Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

Objective : To investigate the effect of long non-coding RNA LUCAT1 (lncRNA LUCAT1) on the biological behavior of MIA PaCa-2 in human pancreatic cancer cells , and to explore the potential role of LUCAT1 in the malignant progression of pancreatic cancer. Methods : The mutation and expression of LUCAT1 in pancreatic cancer were analyzed by GEPIA , the expression levels of LUCAT1 in human pancreatic ductal cells HPNE and hu- man pancreatic cancer cells were detected by q-PCR , and the expression and distribution of LUCAT1 in human pancreatic cancer tissues were detected by FISH . CCK-8 assay and Transwell assay were used to detect the effects of LUCAT1 on the proliferation , apoptosis , drug resistance , and migration of MIA PaCa-2 cells . Gene ensemble enrichment analysis was performed to compare the related signaling pathways involved in LUCAT1 , and Western blot assay was used to verify the protein expression level . Results : The results of GEPIA analysis showed that the expression level of LUCAT1 in human pancreatic cancer tissues was up-regulated , and the expression of LUCAT1 in human pancreatic cancer cells was significantly higher ( P < 0. 05 ) . Knockdown and overexpression of LUCAT1 could affect the proliferation , apoptosis , gemcitabine resistance , migration and invasion of pancreatic cancer cells , and the differences were statistically significant (P < 0. 05) . In addition , LUCAT1 affected p-Akt expression levels in pancreatic cancer and was inhibited after treatment with Akt inhibitor MK-2206 . Conclusion LUCAT1 regulates the malignant progression of MIA PaCa-2 in pancreatic cancer cells through the PI3K-Akt signaling pathway.

Multiple myeloma (MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10 (NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing (acRIP-seq) and ribosome profiling sequencing (Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170 (CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover, CEP170 overexpression promoted cellular proliferation and chromosomal instability (CIN) in MM. Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP1 70 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.

At present, the exact pathogenesis of dental fluorosis is not clear, and there is no exact standard of enamel acid etching in the adhesive restoration of dental fluorosis. Atomic force microscope represents a great progress in high-resolution imaging of biomaterials, and its advantage is that it can provide three-dimensional images and quantitative data of observed samples at the nanometer level. In recent years, the application of atomic force microscope in enamel study has made some progress. Whether the quantitative analysis of enamel ultrastructure can become a new way to study the pathogenesis of dental fluorosis and find the best repair method is worthy of further exploration. This paper reviews the application of atomic force microscope in the study of enamel with dental fluorosis.

Objective:To understand the survival status and related influencing factors of HIV-infected children aged ≤14 years old, in China.Methods:HIV-infected children were selected from the China’s HIV/AIDS Comprehensive Response Information Management System (CRIMS). A retrospective cohort study was conducted to investigate the situation of survival on infected children. Cox proportional hazard regression model was used to screen the factors affecting the survival time.Results:This study involved 8 029 cases of infected children, with a median survival time of 179.75 months. The cumulative survival probabilities at 1 year, 2 years, 5 years, and 10 years after the diagnosis, were 99.13 %, 97.95 %, 90.11 % and 78.63 %, respectively. Results from the multivariate Cox proportional hazard regression analysis showed that children who did not receive antiviral therapy were 12.81 times more likely to die than the ones who received the antiretroviral therapy (95 %CI: 11.40-14.27). Male HIV-infected children were 1.20 (95 %CI: 1.10-1.32) times more likely to die than the female HIV-infected children. The risk of death among HIV positive children at the age of 3 to 5 years was 0.67 (95 %CI: 0.60-0.76) times of those children who were diagnosed at the age of 2 years old or younger. The risk of death among children infected with HIV in Northwest was 0.52 (95 %CI: 0.29-0.95) times higher than the ones from the Northeast areas of China. The risk of death among children who received antiviral treatment (ART) in the residential areas was 1.96 (95 %CI: 1.48-2.61) times than those children who did not. The risk of death from children who did not receive health care services was 2.07 times of those children who did (95 %CI: 1.88-2.29). Conclusions:The median survival time of HIV-infected children aged ≤14 years old was 179.75 months, in China. Our findings revealed that initiation of antiviral therapy, female, age, place of receiving ART (out of the residential areas), living in Northwest China, care services and being diagnosed at older age etc. were protective factors influencing the survival time of infected children.

OBJECTIVETo research the central molecular mechanism of gastric motility in functional dyspepsia (FD) rats treated with electroacupuncture (EA) at and points of stomach.

METHODSA total of 30 SD rats were randomized into a blank group, a model group, a Zhongwan+Weishu group, a Weishu group and a Zhongwan group, 6 rats in each group. FD rats were established by moderate clipping tail infuriation and irregular feeding except in the blank group. EA was used at "Zhongwan"(CV 12),"Weishu"(BL 21), and"Zhongwan"(CV 12) +"Weishu"(BL 21) in the corresponding groups for 7 days, once a day, and 20 min a time. No intervention was used in the blank and model groups. Grabbing and fixation were applied in the model group. Gastric antrum motion range and frequency were recorded by gastrointestinal pressure transducer. The expression of subunit NR1 of N-methyl-D-aspartate recepter (NMDAR) in dorsal motor nucleus of the vagus (DMV) was determined by Western blotting. The content of serum nitric oxide (NO) was measured by ELISA.

RESULTSCompared with the blank group, the gastric antrum motion range and NR1 in the DMV decreased and the serum NO content increased in the model group (all <0.05). Compared with the model group, the gastric antrum motion range and NR1 in the DMV increased and the serum NO content decreased in the three EA groups (all <0.05). Compared with the Zhongwan and Weishu groups, the gastric antrum motion range and NR1 in the DMV increased in the Zhongwan + Weishu group (all <0.05). Compared with Zhongwan + Weishu and Zhongwan groups, the expression of NO in the Weishu group decreased (both <0.05). The gastric antrum motion frequency among the 5 groups had no statistical significance (all >0.05).

CONCLUSIONEA at the and points can regulate the gastric motility in FD rats which may be by modulating the activity of NMDAR in the central DMV region, thus regulating the serum NO content.

Acupuncture Points ; Animals ; Dyspepsia ; therapy ; Electroacupuncture ; Gastrointestinal Motility ; N-Methylaspartate ; metabolism ; Nitric Oxide ; blood ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Stomach ; Vagus Nerve ; metabolism

Objective To understand the prevalence rate and related factors of chronic kidney disease (CKD) among elderly people aged more than 65 years old in the 66th regiment of the fourth division of A Crops in Xinjiang .Methods A total of 2 030 elderly people aged more than 65 years old in the 66th regiment of the fourth division of XPCC were distributed in 6 communities . Totally 334 permanent residents aged more than 65 years old were chosen from 2 communities by the stratified random sampling method .The renal injury indicators and related factors were detected .Results Among 329 residents with intact data ,after the age correction ,the prevalence rate of albuminuria ,hematuria and renal function decrease were 22 .2% ,14 .2% ,4 .9% ,respectively .The prevalence rate of CKD in this group was 32 .8% ,CKD stage 1―3 were dominated .The awareness rate was 15 .1% .The multiva‐riate Logistic regression analysis showed that gender and hypertension were independently associated with CKD .Conclusion The prevalence rate of CKD among elderly people aged over 65 years old in the 66th regiment of the fourth division of this Crops is high‐er .The related factors are gender and hypertension .

Background: Serum immunoglobulin A antibodies against Epstein–Barr virus (EBV), viral capsid antigen (VCA?IgA) and early antigen (EA?IgA), are used to screen for nasopharyngeal carcinoma (NPC) in endemic areas. However, their routine use has been questioned because of a lack of specificity. This study aimed to determine the distributions of different subtypes of antibody and to illustrate how the natural variation patterns affect the specificity of screening in non?NPC participants. Methods: The distribution of baseline VCA?IgA was analyzed between sexes and across 10?year age groups in 18,286 non?NPC participants using Chi square tests. Fluctuations in the VCA?IgA level were assessed in 1056 non?NPC participants with at least two retests in the first 5?year period (1987–1992) after the initial screening using the Kaplan–Meier method. Results: The titers of VCA?IgA increased with age (P < 0.001). Using a previous serological definition of high NPC risk, nasopharyngeal endoscopy and/or nasopharyngeal biopsy would be recommended in 55.5% of the non?NPC partici?pants with an initial VCA?IgA?positive status and in 20.6% with an initial negative status during the 5?year follow?up. However, seroconversions were common; 85.2% of the participants with a VCA?IgA?positive status at baseline con?verted to negative, and all VCA?IgA?negative participants changed to positive at least once during the 5?year follow?up. The EA?IgA status had a high seroconversion probability (100%) from positive to negative; however, it had a low probability (19.6%) from negative to positive. Conclusions: Age? and sex?specific cutoff titer values for serum anti?EBV antibodies as well as their specific titer fluc?tuation patterns should be considered when defining high NPC risk criteria for follow?up diagnostics and monitoring.

Retinoid X receptor α (RXRα) and its N-terminally truncated version tRXRα play important roles in tumorigenesis, while some RXRα ligands possess potent anti-cancer activities by targeting and modulating the tumorigenic effects of RXRα and tRXRα. Here we describe NSC-640358 (N-6), a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRα and inhibits the transactivation of RXRα homodimer and RXRα/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRα, essential for 9-cis-retinoic acid binding and activating RXRα transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra π-π stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRα-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor α (TNFα)-induced AKT activation and stimulates TNFα-mediated apoptosis in cancer cells in an RXRα/tRXRα dependent manner. The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRα to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRα ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFα-mediated cancer cell apoptosis by targeting RXRα/tRXRα.
Apoptosis ; drug effects ; Cell Line, Tumor ; Enzyme Activation ; drug effects ; Humans ; Ligands ; Molecular Docking Simulation ; Nuclear Receptor Subfamily 4, Group A, Member 1 ; genetics ; metabolism ; Oximes ; metabolism ; pharmacology ; Protein Conformation ; Proto-Oncogene Proteins c-akt ; metabolism ; Pyrazoles ; metabolism ; pharmacology ; Retinoid X Receptor alpha ; chemistry ; genetics ; metabolism ; Thiazoles ; metabolism ; pharmacology ; Transcription, Genetic ; drug effects ; Transcriptional Activation ; drug effects ; Tumor Necrosis Factor-alpha ; metabolism