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Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen. [ABSTRACT FROM AUTHOR]

Recent discovery of the ribosomal protein (RP) RPL11 interacting with and inhibiting the E3 ubiquitin ligase function of MDM2 established the RP-MDM2-p53 signaling pathway, which is linked to biological events, including ribosomal biogenesis, nutrient availability, and metabolic homeostasis. Mutations in RPs lead to a diverse array of phenotypes known as ribosomopathies in which the role of p53 is implicated. Here, we generated conditional RPL11-deletion mice to investigate in vivo effects of impaired RP expression and its functional connection with p53. While deletion of one Rpl11 allele in germ cells results in embryonic lethality, deletion of one Rpl11 allele in adult mice does not affect viability but leads to acute anemia. Mechanistically, we found RPL11 haploinsufficiency activates p53 in hematopoietic tissues and impedes erythroid precursor differentiation, resulting in insufficient red blood cell development. We demonstrated that reducing p53 dosage by deleting one p53 allele rescues RPL11 haploinsufficiencyinduced inhibition of erythropoietic precursor differentiation and restores normal red blood cell levels in mice. Furthermore, blocking the RP-MDM2-p53 pathway by introducing an RP-binding mutation in MDM2 prevents RPL11 haploinsufficiency--caused p53 activation and rescues the anemia in mice. Together, these findings demonstrate that the RP-MDM2-p53 pathway is a critical checkpoint for RP homeostasis and that p53-dependent cell cycle arrest of erythroid precursors is the molecular basis for the anemia phenotype commonly associated with RP deficiency. [ABSTRACT FROM AUTHOR]

A new process of flue gas desulfurization in circulating fluidized bed with flue gas bypass ducts is presented, k-ε Model, Discrete Phase Model and Finite-Rate Chemistry Model are proposed to simulate the desulfurization process characteristics in circulating fluidized bed reactor. The proposed model is validated by the comparison of experimental data and simulation results. The results show that the desulfurization reactor with bypass ducts is superior to the reactor without bypass ducts. The reactor with bypass ducts has higher desulfurization efficiencies and lower flow resistances than the reactor without bypass ducts, and it is more suitable for flue gas flow variation. Desulfurization reaction rate is controlled by absorption reaction on sorbent particles surface. When water content and Ca/S ratio increase, desulfurization efficiency of the reactor with bypass ducts increases. When SO2 concentration increases, desulfurizatio efficiency decreases. [ABSTRACT FROM AUTHOR]

The low-pathogenic H7N9 influenza viruses that emerged in 2013 acquired an insertion of four amino acids in their hemagglutinin cleavage site and thereby became highly pathogenic to chickens in 2017. Previous studies indicated that these highly pathogenic H7N9 viruses are virulent in chickens but have distinct pathotypes in mice. A/chicken/Guangdong/SD098/2017 (CK/SD098) is avirulent, with a 50% mouse lethal dose (MLD50) of >7.5 log10 50% egg infectious dose (EID50), whereas A/chicken/Hunan/S1220/2017 (CK/S1220) is virulent in mice, with an MLD50 of 3.2 log10 EID50. In this study, we explored the genetic determinants that contribute to the difference in virulence between these two H7N9 viruses by generating a series of reassortants and mutants in the CK/S1220 virus background and testing their virulence in mice. We found that the reassortant CK/1220-SD098-NP, carrying the nucleoprotein (NP) of CK/SD098, was avirulent in mice, with an MLD50 of >107.5 EID50. The NPs of these two viruses differ by two amino acids, at positions 286 and 437. We further demonstrated that the amino acid mutations A286V and T437M of NP independently slowed the process of NP import to and export from the nucleus and thus jointly impaired the viral life cycle and attenuated the virulence of these H7N9 viruses in mice. Our study identified new virulence determinants in NP and provided novel targets for the development of live attenuated vaccines and antiviral drugs against influenza viruses. [ABSTRACT FROM AUTHOR]

We analyzed eight H10N8 viruses isolated from ducks and chickens in live poultry markets from 2009 to 2013 in China. These viruses showed distinct genetic diversity and formed five genotypes: the four duck isolates formed four different genotypes, whereas the four chicken viruses belong to a single genotype. The viruses bound to both human- and avian-type receptors, and four of the viruses caused 12.7% to 22.5% body weight loss in mice. [ABSTRACT FROM AUTHOR]

Tissue repair/wound healing, in which angiogenesis plays an important role, is a critical step in many diseases including chronic wound, myocardial infarction, stroke, cancer, and inflammation. Recently, we were the first to report that orphan nuclear receptor TR3/Nur77 is a critical mediator of angiogenesis and its associated microvessel permeability. Tumor growth and angiogenesis induced by VEGF-A, histamine, and serotonin are almost completely inhibited in Nur77 knockout mice. However, it is not known whether TR3/Nur77 plays any roles in wound healing. In these studies, skin wound-healing assay was performed in 3 types of genetically modified mice having various Nur77 activities. We found that ectopic induction of Nur77 in endothelial cells of mice is sufficient to improve skin wound healing. Although skin wound healing in Nur77 knockout mice is comparable to the wild-type control mice, the process is significantly delayed in the EC-Nur77-DN mice, in which a dominant negative Nur77 mutant is inducibly and specifically expressed in mouse endothelial cells. By a loss-of-function assay, we elucidate a novel feed-forward signaling pathway, integrin β4 → PI3K → Akt → FAK, by which TR3 mediates HUVEC migration. Furthermore, TR3/Nur77 regulates the expression of integrin β4 by targeting its promoter activity. In conclusion, expression of TR3/Nur77 improves wound healing by targeting integrin β4. TR3/Nur77 is a potential candidate for proangiogenic therapy. The results further suggest that TR3/Nur77 is required for pathologic angiogenesis but not for developmental/physiologic angiogenesis and that Nur77 and its family members play a redundant role in normal skin wound healing. [ABSTRACT FROM AUTHOR]

In February 2014, while investigating the source of a human infection with influenza A(H7N9) virus in northern China, we isolated subtypes H7N2 and H9N2 viruses from chickens on the patient's farm. Sequence analysis revealed that the H7N2 virus is a novel reassortant of H7N9 and H9N2 viruses. Continued surveillance is needed. [ABSTRACT FROM AUTHOR]

Background Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is reported to exert anti-tumor effects by upregulating the expression of the natural killer group 2D (NKG2D) ligands on tumor cells; however, the mechanisms vary in different tumor types, and the effect and mechanism of action of VPA in pancreatic cancer cells are unknown. Methods The present study evaluated the effect of VPA to susceptibility of pancreatic cancer cells to the NK cell-mediated lysis in vitro and in vivo. Then we investigated the mechanism which the effect of VPA depend on. Results The lactate dehydrogenase assay (LDH) and xenograft experiment demonstrated that VPA significantly sensitized pancreatic cancer cells to NK cell-mediated lysis in vitro and in vivo. Quantitative real time- polymerase chain reaction (qRT-PCR) and flow cytometry demonstrated that VPA upregulated the mRNA and cell surface expression of the NKG2D ligands major histocompatibility complex class I-related chain A and B (MICA and MICB) in pancreatic cancer cells. Effects of VPA both in vitro and in vivo were significantly attenuated by the PI3K/Akt pathway inhibitor LY294002 or a siRNA targeting PI3K catalytic subunit alpha isoform (PI3KCA). Conclusion VPA enhances the susceptibility of pancreatic cancer cells to NK cell-mediated cytotoxicity both in vitro and in vivo by upregulating the expression of MICA and MICB via a PI3K/Akt signaling pathway-dependent mechanism. [ABSTRACT FROM AUTHOR]

Background: Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is reported to exert anti-tumor effects by upregulating the expression of the natural killer group 2D (NKG2D) ligands on tumor cells; however, the mechanisms vary in different tumor types, and the effect and mechanism of action of VPA in pancreatic cancer cells are unknown. Methods: The present study evaluated the effect of VPA to susceptibility of pancreatic cancer cells to the NK cell-mediated lysis in vitro and in vivo. Then we investigated the mechanism which the effect of VPA depend on. Results: The lactate dehydrogenase assay (LDH) and xenograft experiment demonstrated that VPA significantly sensitized pancreatic cancer cells to NK cell-mediated lysis in vitro and in vivo. Quantitative real time-polymerase chain reaction (qRT-PCR) and flow cytometry demonstrated that VPA upregulated the mRNA and cell surface expression of the NKG2D ligands major histocompatibility complex class I-related chain A and B (MICA and MICB) in pancreatic cancer cells. Effects of VPA both in vitro and in vivo were significantly attenuated by the PI3K/Akt pathway inhibitor LY294002 or a siRNA targeting PI3K catalytic subunit alpha isoform (PI3KCA). Conclusion: VPA enhances the susceptibility of pancreatic cancer cells to NK cell-mediated cytotoxicity both in vitro and in vivo by upregulating the expression of MICA and MICB via a PI3K/Akt signaling pathway-dependent mechanism. [ABSTRACT FROM AUTHOR]

Understanding in-situ stresses is the foundation for investigating deep rock mechanics. In practice, the fracture morphology of a disced core can often reflect its in-situ environment and disturbance-induced fracture process to some extent. In this study, three-dimensional dynamic scanning technology is used to reconstruct the fracture morphology of the disced cores extracted from Songke-2 as well as part of the Chinese Continental Scientific Drilling Project. The roughness of various regions of the fracture surfaces of the cores is investigated. Additionally, a parametric system is developed for the quantitative study of the integrity coefficient of the disced rock samples. Furthermore, the mechanisms and characteristics of the fractures along the stress paths are investigated. According to the findings, when shallow cores undergo discing, they have notable saddle-shaped coarse fractures, which may be related to the properties of the cores at these depths. Deep cores demonstrate discing behavior, but the generated discs are relatively thick. Deep core fracture surfaces are mostly smooth and straight, possibly propagating from the outside to the inside. Under excavation disturbance in the hydrostatic state, the extreme values of the maximum tensile stress at the core stubs show a saddle-shaped distribution. In general, the results of this study can serve as a theoretical foundation for the quantitative assessment of the intactness of disced cores. Furthermore, because disc patterns and characteristics are associated with stress states, this approach can be used to evaluate in-situ stress environments. [ABSTRACT FROM AUTHOR]

To gain insight into the ecology of avian influenza viruses (AIV), we conducted active influenza virus surveillance in domestic ducks on farms located on the flyway of migratory birds in the Dongting Lake region of Hunan Province, China, from winter 2011 until spring 2012. Specimens comprising 3,030 duck swab samples and 1,010 environmental samples were collected from 101 duck farms. We isolated AIV of various HA subtypes, including H3, H4, H5, H6, H9, H10, H11, and H12. We sequenced the entire coding sequences of the genomes of 28 representative isolates constituting 13 specific subtypes. When the phylogenetic relationships among these isolates were examined, we observed that extensive reassortment events had occurred. Among the 28 Dongting Lake viruses, 21 genotypes involving the six internal genes were identified. Furthermore, we identified viruses or viral genes introduced from other countries, viral gene segments of unknown origin, and a novel HA/NA combination. Our findings emphasize the importance of farmed domestic ducks in the Dongting Lake region to the genesis and evolution of AIV and highlight the need for continued surveillance of domestic ducks in this region. [ABSTRACT FROM AUTHOR]