Down-regulation of murine beta-defensin-2 in Lewis lung carcinoma cells results in accelerated growth of tumor cells in vitro and in vivo

To evaluate the anti-tumor activity of murine beta-defensin-2 (mBD-2) expression in vitro and in vivo. Materials and Methods: Based on pcDNA3 vector, constructs containing mBD-2 cDNA coding mature defensin molecule (pcDNA3-mBD2), and Igk-mBD-2 insertion, coding secretory sequence plus mature defensin molecule (pcDNA3-Igk-mBD-2) were generated. Lewis lung carcinoma (3LL) cells were transfected in vitro with these plasmids and with blank pcDNA3 vector, and the proliferative rate and clonogenic ability of obtained cell lines cultivated in vitro were analyzed using 3H-incorporation technique and colony formation in semi-soft medium, respectively. Expression of mBD-2 mRNA was studied by semiquantative RT-PCR analysis. Also, transfected cells were transplanted to C57B mice, and the patterns of tumor growth in vivo were analyzed by routine techniques. Results: We have found out that in the 3LL cells transfected with pcDNA3-mBD-2 and pcDNA3-Igk-mBD-2, the expression of mBD-2 mRNA is significantly down regulated compared to wild-type cells and 3LL cells transfected with blank vector. The cells with suppressed mBD-2 expression differed from parental cells and cells transfected with blank vector by higher proliferation rate (p < 0.001) and higher clonogenic ability. The 3LL-mBD-2 and 3LL-Igk-mBD-2 cells that are transplanted to C57B mice gave rise to more aggressive tumors that possessed significantly higher growth rate (p < 0.01) than those that arise from wild-type 3LL cells. Conclusion: The obtained results are evidencing on a possible tumor-suppressing role of mBD-2 expression.Цель: настоящая работа посвящена анализу противоопухолевых свойств бета-дефенсина-2 мыши (mBD-2) in vitro and in vivo. Материалы и методы: на основе pcDNA3.1+ вектора были созданы 2 плазмидных конструкта, кодирующих зрелую форму mBD-2, содержащие или несодержащие сигнальную последовательность Igk (pcDNA3mBD-2 и pcDNA3Igk-mBD-2 соответственно). Путем трансфекции клеток 3LL полученными векторами, а также контрольным вектором pcDNA3.1+ были получены клеточные линии (3LL-mBD-2, 3LL-Igk-mBD-2 и 3LL-pcDNA3), для которых были проведены исследования их пролиферативной активности, определенной по уровню включения 3 Н-тимидина в ДНК, и способности к колониеобразованию в среде, содержащей метилцеллюлозу. Экспрессию гена mBD-2 исследовали с помощью полуколичественного ОТ-ПЦР-анализа. Трансфецированные клетки были имплантированы мышам линии C57BL, после чего была проанализирована динамика роста опухоли. Результаты: установлено, что в трансфектных клеточных линиях 3LL-mBD-2 и 3LL-Igk-mBD-2 уровень экспрессии mBD-2 снижен по сравнению с контрольными. Эти клетки характеризовались достоверным повышением уровня пролиферации (р < 0,001) и способности к колониеобразованию. Клетки сублиний 3LLmBD-2 и 3LL-Igk-mBD-2, трансплантированные мышам линии C57BL, вызывали развитие более агрессивных опухолей, обладающих значительно более высокой скоростью роста (p < 0,01), чем таковые, вызванные перевивкой клеток 3LL. Выводы: полученные результаты свидетельствуют о возможной роли mBD-2 как опухолевого супрессора

Administration of vitamin D3 improves antimetastatic efficacy of cancer vaccine therapy of Lewis lung carcinoma

Aim: To analyze antitumor efficacy of experimental cancer vaccine therapy combined with introduction of vitamin D3 (VD3) for treatment of Lewis lung carcinoma (3LL). Materials and Methods: Cancer vaccines composed from recombinant murine beta-defensin-2 (mBD-2) and 3LL cell lysate, or DNA, coding for mBD-2-Muc1 fusion construct cloned in pcDNA3+ vector, were prepared and used for intradermal vaccination. Experimental cancer vaccines introduced i. d. at therapeutic and prophylactic regimens to 3LLbearing C57Bl mice, were applied alone or in combination with VD3 (administered per os) and/or low-dose cyclophosphamide (CP, administered intraperitoneal). Efficacy of treatments was analyzed by primary tumor growth dynamics indexes and by metastasis rate in vaccinated animals. Results: As it has been shown, administration of the protein-based vaccine composed from mBD-2 and 3LL cell lysate in combination with VD3 and CP, but not in VD3 free setting, led to significant suppression of primary tumor growth (p < 0.005) and had significant antimetastatic effect. Introduction of VD3 with or without CP in the scheme of treatment with mBD-2-Muc1-DNA vaccine at therapeutic regimen has led to significant suppression of primary tumor (p < 0.05) and metastasis volumes (p < 0.005), while in the groups of animals treated with DNA-vaccine + VD3 with or without CP at prophylactic regimen, significant antimetastatic effect (p < 0.05) and elevation of average life-span (p < 0.05) have been registered. Conclusion: The results of this pilot study have shown promising clinical effects of VD3 administration in combination with cancer vaccinotherapy in vivo

COVID-19 and kidneys

COVID-19 poses a real threat to patients with comorbid conditions such as diabetes mellitus (DM), hypertension, cardiovascular, renal or hepatic disorders. Kidney damage is very likely in people with diabetes who have undergone a new infection, and the risk of developing acute renal injury is associated with mortality. Potential mechanisms of kidney involvement in the&nbsp;clinical picture of the disease may include cytokine damage, cross-organ damage, and systemic effects that determine the treatment strategy. These mechanisms are closely interrelated and are important for individuals on extracorporeal therapy and kidney transplants. Autopsy data provide evidence of SARS-CoV-2 virus invasion into kidney tissue with damage to tubular epithelium cells and podocytes, and red blood cell aggregation in severely COVID-19 patients. By including individuals with chronic kidney disease in planned COVID-19 research protocols, an evidence base for effective and safe treatments can be generated

Quasi-stationary States of Dust Flows Under Poynting-Robertson Drag: New Analytical and Numerical Solutions

The effect of solar or stellar radiation on dust particles' trajectories (the Poynting-Robertson drag) has been studied by a number of authors and applied to interplanetary dust dynamics in numerical computations. Meanwhile some important features of dust flows can be studied analytically by implementing our novel hydrodynamical approach to use the continuity equation written in the particle's orbital elements as coordinates (Gor'kavyi, Ozernoy, & Mather 1997). By employing this approach and integrating the continuity equation, we are able to find two integrals of motion when the Poynting-Robertson drag dominates the dissipative forces in the dust flow. These integrals of motion enable us to explore basic characteristics of dust flows from any sources in the Solar system (such as asteroids, comets, Kuiper belt, etc.) or in another planetary system. In particular, we have reproduced the classical solution $n(r)\propto r^{-1}$ that approximately represents the overall distribution of dust in the Solar system. We have also investigated various factors that could be responsible for the deviations of the power law index in $n(r)\propto r^{\delta}$ from $\delta=-1$, including the influences of the orbital characteristics of dust sources, the evaporation of dust particles, as well as mixtures of dust particles of both asteroidal and cometary origin. We have calculated the masses and number densities of asteroidal and cometary components of the zodiacal cloud at different distances from the Sun.Comment: Accepted for publication in ApJ, v. 488, Oct. 10, 1997; 22 pages, Latex, 12 Postscript figure

Remarks on the "non-canonicity puzzle": Lagrangian symmetries of the Einstein-Hilbert action

Given the non-canonical relationship between variables used in the Hamiltonian formulations of the Einstein-Hilbert action (due to Pirani, Schild, Skinner (PSS) and Dirac) and the Arnowitt-Deser-Misner (ADM) action, and the consequent difference in the gauge transformations generated by the first-class constraints of these two formulations, the assumption that the Lagrangians from which they were derived are equivalent leads to an apparent contradiction that has been called "the non-canonicity puzzle". In this work we shall investigate the group properties of two symmetries derived for the Einstein-Hilbert action: diffeomorphism, which follows from the PSS and Dirac formulations, and the one that arises from the ADM formulation. We demonstrate that unlike the diffeomorphism transformations, the ADM transformations (as well as others, which can be constructed for the Einstein-Hilbert Lagrangian using Noether's identities) do not form a group. This makes diffeomorphism transformations unique (the term "canonical" symmetry might be suggested). If the two Lagrangians are to be called equivalent, canonical symmetry must be preserved. The interplay between general covariance and the canonicity of the variables used is discussed.Comment: 23 page

Formation of a system of target indicators for rating and integral evaluation of the efficiency of the organization of the provision of medical care to patients with diabetes mellitus in the Russian Federation regions

AIM: Formation of a system of target indicators for rating and integral assessment of the effectiveness and efficiency of the organization of medical care for patients with diabetes mellitus in the Russian Federation regions.MATERIALS AND METHODS: The study was an expert survey in the form of a structured interview. At the first stage, we performed the primary selection of indicators. At the second stage, the selection of experts took place in accordance with the inclusion criteria, and the assessment of the level of expert competence was assessed based on a self-assessment survey. Further, criteria we formulated for expert evaluation of the significance of the selected indicators in accordance with the principles used in the development of national and federal projects. The indicators were divided into two groups: additional (process) and main (outcome). To quantify the degree of agreement between the experts’ answers, Kendall’s concordance coefficient (W) was calculated. The significance of differences was assessed using the nonparametric Friedman test.RESULTS: Only indicators with a high degree of agreement between experts and the presence of statistical significance in terms of the concordance coefficient are recommended as target indicators. The following main and additional indicators satisfy these requirements: mortality from cardiovascular complications of type 2 diabetes (people per 100,000 population); the proportion of patients with type 1 and 2 diabetes mellitus provided with medical devices out of the total number of patients with type 1 and 2 diabetes mellitus (percentage); the proportion of patients with type 1 and 2 diabetes mellitus with high amputations of all patients with type 1 and 2 diabetes mellitus with any amputations (percentage); and other indicators.CONCLUSION: We selected indicators that can be used both for the integral rating of the constituent entities of the Russian Federation, and in the formation of federal projects or departmental target programs. The results of the study can also be used to organize a system for monitoring the effectiveness of the implementation of these projects and programs

Расчёт показателей результативности работы системы управления воздушным движением как системы массового обслуживания с отказами

The article give reasons for possibility of the investigation of the ATC system as a queuing system with failures. The concept of the failure is explained through the extreme condition of an ATC Unit. Criteria of the system’s performance productivity within the theory of queuing are given. The results of the calculations of the system’s productivity are provided.Обосновывается возможность исследования системы управления воздушным движением (УВД) как системы массового обслуживания с отказами. Через предельное состояние диспетчерского пункта объясняется понятие отказа. Даются критерии результативности работы системы в рамках теории массового обслуживания. Приводятся результаты расчёта результативности работы

Time in range is a tool for assessing the quality of glycemic control in diabetes

The presence of continuous glucose monitoring (CGM) systems has expanded diagnostic capabilities. The implementation of this technology into clinical practice allowed to determine the patterns and tendencies of excursions in glucose levels, to obtain reliable data concerning short-term glycemic control. Taking into consideration the large amount of obtained information using CGM systems, more than 30 different indicators characterizing glycemic variability were proposed. However, it is very difficult for a practitioner to interpret the data obtained due to the variety of indicators and the lack of their target values. The first step in the standardization of indices was the creation of the International Guidelines for CGM in 2017, where the Time in Range (TIR) (3,9–10,0 mmol/l, less often 3,9–7,8 mmol/l) was significant. To complement the agreed parameters and simplify the interpretation of obtained data using CGM, in 2019 the recommendations were prepared for the International Consensus on Time in Range, where TIR was validated as an additional component of the assessment of glycemic control along with HbA1c. In the literature review the issues of the association of TIR with the development of micro- and macrovascular complications in type 1 and 2 diabetes are considered. The relationship with other indicators of the glycemic control assessment was also analyzed and the dependence of insulin therapy on TIR was shown. TIR is a simple and convenient indicator, it has a proven link with micro- and macrovascular complications of diabetes and can be recommended as a new tool for assessing the glycemic control. The main disadvantage of TIR usage is the insufficient apply of CGM technology by the majority of patients with diabetes

Vaccination of patients with diabetes mellitus

Diabetes mellitus stays an important medical, economic and social problem worldwide. Infectious diseases in people with diabetes mellitus are often more severe with an increased frequency of hospitalizations and complications. The presence of chronic hyperglycemia leads to decreased immune function and an increased predisposition to infections. Infections lead to uncontrolled hyperglycemia, which worsens the course of infections, thus forming a vicious circle of violations.Mass vaccination with an emphasis on people belonging to the high-risk group reduces the number of infected and, hospitalized people, and also has clear economic advantages. However, in many countries the proportion of vaccinated remains low.Vaccine prophylaxis in Russia is regulated by a number of regulatory legal acts, of which the main one is Federal Law No. 157-FZ of September 17, 1998 (edited on July 2, 2021) «About Immunoprophylaxis of Infectious Diseases». Each country has a National Vaccination Schedule, which shows a routine vaccination schedule at a specific age against infections that are widespread and / or pose a serious threat to health and life), as well as a National Epidemic Indication Vaccination Schedule. In Russia, these documents are approved by Order of the Ministry of Health of the Russian Federation of March 21, 2014 N 125n «About the approval of the national calendar of preventive vaccinations and the calendar of preventive vaccinations for epidemic indications.»This article discusses vaccination against the most socially significant infections associated with a high worldwide prevalence and increased risk among people with diabetes

The incidence and aggravating factors of male hypogonadism in type 2 diabetes

BACKGROUND: Male hypogonadism is associated with type 2 diabetes mellitus (T2DM), therefore, it is of interest to study its frequency. The clinical symptoms of hypogonadism are not specific, and laboratory diagnostics is the basis for its detection. The optimal method for this diagnostics is isotope dilution liquid chromatography/tandem mass spectrometry, which was used in our study. AIMS: Assessment of the incidence and aggravating factors of male hypogonadism in type 2 diabetesMATERIALS AND METHODS: A full-design, cross-sectional, screening, single-center, non-interventional study included men with T2DM, who were he was treated in Endocrinology Research Centre, Moscow. The study was conducted from October 2021 to January 2022. Medical history assessment, physical examination with determination of body mass index (BMI), measurement estimation of total testosterone by isotope dilution liquid chromatography/tandem mass spectrometry, glycated hemoglobin (HbA1c) and lipid profiles were performed. The groups were compared using the Mann-Whitney U-test for quantitative indicators and χ² with Yates’ correction for qualitative ones. Differences were considered statistically significant with p0,05.RESULTS: Hypogonadism was detected in 355 (70.3%) men with T2DM. Patients with hypogonadism had statistically significantly higher BMI, worse glycemic control, lower HDL levels, and higher triglycerides than eugonadal men. An additional comparative analysis among non-obese individuals showed the presence of statistically significant differences in the level of HbA1c (higher in hypogonadal men) and HDL (lower in hypogonadal men). An analysis of hypogonadal patients depending on the presence of obesity showed statistically significant differences between groups in the level of total testosterone (lower in obese men) and triglycerides (higher in obese men).CONCLUSIONS: The prevalence of male hypogonadism in type 2 diabetes was 70,3%. Its development was associated with obesity and poor glycemic control