Treatment of Metastatic Renal Cell Carcinoma with Checkpoint Inhibitors in Clinical Practice in the Volga-Ural Region of the Eurasian Continent.

INTRODUCTION: Renal cancer ranks 10th in the mortality structure of the Russian Federation. The introduction of checkpoint inhibitors has changed the paradigm of treatment of patients with malignant neoplasms. METHOD: Data from clinical trials have shown good progression-free median and median overall survival. Each cancer center has been accumulating its own experience in treating patients with renal cell cancer by applying modern target drugs and immunotherapy. RESULT: In routine clinical practice, oncologists do not get the results that have been demonstrated in clinical trials when evaluating the effectiveness of the therapy. CONCLUSION: In this single-center clinical study, we discuss the results of using nivolumab as mono-therapy and the combination of nivolumab with ipilimumab in metastatic renal parenchyma cancer patients.

miRNA Expression Patterns in Early- and Late-Stage Prostate Cancer Patients: High-Throughput Analysis.

Prostate cancer (PCa) is one of the most common types of cancer among men. To date, there have been no specific markers identified for the diagnosis and prognosis or response to treatment of this disease. Thus, there is an urgent need for promising markers, which may be fulfilled by small non-coding RNAs known as microRNAs (miRNAs). Therefore, the present study aimed to investigate the miRNA profile in tissue samples obtained from patients with PCa using microarrays, followed by reverse transcriptase quantitative PCRs (RT-qPCRs). In the discovery phase, 754 miRNAs were screened in tissues obtained from patients (n = 46) with PCa in early and late stages. Expression levels of miRNA-324-3p, miRNA-429, miRNA-570, and miRNA-616 were found to be downregulated, and miRNA-423-5p expression was upregulated in patients with early-stage cancer compared to the late-stage ones. These five miRNAs were further validated in an independent cohort of samples (n = 39) collected from patients with PCa using RT-qPCR-based assays. MiRNA-324-3p, miRNA-429, miRNA-570, and miRNA-616 expression levels remained significantly downregulated in early-stage cancer tissues compared to late-stage tissues. Remarkably, for a combination of three miRNAs, PSA levels and Gleason scores were able to discriminate between patients with early-stage PCa and late-stage PCa, with an AUC of 95%, a sensitivity of 86%, and a specificity close to 94%. Thus, the data obtained in this study suggest a possible involvement of the identified miRNAs in the pathogenesis of PCa, and they may also have the potential to be developed into diagnostic and prognostic tools for PCa. However, further studies with a larger cohort are needed.

MicroRNA Expression Signatures in Clear Cell Renal Cell Carcinoma: High-Throughput Searching for Key miRNA Markers in Patients from the Volga-Ural Region of Eurasian Continent.

Clear cell renal cell carcinoma (ccRCC) is characterized by high molecular genetic heterogeneity, metastatic activity and unfavorable prognosis. MicroRNAs (miRNA) are 22-nucleotide noncoding RNAs that are aberrantly expressed in cancer cells and have gained serious consideration as non-invasive cancer biomarkers. We investigated possible differential miRNA signatures that may differentiate high-grade ccRCC from primary disease stages. High-throughput miRNAs expression profiling, using TaqMan OpenArray Human MicroRNA panel, was performed in a group of 21 ccRCC patients. The obtained data was validated in 47 ccRCC patients. We identified nine dysregulated miRNAs (miRNA-210, -642, -18a, -483-5p, -455-3p, -487b, -582-3p, -199b and -200c) in tumor ccRCC tissue compared to normal renal parenchyma. Our results show that the combination of miRNA-210, miRNA-483-5p, miRNA-455 and miRNA-200c is able to distinguish low and high TNM ccRCC stages. Additionally, miRNA-18a, -210, -483-5p and -642 showed statistically significant differences between the low stage tumor ccRCC tissue and normal renal tissue. Contrariwise, the high stages of the tumor process were accompanied by alteration in the expression levels of miRNA-200c, -455-3p and -582-3p. Although the biological roles of these miRNAs in ccRCC are not totally clear, our findings need additional investigations into their involvement in the pathogenesis of ccRCC. Prospective studies with large study cohorts of ccRCC patients are important to further establish the clinical validity of our miRNA markers to predict ccRCC.

Exosomal MicroRNA Levels Associated with Immune Checkpoint Inhibitor Therapy in Clear Cell Renal Cell Carcinoma.

Immunotherapy with immune checkpoint inhibitors (ICIs) has shown high efficiency in clear cell renal cell carcinoma (ccRCC) treatment. However, the response to therapy among patients varies greatly. Modern studies demonstrate the high potential of exosomal miRNAs as diagnostic and prognostic markers in oncopathology. This study aimed to evaluate exosomal miRNA expression profiles of miRNAs-144, -146a, -149, -126, and -155 in patients with clear cell renal cell carcinoma treated with immune checkpoint inhibitors. The study included 35 patients whose venous blood samples were taken before and after ICI therapy. Expression analysis was performed using real-time quantitative PCR. It was demonstrated that the level of microRNA-146a increased after therapy (median(IQR) 12.92(4.06-18.90)) compared with the level before it (median(IQR) 7.15(1.90-10.50); p-value = 0.006). On the contrary, microRNA-126 was reduced after therapy with immune checkpoint inhibitors (median(IQR) 0.85(0.55-1.03) vs. 0.48(0.15-0.68) before and after therapy, respectively; p-value = 0.0001). In addition, miRNA-146a expression was shown to be reduced in patients with a higher grade of immune-related adverse events (p-value = 0.020). The AUC value for the miRNA-146a and miRNA-126 combination was 0.752 (95% CI 0.585-0.918), with the sensitivity at 64.3% and the specificity at 78.9%. Thus, while it can be assumed that miRNA-146a and miRNA-126 can be used as predictors for ICI therapy effectiveness, additional in-depth studies are required.

Exosomal miRNA-155 and miRNA-146a are promising prognostic biomarkers of the severity of hemorrhagic fever with renal syndrome.

Introduction: Hemorrhagic fever with renal syndrome (HFRS), caused by Orthohantaviruses, occupies one of the leading places among natural focal human diseases, for which there are no modern accurate and highly sensitive diagnostic methods. To improve this situation, a better understanding of the Hantavirus pathogenesis of HFRS is required. Determination of the expression level of exosomal microRNAs (miRNAs) in the serum/plasma of patients makes them potential biomarkers for diagnosing and predicting HFRS. The purpose of this study was to analyze the expression level of miRNA-146a, miRNA-126, miRNA-218, miRNA-410, miRNA-503 and miRNA-155 in patients with HFRS at different stages (fever stage, polyuric stage and convalescence stage) and with different severity of the course this disease. Materials and methods: The moderate group of patients with HFRS included 105 patients, the severe group included 99 patients, and the severe group with complications included 84 patients. Blood samples from patients with HFRS for molecular genetic analysis were collected three times: during the initial febrile period (days 1-4 of illness), the polyuric period (days 15-22 of the disease), and during convalescence. Total RNA isolation was performed using the exoRNeasy Midi Kit (Qiagen, Germany). Quantitative real-time PCR (qRT-PCR) was performed using the miRCURY LNA SYBR Green PCR Kit (Qiagen, Germany) and the LightCycler96 real-time PCR product detection system (Roche, Switzerland). Results: When comparing the expression level of exosomal miRNAs in groups of patients with different severity of the disease, a statistically significant increase in the expression level of miRNA-146a was revealed in patients with severe HFRS with complications (Fold change 2.694; p = 0.0022) compared to the group with a moderate disease form, as well as an increase in miRNA-155 expression in patients with severe and severe HFRS with complications compared to the moderate form (Fold change 1.861; p = 0.0492; Fold change 1.976; p = 0.001, respectively). Comparative analysis of the expression level of other miRNAs in patients with HFRS at various stages and with different severity of HFRS did not reveal any statistically significant results (P > 0.05). Conclusions: MiRNA-155 and miRNA-146a may be promising prognostic biomarkers in HFRS. However, further investigations are needed to evaluate the changes in the expression of miRNAs and the network of genes that can be potential targets for the studied miRNAs in order to elucidate the molecular mechanisms that can influence the occurrence and development of HFRS.

MicroRNA Processing Pathway-Based Polygenic Score for Clear Cell Renal Cell Carcinoma in the Volga-Ural Region Populations of Eurasian Continent.

The polygenic scores (PGSs) are developed to help clinicians in distinguishing individuals at high risk of developing disease outcomes from the general population. Clear cell renal cell carcinoma (ccRCC) is a complex disorder that involves numerous biological pathways, one of the most important of which is responsible for the microRNA biogenesis machinery. Here, we defined the biological-pathway-specific PGS in a case-control study of ccRCC in the Volga-Ural region of the Eurasia continent. We evaluated 28 DNA SNP variants, located in microRNA biogenesis genes, in 464 individuals with clinically diagnosed ccRCC and 1042 individuals without the disease. Individual genetic risks were defined using the SNP-variant effects derived from the ccRCC association analysis. The final weighted and unweighted PGS models were based on 21 SNPs, and 7 SNPs were excluded due to high LD. In our dataset, microRNA-machinery-weighted PGS revealed 1.69-fold higher odds (95% CI [1.51-1.91]) for ccRCC risk in individuals with ccRCC compared with controls with a p-value of 2.0 × 10-16. The microRNA biogenesis pathway weighted PGS predicted the risk of ccRCC with an area under the curve (AUC) = 0.642 (95%nCI [0.61-0.67]). Our findings indicate that DNA variants of microRNA machinery genes modulate the risk of ccRCC in Volga-Ural populations. Moreover, larger powerful genome-wide association studies are needed to reveal a wider range of genetic variants affecting microRNA processing. Biological-pathway-based PGSs will advance the development of innovative screening systems for future stratified medicine approaches in ccRCC.

The opportunities and challenges of telemedicine during COVID-19 pandemic.

At the end of 2019, patients with pneumonia of unknown etiology appeared in the city of Wuhan (China). After a short time, this infection affected not only the people of China but also the whole world. On March 11, 2020, the World Health Organization declared the disease a pandemic. A viral agent was identified - severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), and the disease itself was named "2019 novel coronavirus infection" (COVID-19). Telemedicine technologies are a form of medical care and training that can counteract the spread of a COVID-19 epidemic by eliminating direct contact of both medical workers with patients and medical workers and patients with each other. Lack of personal protective equipment, the suspension of clinical clerkship and supervision, and a reduction in the number of elective surgical cases inevitably affect medical and surgical education. Interesting solutions using virtual learning, video conferencing, social media, and telemedicine could effectively address the sudden discontinuation of medical education. In fact, it is currently the ideal combination of teleworking and study. Telemedicine can play an important role in this pandemic by minimizing the spread of the virus, leveraging healthcare providers' time, and alleviating the challenges of medical education. The aim of this study was to identify the role of telemedicine services in the management and controlling of diseases as well as on medical education during the COVID-19 outbreak.

Diagnostic and prognostic potential of circulating miRNAs for intracranial aneurysms.

Intracranial aneurysm (IA) is an abnormal focal dilation of an artery in the brain that results from a weakening of the inner muscular layer of a blood vessel wall. IAs represent the most common etiology of nontraumatic subarachnoid hemorrhage (SAH). Despite technological advances in the treatment and use of new diagnostic methods for IAs, they continue to pose a significant risk of mortality and disability. Thus, early recognition of IA with a high risk of rupture is crucial for the stratification of patients with such a formidable disease. MicroRNAs (miRNA) are endogenous noncoding RNAs of 18-22 nucleotides that regulate gene expression at the post-transcriptional level through interaction with 3'-untranslated regions (3'UTRs) of the target mRNAs. MiRNAs are involved in the pathogenesis of IAs, including in the mechanisms of formation, growth, and rupture. It is known that in many biological fluids of the human body, such as blood or cerebrospinal fluid (CSF), numerous miRNAs, called circulating miRNAs, have been detected. The expression profile of circulating miRNAs represents a certain part of the cells in which they are modified and secreted in accordance with the physiological or pathological conditions of these cells. Circulating miRNAs can be secreted from cells into human biological fluids in extracellular vesicles or can be bound to Ago2 protein, which makes them resistant to the effects of RNAse. Therefore, circulating miRNAs are considered as new potential biomarkers of interest in many diseases, including IA.

Novel MicroRNA Binding Site SNPs and the Risk of Clear Cell Renal Cell Carcinoma (ccRCC): A Case-Control Study.

BACKGROUND: Renal cell carcinoma represents 3% of all adult malignancies. MicroRNAs exhibit specific functions in various biological processes through their interaction with cellular mRNA involved in apoptosis and cell cycle control. Recent studies have reported the potential association of single-nucleotide polymorphisms (SNPs) in miRNA-binding sites of VHL-HIF1α pathway genes with renal cancer development and progression. OBJECTIVE: The objective of this study is to investigate SNPs invoking an alteration in the nature of interaction with miRNA binding sites of VHL-HIF1α pathway genes. PATIENTS & METHODS: Total 450 cases of histologically and clinically verified ccRCC and 490 controls were included in our study. Genotyping was performed using a TaqMan PCR allelic discrimination method. Kaplan-Meier method of statistical analysis was implemented to analyze the overall patient survival rate. RESULTS: Polymorphism rs10491534 in TSC1 gene was significantly associated with risk of developing advanced ccRCC. Allele G of rs1642742 in VHL gene was significantly prevalent in ccRCC compared with control group aged 55 and older (OR = 1.5566; CI [1.1532-2.1019]). Results from the dominant model combining individuals with AG or AA genotype showed that the A allele bearers of CDCP1 rs6773576 exhibited higher risk of death compared to GG carriers (HR 3.93, 95% CI 1.76-17.21, log-rank P = 0.0033). CONCLUSION: The present study delineated the association of miRNA binding site variants in VHL-HIF1α pathway genes with the ccRCC risk, which may affect clinical outcome.

Management strategy for cancer patients in the context of the COVID-19 epidemic.

Coronavirus infection 2019 (COVID-19) has emerged a very dangerous infectious disease that occurs as an acute respiratory viral infection with complications, including pneumonia with acute respiratory distress syndrome or respiratory failure with a risk of death. As already confirmed, COVID-19 is caused by the new severe acute respiratory syndrome-2 coronavirus (SARS-CoV-2). We describe our strategy for the management of cancer patients based on the experience of the medical staff of the Regional Clinical Oncology Center of the Republic of Bashkortostan. We hope this can serve as a guide for oncologists to provide emergency care in the context of the COVID-19 epidemic.

The Role of Long Non-Coding RNAs in Intracranial Aneurysms and Subarachnoid Hemorrhage.

Intracranial aneurysms (IAs) represent the most complex and relevant problem of modern neurology and neurosurgery. They serve as one of the main causes of non-traumatic subarachnoid hemorrhage (SAH), causing up to 85% of all cases of intracranial hemorrhage, which is associated with frequent disability and high mortality among patients. Unfortunately, the molecular mechanisms of the development and rupture of IAs are still under study. Long non-coding RNAs (lncRNAs) are non-coding RNAs that typically have a length of more than 200 nucleotides. It is known that lncRNAs regulate many processes, such as transcription, translation, cell differentiation, regulation of gene expression, and regulation of the cell cycle. In recent years, a lot of evidence has established their role in human diseases from oncology to cardiovascular disease. Recent studies have shown that lncRNAs may be involved in the pathogenesis of IAs. The study of lncRNAs and its targets in various pathological conditions of a person is a rapidly developing field, and it is likely that the knowledge obtained from these studies regarding the pathogenesis of intracranial aneurysms will have the potential to use lncRNAs in therapy, as well as in the diagnosis and prediction of high aneurysms risk of rupture.

The current state of MiRNAs as biomarkers and therapeutic tools.

MicroRNAs (miRNAs) are non-coding RNAs with a length of 18-22 nucleotides that regulate about a third of the human genome at the post-transcriptional level. MiRNAs are involved in almost all biological processes, including cell proliferation, apoptosis, and cell differentiation, but also play a key role in the pathogenesis of many diseases. Most miRNAs are expressed within the cells themselves. Due to various forms of transport from cells like exosomes, circulating miRNAs are stable and can be found in human body fluids, such as blood, saliva, cerebrospinal fluid, and urine. Circulating miRNAs are of great interest as potential noninvasive biomarkers for tumors, lipid disorders, diabetes mellitus, and cardiovascular diseases. However, the possibility of their use in the clinic is limited, and this is associated with a number of problems since currently there are significant differences between the procedures for processing samples, methods of analysis, and especially strategies for standardizing results. Moreover, miRNAs can represent not only potential biomarkers but also become new therapeutic agents and be used in modern clinical practice, which again confirms the need for their study.

MicroRNA-200 family expression analysis in metastatic clear cell renal cell carcinoma patients.

The aim of this study is to analyse the of expression levels of microRNA-200 family members in patients with metastatic clear cell renal cell carcinoma (ccRCC). Analysis of microRNA expression was performed on 23 paired DNA samples extracted from kidney tumour tissue and the surrounding normal renal parenchyma. MicroRna-200c was found to have significantly lower expression (in kidney tumour tissue compared to normal renal parenchyma. No other microRna-200 family members showed statistically significant differences in expression levels between tumour and normal kidney tissue. Recent data suggest that the role of microRNA-200c in tumour pathogenesis is rather contradictory, and the underlying mechanisms by which microRNA-200c affects the carcinogenic potential of malignant cells remains unclear and requires further investigation at the molecular level.