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G2/M inhibitors as pharmacotherapeutic opportunities for glioblastoma:the old,the new,and the future

Cancer Biology & Medicine 2018年第4期15卷 354-374页

作者： Angel Mauricio Castro-Gamero Julia Alejandra Pezuk maria sol brassesco Luiz Gonzaga Tone Human Genetics Laboratory Institute of Natural SciencesFederal University of Alfenas(UNIFAL-MG)Alfenas 37130-001Brazil Biotechnology and Innovation in Health Program and Pharmacy Program Anhanguera University Sao Paulo(UNIANSP)Sao Paulo 05145-200Brazil Department of Biology Faculty of PhilosophySciences and Letters at Ribeirao PretoUniversity of Sao PauloRibeirao Preto 14040-901Brazil Department of Pediatrics Department of Genetics Ribeirao Preto School of MedicineUniversity of Sao PauloRibeirao Preto 14049-900Brazil

Glioblastoma(GBM) is one of the deadliest tumors and has a median survival of 3 months if left untreated. Despite advances in rationally targeted pharmacological approaches, the clinical care of GBM remains palliative in intent. Since the majority of altered signaling cascades involved in cancer establishment and progression eventually affect cell cycle progression, an alternative approach for cancer therapy is to develop innovative compounds that block the activity of crucial molecules needed by tumor cells to complete cell division. In this context, we review promising ongoing and future strategies for GBM therapeutics aimed towards G2/M inhibition such as anti-microtubule agents and targeted therapy against G2/M regulators like cyclin-dependent kinases,Aurora inhibitors, PLK1, BUB, 1, and BUBR1, and survivin. Moreover, we also include investigational agents in the preclinical and early clinical settings. Although several drugs were shown to be gliotoxic, most of them have not yet entered therapeutic trials. The use of either single exposure or a combination with novel compounds may lead to treatment alternatives for GBM patients in the near future.

关键词： Chemotherapy PLK1 AURK survivin BUB BUR1

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Does DKC1 Mutation Suffice to Define the Phenotype Severity of Hoyeraal-Hreidarsson Syndrome?

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Open Journal of Blood Diseases 2013年第1期3卷 57-61页

作者： Elvis Terci Valera maria sol brassesco Sabrine Teixeira Ferraz Persio Roxo Jr Barbara Lemos-Santana Tom Vulliamy Rodrigo Tocantins Calado Carlos Alberto Scrideli Luiz Gonzaga Tone Division of Pediatric Oncology Department of PediatricsBairro Monte AlegreRibeirao PretoBrazil Faculty of Medicine of Ribeirao Preto University of Sao PauloRibeirao PretoBrazil Department of Internal Medicine Faculty of Medicine of Ribeirao PretoUniversity of Sao PauloRibeirao PretoBrazil Centre for Paediatrics Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK.

Both dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson Syndrome (HHS) are rare inherited bone marrow failure conditions. HHS is considered to be a variant of DC in which neurological deficits and immunodeficiencies are also present. We describe a very interesting familial cluster where an invariant point mutation of DKC1 located in the exon 11 is observed in the carrier mother and in two decedent males. The older child developed the classical phenotype of HHS at a very early age. The second affected child remains poorly symptomatic, with only mild haematological changes. Telomere shortening, with different severity, is also present in both cases. This paper discusses the clinical spectrum of inherited BM failure syndromes from the perspective different clinical presentation within a family with a DKC1 mutation.

关键词： DKC1 Mutation Dyskeratosis Congenital Hoyeraal-Hreidarsson Syndrome Bone Marrow Failure

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Base Excision Repair Inhibition by Methoxyamine Impairs Growth and Sensitizes Osteosarcoma Cells to Conventional Treatments

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Journal of Cancer Therapy 2014年第4期5卷 307-314页

作者： Ana Paula Montaldi Julia Alejandra Pezuk Elza Tiemi Sakamoto-Hojo Luiz Gonzaga Tone María sol brassesco Department of Biology Faculty of Philosophy Sciences and Letters at Ribeirao Preto University of Sao Paulo Sao Paulo Brazil Department of Genetics Faculty of Medicine of Ribeirao Preto University of Sao Paulo Sao Paulo Brazil Department of Pediatrics Faculty of Medicine of Ribeirao Preto University of Sao Paulo Sao Paulo Brazil

The outcome of patients with osteosarcoma has not significantly improved in the last three decades. Therefore, there is still a need for the development of more effective therapeutic strategies. Methoxyamine (MX) is a base excision repair (BER) inhibitor that has shown anticancer potential by sensitizing a variety of tumor cells to ionizing radiation and chemotherapeutic drugs. In the present study, the in vitro antiproliferative effects of MX were evaluated in two osteosarcoma cell lines, HOS and MG-63. Evaluation of the influence on radiosensitivity and drug interactions in simultaneous treatments with methotrexate, doxorubicin, and cisplatin was also performed. Exposure to MX significantly decreased cell proliferation and mediated a substantial increase of apoptosis. Moreover, our results showed that MX synergized with ionizing radiation in both cell lines while potentiated the antitumor effects of cisplatin and methotrexate. Altogether, the results presented herein demonstrate the feasibility of inhibiting the BER pathway, which may in future be a promising strategy for overcoming intrinsic tumor resistance and to improve the outcome of patients with osteosarcoma.

关键词： Osteosarcoma Methoxyamine BER Cell Lines

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Meteorological and Climate Modelling Services Tailored to Viticulturists

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Atmospheric and Climate Sciences 2021年第1期11卷 148-164页

作者： Ignasi Porras Josep maria solé Raül Marcos Raúl Arasa Meteosim SL Barcelona Spain Barcelona Supercomputing Center (BSC) Barcelona Spain

Grape production is likewise inherently interconnected to climate and weather, and, although grapes may grow worldwide, premium wine-grape production occurs in Mediterranean-like climate ranges. Changes in climate and weather patterns are threatening premium wine-grapes, directly affecting the European wine industry. This is because grapevines are extremely sensitive to their surrounding environment, with seasonal variations in yield much higher than other common crops, such as cereals. With a view to making South European wine industry resilient to climate change, VISCA (Vineyards Integrated Smart Climate Application) project has deployed a Climate Service (CS) Decision Support System (DSS) tool that provides to wine producers with well-founded information to be able to apply correctly adaptation strategies on specific grape varieties and locations, and to achieve optimum production results (e.g., yield and quantity). In this paper we show the meteorological, seasonal and climatic models and data sets used to answer the viticulturist needs;from short-term and mid-term forecast to seasonal forecast and climate projections.

关键词： Weather Extreme Events Adaptation to Climate Change Climate Services Wine Industry VISCA

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The Unexpected Capability of Melanin to Split the Water Molecule and the Alzheimer’s Disease

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Neuroscience & Medicine 2011年第3期2卷 217-221页

作者： maria del Carmen Arias-Esparza Ruth Isabel solís Arias Paola Eugenia solís Arias Martha Patricia solís Arias A. solís-Herrera 不详

We began a study about the three main causes of blindness in 1990, because their incidence and prevalence have not changed in the last forty years. Twelve years later we concluded that the main source of energy for the human retina is water, not ATP. And this is also true for the entire human body. Water is the main source of energy. The amazing capability of eukaryotic cells to break or dissociate the water molecule was unsuspected to us because it takes 2000℃ degrees to dissociate water in a laboratory environment, and until today, it was believed that only plants were capable of accomplishing this. Photosynthesis occurs in humans as it does in plants. The water that we drink every day is not just to wash away detritus and toxins;it is not just a cleaner, nor a simple solvent. When our body dissociates the water molecule, cells are able to get their energy from Hydrogen (Hydrogen is the energy carrier that Nature uses the most). Water is our main source of energy. If our body couldn’t acquire energy from water, we would need to eat between 50 - 170 kg (110 - 374 lbs) daily. In any system, when a generalized failure occurs, we must suspect energy first. Parkinson and Alzheimer’s Disease are examples of a generalized failure. That explains why it is not uncommon that patients improve dramatically with pharmacological stimulation of the human photosynthesis process. Recall that the brain needs energy not only to grow or to perform its functions, but also to preserve its form and shape. The best energy for human cells is Hydrogen.

关键词： Melanin Water Dissociation Energy Glucose Alzheimer Biomass

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Global Standards and Local Policies for School Diabetes Care

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Health 2015年第12期7卷 1642-1650页

作者： María J. Miranda Velasco maria Gloria solís Galán Enma Domínguez Martín Department of Educational Sciences University of Extremadura Coordinator of Research Group Education and Health Innovation Cáceres Spain Department of Educational Sciences University of Extremadura Research Group Education and Health Innovation Cáceres Spain Research Group Education and Health Innovation Cáceres Spain

Objectives: The purpose of this study is to analyse the practical implementation of regional and na-tional policies through the Protocol of Care of Children and Adolescents in School (2010) in Extremadura Region (Spain), and to compare its contents with the international standards of diabetes care at school defined by American Diabetes Association and International Diabetes Federation. The measures not only affect the security and diabetes care, but also inclusion and the right to health. Methods: A documental comparative analysis between the local and international standards about diabetes care in school setting is carried out. This analysis is framed in a larger project focused on the study of health promoting school and diabetes education, in which perceptions of children and adolescents with diabetes, their parents and school staff were studied. Results: The Protocol of Care of Children and Adolescents in School (2010) contains some international recommendations about the care of T1DM at school, but in other cases the measures are non-specific. The distribution of responsibilities for care at school is unclear and no monitoring and evaluation indicators are defined. Some elements are identified to be implemented in the tool to favour the security, management of T1DM care and wellbeing. In general, these elements refer to school plan for diabetes care, school organization and teachers, and school community training. Conclusion: It is required to develop specific policies and decisive action to ensure the right to health of children with diabetes and the full application of international standards for diabetes care at school.

关键词： Health Policy Childhood and Adolescents Diabetes Care School Setting Inclusion

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Alveolar rhabdomyosarcoma with breast involvement

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Chinese Medical Journal 2013年第5期126卷 998-998页

作者： Elvis Terci Valera María sol brassesco Valdair Francisco Muglia Carlos Alberto Scrideli Luiz Gonzaga Tone Division of Pediatric Oncology Department of PediatricsFaculty of Medicine of Ribeir(a)o Preto University of S(a)o Paulo Brazil Division of Radiology Internal Medicine Department Faculty of Medicine of Ribeir(a)o Preto University of S(a)o Paulo Brazil

To the editor： We have read with interest the recently published article by Li et al focusing on the clinicopathologic features and biological behavior of five female patients presenting with rhabdomyosarcoma （RMS） of the breast. Actually, the occurrence of RMS in this location, either primarily or as a metastatic disease, is a very rare event and the impact of this clinical presentation on treatment and outcome remains poorly defined. Moreover, the diagnosis of breast involvement by RMS may be challenging, particularly due to the rarity of this clinical presentation.

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Assessment of Climate Change in Nicaragua: Analysis of Precipitation and Temperature by Dynamical Downscaling over a 30-Year Horizon

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Atmospheric and Climate Sciences 2016年第3期6卷 445-474页

作者： Josep maria solé Raúl Arasa Miquel Picanyol Mª Ángeles González Anna Domingo-Dalmau Marta Masdeu Ignasi Porras Bernat Codina Technical Department Meteosim S.L. Barcelona Spain Department of Astronomy and Meteorology University of Barcelona Barcelona Spain

The present study has generated and analyzed Climate Change projections in Nicaragua for the period 2010-2040. The obtained results are to be used for evaluating and planning more resilient transport infrastructures in the next decades. This study has focused its efforts to pay attention into the effect of Climate Change on precipitation and temperature from a mean and extreme event perspective. Dynamical Downscaling approach on a 4 km resolution grid has been chosen as the most appropriate methodology for the estimation of the projected climate, being able to account for local-scale factors like complex topography or local land uses properly. We selected MPI-ESM-MR as the global climate model with the best skill scores in terms of precipitation and temperature in Nicaragua. MPI-ESM-MR was coupled to a mesoscale model. We chose WRF mesoescale model as the most appropriate regional model and we optimized their physical and dynamical options in order to minimize the model uncertainty in Nicaragua. For this, model output against the available in-situ measurements from the national meteorological station network and satellite data were compared. Climate change signal was estimated by comparing the different climate statistics calculated from a model run over an historical period, 1980-2009, with a model run over a projected period, 2010-2040. The obtained results from the projected climate show an increase of the mean temperature between 0.6°C and 0.8°C and an increase of the number of days per year with maximum daily temperatures higher than 35°C. Regarding precipitation, annual projected amounts do not change remarkably with respect to the historical period. However, significant changes in the distribution of the precipitation within the wet period (May-October) were observed. Moreover, an increment between 5% and 10% of the number of days without precipitation is expected. Finally, Intensity-Duration-Frequency (IDF) projected curves show an increment of the rainfall

关键词： WRF Climate Change Global Warming Dynamical Downscaling Precipitation Projections IDF

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Perovskite type lanthanum manganite：Morpho-structural analysis and electrical investigations

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Journal of Rare Earths 2018年第5期36卷 499-504页

作者： Paula Sfirloaga maria Poienar Iosif Malaescu Antoanetta Lungu Paulina Vlazan Institute for Research and Development in Electrochemistry and Condensed Matter P. Andronescu Street No.1 300224 Timisoara Romania West University of Timisoara Vasile Parvan 4 300223 Romania

Perovskite-type oxides of LaMnO3 were synthesized by means of the sol-gel method, in the presence of citric acid as gelling agent. The precursors used were Mn（NO3）2·H2O, La2O3, and NaOH,mixed in the stoichiometric ratio to obtain perovskite materials. The obtained gel was heat-treated at 400, 600 and 800 ℃ respectively, for 6 h. X-ray diffraction and FT-IR spectroscopy were used to analyze the phase transformation as a function of temperature, and the Rietveld refinement was used in order to characterize the materials obtained structurally. The average crystallite size of the products was calculated from XRD data and the average particle size was measured from the TEM micrographs. At 600 ℃, the synthesized compound is well-crystallized, showcases a perovskite structure（Pm-3m space group）, and exhibits uniform and homogeneous hexagonally-shaped particles, with sizes in the 20-50 nm *** impedance measurements in the 20-2 × 10^6 Hz frequency range were carried out at different temperatures（26-115 ℃）, and the electrical conduction mechanism is discussed.

关键词： Rare earths sol-gel method Physico-chemical properties Electrical investigations

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Lanthanide complexes with β-diketones and coumarin derivates:synthesis,thermal behaviour,optical and pharmacological properties and immobilisation

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Journal of Rare Earths 2010年第S1期28卷 66-74页

作者： maria Milanova Joana Zaharieva Iliya Manolov Miroslava Getzova Dimitr To dorovsky Department of Inorganic Chemistry University of SofiaBulgaria 1J. Bourc hier Blvd.1164 SofiaBulgaria Department of Organic Chemistry Medical Un iversity2Dunav Str.1000 SofiaBulgaria

The paper presents the results of the synthesis of complexes of the ty pe Eu(DBM) 3 and Eu(DBM) 3·Q(DBM-dibenzoylmethane,Q-1,10-phenantroline or 4,7-d iphenyl-1,10-phenantroline) and of Tb-and Nd-complexes with the newly-synthesis ed coumarin derivates 3,3’-[(4-chlorphenyl) methylene) bis(4-hydroxy-2H-chromen-2-one) ,3,3’-[(3,5-dimethoxy-4-hydroxy) methylene) bis(4-hydroxy-2H-chromen-2-one) ,etc. Elemental and thermogravimetric analysis,IR,UV,NMR and fluorescence spe ctroscopy and X-ray analysis were applied for characterisation of the complexes. Some peculiarities of the synthetic procedures for both types of complexes were discussed and the influence of the synthetic approach,pH of the reaction mediu m,temperature of synthesis and drying of the complexes on the composition,stab ility and optical properties was reported. The immobilisation of the complexes i n thin films based on sol-gel produced SiO2 and on polymethylmethacrylate was st udied. The optimal conditions for preparation of the matrices(composition of th e starting system,temperature and time of sol aging,etc.) were recommended. Th e film morphology was evaluated by fluorescence,scanning electron and atomic fo rce microscopy. The interaction of the lanthanide ions with the matrices and the influence of their nature,the effect of the in-situ polymerisation and other f actors on photoluminescent excitation and emission spectra and excited state lif e-times of the complexes were followed. The effect of the second ligand on the p hotoluminescence properties of the immobilised diketonates was further elucidate d. Processes involved in the thermal decomposition of the complexes and microcom posites produced on their base were proposed. Preliminary results on the pharmac ological properties of the coumarin complexes reported showed unambiguously high er cytotoxicity of the Nd complex in comparison with that of the respective ligand.

关键词： rare earths complexes thin films β-diketones coumarin derivates optical properties pharmacological properties morphology

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