BACKGROUND: Enzalutamide, a second-generation androgen receptor (AR) pathway inhibitor, is widely used in the treatment of castration-resistant prostate cancer. However, after a period of enzalutamide treatment, patients inevitably develop drug resistance. In this study, we characterized leucine-rich repeated G-protein-coupled receptor 5 (LGR5) and explored its potential therapeutic value in prostate cancer. METHODS: A total of 142 pairs of tumor and adjacent formalin-fixed paraf-fin-embedded tissue samples from patients with prostate cancer were collected from the Pathology Department at Sun Yat-sen Memorial Hos-pital. LGR5 was screened by sequencing data of enzalutamide-resistant cell lines combined with sequencing data of lesions with different Gleason scores from the same patients. The biological function of LGR5 and its effect on enzalutamide resistance were investigated in vitro and in vivo . Glutathione-S-transferase (GST) pull-down, coimmunoprecipitation, Western blotting, and immunofluorescence assays were used to explore the specific binding mechanism of LGR5 and related pathway changes. RESULTS: LGR5 was significantly upregulated in prostate cancer and negatively correlated with poor patient prognosis. Overexpression of LGR5 promoted the malignant progression of prostate cancer and reduced sensitivity to enzalutamide in vitro and in vivo . LGR5 promoted the phosphorylation of glycogen synthase kinase-3β (GSK-3β) by binding heat shock protein 90,000 alpha B1 (HSP90AB1) and mediated the activation of the Wingless/integrated (WNT)/β-catenin signaling pathway. The increased β-catenin in the cytoplasm entered the nucleus and bound to the nuclear AR, promoting the transcription level of AR, which led to the enhanced tolerance of prostate cancer to enzalutamide. Reducing HSP90AB1 binding to LGR5 significantly enhanced sensitivity to enzalutamide. CONCLUSIONS LGR5 directly binds to HSP90AB1 and mediates GSK-3β phosphorylation, promoting AR expression by regulating the WNT/β-catenin signaling pathway, thereby conferring resistance to enzalutamide treatment in prostate cancer.
Male ; Humans ; Phenylthiohydantoin/pharmacology* ; Benzamides ; Receptors, G-Protein-Coupled/genetics* ; Nitriles ; Cell Line, Tumor ; HSP90 Heat-Shock Proteins/metabolism* ; Drug Resistance, Neoplasm/genetics* ; Prostatic Neoplasms/drug therapy* ; beta Catenin/metabolism* ; Receptors, Androgen/genetics* ; Animals ; Mice ; Wnt Signaling Pathway/physiology*

Objective:To analyze the correlation between frailty and health literacy in elderly patients with chronic cardiac insufficiency.Methods:The convenience sampling method was used to select 290 elderly patients with chronic cardiac insufficiency who were hospitalized in the Department of Geriatrics and Department of Cardiovascular Medicine of a tertiary first-class hospital in Wuhu City from Mar 2022 to Jun 2022.The patients were investigated with the general information questionnaire,FRAIL scale,Health Literacy Management Scale,etc.Spearman analysis was used to analyze the correlation between frailty and health literacy.Binary logistic regression were used to analyze the risk factors of frailty in elderly patients with chronic cardiac insufficiency.Results:The incidence of frailty in elderly patients with chronic cardiac insufficiency was 22.8% .Spearman analysis showed that the total score of health literacy was negatively correlated with frailty(r=-0.291,P= 0.000).Results of binary logistic regression analysis showed that health literacy score(OR=0.419,95% CI:0.266-0.908),long-term insomnia(OR=6.466,95% CI:2.099-19.914),nutritional risk(OR=11.202,95% CI:3.983-31.508),depression risk(OR=10.014,95% CI:1.963-51.075),chronic disease types≥5(OR=12.784,95% CI:3.811-42.878),exercise self-efficacy(OR=0.512,95% CI:0.304-0.956),and chronic disease information acquisition ability(OR=0.512,95% CI:0.304-0.956)were independent predictors of frailty in elderly patients with chronic cardiac insufficiency(P＜0.05).Conclusions:The incidence of frailty in elderly patients with chronic cardiac insufficiency is high,and clinical staff should pay more attention to the elderly with frailty,especially patients with long-term insomnia,risk of nutrition and depression,coexistence of chronic diseases,low level of health literacy and exercise self-efficacy.Targeted measures should be actively taken to improve the quality of life of patients and reduce the readmission rate.

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demon-strated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel anti-angiogenic therapy for endometriosis.

Objective:To evaluate the safety and efficacy of percutaneous transhepatic papillary balloon dilation (PTPBD) combined with flexible ureteroscopy-guided dual-frequency double-pulse ND:YAG (FREDDY) laser lithotripsy (PTPBD-FREDDY) for the treatment of giant (>1.5 cm diameter) common bile duct stones.Methods:A retrospective analysis was conducted on 26 patients with large-diameter difficult choledocholithiasis admitted to two medical centers from December 2017 to October 2021. Among these patients, four could not tolerate surgery or endoscopic treatment, six experienced failure of endoscopic treatment, and 16 refused to undergo endoscopic or surgical treatment. All patients underwent the PTPBD-FREDDY procedure. The FREDDY laser lithotripsy was performed under ureteroscopic guidance, followed by a balloon to push the stones into the duodenum. The primary endpoint was the technical success rate, and the secondary endpoints included the rate of stone recurrence and related complications.Results:All 26 patients successfully completed the operation, achieving a technical success rate of 100%. The average lithotripsy frequency and operation time for bilirubin stones were significantly higher than those of mixed stones and cholesterol stones ( P<0.01). The main postoperative complications included mild fever ( n=3), abdominal pain ( n=3), nausea ( n=2) and vomiting ( n=1). One patient experienced biliary tract bleeding, which improved after conservative treatment. No serious complications such as pancreatitis, sepsis, or biliary perforation were observed. After 2 years of follow-up, no cases of stone recurrence were observed. Conclusions:PTPBD-FREDDY is a safe and effective treatment for patients with giant common bile duct stones. It provides a new therapeutic option for patients with giant choledocholithiasis who can not tolerate surgery or have failed endoscopic treatment, demonstrating promising prospects.

Objective To explore the importance of head fixation in chest wall field combined with supraclavicular field radiotherapy for breast cancer by comparing the displacement error and dosimetric differences caused by multi-functional body board and breast bracket.Methods Thirty patients with breast cancer were randomly divided into groups A and B.In group A,patients were fixed with multi-functional body board and head thermoplastic film.In group B,patients were fixed with traditional breast brackets.Each patient received CBCT scan before and after radiotherapy.Both setup errors and intra-fractional displacements in the x-,y-and z-axis,V100 and V95 were calculated.Statistical analyses were performed using the independent sample t-test.Results The displacement errors in groups A and B before and after radiotherapy were (1.24± 0.42),(1.71± 0.61) and (2.25± 1.04) mm vs.(3.67± 2.05),(3.78± 1.74),(4.65±2.66) mm in the x-,y-and z-axis,respectively (P=0.033,0.027,0.020).The intra-fractional displacements in groups A and B were (1.10±0.66),(1.13±0.59),(1.11 ±0.62) mm vs.(2.48±0.88),(2.21 ±0.98),(3.53±2.01) mm in the x-,y-and z-axis,respectively (P=0.030,0.021,0.013).The V100 in groups A and B were (94.27± 3.20) ％ and (99.08± 0.60) ％ (P =0.065),and (89.48± 4.70) ％ and (96.53± 2.50) ％ for V95 (P =0.002),respectively.Conclusion The risk of displacement error is significantly reduced using multi-functional body board,which enhances the accuracy of radiation dose in chest wall and supraclavicular fields of breast cancer patients.

BACKGROUND: Tumor recurrence and drug resistance are the main causes of death in tumor patients. The family of acetaldehyde dehydrogenase (ALDH) is closely related to the proliferation, migration, invasion and resistance of tumor cells, and different ALDH subtypes are expressed in different tumor cells. The aim of this study is to elucidate the ALDH subtype in human lung adenocarcinoma HCC-827/GR cells, which resistant to the gefitinib. METHODS: The human lung adenocarcinoma HCC-827 cells were used to generate the gefitinib-resistant HCC-827/GR cells; the expression of ALDH subtype in either HCC-827 or HCC-827/GR was detected by flow cytometry; The proliferative capacity and sensitivity to gefitinib of hcc-827/GR cells were analyzed by MTT assay before and after treatment with 100 μmol/L diethyllaminaldehyde (DEAB); Real-time quantitative PCR was used to detect the expression of ALDH subtypes at mRNA levels in hcc-827 cells and hcc-827/GR cells. RESULTS: Compared with HCC-827 cells, the positive rate of ALDH in HCC-827/GR cells increased. The proliferation ability of HCC-827/GR cells decreased after treatment with 100 μmol/L DEAB. Compared with HCC-827 cells, the expression of ALDH1A1 and ALDH1L1 mRNA was increased in hcc-827/GR cells, but the ALDH3B2 expression was decreased. CONCLUSIONS ALDH might be used as a molecular biomarker to test the gefitinib-resistant to lung adenocarcinoma cancer cells, and the ALDH1A1 may play a role in gefitinib resistance in lung cancer.
Adenocarcinoma ; pathology ; Adenocarcinoma of Lung ; Aldehyde Oxidoreductases ; antagonists & inhibitors ; genetics ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; genetics ; Enzyme Inhibitors ; pharmacology ; Gefitinib ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Lung Neoplasms ; pathology ; Quinazolines ; pharmacology

Objective:To discuss the diagnostic value of miR-26a/b and relationship of this microRNA with clinicopathological features in patients with gastric cancer. Methods:The expression of serum miR-26a/b was detected in 121 patients with gastric cancer and 116 healthy controls using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The relationship of miR-26a/b and clinicopathological parameters of patients were analyzed. The receiver operating curve (ROC) was constructed to in vestigate the value of miR-26a/b in the diagnosis of gastric cancer. Results:The relative expression levels of serum miR-26a and miR-26b in patients with gastric cancer were lower than those in the control group (1.60±1.02 vs. 5.35±0.44;1.44±0.71 vs. 5.35±0.71;P<0.05). The relative expression level of miR-26a/b correlated with TNM stage, and the relative expression level of miR-26a also correlated with invasion depth and lymph node metastasis (P<0.05), but not with sex, age, tumor size, or histological type (P>0.05). The area under the ROC curve of miR-26a was 0.828 (95％CI:0.776～0.881), with sensitivity of 73.3％and specificity of 81.0％, while the area under the ROC curve of miR-26b was 0.853 (95％CI:0. 801～0.906), with sensitivity of 68.1％and specificity of 99.2％. Conclusion:The expression of miR-26a/b significantly reduced in patients with gastric cancer, and its expression level correlated with the clinical stage, invasion depth, and lymph node metastasis. MiR-26a/b has potential diagnostic value for gastric cancer.

Objective:To investigate the role and mechanism of miR-143 in the proliferation and migration of gastric cancer (GC) cells. Methods:Western blot was performed to detect the expression level of avian erythroblastosis oncogene B-3 (ERBB3) in GC tissues, paired non-cancerous tissues, and SGC7901 GC cells. RT-qPCR was conducted to determine the mRNA and miR-143 of ERBB3 quantita-tively. Bioinformatics tools were used to predict the target gene of miR-143. Luciferase reporter assay was carried out to confirm the predicted target gene. Transwell and EdU assays were applied to observe the migration and proliferation of SGC7901 GC cells transfect-ed with miR-143 mimics/inhibitor/NC mimics/inhibitor. Results:Compared with the expression levels of ERBB3 and miR-143 in the paired non-cancerous tissues, the expression level of ERBB3 was upregulated and the expression level of miR-143 was downregulated in GC tissues. In the prediction of the potential target gene, miR-143 could bind to a specific sequence of the 3′-untranslated regions (UTR) of the mRNA of ERBB3. This finding was supported by luciferase reporter assay results. In vitro, ERBB3 protein expression and cell migration and proliferation were suppressed significantly in the SGC7901 cells transfected with miR-143 mimics. By contrast, these processes were remarkably enhanced when the cells were transfected with miR-143 inhibitor. Conclusion:miR-143 can suppress the migration and proliferation of GC cells by downregulating the expression of ERBB3.

Objective: Heart failure (HF) patients are usually associated with liver function impairment, Child-Turcotte-Pugh (CTP) scores can evaluate liver function, but its effect in HF patients has been unclear. We want to study the application of CTP scores in predicting the risk of death for in-hospital HF patients. Methods: A total of 1180 consecutive in-hospital HF patients were enrolled. According to CTP scores evaluated liver function at admission, the patients were divided into 3 groups: CTP grade A group, n=951, CTP grade B group, n=206 and CTP grade C group, n=23. The endpoint of this study was all-cause death. Results: There were 180 patients died at 1 year follow-up period, the in-hospital and 1 year mortalities were increased with the elevated CTP grades accordingly: for in-hospital mortalities in CTP grade A, B and C groups were (0.8%, 11.7% and 56.5%) respectively, P< 0.001; for 1 year mortalities were (9.6%, 34.5% and 78.3%) respectively, P< 0.001. Multivariable Cox regression analyses indicated that the higher CTP grades, the higher risk of in-hospital and 1 year mortalities in HF patients. The area under curve for CTP scores in predicting the in-hospital and 1 year mortalities were 0.88 and 0.74 respectively. Kaplan-Meier survival analysis presented that the patients with improved CTP scores from grade B or C to grade A at discharge had the higher 1 year survival rate than those without improvement, P=0.028.
Conclusion: CTP scores may independently predict the risk of death for in-hospital HF patients, the levels of CTP scores might be used for evaluating the efficacy of in-hospital treatment.