ObjectiveThis study aimed to evaluate the clinical efficacy of Ruyi Zhenbaowan（RYZBW）in the treatment of initial and early knee osteoarthritis （KOA） through a prospective multicenter，randomized，double-blind，and placebo-parallel controlled trial. MethodFrom October 13^th， 2021 to December 25^th， 2021， 240 KOA subjects meeting the acceptance criteria were enrolled in 15 sub-centers including Wangjing Hospital， Chinese Academy of Chinese Medical Sciences， and they were randomly divided into observation group and control group， with 120 cases in each group. The intervention measures for the observation group were RYZBW + health education， and the intervention measures for the control group were RYZBW placebo + health education. The intervention period in both groups was four weeks， and they were followed up for four weeks after the intervention. The primary outcome measure was the total score of Western Ontario and McMaster University Osteoarthritis Index score （WOMAC score）， and the secondary outcome measures were the response rate of visual scale （VAS） pain score， WOMAC sub item scores （joint pain， joint stiffness， and joint function）， quality of life （SF-12） score， and traditional Chinese medicine （TCM） syndrome score. Result（1） Efficacy evaluation. The marginal model results showed that the observation group was better than the control group in improving the WOMAC total score and WOMAC pain score in the treatment of KOA with RYZBW， and the difference was statistically significant （P<0.05）. There was no significant difference between the two groups in improving VAS score response rate， WOMAC function score， WOMAC stiffness score， SF12-PCS （quality of life-physical health） score， SF12-MCS （quality of life-mental health） score， and TCM syndrome score. （2） Subgroup analysis. ① In terms of VAS score response rate， the response rate of the observation group was higher than that of the control group for subjects with baseline VAS score of （4， 5］， and the difference was statistically significant （P<0.05）. ② In terms of TCM syndrome score， for subjects aged ［56， 60］ and ［61， 65］， the decrease in total TCM syndrome score in the observation group was better than that in the control group， and the difference was statistically significant （P<0.05）. ConclusionTibetan medicine RYZBW has good clinical efficacy in improving WOMAC total score， VAS score response rate， WOMAC pain score， WOMAC function score， and TCM syndrome score for patients with initial and early KOA， which can fill the lack of Tibetan medicine RYZBW in the treatment of KOA and make a demonstration study for the inheritance and development of ethnic medicine.

Objective:To observe and determine the gene mutation site and clinical phenotype of a NDP gene mutant family, and provide a basis for the prenatal diagnosis of offspring. Methods:A pedigree investigation study. Two patients and 6 family members of a third-generation Han family with NDP gene mutation who were admitted to the Maternal and Child Health Hospital of Gansu Province from July 2019 to December 2021 were included in the study. The patients and their parents underwent the examination of pupil light reflex, strip light imaging, visual acuity evaluation, fundus color photography, and wide-field fluorescein fundus angiography (FFA). Peripheral blood of all the subjects was collected, the pathogenic genes were screened by whole exome sequencing, and NDP genes were detected by amplification of multiple ligated probes. DNA prenatal diagnosis was performed by amniocentesis at 19th weeks of the mother's third gestation. Results:Proband (Ⅲ1), male, 4 years old, full term natural delivery. At about 40 days after birth, B-mode ultrasonography indicated total retinal detachment in both eyes. Normal hearing and intelligence. Fundus examination was not performed. First sibling of proband (Ⅲ2, big younger brother), ophthalmologic examination 30 days after birth, retinal detachment in both eyes. Proband's mother (Ⅱ2) had unvascularized peripheral temporal retina in both eyes. Wide-angle FFA examination showed no vascularization of the peripheral temporal retina in both eyes, and slight leakage of peripheral vascular fluorescein. The proband's second sibling (Ⅲ3, little younger brother) was screened for neonatal eye disease 1 day after birth. No abnormalities were observed outside both eyes. Cornea and lens transparent. No abnormalities were observed in the optic disc and macula in both eyes. No vascular curvature was observed in the peripheral retina. The results of gene detection showed that there was hemizygote deletion in exon 2 of NDP gene of the proband (Ⅲ1) and its big younger brother (Ⅲ2). His mother (Ⅱ2) had heterozygosity deletion in exon 2 of NDP gene. The phenotype and genetic test results of the proband's father (Ⅱ1), uncle (Ⅱ3), maternal grandfather (Ⅰ1) and maternal grandmother (Ⅰ2) were not abnormal. Conclusions:The hemizygote deletion in exon 2 of NDP gene is a pathogenic variation in the native family. The clinical phenotypes of different genders are different. Prenatal diagnosis is an effective way to block hereditary diseases in families.

Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist used for the treatment of castration-resistant prostate cancer (CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance (ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR (ARfl) or dominantly active androgen receptor splice variant 7 (ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.

Objective To explore the predictive value of the expression of CD44v6 and EGFR on the efficacy of neoadjuvant chemotherapy (NACT) in stageⅡ-Ⅲ cervical cancer. Methods A total of 53 patients with stageⅡ-Ⅲ cervical cancer diagnosed by pathology were selected. All patients received two cycles of paclitaxel+platinum NACT. The pathological tissue samples of cervical tumors before NACT treatment were collected. The expression of CD44v6 and EGFR were detected by the immunohistochemical SP method, and we analyzed their predictive value of NACT in stageⅡ-Ⅲ cervical cancer. Results Among the 53 patients, 38 were in the NACT effective group (CR+PR), and 15 were in the NACT ineffective group (SD+PD). The expression of CD44v6 in the ineffective group was significantly higher than that in the effective group (P < 0.05). The expression of CD44v6 was significantly different in patients with CR, PR, and SD (P < 0.05). The AUC of CD44v6 to NACT effect on stage Ⅱ-Ⅲ cervical cancer was 0.74 (P < 0.05). The patients in the high expression group of CD44v6 had worse efficacy in NACT than those in the low expression group of CD44v6 (P < 0.05). Pearson test showed that CD44v6 and EGFR expression were correlated (R=0.34, P < 0.05). Conclusion High expression of CD44v6 may reduce the efficacy of NACT in stageⅡ-Ⅲ cervical cancer, suggesting that the expression of CD44v6 has a certain predictive value and clinical significance in the efficacy of paclitaxel+platinum NACT on cervical cancer. Moreover, CD44v6 is positively correlated with EGFR expression.

Objective: To compare the effectiveness and clinical safety between the two through the observation of Orthokeratology lens and multifocal soft lens. Methods: By using prospective longitudinal design, sixty patients (120 eyes) with orthokeratology lens and multifocal soft lens were selected. After 1, 3, 6 and 12 months, our tests were conducted, including ocular surface disease index (OSDI) questionnaire, tear break up time(BUT), corneal fluerescein staining (CSF) and meibomian gland function assessment, before and after wearing glasses, ocular axis and refraction in 6,12 and 18 months after were evaluated to assess the effect of myopia control. Results: But in the orthokeratology lens group was lower than the soft lens group after two months. The difference was statistically significant( t=4.35, P <0.05). After 1 month of wearing glasses, BUT in the orthokeratologylens group was shorter than before( F=305.83, P <0.05). In the group of soft lens, there was no statistically significance before and after wearing glasses( F= 0.38, P >0.05). There was no difference in corneal fluorescence staining (CSF) and meibomian gland function between the two groups before and after wearing glasses.( F time=1.55, 1.38, 10.15, 1.50, P >0.05, F group=2.31, 0.02， P >0.05). After 18 months of wearing orthokeratology lens, the average degree of spherical lens increased by -0.53 D, which was different from that before wearing( F=6.54, P <0.05). After wearing soft lens 18 month, the average degree of spherical lens increase by -0.34 D, which was different from that before wearing( F=2.88, P <0.05). After 18 months of wearing glasses, there were differences in the growth of ocular axis between the two groups( F =2.73, 2.83, P <0.05). Conclusion Orthokeratology lens and multifocal soft lens are both safe and effective measures to control myopia.

Objective To collect the serum samples of patients with nonalcoholic fatty liver disease (NAFLD), and to investigate the changes in serum metabolic biomarkers before and after lifestyle intervention. Methods A total of 23 patients who were diagnosed with NAFLD in Department of Gastroenterology and Inpatient Department, Putuo District Central Hospital of Shanghai, from January 2019 to January 2020 were enrolled, and all patients received the intervention with aerobic exercise and equicaloric low-carbohydrate high-protein diet. A total of 13 healthy volunteers who underwent physical examination in Physical Examination Center were enrolled as control group. For the patients with NAFLD, basic information was collected before and after intervention, blood samples were collected twice to measure liver function, blood glucose, and blood lipids, and part of serum was used for serum metabolomics analysis. The serum samples were analyzed by ultra-performance liquid chromatography/tandem high-resolution mass spectrometry. The data collected were processed in Compound Discover, and then principal component analysis (PCA) and orthogonal partial least squares discriminant analysis were used to establish the profile of differentially expressed blood metabolites between patients and healthy people and perform the enrichment analysis of differentially expressed metabolic pathways. The independent samples t -test was used for comparison of normally distributed continuous data between two groups, and the Wilcoxon non-parametric test was used for comparison of non-normally distributed continuous data between two groups. Results After lifestyle intervention, the patients had significant reductions in body mass index ( P < 0.01), body weight ( P < 0.01), and serum biochemical parameters alkaline phosphatase, albumin, gamma-glutamyl transpeptidase, and alanine aminotransferase (all P < 0.05), as well as a significant reduction in total protein ( P < 0.01), while there were no significant improvements in cholinesterase, aspartate aminotransferase, and glucose. As for the four items for blood lipids, there was a significant reduction in triglyceride ( P < 0.01), while there were no significant improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol. The metabolomics analysis showed that 33 serum metabolites changed significantly after lifestyle intervention. In addition, PCA results showed that after intervention, the level of metabolites in patients tended to be normal. The signaling pathway analysis showed that exercise and diet mainly affected the pathways of bile acid, unsaturated fatty acid synthesis, and phenylalanine metabolism. Conclusion Lifestyle intervention can achieve varying degrees of reduction in the body weight of patients with NAFLD, improve serum biochemical parameters, and regulate the abnormal metabolic pathway in patients with NAFLD, which has important clinical value and significance for guiding clinicians to formulate reasonable diet and exercise strategies for patients with NAFLD and prevent the progression of NAFLD.

PURPOSE: Breast cancer is the most commonly occurring cancer among women worldwide, and therefore, improved approaches for its early detection are urgently needed. As microRNAs (miRNAs) are increasingly recognized as critical regulators in tumorigenesis and possess excellent stability in plasma, this study focused on using miRNAs to develop a method for identifying noninvasive biomarkers. METHODS: To discover critical candidates, differential expression analysis was performed on tissue-originated miRNA profiles of 409 early breast cancer patients and 87 healthy controls from The Cancer Genome Atlas database. We selected candidates from the differentially expressed miRNAs and then evaluated every possible molecular signature formed by the candidates. The best signature was validated in independent serum samples from 113 early breast cancer patients and 47 healthy controls using reverse transcription quantitative real-time polymerase chain reaction. RESULTS: The miRNA candidates in our method were revealed to be associated with breast cancer according to previous studies and showed potential as useful biomarkers. When validated in independent serum samples, the area under curve of the final miRNA signature (miR-21-3p, miR-21-5p, and miR-99a-5p) was 0.895. Diagnostic sensitivity and specificity were 97.9% and 73.5%, respectively. CONCLUSION: The present study established a novel and effective method to identify biomarkers for early breast cancer. And the method, is also suitable for other cancer types. Furthermore, a combination of three miRNAs was identified as a prospective biomarker for breast cancer early detection.
Area Under Curve ; Biomarkers ; Biomarkers, Tumor ; Breast Neoplasms* ; Breast* ; Carcinogenesis ; Data Mining ; Early Detection of Cancer ; Female ; Genome ; Humans ; Methods ; MicroRNAs* ; Plasma ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Reverse Transcription ; Sensitivity and Specificity

Objective To evaluate computed tomography venography (CTV) in diagnosis of iliac vein stenosis or occlusion.Methods From Jun 2015 to Jun 2017,168 CVD patients with CEAP clinically graded at 4 to 6 underwent evaluation with digital subtraction angiography (DSA) CTV and colour Doppler ultrasound.Taking DSA as standard,the diagnostic value of CTV and colour Doppler ultrasound were analyzed and compared.Results DSA established diagnosis of 95 cases,compared with DSA,CTV's and colour Doppler ultrasound's sensitivity,specificity,positive likelihood ratio and negative likelihood ratio was 87.4％ and 64.2％,94.5％ and 98.6％,15.89 and 45.86 and 0.13 and 0.36.Compared with colour Doppler ultrasound,CTV's sensitivity was significantly higher (P ＜ 0.05,the 95 ％ confidence intervals were 0.764-14.257),and there was no significant difference between them in aspect of specificity (P =0.375,the 95％ confidence intervals were 0.943-0.986),Kappa value was 0.809(P ＜0.05,the 95％ confidence intervals were 0.714-0.893),0.597 (P ＜ 0.05,the 95％ confidence intervals were 0.464-0.717).Conclusion In the diagnosis of CVD combined with iliac and femoral venous stenosis,CTV has outstanding sensitivity,specificity,and good conformancy with that of DSA.

Objective:By observing the hippocampus 5-HT1A receptor expression, MDA content and SOD activity and the effect of lentinan mouse model of chronic stress behavior,serum TNF-αand IL-6 content.To investigate the mechanism of antidepressant LNT.Methods:Healthy adult mice were 50,male,body weight (20 ±2) g,SPF grade,based on 1% sucrose water partial addicted degrees and were randomly divided into four groups,namely,normal control group (Normal controls,NG),model in the control group ( Model control,MG) ,LNT dose group ( L-LNT,2.5 mg/kg;H-LNT,5.0 mg/kg).Before the experiment began modeling 1 h daily oral administration,continuous administration 28 d, each experimental group administered according 1.0 ml/100 g weight.Application chronic unpredictable mild stress model of depression produced,and make improvements.Normal control group,not to stimulate,food and water properly.Model group and the experimental intervention group with the lone support,fasting,water deprivation (24 h),and accept the unpredictable stressors,the 28 d of the experiment,the animals were randomized to receive daily each only one stimulus, within five days after making the choreography the stimulus program was not repeated and unpredictable.Animals were observed daily behavior change,with a strange environment to start feeding feeding experimentally observed incubation period,forced swim stress test record swim immobility time,enzyme-linked immunosorbent assay of serum TNF-α,IL-6 content ,NBT assay of total SOD activity,thio-barbituric acid (thiobarbituric acid,TBA) MDA content assay,immune proteins mark (Western blot) to detect 5-HT1A receptor expression levels.Results:MG mice in an unfamiliar environment, feeding latency was significantly prolonged after giving LNT intervention can shorten lead to chronic stress in mice feeding latency in an unfamiliar environment,prolonged chronic stress leads to significantly reduce the stress in mice swimming in water immobility time extension,and 5-HT1A receptor expression enhancing,LNT intervention group increased SOD,MDA content decreased serum TNF-αand IL-6 was significantly reduced,compared with the model group MG indicators above improvements were statistically significant ( P<0.05 or P<0.01 ).Conclusion:LNT can significantly antagonize depressive symptoms in mouse models of chronic stress,increased locomotor activity in mice time;LNT increase SOD,MDA content may antagonize the antidepressant effects and mechanisms related to LNT.

Objective:To investigate the effects of Daidzein on behavior of chronic stress depression rats and the expression of hippocampal brain-derived neurotrophic factor ( BDNF ) , neuropeptide Y ( NPY ) and non-specific immune regulation.Methods: 40 healthy adult male SD rats with body weight(210±19)g,clean grade,were chosen and fed with 1%sucrose solution for 4 d to change drinking habits.On the fifth day rats were subjected to water deprivation for 24 h without fasting.On the sixth day rats were fed with 1%surcrose solution.4 h later, preference of 1% surcrose solution was examined.According to the 1% sucrose solution preference and weight rats were randomly divided into 4 groups,normal control group(CG),model control group,(MG),fluoxetine group(FG,10.0 mg/kg),daidzein group(DG,80.0 mg/kg).At the same time of establishing model,rats were administered orally once a day for 32 d.The depression model was established by chronic unpredictable mild stress model and separation.The behavioral changes of the rats were observed, and expression of BNDF in hippocampus and NPY was measured by Western blot technology and immunohistochemistry.It was observed the proliferation function of lymphocytes,spleen index,the number of peripheral blood leukocytes and antibody-secreting cell function.Results: Compared with the normal control group(CG),the weight of rats with chronic stress protocol was lower, 1%sucrose consumption decreased,scores of rats in the open field test dropped significantly,the immobility time in the forced swimming test prolonged,the level of expression of BNDF and NPY decreased,all the differences above were statistically sig-nificant(P<0.01).Compared with model group,weight of rats in fluoxetine treatment group(FG) and daidzein treatment group(DG)in-creased,sugar consumption,scores in the open field test and the levels of expression of BNDF and NPY significantly increased,the differences were statistically significant( P<0.05 or P<0.01 ).The number of peripheral blood leukocytes and antibody-secreting cell function and proliferation of lymphocytes force in daidzein treatment group was significantly higher than the model group,daidzein dose spleen index was significantly higher than the model group(P<0.01).Conclusion: The daidzein can antagonize depressive symptoms in chronic stress mice,daidzein may increased content of BDNF in hippocampus and NPY protein, and enhanced the role of humoral immune response and lymphocyte proliferation in rats with chronic stress model.The mechanisms of antidepressant effects of daidzein might be related to the increase of content of BDNF in hippocampus and NPY protein and non -specific immune regulation.