Specifics of Pharmacokinetics and Biodistribution of 5-Fluorouracil Polymeric Complex.

One of the promising and relevant directions in the treatment of oncological diseases is currently the development of a system for the delivery of antitumor drugs based on polyanions. Therefore, the aim of this work was to study the specifics of pharmacokinetics and biodistribution of a 5-Fluorouracil polymeric complex compared with commercial 5-Fluorouracil. MATERIALS AND METHODS: Monomeric methacrylic acid was used to synthesize polymers; 2-phenylpropane-2-ilbenzodithioate was used for the synthesis of poly(methacrylic acid). To study the molecular-weight characteristics of poly(methacrylic acid) by gel permeation chromatography, an experimental neoplasm model was obtained by grafting PC-1 cancer cells. Blood samples were drawn from the tail vein at different points in time. The rats were sacrificed via decapitation after drawing the last pharmacokinetic blood sample. To study the biodistribution, internal organs were isolated and analyzed. The measurements were carried out by high-performance liquid chromatography. RESULTS: Our results demonstrate that incorporation in a polymeric complex changes the pharmacokinetics and biodistribution profile of 5-FU. The polymeric complex was shown to accumulate to a higher level in the lung and spleen. CONCLUSION: The results obtained are the basis for further studies to verify the efficacy of the 5-Fluorouracil polymeric complex.

Enzymatic Synthesis of 2-Chloropurine Arabinonucleosides with Chiral Amino Acid Amides at the C6 Position and an Evaluation of Antiproliferative Activity In Vitro.

A number of purine arabinosides containing chiral amino acid amides at the C6 position of the purine were synthesized using a transglycosylation reaction with recombinant E. coli nucleoside phosphorylases. Arsenolysis of 2-chloropurine ribosides with chiral amino acid amides at C6 was used for the enzymatic synthesis, and the reaction equilibrium shifted towards the synthesis of arabinonucleosides. The synthesized nucleosides were shown to be resistant to the action of E. coli adenosine deaminase. The antiproliferative activity of the synthesized nucleosides was studied on human acute myeloid leukemia cell line U937. Among all the compounds, the serine derivative exhibited an activity level (IC50 = 16 µM) close to that of Nelarabine (IC50 = 3 µM) and was evaluated as active.

The Effect of Casting Technique and Severe Straining on the Microstructure, Electrical Conductivity, Mechanical Properties and Thermal Stability of the Al-1.7 wt.% Fe Alloy.

This paper features the changes in microstructure and properties of an Al-Fe alloy produced by casting with different solidification rates followed by severe plastic deformation and rolling. Particularly, different states of the as-cast Al-1.7 wt.% Fe alloy, obtained by conventional casting into a graphite mold (CC) and continuous casting into an electromagnetic mold (EMC), as well as after equal-channel angular pressing and subsequent cold rolling, were studied. Due to crystallization during casting into a graphite mold, particles of the Al6Fe phase are predominantly formed in the cast alloy, while casting into an electromagnetic mold leads to the formation of a mixture of particles, predominantly of the Al2Fe phase. The implementation of the two-stage processing by equal-channel angular pressing and cold rolling through the subsequent development of the ultrafine-grained structures ensured the achievement of the tensile strength and electrical conductivity of 257 MPa and 53.3% IACS in the CC alloy and 298 MPa and 51.3% IACS in the EMC alloy, respectively. Additional cold rolling led to a further reduction in grain size and refinement of particles in the second phase, making it possible to maintain a high level of strength after annealing at 230 °C for 1 h. The combination of high mechanical strength, electrical conductivity, and thermal stability can make these Al-Fe alloys a promising conductor material in addition to the commercial Al-Mg-Si and Al-Zr systems, depending on the evaluation of engineering cost and efficiency in industrial production.

Laser Therapy Changes the Expression of Matrix Metalloproteinases in Bleomycin-Induced Skin Fibrosis.

Matrix metalloproteinases (MMPs) are often considered biomarkers of skin fibrosis. At the early stages of the pathological process, an elevation of their enzymatic activity causes significant changes in the composition of the extracellular matrix. MMPs secreted by immune cells facilitate their migration to the site of damage. Then, the immune cells eliminate the affected cells and biomolecules. Moreover, bidirectional changes in the activity of proteolytic enzymes, including MMPs, accompany wound healing. This study aimed to assess changes in the expression of Mmp2, Mmp3, and Mmp9 after treating mice with laser therapy using the experimental model of bleomycin-induced skin fibrosis. Using immunohistochemistry, we characterized the histological features of scarred skin. We also analyzed changes in the expression of MMPs using real-time polymerase chain reaction before and after laser irradiation. We showed that treatment of the mice with a CO2 laser partially normalized the histological features of scarred skin. We also noticed a decrease in the expression of Mmp2, Mmp3 (both p < 0.05), and Mmp9 (p = 0.065) during scar healing. The obtained results suggest that normalization of skin homeostasis requires control of MMP activity via induction of genes.

Effect of Poly(methacrylic acid) on the Cytokine Level in an In Vivo Tumor Model.

Cancer is a leading cause of mortality globally. Despite remarkable improvements in cancer-treatment approaches, disease recurrence and progression remain major obstacles to therapy. While chemotherapy is still a first-line treatment for a variety of cancers, the focus has shifted to the development and application of new approaches to therapy. Nevertheless, the relationship between immune response, neoplastic diseases and treatment efficiency is not fully understood. Therefore, the aim of the study was to investigate the immunopharmacological effects of methacrylic acid homopolymer in an in vivo tumor model. MATERIALS AND METHODS: Monomeric methacrylic acid was used to synthesize polymers. Methacrylic acid was polymerized in dioxane in the presence of 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid. To study the molecular weight characteristics of PMAA by GPC, carboxyl groups were preliminarily methylated with diazomethane. An experimental cancer model was obtained by grafting RMK1 breast cancer cells. The serum levels of IL-6, IL-10, IL-17, transforming growth factor ß1 (TGF-ß1), and tumor necrosis factor α (TNF-α) were measured by ELISA. RESULTS: The effect of PMAA on the serum concentrations of several cytokines was studied upon its single administration to laboratory animals in early neoplastic process. The IL-6, IL-17 and TGF-ß1 concentrations were found to change significantly and reach the level observed in intact rats. The IL-10 concentration tended to normalize. CONCLUSION: The positive results obtained are the basis for further studies on the effect of methacrylic-acid polymers with different molecular-weight characteristics on the neoplastic process.

A New Complex Minimally Invasive Thread Lift Method for One-Time Three-Step Fixation of the Face and Neck Soft Tissues.

Background In recent years thread lift has become widespread; however, existing methods need to improve their long-term outcome, which requires considering topographic anatomy of face and neck, especially the ligamentous apparatus. This study aims to assess the effectiveness and safety of an innovative method of one-time three-step thread facelift, which provides an additional support to the ligamentous structures of the upper, middle, and lower thirds of the face and neck. Methods The study included 357 patients aged 32 to 67 years with various morphotypes of aging. The original method of thread lift was applied, and its effectiveness was followed up for to 2 years. The Wrinkle Severity Rating Score (WSRS) and Global Aesthetic Improvement Scale (GAIS) scores were used for assessment by investigators, independent observers, and patients. Statistical significance was determined using paired t -test and chi-square test. Results The mean WSRS score was 3.88 ± 0.88 before the thread lift, 1.93 ± 0.81 one month after the procedure, and 2.36 ± 0.85 after 2 years of follow-up. The mean GAIS was 4.80 ± 0.04 one month after thread lift, and 4.01 ± 0.04 after 2 years, while in the patients' assessment Global Satisfaction Scale was 4.86 ± 0.02 and 4.10 ± 0.02, respectively. There were no clinically significant complications throughout the observation period. Conclusion The new method of one-time three-step thread fixation of the soft tissues of the face and neck demonstrated a high degree of satisfaction by both experts and patients after 2 years of follow-up. It showed high efficacy and safety, including in the group of patients with pronounced age-related changes of the skin of face and neck.

Evaluation of 131I transfer in the environment based on the available measurements made in Belarus after the Chernobyl accident.

This study evaluates the 131I transfer from ground deposition to the human thyroid gland after the Chernobyl accident using measurements of 131I concentrations in 1,252 soil, 124 grass, and 136 cow's milk samples as well as 131I thyroid activity measured in 3,100 individuals included in the Belarusian-American cohort. The following parameters of an 131I environmental transfer model used to calculate thyroid doses were evaluated in this study: (i) the interception factor of 131I by pasture grass, which was described by a purely empirical equation, (ii) the removal rate of 131I from pasture grass due to weathering and growth dilution, estimated to be 0.0676 d-1 (half-life of 10.3 d), (iii) the removal rate of 131I from cow's milk, estimated to be 0.0686 d-1 (half-life of 10.1 d), and (iv) the transfer coefficient of 131I from feed to cow's milk, arithmetic mean ± standard deviation of (6.7 ± 8.7) × 10-3 d L-1 (median = 4.0 × 10-3 d L-1). The individual model-based and measurement-based 131I thyroid activities for the Belarusian-American cohort members were calculated using different starting points of 131I transfer in the chain 'ground deposition' → 'vegetation' → 'cow's milk' → 'human thyroid', i.e., the measured 131I concentrations in soil, grass, and cow's milk. De novo thyroid doses from 131I for the 3,100 cohort members were calculated in this study using measured 131I activity concentrations in soil, grass, and cow's milk and were compared with those estimated previously for the same individuals using model-based 131I activity concentrations. It was shown that the use of measured instead of model-based 131I concentrations, in general, did not improve the measurement-based thyroid dose estimates. This is likely to be because there was already a good generic data base for the parameters used in this assessment. This finding indicates that, although the measurements of environmental samples are essential to estimate the parameter values of the 131I transfer model, the individual measurements of 131I thyroid activity are the most valuable information for estimating individual thyroid doses.

A Study of the Genomic Variations Associated with Autistic Spectrum Disorders in a Russian Cohort of Patients Using Whole-Exome Sequencing.

This study provides new data on the whole-exome sequencing of a cohort of children with autistic spectrum disorders (ASD) from an underexplored Russian population. Using both a cross-sectional approach involving a control cohort of the same ancestry and an annotation-based approach involving relevant public databases, we explored exonic single nucleotide variants and copy-number variation potentially involved in the manifestation of ASD. The study results reveal new potential ASD candidate-variants found in the studied Russian cohort and show a high prevalence of common ASD-associated genomic variants, especially those in the genes known to be associated with the manifestation of intellectual disabilities. Our screening of an ASD cohort from a previously understudied population allowed us to flag at least a few novel genes (IGLJ2, FAM21A, OR11H12, HIP1, PRAMEF10, and ZNF717) regarding their potential involvement in ASD.

Differential Expression of Estrogen-Responsive Genes in Women with Psoriasis.

In women, the flow of psoriasis is influenced by each phase of a woman's life cycle. According to previous findings, significant changes in the levels of sex hormones affect the severity of the disease. Aim: The aim of this study was to identify the estrogen-responsive genes that could be responsible for the exacerbation of psoriasis in menopausal women. Methods: Skin samples of lesional skin donated by psoriasis patients (n = 5) were compared with skin samples of healthy volunteers (n = 5) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The set of differentially expressed proteins was subjected to protein ontology analysis to identify differentially expressed estrogen-responsive proteins. The expression of discovered proteins was validated by qPCR and ELISA on four groups of female participants. The first group included ten psoriasis patients without menopause; the second included eleven postmenopausal patients; the third included five healthy volunteers without menopause; and the fourth included six postmenopausal volunteers. Moreover, the participants' blood samples were used to assess the levels of estradiol, progesterone, and testosterone. Results: We found that the levels of estradiol and progesterone were significantly lower and the levels of testosterone were significantly higher in the blood of patients compared to the control. The protein ontology analysis of LC-MS/MS data identified six proteins, namely HMOX1, KRT19, LDHA, HSPD1, MAPK1, and CA2, differentially expressed in the lesional skin of female patients compared to male patients. ELISA and qPCR experiments confirmed differential expression of the named proteins and their mRNA. The genes encoding the named proteins were differentially expressed in patients compared to volunteers. However, KRT19 and LDHA were not differentially expressed when we compared patients with and without menopause. All genes, except MAPK1, were differentially expressed in patients with menopause compared to the volunteers with menopause. HMOX1, KRT19, HSPD1, and LDHA were differentially expressed in patients without menopause compared to the volunteers without menopause. However, no significant changes were found when we compared healthy volunteers with and without menopause. Conclusion: Our experiments discovered a differential expression of six estrogen-controlled genes in the skin of female patients. Identification of these genes and assessment of the changes in their expression provide insight into the biological effects of estrogen in lesional skin. The results of proteomic analysis are available via ProteomeXchange with identifier PXD021673.

Immunopharmacological Properties of Methacrylic Acid Polymers as Potential Polymeric Carrier Constituents of Anticancer Drugs.

Cytostatic chemotherapeutics provide a classical means to treat cancer, but conventional treatments have not increased in efficacy in the past years, warranting a search for new approaches to therapy. The aim of the study was, therefore, to obtain methacrylic acid (MAA) (co)polymers and to study their immunopharmacological properties. 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl] pentanoic acid (CDSPA) and 2-cyano-2-propyl dodecyl trithiocarbonate (CPDT) were used as reversible chain transfer agents. Experiments were carried out in Wistar rats. The MTT assay was used to evaluate the cytotoxic effect of the polymeric systems on peritoneal macrophages. An experimental tumor model was obtained by grafting RMK-1 breast cancer cells. Serum cytokine levels of tumor-bearing rats were analyzed. The chain transfer agents employed in classical radical polymerization substantially reduced the molecular weight of the resulting polymers, but a narrow molecular weight distribution was achieved only with CDSPA and high CPDT concentrations. Toxicity was not observed when incubating peritoneal macrophages with polymeric systems. In tumor-bearing rats, the IL-10 concentration was 1.7 times higher and the IL-17 concentration was less than half that of intact rats. Polymeric systems decreased the IL-10 concentration and normalized the IL-17 concentration in tumor-bearing rats. The maximum effect was observed for a MAA homopolymer with a high molecular weight. The anion-active polymers proposed as carrier constituents are promising for further studies and designs of carrier constituents of drug derivatives.

DNA Methylation Alterations in Blood Cells of Toddlers with Down Syndrome.

Recent research has provided evidence on genome-wide alterations in DNA methylation patterns due to trisomy 21, which have been detected in various tissues of individuals with Down syndrome (DS) across different developmental stages. Here, we report new data on the systematic genome-wide DNA methylation perturbations in blood cells of individuals with DS from a previously understudied age group-young children. We show that the study findings are highly consistent with those from the prior literature. In addition, utilizing relevant published data from two other developmental stages, neonatal and adult, we track a quasi-longitudinal trend in the DS-associated DNA methylation patterns as a systematic epigenomic destabilization with age.

Value-based approach to blood pressure telemonitoring and remote counseling in hypertensive patients.

PURPOSE: Blood pressure telemonitoring and remote counselling (BPTM) improves blood pressure (BP) control in patients with hypertension (HTN). Studies assessing the efficacy of BPTM from a value-based perspective are lacking. We investigated whether BPTM fits all principles of the value-based approach (clinical and economic effectiveness, improvement in patient-reported outcome/experience measures (PROM/PREM)). MATERIALS AND METHODS: Two hundred and forty ambulatory patients with uncontrolled HTN were randomised in a 2: 1 manner to BPTM (n = 160, mean age 47 y.o.) and usual care (UC, n = 80; 49 y.o.) with baseline and 3-month follow-up clinic visits. BPTM employed a mobile application (for patients) and a desktop version (for clinician), which allowed communication and exchange of medical data. The main outcomes were changes in office and ambulatory systolic (S) BPs, rate of BP control. The incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) were evaluated in economic analysis. The MOS SF-36 score was taken as a PROM, and the PEQ score was used as a PREM. RESULTS: Larger decreases in office and ambulatory SBPs (-16.8 and -8.9 mm Hg, respectively; p < .05) was achieved in BPTM group while the treatment intensity was equal (2.4 drugs). The ICER 11.1 EUR/-1 mm Hg 24-hour SBP/1 year was 75% effective as per willingness-to-pay threshold. BPTM improved PROM (+2.1 in mean MOS SF-36; p = .04), reduced long-term mortality (+0.11 life years gained), leading to +0.49 quality-adjusted life years (QALYs) gained as compared with UC. The ICUR was 4 169.4 EUR/QALY gained. Patient-reported experience was higher in the BPTM (+10 PEQ, p = .01). The UC group showed minor changes in MOS SF-36 and PEQ (+1.3; +6, respectively; p n.s.). CONCLUSIONS: Being cost-effective, BPTM incorporates both clinical benefits and patient-perceived value. Larger randomised studies are needed to confirm our findings.

Male pseudohermaphroditism: A case study of 46,XY disorder of sexual development using whole-exome sequencing.

The study shows that whole-exome sequencing is a promising approach to detect novel variants-and gene candidates in DSD, that, as a future direction, may improve the diagnostic gene panels for this heterogeneous disorder.

Tumor-associated macrophages: Role in the pathological process of tumorigenesis and prospective therapeutic use (Review).

The aim of the present study was to evaluate the current body of knowledge regarding tumor-associated macrophages (TAMs) and their potential use in antitumor therapy, based on their role in the pathological process of tumorigenesis. For this purpose, a critical analysis of published data and summarization of the findings available from original studies, focusing on the role of TAMs in the pathological process, and their potential therapeutic application was performed. Promising key avenues of research were identified in this field. The following issues seem the most promising and thus worth further investigation: i) The process of M1/M2 macrophage polarization, macrophage characteristics at intermediate polarization steps and their role in the tumor process; ii) determining the conditions necessary for transitions between the M1 and M2 macrophage phenotypes and the role of signals from the microenvironment in this process; iii) cause-and-effect associations between the quantity and quality of macrophages, and the prognosis and outcome of the pathological process; iv) modulation of macrophages and stimulation of their phagocytic activity with drugs; v) targeted vector-based systems for drug delivery to macrophages; and vi) targeted drug delivery systems with macrophages as carriers, thus potentially combining chemotherapy and immunotherapy.

Activity concentrations of 131I and other radionuclides in cow's milk in Belarus during the first month following the Chernobyl accident.

The accident at the Chernobyl nuclear power plant (NPP) in Ukraine on April 26, 1986 led to a considerable release of radioactive material resulting in environmental contamination over vast areas of Belarus, Ukraine and western Russian Federation. The major health effect of the Chernobyl accident was an increase in thyroid cancer incidence in people exposed as children and adolescents, so much attention was paid to the thyroid doses resulting from intakes of 131I. Because cow's milk consumption was the main source of 131I intake by people, it was important to measure the 131I activity concentrations in cow's milk to calculate, or to validate, the thyroid doses to the exposed population. Almost 11,000 measurements of total beta-activity in cow's milk were performed using a DP-100 device during the first month after the Chernobyl accident in the most contaminated regions of Belarus. Using an ecological model and calibration coefficients for the DP-100 device the activity concentration of 131I in cow's milk was derived as well as the activity concentrations of the other radiologically important radionuclides, namely 134Cs, 137Cs, 89Sr and 90Sr. The activity concentrations of other radionuclides, such as 90Y, 132Te, 132I, 133I, 136Cs, 140Ba, 140La, 141Ce and 144Ce, in cow's milk were also estimated and were shown to be of minor importance. The concentrations of 95Zr, 95Nb, 103Ru and 106Ru in cow's milk were negligible. The data obtained in this study were validated by comparing derived 131I and 137Cs concentrations in cow's milk with gamma-spectrometry measurements performed in milk produced in the same location close to the same date. The results of this study were essential to assess and validate the radiation doses received by the subjects of epidemiological studies related to the health consequences of the Chernobyl accident.

Effects of early social deprivation on epigenetic statuses and adaptive behavior of young children: A study based on a cohort of institutionalized infants and toddlers.

Early social deprivation (i.e., an insufficiency or lack of parental care) has been identified as a significant adverse early experience that may affect multiple facets of child development and cause long-term outcomes in physical and mental health, cognition and behavior. Current research provides growing evidence that epigenetic reprogramming may be a mechanism modulating these effects of early adversities. This work aimed to investigate the impact of early institutionalization-the immersion in an extreme socially depriving environment in humans-on the epigenome and adaptive behavior of young children up to 4 years of age. We conducted a cross-sectional study involving two comparison groups: 29 children raised in orphanages and 29 children raised in biological families. Genome-wide DNA methylation profiles of blood cells were obtained using the Illumina MethylationEPIC array; the level of child adaptive functioning was assessed using the Vineland Adaptive Behavior Scales-II. In comparison to children raised in families, children residing in orphanages had both statistically significant deficits in multiple adaptive behavior domains and statistically significant differences in DNA methylation states. Moreover, some of these methylation states may directly modulate the behavioral deficits; according to preliminary estimates, about 7-14% of the deviation of adaptive behavior between groups of children may be determined by their difference in DNA methylation profiles. The duration of institutionalization had a significant impact on both the adaptive level and DNA methylation status of institutionalized children.

Mitogenomic diversity in Russians and Poles.

Complete mtDNA genome sequencing improves molecular resolution for distinguishing variation between individuals and populations, but there is still deficiency of mitogenomic population data. To overcome this limitation, we used Sanger-based protocol to generate complete mtDNA sequences of 376 Russian individuals from six populations of European part of Russia and 100 Polish individuals from northern Poland. Nearly complete resolution of mtDNA haplotypes was achieved - about 97% of haplotypes were unique both in Russians and Poles, and no haplotypes overlapped between them when indels were considered. While European populations showed a low, but statistically significant level of between-population differentiation (Fst=0.66%, p=0), Russians demonstrate lack of between-population differences (Fst=0.22%, p=0.15). Results of the Bayesian skyline analysis of Russian mitogenomes demonstrate not only post-Last Glacial Maximum expansion, but also rapid population growth starting from about 4.3kya (95% CI: 2.9-5.8kya), i.e. in the Bronze Age. This expansion strongly correlates with the Kurgan model established by archaeologists and confirmed by paleogeneticists.

Database of meteorological and radiation measurements made in Belarus during the first three months following the Chernobyl accident.

Results of all available meteorological and radiation measurements that were performed in Belarus during the first three months after the Chernobyl accident were collected from various sources and incorporated into a single database. Meteorological information such as precipitation, wind speed and direction, and temperature in localities were obtained from meteorological station facilities. Radiation measurements include gamma-exposure rate in air, daily fallout, concentration of different radionuclides in soil, grass, cow's milk and water as well as total beta-activity in cow's milk. Considerable efforts were made to evaluate the reliability of the measurements that were collected. The electronic database can be searched according to type of measurement, date, and location. The main purpose of the database is to provide reliable data that can be used in the reconstruction of thyroid doses resulting from the Chernobyl accident.

Russian ethnic history inferred from mitochondrial DNA diversity.

With the aim of gaining insight into the genetic history of the Russians, we have studied mitochondrial DNA diversity among a number of modern Russian populations. Polymorphisms in mtDNA markers (HVS-I and restriction sites of the coding region) of populations from 14 regions within present-day European Russia were investigated. Based on analysis of the mitochondrial gene pool geographic structure, we have identified three different elements in it and a vast "intermediate" zone between them. The analysis of the genetic distances from these elements to the European ethnic groups revealed the main causes of the Russian mitochondrial gene pool differentiation. The investigation of this pattern in historic perspective showed that the structure of the mitochondrial gene pool of the present-day Russians largely conforms to the tribal structure of the medieval Slavs who laid the foundation of modern Russians. Our results indicate that the formation of the genetic diversity currently observed among Russians can be traced to the second half of the first millennium A.D., the time of the colonization of the East European Plain by the Slavic tribes. Patterns of diversity are explained by both the impact of the native population of the East European Plain and by genetic differences among the early Slavs.