Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway in TP53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC. Our findings suggest that targeting the JAK2-STAT3-UCHL3-ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.

Background::Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) can profoundly affect the mental health of the people living with HIV (PLWH), with higher rates of anxiety, depression, and sleep disturbances. The disparities in neuropsychological problems evaluated by physicians and self-assessed by patients are still unknown.Methods::A total of 5000 PLWH and 500 physicians from 167 hospitals were enrolled in this cross-sectional study from September 2022 to February 2023. 4-Item Patient Health Questionnaire (PHQ-4) was used for the evaluation of depressive issues and anxiety issues by PLWH. Each physician assessed 10 PLWH under their care for the presence of depressive or anxiety issues. The primary outcomes of this study are the concordance rates on the depressive issues and anxiety issues evaluation between physicians and PLWH. The Cohen’s kappa test was used to assess the agreement between physicians and PLWH.Results::The concordance rate for the evaluation of depressive issues is 73.84% (95% confidence interval [CI]: 72.60-75.04%), and it is significantly different from the expected rate of 80% ( P <0.001). Similarly, the concordance rate for the evaluation of anxiety issues is 71.74% (95% CI: 70.47-72.97%), which is significantly different from the expected rate of 80% as per the null hypothesis ( P <0.001). The overestimation rate by physicians on depressive issues is 12.20% (95% CI: 11.32-13.14%), and for anxiety issues is 12.76% (95% CI: 11.86-13.71%). The mismatch rate for depressive issues is 26.16% (95% CI: 24.96-27.40%), and for anxiety issues is 28.26% (95% CI: 27.02-29.53%). The underestimation rate by physicians on depressive issues is 13.96% (95% CI: 13.03-14.95%), and for anxiety issues is 15.50% (95% CI: 14.52-16.53%). For the treatment regiments, PLWH sustained on innovative treatment regimen (IR) related to a lower prevalence of depressive issues (odds ratio [OR] = 0.71, 95% CI: 0.59-0.87, P = 0.003) and a lower prevalence of anxiety issues (OR = 0.63, 95% CI: 0.52-0.76, P <0.001). PLWH switch from conventional treatment regimen (CR) to IR also related to a lower prevalence of depressive issues (OR = 0.79, 95% CI: 0.64-0.98) and a lower prevalence of anxiety issues (OR = 0.81, 95% CI: 0.67-0.99). Conclusion::Nearly one in three PLWH had their condition misjudged by their physicians. The findings underscore the need for improved communication and standardized assessment protocols in the care of PLWH, especially during the acute phase of HIV infection.

[摘 要] 目的：体内外实验探讨木鳖子单体化合物对羟基桂皮醛[Momordica cochinchinensis(Lour.)Spreng.p-hydroxycinnamaldehyde，CMSP]对小鼠黑色素瘤移植瘤生长和转移的影响及其作用机制。方法：建立荷瘤小鼠动物模型，并将18只C57BL/6小鼠随机分成3组（每组6只）：对照组（腹腔注射0.1 ml生理盐水）、CMSP治疗组（分别腹腔注射0.1 ml 1、2 mg/ml CMSP），给药的第5天开始，每次给药前用卡尺分别测量和计算小鼠移植瘤的体积，实验结束后称量移植瘤的质量；H-E染色后光镜观察肝组织的病理学变化；免疫组织化学SP法观察移植瘤组织E-cadherin和vimentin蛋白的表达。采用细胞划痕和Transwell实验分别检测CMSP实验组（10、20 µg/ml）黑色素瘤B16细胞24、48 h的迁移能力，qPCR法检测CMSP处理24 h后B16细胞EMT相关mRNA表达，WB法检测CMSP处理B16细胞48 h后β-catenin、p-β-catenin（Ser675）、vimentin和E-cadherin蛋白的表达水平。结果：CMSP治疗组小鼠移植瘤平均体积和肿瘤质量明显降低（均P<0.05）；对照组小鼠肝脏中转移灶的数量明显多于CMSP（1、2 mg/kg）治疗组（均P<0.05），CMSP（2 mg/kg）处理组小鼠的肝组织内未发现明显转移灶。CMSP治疗组（1、2 mg/kg）移植瘤组织中E-cadherin蛋白表达水平明显高于对照组（均P<0.05），而vimentin蛋白表达显著低于对照组（均P<0.01）。体外实验中，CMSP实验组（10、20 μg/ml）B16细胞24、48 h后划痕愈合率较对照组均明显降低（均P<0.05）。20 μg/ml CMSP处理B16细胞24、48 h后穿过Transwell小室的细胞数较对照组则显著下降（均P<0.01）。CMSP（10、20 μg/ml）处理B16细胞后β-catenin mRNA表达水平较对照组明显降低（均P<0.01），E-cadherin mRNA表达水平则明显升高（均P<0.05），而vimentin mRNA表达水平在10 μg/ml处理组与对照组相比差异无统计学意义（P>0.05），20 μg/ml处理组则明显降低（P<0.01）。与对照组相比，CMSP实验组（10、20 μg/ml）处理B16细胞后β-catenin、p-β-catenin和vimentin蛋白表达均显著降低（均P<0.01），而E-cadherin蛋白表达则明显升高（均P<0.01）。结论：CMSP能够抑制小鼠黑色素瘤移植瘤的生长和转移，其作用机制可能与抑制wnt/β-catenin通路的活性相关。

OBJECTIVE:To investigate the effects of leukotriene receptor antagonist montelukast on inflammatory factor,air-way anatomy and lung function of children with cough variant asthma. METHODS:A total of 86 children with cough variant asth-ma selected from our hospital during Apr. 2010 to Aug. 2015 were divided into control group and observation group according to random number table,with 43 cases in each group. Control group was given Budesonide aerosol 0.4 mg,bid;observation group was given Montelukast sodium chewable tablets with different dose according to age(4 mg for 2-6 year-old,tid;5 mg for 7-12 year-old,tid).A treatment course of 2 groups lasted for 4 weeks,and both groups received 2 courses of treatment. The levels of inflammatory factor,airway anatomy and lung function indexes were detected in 2 groups before and after treatment,and the oc-currence of ADR was also observed. RESULTS:Before treatment,there was no statistical significance in above indexes between 2 groups(P>0.05). Compared to before treatment,the levels of IL-4,IL-6,IL-8,TNF-α and hs-CRP in 2 groups were de-creased significantly after treatment;airway wall thickness,basement membrane thickness,airway wall thickness/outside diameter ratio,total area of airway wall,total area of airway wall/total area of airway were decreased significantly,while FVC,FEV1, FEV1/FVC,PEF were increased significantly;the indexes in observation group were significantly better than control group,with statistical significance(P<0.05). There was no statistical significance in the incidence of ADR between 2 groups(P>0.05). CONCLUSIONS:For pediatric cough variant asthma,montelukast can significantly improve inflammatory reaction,airway status and lung function with good safety.

Objective To clarify the relationship between tumor necrosis factor alpha (TNF-α) and leptin in nonalcoholic fatty liver disease.Methods The real-time quantitative PCR (q-PCR) and enzymelinked immunosorbent adsorption experiment(ELISA) were used to detect the expression and correlation of TNFα and leptin in blood cells and serum from the normal group, non-alcoholic simple fatty liver(NAFL) group, nonalcoholic steatohepatitis (NASH) group and cirrhosis group.Results At the level of mRNA, the transcription of TNF-α in cirrhosis group was 14.03 times, 12.07 times and 11.05 times of the normal group, NAFL group and NASH group,and the difference was significant(P＜0.05).Leptin transcription of cirrhosis group was 1.95 times,0.79 times and 1.45 times of normal group, NAFL group and of NASH group(P＞0.05).And in the cirrhosis group, the expression of TNF-α was 7.52 times higher than Leptin (P＜ 0.01).In expression level of protein,TNF-α and leptin in cirrhosis group was 1.98 times and 2.39 times higher than the normal group, 1.24 times and 1.30 times higher than the NAFL group, 1.27 times and 1.37 times higher than NASH, and the difference was significant(P＜0.05).Moreover the expression of TNF-α was significantly higher than that of Leptinin groups above(P＜0.01).Conclusion TNF-α and Leptin are less expression in lymphocytes, but more expression in serum.And TNF-α and Leptin affect the evolution of NAFLD, and present a positive correlation, which lead to the occurrence of NAFLD.Comparing the two methods, detection of serum is more sensitive and more suitable for clinical study than lymphocyte.

OBJECTIVETo analyze the implement performance of China Infectious Diseases Automated-alert and Response System (CIDARS) of 31 provinces in mainland China, and to provide the evidences for further promoting the application and improvement of this system.

METHODSThe amount of signals, response situation and verification outcome of signals related to 32 infectious diseases of 31 provinces in mainland China in CIDARS were investigated from 2011 to 2013, the changes by year on the proportion of responded signals and timeliness of signal response were descriptively analyzed.

RESULTSA total of 960 831 signals were generated nationwide on 32 kinds of infectious diseases in the system, with 98.87% signals (949 936) being responded, and the median (the 25(th) percentile to the 75(th) percentile (P25-P75) ) of time to response was 1.0 (0.4-3.3) h. Among all the signals, 242 355 signals were generated by the fixed-value detection method, the proportion of responded signals was 96.37% (62 349/64 703), 98.75% (68 413/69 282) and 99.37% (107 690/108 370), respectively, and the median (P25-P75) of time to response was 1.3 (0.3-9.7), 0.8(0.2-4.9) and 0.7 (0.2-4.2) h, respectively. After the preliminary data verification, field investigation and laboratory test by local public health staffs, 100 232 cases (41.36%) were finally confirmed.In addition, 718 476 signals were generated by the temporal aberration detection methods, and the average amount of signal per county per week throughout the country were 1.53, and 8 155 signals (1.14%) were verified as suspected outbreaks. During these 3 years, the proportion of signal response was 98.89% (231 149/233 746), 98.90% (254 182/257 015) and 99.31% (226 153/227 715), respectively, and the median (P25-P75) of time to response was 1.1 (0.5-3.3), 1.0 (0.5-2.9) and 1.0 (0.5-2.6) h, respectively.

CONCLUSIONFrom 2011 to 2013, the proportion of responded signals and response timeliness of CIDARS maintained a rather high level, and further presented an increasing trend year by year. But the proportion of signals related to suspected outbreaks should be improved.

China ; Communicable Diseases ; Disease Notification ; Disease Outbreaks ; prevention & control ; Humans ; Population Surveillance ; methods

Timely reporting, effective analyses and rapid distribution of surveillance data can assist in detecting the aberration of disease occurrence and further facilitate a timely response. In China, a new nationwide web-based automated system for outbreak detection and rapid response was developed in 2008. The China Infectious Disease Automated-alert and Response System (CIDARS) was developed by the Chinese Center for Disease Control and Prevention based on the surveillance data from the existing electronic National Notifiable Infectious Diseases Reporting Information System (NIDRIS) started in 2004. NIDRIS greatly improved the timeliness and completeness of data reporting with real time reporting information via the Internet. CIDARS further facilitates the data analysis, aberration detection, signal dissemination, signal response and information communication needed by public health departments across the country. In CIDARS, three aberration detection methods are used to detect the unusual occurrence of 28 notifiable infectious diseases at the county level and to transmit that information either in real-time or on a daily basis. The Internet, computers and mobile phones are used to accomplish rapid signal generation and dissemination, timely reporting and reviewing of the signal response results. CIDARS has been used nationwide since 2008; all Centers for Disease Control and Prevention (CDC) in China at the county, prefecture, provincial and national levels are involved in the system. It assists with early outbreak detection at the local level and prompts reporting of unusual disease occurrences or potential outbreaks to CDCs throughout the country.