Experiment K-6-16. Morphological examination of rat testes. The effect of Cosmos 1887 flight on spermatogonial population and testosterone level in rat testes

Testes from rats flown on Cosmos 1887 for twelve and a half days were compared to basal control, synchronous control and vivarium maintained rats. When the mean weights of flight testes, normalized for weight/100 gms, were compared to the vivarium controls they were 6.7 percent lighter. Although the flight testes were lighter than the synchronous, the difference is not significant. Counts of spermatogonial cells from 5 animals in each group revealed a 4 percent decrease in flight compared to vivarium controls. In both cases the t-Test significance was less than 0.02. The serum testosterone levels of all animals (flight, synchronous and vivarium) were significantly below the basal controls

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKCδ and inhibiting PKCα. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC50 of PEP005 ranged from 0.01–140 μM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 μM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKCδ and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours

“CYTOKINE” MODEL OF PATHOGENESIS OF CHRONIC HEART FAILURE AND THE OPPORTUNITIES OF NEW THERAPEUTIC STRATEGY IN DECOMPENSATED PATIENTS

Neurohumoral model of pathogenesis of chronic heart failure (CHF) made it possible to develop new therapeutic approaches in patients with CHF . However , it became obvious that the ways of activation of neurohumoral systems in CHF are much more complicated. The increase in local synthesis of hormones causes the activation of inflammatory cytokines and protooncogenes, which have various negative effects. This allowed formulating immunoinflammatory conception of CHF pathogenesis, according to which the increase in interleukine-6 blood level is the marker of unfavorable prognosis for CHF , and the level of tumor necrosis factor-α (TNF-α) straightly correlates with severity of clinical condition and neurohumoral activity in CHF . The growth of TNF-α in CHF progressing as well as its reduction in successful treatment do not exclude the probability of positive effect of therapy , focused on the reduction of TNF-α concentration. The pathogenesis peculiarities of CHF including cytokine aggression demand the necessity of development of new therapy approaches with the use of cytokine system modulators

THE ROLE OF INCLUSIVE GAMES IN FORMING AN INCLUSIVE CULTURE

В настоящее время растет количество людей с различными нозологиями. В связи с этим постоянно появляются новые формы взаимодействий между людьми, которые позволяют лучше адаптироваться в обществе. В статье рассматриваются методические рекомендации к проведению Инклюзивных игр и значение инклюзии в обществе и образовательной среде. Приводится пример проведения Инклюзивных игр в Детском образовательном учреждении. Как показало исследование, проведение инклюзивных мероприятий способствует социализации человека с ограниченными возможностями и проявлению у участников мероприятия экстрабилити.Currently, the number of people with various nosologies is growing. In this regard, new forms of interactions between people are constantly emerging that allow them to better adapt in society. The article discusses methodological recommendations for holding Inclusive Games and the importance of inclusion in society and the educational environment. An example of holding inclusive games in a children's educational institution is given. As the study showed, holding inclusive events contributes to the socialization of a person with disabilities and the manifestation of extrability among the participants of the event

Antiproliferative effects of sapacitabine (CYC682), a novel 2′-deoxycytidine-derivative, in human cancer cells

This study assessed the antiproliferative activity of sapacitabine (CYC682, CS-682) in a panel of 10 human cancer cell lines with varying degrees of resistance or sensitivity to the commonly used nucleoside analogues ara-C and gemcitabine. Growth inhibition studies using sapacitabine and CNDAC were performed in the panel of cell lines and compared with both nucleoside analogues and other anticancer compounds including oxaliplatin, doxorubicin, docetaxel and seliciclib. Sapacitabine displayed antiproliferative activity across a range of concentrations in a variety of cell lines, including those shown to be resistant to several anticancer drugs. Sapacitabine is biotransformed by plasma, gut and liver amidases into CNDAC and causes cell cycle arrest predominantly in the G2/M phase. No clear correlation was observed between sensitivity to sapacitabine and the expression of critical factors involved in resistance to nucleoside analogues such as deoxycytidine kinase (dCK), human equilibrative nucleoside transporter 1, cytosolic 5′-nucleotidase and DNA polymerase-α. However, sapacitabine showed cytotoxic activity against dCK-deficient L1210 cells indicating that in some cells, a dCK-independent mechanism of action may be involved. In addition, sapacitabine showed a synergistic effect when combined with gemcitabine and sequence-specific synergy with doxorubicin and oxaliplatin. Sapacitabine is therefore a good candidate for further evaluation in combination with currently used anticancer agents in tumour types with unmet needs

HIV pre-exposure prophylaxis during the SARS-CoV-2 pandemic: Results from a prospective observational study in Germany.

Aims: Since 2017, HIV pre-exposure prophylaxis (PrEP) care has been provided through an intersectoral collaboration at WIR (Walk-in-Ruhr, Center for Sexual Health and Medicine, Bochum, Germany). The aim of this study was to establish possible impact of COVID-restrictions on the sexual behavior of PrEP users in North Rhine-Westphalia. Methods: The current PrEP study collected data of individuals using PrEP, their sexual behavior and sexually transmitted infections (STIs) before (each quarter of year 2018) and during the COVID-19 pandemic (each quarter of year 2020). Results: During the first lockdown in Germany from mid-March until May 2020, PrEP-care appointments at WIR were postponed or canceled. Almost a third of PrEP users had discontinued their PrEP intake in the 2nd quarter of 2020 due to alteration of their sexual behavior. The number of sexual partners decreased from a median of 14 partners in the previous 6 months in 1st quarter of 2020, to 7 partners in 4th quarter of 2020. Despite such a significant reduction in partner number during the pandemic in comparison to the pre-pandemic period, a steady rate of STIs was observed among PrEP users in 2020. Conclusion: The SARS-CoV-2-pandemic has impacted PrEP-using MSM in North Rhine-Westphalia with respect to their PrEP intake regimen and sexual behavior in 2020. Our study revealed a steady rate of STI among PrEP users even during the pandemic, thus highlighting the importance of ensuring appropriate HIV/STI prevention services in times of crisis

Our first experience of transcatheter pulmonary valve replacement

The treatment of pulmonary valve disease is one of the urgent problems of modern cardiology and cardiac surgery. In most cases, pulmonary valve abnormalities are congenital. Synthetic conduits (homografts) and bioprosphetic valves are currently used in the surgical treatment of patients with the diseases mentioned above. Pulmonary valve surgical prosthetics allows one to normalize the circulatory dynamics and condition of the patient, however, time-dependent degradation results in conduit and valve dysfunction. The abnormal circulatory dynamics caused by valve and conduit dysfunction is linked to exercise intolerance, arrhythmia, right ventricular failure, and sudden death. Starting in childhood, affected patients undergo repeated openheart surgeries to restore valve function and potentially reduce morbidity and mortality. Percutaneous transcatheter treatment of the pulmonary valve stenosis with the Melody® valve (Medtronic Inc.) has been performed in a large number of patients worldwide. Despite minimal invasiveness, this procedure restores pulmonary valve function and reduces repeated open-heart interventions. Recent clinical trials have shown excellent and durable results in terms of both restoring valve function and decreasing right ventricular outflow tract obstruction. In this study, we want to reflect the relevance of the Melody transcatheter valve and present our first experience of its usage

Adapting agricultural water use to climate change in a post-Soviet context: challenges and opportunities in southeast Kazakhstan

The convergence of climate change and post-Soviet socio-economic and institutional transformations has been underexplored so far, as have the consequences of such convergence on crop agriculture in Central Asia. This paper provides a place-based analysis of constraints and opportunities for adaptation to climate change, with a specific focus on water use, in two districts in southeast Kazakhstan. Data were collected by 2 multi-stakeholder participatory workshops, 21 semi-structured in-depth interviews, and secondary statistical data. The present-day agricultural system is characterised by enduring Soviet-era management structures, but without state inputs that previously sustained agricultural productivity. Low margins of profitability on many privatised farms mean that attempts to implement integrated water management have produced water users associations unable to maintain and upgrade a deteriorating irrigation infrastructure. Although actors engage in tactical adaptation measures, necessary structural adaptation of the irrigation system remains difficult without significant public or private investments. Market-based water management models have been translated ambiguously to this region, which fails to encourage efficient water use and hinders adaptation to water stress. In addition, a mutual interdependence of informal networks and formal institutions characterises both state governance and everyday life in Kazakhstan. Such interdependence simultaneously facilitates operational and tactical adaptation, but hinders structural adaptation, as informal networks exist as a parallel system that achieves substantive outcomes while perpetuating the inertia and incapacity of the state bureaucracy. This article has relevance for critical understanding of integrated water management in practice and adaptation to climate change in post-Soviet institutional settings more broadly

Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent