Search

Within the 9th European Framework programme, since 2021 EUROfusion is operating five tokamaks under the auspices of a single Task Force called ‘Tokamak Exploitation’. The goal is to benefit from the complementary capabilities of each machine in a coordinated way and help in developing a scientific output scalable to future largre machines. The programme of this Task Force ensures that ASDEX Upgrade, MAST-U, TCV, WEST and JET (since 2022) work together to achieve the objectives of Missions 1 and 2 of the EUROfusion Roadmap: i) demonstrate plasma scenarios that increase the success margin of ITER and satisfy the requirements of DEMO and, ii) demonstrate an integrated approach that can handle the large power leaving ITER and DEMO plasmas. The Tokamak Exploitation task force has therefore organized experiments on these two missions with the goal to strengthen the physics and operational basis for the ITER baseline scenario and for exploiting the recent plasma exhaust enhancements in all four devices (PEX: Plasma EXhaust) for exploring the solution for handling heat and particle exhaust in ITER and develop the conceptual solutions for DEMO. The ITER Baseline scenario has been developed in a similar way in ASDEX Upgrade, TCV and JET. Key risks for ITER such as disruptions and run-aways have been also investigated in TCV, ASDEX Upgrade and JET. Experiments have explored successfully different divertor configurations (standard, super-X, snowflakes) in MAST-U and TCV and studied tungsten melting in WEST and ASDEX Upgrade. The input from the smaller devices to JET has also been proven successful to set-up novel control schemes on disruption avoidance and detachment.

After a long device enhancement phase, scientific operation resumed in 2022. The main new device components are the water cooling of all plasma facing components and the new water-cooled high heat flux divertor units. Water cooling allowed for the first long-pulse operation campaign. A maximum discharge length of 8 min was achieved with a total heating energy of 1.3 GJ. Safe divertor operation was demonstrated in attached and detached mode. Stable detachment is readily achieved in some magnetic configurations but requires impurity seeding in configurations with small magnetic pitch angle within the edge islands. Progress was made in the characterization of transport mechanisms across edge magnetic islands: Measurement of the potential distribution and flow pattern reveals that the islands are associated with a strong poloidal drift, which leads to rapid convection of energy and particles from the last closed flux surface into the scrape-off layer. Using the upgraded plasma heating systems, advanced heating scenarios were developed, which provide improved energy confinement comparable to the scenario, in which the record triple product for stellarators was achieved in the previous operation campaign. However, a magnetic configuration-dependent critical heating power limit of the electron cyclotron resonance heating was observed. Exceeding the respective power limit leads to a degradation of the confinement.

In 2021 JET exploited its unique capabilities to operate with T and D–T fuel with an ITER-like Be/W wall (JET-ILW). This second major JET D–T campaign (DTE2), after DTE1 in 1997, represented the culmination of a series of JET enhancements—new fusion diagnostics, new T injection capabilities, refurbishment of the T plant, increased auxiliary heating, in-vessel calibration of 14 MeV neutron yield monitors—as well as significant advances in plasma theory and modelling in the fusion community. DTE2 was complemented by a sequence of isotope physics campaigns encompassing operation in pure tritium at high T-NBI power. Carefully conducted for safe operation with tritium, the new T and D–T experiments used 1 kg of T (vs 100 g in DTE1), yielding the most fusion reactor relevant D–T plasmas to date and expanding our understanding of isotopes and D–T mixture physics. Furthermore, since the JET T and DTE2 campaigns occurred almost 25 years after the last major D–T tokamak experiment, it was also a strategic goal of the European fusion programme to refresh operational experience of a nuclear tokamak to prepare staff for ITER operation. The key physics results of the JET T and DTE2 experiments, carried out within the EUROfusion JET1 work package, are reported in this paper. Progress in the technological exploitation of JET D–T operations, development and validation of nuclear codes, neutronic tools and techniques for ITER operations carried out by EUROfusion (started within the Horizon 2020 Framework Programme and continuing under the Horizon Europe FP) are reported in (Litaudon et al Nucl. Fusion accepted), while JET experience on T and D–T operations is presented in (King et al Nucl. Fusion submitted).

After 1917, under the influence of new social conditions, the beginning of industrialization in the USSR and the policy of development of the outskirts, a new type of migration emerged, entitled in official documents of that time as “relocating workers to remote areas”. The systematization of legislative regulation of this type of migration in the absence of well-established statistical accounting is the purpose of the study, the results of which are presented in this article. The 1920s became a noticeable frontier in the long history of Russia’s settlement of the eastern regions, but the costly practice of attracting specialists, developed in the mid-1920s in the framework of the departmental approach, cannot be considered effective from the point of view of the formation of a stable population in these areas.

Aim: to present the value of interventional radiology techniques in the treatment of a patient with liver metastasis of colorectal cancer.Key points. In 2013, a 60-year-old patient with stage IIIB sigmoid colon cancer, pT3N2M0 underwent resection of the sigmoid colon with the formation of hardware rectosigmoanastomosis, 6 courses of adjuvant chemotherapy were performed. In 2015, a control examination revealed metastatic liver damage. Liver resection could not be performed due to the small future residual volume, and systemic chemotherapy was not effective. The patient underwent 3 cycles of regional chemotherapy. Taking into account the pronounced positive dynamics, in the form of a decrease in tumor size and a decrease in cancer markers, the patient managed to perform an extended right-sided hemihepatectomy. No progression of the tumor process was detected during the follow-up.Conclusion. Modern possibilities of X-ray endovascular methods allow to achieve results in the treatment of patients with colorectal cancer metastases in the liver such as a decrease in metastases in size, that make liver resection possible.

Background: A palliative or symptomatic treatment is indicated for 7080% of patients with Klatskins tumor because of the advanced lesion volume and the patients grave condition. Hepatic arterial infusion chemotherapy, chemoembolization, radioembolization are successfully used in the treatment of hepatocellular carcinoma and liver metastases. Aim: to estimate the immediate and long-term results of photodynamic therapy (PDT) and its combination with hepatic arterial infusion in inoperable patients with Klatskin tumors. Methods: Between 2010 and 2021, 83 palliative PDT sessions (from 1 to 8, average 2.4) were performed in 82 patients as a single treatment or in combination with hepatic arterial infusion. In all cases, percutaneous transhepatic biliary drainage was previously performed; no chemotherapy was applied. Two groups of 48 patients were stratified according to the ECOG status (23) and the numbers of PDT sessions (no more than two). The treatment group of the combination therapy consisted of 24 patients (13 male, 11 female) aged 38 to 85 (mean 63) years with the ECOG status of 24 (mean 2.4). This group received PDT with hepatic arterial infusion using a GemCis regimen. On average, 1.4 PDT sessions were performed, the treatment started on the 89th (27225) day after the biliary drainage. The hepatic arterial infusion was performed on the 2d3th day after the PDT. The control group received only PDT and consisted of 24 patients (13 male, 11 female) aged 51 to 83 (66 on average) years, with the ECOG status of 23 (mean 2.6). On average, 1.4 PDT sessions were performed, starting on the 106th (32405) day after the biliary drainage. Results: There were no serious adverse events associated with PDT in both groups. Toxic complications of hepatic arterial infusion were observed in 13 of 24 patients (54%): III grade hematological (54%) and gastrointestinal (69%); all were eliminated with medical therapy. Complications of the percutaneous transhepatic biliary drainage in three patients (hemobilia, n=2, and sepsis, n=1) were estimated as grade III by the CIRSE classification (2017) and successfully treated without surgery. In the combination treatment group, the overall mean survival and median survival were higher than those in the control group: 327.939.8 days (10.9 mo) versus 246.931.2 days (8.2 mo) and 275 days versus 244 days. However, these differences did not reach the statistical significance (p=0.12). Conclusions: PDT is a safe method of a palliative treatment of critically ill patients with Klatskin tumor (ECOG 23). PDT alone has limited clinical efficacy. A combination of PDT and hepatic arterial infusion does not cause serious complications and may increase the survival rates.

Objective. To assess the overall and disease-free survival rates in patients with EGFR-mutated lung adenocarcinoma, who underwent surgery after achieving the objective response to tyrosine kinase inhibitor (TKI) therapy.Material and Methods. The overall and disease-free survival rates were analyzed in 18 patients with EGFR-positive lung adenocarcinoma, which was inoperable at presentation due to locally advanced disease or the evidence of distant metastasis. In accordance with the clinical standards, patients were recommended for TKI therapy. Surgical resection was performed after achieving the objective tumor response to TKI therapy. The control group included 23 patients with EGFR mutation-positive lung adenocarcinoma, who did not undergo surgery after receiving TKI therapy.Results. The study revealed a statistically significant effect of surgical resection on the overall survival (OS) in patients with EGFR mutation-positive stage III–IV lung adenocarcinoma after response to TKI therapy (p=0.004). However, there was no statistically significant effect on the disease-free survival (DFS) (p=0.40). There was a tendency to increase in the median OS in patients of the study group (46 months) compared to that in patients of the control group (26 months). Surgery in the study group was characterized with some technical difficulties associated with severe fibrosis. However, this did not affect the duration of surgery and the volume of blood loss.Conclusion. Tumor resection in patients with EGFR mutation-positive stage III–IV lung adenocarcinoma is feasible and safe, but requires highly qualified team surgeons in well-equipped medical centers. Our study revealed that the combination of EGFR-TKI and tumor resection provided better PFS and OS than EGFR-TKI alone. However, further studies are required.

Background. Novel agents immune checkpoint inhibitors fundamentally changed the prognosis for life in patients with metastatic and/or inoperable melanoma. The development, studies, and approval of a new original PD1 inhibitor in Russia in 2020 prompted the professional community to conduct a prospective observational study in the Russian Federation to assess the real-world efficacy and safety of prolgolimab, as real-world patients differ from the refined population in clinical trials. Aim. To evaluate the real-world efficacy and safety of prolgolimab in patients with metastatic and/or inoperable melanoma. Materials and methods. From October 2020 to October 2022, the study enrolled 700 patients with metastatic and/or inoperable melanoma receiving prolgolimab in real clinical settings in oncological institutions of various levels in the Russian Federation. The main inclusion criteria were: pathology-confirmed diagnosis of melanoma, metastatic and/or inoperable type, use of prolgolimab outside of clinical trials, and signed informed consent by the patient. Objective response rate (ORR) was considered the main criterion for evaluating the efficacy of therapy, and the safety criterion was the incidence of grade 34 adverse events. Statistical analysis was performed using the SPSS 20.0 software package. Results. The ORR for patients with skin melanoma treated with prolgolimab in the first line therapy (n= 207/337) was 48.3% (n=100), the disease stabilization was reported in 30.4% (n=63), and progression in 21.3% (n=44) of patients. There were no significant differences in response to therapy between patients with/withoutBRAFmutation, although ORR was higher in patients withBRAFmutation: the ORR for patients withBRAFmutation was 57.9% (n=33), and forBRAFnon-mutated patients, 44.4% (n=52;p=0.222). At a median follow-up of 5 months, the median PFS was 10 months (95% confidence interval 7.3512.64). The incidence of grade 34 treatment-related adverse events according to CTCAE 5.0 was 2% (n=12), and 12% (n=82) for grade 12 adverse events. Conclusion. The results confirm the high efficacy and satisfactory tolerability of prolgolimab in patients with metastatic and/or inoperable melanoma in real-world settings. There were no significant differences in ORR between patients with or withoutBRAFmutation.

Background: Transcutaneous transhepatic endobiliary forceps biopsy is an accepted method for verification of extrahepatic cholangiocarcinoma, but its sensitivity ranges from zero to 94%. In the recent years, optical coherence tomography (OCT) has been actively used to diagnose malignancies. Aim: To assess diagnostic accuracy of the OCT-assisted intraductal forceps biopsy in patients with Klatskin tumor. Materials and methods: From 2013 to 2021, 161 patients with preliminary diagnosis of Klatskin tumor were seen in Russian Scientific Center of Radiology and Surgical Technologies named after Academician A.M. Granov. The retrospective study included 48 patients and 51 procedures of the forceps biopsy. In 14 (29%) patients of the main study group, the biopsy procedure was performed with OCT assistance, whereas the control group (34 patients, 71%) had their biopsies without the OCT. Results: All procedures were technically successful. In the main and in the control study groups, sensitivity was 92.3% versus 73.3% (p = 0.32) and specificity 100% versus 85.7% (p = 0.88), respectively. Malignant neoplasm of the biliary tract was found in 13 cases versus 23 in the control group, with the degree of the tumor differentiation being determined in 64.3% (n = 9), versus 48.7% (n = 18) (p = 0.89), respectively. There were no adverse events associated with OCT and biopsy sampling in the main study group. In the control group, 4/37 procedures (10.8%) were associated with hemobilia, which was successfully treated conservatively within 24 hours without any prolongation of the hospital stay. Conclusion: Our preliminary results indicate that antegrade endobiliary forceps biopsy is a safe and informative technique. The OCT navigation increases the sensitivity and specificity of the diagnosis. This allows for a personalized choice of chemotherapy. OCT is a promising technique for differential diagnosis of Klatskin tumor from benign biliary strictures. Further large-scale studies are required to introduce it into everyday practice.

Background: Surgical resection is the treatment of choice for Klatskin tumor, when possible, but unfortunately, many patients present with the late-stage and unresectable disease. A large number of studies have confirmed that arterial chemotherapy is safe and effective for the palliative treatment of primary and secondary hepatic malignancies. Aim: To evaluate the safety and efficacy of hepatic arterial infusion in patients with Klatskin tumor. Methods: Between 2010 and 2021, 14 of 119 patients with inoperable Klatskin tumor were treated with hepatic arterial infusion of GemCis at the A.M. Granov RRCRST. All the patients had obstructive jaundice and received percutaneous transhepatic biliary drainage. Chemotherapy was started when the serum bilirubin level became normal (averagely on the 106th day from percutaneous transhepatic biliary drainage). In total, 19 (from 1 to 4 per patient) hepatic arterial infusion cycles were performed. Results: Percutaneous transhepatic biliary drainage complications such as cholangitis (n=2) and local peritonitis (n=1) developed in 3 patients (21%) and were successfully treated using minimally invasive techniques. The toxicity of chemotherapy was observed in 8 of 14 patients (57%): III degree hematological toxicity (43%) and gastrointestinal toxicity (50%); these complications were cured by medical therapy. The overall mean survival was 286 days (9.6 months), the median survival was 283 days (9.4 months). Conclusions: Our preliminary results show that hepatic arterial infusion in patients with Klatskin tumor is safe, but has limited effectiveness. The combination of arterial infusion with other methods such as radiotherapy, intra-ductal photodynamic therapy, radiofrequency ablation, target therapy, should be investigated.

Introduction. The emergence of new epidemiologically significant variants of SARS-CoV-2 has shifted emphasis to development of a live vaccine, which would be able to provide protection against a wide range of antigenic variants of the virus. The aim of the study was to obtain SARS-CoV-2 variants attenuated through cold adaptation and to provide their biological characterization. Materials and methods. The Dubrovka laboratory strain of SARS-CoV-2 and its variants were cultured on Vero and Calu-3 cells. The virus quantification was performed by virus titration in Vero cells and by real-time reverse transcription-polymerase chain reaction. SARS-CoV-2 virions were analyzed using transmission electron microscopy. Genome sequences of the virus were identified by nanopore sequencing. The attenuation (att) phenotype of SARS-CoV-2 variants was identified using Syrian hamsters as an animal model for COVID-19. Results. Cold-adapted (ca) SARS-CoV-2 variants Dubrovka-ca-B4 and Dubrovka-ca-D2 were produced by continued passaging of the Dubrovka strain in the Vero cell culture at the temperature being gradually decreased to 23C and by subsequent cloning. Up to 20 nucleotide substitutions and 18 amino acid substitutions were detected in genomes of ca-variants. Ca-variants, as distinct from the parent Dubrovka strain, actively replicated at 23C, while the Dubrovka-ca-D2 variant had a temperature-sensitive (ts) phenotype (did not replicate at 39C). Ca-variants of the virus replicated poorly at 37C in the Calu-3 human lung cell culture, which, along with the ts-phenotype, can be a marker of virus attenuation for humans. In the intranasally infected Syrian hamsters, ca-variants of the virus demonstrated an attenuation phenotype: they did not cause loss of appetite, fatigue, drowsiness, did not slow down weight gain, replicating much more slowly in the lungs and brain compared to the virulent Dubrovka strain. Conclusion. The obtained attenuated SARS-CoV-2 ca-variants, Dubrovka-ca-B4 and Dubrovka-ca-D2, should be studied further as candidate vaccine strains for a live attenuated vaccine against COVID-19.

Aim. To evaluate the safety and accuracy of percutaneous transhepatic biliary biopsy in patients with suspected Klatskin tumor.Materials and methods. Between 2013–2020, percutaneous transhepatic biliary drainage (PTBD) was performed in 52 patients with Klatskin tumor, complicated by obstructive jaundice. After successful PTBD, the diagnosis was verified by antegrade access. 74 procedures were performed: brush (n = 36; 48.6 %) or forceps biopsies (n = 38; 51.4 %).Results. There were no adverse events associated with a brush biopsy. Only grade I complications were after the forceps technique: 3 patients (7.9 %) developed hemobilia, which was corrected conservatively. Malignant lesions of the biliary tract were detected by forceps technique in 79.0 %, brush biopsy in 66.7 % (p >0,05). The degree of tumor differentiation was determined in 60.0 % (n = 18) vs 12.5 % (n = 3) (p < 0,01), respectively.Sensitivity and specificity of forceps biopsy were slightly higher than in brush: 82.4 % and 75.0 % vs 73.3 % and 66.7 % (p >0,05).Conclusions. Antegrade percutaneous transhepatic biliary biopsy is safe for both brush and forceps techniques. However, forceps biopsy has higher sensitivity and specificity in the diagnosis Klatskin tumor and better possibility of determining the degree of malignancy differentiation.

A central event in the pathogenesis of Alzheimer’s disease (AD) is the accumulation of senile plaques composed of aggregated amyloid-β (Aβ) peptides. The main class of drugs currently used for the treatment of AD are the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In this study, it has been shown that Aβ augmented AChE activity in vitro, maximum activation of 548 ± 5% was achieved following 48 h of incubation with 10 μM of Aβ1–40, leading to a 7.7-fold increase in catalytic efficiency. The observed non-competitive type of AChE activation by Aβ1–40 was associated with increased Vmax and unchanged Km. Although BChE activity also increased following incubation with Aβ1–40, this was less efficiently achieved as compared with AChE. Ex vivo electrophysiological experiments showed that 10 μM of Aβ1–40 significantly decreased the effect of the AChE inhibitor huperzine A on the synaptic potential parameters.

Rationale: Non-small cell lung cancer (NSCLC) is an aggressive disease with median survival of 1214 months in inoperable patients in the pre-immunotherapy era. Nowadays, under treatment with checkpoint inhibitors median survival is 1922 months. However, only a proportion of patients are sensitive to immune therapy. In this regard, inclusion into clinical trials remains a priority option for patients from medical perspective. Aim: To compare the results in NSCLC patients treated in accordance with the current clinical guidelines and in international clinical trials using the propensity score matching. Materials and methods: The study included data from 344 patients with histologically verified unresectable advanced NSCLC without activating mutations, who received the 1st line systemic medical therapy at various combinations (single agent chemotherapy, platinum doublet-based therapy, chemoimmunotherapy, single agent immunotherapy) within the compulsory health insurance (CHI), and from 90 patients, who received therapy in clinical trials. A direct comparison of long-term treatment results was carried out with the log-rank method. To exclude any influence of individual factors on survival rates, an univariate regression analysis and pseudorandomization accounting for these factors were carried out. Results: The direct comparison of the treatment results showed a higher progression-free survival rate in the patients treated according to clinical trial protocols, than in those treated under CHI (13.3 [95% confidence interval (CI) 8.118.5] months vs 6.4 [95% CI 5.96.9] months). Pseudorandomization of patients based on a combination of statistically significant parameters from the CHI and clinical trial groups showed a significantly longer time to progression in the trial group (13.3 [95% CI 8.318.3] vs 6.3 [95% CI 4.87.7] months). Conclusion: Participation in clinical trials is per se a factor that can significantly impact the longer duration of the treatment effect. This indicates the necessity of the most active use of this tool in clinical practice.

Background: Iron has dual properties: it may promote both tumor growth and cell apoptosis. Compared to healthy cells, cancer cells are more dependent on the iron levels. Ferroptosis can be triggered directly in cancer cells, which would result in their self-destruction. Identification of iron balance abnormalities and their correction could impact the effects of specific treatments in cancer patients. Aim: To assess the prevalence of iron deficiency in patients with metastatic colorectal cancer (mCRC) and to identify an association of low serum iron levels with clinical and morphological characteristics of the disease. Materials and methods: The study included 69 treatment-nave patients with mCRC. Iron deficiency was defined as low serum iron levels before the initiation of any specific therapy: serum iron concentration 10.7 mcmol/L in men and 9.0 mcmol/L in women. Results: The mean age of the mCRC patients was 61.1 years (range, 28 to 83 years), 35/69 (50.7%) were men. The bigger proportion of the tumors was left-sided (62.3%). In 48.3% of the patients, the disease was diagnosed at the metastatic stage. The most frequent locations of metastasis were liver (41.3%) and lungs (32.1%). 55.1% (38/69) of the patients had undergone a non-radical resection or primary curative surgery. KRAS mutations were found in 37.7% of the patients. Low serum iron levels were found in 53.6% (37/69) of the total sample of the mCRC patients and in 72.4% (19/38) of the patients with a non-resected primary tumor (p = 0.05). Conclusion: Irrespective on the clinical and morphological characteristics, the majority of patients with metastatic colorectal cancer have iron deficiency anemia before the initiation of specific anti-tumor therapy.

Objective: to demonstrate the experience of unresectable hilar cholangiocarcinoma treatment using neoadjuvant therapy followed by liver transplantation (LT).Materials and methods. From 2017 to 2021, six patients were included in the treatment protocol for unresectable Klatskin tumor followed by liver transplantation at Granov Russian Scientific Center for Radiology and Surgical Technology. The neoadjuvant therapy included endobiliary photodynamic therapy (PDT), as well as regional and systemic chemotherapy. Each method was used at least three times for 4 to 5 months with radiological evaluation and measurement of CA 19-9 levels. Patients were placed on the waiting list when the tumor marker reduced, or when there were no radiological signs of disease progression and there was no acute cholangitis. The recipients underwent laparoscopic abdominal revision for carcinomatosis and assessment of lymph nodes in the hepatoduodenal ligament with urgent morphological examination. Where there was no extrahepatic spread, LT was performed according to the classical technique with paracaval, para-aortic and hepatoduodenal lymphodissection, biliodigestive anastomosis by an isolated Roux loop of small intestine. The operation was performed in three patients, all of them were men aged 40 to 55 years (mean 48). The mean time from the start of treatment to transplantation was 9.3 months (range 6 to 14). Mean CA 19-9 level at the time of intervention was 81.3 IU/mL (8 to 212).Results. In three patients, CA 19-9 levels more than doubled on average over four months despite treatment. According to data from computed tomography RECIST assessment, two of the patients showed disease progression. In one patient, carcinomatosis was detected by diagnostic laparoscopy. In three patients, CA 19-9 levels decreased more than fourfold. Two of these patients were radiologically confirmed to have the disease stabilized, and one had a partial response. One patient died from sepsis three years after transplantation as a result of secondary biliary cirrhosis and biliary abscesses without signs of progression. Two patients are still alive after 6 and 21 months without signs of tumor progression.Conclusion. LT for unresectable Klatskin tumor is effective in controlling the bioactivity of the tumor through the use of neoadjuvant therapy

Objective: to compare the efficacy and toxicity of aflibercept and bevacizumab in combination with fOLfIRI in secondline therapy for patients with metastatic colon cancer.Materials and methods. we performed a retrospective analysis of data on patients with metastatic colon cancer treated in 9 clinics in the Russian federation. The inclusion criteria were as follows: metastatic or locally advanced colon cancer; treatment with bevacizumab or aflibercept plus fOLfIRI in the second-line therapy. The primary outcome measure was progression-free survival (PfS). Secondary outcome measures included objective response rate and incidence of adverse events.Results. A total of 271 patients with metastatic colon cancer who received second-line therapy with bevacizumab (n = 81) or aflibercept (n = 190) between 2014 and 2018 were selected for this study. Study groups were matched for main prognostic signs. The objective response rate was 18.1 % in the bevacizumab group and 20.5 % in the aflibercept group (p = 0.7). The median PfS was 5 months (95 % confidence interval 3.8–6.1) in the aflibercept group and 7 months (95 % confidence interval 0.81–2.1) in the bevacizumab group (hazard ratio 1.4; 95 % confidence interval 0.99–2.1; p = 0.04). multivariate regression analysis demonstrated that the type of the targeted drug independently had no effect on PfS (hazard ratio 1.3; 95 % confidence interval 0.9–1.9; p = 0.2). we observed no statistically significant differences in the incidence of complications of any grades between the groups (58 % vs 72 %, p = 0.1). Patients receiving aflibercept were more likely to develop grade III–Iv arterial hypertension (2 % vs 9.5 %) and diarrhea (0 % vs 5.4 %), whereas thrombotic complications were more common in the bevacizumab group (10 % vs 1.8 %).Conclusion. we observed no significant differences in objective response rate and PfS between patients with metastatic colon cancer receiving bevacizumab or aflibercept in combination with fOLfIRI as second-line therapy. The toxicity profiles were different. Our findings can be used for choosing an optimal targeted drug for second-line treatment.

Being an abundant renewable source of aromatic compounds, lignin is an important component of future bio-based economy. Currently, biotechnological processing of lignin through low molecular weight compounds is one of the conceptually promising ways for its valorization. To obtain lignin fragments suitable for further inclusion into microbial metabolism, it is proposed to use a ligninolytic system of white-rot fungi, which mainly comprises laccases and peroxidases. However, laccase and peroxidase genes are almost always represented by many non-allelic copies that form multigene families within the genome of white-rot fungi, and the contributions of exact family members to the overall process of lignin degradation has not yet been determined. In this article, the response of the Trametes hirsuta LE-BIN 072 ligninolytic system to the presence of various monolignol-related phenolic compounds (veratryl alcohol, p-coumaric acid, vanillic acid, and syringic acid) in culture media was monitored at the level of gene transcription and protein secretion. By showing which isozymes contribute to the overall functioning of the ligninolytic system of the T. hirsuta LE-BIN 072, the data obtained in this study will greatly contribute to the possible application of this fungus and its ligninolytic enzymes in lignin depolymerization processes.

Introduction. Giant phiKZ-like bacteriophages have a unique protein formation inside the capsid, an inner body (IB) with supercoiled DNA molecule wrapped around it. Standard cryo-electron microscopy (cryo-EM) approaches do not allow to distinguish this structure from the surrounding nucleic acid of the phage. We previously developed an analytical approach to visualize protein-DNA complexes on Escherichia coli bacterial cell slices using the chemical element phosphorus as a marker. In the study presented, we adapted this technique for much smaller objects, namely the capsids of phiKZ-like bacteriophages. Material and methods. Following electron microscopy techniques were used in the study: analytical (AEM) (electron energy loss spectroscopy, EELS), and cryo-EM (images of samples subjected to low and high dose of electron irradiation were compared). Results. We studied DNA packaging inside the capsids of giant bacteriophages phiEL from the Myoviridae family that infect Pseudomonas aeruginosa. Phosphorus distribution maps were obtained, showing an asymmetrical arrangement of DNA inside the capsid. Discussion. We developed and applied an IB imaging technique using a high angle dark-field detector (HAADF) and the STEM-EELS analytical approach. Phosphorus mapping by EELS and cryo-electron microscopy revealed a protein formation as IB within the phage phiEL capsid. The size of IB was estimated using theoretical calculations. Conclusion. The developed technique can be applied to study the distribution of phosphorus in other DNA- or RNA-containing viruses at relatively low concentrations of the element sought.

In the presented case, the patient after orthotopic liver transplantation from an optimal cadaveric donor against the background of a smooth postoperative period and satisfactory graft function was followed by a series of biliary complications in the form of ongoing necrosis of the bile ducts of the graft, which required repeated surgical interventions, which led to the formation of a separate bicholangiostomy. The patient was put on the waiting list for a repeated liver transplantation. The developed complications led to sepsis, multiple organ failure and unstable hemodynamics, that required using of substitution therapy and high doses of inotropic, vasopressor drugs. A decision was made to assign the patient a «high-urgency» status with priority graft obtaining, and the coordination centers of St. Petersburg, Moscow, Leningrad and Moscow Regions and FMBA were notified. From the assignment of the «high urgency» status to receiving an organ has passed 10 hours. Hepatectomy with the formation of a temporary portocaval shunt began in advance of the donor liver’s admission to the clinic, which made it possible to stabilize the hemodynamic parameters and the recipient’s condition. However, against the background of massive blood loss, at the stage of graft revascularization, two episodes of cardiac arrest occurred, requiring indirect heart massage with chest and diaphragm compressions. Due to severe peripheral circulatory insufficiency, dry gangrene of the nail phalanx of the right forefinger was developed. Nevertheless, from the first postoperative day and thereafter, the graft demonstrated satisfactory function. Two months after the repeated transplantation, the patient was discharged in satisfactory condition. Subsequently, the index finger was amputated. Six months after the second operation, the patient returned to the work of a teacher.

Human FACT (FACT) is a multifunctional histone chaperone involved in transcription, replication and DNA repair. Curaxins are anticancer compounds that induce FACT-dependent nucleosome unfolding and trapping of FACT in the chromatin of cancer cells (c-trapping) through an unknown molecular mechanism. Here, we analyzed the effects of curaxin CBL0137 on nucleosome unfolding by FACT using spFRET and electron microscopy. By itself, FACT adopted multiple conformations, including a novel, compact, four-domain state in which the previously unresolved NTD of the SPT16 subunit of FACT was localized, apparently stabilizing a compact configuration. Multiple, primarily open conformations of FACT-nucleosome complexes were observed during curaxin-supported nucleosome unfolding. The obtained models of intermediates suggest “decision points” in the unfolding/folding pathway where FACT can either promote disassembly or assembly of nucleosomes, with the outcome possibly being influenced by additional factors. The data suggest novel mechanisms of nucleosome unfolding by FACT and c-trapping by curaxins.

To date, liver transplantation remains the only effective treatment for patients with cirrhosis. Due to lack of other effective, alternative therapeutic methods, the search and development of new treatment technologies is problem number one. The development of cellular technologies is promising for use in clinical practice. Using this observation as an example, the safety and efficacy of cell therapy technology for prolonged stay on the liver transplant waiting list by a patient with cirrhosis is shown. After intraportal injection of autologous bone marrow-derived mononuclear cells, liver cirrhosis stabilized on the CTP and MELD-Na scales for 22 months of observation, which allowed the patient to wait for an organ and successfully undergo liver transplantation.

Purpose of the study. There is the generalized analysis of administration of vinflunine in real clinical practice in St.Petersburg Clinical Scientific and Practical Center of Specialized medical Care (oncological).Materials and methods. This analysis gathered 27 patients with urothelial carcinoma treated using this medicine in St.Petersburg Clinical Scientific and Practical Center of Specialized medical Care (oncological). We assessed efficacy, safety profile of vinflunine in this subset of patients.Results. Clinical efficacy of vinflunine (complete response + partial response + stable disease) was 51,86 %, one patient demonstrated complete response. Median of response duration accounts for 3,4 months. Adverse events were observed in 28,4 %, most of them were 1-2 grades. 2 patients stopped therapy due to adverse events.Conclusion. In our analysis vinflunine was more effective than in randomized clinical trial and other studies from real practice in Europe. Thus, confirm expediency to administer of vinflunine for metastatic urothelial carcinoma.

Introduction. mBRAF mCRC has the aggressive phenotype. The incidence of such mutation in Europe and the USA is around 8–14%, in Asian countries – 4–8%. The purpose of this population-based study was to determine the incidence and identifying prognostic factors in pts with mBRAF mCRC in Russia. Materials and methods. A multicenter retrospective analysis of clinical data and treatment results of pts with mBRAF mCRC was performed. The main method for determining mutations was a PCR. The main efficacy endpoint was progression free survival (PFS) at the 1 st line. Multivariate analysis was performed using Cox regression model. Results and discussion. 437 out of 8648 pts (5.17%) with a known mutational status had mBRAF (V600). Clinical data were collected from 131/437 (30%): the right-sided primary tumor – in 58,6%, left-sided – in 19%, rectum – in 21,4%. ORR in pts with mBRAF was 31%, median PFS was 6 months. We didn’t revealed any differences between FOLFOXIRI and doublets (XELOX/FOLFOX or XELIRI/FOLFIRI) in terms of PFS (HR 0.9, 95% CI 0.49–1.52, р = 0.6) and OS (HR 1.5, 95% CI 0.61–4.1, р = 0.35) in pts with mBRAF. Conclusions. The incidence of mBRAF gene in the population of pts with mCRC in the Russia is low and we found a high incidence of localization of the primary tumor in the rectum. We didn’t reveal any differences between the usual duplets and standard regimen for such mutation - FOLFOXIRI in term of 1 st line PFS.

Objective: to compare the efficacy and tolerability of second‑line chemotherapy with original bevacizumab (Avastin) and biosimilar bevacizumab produced by “Biocad” (Avegra) in patients with metastatic colon cancer.Materials and methods. This retrospective observational study included patients with metastatic colon cancer treated in 9 clinics in the Russian Federation. Inclusion criteria were as follows: metastatic or locally advanced colon cancer and second‑line therapy with bevacizumab (Avastin or Avegra). The primary outcome measure was overall survival (OS). Secondary outcome measures included progression‑free survival (PFS), disease control rate (DCR), and incidence of adverse events associated with antiangiogenic therapy.Results. We identified 209 patients with metastatic colon cancer who received second‑line therapy with biosimilar bevacizumab (n = 37; 17.7 %) or original bevacizumab (n = 90; 43 %) or no targeted therapy (n = 82; 39.3 %) between 2014 and 2018. Patients in these three groups were matched for their main prognostic characteristics. The DCR was 59.5 % in the group of biosimilar bevacizumab, 58.9 % in the group of original bevacizumab, and 50 % in the control group (without targeted therapy). PFS was 6 months in the chemotherapy group and 8 months in the groups of bevacizumab (hazard ratio (HR) 0.77; 95 % confidence interval (CI) 0.65–0.91; p = 0.002); the difference in PFS between patients receiving biosimilar bevacizumab and original bevacizumab was insignificant (HR 1.3; 95 % CI 0.81–2.1; р = 0.3). Median OS was 16 months in the chemotherapy group, 30 months in the biosimilar bevacizumab group, and 20 months in the original bevacizumab group (HR 0.89; 95 % CI 0.72–1.1; р = 0.3). We observed a tendency to longer OS in patients receiving biosimilar bevacizumab (HR 0.44; 95 % CI 0.17–1.1; р = 0.08). Bevacizumab‑ associated toxicity was limited to arterial hypertension and was registered in 4 patients with only one patient who developed grade III hypertension.Conclusions. There was no significant difference in PFS between patients receiving biosimilar and original drug, while OS was higher in the group of biosimilar bevacizumab. Both medicines demonstrated similar toxicity. Therapy with biosimilar bevacizumab ensured lower incidence of hypertension and proteinuria compared to the original drug. An additional prospective observational study assessing the efficacy and tolerability of biosimilar bevacizumab in colon cancer patients is needed.

Background. Clinical reports on the coronavirus disease 2019 (COVID-19) suggest its higher incidence and worse outcomes in cancer patients. Considering a rapid pace of the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) pandemic, more data on the risk of contagion and syndrome course is required with this patient group.Aim. Estimation of the infection rate in cancer patients managed at the Oncology Centre.Materials and methods. This retrospective study included cancer patients managed at the Oncology Centre between 9 April 2020 and 27 May 2020 and routinely tested for SARS-CoV-2 in polymerase chain reaction (PCR) assays and/or COVID-19 in chest computed tomography (CT).Results and discussion. A total of 2,628 patients were included in the study, with 119 (4.5 %) confirmed to have COVID-19; 45/119 were PCR-positive, 95/119 had viral pneumonia in CT, 21/119 were positive for both tests. A total of 47.9 % cases were asymptomatic, 11.8 % revealed a mild single-symptom disease. COVID-19 ended in death in 2 (2.5 %) of 80 cases with a known outcome. In PCR results of both patient and staff screening, the virus detection rate was 3.0 % and 2.4 %, respectively (p = 0.33).Conclusion. A COVID-19 screening revealed no significant difference in the risk of contagion between cancer patients and staff of the Oncology Centre. PCR tests may perform false negative for COVID-19 in cancer patients and should be coupled with CT scanning. The infection is asymptomatic or clinically mild in most other cases.

Aim. Assessment of the utility and advantage of videoendoscopic inguinal femoral lymphadenectomy (VE-LAD) over the standard open technique (OLAD) in patients with malignant skin melanoma and metastatic lesions of regional inguinal and/or femoral lymph nodes.Materials and methods. The Saint-Petersburg Clinical Research Centre for Specialty Medical Aid in Oncology managed 86 inguinal femoral LADs in melanoma patients over 2013–2016. VE-LAD was rendered in 48 (54.7 %) cases, and OLAD otherwise.Results and discussion. A total of 72 patients were included in the study. VE-LAD was performed in 48 (54.7 %) cases, and OLAD otherwise. An average VE-LAD duration was 90 (60 to 160) min. Severe complications were observed in 4/48 (8 %) VE-LAD and 16/24 (66 %) OLAD cases, which reveals a significantly lower complication rate in the study cohort (chi-square p > 0.000). Lymphorrhoea was shorter in the study cohort (> 7 days in 5 patients vs. 3/24 and > 14 days only in 11/24 OLAD cases; chi-square p > 0.000). No significant differences in relapse-free survival were observed between the cohorts, with higher absolute values of 22.6 months in the VE-LAD (95 % CI 14.8–30.4, p = 0.087) vs. 9.4 months (95 % CI 0.0–18.9, p = 0.087) in OLAD cohort. A median OS was 52.3 months (95 % CI 30.5–74.1, p = 0.996) in the VE-LAD vs. 39.9 months (95 % CI 30.6–49.2, p = 0.996) in OLAD cohort.Conclusion. Videoendoscopic inguinal femoral lymphadenectomy allows a radical inguinal femoral lymph node removal alike in conventional surgical dissection. Our results indicate the method performance towards reduced postoperative wound complications. The oncological indicators are comparable to the traditional surgery cohort.

Background. Malignant melanoma is steadily exaggerating over the recent decades. Nonetheless, improved systemic therapies have substantially increased life expectancy in patients with a locally advanced or disseminated disease. Higherincidence recurrent melanocytic skin lesions become essentially problematic and require more attention and control.Aim. Cross-survey on the incidence of synchronous multiple primary melanomas in patients with solitary melanoma and those with other operable solid tumours.Materials and methods. A total of 289 patients with suspected malignant pigmented skin melanoma were included in the survey. Patients were divided in two cohorts by the presence of primary skin melanoma and its tractability for radical excision. Patients with operable melanoma comprised the study cohort, and those with other solid tumours were the control.Results and discussion. The survey covered 289 patients, with 148 in the study and 141 in the control cohort. The study148 patients revealed 112 malignant pigmented melanomas, but none in the control cohort. A chi-square statistical analysis of clinical values in single and multiple melanoma cases showed a slightly higher prevalence of first-visit melanomas in patients with synchronous tumours (30% pT4 — p = 0.007).Conclusion. The observed 10% rate of second melanoma in the study cohort and a zero melanoma incidence in the control support the alternative hypothesis of a higher rate of newly detected melanomas in primarily diagnosed melanoma patients vs. those with solid tumours.

Inactivated vaccines are promising tools for tackling the COVID-19 pandemic. We applied several protocols for SARS-CoV-2 inactivation (by β-propiolactone, formaldehyde, and UV radiation) and examined the morphology of viral spikes, protein composition of the preparations, and their immunoreactivity in ELISA using two panels of sera collected from convalescents and people vaccinated by Sputnik V. Transmission electron microscopy (TEM) allowed us to distinguish wider flail-like spikes (supposedly the S-protein’s pre-fusion conformation) from narrower needle-like ones (the post-fusion state). While the flails were present in all preparations studied, the needles were highly abundant in the β-propiolactone-inactivated samples only. Structural proteins S, N, and M of SARS-CoV-2 were detected via mass spectrometry. Formaldehyde and UV-inactivated samples demonstrated the highest affinity/immunoreactivity against the convalescent sera, while β-propiolactone (1:2000, 36 h) and UV-inactivated ones were more active against the sera of people vaccinated with Sputnik V. A higher concentration of β-propiolactone (1:1000, 2 h) led to a loss of antigenic affinity for both serum panels. Thus, although we did not analyze native SARS-CoV-2 for biosafety reasons, our comparative approach helped to exclude some destructive inactivation conditions and select suitable variants for future animal research. We believe that TEM is a valuable tool for inactivated COVID-19 vaccine quality control during the downstream manufacturing process.

Introduction. The presence of a germinal BRCA mutation occurs in 3–4% of all breast cancer (BC) patients with various biological subtypes, but significantly with a high frequency in patients with a triple negative biological subtype (in 10–20% of cases). For the treatment of patients with HER2-negative metastatic breast cancer associated with gBRCA mutation, the effectiveness of biologically targeted drugs from the group of PARP inhibitors (olaparib and talazoparib) has been proven.Purpose. Comparison of the results of our experience with the use of talazoparib in patients with HER2-gBRCA+ + mBC with the data of the EMBRACA registration study.Materials and methods. As part of the multicenter compassionate use program (CUP) with the support of Pfizer, 24 patients with HER2-negative metastatic gBRCA-associated mutation metastatic breast cancer (HER2-gBRCA+ breast cancer) received biologically targeted therapy with the PARP inhibitor talazoparib at a standard oral dose of 1 mg per day for vital indications . The average age of patients with HER2-gBRCAm+ breast cancer was 50 years (29–90 years).Results. Objective response (OR) was registered in 29% of cases, disease control (OR+stabilization) – in 71% of cases. The median progression-free survival (PFS) was 6.5 months (95% CI [3–10]). Objective response, disease control, and median PFS were evaluated depending on the biological subtype, the number of lines of previous therapy, and the presence of platinum-containing agents in the anamnesis.Objective response and disease control were evaluated depending on the biological subtype: in patients with ER+HER2-mBC versus patients with triple negative subtype, OR was 33% vs 22%, and disease control was 83% vs 61%, respectively. In the presence of < 3 vs ≥ 3 lines of therapy for metastatic disease in the anamnesis, OR was 31% vs 12.5%, disease control – 75% vs 50% of cases, respectively. In the presence or absence of platinum-containing agents in the anamnesis, OR was observed in 22% vs 33% of cases, and disease control – 67% vs 67%, respectively.In patients with the luminal subtype versus patients with the triple negative subtype, the PFS was 9 months vs 5 months, respectively (HR = 0.705; 95% CI [0.231–2.147]; p = 0.5208). Median PFS in the presence of

Introduction. Trifluridine/Tipiracil (FTD/TPI) is a new chemotherapeutic drug approved in more than 60 countries for use in patients with metastatic colorectal cancer who have registered progression or intolerance to treatment with fluoropyrimidines, oxaliplatin and irinotecan, anti-VEGRand anti-EGFR-targeted agents. This study evaluated for the first time the effectiveness and tolerability of FTD/TPI therapy in the Russian patient population.Materials and methods. A confirmatory open-label single-arm non-randomized trial was conducted in 2 clinical centres in Russia. The main criteria for inclusion were: conduction of at least the 2nd line of standard systemic therapy for metastatic colon adenocarcinoma. The primary efficacy criteria were: 2-month progression-free survival; secondary – median progressionfree survival, disease control frequency, safety assessment, overall survival. Research number: NCT03274882.Results. A total of 26 patients were included in the study; the median age was 60.5 years (30 to 78); 19 (73%) women; and 4 patients with ECOG 0 and 22 – with ECOG 1. All patients were previously treated with the inclusion of oxaliplatin, irinotecan, fluoropyrimidines, 21 (81%) – bevacizumab, 6 (23%) – anti-EGFR antibodies, and 2 (7.7%) – regorafenib. The median for treatment courses was 4 (1–21), 11 (42.3%) patients were treated for 6 months or more. The two-month progression-free survival rate was 52% with a median progreesion-free survival rate of 4 months (95% CI 1.8–7.4 months). The median of total survival rate was 11 months (95% CI 5,2–16,8 months). Disease control was achieved in 60%. Neutropenia, nausea, vomiting, anemia, weakness prevailed among undesirable events associated with treatment (≥5 patients). The majority of complications were of the 1st–2nd degree. Among the undesirable events of the 3rd–4th degree, neutropenia was more common, while in 3 patients febrile neutropenia of the 3rd degree was registered.Conclusions. In the Russian population of patients with colorectal chemorefractory cancer, the drug FTD/TPI (TAS-102) shows efficacy and tolerability comparable to the RECOURSE registration study.

Objective: classical methods of determining arterial blood supply of the graft following orthotopic liver transplantation (OLT) reflect the presence of blood flow in the trunk and large branches of the A. hepatica, without the characteristic of completeness of blood filling of peripheral sections, which is very important for objective evaluation of function. The aim of this study is to establish the diagnostic value of a direct perfusion study (IFlow) of the graft. Materials and methods. From 1998 to 2019, 245 OLTs were conducted. From 2015 to 2019, arterial changes were detected in 24 (23%) patients after 104 OLTs. A perfusion study was performed in 9 patients with suspected arterial graft failure. According to the IFlow study, liver hypoperfusion due to stenosis and/or splenic steal syndrome was detected in 8 cases and became an indication for therapeutic intervention. Results. Hepatic stenting and/or splenic artery embolization was performed to improve arterial blood supply to the liver. Endovascular procedures performed restored the perfusion index from 0.24 (0.01–0.89) to 0.61 (0.35–0.98). Conclusion. Absence of ultrasound and multispiral computed tomography signs of arterial complications does not rule out the need for perfusion angiography. Perfusion angiography allows to objectify the angiography data and perform corrective intervention in good time.

Lacticaseibacillus paracasei (formerly Lactobacillus paracasei) is a nomadic lactic acid bacterium (LAB) that inhabits a wide variety of ecological niches, from fermented foodstuffs to host-associated microenvironments. Many of the isolated L. paracasei strains have been used as single-strain probiotics or as part of a symbiotic consortium within formulations. The present study contributes to the exploration of different strains of L. paracasei derived from non-conventional isolation sources—the South African traditional fermented drink mahewu (strains MA2 and MA3) and kefir grains (strains KF1 and ABK). The performed microbiological, biochemical and genomic comparative analyses of the studied strains demonstrated correlation between properties of the strains and their isolation source, which suggests the presence of at least partial strain adaptation to the isolation environments. Additionally, for the studied strains, antagonistic activities against common pathogens and against each other were observed, and the ability to release bioactive peptides with antioxidant and angiotensin I-converting enzyme inhibitory (ACE-I) properties during milk fermentation was investigated. The obtained results may be useful for a deeper understanding of the nomadic lifestyle of L. paracasei and for the development of new starter cultures and probiotic preparations based on this LAB in the future.

Introduction. The randomized MPACT study showed that nab-paclitaxel plus gemcitabine results in statistically significantly longer life expectancy. The objective of this retrospective study is to obtain relevant data on the efficacy of this combination in real clinical practice in Russia. Materials and methods. The study included patients with morphologically proven locally advanced or metastatic pancreatic cancer, with a general condition assessed on the ECOG scale between 0-2, which received gemcitabine and nab-paclitaxel. Immediate and long-term treatment outcomes were evaluated. Results. 142 patients, who received treatment from 2009 to 2019 in 17 centers from 11 regions of Russia, were included in the study. Assessment of the objective effect was made in 134 patients. Objective effects were detected in 34 (25.4%) cases. The median time-to-progression was 6.1 months (95% confidence interval (CI) 4.8-7.4), the median length of life was 14.2 months (95% CI 10.6-17.9). An elevated CA19-9 level is the only independent adverse prognostic factor for progression-free survival (RR = 8.0, 95% CI 1.4 -43.8, p = 0.02) according to Cox multivariate regression analysis. The number of previously conducted chemotherapy lines (p = 0.34), ECOG status (p = 0.70), age over 70 years (p = 0.45), serious comorbidity (p = 0.97) did not have a statistically significant effect on progression-free survival. Findings. The gemcitabine and nab-paclitaxel combination has a relatively higher efficacy in advanced pancreatic cancer. The immediate and long-term results of its use in real clinical practice in Russia are consistent with data obtained in the Western countries.

Currently, functional dairy products pave a promising way for the prophylaxis of essential hypertension, and the search for new strains capable of producing such products is a constant challenge for scientists around the world. In this study, the antihypertensive properties of milk fermented with several strains of traditional yogurt starters (Lactobacillus delbrueckii strains Lb100 and Lb200; Lactococcus lactis strains dlA, AM1 and MA1; Streptococcus thermophilus strains 159 and 16t) and one strain of non-conventional probiotic starter (Lacticaseibacillus paracasei ABK) were assessed. The in vitro assessment using angiotensin-converting enzyme inhibition assay was performed for all fermentation products, and the best performed products were tested in vivo using Spontaneously Hypertensive Rat (SHR) animal model. In addition, for the best performed products the fatty acid (FA) composition and FA-related nutritional indices were determined. As a result, the milk fermented with two strains (Lb. delbrueckii LB100 and Lc. lactis AM1) demonstrated significant antihypertensive effect during both in vitro and in vivo experiments. Moreover, the milk fermented with Lb. delbrueckii Lb100 demonstrated significantly better FA-related nutritional indexes and lowered total cholesterol in SHRs upon regular consumption. The obtained results can be used in the future to develop new starter cultures producing effective functional antihypertensive dairy products.

Tick-borne encephalitis virus (TBEV) is an enveloped RNA virus, a member of the genus Flavivirus (family Flaviviridae). Here, we provide a detailed analysis of the size and structure of the inactivated TBEV vaccine strain Sofjin-Chumakov. Four analytical methods were used to analyze individual TBEV particles—negative staining TEM, cryo-EM, atomic force microscopy (AFM), and nanoparticle tracking analysis (NTA). All methods confirmed that the particles were monodisperse and that their mean size was ~50 nm. Cryo-EM data allowed us to obtain a 3D electron density model of the virus with clearly distinguishable E protein molecules. STEM-EELS analysis detected phosphorus in the particles, which was interpreted as an indicator of RNA presence. Altogether, the described analytical procedures can be valuable for the characterization of inactivated vaccine virus samples.

White-rot basidiomycete fungi are a unique group of organisms that evolved an unprecedented arsenal of extracellular enzymes for an efficient degradation of all components of wood such as cellulose, hemicelluloses and lignin. The exoproteomes of white-rot fungi represent a natural enzymatic toolbox for white biotechnology. Currently, only exoproteomes of a narrow taxonomic group of white-rot fungi—fungi belonging to the Polyporales order—are extensively studied. In this article, two white-rot fungi, Peniophora lycii LE-BIN 2142 from the Russulales order and Trametes hirsuta LE-BIN 072 from the Polyporales order, were compared and contrasted in terms of their enzymatic machinery used for degradation of different types of wood substrates—alder, birch and pine sawdust. Our findings suggested that the studied fungi use extremely different enzymatic systems for the degradation of carbohydrates and lignin. While T. hirsuta LE-BIN 072 behaved as a typical white-rot fungus, P. lycii LE-BIN 2142 demonstrated substantial peculiarities. Instead of using cellulolytic and hemicellulolytic hydrolytic enzymes, P. lycii LE-BIN 2142 primarily relies on oxidative polysaccharide-degrading enzymes such as LPMO and GMC oxidoreductase. Moreover, exoproteomes of P. lycii LE-BIN 2142 completely lacked ligninolytic peroxidases, a well-known marker of white-rot fungi, but instead contained several laccase isozymes and previously uncharacterized FAD-binding domain-containing proteins.

In this present case report during liver transplantation a patient was developed dissection of hepatic artery (HA) which was noticed after arterial reconstruction step. In one hour after surgery at intervention operating room stent placement of HA was performed. At early postoperative period by hepatic angiography study indicated for a second stent placement of HA, also embolization of splenic artery to treat a steal syndrome. After 2 weeks a patient developed thrombosis of recently placed stents which was required vascular reconstruction of HA by using autovenous graft. The condition complicated by development of a cholangiogenous hepatic abscesses and sepsis despite of all used possible methods of liver graft revascularization. However, used methods of vascular correction, which combined of timely carried out intensive care and antibiotic therapy according microbiology laboratory results allows saving graft function. After treatment of septic complications and patient’s somatic status stabilization and normalization of laboratory results liver retransplantation was performed.

Despite our achievements in modern medicine, arterial hypertension (AH) remains one of the main causes of fatal complications, such as myocardial infarction and acute cerebrovascular accident leading to disability and mortality of patients, including those of working age. The prevalence of hypertension is significantly higher among old and senile age population, however, it has recently tended to increase in young and middle-aged people. Thus, the Russian epidemiological ESSE-RF study, in which representative sample of the Russian population aged 25–64 years were studied, showed that the prevalence of hypertension in individuals of that age group was 44%. It was predicted that the world’s burden of hypertension would increase by 15–20% to approximately 1.5 million people in the year 2015. Due to the high incidence of hypertension and complications associated with hypertension development, further study of pathogenetic mechanisms, development of diagnostic examination methods, prophylactic measures and the search for new treatment options with fixed-dose combination drugs is an important area of modern medicine. This article provides an overview of clinical studies of the components (lisinopril and indapamide) of a rational ACE inhibitor–diuretic combination and a clinical example.

The article discusses the structural and semantic features of a regional newspaper text on environmental topics. The material contains 30 texts from the socio-political newspaper “Rech” of the city of Cherepovets, Vologda Oblast, published during 2017 - the Year of Ecology in Russia. It is shown that the newspaper text on environmental topics has the structure of an inverted pyramid, when important information is presented at the beginning of the article, and detailing is presented in the second part; the photographs accompanying the texts have a different visual-grammatical structure and can be interpreted as one-part and two-part sentences. In the semantic aspect, it is revealed that a larger number of contextual synonymous pairs than sets are formed; gradual antonyms are used; lexical units are included that fix the anthropocentric model of the interaction of man and nature. It is identified that there is a two-way interaction between the environmental event and the text: the event is the basis for creating the text, and vice versa, a newspaper text covering an environmental problem may precede one event or another. It is indicated that the newspaper text on environmental topics is characterized by a homogeneous presentation of the material, anthropocentricity and polyphonicity; softening the presentation of problematic information is achieved through the use of literary synonyms, gradual antonyms and relevant illustrations.

The article deals with the semantics of the term “populism” and its re-lexicalization via changing the meaning from neutral to negative. The author gives examples of the third-wave American populist leaders’ speeches, namely those made by Ugo Chaves, Nicolas Maduro, Evo Morales and Daniel Ortega, and reveals linguistic means of populism, as well as discursive strategies: proliferation (lexical loading) of key concepts, such as “pueblo”, “nación”, “patria” (“people”, “nation”, “motherland”), constructing discursive “I” in a pattern “I am my people”, the use of discursive strategies of polarization that helps political leaders delegitimize the opponent and construct the para-reality to legalize and symbolize self-power. The populist discourse is marked semantically by key words pueblo, nación, patria, special contextual coloring is designed with set expressions like la voz del pueblo (voice of the people), by forming occasional derivatives that break language norms, by actualizing oppositions “friend - enemy”, “acquaintance – stranger”, “people – outsider”, by applying to slogans and precedent phenomena. The participation of precedent phenomena in discursive strategies of populism is highlighted in the choice of precedent names (i.e. Simón Bolívar, Augusto César Sandino, Rubén Darío), it is directed at affiliating modern political leaders with prominent leader of the past, thus pointing to national values and providing legitemisy of the politicains in power.

Objective: to identify factors associated with efficacy of an aflibercept-chemotherapy combination in patients with metastatic colon cancer.Materials and methods. This retrospective multicenter study was conducted in 20 clinics from 15 regions of the Russian Federation. The main efficacy outcome was progression-free survival (PFS). We performed univariate and multivariate analysis to assess the impact of various factors of PFS.Results. Two hundred and fifty-seven patients received aflibercept-containing chemotherapy; of them, 175 participants (68.1 %) received it as a second-line therapy. The objective response rate and median PFS were 18.7% and 5 months (95% confidence interval (CI) 4.2—5.8) respec -tively. The following factors were found to have a positive effect of PFS at multivariate analysis: grade I—II adverse events to aflibercept therapy (hazard ratio (HR) 0.58; 95 % CI 0.38—0.89; p = 0.01), therapy for concomitant diseases (HR 0.47; 95 % CI 0.29—0.76; p = 0.002), and ECOG performance status of 0 (HR 0.53; 95 % CI 0.34—0.81; p = 0.004). Patient with all 3 factors present had median PFS of 9 months, whereas patients without them demonstrated PFS of only 3 months (HR 1.9; 95 % CI 1.5—2.6; p

Introduction. This article presents data on the manifestations of changes in the microenvironment of the peritoneal cavity in patients with carcinomatosis, expressed by the mineralization of the peritoneum, which in turn leads to functional changes in drainage of the peritoneal cavity.Materials and methods. We examined autopsy tissue of the peritoneum with symptoms of carcinomatosis and intact peritoneum using comparative scanning electron microscopy.Results and discussion. The study of the ultrastructure of peritoneum in patients with PC, revealed the phenomenon of SLL mineralization. The resulting elemental composition profile showed a high content of Ca, P, Na.Conclusions. 1. Carcinomatosis is not a local, but rather a systemic process. Determining the role of mineralization in carcinomatosis is of fundamental importance in carcinogenesis. 2. The serous membranes mineralization in patients with carcinomatosis can become a new treatment target, the impact on which may increase life expectancy and improve the quality of life. 3. The serous membranes demineralization can serve as a part of a combination treatment that includes the subsequent endolymphatic anti-tumour drug therapy.

Background: Acinetobacter baumannii is an opportunistic pathogen and one of the six most important multidrug resistant microorganisms in hospitals worldwide. Some of its strains are resistant to most of the antibiotics, A. baumannii is included into the Priority 1 part of Global Priority List of Antibiotic-resistant Bacteria. Phage therapy is considered to be an alternative strategy to antibiotic treatments. Methods: A. baumannii strain NIPH601 cells were grown till OD6000.4 and infected with the phage at MOI 10:1. After complete lysis took place cell debris was spined down and phage particles were precipitated with the PEG6000 (final concentration 10% PEG 6000, 0.5 NaCl). Virus particles were collected by centrifugation, resuspended at SM buffer and applied on CsCl step gradient. Gradient was spinned down for 2 hours at 40000g and the fraction containing phage particles was collected and dialyzed against SM buffer. Purified phage particles were applied to Quantifoil 1.2/1.3 grids and plunge-froze in Vitrobot Mark IV (TFS) Micrographs were collected in HKU, Shenzhen campus with Titan Krios cryoelectron microscope (TFS), equipped with Gatan K3 direct electron detector. The micrographs were acquired with 1.06 Å pixel size and 1.5 um average defocus value in counting mode with 50 frames and 1.2 e/Å2/frame dose rate. All image processing was performed with Relion3.0 software, except for the particle picking step performed with cryolo. Results: Lytic A. baumannii phage TaPaz belongs to the family Myoviridae. BLAST search over NCBI “nr” (non-redundant) database revealed close homology with previously published sequences of Acinetobacter phage vB_AbaM_B9 and Acinetobacter phage BS46. However, no structural information about any homologous proteins was found among the PDB structures. The cryo-EM map was reconstructed with single particle analysis independently for the capsid, tail and baseplate regions. The capsid was reconstructed at 3.9 Å resolution with I3 symmetry applied (Fig. 1A). The baseplate region of the phage was reconstructed at 3.5 Å resolution with C3 symmetry (Fig. 1B). The tail region was reconstructed at 2.6 Å resolution with helical symmetry (Rise 36.4 Å, Twist 25.7 deg). Initial atomic model for the tail region was built from sequence with Deeptracer and was further refined in coot (Fig. 1C). Conclusion: We successfully obtained the near-atomic resolution structural map of phage TaPaz. The data obtained contribute to enhancing knowledge of structural diversity of bacterial viruses infecting A. baumannii.

The objective was of the study to evaluate the role of preoperative x-ray endovascular interventions – transcatheter arterial chemoembolization (TACE) and portal vein embolization (PVE) – for improvement of resectability of colorectal liver metastases.Material and methods. Between 1997 and 2017, we treated 11 patients who simultaneously had large-volume (60–70 %) of right liver lobe colorectal metastases and small future remnant liver. The treatment was started from 1–4 cycles of TACE to reduce or stabilize the rapid growth of the tumor. In case of good effect, we performed PVE and then we performed liver resection.Results. There were no major complications of TACE or PVE. After 1–4 cycles of TACE, the volume of metastases showed partial decrease or stabilization. The following PVE allowed to increase the future remnant volume of the left liver lobe up to a safe 40–45 %. Right – sided hemihepatectomy was performed in 6 patients and extended right-sided hemihepatectomy in 5 patients. There were no postoperative mortality or severe complications. At present, 4 patients are alive without recurrence during 1.5–8 years, and 4 other patients received endovascular treatment for local recurrence are alive during 1.5–5 years. The 3 patients died from tumor progression during 13–30 months. CONCLUSION. In patients with simultaneously extensive for resection volume of right liver lobe metastases and small left liver lobe, the primary treatment with TACE is reasonable. Only after the documentation of tumor decrease or stabilization, it is necessary to determine the timing of PVE and following major liver resection. This order of treatment procedures allows to improve resectability in cases with extensive, large-volume, rapidly grown malignant liver lesions.