[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.

Transtraumatic Epidural Electrostimulation of the Spinal Cord in a Pig Model.

The effect of transtraumatic epidural electrostimulation (TEES) above (T5) and below (L2) spinal cord injury in the lower thoracic region (T8-T9) in combination with treadmill exercise in pigs was evaluated using electrophysiological examination methods and behavioral tests. Two weeks after spinal cord injury, motor evoked potentials of m. soleus were recorded during electrostimulation at the level of T5 and L2 segments, which indicated activation of spinal cord structures above and below the focus of injury. After 6 weeks of TEES in combination with physical training, restoration of the characteristics of M-response and H-reflex of the soleus muscle in response to stimulation of the sciatic nerve, improvement of joint mobility, and appearance of voluntary motor activity in the hindlimbs were observed. Neuromodulation with TEES had been proven to be an effective way to stimulate posttraumatic spinal cord regeneration and can be used in the development of a neurorehabilitation protocol for patients with spinal cord injury.

[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).

[Analysis of the results of ERAS protocol in real-life clinical practice AFTER radical cystectomy (the first prospective multicenter study in Russia)].

AIM: to carry out a multicenter prospective analysis of the results of the ERAS protocol in patients undergoing radical cystectomy in real-life clinical practice. The aims of the study were to assess the complication and mortality rate after radical cystectomy using the ERAS protocol and to assess how often ERAS protocol was imple- mented. MATERIALS AND METHODS: a multicenter study was carried out in 4 clinics in Russia. A total of 134 patients who underwent radical cystectomy in 2017 were prospectively analyzed. Open and laparoscopic radical cystectomy was performed in 35 (26.1%) and 99 (73.9%) patients, respectively. Bricker procedure prevailed as a method for urine derivation (91.7%). Complication and mortality rate, and each principle of ERAS protocol was analyzed both in the general sample of patients and separately for open and laparoscopic radical cystectomy. RESULTS: length of hospitalization before the radical cystectomy was 1 (1-2) day. The median duration of surgery was 260 (205-300) minutes, median blood loss was 300 (200-400) ml. The median of the patients time in ICU was 1 (0-2) day. A total of 95 (70%) complications were recorded in the 90-day period after the surgery, including Clavien I-II category in 52 (38.8%) cases and Clavien III-IV in 43 (32%) cases. Of these, gastrointestinal tract complications were predominated. Gastroparesis requiring a nasogastric tube was observed in 16 (11.9%) patients. Ileus developed in 43 (32.1%) cases, and 22 patients (16.4 %) were managed conservatively; however, 21 patients (15.7%) undergone to reoperation. A 90-days mortality reached 5.2% and the main causes included multiple organ failure as a complication of peritonitis, acute heart failure after myocardial infarction and massive bleeding. Re-hospitalization rate was 9.7% (n=13). Length of stay was 12 (9-16) days. According to univariate and multivariate analysis, an absence of antibacterial prophylaxis, a history of coronary heart disease and the patients age more than 75 years were predictors of an increased complication rate. A 30-days mortality rate is 5.2%, and re-hospitalization was required in 9.7% (n=13) cases. An average length of stay was 12 (9-16) days. Frequency of implementation of ERAS protocol in each of the participating clinic varied. Open and laparoscopic radical cystectomy have insignificant differences in some intra- and postoperative parameters, but, in general, both approaches are comparable in terms of complications, mortality, and length of stay. CONCLUSION: 1. Despite the use of the ERAS protocol, radical cystectomy has a high frequency of complications (up to 70%); most of them are Clavien I-II. A 30-days mortality rate is 5.2%, and re-hospitalization is required in 9.7% cases. 2. Univariate and multivariate analysis showed that an absence of antibacterial prophylaxis, a coronary heart disease and the patients age more than 75 years are predictors of an increased complication rate. 3. Open and laparoscopic radical cystectomy have insignificant differences in some intra- and postoperative parameters, but, in general, both approaches are comparable in terms of complications, mortality, and length of stay. 4. To obtain more convincing data on the ERAS protocol after radical cystectomy, long-term studies are required.

[DNA repair XRCC1, XPD genes polymorphism as associated with the development of bladder cancer and renal cell carcinoma].

We examined the correlations between the polymorphic alleles of the DNA repair genes XRCC1 (c.839G> A, rs25489; and c.1196A> G, rs25487), XPA (c.-4A> G, rs1800975), and XPD (c.2251A> C, rs13181) and the progression and severity of neoplasias in the bladder and kidney in patients of three distinct ethnic groups, Bashkir, Russians, and Tatar, residing in the Republic of Bashkorostan. The study enrolled 468 cancer patients and 351 healthy individuals. Genotyping for polymorphic alleles was carried out using the PCR-RFLP method. We identified a correlation between allele A of the c.839 G>A locus of the XRCC1 gene and the incidence of the bladder cancer (BC) and kidney cancer (KC) in the Tatar study group, using the additive genetic effects model (Odds Ratio (OR) = 5.23 and OR = 3.90). In turn, the heterozygous G/A genotype was present at a significantly higher frequency in the KC patients of Bashkir ethnic origin, compared with the control group (p = 0.0061, OR= 4.72). Additional analysis with consideration of participants' smoking status showed that the G/A genotype is significantly more frequent in smokers with BC (OR = 1.96, p = 0.05) then in healthy smokers. We also determined, using the recessive genetic model, that the genotype A/A of the c. 1196A>G locus of the XRCC1 gene was correlated with a higher risk of BC in the Russian cohort (OR = 2.29, p = 0.0082) and an increased incidence of KC in the Bashkir group (OR = 4.06, p = 0.05). A similar correlation was obtained for smokers. In contrast, the allele c.2251 A>C in the XPD gene correlated with a lower risk for BC and KC in the Tatars (p = 0.0003, OR = 0.48 and p < 0.0001, OR = 0.37) in the additive model and in the Bashkirs (p = 0.0083, OR = 0.12) and Russians (p = 0.0001, OR = 0.14) in the recessive model. Further, we uncovered that polymorphism c.839 G>A in the XRCC1 gene contributes to the progression of noninvasive and invasive BC and promotes KC at early and advanced stages of the disease. Thus, we identified similar correlations between DNA repair gene polymorphism and the incidence and progression of BC and KC. We propose that this result points to the involvement of common pathogenetic mechanisms in the initiation and progression of the urinary neoplasias.

[Results of open multicenter study of the safety of doxazosin in combination with indigal in men with stages I-II prostatic adenoma].

The article presents a method of conservative treatment of men with I-II stage prostatic adenoma using a combination of doxazosin and indigal, which has antioxidant, antiproliferative and anti-inflammatory properties, that allowed improving urodynamic parameters and reducing the progression prostate adenoma, minimizing the adverse effects of treatment.

Analysis of the efficiency of gene-cell therapy in transgenic mice with amyotrophic lateral sclerosis phenotype.

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by progressive death of cerebral and spinal motorneurons. Using behavioral tests we studied the efficiency of gene-cell therapy in SOD1 G93A transgenic mice receiving xenotransplantation of human umbilical cord blood mononuclear cells genetically modified with adenoviral vectors encoding vascular endothelial growth factor (VEGF) and reporter green fluorescent protein (EGFP) genes. The cells were transplanted to mice on week 27 of life (preclinical stage of the disease). Behavioral tests (open field, grip strength test) showed that transplantation of umbilical cord blood mononuclear cells expressing VEGF significantly improved the parameters of motor and explorative activity, grip strength, and animal survival. Thus, gene-cell therapy based on genetically modified mononuclear cells expressing VEGF can be efficient for the treatment of amyotrophic lateral sclerosis.