread of death signals to adjacent cells, we hypothesized that the increase in pCx43 could be an adaptative response implemented by cells to defend neighbouring cells by Trastuzumab and Doxorubicin sequential administration. However, the other side of the coin is the resulting conduction abnormalities.     

Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis,Diagnosis and Therapy

Type 2 transglutaminase (TG2) is the main autoantigen in coeliac disease (CD), a widespread inflammatory enteropathy caused by the ingestion of gluten-containing cereals in genetically predisposed individuals. As a consequence, serum antibodies to TG2 represent a very useful marker in CD diagnosis. However, TG2 is also an important player in CD pathogenesis, for its ability to deamidate some Gln residues of gluten peptides, which become more immunogenic in CD intestinal mucosa. Given the importance of TG2 enzymatic activities in CD, several studies have sought to discover specific and potent inhibitors that could be employed in new therapeutical approaches for CD, as alternatives to a lifelong gluten-free diet. In this review, we summarise all the aspects regarding TG2 involvement in CD, including its enzymatic reactions in pathogenesis, the role of anti-TG2 antibodies in disease management, and the exploration of recent strategies to reduce deamidation or to use transamidation to detoxify gluten.     

Modeling Lung Carcinoids with Zebrafish Tumor Xenograft

Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)^y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.     

A Novel Morphological Parameter Predicting Fibrotic Evolution in Myeloproliferative Neoplasms: New Evidence and Molecular Insights

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) represent a group of hematological disorders that are traditionally considered as indistinct slow progressing conditions; still, a subset of cases shows a rapid evolution towards myelofibrotic bone marrow failure. Specific abnormalities in the megakaryocyte lineage seem to play a central role in this evolution, especially in the bone marrow fibrosis but also in the induction of myeloproliferation. In this review, we analyze the current knowledge of prognostic factors of MPNs related to their evolution to myelofibrotic bone marrow failure. Moreover, we focused the role of the megakaryocytic lineage in the various stages of MPNs, with updated examples of MPNs in vitro and in vivo models and new therapeutic implications.     

Turbo decoding of product codes using adaptive belief propagation

The adaptive belief propagation (ABP) algorithm was recently proposed by Jiang and Narayanan for the soft decoding of Reed-Solomon (RS) codes. In this paper, simplified versions of this algorithm are investigated for the turbo decoding of product codes. The complexity of the turbo-oriented adaptive belief propagation (TAB) algorithm is significantly reduced by moving the matrix adaptation step outside of the belief propagation iteration loop. A reduced-complexity version of the TAB algorithm that offers a trade-off between performance and complexity is also proposed. Simulation results for the turbo decoding of product codes show that belief propagation based on adaptive parity check matrices is a practical alternative to the currently very popular Chase-Pyndiah algorithm.     

Derivate des Phosphorsäure-o-phenylenesters. XV [1]. Synthese von Tris-(o-phenylendioxy)-phosphorat(V)

Derivatives of o-Phenylenephosphate. XV. Synthesis of Tris-(o-phenylenedioxy)-phosphorate(V) The structure of an orthophosphate which had been supposed earlier to represent type 1 , has been proven to be a compound having only one P-nucleus in the molecule, with a penta( 4 ) resp. hexacoordinated ( 5 ) structure depending on the solvent. The triethyl-ammonium salt 8 of this first example of a hexacoordinated phosphoric acid with 6 P O-bonds ( 5 ) is formed simply from tri- als well as from tetra- and pentacoordinated derivatives of phosphorous resp. phosphoric or thiophosphoric acid.     

Glioblastoma Stem Cells—Useful Tools in the Battle against Cancer

Glioblastoma stem cells (GSCs) are cells with a self-renewal ability and capacity to initiate tumors upon serial transplantation that have been linked to tumor cell heterogeneity. Most standard treatments fail to completely eradicate GSCs, causing the recurrence of the disease. GSCs could represent one reason for the low efficacy of cancer therapy and for the short relapse time. Nonetheless, experimental data suggest that the presence of therapy-resistant GSCs could explain tumor recurrence. Therefore, to effectively target GSCs, a comprehensive understanding of their biology and the survival and developing mechanisms during treatment is mandatory. This review provides an overview of the molecular features, microenvironment, detection, and targeting strategies of GSCs, an essential information required for an efficient therapy. Despite the outstanding results in oncology, researchers are still developing novel strategies, of which one could be targeting the GSCs present in the hypoxic regions and invasive edge of the glioblastoma.     

Immunochemical or fluorescent labeling of vesicular subcellular fractions for microscopy imaging

We describe a procedure for the labeling of membranous vesicular purified subcellular fractions, to image them, typically by confocal laser scanning microscopy. Being intracellular organelles, these fractions, once purified cannot be attached to glass slides as for cells. Fractions are labeled “in batch” without prior embedding or freezing. Each labeling step performed by passages of resuspension/centrifugation is followed by washings. Then samples are dispersed on the glass slides. Mammalian retinal rod outer segment disks, intact brain stem myelin vesicles, and brain synaptosomes were chosen, as these subcellular fractions can be purified by well established procedures. These fractions were immunolabeled with specific antibodies. Moreover, by the earlier procedure, we show that the mitochondrial vital membrane potential probe MitoTracker Deep Red 633 stains myelin vesicles and rod disks before fixation, consistently with our previous reports of a respiring capacity of these membranes. Therefore, the technique seems adequate to become an instrument to study the structure and the function of these and other subcellular fractions. Microsc. Res. Tech. 73:1086–1090, 2010. © 2010 Wiley‐Liss, Inc.     

Clockless Stochastic Decoding of Low-Density Parity-Check Codes: Architecture and Simulation Model

This paper introduces clockless stochastic decoding for high-throughput low-density parity-check (LDPC) decoders. Stochastic computation provides ultra-low-complexity hardware using simple logic gates. Clockless decoding eliminates global clocking, which eases the worst-case timing restrictions of synchronous stochastic decoders. The lack of synchronization might use outdated bits to update outputs in computation nodes; however, it does not significantly affect output probabilities. A timing model of clockless-computation behaviours under a 90 nm CMOS technology is used to simulate the BER performance of the proposed decoding scheme. Based on our models, the proposed decoding scheme significantly reduces error floors due to the “lock-up” problem and achieves superior BER performance compared with conventional synchronous stochastic decoders. The timing model includes metastability to verify the affect on BER performance.