Физико-химические свойства мутантных форм L-аспарагиназы из Rhodospirillum rubrum, обладающих антителомеразной активностью

Rru_A3730 protein is a bacterial Rhodospirillum rubrum L-asparaginase (RrA), which is known by its anticancer activity. RrA variants with point amino acid substitutions in the region of 150 amino acids residues: RrA17N, K149E, RrAE149R, V150P, F151T, RrА17N, E149R, V150P, RrAE149R, V150P, showed antiproliferative properties, and also by their ability to suppress telomerase activity. This work is devoted to comparison of physical-chemical and catalytic properties of these mutant forms of RrA. It is shown that pH optimum is in the alkaline zone (8.5 – 9.3); L-glutaminase and D-asparaginase activity is respectively not more than 0.1% and 1.6% of L-asparaginase for all studied variants of RrA. The presence of the N17-terminal amino acid sequence MASMTGGQMGRGSSRQ of the capsid protein of bacteriophage T7 in the RrA structure leads to an increase in the thermal stability of mutant RrA analogues (from 50°C to 56°C) and their resistance to denaturation in the presence of 3 – 4 M urea. It is of Metal ions exhibit multidirectional effects on L-asparaginase activity of RrA. K+, Ca2+, Zn2+, Cs+, Co2+ in significantly affect the activity of L-asparaginase, while Mn2+, Cu2+, Fe3+ ions inhibit it. There was no correlation between antitelomerase (antiproliferative) activity and kinetic properties of mutant forms of L-asparaginase RrA.Белок Rru_A3730, известный как бактериальная L-аспарагиназа Rhodospirillum rubrum, представляет интерес в качестве потенциального противоопухолевого средства, особенно её варианты с точечными аминокислотными заменами в районе 150 аминокислотного остатка (а.к.о.): RrA17N, K149E, RrAE149R, V150P, F151T, RrА17N, E149R, V150P, RrAE149R, V150P, обладающие не только антипролиферативными свойствами, но и способностью подавлять активность теломеразы. Данная работа посвящена сравнению физико-химических и каталитических свойств этих мутантных форм RrA. Показано, что для всех изученных вариантов RrA рН оптимум находится в щелочной зоне (8.5 – 9.3); L-глутаминазная и D-аспарагиназная активность составляют, соответственно, не более 0.1% и 1.6% от L-аспарагиназной. Присутствие 17N-концевой аминокислотной последовательности MASMTGGQQMGRGSSRQ капсидного белка бактериофага Т7 в структуре RrA приводит к повышению термостабильности мутантных аналогов RrA (от 50°С до 56°С) и их устойчивости к денатурации в присутствии 3 – 4 М мочевины. Выявлен разнонаправленный эффект ионов металлов на L-аспарагиназную активность вариантов RrA: ионы K+, Ca2+, Zn2+, Cs+, Co2+ существенно не влияют на активность L-аспарагиназы, добавление ионов Mn2+, Cu2+, Fe3+ приводит к снижению активности. Не обнаружено корреляции между антителомеразной (антипролиферативной) активностью и кинетическими свойствами мутантных форм L-аспарагиназы RrA

L-Asparaginase for newly diagnosed extra-nodal NK/T-cell lymphoma: systematic review and meta-analysis

Objectives: The aim of this review was to compare the efficacy of asparaginase (ASP)-containing vs ASP-absent regimens in the first-line treatment of ENKTL patients. Methods: The PRISMA protocol was used to search PubMed and Embase for both controlled and uncontrolled studies of ASP or alternative chemotherapy (CT) for newly diagnosed ENKTL, published in English by March 2017. The regimens were compared to calculate relative risk (RR) with 95% confidence interval (CI) of the overall response rate (ORR), complete response (CR) or partial response (PR). Results: Out of 38 studies included, eight were controlled trials, with the pooled RR of ORR in stage I-II 1.54 (95% CI 1.34–1.77); stage I-IV 1.34 (95% CI 1.09–1.64). In stage III-IV CT combined with radiotherapy (RT), RR of ORR was 2.30 (95% CI 1.66–3.18). ASP was also superior in achieving CR. When all single arms combined, RR of ORR after CT with ASP was 1.52 (95% CI 1.38–1.67) in stage I-II (15 studies); 1.44 (95% CI 1.32–1.57) in all stages (29 studies); 1.31 (95% CI 1.24–1.38) and 1.66 (95% CI 1.18–2.34) in stages I-II and III-IV combined with RT, correspondingly. Conclusions: ASP-based CT significantly improved ORR and CR in patients with newly diagnosed both early-stage and advanced-stage ENKTL. © 2017 Informa UK Limited, trading as Taylor & Francis Group

L-Asparaginase for newly diagnosed extra-nodal NK/T-cell lymphoma: systematic review and meta-analysis

Objectives: The aim of this review was to compare the efficacy of asparaginase (ASP)-containing vs ASP-absent regimens in the first-line treatment of ENKTL patients. Methods: The PRISMA protocol was used to search PubMed and Embase for both controlled and uncontrolled studies of ASP or alternative chemotherapy (CT) for newly diagnosed ENKTL, published in English by March 2017. The regimens were compared to calculate relative risk (RR) with 95% confidence interval (CI) of the overall response rate (ORR), complete response (CR) or partial response (PR). Results: Out of 38 studies included, eight were controlled trials, with the pooled RR of ORR in stage I-II 1.54 (95% CI 1.34–1.77); stage I-IV 1.34 (95% CI 1.09–1.64). In stage III-IV CT combined with radiotherapy (RT), RR of ORR was 2.30 (95% CI 1.66–3.18). ASP was also superior in achieving CR. When all single arms combined, RR of ORR after CT with ASP was 1.52 (95% CI 1.38–1.67) in stage I-II (15 studies); 1.44 (95% CI 1.32–1.57) in all stages (29 studies); 1.31 (95% CI 1.24–1.38) and 1.66 (95% CI 1.18–2.34) in stages I-II and III-IV combined with RT, correspondingly. Conclusions: ASP-based CT significantly improved ORR and CR in patients with newly diagnosed both early-stage and advanced-stage ENKTL. © 2017 Informa UK Limited, trading as Taylor & Francis Group

Defining the toxicity of current regimens for extranodal NK/T cell lymphoma: a systematic review and metaproportion

Objectives: The aim of this study is to compare the toxicity profiles of SMILE versus less intense L-asparaginase-containing regimens, CCRT or “sandwich” RT+CT regimens. Methods: PRISMA protocol was used to search Pubmed and Embase for studies of treatment regimens for extranodal NK/T-cell lymphoma, nasal type (ENKTL) in English published before March 2018. Pooled data were grouped into five categories: A) CHOP-like regimens; B) Gemcitabine-based regimens; C) SMILE-like regimens; D) Concurrent and “sandwich” RT + CT; and E) Methotrexate-based combinations. We pooled prevalence of selected adverse events from each study to calculate the weighted overall prevalence using meta-proportion in Stata. Results: Group C was the most toxic with the pooled neutropenia 72% (95 CI 64;80) and thrombocytopenia 48% (95% CI 40;55) prevalence. The use of Group D treatment regimens was associated with the lowest anemia (10% (95% CI 1;19)) prevalence. Group E was the least toxic with regard to thrombocytopenia (6% (95% CI 1;11). Conclusion: Our analysis confirms that SMILE regimen, which is current standard to treat advanced-stage ENKTL may be associated with more severe hematological toxicity compared to other L-asparaginase combinations, including methotrexate-based (AspaMetDex, MESA and MEDA) or gemcitabine-based (GELOX, PGEMOX, DDGP, GDL, GOLD, GLIDE) or CCRT-based regimens. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group

Homogeneous precipitation of magnesium phosphates from seawater solutions

International audienceHomogeneous (unseeded) nucleation of Mg phosphate from modified Ca-free seawater solutions was investigated at 20°C and pH of 8. Precipitated solid phase was characterized using chemical analysis, X-ray diffraction, scanning electron microscopy, and IR-spectroscopy. Effect of aqueous phosphate and ammonia concentrations and the intensity of stirring on the induction period time ( τ) of Mg phosphates nucleation were studied. A linear relationship between logarithm of bobbierite (Mg 3(PO 4) 2 · 8H 2O) saturation index and log τ was established with a slope close to 2. Aqueous NH 4+ (up to 0.002 M) has no effect on the nucleation kinetics and does not incorporate in the precipitated solid phase. Stirring of solution has a dramatic effect on nucleation kinetics: the induction period decreases by a factor of 100-10 000 in unstirred solutions compared to stirred ones. The relative diffusion/chemical reaction control mechanism of Mg phosphates precipitation from supersaturated solutions is discussed. It is shown that spontaneous inorganic precipitation of Mg-(ammonium) phosphates (struvite and bobbierite) in modern marine environment is impossible because of very sluggish kinetics

Experimental evaluation of synergism of cisplatin with L-lysine-α- oxidase

Synergism effects of cisplatin and L-lysine-α-oxidase (LO), while sequential (no interval) administration of drugs depends on the tumor model and duration of treatment. Synergism is identified at intraperitoneal daily (during 3 days) administration of cisplatin to experimental animals in single doses of 1.5 or 3.0 mg / kg and intravenously 5-fold after 48 h administration of LO and also administered intravenously in cumulative doses of 300-600 E / kg discretely, the first dose - doubled. Synergism of cisplatin and LO is showed by significant (p<0,05) therapeutic gain against cisplatin at such indicators as increased survival of mice with P388 tumor and increased inhibition of primary tumor melanoma B16

Experimental evaluation of synergism of cisplatin with L-lysine-α- oxidase

Synergism effects of cisplatin and L-lysine-α-oxidase (LO), while sequential (no interval) administration of drugs depends on the tumor model and duration of treatment. Synergism is identified at intraperitoneal daily (during 3 days) administration of cisplatin to experimental animals in single doses of 1.5 or 3.0 mg / kg and intravenously 5-fold after 48 h administration of LO and also administered intravenously in cumulative doses of 300-600 E / kg discretely, the first dose - doubled. Synergism of cisplatin and LO is showed by significant (p<0,05) therapeutic gain against cisplatin at such indicators as increased survival of mice with P388 tumor and increased inhibition of primary tumor melanoma B16

Oxidative Stress and Redox-Dependent Signaling in Prostate Cancer

Abstract: Tumor emergence and progression is complicated by the dual role of reactive oxygen species (ROS). Low concentrations of ROS are essential for many intracellular metabolic processes and cell proliferation, while excessive ROS generation disrupts the mechanisms of cancer suppression, leading to the cell damage and death. A long-term imbalance in the ROS/antioxidant ratio and upregulation of the ROS generation due to the reduced efficacy of the antioxidant defense system cause chronic oxidative stress resulting in the damage of proteins, lipid, and DNA molecules and cancer development. Numerous data demonstrate that prostate cancer (the most common cancer in males) is associated with the development of oxidative stress. However, the reasons for the emergence of prostate cancer, as well as changes in the redox signaling and cellular redox homeostasis in this disease, are still poorly understood. The review examines the role of prooxidant and antioxidant enzyme systems, the imbalance in their activity leading to the oxidative stress development, changes in the key components of redox signaling, and the role of microRNAs in the modulation of redox status of cancer cells in prostate cancer. © 2022, Pleiades Publishing, Ltd

Experimental study of the efficacy of L-lysine-a-oxidase Trichoderma CF. Aureoviride Rifai on models of xenografts of human tumors in athymic mice and evaluation of synergism with cisplatin or topoisomerase inhibitors

The effectiveness of L-lysine-alpha oxidase Trichoderma cf. Aureoviride Rifai BKMF-4268D (LO) on models of subcutaneous xenografts of human tumors in athymic mice as well as the effectiveness of combination therapy with known antitumor drugs: cisplatin, irinotecan, etoposide on models of P388 lymphocytic leukemia, Lewis lung (LLC) and B16 melanoma was evaluated. The intraperitoneal injection of LO in a discrete regime at doses of 150-75-75-75-75 E/kg demonstrated inhibition of growth of all studied xenografts of human tumors in athymic mice. The combination of irinotecan+LO on the LLC model gave a significant summative therapeutic benefit with an increase in mouse life expectancy up to 35%. Cisplatin and LO realized a significant (p <0.05) therapeutic benefit against cisplatin according to an additive increase in the survival rate of mice with P388, UPJ = 208% vs. 128%; increased inhibition of growth of the primary node of melanoma B16, TPOmax = 87% vs. 58%. The addition of LO to etoposide did not lead to a significant improvement in the effect on the P388 model. The sensitivity to LO model of colon cancer and the presence of synergism with platinum and irinotecan drugs made LO a promising agent for the study in treatment for colon cancer

Predictive value of ¹⁸F-FDG accumulation in visceral fat activity to detect epithelial ovarian cancer metastases

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, with relapse occurring in about 70% of advanced cases with poor prognosis. The study aimed to assess functional visceral fat activity (VAT) evaluated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) as a predictor of metastases in epithelial ovarian cancer. Methods: We assessed 53 patients with histologically confirmed EOC who underwent 18F-FDG PET/CT after a surgical treatment and courses of chemotherapy. Age, histology, stage, and tumor grade were recorded. Functional VAT was measured by maximum standardized uptake value (SUVmaJ using 18F-FDG PET/CT and tested as a predictor of later metastases in eight abdominal locations and pelvis cavity in the adjusted regression models. We also identified the best areas under the curve (AUC) for SUVmx with the corresponding sensitivity (Se) and specificity (Sp). Results: In both adjusted for regression models and ROC analysis, 18F-FDG accumulation in RE (cut-off SUVmax 1.18; Se 64%; Sp 64%; AUC 0.669; p=0.035) could predict later metastases in EOC patients, as opposed to age, sex, primary tumor location, tumor grade, and histology. Conclusions: VAT SUVmx is significantly associated with later metastases in EOC patients and can be used as their predictor.Актуальность: Эпителиальный рак яичников (Epithelial Ovarian Cancer, EOC) является наиболее злокачественным гинекологическим новообразованием, рецидив которого происходит примерно в 70°% запущенный: случаев и отличается неблагоприятным прогнозом. Цель исследования - оценить функциональную активность висцеральной жировой ткани (VAT) методом позитронно-эмиссионной томографии с 18F-фтордезоксиглюкозой, совмещённой с компьютерной томографией (18F-FDG ПЭТ/КТ) в качестве предиктора метастазирования EOC. Методы: Нами быти обследованы 53 пациента с гистологически верифицированным диагнозом EOC, которым быта проведена I8F-FDG ПЭТ/КТ после хирургического лечения и курсов химиотерапии. Оценке подверглись такие показатели, как возраст пациентов, гистологический тип, стадия и степень опухолевого процесса. Функциональная активность VAT быта измерена с помощью показателя максимального стандартизированного уровня накопления (SUVmax) и полученный цифровой уровень накопления определен на скорректированных регрессионных моделях в качестве предиктора поздних метастазов брюшной полости и малого таза. Также быти получены наилучшие показатели площади под кривой (AUC) для SUVmax с соответствующей чувствительностью (Se) и специфичностью (Sp). Результаты: Накопление 18F-FDG в RE (SUVmax 1,18; Se 64%; Sp 64%; AUC 0,669; p=0,035), как при корректировке регрессионных моделей, так и при анализе ROC-кривой, может предсказывать более поздние метастазы, чем возраст, пол, локализация первичной опухоли, степень рака и гистологический тип рака у пациентов с EOC. Заключение: Уровень накопления SUVmax в VAT связан с поздним метастазированием в лимфатические узлы, что имеет прогностическую ценность для выбора тактики и контроля лечения у пациентов с EOC