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.

Objective:This study aimed to construct a risk prediction model for obstructive sleep apnea（OSA） related hypertension based on the nomogram, and to explore the independent risk factors for OSA-related hypertension, so as to provide reference for clinical treatment decision-making. Methods:The clinical data of OSA patients diagnosed by polysomnography from October 2019 to December 2021 were collected retrospectively and randomly divided into training sets and validation sets. A total of 1 493 OSA patients with 27 variables were included. The least absolute shrinkage and selection operator（Lasso） logistic regression model was used to select potentially relevant features and establish a nomogram for OSA-related hypertension.The performance and clinical benefits of this nomogram were verified in terms of discrimination, calibration ability and clinical net benefit. Results:Multivariate logistic regression showed that body mass index（BMI）, family history of hypertension, lowest oxygen saturation（LSaO2）, age and cumulative percentage of total sleep time with oxygen saturation below 90% were independent risk factors for OSA-related hypertension. Lasso logistic regression identified BMI, family history of hypertension, LSaO2 and age as predictive factors for inclusion in the nomogram. The nomogram provided a favorable discrimination, with a C-indexes of 0.835（95% confidence interval[CI ]0.806-0.863） 0.865（95%CI 0.829-0.900） for the training and validation cohort, respectively, and well calibrated. The clinical decision curve analysis displayed that the nomogram was clinically useful. Conclusion:Compared with cumulative percentage of total sleep time with blood oxygen saturation below 90%, LSaO2 may have a greater impact on the incidence of OSA-related hypertension, and the effects of different times and degrees of hypoxia on OSA-related hypertension should be further explored in the future. Apnea hypopnea index involvement is weak in predicting OSA-related hypertension, and the blood oxygen index may be a better predictor variable. Furthermore, we established a risk prediction model for OSA-related hypertension patients using nomogram, and demonstrated that this prediction model was helpful to identify high-risk OSA-related hypertension patients. This model can provide early and individualized diagnosis and treatment plans, protect patients from the serious.
Humans ; Sleep Apnea, Obstructive/complications* ; Nomograms ; Hypertension/epidemiology* ; Male ; Female ; Risk Factors ; Middle Aged ; Retrospective Studies ; Polysomnography ; Logistic Models ; Body Mass Index ; Adult

Objective To elucidate the regulatory effects of Glycerol Kinase(GLPK)on the inflammatory response induced by lipopolysaccharide(LPS)in mouse Raw264.7 macrophages.Methods Raw264.7 macrophages were cultured in vitro,and an inflammatory model was established through LPS induction.The transcriptional levels of inflammatory cytokines NF-κB,TNF-α,IL-6,and IL-1β were quantified using RT-qPCR.The expression and localization of GLPK were examined via Western blot and immunofluorescence.Additionally,Western blot analysis was employed to detect the levels of cellular pan-succinylation and H3K23su expression.ChIP-qPCR was utilized to assess the enrichment of H3K23su modification at the IL-10 promoter.The total reactive oxygen species production was measured using DCFH-DA probes,while mitochondrial ROS levels were determined with Mito-SOX probes.Mitochondrial membrane potential changes,indicative of mitochondrial dysfunction,were evaluated using JC-1 fluorescent probes.Furthermore,GLPK overexpression plasmids were transfected into cells to investigate the effects of GLPK on inflammatory responses,mitochondrial function,and epigenetic modifications.Results LPS treatment led to mitochondrial dysfunction,inflammatory responses exacerbation,succinylation modifications reduction,and GLPK protein expression decrease in Raw264.7 cells.Overexpression of GLPK in LPS-treated cells improved mitochondrial function and reduced the transcription of pro-inflammatory cytokines.ChIP-qPCR analysis revealed that GLPK overexpression could reverse the LPS-induced suppression of H3K23su modification at the IL-10 promoter,thereby attenuating the inflammatory response.Conclusion LPS mediates inflammatory responses in Raw264.7 macrophages through a GLPK-dependent H3K23 succinylation modification mechanism.

Objective To elucidate the regulatory effects of Glycerol Kinase(GLPK)on the inflammatory response induced by lipopolysaccharide(LPS)in mouse Raw264.7 macrophages.Methods Raw264.7 macrophages were cultured in vitro,and an inflammatory model was established through LPS induction.The transcriptional levels of inflammatory cytokines NF-κB,TNF-α,IL-6,and IL-1β were quantified using RT-qPCR.The expression and localization of GLPK were examined via Western blot and immunofluorescence.Additionally,Western blot analysis was employed to detect the levels of cellular pan-succinylation and H3K23su expression.ChIP-qPCR was utilized to assess the enrichment of H3K23su modification at the IL-10 promoter.The total reactive oxygen species production was measured using DCFH-DA probes,while mitochondrial ROS levels were determined with Mito-SOX probes.Mitochondrial membrane potential changes,indicative of mitochondrial dysfunction,were evaluated using JC-1 fluorescent probes.Furthermore,GLPK overexpression plasmids were transfected into cells to investigate the effects of GLPK on inflammatory responses,mitochondrial function,and epigenetic modifications.Results LPS treatment led to mitochondrial dysfunction,inflammatory responses exacerbation,succinylation modifications reduction,and GLPK protein expression decrease in Raw264.7 cells.Overexpression of GLPK in LPS-treated cells improved mitochondrial function and reduced the transcription of pro-inflammatory cytokines.ChIP-qPCR analysis revealed that GLPK overexpression could reverse the LPS-induced suppression of H3K23su modification at the IL-10 promoter,thereby attenuating the inflammatory response.Conclusion LPS mediates inflammatory responses in Raw264.7 macrophages through a GLPK-dependent H3K23 succinylation modification mechanism.

ObjectiveTo investigate the status of self-efficacy, quality of care and quality of life of people with physical disabilities, and analyze the relationship among them. MethodsFrom January, 2019 to December, 2020, 357 people with physical disabilities in Shandong were selected with cluster stratified random sampling, and all the participants were investigated with a general questionnaire, World Health Organization Quality of Life-Disability Scales, General Self-Efficacy Scale and World Health Organization Quality of Care and Support Scale-Disability Scale on internet. ResultsA total of 357 questionnaires were collected, in which 350 were valid. The total score was (115.00±20.70) for quality of life, (23.33±5.78) for self-efficacy, and (50.43±10.56) for quality of care. The quality of life and its each domain was positively correlated with self-efficacy (r > 0.282, P < 0.01), quality of care, care information acquisition, care giving and care environment (r > 0.369, P < 0.01). Employment, self-efficacy and quality of care associated with the quality of life (t > 4.386, P < 0.001); employment, self-efficacy, care giving and care environment associated with the physiological, psychological and environment domains of the quality of life (t > 2.926, P < 0.01); parents as main caregivers, employment, self-efficacy, care giving and care environment associated with social relationships domain of the quality of life (|t| > 2.525, P < 0.05); parents as main caregivers, employment, care giving and care environment associated with the disability domain of the quality of life (|t| > 2.209, P < 0.05). ConclusionThe quality of life needs to be improved for the people with physical disabilities. Self-efficacy and quality of care may impact the quality of life; and it is needed to focus on the people with physical disabilities who are unemployed and whose parents are the main caregivers.

Objective To study the regulatory effect of herba epimedii(HE)combined with fructus ligustri lucidi(FLL)on auto-phagy,apoptosis and proliferation activity of airway smooth muscle cells(ASMCs)induced by rapamycin(RAP).Methods Primary ASMCs of rats were cultured and randomly divided into five groups:normal group,RAP group,HE group,FLL group and compatible group.Normal rat serum or medicated rat serum was added separately according to the group.Except for normal group,all other groups were simultaneously added with RAP-induced ASMCs,which were examined after 48h.Transmission electron microscope was used to observe cell microstructure;MTT assay was used to detect cell viability;immunocytochemistry was used to detect protein expression of proliferation protein ki-67 to evaluate the proliferation activity of cells;Annexin V-FITC/P1 assay was used to detect the apoptosis ac-tivity of cells;Western blot and cell immunofluorescence were used to detect the protein expressions of LC3,Beclin-1,mTOR,p-mTOR,Bax,Bcl-2,caspase-3 and p53.Results The compatibility of HE and FLL significantly inhibited RAP-induced autophagy in ASMCs,and down-regulated LC3-Ⅱ/Ⅰ protein ratio(P＜0.05)and Beclin-1 protein expression(P＜0.01),alleviated the re-duction of cell viability and proliferation activity(all P＜0.01),and depressed apoptosis activity(P＜0.01).The above effects of com-patibility of HE and FLL were better than those of HE and FLL alone(P＜0.05,P＜0.01).In addition,the compatible group could up-regulate the expression of caspase-3 protein(P＜0.05)and down-regulate the expression of p53 protein(P＜0.01);However,there was no significant effect on the mTOR,p-mTOR,Bax and Bcl-2 protein.Conclusion The compatibility of HE and FLL could suppress the excessive autophagy/apoptosis level of RAP-induced ASMCs,restore the cell viability and proliferation activity of ASMCs,and avoid excessive damage of ASMCs.

BACKGROUND: Metastasis is the main cause of tumor-associated death and mainly responsible for treatment failure of breast cancer. Autophagy accelerates tumor metastasis. In our work, we aimed to investigate the possibility of microRNAs (miRNAs) which participate in the regulation of autophagy to inhibit tumor metastasis. METHODS: MiRNA array and comprehensive analysis were performed to identify miRNAs which participated in the regulation of autophagy to inhibit tumor metastasis. The expression levels of miR-3653 in breast cancer tissues and cells were detected by quantitative real-time polymerase chain reaction. In vivo and in vitro assays were conducted to determine the function of miR-3653. The target genes of miR-3653 were detected by a dual luciferase reporter activity assay and Western blot. The relationship between miR-3653 and epithelial-mesenchymal transition (EMT) was assessed by Western blot. Student's t -test was used to analyze the difference between any two groups, and the difference among multiple groups was analyzed with one-way analysis of variance and a Bonferroni post hoc test. RESULTS: miR-3653 was downregulated in breast cancer cells with high metastatic ability, and high expression of miR-3653 blocked autophagic flux in breast cancer cells. Clinically, low expression of miR-3653 in breast cancer tissues (0.054 ± 0.013 vs . 0.131 ± 0.028, t  = 2.475, P  = 0.014) was positively correlated with lymph node metastasis (0.015 ± 0.004 vs . 0.078 ± 0.020, t  = 2.319, P  = 0.023) and poor prognosis ( P  < 0.001). miR-3653 ameliorated the malignant phenotypes of breast cancer cells, including proliferation, migration (MDA-MB-231: 0.353 ± 0.013 vs . 1.000 ± 0.038, t  = 16.290, P  < 0.001; MDA-MB-468: 0.200 ± 0.014 vs . 1.000 ± 0.043, t  = 17.530, P  < 0.001), invasion (MDA-MB-231: 0.723 ± 0.056 vs . 1.000 ± 0.035, t  = 4.223, P  = 0.013; MDA-MB-468: 0.222 ± 0.016 vs . 1.000 ± 0.019, t  = 31.050, P  < 0.001), and colony formation (MDA-MB-231: 0.472 ± 0.022 vs . 1.000 ± 0.022, t  = 16.620, P  < 0.001; MDA-MB-468: 0.650 ± 0.040 vs . 1.000 ± 0.098, t  = 3.297, P  = 0.030). The autophagy-associated genes autophagy-related gene 12 ( ATG12 ) and activating molecule in beclin 1-regulated autophagy protein 1 ( AMBRA1 ) are target genes of miR-3653. Further studies showed that miR-3653 inhibited EMT by targeting ATG12 and AMBRA1 . CONCLUSIONS Our findings suggested that miR-3653 inhibits the autophagy process by targeting ATG12 and AMBRA1 , thereby inhibiting EMT, and provided a new idea and target for the metastasis of breast cancer.
Cell Line, Tumor ; Epithelial-Mesenchymal Transition/genetics* ; MicroRNAs/metabolism* ; Autophagy/genetics* ; Genes, Regulator ; Gene Expression Regulation, Neoplastic/genetics* ; Cell Proliferation/genetics* ; Cell Movement/genetics* ; Neoplasms/genetics*

Objective To investigate the expressions and clinical significanees of suppressors of cytokine signaling-1 (SOCS-1) and SOCS-3 in myocardium of patients with sudden cardiac death (SCD). Method This study included myocardial autopsy specimens of 24 patients admitted between 2005 and 2006. Of them, 9 cases had the findings of autopsy examination consistent with coronary atberosclerosis (non-myocardial infarction) leading to SCD (non-MI group), 7 patients died of acute myocardial infarction (MI group) and 8 patients died of traffic accidents and trauma The expressions of SOCS-1 mRNA and SOCS-3 mRNA in the myocardium of non-MI and con-trol group were detected by using RT-PCR. The levels of SOCS-1 protein and SOCS-3 protein were detected by us-ing immunohistochemistry. Statistical analysis were performed by using SPSS version 13.0 software and the data were processed with ANOVA test. Results The expressions of SOCS-1 mRNA and SOCS-3 mRNA in non-MI and MI groups were were significantly higher than those in control group (0. 788±0. 101) and (0. 741±0.111) vs.(0.436±0.044) (P <0.01); (0.841±0.092) and (0.776±0.070) vs.(0.454±0.076), P <0.01, re-spectively). The antibody-positive cells of SOCS-1 protein in myocardium of non-MI group and MI group were significantly higher than those in myoeardium of control group (320.00±48.48) and (347.14±70.88) vs.(42.50±10.35) (P < 0.01), respectively. The antibody-positive cells of SOCS-3 protein in myoeardium of non-MI group and MI group were significantly higher than those in myocardium of control group (381.11±59.25) vs.(40.00±10.69), (P < 0.01)and (332.86±111.91) vs. (40.00±10.69), (P =0.001). Conclusions The expressions of SOCS rnRNA and SOCS-3 mRNA in myoeardium of patients with SCD from coronary diseases are significantly increased contributing to the pathogenesis of SCD.

OBJECTIVETo identify valid measures for preventing outbreaks of severe acute respiratory syndrome (SARS) among protected healthcare workers in isolation units.

METHODSArchitectural factors, admitted SARS cases and infection of healthcare workers in different isolation wards between January 30 and March 30, 2003 were analyzed.

RESULTSFour types of isolation wards were analyzed, including the ward where the thirty-first bed was located on the twelfth floor, the laminar flow ward in the Intensive Care Unit where the tenth bed was located on the fifteenth floor, the ward where the twenty-seventh bed was located on the thirteenth floor of the Lingnan Building, and thirty wards on the fourteenth to eighteenth floors of the Zhongshan Building. The ratios (m(2)/m(3)) of the area of the ventilation windows to the volume of the rooms were 0, 0, 1:95 and 1:40, respectively. Numbers of SARS cases in the wards mentioned above were 1, 1, 1 and 96, respectively. Total times of hospitalization were 43, 168, 110 and 1272 hours, respectively. The infection rates of the healthcare workers in the areas mentioned above were 73.2%, 32.1%, 27.5% and 1.7%, respectively. The difference in the infection rates was of statistical significance.

CONCLUSIONSIsolating SARS cases in wards with good ventilation could reduce the viral load of the ward and might be the key to preventing outbreaks of SARS among healthcare workers along with strict personal protection measures in isolation units.

Adult ; Disease Outbreaks ; prevention & control ; Facility Design and Construction ; Female ; Hospital Units ; Humans ; Infectious Disease Transmission, Patient-to-Professional ; prevention & control ; Male ; Middle Aged ; Patient Isolation ; Severe Acute Respiratory Syndrome ; prevention & control ; Ventilation