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

Correlation Between Teaching and Learning in the Process of Mastering Students' Foreign Language Speech Activities and Verbal Communication

В статье рассматриваются проблемы соотношения и взаимосвязи обучения и учения в процессе овладения студентами иноязычной речевой деятельностью всех видов и речевым общением, раскрываются закономерности и особенности деятельности обучающего, учителя, преподавателя и обучающегося, учащихся, студентов.The article considers the correlation between teaching and learning in the process of mastering students' foreign language speech activities of all types, as well as foreign language verbal communication. It reveals the patterns and features of the activities performed by teachers and students

Verbal and thinking activity in the process of referential and informational reading of source texts and developing the program of their semantic content

The article investigates the issues of verbal and thinking activity in the process of the flexible referential and informational reading.В статье исследуются вопросы речемыслительной деятельности думания в процессе гибкого референтного и информативного чтения исходных текстов перевода и создания программы их смыслового содержания, рассматривается и описывается первый этап сложной билингвальной речевой деятельности письменного перевода, основывающейся на функционировании в тесной связи форм, единиц мышления, языка и речи, на актуализации смысловых вербальных решений как единиц рецептивной речевой деятельности переводческого чтения в фазе смыслоформирования

Changes of photosynthesis and carbon metabolism in Typha angustifolia L grown in conditions of nitrate nitrogen overload

Nitrates may induce alterations in NO-signaling system and change photosynthesisin plants. Significant reduction of 14CO2 fixation was noted at concentration of 3.96mM NaNO3 in an aquatic macrophyte (Typha angustifolia L.). Assimilation of 14CO2 seven days after the introduction of nitrates did not differ between control and experimental samples. There were changes in distribution of 14C among products of 4CO2 fixation 4 h after NaNO3 addition, resulting in increased sugar radioactivity in experimental plants. It was suggested that the observed changes may have regulatory importance

Reproductive parameters and the use of MOET in transgenic founder goat carrying the human granulocyte colony-stimulating factor (hG-CSF) gene.

Abstract: This study aimed to monitor estrous cycle parameters of a human granulocyte colony-stimulating factor (hG-CSF)-transgenic founder female goat and to perform superovulation and embryo recovery (surgical or transcervical method) for further transfer to recipients to quickly obtain offspring. Two experiments were performed using a transgenic (TF) and a non-transgenic (NTF) female. In experiment 1, three estrous cycles were monitored for the following parameters: estrus behavior, progesterone concentration and ovarian activity. In experiment 2, two superovulation/embryo recovery sessions were performed and the recovered embryos were transferred to previously prepared recipients. Data were compared by either t test or Fisher's exact test. The mean interval between natural estrus was 20.7 ± 0.6 and 19.7 ± 0.6 (P > 0.05) days for the TF and NTF, respectively. Progesterone concentrations and ovarian activity were normal and similar between goats. The ovulation rate was similar between TF and NTF (12.0 ± 1.4 vs. 18.0 ± 4.2 CL; P > 0.05). No significant differences in embryo recovery rate (P > 0.05) were observed between the surgical and transcervical methods for TF (69.2 vs. 72.7%) or NTF (100.0 vs. 86.7%). Sixteen embryos from the TF were transferred to recipients, and eight kids were born. Among these kids, the transgene was identified in three (two males and one female), resulting in a transgenesis rate of 37.5%. In summary, the TF is a true founder, since she proved fertility and capacity of transmitting the hG-CSF transgene to progeny, suggesting that the analyzed reproductive traits were not compromised by the presence of the transgene

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

Project of a Psychocorrection Program to Athletes of Wheelchair Curling

Рукопись поступила в редакцию: 04.05.2023. Принята к публикации: 12.06.2023.Received: 04.05.2023. Accepted: 12.06.2023.В статье описана психокоррекционная программа для спортсменов сборной России по кёрлингу на колясках, направленная на улучшение показателей высших психических функций и стрессоустойчивости. На Чемпионате Мира 2021 команда заняла 3-е место, уступив в полуфинале, потому что не смогла справиться с напряжением и психологической нестабильностью в ответственный момент. На прошедших в марте 2022 года Зимних Паралимпийских играх спортсмены сборной России по кёрлингу на колясках должны были быть эмоционально устойчивы, способны удерживать на протяжении всего турнира высокую концентрацию внимания и «безошибочную» образную память. Для достижения цели тренерским штабом сборной России была предложена идея разработки программы психологической коррекции. Данное исследование является продолжением исследования диагностики особенностей психоэмоциональных состояний спортсменов, которое было проведено в 2021 году. По результатам диагностики спортивным психологом была разработана коррекционная программа. В основу программы вошли приемы управления дыханием, визуализации, способы управления мышечным тонусом, а также формирование навыка «заземления» для снижения уровня тревожности перед соревнованиями. Для мобилизации состояния спортсменам предлагаются упражнения на верхнее дыхание, а для спокойствия и сосредоточения – 4 этапа единого цикла нижнего дыхания. Спортсменам также рекомендуется проводить профилактику мышечных зажимов, выполняя упражнения на 3 фазы «напрячь – прочувствовать – расслабить». В 2021 году был проведен педагогический эксперимент продолжительностью десять месяцев для оценки эффективности разработанной методики. В исследовании приняло участие 9 спортсменов – членов основного и расширенного составов сборной России по кёрлингу на колясках в возрасте от 28 до 49 лет: 6 мужчины и 3 женщины.The article describes a correctional program for athletes of the Russian national wheelchair curling team, aimed at improving the indicators of higher mental functions and stress resistance. At the 2021 World Cup, the team took 3rd place, losing in the semifinals, because they could not cope with tension and psychological instability at a crucial moment. At the Winter Paralympic Games held in March 2022, the athletes of the Russian wheelchair curling team had to be emotionally stable, able to maintain high concentration of attention and an unmistakable figurative memory throughout the tournament. To achieve this goal, the coaching staff of the Russian national team proposed the idea of developing a program of psychological correction. This study is a continuation of the diagnosis of the characteristics of the psycho-emotional states of athletes, which was conducted in 2021. Based on the results of the diagnosis, a sports psychologist developed a correctional program. The program is based on breathing control techniques, visualization, ways to control muscle tone, as well as the formation of grounding skills to reduce anxiety levels before competitions. To mobilize the condition, athletes are offered exercises for upper breathing, and for calm and concentration – 4 stages of a single cycle of lower breathing. Athletes are also recommended to prevent muscle clamps by performing exercises for 3 phases "strain – feel – relax". In 2021, a pedagogical experiment lasting ten months was conducted to evaluate the effectiveness of the developed methodology. The study involved 9 athletes – members of the main and extended squads of the Russian wheelchair curling team aged 28 to 49 years: 6 men and 3 women

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

Features of the microbiota of the cervical canal in pregnant women and puerperaswith inflammatory diseases of the pelvic organs

The articledeals the qualitative composition of the microbiota of the cervical canal in pregnant women and puerperas who are hospitalized with inflammatory diseases of the pelvic organs.В статье рассмотрен качественный состав микробиоты цервикального канала у беременных женщин и родильниц, находящихся на стационарном лечении с воспалительными заболеваниями органов малого таза