Molecular characteristics of mismatch repair genes in sporadic colorectal tumors in Czech patients

BACKGROUND: Mismatch repair (MMR) genes are known to be frequently altered in colorectal cancer (CRC). Both genetics and epigenetics modifications seems to be relevant in this phenomenon, however it is still not clear how these two aspects are interconnected. The present study aimed at characterizing of epigenetic and gene expression profiles of MMR genes in sporadic CRC patients from the Czech Republic, a country with one of the highest incidences of this cancer all over Europe. METHODS: Expression levels and CpG promoter methylation status of all MMR genes were evaluated in DNA from tumor and adjacent mucosal samples of 53 incident CRC patients. RESULTS: We have found significantly increased transcription levels in EXO1 gene in tumor tissues (P = 0.05) and significant over-expression of MSH3 gene in colon tumors when compared to adjacent mucosal tissues (P = 0.02). Interestingly, almost all MMR genes were differently expressed when localization of tumors was compared. In particular, colon tumors showed an up-regulation of EXO1, MSH2, MSH3, MSH6, and PMS2 genes in comparison to rectal tumors (P = 0.02). Expression levels of all MMR genes positively correlated between each other. The promoter methylation of MLH1 gene was observed in 9% of CRC tissues only. CONCLUSIONS: In our study, we have observed different pattern of MMR genes expression according to tumor localization. However, a lack of association between methylation in MMR genes and their corresponding expressions was noticed in this study, the relationship between these two aspects is worthy to be analyzed in larger population studies and in pre-malignant stages

Future physical education teachers’ marketing business motivations survey

Objective of the study was to survey marketing business motivations of future physical education teacher

The development of radio and 3G based telemetry system for the remote gas accounting and control nodes

In this article we have described the use of vortex and recently developed ultrasonic flowmeters with high dynamic range of 1 to 1500 for industrial applications. Its software and the software of corresponding computing device is able to avoid gas leakage, to minimize energy consumption and to save human resources while maintaining metrological data. Described is the low power consumption that makes it possible to use this ultrasonic flowmeter in hard remote environment without direct management for a period of several month

Fine-tuning of Silica Coating Procedure for Preparation of Biocompatible and Bright Pbs/Sio2 Qds

Near-infrared semiconductor PbS quantum dots (QDs) with emission in biological transparency window are promising material for in vivo biolabelling and deep-tissue imaging of biological specimen. Among various approaches that render initially hydrophobic and toxic QDs biocompatible, the growth of a silica shell on the QD surface represents an efficient method to minimize QD toxicity. Nevertheless, it is important to preserve QDs emission properties after the silica coating procedure. Here we report on the optimal parameters of this procedure which allow to obtain a stable silica shell and maintain the optical properties of initial PbS QDs. Furthermore, we show that PbS QDs with the optimal SiO2 shell retain their luminescence quantum yield even after condensation into a solid film. Thus, our procedure can become a basis in development of bright, receptor-targeted NIR fluorescent probes for in vivo tumor imaging. Keywords: quantum dot, SiO2 shell, bioimagin

Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma

In the primary analysis of the phase III COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demonstrated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.8 months after the primary analysis). In total, 522 patients were randomized (DARA SC, n=263; DARA IV, n=259). With longer follow-up, DARA SC and DARA IV continued to show consistent efficacy and maximum trough daratumumab concentration as compared with the primary analysis. The overall response rate was 43.7% for DARA SC and 39.8% for DARA IV. The maximum mean (standard deviation [SD]) trough concentration (cycle 3, day 1 pre-dose) of serum DARA was 581 (SD, 315) µg/mL for DARA SC and 496 (SD, 231) µg/mL for DARA IV. Median progression-free survival was 5.6 months for DARA SC and 6.1 months for DARA IV; median overall survival was 28.2 months and 25.6 months, respectively. Grade 3/4 treatment-emergent adverse events occurred in 50.8% of patients in the DARA SC group and 52.7% in the DARA IV group; the most common (≥10%) were thrombocytopenia (DARA SC, 14.2%; DARA IV, 13.6%), anemia (13.8%; 15.1%), and neutropenia (13.1%; 7.8%). The safety profile remained consistent with the primary analysis after longer follow-up. In summary, DARA SC and DARA IV continue to demonstrate similar efficacy and safety, with a low rate of infusion-related reactions (12.7% vs. 34.5%, respectively) and shorter administration time (3-5 minutes vs. 3-7 hours) supporting DARA SC as a preferable therapeutic choice

Once-weekly selinexor, bortezomib, and dexamethasone versus twice-weekly bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label phase 3 trial

Background Selinexor with dexamethasone has demonstrated activity in patients with heavily pretreated multiple myeloma (MM). In a phase 1b/2 study, the combination of oral selinexor with the proteasome inhibitor (PI) bortezomib, and dexamethasone (SVd) induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. The aim of this trial was to evaluate the clinical benefit of weekly SVd versus standard bortezomib and dexamethasone (Vd) in patients with previously treated MM. Methods This phase 3, randomised, open label trial was conducted at 123 sites in 21 countries. Patients who were previously treated with one to three lines of therapy, including PIs were randomised (1:1) to selinexor (100 mg once-weekly) plus bortezomib (1·3 mg/m2 once-weekly) and dexamethasone (20 mg twice-weekly) [SVd] or bortezomib (1·3 mg/m2 twice-weekly) and dexamethasone (20 mg 4 times per week) [Vd]. Randomisation was done using interactive response technology and stratified by previous PI therapy, lines of treatment, and MM stage. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. Findings Between June 2017 and February 2019, 402 patients were randomised: 195 to SVd and 207 to Vd. Median PFS was 13·93 (95% CI 11·73–NE) with SVd versus 9·46 months (8·11–10·78) with Vd; HR 0·70, [95% CI 0·53–0·93]; P=0.0075. Most frequent grade ≥3 adverse events (SVd vs Vd) were thrombocytopenia (77 [40%] vs 35 [17%]), fatigue (26 [13%] vs 2 [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy rates (overall, 32·3% vs 47·1%; OR 0·52, [95% CI 0·35-0·79]; P=0.0010 and grade ≥2, 21·0% vs 34·3%; OR 0·50, [95% CI 0·32-0·79]; P=0.0013) were lower with SVd. There were 47 (24%) deaths on SVd and 62 (30%) on Vd. Interpretation Once-weekly SVd is a novel, effective, and convenient treatment option for patients with MM who have received 1-3 prior therapies. Funding Karyopharm Therapeutics In

Інновації в бізнес-управлінні: мотиваційні фактори та бар’єри

У статті проаналізовано ефективність функціонування підприємницької сектору як однієї із рушійних сил економічного розвитку країни. Авторами відмічено, що підприємницький сектор генерує найбільшу питому вагу ВВП за рахунок податків від реалізації продукції. Ефективний розвиток підприємництва вимагає формування сприятливого бізнес-клімату для відкриття власної справи та виходу на ринок. Метою статті є оцінювання впливу мотиваційних факторів та бар'єрів на розвиток підприємницького сектору. У ході дослідження проаналізовано методи управління бізнес-середовищем та фінансовою діяльністю з точки зору менеджменту, інновацій, ініціативності та підтримки підприємницької діяльності. Методологічним інструментарієм дослідження є класичні методи наукового аналізу, синтез та методи збору даних. У роботі застосовано базовий евристичний підхід для аналізу наукового доробку щодо проблематики дослідження та моніторингу показників бізнес-клімату та розвитку малого та середнього підприємництва у Словацькій республіці, у країнах ЄС-27 та світі. Вихідні дані для дослідження сформовано на основі даних Європейської комісії, звіту Flash Eurobarometer та Світового банку. Детерміновану вибірку даних сформовано на основі результатів опитування 426 респондентів Словацької республіки. Перевірку гіпотез дослідження здійснено за допомогою критеріїв Фрідмана, Колмогорова-Смирнова та Краскела-Уолліса. Результати емпіричного аналізу засвідчили про наявність суттєвої відмінності впливу між мотиваційними факторами при відкритті власної справи. Авторами встановлено, що у Словацькій республіці існують суттєві бар’єри, які значно обмежують подальший розвиток бізнесу. За результатами дослідження виокремлено низку рекомендацій щодо покращення поточного стану бізнессередовища, шляхом підтримки мотиваційних факторів та подолання бар’єрів при відкритті власної справи у Словацькій республіці.The business sector represents one of the most important parts of the modern economy. It creates and secures most products and services, contributing to most of the sales tax revenues. Business development is not possible without creating a favourable business environment and suitable conditions for creating and entering new business into the market. This paper focuses on the evaluation of some business environment factors in starting a business. Attention is attended to the business environment and funding activities management, including the managerial assessment of proactive, innovative, and business-supporting activities. Besides, this study encompasses the issues of obstacles and barriers to starting a business. The interest of the article is to point out the state and problems in the field of start-up entrepreneurs and the importance of supporting motivational factors and removing barriers by improving the business environment. Methodological tools of the research are classical methods of science analytics, synthesis, and data selection. The basic heuristic approach consists of professional literature on the subject matter, and secondary sources obtained from European Commission, Eurostat – Flash Barometer, and the World Bank to monitor selected indicators of the business environment and SMEs in Slovakia, EU-27 countries and the world. The primary information was represented with the questionnaire-based survey conducted throughout the Slovak Republic, in which a total count of 426 respondents participated. For hypothesis testing, the Friedman Test, Kolmogorov – Smirnov test, and Kruskal – Wallis test was used. The empiric results confirmed the significant differences between motivational factors for starting doing business. At the same time, there are still significant barriers to enter the business in Slovakia, which considerably limit the further development of doing business in Slovakia. The article provides recommendations for improving the business environment’s current status and entering into business in the Slovak Republic

Final analysis of the phase 3 non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma

In the primary analysis of the phase III COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demon-strated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.8 months after the primary analysis). In total, 522 patients were randomized (DARA SC, n=263; DARA IV, n=259). With longer follow-up, DARA SC and DARA IV continued to show consistent efficacy and maximum trough daratumumab concentration as compared with the primary analysis. The overall response rate was 43.7% for DARA SC and 39.8% for DARA IV. The maxi-mum mean (standard deviation [SD]) trough concentration (cycle 3, day 1 pre-dose) of serum DARA was 581 (SD, 315) mu g/mL for DARA SC and 496 (SD, 231) mu g/mL for DARA IV. Median progression-free survival was 5.6 months for DARA SC and 6.1 months for DARA IV; median overall survival was 28.2 months and 25.6 months, respectively. Grade 3/4 treatment-emergent adverse events occurred in 50.8% of patients in the DARA SC group and 52.7% in the DARA IV group; the most common (>= 10%) were thrombocytopenia (DARA SC, 14.2%; DARA IV, 13.6%), anemia (13.8%; 15.1%), and neutropenia (13.1%; 7.8%). The safety profile remained consistent with the primary analysis after longer follow-up. In summary, DARA SC and DARA IV continue to demonstrate similar efficacy and safety, with a low rate of infusion-related reactions (12.7% vs. 34.5%, respectively) and shorter administration time (3-5 minutes vs. 3-7 hours) supporting DARA SC as a preferable therapeutic choice. (Clinicaltrials gov. Identifier: NCT03277105