TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death

Newborn mice carrying targeted mutations in genes encoding neurotrophins or their signaling Trk receptors display severe neuronal deficits in the peripheral nervous system but not in the CNS. In this study, we show that trkB (¿/¿) mice have a significant increase in apoptotic cell death in different regions of the brain during early postnatal life. The most affected region in the brain is the dentate gyrus of the hippocampus, although elevated levels of pyknotic nuclei were also detected in cortical layers II and III and V and VI, the striatum, and the thalamus. Furthermore, axotomized hippocampal and motor neurons of trkB (¿/¿) mice have significantly lower survival rates than those of wild-type littermates. These results suggest that neurotrophin signaling through TrkB receptors plays a role in the survival of CNS neurons during postnatal development. Moreover, they indicate that TrkB receptor signaling protects subpopulations of CNS neurons from injury- and axotomy-induced cell death

Computed tomography assesment in the characterization of mouse model for Costello Syndrome

Proceeding of: 2008 World Molecular Imaging Congress (WMIC 2008), 10-13 september 2008. Nice, Franc

The extraordinary evolutionary history of the reticuloendotheliosis viruses

The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events

Targeting the MAPK Pathway in KRAS-Driven Tumors.

KRAS mutations occur in a quarter of all of human cancers, yet no selective drug has been approved to treat these tumors. Despite the recent development of drugs that block KRASG12C, the majority of KRAS oncoproteins remain undruggable. Here, we review recent efforts to validate individual components of the mitogen-activated protein kinase (MAPK) pathway as targets to treat KRAS-mutant cancers by comparing genetic information derived from experimental mouse models of KRAS-driven lung and pancreatic tumors with the outcome of selective MAPK inhibitors in clinical trials. We also review the potential of RAF1 as a key target to block KRAS-mutant cancers.This work was supported by grants from the European Research Council (ERC-AG/695566, THERACAN), the Spanish Ministry of Science, Innovation and Universities (RTI2018-094664-B-I00 and RTC2017-6576-1), the Autonomous Community of Madrid (B2017/BMD-3884 iLUNG-CM), and the Asociacion Espanola contra el Cancer (GC166173694BARB). M.B. is a recipient of an Endowed Chair from the AXA Research Fund.S

Targeting KRAS mutant lung cancer: light at the end of the tunnel.

For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRASG12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen-activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.This work was supported by grants from the European Research Council (ERC-2015-AdG/695566, THERACAN), the Spanish Ministry of Science, Innovation and Universities (RTC-2017-6576, RTI2018-094664-BI00) the Autonomous Community of Madrid (B2017/BMD-3884 iLUNG-CM) and the CRIS Cancer Foundation (to MB) as well as the Spanish Ministry of Science and Innovation (PID2020-116705RB-100) (to MD). MB is a recipient of an Endowed Chair from the AXA Research Fund.S

A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men

Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD

The TC21 oncoprotein interacts with the Ral guanosine nucleotide dissociation factor.

TC21 is a highly oncogenic member of he Ras superfamily of small GTP binding proteins. We have used the yeast two hybrid system to identify proteins that interact with an oncogenic form of the TC2I protein. cDNA clones encoding the carboxy-terminal region of the RalGDS protein were isolated from human B-cell and HeLa cDNA libraries. RalGDS is an exchange factor that stimulates GDP dissociation from Ral, another member of the Ras superfamily of proteins. The interaction between RalGDS to TC21 is direct and appears to be mediated by the effector domain of TC21 and the carboxy-terminal region of RalGDS. Moreover, RalGDS only binds to TC21 in its active, GTP-loaded configuration. These results suggest that RalGDS might be an effector molecule for TC21 and may participate in cross-talking between Ral and TC2I signalling pathways.pre-print459 K

Interacción de antibióticos con el centro activo peptidil transferasa del ribosoma eucariótico

Tesis inédita de la Universidad de Madrid, Facultad de Ciencias, Sección de Químicas, 1974.Universidad de MadridTRUEProQuestpu

La oncología en el siglo XXI: de las terapias personalizadas a la inmunoterapia

La Lección Cajal es una conferencia anual dictada desde 2019 en la Universidad de Zaragoza por una figura académica relevante en su campo del saber, impulsada por el Vicerrectorado de Cultura y Proyección Social para conmemorar el 150 aniversario de la entrada de Santiago Ramón y Cajal en esta universidad, su «venerada alma mater». MARIANO BARBACID estudió Ciencias Químicas en la Universidad Complutense y se doctoró en 1974. Entre 1974 y 1977 completó su formación postdoctoral en el Instituto del Cáncer (NCI) de Estados Unidos. En 1978 formó su propio grupo de investigación en el NCI, donde trabajó hasta 1988. Durante la siguiente década (1988-1998) fue vicepresidente de Oncología Preclínica de la multinacional Bristol-Myers Squibb. En 1998 regresó a España para fundar y diri- gir el Centro Nacional de Investigaciones Oncológicas (CNIO). El Dr. Barbacid es miembro extranjero de la Academia de Ciencias de EE. UU., un honor que tan solo ostentan otros siete investigado- res españoles. En 2014 fue nombrado Fellow de la Academia de la Asociación Americana de Investigación en Cáncer (AACR), el primer español en recibir esta distinción. Es doctor honoris causa por la Universidad Internacional Menéndez Pelayo (1995), la Universidad de Cantabria (2011) y la Universidad de Barcelona (2014). En 2011 reci- bió la Gran Cruz del Dos de Mayo, la más alta distinción que otorga la Comunidad de Madrid. Entre los premios internacionales destacan la Medalla Burkitt (Irlanda, 2017), la Medalla de Honor de la Agencia Internacional del Cáncer de la Organización Mundial de la Salud (Francia, 2007) y el Premio Charles Rodolphe Brupbacher (Suiza, 2005). En la actualidad, el «Índice h» (Hirsch Index) del Dr. Barbacid es de 121, el más alto de España en las áreas de Bioquímica y Biología Molecular y el segundo más alto en Oncología