Tapentadol is a centrally acting analgesic with a dual mechanism of action of mu receptor agonism and norepinephrine reuptake inhibition. Tapentadol immediate-release is approved by the US Food and ...Drug Administration for the management of moderate-to-severe acute pain. It was developed to decrease the intolerability issue associated with opioids. Tapentadol extended-release has a 12-hour duration of effect, and has recently been evaluated for pain in patients with chronic osteoarthritis, low back pain, and pain associated with diabetic peripheral neuropathy. Tapentadol extended-release was found to provide safe and highly effective analgesia for the treatment of chronic pain conditions, including moderate-to-severe chronic osteoarthritis pain and low back pain. Initial trials demonstrating efficacy in neuropathic pain suggest that tapentadol has comparable analgesic effectiveness and better gastrointestinal tolerability than opioid comparators, and demonstrates effectiveness in settings of inflammatory, somatic, and neuropathic pain. Gastrointestinal intolerance and central nervous system effects were the major adverse events noted. Tapentadol will need to be rigorously tested in chronic neuropathic pain, cancer-related pain, and cancer-related neuropathic pain.
Global environmental changes may cause dramatic insect declines but over century-long time series of certain species' records are rarely available for scientific research. The Menetries' Tiger Moth ...(Arctia menetriesii) appears to be the most enigmatic example among boreal insects. Although it occurs throughout the entire Eurasian taiga biome, it is so rare that less than 100 specimens were recorded since its original description in 1846. Here, we present the database, which contains nearly all available information on the species' records collected from 1840s to 2020. The data on A. menetriesii records (N = 78) through geographic regions, environments, and different timeframes are compiled and unified. The database may serve as the basis for a wide array of future research such as the distribution modeling and predictions of range shifts under climate changes. It represents a unique example of a more than century-long dataset of distributional, ecological, and phenological data designed for an exceptionally rare but widespread boreal insect, which primarily occurs in hard-to-reach, uninhabited areas of Eurasia.
Background and Aims
Hepatoblastoma (HBL) is a devastating pediatric liver cancer with multiple treatment options, but it ultimately requires surgery for a cure. The most malicious form of HBL is a ...chemo‐resistant aggressive tumor that is characterized by rapid growth, metastases, and poor response to treatment. Very little is known of the mechanisms of aggressive HBL, and recent focuses have been on developing alternative treatment strategies. In this study, we examined the role of human chromosomal regions, called aggressive liver cancer domains (ALCDs), in liver cancer and evaluated the mechanisms that activate ALCDs in aggressive HBL.
Results
We found that ALCDs are critical regions of the human genome that are located on all human chromosomes, preferentially in intronic regions of the oncogenes and other cancer‐associated genes. In aggressive HBL and in patients with Hepatocellular (HCC), JNK1/2 phosphorylates p53 at Ser6, which leads to the ph‐S6‐p53 interacting with and delivering the poly(adenosine diphosphate ribose) polymerase 1 (PARP1)/Ku70 complexes on the oncogenes containing ALCDs. The ph‐S6‐p53‐PARP1 complexes open chromatin around ALCDs and activate multiple oncogenic pathways. We found that the inhibition of PARP1 in patient‐derived xenografts (PDXs) from aggressive HBL by the Food and Drug Administration (FDA)–approved inhibitor olaparib (Ola) significantly inhibits tumor growth. Additionally, this is associated with the reduction of the ph‐S6‐p53/PARP1 complexes and subsequent inhibition of ALCD‐dependent oncogenes. Studies in cultured cancer cells confirmed that the Ola‐mediated inhibition of the ph‐S6‐p53‐PARP1‐ALCD axis inhibits proliferation of cancer cells.
Conclusions
In this study, we showed that aggressive HBL is moderated by ALCDs, which are activated by the ph‐S6‐p53/PARP1 pathway. By using the PARP1 inhibitor Ola, we suppressed tumor growth in HBL‐PDX models, which demonstrated its utility in future clinical models.
In this study, we aimed to determine the incidence of reintervention and calcification of xenografts in paediatric patients who underwent placement of the right ventricle-to-pulmonary artery valved ...conduits.
We retrospectively analysed clinical data of paediatric patients (1 day-18 years) who underwent right ventricular outflow tract reconstruction using xenograft from 2000 to 2016 at a single centre.
A total of 301 patients underwent the placement of 337 xenografts, including glutaraldehyde-treated bovine jugular vein (n = 171, 50.7%), glutaraldehyde-treated bovine pericardial valved conduit (n = 75, 22.3%), diepoxy-treated porcine aortic conduit (n = 58, 17.2%) and diepoxy-treated bovine pericardial valved conduit (DE-PVC) (n = 33, 9.8%). There were 284 (84.3%) primary implantations and 53 (15.7%) reimplantations. The median follow-up was 4.2 years (range 1.5 months-14.5 years). The multivariate regression analysis did not reveal statistically significant associations of the first reintervention with the type of xenograft (P = 0.78). At reintervention, calcification of the wall and/or cusps was the main cause of conduit dysfunction in 66.4% of cases. On the basis of the multivariate Cox regression analysis, xenograft types were significant predictors of reintervention caused by conduit calcification (P = 0.012). The diepoxy-treated porcine aortic conduit group had the risk of calcification 3 times higher than the glutaraldehyde-treated bovine jugular vein group (P < 0.001).The glutaraldehyde-treated bovine pericardial valved conduit and diepoxy-treated bovine pericardial valved conduit groups had the risk of calcification comparable with the glutaraldehyde-treated bovine jugular vein group in multivariate proportional hazards model (P = 0.36 and P = 0.59, respectively).
We have not revealed significant difference in the freedom from first reintervention among types of conduit. Calcification leading to the conduit dysfunction was present in all groups; however, diepoxy-treated porcine aortic conduits demonstrated suboptimal results in terms of calcification at follow-up.
Anthrax is a concern for public health and veterinary medicine in Russia. The available phylogenetic data on isolates from Russia and neighboring CIS countries are clearly not enough to gain a better ...understanding of their position in the global phylogenetic population structure of this pathogen. In this study, we analyzed the genomes of 66 Bacillus anthracis strains, which were isolated between 1935 and 2019 from different sources in Russia, as well as in Ukraine, Azerbaijan, Georgia, Armenia and Moldova.
Whole genome SNP analysis of genomes of 66 strains obtained in this study along with 222 B. anthracis genomes available in the GenBank database revealed 7242 SNPs used to construct a phylogenetic reconstruction with the method of Maximum Likelihood. Studied strains belong to 6 different genetic groups: A.Br.008(A.Br.008/009), A.Br.081(Ames), A.Br.014(A.Br.Aust94), A.Br.082(A.Br.001/002), A.Br.034(A.Br.005/006, Ancient A) and B.Br.002 (B.Br.001/002). Within the group A.Br.014(A.Br.Aust94) a subcluster A.Br.029 of strains isolated in Georgia, Armenia, Azerbaijan, Russia (Republic of Dagestan) and Turkey, named Caucasus-East Anatolia (CEA), was identified. In the subgroup A.Br.105(Tsiankovskii) the cluster A.Br.117 of strains from Russia, Ukraine and Slovakia are assigned, in the subgroup A.Br118 (STI) - cluster A.Br.123 with strains from Russia and Georgia and cluster A.Br.125 with strains from Republic of Dagestan. New subclusters B.Br.017(“EUROPE”) were identified in the B.Br.002(B.Br.001/002) cluster, represented by strains from the European part of Russia, as well as from South Korea and Finland. For 8 clusters and subclusters, the SNP markers were identified.
The study confirmed a significant genetic diversity of the strains isolated in Russia and border countries and clarified their position in the phylogenetic structure of the global B. anthracis population. New genetic clusters A.Br.029 (CEA), A.Br.117, A.Br.123, A.Br.125, and B.Br.017 («EUROPE») were defined. 96 marker SNPs specific for these clusters were identified.
•6 genetic groups of Russia's and bordering countries' Bacillus anthracis isolates.•Some isolates from North, South Caucasus and Turkey form the same genetic cluster.•5 new genetic clusters for studied strains identified.•86 specific genetic markers for new clusters revealed.
The analysis of modern scientific literature indicates insufficient knowledge of the variable component use in the sports training program for acrobat girls aged 11-12 for their coordination ...abilities and vestibular stability development. Research aim is to evaluate the effectiveness of «Help» methodology proposed by us for female athletes', aged 11-12, engaged in sports acrobatics at the stage of sports specialization, coordination abilities development. Materials and methods. The participants of the research project were two groups of girls (n=20), aged 11-12, who were engaged in sports acrobatics. The main training sessions in the control (CG) and experimental group (EG) were conducted according to the Russian standard «Sports Acrobatics» (2014). In the annual training macrocycle of the experimental group, the method of performing exercises was expanded. A special set of sports equipment was selected: a balancing disc and a «Bosu» hemisphere, an agility ladder, a trampoline and a skateboard. All exercises on sports equipment were performed in the first half of the main part of the lesson. The skateboard and the «Bosu» hemisphere were additionally used in active games. We called the developed method of coordination training «Help», which is based on the principle of complicating the conditions for performing exercises. In both groups, stage-by-stage testing of the athletes' overall physical, coordination and technical fitness and vestibular stability was carried out. Results. After the research project completion, the athletes of the CG and EG had an improvement in the indicators values in all tests. The EG athletes, engaged in the «Help» method had more growth values in all tests than the CG athletes. The greatest increase was found in EG girls in tests characterizing general flexibility and speed endurance. At the end of the pedagogical experiment, a significant improvement in the tests of dynamic coordination and vestibular stability was also found in girls of both groups. The greatest increase in the indicators values of coordination tests was shown by EG athletes, engaged in «Help» experimental method. Training according to the experimental method significantly improved the indicators values in the tests of the EG athletes' technical readiness, compared with the CG. Conclusions. The results of testing «Help» method in sports acrobatics classes showed an increase in coordination qualities, vestibular stability, general and technical readiness in girls aged 11-12. The emergence of new complex coordination sports and their inclusion in major international competitions requires the sports community and scientists to search for new pedagogical technologies and techniques for training athletes.
Introduction. Bacillus anthracis, the pathogen of a particularly dangerous zoonotic disease known as anthrax, requires strict epidemiological control and is characterized by high genetic homogeneity, ...which necessitates the development of genotyping methods. The aim of the study were to to find and characterize the VNTR and INDEL loci of B. anthracis and to develop on their basis a genotyping technique by PCR with electrophoretic detection of the results. Materials and methods. Marker search and phylogenetic analysis were performed on a sample of 388 genomes of B. anthracis strains, 322 from the GenBank collection (RefSeq) and 66 from the collection of the Stavropol Anti-Plague Institute of Rospotrebnadzor. Phylogenetic analysis was performed on the basis of SNP crustal alignment using the Parsnp program. The search for markers was carried out using the Mauve program and author's scripts in Python. PCR was performed using a ScreenMix-HS kit (CJSC "Eurogen", Russia). Results. Genomic variations of B. anthracis strains (SNP — 25,664, SNR — 14,387, VNTR — 693, INDEL — 14,667) were found, bioinformatic analysis of which revealed nine new VNTR and six INDEL molecular markers most suitable for genotyping. The genetic (allelic) variants of the markers are described. Primers were selected for the found markers and a PCR protocol with detection by electrophoresis in agarose gel was developed. When typing using VNTR markers was applied, the strains were divided into nine clusters: A.Br.Ames, A.Br.001/002, A.Br.Aust94, A.Br.005/006, A.Br.008/009 (Tsiankovskii), A.Br.008/009 (STI), A.Br.008/009 (A.Br.125), A.Br.008/009 (strain 228/269), B.Br.001/002. When typing using INDEL markers, the strains were divided into six clusters: A.Br.Ames, A.Br.001/002, A.Br.Aust94, A.Br.008/009(Tsiankovskii), B.Br.001/002(B.Br.014), as well as a cluster comprising several genetic lineages: A.Br.008/009 (STI), A.Br.008/009 (A.Br.125), A.Br.005/006 и B.Br.001/002. Conclusion. The use of the developed methodology for the identification of variable VNTR and INDEL loci makes it possible to reliably determine the phylogenetic position of B. anthracis strains and is promising for use in the epidemiological investigation of anthrax outbreaks.
Background & Aims: Epigenetic regulation of gene expression plays a critical role in the development of liver cancer; however, the molecular mechanisms of epigenetic-driven liver cancers are not well ...understood. The aims of this study were to examine molecular mechanisms that cause the dedifferentiation of hepatocytes into cancer cells in aggressive hepatoblastoma and test if the inhibition of these mechanisms inhibits tumor growth. Methods: We have analyzed CCAAT/Enhancer Binding Protein alpha (C/EBPα), Transcription factor Sp5, and histone deacetylase (HDAC)1 pathways from a large biobank of fresh hepatoblastoma (HBL) samples using high-pressure liquid chromatography–based examination of protein–protein complexes and have examined chromatin remodeling on the promoters of markers of hepatocytes and p21. The HDAC1 activity was inhibited in patient-derived xenograft models of HBL and in cultured hepatoblastoma cells and expression of HDAC1-dependent markers of hepatocytes was examined. Results: Analyses of a biobank showed that a significant portion of HBL patients have increased levels of an oncogenic de-phosphorylated-S190-C/EBPα, Sp5, and HDAC1 compared with amounts of these proteins in adjacent regions. We found that the oncogenic de-phosphorylated-S190-C/EBPα is created in aggressive HBL by protein phosphatase 2A, which is increased within the nucleus and dephosphorylates C/EBPα at Ser190. C/EBPα–HDAC1 and Sp5–HDAC1 complexes are abundant in hepatocytes, which dedifferentiate into cancer cells. Studies in HBL cells have shown that C/EBPα–HDAC1 and Sp5–HDAC1 complexes reduce markers of hepatocytes and p21 via repression of their promoters. Pharmacologic inhibition of C/EBPα–HDAC1 and Sp5–HDAC1 complexes by Suberoylanilide hydroxamic acid (SAHA) and small interfering RNA–mediated inhibition of HDAC1 increase expression of hepatocyte markers, p21, and inhibit proliferation of cancer cells. Conclusions: HDAC1-mediated repression of markers of hepatocytes is an essential step for the development of HBL, providing background for generation of therapies for aggressive HBL by targeting HDAC1 activities.
In Memoriam - Graham de Vahl Davis Arinç, Faruk; Bayazitoglu, Yildiz; Bontoux, Patrick ...
International journal of heat and mass transfer,
20/May , Letnik:
152
Journal Article
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