Molecular dynamics simulations and docking of non-nucleoside reverse transcriptase inhibitors (NNRTIs): a possible approach to personalized HIV treatment : from 7th German Conference on Chemoinformatics: 25 CIC-Workshop Goslar, Germany, 6 - 8 November 2011

The human immunodeficiency virus (HIV) is currently ranked sixth in the worldwide causes of death [1]. One treatment approach is to inhibit reverse transcriptase (RT), an enzyme essential for reverse transcription of viral RNA into DNA before integration into the host genome [2]. By using non-nucleoside RT inhibitors (NNRTIs) [3], which target an allosteric binding site, major side effects can be evaded. Unfortunately, high genetic variability of HIV in combination with selection pressure introduced by drug treatment enables the virus to develop resistance against this drug class by developing point mutations. This situation necessitates treatment with alternative NNRTIs that target the particular RT mutants encountered in a patient. Previously, proteochemometric approaches have demonstrated some success in predicting binding of particular NNRTIs to individual mutants; however a structurebased approach may help to further improve the predictive success of such models. Hence, our aim is to rationalize the experimental activity of known NNRTIs against a variety of RT mutants by combining molecular modeling, long-timescale atomistic molecular dynamics (MD) simulation sampling and ensemble docking. Initial control experiments on known inhibitor-RT mutant complexes using this protocol were successful, and the predictivity for further complexes is currently being evaluated. In addition to predictive power, MD simulations of multiple RT mutants are providing fundamental insight into the dynamics of the allosteric NNRTI binding site which is useful for the design of future inhibitors. Overall, work of this type is hoped to contribute to the development of predictive efficacy models for individual patients, and hence towards personalized HIV treatment options

Molecular dynamics simulations and docking of non-nucleoside reverse transcriptase inhibitors (NNRTIs): a possible approach to personalized HIV treatment

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A Precious-Metal-Free Hybrid Electrolyzer for Alcohol Oxidation Coupled to CO2 -to-Syngas Conversion.

Electrolyzers combining CO2 reduction (CO2 R) with organic substrate oxidation can produce fuel and chemical feedstocks with a relatively low energy requirement when compared to systems that source electrons from water oxidation. Here, we report an anodic hybrid assembly based on a (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) electrocatalyst modified with a silatrane-anchor (STEMPO), which is covalently immobilized on a mesoporous indium tin oxide (mesoITO) scaffold for efficient alcohol oxidation (AlcOx). This molecular anode was subsequently combined with a cathode consisting of a polymeric cobalt phthalocyanine on carbon nanotubes to construct a hybrid, precious-metal-free coupled AlcOx-CO2 R electrolyzer. After three-hour electrolysis, glycerol is selectively oxidized to glyceraldehyde with a turnover number (TON) of ≈1000 and Faradaic efficiency (FE) of 83 %. The cathode generated a stoichiometric amount of syngas with a CO:H2 ratio of 1.25±0.25 and an overall cobalt-based TON of 894 with a FE of 82 %. This prototype device inspires the design and implementation of nonconventional strategies for coupling CO2 R to less energy demanding, and value-added, oxidative chemistry

Проектирование системы электроснабжения перевалопогрузочного комплекса морского порта

Объектом исследования является электрическая часть перевалопогрузочного комплекса ОАО «Восточный порт». Цель работы – проектирование системы электроснабжения перевалопогрузочного комплекса морского порта. В процессе исследования проводился сбор исходных данных в ходе производственной практики на объекте исследования. В результате была спроектирована схема электроснабжения от подстанции энергосистемы, до конечного электроприемника. Были выбраны кабели и провода, коммутационное оборудование. Также был произведен экономический расчет капитальных затрат на сооружение данной схемы, определены условия безопасности и гигиены труда рабочих предприятия.The object of the research is part of an electric perevalopogruzochnogo complex JSC "Vostochny Port". The purpose of the work - design of power supply system perevalopogruzochnogo seaport complex. The study was conducted to collect baseline data in the course of practical training on the subject of the study. As a result, power supply circuit has been designed from the substation grid, appliance, to the end. Cables and wires, switching equipment were chosen. There was also made economic calculation of capital costs for the construction of the scheme, identified the security conditions and hygiene of workers of the enterprise

Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions

Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel–Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC₅₀ of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems

Galanin and Adrenomedullin Plasma Responses During Artificial Gravity on a Human Short-Arm Centrifuge

Galanin and adrenomedullin plasma responses to head-up tilt and lower body negative pressure have been studied previously. However, to what extent short-arm human centrifugation (SAHC) affects these responses is not known. In this study, we assessed how the application of variable gradients of accelerations (ΔGz) via shifting of the rotation axis during centrifugation affects selected hormonal responses. Specifically, we tested the hypothesis, that cardiovascular modulating hormones such as galanin and adrenomedullin will be higher in non-finishers (participants in whom at least one of the pre-defined criteria for presyncope was fulfilled) when compared to finishers (participants who completed the entire protocol in both sessions) during SAHC exposure. Twenty healthy subjects (10 women and 10 men) were exposed to two g-levels [1 Gz and 2.4 Gz at the feet (Gz_Feet)] in two positions (axis of rotation placed above the head and axis of rotation placed at the heart level). Elevated baseline levels of galanin appeared to predict orthostatic tolerance (p = 0.054) and seemed to support good orthostatic tolerance during 1 Gz_Feet SAHC (p = 0.034). In finishers, 2.4 Gz_Feet SAHC was associated with increased galanin levels after centrifugation (p = 0.007). For adrenomedullin, the hypothesized increases were observed after centrifugation at 1 Gz_Feet (p = 0.031), but not at 2.4 Gz_Feet, suggesting that other central mechanisms than local distribution of adrenomedullin predominate when coping with central hypovolemia induced by SAHC (p > 0.14). In conclusion, baseline galanin levels could potentially be used to predict development of presyncope in subjects. Furthermore, galanin levels increase during elevated levels of central hypovolemia and galanin responses appear to be important for coping with such challenges. Adrenomedullin release depends on degree of central hypovolemia induced fluid shifts and a subject’s ability to cope with such challenges. Our results suggest that the gradient of acceleration (ΔGz) is an innovative approach to quantify the grade of central hypovolemia and to assess neurohormonal responses in those that can tolerate (finishers) or not tolerate (non-finishers) artificial gravity (AG). As AG is being considered as a preventing tool for spaceflight induced deconditioning in future missions, understanding effects of AG on hormonal responses in subjects who develop presyncope is important

Research productivity during orthopedic surgery residency correlates with pre‑planned and protected research time: a survey of German‑speaking countries

Purpose The purpose of this study was to identify modifiable factors associated with research activity among residents working in orthopedic surgery and traumatology. Methods Residents at 796 university-affiliated hospitals in Austria, Germany, and Switzerland were invited to participate. The online survey consisted of questions that ascertained 13 modifiable and 17 non-modifiable factors associated with the residents’ current research activities. Responses of 129 residents were analyzed. Univariate linear regression was used to determine the association of individual factors with the current research activity (hours per week). The impact of significant non-modifiable factors (with unadjusted p values < 0.05) was controlled for using multivariate linear regression. Results The univariate analysis demonstrated six non-modifiable factors that were significantly associated with the current research activity: a University hospital setting (p < 0.001), an A-level hospital setting (p = 0.024), Swiss residents (p = 0.0012), the completion of a dedicated research year (p = 0.007), female gender (p = 0.016), and the department’s size (p = 0.048). Multivariate regression demonstrated that the number of protected research days per year (p < 0.029) and the percentage of protected days, that were known 1 week before (p < 0.001) or the day before (p < 0.001), were significantly associated with a higher research activity. Conclusions As hypothesized, more frequent and predictable protected research days were associated with higher research activity among residents in orthopedic surgery and traumatology. Level of evidence III

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy