Panels and models for accurate prediction of tumor mutation burden in tumor samples

Immune checkpoint blockade (ICB) is becoming standard-of-care in many types of human malignancies, but patient selection is still imperfect. Tumor mutation burden (TMB) is being evaluated as a biomarker for ICB in clinical trials, but most of the sequencing panels used to estimate it are inadequately designed. Here, we present a bioinformatics-based method to select panels and mathematical models for accurate TMB prediction. Our method is based on tumor-specific, forward-step selection of genes, generation of panels using a linear regression algorithm, and rigorous internal and external validation comparing predicted with experimental TMB. As a result, we propose cancer-specific panels for 14 malignancies which can offer reliable, clinically relevant estimates of TMBs. Our work facilitates a better prediction of TMB that can improve the selection of patients for ICB therapy.Fil: Martinez Perez, Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Molina Vila, Miguel Angel. Hospital Universitario Quirón Dexeus; EspañaFil: Marino, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Comparison of Met Office regional model soil moisture with COSMOS‐UK field‐scale in situ observations

The UK Met Office state-of-the-art, deterministic, convection-permitting, coupled land-atmosphere, regional weather forecasting system, known as the UKV or UK Variable resolution model (Tang et al. Meteorological Applications, 2013; 20:417–426), has been operational since 2015. Science updates are regularly made to the UKV land surface data assimilation scheme when those updates improve predictions of screen temperature and humidity, since these quantities have a direct impact on atmospheric states and weather forecasts. Less attention has been paid to whether UKV soil moisture analyses are close to independent, in-situ soil moisture observations, partly because it is difficult to make meaningful comparisons between 1.5 km2 gridded model outputs and traditional point sensor measurements. Soil moisture is recognized to be important when hydrological forecasts for runoff and rivers are required. This is because soil moisture controls the extent to which rainfall can infiltrate the soil, and the amount of surface runoff affects the timing of peak river flows (Ward & Robinson, Principles of Hydrology. McGraw-Hill Publishing Company; 2000; Singh et al. Water Resources Research, 2021, 57, e2020WR028827). Gómez et al. (Remote Sensing, 2020; 12:3691) report benefits to river flow forecasts when using soil moisture data assimilation in the UKV system instead of a daily downscaled product from the Met Office global model. The Met Office measures soil temperature and soil moisture at Cardington (Osborne & Weedon, Journal of Hydrometeorology, 2021, 22:279–295); there is no other UK Met Office site at which soil moisture is measured. In this study, we use field-scale (~200 m radius) soil moisture measurements from the UK Centre for Ecology and Hydrology's (UKCEH's) COSMOS-UK network to provide independent verification and analysis of UKV soil moisture during summer 2018, an unusually dry period in the United Kingdom. We find that the match to COSMOS-UK soil moisture observations is generally good, and that changes made to the land data assimilation approach during a recent operational upgrade had a generally beneficial impact on UKV soil moisture analyses under very dry conditions

Formulación de estrategias que permitan que la administración tributaria ejerza una mayor vigilancia sobre los contribuyentes a fin de reducir los índices de evasión tributaria en el impuesto al valor agregado.

La existencia de Evasión Tributaria en el Impuesto al Valor Agregado se ha venido presentando a lo largo del tiempo en nuestro país, es por ello que la Administración Tributaria Central ha estado constantemente promoviendo tareas que impulsen y mejoren los niveles de recaudación fiscal. En el presente trabajo de investigación buscamos establecer si la presencia de la evasión tributaria en el IVA tuvo una significativa incidencia en los niveles de recaudación fiscal durante los periodos de estudio que fueron los años 2011 – 2012.Para el desarrollo de la presente tesis se realizaron entrevistas tanto a funcionarios del Servicio de Rentas Internas como a expertos en temas tributarios, mismas que nos permitieron obtener la información necesaria para determinar la validez de las hipótesis planteadas. Dentro de los análisis realizados pudimos determinar que todas las reformas y actualizaciones en las normativas tributarias referentes al IVA y los diferentes mecanismos de control empleados por la Administración Tributaria, han contribuido significativamente a continuar cerrando la brecha de evasión tributaria existente en este impuesto, esto se corroboró en los informes de recaudación anual emitidos por el Servicio de Rentas Internas donde se evidencia claramente la disminución de estos índices y en el incremento los valores recaudados. Además, entre las principales conclusiones a las que llegamos podemos mencionar que el Impuesto al Valor Agregado siendo el impuesto indirecto con mayor contribución en la recaudación total es un impuesto fácil de evadir mediante el empleo de estrategias comunes, por lo antes mencionado consideramos de gran importancia la implementación de nuevas medidas preventivas y nuevos métodos de control que permitan que se ejerza una mayor presión sobre los contribuyentes, también creemos que es necesario que la Administración Tributaria implemente nuevos servicios de información y capacitaciones para que los contribuyentes tengan una excelente formación tributaria

DisPhaseDB: An integrative database of diseases related variations in liquid–liquid phase separation proteins

Motivation: Proteins involved in liquid–liquid phase separation (LLPS) and membraneless organelles (MLOs) are recognized to be decisive for many biological processes and also responsible for several diseases. The recent explosion of research in the area still lacks tools for the analysis and data integration among different repositories. Currently, there is not a comprehensive and dedicated database that collects all disease-related variations in combination with the protein location, biological role in the MLO, and all the metadata available for each protein and disease. Disease-related protein variants and additional features are dispersed and the user has to navigate many databases, with a different focus, formats, and often not user friendly. Results: We present DisPhaseDB, a database dedicated to disease-related variants of liquid–liquid phase separation proteins. It integrates 10 databases, contains 5,741 proteins, 1,660,059 variants, and 4,051 disease terms. It also offers intuitive navigation and an informative display. It constitutes a pivotal starting point for further analysis, encouraging the development of new computational tools. The database is freely available at http://disphasedb.leloir.org.ar.Fil: Navarro, Alvaro Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Orti, Fernando Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Martinez Perez, Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Alonso, Macarena. Fundación Instituto Leloir; ArgentinaFil: Simonetti, Franco Lucio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Iserte, Javier Alonso. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Marino Buslje, Cristina. Fundación Instituto Leloir; Argentin

The axis IL-10/claudin-10 is implicated in the modulation of aggressiveness of melanoma cells by B-1 lymphocytes

B-1 lymphocytes are known to increase the metastatic potential of B16F10 melanoma cells via the extracellular signal-regulated kinase (ERK) pathway. Since IL-10 is associated with B-1 cells performance, we hypothesized that IL-10 could be implicated in the progression of melanoma. In the present work, we found that the C57BL/6 mice, inoculated with B16F10 cells that were co-cultivated with B-1 lymphocytes from IL-10 knockout mice, developed fewer metastatic nodules than the ones which were injected with the melanoma cells that were cultivated in the presence of wild-type B-1 cells. The impairment of metastatic potential of the B16F10 cells was correlated with low activation of the ERK signaling pathway, supporting the idea that the production of IL-10 by B-1 cells influences the behavior of the tumor. A microarray analysis of the B-1 lymphocytes revealed that IL-10 deficiency is associated with down-regulation of the genes that code for claudin-10, a protein that is involved in cell-to-cell contact and that has been linked to lung adenocarcinoma. In order to determine the impact of claudin-10 in the cross-talk between B-1 lymphocytes and the B16F10 tumor cells, we took advantage of small interfering RNA. The silencing of claudin-10 gene in B-1 lymphocytes inhibited activation of the ERK pathway and abrogated the B-1-induced aggressive behavior of the B16F10 cells. Thus, our findings suggest that the axis IL-10/claudin-10 is a promising target for the development of therapeutic agents against aggressive melanoma.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Univ Paulista, Environm & Expt Pathol Program, Sao Paulo, SP, BrazilUniv Fed Sao Paulo Escola Paulista Med UNIFESP EPM, Dept Microbiol Immunol & Parasitol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Pharmaceut Sci, Campus Diadema, Diadema, SP, BrazilCtr Univ Sao Camilo, Sao Paulo, SP, BrazilUniv Fed Sao Paulo Escola Paulista Med UNIFESP EPM, Nephrol Div, Dept Med, Sao Paulo, SP, BrazilUniv Fed Sao Paulo Escola Paulista Med UNIFESP EPM, Dept Microbiol Immunol & Parasitol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Pharmaceut Sci, Campus Diadema, Diadema, SP, BrazilUniv Fed Sao Paulo Escola Paulista Med UNIFESP EPM, Nephrol Div, Dept Med, Sao Paulo, SP, BrazilFAPESP: 11/50256-6FAPESP: 08/50632-5FAPESP: 2016/02189-1CNPq: 472035/2011-8CNPq: 308374/2016-9Web of Scienc

Impact of the Reticular Stress and Unfolded Protein Response on the inflammatory response in endometrial stromal cells

During decidualization, endometrial stromal cells undergo reticular stress (RS) and unfolded protein response (UPR), allowing the endoplasmic reticulum-expansion and immunomodulators production. Physiological RS generates the activation of sensing proteins, inflammasome activation and mature-IL-1β secretion, associated with pro-implantatory effects. We focus on the impact of RS and UPR on decidualized cells and whether they induce a physiological sterile inflammatory response through IL-1β production. Human endometrial stromal cell line (HESC) after decidualization treatment with MPA + dibutyryl-cAMP (Dec) increased the expression of RS-sensors (ATF6, PERK and IRE1α) and UPR markers (sXBP1 and CHOP) in comparison with Non-dec cells. Then we found increased NLRP3 expression in Dec cells compared with Non-dec cells. In fact STF-083010 (an IRE1α inhibitor) prevented this increase. Downstream, increased levels of active caspase-1 on Dec cells were detected by FAM-Flica Caspase-1 associated with an increase in IL-1β production. Moreover, the treatment with STF-083010 decreased the invasion index observed in Dec cells, evaluated by an in vitro model of implantation. In endometrial biopsies from recurrent spontaneous abortion patients an increased expression of IRE1α was found in comparison with fertile women; while recurrent implantation failure samples showed a lower expression of sXBP1, TXNIP and NLRP3 than fertile women, suggesting that RS/UPR tenors might condition endometrial receptivity.Fil: Grasso, Esteban Nicolas. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Gori, María Soledad. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Soczewski, Elizabeth Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernández, Laura del Carmen. Universidad de Buenos Aires; ArgentinaFil: Gallino, Lucila. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Vota, Daiana Marina. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Martínez, G.. Universidad de Buenos Aires; ArgentinaFil: Irigoyen, M.. Fertilidad San Isidro; ArgentinaFil: Ruhlmann, C.. Fertilidad San Isidro; ArgentinaFil: Lobo, T.F.. Department of Obstetrics, Universidade Federal de São Paulo, São Paulo, Brazil; BrasilFil: Salamone, Gabriela Veronica. Universidade Federal de Sao Paulo;Fil: Mattar, Rosana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Daher, S.. Universidade Federal de Sao Paulo; . Department of Obstetrics, Universidade Federal de São Paulo, São Paulo, Brazil; BrasilFil: Perez Leiros, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Ramhorst, Rosanna Elizabeth. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentin

Radiotherapy resistance acquisition in Glioblastoma. Role of SOCS1 and SOCS3

Glioblastoma multiforme (GBM) is a poor prognosis type of tumour due to its resistance to chemo and radiotherapy. SOCS1 and SOCS3 have been associated with tumour progression and response to treatments in different kinds of cancers, including GBM. In this study, cell lines of IDH-wildtype GBM from primary cultures were obtained, and the role of SOCS1 and SOCS3 in the radiotherapy response was analysed. Fifty-two brain aspirates from GBM patients were processed, and six new cell lines of IDH-wildtype GBM were established. These new cell lines were characterized according to the WHO classification of CNS tumours. SOCS1 and SOCS3 expression levels were determined, at mRNA level by Q-PCR, at protein level by immunocytochemistry, and Western blot analysis. The results showed that SOCS1 and SOCS3 are overexpressed in GBM, as compared to a non-tumoral brain RNA pool. SOCS1 and SOCS3 expression were reduced by siRNA, and it was found that SOCS3 inhibition increases radioresistance in GBM cell lines, suggesting a key role of SOCS3 in radioresistant acquisition. In addition, radioresistant clonal populations obtained by selective pressure on these cell cultures also showed a significant decrease in SOCS3 expression, while SOCS1 remained unchanged. Furthermore, the induction of SOCS3 expression, under a heterologous promoter, in a radiotherapy resistant GBM cell line increased its radiosensitivity, supporting an important implication of SOCS3 in radiotherapy resistance acquisition. Finally, the treatment with TSA in the most radioresistant established cell line produced an increase in the effect of radiotherapy, that correlated with an increase in the expression of SOCS3. These effects of TSA disappeared if the increase in the expression of SOCS3 prevented with an siRNA against SOCS3. Thus, SOCS3 signal transduction pathway (JAK/STAT) could be useful to unmask new putative targets to improve radiotherapy response in GBM.This article has been funded by a grant from “Instituto de Salud Carlos III” (Grant PI012/02025), co-supported by FEDER funds, to M. Saceda; “Fundación ERESA” small project to M.Saceda, FISABIO grant (UGP-15-237) to V. M. Barberá, and a donation from AFECANCER to M.Saceda

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations