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 explore the displacement and pressure distribution of American Chiropractic in a model of third lumbar syndrome based on finite element analysis. METHODS: On March 2021, CT and MRI images of a 23-year-old male patient with right third lumbar syndrome were selected. A 3D stl model was established using Mimics and CATIA, and the data was imported into Hypermesh, Abaqus & ANSYS. The elastic modulus and Poisson's ratio of the affected side material were adjusted to establish its finite element model. Based on the comparison of the operating positions and routines of the American Chiropractic and the lumbar spine oblique pull method, but with differences in the focus and direction of force, the experimental group simulated the American Chiropractic with the healthy side (left side) lying position of the model. The upper endplate of L₃ and the lower part below L₃ twisted accordingly with the body position, we applied a vertical forward thrust of 246 N to the plane formed by the L₄, L₅ spinous processes and L₄ upper articular processes;The control group simulates the oblique pull method of the lumbar spine, requiring the model to lie on the healthy side (left side), fix the upper endplate of L₄, and perform a horizontal rotation along the longitudinal axis of L₃ vertebral body. At this time, the contact force in the upward direction is also set to 246 N. Compare the displacement and stress differences between the L₁-L₅ intervertebral bodies, intervertebral discs, articular processes, and transverse process muscles in two intervention models. RESULTS: ① Under safe load conditions, a test force of 246 N was applied to the model, and the maximum vertebral displacement occurred on the right side of the L₃ vertebral body (1.197 mm) after manual intervention in the control group. The vertebral displacement between L₁-L₅ induced by manual intervention in the experimental group was smaller than that of the control group's manual intervention (P<0.05). ② The maximum vertebral body stress occurred on the right side of the L₃ vertebral body after manual intervention in the control group (98.425 MPa). The stress on each vertebral body formed by the experimental group's manual intervention was lower than that of the control group's manual intervention (P<0.05). ③The maximum intervertebral disc stress occurred on the right side of the L_2,3 intervertebral disc (6.282 MPa) after manual intervention in the control group. ④ The maximum joint process stress occurred on the right side of the L₄ upper joint process after manual intervention in the experimental group (1.587 MPa). The joint process stress on the left side below L₁ and the left side above and below L₂ induced by manual intervention in the experimental group was lower than that of the control group (P<0.05). ⑤The maximum stress on the intertransverse process muscle was observed at the right lateral L₃ process end (31.960 MPa) of L_3,4 in the control group after manual intervention. The stress on the L_2,3 and L_4,5 segments of the intertransverse process muscle induced by manual intervention in the experimental group was lower than that of the control group's manual intervention (P<0.05). CONCLUSION The mechanical feedback of the L₁-L₅ vertebral body, the lower left side of the articular process L₁, the upper and lower left side of the articular process L₂, and the L_2,3 and L_4,5 segments of the transverse process muscle in the model indicates that performing American Chiropractic for the treatment of third lumbar transverse process syndrome can accurately hit the target pain point and allow the patient's tissue to form a low stress and low tension state after manual operation, thereby reducing the possibility of tissue damage caused by hypertonia after intervertebral joint movement, making it relatively safe. The application of American Chiropractic will be a new supplement to the traditional treatment plan for third lumbar transverse process syndrome.
Humans ; Finite Element Analysis ; Male ; Lumbar Vertebrae/physiopathology* ; Biomechanical Phenomena ; Young Adult ; Manipulation, Chiropractic ; Adult ; Tomography, X-Ray Computed ; Magnetic Resonance Imaging

[Objective] To analyze the correlation of serum creatinine (Cr), hemoglobin (HGB) and body mass index (BMI) with osteoporosis in middle-aged and elderly Tibetan residents in Xizang and its predictive value for osteoporosis. [Methods] Between November 2021 and August 2023, using multistage random cluster sampling method information on demographics, we collected blood indices and bone mineral density from 564 middle-aged and elderly Tibetan residents in Ali (Pulan, Zada, Ritu, and Rezhe counties), Nagchu (Nagchu, Nyima, Amdo, Shuanghu, and Bango counties), Shannan (Lunzi county), and Lhasa (Nimu county), Tibetan regions. They were divided into osteoporosis group (90 cases) and non-osteoporosis group (474 cases) according to whether they suffered from osteoporosis or not. Pearson correlation method was used to analyze the correlation between bone mineral density (BMD) and each variable. Binary Logistic regression was used to analyze the related influencing factors of osteoporosis in middle-aged and elderly Tibetan residents, and the regression equation model of predicting the risk factors of osteoporosis was constructed. The fitting degree of the model was tested by Hosmer-Lemeshow test model. Receiver operating characteristic (ROC) curve was used to evaluate the predictive efficacy of serum Cr, HGB and BMI combined tests on osteoporosis in middle-aged and elderly Tibetan residents in Xizang. [Results] The prevalence of osteoporosis was higher in females than in males. Among the osteoporosis group, height and weight, alanine aminotransferase, glutamine aminotransferase, urea nitrogen, uric acid, total cholesterol, triglyceride, low-density lipoprotein cholesterol, homocysteine, serum Cr, HGB and BMI were significantly lower (P<0.05). Correlation analysis showed that age was negatively correlated with BMD, while body weight, serum Cr, HGB and BMI were positively correlated with BMD (P<0.05). Multivariate binary Logistic results showed that age (OR=1.085), serum Cr (OR=0.891), BMI (OR=0.475), and HGB (OR=0.966) were the influencing factors for the occurrence of osteoporosis (P<0.05). To establish a prediction model for the risk of osteoporosis, Logit(P)=6.265+ 0.086×age + (-0.109×Cr)+ (-0.020×HGB)+ (-0.213×BMI). The area under the ROC curve was 0.932, the sensitivity was 88.9%, and the specificity was 82.5%. Hosmer-Lemeshow test model had a good fit (P=0.960). According to Logit(P) model, L score=-29.413+ (-0.404×age)+ 0.512×Cr+ 0.094×HGB+ BMI could be calculated. When L score >8.9, the patient could be diagnosed with the disease. [Conclusion] The decrease in serum Cr, HGB and BMI is a risk factor for osteoporosis in Tibetan aged residents. Age was negatively correlated with BMD, while serum Cr, HGB and BMI were positively correlated with BMD. The combined model of age, serum Cr, HGB and BMI can significantly improve the diagnostic efficiency of osteoporosis in the elderly Tibetans in Xizang.

Objective To investigate the risk factors for pediatric acute perforation appendicitis,and to construct a nomogram predictive model and conduct the verification.Methods A total of 426 children patients with appendectomy in this hospital from June 30,2020 to June 30,2022 were selected as the study subjects 340 children with acute appendicitis admitted to the hospital from 30 June 2020 to 28 February 2022 were the training set and 86 children patients with appendicitis hospitalized in this hospital from March 1,2022 to June 30,2022 conducted the external validation(verification set).The univariate and multivariate logistic regression models were employed to analyze the independent risk factors of pediatric acute perforation appendicitis.The nomograms predictive model was constructed.The receiver operating characteristic(ROC)curve and calibra-tion curve were used to evaluate the predictive efficiency of the model.The decision curve analysis(DCA)was used to evaluate the application value of the model.Results Of the 426 children,198 were perforated and 228 were not perforated.The univariate and multivariate logistic regression analyses revealed that elevated C-reac-tive protein(CRP),presence of stercorolith in appendiceal cavity,time of onset to visiting hospital ≥2 d and body temperature ≥37.3 ℃ were the independent risk factors for pediatric acute perforation appendicitis(P＜0.05).The Hosmer-Lemeshow test demonstrated that the nomogram predictive model had good fitting(P=0.869),and the area under the curve(AUC)for the training and validation sets were 0.808 and 0.860 respectively,showing the good predictive ability of the model.The calibration curve closely approach the ideal diagonal.The model showed good discrimination,consistency and accuracy.The DC A revealed that the curve was far away from oblique and horizontal lines,and the model had good clinical practicability.Conclusion The constructed nomogram model of pediatric acute perforation appendicitis has good predictive ability and may help clinic to identify as early as possible.

Objective To describe the current state of research and future research hotspots through a metrological analysis of the literature in the field of forensic anthropological remains identification re-search.Methods The data retrieved and extracted from the Web of Science Core Collection (WoSCC),the core database of the Web of Science information service platform (hereinafter referred to as "WoS"),was used to analyze the trends and topic changes in research on forensic identification of human re-mains from 1991 to 2022.Network visualisation of publication trends,countries (regions),institutions,authors and topics related to the identification of remains in forensic anthropology was analysed using python 3.9.2 and Gephi 0.10.Results A total of 873 papers written in English in the field of forensic anthropological remains identification research were obtained.The journal with the largest number of publications was Forensic Science International (164 articles).The country (region) with the largest number of published papers was China (90 articles).Katholieke Univ Leuven (Netherlands,21 articles) was the institution with the largest number of publications.Topic analysis revealed that the focus of forensic anthropological remains identification research was sex estimation and age estimation,and the most commonly studied remains were teeth.Conclusion The volume of publications in the field of forensic anthropological remains identification research has a distinct phasing.However,the scope of both international and domestic collaborations remains limited.Traditionally,human remains identifica-tion has primarily relied on key areas such as the pelvis,skull,and teeth.Looking ahead,future re-search will likely focus on the more accurate and efficient identification of multiple skeletal remains through the use of machine learning and deep learning techniques.

Objective:To investigate the application value of transanal intersphincteric resec-tion under direct vision in the Jackknife position in the anal preserving surgery for ultra-low rectal cancer.Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 15 patients with ultra-low rectal cancer who underwent transanal intersphincteric resection under direct vision in the Jackknife position, combined with laparoscopic total mesorectal excision in Huizhou Municipal Central Hospital from September 2021 to November 2022 were collected. There were 9 males and 6 females, aged (63±9)years. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers. Results:(1) Surgical and postoperative outcomes. All the 15 patients underwent operations successfully, without conversion to open abdo-minal operation. There were 5 cases of partial ISR and 10 cases of subtotal ISR. The operation time and volume of intraoperative blood loss of 15 patients were (260±30)minutes and 20(range, 10-30)mL, respectively. The distance from anastomosis to anal margin was (1.6±0.8)cm. The duration of post-operative hospital stay was 10(range, 8-13)days, and all 15 patients underwent colonic and anasto-mosis with staplers and protective ileostomy at the terminal ileum. Three patients had postoperative complications within 30 days after surgery, of whom 1 case with grade A anastomotic leakage was cured after conservative treatment and 2 cases with anastomotic membranous stenosis were cured by anal enlargement. (2) Postoperative pathological examination. The number of lymph nodes dissected of 15 patients was 18 ±6, and the distance between the tumor and distal resection margin was 1.3(range, 1.0-2.0)cm. The surgical specimens of all 15 patients showed complete mesorectum and negative for proximal, distal and circumferential margins. Results of postoperative pathological examination showed that there was 1 case in stage pT1N0M0, 9 cases in stage pT2N0M0, 1 case in stage pT2N1M0, 1 case in stage ypT0N0M0, 2 cases in stage ypT2N0M0, 1 case in ypT3N1M0 stage. The histological subtype showed 11 cases of moderately differentiated adenocarcinoma and 4 cases of well-differentiated adenocarcinoma. (3) Follow-up. All 15 patients were followed up for 15(range, 12-24)months. No local recurrence and distant metastasis of the tumor was found, and no tumor-related death occurred. All 15 patients underwent stoma closure. The postoperative anal function assessment of 15 patients showed no disorder in 5 cases, mild disorder in 8 cases and severe disorder in 2 cases.Conclusion:Transanal intersphincteric resection under direct vision in the Jackknife position in the anal preserving surgery for ultra-low rectal cancer is safe and feasible.

ObjectivesTo understand the prevalence of hyperhomocysteinemia （HHcy） in the Tibetan population in Northwest Xizang， and its association with lipids and blood uric acid， and to explore the prevention and treatment strategies for chronic diseases such as HHcy in Northwest Xizang. MethodsIn this survey， questionnaires， physical examinations， and biochemical tests were conducted on 3432 Tibetan residents aged 18 years and older who had resided in Northwest Xizang （Ngari Prefecture， Nagqu City） for more than 6 months using a multistage stratified whole cluster random sampling method. ResultsThe prevalence of HHcy among Tibetan residents in Northwest Xizang was 75.7%， much higher than that of the average population in China （37.2%）. Blood uric acid、high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were risk factors for HHcy. ConclusionThe prevalence of HHcy is higher in the Tibetan population in northwest Xizang. Therefore， the local governments should urge people to establish a healthy lifestyle and enhance early intervention for HHcy by improving diet and lifestyle， thereby reducing the risk of cardiovascular， cerebrovascular and other related diseases.

OBJECTIVE: To investigate whether electroacupuncture (EA) at sensitized acupoints could reduce sympathetic-sensory coupling (SSC) and neurogenic inflammatory response by interfering with 5-hydroxytryptamine (5-HT)ergic neural pathways to relieve colitis and somatic referred pain, and explore the underlying mechanisms. METHODS: Rats were treated with 5% dextran sodium sulfate (DSS) solution for 7 days to establish a colitis model. Twelve rats were randomly divided into the control and model groups according to a random number table (n=6). According to the "Research on Rat Acupoint Atlas", sensitized acupoints and non-sensitized acupoints were determined. Rats were randomly divided into the control, model, Zusanli-EA (ST 36), Dachangshu-EA (BL 25), and Xinshu (BL 15) groups (n=6), as well as the control, model, EA, and EA + GR113808 (a 5-HT inhibitor) groups (n=6). The rats in the control group received no treatment. Acupuncture was administered on 2 days after modeling using the stimulation pavameters: 1 mA, 2 Hz, for 30 min, with sparse and dense waves, for 14 consecutive days. GR113808 was injected into the tail vein at 5 mg/kg before EA for 10 min for 7 consecutive days. Mechanical sensitivity was assessed with von Frey filaments. Body weight and disease activity index (DAI) scores of rats were determined. Hematoxylin and eosin staining was performed to observe colon histopathology. SSC was analyzed by immunofluorescence staining. Immunohistochemical staining was performed to detect 5-HT and substance P (SP) expressions. The calcitonin gene-related peptide (CGRP) in skin tissue and tyrosine hydroxylase (TH) protein levels in DRG were detected by Western blot. The levels of hyaluronic acid (HA), bradykinin (BK), prostaglandin I2 (PGI2) in skin tissue, 5-HT, tryptophan hydroxylase 1 (TPH1), serotonin transporters (SERT), 5-HT 3 receptor (5-HT3R), and 5-HT 4 receptor (5-HT4R) in colon tissue were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: BL 25 and ST 36 acupoints were determined as sensitized acupoints, and BL 15 acupoint was used as a non-sensitized acupoint. EA at sensitized acupoints improved the DAI score, increased mechanical withdrawal thresholds, and alleviated colonic pathological damage of rats. EA at sensitized acupoints reduced SSC structures and decreased TH and CGRP expression levels (P<0.05). Furthermore, EA at sensitized acupoints reduced BK, PGI2, 5-HT, 5-HT3R and TPH1 levels, and increased HA, 5-HT4R and SERT levels in colitis rats (P<0.05). GR113808 treatment diminished the protective effect of EA at sensitized acupoints in colitis rats (P<0.05). CONCLUSION EA at sensitized acupoints alleviated DSS-induced somatic referred pain in colitis rats by interfering with 5-HTergic neural pathway, and reducing SSC inflammatory response.
Rats ; Animals ; Electroacupuncture ; Rats, Sprague-Dawley ; Serotonin ; Acupuncture Points ; Pain, Referred ; Calcitonin Gene-Related Peptide ; Signal Transduction ; Colitis/therapy* ; Indoles ; Sulfonamides

Objective To develop an LC-MS/MS method for the simutaneous determination of glycyrrhizin(GLY)and its main active metabolite glycyrrhetinic acid(GA)in human plasma.Methods Sample preparation was done by protein precipitation with methanol.Chromatographic separation was achieved by a Synergi TM 4 pm Fusion-RP 80A(2.0 mm × 50 mm,4 μm)column with a gradient mobile phase consisting of acetonitrile(containing 0.1％formic acid)-water(containing 0.1％formic acid),at a flow rate of 0.6 mL·min-1.GLY and GA were monitored using negative electrospray triple quadrupole mass spectrometer via multiple reaction monitoring(MRM)mode.The specificity,calibration curve and range,accuracy and precision,recovery,matrix effect,dilution integrity and stability were validated.Results The validated method had an excellent linearity in the range of 0.30-80.00 ng·mL-1 and 1.80-480.00 ng·mL-1 for GLY and GA,with the limits of quantification were 0.30 and 1.80 ng·mL-1.Recovery efficiencies were in the range of 98.14％-109.10％and 97.25％-100.87％for GLY and GA.No significant matrix effects were found for the two analytes.Intra-day and inter-day precisions of four quality control concentrations were less than 10.72％.Intra-day and inter-day accuracies were determined to be 95.38％-109.34％with all accuracy measurements.Conclusion The validated method was rapid,sensitive,selective and accurate for the quantification of GLY and its active metabolite GA,successfully used to the pharmacokinetics study of GLY and its active metabolite in human.

Objective To investigate the effect of varying blood pressure stratification on renal function in the diabetic population.Methods A prospective cohort study was conducted,enrolling 9 489 diabetic patients from a total of 101 510 Kailuan Group employees who underwent health examinations between July 2006 and October 2007.The follow-up period was(8.6±4.0)years.Participants were categorized into four groups based on their baseline blood pressure levels:normal blood pressure(systolic blood pressure<120 mmHg and diastolic blood pressure<80 mmHg),elevated blood pressure(systolic blood pressure 120-130 mmHg and diastolic blood pressure<80 mmHg),stage 1 hypertension(systolic blood pressure 130-140 mmHg and/or diastolic blood pressure 80-90 mmHg),and stage 2 hypertension(systolic blood pressure≥140 mmHg and/or diastolic blood pressure≥90 mmHg).The incidence density of chronic kidney disease(CKD)was compared among these groups.A multivariate Cox proportional hazards regression model was employed to assess the effects of different blood pressure levels on renal function in diabetic patients,with the stability of the results confirmed using a multivariate time-dependent Cox proportional hazards model.Sensitivity analysis was conducted after excluding cases of cardiovascular disease(CVD)during follow-up,and cases using antihypertensive and antidiabetic medications at baseline.Results(1)At baseline,stage 1 hypertension patients demonstrated statistically significant higher differences with age and body mass index(BMI)compared to normal blood pressure group(P<0.05).(2)By the end of the follow-up,2 294 cases of CKD were identified,including 1 117 cases of estimated glomerular filtration rate(eGFR)decline and 1 575 cases of urinary protein.The incidences density of CKD,eGFR decline and urinary protein for stage 1 hypertension group were 39.4,16.3 and 25.5 per thousand person-years,respectively,all of which were statistically significant different from normal blood pressure group(log-rank test,P<0.01).(3)Multivariate Cox regression analysis revealed that,compared to the normal blood pressure group,stage 1 hypertension was associated with a 29%increased risk of CKD(HR=1.29,95%CI 1.09-1.52)and a 40%increased risk of eGFR decline(HR=1.40,95%CI 1.08-1.80)in diabetic individuals.Conclusion Stage 1 hypertension significantly increases the risk of CKD and eGFR decline in diabetic individuals,with a particularly notable effect on the risk of eGFR decline.