Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

OBJECTIVES: To explore the mechanism that mediate the therapeutic effect of quercetin on heart failure. METHODS: We searched the TCMSP and Swiss ADME databases for the therapeutic targets of quercetin and retrieved heart failure targets from the Genecards and OMIM databases. The intersecting targets were analyzed with GO and KEGG pathway analysis using DAVID database, and the key genes were identified via PPI analysis. Molecular docking between the core targets and quercetin was performed using PyMOL and AutoDock Tools. In a heart failure model established in H9C2 cardiomyocytes by treatment with isoproterenol, the effect of quercetin on the expressions of the MAPK signaling pathway was tested. RESULTS: A total of 60 intersecting targets were identified. Enrichment analysis revealed that quercetin may inhibit heart failure through the MAPK signaling pathway. The core genes, including AMPK3 and BCL-2, were identified as potential key regulators in quercetin-mediated improvement of heart failure. Cellular experiments demonstrated that quercetin significantly reduced isoproterenol-induced apoptosis of cardiomyocytes in a dose-dependent manner and obviously decreased the Bax/Bcl-2 ratio and the expression levels of caspase-3, ERK and p38 in the cells. CONCLUSIONS Quercetin improves heart failure possibly by inhibiting cardiomyocyte apoptosis through the MAPK signaling pathway.
Quercetin/pharmacology* ; Myocytes, Cardiac/drug effects* ; Heart Failure/metabolism* ; Apoptosis/drug effects* ; MAP Kinase Signaling System/drug effects* ; Rats ; Animals ; Isoproterenol

Objective To investigate the risk factors for bronchopulmonary dysplasia(BPD)in twin preterm infants with a gestational age of<34 weeks,and to provide a basis for early identification of BPD in twin preterm infants in clinical practice.Methods A retrospective analysis was performed for the twin preterm infants with a gestational age of<34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020.According to their conditions,they were divided into group A(both twins had BPD),group B(only one twin had BPD),and group C(neither twin had BPD).The risk factors for BPD in twin preterm infants were analyzed.Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins.Results A total of 904 pairs of twins with a gestational age of<34 weeks were included in this study.The multivariate logistic regression analysis showed that compared with group C,birth weight discordance of>25%between the twins was an independent risk factor for BPD in one of the twins(OR=3.370,95%CI:1.500-7.568,P<0.05),and high gestational age at birth was a protective factor against BPD(P<0.05).The conditional logistic regression analysis of group B showed that small-for-gestational-age(SGA)birth was an independent risk factor for BPD in individual twins(OR=5.017,95%CI:1.040-24.190,P<0.05).Conclusions The development of BPD in twin preterm infants is associated with gestational age,birth weight discordance between the twins,and SGA birth.

Objective To investigate the expression of magnesiun transporter 1 protein(MagT1)in peripheral blood T lymphocytes of patients with systemic lupus erythematosus(SLE),and elucidate its clinical significance.Methods A total of 79 SLE patients admitted to the People's Hospital of Xishuangbanna Dai Autonomous Prefecture from January 2019 to June 2021 were selected as the study subjects,and SLE patients were divided into moderate to severe group(SLEDAI ≥ 10,n=32)and mild group(SLEDAI＜10,n=47),according to SLE disease activity index(SLEDAI)score.Another 40 healthy patients who underwent physical examinations during the same period were selected as control group.The levels of clinical biochemical and serum immune-related indexes were recorded.The expressions of MagT1 mRNA and protein in peripheral blood T lymphocytes were detected by quantitative real-time PCR(qRT-PCR)and Western Blot methods.The correlation between the expression of MagT1 protein in peripheral blood T lymphocytes and biochemical and immunity-related indexes was analyzed by Pearson correlation analysis.Receiver working characteristic(ROC)curve was drawn to analyze the diagnostic value of MagT1 protein expression of peripheral blood T lymphocytes in diagnosing SLE and its severity.Results Compared with the control group,the expression levels of MagT1 mRNA[0.65(0.36,0.99),0.23(0.07,0.36)vs 1.20(0.83,1.37)]and MagT1 protein[0.35(0.22,0.42),0.22(0.15,0.27)vs 0.53(0.40,0.63)]of peripheral blood T lymphocytes in the mild group and the moderate to severe group were reduced,with significant differences(Z=5.247,7.078;5.128,7.257,all P＜0.05).Compared with the mild group,the expression levels of MagT1 mRNA[0.65(0.36,0.99)vs 0.23(0.07,0.36)]and protein[0.35(0.22,0.42)vs 0.22(0.15,0.27)]of peripheral blood T lymphocytes in the moderate to severe group were reduced,with significant differences(Z=5.169,3.599,all P＜0.05).Pearson correlation results showed that MagT1 protein expression in peripheral blood T lymphocytes was positively correlated with serum hemoglobin(HGB),complement 3(C3)and C4 levels(r=0.496,0.637,0.588,all P＜0.05),but was negatively correlated with serum erythrocyte sedimentation rate(ESR),hypersensitive C-reactive protein(hs-CRP),IgG levels and SLEDAI(r=-0.598,-0.476,-0.646,-0.514,all P＜0.05).The results of the ROC curve showed that the area under the curve in diagnostic SLE for the expression level of peripheral blood T lymphocyte MagT1 protein was 0.893(95％CI:0.838～0.948),with a sensitivity and a specificity of 90.0％and 67.1％,respectively,and the area under the curve in diagnostic SLE severity was 0.739(95％CI:0.631～0.848),with a sensitivity and a specificity of 57.4％and 84.4％,respectively.Conclusion The expressions of peripheral blood T lymphocyte and MagT1 were down regulated in SLE patients,and they had a negative trend with the severity of SLE.They may have a certain diagnostic value for the diagnosis and severity of SLE.

Based on the clinical characteristics of multiple sclerosis （MS） in traditional Chinese medicine （TCM） and western medicine and literature analysis， this paper aims to formulate the diagnostic criteria of TCM and western medicine for MS. Moreover， the modeling methods of experimental autoimmune encephalomyelitis （EAE）， animals for the modeling， and characteristics of the models were analyzed and summarized， and the consistency between the EAE models and the diagnostic criteria of TCM and western medicine was evaluated. The results showed that animal models had low consistency with the clinical characteristics in TCM （highest consistency 68%） and western medicine （highest consistency 60%）. Pathological models account for the majority of animal models for MS research， but there is a lack of intuitive performance indicators. Thus， it is difficult to comprehensively evaluate the models. The mental state， limb numbness， lack of strength， loss of muscle tone， tremor， and balance disorders of the mice are among the diagnostic criteria in western medicine. In TCM diagnostic criteria， the major symptoms which are reflected in animal behavior， such as physical fatigue， lack of strength， mental fatigue， distinclination to talk， and weak heavy numb limbs， are consistent with the western diagnostic criteria. The minor symptoms， including mental decline， bitter taste in mouth， frequent and urgent urination， fecal incontinence， and aggravated fever， are not well reflected in the models. According to TCM， MS is caused by deficiency of kidney essence and external contraction of pathogen， but no index is available for evaluating the external contraction of pathogen in existing animal models. The key to experimental research on MS is to establish an appropriate animal model based on the clinical pathogenesis and characteristics. However， there is a lack of MS animal model with TCM characteristics for syndrome classification. Therefore， renewed efforts should be made to prepare animal models with both TCM and western medicine characteristics that can be used in both basic experiments and clinical research.

In this study, three new germacranolide sesquiterpenes (1-3), together with six related known analogues (4-9) were isolated from the whole plant of Carpesium cernuum. Their structures were established by a combination of extensive NMR spectroscopic analysis, HR-ESIMS data, and ECD calculations. The anti-leukemia activities of all compounds towards three cell lines (HEL, KG-1a, and K562) were evaluated in vitro. Compounds 1-3 exhibited moderate cytotoxicity with IC
Antineoplastic Agents, Phytogenic/pharmacology* ; Asteraceae/chemistry* ; Drug Screening Assays, Antitumor ; Humans ; K562 Cells ; Phytochemicals/pharmacology* ; Sesquiterpenes, Germacrane/pharmacology*

Objective To investigate and make the countermeasures of sexual harassment of female nursing students suffered during clinical clerkship.Methods A self -designed questionnaire was adopted to survey 136 students nurses.Results 65 students nurses suffered from various sexual harassment,which mainly from young male patients,there was no significant difference between various academic qualification nurses (P ＞0.05) ; 50.8% victims ignored but were annoyed for it; 92.3% students nurses were harassed when their teachers were not around.69.2% victims' mode was influenced by sexual harassment.Conclusions The universities and the hospitals should take the situation that nursing students suffer sexual harassment during clinical clerkship into account,and take practicable measures for them to accomplish their clinical clerkship.

OBJECTIVETo study the BRCA1 mutations in patients with early-onset breast cancer and their affected relatives in Guangdong province and explore the relationship between BRCA1 mutation and the expressions of estrogen receptor(ER), progesterone receptor(PR), HER2 and ALN.

METHODSFrom 58 patients with early-onset breast cancer and their affected relatives, the genomic DNA was extracted from the peripheral blood mononuclear cells and the coding regions of the BRCA1 gene was amplified using polymerase chain reaction. BRCA1 gene mutations were screened by denaturing high performance liquid chromatography (DHPLC) and subsequent direct DNA sequencing. The expression of ER, PR, HER2 and ALN were detected with immunohistochemistry and their relations with the gene mutation were analyzed.

RESULTSDisease-related BRCA1 mutations were detected in 2 of the 58 patients, who were younger than 35 years old, including 1 with a novel splice-site mutation (IVS5-1 G-->A). No association was found between this novel mutation and the expressions of ER, PR, HER2 and ALN.

CONCLUSIONThe incidence of BRCA1 mutation is significantly lower in patients with early-onset breast cancer and their affected relatives in Guangdong province than in the Western populations. The novel mutation identified in BRCA1 gene may represent a mutation characteristic of the patients in Guangdong province. BRCA1 gene mutations may not have any relation with the expression of ER, PR, HER2 and ALN.

Adult ; Age of Onset ; Base Sequence ; Breast Neoplasms ; genetics ; China ; DNA Mutational Analysis ; Female ; Genes, BRCA1 ; Genotype ; Humans ; Molecular Sequence Data ; Mutation ; Receptor, ErbB-2 ; genetics ; Receptors, Estrogen ; genetics ; Receptors, Progesterone ; genetics

Objective To analyze the efficacy of electric sacral neuromdulation and resiniferatoxin in patients with female overactive bladder.Methods 32 cases with IOAB female patients accepted percutaneous test sitmulation of the electric sacral nerves at S3 ,and treated by intravesical instillation with 100ml of 100nmol/L RTX.The effica- cy of voiding status were evaluated.The improvement of female patients life were evaluated comparing the rating of depression and anxiety.Results There were significant improvements in 32 cases in variables included the number of voiding,volume voided and signs every day and urgent uresis.In the rating of depression and anxiety,the patients improved a litter and still had stimulating symptom in urethra and bladder.Conclusion The treatment of IOAB with single administratoon of electric sacral neuromdulation and resiniferatoxin is effective,and can successfully im- prove the symptom with little side effects.