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:Investigate the safety and feasibility of using the new self-designed implanting applicator in vaginal three-dimensional intracavitary brachytherapy after hysterectomy for gynecological cancer, and to explore the clinical value of the self-designed implanting applicator.Methods:Sixty-two gynecological cancer patients who underwent brachytherapy in Sun Yat-sen University Cancer Center were selected in this study. Each patient received three-dimensional intracavitary brachytherapy because of the indication of postoperative radiotherapy. Each patient was treated with different types of self-designed implanting applicators according the condition of postoperative vagina,and the vaginal tube and implant needle were placed in the template according to the preset channnel. Based on the actual CT images, the high-risk clinical target volume (HR-CTV), and organs at risk were defined according to unified target area delineation criteria and then the brachytherapy plan was conducted. The prescription dose of high-risk clinical target volume (HR-CTV) was 5.5 Gy/time. The parameters such as target area, organs at risk volume and irradiated dose were evaluated by DVH diagram.Results:Sixty-two patients successfully completed brachytherapy under the guidance of self-designed implanting applicator. A total of 140 implantation treatments were performed. The total average dose of HR-CTV D90% was (575.48±22.30) cGy, the mean dose D 2cm3 of bladder, rectum and sigmoid colon were (328.69±102.71), (369.14±46.59) and (27.28±71.27) cGy, the small intestine did not drop the target area, so there was no statistics. There was statistical significance between target volume and organs at risk dose ( P<0.05). Conclusions:The new self-designed implanting applicator has obvious clinical advantages in vaginal three-dimensional intracavitary brachytherapy after hysterectomy for gynecological cancer, meets the requirements of the preset planning dose,and it is sample to operate and highly safe,which indicated a bright future of the clinical application.

"The Expert Group on Tumor Ablation Therapy of Chinese Medical Doctor Association, The Tumor Ablation Committee of Chinese College of Interventionalists, The Society of Tumor Ablation Therapy of Chinese Anti-Cancer Association and The Ablation Expert Committee of the Chinese Society of Clinical Oncology" have organized multidisciplinary experts to formulate the consensus for thermal ablation of pulmonary subsolid nodules or ground-glass nodule (GGN). The expert consensus reviews current literatures and provides clinical practices for thermal ablation of GGN. The main contents include: (1) clinical evaluation of GGN, (2) procedures, indications, contraindications, outcomes evaluation and related complications of thermal ablation for GGN and (3) future development directions.
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Objective To investigate the application prospect of the most extensive genome engineering pig internationally in preclinical xenotransplantation. Methods Porcine endogenous retrovirus (PERV) knockout combined with 3 major heterologous antigen gene knockouts and 9 humanized genes for inhibition of complement activation, regulation of coagulation disorders, anti-inflammatory and anti-phagocytosis were transferred into a pig (PERV-KO/3-KO/9-TG) as a donor, and the heart, liver and kidney were obtained and transplanted to 3 Rhesus macaque recipients respectively to establish a preclinical research model of pig-to-Rhesus macaque xenotransplantation. The functional status of xenografts after blood flow reconstruction was observed and the survival of recipients was summarized. The hemodynamics of xenografts were monitored. The change of hematological indexes of each recipient was compared. The histopathological manifestation of xenografts was observed. Results After the blood flow was reconstructed, all xenografts showed ruddy color, soft texture and good perfusion. The transplant heart, liver and kidney showed full arterial and venous blood flow and good perfusion at 1 d after operation. The postoperative survival time of heart, liver, and kidney transplant recipients was 7, 26, and 1 d, respectively. The levels of creatine kinase, creatine kinase isoenzyme, and lactate dehydrogenase increased in heart transplant recipient at 1 d after operation, and gradually recovered to near normal levels at 6 d after operation. All indexes increased sharply at 7 d after operation. The level of aspartate aminotransferase increased in liver transplant recipients at 2 d after operation, and the alanine aminotransferase basically returned to normal at 10 d after operation, but the total bilirubin continued to increase. Both aspartate aminotransferase and alanine aminotransferase increased at 12 d after operation, and reached a peak at 15 d after operation. The kidney transplant recipient developed mild proteinuria at 1 d after operation, and died of sudden severe arrhythmia. Histopathology showed that the tissue structure of cardiac and renal xenografts was close to normal, and liver xenografts presented with patchy necrosis, the liver tissue structure was disordered, accompanied by inflammatory damage, interstitial hemorrhage and thrombotic microangiopathy. Conclusions PERV-KO/3-KO/9-TG pig shows advantages in overcoming hyperacute rejection, mitigating humoral rejection and coagulation dysregulation. However, whether it can be used as potential donor for clinical xenotransplantation needs further evaluation.

Objective To explore the damage of spiral ganglion neurons(SGNs),the protective effects of different dosages of healthy ear compound (HEC)from traditional Chinese medicine(TCM) against age-induced SGNs degeneration and its possible mechanism in spiral ganglion neurons(SGNs)of C57BL/6J mice.Methods Totally 36 C57BL/6J mice just after ablactation were randomly divided into four groups.Normal control group (n =6)drank tap water daily from ablactation to 2 months old.Ageing-related SGNs apoptosis control group(n=12)drank tap water daily from ablactation to 7 months old.High dose TCM group(n=12)at drank 3.65 g/kg/d of HEC from ablactation to 7 months old.Low dose TCM group(n=6)drank 0.91 g/kg/d of HEC from ablactation to 7 months old.The animal cochleae were immediately removed at the termination of the experiment.In each group,the cochleae of 6 animals were used for paraffin embedding,slicing and toluidine blue staining to observe neuronal morphological changes.The caspase-3 mRNA expression study was performed by real-time PCR technique in 6 cochleae of High dose TCM group and ageing-related SGNs apoptosis control group.Results The morphological structure of cochlear SGNs represented healthy and normal density in normal control group at 2 months old.In contrast,amount or density of SGNs in cochlear basilar part was significantly damaged and reduced in ageing-related SGNs apoptosis control group at 7 months old(P＜ 0.001).But the high dose TCM group at 7 months of age was similar to the normal control group at 2 months old in morphological structure,amount or density of SGNs(P＞0.05).The low dose TCM group was significantly different from other 3 groups in amount or density of SGNs (P＜0.001).However,SGNs in the middle part and apical part showed integrity in each group.In addition,the expression level of caspase-3 in the cochlea of high dose TCM group was also obviously different with age-related SGNs apoptosis control group(P＜0.01) Conclusions Ageing-related damage of SGNs in C57BL/6J mice begins from the base of cochlea and progresses towards the apex.The HEC of TCM could significantly protect SGNs against age-induced apoptosis in SGNs.The efficacy of the high dose TCM is better than that of the low dose TCM.Its SGNs protective mechanisms might be related to involving the caspase-mediated cell apoptotic pathway.

Objective To explore the application of multi-overlap immunofluorescence techniques in the morphological research of nerve cells,and provide a new method of targeted research on nerve cells.Methods Ten Balb/c mice were selected and randomly divided into experimental group of severe traumatic brain injury (STBI) and sham control group (n=5);mice in the experimental group were induced STBI models by controlled cortical impact (CCI) method,and the neurological severity scale (NSS) scores were 8 in them.All animals were terminated on day 7.The gene and protein expressions of neuronal nuclei antigen (NeuN),glial fibrillary acidic protein (GFAP) and bromodeoxyuridine (BrdU),and the morphology expression of4',6-diamidino-2-phenylindole (DAPI) were observed under confocal microscopy by applying multi-overlap immunofluorescence techniques.Results The images got by multi-overlap immunofluorescence techniques possessed the characteristics of bright and clear color,strong morphological sense on the expressions.The more obvious expressions of BrdU+NeuN+GFAP+DAPI in the STBI group could be noted as compared with those in the sham control group;the relative expression quantity of BrdU+NeuN+DAPI was significantly different between the two groups (P＜0.05).Conclusion STBI in mice could induce self-regenerated phenomenon on cerebral neural cells or astrocyte;these new techniques provide new scientific means in the targeted study of development,proliferation,apoptosis or death of nerve cells and its mechanism.

Objective To study the mini-invasive surgical treatment for cholelithiasis disease in the primary hospital. Methods Laparoseope,duodenoscope and choledochoscope were combined to treat 293 cases with cholelith-iasis which included 2 cases cholecystolithisasis, 131 cases were cholecystolithiasis with secondary choledocholith,28 cases with primary choledocholith,39 cases with calculus of intrahepatic duct,93 cases with calculus of intrahepatic or extrahepatic duct. Results The program had minor trauma, mild suffering, and less operative complications,compared with traditional open operations. Conclusion The combined treatment of laparoscopy, duodenoscopy, choledochoscope and surgery for the cholelithiasis in the primary hospital is feasible, safe and effective.

Objective: A traditional Chinese medicine(TCM) transformed from Jian Er Ⅱ,Cong Er capsule was studied in protection against age-induced degeneration in cochlear spiral ganglion neurons and auditory nerve fibers in C57 BL /6J mice.A possible protective mechanism was also discussed.Methods : 40 neonatal C57 BL /6J mice were randomly divided into 2 groups with an average of 20 animals in each group.The animals in control group were fed with regular mouse feedstuff and regular water after ablactation,while animals in experimental group were fed the same mouse food after ablactation,but drink the medical solution of Cong Er capsule instead of regular water from two months of age.Animals were terminated at 7 months of age.The cochlea were removed and processed for a series of modiolus sections.The density of spiral ganglion neurons in Rosenthal's canal in different turns was counted,and the auditory nerve fibers in habenula perforata at basal turn and apical turn were also quantified respectively.Statistical comparative analysis was performed between the two groups.Results: Density of spiral ganglion neurons in cochlear basal turn in control group was significantly reduced.In survival ganglion neurons,an obvious degeneration was observed in control group.The number of auditory nerve fibers in cochlear basal turn also decreased.In contrast,Cong Er capsule treated animals had an increase in survival ganglions and auditory nerve fibers,especially,a significant difference was seen in density of spiral ganglion neurons in the basal turn between the two groups(P

Objective: To observe the preventive effect of Bu Shen Jian Pi Capsule on age-related cochlear hair cells apoptosis in C57 BL /6J mice,and research its mechanism of action.Methods: 30 new born C57 BL /6J mice were divided into 2 groups,with 10 animals in control group(CG) and 20 animals in Bu Shen Jian Pi Capsule (experimental group,EG).The animals in CG were fed regularly,while those in EG were fed regularly at the first one months after the birth and then,commonly fed water was substituted by the medical solution of Bu Shen Jian Pi Capsule for these animals in EG.The experimental course lasted for seven months.The cochleas of the two groups of mice were taken out for cochlear surface preparation,then being observed under optical microscope with a comparative analysis on the status of degenerative changes in the hair cells of cochlear between the tow groups.Results: Cochlear hair cells damage of CG animals showed aggravating tendency with the increase of the age,and followed the developmental rules of lesion progression in cochlear hair cells from the basal turn to the apical turn and with the number of outer hair cells loss greater than that of inner hair cells.In contrast,the cochlear damage of animals of EG was relatively milder than that in animals of CG,compared among the animals at the same age between them.Conclusion: This study showed that Bu Shen Jian Pi Capsule could postpone age-related cochlear hair cells apoptosis in C57 BL /6J mice,therefore,it suggested that Bu Shen Jian Pi Capsule might possess the pharmacological action of preventing presbyacusis.We assume the possible protective mechanism of Bu Shen Jian Pi Capsule might be related to increase of cells cAMP,regulation of metabolism of nucleic acid,and protectoin or stabilization of DNA structure.