PFKFB3 overexpression in monocytes of patients with colon but not rectal cancer programs pro-tumor macrophages and is indicative for higher risk of tumor relapse

Introduction: Circulating monocytes are main source for tumor-associated macrophages (TAMs) that control tumor growth, angiogenesis, metastasis and therapy resistance. We raised the questions how monocyte programming is affected by growing tumors localized in colon and rectal sections, and how treatment onsets affect monocyte programming in the circulation. Methods: Patients with rectal cancer and colon cancer were enrolled in the study. Peripheral blood monocytes were characterized by phenotypic analysis using flow cytometry, by transcriptomic analysis using RNA sequencing and by gene expression analysis using real-time RT-PCR. Phenotypic analysis was performed with IF/confocal microscopy. Spatial transcriptomic analysis was applied using GeoMX DSP-NGS. Results: In patients with rectal cancer, increased amount of CCR2+ monocytes was indicative for the absence of both lymphatic and hematogenous metastasis. In contrast, in patients with colon cancer CD163+ monocytes were indicative for LN metastasis. NGS analysis identified tumor-specific transcriptional programming of monocytes in all CRC patients compared to healthy individuals. The key transcriptional difference between monocytes of patients with colon and rectal cancer was increased expression of PFKFB3, activator of glycolysis that is currently considered as therapy target for major solid cancers. PFKFB3-expressing monocyte-derived macrophages massively infiltrated tumor in colon. Nanostring technology identified correlation of PFKFB3 with amount and tumor-promoting properties of TAMs in colon but not in rectal cancer. PFKFB3 was indicative for tumor relapse specifically in colon cancer. Discussion: Our findings provide essential argument towards CRC definition to cover two clinically distinct cancers – colon cancer and rectal cancer, that differentially interact with innate immunity

Первичный серологический статус и иммунологическая эффективность вакцинации против Streptococcus pneumoniae и Haemophilus influenzae типа b у детей с бронхолегочной дисплазией: когортное исследование

Background. The primary serological status of children with bronchopulmonary dysplasia (BPD) with respect to respiratory significant pathogens remains unstudied. Wherein, the efficacy of vaccination of children with BPD against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) has been studied in a small number of studies which results are contradictory.Objective. Our aim was to study the pre-vaccinal serological status with regard to S. pneumoniae and Hib and the immunological efficacy of vaccination against these infections in children with BPD.Methods. The study included children with BPD without exacerbation. The immunological efficacy of conjugate vaccines — pneumococcal 13-valent and against Haemophilus influenza type b — was assessed by the level of IgG against S. pneumoniae and Hib using the ELISA method. The level of antibodies was determined before vaccination and 1 or 3–6 months afterwards.Results. The study included 32 children with BPD, mean age at the time of determining primary serological status was 13.3±1.3 months, at the time of vaccination — 15.2±1.5 months. The mean gestational age was 28.7±0.8 weeks, the body weight at birth was 1225±180 g. Before vaccination, all children with BPD had no protective antibody titre against S. pneumoniae and Hib averaging 0.2±0.034 and 0.13±0.0106 mg/L, respectively. One month after vaccination, the level of antibodies to S. pneumoniae reached 12.9±2.34 mg/L to Hib — 3.34±0.769 mg/L.Conclusion. After immunization with a pneumococcal 13-valent conjugate vaccine and a conjugate vaccine against Haemophilus influenzae type b, the concentration of IgG against S. pneumoniae exceeded the protective level in all examined patients (100%), the concentration to Hib — in 29 (90.6%).Обоснование. Первичный серологический статус детей с бронхолегочной дисплазией (БЛД) в отношении респираторно значимых патогенов остается неизученным. При этом эффективность вакцинации детей с БЛД против Streptococcus pneumoniae и Haemophilus influenzae типа b (Hib) изучалась в небольшом числе исследований, результаты которых противоречивы. Цель исследования — изучить довакцинальный серологический статус в отношении S. pneumoniae и Hib и иммунологическую эффективность вакцинации против этих инфекций у детей с БЛД.Методы. В исследование включали детей с БЛД, вне обострения. Иммунологическую эффективность конъюгированных вакцин — 13-валентной пневмококковой и против гемофильной инфекции типа b — оценивали по уровню IgG к S. pneumoniae и Hib методом ELISA. Уровень антител определяли до вакцинации и спустя 1 и 3–6 мес.Результаты. Включено 32 ребенка с БЛД средний возраст которых на момент определения первичного серологического статуса составил 13,3±1,3 мес, на момент вакцинации — 15,2±1,5 мес. Средний гестационный возраст — 28,7±0,8 нед, масса тела при рождении — 1225±180 г. У всех детей с БЛД до вакцинации отсутствовал защитный титр антител к S. pneumoniae и Hib, составив в среднем 0,2±0,034 и 0,13±0,0106 мг/л соответственно. Через 1 мес после вакцинации уровень антител к S. pneumoniae достигал 12,9±2,34 мг/л, к Hib — 3,34±0,769 мг/л.Заключение. После иммунизации 13-валентной пневмококковой конъюгированной вакциной и конъюгированной вакциной против гемофильной инфекции типа b концентрация IgG к S. pneumoniae превышала защитный уровень у всех обследованных пациентов (100%), концентрация к Hib — у 29 (90,6%).Конфликт интересовЛ.С. Намазова-Баранова — получение исследовательских грантов от фармацевтических компаний Пьер Фабр, Genzyme Europe B.V., ООО «Астра зенека Фармасьютикалз», Gilead / PRA «Фармасьютикал Рисерч Ассошиэйтс СиАйЭс», Teva Branded Pharma ceuti cal products R&D, Inc. / ООО «ППД Девелопмент (Смоленск)», «Сталлержен С.А.» / «Квинтайлс ГезмбХ» (Австрия). М.В. Федосеенко — получение гонораров от компании Sanofi, Pfizer за чтение лекций

Controlling the Innovative Supply Chain Activities for Improving the Competitive Ability of Companies

As part of the supposed approach to strengthen the competitive capacity of industrial companies based on the implementation of the control of innovative activities in the supply chain, the flexible evaluation system was developed, differentiated according to the strategic and tactical objectives of the existing growth of competitive capacity. The strategic management of innovation process supposes achievement of competitive advantages based upon maximal usage of the experience of innovative supply chain activity organization and accounting of new factors, which influence on their change. To solve this problem have been analyzed conditions that determine the appearance and replace the six models of innovative process, allocated based on the modern world scientific experience. The logic of their development allows us to see the important characteristics of their changes, explain the effectiveness of the change process models, through the manifestation of the cumulative and complementary effects. The authors proposed a system of indicators to monitor the degree of manifestation of these effects in the study. In the course of the calculations have been identified changes in the patterns of the innovation process in the Russian mining and metallurgical complex and at the same time as there was a cumulative and complementary effect in changing patterns, and thus the efficiency of controlling innovation. The results suggest that the implementation of controlling innovation in mining and metallurgical enterprises cannot be called successful. Sustained growth was observed on single indicators. In mass production, they have a high degree of variability, or a downward trend. Nowadays, there are a few number of Innovative companies. Keywords- companies, innovation processes, supply chain activity, indicators, competitive ability

The lichen biota of the Meshchera National Park (Vladimir Region, Russia) and Meshchersky National Park (Ryazan Region, Russia)

The article presents the results of lichenological studies at the territories of Meshchersky National Park (Klepiky district and Ryazan district of the Ryazan Region, Russia) and Meshchera National Park (Gus-Khrustalny district of the Vladimir Region, Russia). Both Protected Areas represent an entire natural-anthropogenic area created in 1992 to preserve the unique forests and wetlands of the Meshchera Lowland, and to restore forest-marsh territories damaged by draining and long-term extraction of peat. Both the national parks are located in the centre of the Meshchera Lowland, in the basin of the River Pra (left-side tributary of the River Oka), and its tributaries – the River Buzha and the River Pol. In 2008–2018, we studied the lichen diversity using the traditional route method with more detailed studies within 64 sample plots. The following habitat types were inspected: pine forests, mixed forests and small-leaved forests, floodplain oak forest, swamps, meadows and heaths, shores of water bodies, and anthropogenic biotopes. Material of previous studies was also included in the analysis. An annotated list included 199 lichen species and eight non-lichenised fungus-related species which are traditionally counted in lichen lists. They belong to 88 genera and 43 families. The similarity of the lichen lists of the two national parks is 0.63 according to the Sørensen-Dice index. Cladonia bacilliformis, Lecania naegelii, Peltigera polydactylon, Porpidia crustulata, Pycnora praestabilis, and Xylopsora caradocensis were new species for the Vladimir region. Cladonia bacilliformis, C. cervicornis, C. floerkeana, and Stictis mollis were new species for the Ryazan region. Cetraria ericetorum, Cladonia bacilliformis, C. cervicornis, C. floerkeana, Peltigera extenuata, Stictis mollis were new species for the Meshchersky National Park. Chaenotheca furfuracea, Cladonia bacilliformis, Lecania naegelii, Peltigera polydactylon, Porpidia crustulata, Pycnora praestabilis, Xylopsora caradocensis were new for the Meshchera National Park. Acrocordia gemmata, Bacidia rubella, Chaenotheca stemonea, Chaenothecopsis pusiola, and Cladonia parasitica were considered as indicators of old-growth and undisturbed forests. Four rare species (Bryoria fuscescens, B. nadvornikiana, Cetraria ericetorum, and Peltigera extenuata) are listed in the Red Data Book of the Ryazan region. The following 19 species are rare for the centre of European Russia: Absconditella delutula, Acarospora versicolor, Arthonia fusca, Bacidia friesii, Biatora albohyalina, Cladonia sulphurina, Lecania suavis, Lecanora fuscescens, Micarea erratica, Microcalicium ahlneri, Ochrolechia androgyna, Porpidia soredizodes, Rhizocarpon reductum, Stictis mollis, Thelocarpon laureri, Thelloma ocellatum, Toninia athallina, Trapelia placodioides, and Xanthoparmelia stenophylla. In total, the species richness of lichen biotas in both national parks is equivalent to that in the Oka State Nature Reserve (208 species)

Closed-Form Hyper-Rayleigh Mode Analysis of the Fluctuating Double-Rayleigh with Line-of-Sight Fading Channel

The research studies hyper-Rayleigh behavior of a wireless communication system functioning in the presence of the generalized multipath fading. Although the initial metric (hyper-Rayleigh mode (HRM)) is quite informative, it is defined only asymptotically (i.e., for the infinitely increasing SNR). In spite of mathematical simplifications brought by such a definition (i.e., in this case most of the performance characteristics defining the HRM can be easily evaluated), it sufficiently limits its applications since, evidently, the real-life systems function in the presence of a finite (and usually not very high) SNR. The study presents a novel approach to the fading channel analysis (i.e., finite signal-to-noise ratio hyper-Rayleigh mode (fHRM)). The proposed metric (fHRM) is studied on the newly presented channel model-fluctuating double-Rayleigh with Line-of-Sight (fdRLoS) fading model. To accomplish this, the novel expressions for two channel-dependent system characteristics (i.e., the Amount of Fading (AoF) and the Outage Probability (OP)) were derived in exact form valid for arbitrary fading parameters. Based on the derived expressions, the finite SNR hyper-Rayleigh map is obtained, which helps to identify the parameters’ values corresponding to the specific propagation scenarios, which were further deployed to analyze the problem of the communication link physical layer security quantified in terms of the probability of strictly positive secrecy capacity (SPSC). Numerical verification of the derived closed-form expressions was performed. Several peculiarities of the system performance are observed and discussed

Primary Serological Status and Immunological Efficacy of Vaccination against Streptococcus Pneumoniae and Haemophilus Influenzae Type b in Children with Bronchopulmonary Dysplasia: a Cohort Study

Background. The primary serological status of children with bronchopulmonary dysplasia (BPD) with respect to respiratory significant pathogens remains unstudied. Wherein, the efficacy of vaccination of children with BPD against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) has been studied in a small number of studies which results are contradictory.Objective. Our aim was to study the pre-vaccinal serological status with regard to S. pneumoniae and Hib and the immunological efficacy of vaccination against these infections in children with BPD.Methods. The study included children with BPD without exacerbation. The immunological efficacy of conjugate vaccines — pneumococcal 13-valent and against Haemophilus influenza type b — was assessed by the level of IgG against S. pneumoniae and Hib using the ELISA method. The level of antibodies was determined before vaccination and 1 or 3–6 months afterwards.Results. The study included 32 children with BPD, mean age at the time of determining primary serological status was 13.3±1.3 months, at the time of vaccination — 15.2±1.5 months. The mean gestational age was 28.7±0.8 weeks, the body weight at birth was 1225±180 g. Before vaccination, all children with BPD had no protective antibody titre against S. pneumoniae and Hib averaging 0.2±0.034 and 0.13±0.0106 mg/L, respectively. One month after vaccination, the level of antibodies to S. pneumoniae reached 12.9±2.34 mg/L to Hib — 3.34±0.769 mg/L.Conclusion. After immunization with a pneumococcal 13-valent conjugate vaccine and a conjugate vaccine against Haemophilus influenzae type b, the concentration of IgG against S. pneumoniae exceeded the protective level in all examined patients (100%), the concentration to Hib — in 29 (90.6%)

Novel Bis-Ammonium Salts of Pyridoxine: Synthesis and Antimicrobial Properties

A series of 108 novel quaternary bis-ammonium pyridoxine derivatives carrying various substituents at the quaternary nitrogen’s and acetal carbon was synthesized. Thirteen compounds exhibited antibacterial and antifungal activity (minimum inhibitory concentration (MIC) 0.25–16 µg/mL) comparable or superior than miramistin, benzalkonium chloride, and chlorhexidine. A strong correlation between the lipophilicity and antibacterial activity was found. The most active compounds had logP values in the range of 1–3, while compounds with logP > 6 and logP < 0 were almost inactive. All active compounds demonstrated cytotoxicity comparable with miramistin and chlorhexidine on HEK-293 cells and were three-fold less toxic when compared to benzalkonium chloride. The antibacterial activity of leading compound 5c12 on biofilm-embedded Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli or Pseudomonas aeruginosa was comparable or even higher than that of the benzalkonium chloride. In vivo 5c12 was considerably less toxic (LD50 1705 mg/kg) than benzalkonium chloride, miramistine, and chlorhexidine at oral administration on CD-1 mice. An aqueous solution of 5c12 (0.2%) was shown to be comparable to reference drugs efficiency on the rat’s skin model. The molecular target of 5c12 seems to be a cellular membrane as other quaternary ammonium salts. The obtained results make the described quaternary bis-ammonium pyridoxine derivatives promising and lead molecules in the development of the new antiseptics with a broad spectrum of antimicrobial activity

Влияние COVID-19 на антибиотикорезистентность в педиатрической популяции

There is data on the irrational use of antimicrobial drugs in pediatric population during the COVID-19 pandemic. This could lead to potential development of antibiotic resistance and increased morbidity and mortality among this vulnerable population group. The aim of this review is to study the role of COVID-19 in antimicrobial drugs administration and antibiotic resistance development, as well as to determine a set of measures for its prevention. Recent studies results have shown that COVID-19 pandemic had both direct and indirect impact on antibiotic resistance development in pediatric population. The COVID-19 outbreak has revealed weaknesses in health systems around the world. Antibiotics administration in patients with coronavirus infection during this period exceeded the number of cases with bacterial co-infection or other diseases. Thus, it indicates irrational antibiotic treatment. There were cases of inappropriate antibiotics administration during the crisis caused by the COVID-19 pandemic even in regions with long-term rational antibiotic treatment programs. One of the most viable methods to combat antibiotic resistance is to improve approaches in health care and to increase preparedness to infectious outbreaks. Increasing clinical competence of medical workers, accessibility of medical facilities, permanent supply of high-quality and cheap antibiotics, vaccines, reducing COVID-19 testing time, and adequate administration of antibacterial agents are the measures that can prevent diseases caused by drug resistance. All stakeholders (health authorities, regulating authorities, politicians, scientific community, pharmaceutical companies) have to collaborate and achieve results to implement all the mentioned above protection measures.Имеются данные о нерациональном использовании противомикробных препаратов в педиатрической популяции в период COVID-19. Это может привести к потенциальному развитию резистентности к антибактериальным лекарственным средствам и увеличению заболеваемости и смертности среди этой уязвимой группы населения. Целью обзорной статьи является изучение влияния COVID-19 на применение противомикробных препаратов и развитие антибиотикорезистентности, а также определение комплекса мер по ее предотвращению. Результаты недавних исследований показывают, что пандемия COVID-19 оказывает прямое и косвенное влияние на развитие резистентности к противомикробным препаратам среди педиатрического населения. Вспышка COVID-19 способствовала выявлению недостатков, присущих системам здравоохранения во всем мире. В этот период использование антибиотиков у больных коронавирусной инфекцией превышало число случаев с присоединенной бактериальной коинфекцией и иными заболеваниями, что свидетельствует о нерациональности антимикробной терапии. Даже в регионах, где программы по рациональной антибиотикотерапии действуют уже давно, были обнаружены недостатки в использовании противомикробных препаратов во время кризиса, обусловленного пандемией COVID-19. Одним из наиболее эффективных методов борьбы с антибиотикорезистентностью является совершенствование подходов в здравоохранении и повышение готовности к вспышкам инфекций. Повышение клинической компетентности медицинских работников, доступность медицинских учреждений, постоянный запас высококачественных и недорогих противомикробных препаратов, вакцин, сокращение времени проведения анализа на COVID-19, осторожное использование антибактериальных средств — вот меры, принятие которых способствует предотвращению заболеваний, обусловленных возникновением лекарственной резистентности. Для установления вышеуказанных мер защиты все заинтересованные стороны (органы здравоохранения, регулирующие агентства, политики, научное сообщество, фармацевтические компании) должны объединяться для совместной работы и достижения результатов