In traditional indentation test methods for obtaining Norton's law of creep materials, an empirical correlation formula represents the relationship between the indentation strain rate and the ...uniaxial reference strain rate or indentation displacement rate. This study proposes an equivalent method for representative volume elements (RVE) of creep materials from a complex stress state to a simple stress state. Considering Norton's law as a constitutive relationship based on the equivalent method of stress state, a semi-analytical model describing the creep displacement vs. time relationship of flat cylindrical indentation (flat indentation) and a method for determining the parameters of the model were established under constant load conditions in this investigation. The finite element analysis (FEA), creep test results of zinc alloy ZA27, and results in the current literature were used to verify the semi-analytical creep model. The results showed that Norton's law and the displacement rate predicted by different indentation creep models are relatively close, and the partial results predicted by the new model are slightly better than those obtained by methods reported in the literature.
Background Midostaurin combined with chemotherapy is currently used to treat newly diagnosed acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 (FLT3)-mutations. However, ...midostaurin acts as an antagonist to some chemotherapeutic agents in leukemia cell lines without FLT3 mutations. All-trans retinoic acid (ATRA) induces apoptosis when used in combination with midostaurin in FLT3-mutated AML cells. This combination has been shown to be safe in AML patients. However, the effect of this combination has not been investigated in AML without FLT3 mutations. Methods Cell proliferation was assessed by a cell counting assay. Cell death was evaluated by cell viability and Annexin-V assays. Cell differentiation was assessed by CD11b expression profiling and morphological analysis. To explore the underlying mechanisms, we studied the role of caspase3/7, Lyn, Fgr, Hck, RAF, MEK, ERK, AKT, PU.1, CCAAT/enhancer binding protein beta (C/EBPbeta) and C/EBPepsilon by Western blot analysis and immunoprecipitation assays. Antitumor activity was also confirmed in mouse xenograft models established with AML cells. Results In this study, 0.1 - 0.25 muM midostaurin (mido(L)) combined with ATRA induced differentiation while 0.25 - 0.5 muM midostaurin (mido(H)) combined with ATRA triggered apoptosis in some AML cell lines without FLT3-mutations. Midostaurin combined with ATRA (mido-ATRA) also exhibited antitumor activity in mouse xenograft models established with AML cells. Mechanistically, mido(H)-ATRA-induced apoptosis was dependent on caspase-3/7. Mido(L)-ATRA inhibited Akt activation which was associated with decreased activity of Lyn/Fgr/Hck, resulted in dephosphorylation of RAF S259, activated RAF/MEK/ERK, along with upregulating the protein levels of C/EBPbeta, C/EBPepsilon and PU.1. A MEK specific inhibitor was observed to suppress mido(L)-ATRA-induced increases in the protein levels of C/EBPs and PU.1 and mido(L)-ATRA-induced differentiation. Furthermore, inhibition of Akt activity promoted mido(L)-ATRA-induced downregulation of RAF S259 phosphorylation and mido(L)-ATRA-induced differentiation. Therefore, Lyn/Fgr/Hck-associated Akt inhibition activated RAF/MEK/ERK and controlled mido(L)-ATRA-induced differentiation by upregulation of C/EBPs and PU.1. Mido(L)-ATRA also promoted assembly of the signalosome, which may facilitate RAF activation. Conclusions Midostaurin combined with ATRA exerts antitumor activity against AML with wild-type FLT3 mutations in vitro and in vivo. These findings may provide novel therapeutic strategies for some AML patients without FLT3 mutations and imply a new target of midostaurin. Keywords: Acute myeloid leukemia, All-trans retinoic acid, Apoptosis, Differentiation, Midostaurin
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The precise vertex reconstruction for large liquid scintillator detectors is essential. A novel machine learning-based method was successfully developed to reconstruct an event vertex in JUNO. In ...this study, the performance of machine learning-based vertex reconstruction was further improved by optimizing the input images of neural networks. By separating the information of different types of PMTs and adding the information of the second hit of PMTs, the vertex resolution was improved by approximately 9.4 % at 1 MeV and 9.8 % at 11 MeV.
The electrochemical behavior and change in the passive film formation of SS316L are investigated under polymer electrolyte membrane fuel cell (PEMFC) simulated (pH from 3 to 6 containing F
−, SO
4
2− ...and Cl
− anions) and accelerated conditions (0.5 M and 1 M H
2SO
4 + 2 ppm HF). Potentiodynamic, potentiostatic, and EIS measurements are performed to investigate the electrochemical behavior of the SS316L specimens in both the anode and cathode PEMFC environments. The chemical composition of the passive film, surface topography of the specimens, and degree of metal ion release is characterized by XPS, SEM, and ICP-OES, respectively. The results reveal that the nature of the passive film depends on the pH value, external medium/environment, as well as applied potential during polarization. The corrosion behavior of SS316L is closely related to the chemical composition and structure of the passive film.
► The electrochemical behavior of SS316L in the simulated and accelerated solutions is determined simultaneously investigated by potentiodynamic, potentiostatic, and EIS measurements. ► The chemical composition, surface topography, and metal ion release are investigated by XPS, SEM, and ICP measurements, respectively. ► The relationship between passive film composition in different environments and corrosion resistance are determined and discussed.
Background
This study aims to analyze the correlation between ARHGAP4 in the expression and clinical characteristics of colorectal cancer (CRC), and the influence of ARHGAP4 expression on the ...prognosis of CRC, and to evaluate whether ARHGAP4 is a potential prognostic oncotarget for CRC.
Methods
ARHGAP4 was identified using the Gene Expression Omnibus database through weighted gene coexpression network analysis. Using the Gene Expression Profiling Interactive Analysis to perform and analyze the expression and prognosis of ARHGAP4 in CRC. The expression of AGRGAP4 and immune cells was analyzed by the Tumor IMmune Estimation Resource online database. Finally, immunohistochemistry was used to analyze the expression difference and prognosis of ARHGAP4 in CRC and adjacent normal tissues, as well as the relationship between AGRGAP4 expression and clinical features of CRC.
Results
We identified ARHGAP4 that is related to the recurrence of CRC from GSE97781 data. ARHGAP4 has not been reported in CRC. The high expression of ARHGAP4 in select colon adenocarcinoma indicates a poor prognosis by database analysis. In our clinical data results, ARHGAP4 is highly expressed in CRC and lowly expressed in normal tissues adjacent to cancer. Compared with the low-expression group, the high-expression group has a significantly poorer prognosis. In colon cancer, the B-cell, macrophage, neutrophil, and dendritic-cell levels are downregulated after ARHGAP4 gene knockout; the levels of CD8
+
and CD4
+
T cells, neutrophils, and dendritic cells are upregulated after the amplification of the ARHGAP4 gene. In addition, ARHGAP4 expression is related to N,M staging and clinical staging.
Conclusion
ARHGAP4 is highly expressed in CRC, and the high expression of ARHGAP4 has a poor prognosis. The expression of ARHGAP4 in CRC is related to the immune cells such as B cells, CD8
+
and CD4
+
T cells, macrophages, neutrophils, and dendritic cells. ARHGAP4 is correlated with N,M staging and clinical staging in CRC. ARHGAP4 may be a potential biomarker for the prognosis of CRC.
Acute abdomen represents a great surgical challenge. Damage control surgery has been a better approach in acute abdominal emergencies to reduce the risk of mortality compared with primary definitive ...surgery.
A 52-year-old man presented with nonspecific abdominal pain for 2 days. Physical examination and computed tomography scan suggested abdominal viscera perforation and acute diffuse peritonitis. Segmental resections and sigmoidostomy were performed, the abdomen was temporarily closed with a 3-liter infusion bag and maintained for 72 hours. Small intestinal ischemic necrosis was found, partial resection of small intestine was performed later, and abdomen was still closed with the 3-liter infusion bag and maintained for 10 days. One month later, intermediate split thickness self-free skin graft transplantation was performed. Abdomen was closed 6 months later.
Damage control surgery with free skin graft transplantation can be successfully applied in severe abdominal infection in patients with an open abdomen. The study was in compliance with the Helsinki Congress and the Declaration of Istanbul.
Damage control surgery has been a better approach in acute abdominal emergencies to reduce the risk of mortality compared with definitive surgery. Although laparostomy is a useful treatment of abdominal sepsis, successful management with free skin graft transplantation after laparostomy has rarely been reported in stercoral perforation. We report a patient with severe abdominal sepsis treated with damage control surgery with free skin graft transplantation. The patient was discharged with good recovery.
All-trans retinoic acid (ATRA) is only effective in acute promyelocytic leukemia (APL), but not in other subtype of acute myeloid leukemia (AML). Salinomycin targets tumor cells rather than ...non-tumorigenic cells, and WNT/β-catenin pathway inhibition is one of the mechanisms of its anti-tumor activity. There is a crosstalk between RA and WNT/β-catenin pathway. Here, we investigate the effect of the combination of salinomycin and ATRA (S+RA) in non-APL AML cells.
Apoptosis was evaluated by cell viability and Annexin-V assay. Cell differentiation was analyzed by CD11c expression and morphology. To explore the underlying mechanisms, Western blot analysis and mitochondrial transmembrane potentials (ΔΨm) were used.
S+RA induced differentiation and apoptosis in AML cell lines and AML primary cells. S+RA inhibited the β-catenin signal pathway as determined by the decreased protein levels of β-catenin, the low-density lipoprotein receptor-related proteins 6 (LRP6), and its downstream proteins such as survivin, c-Myc, caspase-3/7, cdc25A and cyclinD1 and reduced phosphorylation level of GSK3β S9. S+RA also increased the protein levels of CCAAT/enhancer-binding proteins (C/EBPs) and PU.1 and collapsed Δψm. The above molecular and cellular changes induced by S+RA were inhibited by β-catenin specific activator and promoted by β-catenin specific inhibitor.
S+RA induced differentiation by β-catenin-inhibition-mediated up-regulation of C/EBPs and PU.1 and suppression of c-Myc. S+RA triggered apoptosis through β-catenin-inhibition-regulated ΔΨm collapse and caspase-3/7 activation. Taken together, our findings may provide novel therapeutic strategies for AML patients by targeting the WNT/β-catenin pathway.
Cytotoxicity of CuO nanoparticles (NPs) are an impediment in utilizing them as an effective nanocarriers of chemotherapeutic drugs for targeted drug delivery in nasopharyngeal cancer. In our current ...study, we have designed a two-step synthesis and coating of CuO NPs with different concentrations of PLGA (polylactide-co-glycolide) to reduce the cytotoxicity. This was further conjugated with folic acid to enhance targeting to specific tissue. The multiple drugs loaded in the NPs were two potent anticancer drugs doxorubicin and docetaxel. A complete characterization studies including micrographic analysis, zeta potential measurements, polydispersity index, Fourier transform infrared spectroscopy (FTIR), encapsulation and loading efficiencies, stability and in vitro release studies were done. Cytoxicity studies were done with MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, acridine orange/ethidium bromide and DAPI (4, 6-diamidino-2-phenylindole, dihydrochloride) staining procedures. Impediametric studies were also carried out to reinforce the reduction in cytotoxicity. Finally the cellular uptake of the NPs was seen. It was evident from the results that the multiple drugs loaded CuO NPs formed with PLGA coating were uniform, non-agglomerated in size ranging from 180 to 195 nm. The FTIR revealed no major changes in drug peaks. Encapsulation and loading efficiencies showed sufficient amount of drug being loaded into the NPs. The drug loaded NPs showed no change in size or zeta potential even after a period of 30 days. The cytotoxicity studies revealed significant reduction in toxicity after coating the surface treated with PLGA as evident from the microscopic analysis of cells. Hence the current study may be prioritized and further in vivo
/
in vitro studies may be carried out.
•A strain energy equivalence principle is originally proposed.•A unified model relating load, displacement, and material properties is proposed.•For the eight SCs analyzed in this study, the unified ...model predictions agree well with the FEA results.•By using this model, required material properties could be easily obtained by self-designed SCs.
A unified elastoplastic model was proposed to describe the relation among load, displacement, and uniaxial constitutive parameters of ductile materials according to the von Mises energy equivalence principle at a special location or energy center in the deformed region of a structural component (SC). Two pairs of parameters were considered in the model: one was related to the volume of deformed region and the other to the Mises equivalent strain at the energy center. In addition, they are easily determined by finite element analysis (FEA). For eight kinds of SCs under proportional loading, the load–displacement behaviors of various materials predicted by the unified model were highly consistent with the results of FEA.
Based on the equivalent energy principle (EEP), an explicit theoretical model between conical indentation response and uniaxial mechanical parameters is derived. In order to avoid the defect that ...sharp indentation technique always requires at least two indenters to penetrate different positions successively and the compatibility between the indentation points, an energy-based combined dual-conical indentation (CDI) model is created by using a novel combined indenter with dual conical surfaces. A typical piecewise load-depth curve is observed during the combined dual-conical indentation and two characteristic loading curvatures are respectively acquired from the single penetration response. Numerical verifications for the novel method are conducted by finite element analysis (FEA) within a large range of elastic–plastic materials. For six kinds of metallic materials, based on the stable load-depth curves obtained by the combined indentation tests, the uniaxial stress–strain curves as well as the yield stress, strain hardening exponent and tensile strength are predicted by CDI model. The results show that the predictions of CDI method are consistent with those from uniaxial tension. The novel method is expected to be more convenient for mechanical testing and evaluation of materials or structures.
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