Doxorubicin and other anthracyclines in cancers: activity, chemoresistance and its overcoming

Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by severe side effects and toxicity that occur during or after treatment, including cardiotoxicity. The mode of action of anthracyclines is complex, with several mechanisms proposed. It is possible that their high toxicity is due to the large set of processes involved in anthracycline action. The development of resistance is a major barrier to successful treatment when using anthracyclines. This resistance is based on a series of mechanisms that have been studied and addressed in recent years. This work provides an overview of the anthracyclines used in cancer therapy. It discusses their mechanisms of activity, toxicity, and chemoresistance, as well as the approaches used to improve their activity, decrease their toxicity, and overcome resistance

Characterization of perfluorocarbon relaxation times and their influence on the optimization of fluorine-19 MRI at 3 tesla.

To characterize and optimize javax.xml.bind.JAXBElement@7524a985 F MRI for different perfluorocarbons (PFCs) at 3T and quantify the loss of acquisition efficiency as a function of different temperature and cellular conditions. The T javax.xml.bind.JAXBElement@1ef4ca84 and T javax.xml.bind.JAXBElement@295b7e6f relaxation times of the commonly used PFCs perfluoropolyether (PFPE), perfluoro-15-crown-5-ether (PFCE), and perfluorooctyl bromide (PFOB) were measured in phantoms and in several different conditions (cell types, presence of fixation agent, and temperatures). These relaxation times were used to optimize pulse sequences through numerical simulations. The acquisition efficiency in each cellular condition was then determined as the ratio of the signal after optimization with the reference relaxation times and after optimization with its proper relaxation times. Finally, PFC detection limits were determined. The loss of acquisition efficiency due to parameter settings optimized for the wrong temperature and cellular condition was limited to 13%. The detection limits of all PFCs were lower at 24 °C than at 37 °C and varied from 11.8 ± 3.0 mM for PFCE at 24 °C to 379.9 ± 51.8 mM for PFOB at 37 °C. Optimizing javax.xml.bind.JAXBElement@30187e57 F pulse sequences with a known phantom only leads to moderate loss in acquisition efficiency in cellular conditions that might be encountered in in vivo and in vitro experiments. Magn Reson Med 77:2263-2271, 2017. © 2016 International Society for Magnetic Resonance in Medicine

New regional Bryophyte records from Argentina

Argentina es el octavo país más grande del mundo y el cuarto más grande de América. Tiene una posición biogeográfica única y privilegiada por sus características fisiográficas y una variedad de climas y relieves en diferentes partes del país. Esto ha permitido el desarrollo de una flora de briofitas exuberante y diversificada. Los últimos listados indican que la flora de musgos, hepáticas y antocerotes incluye 990 Bryophyta, 562 Marchantiophyta y 15 Anthocerotophyta. Sin embargo, el número exacto de briófitos en Argentina está cambiando constantemente a medida que surgen informes regulares que cubren localidades no exploradas. El objetivo de este trabajo es contribuir al conocimiento de la diversidad de briofitas en Argentina con nuevos registros regionales en el país.Fil: Suarez, Guillermo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Jimenez, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Colotti, Maria Teresita de Jesus. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Cabral, R. A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaXXXVII Jornadas Argentinas de BotánicaTucumánArgentinaSociedad Argentina de Botánic

Chemical shift encoding (CSE) for sensitive fluorine-19 MRI of perfluorocarbons with complex spectra.

To implement a fluorine-19 ( <sup>19</sup> F) chemical shift encoding (CSE) approach for the sensitive imaging of molecules with multi-resonance spectra to remove their chemical shift displacement (CSD) artifacts, and to characterize its sensitivity versus established pulse sequences. The feasibility of CSE spoiled gradient echo (GRE) and balanced steady-state free precession (bSSFP) was first demonstrated in a phantom study. The dependence of the sensitivity of CSE-bSSFP on several pulse sequence parameters was then established, after which the occurrence of out-of-plane excitation was assessed for 2D and 3D techniques. Next, the sensitivity (in mm <sup>-3</sup> s <sup>-0.5</sup> ) of both CSE techniques was compared to bSSFP ultrashort echo time (bSSFP-UTE) imaging and multi-chemical-shift-selective turbo spin echo (MCSS-TSE) in a second phantom study. Finally, the sensitivity of the CSE-bSSFP, bSSFP-UTE, and MCSS-TSE pulse sequences was compared in a preliminary in vivo mouse study. Both CSE approaches were successfully implemented and resulted in negligible residual CSD artifacts, while large-volume 3D acquisitions should be considered to reduce problems related to out-of-plane excitation. CSE-bSSFP was shown to have a higher sensitivity than the bSSFP-UTE and MCSS-TSE pulse sequences (15.8 ± 1.3 vs. 11.7 ± 1.0 vs. 13.3 ± 0.9 mm <sup>-3</sup> s <sup>-0.5</sup> , respectively, P < 0.001), whereas CSE-GRE technique had a lower sensitivity (4.8 ± 1.1 mm <sup>-3</sup> s <sup>-0.5</sup> ). CSE <sup>19</sup> F MR imaging enables the unambiguous visualization of compounds with complex spectra, and provides high sensitivity both in vitro and in vivo. Magn Reson Med 79:2724-2730, 2018. © 2017 International Society for Magnetic Resonance in Medicine

N6L pseudopeptide interferes with nucleophosmin protein-protein interactions and sensitizes leukemic cells to chemotherapy.

Abstract NPM1 is a multifunctional nucleolar protein implicated in several processes such as ribosome maturation and export, DNA damage response and apoptotic response to stress stimuli. The NPM1 gene is involved in human tumorigenesis and is found mutated in one third of acute myeloid leukemia patients, leading to the aberrant cytoplasmic localization of NPM1. Recent studies indicated that the N6L multivalent pseudopeptide, a synthetic ligand of cell–surface nucleolin, is also able to bind NPM1 with high affinity. N6L inhibits cell growth with different mechanisms and represents a good candidate as a novel anticancer drug for a number of malignancies of different histological origin. In this study we investigated whether N6L treatment could drive antitumor effect in acute myeloid leukemia cell lines. We found that N6L binds NPM1 at the N-terminal domain, co-localizes with cytoplasmic, mutated NPM1, and interferes with its protein-protein associations. N6L toxicity appears to be p53 dependent but interestingly, the leukemic cell line harbouring the mutated form of NPM1 is more resistant to treatment, suggesting that NPM1 cytoplasmic delocalization confers protection from p53 activation. Moreover, we show that N6L sensitizes AML cells to doxorubicin and cytarabine treatment. These studies suggest that N6L may be a promising option in combination therapies for acute myeloid leukemia treatment

A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition

Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin–trypanothione reductase–NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis

Sistemática y filogenia de briofitas y plantas vasculares sin semilla en el cono sur

Este proyecto propone el estudio sistemático y filogenético de las briofitas (Bryophyta,Marchantiophyta y Anthocerotophyta) y helechos (Clase Polypodiopsidae) en el Cono Sur. En relación a las briofitas, durante el último siglo se describieron numerosas especies para el área, sin embargo de muchas de ellas se desconoce su situación taxonómica real ya que no fueron revisadas posteriormente. En el caso de los helechos, el conocimiento de su diversidad y estado taxonómico es mayor, sin embargo durante los últimos 30 años los estudios moleculares han revolucionado enteramente la circunscripción de los grupos en búsqueda de la monofilia de los mismos y actualmente la mayoría de ellos no se encuentran totalmente resueltos. En vista de esta situación, en este proyecto nos propusimos inventariar, monitorear e identificar briófitas y helechos en el contexto de tipos de vegetación en el Cono Sur que propendan al conocimiento de la riqueza de especies. Para cumplir con estos objetivos se efectúan relevamientos florísticos en áreas escasamente inventariadas con énfasis en el NOA y NEA. Los especímenes se estudian en base a la metodología clásica para estos organismos; la identificación se realiza por medio de los ?tipos históricos? solicitados en calidad de préstamo a instituciones nacionales e internacionales. Como resultados del primer año de funcionamiento del proyecto, se ha incrementado el número de especímenes briológicos y pteridológicos que forman parte del herbario LIL, que permiten mantener un canje activo con instituciones internacionales. Para briofitas se realizaron estudios y descripciones morfo-anatómicas de especies nuevas para el área de estudio, así como nuevas para la ciencia: Mitthenothamnium reduncum (Schimp. ex Mitt.) Ochyra, Asterella chilensis (Nees & Mont.) A. Evans, Pleuridium tucumanensis M. T. Colotti, G. M. Suárez y D. F. Peralta sp. nov., Symphyogyna brasiliensis Nees, Syzygiella teres (Carrington & Pearson) Váña y Fissidens submarginatus Bruch., entre otras. A su vez, se realizaron actualizaciones nomenclaturales, efectuando revisiones a nivel de familia y género. Se contribuyó con estudios filogenéticos para evaluar la monofilia de grupos conflictivos mediante datos morfológicos y moleculares. Para helechos, se llevaron a cabo descripciones morfo-anatómica para la identificación de especies nativas del Cono Sur: Doryopteris triphylla (Lam.) Christ, Pleopeltis macrocarpa (Bory ex. Willd) Kaulf, Notholaena sulphurea (Cav.) Sm., entre otras. Se investigaron las secreciones vegetales de dichas especies, destacando su potencial uso en el campo agronómicomedicinal. Tanto para musgos como para helechos se realizaron trabajos de divulgación científica destinados a comunidades científicas no afines a la botánica y población en general no afín a la ciencia. Cabe destacar también, el desarrollo en curso de material didáctico estudiantil y docente de nivel medio en escuelas universitarias.Fil: Suarez, Guillermo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Colotti, M. T.. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Neira, Diego Amando. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Flores, J. R.. University of Helsinki; FinlandiaFil: Jimenez, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Cabral, R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Hernández, Micaela Anahí. Fundación Miguel Lillo. Dirección de Botánica; ArgentinaFil: Jimenez, L. I.. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Catalano, Santiago Andres. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaXIV Jornadas Internas de Comunicaciones en Investigación, Docencia y ExtensiónSan Miguel de TucumánArgentinaUniversidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lill

K201 (JTV-519) alters the spatiotemporal properties of diastolic Ca2+ release and the associated diastolic contraction during β-adrenergic stimulation in rat ventricular cardiomyocytes

K201 has previously been shown to reduce diastolic contractions in vivo during β-adrenergic stimulation and elevated extracellular calcium concentration ([Ca2+]o). The present study characterised the effect of K201 on electrically stimulated and spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca2+ release and contractile events in isolated rat cardiomyocytes during β-adrenergic stimulation and elevated [Ca2+]o. Parallel experiments using confocal microscopy examined spontaneous diastolic Ca2+ release events at an enhanced spatiotemporal resolution. 1.0 μmol/L K201 in the presence of 150 nmol/L isoproterenol (ISO) and 4.75 mmol/L [Ca2+]o significantly decreased the amplitude of diastolic contractions to ~16% of control levels. The stimulated free Ca2+ transient amplitude was significantly reduced, but stimulated cell shortening was not significantly altered. When intracellular buffering was taken into account, K201 led to an increase in action potential-induced SR Ca2+ release. Myofilament sensitivity to Ca2+ was not changed by K201. Confocal microscopy revealed diastolic events composed of multiple Ca2+ waves (2–3) originating at various points along the cardiomyocyte length during each diastolic period. 1.0 μmol/L K201 significantly reduced the (a) frequency of diastolic events and (b) initiation points/diastolic interval in the remaining diastolic events to 61% and 71% of control levels respectively. 1.0 μmol/L K201 can reduce the probability of spontaneous diastolic Ca2+ release and their associated contractions which may limit the propensity for the contractile dysfunction observed in vivo

Metabolic Variation during Development in Culture of Leishmania donovani Promastigotes

The genome sequencing of several Leishmania species has provided immense amounts of data and allowed the prediction of the metabolic pathways potentially operating. Subsequent genetic and proteomic studies have identified stage-specific proteins and putative virulence factors but many aspects of the metabolic adaptations of Leishmania remain to be elucidated. In this study, we have used an untargeted metabolomics approach to analyze changes in the metabolite profile as promastigotes of L. donovani develop during in vitro cultures from logarithmic to stationary phase. The results show that the metabolomes of promastigotes on days 3–6 of culture differ significantly from each other, consistent with there being distinct developmental changes. Most notable were the structural changes in glycerophospholipids and increase in the abundance of sphingolipids and glycerolipids as cells progress from logarithmic to stationary phase

Temporal Network Based Analysis of Cell Specific Vein Graft Transcriptome Defines Key Pathways and Hub Genes in Implantation Injury

Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia, related in part to implantation injury. The cell-specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells (EC) and medial smooth muscle cells (SMC) from canine vein grafts, 2 hours (H) to 30 days (D) following surgery. Our results demonstrate a robust genomic response beginning at 2 H, peaking at 12–24 H, declining by 7 D, and resolving by 30 D. Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses, apoptosis, mitosis, and extracellular matrix reorganization in both cell types. Through backpropagation an integrated network was built, starting with genes differentially expressed at 30 D, followed by adding upstream interactive genes from each prior time-point. This identified significant enrichment of IL-6, IL-8, NF-κB, dendritic cell maturation, glucocorticoid receptor, and Triggering Receptor Expressed on Myeloid Cells (TREM-1) signaling, as well as PPARα activation pathways in graft EC and SMC. Interactive network-based analyses identified IL-6, IL-8, IL-1α, and Insulin Receptor (INSR) as focus hub genes within these pathways. Real-time PCR was used for the validation of two of these genes: IL-6 and IL-8, in addition to Collagen 11A1 (COL11A1), a cornerstone of the backpropagation. In conclusion, these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury, and identifying novel targets for its prevention