المؤلفون: Fanyi Meng, Zhiyue Yin, Feifei Lu, Weipeng Wang, Hongjian Zhang

المصدر: Thoracic Cancer, Vol 15, Iss 4, Pp 316-326 (2024)

مصطلحات موضوعية: B7‐H3, cancer‐associated fibroblasts, LPAR1, lysophosphatidic acid, non‐small cell lung cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Lysophosphatidic acids (LPAs) belong to a class of bioactive lysophospholipids with multiple functions including immunomodulatory roles in tumor microenvironment (TME). LPA exerts its biological effects via its receptors that are highly expressed in fibroblasts among other cell types. As cancer‐associated fibroblasts (CAFs) are a key component of the TME, it is important to understand LPA signaling and regulation of receptors in fibroblasts or CAFs and associated regulatory roles on immunomodulation‐related molecules. Methods Cluster analysis, immunoblotting, real‐time quantitative‐PCR, CRISPR‐Cas9 gene editing system, immunohistochemical staining, coculture model, and in vivo xenograft model were used to investigate the effects of LPA‐LPAR1 on B7‐H3 in tumor promotion of CAFs. Results In this study, we found that LPAR1 and CD276 (B7‐H3) were generally highly expressed in fibroblasts with good expression correlation. LPA induced B7‐H3 up‐expression through LPAR1, and stimulated fibroblasts proliferation that could be inhibited by silencing LPAR1 or B7‐H3 as well as small molecule LPAR1 antagonist (Ki16425). Using engineered fibroblasts and non‐small cell lung carcinoma (NSCLC) cell lines, subsequent investigations demonstrated that CAFs promoted the proliferation of NSCLC in vitro and in vivo, and such effect could be inhibited by knocking out LPAR1 or B7‐H3. Conclusion The present study provided new insights for roles of LPA in CAFs, which could lead to the development of innovative therapies targeting CAFs in the TME. It is also reasonable to postulate a combinatory approach to treat malignant fibrous tumors (such as NSCLC) with LPAR1 antagonists and B7‐H3 targeting therapies.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1759-7706Test; https://doaj.org/toc/1759-7714Test

الوصول الحر: https://doaj.org/article/c9183bf5e9a444789a428ff7f38e7408Test

المؤلفون: Chuanjin Yao, Fanyi Meng, Hexing Zhang, Tianyuan Di, Yiran Zhou, Xinge Du

المصدر: ACS Omega, Vol 8, Iss 51, Pp 49046-49056 (2023)

مصطلحات موضوعية: Chemistry, QD1-999

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2470-1343Test

الوصول الحر: https://doaj.org/article/15dd0cf380d94fd994143d6faa9a8666Test

المؤلفون: Hu Zhang, Chenlu Mu, Yu Gu, Fanyi Meng, Xiali Qin, Hailong Cao

المصدر: Pharmacological Research, Vol 202, Iss , Pp 107108- (2024)

مصطلحات موضوعية: Ulcerative colitis, Biologic therapies, Treatment failure, Second-line treatment, Meta-analysis, Therapeutics. Pharmacology, RM1-950

الوصف: Background: Optimizing second-line biologic therapies for adult ulcerative colitis (UC) post first-line failure is essential. Objective: Compare second-line biologic therapy efficacy in adult UC patients with prior treatment failure. Methods: A comprehensive search of electronic databases up to May 2023 was conducted to assess second-line biologic therapy efficacy using a random effects model. Parameters analyzed included clinical remission rate, clinical response rate, mucosal healing rate, annual discontinuation rate, and colectomy rates. Results: Forty-three research papers were analyzed. Clinical remission rates for second-line biologics were ranked at 6–14 weeks: Infliximab (30%) was followed by Vedolizumab (29%), Ustekinumab (27%), and Adalimumab (19%). At 52–54 weeks, the order shifted, with Vedolizumab (35%) followed by Infliximab (32%), Ustekinumab (31%), and Adalimumab (26%). The mucosal healing rate was 21%, ranked as: Infliximab (31%), Vedolizumab (21%), Adalimumab (21%), and Ustekinumab (14%). The annual discontinuation rate stood at 20%, with Adalimumab (25%), Vedolizumab (18%), Infliximab (17%), and Ustekinumab (16%). Discontinuation rates due to primary failure (PF), secondary failure (SF), and adverse events (AE) were 6%, 12%, and 3%, respectively. The annual colectomy rate was 9%, with Adalimumab (15%) followed by Vedolizumab (10%), Ustekinumab (9%), and Infliximab (5%), and colectomy rates of 10% due to PF, 12% due to SF, and 4% due to AE. Conclusion: For UC patients with first-line treatment failure, it is recommended to prioritize infliximab or vedolizumab as second-line biologic therapies, while avoiding adalimumab as the primary choice. Further clinical trials are necessary to assess ustekinumab efficacy accurately.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S1043661824000525Test; https://doaj.org/toc/1096-1186Test

الوصول الحر: https://doaj.org/article/c8987ad75fdf45709cdc94c6f7d3db70Test

المؤلفون: Mengmeng Wang, Zhoudong Zhang, Mengxi Chen, Yixin Lv, Sheng Tian, Fanyi Meng, Yawen Zhang, Xuqin Guo, Yinshuang Chen, Man Yang, Jiawei Li, Tian Qiu, Fang Xu, Zhi Li, Qi Zhang, Jie Yang, Jing Sun, Hongjian Zhang, Haiyang Zhang, Huanqiu Li, Weipeng Wang

المصدر: Cell Death and Disease, Vol 14, Iss 8, Pp 1-13 (2023)

مصطلحات موضوعية: Cytology, QH573-671

الوصف: Abstract Metastatic colorectal cancer (mCRC) is a major cause of cancer-related mortality due to the absence of effective therapeutics. Thus, it is urgent to discover new drugs for mCRC. Fucosyltransferase 8 (FUT8) is a potential therapeutic target with high level in most malignant cancers including CRC. FUT8 mediates the core fucosylation of CD276 (B7-H3), a key immune checkpoint molecule (ICM), in CRC. FUT8-silence-induced defucosylation at N104 on B7-H3 attracts heat shock protein family A member 8 (HSPA8, also known as HSC70) to bind with 106-110 SLRLQ motif and consequently propels lysosomal proteolysis of B7-H3 through the chaperone-mediated autophagy (CMA) pathway. Then we report the development and characterization of a potent and highly selective small-molecule inhibitor of FUT8, named FDW028, which evidently prolongs the survival of mice with CRC pulmonary metastases (CRPM). FDW028 exhibits potent anti-tumor activity by defucosylation and impelling lysosomal degradation of B7-H3 through the CMA pathway. Taken together, FUT8 inhibition destabilizes B7-H3 through CMA-mediated lysosomal proteolysis, and FDW028 acts as a potent therapeutic candidate against mCRC by targeting FUT8. FDW028, an inhibitor specifically targeted FUT8, promotes defucosylation and consequent HSC70/LAMP2A-mediated lysosomal degradation of B7-H3, and exhibits potent anti-mCRC activities.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-4889Test

الوصول الحر: https://doaj.org/article/7a9c042799264e70a9230d15a9ae936aTest

المؤلفون: Qixin Sun, Bingyi Wu, Fanyi Meng, Qianqian Yao, Zhiwei Huang, Jianhui Xu, Zhigang Zhu

المصدر: Hematology, Vol 28, Iss 1 (2023)

مصطلحات موضوعية: Sorafenib, c-Cbl gene, chemoresistance, leukemia, Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: ABSTRACTChemotherapeutic regimens containing sorafenib are widely used in salvage treatment for patients with relapsed and refractory acute leukemia, especially those with FLT3-ITD mutations. However, the therapeutic effects in individuals are heterogeneous, and the effective maintenance period is relatively short. Our clinical analysis showed patients with high c-kit (CD117) expression in leukemia cells generally had a better response to sorafenib, but the reason for this finding was not clear. c-kit (CD117) is a receptor tyrosine kinase, and its signal inactivation and hydrolytic metabolism are regulated by the CBL protein, a Ring finger E3 ubiquitin ligase, encoded by the c-CBL gene. And we also found that the c-CBL gene expression in refractory and relapsed patients was significantly lower than that in healthy hematopoietic stem cell donors. Therefore, we assumed that there is a relationship among c-CBL gene function, high expression of c-kit (CD117) and a better clinical response to sorafenib. To confirm this hypothesis, we packaged interfering lentiviruses and overexpressed adenoviruses targeting the c-CBL gene respectively, and infected leukemia cell lines with these viruses to regulate the expression of the c-CBL gene, and observed the subsequent changes of these cells in various biological behaviors. Our results showed when the c-CBL gene was silenced, the cells proliferation was accelerated, drug sensitivity to cytarabine or sorafenib was decreased, and apoptosis ratio was decreased. And all these phenomena were reversed when the gene was overexpressed, which confirmed the expression of c-CBL gene was related to drug resistance in leukemia cells. At last, we explored the possible molecular mechanisms underlying these phenomena.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1607-8454Test

الوصول الحر: https://doaj.org/article/86776d4414744984a6d7c9a8c6edc0b7Test

المؤلفون: Huajiao Shen, Yongqiang Wang, Fanyi Meng, Kaixue Ma

المصدر: Electronics Letters, Vol 59, Iss 22, Pp n/a-n/a (2023)

مصطلحات موضوعية: coplanar transmission lines, differential geometry, directional couplers, microwave circuits, microwave devices, slow‐wave structures, Electrical engineering. Electronics. Nuclear engineering, TK1-9971

الوصف: Abstract This letter presents a compact fully differential branch‐line coupler. It is composed of folded substrate integrated suspended parallel strip line (SISPSL), which can generate slow‐wave effect and help reduce the circuit size. The used SISPSL type line is a fusion of double‐sided parallel‐strip line (DSPSL) and substrate integrated suspended line (SISL), which has the advantage of self‐packaging as compared with traditional DSPSL exposed to air. A DC to 30‐GHz differential transition from grounded coplanar waveguide (GCPW) to SISPSL is designed to test the SISPSL differential coupler. The implemented SISPSL branch‐line coupler has a compact size of 0.056 λg × 0.05 λg.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/0013-5194Test; https://doaj.org/toc/1350-911XTest

الوصول الحر: https://doaj.org/article/b750021f3f8944dc96763402fc219a0eTest

المؤلفون: Fanyi Meng, Siqi Zhang, Juan Xie, Yuan Zhou, Qingling Wu, Binyan Lu, Shixin Zhou, Xiangyu Zhao, Yang Li

المصدر: Journal of Hematology & Oncology, Vol 16, Iss 1, Pp 1-18 (2023)

مصطلحات موضوعية: Induced pluripotent stem cells, NK-cell differentiation, CD16 fusion receptor, Immunotherapy, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background The cytotoxicity of NK cells is largely dependent on IgG Fc receptor CD16a, which mediates antibody-dependent cell-mediated cytotoxicity (ADCC). The high-affinity and non-cleavable CD16 (hnCD16) is developed and demonstrated a multi-tumor killing potential. However, the hnCD16 receptor activates a single CD16 signal and provides limited tumor suppression. How to exploit the properties of hnCD16 and incorporate NK cell-specific activation domains is a promising development direction to further improve the anti-tumor activity of NK cells. Methods To expand the applications of hnCD16-mediated ADCC for NK cell-based immunotherapy in cancer, we designed the hnCD16 Fusion Receptor (FR) constructs with the ectodomain of hnCD16 fused with NK cell-specific activating domains in the cytoplasm. FR constructs were transduced into CD16-negative NK cell line and human iPSC-derived NK (iNK) cells and effective FR constructs were screened. The up-regulation of immune activation- and cytokine-releasing-related pathways in FR-transduced NK cells was screened and validated by RNA sequencing and multiplex cytokines release assay, respectively. The tumor-killing efficiency was tested in vitro and in vivo via co-culture with tumor cell lines and xenograft mice-bearing human B-cell lymphoma, respectively. Results We screened the most effective combination to kill B cell lymphoma, which was fused with the ectodomain of hnCD16a, NK-specific co-stimulators (2B4 and DAP10) and CD3ζ in cytoplasmic domains. The screened construct showed excellent cytotoxicity effects and sharp multiple cytokines releasing both in the NK cell line and iNK cells. The transcriptomic analysis and validation assays of hnCD16- and hnCD16FR-transduced NK cells showed that hnCD16FR transduction remodeled immune-related transcriptome in NK cells, where significant upregulation of genes related to cytotoxicity, high cytokines releasing, induced tumor cell apoptosis, and ADCC in comparison with hnCD16 transduction were highlighted. In vivo xenograft studies demonstrated that a single low-dose regimen of engineered hnCD16FR iPSC-derived NK cells co-administered with anti-CD20 mAb treatment mediated potent activity and significantly improved survival. Conclusion We developed a novel hnCD16FR construct that exhibits more potent cytotoxicity than reported hnCD16, which is a promising approach to treat malignancies with improved ADCC properties. We also offer a rationale for NK activation domains that remodel immune response to enhance CD16 signaling in NK cells.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1756-8722Test

الوصول الحر: https://doaj.org/article/320a1369294d4380818615302e231008Test

المؤلفون: Dongyang Sun, Wenqiang Shen, Zijie Qian, Fanyi Meng, Yutong Sha, Kai Zhou

المصدر: IEEE Access, Vol 11, Pp 48881-48892 (2023)

مصطلحات موضوعية: Power quality, doubly-fed induction generator (DFIG), grid side converter (GSC), phase locked loop (PLL), sub-synchronous oscillation frequency change, adaptive quasi-resonant controller, Electrical engineering. Electronics. Nuclear engineering, TK1-9971

الوصف: This paper focuses on the power grid oscillation of grid-side converter (GSC) in doubly-fed induction generator (DFIG) caused by grid sub-synchronous oscillation (SSO), and designs a measure to improve the output power quality of GSC. Firstly, the influence mechanism of multipath disturbance of GSC under SSO is sorted out, and the disturbance factors and action modes are clarified. Secondly, the influence of SSO on the output estimation of phase-locked loop (PLL) in the control strategy and power calculation process is analyzed. Furthermore, the mathematical model of GSC output power considering the influence of PLL is established. At the same time, the key factors of SSO for GSC power oscillation suppression strategy are determined by analyzing the oscillation suppression effect of quasi-resonant controller when SSO amplitude, frequency and phase change. Based on the above theoretical analysis and research, the resonant controller is used to eliminate the estimation error of the PLL; at the same time, an adaptive algorithm is designed according to the mechanism analysis of SSO characteristic changes to improve the fixed resonant frequency of the quasi-resonant controller, and a DFIG-GSC sub-synchronous power oscillation suppression strategy based on the adaptive quasi-resonant controller is proposed, thus eliminating the influence of SSO on the multipath disturbance of GSC and improving the power quality of its output. Finally, the effectiveness of the proposed suppression strategy is verified by simulation and experimental results.

وصف الملف: electronic resource

العلاقة: https://ieeexplore.ieee.org/document/10129011Test/; https://doaj.org/toc/2169-3536Test

الوصول الحر: https://doaj.org/article/d4266d10c41f41798582d48493dab7b1Test

المؤلفون: Nazar Budaiev, Adam Ginsburg, Desmond Jeff, Ciriaco Goddi, Fanyi Meng, Álvaro Sánchez-Monge, Peter Schilke, Anika Schmiedeke, Taehwa Yoo

المصدر: The Astrophysical Journal, Vol 961, Iss 1, p 4 (2024)

مصطلحات موضوعية: Star formation, Initial mass function, Star forming regions, Protostars, Young stellar objects, Astrophysics, QB460-466

الوصف: We present 500 and 700 au resolution 1 and 3 mm Atacama Large Millimeter/submillimeter Array observations, respectively, of protostellar cores in protoclusters Sagittarius B2 (Sgr B2) North (N) and Main (M), parts of the most actively star-forming cloud in our Galaxy. Previous lower-resolution (5000 au) 3 mm observations of this region detected ∼150 sources inferred to be young stellar objects (YSOs) with M > 8 M _⊙ . With a 10-fold increase in resolution, we detect 371 sources at 3 mm and 218 sources in the smaller field of view at 1 mm. The sources seen at low resolution are observed to fragment into an average of two objects. About one-third of the observed sources fragment. Most of the sources we report are marginally resolved and are at least partially optically thick. We determine that the observed sources are most consistent with Stage 0/I YSOs, i.e., rotationally supported disks with an active protostar and an envelope, that are warmer than those observed in the solar neighborhood. We report source-counting-based inferred stellar mass and the star formation rate of the cloud: 2800 M _⊙ and 0.0038 M _⊙ yr ^−1 for Sgr B2 N and 6900 M _⊙ and 0.0093 M _⊙ yr ^−1 for Sgr B2 M, respectively.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1538-4357Test

الوصول الحر: https://doaj.org/article/9e27edfb81124c24804d9feca18847efTest

المؤلفون: Desmond Jeff, Adam Ginsburg, Alyssa Bulatek, Nazar Budaiev, Álvaro Sánchez-Monge, Mélisse Bonfand, Cara Battersby, Fanyi Meng, Peter Schilke, Anika Schmiedeke

المصدر: The Astrophysical Journal, Vol 962, Iss 1, p 48 (2024)

مصطلحات موضوعية: Protoclusters, Chemical abundances, Astrochemistry, Galactic center, Star forming regions, Star formation, Astrophysics, QB460-466

الوصف: We report the discovery of nine new hot molecular cores in the Deep South (DS) region of Sagittarius B2 using Atacama Large Millimeter/submillimeter Array Band 6 observations. We measure the rotational temperature of CH _3 OH and derive the physical conditions present within these cores and the hot core Sgr B2(S). The cores show heterogeneous temperature structure, with peak temperatures between 252 and 662 K. We find that the cores span a range of masses (203–4842 M _⊙ ) and radii (3587–9436 au). CH _3 OH abundances consistently increase with temperature across the sample. Our measurements show the DS hot cores are structurally similar to Galactic disk hot cores, with radii and temperature gradients that are comparable to sources in the disk. They also show shallower density gradients than disk hot cores, which may arise from the Central Molecular Zone’s higher density threshold for star formation. The hot cores have properties which are consistent with those of Sgr B2(N), with three associated with Class II CH _3 OH masers and one associated with an ultra-compact H ii region. Our sample nearly doubles the high-mass star-forming gas mass near Sgr B2(S) and suggests the region may be a younger, comparably massive counterpart to Sgr B2(N) and (M). The relationship between peak CH _3 OH abundance and rotational temperature traced by our sample and a selection of comparable hot cores is qualitatively consistent with predictions from chemical modeling. However, we observe constant peak abundances at higher temperatures ( T ≳ 250 K), which may indicate mechanisms for methanol survival that are not yet accounted for in models.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1538-4357Test

الوصول الحر: https://doaj.org/article/aa7ff9f5f32540bbb35b2ef60777e1fbTest