RNASEH2B loss and PARP inhibition in advanced prostate cancer.

BACKGROUND: Clinical trials have suggested antitumor activity from PARP inhibition beyond homologous recombination deficiency (HRD). RNASEH2B loss is unrelated to HRD and preclinically sensitizes to PARP inhibition. The current study reports on RNASEH2B protein loss in advanced prostate cancer and its association with RB1 protein loss, clinical outcome and clonal dynamics during treatment with PARP inhibition in a prospective clinical trial. METHODS: Whole tumor biopsies from multiple cohorts of patients with advanced prostate cancer were interrogated using whole-exome sequencing (WES), RNA sequencing (bulk and single nucleus) and immunohistochemistry (IHC) for RNASEH2B and RB1. Biopsies from patients treated with olaparib in the TOPARP-A and TOPARP-B clinical trials were used to evaluate RNASEH2B clonal selection during olaparib treatment. RESULTS: Shallow co-deletion of RNASEH2B and adjacent RB1, co-located at chromosome 13q14, was common, deep co-deletion infrequent, and gene loss associated with lower mRNA expression. In castration-resistant PC (CRPC) biopsies, RNASEH2B and RB1 mRNA expression correlated, but single nucleus RNA sequencing indicated discordant loss of expression. IHC studies showed that loss of the two proteins often occurred independently, arguably due to stochastic second allele loss. Pre- and post-treatment metastatic CRPC (mCRPC) biopsy studies from BRCA1/2 wildtype tumors, treated on the TOPARP phase II trial, indicated that olaparib eradicates RNASEH2B-loss tumor subclones. CONCLUSION: PARP inhibition may benefit men suffering from mCRPC by eradicating tumor subclones with RNASEH2B loss. CLINICALTRIALS: gov NCT01682772FUNDING. AstraZeneca; Cancer Research UK; Medical Research Council; Cancer Research UK; Prostate Cancer UK; Movember Foundation; Prostate Cancer Foundation.

Creation of Standardized Common Data Elements for Diagnostic Tests in Infectious Disease Studies: Semantic and Syntactic Mapping.

BACKGROUND: It is necessary to harmonize and standardize data variables used in case report forms (CRFs) of clinical studies to facilitate the merging and sharing of the collected patient data across several clinical studies. This is particularly true for clinical studies that focus on infectious diseases. Public health may be highly dependent on the findings of such studies. Hence, there is an elevated urgency to generate meaningful, reliable insights, ideally based on a high sample number and quality data. The implementation of core data elements and the incorporation of interoperability standards can facilitate the creation of harmonized clinical data sets. OBJECTIVE: This study's objective was to compare, harmonize, and standardize variables focused on diagnostic tests used as part of CRFs in 6 international clinical studies of infectious diseases in order to, ultimately, then make available the panstudy common data elements (CDEs) for ongoing and future studies to foster interoperability and comparability of collected data across trials. METHODS: We reviewed and compared the metadata that comprised the CRFs used for data collection in and across all 6 infectious disease studies under consideration in order to identify CDEs. We examined the availability of international semantic standard codes within the Systemized Nomenclature of Medicine - Clinical Terms, the National Cancer Institute Thesaurus, and the Logical Observation Identifiers Names and Codes system for the unambiguous representation of diagnostic testing information that makes up the CDEs. We then proposed 2 data models that incorporate semantic and syntactic standards for the identified CDEs. RESULTS: Of 216 variables that were considered in the scope of the analysis, we identified 11 CDEs to describe diagnostic tests (in particular, serology and sequencing) for infectious diseases: viral lineage/clade; test date, type, performer, and manufacturer; target gene; quantitative and qualitative results; and specimen identifier, type, and collection date. CONCLUSIONS: The identification of CDEs for infectious diseases is the first step in facilitating the exchange and possible merging of a subset of data across clinical studies (and with that, large research projects) for possible shared analysis to increase the power of findings. The path to harmonization and standardization of clinical study data in the interest of interoperability can be paved in 2 ways. First, a map to standard terminologies ensures that each data element's (variable's) definition is unambiguous and that it has a single, unique interpretation across studies. Second, the exchange of these data is assisted by "wrapping" them in a standard exchange format, such as Fast Health care Interoperability Resources or the Clinical Data Interchange Standards Consortium's Clinical Data Acquisition Standards Harmonization Model.

Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial.

BACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

The protective effect of tumor necrosis factor-alpha inhibitors in COVID-19 in patients with inflammatory rheumatic diseases compared to the general population-A comparison of two German registries.

Objectives: To investigate, whether inflammatory rheumatic diseases (IRD) inpatients are at higher risk to develop a severe course of SARS-CoV-2 infections compared to the general population, data from the German COVID-19 registry for IRD patients and data from the Lean European Survey on SARS-CoV-2 (LEOSS) infected patients covering inpatients from the general population with SARS-CoV-2 infections were compared. Methods: 4310 (LEOSS registry) and 1139 cases (IRD registry) were collected in general. Data were matched for age and gender. From both registries, 732 matched inpatients (LEOSS registry: n = 366 and IRD registry: n = 366) were included for analyses in total. Results: Regarding the COVID-19 associated lethality, no significant difference between both registries was observed. Age > 65°years, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, spondyloarthritis and the use of rituximab were associated with more severe courses of COVID-19. Female gender and the use of tumor necrosis factor-alpha inhibitors (TNF-I) were associated with a better outcome of COVID-19. Conclusion: Inflammatory rheumatic diseases (IRD) patients have the same risk factors for severe COVID-19 regarding comorbidities compared to the general population without any immune-mediated disease or immunomodulation. The use of rituximab was associated with an increased risk for severe COVID-19. On the other hand, the use of TNF-I was associated with less severe COVID-19 compared to the general population, which might indicate a protective effect of TNF-I against severe COVID-19 disease.

Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer.

Therapies that abrogate persistent androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BCL-2-associated athanogene-1 (BAG-1) mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies, we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited "on-target" toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment-resistant prostate cancer cell lines and patient-derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation as the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2-mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.

Sobrepeso y obesidad en escolares de la Región de Magallanes y Antártica Chilena, Chile, (2009 ­ 2019), y comparación de dos metodologías para el diagnóstico / Overweight and obesity in schoolchildren in the Magallanes and Chilean Antarctica Region, Chile, (2009 - 2019), and comparison of two methodologies for diagnosis

Introducción. En Chile la prevalencia de obesidad total en población escolar alcanza al 31% y la obesidad severa al 10,8%. La Región de Magallanes y Antártica Chilena, es una de las más afectadas por esta epidemia. El diagnóstico nutricional confiable y una intervención oportuna pueden evitar que los niños enfermen y deterioren su calidad de vida. Objetivo: Analizar la tendencia del estado nutricional de escolares de la Región de Magallanes, según datos reportados por la Junta Nacional de Auxilio Escolar y Becas, JUNAEB, entre 2009-2019 y comparar resultados del año 2010 con un estudio propio. Materiales y métodos. Se analizó el estado nutricional de 71.334 escolares de la Región de Magallanes y Antártica Chilena por nivel educacional y variables demográficas, según información de JUNAEB. Luego se compararon los resultados de escolares de 1º básico del año 2010, obtenidos a través de dos metodologías: fuente secundaria, Encuesta JUNAEB, y fuente primaria, estudio antropométrico realizado en la misma región y año. Resultados. Según datos de JUNAEB el exceso ponderal se incrementó en escolares de la región en 4,4 % entre 2009 y 2019, el grupo más afectado fue 1º básico. En el año 2010 la prevalencia de obesidad para escolares de 1º básico según JUNAEB fue 21,8% y según estudio regional propio fue 25,7%. Conclusiones. La malnutrición por exceso afecta al 53,8% de los escolares de la Región de Magallanes y podría ser mayor, considerando que la información censal podría estar subestimando el sobrepeso y obesidad. Es urgente intervenir para evitar perpetuar esta epidemia(AU)

Introduction. In Chile the prevalence of total obesity in school population reaches 31% and severe obesity 10.8%. The Magallanes and Chilean Antarctica Region is one of the most affected by this epidemic. Reliable nutritional diagnosis and timely intervention can prevent children from getting sick and deteriorating their quality of life. Objective. To analyze the trend of nutritional status of schoolchildren in the Magallanes Region, according to data reported by the National Board of School Aid and Scholarships, JUNAEB between 2009-2019 and compare results from 2010 with our own study. Materials and methods. The nutritional status of 71,334 schoolchildren in the Magallanes Region and Chilean Antarctica was analyzed by educational level and demographic variables, according to information from JUNAEB. Then, the results of schoolchildren in 1st grade in 2010 were compared, obtained through two methods: secondary source, JUNAEB survey, and primary source, anthropometric study carried out in the same region and year. Results. According to JUNAEB data, overweight increased in school children in the region by 4.4% between 2009 and 2019, the most affected group was 1st grade. In 2010 the prevalence of obesity for 1st grade schoolchildren according to JUNAEB was 21.8% and according to our own regional study it was 25.7%. Conclusions. Excess malnutrition affects 53.8% of school children in the Magallanes Region and could be higher, considering that census information could be underestimating overweight and obesity. It is urgent to intervene to avoid perpetuating this epidemic(AU)

Medición de IgE total en suero por enzimainmunoanálisis con tres reactivos comerciales / Measurement of total serum IgE by enzyme-immunoanalysis with 3 commercial kits

We measured total serum IgE in 14 patients with allergic diseases and 16 healthy subjects, using 3 commercial ELISA kits. The correlation of results among the 3 kits was analized using Passing and Bablock regression parameters. Results show that measurements of the different kits do not coincide. One kit shows differences using sera from allergic patients. It is concluded that it is not possible to determine exactly the amount of IgE using these kits, specially in subjects with elevated levels

Antígeno pre S1 en diferentes formas de infección con el virus de la hepatitis B / Pre S1 antigen in different forms hepatitis B virus infection

Pre S1 antigen was measured using an ELISA technique in patients with different forms of hepatitis B virus infection. It was detected in 10 of 19 patients with acute hepatitis B (53 percent), 12 of 15 chronic hepatitis B virus carriers (80 percent), 9 of 11 patients with chronic hepatitis b (82 percent) and 3 of 4 patients with hepatoma and positive markers of hepatitis B virus infection. Pre S1 remained positive beyond 150 days in two patients with acute hepatitis that evolved to chronicity. Among subjects with chronic hepatitis B that received interferon, pre S1 antigen negativized only in the patient that had a complete response. Pre S1 detection is an index of hepatitis B virus replication and its persistence determines chronicity. Its negativization after antiviral therapy should have a predictive value