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Introduction. Testicular germ cell tumor is a relatively rare disease. Its high social significance is due to the fact that this pathology occurs in young patients. The standard schemes of polychemotherapy determine the potential possibility of effective treatment for most of the patients even with an advanced disease. Several circulating markers (alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase) are being used for therapy monitoring, but the low diagnostic specificity of these molecules determines the need to develop new approaches. Over the past years, circulating microRNA, for instance miR-371a-3p, appeared to be promising marker for testicular germ cell tumor monitoring. However, to develop and to implement in practice the microRNA-based diagnostic technologies, it’s necessarily to understand the features of the microRNA expression alterations specific for different histological types of testicular germ cell tumor.The study objective – to evaluate changes in the expression of several potential marker microRNA molecules (miR-302/ miR-367, miR-371/miR-373) in testicular germ cell tumor samples of various histological types.Materials and methods. Testicular germ cell tumor samples (n = 61), including seminomas, embryonic carcinomas, post-pubertal teratomas, yolk sac tumors, chorioncarcinomas, and corresponding normal tissue samples (n = 61) were included in the study. The analysis of selected miRNA expression was performed by reverse transcription and polymerase chain reaction.Results. We identified the changes in the expression profile of the miR-302/miR-367 cluster typical for semines, embryonic carcinomas, post-pubertal teratomas, yolk sac tumors and chorioncarcinomas, as well as changes in the expression profile of the miR-371/miR-373 cluster, universal for all histotypes except chorioncarcinomas. Inhibition of miR-10b and miR-145 expression in semines, embryonic carcinomas, and post-pubertal teratomas was demonstrated.Conclusion. Activation of miR-302b, miR-302d, miR-371a expression and inhibition of miR-10b, miR-145 expression in the tissue of the most common variants of testicular germ cell tumor is a characteristic feature of these tumors. The detected changes are significant and can lead to corresponding changes in the profile of circulating microRNAs.

The article examines the functions of birds of prey in medieval German epic poems and chivalric romance. Despite a number of common European meanings assigned to falcons and hawks in medieval bestiaries and hunting treatises, the semantics of hunting birds may have differed significantly in works of different national and genre traditions. The Nibelungenlied and Kudrun were epic in origin and content, but created in the era of the courtesan. The poets’ desire to “modernize” the sound of ancient tales manifested itself at different levels of the text, including hunting birds’ scenes. These scenes also demonstrate the strength of the genre nature of these poems, when elements “borrowed” from the courtly culture are transformed to fit adequately into the epic text. The article analyses scenes involving hunting birds in the most important 13th-century chivalric romances by Hartmann von Aue, Wolfram von Eschenbach, Gottfried von Strassburg and Chrétien de Troyes.

ABSTRACTRuminococcus gnavus is a prevalent gut microbe reported to occur in higher abundance among individuals with inflammatory bowel disease (IBD). This study reports the isolation and characterization of six bacteriophages (phages) isolated from human fecal material and environmental samples that infect this species. Isolated phages have a siphovirus morphology, with genomes ranging between 36.5 and 37.8 kbp. Genome analysis indicates that the phages have a temperate lifestyle, which was confirmed by their ability to form lysogens on their host bacterial species. In contrast to the finding that phages lyse their host in liquid medium, results from a mouse trial indicate these phages can co-exist with the host bacterium in the gut without causing a significant reduction of R. gnavus. The bacterial counts in the feces of phage-treated mice did not significantly differ in the presence of phage. Furthermore, analysis of publicly available gut virome sequence data indicates a high abundance of these phages among individuals suffering from IBD. This work provides the first insight into how phages interact with R. gnavus in the human gut microbiome.

A longitudinal analysis of unamplified fecal virome of healthy controls and IBD patients reveals interpersonal variability is a factor that limits our ability to identify associations between the virome composition and IBD.

Introduction. It is known that fires are one of the most large-scale emergencies. It is possible to systematize and formalize their causes only if you take into account the effective analysis of statistical data. The scientific problem lies in the lack of effective mathematical tools and techniques that allow the use of fire statistics as an emergency prevention tool. The solution of this problem is relevant for science and technology. Based on the identified problem, the purpose of this study is formulated, which consists in the analysis of fire statistics and its formalization in predicting emergencies.Problem Statement. The objective of this study is to analyze the state and causes of fires, as well as to find a tool for their prediction.Theoretical Part. The methodological tools for solving this problem are the use of multiple regression and correlation analysis methods that allow criticizing and formalizing the available fire statistics. It is established that an acceptable parameter characterizing the reliability and closeness of the connection of empirical data with their mathematical function in relation to the task is the correlation coefficient.Conclusions. It is proved that an effective tool for predicting fires is the use of linear regression analysis methods. The practical significance of the results obtained for science and technology lies in the possibility of creating digital tools for predicting and preventing emergencies, which will significantly reduce resource costs for eliminating their consequences.

Abstract We compiled a human metagenome assembled plasmid (MAP) database and interrogated differences across multiple studies that were originally designed to investigate the composition of the human microbiome across various lifestyles, life stages and events. This was performed as plasmids enable bacteria to rapidly expand their functional capacity through mobilisation, yet their contribution to human health and disease is poorly understood. We observed that inter-sample β-diversity differences of plasmid content (plasmidome) could distinguish cohorts across a multitude of conditions. We also show that reduced intra-sample plasmidome α-diversity is consistent amongst patients with inflammatory bowel disease (IBD) and Clostridioides difficile infections. We also show that faecal microbiota transplants can restore plasmidome diversity. Overall plasmidome diversity, specific plasmids, and plasmid-encoded functions can all potentially act as biomarkers of IBD or its severity. The human plasmidome is an overlooked facet of the microbiome and should be integrated into investigations regarding the role of the microbiome in promoting health or disease. Including MAP databases in analyses will enable a greater understanding of the roles of plasmid-encoded functions within the gut microbiome and will inform future human metagenome analyses.

Background. Neoadjuvant chemotherapy (NACT) with dual anti-HER2 blockade has become a priority in the treatment of patients with HER2+ breast cancer (BC) stages IIIII. However, the question of the accordance of various systems for assessing tumor response to NACT, as well as identifying predictor factors for achieving a complete pathomorphological response (pCR) in HER2+ BC remains open. Aim. To assess the accordance of various systems for assessing tumor response to neoadjuvant chemotherapy (NACT) in patients with HER2+ BC and to identify predictor factors for achieving pCR and residual cancer burden. Materials and methods. The study included 49 women with HER2+ BC stage IIIII, who underwent NACT with anti-HER2 blockade, followed by surgical treatment and morphological analysis of the results. The median age of the patients was 47 years; 91.8% had tumor size T2, N+ status 71.4%; tumor grade G3 73.5%, luminal and non-luminal HER2+ subtype 44.9 and 55.1% of patients, respectively. Ki6730% was observed in 93.9% of cases, the level of TILs in the tumor was 10%, 1020% and 20% in 38.1, 9.5 and 52.4% of cases, respectively. The patients received combinations of anthracyclines and taxanes or the anthracycline-free regimen of docetaxel + carboplatin; 87.8% of patients received a dual blockade of trastuzumab + pertuzumab, and 12.2% trastuzumab. After the end of NACT, all patients underwent a radical surgery (mastectomy or breast-conserving) with an assessment of the pathomorphological response, the pathomorphological stage of ypTN, and the residual cancer burden according to the RCB system. Results. The rate of complete pathomorphological response (tpCR/RCB-0/ypT0N0) in HER2+ BC was 61.2%; significant predictors of achieving tpCR were only 3 factors: primary operable BC stages (T13N01) the rate of tpCR was 71.4%, the level of TILs20% the proportion of tpCR reached 95.5%, and the dual anti-HER2 therapy (trastuzumab + pertuzumab) tpCR was 65.1%. Residual tumor was presented by classes RCB-I, RCB-II, RCB-III in 10.2, 24.5, 4.1%. The RCB-I class included of patients with a residual tumor less than 1.0 cm in the absence of regional lymph node involvement (80% of cases); class RCB-II was represented by the presence of a residual tumor less than 2.0 cm in combination with the absence or presence of residual metastases in 13 lymph nodes (83.4%), and class RCB-III was presented the residual tumors 2.0 cm and N12 status in 100% of cases (p0.0001). Conclusion. Modern NACT with dual anti-HER2 blockade (trastuzumab + pertuzumab) are highly effective the rate of tpCR is 61.2%, and in the presence of high TILs20% reaches 95.5%. Residual tumor in most cases was presented by class RCB-I or RCB-II, only 4% of patients had massive residual tumor load (class RCB-III).

Abstract Background The crAss-like phages are ubiquitous and highly abundant members of the human gut virome that infect commensal bacteria of the order Bacteroidales. Although incapable of lysogeny, these viruses demonstrate long-term persistence in the human gut microbiome, dominating the virome in some individuals. Results Here we show that rapid phase variation of alternate capsular polysaccharides in Bacteroides intestinalis cultures plays an important role in a dynamic equilibrium between phage sensitivity and resistance, allowing phage and bacteria to multiply in parallel. The data also suggests the role of a concomitant phage persistence mechanism associated with delayed lysis of infected cells, similar to carrier state infection. From an ecological and evolutionary standpoint, this type of phage-host interaction is consistent with the Piggyback-the-Winner model, which suggests a preference towards lysogenic or other “benign” forms of phage infection when the host is stably present at high abundance. Conclusion Long-term persistence of bacteriophage and host could result from mutually beneficial mechanisms driving bacterial strain-level diversity and phage survival in complex environments.

Abstract Background The gut phageome comprises a complex phage community of thousands of individual strains, with a few highly abundant bacteriophages. CrAss-like phages, which infect bacteria of the order Bacteroidales, are the most abundant bacteriophage family in the human gut and make an important contribution to an individual’s core virome. Based on metagenomic data, crAss-like phages form a family, with four sub-families and ten candidate genera. To date, only three representatives isolated in pure culture have been reported: ΦcrAss001 and two closely related phages DAC15 and DAC17; all are members of the less abundant candidate genus VI. The persistence at high levels of both crAss-like phage and their Bacteroidales hosts in the human gut has not been explained mechanistically, and this phage-host relationship can only be properly studied with isolated phage-host pairs from as many genera as possible. Results Faeces from a healthy donor with high levels of crAss-like phage was used to initiate a faecal fermentation in a chemostat, with selected antibiotics chosen to inhibit rapidly growing bacteria and selectively enrich for Gram-negative Bacteroidales. This had the objective of promoting the simultaneous expansion of crAss-like phages on their native hosts. The levels of seven different crAss-like phages expanded during the fermentation, indicating that their hosts were also present in the fermenter. The enriched supernatant was then tested against individual Bacteroidales strains isolated from the same faecal sample. This resulted in the isolation of a previously uncharacterised crAss-like phage of candidate genus IV of the proposed Alphacrassvirinae sub-family, ΦcrAss002, that infects the gut commensal Bacteroides xylanisolvens. ΦcrAss002 does not form plaques or spots on lawns of sensitive cells, nor does it lyse liquid cultures, even at high titres. In keeping with the co-abundance of phage and host in the human gut, ΦcrAss002 and Bacteroides xylanisolvens can also co-exist at high levels when co-cultured in laboratory media. Conclusions We report the isolation and characterisation of ΦcrAss002, the first representative of the proposed Alphacrassvirinae sub-family of crAss-like phages. ΦcrAss002 cannot form plaques or spots on bacterial lawns but can co-exist with its host, Bacteroides xylanisolvens, at very high levels in liquid culture without impacting on bacterial numbers. Video abstract

Young women with reproductive tract neoplasms who receive treatment leading to termination of ovarian function often suffer from menopause symptoms that contribute to dramatic drop in quality of life. Climacteric symptoms in women with iatrogenic menopause are more severe than in case of natural menopause, especially in women with reproductive tract neoplasms. They lead to dramatic drop in quality of life and are one of the main reasons to stop applying endocrine therapy in women with hormone-positive tumors, which leads to decrease in disease free survival and to decline the prognosis. The most effective treatment option for climacteric symptoms of moderate to severe degrees is menopause hormone therapy; however, such therapy is not suitable for patients with estrogen-dependent tumors in past medical history due to the likelihood risk of progression of cancer, as well as the risk of venous thrombosis, the frequency of which in cancer patients increases. Non-hormonal pharmacological and non-pharmacological correction methods are used as first-line therapy for menopause disorders in women with estrogen-dependent tumors of the reproductive system. Among non-hormonal non-pharmacological correction methods actively study such methods as acupuncture, yoga, exercise to control weight, and a diet rich in phytoestrogens. The most effective non-hormonal methods of correcting vasomotor symptoms are serotonin and norepinephrine reuptake inhibitors. However, currently in Russia these drugs can be prescribed only by a psychiatrist. The finding of effective and safe non-hormonal methods to correct menopause symptoms in women with hormone-positive reproductive tract tumors is the important task in practice among doctors in different specialties.

The involvement of axillary lymph nodes is one of the most important prognostic factors, significantly affecting the treatment strategy for early breast cancer (BC). The risk of axillary lymph node metastases depends directly on a number of factors (age of women, size of tumor, presence of lymphovascular invasion and biological characteristics of cancer). The evaluation of regional lymph node status in patients with early BC includes the clinical examination of regional zones and the ultrasound study (US), using these methods can help to study lymph nodes shape, borders, margins and structure. The sensitivity of ultrasound in the evaluation of regional lymph nodes status directly depends on the biological subtype of the tumor; the minimum level of ultrasound sensitivity in the evaluation of lymph nodes status is detected for luminal HER2-negative cancer (less than 40%), and maximum sensitivity is detected for triple negative and HER2-positive subtypes (6871%). Clinical examination and modern ultrasound are the most accessible methods for the evaluation of regional lymph nodes status, but the possibility to misjudge metastatic process can be detected in 1/4 of patients. Verification of the diagnosis in the preoperative phase (fine-needle aspiration biopsy/core-needle biopsy under ultrasound guidance) allows minimize the number of errors for the regional staging. The sentinel lymph node biopsy (SLNB) is the gold standard of regional treatment in patients with early stage BC, nowadays. The randomized trials (NSABP B-32, ACOSOG q0011) show the safety of recession of performing regional lymph node dissection in favor of SLNB not only in case of clinically negative lymph nodes, but also in patients with metastases in 2 sentinel lymph nodes, upon condition that organ-conservative treatment and subsequent radiation therapy will be used. High-quality regional staging, the choice of the therapeutic algorithm in accordance with the biological characteristics of carcinoma, the application of the most effective modern drug regimes, the optimal radiation therapy allow not only minimize the extent of surgery, but also achieve high long-term survival results, provide excellent functional results and high quality of life in patients with the involvement of axillary lymph nodes.

Recent years have been marked by the growing interest towards virulent and temperate bacteriophage populations inhabiting the human lower gastrointestinal tract – the gut phageome. A number of studies demonstrated high levels of specificity and temporal stability of individual gut phageomes, as well as their specific alterations in disease cohorts, in parallel with changes in the bacteriome. It has been speculated that phages might have an active role in shaping the taxonomic composition and functional properties of the human gut bacteriome. An overwhelming majority of gut bacteriophages, however, remain uncultured, unclassified, and their specific hosts and infection strategies are still unknown. They are often referred to as “the viral dark matter”. A possible breakthrough in understanding of the phageome can only become possible when a significant proportion of the “the viral dark matter” is identified and linked to bacterial hosts. Here, we describe a method that enables rapid discovery and host-linking of novel bacteriophages in the gut via a combination of serial enrichment cultures and shotgun metagenomics of viral DNA. Using this approach dozens of novel and previously known bacteriophages were detected, including the ones infecting difficult-to-culture anaerobic bacteria. The majority of phages failed to produce lysis and propagate on host cultures in traditional assays. The newly identified phages include representatives of Siphoviridae, Myoviridae, Podoviridae, and crAss-like viruses, infecting diverse bacterial taxa of Bacteroidetes, Firmicutes, Actinobacteria, Verrucomicrobia and Proteobacteria phyla. The proposed new method has a potential for high-throughput screening applications for mass discovery of new phages in different environments.

Bacteriophages of the crAssphage family have not yet been isolated, despite being highly abundant in the human gut. Here, Shkoporov et al. isolate in pure culture one of these viruses and show that it infects the human gut symbiont Bacteroides intestinalis.

Aim: To perform a comparative analysis with simultaneous measurement of vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF1) and matrix metalloproteinase 7 (MMP7) in serum samples taken from healthy women and ovarian cancer patients; to perform association of these markers with their expression in primary tumors depending on clinical, morphological and biochemical characteristics of the disease and its prognosis. Materials and methods: We assessed 54 treatment-naïve patients with ovarian cancer aged from 23 to 74 years (mean ± SD, 53.2 ± 1.9), being at various FIGO stages of the disease. The control group consisted of 120 healthy women of matched age and reproductive status, in whom serum biomarker levels were studied. Patient survival was assessed by the Kaplan-Meier method, with survival curves compared with log-rank test. All analyses were done with “STATISTICA” and SPSS software. Results: Serum VEGF levels in ovarian cancer patients were significantly (p 505 pg/ml (upper quartile in the control). With 505 pg/ml taken as a threshold, the test had sensitivity of 79.6% and specificity of 75%. Another cut-off value of serum VEGF level between the patients with ovarian cancer and the control group (510 pg/ml) was derived from ROC curves and 75% sensitivity and 78.2% specificity. No acceptable cut-off value for serum IGF1 to differentiate between the patients with ovarian cancer and the controls could be obtained from the ROC curves. Serum MMP7 levels in the patients with ovarian cancer were significantly higher than those in the control group (Mann-Whitney test p

The 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, 3-amino-1,5-dihydro-2H-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2H-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2H-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, which were prepared via their reaction with carbodiimides.

Ovarian cancer (OC) is the fifth most common cancer in women in developed countries. Despite advances in treatment of epithelial OC: improving techniques and increasing aggressive surgery, the appearance of new cytostatics, targeted drugs, - the overall survival (OS) rates are unsatisfactory (the overall 5-year survival is 38%) and there is still an urgent need in development of new therapeutic agents to improve the results of treatment women with this disease. Olaparib is the first poly (ADP-ribose) polymerase (PARP) inhibitor, which demonstrates the high efficacy of treatment patients with OC associated with mutations in the BRCA genes. And olaparib is approved as a maintenance monotherapy in the treatment of women with platinum sensitive recurrent BRCA-associated OC. This review deals with the information concerning the efficiency and toxicity of olaparib, showing practical guidance on the application. The article focuses on the toxic effects of the drug, which can occur during olaparib therapy, and shows the guidance on management of the disease. Nausea, vomiting, fatigue and anemia are the most commonly reported side effects of olaparib application in clinical studies. Side effects are usually recorded in mild to moderate degree and nondurable. Using proper application and timely monitoring for side effects one can control many toxic actions.

The development of cytostatic therapy in the treatment of ovarian and cervical cancer has resulted in a deadlocked situation. Thus, the basic aim of the investigations was to examine the biological basis of these diseases, last years. Angiogenesis is one of the main factors of the tumor microenvironment, associated with tumor growth and metastasis. In this regard, new drugs that work by inhibiting angiogenesis have started to appear. One of the first drugs studied in randomized phase III studies was bevacizumab. The application of bevacizumab demonstrated the significant increase both in progression free-survival and life expectancy in high-risk group of patients with ovarian cancer and in patients with recurrent and advanced cervical cancer.

New treatment options of chronic diseases, concerning the different selection of therapy regimens, as well as the system of drug administration (outpatiently, domiciliary, at hospital) started up over the last decade. The patient's awareness of the availability of treatment alternatives is an important benefit factor in terms of adherence of patients to treatment and preserving quality of life. The aim of this study was to examine the factors influencing the choice of medication administration route, used in case of various nosologies. In view of this we analyzed all publications in the PubMed database in the period of 1990 to 2016, concerning the comparison of efficacy, safety, pharmacoeconomic, patient preferences, in case of different medication administration route. As a result of the database analysis we incontestably proved that the basic criteria of medication selection were efficiency, safety, pharmacoeconomic aspects and patient preference. Patient preference is an important factor in achieving high adherence to treatment, increasing the efficiency of medical technology and enhancing quality of life.

In recent years, the main scientific directions concerning ovarian cancer have been associated with the attempt to individualize the treatment based on prognostic and predictive molecular biological markers. The damage in BRCA1 and BRCA2 genes is identified in 10-15% of ovarian cancer cases. The main function of BRCA proteins is responsibility for repairing double-strand break in DNA by a mechanism of homologous recombination. The result of BRCA gene dysfunction is BRCA-associated DNA damage repair mechanism. As a result, these tumors can be extremely sensitive to DNA-damaging cytostatic agents - such as platinum-based drugs. Several studies show the better survival rates of patients with BRCA mutations in comparison with sporadic ovarian cancer. The information concerning the course of disease and treatment characteristics of patients with ovarian cancer associated with BRCA1, 2 mutations in the Russian population of patients is extremely limited.

We studied a role of the inducible heat shock protein 70 (Hsp70) in cellular response to radiosensitizing treatments with inhibitors of the heat shock protein 90 (Hsp90) chaperone activity. Cell lines derived from solid tumors of different origin were treated with the Hsp90 inhibitors (17AAG, geldanamycin, radicicol, NVP-AUY922) or/and γ-photon radiation. For comparison, human cells of the non-cancerous origin were subjected to the same treatments. We found that the Hsp90 inhibitors yielded considerable radiosensitization only when they cause early and pronounced Hsp70 induction; moreover, a magnitude of radiosensitization was positively correlated with the level of Hsp70 induction. The quantification of Hsp70 levels in Hsp90 inhibitor-treated normal and cancer cells enabled to predict which of them will be susceptible to any Hsp90-inhibiting radiosensitizer as well as what concentrations of the inhibitors ensure the preferential cytotoxicity in the irradiated tumors without aggravating radiation damage to adjacent normal tissues. Importantly, the Hsp70 induction in the Hsp90 inhibitor-treated cancer cells appears to be their protective response that alleviates the tumor-sensitizing effects of the Hsp90 inactivation. Combination of the Hsp70-inducing inhibitors of Hsp90 with known inhibitors of the Hsp induction such as quercetin, triptolide, KNK437, NZ28 prevented up-regulation of Hsp70 in the cancer cells thereby increasing their post-radiation apoptotic/necrotic death and decreasing their post-radiation viability/clonogenicity. Similarly, co-treatment with the two inhibitors conferred the enhanced radiosensitization of proliferating rather than quiescent human vascular endothelial cells which may be used for suppressing the tumor-stimulated angiogenesis. Thus, the easily immunodetectable Hsp70 induction can be a useful marker for predicting effects of Hsp90-inhibiting radiosensitizers on tumors and normal tissues exposed to ionizing radiation. Moreover, targeting the Hsp70 induction in Hsp90 inhibitor-treated cancer cells and tumor vasculature cells may beneficially enhance the radiosensitizing effect.

Development of first-line cytostatic therapy in ovarian cancer is slow, and as a result, the main research aim today is to study the biology of the disease. Angiogenesis is one of the main factors of the tumor microenvironment, resulting in growth and metastasis. As a result have been investigated the drugs inhibiting angiogenesis. The first drug being studied in phase III trial of the randomized studies was bevacizumab, which demonstrated the significant increase in both progression-free survival and survival in the high risk group. Other antiangiogenics such as pazopanib, nintenanib, also demonstrated high efficacy in patients with ovarian cancer.

Given the high rate of recurrence of epithelial ovarian cancer after radical treatment is necessary to improve the therapeutic approach to its treatment. New drug of marine origin trabectedin has shown high efficacy in monotherapy and in combination with different cytostatics in the treatment of platinum-sensitive recurrent of ovarian cancer. A randomized trial OVA-301 showed the greatest benefit of a combination of trabectedin with pegylated liposomal doxorubicin in the subgroup of patients with partially platinum-sensitive recurrent of ovarian cancer. Acceptable toxicity profile of the drug, presented mainly neutropenia and transient increase of transaminases, making it promising for further study.

Antitumor activity of trabectedin as a monotherapy in different solid tumors (soft tissue sarcoma, ovarian cancer, breast cancer, melanoma) contributed to research trabectedin-based drug combinations. Phase I trials were searching for optimal dose and schedule of administration trabectedin and trabectedin-based combinations. This review considers aspects of clinical applications and toxic profile of trabectedin alone and combinations, including a rare adverse event – rhabdomyolysis and data of own experience.

Non-compaction of the ventricular myocardium (NCM) is a genetic cardiomyopathy usually due to mutationof the G4.5 gene located in the Xq28 chromosomal region. This congenital disorder is characterized by pronounced trabeculations and intertrabecular recesses resulting from abnormal embryogenesis between the fifth and eighth fetal weeks. The reported prevalence in the general population is between 0.014% and 1.3%. The classic triad of complications includes heart failure, ventricular arrhythmias and systemic embolic events, although some patients have an asymptomatic form. NCM is commonly diagnosed by echocardiography, but contrast ventriculography, CT and MRI can also be used. Here we present a case of left ventricle NCM, manifested after respiratory infection, in a pregnant patient with congenital thrombophilia and a history of myocardial infarction.

Последнее десятилетие характеризуется появлением и быстрым развитием нового направления лекарственной противоопухолевой терапии – таргетной терапии. Точкой приложения препаратов таргетной терапии являются определенные молекулярные структуры, мишени. Одной из таких мишеней являются рецепторы к эпидермальному фактору роста (EGFR), известные также как HER1 или ErbB1. EGFR относится к семейству ErbB-рецепторов. Информационные сигналы, возникающие при активации этих рецепторов, участвуют в механизмах пролиферации или дифференцировки клеток, стимулируют процесс клеточного деления. Рецептор эпидермального фактора роста состоит из экстрацеллюлярного домена, связывающегося с лигандом, гидрофобной липофильной трансмембранной части и внутриклеточного цитоплазматического домена, содержащего тирозинкиназный домен. Специфическими лигандами для EGFR являются эпидермальный фактор роста (EGF) и трансформирующий фактор роста (TGF)-α. Их связывание с экстрацеллюлярным доменом приводит к димеризации рецепторов. При этом могут образовываться как гомодимеры с другими EGFR, так и гетеродимеры с другими представителями семейства Erb, например с HER2, 3, 4. Димеризация стимулирует аутофосфорилирование тирозинкиназного домена, что в свою очередь активирует внутриклеточные каскады ферментативных реакций, передающих сигнал в ядро клетки, включая Ras-MAPK- и PI-3K-Akt пути.Гиперэкспрессия рецепторов эпидермального фактора роста обнаружена во многих злокачественных опухолях человека, включая рак толстой кишки, области головы и шеи, рак легкого, шейки матки, молочной железы, желудка, а также глиобластому, рак мочевого пузыря, яичников.Показано, что гиперэкспрессия EGFR в опухоли коррелирует с плохим клиническим прогнозом, стимулируя быстрый рост, размножение, а также дедифференцировку опухолевых клеток, блокируя апоптоз. Ферментативные реакции, участвующие во внутриклеточной передаче сигнала от EGFR, в частности PI-3K-Akt-путь, стимулируют также выработку фактора роста эндотелия сосудов, что приводит к активному неоангиогенезу и способствует быстрому метастазированию опухоли.Цетуксимаб (Эрбитукс) является моноклональным антителом IgG1, которое связывается с экстрацеллюлярным доменом EGFR, блокируя таким образом лигандиндуцированное фосфорилирование тирозинкиназного домена и активацию внутриклеточных путей передачи сигнала. Препарат обладает высокой специфичностью, его аффинитет к EGFR в 10 раз превышает аффинитет естественных лигандов EGF и TGF-α. Связывание Цетуксимаба с EGFR приводит также к димеризации рецептора с последующим эндоцитозом и внутриклеточной деградацией антитело-рецепторного комплекса. За счет этого механизма происходит снижение плотности EGFR на поверхности клетки.Как моноклональное антитело класса IgG1 Цетуксимаб способен активизировать NK-клетки и другие иммунные эффекторы, вызывающие лизис опухолевых клеток.