The prince and the pauper. A tale of anticancer targeted agents

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater

MANEJO DEL TRATAMIENTO ANTICOAGULANTE EN PACIENTES CON FIBRILACIÓN AURICULAR Y CÁNCER

Los pacientes con fibrilación auricular y cáncer son cada vez más frecuentes en las consultas. Son pacientes que, en su mayoría, añadido al tratamiento de fibrilación auricular y cáncer, requerirán de tratamiento anticoagulante. Es preciso buscar el equilibrio entre la necesidad de reducir el riesgo trombótico sin incrementar el riesgo hemorrágico, lo cual puede resultar complejo. Para el manejo de la anticoagulación no se dispone de ensayos clínicos específicos en pacientes con FA y cáncer que ayuden en la elección del anticoagulante más adecuado. Es preciso buscar evidencia científica en otro tipo de estudios como metaanálisis, consensos y guías de sociedades científicas. Con este trabajo fin de grado pretendo revisar y recoger la evidencia disponible y actualizada acerca del manejo de la anticoagulación en los pacientes con fibrilación y cáncer activo<br /

CUL3BPM E3 ubiquitin ligases regulate MYC2, MYC3, and MYC4 stability and JA responses

The jasmonate (JA)-pathway regulators MYC2, MYC3, and MYC4 are central nodes in plant signaling networks integrating environmental and developmental signals to fine-tune JA defenses and plant growth. Continuous activation of MYC activity is potentially lethal. Hence, MYCs need to be tightly regulated in order to optimize plant fitness. Among the increasing number of mechanisms regulating MYC activity, protein stability is arising as a major player. However, how the levels of MYC proteins are modulated is still poorly understood. Here, we report that MYC2, MYC3, and MYC4 are targets of BPM (BTB/POZ-MATH) proteins, which act as substrate adaptors of CUL3-based E3 ubiquitin ligases. Reduction of function of CUL3BPM in amiR-bpm lines, bpm235 triple mutants, and cul3ab double mutants enhances MYC2 and MYC3 stability and accumulation and potentiates plant responses to JA such as root-growth inhibition and MYC-regulated gene expression. Moreover, MYC3 polyubiquitination levels are reduced in amiR-bpm lines. BPM3 protein is stabilized by JA, suggesting a negative feedback regulatory mechanism to control MYC activity, avoiding harmful runaway responses. Our results uncover a layer for JA-pathway regulation by CUL3BPM-mediated degradation of MYC transcription factors.This work was funded by Spanish Ministry for Science and Innovation Grants BIO2016-77216-R (Ministerio de Economia [MINECO]/Fondos Europeos de Desarrollo Regional [FEDER]) (to R.S.) and BIO2016-80551-R (MINECO/FEDER) (to V.R.). E.C. was the recipient of a Formación de Personal Investigador grant from MINECO (Reference BES-2017-081147). The mass spectrometry instrumentation was funded by the University of Strasbourg (IdEx “Equipement mi-Lourd” 2015) and by “Laboratoires d’Excellence” Grant ANR-10-LABX-0036 (NETRNA)

Transcriptional upregulation of four genes of the lysine biosynthetic pathway by homocitrate accumulation in Penicillium chrysogenum: homocitrate as a sensor of lysine-pathway distress

The lysine biosynthetic pathway has to supply large amounts of α-aminoadipic acid for penicillin biosynthesis in Penicillium chrysogenum. In this study, we have characterized the P. chrysogenum L2 mutant, a lysine auxotroph that shows highly increased expression of several lysine biosynthesis genes (lys1, lys2, lys3, lys7). The L2 mutant was found to be deficient in homoaconitase activity since it was complemented by the Aspergillus nidulans lysF gene. We have cloned a gene (named lys3) that complements the L2 mutation by transformation with a P. chrysogenum genomic library, constructed in an autonomous replicating plasmid. The lys3-encoded protein showed high identity to homoaconitases. In addition, we cloned the mutant lys3 allele from the L2 strain that showed a G1534 to A1534 point mutation resulting in a Gly495 to Asp495 substitution. This mutation is located in a highly conserved region adjacent to two of the three cysteine residues that act as ligands to bind the iron-sulfur cluster required for homoaconitase activity. The L2 mutant accumulates homocitrate. Deletion of the lys1 gene (homocitrate synthase) in the L2 strain prevented homocitrate accumulation and reverted expression levels of the four lysine biosynthesis genes tested to those of the parental prototrophic strain. Homocitrate accumulation seems to act as a sensor of lysine-pathway distress, triggering overexpression of four of the lysine biosynthesis genes.Fil: Teves, Franco. Universidad de León; EspañaFil: Lamas Maceiras, Mónica. Universidad de León; EspañaFil: García Estrada, Carlos. Instituto de Biotecnología de León; EspañaFil: Casqueiro, Javier. Instituto de Biotecnología de León; España. Universidad de León; EspañaFil: Naranjo, Leopoldo. Universidad de León; EspañaFil: Ullán, Ricardo V.. Instituto de Biotecnología de León; EspañaFil: Scervino, Jose Martin. Instituto de Biotecnología de León; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; ArgentinaFil: Wu, Xiaobin. Instituto de Biotecnología de León; EspañaFil: Velasco Conde, Tania. Instituto de Biotecnología de León; EspañaFil: Martín, Juan F.. Instituto de Biotecnología de León; España. Universidad de León; Españ

Development of the Aerial Remote Triage System: Result of a survey of international expert

The use of drones for triage in mass-casualty incidents has recently emerged as a promising technology. However, there is no triage system specifically adapted to a remote usage. Our study aimed to develop a remote triage procedure using drones. The research was performed in three stages: literature review, the development of a remote triage algorithm using drones and evaluation of the algorithm by experts. Qualitative synthesis and the calculation of content validity ratios were done to achieve the Aerial Remote Triage System. This algorithm assesses (in this order): major bleeding, walking, consciousness and signs of life; and then classify the injured people into several priority categories: priority 1 (red), priority 2 (yellow), priority 3 (green) and priority * (violet). It includes the possibility to indicate save-living interventions to injured people and bystanders, like the compression of bleeding injuries or the adoption of the recovery position. The Aerial Remote Triage System may be a useful way to perform triage by drone in complex emergencies when it is difficult to access to the scene due to physical, chemical or biological risks

IGF1 Gene Therapy Modifies Microglia in the Striatum of Senile Rats

Microglial cells become dystrophic with aging; this phenotypic alteration contributes to basal central nervous system (CNS) neuroinflammation being a risk factor for age related neurodegenerative diseases. In previous studies we have observed that insulin like growth factor 1 (IGF1) gene therapy is a feasible approach to target brain cells, and that is effective to modify inflammatory response in vitro and to ameliorate cognitive or motor deficits in vivo. Based on these findings, the main aim of the present study is to investigate the effect of IGF1 gene therapy on microglia distribution and morphology in the senile rat. We found that IGF1 therapy leads to a region-specific modification of aged microglia population

Polypeptide N-acetylgalactosamine transferase 3: a post-translational writer on human health

Polypeptide N-acetylgalactosamine transferase 3 (ppGalNAc-T3) is an enzyme involved in the initiation of O-GalNAc glycan biosynthesis. Acting as a writer of frequent post-translational modification (PTM) on human proteins, ppGalNAc-T3 has key functions in the homeostasis of human cells and tissues. We review the relevant roles of this molecule in the biosynthesis of O-GalNAc glycans, as well as in biological functions related to human physiological and pathological conditions. With main emphasis in ppGalNAc-T3, we draw attention to the different ways involved in the modulation of ppGalNAc-Ts enzymatic activity. In addition, we take notice on recent reports of ppGalNAc-T3 having different subcellular localizations, highlight critical intrinsic and extrinsic functions in cellular physiology that are exerted by ppGalNAc-T3-synthesized PTMs, and provide an update on several human pathologies associated with dysfunctional ppGalNAc-T3. Finally, we propose biotechnological tools as new therapeutic options for the treatment of pathologies related to altered ppGalNAc-T3. KEY MESSAGES: ppGalNAc-T3 is a key enzyme in the human O-GalNAc glycans biosynthesis. enzyme activity is regulated by PTMs, lectin domain and protein-protein interactions. ppGalNAc-T3 is located in human Golgi apparatus and cell nucleus. ppGalNAc-T3 has a central role in cell physiology as well as in several pathologies. Biotechnological tools for pathological management are proposed.Fil: Garay, Yohana Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Cejas, Romina Beatríz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Lorenz, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; ArgentinaFil: Zlocowski, Natacha. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Parodi, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Ferrero, Franco Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Angeloni, Genaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Alfonso García, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Sendra, Victor German. Tufts University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lardone, Ricardo Dante. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Irazoqui, Fernando Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentin

A cross-sectional study examining the parametric thyroid feedback quantile index and its relationship with metabolic and cardiovascular diseases

The usual inverse correlation between thyrotropin (TSH) and thyroid hormone disappears in syndromes of central resistance to thyroid hormone, where both are high. TSH and thyroid hormone are also simultaneously high when there is an elevation of the set point of the thyroid regulation axis. This can be estimated with indices, such as the Parametric Thyroid Feedback Quantile-based Index (PTFQI), which was designed for the general population. The PTFQI is positively associated with diabetes prevalence, but association with other pathologies has not been yet explored. The aim of this project was to explore the potential relationship of the PTFQI with metabolic and cardiovascular disease in a sample of ambulatory adult patients from Spain

Ideas del profesorado de secundaria en formación inicial sobre la contaminación y transformaciones energéticas en los coches eléctricos y de combustible

El coche es un contexto ideal para trabajar conocimientos y desarrollar competencias en la enseñanza de las ciencias. Este trabajo presenta las ideas iniciales sobre la contaminación y transformaciones energéticas que tienen lugar en los coches eléctricos y de combustible de 52 profesores en formación inicial que cursaban el Máster en Profesorado de Educación Secundaria en la Universidad de Málaga en las especialidades de Física y Química, y Biología y Geología. El instrumento utilizado para la recogida de datos fue un cuestionario de cuatro preguntas que abordaba dicha temática con preguntas de respuesta abierta y cerrada. Se realizó un análisis cualitativo y cuantitativo. Los resultados ponen de manifiesto escasas dificultades en torno a las transformaciones energéticas que tienen lugar en coches eléctricos y de combustible, y graves obstáculos en la identificación de gases como contaminantes (nitrógeno y ozono estratosférico) o el desconocimiento del papel del dióxido de carbono.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Controlling endemic Neospora caninum-related abortions in a dairy herd from Argentina

After diagnosis of endemic abortions due to neosporosis in a commercial dairy farm, routes of Neospora caninum-transmission were evaluated in order to choose the best strategy for reducing its seroprevalence and related abortions. Fifty two dam-calf pairs were bled at parturition. Additionally, 22 female calves were also sampled at regular 3 month intervals until 18–22 months. N. caninum specific antibodies were assayed by IFAT. Serum samples were tested at a dilution 1:25 for calves before colostrum intake and heifers before mating and 1:100 for multiparous cows. Only serum samples from IFAT seropositive cattle involved in the evaluation of the routes of transmission were assessed by a commercial IgG avidity ELISA. Seropositive cows or heifers were artificially inseminated with semen from Hereford bulls. The progenies from these female animals were sent to a feed lot to produce meat. Different generalized linear models (GLM) were used to study the relationship between abortion, age category, and serostatus. Seropositive heifers were more likely to have a record of abortion (OR 2.7; 95% CI 1.6–4.7). Vertical transmission frequency was 55.5% (5 seropositive calves/9 seropositive cows). Horizontal transmission was 22.7% (5 female calves seroconverted at least one time/22 females calves sampled during 24 months) and these 5 female calves had low avidity. In heifers, both seroprevalence and abortion rates decreased from 22.1 and 8.4% of 475 in 2009 to 6.1 and 4.3% of 578 in 2015, respectively (p < 0.01). Over 5 years, N. caninum-seroprevalence and the related abortions in heifers decreased after the control strategy was assessed.EEA BalcarceFil: Lagomarsino, Horacio. Actividad privada; ArgentinaFil: Scioli, Agustín. Actividad privada; ArgentinaFil: Rodríguez, Alejandro. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; Argentina.Fil: Armendano, Joaquín. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; Argentina.Fil: Fiorani, Franco. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Bence, Ángel. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias; Argentina.Fil: García, Joaquín. Actividad privada; ArgentinaFil: Hecker, Yanina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Gual, Ignacio. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; Argentina.Fil: Cantón, Germán. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; ArgentinaFil: Odeón, Anselmo Carlos. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce, ArgentinaFil: Campero, Carlos. Actividad privada; ArgentinaFil: Moore, Dadín. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina