Identification of a Twelve-microRNA Signature with Prognostic Value in Stage II Microsatellite Stable Colon Cancer

Simple Summary Colorectal cancer (CRC) is one of the most prevalent cancers, and approximately a quarter of patients diagnosed at stage II exhibit a significant risk of recurrence. In this study, we successfully identified a microRNA (miRNA) signature allowing the recognition of patients at high recurrence risk. The validity of these findings has been confirmed through an entirely separate group of patients diagnosed with stage II microsatellite stability (MSS) colon adenocarcinoma (COAD). Most of the miRNAs present in the signature have demonstrated prognostic relevance in various other cancer types. Upon examining their gene targets, we discovered that some of these miRNAs are intricately involved in pivotal pathways of cancer progression. We aimed to identify and validate a set of miRNAs that could serve as a prognostic signature useful to determine the recurrence risk for patients with COAD. Small RNAs from tumors of 100 stage II, untreated, MSS colon cancer patients were sequenced for the discovery step. For this purpose, we built an miRNA score using an elastic net Cox regression model based on the disease-free survival status. Patients were grouped into high or low recurrence risk categories based on the median value of the score. We then validated these results in an independent sample of stage II microsatellite stable tumor tissues, with a hazard ratio of 3.24, (CI95% = 1.05-10.0) and a 10-year area under the receiver operating characteristic curve of 0.67. Functional analysis of the miRNAs present in the signature identified key pathways in cancer progression. In conclusion, the proposed signature of 12 miRNAs can contribute to improving the prediction of disease relapse in patients with stage II MSS colorectal cancer, and might be useful in deciding which patients may benefit from adjuvant chemotherapy

Sepse: uma discussão sobre as mudanças de seus critérios diagnósticos / Sepse: a discussion on the changes of its diagnostic criteria

No início de 2016 ocorreu o Terceiro Consenso Internacional para a Definição de Sepse e Choque Séptico (Sepsis-3), no qual algumas mudanças foram adotadas em relação aos antigos critérios diagnósticos, e com elas surgiram dúvidas e discussões a respeito de suas adequações, vantagens e desvantagens. Para melhor esclarecimento destas questões realizamos esta revisão da literatura, cujos resultados indicaram que as atualizações das definições de sepse trazem vantagens em relação ao entendimento de sua definição e fisiopatologia, além de trazer maior importância a qualquer quadro de sepse. Entretanto, o novo escore ainda apresenta problemas como: dificuldade do uso, retardo do diagnóstico, ausência de validação prospectiva do Quick Sequential Organ Failure Assessment (qSOFA), diminuição da importância do lactato e redução da sensibilidade. Desse modo, os critérios de Systemic Inflammatory Response Syndrome (SIRS) ainda não podem ser totalmente abandonados, principalmente nos países em desenvolvimento. Além disso, ainda é necessária a realização de mais estudos prospectivos sobre o assunto e que levem em consideração dados de países em desenvolvimento, como mortalidade, recursos e epidemiologia.

FGF21 gene therapy as treatment for obesity and insulin resistance

Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.This work was supported by grants from Ministerio de Economía y Competi- tividad (MINECO) and FEDER, Plan Nacional I+D+I (SAF2014-54866R), andGeneralitat de Catalunya (2014SGR1669and ICREA Academia Award to F.B.), Spain, from the European Commission (MYOCURE, PHC-14-2015 667751) and the European Foundation for the Study of Diabetes (EFSD/MSD European Research Programme on Novel Therapies for Type 2 Diabetes,2013). V.J. was recipient of a post-doctoral research fellowship from EFSD/ Lilly. E.C., V.S., and C.M. received a predoctoral fellowship from Ministerio de Educación, Cultura y Deporte, and J.R. from Ministerio de Economía y Competitividad, Spain. The authors thank Marta Moya and Maria Molas for technical assistance.S

Molecularly imprinted polypyrrole based electrochemical sensor for selective determination of 4-ethylphenol

This work describes the development of an electrochemical sensor based on a molecularly imprinted polymer (MIP) for sensitive and selective determination of 4-ethylphenol in wine. The sensor has been built by means of the electrosynthesis of the MIP on a glassy carbon electrode surface using cyclic voltammetry. The electropolymerization has been performed in the presence of 4-ethylphenol and pyrrole as template molecule and functional monomer, respectively. The influence of the molar ratios of template molecules to functional pyrrole monomers and the time needed to remove the template have been optimized taking into account the differential pulse voltammetric response of 4-ethylphenol. Under the optimal experimental conditions the developed MIP/GCE sensor shows good capability of detection (0.2 μM, α = β = 0.05) and reproducibility (3.0%) in the concentration range from 0.2 to 34.8 μM. The influence of possible interfering species in the analytical response has been studied and the sensor has successfully been applied to the determination of 4-ethylphenol in different wine samples.Junta de Castilla y León (BU018G19

Estado, violencias y ciudadanía en México. Realidad y teoría, entre lo micro y lo macro

Este libro, en general, es un intento por analizar tres categorías: el Estado, la violencia y la ciudadanía, esperamos contribuir desde los particulares enfoques a la reflexión de un tema muy vigente y lastimoso, al cual ha arribado no sólo México en abstracto, sino también, y principalmente, su realidad institucional, la cual se expresa como cosa cotidiana del mundo de principios del siglo XXI en el que vivimos.Proyecto realizado con financiamiento de la Secretaría de Educación Pública-Subsecretaría de Educación Superior-Dirección General de Educación Superior Universitaria. Número del convenio con la SEP: 2018-15-001-017

Uso consensuado de un recurso escaso: desarrollo participativo de guías de buenas prácticas ganaderas para humedales patagónicos

El uso y manejo sostenible de humedales patagónicos (mallines), fuente estratégica de agua y forraje para la región, requiere cada vez mayor atención en un escenario de cambio climático e historia de desertificación que amenazan la provisión de servicios ecosistémicos. En este trabajo se presenta el avance en Patagonia del Proyecto de INTA “Humedales de la República Argentina”. En una primera instancia, se finalizó con el mapa de distribución probabilística de humedales, necesario para dar ubicación espacialmente explícita. En una segunda instancia, y conscientes de que sin consenso la aplicación de medidas puede no llegar a implementarse, se inició una etapa de coconstrucción participativa de una Guía de Buenas Prácticas (GBP) para mallines. Para ello, se generó una consulta electrónica masiva, abierta y exploratoria para indagar sobre los usuarios de mallines sus conocimientos acerca de sus bondades ecológico-productivas, su opinión acerca de 5 prácticas de manejo comúnmente difundidas y propuestas alternativas de uso y manejo no contempladas. Basados en esa información, en diciembre de 2022, se desarrolló de manera simultánea (nodos Bariloche, Esquel y Río Gallegos) el primer taller participativo de la región, invitando a representantes de diversos ámbitos (productivo, ambiental, científico, gubernamental, etc.) a participar del encuentro presencial. Los resultados preliminares muestran que las prácticas propuestas son, en general, las que prevalecen en el conocimiento mayoritario, que las prácticas alternativas propuestas muchas veces son variantes de estas primeras y que, dentro de este primer grupo, existen preferencias a la hora de ejecutarlas. Las dificultades en aplicación se caracterizaron principalmente como económicas, seguidas de falta de conocimiento de su aplicación o de los efectos generados. A partir de estos encuentros y la nueva información disponible, se está elaborando la versión inicial de las GBP para mallines de la Patagonia argentina. Se espera que sea un producto de utilidad para el uso sustentable de los recursos naturales de la región y que, a partir del seguimiento de su implementación y el diálogo constante con los usuarios, reciba las actualizaciones necesarias.EEA BarilocheFil: Enriquez, Andrea Soledad. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche; ArgentinaFil: Enriquez, Andrea Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; ArgentinaFil: Aramayo, Maria Valeria Del Lu. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche; ArgentinaFil: Buono, Gustavo Gabriel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Chubut; Argentina.Fil: Curcio, Matías Hernán. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agroforestal Esquel; ArgentinaFil: Fernandez, Manuela Teresa. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; ArgentinaFil: Fernandez, Manuela Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; ArgentinaFil: García Martínez, Guillermo Carlos. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agroforestal Esquel; ArgentinaFil: Navarro, María Fabiana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Suelos; Argentina.Fil: Paredes, Paula Natalia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Santa Cruz; Argentina.Fil: Umaña, Fernando. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche; ArgentinaFil: Utrilla, Victor Ricardo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Santa Cruz; Argentina.Fil: Vargas, Paola Patricia. Instituto Nacional de Tecnología Agropecuaria (INTA). Dirección Nacional Asistente Transferencia y Extensión; ArgentinaFil: Cremona, Maria Victoria. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche; Argentin

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Risk factors for non-diabetic renal disease in diabetic patients

Background. Diabetic patients with kidney disease have a high prevalence of non-diabetic renal disease (NDRD). Renal and patient survival regarding the diagnosis of diabetic nephropathy (DN) or NDRD have not been widely studied. The aim of our study is to evaluate the prevalence of NDRD in patients with diabetes and to determine the capacity of clinical and analytical data in the prediction of NDRD. In addition, we will study renal and patient prognosis according to the renal biopsy findings in patients with diabetes. Methods. Retrospective multicentre observational study of renal biopsies performed in patients with diabetes from 2002 to 2014. Results. In total, 832 patients were included: 621 men (74.6%), mean age of 61.7 6 12.8 years, creatinine was 2.8 6 2.2 mg/dL and proteinuria 2.7 (interquartile range: 1.2–5.4) g/24 h. About 39.5% (n ¼ 329) of patients had DN, 49.6% (n ¼ 413) NDRD and 10.8% (n ¼ 90) mixed forms. The most frequent NDRD was nephroangiosclerosis (NAS) (n ¼ 87, 9.3%). In the multivariate logistic regression analysis, older age [odds ratio (OR) ¼ 1.03, 95% CI: 1.02–1.05, P < 0.001], microhaematuria (OR ¼ 1.51, 95% CI: 1.03–2.21, P ¼ 0.033) and absence of diabetic retinopathy (DR) (OR ¼ 0.28, 95% CI: 0.19–0.42, P < 0.001) were independently associated with NDRD. Kaplan–Meier analysis showed that patients with DN or mixed forms presented worse renal prognosis than NDRD (P < 0.001) and higher mortality (P ¼ 0.029). In multivariate Cox analyses, older age (P < 0.001), higher serum creatinine (P < 0.001), higher proteinuria (P < 0.001), DR (P ¼ 0.007) and DN (P < 0.001) were independent risk factors for renal replacement therapy. In addition, older age (P < 0.001), peripheral vascular disease (P ¼ 0.002), higher creatinine (P ¼ 0.01) and DN (P ¼ 0.015) were independent risk factors for mortality. Conclusions. The most frequent cause of NDRD is NAS. Elderly patients with microhaematuria and the absence of DR are the ones at risk for NDRD. Patients with DN presented worse renal prognosis and higher mortality than those with NDRD. These results suggest that in some patients with diabetes, kidney biopsy may be useful for an accurate renal diagnosis and subsequently treatment and prognosis

Menstrual and Reproductive Factors and Risk of Gastric and Colorectal Cancer in Spain

BACKGROUND: Sex hormones play a role in gastric cancer and colorectal cancer etiology, however, epidemiological evidence is inconsistent. This study examines the influence of menstrual and reproductive factors over the risk of both tumors. METHODS: In this case-control study 128 women with gastric cancer and 1293 controls, as well as 562 female and colorectal cancer cases and 1605 controls were recruited in 9 and 11 Spanish provinces, respectively. Population controls were frequency matched to cases by age and province. Demographic and reproductive data were directly surveyed by trained staff. The association with gastric, colon and rectal cancer was assessed using logistic and multinomial mixed regression models. RESULTS: Our results show an inverse association of age at first birth with gastric cancer risk (five-year trend: OR = 0.69; p-value = 0.006). Ever users of hormonal contraception presented a decreased risk of gastric (OR = 0.42; 95%CI = 0.26-0.69), colon (OR = 0.64; 95%CI = 0.48-0.86) and rectal cancer (OR = 0.61; 95%CI = 0.43-0.88). Postmenopausal women who used hormone replacement therapy showed a decreased risk of colon and rectal tumors. A significant interaction of educational level with parity and months of first child lactation was also observed. CONCLUSION: These findings suggest a protective role of exogenous hormones in gastric and colorectal cancer risk. The role of endogenous hormones remains unclear