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

Ulcerative colitis (UC) is a chronic inflammatory disorder with a complex etiology, characterized by intestinal inflammation and barrier dysfunction. Platycodon grandiflorus polysaccharides (PGP), the primary component of Platycodon grandiflorus, and hesperidin (Hesp), a prominent active component in Citrus aurantium L. (CAL), have both demonstrated anti-inflammatory properties. This study aims to elucidate the underlying mechanism of the synergistic effect of PGP combined with Hesp on UC, focusing on the coordinated interaction between the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways. A mouse model of UC induced by dextran sulfate sodium (DSS) and a cell model using lipopolysaccharide (LPS)-induced RAW264.7/IEC6 cells were employed to investigate the in vitro and in vivo anti-inflammatory effects of PGP combined with Hesp on UC and its potential mechanism of action. The results indicated that compared to the effects of either drug alone, the combination of PGP and Hesp significantly modulated inflammatory factor levels, inhibited oxidative stress, regulated colonic mucosal immunity, suppressed apoptosis, and restored intestinal barrier function in vitro and in vivo. Further in vitro studies revealed that PGP significantly inhibited the PI3K/AKT signaling pathway, while Hesp significantly inhibited the JAK2/STAT3 signaling pathway. The use of inhibitors and activators targeting both pathways validated the synergistic effects of PGP combined with Hesp on the PI3K/AKT and JAK2/STAT3 signaling pathways. These findings suggest that PGP combined with Hesp exhibits a synergistic effect on DSS-induced colitis, potentially mediated through the phosphatase and tensin homolog (PTEN)/PI3K/AKT and interleukin-6 (IL-6)/JAK2/STAT3 signaling pathways.
Animals ; STAT3 Transcription Factor/genetics* ; Janus Kinase 2/genetics* ; Polysaccharides/administration & dosage* ; Colitis, Ulcerative/chemically induced* ; Mice ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/genetics* ; Drug Synergism ; Male ; Hesperidin/administration & dosage* ; Platycodon/chemistry* ; Phosphatidylinositol 3-Kinases/genetics* ; Disease Models, Animal ; RAW 264.7 Cells ; Mice, Inbred C57BL

Objective To investigate the differences and the immunocompatibility of wild-type (WT), four-gene modified (TKO/hCD55) and six-gene modified (TKO/hCD55/hCD46/hTBM) pig erythrocytes with human serum. Methods The blood samples were collected from 20 volunteers with different blood groups. WT, TKO/hCD55, TKO/hCD55/hCD46/hTBM pig erythrocytes, ABO-compatible (ABO-C) and ABO-incompatible (ABO-I) human erythrocytes were exposed to human serum of different blood groups, respectively. The blood agglutination and antigen-antibody binding levels (IgG, IgM) and complement-dependent cytotoxicity were detected. The immunocompatibility of two types of genetically modified pig erythrocytes with human serum was evaluated. Results No significant blood agglutination was observed in the ABO-C group. The blood agglutination levels in the WT and ABO-I groups were higher than those in the TKO/hCD55 and TKO/hCD55/hCD46/hTBM groups (all P<0.001). The level of erythrocyte lysis in the WT group was higher than those in the ABO-C, TKO/hCD55 and TKO/hCD55/hCD46/hTBM groups. The level of erythrocyte lysis in the ABO-I group was higher than those in the TKO/hCD55 and TKO/hCD55/hCD46/hTBM groups (both P<0.01). The pig erythrocyte binding level with IgM and IgG in the TKO/hCD55 group was lower than those in the WT and ABO-I groups. The pig erythrocyte binding level with IgG and IgM in the TKO/hCD55/hCD46/hTBM group was lower than that in the WT group and pig erythrocyte binding level with IgG was lower than that in the ABO-I group (all P<0.05). Conclusions The immunocompatibility of genetically modified pig erythrocytes is better than that of wild-type pigs and close to that of ABO-C pigs. Humanized pig erythrocytes may be considered as a blood source when blood sources are extremely scarce.

Purpose: Mixed-lineage leukemia protein 4 (MLL4/KMT2D) is a histone methyltransferase, and its mutation has been reported to be associated with a poor prognosis in many cancers, including lung cancer. We investigated the function of MLL4 in lung carcinogenesis. Materials and Methods: RNA sequencing (RNA-seq) in A549 cells transfected with control siRNA or MLL4 siRNA was performed. Also, we used EdU incorporation assay, colony formation assays, growth curve analysis, transwell invasion assays, immunohistochemical staining, and in vivo bioluminescence assay to investigate the function of MLL4 in lung carcinogenesis. Results: We found that MLL4 expression was downregulated in non–small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues and tended to decrease with disease stage progression. We analyzed the transcriptomes in control and MLL4- deficient cells using high-throughput RNA deep sequencing (RNA-seq) and identified a cohort of target genes, such as SOX2, ATF1, FOXP4, PIK3IP1, SIRT4, TENT5B, and LFNG, some of which are related to proliferation and metastasis. Our results showed that low expression of MLL4 promotes NSCLC cell proliferation and metastasis and is required for the maintenance of NSCLC stem cell properties. Conclusion Our findings identify an important role of MLL4 in lung carcinogenesis through transcriptional regulation of PIK3IP1, affecting the PI3K/AKT/SOX2 axis, and suggest that MLL4 could be a potential prognostic indicator and target for NSCLC therapy.

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.

Objective:To investigate the factors and mechanisms in forming uric acid stones in patients with type 2 diabetes (T2DM).Methods:106 patients with diabetes were divided into observation group and control group according to the combination of urinary calculi,53 cases in each group,The differences of clinical data and biochemical indexes between the two groups were compared,The relationship between type 2 diabetes mellitus and urinary stones was analyzed by multi factor regression analysis.Results:There were no significant difference in observation group and control group in age,sex,SBP,DBP,TC,FBG,2hPBG and HbA1C (P＞0.05),and there were of statistical difference significance in BMI,urinary pH,HOMA-IR,SUA,TUA in the two gruops (P ＜0.05) and the Logistic regression analysis showed blood uric acid,the urinary pH,HOMA-IR,SUA were independent risk factors in urolithiasis in T2DM (P ＜ 0.05).Conclusion:High uric acid hematic disease,high uric acid excretion,insulin resistance,overweight or obesity,high blood triglycerides in patients with type 2 diabetes is risk factors for urinary stone formation,in which blood uric acid,urinary pH,HOMA-IR is the independent risk factor for type 2 diabetic patients with urinary calculi.

Objective To investigate the changes and clinical significance of CD19 ,CD20 ,CD3-CD16+ CD56+ (NK cells) and CD3+CD16+CD56+ (NKT cells) in the children with epilepsy .Methods 125 cases of children with epilepsy children confirmed by Pediatric neurology specialists in Zhongshan People's Hospital from January 2013 to March 2016 were selected as epilepsy group , while 125 cases of healthy children were selected as control group ,and the levels of CD19 ,CD20 ,NK cells and NKT cells in periph-eral blood of two groups were detected by flow cytometry .Results CD19 ,CD20 ,NK cells and NKT cells levels in epilepsy group were higher than those in control group ,and the difference was statistically significant (P<0 .05) .For ROC curve analysis ,CD19 optimal cutoff value of 9 .4 ,the area under the curve was 90 .3% ,with 91 .7% sensitivity .CD20 optimal cutoff value of 7 .75 ,the ar-ea under the curve was 87 .3% ,with 91 .7% sensitivity .NK cells optimal cutoff value of 8 .55 ,the area under the curve was 80 .5% , with 95 .8% sensitivity .NKT cells optimal cutoff value of 0 .35 ,the area under the curve was 76 .9% ,with 91 .7% sensitivity .Con-clusion CD19 ,CD20 ,NK cells and NKT cells can be used as important indexes for monitoring immune conditions in children with epilepsy .

Objective To explore the effects of Orem self-care theory on the initiative and core competence of psychiatric nurses. Methods A total of 100 in-service registered nurses in the clinical department of our hospital were selected and used self-control test on them. Then we evaluated and compared their initiative and core competence respectively at the begin and the end of one year′s Orem self-care theory practice in Psychiatric Ward. Results The initial score of initiative was (23. 43+2. 25) and the score of core competence was (131. 43 ± 7. 19) before the practice of Orem self-care theory. While the score of initiative was (30. 17 ± 2. 26), the score of core competence was (150. 80 ± 6. 73) after 1 year′s the practice of Orem self-care theory (P<0. 01). Conclusions Application of Orem self-care theory in Psychiatric Ward can enhance the work initiative and give full expression to the core competence of nurses.

BACKGROUND:Extraction of a wel fixed cementless femoral stem or a cemented stem is difficult during revision of total hip arthroplasty. The extended trochanteric osteotomy provides excellent methods, and combining with long-stem cementless prosthesis can better reduce postoperative complications.
OBJECTIVE:To retrospectively analyze the recent clinical curative effect after extended trochanteric osteotomy combined with long-stem cementless prosthesis in hip revision.
METHODA total of 25 patients undergoing hip revision were selected from the Department of Osteoarthrosis, Pingdingshan First People’s Hospital, China from May 2008 to May 2013. Of them, 17 patients were subjected to the extended trochanteric osteotomy combined with single-incision and double-approaches. The femurs were reconstructed with long-stem cementless prosthesis. Al patients were fol owed-up for 12 to 60 months. Pre-operative and post-operative Harris hip scores, the post-operative complications, the bone cutting length, the length of stem in contact with cortical bone, the length of the end of bone cutting to the end of the prosthesis were recorded.
RESULTS AND CONCLUSION:17 patients were fol owed-up. The mean length of bone was 17 cm (15-23 cm). The mean length of stem in contact with cortical bone was 6.4 cm (4-11 cm). The mean length of the end of bone to the end of the prosthesis was 11.5 cm (8-18.5 cm). After fol ow-up, the mean Harris hip scores were improved from (39.0 ± 13.6) scores preoperatively to (75.0 ± 14.9) scores postoperatively (P<0.01). Subsidence occurred in two hips. The cutting sites of 17 cases of extended trochanteric osteotomy were fixed wel . These data suggested that the operation through single-incision and double-approach to the hip, while preserving the attachment of the external rotators and posterior capsule, wil strength rear hip stability and prevent postoperative dislocations. Recent effects were satisfactory, but the long-term outcomes should be further investigated.