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 evaluate the preventive effect of an antimicrobial peptide spray on chemoradiotherapy-induced oral mu-cositis in patients with hematologic malignancies.Methods:From December 2021 to July 2023,a total of 191 newly diagnosed pa-tients with hematologic malignancies undergoing concurrent chemoradiotherapy at our hospital were included in the study.Patients were divided into a treatment group(n=124,received antimicrobial peptide spray)and a control group(n=67,received placebo spray).All patients underwent standardized chemoradiotherapy regimens and oral care.Outcomes compared between groups includ-ed the incidence and severity of oral mucositis,ulcer healing time,pain scores,antibiotic usage,inflammatory markers[C-reactive protein(CRP),procalcitonin(PCT)],duration of neutropenia,adverse events,and quality of life.Results:The incidence of oral mucositis in the treatment group was significantly lower than in the control group(12.90％vs.31.34％,P＜0.05),with a relative risk reduction(RRR)of 58.84％,absolute risk reduction(ARR)of 18.44％,and a number needed to treat(NNT)of 5.423.The treatment group showed shorter ulcer healing time,lower pain scores,reduced antibiotic usage and intensity,lower mean levels of CRP and PCT,and a shorter duration of neutropenia.The incidence of exacerbated local pain and drug-related adverse reactions was also significantly lower in the treatment group,compared to the control group(P＜0.05),with no evident systemic toxicity ob-served.Patients in the treatment group reported higher quality of life and satisfaction scores(both P＜0.05).Conclusion:The an-timicrobial peptide spray effectively reduces the incidence and severity of chemoradiotherapy-associated oral mucositis,mitigates in-flammation and infection risk,and improves quality of life.

Objective:To evaluate the preventive effect of an antimicrobial peptide spray on chemoradiotherapy-induced oral mu-cositis in patients with hematologic malignancies.Methods:From December 2021 to July 2023,a total of 191 newly diagnosed pa-tients with hematologic malignancies undergoing concurrent chemoradiotherapy at our hospital were included in the study.Patients were divided into a treatment group(n=124,received antimicrobial peptide spray)and a control group(n=67,received placebo spray).All patients underwent standardized chemoradiotherapy regimens and oral care.Outcomes compared between groups includ-ed the incidence and severity of oral mucositis,ulcer healing time,pain scores,antibiotic usage,inflammatory markers[C-reactive protein(CRP),procalcitonin(PCT)],duration of neutropenia,adverse events,and quality of life.Results:The incidence of oral mucositis in the treatment group was significantly lower than in the control group(12.90％vs.31.34％,P＜0.05),with a relative risk reduction(RRR)of 58.84％,absolute risk reduction(ARR)of 18.44％,and a number needed to treat(NNT)of 5.423.The treatment group showed shorter ulcer healing time,lower pain scores,reduced antibiotic usage and intensity,lower mean levels of CRP and PCT,and a shorter duration of neutropenia.The incidence of exacerbated local pain and drug-related adverse reactions was also significantly lower in the treatment group,compared to the control group(P＜0.05),with no evident systemic toxicity ob-served.Patients in the treatment group reported higher quality of life and satisfaction scores(both P＜0.05).Conclusion:The an-timicrobial peptide spray effectively reduces the incidence and severity of chemoradiotherapy-associated oral mucositis,mitigates in-flammation and infection risk,and improves quality of life.

Objective To observe the effect of preoperative enteral nutritional support combined with modified Ivor-Lewis surgery for esophageal cancer on lung function and mRNA expression of GATA-binding protein 3(GATA3)and forkhead protein P3(Foxp3)in peripheral blood.Methods Sixty esophageal cancer patients who underwent modified Ivor-Lewis surgery in our hospital from January 2022 to October 2023 were selected and divided into two groups by simple random method.The control group was given conventional diet before operation,and the observation group was given enteral nutrition support before operation.The two groups were compared in terms of nutritional support.Results Both groups showed significantly decreases in one-second exertion expiratory volume/exertion lung volume(FEV1/FVC)(P<0.05),FVC(P<0.05),FEV1(P<0.05)and the levels of peripheral blood GATA3(P<0.05),Foxp3 mRNA(P<0.05)expression compared with those at admission(P<0.05),but no significant differences in pulmonary function(P>0.05),peripheral blood GATA3(P>0.05),and Foxp3 mRNA(P>0.05)expression between them at 1 week postoperatively.Both groups exhibited significantly lower levels of albumin,prealbumin,haemoglobin,transferrin,PNI and body mass and body mass index at admis-sion as compared to those at one week after surgery(P<0.05).The observation group showed significantly higher levels of albumin,prealbumin,haemoglobin,transferrin,and PNI at 1 week postoperatively(P<0.05),but no significant differences in ventilation time,defecation time,drain retention time,hospitalisation time,and compli-cation rate as compared to the control group(P>0.05).Conclusion Preoperative enteral nutritional support combined with modified Ivor-Lewis surgery for esophageal cancer improves postoperative nutritional status,and ren-ders less effect on postoperative lung function and peripheral blood GATA3 and Foxp3 mRNA expression.

Organ shortage has become one of the major challenges hindering the development of organ transplantation. Xenotransplantation is one of the most valuable methods to resolve global organ shortage. In recent years, the development of genetic engineering technique and research and development of new immunosuppressant have provided novel theoretical basis for xenotransplantation. International scholars have successively carried out researches on xenotransplantation in genetically modified pigs to non-human primates or brain death recipients, making certain substantial progresses. However, most of the researches are still in the preclinical stage, far from clinical application. Therefore, according to the latest preclinical experimental research progress at home and abroad, the history of xenotransplantation, the development of gene modification technology, xenotransplantation rejection and immunosuppression regimens were reviewed, aiming to provide reference for subsequent research of xenotransplantation, promote clinical application of xenotransplantation and bring benefits to more patients with end-stage diseases.

Objective:To explore the mechanism of noise-induced hidden hearing loss by proteomics.Methods:In October 2022, 64 SPF male C57BL/6J mice were divided into control group and noise exposure group with 32 mice in each group according to random sampling method. The noise exposure group was exposed to 100 dB sound pressure level, 2000-16000 Hz broadband noise for 2 h, and the mouse hidden hearing loss model was established. Auditory brainstem response (ABR) was used to test the change of hearing threshold of mice on the 7th day after noise exposure, the damage of basal membrane hair cells was observed by immunofluorescence, and the differentially expressed proteins in the inner ear of mice in each group were identified and analyzed by 4D-Label-free quantitative proteomics, and verified by Western blotting. The results were statistically analyzed by ANOVA and t test. Results:On the 7th day after noise exposure, there was no significant difference in hearing threshold between the control group and the noise exposure group at click and 8000 Hz acoustic stimulation ( P>0.05) . The hearing threshold in the noise exposure group was significantly higher than that in the control group under 16000 Hz acoustic stimulation ( P<0.05) . Confocal immunofluorescence showed that the basal membrane hair cells of cochlear tissue in noise exposure group were arranged neatly, but the relative expression of C-terminal binding protein 2 antibody of presynaptic membrane in middle gyrus and basal gyrus was significantly lower than that in control group ( P<0.05) . GO enrichment analysis showed that the functions of differentially expressed proteins were mainly concentrated in membrane potential regulation, ligand-gated channel activity, and ligand-gated ion channel activity. KEGG pathway enrichment analysis showed that differentially expressed proteins were significantly enriched in phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling pathway, NOD-like receptor signaling pathway, calcium signaling pathway, etc. Western blotting showed that the expression of inositol 1, 4, 5-trisphosphate receptor 3 (Itpr3) was increased and the expression of solute carrier family 38 member 2 (Slc38a2) was decreased in the noise exposure group ( P<0.05) . Conclusion:Through proteomic analysis, screening and verification of the differential expression proteins Itpr3 and Slc38a2 in the constructed mouse noise-induced hidden hearing loss model, the glutaminergic synaptic related pathways represented by Itpr3 and Slc38a2 may be involved in the occurrence of hidden hearing loss.

Objective:To explore the mechanism of noise-induced hidden hearing loss by proteomics.Methods:In October 2022, 64 SPF male C57BL/6J mice were divided into control group and noise exposure group with 32 mice in each group according to random sampling method. The noise exposure group was exposed to 100 dB sound pressure level, 2000-16000 Hz broadband noise for 2 h, and the mouse hidden hearing loss model was established. Auditory brainstem response (ABR) was used to test the change of hearing threshold of mice on the 7th day after noise exposure, the damage of basal membrane hair cells was observed by immunofluorescence, and the differentially expressed proteins in the inner ear of mice in each group were identified and analyzed by 4D-Label-free quantitative proteomics, and verified by Western blotting. The results were statistically analyzed by ANOVA and t test. Results:On the 7th day after noise exposure, there was no significant difference in hearing threshold between the control group and the noise exposure group at click and 8000 Hz acoustic stimulation ( P>0.05) . The hearing threshold in the noise exposure group was significantly higher than that in the control group under 16000 Hz acoustic stimulation ( P<0.05) . Confocal immunofluorescence showed that the basal membrane hair cells of cochlear tissue in noise exposure group were arranged neatly, but the relative expression of C-terminal binding protein 2 antibody of presynaptic membrane in middle gyrus and basal gyrus was significantly lower than that in control group ( P<0.05) . GO enrichment analysis showed that the functions of differentially expressed proteins were mainly concentrated in membrane potential regulation, ligand-gated channel activity, and ligand-gated ion channel activity. KEGG pathway enrichment analysis showed that differentially expressed proteins were significantly enriched in phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling pathway, NOD-like receptor signaling pathway, calcium signaling pathway, etc. Western blotting showed that the expression of inositol 1, 4, 5-trisphosphate receptor 3 (Itpr3) was increased and the expression of solute carrier family 38 member 2 (Slc38a2) was decreased in the noise exposure group ( P<0.05) . Conclusion:Through proteomic analysis, screening and verification of the differential expression proteins Itpr3 and Slc38a2 in the constructed mouse noise-induced hidden hearing loss model, the glutaminergic synaptic related pathways represented by Itpr3 and Slc38a2 may be involved in the occurrence of hidden hearing loss.

BACKGROUND: Chronic noise exposure is one environmental hazard that is associated with genetic susceptibility factors that increase Alzheimer's disease (AD) pathogenesis. However, the comprehensive understanding of the link between chronic noise stress and AD is limited. Herein, we investigated the effects of chronic noise exposure on AD-like changes in senescence-accelerated mouse prone 8 (SAMP8). METHODS: A total of 30 male SAMP8 mice were randomly divided into the noise-exposed group, the control group, and aging group (positive controls), and mice in the exposure group were exposed to 98 dB SPL white noise for 30 consecutive days. Transcriptome analysis and AD-like neuropathology of hippocampus were examined by RNA sequencing and immunoblotting. Enzyme-linked immunosorbent assay and real-time PCR were used to further determine the differential gene expression and explore the underlying mechanisms of chronic noise exposure in relation to AD at the genome level. RESULTS: Chronic noise exposure led to amyloid beta accumulation and increased the hyperphosphorylation of tau at the Ser202 and Ser404 sites in young SAMP8 mice; similar observations were noted in aging SAMP8 mice. We identified 21 protein-coding transcripts that were differentially expressed: 6 were downregulated and 15 were upregulated after chronic noise exposure; 8 genes were related to AD. qPCR results indicated that the expression of Arc, Egr1, Egr2, Fos, Nauk1, and Per2 were significantly high in the noise exposure group. These outcomes mirrored the results of the RNA sequencing data. CONCLUSIONS These findings further revealed that chronic noise exposure exacerbated aging-like impairment in the hippocampus of the SAMP8 mice and that the protein-coding transcripts discovered in the study may be key candidate regulators involved in environment-gene interactions.

Objective To observe the reception of using pig bone marrow stromal cells (BMSCs) that were transfected with human tissue factor pathway inhibitor (TFPI) to resolve the dysregulation of coagulation after liver xenotransplantation.Methods Pig BMSCs were immortalized by transfection with lentivirus containing SV40T and then transfection with human TFPI.At last the cells were tested for their ability to inhibit clotting in a model by co-incubation of human plasma,human monocytes and pig aortic endothelial cells.Results After transfection with SV40T,pig BMSCs were immortalized and similar to primary cells.The immortalized pig BMSCs showed a stable TFPI expression after transfection with human TFPI by lentivirus.Moreover,they showed the potential of regulating coagulation dysregulation in vitro.Conclusion Pig BMSCs transfected with human TFPI could solve the regulation dysregulation caused by TF activation effectively,and have the potential of resolving coagulation dysregulation in liver xenotransplantation.

OBJECTIVE:To study the protective effects of autophagy inhibitor 3-Methyladenine (3-MA) against lipopolysac-charide(LPS)-induced acute lung injury in mice and its mechanism. METHODS:Mice were randomly divided into normal control group,model group (LPS 15 mg/kg),drug control group (3-MA 20 mg/kg),low-dose and high-dose groups (LPS 15 mg/kg+3-MA 20,40 mg/kg),with 10 mice in each group. Except for normal control group and drug control group,other groups were giv-en LPS intraperitoneally to induce acute lung injury model,and drug control group and low-dose and high-dose groups were given equivalent dose of 3-MA intraperitoneally 1 h before modeling. 6 h after modeling,lung wet/drug mass ratio (W/D) was deter-mined respectively,and pathology change of lung tissue was observed by HE staining. TNF-α,NF-κB p65,LC3BⅡ/Ⅰ and Cleaved-caspase-3 protein expression were detected by Western blot. RESULTS:Compared with normal control group,W/D, TNF-α,NF-κB p65,LC3BⅡ/Ⅰ and Cleaved-caspase-3 protein expression increased in model group (P<0.01). Compared with model group,W/D,the expression of TNF-α,NF-κB p65,LC3BⅡ/Ⅰ and Cleaved-caspase-3 protein decreased in low-dose group (P<0.05),white just only LC3BⅡ/Ⅰ protein decreased high-dose group(P<0.01). CONCLUSIONS:In LPS-induced acute lung injury model in mice,the excessive autophagy could activate the NF-κB pathway and involve the inflammatory responses and induce lung cells apoptosis. The moderate autophagy inhibition by 3-MA can ameliorate inflammatory response and protect lung tissue.