Fibrolamellar hepatocellular carcinoma (FLC) is a disease that occurs in children and young adults. The development of FLC is associated with creation of a fusion oncoprotein DNAJB1‐PKAc kinase, ...which activates multiple cancer‐associated pathways. The aim of this study was to examine the role of human genomic regions, called cancer‐enhancing genomic regions or aggressive liver cancer domains (CEGRs/ALCDs), in the development of FLC. Previous studies revealed that CEGRs/ALCDs are located in multiple oncogenes and cancer‐associated genes, regularly silenced in normal tissues. Using the regulatory element locus intersection (RELI) algorithm, we searched a large compendium of chromatin immunoprecipitation–sequencing (ChIP) data sets and found that CEGRs/ALCDs contain regulatory elements in several human cancers outside of pediatric hepatic neoplasms. The RELI algorithm further identified components of the β‐catenin–TCF7L2/TCF4 pathway, which interacts with CEGRs/ALCDs in several human cancers. Particularly, the RELI algorithm found interactions of transcription factors and chromatin remodelers with many genes that are activated in patients with FLC. We found that these FLC‐specific genes contain CEGRs/ALCDs, and that the driver of FLC, fusion oncoprotein DNAJB1‐PKAc, phosphorylates β‐catenin at Ser675, resulting in an increase of β‐catenin–TCF7L2/TCF4 complexes. These complexes increase a large family of CEGR/ALCD‐dependent collagens and oncogenes. The DNAJB1‐PKAc–β‐catenin–CEGR/ALCD pathway is preserved in lung metastasis. The inhibition of β‐catenin in FLC organoids inhibited the expression of CEGRs/ALCDs‐dependent collagens and oncogenes, preventing the formation of the organoid's structure. Conclusion: This study provides a rationale for the development of β‐catenin‐based therapy for patients with FLC.
A fusion protein kinase DNAJB1‐PKAc is the main driver of adolescent liver cancer fibrolamellar HCC. Our paper presents molecular mechanisms by which this kinase causes FLC. We also provide evidence that the inhibition of DNAJB1‐PKAc‐beta catenin pathway could be considered as a therapy for FLC.
The timeliness of this research is determined by the large-scale changes taking place in the world economy under the influence of digitalization, which accelerated during the COVID-19 pandemic. These ...processes affect the direction of transformational changes in property taxation. The object of the study is property taxation in the context of the proliferation of various forms of digital assets, which are virtual property. The purpose of the article is to find correlations between digitalization, the need to limit overconsumption, which has increased during the pandemic of a new coronavirus infection, and the prospects for changes in property taxation. The possibilities of state tax regulation and interstate cooperation in the context of property taxation are considered. The prospects for expanding the effect of property taxation to the virtual spaces of the metauniverse are highlighted. The article uses general scientific research methods such as analysis, synthesis, generalization and analogy, and contains historical and cross-country comparison. The information base is formed on the basis of data from international organizations, consulting, analytical and research companies, as well as government agencies. As a result of the research, the hypothesis was confirmed that the current changes in the global economy require transformation of approaches to property taxation both at the state and international levels, taking into account the expansion of modern technology capabilities and the need to limit excessive consumption. Recommendations have been formulated to expand the scope of property taxation in virtual spaces and to increase the level of the wealth taxation of the wealthiest segments of the population possessing virtual forms of ownership.
Finding new, safe strategies to prevent and control rheumatoid arthritis is an urgent task. Bioactive peptides and peptide‐rich protein hydrolyzate represent a new trend in the development of ...functional foods and nutraceuticals. The resulting tissue hydrolyzate of the chicken embryo (CETH) has been evaluated for acute toxicity and tested against chronic arthritis induced by Freund's full adjuvant (modified Mycobacterium butyricum) in rats. The antiarthritic effect of CETH was studied on the 28th day of the experiment after 2 weeks of oral administration of CETH at doses of 60 and 120 mg/kg body weight. Arthritis was evaluated on the last day of the experiment on the injected animal paw using X‐ray computerized microtomography and histopathology analysis methods. The CETH effect was compared with the non‐steroidal anti‐inflammatory drug diclofenac sodium (5 mg/kg). Oral administration of CETH was accompanied by effective dose‐dependent correction of morphological changes caused by the adjuvant injection. CETH had relatively high recovery effects in terms of parameters for reducing inflammation, inhibition of osteolysis, reduction in the inflammatory reaction of periarticular tissues, and cartilage degeneration. This study presents for the first time that CETH may be a powerful potential nutraceutical agent or bioactive component in the treatment of rheumatoid arthritis.
Finding new, safe strategies to prevent and control rheumatoid arthritis is an urgent task. Bioactive peptides and peptide‐rich protein hydrolyzate represent a new trend in the development of functional foods and nutraceuticals. This study presents for the first time that CETH may be a powerful potential nutraceutical agent or bioactive component in the treatment of rheumatoid arthritis.
This study evaluated the ability of bisphosphonates (BPAs) of different molecular structures to mitigate the calcification of porcine aortic wall (PAW) and bovine jugular vein wall (BJVW). Tissues ...cross‐linked with glutaraldehyde (GA) or diepoxide (DE) were modified with pamidronic acid (PAM), alendronic acid (ALE), neridronic acid (NER) (type 1 BPAs); 2‐(2′‐carboxyethylamino)ethylidene‐1,1‐bisphosphonic acid (CEABA), 2‐(5‐carboxypentylamino)ethylidene‐1,1‐bisphosphonic acid (CPABA) (type 2); and zoledronic acid (ZOL) (type 3). After implanting the tissue samples subcutaneously in 100 rats, calcification was examined using atomic absorption spectrophotometry (60‐day explants) and light microscopy after von Kossa staining (10‐ and 30‐day explants). The calcium contents in GA‐BJVW and GA‐ and DE‐PAW increased up to 100–120 mg/g after 60 days, while being 3 times lower in DE‐BJVW. In modified and nonmodified PAW samples, calcium phosphates appeared by day 10 and were associated with elastic fibers and devitalized cellular elements. In all groups of BJVW samples, mineralization began in elastic fibers near the subendothelial layer. In addition, calcified collagen was found in the GA‐BJVW samples. Minimal calcification was found in GA‐PAW treated with type 1 BPAs and CEABA. For DE‐PAW and GA‐BJVW, the calcium level significantly decreased with PAM and CEABA. Meanwhile, ALE and NER were effective for DE‐BJVW.
We report a new facile method for the synthesis of prolate cobalt ferrite nanoparticles without additional stabilizers, which involves a co-precipitation reaction of Fe
and Co
ions in a static ...magnetic field. The magnetic field is demonstrated to be a key factor for the 1D growth of cobalt ferrite nanocrystals in the synthesis. Transmission electron microscopy (TEM), X-ray diffraction (XRD), and Raman spectroscopy are applied to characterize the morphology and structure of the obtained nanoparticles. According to TEM, they represent nanorods with a mean length of 25 nm and a diameter of 3.4 nm that have a monocrystalline structure with characteristic plane spacing of 2.9 Å. XRD and Raman spectroscopy confirm the spinel CoFe
O
structure of the nanorods. After aging, the synthesized nanorods exhibit maximum saturation magnetization and coercivity equal to 30 emu/g and 0.3 kOe, respectively. Thus, the suggested method is a simple and "green" way to prepare CoFe
O
nanorods with high aspect ratios and pronounced magnetic properties, which are important for various practical applications, including biomedicine, energy storage, and the preparation of anisotropic magnetic nanocomposites.
Titanium-based alloys are widely used in aerospace engineering. They have good mechanical and corrosion properties but, in some cases, the material itself or the coating should meet some additional ...requirements. For example, it may be a requirement of high reflectance to provide effective temperature control. Wollastonite is a promising component for reflective coatings because it improves both their whiteness and mechanical properties. This paper presents the results of studying the composition, the structure and the adhesive strength of wollastonite-containing silicate coatings to titanium substrate. The surface of titanium samples was pre-treated by laser cladding with TiC and etching to provide surface porosity. It has been shown that such treatment allows a significantly increase in the adhesive strength of the coating to the substrate. A decrease in the adhesive strength was observed on titanium samples with an excess of TiO2 on the surface. This is caused by the formation of crystalline PbTiO3 at the interface.
Introduction: Dorsal root ganglion (DRG) stimulation is a Food and Drug Administration-approved treatment for treating complex regional pain syndrome, which typically originates from one or two ...peripheral nerves. We present a case of a complex chronic pain pattern following a gunshot wound (GSW) to the abdomen that was not isolated to a single nerve. Case: We report on a US Army soldier treated at a level 1 military trauma center for a complex chronic pain pattern following a GSW to the abdomen. He suffered from severe, debilitating, and poorly controlled complex pain in the left lower extremity, left lower abdomen, and left flank following a penetrating GSW to the abdomen and left flank area. Multiple treatment modalities were attempted initially, including medication management, physical therapy, and complimentary and integrative treatment techniques. The patient continued to experience significant pain with severe impact on the quality of life and limitation to activities of daily living. Results: DRG stimulation was used to target the DRG of left T11 (to cover neuropathic lower abdominal pain on the left), left L2 (to cover no-ciceptive axial low back pain and neuropathic posterior flank pain), and S1 (to cover neuropathic pain in the left postero-lateral thigh and calf). The patient reported complete resolution of his pain condition with trial stimulation and subsequent implantation. Patient reported significant improvement of the quality of life and functionality. Conclusion: DRG stimulation offers an efficient alternative modality for treatment of a complex pain pattern involving several areas. References: 1) Morgalla M, Fortunato M, Lepski G, Chander B. Dorsal root ganglion stimulation (DRGS) for the treatment of chronic neuropathic pain: A single-center study with long-term prospective results in 62 cases. Pain Physician 2018;21(4):E377-87. 2) Deer TR, Levy RM, Kramer J, et al. Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: A randomized comparative trial. Pain 2017;158(4):669-81. 3) Liem L, Russo M, Huygen FJ, et al. One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain. Neuromodulation 2015;18(1):41-8.
Optical sensing is an inexpensive and simple technique in water pollution control that offers high sample throughput and field applications. In this work, we applied an innovative reaction-based ...optical fingerprinting strategy for the recognition of clean and synthetically contaminated waters. Samples of spring, well, borehole, pond, and tap water were introduced into the reaction mixtures containing carbocyanine dyes, the absorbance and fluorescence of which were monitored photographically at different times; the data were processed by linear discriminant analysis. Up to 11 clean water samples were completely discriminated; the samples artificially polluted with the soluble fraction of different brand engine oil water-soluble fraction (WSF) and iron(2+) supplied as Mohr’s salt were discriminated from uncontaminated ones; the presence of 35-fold diluted WSF in water was also detected. Iron(2+) was detected in water samples at 3 μg/L using the same indicator reactions. The proposed strategy can be useful in water pollution monitoring.
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.
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.
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.
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.
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