Recent Progress in Pharmaceutical Therapies for Castration-Resistant Prostate Cancer

Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. All these drugs demonstrate improvement on overall survival, expect for Denosumab, which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone-metastasis-free survival. Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920), androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176) and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments. Under these flourishing circumstances, more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients

Synthesis and Biological Evaluation of Thieno[3,2-d]- pyrimidinones, Thieno[3,2-d]pyrimidines and Quinazolinones: Conformationally Restricted 17b-Hydroxysteroid Dehydrogenase Type 2 (17b-HSD2) Inhibitors

In this study, a series of conformationally restricted thieno[3,2-d]pyrimidinones, thieno[3,2-d]pyrimidines and quinazolinones was designed and synthesized with the goal of improving the biological activity as 17-hydroxysteroid dehydrogenase type 2 inhibitors of the corresponding amidothiophene derivatives. Two moderately active compounds were discovered and this allowed the identification of the biologically active open conformer as well as the extension of the enzyme binding site characterisation

Influence of music on empirical brain networks

We analyze the influence of music in a network of FitzHugh-Nagumo oscillators with empirical structural connectivity measured in healthy human subjects. We report an increase of coherence between the global dynamics in our network and the input signal induced by a specific music song. We show that the level of coherence depends crucially on the frequency band. We compare our results with experimental data, which also describe global neural synchronization between different brain regions in the gamma-band range and its increase just before transitions between different parts of the musical form (musical high-level events). The results also suggest a split in musical form-related brain synchronization between high brain frequencies, associated with neocortical activity, and low frequencies in the range of dance movements, associated with interactivity between cortical and subcortical regions. Finally, we discuss the general modalities of the influence of music on the human brain.Comment: 24 pages, 10 figures. arXiv admin note: text overlap with arXiv:2103.1380

Разработка технологического процесса изготовления вала

Выпускная квалификационная работа состоит из 107 страниц, 8 глав, 53 рисунков, 7 источников и 10 таблиц. Объектом исследования является деталь - вал, а предметом - технология ее (детали) изготовления. Цель работы - спроектировать технологический процесс изготовления детали вал для среднесерийного производства. В работе проводятся расчеты припусков, режимов резания и штучно-калькуляционного времени. Осуществляется выбор оборудования, режущего и измерительного инструмента. Разрабатывается специальное приспособления для фрезерования шпоночных пазов.Final qualifying work consists of 107 pages, 8 chapters, 53 figures, 7 tables and 10 sources. The object of this study is to detail - the shaft, and the subject - its technology (parts) of manufacture. The purpose of work - to design the technological process of manufacturing parts shaft for medium series production. The work carried out calculations of allowances, cutting conditions and piece-calculation time. Implemented by the choice of equipment, cutting and measuring tools. Developing special tools for milling keyways

Silicon-Organic Hybrid (SOH) Mach-Zehnder Modulators for 100 Gbit/s On-Off Keying

Electro-optic modulators for high-speed on-off keying (OOK) are key components of short- and mediumreach interconnects in data-center networks. Besides small footprint and cost-efficient large-scale production, small drive voltages and ultra-low power consumption are of paramount importance for such devices. Here we demonstrate that the concept of silicon-organic hybrid (SOH) integration is perfectly suited for meeting these challenges. The approach combines the unique processing advantages of large-scale silicon photonics with unrivalled electro-optic (EO) coefficients obtained by molecular engineering of organic materials. In our proof-of-concept experiments, we demonstrate generation and transmission of OOK signals with line rates of up to 100 Gbit/s using a 1.1 mm-long SOH Mach-Zehnder modulator (MZM) which features a {\pi}-voltage of only 0.9 V. This experiment represents not only the first demonstration of 100 Gbit/s OOK on the silicon photonic platform, but also leads to the lowest drive voltage and energy consumption ever demonstrated at this data rate for a semiconductor-based device. We support our experimental results by a theoretical analysis and show that the nonlinear transfer characteristic of the MZM can be exploited to overcome bandwidth limitations of the modulator and of the electric driver circuitry. The devices are fabricated in a commercial silicon photonics line and can hence be combined with the full portfolio of standard silicon photonic devices. We expect that high-speed power-efficient SOH modulators may have transformative impact on short-reach optical networks, enabling compact transceivers with unprecedented energy efficiency that will be at the heart of future Ethernet interfaces at Tbit/s data rates

Microwave-Assisted Syntheses of Amino Acid Ester Substituted Benzoic Acid Amides: Potential Inhibitors of Human CD81-Receptor HCV-E2 Interaction

Results from our group showed benzyl salicylate to be a moderate inhibitor of the CD81-LEL–HCV-E2 interaction. To increase the biological activity, heterocyclic substituted benzoic acids were coupled to amino acid esters via microwave assisted DCC-reaction. The prepared compounds were tested for their inhibitory potency by means of a fluorescence labeled antibody assay system using HUH7.5 cells

Phosphonate as a Stable Zinc-Binding Group for "Pathoblocker" Inhibitors of Clostridial Collagenase H (ColH)

Microbial infections are a significant threat to public health, and resistance is on the rise, so new antibiotics with novel modes of action are urgently needed. The extracellular zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyses tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a hydrolytically cleavable thiocarbamate unit) provided efficient ColH inhibition. We now report the synthesis and biological evaluation of a range of zinc‐binding group (ZBG) variants of this thiol‐derived inhibitor, with the mercapto unit being replaced by other zinc ligands. Among these, an analogue with a phosphonate motif as ZBG showed promising activity against ColH, an improved selectivity profile, and significantly higher stability than the thiol reference compound, thus making it an attractive candidate for future drug development