Una descripción distinta de la orientación en las lenguas de signos

Sign languages are a very interesting object of linguistic study, posing challenges not present in oral languages. One of these challenges is describing and transcribing the internal structure of the language in a way that is adequate to its characteristics but also compatible with existing linguistic practice. The phonology of sign languages is of special interest. We focus on one phonological feature: that of hand orientation. We propose an interpretation and description system that better captures underlying meaning and structure, and that is more appropriate for its formal and computational treatment.Las lenguas de signos son un objeto de estudio lingüístico de gran interés. Presentan retos y dificultades distintos a los de las lenguas orales, como describir y transcribir la estructura interna de la lengua de una manera adecuada a sus características únicas pero también compatible con la práctica lingüística actual. El caso de la fonología es especialmente interesante. Nos centramos en un rasgo fonológico concreto: la orientación de la mano. Proponemos una interpretación y un sistema de descripción que capturan mejor la semántica y la estructura subyacente, y que además permiten un tratamiento formal y computacional más adecuado.This research is partially supported by the IDiLyCo project (TIN2015-66655-R) funded by the Spanish Ministry of Economy, Industry and Competitiveness

Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach

It is well known that activating mutations in the KRAS and NRAS genes are associated with poor response to anti-EGFR therapies in patients with metastatic colorectal cancer (mCRC). Approximately half of the patients with wild-type (WT) KRAS colorectal carcinoma do not respond to these therapies. This could be because the treatment decision is determined by the mutational profile of the primary tumor, regardless of the presence of small tumor subclones harboring RAS mutations in lymph nodes or liver metastases. We analyzed the mutational profile of the KRAS, NRAS, BRAF and PI3KCA genes using low-density microarray technology in samples of 26 paired primary tumors, 16 lymph nodes and 34 liver metastases from 26 untreated mCRC patients (n=76 samples). The most frequent mutations found in primary tumors were KRAS (15%) and PI3KCA (15%), followed by NRAS (8%) and BRAF (4%). The distribution of the mutations in the 16 lymph node metastases analyzed was as follows: 4 (25%) in KRAS gene, 3 (19%) in NRAS gene and 1 mutation each in PI3KCA and BRAF genes (6%). As expected, the most prevalent mutation in liver metastasis was in the KRAS gene (35%), followed by PI3KCA (9%) and BRAF (6%). Of the 26 cases studied, 15 (58%) displayed an overall concordance in the mutation status detected in the lymph node metastases and liver metastases compared with primary tumor, suggesting no clonal evolution. In contrast, the mutation profiles differed in the primary tumor and lymph node/metastases samples of the remaining 11 patients (48%), suggesting a spatial and temporal clonal evolution. We confirm the presence of different mutational profiles among primary tumors, lymph node metastases and liver metastases. Our results suggest the need to perform mutational analysis in all available tumor samples of patients before deciding to commence anti-EGFR treatment.This work has been partially supported by grants from the Instituto de Salud Carlos III (ISCIII; Ministerio de Sanidad y Consumo, Madrid, Spain) (PI18/00282), the Gerencia Regional de Salud de Castilla y León, Valladolid, Spain (GRS1302/A/16), the RTICC of the ISCIII (RD12/0020/0035-FEDER, RD12/0036/0048-FEDER) and CIBERONC (CB16/12/00400 and CB16/12/00233), the Fundación Memoria de Don Samuel Solórzano Barruso (Salamanca, Spain) and the Fundación Eugenio Rodríguez Pascual, (Madrid, Spain). JM Sayagués and ME Sarasquete are supported by grants (CES11/004 and CP13/00080) from the ISCIII, Ministerio de Ciencia e Innovación, Madrid, Spain

Tracking the antibody immunome in sporadic colorectal cancer by using antigen self-assembled protein arrays

© 2021 by the authors.Sporadic Colorectal Cancer (sCRC) is the third leading cause of cancer death in the Western world, and the sCRC patients presenting with synchronic metastasis have the poorest prognosis. Genetic alterations accumulated in sCRC tumor cells translate into mutated proteins and/or abnormal protein expression levels, which contribute to the development of sCRC. Then, the tumor-associated proteins (TAAs) might induce the production of auto-antibodies (aAb) via humoral immune response. Here, Nucleic Acid Programmable Protein Arrays (NAPPArray) are employed to identify aAb in plasma samples from a set of 50 sCRC patients compared to seven healthy donors. Our goal was to establish a systematic workflow based on NAPPArray to define differential aAb profiles between healthy individuals and sCRC patients as well as between non-metastatic (n = 38) and metastatic (n = 12) sCRC, in order to gain insight into the role of the humoral immune system in controlling the development and progression of sCRC. Our results showed aAb profile based on 141 TAA including TAAs associated with biological cellular processes altered in genesis and progress of sCRC (e.g., FSCN1, VTI2 and RPS28) that discriminated healthy donors vs. sCRC patients. In addition, the potential capacity of discrimination (between non-metastatic vs. metastatic sCRC) of 7 TAAs (USP5, ML4, MARCKSL1, CKMT1B, HMOX2, VTI2, TP53) have been analyzed individually in an independent cohort of sCRC patients, where two of them (VTI2 and TP53) were validated (AUC ~75%). In turn, these findings provided novel insights into the immunome of sCRC, in combination with transcriptomics profiles and protein antigenicity characterizations, wich might lead to the identification of novel sCRC biomarkers that might be of clinical utility for early diagnosis of the tumor. These results explore the immunomic analysis as potent source for biomarkers with diagnostic and prognostic value in CRC. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these novel sCRC immunomic biomarkers.We gratefully acknowledge financial support from the Spanish Health Institute Carlos III (ISCIII) for the grants: FIS PI14/01538, FIS PI17/01930 and CB16/12/00400. We also acknowledge Fondos FEDER (EU) “Una manera de hacer Europa” and Junta Castilla-León (COVID19 grant COV20EDU/00187). Fundación Solórzano FS/38-2017. The Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019/0023, of the PE I + D + I 2017-2020, funded by ISCIII and FEDER. CNPq-National Council for Scientific and Technological Development (Brazil) (306258/2019-6) and FAPERJ-Foundation for Research Support of Rio de Janeiro State for the financial support (E-26/201.670/2017 and 210.379/2018). M. González-González is supported by MINECOPTA2019-017870-I.A. Landeira-Viñuela is supported by VIII Centenario-USAL PhD Program. P.J.-V. is supported by JCYL PhD Program and scholarship JCYL-EDU/601/2020. P.D. and E.B. are supported by a JCYL-EDU/346/2013 Ph.D. scholarship

Prevalence of infections by hepatitis B, C, D and E viruses in Bolivia.

[ES] En Bolivia no se han realizado estudios específicos sobre los virus de la hepatitis, por lo que su prevalencia y patrones de circulación son prácticamente desconocidos. De 1992 a 1996 se realizó un estudio seroepidemiológico con el fin de adquirir una primera visión de conjunto sobre las prevalencias de las infecciones por virus de la hepatitis B (VHB), C (VHC), D (VHD) y E (VHE) en distintas poblaciones de Bolivia. Sobre la base de los datos obtenidos en otros lugares de América Latina, se prestó atención especial al estudio de las comunidades autóctonas de la región amazónica. En las zonas rurales del altiplano andino, la infección por VHB presentó una prevalencia general que correspondería a una situación de endemia media o baja (11,2%) y no se encontró ningún portador de anticuerpos contra VHC o VHD. En dos poblaciones de alto riesgo de la ciudad de Cochabamba (niños sin hogar y trabajadoras del sexo), la prevalencia de infección por VHB fue similar (11,6%) y podría considerarse baja en comparación con la de otras poblaciones análogas de núcleos urbanos en América Latina. La correspondiente al VHC (un caso positivo, 0,5%) sería parecida a la descrita en esas mismas poblaciones, si bien el escaso número de muestras estudiadas no permite extraer conclusiones más firmes. En concordancia con observaciones anteriores de comunidades similares de zonas tropicales de Suramérica, en las poblaciones autóctonas de la Amazonia boliviana la infección por VHB es sumamente endémica (prevalencia general de 74,0%), pero no se ha detectado la circulación de VHC. Se sabe que la transmisión de VHB es horizontal y tiene lugar desde edades muy tempranas, pero se desconocen los mecanismos de esa actividad. A los 10 años de edad, más de la mitad de la población ya ha experimentado la infección natural que, 10 años más tarde, se habrá difundido a prácticamente toda la población. La tasa muy baja de individuos positivos al HbsAg (1,6%), la ausencia de ADN vírico en las muestras con reactividad aislada a anti-HBc y la alta prevalencia de anti-HBs entre los individuos que presentan marcadores de infección natural (92,4%) excluyen la participación de la transmisión vertical en el mantenimiento de la endemia. Hasta el momento, no se ha documentado ningún brote de infección por VHD en estas comunidades, pero la alta endemia de infección por VHB alerta sobre el riesgo de posibles brotes en el futuro. Los resultados obtenidos con las pruebas de anticuerpos contra VHE sugieren que este virus circula ampliamente en Bolivia y que podría haber producido brotes recientes en el departamento de Cochabamba. Se recomienda vacunar contra VHB en las poblaciones endémicas como medida de corto plazo; buscar activamente en todo el país brotes y casos esporádicos de hepatitis E y continuar realizando estudios que permitan evaluar las repercusiones sanitarias de la situación documentada en este estudio. [EN] In Bolivia, no studies have been carried out specifically on hepatitis viruses. Thus, their prevalence and circulation patterns are virtually unknown. A seroepidemiologic study was performed from 1992 to 1996 to generate a preliminary idea of the overall prevalence of infection from hepatitis B, C, D, and E viruses (HBV, HCV, HDV, and HEV, respectively) in different Bolivian population groups. Prompted by the data obtained in other areas of Latin America, the study focused on indigenous communities in the Amazon region. In rural areas of the high Andean plateau, HBV infection showed an overall prevalence compatible with medium to low endemicity (11.2%), and no carriers of HCV or HDV antibodies were found. In two high-risk groups in the city of Cochabamba (homeless children and sexual workers), the prevalence of HBV infection was similar (11.6%) and could be considered low by comparison to that of similar population groups in Latin American urban centers. The prevalence of HCV (one positive case, or 0.5%) was similar to that found in similar population groups, although the small number of samples precludes drawing more definite conclusions. As has been noted previously with similar communities in tropical areas of South America, HBV infection is highly endemic in indigenous populations of the Bolivian Amazon (with an overall prevalence of 74.0%), but circulation of HCV has not been detected. It is a well-known fact that HBV is horizontally transmitted and that transmission can take place very early in life, but the mechanisms involved are unknown. By 10 years of age, more than half the population has already had the natural infection that, in approximately 10 more years will have affected virtually the entire population. The very low rate of positivity to HBsAg (1.6%), the absence of viral DNA in samples showing isolated positivity to anti-HBc, and the high prevalence of anti-HBs among individuals who show markers for natural infection (92.4%) suggest vertical transmission plays no role in persistent endemicity. So far, no outbreak of HDV infection has been documented in these communities, but the high endemicity shown by HBV points to the possibility of future outbreaks. Results obtained with tests for the detection of antibodies against HEV suggest that this virus is circulating widely in Bolivia and that it could have caused recent outbreaks in Cochabamba state. Vaccination against HBV in endemic populations is recommended as a short-term measure. Also recommended are actively searching for outbreaks and sporadic cases of hepatitis E in the entire country and performing additional research that will help in assessing the public health consequences of the situation described in this article.S

Combined assessment of the TNM stage and BRAF mutational status at diagnosis in sporadic colorectal cancer patients

The prognostic impact of KRAS mutations and other KRAS-related and nonrelated genes such as BRAF, NRAS and TP53, on sporadic colorectal cancer (sCRC) remain controversial and/or have not been fully established. Here we investigated the frequency of such mutations in primary sCRC tumors and their impact on patient progression-free survival (PFS) and overall survival (OS). Primary tumor tissues from 87 sCRC patients were analysed using a custom-built next generation sequencing (NGS) panel to assess the hotspot mutated regions of KRAS/NRAS (exons 2, 3 and 4), BRAF (exon 15) and TP53 (all exons). Overall, mutations in these genes were detected in 46/87 sCRC tumors analyzed (53%) with the following frequencies per gene: TP53, 33%; KRAS, 28%; BRAF, 7%; and NRAS, 1%. A significant association was found between KRAS mutations and right side colon tumor location (p=0.05), well-differentiated tumors (p=0.04) and absence of lymphovascular invasion (p=0.05). In turn, BRAF-mutated tumors frequently corresponded to poorlyor moderately-differentiated sCRC (p=0.02) and showed a higher frequency of peritoneal carcinomatosis (p=0.006) and microsatellite instability (p=0.007). From the prognostic point of view, the BRAF mutational status together with the TNM stage were the only variables that showed an independent adverse impact on patient outcome in the multivariate analyses for both PFS and OS. Based on these results a scoring system was built and patients were classified into three prognostic subgroups with different PFS rates at 2 years: 91% vs. 77% vs. 0%, respectively (p < 0.0001). Additional prospective studies in larger series of sCRC patients where mutations in genes other than those investigated here are required to validate the utility of the proposed predictive model.This work has been partially supported by grants from the Instituto de Salud Carlos III (ISCIII; Ministerio de Sanidad y Consumo, Madrid, Spain) (PI12/02053-FIS), Gerencia Regional de Salud de Castilla y León, Valladolid, Spain (GRS1302/A/16), Consejería de Sanidad (Junta de Castilla y León, Valladolid, Spain) (BIO/SA46/14, BIO/SA02/13), RTICC from the ISCIII (RD12/0020/0035-FEDER, RD12/0036/0048-FEDER) and CIBERONC (CB16/12/00400 and CB16/12/00233), Fundación Memoria de Don Samuel Solórzano Barruso, (Salamanca, Spain) and Fundación Eugenio Rodríguez Pascual, (Madrid, Spain). JM Sayagués and ME Sarasquete are supported by grants (CES11/004 and CP13/00080) from the ISCIII, Ministerio de Ciencia e Innovación, Madrid, Spain.Peer Reviewe

Genomic characterization of liver metastases from colorectal cancer patients

Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFβ signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.This work has been partially supported by grants from the Instituto de Salud Carlos III (ISCIII; Ministerio de Sanidad y Consumo, Madrid, Spain) (PI12/02053-FIS), Gerencia Regional de Salud de Castilla y León, Valladolid, Spain (GRS1302/A/16), Consejería de Sanidad (Junta de Castilla y Leon, Valladolid, Spain) (BIO/SA02/13 and BIO/SA46/14), RTICC from the ISCIII (RD12/0020/0035-FEDER, RD12/0036/0048-FEDER), Fundación Memoria de Don Samuel Solórzano Barruso, (Salamanca, Spain) and Fundación Eugenio Rodríguez Pascual, (Madrid, Spain). JM Sayagués and ME Sarasquete are supported by grants (CES11/004 and CP13/00080; respectively) from the ISCIII, Ministerio de Ciencia e Innovación, Madrid, Spain.Peer Reviewe

Prognostic impact of a novel gene expression profile classifier for the discrimination between metastatic and non-metastatic primary colorectal cancer tumors

Despite significant advances have been achieved in the genetic characterization of sporadic colorectal cancer (sCRC), the precise genetic events leading to the development of distant metastasis remain poorly understood. Thus, accurate prediction of metastatic disease in newly-diagnosed sCRC patients remains a challenge. Here, we evaluated the specific genes and molecular pathways associated with the invasive potential of colorectal tumor cells, through the assessment of the gene expression profile (GEP) of coding and non-coding genes in metastatic (MTX) vs. non-metastatic (non-MTX) primary sCRC tumors followed for >5 years. Overall, MTX tumors showed up-regulation of genes associated with tumor progression and metastatic potential while non-MTX cases displayed GEP associated with higher cell proliferation, activation of DNA repair and anti-tumoral immune/inflammatory responses. Based on only 19 genes a specific GEP that classifies sCRC tumors into two MTX-like and non-MTX-like molecular subgroups was defined which shows an independent prognostic impact on patient overall survival, particularly when it is combined with the lymph node status at diagnosis. In summary, we show an association between the global GEP of primary sCRC cells and their metastatic potential and defined a GEP-based classifier that provides the basis for further prognostic stratification of sCRC patients who are at risk of distant metastases.This work has been partially supported by grants from the Instituto de Salud Carlos III (ISCIII; Ministerio de Economía y Competitividad, Madrid, Spain) (PI12/02053-FIS and PI17/01779-FIS), Gerencia Regional de Salud de Castilla y León, Valladolid, Spain (GRS1302/A/16), Consejería de Sanidad (Junta de Castilla y Leon, Valladolid, Spain) (BIO/SA02/13), RTICC and CIBERONC from the ISCIII (RD12/0020/0035-FEDER, RD12/0036/0048-FEDER, CB16/12/00400), Fundación Memoria de Don Samuel Solórzano Barruso, (Salamanca, Spain) and Fundación Eugenio Rodríguez Pascual, (Madrid, Spain). ML Gutiérrez and JM Sayagués are supported by grants: PTA2014-09963-I and CES11/004 from the ISCIII.Peer Reviewe

Prognostic utility of serum free light chain ratios and heavy-light chain ratios in multiple myeloma in three PETHEMA/GEM phase III clinical trials.

We investigated the prognostic impact and clinical utility of serum free light chains (sFLC) and serum heavy-light chains (sHLC) in patients with multiple myeloma treated according to the GEM2005MENOS65, GEM2005MAS65, and GEM2010MAS65 PETHEMA/GEM phase III clinical trials. Serum samples collected at diagnosis were retrospectively analyzed for sFLC (n = 623) and sHLC (n = 183). After induction or autologous transplantation, 309 and 89 samples respectively were available for sFLC and sHLC assays. At diagnosis, a highly abnormal (HA) sFLC ratio (sFLCr) (32) was not associated with higher risk of progression. After therapy, persistence of involved-sFLC levels >100 mg/L implied worse survival (overall survival [OS], P = 0.03; progression-free survival [PFS], P = 0.007). Among patients that achieved a complete response, sFLCr normalization did not necessarily indicate a higher quality response. We conducted sHLC investigations for IgG and IgA MM. Absolute sHLC values were correlated with monoclonal protein levels measured with serum protein electrophoresis. At diagnosis, HA-sHLCrs (73) showed a higher risk of progression (P = 0.006). Additionally, involved-sHLC levels >5 g/L after treatment were associated with shorter survival (OS, P = 0.001; PFS, P = 0.018). The HA-sHLCr could have prognostic value at diagnosis; absolute values of involved-sFLC >100 mg/L and involved-sHLC >5 g/L could have prognostic value after treatment