Integrative clinical transcriptome analysis reveals TMPRSS2-ERG dependency of prognostic biomarkers in prostate adenocarcinoma

In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated gene- signatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E-status. Using gene-set enrichment analyses, we uncovered that metastatic T2E-positive and T2E-negative PCa arecharacterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for theirassociation with event-free survival in a validation cohort (n=272), we identifiedfive genes (ASPN,BGN,COL1A1,RRM2andTYMS)—three of which are included in commercially available prognostic tests—whose high expression was significantlyassociated with worse outcome exclusively in T2E-negative PCa. Among these genes,RRM2andTYMSwere validated byimmunohistochemistry in another validation cohort (n=135), and several of them proved to add prognostic information tocurrent clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkerswere identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which ispersenot astrong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that themolecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa. What’s new? Genetic rearrangements involving androgen-regulated transmembrane protease serine 2 and genes from the ETS transcription factor family (T2E), most commonly ERG and ETV1, occur in half of prostate cancers but are currently not considered in risk predictions. The authors integrate clinical and transcriptomic data from multiple studies and show that the prognostic value of biomarkers critically depends on the T2E-status. They identify five biomarkers that predict negative outcome exclusively in T2E-negative prostate cancers, which has implications for outcome prediction based on the molecular subtype.Deutsche Forschungsgemeinschaft 391665916Deutsche Krebshilfe 70112257Dr Leopold and Carmen Ellinger FoundationDr Rolf M. Schwiete FoundationFriedrich-Baur FoundationGert and Susanna Mayer FoundationKind-Philipp FoundationMatthias-Lackas FoundationMehr LEBEN fur Krebskranke Kinder-Bettina-Brau-StiftungWilhelm Sander-Stiftung 2016.167.

The experimental model of laboratory animals’ intoxication by polyacrylonitrile pyrolysis products

Purpose of research – To develop an experimental model of intoxication of laboratory animals by polyacrylonitrile pyrolysis products. Materials and methods. The study was performed on the rats. Pyrolysis of polyacrylonitrile fibers was carried out at temperature of 270–350 °C. The laboratory animals were exposed to static inhalation intoxication by pyrolysis products for 15 min. Vital signs were determined in animals before and 5 minutes after intoxication. Arterial blood oxygenation index and acid-base state parameters were evaluated at 10 min after exposure. Qualitative detection of cyanides in brain and myocardial samples obtained 15 minutes after intoxication was carried out by gas chromatography. Results and discussion. It was found that the weight of the material (containing 85 % polyacrylonitrile), which pyrolysis products lead to the death of 50 % of laboratory animals within 24 hours after exposure, was 0.81 ± 0.15 g. The animals showed signs of poisoning by substances interrupting the processes of cell bioenergy when exposed to pyrolysis products obtained under specified conditions. The evident bradycardia and bradypnea (p < 0,05), and significant decrease in rectal temperature was marked. The exposed animals did not differ (p > 0,05) from the rats of the control group by the parameters of oxygenation. The signs of decompensated metabolic acidosis were detected in blood. The cyanide peak was detected by gas chromatography with a retention time of 3.78 min in brain and heart muscle biopsies. The experimental model, in which inhalation exposure of pyrolysis products of polyacrylonitrile fibers led to severe intoxication of laboratory animals, was developed. The model can be used to search for means of etiotropic and pathogenetic therapy of poisoning by combustion products of nitrogen-containing polymeric materials

Двойное слепое рандомизированное исследование токсического воздействия лидокаина и ропивакаина на седалищный нерв и двуглавую мышцу крыс

The purpose of the study was to examine the damaging activity of Lidocaine and Ropivacaine on the sciatic nerve and biceps muscle of rats. A double blind randomized study was conducted. The control group received injectiona of 0.9% NaCl. The following concentrations of Lidocaine were examined – 0.5, 1, 1.5, and 2. For Ropivacaine, these concentrations were 0.25, 0.5, 0.75, and 1. Under the US control, 0.2 ml were injected along the perineural sciatic nerve and 0.2 ml into the two-headed muscle. The drugs were taken out in 1 hour after their injection. When injecting 0.9% NaCl no cell necrosis or apoptosis in the muscle and nerve were found, only single cells of inflammatory type were found. The administration of all concentrations of local anesthetics caused inflammatory filtration and damage to muscle tissue and nerve stems compared to 0.9% NaCl. Increased expression of damage and inflammatory infiltration depended on the concentration of the local anesthetic. The higher the concentration of Lidocaine or Ropivacaine was, the greater were the damage and inflammatory changes. The study demonstrated neurotoxic and miotoxic activity of all concentrations of Lidocaine and Ropivacaine compared to 0.9% NaCl. The dependence of damage strengthening and the growth of inflammatory filtration in the muscle and peripheral nerve on the increased concentration of the local anesthetic was revealed.Местные анестетики, проникая внутрь клетки, кроме блокады натриевых каналов, воздействуют на другие процессы, способствуя развитию апоптоза клетки. Цель исследования: изучение повреждающего действия лидокаина и ропивакаина на седалищный нерв и двуглавую мышцу крыс.Двойное слепое рандомизированное исследование. Контрольная группа с введением 0,9%-ного раствора NaCl. Исследуемые концентрации лидокаина – 0,5, 1, 1,5, 2%; ропивакаина – 0,25, 0,5, 0,75, 1%. Под ультразвуковым контролем вводили по 0,2 мл периневрально седалищного нерва и 0,2 мл внутрь двуглавой мышцы. Забор препаратов осуществляли через 1 ч после введения. При инъекции 0,9%-ного раствора NaCl некроза клеток или апоптоза в мышце и нерве не обнаружено, выявлены единичные клетки воспалительного типа. Введение всех концентраций местных анестетиков вызывало воспалительную инфильтрацию и повреждение мышечной ткани и нервных стволов по сравнению с 0,9%-ным раствором NaCl. Увеличение выраженности повреждения и воспалительной инфильтрации зависело от концентрации местного анестетика. Чем выше концентрация ропивакаина или лидокаина, тем больше повреждение и воспалительные изменения.Исследование показало наличие нейро- и миотоксичного действия всех концентраций лидокаина и ропивакаина по сравнению с 0,9%-ным раствором NaCl. Выявлена зависимость усиления повреждения и нарастания воспалительной инфильтрации в мышце и периферическом нерве от увеличения концентрации местного анестетика

NEW DYES BASED ON THIENO[3,2-b]INDOLE WITH AN EXTENDED Π-CONJUGATION SYSTEM FOR DYE-SENSITIZED SOLAR CELLS

This work was supported by the Russian Foundation for Basic Research, project # 22-73-00291

Разреженная декомпозиция скеилограммы вибрации для мониторинга технического состояния роторного оборудования

The article describes an algorithm for the sparse decomposition of vibration signals scalogram for searching of the frequency domains with a significant energy contribution. The developed algorithm is proposed to be used for monitoring the technical condition of rotary equipment. The article presents the testing results of the sparse scalegram decomposition algorithm on the vibration signals of industrial equipment.В статье рассмотрен алгоритм разреженной декомпозиции скейлограммы вибрационных сигналов для поиска частотных областей со значительным энергетическим вкладом. Разработанный алгоритм предложено использовать для мониторинга технического состояния роторного оборудования. В статье приведены результаты тестирования алгоритма разреженной декомпозиции скейлограммы на сигналах вибрации промышленного оборудования

Integrative clinical transcriptome analysis reveals TMPRSS2‐ERG dependency of prognostic biomarkers in prostate adenocarcinoma

In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2‐ERG (T2E)‐fusion oncoproteins defining two molecular subtypes (T2E‐positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene‐signatures associated with metastasis in T2E‐positive and T2E‐negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis‐associated gene‐signatures regarding the T2E‐status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E‐status. Using gene‐set enrichment analyses, we uncovered that metastatic T2E‐positive and T2E‐negative PCa are characterized by distinct gene‐signatures. In addition, by testing genes shared by several functional gene‐signatures for their association with event‐free survival in a validation cohort (n = 272), we identified five genes (ASPN, BGN, COL1A1, RRM2 and TYMS)—three of which are included in commercially available prognostic tests—whose high expression was significantly associated with worse outcome exclusively in T2E‐negative PCa. Among these genes, RRM2 and TYMS were validated by immunohistochemistry in another validation cohort (n = 135), and several of them proved to add prognostic information to current clinicopathological predictors, such as Gleason score, exclusively for T2E‐negative patients. No prognostic biomarkers were identified exclusively for T2E‐positive tumors. Collectively, our study discovers that the T2E‐status, which is per se not a strong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that the molecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa

The clinical relevance of oliguria in the critically ill patient : Analysis of a large observational database

Funding Information: Marc Leone reports receiving consulting fees from Amomed and Aguettant; lecture fees from MSD, Pfizer, Octapharma, 3 M, Aspen, Orion; travel support from LFB; and grant support from PHRC IR and his institution. JLV is the Editor-in-Chief of Critical Care. The other authors declare that they have no relevant financial interests. Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Urine output is widely used as one of the criteria for the diagnosis and staging of acute renal failure, but few studies have specifically assessed the role of oliguria as a marker of acute renal failure or outcomes in general intensive care unit (ICU) patients. Using a large multinational database, we therefore evaluated the occurrence of oliguria (defined as a urine output 16 years) patients in the ICON audit who had a urine output measurement on the day of admission were included. To investigate the association between oliguria and mortality, we used a multilevel analysis. Results: Of the 8292 patients included, 2050 (24.7%) were oliguric during the first 24 h of admission. Patients with oliguria on admission who had at least one additional 24-h urine output recorded during their ICU stay (n = 1349) were divided into three groups: transient - oliguria resolved within 48 h after the admission day (n = 390 [28.9%]), prolonged - oliguria resolved > 48 h after the admission day (n = 141 [10.5%]), and permanent - oliguria persisting for the whole ICU stay or again present at the end of the ICU stay (n = 818 [60.6%]). ICU and hospital mortality rates were higher in patients with oliguria than in those without, except for patients with transient oliguria who had significantly lower mortality rates than non-oliguric patients. In multilevel analysis, the need for RRT was associated with a significantly higher risk of death (OR = 1.51 [95% CI 1.19-1.91], p = 0.001), but the presence of oliguria on admission was not (OR = 1.14 [95% CI 0.97-1.34], p = 0.103). Conclusions: Oliguria is common in ICU patients and may have a relatively benign nature if only transient. The duration of oliguria and need for RRT are associated with worse outcome.publishersversionPeer reviewe

Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas

Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins (MMR)) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer. This article is protected by copyright. All rights reserved

A double-blind randomized study on the toxicity of lidocaine and ropivacaine on sciatic nerve and biceps muscle of rats

The purpose of the study was to examine the damaging activity of Lidocaine and Ropivacaine on the sciatic nerve and biceps muscle of rats. A double blind randomized study was conducted. The control group received injectiona of 0.9% NaCl. The following concentrations of Lidocaine were examined – 0.5, 1, 1.5, and 2. For Ropivacaine, these concentrations were 0.25, 0.5, 0.75, and 1. Under the US control, 0.2 ml were injected along the perineural sciatic nerve and 0.2 ml into the two-headed muscle. The drugs were taken out in 1 hour after their injection. When injecting 0.9% NaCl no cell necrosis or apoptosis in the muscle and nerve were found, only single cells of inflammatory type were found. The administration of all concentrations of local anesthetics caused inflammatory filtration and damage to muscle tissue and nerve stems compared to 0.9% NaCl. Increased expression of damage and inflammatory infiltration depended on the concentration of the local anesthetic. The higher the concentration of Lidocaine or Ropivacaine was, the greater were the damage and inflammatory changes. The study demonstrated neurotoxic and miotoxic activity of all concentrations of Lidocaine and Ropivacaine compared to 0.9% NaCl. The dependence of damage strengthening and the growth of inflammatory filtration in the muscle and peripheral nerve on the increased concentration of the local anesthetic was revealed