Objective To investigate the efficacy and safety of camrelizumab monoclonal antibody combined with molecular-targeted therapy in elderly patients with unresectable or advanced hepatocellular carcinoma(HCC).Methods A retrospective analysis was performed for the patients with unresectable/advanced HCC who attended six hospitals from January 1,2019 to March 31,2021,and all patients received camrelizumab monoclonal antibody treatment,among whom 84.8%also received targeted therapy.According to the age of the patients,they were divided into elderly group(≥65 years)and non-elderly group(＜65 years).The two groups were assessed in terms of overall survival(OS),progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),and immune-related adverse events(irAE).The chi-square test or the Fisher's exact test was used for comparison of categorical data between groups;the independent samples t-test was used for comparison of normally distributed continuous data,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups.The Kaplan-Meier method was used for survival analysis,and the log-rank test was used for comparison of survival curves.Univariate and multivariate Cox proportional hazards regression analyses were used to determine the independent influencing factors for PFS and DCR at 6 months.Results A total of 99 HCC patients were enrolled,with 27 in the elderly group and 72 in the non-elderly group.The elderly group had an OS rate of 67.8%,an ORR of 44.4%,and a DCR of 74.1%at 12 months and a median PFS of 6.4(95%confidence interval[CI]:3.0-12.4)months,with no significant differences compared with the non-elderly group(all P＞0.05).The median OS was unavailable for the elderly group,while the non-elderly group had an OS of 18.9(95%CI:13.0-24.8)months;there was no significant difference between the two groups(P=0.485).The univariate and multivariate Cox regression analyses showed that major vascular invasion(MVI)was an independent risk factor for PFS(hazard ratio[HR]=2.603,95%CI:1.136-5.964,P=0.024)and DCR(HR=3.963,95%CI:1.671-9.397,P=0.002)at 6 months,while age,sex,etiology of HBV infection,presence of extrahepatic metastasis,Child-Pugh class B,and alpha-fetoprotein＞400 ng/mL were not associated with PFS or DCR at 6 months.For the elderly group,the incidence rates of any irAE and grade 3/4 irAE were 51.9%and 25.9%,respectively,with no significant differences compared with the non-elderly group(P＞0.05),and skin disease was the most common irAE in both groups(39.4%).Conclusion Camrelizumab monoclonal antibody combined with molecular-targeted therapy has similar efficacy and safety in patients with unresectable/advanced HCC aged≥65 years and those aged＜65 years.MVI is associated with suboptimal response to immunotherapy and poor prognosis.

Objective To investigate the mechanism through which RgpB,a virulence factor of Porphyromonas gingivalis(Pg),induces chemoresistance in esophageal squamous carcinoma.Methods The autophagy-regulating factors that interact with RgpB were screened by immunoprecipitation-mass spectrometry.The interaction between RgpB and the autophagy regulator TBC1D5 was investigated using co-immunoprecipitation.The impact of Pg infection on the expression of esophageal cancer cell membrane receptor molecule Cx43 was assessed using Western blotting.Immunofluorescence assay was used to analyze the relationship among Lamp1,Cx43 and TBC1D5.The effect of Pg infection on autophagosome-lysosome fusion was evaluated using autophagy double fluorescence technique.The effects of Pg infection and a Cx43 inhibitor on proliferation of esophageal cancer cells after chemotherapy were examined with plate cloning assay and CCK-8 method.Results Immunoprecipitation-mass spectrometry identified TBC1D5 as an autophagy regulator interacting with RgpB,and co-immunoprecipitation suggested that RgpB could directly bind to TBC1D5.In Pg-infected esophageal cancer cells,the expression of Cx43 on the cell membrane was significantly higher than that in non-infected cells.Immunofluorescence assay showed that the expression of Cx43 on the membrane of esophageal cancer cells increased significantly after Pg infection,which blocked autophagosome-lysosome fusion as shown by stubRFP-sensGFP-LC3 lentivirus study.Plate cloning assay and CCK-8 assay showed that the Cx43 inhibitor significantly attenuated the effect of Pg infection for promoting proliferation of esophageal cancer cells after chemotherapy.Conclusion Pg infection in esophageal cancer blocked autophagosome-lysosome fusion in the tumor cells,thereby preventing Cx43 from lysosomal degradation and leading to chemoresistance of esophageal cancer.

Objective To investigate the mechanism through which RgpB,a virulence factor of Porphyromonas gingivalis(Pg),induces chemoresistance in esophageal squamous carcinoma.Methods The autophagy-regulating factors that interact with RgpB were screened by immunoprecipitation-mass spectrometry.The interaction between RgpB and the autophagy regulator TBC1D5 was investigated using co-immunoprecipitation.The impact of Pg infection on the expression of esophageal cancer cell membrane receptor molecule Cx43 was assessed using Western blotting.Immunofluorescence assay was used to analyze the relationship among Lamp1,Cx43 and TBC1D5.The effect of Pg infection on autophagosome-lysosome fusion was evaluated using autophagy double fluorescence technique.The effects of Pg infection and a Cx43 inhibitor on proliferation of esophageal cancer cells after chemotherapy were examined with plate cloning assay and CCK-8 method.Results Immunoprecipitation-mass spectrometry identified TBC1D5 as an autophagy regulator interacting with RgpB,and co-immunoprecipitation suggested that RgpB could directly bind to TBC1D5.In Pg-infected esophageal cancer cells,the expression of Cx43 on the cell membrane was significantly higher than that in non-infected cells.Immunofluorescence assay showed that the expression of Cx43 on the membrane of esophageal cancer cells increased significantly after Pg infection,which blocked autophagosome-lysosome fusion as shown by stubRFP-sensGFP-LC3 lentivirus study.Plate cloning assay and CCK-8 assay showed that the Cx43 inhibitor significantly attenuated the effect of Pg infection for promoting proliferation of esophageal cancer cells after chemotherapy.Conclusion Pg infection in esophageal cancer blocked autophagosome-lysosome fusion in the tumor cells,thereby preventing Cx43 from lysosomal degradation and leading to chemoresistance of esophageal cancer.

Objective : To investigate the protective effect of dulaglutide on acute kidney injury (AKI) induced by lipopolysaccharide (LPS) . Methods : Twenty⁃four male C57BL/6 mice were randomly divided into Control group (normal saline) , LPS group (LPS 15 mg/kg) , LPS + Dul group (LPS 15 mg/kg + Dulaglutide 0. 6 mg/kg) and Dul group (Dulaglutide 0. 6 mg/kg) with 6 mice in each group. The drug was administered by intraperitoneal injection. After drug intervention for 24 h , the body weight and kidney weight of mice were recorded , and kidney tissue and serum samples were collected. The pathological changes in kidney tissue were observed by HE staining. The serum urea nitrogen (BUN) and creatinine (CRE) levels were detected by the kit. The levels of cytokines interleukin (IL⁃6) , tumor necrosis factor (TNF⁃α ) and IL⁃1β in the kidney were detected by qRT⁃PCR. The contents of macrophage marker F4/80 and myeloperoxidase (MPO) in kidney were determined by immunohistochemistry. Results : Compared with Control group , mice in LPS group lost weight and increased kidney weight ( P < 0. 001) . Moreover, the levels of BUN and CRE increased (P < 0. 001 , P < 0. 01) . Meanwhile , the mRNA levels of IL⁃6 , IL⁃1β and TNF⁃α increased (P < 0. 05) . There was obvious pathological damage in kidney tissue. In addition , macrophage and neutrophil infiltration increased in LPS group ( P < 0. 001) . Compared with LPS group , mice in LPS + Dul group gained weight and lost kidney weight (P < 0. 05 , P < 0. 001) . Moreover, the levels of BUN and CRE in LPS + Dul group decreased (P < 0. 01) . The renal histological scores were reduced (P < 0. 05) . In addition , the levels of IL⁃6 , IL⁃1β and TNF⁃α in kidney tissue decreased (P < 0. 05 or P < 0. 01) . Moreover, the infiltration of macrophages and neutrophils in kidney was reduced (P < 0. 01) . Conclusion Dulaglutide has a protective effect on LPS⁃induced sepsis AKI , which may be related to reduce the expression of inflammatory media⁃ tors and decrease the infiltration of inflammatory cell.

Recent research has highlighted structural and functional abnormalities in the cerebral cortex of patients with premature ejaculation (PE). These anomalies could play a pivotal role in the physiological mechanisms underlying PE. This study leveraged functional magnetic resonance imaging (fMRI), a noninvasive technique, to explore these neural mechanisms. We conducted resting-state fMRI scans on 36 PE patients and 22 healthy controls (HC), and collected data on Premature Ejaculation Diagnostic Tool (PEDT) scores and intravaginal ejaculation latency time (IELT). Employing a surface-based regional homogeneity (ReHo) approach, we analyzed local neural synchronous spontaneous activity, diverging from previous studies that utilized a volume-based ReHo method. Areas with significant ReHo differences between PE and HC groups underwent surface-based functional connectivity (FC) analysis. Significant discrepancies in ReHo and FC across the cortical surface were observed in the PE cohort. Notably, PE patients exhibited decreased ReHo in the left triangular inferior frontal gyrus and enhanced ReHo in the right middle frontal gyrus. The latter showed heightened connectivity with the left lingual gyrus and the right orbital superior frontal gyrus. Furthermore, a correlation between ReHo and FC values with PEDT scores and IELT was found in the PE group. Our findings, derived from surface-based fMRI data, underscore specific brain regions linked to the neurobiological underpinnings of PE.
Male ; Humans ; Premature Ejaculation ; Brain Mapping/methods* ; Brain ; Cerebral Cortex ; Magnetic Resonance Imaging/methods*

There is still a serious challenge of the measurement of critical quality attributes (CQAs) related to clinical efficacy for Chinese materia medica manufacturing. To overcome this challenge, an integrated strategy of biosensor and ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was proposed using Tongren niuhuang qingxin pills as a trial. Firstly, an original biosensor was created using a semiconductor chip material high electron mobility transistor (HEMT) as the transducer and the macrophage migration inhibitory factor (MIF) as the identification element. By this MIF-HEMT biosensor, the efficacy on stoke of different components from Tongren niuhuang qingxin pills was measured. It was clear that all three components of Tongren niuhuang qingxin pills had strong therapeutic effects on stroke, especially the section A, the K_D of which reached to 8.722×10^-10 g·mL^-1. Furthermore, MIF-HEMT biosensor integrated UPLC-MS/MS was introduced to identify the efficacy CQAs of different components of Tongren niuhuang qingxin pills. As a result, 19 potential CQAs, such as albiforin, paeoniflorin, and prim-O-glucosylcimifugin, were measured as the efficacy CQAs of Tongren niuhuang qingxin pills on stroke treatment by MIF. These results provided vital measurement techniques and methodological guidance for the CQAs study of Tongren niuhuang qingxin pills intervention in MIF-induced stroke treatment. This also provided an essential guideline for the efficient utilization and quality control measurement of high-quality classical recipes.

Objective     To summarize the progress and trend on clinical drug trials of esophageal squamous cell carcinoma in China. Methods     Based on the clinical drug trial registration and information disclosure platform and the drug data query system of the National Medical Products Administration, the characteristics of clinical trials, investigational drugs and listed drugs of esophageal squamous cell carcinoma in China from 2012 to 2021 were analyzed. Results     From 2012 to 2021, a total of 49 clinical drug trials of esophageal squamous cell carcinoma were registered in China, accounting for 1.6% of all clinical trials of anticancer drugs. Among them, there were 39 (79.6%) trials initiated by domestic pharmaceutical enterprises, 6 (12.2%) for adjuvant and neoadjuvant treatment, and 9 (18.4%) for local treatment. There were differences in the treatment line distribution between global and domestic enterprise-initiated trials (P=0.032). The above trials covered 29 investigational drugs, including 23 (79.3%) targeted drugs, most of which targeted programmed death-1, programmed death-ligand 1 and epidermal growth factor receptor. From 2012 to 2021, there were 2 drugs for esophageal squamous cell carcinoma listed in China, both of which were approved for the first-line and second-line treatment. Conclusion     Great achievements have been made in the clinical development of esophageal squamous cell carcinoma drugs in China. It is suggested that domestic enterprises increase the investment of esophageal squamous cell carcinoma, pay attention to adjuvant and local treatment, explore novel targets and drug categories, and focus on the details of pivotal trials.

Objective:To evaluate the value of ultrasonography in evaluating the influential factors of early insufficient flow after central venous catheter placement in dialysis patients.Methods:Three hundred and twenty seven hemodialysis patients who underwent central venous catheterization at the Affiliated Hospital of Chengde Medical College from May 2016 to June 2019 were selected. According to the catheter flow, the patients were divided into the low catheter flow group(43 cases) and the normal catheter flow group(284 cases). The distribution variance of clinical features(age, gender, blood pressure) were compared and whether some ultrasonic parameters(position of catheter tip, left ventricular ejection fraction, left atrial end-systolic diameter, left ventricular end-diastolic diameter, distance from the catheter tip to superior vena cava beyond right atrial opening) had influence on the insufficient catheter flow in the early stage between the two groups were analyzed.Results:The differences of left ventricular ejection fraction, left atrial end-systolic diameter and position of catheter tip between the two groups were statistically different( P<0.05). However, univariate and multivariate analyses showed that there were significant differences in catheter tip approaches and touches the wall of right atrium( OR=5.393, 95% CI=2.039-14.263, P=0.001), increased left atrial end-systolic diameter( OR=0.321, 95% CI=0.124-0.827, P=0.019), left ventricular ejection fraction in critical range( OR=2.953, 95% CI=1.113-7.835, P=0.030) and decreased left ventricular ejection fraction( OR=5.828, 95% CI=1.869-18.174, P=0.002) were the independent risk factors of early insufficient catheter flow. Conclusions:Insufficient catheter flow after central venous catheterization is related to catheter position, left atrial end-systolic diameter and left ventricular ejection fraction. Ultrasonography evaluation is a primary method to observe the position of the catheter tip in dialysis patients and diagnose the early insufficient catheter flow after central venous catheterization.

Objective To investigate the population genetic data of 47 autosomal insertion/deletion （InDel） polymorphism genetic markers involved in AGCU InDel 50 kit in Guangdong Han, Guangxi Zhuang, Guangxi Yao, Guangxi Jing, and Guangxi Mulam, and to evaluate their application in forensic DNA identification. Methods Multiplex amplification of the 768 unrelated individuals from the 5 ethnic groups mentioned above was performed with the AGCU InDel 50 kit. Genotyping was carried out by 3500xL gene analyzer, population genetic parameters were gathered and polymorphism analysis was performed. Results No linkage disequilibrium was found among 47 autosomal InDel loci in the 5 ethnic groups. The distribution of genotype frequency of 47 autosomal InDel loci confirmed to the Hardy-Weinberg equilibrium in Guangdong Han and Guangxi Zhuang. Except for rs139934789, the other 46 loci confirmed to the Hardy-Weinberg equilibrium in Guangxi Yao, Guangxi Jing, and Guangxi Mulam. The results of genetic variation analysis among the populations showed that 1.12% of genetic variation was caused by ethnic group differences. The cumulative discrimination power of 47 autosomal InDel loci for the 5 ethnic groups were all above 0.999 999 999 999 999. The cumulative probability of exclusion for each ethnic group was less than 0.999 9. The two Y-InDels were identified in all male individuals and were absent in all female individuals. Conclusion Except for rs139934789, the other 46 InDel loci have a relatively good genetic polymorphism in the 5 Chinese ethnic groups, and can be used for forensic individual identification and as effective supplements for paternity testing.
Asian People/genetics* ; China ; Ethnicity/genetics* ; Female ; Gene Frequency ; Genetic Loci ; Genetics, Population ; Humans ; INDEL Mutation ; Male ; Microsatellite Repeats ; Polymorphism, Genetic

OBJECTIVE: To explore the anti-nociceptive effect of patchouli alcohol (PA), the essential oil isolated from Pogostemon cablin (Blanco) Bent, and determine the mechanism in molecular levels. METHODS: The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to confirm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor (MOR). Cyclooxygenase 2 (COX2) and MOR of mouse brain were expressed for determination of PA's target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA. RESULTS: PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution (P<0.01) and allodynia after intra-plantar formalin (P<0.01) in mice. PA also up-regulated COX2 mRNA and protein (P<0.05) with a down-regulation of MOR (P<0.05) both in in vivo and in vitro experiments, which devote to the analgesic effect of PA. A decrease in the intracellular calcium level (P<0.05) induced by PA may play an important role in its anti-nociceptive effect. PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect. CONCLUSIONS Both COX2 and MOR are involved in the mechanism of PA's anti-nociceptive effect, and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA's effect on MOR.