[Predictors of therapeutic efficacy of immune response checkpoint inhibitors in clear cell renal cell carcinoma].

Immunotherapy in oncologic diseases involves the use of drugs which stimulate the immune system and indirectly suppress tumor cells growth. These agents have expanded the treatment options for cancer patients. Despite the impressive success achieved in the development of immune checkpoint inhibitors (ICIs) and subsequent approval in a broader spectrum of malignant tumors, most patients are not responded the therapy. Currently available predictive markers of efficacy are nonspecific. However, microRNAs are of particular interest, which regulate gene expression and are involved in the carcinogenesis and therapy resistance. Therefore, it is clear that for the most efficient and cost-effective use of ICIs, it is important to have validated biomarkers that will accurately predict the therapeutic response. The published results on molecular genetic changes in patients with renal cell carcinoma (RCC) were analyzed and summarized in order to determine possible prognostic biomarkers when prescribing ICI therapy.

Exosomal miRNA-146a is downregulated in clear cell renal cell carcinoma patients with severe immune-related adverse events.

Here we report the results of the pilot project of exosomal miRNA expression levels in clear cell renal cell carcinoma (ccRCC) patients with different clinical response to ICIs (nivolumab) and treatment related toxicity. Immune-related adverse events (irAEs) are a major cause of immune checkpoint inhibitors cancellation and therapy failure. Modern studies demonstrate evidence that exosomes are of great importance in the formation of tumor resistance to ICIs drugs and therapy. We performed exosomal miRNA-146a expression analysis using qPCR on 86 ccRCC patients and revealed a statistically significant (p = 0.01) decreased expression level in ccRCC patients with CTCAE grade 3-4 (M±SEM 1.71 ± 0.13) compared to CTCAE grade 0-2 group (M±SEM 2.30 ± 0.24). The expression levels of miRNA-126, miRNA-218 and miRNA-410 did not show statistically significant differences in the comparison groups (p > 0.05). Association analysis of rs2910164 in the miRNA-146a gene demonstrated that CC genotype and C allele carriers had higher risk of developing severe irAEs (p = 0.03, OR = 6.12; p = 0.01, OR = 2.42, respectively) compare with GG and GC carriers. That is the first attempt to identify biomarkers of ICIs treatment efficacy for ccRCC in the Volga-Ural region based on exosomal miRNAs analysis.

Methylation and expression levels of microRNA-23b/-24-1/-27b, microRNA-30c-1/-30e, microRNA-301a and let-7g are dysregulated in clear cell renal cell carcinoma.

BACKGROUND: Renal cell carcinoma is the most common form of kidney cancer in adults. DNA methylation of regulatory sequences at the genomic level and interaction between microRNAs and the messenger RNAs of target genes at the posttranscriptional level contribute to the dynamic regulation of gene activity. Aberrations in these mechanisms can result in impaired functioning of cell signaling pathways, such as that observed in malignant tumors. We hypothesized that microRNA genes methylation may be associated with renal cancer in patients. METHODS AND RESULTS: We examined methylation levels of 22 microRNA genes in tumor and normal kidney tissue of 30 patients with TNM Stage III clear cell renal cell carcinoma using a pathway-specific real-time polymerase chain reaction array (EpiTect Methyl II PCR Arrays, Qiagen). MicroRNA expression analysis by quantitative polymerase chain reaction was also performed. Significant differences in methylation levels were found in two genes and in two clusters of microRNA genes. MicroRNA-23b/-24-1/-27b, microRNA -30c-1/-30e and let-7 g was hypermetylated in clear cell renal cell carcinoma tissue, microRNA -301a was hypomethylated in tumor compared with the adjacent normal tissues. Expression of microRNA-301a, microRNA-23b in the clear cell renal cell carcinoma tissues was significantly overexpressed when compared with the adjacent normal tissues and let-7 g was significantly downregulated in tumor. CONCLUSIONS: Our results may indicate the contribution of microRNA-301a, microRNA-23b and let-7 g in the pathogenesis of renal cancer, but further studies are needed to determine the functional significance of the detected changes.

[The potential role of mirnas in the pathogenesis of hemorrhagic fever with renal syndrome].

Hemorrhagic fever with renal syndrome (HFRS) is an acute natural focal viral disease caused by viruses of the genus hantavirus, characterized by damage to small blood vessels, kidneys, lungs and other organs of a person. MicroRNAs (miRNAs) are 18-22 nucleotide endogenously expressed RNA molecules that inhibit gene expression at the post-transcriptional level by binding to the 3-untranslated region of the target mRNA. It has been proven that miRNAs play a significant role in various biological processes, including the cell cycle, apoptosis, cell proliferation and differentiation. It has been proven that miRNAs may be involved in the pathogenesis of infectious diseases, including HFRS. Hantavirus infection predominantly affects endothelial cells and causes dysfunction of the endothelium of capillaries and small vessels. It is known that the immune response induced by Hantavirus infection plays an important role in disrupting the endothelial barrier. In a few studies, both in vitro and in vivo, it has been shown that endothelial dysfunction and the immune response after infection with Hantavirus can be partially regulated by miRNAs by acting on certain genes. Most of the miRNAs is expressed within the cells themselves. However, in some biological fluids of the human body, for example, plasma or blood serum, numerous miRNAs, called circulating miRNAs, have been found. Circulating miRNAs can be secreted by cells into human biological fluids as part of extracellular vesicles as exosomes or be part of an RNA-bound protein complex as miRNA-Argonaute 2 (Ago2). These miRNAs are resistant to nucleases, which makes them attractive as potential biomarkers in various human diseases. There is no specific antiviral therapy for HFRS, and the determination of laboratory parameters that are used to diagnose, assess the severity, and predict the course of the disease remains a challenge due to the peculiarities of the pathophysiology and clinical course of the disease. Studying the role of miRNAs in HFRS seems to be expedient for the development of specific and effective therapy, as well as for use as diagnostic and prognostic biomarkers (in relation to circulating miRNAs).

[Foveolar effects of dexamethasone intravitreal implant in central retinal vein occlusion].

AIM: To evaluate functional and morphometric parameters of the central retina in patients with postocclusive macular edema treated with dexamethasone intravitreal implant injection. MATERIAL AND METHODS: We examined 5 patients (5 eyes) with newly diagnosed central retinal vein occlusion complicated by macular edema, including 4 men and 1 woman aged 55.8±3.65 years (experimental group). All the patients received a single injection of dexamethasone intravitreal implant. The maximum follow-up period was 12 months. The control group consisted of 5 presbiopic patients (10 eyes) aged 59.14±3.14 years. RESULTS: One month after injection, the best corrected visual acuity (BCVA) and central retinal light sensitivity improved (from 0.09±0.03 to 0.19±0.05 and from 3.18±0.19 to 11.07±0.97 dB, correspondingly), while foveolar thickness decreased from 425.36±57.87 to 273.75±36.65 µm. One year after the treatment, BCVA remained high and averaged 0.21±0.14. The total light sensitivity also remained higher than that at baseline, however, decreased down to 4.8±0.76 dB. Optical coherence tomography showed some flatness of the fovea. Foveolar thickness appeared 1.5 times higher than that in the control group and 1.2 times higher than that at the 1-month follow-up after dexamethasone intravitreal implant injection. Over the whole follow-up period, IOP has never significantly exceeded the baseline, optical media remained clear. CONCLUSION: 1. Dexamethasone intravitreal implant has been shown effective in resolving postocclusive macular edema, improving visual functions, and increasing central retinal light sensitivity within the first month after injection. 2. Positive changes in morphometric parameters of the central retina induced by the injection involve inner segments of photoreceptors as well as the outer nuclear, outer plexiform and inner nuclear layers. The morphofunctional effect persists for no less than 12 months after injection. 3. Over the 1-year follow-up period, there has been no negative influence of the implant on either intraocular pressure level, or lens transparency.

[MicroRNAs as potential noninvasive markers in the diagnosis of urological malignancies].

Small non-coding RNAs (microRNAs) are involved in almost all biological mechanisms of carcinogenesis. Due to their stability in biological fluids microRNAs may serve a perspective biomarker for diagnosis and prognosis of oncological diseases. The review is dedicated to the analysis of microRNAs, as potential diagnostic markers of urological malignancies. Recent advances in the knowledge of miRNAs origin in body fluids, their stability and application as a potentially new class of biomarkers in medicine are summarized and discussed in the article.

[Mutational landscape of prostate tumors revealed by whole-exome sequencing].

The results of the whole-exome DNA sequencing of eight prostate adenocarcinoma patients are presented. DNA was isolated from the peripheral blood as well as healthy and tumor prostate tissue from each patient. Bioinformatics analysis was conducted and the most significant mutations in prostate cancer patients were revealed. The obtained data could be important for understanding of the molecular mechanisms of prostate cancer pathogenesis and facilitate development of new approaches for treatment of the disease.

[The Role of MiRNAs in the Development of Prostate Cancer].

MicroRNAs (MiRNAs) act as key post-transcriptional regulators of gene expression. This review examines current advances in the study of the role of miRNAs in cancer, including prostate cancer. Issues devoted to the nomenclature, biogenesis, the role of miRNAs as oncogenes and tumor suppressors, and their role in the diagnosis, treatment, and prognosis of prostate cancer are discussed. Assessment ofthe role of miRNAs in the development of prostate cancer will promote early diagnosis and will be important for the development of new approaches to the disease treatment.