Objective To analyze the epidemiological burden of glaucoma in China based on data from the Global Burden of Disease 2019(GBD 2019)database to provide a theoretical basis for the prevention and control of glaucoma in China.Methods Analysis of the glaucoma epidemic trend and age,period,and gender trends in China from 1990 to 2019 and the correlation between glaucoma and the Socio-Demographic Index(SDI)were conducted according to relevant data on the number of patients,prevalence,disability-adjusted life years(DALYs)and DALY rates downloaded from the GBD 2019 database.Results In 2019,China was ranked globally first for the number of people with glaucoma and second for DALYs due to glaucoma.In 2019,China's glaucoma prevalence was among the highest globally,with the number of pa-tients being 1.92 times that of 1990.Both the prevalence and the DALY rate demonstrated a persistent upward trajectory.The demographic distribution of patients with glaucoma in China revealed a curve which peaked among middle-aged individ-uals,with higher prevalence observed in males than females.An inverse correlation was identified between SDI and the age-standardized prevalence and DALY rates,which exhibited a negative average annual percentage change,indicative of a pro-gressive decline with rising SDI.Conclusion From 1990 to 2019,China experienced a significant increase in the burden of glaucoma,ranking among the highest globally,with a positive correlation observed between the disease burden and the level of social development.

RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis, but the targets and molecular functions of RBM46 remain unknown. Here, we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation. Using a recently reported, high-resolution technique known as LACE-seq and working with low-input cells, we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes. We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions. In Rbm46 knockout mice, the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation, resulting in the failed assembly of axial elements, synapsis disruption, and meiotic arrest. Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.
Animals ; Mice ; 3' Untranslated Regions/genetics* ; Cell Cycle Proteins/metabolism* ; Gametogenesis/genetics* ; Meiosis/genetics* ; Nuclear Proteins/genetics* ; RNA-Binding Proteins/genetics*

More than 85% of patients with uveal melanoma (UM) carry a GNAQ or GNA11 mutation at a hotspot codon (Q209) that encodes G protein α subunit q/11 polypeptides (Gα_q/11). GNAQ/11 relies on palmitoylation for membrane association and signal transduction. Despite the palmitoylation of GNAQ/11 was discovered long before, its implication in UM remains unclear. Here, results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells. Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11^Q209L-induced malignant transformation in NIH3T3 cells. Importantly, the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells, which are much more dependent on Gα_q/11 signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations. Furthermore, the palmitoylation inhibitor, 2-bromopalmitate, also specifically disrupted Gα_q/11 downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor, ABT-199, in vitro. The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.
Humans ; Mice ; Animals ; Lipoylation ; NIH 3T3 Cells ; Uveal Neoplasms/genetics* ; Melanoma/genetics* ; Cell Proliferation ; Proto-Oncogene Proteins c-bcl-2 ; GTP-Binding Protein alpha Subunits, Gq-G11/genetics*

Objective:To explore the structural alterations in functional brain areas of patients with diabetic peripheral neuropathy (DPN) using voxel-based morphometry (VBM), and to investigate the abnormal region of grey matter and its distribution in DPN.Methods:A total of 124 patients with DPN and 88 patients with type 2 diabetes without DPN (NDPN) diagnosed in Haikou Hospital and the First Affiliated Hospital of Guangdong Pharmaceutical University from June 2019 to December 2020 were selected as the study subjects, and 40 healthy volunteers matched with gender and age were included as the control group.All subjects underwent whole-brain MRI examination, and 3D-T1WI data were collected for post-processing and analysis based on voxel morphological analysis.Results:Compared with NDPN patients, decreased gray matter volume in DPN patients was observed in the bilateral anterior central gyrus and thalamus, with statistical signifcant difference ( P<0.05), and there was no significant difference between the two sides ( P>0.05). Compared with healthy control group, decreased gray matter volume in DPN was observed in the the bilateral anterior central gyrus, central posterior gyrus, superior frontal gyrus and thalamus, with statistical signifcant difference ( P<0.05) and there was no significant difference between the two sides ( P>0.05). Conclusions:DPN patients also have decreased volumes of the brain greymatter, suggesting that the occorrence of DPN patients may be caused by the of injury of central structure.

Cullin-RING E3 ubiquitin ligase (CRL)-4 is a member of the large CRL family in eukaryotes. It plays important roles in a wide range of cellular processes, organismal development, and physiological and pathological conditions. DDB1- and CUL4-associated factor 8 (DCAF8) is a WD40 repeat-containing protein, which serves as a substrate receptor for CRL4. The physiological role of DCAF8 is unknown. In this study, we constructed Dcaf8 knockout mice. Homozygous mice were viable with no noticeable abnormalities. However, the fertility of Dcaf8-deficient male mice was markedly impaired, consistent with the high expression of DCAF8 in adult mouse testis. Sperm movement characteristics, including progressive motility, path velocity, progressive velocity, and track speed, were significantly lower in Dcaf8 knockout mice than in wild-type (WT) mice. However, the total motility was similar between WT and Dcaf8 knockout sperm. More than 40% of spermatids in Dcaf8 knockout mice showed pronounced morphological abnormalities with typical bent head malformation. The acrosome and nucleus of Dcaf8 knockout sperm looked similar to those of WT sperm. In vitro tests showed that the fertilization rate of Dcaf8 knockout mice was significantly reduced. The results demonstrated that DCAF8 plays a critical role in spermatogenesis, and DCAF8 is a key component of CRL4 function in the reproductive system.
Animals ; Cullin Proteins/genetics* ; DNA-Binding Proteins/genetics* ; Factor VIII ; Male ; Mice ; Mice, Knockout ; Spermatogenesis/genetics* ; Ubiquitin-Protein Ligases

Zfyve16 (a.k.a. endofin or endosome-associated FYVE-domain protein), a member of the FYVE-domain protein family, is involved in endosomal trafficking and in TGF-β, BMP, and EGFR signaling. The FYVE protein SARA regulates the TGF-β signaling pathway by recruiting Smad2/3 and accelerating their phosphorylation, thereby altering their susceptibility to TGF-β-mediated T cell suppression. Zfyve16 binds to Smad4 and their binding affects the formation of Smad2/3-Smad4 complex in TGF-β signaling. However, the in vivo function of Zfyve16 remains unknown. In this study, we generated a Zfyve16 knockout mouse strain (Zfyve16) and examined its hematopoietic phenotypes and hematopoietic reconstruction ability. The proportion of Tcells in the peripheral blood of Zfyve16 mice increases compared with that in wild-type mice. This finding is consistent with the role of Zfyve16 in facilitating TGF-β signaling. Unpredictably, B cell proliferation is inhibited in Zfyve16 mice. The proliferation potential of Zfyve16 B-lymphoid cells also significantly decreases in vitro. These results suggest that Zfyve16 inhibits the proliferation of T cells, possibly through the TGF-β signaling, but upregulates the proliferation of B-lymphoid cells.
Animals ; B-Lymphocytes ; metabolism ; CD4-Positive T-Lymphocytes ; metabolism ; Cell Movement ; Cell Proliferation ; genetics ; Intracellular Signaling Peptides and Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Mice ; Mice, Knockout ; Serine Endopeptidases ; genetics ; metabolism ; Signal Transduction ; Smad Proteins, Receptor-Regulated ; metabolism ; Transforming Growth Factor beta ; metabolism ; Up-Regulation

Objective To investigate the consistency of mRECIST criterion and RECIST criterion in evaluating the curative effect of transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) for primary hepatocellular carcinoma (PHC) which condition exceeds Milan liver transplantation standard in order to determine which criterion can evaluate the curative effect better.Methods A total of 78 PHC patients,whose lesion's extent exceeded Milan standard and who had received TACE combined with RFA therapy,were included in this study.The curative effect was separately evaluated by mRECIST criterion and RECIST criterion.KAPPA coefficient was calculated to determine the consistency of the evaluation results by the two criteria.By using Kaplan-Mier method,the median survival time (MST) of patients achieving different remission degree was calculated.Log-rank test was used to draw survival curve.The MST and the survival curve of patients with different remission degree were statistically compared between the two criteria.Results By using SPSS19.0 software,the KAPPA coefficient of the evaluation results of the two criteria was 0.243 (x2=5.250,P＜0.01).The MST of patients,which was calculated by Kaplan-Mier method,had multiple overlapping parts with SD and PR curves that were drawn by log-rank test based on RECIST criterion,the difference between the two was not statistically significant (P＞0.05).When mRECIST criterion was based on,the survival curve of patients with different remission degree was relatively balanced and showed no overlapping parts,the difference between the two was statistically significant (P＜0.01).Conclusion (1) The mRECIST criterion is not suitable for the evaluation of the curative effect of PHC patients whose lesion's extent exceeds Milan standard,and mRECIST criterion can not apply to make evaluation of the curative effect for PHC when the lesion's border is unclear and its enhancement is not obvious.(2) mRECIST criterion can more accurately evaluate the curative effect of TACE combined with PRA in treating PHC which extent exceeds Milan liver transplantation standard.

Objective To investigate the clinical effects of autologous tumor immune cells (DC-CIK)assisted interventional therapy in the treatment of advanced primary liver cancer.Methods Totally 76 patients with advanced primary liver cancer were divided into 2 groups with 38 cases in each group by random number table method.The control group were merely treated with interventional therapy while the ob-servation group were treated with autologous DC-CIK cell assisted interventional therapy.The short-term curative effect,adverse reactions,liver function indexes before and after treatment,alpha fetal protein (AFP)and changes of immune function were compared between the 2 groups. Results There was no statistically significant difference in short-term curative effect and incidence of adverse reactions between the 2 groups (P >0.05).After treatment,the levels of AST,ALT and AFP in the observation group [(30.4 ±6.0)u/L,(45.2 ±3.8)u/L,(168.5 ± 49.3)mg/L]were significantly lower than those in the control group [(65.1 ±6.3)u/L,(61.8 ±5.3)u/L,(315.2 ±39.5)mg/L],and the differences were statistically significant (P <0.05).After treatment,CD3 +,CD4 + and CD4 +/CD8 + in the observation group were significantly higher than those in the control group (P <0.05).Conclusion Autologous DC-CIK cell assisted interventional therapy can sig-nificantly improve the liver function of patients with advanced primary liver cancer,and it can reduce the level of tumor marker AFP and sig-nificantly improve the immune function of patients.

Objective To investigate the expression and significance of β-catenin and p28GANK in residual hepatocellular carcinoma (HCC)cells after transcatheter arterial chemoembolization (TACE).Methods We collected forty-five cases of surgical specimens of hepatocellular carcinoma after TACE ( TACE group ) and thirty cases of surgery without any treatment (pure surgery group).The expression of β-catenin and p28GANK were detected by using immunohistochemical SP method and compared between the two groups .Results The positive expression of β-catenin and p28GANK in TACE group were 77.78%and 75.56%respectively,which were significantly higher than those in pure surgery group (46.67%and 53.33%respectively,P<0.05).In the residual hepatocellular carcinoma cells of TACE group ,the positive expression of β-catenin showed correlation with the positive expression of p28GANK(Φ=0.318,P =0.033).The high expression of β-catenin and p28GANK were closely related to portal vein thrombosis and distant metastasis (P<0.05).Conclusion The ex-pression of β-catenin and p28GANK in the residual hepatocellular carcinoma cells were increased significantly after TACE.The high expression of β-catenin and p28GANK were closely related to portal vein thrombosis and distant metastasis.The high expression of β-catenin and p28GANK may be one of the reasons of hepatocellular carcinoma invasiveness and metastasis .

Primary liver cancer ( PLC) is one of the most invasive malignant tumors in the clinics .The PLC within Milan criteria can be cured by liver transplantation or liver resection .However,PLC exceeding Milan criteria has been a question for us to overcome all the time .In recent years ,transcatheter arterial chemoemboliza-tion( TACE) and its combination therapy for PLC exceeding Milan criteria have made some breakthrough .A great deal of literatures have confirmed that TACE and its combined therapy for PLC exceeding Milan criteria can im -prove the survival rate obviously,it also contains many advantages,such as low cost,safe,painless,minimally in-vasive,repetitive operation and so on .The progress of TACE for PLC exceeding Milan criteria in recent years is summarized in this paper .