Objective:To investigate the efficacy and safety of omalizumab in the treatment of chronic urticaria (CU) patients with poor response to H1 antihistamines.Methods:CU patients, who showed poor response to H1 antihistamines and received omalizumab treatment, were collected from the Department of Dermatology, Xiangya Hospital, Central South University from June 2020 to June 2021. The efficacy of omalizumab was evaluated by using the 7-day urticaria activity score (UAS7) and urticaria control test (UCT) score at weeks 4, 12 and 24 after the start of treatment. The t-test, chi-square test, and Pearson correlation analysis were used to analyze the relationship between the clinical characteristics and efficacy. Results:A total of 121 CU patients who met the inclusion criteria and had relatively complete medical records were included in this study, including 54 males (44.63%) and 67 females (55.37%) , and their ages ranged from 13 to 70 years (39.88 ± 14.36 years) ; 88 patients were diagnosed with chronic spontaneous urticaria (72.73%) , 10 with chronic inducible urticaria (8.26%) , and 23 with chronic spontaneous urticaria accompanied by chronic inducible urticaria (19.01%) . At week 4 after the start of omalizumab treatment, the response rate was 50.86% (59/116) , and the complete response rate was 25.86% (30/116) ; at week 12, the response rate was 78.26% (54/69) , and the complete response rate was 34.78% (24/69) ; at week 24, the response rate was 64.71% (22/34) , and the complete response rate was 23.53% (8/34) . At week 4, CU patients with baseline serum total IgE levels of < 40 IU/ml had a lower response rate (26 cases, 30.77%) than those with baseline serum total IgE levels of ≥ 40 IU/ml (61 cases, 65.57%; χ2 = 8.93, P = 0.004) . Correlation analysis showed that the age at treatment, age at onset, allergic diseases, concomitant symptoms, baseline erythrocyte sedimentation rates, and baseline C-reactive protein levels were significantly correlated with the UCT scores (all P < 0.05) , while the course of disease, clinical types, serum total IgE levels, peripheral blood counts, dermatology life quality index scores, and UAS7 scores were not significantly correlated with the UCT scores. Among the 121 CU patients, 8 (6.61%) reported mild to moderate adverse reactions. Conclusion:Omalizumab could effectively improve clinical symptoms and signs of CU patients with poor response to H1 antihistamines, and was well tolerated;omalizumab treatment may be more beneficial to patients without allergic comorbidities such as allergic rhinitis, without concomitant symptoms such as angioedema, and with lower erythrocyte sedimentation rates and C-reactive protein levels.

CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a transmembrane glycoprotein that is highly expressed in tumor cells, particularly melanoma cells, and plays critical roles in tumor cell metastasis through the regulation of matrix metalloprotease (MMP) expression. In this study, we identified Fyn as a novel interacting protein of CD147. Fyn is a member of the Src family of nonreceptor tyrosine kinases that regulates diverse physiological processes, such as T lymphocyte differentiation, through the TCR signaling pathway. Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Two phosphospecific antibodies against Y140 and Y183 were developed to validate the phosphorylation of CD147 by Fyn. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment. In addition, CD147-FF significantly blocked MMP-9 expression as well as cell migration. Moreover, we found that Fyn is overexpressed in clinical melanoma tissues as well as in melanoma cell lines. Knockdown of Fyn expression markedly attenuated the malignant phenotype of melanoma cells in vitro and in vivo through downregulation of CD147 phosphorylation, indicating that Fyn/CD147 is a potential target molecule in melanoma treatment. Finally, through virtual screening, we identified amodiaquine as a potential inhibitor targeting the Fyn/CD147 axis. Amodiaquine treatment dramatically inhibited the phosphorylation of CD147 by Fyn, thus attenuating melanoma cell growth and invasion in vitro and in vivo, suggesting that amodiaquine is a promising inhibitor for melanoma treatment.

This paper introduces an efficient extraction method based on organic and sulfuric complex acid system, to achieve the clean recovery of scattered metals from zinc leaching residue. The tartaric (TAR) and sulfuric complex acid significantly improved the leaching of Ge but had little effect on the leaching efficiency of Ga. A maximum extraction efficiency of 93.1% of Ge and 84.3% of Ga, was obtained at a sulfuric acid concentration of 100 g/L, TAR concentration of 20 g/L, leaching time of 1 h, and temperature of 80 degrees C, with a liquid-solid ratio of 10 mL/g, and a mixing rate of 250 rpm. The leaching process and mechanism were investigated by XRD, SEM, EPMA and UV-Vis. The findings showed that TAR acid plays a key role in the dissociation of the mineral phase containing Ge, as well as the promotion of Ge dissolution. Compared with the conventional sulfuric acid system, the TAR containing complex acid could effectively promote the decomposition of some iron ore phases, like beaverite, in which Ge tends to be embedded and enriched, in association with Fe. Additionally, the improved leaching efficiency of Ge was attributed to the formation of soluble TAR-Ge complexes, which were confirmed by UV-Vis.

CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.

Although accumulating evidence had revealed that NFAT1 has oncogenic characteristics, the role of this molecule in melanoma cells remains unclear. Previous studies proved that CD147 plays a crucial function in melanoma cell metastasis and invasion through matrix metalloproteinase 9 (MMP-9) expression; however, the details of how CD147 regulates MMP-9 expression remain elusive. In this study, we demonstrated that CD147 and NFAT1 are overexpressed in the tissues of patients with primary and metastatic melanoma, which has shown a positive correlation. Further, we observed that CD147 regulates NFAT1 activation through the [Ca2+](i)-calcineurin pathway. Knockdown of NFAT1 significantly suppresses melanoma metastasis, and we demonstrated that CD147 affects melanoma metastasis in an NFAT1-dependent manner. Moreover, we verified that NFAT1 directly binds to MMP-9 promoter. Inhibition of CD147 expression significantly abrogates MMP-9 promoter luciferase gene reporter activity as well as NFAT1 association with MMP-9 promoter. Taken together, this study demonstrated that CD147 affects MMP-9 expression through regulating NFAT1 activity and provided a novel mechanism by which NFAT1 contributes to melanoma metastasis through the regulation of MMP-9.

Purines, among most influential molecules, are reported to have essential biological function by regulating various cell types. A large number of studies have led to the discovery of many biological functions of the purine nucleotides such as ATP, ADP, and adenosine, as signaling molecules that engage G protein-coupled or ligand-gated ion channel receptors. The role of purines in the regulation of cellular functions at the gene or protein level has been well documented. With the advances in multiomics, including those from metabolomic and bioinformatic analyses, metabolic reprogramming was identified as a key mechanism involved in the regulation of cellular function under physiological or pathological conditions. Recent studies suggest that purines or purine-derived products contribute to important regulatory functions in many fundamental biological and pathological processes related to metabolic reprogramming. Therefore, this review summarizes the role and potential mechanism of purines in the regulation of metabolic reprogramming. In particular, the molecular mechanisms of extracellular purine- and intracellular purine-mediated metabolic regulation in various cells during disease development are discussed. In summary, our review provides an extensive resource for studying the regulatory role of purines in metabolic reprogramming and sheds light on the utilization of the corresponding peptides or proteins for disease diagnosis and therapy.

Background Chronic spontaneous urticaria (CSU) is a common and recurrent autoimmune-related disease with unclear pathogenesis. Dysfunction of immune cells, such as T cells, mast cells, and basophils, is involved. Bacillus Calmette–Guerin polysaccharide nucleic acid (BCG–PSN), an immunomodulator partially extracted from BCG, can be used in the combined treatment of CSU with an unknown mechanism. Methods To study the therapeutic effect and mechanism of BCG–PSN on CSU, we initially assessed the clinical efficacy in 110 enrolled CSU patients of 4-week antihistamine monotherapy vs. antihistamine plus BCG–PSN combined therapy. Subsequently, to explore the further mechanism of BCG-PSN, the mast cell line RBL-2H3 pretreated with BCG-PSN was used to evaluate the transcriptional expression profiles via lncRNA sequencing. Real time PCR was conducted to validate the candidate gene expression. Results We found no significant difference in treatment efficacy between the BCG–PSN group (71.7%) and the monotherapy group (71.9%). However, the average time of complete relief in the BCG–PSN group was significantly shorter than that in the monotherapy group (36.77 ± 17.33 vs. 51.27 ± 16.80, p = 0.026). In vitro experiments showed that BCG-PSN inhibited β-hexosaminidase release rates in IgE-sensitized RBL-2H3 cells (p < 0.001). Sequencing data revealed the expression profiles of functional genes, including a significant decrease in Erb-B2 receptor tyrosine kinase 4, which can be regulated by the nuclear factor kappa B (NF-κB) pathway. Discussion CSU is a chronic, recurrent disease with complex pathogenesis. Mast cells and basophils are the primary target cells of the disease. BCG–PSN decrease the β-HEX release rates and regulated IgE-mediated mast cell activation in RBL-2H3 cells by mediating immune-related gene expression including ERBB4. These findings suggest that BCG–PSN may mediate ERBB4 expression via the NF-κB pathway and may have value in the treatment of CSU.

Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema, and nearly 35% patients respond poorly to non‐sedating H1 antihistamine treatment. CRP gene encodes the C‐reactive protein, which is involved in the pathogenesis of CSU. To investigate the impacts of CRP polymorphisms on the susceptibility and therapeutic efficacy in the South Han CSU patients, we enrolled 145 CSU patients in our study. After 4‐week non‐sedating H1 antihistamine monotherapy treatment, more than 50% reduction of the severity score is considered as effective, or else non‐effective. The CRP rs3093059T/C and rs2794521G/A genotypes of patients were determined by Sequenom MassARRAY. Functional studies including relative luciferase assay and β‐hexosaminidase assay were conducted in HEK293T cells or RBL‐2H3 cells to explore the function of variants. Forty (62.50%) CSU patients were effective when treated with mizolastine, and 55 (72.4%) patients were effective in the desloratadine group. We found that the patients carried with rs3093059TT genotype were significantly associated with good response (OR = 4.20, P = 0.015), had lower serum CRP, IL‐6 and TNF‐α levels than the CT/CC genotypes. In vitro, the rs3093059C allele exhibited significantly higher luciferase activity than wild allele (P < 0.001). From the β‐hexosaminidase assay, we observed the inhibiting degranulation effects by mizolastine and this effect is weakened when with a higher dose CRP in RBL‐2H3 cells. Our findings suggested that CSU patients carrying the rs3093059C allele may respond poorly to mizolastine with elevated serum CRP level.

基于有限元分析软件ABAQUS建立了高速切削Ti6Al4V的二维正交切削有限元模型,仿真研究了高速切削加工时切削速度、切削深度对切削力大小、切削力波动频率以及锯齿形切屑形态的影响.结果表明:平均切削力在90 m/min～360 m/min的切削速度范围内趋于平稳,随着切削深度的增大而增大;切削力波动频率随切削深度的增加而减小,随切削速度的增大而增大;切屑锯齿化程度及锯齿化步距都随切削速度及切削深度的增大而增大.

BACKGROUND:T helper 17 (Th17) cells have proven to be crucial in the pathogenesis of neutrophils-dominant asthma. Hypoxia inducible factor-1α (HIF-1α) is involved in allergic responses in asthma. Our previous studies indicated that Methtyl-CpG binding domain protein 2 (MBD2) expression was increased in asthma patients. The aim of the present study is to understand how MBD2 interacts with HIF-1α to regulate Th17 cell differentiation and IL-17 expression in neutrophils-dominant asthma.METHODS:A neutrophils-dominant asthma mouse model was established using female C57BL/6 mice to investigate Th17 cell differentiation and MBD2 and HIF-1α expression regulation using flow cytometry, western blot or qRT-PCR. MBD2 and HIF-1α genes were silenced or overexpressed through lentiviral transduction to explore the roles of MBD2 in Th17 cell differentiation and IL-17 release in neutrophils-dominant asthma.RESULTS:A neutrophilic inflammatory asthma phenotype model was established successfully. This was characterized by airway hyperresponsiveness (AHR), increased BALF neutrophil granulocytes, activated Th17 cell differentiation, and high IL-17 levels. MBD2 and HIF-1α expression were significantly increased in the lung and spleen cells of mice with neutrophils-dominant asthma. Through overexpression or silencing of MBD2 and HIF-1α genes, we have concluded that MBD2 and HIF-1α regulate Th17 cell differentiation and IL-17 secretion. Moreover, MBD2 was also found to regulate HIF-1α expression.CONCLUSIONS:Our findings have uncovered new roles for MBD2 and HIF-1α, and provide novel insights into the epigenetic regulation of neutrophils-dominant asthma.

采用多元线性回归分析方法研究了切削速度、进给量和切削深度对铣削力的影响规律,借助最小二乘法原理对切削力经验公式回归系数进行参数估计和优化,并对经验公式进行相关性检验.检验结果表明,相关显著性很高.

TRAF6, a well-known adapter molecule, plays pivotal role in TLR/IL-1R associated signaling pathway. Although TRAF6 has been shown to have oncogenic activity in various malignant tumors, the details remain unclear. In this study, we demonstrated that TRAF6 facilitates Ras (G12V) and EGF-induced cellular transformation through EGFR. Silencing of TRAF6 expression significantly downregulated AP-1 activity, as well as MMP-2,9 expression after EGF stimulation. Furthermore, we found that TRAF6 plays an essential role in cutaneous squamous cell carcinoma (cSCC) malignant phenotypes, affecting cell growth and migration. CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is over-expressed in tumors and induces tumorigenesis. Our results showed that CD147 formed complex with EGFR and TRAF6. Knockdown of TRAF6 disrupted the CD147-EGFR complex, thereby inducing EGFR endocytosis. Therefore, TRAF6 might be a novel molecular target for cSCC prevention or therapy.

Leptin is a well-known adipokine that plays a critical role in immune responses. To further explore the immunological roles of leptin, we developed a transgenic leptin pig controlled by the pig leptin (pleptin) promoter to overexpress leptin. Symptoms typically associated with systemic lupus erythematosus (SLE) were evident in this transgenic pig strain, including anemia, leukopenia, and thrombocytopenia as well as kidney and liver impairment. Histologically, there were increased immunoglobulin G (IgG) levels, elevated antiplatelet antibody (APA) levels, and deposition of immune complexes in the kidney and liver. In addition, anti-double-stranded DNA antibodies (dsDNAs), antinuclear antibodies (ANAs), and antinucleosome antibodies (ANuAs) were all significantly increased in serum immunological examinations. These findings were also accompanied by repression of the regulatory T cell (Treg) ratio. Significantly, glucocorticoid experimental therapies partially relieved the autoimmune responses and bleeding symptoms observed in these transgenic leptin pigs. Together, these results indicate that leptin plays a critical role in the development of autoimmune disorders and demonstrate that our transgenic leptin pigs can act as a valuable model of SLE.

Cluster of differentiation (CD)147, as a transmembrane glycoprotein, is highly expressed in a variety of tumors. Accumulating evidence has demonstrated that CD147 serves critical roles in tumor cell death and survival; however, the underlying mechanism requires further investigation. In the present study, it was revealed that CD147 knockdown significantly increased melanoma cell apoptosis. In addition, downregulation of CD147 reversed the malignant phenotype of melanoma, as demonstrated by the induction of tumor cell apoptosis in a xenograft mouse model. In addition, a human apoptosis antibody array was performed and 9 differentially expressed apoptosis-related proteins associated with CD147 were identified, including insulin-like growth factor-binding protein 2 (IGFBP2). Additionally, CD147 knockdown was observed to significantly decreased IGFBP2 expression at the mRNA and protein levels in melanoma cells. Providing that IGFBP2 is a downstream molecule in the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, the effects of CD147 on this particular pathway were investigated. Interestingly, the expression of phosphorylated (p)-AKT and p-mechanistic target of rapamycin was attenuated, whereas PTEN was markedly upregulated in CD147-underexpressing melanoma cells. Furthermore, application of a PI3K-specific inhibitor also decreased IGFBP2 expression. Importantly, IGFBP2 was highly expressed in clinical tissues of melanoma compared with the control group, and its expression exhibited a positive association with CD147. The present study revealed that CD147 served a critical role in mediating the apoptosis of melanoma cells via IGFBP2 and the PTEN/PI3K/AKT signaling pathway. IGFBP2 and CD147 were observed to be overexpressed in clinical melanoma tissues; IGFBP2 was shown to be positively associated with CD147 expression, suggesting that CD147 may be considered as a potential therapeutic target for chemotherapy or prevention for in melanoma.

Background Acitretin is a second-generation synthetic retinoid, and is widely used for treating the severe psoriasis vulgaris. However, it should be chosen with caution for its cardiovascular risk, and it is reported that acitretin may increase the serum lipids. The purpose of this study is to investigate the relationship between the Frizzled-related proteins 4 (SFRP4) rs1802073 polymorphism and the changes of serum lipids in Chinese psoriatic patients during the treatment with acitretin. Methods In our study, 100 psoriatic patients were recruited systematically treated with acitretin (30 mg/day) for at least eight weeks. Data of the patients’ demographic and clinical characteristics and the results of serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were collected pre- and post-treatment. Results A total of 84 psoriatic patients were enrolled and divided into three groups by SFRP4 rs1802073 genotypes. The patients who carried with TT genotype had maintained levels of TG and LDL-C after acitretin treatment, while patients with GG/GT genotypes had significantly elevated levels of serum TG and LDL-C compared to the TT genotype (ΔTG%: 27.53 ± 59.13 vs −1.47 ± 37.79, p = 0.026, ΔLDL-C%: 10.62 ± 26.57 vs −1.29 ± 17.07, p = 0.042). The association of rs1802073 with TG and LDL-C profiles remained significant after adjusting for age, gender, and body mass index. Although without significance, the pre-post change in serum level of TC across rs1802073 GG/GT genotypes demonstrated a trend similar to TG and LDL, and the serum level of HDL-C demonstrated a trend opposite to TG, TC and LDL. Conclusions Our results demonstrated that SFRP4 rs1802073 polymorphism was found to be associated with elevated serum lipid levels after acitretin treatment, and it may serve as a genetic marker of safe and precise treatment for individual psoriatic patients.

The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis.

Mg2+ and PO43+ were added into the synthetic wastewater, leading to the dissociation of the complex ions in the wastewater, and resulting in removal of copper and ammonia therein. The effects of agents addition amount, pH, and reaction time on the removal efficiency of copper and ammonia were investigated. In particular, two-sectional struvite formation (TSSF) process was established for copper and ammonia removal. MgCl2 and Na2HPO4 were added by following 90% addition in the first section and remained 10% in the second during the TSSF process. Compared with one sectional struvite formation, TSSF possessed much better performance. Under condition of n(NH3-N): n(Mg): n(P)= 1: 1.2: 1.5 (molar ratio), pH= 9, and reaction time of 30 min, the removal efficiencies of copper and ammonia were 98.9% and 99.96%, respectively. The enhanced performance of TSSF is explained by the competition of ammonia by copper-ammonia complexes and struvite. The dissociation of copper-ammonia complexes is further demonstrated by thermodynamic equilibrium analysis, on the basis of calculations and establishment of predominance phases diagram. Moreover, XRD and EDS analyses further confirmed the formation of struvite and precipitation of copper, which prove the transmission of copper and ammonia from liquid phase into solid phase.

Effect of electric pulse-ultrasonic field on solidification of pure aluminum was investigated by observing the microstructure observation and mechanical properties test. The results show that the equiaxed grain area in longitudinal settion and cross section of pure aluminum solidified under composite field ( electric pulse:voltage 10 V, duty cycle 60%, frequency 50 Hz. Ultrasound:2 kW, 20 kHz) increases by 50. 21% and 47. 22% respectively compared with that without field and the corresponding average grain size decreases from 556 μm2 and 529 μm2 to 64 μm2 and 80 μm2 , respectively. Meanwhile the grain refining effect is better than the single field. Compared with those without field, the hardness, tensile strength and elongation of pure aluminum solidified under composite field increase by 28%, 15. 9% and 12. 83%.

进行涂层硬质合金刀具干式切削45淬硬钢试验,分析了切削参数和刀具涂层对45淬硬钢干式切削温度的影响.切削温度均随着切削速度、进给量及背吃刀量的增大而增大,但不同之处在于,切削温度的增加量随着切削速度的增加而增加,随进给量及背吃刀量的增加而减小;涂层刀具的切削温度明显小于涂层刀具,且随着切削速度的提高,切削温度增加量始终维持在一个较低水平;PVD涂层的隔热性能要普遍优于CVD涂层,所有涂层隔热性能由大到小排序为:YBC251＞ YBM151＞ YBG205＞ YBG102