Search for Collective Phenomena in High Multiplicity Events at Nuclotron and U-70

More than ten-year experimental search for collective phenomena in high multiplicity events has been carried out at the Laboratory of high energy physics at JINR. We present main results, which have been received at the U-70 accelerator (IHEP, Protvino) in the proton collisions and at Nuclotron ( JINR, Dubna) in the nuclear interactions. Fo

Биохимические критерии токсичности терапии высокими дозами метотрексата у детей с остеосаркомой

Methotrexate (Mtx) is a cytotoxic drug from the group of antimetabolites, folic acid antagonists. High-dose (HD) Mtx in pediatric oncology are used for the treatment of osteosarcoma (OS), and other types of tumors. This therapy has allowed to achieve a five-year relapse-free survival rates up to 80 % in patients with OS. However, the high toxicity of Mtx is a serious constraint in achieving the maximum therapeutic effect, which in most cases poses the occurrence of side effects in patients on various organs and systems. Treatment should be under strict laboratory monitoring, primarily therapeutic drug monitoring the concentration of Mtx in serum.246 children (boys – 125, girls – 121) aged 5 to 16 years with osteosarcoma (mean age 12.2 years) who were treated in N.N. Blokhin Russian Cancer Research Center from 2006 to 2013. Patients were conducted from 1 to 8 courses HD Mtx at a dose of 8 or 12 g/m2 , administered within 4 h of infusion on the background of alkaline prehydrate. Leucovorin was administered intravenously, every 6 hours, starting 24 h from the start of the Mtx infusion. 1137 courses of HD Mtx were conducted with FPIA method (analyzer TDx/Flx, Abbott, USA). The technique of monitoring of homocysteine (Hcy) in the blood serum by analyzer Vitros 5/1FS (Johnson & Johnson, USA) during the entire course of high-dose Mtx was tested. In groups calculated pharmacokinetic parameters Mtx were tested: area under the pharmacokinetic curve (MtxAUC), clearance of methotrexate (ClMtx), the elimination half-life (T1/2 ) and the total time of excretion (Ttotal). Normal excretion of Mtx was revealed at 1050 courses Mtx, corresponding to the following values: 4 h – 1109 ± 283 μmol/l; 24 h – 4,67 ± 0,95 μmol/l; 42 h – 0,38 ± 0.16 µmol/l; 48 h – less than 0,23 ± 0.04 µmol/l; 72 h of 0.07 ± 0,03 µmol/l; 96 h of 0.03 ± 0.01 µmol/l. At 87 courses identified delayed Mtx excretion, accounting for 7.6 % of all courses. In all measured parameters: hourly concentration of Mtx, Ttotal, MtxAUC, Clmtx, T1/2 , is obtained statistically significant differences between normal and delayed Mtx excretion. Patients in group of delayed excretion of methotrexate were characterized by the development of hepatotoxicity, there were also observed 4 cases of the occurrence of acute renal failure.Monitoring of biochemical parameters (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase) also revealed differences between the two groups – hepatotoxicity directly depended on MtxAUC, ClMtx and Ttotal, and the amplitude changes in activities of enzymes from course to course by increasing the number of course decreased.Our developed methodology of monitoring of Hcy in serum during the course of HD Mtx revealed that Hcy metabolic interconnected with Mtx – the higher the concentration of Mtx, the greater the amount of Hcy released into the blood. Hcy has a close metabolic relationship with Mtx – it can serve as a marker of the efficiency of suppression of the transformation of folates. During slow excretion of Mtx Hcy significantly increased in the blood, which also suggests that it can serve as a marker of pharmacodynamic effects of HD Mtx.Метотрексат (Mtx) – цитостатический препарат из группы антиметаболитов, антагонистов фолиевой кислоты. Высокие дозы (ВД) Mtx в детской онкологии применяются для лечения остеосаркомы (ОС) и других типов опухолей и позволяют достичь 5-летней безрецидивной выживаемости до 80 %. Однако высокая токсичность Mtx является серьезным ограничением в достижении максимального лечебного действия и в большинстве случаев обусловливает возникновение у больных серьезных побочных эффектов со стороны различных органов и систем. Лечение должно проводиться под строгим контролем лабораторных исследований, в первую очередь терапевтического лекарственного мониторинга (ТЛМ), концентрации Mtx в сыворотке крови и других биохимических показателей.Обследовано 246 детей (125 мальчиков и 121 девочка) в возрасте от 5 до 16 лет с ОС (средний возраст 12,2 года), которые находились на лечении в НИИ ДОГ ФГБНУ «РОНЦ им. Н.Н. Блохина» с 2006 по 2013 г. Больным было проведено от 1 до 8 курсов ВД Mtx – 8 или 12 г/м2 за 4 ч инфузии на фоне щелочной прегидратации. Лейковорин назначался внутривенно через каждые 6 ч, начиная с 24 ч от начала инфузии Mtx. Проведено 1137 курсов ТЛМ Mtx методом флуоресцентно-поляризационного иммуноанализа на анализаторе TDx/Flx (Abbott, США). Отработана методика мониторинга гомоцистеина (Hcy) в сыворотке крови на анализаторе Vitros 5/1FS (Johnson & Johnson, США) в течение всего курса ВД Mtx. В группах рассчитаны фармакокинетические показатели Mtx: площадь под фармакокинетической кривой (MtxAUC), клиренс Mtx (ClMtx), период полувыведения (T1/2 ) и общее время выведения (Ttotal ).При 1050 курсах ВД Mtx выведение Mtx было нормальным и соответствовало следующим значениям: через 4 ч – 1109 ± 283 мкмоль/л; через 24 ч – 4,67 ± 0,95 мкмоль/л; через 42 ч – 0,38 ± 0,16 мкмоль/л; через 48 ч – менее 0,23 ± 0,04 мкмоль/л; через 72 ч – 0,07 ± 0,03 мкмоль/л; через 96 ч – 0,03 ± 0,01 мкмоль/л. Замедленное выведение Mtx выявлено при 87 курсах, что составляет 7,6 % от всех курсов. По всем измеряемым параметрам: концентрации выведения Mtx по часам, Ttotal, MtxAUC, ClMtx, T1/2 – получены статистически достоверные различия между нормальным и замедленным выведением Mtx. Для пациентов группы замедленного выведения было характерно развитие гепатотоксичности, также наблюдались 4 случая возникновения острой почечной недостаточности. Проведение мониторинга биохимических показателей (аланинаминотрансферазы, аспартатаминотрансферазы, лактатдегидрогеназы) также позволило выявить различия между двумя группами – гепатотоксичность непосредственно зависела от MtxAUC, ClMtx и Ttotal, причем амплитуда изменения активностей ферментов от курса к курсу уменьшалась.Отработанная нами методика мониторинга Hcy в сыворотке крови в течение курса ВД Mtx позволила выявить, что Hcy метаболически взаимосвязан с Mtx – чем выше концентрация Mtx, тем большее количество Hcy выбрасывается в кровь. Hcy может служить маркером эффективности подавления трансформации фолатов. При замедленном выведении Mtx уровень Hcy значительно повышается в крови. Это также свидетельствует о том, что он может служить маркером фармакодинамического воздействия ВД Mtx

Observation of narrow baryon resonance decaying into pKs0pK^0_s in pA-interactions at 70GeV/c70 GeV/c with SVD-2 setup

SVD-2 experiment data have been analyzed to search for an exotic baryon state, the $\Theta^+$-baryon, in a $pK^0_s$ decay mode at $70 GeV/c$ on IHEP accelerator. The reaction $pA \to pK^0_s+X$ with a limited multiplicity was used in the analysis. The $pK^0_s$ invariant mass spectrum shows a resonant structure with $M=1526\pm3(stat.)\pm 3(syst.) MeV/c^2$ and $\Gamma < 24 MeV/c^2$. The statistical significance of this peak was estimated to be of $5.6 \sigma$. The mass and width of the resonance is compatible with the recently reported $\Theta^+$- baryon with positive strangeness which was predicted as an exotic pentaquark ($uudd\bar{s}$) baryon state. The total cross section for $\Theta^+$ production in pN-interactions for $X_F\ge 0$ was estimated to be $(30\div120) \mu b$ and no essential deviation from A-dependence for inelastic events $(\sim A^{0.7})$ was found.Comment: 8 pages, 7 figures, To be submitted to Yadernaya Fizika. v3-v5 - Some references added, minor typos correcte

Терапевтический лекарственный мониторинг метотрексата при применении его в высоких дозах для лечения остеосаркомы у детей

In children oncology high doses of methotrexate (HD Mtx) use for treatment of osteosarcoma, acute lymphoblastic leukemia and many others tumors. Due to high intra- and interindividual Mtx pharmacokinetic variability it is essential perform monitoring its concentration in the saliva. The most dangerous phenomena in the case of HD Mtx are so-termed "delayed Mtx excretion", "prolonged Mtx excretion". Their development is multifactorial and unpredictable. Having big actual material we set task: analyze pharmacokinetics HD Mtx in case of osteosarcoma in children, determine its peculiarities, elucidate whether similar or not proceed disorders of Mtx excretion, perform their quantification.В детской онкологии высокие дозы метотрексата (ВД Mtx) используются для лечения остеосаркомы (ОС), острого лимфобластного лейкоза и ряда других опухолей. В связи с высокой интра- и экстраиндивидуальной изменчивостью фармакокинетики Mtx необходимо проводить мониторинг его концентрации в сыворотке крови. Самым опасным явлением при терапии ВД Mtx является т.н. «отсроченная экскреция Mtx», «замедленное выведение Mtx». Их развитие многофакторное и непредсказуемое. В данной работе, имея большой фактический материал, была поставлена задача проанализировать фармакокинетику ВД Mtx при остеосаркоме у детей, выявить ее особенности, установить, однотипно ли протекают нарушения выведения Mtх, провести их количественный анализ

Challenges in QCD matter physics - The Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sqrt(s_NN) = 2.7 - 4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (mu_B > 500 MeV), effects of chiral symmetry, and the equation-of-state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2022, in the context of the worldwide efforts to explore high-density QCD matter.Comment: 15 pages, 11 figures. Published in European Physical Journal

Fabrication, Modeling and Characterization of Multi-Crosslinked Methacrylate Copolymeric Nanoparticles for Oral Drug Delivery

Nanotechnology remains the field to explore in the quest to enhance therapeutic efficacies of existing drugs. Fabrication of a methacrylate copolymer-lipid nanoparticulate (MCN) system was explored in this study for oral drug delivery of levodopa. The nanoparticles were fabricated employing multicrosslinking technology and characterized for particle size, zeta potential, morphology, structural modification, drug entrapment efficiency and in vitro drug release. Chemometric Computational (CC) modeling was conducted to deduce the mechanism of nanoparticle synthesis as well as to corroborate the experimental findings. The CC modeling deduced that the nanoparticles synthesis may have followed the mixed triangular formations or the mixed patterns. They were found to be hollow nanocapsules with a size ranging from 152 nm (methacrylate copolymer) to 321 nm (methacrylate copolymer blend) and a zeta potential range of 15.8–43.3 mV. The nanoparticles were directly compressible and it was found that the desired rate of drug release could be achieved by formulating the nanoparticles as a nanosuspension, and then directly compressing them into tablet matrices or incorporating the nanoparticles directly into polymer tablet matrices. However, sustained release of MCNs was achieved only when it was incorporated into a polymer matrix. The experimental results were well corroborated by the CC modeling. The developed technology may be potentially useful for the fabrication of multi-crosslinked polymer blend nanoparticles for oral drug delivery