Background and purpose:For patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer,trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients.However,the reference original research trastuzumab(Herceptin?)is more expensive.Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment.This clinical trial aimed to evaluate the efficacy,pharmacokinetics,safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab(Herceptin?)in patients with HER2-positive metastatic breast cancer.Methods:This multi-center,randomised,double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China.This study complied with the research protocol,the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials.It was approved by the hospital's medical ethics committee.The clinical trial registration agency is the State Food and Drug Administration(clinical trial approval number:2015L04224;clinical trial registration number:CTR20170516).Written informed consent was obtained from subjects before enrollment.Enrolled patients were randomly assigned to the AK-HER2 group and the control group,respectively receiving AK-HER2 or trastuzumab(initial loading dose 8 mg/kg,maintenance dose 6 mg/kg,every 3 weeks as a treatment cycle,total treatment time is 16 cycles)in combination with docetaxel(75 mg/m2,treatment duration is at least 9 cycles).The primary endpoint of this clinical trial was the objective response rate(ORR9)between the AK-HER2 group and the control group in the 9th cycle.Secondary efficacy endpoints included ORR16,disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS)and 1-year survival rate.In this study,100 subjects(AK-HER2 group to control group=1:1)were randomly selected for blood sample collection after the 6th cycle of medication,The collection time points were 45 minutes after infusion(the end of administration),4,8,24,72,120,168,336,and 504 hours after the end of administration.After collection,blood samples were analyzed by PK parameter set(PKPS).Other evaluation parameters included safety and immunogenicity assessment.Results:A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep.2017 and Mar.2021.In the AK-HER2 group(n=237),129 subjects in the experimental group achieved complete response(CR)or partial response(PR),and the ORR9 was 54.4%.There were 134 subjects in the control group(n=241)who achieved CR or PR,and the ORR9 was 55.6%.The ORR9 ratio between the AK-HER2 group and the control group was 97.9%[90%confidence interval(CI):85.4%-112.2%,P=0.784],which was not statistically significant.In all secondary efficacy endpoints,no statistically significant differences were observed between the two groups.We conducted a mean ratio analysis of pharmacokinetics(PK)parameters between the AK-HER2 group and the control group,and the results suggested that the pharmacokinetic characteristics of the two drugs are similar.The incidence of treatment emergent adverse event(TEAE)leading to drug reduction or suspension during trastuzumab treatment was 3.6%(10 cases)in the AK-HER2 group and 8.1%(22 cases)in the control group.There was statistically significant difference between the two groups(P=0.027).The incidence rate was significantly lower in the AK-HER2 group than in the control group,and there was no statistically significant difference among the other groups.The differences in the positive rates of anti-drug antibodies(ADA)and neutralizing antibodies(NAB)between groups were of no statistical significance(P=0.385 and P=0.752).Conclusion:In patients with HER2-positive metastatic breast cancer,AK-HER2 was comparable to the trastuzumab(Herceptin?)in terms of drug efficacy,pharmacokinetics,safety and immunogenicity.

Objective:To investigate the clinical efficacy of femoral component revision surgery in addressing polyethylene sleeve wear in rotating hinge knee joints.Methods:A retrospective analysis was conducted on 21 patients who underwent treatment for polyethylene sleeve wear in rotating hinge knee joints at the Department of Orthopaedics, the Fourth Medical Center, PLA General Hospital, spanning from August 2008 to April 2023. There were 8 males and 13 females with a median age of 63(38, 76) years. Among them, 11 cases involved the left side, and 10 cases involved the right side. The average body mass index (BMI) was 25.0(22.5, 31.0) kg/m 2, and all cases underwent unilateral knee joint revision. The time interval from receiving the hinge knee joint prosthesis to revision was 10.5(6.0, 17.0) years, with 18 cases undergoing primary revision and 3 cases undergoing revision for the second time. Revision surgery of the femoral component sleeve was performed in all patients due to polyethylene sleeve wear. Visual analogue scale (VAS), range of motion (ROM) of the knee joint, changes in hip-knee-ankle angle (HKA), and Knee Society score (KSS) were collected and recorded to assess the surgical outcomes. Results:All patients were followed up for a median duration of 12.5(11.7, 13.4) months. Preoperatively, the VAS score was 5(3, 7) points, which significantly decreased to 0(0, 1) points at the last follow-up ( Z=5.721, P<0.001). At the last follow-up, the KSS scores decreased from 41.19±13.65 points preoperatively to 79.81±7.80 points, indicating a statistically significant difference ( t=12.560, P<0.001). HKA increased from 174.65°±5.20° preoperatively to 178.71°±2.79°, with a statistically significant difference ( t=5.533, P<0.001). Knee joint ROM increased from 69.05°±34.37° preoperatively to 110.00°±10.12°, also demonstrating a significant improvement ( t=5.960, P<0.001). Notably, patients exhibited knee joint stability with no passive flexion or extension laxity. Conclusion:Femoral component sleeve revision surgery effectively addresses polyethylene sleeve wear in rotating hinge knee joint prostheses, thereby mitigating the substantial loss of bone and soft tissue associated with overall revision procedures. The early postoperative clinical outcomes are promising and indicative of the efficacy of this surgical intervention.

Objective:To observe whether endothelial cells undergo pyroptosis in the inflammatory periodontal environment by using a model in vivo and in vitro, providing an experimental basis for indepth understanding of the underlying pathogenesis of periodontitis. Methods:According to the classification of periodontal diseases of 2018, gingival tissues were collected from periodontally healthy subjects and patients with stage Ⅲ-Ⅳ, grade C periodontitis, who presented Department of Oral and Maxillofacial Surgery and Department of Periodontology, School of Stomatology, The Fourth Military Medical University from April to May 2022. Immunohistochemical staining was performed to detect the expression level and distribution of gasdermin D (GSDMD), a hallmark protein of cell pyroptosis, in gingival tissues. Periodontitis models were established in each group by ligating the maxillary second molar teeth of three mice for 2 weeks (ligation group). The alveolar bone resorption was determined by micro-CT (mice without ligation treatment were used as the control group), and the colocalization of GSDMD and CD31 were quantitatively analyzed by immunofluorescence staining in gingival tissues of healthy and inflammatory mice. Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and treated with lipopolysaccharide (LPS) of Porphyromonas gingivalis (Pg) combined with adenosine triphosphate (ATP) at various concentrations of 0.5, 1.0, 2.5, 5.0, and 10.0 mg/L, respectively, and the 0 mg/L group was set as the control group at the same time. Scanning electron microscopy was used to observe the morphology of HUVECs. Western blotting was used to detect the expression of gasdermin D-N terminal domains (GSDMD-N) protein and immunofluorescence cell staining was used to detect the expression and distribution of GSDMD. Cell counting kit-8 (CCK-8) was used to detect the proliferative ability of HUVECs, and propidium iodide (PI) staining was used to detect the integrity of cell membrane of HUVECs. Results:Immunohistochemistry showed that GSDMD in gingival tissues of periodontitis was mainly distributed around blood vessels and its expression level was higher than that in healthy tissues. Micro-CT showed that alveolar bone resorption around the maxillary second molar significantly increased in ligation group mice compared with control subjects ( t=8.88, P<0.001). Immunofluorescence staining showed significant colocalization of GSDMD with CD31 in the gingival vascular endothelial cells in mice of ligation group. The results of scanning electron microscopy showed that there were pores of different sizes, the typical morphology of pyroptosis, on HUVECs cell membranes in the inflammatory environment simulated by ATP combined with different concentrations of LPS, and 2.5 mg/L group showed the most dilated and fused pores on cell membranes, with the cells tended to lyse and die. Western blotting showed that the expression of GSDMD-N, the hallmark protein of cell pyroptosis, was significantly higher in 2.5 and 5.0 mg/L groups than that in the control group ( F=3.86, P<0.01). Immunofluorescence cell staining showed that the average fluorescence intensity of GSDMD in 2.5 mg/L group elevated the most significantly in comparison with that in the control group ( F=35.25, P<0.001). The CCK-8 proliferation assay showed that compared to the control group (1.00±0.02), 0.5 mg/L (0.52±0.07), 1.0 mg/L (0.57±0.10), 2.5 mg/L (0.58±0.04), 5.0 mg/L (0.55±0.04), 10.0 mg/L (0.61±0.03) groups inhibited cell proliferation ( F=39.95, P<0.001). PI staining showed that the proportion of positive stained cells was highest [(56.07±3.22)%] in 2.5 mg/L group ( F=88.24, P<0.001). Conclusions:Endothelial cells undergo significant pyroptosis in both in vivo and in vitro periodontal inflammatory environments, suggesting that endothelial cell pyroptosis may be an important pathogenic factor contributing to the pathogenesis of periodontitis.

The first bite syndrome is a rare maxillofacial pain syndrome easily ignored by clinicians. The pain caused by it not only makes it difficult for patients to eat and delays surgical wound healing, but also rises fear and anxiety of patients while they eat, which would severely reduce their life quality. There are few case reports about the first bite syndrome in China, and clinicians know little about it. Therefore, the early diagnosis and treatment of such a disease are important. In this review, we thoroughly reviewed the etiology and classification, pathogenesis, clinical manifestation, and current treatments of the first bite syndrome, aiming at providing some suggestions for clinicians.

Objective : To investigate the effect of different decontamination methods, including photodynamic therapy, sandblasting and titanium curette, on titanium surface morphology and bacterial adhesion for the treatment of peri-implant disease. Methods: Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn) were inoculated on the surface of polished titanium specimens, and titanium specimen surfaces were treated with different decontamination methods after incubation. The titanium specimens were divided into a no-treatment control group, photodynamic group, sandblasting group and titanium curette group according to different decontamination methods. The changes in titanium surface roughness were observed by atomic force microscopy (AFM), and the remaining bacteria on the titanium surface were observed by scanning electron microscopy (SEM) and live/dead bacteria staining tests. After reinoculation of Pg and Fn, bacterial readhesion was observed on the surface of decontaminated titanium specimens. Results : The AFM results showed that the surface roughness of the titanium curette group was significantly higher than that of the no-treatment control group, photodynamic group and sandblasting group (P<0.05), and there was no statistically significant difference between the no-treatment control group, photodynamic group and sandblasting group (P>0.05). The results of contact angle measurement showed that the surface contact angle of each treatment group was smaller than that of the no-treatment control group (P<0.05). The SEM results obtained after the titanium specimen surface was decontaminated showed that the number of bacteria on the no-treatment control group surface was higher and the bacteria were relatively concentrated. The bacteria on the surface of the photodynamic group, sandblasting group and titanium curette group were scattered and distributed in small numbers, and most bacteria on the surface of the photodynamic group were ruptured. The results of the live/dead bacteria staining experiment showed that the percentage of dead bacteria on the surface of the photodynamic group was significantly higher than that of the no-treatment control group, sandblasting group and titanium curette group (P<0.05). The remaining bacteria on the surface of the sandblasting group and titanium curette groups were mainly live bacteria. The remaining bacterial adhesion on the surface was significantly reduced for the sandblasting group compared to the no-treatment control group and the photodynamic and titanium curette groups (P<0.05). SEM and live/dead bacteria staining results of bacterial readhesion on the surface of titanium specimens showed that there was an aggregation of Pg on the surface of the titanium curette group, and its surface bacterial adhesion was significantly higher than that of the no-treatment control group, photodynamic group and sandblasting group. Conclusion In mechanical decontamination, sandblasting machines are a better option than photodynamic therapy and titanium curettes; however, sandblasting does not remove all bacterial contamination. For sterilization, photodynamic therapy is more effective than sandblasting and titanium curettes. A combination of sandblasting and photodynamic therapy methods for the treatment of peri-implant disease may be considered in clinical practice.

Severe muscle injury is hard to heal and always results in a poor prognosis. Recent studies found that extracellular vesicle-based therapy has promising prospects for regeneration medicine, however, whether extracellular vesicles have therapeutic effects on severe muscle injury is still unknown. Herein, we extracted apoptotic extracellular vesicles derived from mesenchymal stem cells (MSCs-ApoEVs) to treat cardiotoxin induced tibialis anterior (TA) injury and found that MSCs-ApoEVs promoted muscles regeneration and increased the proportion of multinucleated cells. Besides that, we also found that apoptosis was synchronized during myoblasts fusion and MSCs-ApoEVs promoted the apoptosis ratio as well as the fusion index of myoblasts. Furthermore, we revealed that MSCs-ApoEVs increased the relative level of creatine during myoblasts fusion, which was released via activated Pannexin 1 channel. Moreover, we also found that activated Pannexin 1 channel was highly expressed on the membrane of myoblasts-derived ApoEVs (Myo-ApoEVs) instead of apoptotic myoblasts, and creatine was the pivotal metabolite involved in myoblasts fusion. Collectively, our findings firstly revealed that MSCs-ApoEVs can promote muscle regeneration and elucidated that the new function of ApoEVs as passing inter-cell messages through releasing metabolites from activated Pannexin 1 channel, which will provide new evidence for extracellular vesicles-based therapy as well as improving the understanding of new functions of extracellular vesicles.
Creatine/metabolism* ; Extracellular Vesicles ; Muscle, Skeletal/metabolism* ; Myoblasts/metabolism* ; Regeneration ; Connexins/metabolism*

Objective: In order to find out the prevalence and death of pneumoconiosis in Qingyuan City, to explore the regularity of pneumoconiosis and lay a foundation for the prevention and management of pneumoconiosis. Methods: In August to December 2019, the basic data of pneumoconiosis from 1949 to 2018 were obtained through the monitoring of death causes of residents, occupational disease management system, Guangdong population information system and other means. The reported cases of pneumoconiosis were followed up, and retrospective investigation was conducted to analyze the basic conditions, the length of service exposed to dust, the time of diagnosis, the type of disease, the stage and the combined status of tuberculosis of pneumoconiosis cases. Results: From 1949 to 2018, a total of 466 cases of new pneumoconiosis were reported in Qingyuan City, including 325 cases of death (69.74%) , 114 cases of survival (24.46%) and 27 cases of loss of follow-up (5.80%) . The cases were mainly concentrated in the age group of 40-89 years (80.04%, 373/466) . There were 411 male cases (88.20%) and 7 female cases (1.50%) . The median length of service exposed to dust was 10.7 (6.0, 16.0) years. The diagnosis time of pneumoconiosis cases was mainly from 1949 to 1986 (68.67%, 320/466) , and the death cases were mainly from 1949 to 1986 (82.77%, 269/325) . Silicosis was the main type of pneumoconiosis (398 cases, 85.41%) . 200 cases (42.92%) were diagnosed as stage I pneumoconiosis, 185 cases (39.69%) were stage II pneumoconiosis, 81 cases (17.38%) were stage III pneumoconiosis at the first diagnosis. 102 cases (21.89%) were pneumoconiosis with tuberculosis. The proportion of death and lost follow-up cases diagnosed as stage I pneumoconiosis for the first time was significantly lower than that of survival cases, and the proportion diagnosed as stage II pneumoconiosis and the complication rate of tuberculosis were significantly higher than those of survival cases (χ(2)=15.48, 11.29, 32.73, P<0.001) . Conclusion: Pneumoconiosis in Qingyuan City is mainly silicosis. The number of new cases has been increasing in the past decade, and the prevention and control situation is still severe. The comprehensive prevention and treatment of silica dust should be included in the focus of supervision of government functional departments.
Adult ; Aged ; Aged, 80 and over ; China/epidemiology* ; Dust ; Female ; Humans ; Male ; Middle Aged ; Occupational Diseases/epidemiology* ; Pneumoconiosis/epidemiology* ; Retrospective Studies ; Silicosis/epidemiology*

Objective:To investigate whether bone marrow mesenchymal stem cells (BMMSCs) derived apoptotic extracellular vesicles (ApoEVs) could regulate the polarization of mouse macrophage cell line RAW264.7 and whether BMMSCs derived ApoEVs could attenuate pro-inflammatory condition of RAW264.7 induced by Porphyromonas gingivalis lipopolysaccharide (Pg-LPS), so as to provide experimental evidence and theoretical basis for using BMMSCs derived ApoEVs as a method to treat periodontitis. Methods:The Operetta CLS high-content analysis system was used to observe the time-dependent apoptosis process of BMMSCs. Besides, field emission scanning electron microscopy (FESEM), dynamic light scattering technology and streaming potential method were used to measure the surface characteristics of BMMSCs derived ApoEVs. The Operetta CLS high-content analysis system was used to observe the process of RAW264.7 phagocyting 5-carboxy-tetramethylrhodamine, succinimidyl ester (5-TAMRA-SE) labeled ApoEVs. Real-time quantitative PCR was used to detect the mRNA expression of arginase-1 (Arg-1). Cell immunofluorescence and Western blotting were used to detect the number of inducible nitric oxide synthase (iNOS)(+) macrophages and iNOS protein expression level in each experiment group. Enzyme linked immunosorbent assay was used to detect tumor necrosis factro-α (TNF-α) level in the Pg-LPS induced pro-inflammatory macrophage culture supernatant in each experiment group.Results:After treating with 0.5 μmol/L staurosporine for 12 hours, mouse BMMSCs underwent shrinking with obvious vesicles structure around. The FESEM showed the ApoEVs were in spherical shapes. The size range of ApoEVs was about 100-1 000 nm and the average Zeta potential was -16.6 mV. The Operetta CLS high-content analysis system showed RAW264.7 could phagocytose 5-TAMRA-SE labeled ApoEVs by pseudopodia. The relative mRNA expression of Arg-1 was significantly increased in RAW 264.7 after being treated with interleukin 4 (IL-4) and ApoEVs (261.97±15.91) compared to that with IL-4 alone (115.29±15.42) ( P<0.01). Cell immunofluorescence showed that ApoEVs could reduce the number of iNOS(+) macrophages induced by Pg-LPS (39.33±4.70) comparing to those without ApoEVs (95.33±4.70) ( P=0.007). In the meanwhile, ApoEVs could also down-regulate the iNOS protein level of macrophages induced by Pg-LPS (5.84±1.05) comparing to those without ApoEVs (14.91±3.87) ( P<0.01). Besides, ApoEVs could also reduce the TNF-α secretion in the culture supernatant of pro-inflammatory macrophages induced by Pg-LPS [(21 899.71±409.73) ng/L] comparing to those without ApoEVs [(71 296.50±2 344.22) ng/L] ( P=0.003). Conclusions:BMMSCs derived ApoEVs could regulate the polarization of macrophages and could also attenuate the pro-inflammatory condition of macrophages induced by Pg-LPS.

Objective:To explore mechanisms underlying the rescuing effects of transplanted mesenchymal stem cells (MSCs) derived exosomes on estrogen-deficient osteoporosis.Methods:Mouse estrogen-deficient osteoporosis model was constructed in 12 female C57BL6/J rats and the exosome release was regulated by siRNA.Osteogenic induction,alizarin red staining and qPCR were performed to evaluate the effects of exosomes on recipient MSC functions.The miR-26a mimics and inhibitors and qPCR were used to explore the mechanisms underlying exosome-mediated functional rescue of recipient MSCs.Results:Donor MSCs alleviated estrogen-deficient osteoporosis via exosome release,and the alleviated osteoporosis by exosomes rescued the recipient MSC functions were observed.Moreover,the rescued recipient MSC functions by exosomes transferred miR-26a were found.Conclusion:Donor MSC-derived exosomes may rescue MSC functions and may remit osteoporosis of the recipient through transfering miR-26a.

Objective:To evaluate the effectiveness and safety of endovascular treatment in solving symptomatic cerebral artery tandem lesions.Methods:From June 201 2 to February 201 4,1 2 cases (24 lesions)with symptomatic cerebral artery tandem lesions were accepted for the endovascular treatment. The distributions of the tandem lesions were as follows:the common carotid artery and internal carotid ar-tery (1 case),the internal carotid artery and the proximal of the carotid cavernous sinus segment (3 ca-ses),the internal carotid artery and the distal of the carotid cavernous sinus segment (4 cases),the in-tracranial segment of internal carotid artery and middle cerebral artery M1 segment (2 cases),the first segment of vertebral artery and intracranial segment of vertebral artery (2 cases).All of these cases were treated from distal lesions to proximal lesions except for tandem lesions in the internal carotid artery and the distal of the carotid cavernous sinus segment in order to obtain better support.Tandem lesions were treated in the same operation with local anesthesia or general anesthesia.The procedures of the 1 2 cases retrospectively were analyzed and the peri-operation complications and responsibility region recurrent is-chemic stroke incidents observed.Results:All tandem lesions were solved successfully all at once.There were no peri-operation complications or recurrent ischemic stroke incidents.There were no recurrent is-chemic stroke incidents or stent restenosis cases in the follow-up.Conclusion:It is safe and effective for selective endovascular treatment in solving symptomatic cerebral artery tandem lesions at the same time, but we should take careful preoperative evaluation and improve the operation plan.