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.

Acceptance, Prevalence and Indications for Robot-Assisted Laparoscopy - Results of a Survey Among Urologists in Germany, Austria and Switzerland

Background: Robotic-assisted laparoscopy (RAL) is being widely accepted in the field of urology as a replacement for conventional laparoscopy (CL). Nevertheless, the process of its integration in clinical routines has been rather spontaneous. Objective: To determine the prevalence of robotic systems (RS) in urological clinics in Germany, Austria and Switzerland, the acceptance of RAL among urologists as a replacement for CL and its current use for 25 different urological indications. Materials and Methods: To elucidate the practice patterns of RAL, a survey at hospitals in Germany, Austria and Switzerland was conducted. All surgically active urology departments in Germany (303), Austria (37) and Switzerland (84) received a questionnaire with questions related to the one-year period prior to the survey. Results: The response rate was 63%. Among the participants, 43% were universities, 45% were tertiary care centres, and 8% were secondary care hospitals. A total of 60 RS (Germany 35, Austria 8, Switzerland 17) were available, and the majority (68%) were operated under public ownership. The perception of RAL and the anticipated superiority of RAL significantly differed between robotic and non-robotic surgeons. For only two urologic indications were more than 50% of the procedures performed using RAL: pyeloplasty (58%) and transperitoneal radical prostatectomy (75%). On average, 35% of robotic surgeons and only 14% of non-robotic surgeons anticipated RAL superiority in some of the 25 indications. Conclusions: This survey provides a detailed insight into RAL implementation in Germany, Austria and Switzerland. RAL is currently limited to a few urological indications with a small number of high-volume robotic centres. These results might suggest that a saturation of clinics using RS has been achieved but that the existing robotic capacities are being utilized ineffectively. The possible reasons for this finding are discussed, and certain strategies to solve these problems are offered

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

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

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

СОВРЕМЕННЫЙ ПОДХОД К ДИАГНОСТИКЕ РАКА ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ С ИСПОЛЬЗОВАНИЕМ МАГНИТНО-РЕЗОНАНСНОЙ СПЕКТРОСКОПИИ (КЛИНИЧЕСКОЕ ИССЛЕДОВАНИЕ)

By evaluating abnormal metabolism, magnetic resonance spectroscopy (MRS) is a highly effective tool for diagnosing prostate cancer (PC). Our study has indicated that the level of citrate (Ci) and the ratio of the content of choline (Cho) and creatine (Cr) to that of citrate ((Cho + Cr)/Ci) are the most sensitive and specific indicators. These may be effectively used separately (to diagnose tumor involvement and to determine the degree of tumor differentiation) and as a part of the authors’ discriminant model.The findings suggest that it is expedient to use MRS in the comprehensive diagnosis of PC.Благодаря оценке патологического метаболизма магнитно-резонансная спектроскопия (МРС) является высокоэффективным методом диагностики рака предстательной железы (РПЖ). По результатам нашего исследования наиболее чувствительными и специфически показателями служат содержание цитрата (Ci) и соотношение содержания холина (Cho)  и креатина (Cr) к содержанию цитрата (Cho + Cr/Ci). Эти показатели могут быть эффективно использованы по отдельности (для диагностики опухолевого поражения и определения степени дифференцировки опухоли), а также в составе разработанной нами дискриминантной модели.Полученные результаты свидетельствуют о целесообразности применения МРС в комплексной диагностике РПЖ

Клиническая значимость гене тической характеризации рака предстательной железы: обзор литературы

Molecular and genetic characterization of the prostate cancer seems to be a very relevant issue for clinical practice with regard to diagnostics, prognosis, treatment selection and assessment of therapy efficacy. A lot of fundamental studies assault the genetic basis of the disease and the differences in the phenotypic traits of prostate tumors. However, the significant gap is seen between the huge amount of studies to genetic characterization of prostate cancer, which often have a limited way to translation into the clinical practice or simply were not conceived to be so, and clinical practice. Substantial difficulties on the way are multifocality of the prostate carcinoma, inter- and intrafocal heterogeneity and abundance of recurrent genetic alterations, the role of which is understudied to date. In this review we have aimed at the providing an overview of the current studies, being the most close to translation in clinical practice. The common applications and problems are discussed.В последнее время предпринимаются многочисленные попытки выявления молекулярных генетических особенностей рака предстательной железы (РПЖ). Тем не менее, несмотря на большое количество исследовательских программ по молекулярной биологии и генетике, значение результатов этих работ остается неясным, а выводы имеют ограниченное применение в клинической практике. Во многом это связано с тем, что РПЖ характеризуется выраженной генетической гетерогенностью. Мы провели анализ литературы для выявления путей возможного клинического применения результатов фундаментальных генетических и молекулярно-биологических исследований в отношении РПЖ (трансляции в клинику), основных проблем, возникающих при этом, и перспектив развития данного направления

The Use of High Performance Liquid Chromatography for the Characterization of the Unfolding and Aggregation of Dairy Proteins

peer-reviewedHigh-performance liquid chromatography (HPLC) is routinely used to identify and characterize proteins. HPLC can help to understand protein aggregation processes in dairy products, which are induced by common industrial processing steps such as heat treatment. In this chapter, three complementary chromatographic methods are described, which are based on the principles of size exclusion and reversed-phase chromatography. These methods are used to determine the degree of denaturation and aggregation of proteins, and estimate the molecular weight of these aggregates