Pharmacological modulation of cell functional activity with valproic acid and erythropoietin

Valproic acid (VA) is carboxylic acid with a branched chain, which is used as an antiepileptic drug. VA, which is an antiepileptic drug, is also a teratogen, which causes defects of a neural tube and an axial skeleton, although the mechanisms are not yet fully clear. It is shown that valproic acid reduces the intracellular level of oxygen active form

Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy.

Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions

Determination of the activation energy and the predexponental multiplier of the coking coal cm «Neryungrinskaya»pyrolysis process

An iso-conversion method for determining the kinetic parameters of Ozawa-Flynn-Wall for the process of pyrolysis of coke coal is considered in this work. Five thermogravimetric measurements were carried out and analyzed. The dependence of the activation energy and the pre-exponential factor on the degree of transformation is obtained.В работе рассмотрен низоконверсионный метод определения кинетических параметров Ozawa-Flynn-Wall для процесса пиролиза коксового угля. Было проведено и проанализировано 5 термогравиметрических измерений. Получена зависимость энергии активации и предэкспоненциального множителя от степени превращения

MECHANICAL PROPERTIES ANISOTROPY RESEARCH OF COLD ROLLED TRANSFORMER STEEL

В настоящей работе было проведено испытание на растяжение образцов сплава Fe-3%Si в состоянии после холодной прокатки. Испытания проводили в трёх направлениях: направление прокатки, поперечное и диагональное (45° относительно направления прокатки). Было обнаружено, что величина временного сопротивления в направлении прокатки на 5 % меньше, чем в поперечном направлении.Tensile tests of Fe-3%Si alloy cold rolled samples were carried out in this paper. There were three orientations of samples for tensile tests: rolling direction, transverse direction and diagonal direction (45° to rolling direction). It was discovered that ultimate strength value in rolling direction is less than transverse direction by 5 %

Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study

Abstract Background Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor. Methods In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10–50 mcg/kg) on days 1–5 and 15–19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated. Results In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib. Conclusion IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC. Trial registration ClinicalTrials.gov Identifier: NCT0038928

Effect of the secretome of multipotent mesenchymal stromal cells induced by dexamethasone in vitro on the expression of phospho-NF-κB p65 and Ki-67 in mononuclear cells

To investigate the influence of secretomes from native and dexamethasone-treated adipose-derived multipotent mesenchymal stromal cells (MMSC) on the proliferation of mononuclear cells (MNCs) and on their expression of phospho-NF-κB p65 in vitr

Расчет эффективных механических характеристик подработанного массива горных пород

An approach has been developed to construct functional expressions for calculating the effective mechanical characteristics of the undermined rock massif during its repeated mining, taking into account the disturbance of the different-type massif continuity and the time passed after the undermining. The approach was developed as applied to the conditions of the Starobin potash salt deposit. It is based on introducing special correction factors into the expressions for mechanical characteristics of the massif. At the same time, the state of the undermined massif area is considered in the continuum model approximation. It is shown that one of the most important factors to be considered when constructing the functional dependence for mechanical characteristics of the undermined layered massif is to take into account the mutual slippage of layers and their lamination related to it, because the strength characteristics such as bonding strength and internal friction coefficient mainly change when the massif is undermined. The algorithm for calculating the mechanical properties of the undermined massif proposes the use of correction factors that take into account the heterogeneity of the rock massif; lamination and slippage of the contacting layers; changes in the properties of the undermined massif with variation of the depth of repeated mining; changes in the properties resulting from the technological disturbance of the massif initial equilibrium state (primary undermining, time passed since the primary undermining).Разработан подход к построению функциональных выражений для расчета эффективных механических характеристик подработанного массива горных пород при его повторной подработке с учетом нарушений сплошности массива различного характера и времени, прошедшего после подработки. В основу подхода положено введение специальных поправочных множителей в выражения для механических характеристик массива. При этом состояние подработанной области массива рассматривается в приближении моделей сплошных сред. Показано, что одним из важнейших факторов, который требуется учитывать при построении функциональной зависимости для механических характеристик подработанного слоистого массива, является учет взаимного проскальзывания слоев и связанного с ним их отслоения, так как при подработке массива главным образом изменяются такие прочностные характеристики, как сцепление и коэффициент внутреннего трения. Алгоритм расчета механических характеристик подработанного массива предлагает использование поправочных множителей, учитывающих неоднородность массива горных пород; расслоение и проскальзывание контактирующих слоев; изменения свойств подработанного массива при изменении глубины повторной отработки, изменение свойств в результате технологического нарушения естественного равновесного состояния массива (первичная подработка, время, прошедшее со времени первичной подработки)

Критерии предельного состояния и прочностные характеристики повторно подрабатываемых массивов горных пород

Methodological approaches to the selection of ultimate state criteria and strength characteristics of the repeatedly undermined rock massifs were developed. These approaches were designed to provide parametric support to the geomechanical modelling of the massif stress-strain state and the mining systems of the Starobin potash deposit mine fields planned for the additional mining of the mineral reserves left. It was established that a complex criterion must be used to study the massif ultimate state. Determination of such criterion can be carried out using the developed approaches. The first approach is to select several criteria that evaluate the massif ultimate state by certain types of the massif stress-strain state. These criteria are the following: the criterion of the maximum normal stresses, criterion of the maximum linear strains, the criterion of the maximum shear stresses and the Coulomb–Mohr failure criterion. The second approach is to construct an integrated failure state criterion for materials whose ultimate tensile and compressive stresses differ significantly. In this case, parameters characterizing the type of stress state and properties of the material are introduced. These parameters together determine the destruction character – tear or shear. To describe the rocks behavior in the extreme strength stage of deformation, it is proposed to apply deformation theory of strength using the developed strain failure criterion. When calculating the strength characteristics of the repeatedly undermined rock massif, it is recommended to use a structural attenuation coefficient as the product of several factors, taking into account various types of disturbances in the primary undermined massif and the time factor. The Coulomb–Mohr strength condition is recommended to be used taking into account the composite structural attenuation coefficient. Dependencies have been developed to describe the change in the strength characteristics of rocks in the undermined massif, considering the attenuation coefficient.Разработаны методические подходы к выбору критериев предельного состояния и прочностных характеристик повторно подрабатываемых массивов горных пород, предназначенных для параметрического обеспечения геомеханического моделирования напряженно-деформированного состояния массива и горнотехнических систем участков шахтных полей Старобинского месторождения калийной руды, планируемых для доизвлечения оставленных запасов полезного ископаемого. Установлено, что для изучения предельного состояния массива необходимо применять комплексный критерий. Определение такого критерия можно выполнить с использованием разработанных подходов. Первый подход заключается в выборе нескольких критериев, оценивающих предельное состояние массива по отдельным типам напряженно-деформированного состояния массива: критерия наибольших нормальных напряжений, критерия наибольших линейных деформаций, критерия наибольшего касательного напряжения, критерия Кулона–Мора. Второй подход заключается в построении объединенного критерия предельного состояния предлагаемого вида для материалов, у которых предельные величины напряжений на растяжение и сжатие отличаются существенным образом. При этом вводятся параметры, характеризующие вид напряженного состояния и свойства материала, которые в совокупности определяют характер разрушения – отрыв или срез. Для описания поведения горных пород в запредельной по прочности стадии деформирования предлагается применять деформационную теорию прочности с использованием разработанной зависимости деформационного критерия прочности. При расчете прочностных характеристик повторно подрабатываемого массива горных пород рекомендуется применять коэффициент структурного ослабления в виде произведения нескольких коэффициентов, учитывающих различные типы нарушения первично подработанного массива и временной фактор. Условие прочности Кулона–Мора рекомендуется использовать с учетом составного коэффициента структурного ослабления. Разработаны зависимости, описывающие изменение прочностных характеристик пород в подработанном массиве с учетом коэффициента разрыхления

Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial

PURPOSE: Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In this study, we describe the patterns and time course of response to T-VEC from the phase III OPTiM trial of 436 patients with unresected stages IIIB-IV melanoma. METHODS: Lesion-level response analyses were performed based on the type of lesion (injected or uninjected cutaneous, subcutaneous, or nodal lesions; or visceral lesions [uninjected]), and the best percentage change from baseline of the sum of products of the longest diameters was calculated. Patients randomized to T-VEC (n = 295) who experienced a durable response (continuous partial or complete response for ≥6 months) were evaluated for progression prior to response (PPR), defined as the appearance of a new lesion or >25 % increase in total baseline tumor area. RESULTS: T-VEC resulted in a decrease in size by ≥50 % in 64 % of injected lesions (N = 2116), 34 % of uninjected non-visceral lesions (N = 981), and 15 % of visceral lesions (N = 177). Complete resolution of lesions occurred in 47 % of injected lesions, 22 % of uninjected non-visceral lesions, and 9 % of visceral lesions. Of 48 patients with durable responses, 23 (48 %) experienced PPR, including 14 who developed new lesions only. No difference in overall survival was observed, and median duration of response was not reached in patients with PPR versus those without PPR. CONCLUSIONS: Responses in uninjected lesions provide validation of T-VEC-induced systemic immunotherapeutic effects against melanoma. PPR did not negatively impact the clinical effectiveness of T-VEC

Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users