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.

Background and objective Pembrolizumab(PEM)has been shown to be effective in clinical trials for the treatment of advanced non-small cell lung cancer(NSCLC),but clinical trials were based on cohorts of patients selected on specific criteria,and whether the findings are consistent with real-world patients is debatable.The aim of this study is to evaluate the efficacy and safety of PEM in the treatment of advanced NSCLC based on real-world data.Methods A retro-spective collection of real-world data from patients with advanced NSCLC receiving PEM was conducted.Propensity score matching was used to eliminate inter-group differences and assess the efficacy and safety of PEM compared to chemotherapy.Results Among 450 matched patients,the incidence rates of any-grade adverse events were 79.87％in the PEM group and86.71％inthe chemotherapy group,while the incidence rates of grade＞3 adverse events were 4.03％and 7.31％,respectively.The objective response rates were 48.63％for PEM and 36.00％for chemotherapy(P=0.011).The median progression-free survival was 15.5 months for PEM and 8.8 months for chemotherapy(P＜0.001),and the median overall survival was not reached for PEM and 26.2 months for chemotherapy(P＜0.001).Conclusion PEM treatment for advanced NSCLC demonstrates favorable survival outcomes and acceptable safety in real-world clinical practice.

Objective To understand and summarize the clinicopathological characteristics and differential diagnosis of lymphoepithelial sialadenitis(LESA)-like thymic hyperplasia.Methods The clinicopathological data of patients with LESA-like thymic hyperplasia diagnosed in our hospital from October 1,2019 to September 1,2023 were collected,and the related literatures on their epidemiological characteristics,clinicopathological features,treatments and prognosis were reviewed.Results There were 2 female patients with LESA-like thymic hyperplasia included,at an onset age of 51 and 52 years,respectively.Imaging examination revealed an anterior mediastinal mass in both patients,with the largest diameter of 7.5 and 12.0 cm,respectively.Microscopic morphology and immunophenotype analysis showed there were florid lymphoid follicles with germinal centers.Reticular or nested thymic epithelial,thymic corpuscles and lymphoepithelial lesions without dysplasia were seen in the interfollicular areas as well.Focal cystic changes,cholesterol crystals and the formation of cholesterol granuloma were observed.Our results were similar to the pathological morphology and immunohistochemical phenotype of 46 cases with LESA-like thymic hyperplasia reported in the literature.They had favorable prognosis,except 5 patients progressed to lymphoma.Conclusion LESA-like thymic hyperplasia is a benign disease with unique morphological characteristics and of favorable prognosis.But rare patients can progress to lymphoma,therefore regular and close follow-up is still required.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

ObjectiveAnalyze the current situation, hotspots and development trends of sarcopenia animal model to provide research direction and basic information for sarcopenia animal model research. MethodsEnglish literature of research on animal models of sarcopenia was retrieved from the Web of Science core data (WOS) set from 1900-01-01 to 2022-12-31. Chinese literature related to animal models of sarcopenia was retrieved from CNKI database between 1915 and 2022. The bibliometric analysis software VOSviewer was used to explore the countries, orgonizations, authors, hotspots and frontier directions in these studies. ResultsA total of 2 819 articles on animal models of sarcopenia were retrieved from WOS core database. The first paper was published in 1995. The United States has the largest number of animal model studies of sarcopenia with 1 105 articles. The institution with the most published articles is the University of Florida in the United States, with 69 articles. The University of Hong Kong has the highest number of publications in China, with 20 articles. American author Van Remmen H, with 50 publications, is the author of the most articles. The journal with the largest number of articles published on animal models of sarcopenia is the American journal called FASEB Journal, with 196 articles. In total, 423 articles on animal models of sarcopenia were retrieved from the CNKI database. Author LI Zhuyi has published 19 articles, and is the author of the most articles in China. The keyword co-occurrence clustering analysis of WOS literature search found that the research focus on animal model of sarcopenia can be summarized as the correlation between sarcopenia and metabolism, cytology and regenerative medicine of sarcopenia animal models, the study of sarcopenia animal models in bone, muscle, nerve and exercise therapy. The retrieval results of CNKI database revealed that the most extensive research was about on the model of denervated sarcopenia, and researches on the effects of Chinese medicine on sarcopenia were also widely reported. Through reading the full articles or abstracts of the literature, the animal models of sacopenia mainly include natural aging model, genetic modification model, high-fat diet induction model, disuse model, hormone induction model and complex sarcopenia models of other diseases. ConclusionIn recent years, the study on animal model of sarcopenia has become a hotspot at home and abroad.The bibliometric analysis provides a basis for the research of animal models of sarcopenia in terms of research direction, hotspots, model animal selection, animal model making, and domestic and international communication and cooperation.

ObjectiveTo establish an ischemia-reperfusion model in cynomolgus macaques and to analyse the effects of edaravone intervention. MethodsA total of fifteen adult male cynomolgus macaques were randomly divided into three groups: sham operation (Sham group, n=3), ischemia-reperfusion model (Model group, n=6) and edaravone treatment (Edaravone group, n=6). Ischemic-reperfusion model of cynomolgus macaques was established by clamping the M1 branch of the left cerebral artery for 1 h. After 2 h of reperfusion, the animals in Edaravone group were injected with 0.5 mg/kg edaravone intravenously for intervention treatment, while the animals in Sham and Model groups were injected with an equal volume of normal saline intravenously, twice a day, from the 2nd to 7th day. The behavioral video recordings, clinical observations and neurological deficit scores of cynomolgus macaques were obtained, and brain edema volume and cerebral ischemia volume were statistically analyzed. ResultsCompared with the Sham group, the animals in Model group showed typical symptoms of ischemic stroke, with a significant increase in the neurological deficit score， the volumes of edema and infarct of brain tissue (all P＜0.01). Compared with Model group, the neurological deficit score, the volumes of edema and infarct of brain tissue were significantly reduced in Edaravone group (all P＜0.05). ConclusionAn animal model of ischemia-reperfusion in cynomolgus macaques was successfully established, and edaravone was confirmed to alleviate the damage caused by ischemia-reperfusion.

Objective:To study the relationship between serum osteopontin and osteopontin and type 2 diabetes mellitus (T2DM) complicated with coronary heart disease, and to evaluate the correlation between the levels of serum osteopontin and osteopontin with the severity of coronary artery lesions in T2DM patients.Methods:A total of 100 T2DM patients who were suspected to have stable coronary heart disease and underwent coronary angiography from November 2019 to December 2020 were selected from the Affiliated Hospital of Chengde Medical College, according to coronary angiography results, 60 patients with confirmed coronary heart disease were classified as the case group and 40 patients with non-coronary heart disease were classified as the control group for retrospective analysis. The clinical data and biochemical indicators of all patients were recorded, and Gensini score was calculated. The concentration of osteopontin and osteopontin in serum was quantitatively determined by double-antibody enzyme linked immunosorbent assay method. Independent sample t-test was used to compare the mean of normal distribution measurement data between the two groups. The non normal distribution data are represented by M ( Q1, Q3), and Mann Whitney U test is used for comparison between groups. Composition comparison between count data groups χ 2 inspection. Spearman correlation analysis was used to analyze the correlation between serum osteopontin and osteopontin and Gensini score in patients with T2DM. Results:Univariate analysis showed that serum osteopontin and osteopontin were (13.076(8.433, 23.552) μg/L) and (0.437(0.300, 0.630) μg/L) significantly higher in the case group than in the control group (6.367(4.605, 9.048) μg/L) and (0.299(0.196, 0.399) μg/L) respectively, with statistically significant differences ( Z=5.12, 3.28, all P<0.001). Multi-factor logistic regression analysis showed that osteoprotegerin ( OR=2.887, 95% CI:1.850-8.515, P=0.024) and osteopontin ( OR=13.109, 95%CI: 2.557-67.204, P=0.002) were associated with T2DM combined with coronary heart disease, and the risk of T2DM combined with coronary heart disease increased with higher levels of osteoprotegerin and osteopontin. Spearman correlation analysis showed that serum osteopontin and osteoprotegerin were positively correlated with Gensini score in T2DM patients ( r=0.591, 0.467; all P<0.05). Conclusion:Serum osteopontin and osteoprotegerin are associated with T2DM combined with coronary heart disease, and high serum osteopontin and osteoprotegerin are risk factors for T2DM combined with coronary heart disease; serum osteopontin and osteoprotegerin are positively correlated with the degree of coronary artery disease in T2DM patients.

Puerarin (Pue), known as a phytoestrogen, has salient bioactivities and is promising against cardiovascular diseases. This article summarizes the underlying molecular mechanisms of Pue in treating cardiovascular diseases, especially regulating the intracellular signal transduction, influencing ion channels, modulating the expression of microRNA, and impacting on the autophagy, which are mainly involved in the inflammatory signaling pathways, fatty acid/lipid metabolism, oxidative stress, apoptosis, and the like. The protective effect of Pue against cardiovascular diseases mainly involves attenuating the myocardial injury and decreasing the myocardial fibrosis, improving the myocardial ischemia/reperfusion injury, as well as inhibiting the myocardial hypertrophy and atherosclerosis. The molecular mechanisms of Pue's cardiovascular protective effects for the first time and comment on the state-of-the-art research methods and principles of Pue's regulation of small molecules were reviewed, so as to provide the rationale for its basic research and clinical applications.

ObjectiveTo explore the intervention effect and mechanism of Buzhong Yiqiwan （BZYQ） on colitis mice. MethodSixty-four C57BL/6 mice were randomly divided into 2 weeks blank group， 2 weeks model group， 2 weeks high-dose BZYQ （12 g·kg^-1） group， 2 weeks low-dose BZYQ （6 g·kg^-1） group， 4 weeks blank group， 4 weeks model group， 4 weeks high-dose BZYQ （12 g·kg^-1） group， and 4 weeks low-dose BZYQ （6 g·kg^-1） group. The colitis model was induced in mice by feeding 3% dextran sodium sulfate （DSS） for 7 days. The mice received BZYQ （12 and 6 g·kg^-1） by gavage on the 8^th day after modeling， once per day， and sacrificed on the 2^nd and 4^th weeks， correspondingly. The colon length and weight of mice in each group were measured. Hematoxylin-eosin （HE） staining was used for pathological observation and colonic mucosal inflammation was scored. The mRNA and protein expression of NOD-like receptor thermoprotein domain 3 （NLRP3）， apoptosis-associated speck-like protein containing a CARD （ASC）， and cysteinyl aspartate-specific protease-1 （Caspase-1） was detected by real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. Enzyme-linked immunosorbent assay （ELISA） was used to detect the content of inflammatory cytokines， such as interleukin （IL）-1β， IL-18， and IL-33 in colonic tissues. ResultCompared with the 2 weeks blank group， the 2 weeks model group showed shortened colon length， increased colon weight （P<0.05）， loss of epithelial cells， destruction of gland structure， infiltration of a large number of inflammatory cells in mucosa and submucosa， local crypt abscess， and increase in mucosal inflammation score （P<0.01） as revealed by light microscopy， elevated levels of IL-1β， IL-18， and IL-33 in colonic tissues （P<0.05）， and increased mRNA and protein expression of NLRP3， ASC， and Caspase-1 （P<0.05）. The intervention of BZYQ （12 g·kg^-1） restored colon length， alleviated mucosal injury （P<0.05）， down-regulated the content of IL-18 （P<0.05）， reduced the mRNA expression of NLRP3 and ASC as well as the protein expression of ASC and Caspase-1 compared with the conditions in the 2 weeks model group. Compared with the 4 weeks blank group， the 4 weeks model group showed decreased colon length， increased colon weight （P<0.05）， decreased glands in the mucosal layer， expansion of glandular cavity， atrophy of crypt， local connective tissue hyperplasia and lymphocyte infiltration， increased inflammation score （P<0.01） as revealed by the light microscopy， increased expression of IL-1β， IL-18， and IL-33 （P<0.05）， and elevated mRNA and expression of NLRP3 inflammasome complex （P<0.05）. Compared with the conditions in the 4 weeks model group， the intervention of BZYQ （12 and 6 g·kg^-1） could improve colon length and weight （P<0.05）， and the intervention of BZYQ （12 g·kg^-1） could also improve the inflammation score of the colon （P<0.05）. Different from the acute stage， the intervention of BZYQ （12 and 6 g·kg^-1） increased the content of IL-33 in the intestinal mucosa and up-regulated the mRNA and protein expression of NLRP3 inflammasome complexes ASC and Caspase-1 （P<0.05）. ConclusionBZYQ can relieve the injury of colitis induced by DSS in mice. The mechanism is related to the regulation of intestinal immune response mediated by NLRP3 inflammasome， and it has different regulatory effects in acute and chronic inflammation stages.

Objective:To investigate and determine the epidemic scope of plague natural foci in Yulong County of Yunnan Province, and to assess its epidemic risk, so as to providing basis for monitoring, prevention and control of plague.Methods:In 2017, 2 - 3 natural villages were selected from 8 villages and towns in Yulong County according to geographical landscape, altitude, population and area. During October and November, small mammal hosts and their parasitic fleas were captured by the night trap (cage) method, Yersinia pestis was isolated from host animal organs, and plague F1 antigen and antibody were detected by colloidal gold test. Plague specific antigen was detected by reverse indirect hemagglutination test (RIHA) in self-dead small mammals. Animal serum from dogs, cats and mice were collected for detection of plague F1 antibody by indirect hemagglutination test (IHA). Results:A total of 1 019 host animals including self-dead small mammals were collected, belonging to 22 species, 12 genera, 6 families, 4 orders. Among them, 1 016 small mammals were captured by tools and 996 were outdoors, with the capture rate of 25.28% (996/3 940). The dominant species of small mammals outdoors were Apodemus chevrieri, Rattus (R.) rattus, Eothenomys miletus and Crocidura attenuate, which accounted for 30.32% (302/996), 22.09% (220/996), 17.37% (173/996) and 12.35% (123/996). The common species were Niviventer confucianus, R.nitidus and R.norvegicus, which accounted for 8.13% (81/996), 4.02% (40/996) and 1.81% (18/996). A total of 20 small mammals of 9 species were captured indoors in the residential area, and the capture rate was 1.11% (20/ 1 800). The dominant species were R.norvegicus, R.nitidus and Mus musculus, which accounted for 30.00% (6/20), 25.00% (5/20) and 10.00% (2/20). Eighteen small mammals of 8 species were infected with 67 parasitic fleas, belonging to 5 species, 5 genera, 3 families. The total flea infection rate was 1.77% (18/1 019) and the total flea index was 0.070. Among them, 49 parasitic fleas from 4 small mammals of 3 species were collected indoors. The flea infection rate was 19.05% (4/21) and the flea index was 2.333. Leptopsylla segnis had the highest flea infection rate of 9.52% (2/21) and flea index of 0.571. Ctenocephalides felis had the highest flea index of 1.571 and flea infection rate of 4.76% (1/21). They were the main flea species on the body surface of small mammals in residential areas. There were 14 small mammals infected with parasitic fleas outdoors, and 18 fleas in 5 species were collected with flea infection rate of 1.40% (14/998) and flea index of 0.018. Among them, Leptopsylla segnis had the highest flea infection rate was 0.50% (5/998) and the flea index was 0.005. The flea infection rate of Neopsylla specialis specialis was 0.40% (4/998), and the flea index was 0.004. Ctenophthalmus quadratus had the highest flea index of 0.007, and the flea infection rate ranked the third with 0.30% (3/998). The flea infection rate and flea index of Frontopsylla spadix spadix were the lowest, which were 0.20% (2/998) and 0.002, respectively. Ctenophthalmus quadratus, Leptopsylla segnis and Neopsylla specialis specialis were the dominant parasitic fleas on the surface of outdoor small mammals. A total of 419 indicator animal sera were collected, including 402 dog sera. One of them was positive by IHA, with a positive rate of 0.25% (1/402). Seventeen serum samples were collected from cats and mice, and IHA test results were negative. Yersinia pestis was isolated and cultured from the organs of small mammals and the detection of Yersinia pestis by colloidal gold test was negative. RIHA test of self-dead small mammals was negative. Conclusion:A plague indicator animal positive spot is newly found in the plague natural foci in Yulong County, and the plague epidemic monitoring, prevention and control in this region should be strengthened.