Breaking paradigms: Long non-coding RNAs forming gene fusions with potential implications in cancer.

Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nucleotides with dynamic regulatory functions. They interact with a wide range of molecules such as DNA, RNA, and proteins to modulate diverse cellular functions through several mechanisms and, if deregulated, they can lead to cancer development and progression. Recently, it has been described that lncRNAs are susceptible to form gene fusions with mRNAs or other lncRNAs, breaking the paradigm of gene fusions consisting mainly of protein-coding genes. However, their biological significance in the tumor phenotype is still uncertain. Therefore, their recent identification opens a new line of research to study their biological role in tumorigenesis, and their potential as biomarkers with clinical relevance or as therapeutic targets. The present study aimed to review the lncRNA fusions identified so far and to know which of them have been associated with a potential function. We address the current challenges to deepen their study as well as the reasons why they represent a future therapeutic window in cancer.

CORESIDENCE: National and subnational data on household size and composition around the world, 1964-2021.

The CORESIDENCE Database (CoDB) represents a significant advancement in the field of family studies, addressing existing data gaps and facilitating comprehensive analysis of households' composition and living arrangements at the national and subnational levels. This article introduces the CoDB, developed for the ERC project Intergenerational Coresidence in Global Perspective: Dimensions of Change. The database draws on global-scale individual microdata from four main repositories and national household surveys, encompassing over 150 million individual records representing more than 98% of the world's population. The CoDB provides datasets at the national, subnational, and subnational-harmonized levels, covering 156 countries, 3950 regions, and 1511 harmonized regions for the period 1964-2021. It includes 146 indicators on household composition and family arrangements, allowing researchers to explore intergenerational co-residence patterns, gender dynamics within households, and longitudinal trends in living arrangements. The CoDB fills an important gap in comparative household studies, enabling researchers to undertake ground breaking research at both macro and micro levels, ultimately fostering a deeper understanding of the complex dynamics of family structures and living arrangements.

Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways.

BACKGROUND: The EGFR pathway is involved in intrinsic and acquired resistance to a wide variety of targeted therapies in cancer. Vaccination represents an alternative to the administration of anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab. Here, we tested if anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) could potentiate the activity of drugs targeting the ERK/MAPK and PI3K/Akt pathways. METHODS: Non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and melanoma cell lines harboring KRAS, NRAS, BRAF and PIK3CA mutations were used. Anti-EGF VacAbs were obtained by immunizing rabbits with a fusion protein containing a synthetic, highly mutated variant of human EGF. Cell viability was determined by MTT, total and phosphorylated proteins by Western blotting, cell cycle distribution and cell death by flow cytometry and emergence of resistance by microscopic examination in low density cultures. RESULTS: Anti-EGF VacAbs potentiated the antiproliferative effects of MEK, KRAS G12C, BRAF, PI3K and Akt inhibitors in KRAS, NRAS, BRAF and PIK3CA mutant cells and delayed the appearance of resistant clones in vitro. The effects of anti-EGF VacAbs were comparable or superior to those of panitumumab and cetuximab. The combination of anti-EGF VacAbs with the targeted inhibitors effectively suppressed EGFR downstream pathways and sera from patients immunized with an anti-EGF vaccine also blocked activation of EGFR effectors. CONCLUSIONS: Anti-EGF VacAbs enhance the antiproliferative effects of drugs targeting the ERK/MAPK and PIK3CA/Akt pathways. Our data provide a rationale for clinical trials testing anti-EGF vaccination combined with inhibitors selected according to the patient's genetic profile.

Identification of ABCC3 and its isoforms as potential biomarker in hepatocellular carcinoma.

Liver diseases preceding the occurrence of hepatocellular carcinoma (HCC) play a crucial role in the progression and establishment of HCC, a malignancy ranked as the third deadliest cancer worldwide. Late diagnosis, alongside ineffective treatment, leads patients to a poor survival rate. This scenario argues for seeking novel alternatives for detecting liver alterations preceding the early occurrence of HCC. Experimental studies have reported that ABCC3 protein increases within HCC tumors but not in adjacent tissue. Therefore, we analyzed ABCC3 expression in public databases and investigated the presence of ABCC3 and its isoforms in plasma, urine and its release in extracellular vesicles (EVs) cargo from patients bearing cirrhosis and HCC. The UALCAN and GEPIA databases were used to analyze the expression of ABCC3 in HCC. The results were validated in a case-control study including 41 individuals bearing cirrhosis and HCC, and the levels of ABCC3 in plasma and urine samples, as well as EVs, were analyzed by ELISA and western blot. Our data showed that ABCC3 expression was higher in HCC tissues than in normal tissues and correlated with HCC grade and stage. ABCC3 protein levels were highly increased in both plasma and urine and correlated with liver disease progression and severity. The isoforms MRP3A and MRP3B of ABCC3 were significantly increased in both EVs and plasma/urine of patients bearing HCC. ABCC3 expression gradually increases in HCC tissues, and its protein levels are increased in both plasma and urine of patients with cirrhosis and HCC. MRP3A and MRP3B isoforms have the potential to be prognostic biomarkers of HCC.

Overcoming MET-mediated resistance in oncogene-driven NSCLC.

This study evaluates the efficacy of combining targeted therapies with MET or SHP2 inhibitors to overcome MET-mediated resistance in different NSCLC subtypes. A prevalence study was conducted for MET amplification and overexpression in samples from patients with NSCLC who relapsed on ALK, ROS1, or RET tyrosine kinase inhibitors. MET-mediated resistance was detected in 37.5% of tissue biopsies, which allow the detection of MET overexpression, compared to 7.4% of liquid biopsies. The development of drug resistance by MET overexpression was confirmed in EGFRex19del-, KRASG12C-, HER2ex20ins-, and TPM3-NTRK1-mutant cell lines. The combination of targeted therapy with MET or SHP2 inhibitors was found to overcome MET-mediated resistance in both in vitro and in vivo assays. This study highlights the importance of considering MET overexpression as a resistance driver to NSCLC targeted therapies to better identify patients who could potentially benefit from combination approaches with MET or SHP2 inhibitors.

Spent coffee grounds as feedstock for the production of biosurfactants and the improved recovery of melanoidins.

Spent coffee grounds (SCG) are wastes generated in high amounts worldwide. Their composition makes them a promising feedstock for biotechnological processes. Here we show that the production of the biosurfactant surfactin by submerged culture of a Bacillus subtilis strain growing on SCG is possible, reaching concentrations up to 8.8 mg/L when using SCG at 8.3 g/L in the medium. In addition, we report a synergy between the production of surfactin and the recovery of melanoidins, an added-value compound already present in SCG. More specifically, the concentration of melanoidins in the culture medium increased between 2.1 and 2.5 times thanks to the presence of the B. subtilis in the culture. Furthermore, we have observed a strong interaction between surfactin and melanoidin aggregates through dynamic light scattering measurements, and that both of them can be co-purified with an acid precipitation. We have also characterized the interfacial and antioxidant properties of the cell-free supernatant and surfactin extract, as well as the distribution of the congeners of the biosurfactant. Altogether, this work describes a promising approach to obtain biosurfactants and antioxidant molecules in a single operation, which can be used to design several new formulations of interest for bioremediation, amendment of soils, food and cosmetics.

[Risk factors for metabolic dysfunction-associated fatty liver disease in the Hispanic-Mexican population.] / Factores de riesgo de la enfermedad hepática grasa asociada a disfunción metabólica en población hispano-mexicana.

OBJECTIVE: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a poor attended disease, which has gained attention due the elevated number of cases in countries as Mexico, where the incidence is the number 4th globally. MAFLD develops in obese or overweighted individuals and is characterized by triglycerides accumulation in the liver, this condition can develop to hepatocellular carcinoma. It has been observed that MAFLD depends on the genetics and lifestyle. Due to the high prevalence of this disease among Hispanic population, we focused on this study in the characteristics and prevalence of MAFLD in Mexican patients. METHODS: In this study were included 572 overweighted and obese patients, who underwent a screening analysis using the fatty liver index (IHG), clinical parameters were analysed, demographic and comorbidities. Frequency of variables were obtained, and the data were analysed by Chi-square test or Fisher test, odd ratio (OR) and binary logistic regression. RESULTS: A MALFD prevalence of 37% were obtained, where the history of familiar obesity, paracetamol usage, carbohydrate and fat intake are shown to be risk factors. It was found that high blood pressure, central obesity and hypertriglyceridemia were also associated to the MAFLD development. On the other hand, physical exercise was a protector factor. CONCLUSIONS: Our results show the necessity to study the MAFLD causalities in Mexican patients, focused on the paracetamol intake.

OBJETIVO: La enfermedad hepática grasa asociada a disfunción metabólica (MAFLD) es una enfermedad poco considerada, que ha recibido atención debido al número de casos en países como México, donde ocupa el 4º lugar mundial de incidencia. La MAFLD se desarrolla en personas con sobrepeso u obesidad y se caracteriza por la acumulación de triglicéridos en el hígado, donde puede evolucionar hacia carcinoma hepatocelular. Se ha observado que la MAFLD depende de la genética y del estilo de vida. Tomando en cuenta la alta prevalencia de MAFLD en la población hispana, nos enfocamos en este trabajo en estudiar la prevalencia y características relacionadas con esta enfermedad en pacientes mexicanos. METODOS: En este estudio se incluyeron 572 pacientes con sobrepeso u obesidad, a los cuales se les realizó un análisis de cribado mediante el índice de hígado graso (IHG), se analizaron parámetros clínicos, demográficos y comorbilidades. Se obtuvieron frecuencias de las variables y se analizaron los datos mediante chi cuadrado o exacta de Fisher, razón de momios (OR) y regresión logística binaria. RESULTADOS: Se obtuvo una prevalencia del 37% de MAFLD, donde la historia familiar de obesidad, el uso de paracetamol, así como el consumo de carbohidratos y grasas fueron factores de riesgo para su desarrollo. Se encontró que la hipertensión arterial, la obesidad visceral y la hipertrigliceridemia también estaban asociados al desarrollo de la MAFLD. Por otro lado, el ejercicio fue un factor protector. CONCLUSIONES: Nuestros resultados ponen de manifiesto la necesidad de realizar estudios relacionados con las causalidades de la MAFLD en los pacientes mexicanos, principalmente en el uso del paracetamol.

Efficacy of nutrition therapy with food rich in methionine for treating nonalcoholic fatty liver / Eficacia de la terapia nutricional con alimentos ricos en metionina para el tratamiento de hígado graso no alcohólico

Non-Alcoholic Fatty Liver disease (NAFLD) can lead to Non Alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. The treatment for NAFLD involves modification of caloric intake and physical activity. NAFLD has a pro-oxidant nature; therefore, it is logical to suppose that the antioxidant methionine can be used as a treatment for this disease. Aim. This study aimed to evaluate the effect of high-methionine dietary therapy on patients with NAFLD. Materials and methods. A randomized clinical study was conducted over three months. In this study, 121 NAFLD patients participated, and the age of the participants was ≥ 20 years (experimental group included 56 and control group 65), all of whom were randomized and matched by sex, recluted from the ISSSTE hospital in Xalapa, Mexico. The patients were instructed to consume food to cover the recommended methionine daily doses, and the daily amount consumed was calculated. Methionine effect was measured as NAFLD regression and quality of life improvement. Results. Nutritional therapy induced NAFLD regression and diminished central fat accumulation, blood pressure, and the fatty liver index. Some parameters, such as liver enzymes, did not changed. The quality of life of patients improved after treatment. Conclusions. In this study, we show a hepatoprotective effect induced only in three months of chances in the diet, thus, a longer diet may generate more relevant benefits in the resistant parameters of our study(AU)

La enfermedad del hígado graso no alcohólico (NAFLD) puede conducir a la esteatohepatitis no alcohólica (NASH), la cirrosis y el cáncer de hígado. El tratamiento para NAFLD es la modificación de la ingesta calórica y la actividad física. Debido a que NAFLD tiene una naturaleza pro-oxidante; es lógico suponer que el antioxidante metionina puede utilizarse en el tratamiento de esta enfermedad. Objetivo. el presente trabajo evaluó el papel de la terapia nutricional con alimentos ricos en metioninaen pacientes con NAFLD. Materiales y Métodos. Se realizó un ensayo clínico aleatorizado durante tres meses. Participaron en el estudio 121 pacientes con NAFLD con edad ≥ 20 años (56 en el grupo experimental y 65 en el control), todos aleatorizados y pareados por sexo, reclutados de la Clínica Hospital ISSTE en la ciudad de Xalapa, México, en el año 2015. Se instruyó a los pacientes en consumir los alimentos hasta completar la dosis diaria recomendada de metioninay se calculó la cantidad diaria consumida. Su efecto se midió como la regresión de NAFLD y la mejora de la calidad de vida. Resultados. La terapia nutricional retrocedió NAFLD; disminuyó la acumulación de grasa central, la presión arterial y el índice de hígado graso. Algunos parámetros, como las enzimas de la función hepática, no se modificaron con el tratamiento. Otro parámetro fue la mejora de la calidad de vida de los pacientes tratados. Conclusiones. En este trabajo mostramos un impacto hepatoprotector producido con tan solo tres meses de cambios en la dieta, por lo que una dieta más prolongada podría generar beneficios aún más significativos en los parámetros resistentes en nuestro protocolo(AU)

Factores de riesgo de la enfermedad hepática grasa asociada a disfunción metabólica en población hispano-mexicana / Risk factors for metabolic dysfunction-associated fatty liver disease in the Hispanic-Mexican population

FUNDAMENTOS: La enfermedad hepática grasa asociada a disfunción metabólica (MAFLD) es una enfermedad poco considerada,que ha recibido atención debido al número de casos en países como México, donde ocupa el 4º lugar mundial de incidencia. La MAFLDse desarrolla en personas con sobrepeso u obesidad y se caracteriza por la acumulación de triglicéridos en el hígado, donde puedeevolucionar hacia carcinoma hepatocelular. Se ha observado que la MAFLD depende de la genética y del estilo de vida. Tomando encuenta la alta prevalencia de MAFLD en la población hispana, nos enfocamos en este trabajo en estudiar la prevalencia y características relacionadas con esta enfermedad en pacientes mexicanos. MÉTODOS: En este estudio se incluyeron 572 pacientes con sobrepeso u obesidad, a los cuales se les realizó un análisis de cribadomediante el índice de hígado graso (IHG), se analizaron parámetros clínicos, demográficos y comorbilidades. Se obtuvieron frecuenciasde las variables y se analizaron los datos mediante chi cuadrado o exacta de Fisher, razón de momios (OR) y regresión logística binaria. RESULTADOS: Se obtuvo una prevalencia del 37% de MAFLD, donde la historia familiar de obesidad, el uso de paracetamol, así comoel consumo de carbohidratos y grasas fueron factores de riesgo para su desarrollo. Se encontró que la hipertensión arterial, la obesidadvisceral y la hipertrigliceridemia también estaban asociados al desarrollo de la MAFLD. Por otro lado, el ejercicio fue un factor protector. CONCLUSIONES: Nuestros resultados ponen de manifiesto la necesidad de realizar estudios relacionados con las causalidades dela MAFLD en los pacientes mexicanos, principalmente en el uso del paracetamol.(AU)

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a poor attended disease, which has gained at-tention due the elevated number of cases in countries as Mexico, where the incidence is the number 4 th globally. MAFLD developsin obese or overweighted individuals and is characterized by triglycerides accumulation in the liver, this condition can develop tohepatocellular carcinoma. It has been observed that MAFLD depends on the genetics and lifestyle. Due to the high prevalence of thisdisease among Hispanic population, we focused on this study in the characteristics and prevalence of MAFLD in Mexican patients. METHODS: In this study were included 572 overweighted and obese patients, who underwent a screening analysis using the fatty liverindex (IHG), clinical parameters were analysed, demographic and comorbidities. Frequency of variables were obtained, and the data wereanalysed by Chi-square test or Fisher test, odd ratio (OR) and binary logistic regression. RESULTS: A MALFD prevalence of 37% were obtained, where the history of familiar obesity, paracetamol usage, carbohydrate andfat intake are shown to be risk factors. It was found that high blood pressure, central obesity and hypertriglyceridemia were alsoassociated to the MAFLD development. On the other hand, physical exercise was a protector factor. CONCLUSIONS: Our results show the necessity to study the MAFLD causalities in Mexican patients, focused on the paracetamol intake.(AU)

Análisis de la seroprevalencia frente a sarampión, rubeola y parotiditis en trabajadores sanitarios / Analysis of seroprevalence against measles, rubella and mumps in health workers of two health departments of the Valencian Community (Spain)

FUNDAMENTOS: El personal sanitario es un colectivo profesional expuesto a riesgos ocupacionales. El objetivo de este trabajo fue estimar la ausencia de seroprotección frente a sarampión, rubeola y parotiditis de los trabajadores sanitarios vinculados a dos Departamentos de Salud de la Comunidad Valenciana, considerando edad, sexo, categoría profesional, riesgo laboral y área de desempeño. MÉTODOS: Se realizó un estudio observacional transversal. Los datos fueron recogidos de informes de vigilancia de la salud, que incluían resultados serológicos de 2.674 trabajadores. Las variables sociodemográficas fueron: sexo; grupos de edad (18-34; 35-49; >50 años); clasificación del servicio (riesgo/no riesgo); categoría profesional; área de desempeño profesional (atención primaria/ atención hospitalaria). La variable dependiente fue la ausencia de inmunización frente a sarampión, rubeola y parotiditis identificada por ausencia de niveles serológicos. Para las enfermedades estudiadas se estimó la prevalencia de ausencia de seroprotección y se evaluó la asociación entre la no inmunización con el resto de variables. RESULTADOS: La prevalencia de no inmunización fue del 7,8%, 3,7% y 16,1% para sarampión, rubeola y parotiditis, respectivamente. El análisis mediante regresión logística mostró diferencias estadísticamente significativas en la prevalencia de no inmunización a sarampión en función de grupos de edad (ORa 11,8 y ORa 5,8) y área de desempeño (ORa 0,5), frente a parotiditis en función de grupos de edad (ORa 4,9 y ORa 3,6) y categoría profesional 1 (médicos, farmacéuticos, odontólogos y psicólogos) (ORa 0,6) y frente a rubeola en función del sexo (ORa 4,6). CONCLUSIONES: Es necesario potenciar la vacunación entre los sanitarios, especialmente en aquellos que ejercen sus funciones en áreas de riesgo y entre el personal de menor edad. La vacunación debe promoverse dentro de políticas de seguridad laboral.(AU)

BACKGROUND: Health Personnel are a professional group exposed to occupational risks. The aim of this paper was to estimate the absence of seroprotection against measles, rubella and mumps in health workers linked to two Health Departments of the Valencian Community (Spain) and to study the relationship with age, sex, professional category, occupational risk and performance área. METHODS: A cross-sectional observational study was made. Data were collected from health surveillance reports, which included serological results from 2,674 health workers. The socio-demographic variables were: sex, age groups (18-34; 35-49; >50 years), service classification (risk/no risk), professional category, professional performance area (primary care/hospital care) and the dependent variable was absence of immunization against measles, rubella and mumps identified by the absence of serological levels. For the diseases studied, the prevalence of absence of seroprotection was estimated and the association between non-immunization and the rest of variables was evaluated. RESULTS: Prevalence of non-immunization was 7.8%, 3.7% and 16.1% for measles, rubella and mumps, respectively. Logistic regression analysis showed a significant differences in the prevalence of non-immunization to measles according to age groups (adjusted OR 11.8 and adjusted OR 5.8) and professional performance area (adjusted OR 0.5), compared to mumps according to age groups (adjusted OR 4.9 and adjusted OR 3.6) and professional category 1 (doctors, pharmacists, dentists and psychologists) (adjusted OR 0.6) and against rubella according to sex (adjusted OR 4.6). CONCLUSIONS: It is necessary to maintain vaccination among health workers, especially those who perform their functions in risk areas and among younger personnel. Vaccination should be promoted within occupational safety policies.(AU)

Gender differences in time use across age groups: A study of ten industrialized countries, 2005-2015.

This study uses largescale cross-national time-diary data from the Multinational Time Use Study (MTUS) (N = 201,972) covering the period from 2005 to 2015 to examine gender differences in time use by age groups. The study compares ten industrialized countries across Asia, Europe, and North America. In all ten countries, gender differences in time use are smaller in personal care, sleeping and meals, followed by leisure time (including screen-based leisure and active leisure), and largest in housework, care work and paid work activities. Gender disparities in time use are higher in South Korea, Hungary, and Italy, followed closely by Spain, with moderate gender gaps in Western European countries like France and Netherlands, and lowest differences in Finland and Anglo-Saxon countries, including Canada, US, and the UK. Gender differences in housework and caring time increase from adolescence (10-17 years) to early adulthood (18-29 years), showing strong gender gaps in early/middle adulthood (30-44 years), but narrow again during late adulthood (65 years or older). However, the age gradient in care work and housework is most pronounced in Italy and South Korea, being less prominent in Canada and Finland. Gender gaps in paid work are larger in early/middle adulthood (30-44) and middle/late adulthood (45-64), with strongest age gradients observed in the Netherlands and weaker gradients for the US. Gender differences in active leisure increase by age, especially in Southern European countries, while screen-based leisure shows more stable gender gaps by age groups across different countries. Overall, this study shows that age and gender intersect strongly in affecting time-use patterns, but also that the national context plays an important role in shaping gender-age interactions in time use allocation.

The EPICAL trial, a phase Ib study combining first line afatinib with anti-EGF vaccination in EGFR-mutant metastatic NSCLC.

INTRODUCTION: Combination of anti-EGFR monoclonal antibodies or immune checkpoint inhibitors with TKIs has shown minimal benefit in EGFR mutant (EGFR-mut) NSCLC patients. Consequently, new combination approaches are needed. PATIENTS AND METHODS: The EPICAL was a single arm, phase 1b study to evaluate safety, tolerability and anti-tumor activity of first line afatinib combined with anti-EGF vaccination in advanced EGFR-mut patients. EGFR status and mutations in liquid biopsies were determined by reverse transcriptase-polymerase chain reaction; serum biomarkers by ELISA and Western blotting analysis. RESULTS: The assay enrolled 23 patients, 21 completed the anti-EGF immunization phase. Treatment was well tolerated and no serious adverse events (SAEs) related to the anti-EGF vaccine were reported. Objective response and disease control rates were 78.3% (95%CI = 53.6-92.5) and 95.7% (95%CI = 78.1-99.9), respectively. After a median follow-up of 24.2 months, median progression-free survival (PFS) was 14.8 months (95% CI = 9.5-20.1) and median overall survival (OS) 26.9 months (95% CI = 23.0-30.8). Among the 21 patients completing the immunization phase, PFS was 17.5 months (95% CI = 12.0-23.0) and OS 26.9 months (95% CI = 24.6-NR). At the end of the immunization phase, all 21 patients showed high serum titers of anti-EGF antibodies, while EGF levels had decreased significantly. Finally, treatment with fully immunized patient's sera inhibited the EGFR pathway in tumor cells growing in vitro. CONCLUSIONS: Combination treatment with an anti-EGF vaccine is well tolerated; induces a sustained immunogenic effect and might enhance the clinical efficacy of EGFR TKIs.

Gßγ mediates activation of Rho guanine nucleotide exchange factor ARHGEF17 that promotes metastatic lung cancer progression.

Metastatic lung cancer is a major cause of death worldwide. Dissemination of cancer cells can be facilitated by various agonists within the tumor microenvironment, including by lysophosphatidic acid (LPA). We postulate that Rho guanine nucleotide exchange factors (RhoGEFs), which integrate signaling cues driving cell migration, are critical effectors in metastatic cancer. Specifically, we addressed the hypothetical role of ARHGEF17, a RhoGEF, as a potential effector of Gßγ in metastatic lung cancer cells responding to LPA. Here, we show that ARHGEF17, originally identified as a tumor endothelial marker, is involved in tumor growth and metastatic dissemination of lung cancer cells in an immunocompetent murine model. Gene expression-based analysis of lung cancer datasets showed that increased levels of ARHGEF17 correlated with reduced survival of patients with advanced-stage tumors. Cellular assays also revealed that this RhoGEF participates in the invasive and migratory responses elicited by Gi protein-coupled LPA receptors via the Gßγ subunit complex. We demonstrate that this signaling heterodimer promoted ARHGEF17 recruitment to the cell periphery and actin fibers. Moreover, Gßγ allosterically activates ARHGEF17 by the removal of inhibitory intramolecular restrictions. Taken together, our results indicate that ARHGEF17 may be a valid potential target in the treatment of metastatic lung cancer.

Perforación intestinal causada por COVID-19 / Intestinal perforation caused by COVID-19 / Perfuração intestinal causada por COVID-19

Resumen: A medida que la pandemia por el virus SARS-CoV-2 se propaga por todo el mundo, se informan nuevas manifestaciones clínicas. Además de las manifestaciones respiratorias, se han descrito lesión renal aguda, hipercoagulabilidad, tromboembolia pulmonar y síntomas gastrointestinales. En el Hospital de Infectología del Centro Médico Nacional La Raza, en la Unidad de Cuidados Intensivos se han atendido 148 pacientes de noviembre de 2020 a noviembre de 2021 por COVID-19 de severo a crítico. Presentamos un caso de paciente con SARS-CoV-2 con perforación intestinal por congestión vascular a nivel del ciego por COVID-19 crítico.

Abstract: As the SARS-CoV-2 virus pandemic spreads around the world, new clinical manifestations are being reported. In addition to respiratory manifestations, acute kidney injury, hypercoagulability, pulmonary thromboembolism, and gastrointestinal symptoms have been described. The Hospital de Infectología del Centro Médico Nacional La Raza, in the Intensive Care Unit, has treated 148 patients from November 2020 to November 2021 for COVID-19 from severe to critical. We present the case of a patient with SARS-CoV-2, with intestinal perforation due to vascular congestion at the level of the cecum in a critical COVID-19 patient.

Resumo: À medida que a pandemia do vírus SARS-CoV-2 se espalha pelo mundo, novas manifestações clínicas estão sendo relatadas. Além das manifestações respiratórias, foram descritos lesão renal aguda, hipercoagulabilidade, tromboembolismo pulmonar e sintomas gastrointestinais. O Hospital de Infectologia do Centro Médico Nacional «La Raza¼, na Unidade de Terapia Intensiva, tratou 148 pacientes de novembro de 2020 a novembro de 2021 para COVID-19 de estado grave a crítico. Apresentamos o caso de um paciente com SARS-CoV-2, com perfuração intestinal por congestão vascular ao nível do ceco em um paciente em estado crítico com COVID-19.

The implications of ABCC3 in cancer drug resistance: can we use it as a therapeutic target?

Drug resistance is one of the main causes of chemotherapy failure. Although several factors are involved in cancer drug resistant, the exporter pumps overexpression that mediates the drugs flow to outside the cells and reduces both the drugs intracellular concentration and effectiveness, has been one of the most important challenges. Overexpression of ABCC3, a member of the ABCC subfamily, has been strongly associated to the resistance to multiple drugs. ABCC3 has been found highly expressed in different types of cancers and is associated with poor prognosis and resistance to treatments. In this review, we summarize the molecular mechanisms involved in cancer drug resistance and discuss the current knowledge about the structure, function and role of ABCC3 in drug resistance, as well as, the expression status of ABCC3 in different types of cancer. We also provide evidences that place ABCC3 as a potential therapeutic target for improving the cancer treatment by focusing on the need of developing more effective cancer therapies to target ABCC3 in translational researches.

Linfedema congénito primario bilateral. Reporte de caso / Bilateral primary congenital lymphedema. Case report

RESUMEN Fundamento: El linfedema congénito primario es una condición rara con un componente genético importante que se caracteriza por edema crónico de la zona afectada. Objetivo: Presentar un linfedema congénito primario bilateral y discutir su origen. Presentación de caso: Se presentó un caso de linfedema congénito primario bilateral en un niño de 2 años de edad, sin antecedentes patológicos familiares de la enfermedad. Se discutieron sus posibles causas genéticas ya que existen varias mutaciones que explican su origen. Aunque no se pudieron realizar estudios genéticos para conocer la etiología exacta, existen evidencias clínicas de que no se trata de una enfermedad de Milroy, a menos que se presente como una mutación de novo. Se le realizó al paciente un seguimiento desde su diagnóstico hasta la actualidad. Conclusiones: Existen múltiples mutaciones genéticas que explican el origen de un linfedema congénito primario, por lo que no necesariamente debe tratarse de enfermedad de Milroy cuando este se presente. Se destacó como elemento importante que en este caso no se evidenciaron antecedentes familiares. Se empleó el tratamiento conservador como conducta fundamental a seguir, se evidenció en el paciente una notable mejoría clínica.

ABSTRACT Background: Primary congenital lymphedema is a rare condition with an important genetic component characterized by chronic edema of the affected area. Objective: To present a bilateral primary congenital lymphedema and discuss its origin. Case report: A case of bilateral primary congenital lymphedema was presented in a 2-year-old boy with no any family background of the disease. Its possible genetic causes were discussed since there are several mutations that explain its origin. Although genetic studies could not be performed to know the exact etiology, there is clinical evidence that it is not a Milroy's disease, unless it presents as a de novo mutation. The patient was followed up from diagnosis to the present. Conclusions: There are multiple genetic mutations that explain the origin of a primary congenital lymphedema, so it should not necessarily be Milroy's disease when present. A highlighted and important element was that in this case no any family background was evidenced. Conservative treatment was used as the essential conduct to follow up, a remarkable clinical progress was evidenced in the patient.

Prevalence of SARS-CoV-2 Infection in a Sample of Health Workers in Two Health Departments of the Valencian Community in Spain.

Health care personnel constitutes the most vulnerable group of professionals, as they are employed in a work context with higher exposure to SARS-CoV-2 infection. This study aims to estimate the prevalence of SARS-CoV-2 infection in health personnel (n = 2858) of two health departments in the Valencian community between March 2020 and April 2021, as well as the sociodemographic and work variables predicting higher infection prevalence in this group. A cross-sectional descriptive study was performed on health workers from the health departments of Torrevieja and Elche-Crevillente of the Valencian Community (Spain). After obtaining the samples, the cases were identified through an active infection diagnostic test (AIDT). The analyzed variables were: sex, age (18-34/35-49/>50 years), professional category, health care, risk service, and AIDT. A total of 2858 staff members were studied. Of them, 55.4% (1582) underwent an AIDT, with 9.7% (277) of positive cases. Infection predominated in the age group of 18 to 34 years, 12.6% (OR = 1.98, 95% CI [1.26, 3.11]); nurses, 12.1% (OR = 1.5, 95% CI [1.00, 2.23]); and at-risk services, 11.4% (OR = 1.3, 95% CI [1.06, 1.81]). A very low positivity rate was identified in the health personnel linked to the health departments analyzed during the 14 months of the study period. Based on our results, prevention strategies could focus more intensively on the most at-risk groups, specifically young nurses who work in at-risk services, mainly in emergency and internal medicine.

Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells.

Advanced NSCLC patients harboring EML4-ALK and CCDC6-RET rearrangements derive benefit from treatment with ALK and RET TKIs but not immune checkpoint inhibitors. New immunotherapeutic approaches, such as immunization against growth factors, can be of particular interest for combination treatment in these patients. Here, we investigated the effects of anti-EGF antibodies generated by vaccination (anti-EGF VacAbs), TKIs and combinations in EML4-ALK and CCDC6-RET NSCLC cell lines. We found that EGF and tumor growth factor alpha (TGFα) significantly decreased the antiproliferative activity of the RET inhibitor BLU-667 in CCDC6-RET cells and brigatinib, alectinib and crizotinib in EML4-ALK translocated cells. The addition of anti-EGF VacAbs reversed the effects of EGF and TGFα, potentiated the antitumor effects of the kinase inhibitors and delayed the appearance in vitro of resistant clones. Western blotting demonstrated that the combination of anti-EGF VacAbs with ALK or RET TKIs effectively suppressed EGFR downstream pathways in EML4-ALK translocated and CCDC6-RET cells, respectively. In conclusion, anti-EGF VacAbs significantly increased the antitumor activity of TKIs in ALK and RET-positive cell lines. Clinical trials of an EGF vaccine in combination with ALK and RET TKIs are warranted.

Estado inmunológico frente a la Hepatitis B del personal sanitario en dos departamentos de salud de la Comunidad Valenciana (España) / Immunological Status against Hepatitis B among Healthcare Workers in Two Public Health Departments of the Valencian Community (Spain)

OBJETIVO: Estimar la prevalencia de inmunización frente al virus de la Hepatitis B del personal sanitario, vinculado a los Departamentos de Salud de Torrevieja y Elche-Crevillente, de la Comunidad Valenciana. MÉTODOS: Estudio descriptivo transversal en todos los trabajadores sanitarios de dos departamentos de Salud. Obtenida la muestra se identificó los niveles de anticuerpos de superficie del virus de la Hepatitis B a través de los resultados serológicos ubicados en las historias clínicas. Se consideró inmunizado a títulos de anti-HBs ≥ 10 mlU/ml. Las variables analizadas fueron categorizadas según: Departamento; Género; Edad (18-34; 35-49; > 50 años); categoría profesional (facultativos/Enfermería/Otro personal sanitario/Personal no sanitario); Servicio riesgo contagio (Si/No); Inmunidad (≥ 10 mlU/ml / < 10 mlU/ml / No Dato) y Vacunacion sistemática anti-HBs según fecha nacimiento (Si/No). RESULTADOS: El personal estudiado ascendió a 2674. Predominó el género femenino 68,8%, el grupo de edad 35-49 años, 52,8%, y la categoría profesional de Enfermería, 32,2%. Un 74,9% de los resultados serológicos identificaron niveles de protección anti-HBs, frente al 11,3% no inmune, y un 13,8% que no disponían de información. Del personal con información serológica (2306), obtuvieron porcentajes de no protección más elevadas la categoría masculina, 17,8%. Los niveles de protección fueron inversamente proporcionales según la variable edad, menor inmunidad a mayor edad. El personal no sanitario y los facultativos arrojaron niveles de protección más bajos, 36,9% y 11,1% respectivamente. CONCLUSIONES: A pesar de identificarse una inmunidad elevada, el porcentaje de no inmunizados y de ausencia de información inmunológica plantea la necesidad de implementar nuevas estrategias de comunicación dirigidas a este colectivo

OBJECTIVE: To estimate the prevalence of immunity against Hepatitis B virus among all healthcare workers linked to the Departments of Public Health in Torrevieja and Elx-Crevillent, two municipalities in the Valencian Community, Spain. Methods: Cross-sectional descriptive study of healthcare workers in two different public health departments. Once the sample was obtained, the anti-hepatitis B surface antibody (anti-HBsAb) levels were abstracted based on serological test results recorded in the workers’ medical records. Titers of anti-HBsAB ≥ 10 mlU / ml were considered as evience of immunity. The variables analyzed were classified by department, gender, age (18-34; 35-49; ≥ 50 years); professional category (physicians / nursing / other health personnel / non-health personnel); service at risk of contagion (Yes / No); immunity (≥ 10 mlU/ml, < 10 mlU/ml, missing) and systematic anti-HBs vaccination by date of birth (Yes / No). RESULTS: The study population consisted of 2674 workers. The highest proportions of workers were female (68.8%), between 35 and 49 years of age (52.8%), and employed in nursing,(32.2%). Overall, 74.9% of employees had evidence of hepatitis B immunity, 11.3% had no inmunity, and 13.8% was missing information on serology. Among those employees with serological information (n = 2306), lack of immunity was highest among males (17.8%). Protective titers were inversely proportional to age, with the lowest titers being found in the oldest age groups. Non-healthcare personnel and physicians also had lower levels of protection (36.9% and 11.1%, respectively). CONCLUSIONS: Despite identifying high levels of immunity among healthcare workers, the percentages of non-immunized employees and those lacking immunological information underscores the need to implement new communication strategies aimed at these at-risk groups

[Immunological Status against Hepatitis B among Healthcare Workers in Two Public Health Departments of the Valencian Community (Spain)]. / Estado inmunológico frente a la Hepatitis B del personal sanitario en dos departamentos de salud de la Comunidad Valenciana (España).

OBJECTIVE: To estimate the prevalence of immunity against Hepatitis B virus among all healthcare workers linked to the Departments of Public Health in Torrevieja and Elx-Crevillent,two municipalities in the Valencian Community, Spain. METHODS: Cross-sectional descriptive study of healthcare workers in two different public health departments. Once the sample was obtained, the anti-hepatitis B surface antibody (anti-HBsAb) levels were abstracted based on serological test results recorded in the workers' medical records. Titers of anti-HBsAB ≥10mlU / ml were considered as evience of immunity. The variables analyzed were classified by department, gender, age (18-34; 35-49;≥50 years); professional category (physicians / nursing / other health personnel / nonhealth personnel); service at risk of contagion (Yes / No); immunity (≥10mlU/ml, 〈10mlU/ml,missing) and systematic anti-HBs vaccination by date of birth (Yes / No). RESULTS: The study population consisted of 2674 workers. The highest proportions of workers were female(68.8%), between 35 and 49 years of age (52.8%), and employed in nursing,(32.2%). Overall, 74.9% of employees had evidence of hepatitis B immunity, 11.3% had no inmunity, and 13.8% was missing information on serology. Among those employees with serological information (n=2306), lack of immunity was highest among males (17.8%).Protective titers were inversely proportional to age, with the lowest titers being found in the oldest age groups. Non-healthcare personnel and physicians also had lower levels of protection (36.9% and 11.1%, respectively). CONCLUSIONS: Despite identifying high levels of immunity among healthcare workers, the percentages of non-immunized employees and those lacking immunological information underscores the need to implement new communication strategies aimed at these at-risk groups.

OBJETIVO: Estimar la prevalencia de inmunización frente al virus de la Hepatitis B del personal sanitario, vinculado a los Departamentos de Salud de Torrevieja y Elche-Crevillente, de la Comunidad Valenciana. MÉTODOS: Estudio descriptivo transversal en todos los trabajadores sanitarios de dos departamentos de Salud. Obtenida la muestra se identificó los niveles de anticuerpos de superficie del virus de la Hepatitis B a través de los resultados serológicos ubicados en las historias clínicas. Se consideró inmunizado a títulos de anti-HBs ≥10mlU/ml. Las variablesanalizadas fueron categorizadas según: Departamento; Género; Edad (18-34; 35-49; >50años); categoría profesional (facultativos/Enfermería/Otro personal sanitario/Personal no sanitario); Servicio riesgo contagio (Si/No); Inmunidad (≥10mlU/ml / 〈10mlU/ml / No Dato) y Vacunacion sistemática anti-HBs según fecha nacimiento (Si/No). RESULTADOS: El personal estudiado ascendió a 2674. Predominó el género femenino 68,8%, el grupo de edad 35-49 años, 52,8%, y la categoría profesional de Enfermería, 32,2%. Un 74,9% de los resultados serológicos identificaron niveles de protección anti-HBs, frente al 11,3% no inmune, y un 13,8% que no disponían de información. Del personal con información serológica (2306), obtuvieron porcentajes de no protección más elevadas la categoría masculina, 17,8%. Los niveles de protección fueron inversamente proporcionales según la variable edad, menor inmunidad a mayor edad. El personal no sanitario y los facultativosarrojaron niveles de protección más bajos, 36,9% y 11,1% respectivamente. CONCLUSIONES: A pesar de identificarse una inmunidad elevada, el porcentaje de no inmunizadosy de ausencia de información inmunológica plantea la necesidad de implementar nuevas estrategias de comunicación dirigidas a este colectivo.