Arsenic trioxide down-regulates antiapoptotic genes and induces cell death in mycosis fungoides tumors in a mouse model

Background: Mycosis fungoides (MF) is the most frequent cutaneous T-cell lymphoma (CTCL). Arsenic trioxide (As2O3) has recently been shown to be effective against leukemias, so we studied whether As2O3 induces apoptosis of CTCL cells in vitro. We further investigated if As2O3 is effective in a MF mouse model. Material and methods: Annexin V/7-amino-actinomycin-D stainings were carried out to investigate if As2O3 induced apoptosis of CTCL cell lines. To study the underlying mechanisms, the effects of As2O3 on various transcription factors and apoptosis regulating proteins were analyzed by western blots, electrophoretic mobility shift assays and transcription factor enzyme-linked immunosorbent assays. The ability of As2O3 to induce tumor regression was investigated in a MF mouse model. Results: As2O3-induced apoptosis was paralleled by a reduction of the DNA-binding activities of transcription factors of the NFkB and signal transducer and activator of transcription gene families and reduced expression of the antiapoptotic proteins bcl-1, bcl-xL and mcl-1. Local injections of 200 μM As2O3 into tumors caused complete remissions in five of six mice and one partial remission. Conclusions: As2O3 induced apoptosis of CTCL cells by the down-regulation of transcription factors that stimulate the expression of antiapoptotic genes. Local injection of As2O3 into MF tumor-bearing mice resulted in tumor regressio

Whole-genome sequencing of multidrug-resistant Mycobacterium tuberculosis isolates from Myanmar.

Drug-resistant tuberculosis (TB) is a major health threat in Myanmar. An initial study was conducted to explore the potential utility of whole-genome sequencing (WGS) for the diagnosis and management of drug-resistant TB in Myanmar. Fourteen multidrug-resistant Mycobacterium tuberculosis isolates were sequenced. Known resistance genes for a total of nine antibiotics commonly used in the treatment of drug-susceptible and multidrug-resistant TB (MDR-TB) in Myanmar were interrogated through WGS. All 14 isolates were MDR-TB, consistent with the results of phenotypic drug susceptibility testing (DST), and the Beijing lineage predominated. Based on the results of WGS, 9 of the 14 isolates were potentially resistant to at least one of the drugs used in the standard MDR-TB regimen but for which phenotypic DST is not conducted in Myanmar. This study highlights a need for the introduction of second-line DST as part of routine TB diagnosis in Myanmar as well as new classes of TB drugs to construct effective regimens.Professor Sandy Smith Memorial ScholarshipThis is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/j.jgar.2016.04.00

A mouse model for the Sézary syndrome

<p>Abstract</p> <p>Background</p> <p>The Sézary syndrome is an aggressive leukemic form of cutaneous T cell lymphoma and there is no cure of this disease. Until now there is no true animal model for Sézary syndrome, by which new drugs against the disease could be tested.</p> <p>Methods</p> <p>Immune deficient CB-17 SCID beige mice were injected subcutaneously with HUT78 cells, a cell line, derived from a Sézary syndrome patient. Developing tumors were analyzed by immunohistochemistry.</p> <p>Results</p> <p>Injected HUT78 cells formed tumors at the site of injection. In contrast to the Sézary syndrome in man, no malignant cells were observed in the blood of tumor bearing CB-17 SCID beige mice. The tumors appeared 44-62 days after injection and tumor bearing mice survived further 25 - 62 days until they had to be euthanized according to the guidelines of the Swiss animal protection law, since the tumors had reached the maximal allowed size.</p> <p>Conclusion</p> <p>Although the mouse model does not exactly match the human disease, it will be suited for tests of new substances for the treatment of the Sézary syndrome. The formation of an isolated tumor on the skin has the advantage that the effect of a potential drug can be directly monitored without the use of invasive methods.</p

The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel

<p>Abstract</p> <p>Background</p> <p>Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. Paradoxically, arsenic trioxide can also be used to induce remission in patients with acute promyelocytic leukemia (APL) with a success rate of approximately 80%. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out.</p> <p>Methods</p> <p>Here we applied a systems biology approach to identify gene biomarkers that underlie tumor cell responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 14,500 well characterized human genes were associated with the GI₅₀ data of the NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) database. Selected biomarkers were tested <it>in vitro</it> for the ability to influence tumor susceptibility to arsenic trioxide.</p> <p>Results</p> <p>A significant association was found between the baseline expression levels of 209 human genes and the sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These genes were overlayed onto protein-protein network maps to identify transcriptional networks that modulate tumor cell responses to arsenic trioxide. The analysis revealed a significant enrichment for the oxidative stress response pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in protecting cells against arsenic-induced cell killing was validated in tumor cells using shRNA-mediated knock-down.</p> <p>Conclusions</p> <p>In this study, we show that the expression level of genes in the NRF2 pathway serve as potential gene biomarkers of tumor cell responses to arsenic trioxide. Importantly, we demonstrate that tumor cells that are deficient for NRF2 display increased sensitivity to arsenic trioxide. The results of our study will be useful in understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as the increased applicability of arsenic trioxide as a chemotherapeutic agent in cancer treatment.</p

The Prolyl Isomerase Pin1 Modulates Development of CD8+ cDC in Mice

We have identified a novel role for Pin1 as a modulator of CD8+ cDC development. Consistent with reduced numbers of CD8+ cDC in Pin1-null mice, we find that the absence of Pin1 impairs CD8+ T cell proliferation in response to infection with Listeria monocytogenes. These data suggest that, via regulation of CD8+ cDC production, Pin1 may serve as an important modulator of adaptive immunity

The dominant Anopheles vectors of human malaria in the Asia-Pacific region: occurrence data, distribution maps and bionomic précis

<p>Abstract</p> <p>Background</p> <p>The final article in a series of three publications examining the global distribution of 41 dominant vector species (DVS) of malaria is presented here. The first publication examined the DVS from the Americas, with the second covering those species present in Africa, Europe and the Middle East. Here we discuss the 19 DVS of the Asian-Pacific region. This region experiences a high diversity of vector species, many occurring sympatrically, which, combined with the occurrence of a high number of species complexes and suspected species complexes, and behavioural plasticity of many of these major vectors, adds a level of entomological complexity not comparable elsewhere globally. To try and untangle the intricacy of the vectors of this region and to increase the effectiveness of vector control interventions, an understanding of the contemporary distribution of each species, combined with a synthesis of the current knowledge of their behaviour and ecology is needed.</p> <p>Results</p> <p>Expert opinion (EO) range maps, created with the most up-to-date expert knowledge of each DVS distribution, were combined with a contemporary database of occurrence data and a suite of open access, environmental and climatic variables. Using the Boosted Regression Tree (BRT) modelling method, distribution maps of each DVS were produced. The occurrence data were abstracted from the formal, published literature, plus other relevant sources, resulting in the collation of DVS occurrence at 10116 locations across 31 countries, of which 8853 were successfully geo-referenced and 7430 were resolved to spatial areas that could be included in the BRT model. A detailed summary of the information on the bionomics of each species and species complex is also presented.</p> <p>Conclusions</p> <p>This article concludes a project aimed to establish the contemporary global distribution of the DVS of malaria. The three articles produced are intended as a detailed reference for scientists continuing research into the aspects of taxonomy, biology and ecology relevant to species-specific vector control. This research is particularly relevant to help unravel the complicated taxonomic status, ecology and epidemiology of the vectors of the Asia-Pacific region. All the occurrence data, predictive maps and EO-shape files generated during the production of these publications will be made available in the public domain. We hope that this will encourage data sharing to improve future iterations of the distribution maps.</p

ÉTUDES DE LA CONFORMATION DE PENTAPEPTIDES CYCLIQUES PAR LA RÉSONANCE MAGNÉTIQUE NUCLÉAIRE

L'étude des propriétés du peptide bicyclique S, S'-bis-cyclo-glycyl-L-hemicystyl-glycyl- glycyl-L-prolyl vis-à-vis du transport actif des ions alcalins à travers une membrane nous a conduits à examiner par la spectroscopie RMN différents pentapeptides cycliques tels que ceux décrits dans la première figure [1], [2]. Tous les composés examinés se caractérisent par la présence dans la position (5) d'une proline, soit sous sa forme L, soit sous sa forme D. Les spectres RMN dans le DMSO montrent très clairement l'existence à température ambiante de deux conformations stables en équilibre, qui trouvent leur origine dans l'isomérie cis-trans de la liaison peptidique entre le résidu (4) et la proline (5). Nous nous sommes donc attachés à décrire géométriquement les deux conformères ainsi que leurs populations relatives en fonction de la température et du solvant utilisé [3], [4], [5]. Pour garantir l'univocité de l'identification des différentes glycines, nous avons procédé à la deutériation, premièrement de la glycine (1) et deuxièmement des deux glycines (1) et (4) (Fig. 1). La spectroscopie RMN permet, par l'étude des constantes de couplage J NH-CH, la détermination des angles φ d'un peptide [6]. La variation du déplacement chimique des protons amides en fonction de la température décrit le comportement de ceux-ci vis-à-vis du solvant. Dans certains cas ces mesures peuvent mettre en évidence la présence de ponts hydrogènes intra [7], [8]. Une description détaillée de la conformation du « backbone » d'un peptide exige également la connaissance des angles ψ et ω. C'est pourquoi nous avons complété nos mesures expérimentales par la détermination théorique sur ordinateur de la carte énergétique de chaque conformère en fonction des angles de rotation ψ et ω où les minima d'énergie désignent les conformations cherchées.The study of the bicyclic peptide S, S'-bis-cyclo-glycyl-L-hemicystyl-glycyl-glycyl-Lprolyl for its effect on the active transport of alkali ions through membranes led us to an NMR-investigation of different cyclic pentapeptides sucli as those shown in the first figure [1], [2]. All the compounds investigated have a proline in position (5), either the L-form or the D-form. The NMR spectra in DMSO show clearly two stable conformations in equilibrium at room temperature. The two forms originate from the cis-trans isomerisation of the peptide bond between residue (4) and proline (5). Our goal was to describe the geometry of the two conformations as a function of temperature and solvent [3], [4], [5]. To guarantee the uniqueness of the identifications of the different glycines we deuterated either glycine (1) or both glycines (1) and (4) (Fig. 1). The NMR, coupling constants JNH-CH allow the determination of φ angles of a peptide [6]. The interactions between solvent and amide protons can be deterniined from the temperature dependences of the chemical shifts. In certain cases these methods can yield evidence for intramolecular hydrogen bonds [7], [8]. For the whole description of the backbone of a peptide we must know the ψ and ω angles. Therefore we cornplemented our experimental results by the theoretical calculation on a computer of the energy map of each conformation as a function of rotation angle ψ and ω. The minima of the energy indicate the most probable conformations