BACKGROUND: The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation. METHODS: We conducted a kidney xenotransplantation in a brain-dead human recipient using a porcine kidney with five gene edits (5GE) on March 25, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22 days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation. RESULTS: The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24 h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient. CONCLUSIONS 5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.
Transplantation, Heterologous/methods* ; Kidney Transplantation/methods* ; Heterografts/pathology* ; Immunoglobulins, Intravenous/administration & dosage* ; Graft Survival/immunology* ; Humans ; Animals ; Sus scrofa ; Graft Rejection/prevention & control* ; Kidney/pathology* ; Gene Editing ; Species Specificity ; Immunosuppression Therapy/methods* ; Plasma Exchange ; Brain Death ; Biopsy ; Male ; Aged

Objective To investigate the effectiveness and safety of drug-eluting beads bronchial arterial chemoembolization(DEB-BACE)versus BACE for the treatment of stage Ⅲ-Ⅳ lung squamous cell carcinoma.Methods A total of 104 patients with stage Ⅲ-Ⅳ lung squamous cell carcinoma,who were admitted to the Lishui Municipal Central Hospital of China between January 2013 and August 2021,were enrolled in this study.According to the therapeutic scheme,the patients were divided into DEB-BACE group(n=41)and BACE group(n=63).For patients of DEB-BACE group,Cisplatin at 75 mg/m2 dose and gemcitabine at 1 000 mg/m2 dose(400 mg was used as loaded-drug dose)were injected through a microcatheter,which was followed by embolization with CalliSpheres microspheres loaded with 400 mg of gemcitabine.For patients of BACE group,Cisplatin at 75 mg/m2 and gemcitabatin at 1 000 mg/m2 were injected through a microcatheter,which was followed by arterial embolization with blank microspheres.Three weeks after DEB-BACE or BACE,the patients of both groups were started on intravenous chemotherapy.The primary study endpoint was overall survival(OS).The secondary study endpoints included progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),adverse reactions,and the remission rate of dyspnea.Results Of the 104 patients,63 received BACE sequential intravenous chemotherapy and 41 received DEB-BACE sequential intravenous chemotherapy.The median OS in DEB-BACE group was 23.0 moths,which was obviously longer than 12.0 months in BACE group(P=0.009).Multivariate Cox regression analysis showed that DEB-BACE treatment was an independent risk factor for OS(HR=0.59,95％ CI:0.38-0.91,Log-rank test P=0.018).Meanwhile,the remission rate of dyspnea in DEB-BACE group was significantly higher than that in BACE group(57.1％ vs 30.6％,P＜0.043).Conclusion Compared with BACE sequential intravenous chemotherapy,DEB-BACE sequential intravenous chemotherapy can significantly prolong the survival time of patients with stage Ⅲ-Ⅳ lung squamous cell carcinoma and significantly improve the symptoms of dyspnea,which has important applications in the treatment of patients with advanced lung squamous cell carcinoma.

Objective To evaluate the long-term efficacy of transjugular intrahepatic portosystemic shunt(TIPS)with bare stents and Fluency covered stents in the treatment of portal hypertension,and to discuss its clinical value.Methods The clinical data of 29 patients with intractable ascites or esophagogastric fundus varices rupture and hemorrhage caused by cirrhotic portal hypertension,who received TIPS with bare stents and covered stents at the First Affiliated Hospital of Xinjiang Medical University of China(25 patients)and the Lishui Municipal Central Hospital of China(4 patients)between August 2012 and December 2017,were retrospectively analyzed.The patients were regularly followed up to check the survival status.The postoperative cumulative shunt patency rate and cumulative survival rate of the patients were analyzed by Kaplan-Meier method.Results The technical success rate of TIPS was 100％.The mean portal vein pressure was decreased from preoperative(40.21±3.24)cmH2O to postoperative(24.55±3.55)cmH2O(P＜0.05).The patients were followed up for 5.1-10.5 years.The postoperative 1-,3-,5-,7-year primary cumulative patency rates of the shunt were 89.7％,75.9％,75.9％ and 52.5％,respectively.The postoperative 5-,7-,9-and 10-year cumulative survival rates were 100％,66.9％,66.9％ and 33.4％,respectively.The incidence of hepatic encephalopathy was 13.8％(4/29).Conclusion Using bare stents combined with Fluency covered stents for TIPS is clinically safe and effective in the treatment of portal hypertension.This technique carries higher long-term shunt patency rate and low incidence of hepatic encephalopathy.Therefore,it can be used as a substitute for Viatorr stent when necessary.(J Intervent Radiol,2024,33:295-299)

At present,bronchial arterial chemoembolization(BACE)is a well-established,local minimally-invasive palliative treatment technique for mid-to-advanced primary lung cancer.However,its technical details are still controversial,and it is difficult to standardize each technical detail.Through reviewing the literature,this paper provides a detailed review of BACE,focusing on the source of lung cancer blood supply,embolization materials,particle size of embolization materials,number of treatments,embolization endpoints,selection of anti-tumor drugs,complications,therapeutic effect,etc.(J Intervent Radiol,2024,33:330-334)

Objective To discuss the perioperative care and wound protection of xenotransplantation from genetically edited pigs to monkeys, with the goal of improving the success rate of such experimental procedures. Methods From October 2022 to October 2023, perioperative care and wound protection were performed on 7 recipient rhesus monkeys undergoing xenotransplantation of genetically edited pig tissues and organs. Customized wound protective garments were designed based on monkeys' size and surgical area to protect the wounds, alongside meticulous perioperative care. This included preoperative preparation and medication, intraoperative monitoring of physiological indicators and anesthesia management, and postoperative care comprising wound protection, observation and monitoring, and nutritional support. Results All seven monkeys successfully underwent xenotransplantation. With the aid of protective garments and detailed care, all surgical wounds healed by first intention, and postoperative recovery was satisfactory. Conclusion Proper care and wound protection during xenotransplantation from genetically edited pigs to monkeys not only promote wound healing, but also alleviate pain and harm to animals. This has significant implications for advancing experimental research in pig-monkey xenotransplantation and enhancing animal welfare.

Objective To explore the clinical effect and safety of carrellizumab combined with albumin-bound paclitaxel on the treatment of patients with locally advanced esophageal cancer.Methods Ninety-eight patients with locally advanced esophageal cancer were randomly divided into the study group and the reference group,with 49 cases in each group.The reference group was treated with albumin-bound paclitaxel,while the study group was treated with camrelizumab+albumin-bound paclitaxel.After treatment,the overall efficacy was evaluated,and the disease control rate was calculated.Serum tumor markers[high mobility group protein B1(HMGB1),squamous cell carcinoma associated antigen(SCCA)],PD-1 and PD-L1 levels were detected by enzyme-linked immunosorbent assay(ELISA)before and after treatment.Immunohistochemistry was used to detect the microvascular density(MVD)and the expression levels of PD-1 and PD-L1 in esophageal carcinoma tissue.The percentages of CD3+,CD4+and CD8+cells were detected by flow cytometry.Patients were followed up and adverse reactions and survival were recorded.Results The disease control rate was higher in the study group than that of the control group(P＜0.05).There were no significant differences in all indexes between the groups before treatment(P＞0.05).After treatment,HMGB1 level,SCCA level,MVD,serum PD-1 level and tumor tissue high expression rate of PD-1 were all decreased in the two groups,while serum PD-L1 level,PD-L1 high expression rate and percentages of CD3+,CD4+and CD8+cells were all increased(P＜0.05).Except there was no significant difference in MVD between groups,the other indexes were significantly changed in the study group compared with the control group(P＜0.05).There was no significant difference in the incidence of adverse reactions between the two groups(P＞0.05).The progression-free survival rate was higher in the study group than that of the control group(P＜0.05).Conclusion Carrellizumab combined with albumin-bound paclitaxel in the treatment of locally advanced esophageal cancer can help control lesion progression and inhibit angiogenesis,with good safety.

Objective:To investigate the changing trends in cardiac function following xenogeneic heterotopic heart transplantation of multi-gene edited pig hearts and assess the impact of recipient immune responses on donor heart, laying experimental groundwork for the clinical application of gene editing technology.Methods:On December 16, 2023, xenogeneic heterotopic heart transplantation was performed between pigs and rhesus monkeys. Functional status of the graft under post-transplantation load conditions and recipient immune indicators were observed.Results:The recipient monkeys survived for 40 days with satisfactory functionality of both donor and recipient hearts, and no hyperacute or acute immune rejection reactions were observed.Conclusion:Multi-gene editing technology provides potential for xenotransplantation, yet further exploration is needed for its clinical application.

Objective:To study the effects of cathepsin K(CTSK)on the healing process of tooth extraction socket and type H blood vessel angiogenesis in mice.Methods:Ctsk knockout(Ctsk-/-)mice were generated by CRISPR/Cas9 technology,and genotype sequen-cing,general observation,Micro-CT and immunohistochemistry were performed to confirm successful knockout of Ctsk.Then 8 week-old WT and Ctsk-/-mice were used to establish the tooth extraction modle by extracting the left maxillary first molars,and the mice were sac-rificed at the day 7,10,14,21,28 and 35 respectively(n=3)after tooth extraction.Then samples were subjected to stereo microscope and Micro-CT examination.Immunofluorescence staining was used to study the effect of Ctsk knockout on type H blood vessel angiogene-sis.Results:Ctsk knockout did not affect the soft tissue healing of tooth extraction socket,but significantly promoted the bone healing process,and Ctsk deficency significantly enhanced type H blood vessel angiogenesis in the tooth extraction socket.Conclusion:Ctsk knockout can enhance type H vessel angiogenesis,and promote bone healing process of tooth extraction socket in mice.

Objective To compare the curative effect and safety of drug-eluting beads bronchial artery chemoembolization(DEB-BACE)with those of simple intravenous chemotherapy in treating elderly patients with intermediate to advanced lung cancer.Methods A total of 213 patients aged＞65 years with intermediate to advanced lung cancer,who were admitted to the Lishui Municipal Central Hospital of China between January 2018 and January 2022,were enrolled in this study.According to the therapeutic scheme,the patients were divided into chemotherapy group(n=107)and DEB-BACE group(n=106).After propensity score matching,chemotherapy group and the DEB-BACE group had 42 patients each.The short-term efficacy and the incidence of adverse reactions were compared between the two groups.Survival curve and Log-rank test were used to compare the survival between the two groups.Cox regression analysis was used to analyze the factors influencing the prognostic survival.Results The postoperative one-,3-,and 6-month disease control rate and objective remission rate in DEB-BACE group were better than those in the chemotherapy group.Before propensity score matching,the median progression-free survival(mPFS)time in DEB-BACE group was 7.0 months,which in the chemotherapy group was 6.0 months(P＜0.001).After propensity score matching,the mPFS in DEB-BACE group was 7.0 months,which in the chemotherapy group was 5.0 months(P=0.001).Before propensity score matching,the median overall survival(mOS)time in DEB-BACE group was 23.0 months,which in the chemotherapy group was 20.0 months(P＜0.001).After propensity score matching,the mOS in DEB-BACE group was 24.0 months,which in the chemotherapy group was 18.0 months(P=0.001).Multivariate Cox regression analysis revealed that therapeutic scheme,tumor size,and TNM stage were the influencing factors for OS.In terms of the adverse reactions,the incidences of both the pre-matched and post-matched myelosuppression in DEB-BACE group were lower than those in the chemotherapy group(P＜0.05).Conclusion For the treatment of intermediate to advanced lung cancer in elderly patients,DEB-BACE is superior to simple intravenous chemotherapy in curative efficacy and safety.

Objective To investigate the establishment of a six-gene-edited pig-to-non-human primate kidney xenotransplantation model. Methods The kidney of humanized genetically-edited pig (GTKO/β4GalNT2KO/CMAHKO/hCD55/hCD46/hTBM) was transplanted into a cynomolgus monkey. The survival of the recipient and kidney condition after blood perfusion were observed. The parenchymal echo, blood flow changes, and size of the kidney were monitored on a regular basis. Routine blood test, kidney function test and electrolyte assessment were carried out. Dynamic changes of urine, feces and body mass were monitored. At the end of life, the transplant kidney, heart, liver, spleen, lung, and cecum were collected for pathological examination. Results The recipient died at postoperative 7 d. After blood flow was restored, the kidney was properly perfused, the organ was soft and the color was normal. At the end of the recipient's life, a slight amount of purulent secretion was attached to the ventral side of the kidney, with evident congestion and swelling, showing the appearance of "red kidney". Postoperatively, the echo of renal parenchyma was increased, blood flow was decreased, the cortex was gradually thickened, and a slight amount of effusion surrounded the kidney and abdominal cavity over time. In the recipient, the amount of peripheral red blood cells, hemoglobin, albumin, and platelets was progressively decreased, and serum creatinine level was increased to 308 μmol/L at postoperative 7 d, whereas the K⁺ concentration did not significantly change. Light yellow urine was discharged immediately after surgery, diet and drinking water were resumed within postoperative 3 h, and light yellow and normal-shape stool was discharged. The reddish urine was gradually restored to normal color within postoperative 1 d, which were consistent with the results of the routine urine test. A large amount of brown bloody stool was discharged twice in the morning of 2 d after surgery. Omeprazole was given for acid suppression, and the stool returned to normal at postoperative 4 d. The β₂-microglobulin level was increased to 0.75 mg/L at postoperative 7 d. The body mass was increased by 1.7 kg. Autopsy pathological examination showed interstitial edema and bleeding of the transplant kidney, a large amount of infiltration of lymphocytes and macrophages, infiltration of lymphocytes in the arteriole wall and arterial cavity, accompanied by arteritis changes, lymphocyte infiltration in the cecal stroma and congestion in the spleen tissues. No significant abnormal changes were observed in other organs. Conclusions The humanized genetically-edited pig-to-non-human primate kidney xenotransplantation model is successfully established, and postoperative survival of the recipient is 1 week.