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C26H26N6O5, monoclinic, P21/c (no. 14), a = 10.9393(1) Å, b = 16.8724(2) Å, c = 13.5836(2) Å, β = 102.843(1)°, V = 2444.43(5) Å3, Z = 4, R gt(F) = 0.0318, wRref (F 2) = 0.0827, T = 173 K.

Circulating miRNAs (cirmiRNAs) can be packaged into the exosomes, participating in intercellular communication, which affects the malignant progression and therapy resistance of triple‐negative breast cancer (TNBC). Currently, immune checkpoint inhibitors that regulate T‐cell function, especially antibodies against programmed cell death 1 (PD‐1) or its ligand PD‐L1, are emerging as new promising therapy for TNBC patients. However, only very limited patients showed complete or partial response to anti‐PD‐1 treatment. Dysfunction of CD8+ T cells is one of the key reasons for the immune escape of TNBC. The regulation of exosome‐derived cirmiRNAs on CD8+ T cells in TNBC deserves more investigation. Here, the cirmiR‐20a‐5p level was significantly upregulated in the plasma of TNBC patients and culture supernatant of TNBC cells. High abundance of cirmiR‐20a‐5p was correlated with a worse prognosis of TNBC. cirmiR‐20a‐5p was secreted in the form of exosomes by TNBC cells. Exosomal cirmiR‐20a‐5p was internalized into CD8+ T cells and resulted into the dysfunction of CD8+ T. A mechanism study uncovered that cirmiR‐20a‐5p targeted the nuclear protein ataxia‐telangiectasia (NPAT) and decreased NPAT expression in CD8+ T cells. An in vivo xenograft mouse model showed that cirmiR‐20a‐5p conferred TNBC to anti‐PD‐1 treatment resistance. Collectively, these findings indicated that cirmiR‐20a‐5p released by TNBC cells via exosome promotes cancer cell growth and leads to the immunosuppression by inducing CD8+ T cell dysfunction. This study suggests that targeting cirmiR‐20a‐5p might be a novel strategy for overcoming the resistance of TNBC to anti‐PD‐1 immunotherapy. [ABSTRACT FROM AUTHOR]

In this paper, the Computational Fluid Dynamics–Discrete Element Method (CFD-DEM) coupling method was used to simulate the pneumatic transport of pebble particles in a three-blade spiral tube. The results showed that the flow field distribution rotated along the circumference after loading. The maximum velocity of the flow field after loading was manifested as rotation along the circumference. In addition, the swirl intensity decreased exponentially with the increase in conveying distance, and the maximum swirl intensity had a saturation value. After reaching the saturation value, it is not evident that increasing the initial air velocity significantly affected swirl variation. The smaller the pitch, the greater the initial swirl intensity. The swirling flow was conducive to the fluidization of particles, but it would bring a significant energy loss. Increasing the swirl can increase the degree of particle dispersion. There is an optimal tangential airflow velocity, which allows the particles to fully spin and stay in the suspension zone without being thrown onto the pipe wall by excessive centrifugal force. At this time, the energy efficiency reaches the highest level. A 5.87 m/s velocity was deemed the optimal tangential airflow velocity for conveying 3 mm particles. [ABSTRACT FROM AUTHOR]

C26H26N6O5, monoclinic, P21/c (no. 14), a = 10.9393(1) Å, b = 16.8724(2) Å, c = 13.5836(2) Å, β = 102.843(1)°, V = 2444.43(5) Å3, Z = 4, Rgt(F) = 0.0318, wRref(F2) = 0.0827, T = 173 K. [ABSTRACT FROM AUTHOR]

C26H26N6O5, monoclinic, P21/c (no. 14), a = 10.9393(1) Å, b = 16.8724(2) Å, c = 13.5836(2) Å, β = 102.843(1)°, V = 2444.43(5) Å3, Z = 4, Rgt(F) = 0.0318, wRref(F2) = 0.0827, T = 173 K. [ABSTRACT FROM AUTHOR]

In the present paper, on the basis of molecular hybridization, a series of 4,6-dihydrazone pyrimidine derivatives containing the pyridine moiety were synthesized, structurally characterized, and evaluated in vitro for their antitumor activity. According to the results, all the tested compounds demonstrated broad-spectrum antitumor activity against selected tumor cell lines (MCF-7, BGC-823, A549, and BEL-7402) and no obvious toxicity toward normal cells HL-7702. In particular, compounds 10a and 10f were found to be the most promising antitumor agents among the tested compounds against BGC-823 cells (IC50 = 9.00 μM and 7.89 μM) and BEL-7402 cells (IC50 = 6.70 μM and 7.66 μM), respectively. Compounds 10a and 10f exhibited higher potency against BGC-823 and BEL-7402 than the positive control 5-FU (IC50 = 15.18 μM and 15.81 μM). Further mechanism investigations demonstrated that compounds 10a and 10f could significantly increase the level of cellular ROS and induce early apoptosis of BGC-823 cells in a dose-dependent manner. Moreover, the DNA binding results from UV/Vis, CD spectroscopy, and molecular docking studies indicated that 10a and 10f bind with DNA via groove binding and partial intercalation. These results demonstrated that 10a and 10f may serve as novel lead compounds for the discovery of more dihydrazone pyrimidine derivatives with improved antitumor potency and selectivity. [ABSTRACT FROM AUTHOR]

Primary immune thrombocytopenia ( ITP) is an acquired autoimmune disorder, and loss of immune tolerance has been implicated in ITP pathogenesis. CD8+CD28− suppressor (Ts) cells have an immunosuppression function and are involved in several autoimmune disorders. However, the role of Ts cells in ITP is currently not clear. Here, flow cytometry was used to detect the CD8+CD28−CD127− proportion, which was decreased in active ITP patients compared with that of controls. Function analysis showed that immunosuppression of CD8+CD28− Ts cells in ITP patients was impaired. Mechanistic studies have shown that CD8+CD28− Ts cells from controls can downregulate CD80 and upregulate LILRB4 (ITL3) and LILRB2 (ILT4) expression on CD14+ monocytes, whereas these abilities were not found in Ts cells from ITP patients. Furthermore, Inducible T-cell costimulatory ( ICOS) expression on the Ts cell surface after activation was decreased whereas programmed death 1 and interleukin 10 expression was not changed in ITP patients compared with those of controls. In summary, the down-regulated quantity and function of Ts cells in active patients indicated that a Ts defect was involved in ITP. Moreover, decreased ICOS expression and the loss of the ability to regulate co-stimulator expression on antigen-presenting cells partly explained the defective Ts-mediated suppression. [ABSTRACT FROM AUTHOR]

CD72 is a co-receptor of B cells and regulates B cell activation. Although aberrant expression of CD72 has been reported in primary immune thrombocytopenia ( ITP), it is uncertain whether this aberrant expression is restricted to specific B cell subsets. Furthermore, the mechanisms that regulate CD72 expression are unknown. In this study, we found higher frequency of CD19+ B cells, CD19+CD27+ memory B cells and lower frequency of CD19+CD27− naive B cells in active ITP patients compared with controls and patients in remission. CD72 expression on CD19+CD27+ cells was upregulated in active ITP patients and correlated with platelet count and anti-platelet autoantibodies. In vitro, CD40L could specifically induce CD72 upregulation on CD19+CD27+ B cells. In combination with CD40L, interleukin ( IL) 10 and BAFF (also termed TNFSF13B) further enhanced CD72 expression on CD19+CD27+ B cells, whereas IL21 reduced CD72 upregulation. CD72 mRNA expression after CD40L stimulation was increased in ITP patients and controls. Significant increase of CD40L on CD4+ T cells was correlated with CD72 expression on CD19+CD27+ B cells in ITP patients. In conclusion, upregulation of CD72 expression on CD27+memory B cells might take part in the pathogenesis of ITP. Elevated CD40L on CD4+ cells combined with cytokines might contribute to the upregulation of CD72 expression on CD27+memory B cells. [ABSTRACT FROM AUTHOR]

Stromal cell-derived factor-1 (SDF-1), signaling through CXCR4, is implicated in megakaryopoiesis and platelet production. SDF-1 rs2297630 is a functional polymorphism in linkage disequilibrium with other functional variants in SDF-1. This study aimed to investigate the role of SDF-1 rs2297630 in chronic ITP. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing. Immature platelet fraction (IPF) was performed using Sysmex XE-2100. Anti-platelet autoantibodies were assayed by enzyme-linked immunosorbent assay. The main characteristics at diagnosis and the outcome of chronic ITP in 201 Chinese patients were retrospectively reviewed. There was no significant difference in either genotype or allelic distribution between ITP patients and the controls (p= 0.114;p= 0.787). However, both heterozygote (GA) and homozygote minor allele (AA) patients had significantly increased megakaryocyte quantity compared to homozygote genotype (GG) patients at diagnosis (p =0.011). The mean IPF values of GA and AA genotype patients were higher than those observed in the GG genotype patients when platelet counts ≤50 × 109/L at diagnosis (p= 0.007). Patients with GA and AA genotype showed a higher response rate to standard treatments than patients with GG genotype (p< 0.001). In particular, GA and AA genotype patients had a significantly increased chance of responding to steroids, intravenous immunoglobulin (IVIG), and thrombopoietin analogs (p= 0.007;p= 0.029;p= 0.034, respectively). No significant difference was found between anti-platelet antibodies and genotypes (p= 0.296). In summary, the SDF-1 rs2297630 was associated with platelet production and treatment response in Chinese patients with chronic ITP. [ABSTRACT FROM AUTHOR]

Circulating miRNAs (cirmiRNAs) can be packaged into the exosomes, participating in intercellular communication, which affects the malignant progression and therapy resistance of triple-negative breast cancer (TNBC). Currently, immune checkpoint inhibitors that regulate T-cell function, especially antibodies against programmed cell death 1 (PD-1) or its ligand PD-L1, are emerging as new promising therapy for TNBC patients. However, only very limited patients showed complete or partial response to anti-PD-1 treatment. Dysfunction of CD8 + T cells is one of the key reasons for the immune escape of TNBC. The regulation of exosome-derived cirmiRNAs on CD8 + T cells in TNBC deserves more investigation. Here, the cirmiR-20a-5p level was significantly upregulated in the plasma of TNBC patients and culture supernatant of TNBC cells. High abundance of cirmiR-20a-5p was correlated with a worse prognosis of TNBC. cirmiR-20a-5p was secreted in the form of exosomes by TNBC cells. Exosomal cirmiR-20a-5p was internalized into CD8 + T cells and resulted into the dysfunction of CD8 + T. A mechanism study uncovered that cirmiR-20a-5p targeted the nuclear protein ataxia-telangiectasia (NPAT) and decreased NPAT expression in CD8 + T cells. An in vivo xenograft mouse model showed that cirmiR-20a-5p conferred TNBC to anti-PD-1 treatment resistance. Collectively, these findings indicated that cirmiR-20a-5p released by TNBC cells via exosome promotes cancer cell growth and leads to the immunosuppression by inducing CD8 + T cell dysfunction. This study suggests that targeting cirmiR-20a-5p might be a novel strategy for overcoming the resistance of TNBC to anti-PD-1 immunotherapy., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Increasing evidence has demonstrated the oncogenic roles of long non-coding RNA (lncRNA) hepatocellular carcinoma (HCC)-associated long non-coding RNA (HANR) in the development of HCC and lung cancer; however, the involvement of HANR in triple-negative breast cancer (TNBC) remains largely unknown. Our results demonstrated the significant overexpression of HANR in TNBC tissues and cells. Higher HANR levels significantly correlated with the poorer phenotypes in patients with TNBC. HANR down-regulation inhibited the proliferation and cell cycle progression and increased the apoptosis of TNBC cells. Mechanistically, immunoprecipitation-mass spectrometry revealed hexokinase II (HK2) as a direct binding target of HANR. HANR binds to and stabilizes HK2 through the proteasomal pathway. Consistent with the important role of HK2 in cancer cells, HANR depletion represses the glucose absorbance and lactate secretion, thus reprogramming the metabolism of TNBC cells. An in vivo xenograft model also demonstrated that HANR promoted tumor growth and aerobic glycolysis. This study reveals the role of HANR in modulating the glycolysis in TNBC cells by regulating HK2 stability, suggesting that HANR is a potential drug target for TNBC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder, and loss of immune tolerance has been implicated in ITP pathogenesis. CD8 + CD28 - suppressor (Ts) cells have an immunosuppression function and are involved in several autoimmune disorders. However, the role of Ts cells in ITP is currently not clear. Here, flow cytometry was used to detect the CD8 + CD28 - CD127 - proportion, which was decreased in active ITP patients compared with that of controls. Function analysis showed that immunosuppression of CD8 + CD28 - Ts cells in ITP patients was impaired. Mechanistic studies have shown that CD8 + CD28 - Ts cells from controls can downregulate CD80 and upregulate LILRB4 (ITL3) and LILRB2 (ILT4) expression on CD14 + monocytes, whereas these abilities were not found in Ts cells from ITP patients. Furthermore, Inducible T-cell costimulatory (ICOS) expression on the Ts cell surface after activation was decreased whereas programmed death 1 and interleukin 10 expression was not changed in ITP patients compared with those of controls. In summary, the down-regulated quantity and function of Ts cells in active patients indicated that a Ts defect was involved in ITP. Moreover, decreased ICOS expression and the loss of the ability to regulate co-stimulator expression on antigen-presenting cells partly explained the defective Ts-mediated suppression., (© 2017 John Wiley & Sons Ltd.)

CD72 is a co-receptor of B cells and regulates B cell activation. Although aberrant expression of CD72 has been reported in primary immune thrombocytopenia (ITP), it is uncertain whether this aberrant expression is restricted to specific B cell subsets. Furthermore, the mechanisms that regulate CD72 expression are unknown. In this study, we found higher frequency of CD19 + B cells, CD19 + CD27 + memory B cells and lower frequency of CD19 + CD27 - naive B cells in active ITP patients compared with controls and patients in remission. CD72 expression on CD19 + CD27 + cells was upregulated in active ITP patients and correlated with platelet count and anti-platelet autoantibodies. In vitro, CD40L could specifically induce CD72 upregulation on CD19 + CD27 + B cells. In combination with CD40L, interleukin (IL) 10 and BAFF (also termed TNFSF13B) further enhanced CD72 expression on CD19 + CD27 + B cells, whereas IL21 reduced CD72 upregulation. CD72mRNA expression after CD40L stimulation was increased in ITP patients and controls. Significant increase of CD40L on CD4 + T cells was correlated with CD72 expression on CD19 + CD27 + B cells in ITP patients. In conclusion, upregulation of CD72 expression on CD27 + memory B cells might take part in the pathogenesis of ITP. Elevated CD40L on CD4 + cells combined with cytokines might contribute to the upregulation of CD72 expression on CD27 + memory B cells., (© 2017 John Wiley & Sons Ltd.)

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease. 1α, 25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and vitamin D receptor (VDR) play important immune-suppressive roles in immune system. It has been reported that serum 1,25(OH) 2 D 3 were lower in ITP patients. In this study, we evaluated local 1,25(OH) 2 D 3 level and VDR mRNA expression further, and determined whether 1,25(OH) 2 D 3 /VDR were correlated with T cell dysfunction in ITP patients. We found that 1,25(OH) 2 D 3 /VDR levels were decreased in active ITP patients, and 1,25(OH) 2 D 3 had significant anti-inflammatory effects on ITP patients, including both anti-proliferation of peripheral blood mononuclear cells (PBMCs) and reversing the abnormal T cells polarization. 1,25(OH) 2 D 3 inhibited the differentiation of T helper (Th)1 and Tc1 cells but induced the differentiation of Th2, Tc2 and T regulatory (Treg) cells in ITP patients. However, the percentage of Th17 cells were not affected obviously with 1,25(OH) 2 D 3 . In addition, 1,25(OH) 2 D 3 also suppressed pro-inflammatory cytokines (INF-γ and IL-17A) but promoted anti-inflammatory cytokine (IL-10) secretion in ITP patients. In conclusion, decreased 1,25(OH) 2 D 3 /VDR might participate in the pathogenesis of ITP, and appropriate supplement of 1,25(OH) 2 D 3 may be a promising treatment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To deepen the understanding of clinical manifestations and treatment of patients with positive lupus anticoagulant (LAC)., Methods: The clinical data of 2 patients were analyzed and related literature were reviewed., Results: Case 1, a 31-year-old female, diagnosed as lupus anticoagulant positive, secondary to undifferentiated connective tissue disease, was presented with menorrhagia and thrombocytopenia. Anti-nuclear antibody (ANA) was positive 1:1000 (homogeneous type) with anti-double stranded DNA positive, and dRVVT LA1/LA2 was 3.4. Coagulation function was alleviated after treatment with glucocorticoid and total glucosides of paeony. Case 2, a 59-year-old female was presented with gingival bleeding, hematuria with the level of F II:C 13%. dRVVT LA1/LA2 was 2.0. Anti-nuclear antibody (ANA) was positive 1:1000 (type of cytoplasmic granule), anti-double stranded DNA was positive. The patient was diagnosed as hypoprothrombinemia-lupus anticoagulant syndrome (LAHS) and acquired coagulation factor deficiency. The signs of hemorrhage were alleviated after treatment with methylprednisolone 40 mg/day and cyclophosphamide, while the level of F II:C was below normal., Conclusion: Symptoms of patients with positive LAC are variable. The diagnosis relies on history of disease and laboratory test. Currently, there is no standardized treatment. Cases of LAHS should be thoroughly investigated for any known causes and related disorder.