Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most frequent kidney solid tumor, the clear cell RCC (ccRCC) being the major histological subtype. The probability of recurrence and the clinical behavior of ccRCC will greatly depend on the different clinical and histopathological features, already incorporated to different scoring systems, and on the genomic landscape of the tumor. In this sense, ccRCC has for a long time been known to be associated to the biallelic inactivation of Von Hippel-Lindau (VHL) gene which causes aberrant hypoxia inducible factor (HIF) accumulation. Recently, next generation-sequencing technologies have provided the bases for an in-depth molecular characterization of ccRCC, identifying additional recurrently mutated genes, such as PBRM1 (≈40-50%), SETD2 (≈12%), or BAP1 (≈10%). PBRM1, the second most common mutated gene in ccRCC after VHL, is a component of the SWI/SNF chromatin remodeling complex. Different studies have investigated the biological consequences and the potential role of PBRM1 alterations in RCC prognosis and as a drug response modulator, although some results are contradictory. In the present article, we review the current evidence on PBRM1 as potential prognostic and predictive marker in both localized and metastatic RCC.S

The impact of COVID-19 on sick leave of the persons working in nursing homes in Spain. Usefulness of sick leave for the surveillance of the pandemic evolution.

[ES] Fundamentos: Los centros sociosanitarios representaron entornos de alto riesgo de contagio por SARS-CoV-2, tanto para los residentes como para las personas trabajadoras. Se evaluó el impacto en términos de incapacidad temporal (IT) por COVID-19 en las personas que trabajan en centros sociosanitarios y se comparó con la evolución de la pandemia en la población general de 16 a 65 años, para valorar la utilidad de la IT como indicador complementario de la epidemia por SARS-CoV-2. Métodos: Se realizó un estudio descriptivo de todos los procesos de incapacidad temporal por COVID-19 registrados entre el 15 de febrero de 2020 y el 1 de mayo de 2021 en establecimientos residenciales. Se obtuvieron las ratios de incapacidad temporal por contacto estrecho/incapacidad temporal por infección, las tasas de incapacidad temporal por 100.000 afiliados/ocupados y se compararon con la incidencia acumulada de casos COVID-19 notificados a la Red Nacional de Vigilancia Epidemiológica (RENAVE). Resultados: Se registraron 261.892 procesos de incapacidad temporal. La mediana de la ratio de incapacidad temporal por contacto estrecho/incapacidad temporal por infección en residencias fue de 1,8 (Rango intercuartílico, RIC: 1,1- 3,3), con valores menores a 1 en periodos. Las IT por infección fueron superiores en número, tasa y anteriores en el tiempo a los casos registrados en RENAVE. Por tipo de residencia, la tasa de incapacidad temporal osciló entre 81.679/100.000 ocupados en asistencia en establecimientos residenciales con cuidados sanitaros y 4.895/100.000 en otros establecimientos residenciales. Conclusiones: Los resultados confirmaron el enorme impacto que tuvo la COVID-19 en los centros sociosanitarios y la desigualdad que ha caracterizado este impacto. Apoyan también la posible utilización de la incapacidad temporal como fuente de información alternativa para la vigilancia epidemiológica y de salud pública, lo cual resulta de especial interés en este momento en el que se está planteando una transición en la vigilancia del COVID-19 hacia un sistema que ya no incluya una vigilancia individualizada universal. [EN] Background: The nursing homes represented high-risksettings for SARS-CoV-2 infection, both for residents and forthe employees. The COVID-19 impact on long-term care facilities (LTCFs) is evaluated, measured through the employees sick leave (SL). The pandemic evolution in the general population aged between 16 and 65 years was analyzed together with the sick leave to assess the latter as a complementary indicator of the SARS-CoV-2 surveillance. Methods: A descriptive study of all sick leave processes due to COVID-19 recorded between February 15th 2020and May 1st 2021 in nursing homes was carried out. The close contact sick leave/infection sick leave ratios, the 100,000 affiliated/occupied sick leave rates were computed and compared with the COVID-19 cases cumulative incidence notified to the National Network of epidemiological Surveillance (RENAVE). Results: 261.892 SL processes were recorded. The close contact sick leave/infection sick leave median ratio in nursing homes was 1.8 (Interquartile range, ICR: 1.1-3.3), with values lower than 1 at certain periods. The infection sick leaves were higher in number and ratio and prior to the cases recorded in RENAVE. The sick leave ratio ranged between 81.679/100.000 occupied in nursing homes with medical careand 4.895/100.000 in other residential facilities. Conclusions: The results confirmed the dramatic impact of COVID-19 in nursing homes and the inequalities characterizing this impact. They also confirmed the potential use of sick leave as an alternative source for epidemiological and public health surveillance, especially now, when the transitionof the COVID-19 surveillance to a system not including universal individual surveillance is being discussed.S

Multivariate analysis and extraction of parameters in resistive RAMs using the Quantum Point Contact model

A multivariate analysis of the parameters that characterize the reset process in RRAMs has been performed. The different correlations obtained can help to shed light on the current components that contribute in the Low Resistance State (LRS) of the technology considered. In addition, a screening method for the Quantum Point Contact (QPC) current component is presented. For this purpose the second derivative of the current has been obtained using a novel numerical method which allows determining the QPC model parameters. Once the procedure is completed, a whole RS series of thousands of curves is studied by means of a genetic algorithm. The extracted QPC parameter distributions are characterized in depth to get information about the filamentary pathways associated with LRS in the low voltage conduction regime.Spanish Ministry of Economy and Competitiveness TEC2014-52152-C3-2-R , MTM2013-47929-P (also supported by the FEDER program)IMB-CNM Spanish Ministry of Economy and Competitiveness TEC2014-52152-C3-1-R and TEC2014-54906-JIN (supported by the FEDER program)ENIAC Joint Undertaking-PANACHE project.Spanish ICTS Network MICRONANOFAB

Resistive Switching and Charge Transport in Laser-Fabricated Graphene Oxide Memristors: A Time Series and Quantum Point Contact Modeling Approach

This work investigates the sources of resistive switching (RS) in recently reported laser-fabricated graphene oxide memristors by means of two numerical analysis tools linked to the Time Series Statistical Analysis and the use of the Quantum Point Contact Conduction model. The application of both numerical procedures points to the existence of a filament connecting the electrodes that may be interrupted at a precise point within the conductive path, resulting in resistive switching phenomena. These results support the existing model attributing the memristance of laser-fabricated graphene oxide memristors to the modification of a conductive path stoichiometry inside the graphene oxide.The authors thank the support of the Spanish Ministry of Science, Innovation and Universities under projects TEC2017-89955-P, TEC2017-84321-C4-3-R, MTM2017-88708-P and project PGC2018-098860-B-I00 (MCIU/AEI/FEDER, UE), and the predoctoral grant FPU16/01451

Novel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma

Over the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline DNMT3A gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile. Here, whole-exome sequencing identifies a novel germline DNMT3A variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability. The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients. Structural modelling of the variant in the DNMT3A PWWP domain predicts that the interaction with H3K36me3 will be altered. An increased methylation of DNMT3A target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant. Although further studies are needed to support a causal role of DNMT3A variants in paraganglioma, the description of a new DNMT3A alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to DNMT3A germline variants

Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma

The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy

PBRM1 and KDM5C cooperate to define high-angiogenesis tumors and increased antiangiogenic response in renal cancer

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are key antiangiogenic drugs for renal cancer treatment. While Von Hippel-Lindau dysfunction constitutes the base for VEGFR-TKIs sensitivity, the role for individual and concurrent mutations in the genes encoding for the chromatin remodelers Polybromo-1 (PBRM1) and Lysine Demethylase 5C (KDM5C) is poorly understood. Here, we analyzed the tumor mutational and expression profiles of 155 unselected clear cell RCC (ccRCC) cases treated with first-line VEGFRTKIs and the ccRCC cases of IMmotion151 trial were used for validation. We found that concurrent PBRM1 and KDM5C (PBRM1&KDM5C) mutations occurred in 4-9% of cases and were enriched in Memorial Sloan Kettering Cancer Center favorable-risk patients. In our cohort, tumors only mutated in PBRM1 or concurrently mutated in PBRM1 and KDM5C had increased angiogenesis (P=0.0068 and 0.039; respectively), and tumors only mutated in KDM5C showed a similar trend. Best response to VEGFR-TKIs corresponded to PBRM1&KDM5C mutated cases, followed by those mutated only in KDM5C or only in PBRM1 (P=0.050, 0.040 and 0.027 versus non-mutated cases, respectively), with a trend for longer progression free survival (PFS) in the group with only PBRM1 mutated (HR=0.64; P=0.059). Validation in the IMmotion151 trial revealed a similar correlation with increased angiogenesis and the PFS of patients in the VEGFR-TKI-arm was the longest in PBRM1&KDM5C mutated cases, intermediate for only PBRM1 or only KDM5C mutated patients and the shortest in non-mutated cases (P=0.009 and 0.025, for PBRM1&KDM5C and PBRM1 versus non-mutated cases). In conclusion, somatic PBRM1 and KDM5C mutations are common in patients with metastatic ccRCC and likely cooperate increasing tumor angiogenesis and VEGFR-TKIbased antiangiogenic therapy benefit.Peer reviewe

Gestos, tecnologías y sociedades: Tendencias y emergencias en tiempos de pospandemia

La tecnología hace parte de la humanidad como el medio con el cual la sociedad externaliza, apropia y articulasu existencia con los territorios y otras especies. Su fuerza instrumental responde a unas adaptaciones que en el último siglo han consolidado una relación de interdependencia con la aparatología al tiempo que se han modificado ritmos, lenguajes y formas de concebir la realidad. La tecnología se ha convertido en un agente inherente de la sociedad, y es uno de los factores que afecta y cambia el comportamiento humano y las dinámicas sociales, muestra de esto se evidenció en la pandemia del Coronavirus. Periodo en donde el Estado, la industria, la salud, la educación, etc., reinventaron sus procesos para dar continuidad a la estructura de la vida cotidiana