RHO Exchange Factors in the Regulation of Squamous Cell Stemness and Carcinogenesis

[EN] The squamous cell carcinoma (SCC) is a major cause of cancer mortality. The carcinogenesis of this tumor is linked to a series of molecular derangements that frequently features the deregulation of RHO GTPase signaling. However, the events and agents underpinning such deregulation are yet to be defined. RHO exchange factors (GEFs), the proteins that catalyze the activation of RHO GTPases, have been traditionally contemplated as potential protumorigenic players in this context, but their large numbers and the lack of appropriate models has precluded the elucidation of their true functions in cancer settings. To address this issue, in this thesis we have focused on VAV2 to spearhead the characterization of RHO GEFs as key mediators of tumorigenesis and, more importantly, as candidate targets for novel SCC-directed therapeutic approaches. Here we demonstrate that VAV2 becomes upregulated in cutaneous and head-and-neck SCCs, where it engages a transcriptional program involved in the induction of stem cell-like regenerative proliferation and undifferentiation. Significantly, we show that VAV2 activity predicts disease outcome and that its inhibition within specific catalytic thresholds provides antitumoral benefits without disturbing organismal homeostasis. This work also exposes non-oncogenic roles for this GEF in the physiological maintenance of the cutaneous squamous epithelium, where it regulates the abundance, activity and responsiveness of hair follicle stem cells through the control of their transcriptomic circuits. Lastly, by extending these studies to the whole family of RHO GEFs, our research shows that VAV2 belongs to a small collection of exchange factors with pivotal roles in either the promotion or impairment of SCC tumorigenesis-associated processes. Taken together, our findings unveil hitherto unknown regulators of SCC fitness whose activity can be harnessed to modulate tumor growth and malignancy

Drug vulnerabilities and disease prognosis linked to the stem cell-like gene expression program triggered by the RHO GTPase activator VAV2 in hyperplastic keratinocytes and head and neck cancer

We have recently shown that VAV2, a guanosine nucleotide exchange factor that catalyzes the stimulation step of RHO GTPases, is involved in a stem cell-like (SCL) regenerative proliferation program that is important for the development and subsequent maintenance of the tumorigenesis of both cutaneous (cSCC) and head and neck squamous cell carcinomas (hnSCC). In line with this, we have observed that the levels of the VAV2 mRNA and VAV2-regulated gene signatures are associated with poor prognosis in the case of human papillomavirus-negative hnSCC patients. These results suggest that the SCL program elicited by VAV2 in those cells can harbor therapeutically actionable downstream targets. We have addressed this issue using a combination of both in silico and wet-lab approaches. Here, we show that the VAV2-regulated SCL program does harbor a number of cell cycleand signaling-related kinases that are essential for the viability of undifferentiated keratinocytes and hnSCC patient-derived cells endowed with high levels of VAV2 activity. Our results also show that the VAV2-regulated SCL gene signature is associated with poor hnSCC patient prognosis. Collectively, these data underscore the critical role of this VAV2-regulated SCL program for the viability of both preneoplastic and fully transformed keratinocytes.Fil: Lorenzo Martín, Luis Francisco. Consejo Superior de Investigaciones Científicas; España. Universidad de Salamanca; EspañaFil: Menacho Márquez, Mauricio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Bustelo, Xosé R.. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; Españ

A GIS-based multivariate clustering for characterization and ecoregion mapping from a viticultural perspective

In wine-growing regions, zoning studies define areas according to their potential to produce specific wines and also identify the key drivers behind their variability and optimize vineyard management for sustainable viticulture. However, delineation of homogeneous zones is difficult because of the complex combination of factors which could affect zone classifications. One possibility to capture potential variability is the use of natural environmental properties as they are related to success in grape growing. With the aim of characterizing the spatial variability of the main vine-related environmental variables and determining different zones, climate and topographical data were obtained for Extremadura (southwestern Spain), an important wine region. Firstly, accurate maps of all climate indices were generated by using regression-kriging as the most suitable algorithm in which exhaustive secondary information on elevation was incorporated, and maps of topography-derived variables were obtained using GIS (Geographical Information System) tools. Secondly, principal component analysis and multivariate geographic classification were used to define homogeneous classes, resulting in three zones. Each zone was further characterized by overlaying the zonation map with a geology map and all enviromental layers. It was obtained that although a wide part of the Extremaduran territory has warm climate characteristics, the zones have different viticultural potential and a high proportion of the region lays on suitable substrate. This zonation in Extremadura is the basis for further zoning studies at more detailed field scale and the modeling of vineyard response to climate change.Trabajo financiado por: Junta de Extremadura y Fondos FEDER. Ayuda TIC008 y TPR009peerReviewe

HERC ubiquitin ligases in cancer

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3-HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies

CANCERTOOL: A Visualization and Representation Interface to Exploit Cancer Datasets

[EN] With the advent of OMICs technologies, both individual research groups and consortia have spear-headed the characterization of human samples of multiple pathophysiologic origins, resulting in thousands of archived genomes and transcriptomes. Although a variety of web tools are now available to extract information from OMICs data, their utility has been limited by the capacity of nonbioinformatician researchers to exploit the information. To address this problem, we have developed CANCERTOOL, a web-based interface that aims to overcome the major limitations of public transcriptomics dataset analysis for highly prevalent types of cancer (breast, prostate, lung, and colorectal). CANCERTOOL provides rapid and comprehensive visualization of gene expression data for the gene(s) of interest in well-annotated cancer datasets. This visualization is accompanied by generation of reports customized to the interest of the researcher (e.g., editable figures, detailed statistical analyses, and access to raw data for reanalysis). It also carries out gene-to-gene correlations in multiple datasets at the same time or using preset patient groups. Finally, this new tool solves the time-consuming task of performing functional enrichment analysis with gene sets of interest using up to 11 different databases at the same time. Collectively, CANCERTOOL represents a simple and freely accessible interface to interrogate well-annotated datasets and obtain publishable representations that can contribute to refinement and guidance of cancer-related investigations at all levels of hypotheses and design. Significance: In order to facilitate access of research groups without bioinformatics support to public transcriptomics data, we have developed a free online tool with an easy-to-use interface that allows researchers to obtain quality information in a readily publishable forma

Subtitulado en español de animaciones de procesos de biología molecular que están narradas en inglés

Memoria ID-0063. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2016-2017

Experimental Techniques to Measure Hypnotic Levels During Surgery

[Abstract] The administration of anesthetics during a surgical procedure has been done historically in a manual way with the anesthesiologist deciding what amounts and at what rates to use. Over the last few decades there has been a rapid increase in the automation of many medical areas including anesthesiology, with that increased level of automation have also appeared new ways to measure the level of sedation in patients. Historically, one of the most frequently index used has been the BIS, which has proven rather reliable as an indicator. More recently, another index called PSI has attracted interest of practitioners. In this article a comparison of these two indexes was performed. Data recording BIS and PSI values from surgical operations for several patients were collected and analyzed. The results seem to indicate that it is to be expected that in 95% of the cases the correlation between the BIS and PSI index will be at least 0.6866.This work has been supported by the grant DPI2010-18278 of the Spanish Governmenthttps://doi.org/10.17979/spudc.978849749808

Vagal afferents contribute to sympathoexcitation-driven metabolic dysfunctions

[EN] Multiple crosstalk between peripheral organs and the nervous system are required to maintain physiological and metabolic homeostasis. Using Vav3–deficient mice as a model for chronic sympathoexcitation–associated disorders, we report here that afferent fibers of the hepatic branch of the vagus nerve are needed for the development of the peripheral sympathoexcitation, tachycardia, tachypnea, insulin resistance, liver steatosis, and adipose tissue thermogenesis present in those mice. This neuronal pathway contributes to proper activity of the rostral ventrolateral medulla, a sympathoregulatory brainstem center hyperactive in Vav3 –/– mice. Vagal afferent inputs are also required for the development of additional pathophysiological conditions associated with deregulated rostral ventrolateral medulla activity. By contrast, they are dispensable for other peripheral sympathoexcitation–associated disorders sparing metabolic alterations in liver

Aprendizaje de estrategias de investigación científica en temas de biología fundamental y biomedicina

Memoria ID-0178. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2017-2018

Heart Failure Is a Poor Prognosis Risk Factor in Patients Undergoing Cholecystectomy: Results from a Spanish Data-Based Analysis

Background: The incidence of cholecystectomy is increasing as the result of the aging worldwide. Our aim was to determine the influence of heart failure on in-hospital outcomes in patients undergoing cholecystectomy in the Spanish National Health System (SNHS). Methods: We conducted a retrospective study using the Spanish National Hospital Discharge Database. Patients older than 17 years undergoing cholecystectomy in the period 2007–2015 were included. Demographic and administrative variables related to patients’ diseases as well as procedures were collected. Results: 478,111 episodes of cholecystectomy were identified according to the data from SNHS hospitals in the period evaluated. From all the episodes, 3357 (0.7%) were excluded, as the result the sample was represented by 474,754 episodes. Mean age was 58.3 (+16.5) years, and 287,734 (60.5%) were women (p < 0.001). A primary or secondary diagnosis of HF was identified in 4244 (0.89%) (p < 0.001) and mean age was 76.5 (+9.6) years. A higher incidence of all main complications studied was observed in the HF group (p < 0.001), except stroke (p = 0.753). Unadjusted in-hospital mortality was 1.1%, 12.9% in the group with HF versus 1% in the non HF group (p < 0.001). Average length of hospital stay was 5.4 (+8.9) days, and was higher in patients with HF (16.2 + 17.7 vs. 5.3 + 8.8; p < 0.001). Risk-adjusted in-hospital mortality models’ discrimination was high in both cases, with AUROC values = 0.963 (0.960–0.965) in the APRG-DRG model and AUROC = 0.965 (0.962–0.968) in the CMS adapted model. Median odds ratio (MOR) was high (1.538 and 1.533, respectively), stating an important variability of risk-adjusted outcomes among hospitals. Conclusions: The presence of HF during admission increases in hospital mortality and lengthens the hospital stay in patients undergoing cholecystectomy. However, mortality and hospital stay have significantly decreased during the study period in both groups (HF and non HF patients)