BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13.

The deubiquitinase BAP1 (BRCA1-associated protein 1) is associated with BAP1 tumor predisposition syndrome (TPDS). BAP1 is a tumor suppressor gene whose alterations in cancer are commonly caused by gene mutations leading to protein loss of function. By CRISPR-Cas, we have generated mutations in ubh-4, the BAP1 ortholog in Caenorhabditis elegans, to model the functional impact of BAP1 mutations. We have found that a mimicked BAP1 cancer missense mutation (UBH-4 A87D; BAP1 A95D) resembles the phenotypes of ubh-4 deletion mutants. Despite ubh-4 being ubiquitously expressed, the gene is not essential for viability and its deletion causes only mild phenotypes without affecting 20S proteasome levels. Such viability facilitated an RNAi screen for ubh-4 genetic interactors that identified rpn-9, the ortholog of human PSMD13, a gene encoding subunit of the regulatory particle of the 26S proteasome. ubh-4[A87D], similarly to ubh-4 deletion, cause a synthetic genetic interaction with rpn-9 inactivation affecting body size, lifespan, and the development of germ cells. Finally, we show how ubh-4 inactivation sensitizes animals to the chemotherapeutic agent Bortezomib, which is a proteasome inhibitor. Thus, we have established a model to study BAP1 cancer-related mutations in C. elegans, and our data points toward vulnerabilities that should be studied to explore therapeutic opportunities within the complexity of BAP1 tumors.

Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans.

Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we used C. elegans to explore cisplatin effects on mitochondrial functions and investigate cisplatin-induced neurotoxicity through a high-resolution system for evaluating locomotion. First, we report that a high-glucose diet sensitizes C. elegans to cisplatin at the physiological level and that mitochondrial CED-13 protects the cell from cisplatin-induced oxidative stress. Additionally, by assessing mitochondrial function with a Seahorse XFe96 Analyzer, we observed a detrimental effect of cisplatin and glucose on mitochondrial respiration. Second, because catechol-O-methyltransferases (involved in dopamine degradation) are upregulated upon cisplatin exposure, we studied the protective role of dopamine against cisplatin-induced neurotoxicity. Using a Tierpsy Tracker system for measuring neurotoxicity, we showed that abnormal displacements and body postures in cat-2 mutants, which have dopamine synthesis disrupted, can be rescued by adding dopamine. Then, we demonstrated that dopamine treatment protects against the dose-dependent neurotoxicity caused by cisplatin.

Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin.

Cisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties, namely the onset of resistance to the drug and the cytotoxic effect in patients. Here, we used Caenorhabditis elegans to investigate factors influencing the response to cisplatin in multicellular organisms. In this hermaphroditic model organism, we observed that sperm failure is a major cause of cisplatin-induced infertility. RNA sequencing data indicate that cisplatin triggers a systemic stress response, in which DAF-16/FOXO and SKN-1/NRF2, two conserved transcription factors, are key regulators. We determined that inhibition of the DNA damage-induced apoptotic pathway does not confer cisplatin protection to the animal. However, mutants for the pro-apoptotic BH3-only gene ced-13 are sensitive to cisplatin, suggesting a protective role of the intrinsic apoptotic pathway. Finally, we demonstrated that our system can also be used to identify mutations providing resistance to cisplatin and therefore potential biomarkers of innate cisplatin-refractory patients. We show that mutants for the redox regulator trxr-1, ortholog of the mammalian thioredoxin reductase 1 TRXR1, display cisplatin resistance. By CRISPR/Cas9, we determined that such resistance relies on the presence of the single selenocysteine residue in TRXR-1.This article has an associated First Person interview with the first author of the paper.

Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent.

Purpose: To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells.Experimental Design: We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice.Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin-refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin.Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance. Clin Cancer Res; 24(15); 3755-66. ©2018 AACR.

Nuevas tendencias en el manejo quirúrgico del agujero macular / New trends in the surgical management of macular holes

El agujero macular es un desorden de la interfase vitreorretinal definido como un defecto de espesor completo desde la membrana limitante interna hasta los segmentos externos de los fotorreceptores que normalmente involucra a la fóvea. Es más frecuente en mujeres mayores de 55 años y existe un riesgo de un 10-15 por ciento de afectación del ojo contralateral. Con el aumento de la esperanza de vida, se demandan nuevos retos y técnicas quirúrgicas para este problema de salud. Se realizó una revisión de artículos publicados e indexados en la base de datos de PubMed, que se refirieran a las características y clasificación por tomografía de coherencia óptica del agujero macular y las opciones terapéuticas para este. Nuevas técnicas quirúrgicas se han descrito para los agujeros maculares idiopáticos. El surgimiento de la tomografía de coherencia óptica, sobre todo la de dominio espectral, ha aumentado las posibilidades diagnósticas de tratamiento y seguimiento en las enfermedades de la interfase vitreorretinal, específicamente el agujero macular(AU)

A macular hole is a disorder of the vitreous-retina interface defined as a full-thickness defect from the internal limiting membrane to the external segments of photoreceptors which typically involves the fovea. It is more common among women aged over 55 years, and there is a 10-15 percent risk that the contralateral eye is affected. As life expectancy increases, new challenges come up and new surgical techniques are required for this health problem. A review was conducted of papers published and indexed in the database PubMed which referred to the optical coherence tomography classification and characteristics of macular holes, as well as the therapeutic options to treat it. New surgical techniques have been described for idiopathic macular holes. Introduction of optical coherence tomography, especially spectral domain OCT, has increased the diagnostic possibilities of the treatment and follow-up of vitreous-retina interface disorders, particularly macular holes(AU)

Recommendations for infectious disease screening in migrants to Western Europe with inflammatory arthropathies before starting biologic agents. Results from a multidisciplinary task force of four European societies (SIR, SER, SIMET, SEMTSI) facing the largest impact of the flow of migrants today.

OBJECTIVES: Inflammatory arthritis needs infectious disease screening before starting a biologic agent, however, few data are known about migrant patients, who represent a peculiar population which requires a multidisciplinary approach among international health specialists and should also be considered by health authorities. For this reason, the Italian and Spanish Societies of Rheumatology (SIR and SER) and Tropical Medicine (SIMET and SEMTSI) promoted a multidisciplinary task force in order to produce specific recommendations about screening and advices to be considered in migrant patients with inflammatory arthritis candidate to receive biological therapy, according to their geographical origin. METHODS: The experts provided a prioritised list of research questions and the eligible spectrum of inflammatory arthritis, biologic drugs and infectious disease were defined in order to perform a systematic literature review. A search was made in Medline, Embase and Cochrane library, updated to March 2015. Ubiquitous infections and HBV, HCV, HIV and tuberculosis that are already considered in national and international recommendations, were not included. The strength of each recommendation was determined. RESULTS: The task force members agreed on 7 overarching principles. The risk of reactivation of selected potentially latent infectious disease was addressed in migrants with inflammatory arthritis candidates for biologics was considered and 15 potentially relevant infections were identified. CONCLUSIONS: Fifteen disease-specific recommendations were formulated on the basis of high level of agreement among the experts panel.

The utility of C-reactive protein and procalcitonin for sepsis diagnosis in critically burned patients: A preliminary study.

OBJECTIVE: To assess the utility of C-reactive protein (CRP) and procalcitonin (PCT) as biomarkers of infection in patients with severe burn injury. METHODS: The present study included severe burn injury patients consecutively admitted to the Virgen del Rocío University Hospital (Andalucia, Spain) intensive care unit during a 12-month period. The variables of interest were: age, sex, mechanism of injury, percentage of burned body surface area, the Abbreviated Burn Severity Index (ABSI) and the absence/presence of sepsis. The authors analyzed serum levels of CRP and PCT at admission and every 48 h thereafter until intensive care unit discharge or death. Each determination was considered to be a sample or unit of analysis. RESULTS: A total of 157 determinations were analyzed from 17 severe burn injury patients. Fifty-four samples were considered to be septic, 25 of which corresponded to the first day of a new onset of sepsis. The mean duration of these symptoms was four days (interquartile range two to five days). Significant differences were found in the distributions of CRP and PCT values between sepsis and no-sepsis samples. Analysis of the changes in these biomarkers over time showed that PCT increase (ΔPCT) differentiated these diagnoses, whereas CRP increase (ΔCRP) did not. ROC curve analysis revealed that ΔPCT could predict positive sepsis samples (area under the curve 0.75 [95% CI 0.58 to 0.90]; P=0.003). CONCLUSION: These preliminary results showed that PCT had a better discriminatory capacity than CRP for identifying infectious processes in patients with severe burn injury. A larger sample size would be needed to confirm these results.

OBJECTIF: Évaluer l'utilité de la protéine C réactive (PCR) et de la procalcitonine (PCT) comme biomarqueurs de l'infection chez des grands brûlés. MÉTHODOLOGIE: La présente étude portait sur des grands brûlés admis consécutivement à l'unité de soins intensifs de l'hôpital universitaire Virgen del Rocío d'Andalousie, en Espagne, sur une période de 12 mois. Les variables étudiées étaient l'âge, le sexe, le mécanisme de brûlure, le pourcentage de surface corporelle brûlée, l'indice abrégé de gravité des brûlures (ABSI) et l'absence ou la présence de sepsis. Les auteurs ont analysé les taux sériques de PCR et de PCT des patients à l'admission, puis toutes les 48 heures jusqu'à leur congé des soins intensifs ou à leur décès. Chaque déterminant était considérée comme un échantillon ou une unité d'analyse. RÉSULTATS: Au total, les auteurs ont analysé 157 déterminants chez 17 grands brûlés. Cinquante-quatre échantillons étaient considérés comme septiques, dont 25 correspondaient au premier jour d'apparition du sepsis. Les symptômes duraient en moyenne quatre jours (plage interquartile de deux à cinq jours). Les auteurs ont constaté des différences importantes dans la répartition des valeurs de PCR et de PCT entre les échantillons de sepsis et sans sepsis. L'analyse des changements de ces biomarqueurs au fil du temps a révélé que l'augmentation de la PCT (ΔPCT) distinguait ces diagnostics, contrairement à l'augmentation de la PCR (ΔPCR). L'analyse de la courbe ROC a révélé que la ΔPCT pouvait prédire des échantillons de sepsis positifs (aire sous la courbe de 0,75 [95% IC 0,58 à 0,90]; P=0,003). CONCLUSION: Les résultats préliminaires démontrent que la PCT avait une meilleure capacité discriminatoire que la PCR pour dépister les processus infectieux chez des grands brûlés. Il faudrait un plus gros échantillon pour confirmer ces résultats.

Resultados de dos encuestas dirigidas a inmigrantes y nativos del sureste español: salud, uso de servicios y necesidad de asistencia médica / Results of two surveys of immigrants and natives in Southeast Spain: health, use of services, and need for medical assistance

Objetivo. Comparar la salud, uso de servicios sanitarios y necesidad insatisfecha de atención médica (NIAM) entre inmigrantes y nativos del sureste español. Material y métodos. Estudio transversal de dos muestras representativas de población: inmigrante (n=1150) y nativa (n=1303; Encuesta Nacional de Salud). Se creó una única base de datos con ponderación específica para cada muestra y se estimaron razones de prevalencia (RP) mediante regresión multivariante. Resultados. Marroquíes, ecuatorianos y europeos del este (EE) declararon peor salud que los nativos (RPs [IC95%]: 2.45 [1.91-3.15]; 1.51 [1.28-1.79] y 1.44 [1.08-1.93], respectivamente). Los inmigrantes hicieron mayor uso de las urgencias (excepto EE) y consumieron menos fármacos. Los marroquíes mostraron la mayor diferencia en la frecuencia de NIAM (RP [IC95%]: 12.20 [5.25-28.37]), principalmente por razones laborales (46%). Conclusiones. La salud y el uso de servicios sanitarios difirieron significativamente entre inmigrantes y nativos. Destaca la NIAM alta en marroquíes por causa laboral.

Objective. To compare the self-perceived health, use of health services and unmet need for health care (UNHC) among immigrants and native populations of Southeast Spain. Materials and methods. Cross-sectional study of two representative samples of 1150 immigrants, and 1303 native participants from the National Health Survey. A single database was created with specific weights for each sample, and prevalence ratios (PR) were estimated by multivariate regression. Results. Moroccans, Ecuadorians and Eastern Europeans (EE) reported poorer health than the native population (PRs [CI95%]: 2.45 [1.91-3.15]; 1.51 [1.28-1.79] and 1.44 [1.08-1.93], respectively). Immigrants made greater use of emergencies that natives (except for EE) and had lower use of medication. Moroccan showed the greatest difference in the frequency of UNHC (PR [CI95%]:12.20 [5.25 - 28.37]), mainly because of working limitations (46%). Conclusions. The health status and use of health services among immigrants differ significantly from those of natives. Results highlight the higher frequency of UNHC among immigrants, especially high in Moroccans.

Spanish Rheumatology Society and Hospital Pharmacy Society Consensus on recommendations for biologics optimization in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis.

OBJECTIVE: The aim of this study was to establish guidelines for the optimization of biologic therapies for health professionals involved in the management of patients with RA, AS and PsA. METHODS: Recommendations were established via consensus by a panel of experts in rheumatology and hospital pharmacy, based on analysis of available scientific evidence obtained from four systematic reviews and on the clinical experience of panellists. The Delphi method was used to evaluate these recommendations, both between panellists and among a wider group of rheumatologists. RESULTS: Previous concepts concerning better management of RA, AS and PsA were reviewed and, more specifically, guidelines for the optimization of biologic therapies used to treat these diseases were formulated. Recommendations were made with the aim of establishing a plan for when and how to taper biologic treatment in patients with these diseases. CONCLUSION: The recommendations established herein aim not only to provide advice on how to improve the risk:benefit ratio and efficiency of such treatments, but also to reduce variability in daily clinical practice in the use of biologic therapies for rheumatic diseases.

Blebitis asociada a endoftalmitis. Presentación de casos / Blebytis associated to endophthalmitis. Presentation of a case

La endoftalmitis se conoce como una de las complicaciones más graves y temidas por los oftalmólogos. El 70 % de ellas se presentan después de un proceder quirúrgico. Las infecciones relacionadas con la bula de filtración en la cirugía del glaucoma son infrecuentes y representan el 0,1 % de todas la endoftalmitis, aunque se consideran potencialmente graves. Comprenden la flebitis, que es un término introducido para describir la infección de la bula de filtración, de aspecto mucopurulento, acompañada de una mediana actividad en cámara anterior y en ausencia de vitritis. Este último signo es la diferencia más importante con la blebitis asociada a endoftalmitis, en la cual sí hay compromiso del vítreo, que se asocia a hipopión y severa pérdida visual. Se presentan tres pacientes operados por cirugía filtrante de glaucoma, quienes presentaron un cuadro de blebitis asociada a endoftalmitis en los dos restante, necesitando tratamiento tópico más intraviteo y quirúrgico, respectivamente. Si se realiza un diagnóstico, tratamiento adecuado y oportuno, en estas entidades poco frecuentes pero devastadoras, se minimizan los riesgos y las complicaciones graves, obteniendo un mejor pronóstico visual, lo que llevó a los autores a presentar esta serie de casos.

The endophthalmitis is known a one of the most serious complications feared by the ophthalmologists. 70 % of them appear after a surgical procedure. The infections related with the filtration bulla in the glaucoma surgery are infrequent and represent 0,1 % of all the endophthalmitis, though they are considered potentially serious. They comprehend the blebytis, a term introduced to describe the infection of the filtration bulla, with mucous purulent aspect, accompanied with a medium activity in the anterior chamber and lacking vitritis. This last sign is the most important difference with the blebytis associated to endophthalmitis, in which the vitreous humor is involved, associated to hypopyon and severe visual loss. We present three patients operated by glaucoma filtrating surgery who presented a picture of blebytis associated to endophthalmitis in the other two, needing topical treatment plus intravitreous and surgical, respectively. If an opportune and adequate diagnosis and treatment is made in these infrequent but devastating entities, the serious risks and complications are minimized, obtaining a better visual prognosis. Those were the reasons leading the authors to present these cases.