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 construct a hypertension structured database based on Yi-9B large language model by aiming at the large amount of unstructured data generated in the process of hypertension diagnosis and treatment in order to elevate the efficiency of data management and provide the support for clinical deci-sion-making.Methods The key clinical informations of 114 369 patients with hypertension visiting in the Sec-ond Affiliated Hospital of Army Medical University during 2014-2023 were extracted.The Yi-9B large lan-guage model was used for conducting the entity identification and data structuring,and the database architec-ture was designed for statistical analysis and clinical application.Results After the database structuring process,the mean values of systolic and diastolic blood pressure were(149.98±20.55)mmHg and(86.90±13.75)mmHg,respectively.According to the classification of blood pressure level,the proportions of the nor-mal high value for high risk,very high risk of hypertension grade 1,and very high risk of hypertension grade 2 were the highest,which accounted for 20.73％,27.80％and 19.59％respectively.52.64％of the patients were complicated with heart disease,10.18％with complicating diabetes and 12.71％with complicating hy-perlipidemia.Logistic regression analysis showed that＞50-60 and＞60-70 years old was the high incidence age segment,moreover the systolic blood pressure showed an increasing trend with the age increase,reflecting the universality of hypertension in aging.This database significantly improved the efficiency of diagnosis and treatment in clinical application and realized the efficient analysis and management of data.Conclusion The hyper-tension structured database based on Yi-9B large language model effectively processes the unstructured data,significantly improves the efficiency of data extraction and management,helps to optimize the diagnosis and treatment decision-making,improves the management efficiency and provides the support for intelligent man-agement and personalized diagnosis and treatment.

Objective To construct the predictive model of pressure injury(PI)in the patients with chronic pain based on machine learning,and to analyze its accuracy and rationality,so as to provide an evidence for the predictive evaluation of clinical PI.Methods The clinical medical records data of 396 patients with chronic pain and high risk Braden scores hospitalized in a class 3A hospital of Chongqing City from March 2023 to June 2024 were retrospectively analyzed.Based on the Python3.10 programming language,the decision tree model,random forest model,linear regression model,naive Bayes model and K-Means model were con-structed,and the model performances were compared by accuracy,sensitivity,precision,F1 score and area un-der the receiver operating characteristic(ROC)curve(AUC).Results PI occurred in 35 cases with an inci-dence rate of 8.84%.Age,NRS score,pain site and pain affected sleep were the independent influencing fac-tors for the PI occurrence in the patients with chronic pain.Among 5 kinds of PI risk predictive model,the ac-curacy(0.873),sensitivity(0.874),precision(0.848),F1 score(0.844)and ROC AUC(0.81)of the ran-dom forest model were all higher than those of other models.Conclusion The random forest model has a high predictive performance for PI in the patients with chronic pain,and could be used for the screening and man-agement of high risk groups of PI in the patients with chronic pain.

Objective:To preliminarily investigate the safety and efficacy of programmed death-1(PD-1)inhibitor combined with cord blood-derived natural killer cells(NK cells)in the treatment of advanced malignant solid tumors in an exploratory clinical trial.Methods:Three patients with advanced solid tumors treated at the Second Affiliated Hospital of Xi'an Medical University from December 2019 to December 2021 were enrolled.According to tumor type and CSCO guidelines,patients received multiple treatment cycles(21 days per cycle)consisting of standard chemotherapy,targeted therapy,or bevacizumab combined with PD-1 inhibitor.Umbilical cord blood-derived NK cells(8×107 cells per infusion)were infused at appropriate intervals during the treatment course.Target lesion size,tumor markers,levels of 12 peripheral blood cytokines,and lymphocyte subsets were assessed in each treatment cycle.Adverse events were also monitored throughout the treatment.Results:Following the treatment with PD-1 inhibitor combined with cord blood NK cells,2 patients achieved stable disease(SD,per RECIST 1.1 criteria),with durations of 118 days and 92 days,respectively.After NK cell infusion,patient#1 exhibited a marked decrease in the tumor marker CA199 to normal range and sustained for three follow-up periods;patient#2 showed significant reductions in tumor markers CA199,CA242,and CA724.Conclusion:The combination of NK cells with chemotherapy and PD-1 inhibitor demonstrates potential therapeutic efficacy for solid tumors.No severe immune-related adverse reactions were observed in the three patients enrolled in this study.

Objective To investigate the impact of two different surgical methods, orthotopic kidney transplantation and abdominal heterotopic kidney transplantation, on the surgical outcomes of pig-to-pig kidney transplantation and the short-term survival of recipient pigs after surgery. Methods Twenty-four Bama miniature pigs were divided into two groups, with 12 pigs in each group, and underwent orthotopic kidney transplantation and abdominal heterotopic kidney transplantation, respectively. The perioperative indicators of the recipient pigs, renal blood perfusion, the overall incidence rate of complications and survival rate were compared between the two surgical methods. Results The total surgical time, renal artery anastomosis time, renal vein anastomosis time, cold ischemia time and total ischemia time were all shorter in the abdominal heterotopic kidney transplantation group than in the orthotopic kidney transplantation group, with statistically significant differences (all P<0.05). The number of satisfactory renal perfusion cases was higher in the abdominal heterotopic kidney transplantation group than in the orthotopic kidney transplantation group (83% vs. 75%), but the difference was not statistically significant (P>0.05). The total incidence of postoperative complications was 33% in the heterotopic kidney transplantation group, with a survival rate of 92%, and the cause of death was rupture of the vascular anastomosis. The total incidence of postoperative complications was 50% in the orthotopic kidney transplantation group, with a survival rate of 83%, and the causes of death were renal vein thrombosis and renal artery thrombosis. There were no statistically significant differences in the total incidence of postoperative complications and survival rates between the two groups (all P>0.05). Conclusions Compared with orthotopic kidney transplantation, abdominal heterotopic kidney transplantation showes better surgical outcomes in pig-to-pig kidney transplantation and is more beneficial for the short-term survival of recipient pigs after surgery. This provides experience for improving the stability of pig-to-non-human primate kidney xenotransplantation models in the future.

Long-term glucose metabolism disorders in patient with diabetes is often accompanied by dyslipidemia, especially the elevated level of low-density lipoprotein cholesterol (LDL-C). It is an important risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). Recent studies at home and abroad have also found that diabetes can lead to increased levels of proprotein convertase subtilisin/kexintype 9 (PCSK9). In view of the profound influence of PCSK9 overexpression on low density lipoprotein cholesterol level, cardiovascular risk and atherosclerosis, it is of great significance to explore whether hypoglycemic drugs can reduce the level of PCSK9 in the treatment of diabetes. We summarized the results of the study on the effects of various hypoglycemic drugs on circulating PCSK9 concentration in order to provide ideas for the optimal treatment of diabetes.

Long-term glucose metabolism disorders in patient with diabetes is often accompanied by dyslipidemia, especially the elevated level of low-density lipoprotein cholesterol (LDL-C). It is an important risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). Recent studies at home and abroad have also found that diabetes can lead to increased levels of proprotein convertase subtilisin/kexintype 9 (PCSK9). In view of the profound influence of PCSK9 overexpression on low density lipoprotein cholesterol level, cardiovascular risk and atherosclerosis, it is of great significance to explore whether hypoglycemic drugs can reduce the level of PCSK9 in the treatment of diabetes. We summarized the results of the study on the effects of various hypoglycemic drugs on circulating PCSK9 concentration in order to provide ideas for the optimal treatment of diabetes.

Objective To predict the tissue-level failure strain of the cortical bone and discuss the effects of different running speeds on the mechanical properties of rat femoral cortical bone.Methods The threshold for cortical bone tissue-level failure strain was assigned,and fracture simulation under three-point bending was performed on a rat femoral finite element model.The predicted load-displacement curves in each simulation were compared and fitted with the experimental data to back-calculate the tissue-level failure strain.Results The cortical bone tissue-level failure strains at different running speeds were statistically different,which indicated that different running speeds had certain impacts on the micromechanical properties of the cortical bone structures.At a running speed of 12 m/min,the cortical bone structure expressed the greatest tissue-level failure strain,and at a running speed of 20 m/min,the cortical bone structure expressed the lowest tissue-level failure strain.Conclusions Based on the changing trends of tissue-level failure strain and in combination with the changes in macro-level failure load and tissue-level elastic modulus of cortical bone structures,the effects of different running speeds on the mechanical properties of cortical bone structures were discussed in this study.The appropriate running speed for improving the mechanical properties of the cortical bone was explored,thereby providing a theoretical basis for improving bone strength through running exercises.

Nitrate is the main form of inorganic nitrogen that crop absorbs, and nitrate transporter 2 (NRT2) is a high affinity transporter using nitrate as a specific substrate. When the available nitrate is limited, the high affinity transport systems are activated and play an important role in the process of nitrate absorption and transport. Most NRT2 cannot transport nitrates alone and require the assistance of a helper protein belonging to nitrate assimilation related family (NAR2) to complete the absorption or transport of nitrates. Crop nitrogen utilization efficiency is affected by environmental conditions, and there are differences between varieties, so it is of great significance to develop varieties with high nitrogen utilization efficiency. Sorghum bicolor has high stress tolerance and is more efficient in soil nitrogen uptake and utilization. The S. bicolor genome database was scanned to systematically analyze the gene structure, chromosomal localization, physicochemical properties, secondary structure and transmembrane domain, signal peptide and subcellular localization, promoter region cis-acting elements, phylogenetic evolution, single nucleotide polymorphism (SNP) recognition and annotation, and selection pressure of the gene family members. Through bioinformatics analysis, 5 NRT2 gene members (designated as SbNRT2-1a, SbNRT2-1b, SbNRT2-2, SbNRT2-3, and SbNRT2-4) and 2 NAR2 gene members (designated as SbNRT3-1 and SbNRT3-2) were identified, the number of which was less than that of foxtail millet. SbNRT2/3 were distributed on 3 chromosomes, and could be divided into four subfamilies. The genetic structure of the same subfamilies was highly similar. The average value of SbNRT2/3 hydrophilicity was positive, indicating that they were all hydrophobic proteins, whereas α-helix and random coil accounted for more than 70% of the total secondary structure. Subcellular localization occurred on plasma membrane, where SbNRT2 proteins did not contain signal peptides, but SbNRT3 proteins contained signal peptides. Further analysis revealed that the number of transmembrane domains of the SbNRT2s family members was greater than 10, while that of the SbNRT3s were 2. There was a close collinearity between NRT2/3s of S. bicolor and Zea mays. Protein domains analysis showed the presence of MFS_1 and NAR2 protein domains, which supported executing high affinity nitrate transport. Phylogenetic tree analysis showed that SbNRT2/3 were more closely related to those of Z. mays and Setaria italic. Analysis of gene promoter cis-acting elements indicated that the promoter region of SbNRT2/3 had several plant hormones and stress response elements, which might respond to growth and environmental cues. Gene expression heat map showed that SbNRT2-3 and SbNRT3-1 were induced by nitrate in the root and stem, respectively, and SbNRT2-4 and SbNRT2-3 were induced by low nitrogen in the root and stem. Non-synonymous SNP variants were found in SbNRT2-4 and SbNRT2-1a. Selection pressure analysis showed that the SbNRT2/3 were subject to purification and selection during evolution. The expression of SbNRT2/3 gene and the effect of aphid infection were consistent with the expression analysis results of genes in different tissues, and SbNRT2-1b and SbNRT3-1 were significantly expressed in the roots of aphid lines 5-27sug, and the expression levels of SbNRT2-3, SbNRT2-4 and SbNRT3-2 were significantly reduced in sorghum aphid infested leaves. Overall, genome-wide identification, expression and DNA variation analysis of NRT2/3 gene family of Sorghum bicolor provided a basis for elucidating the high efficiency of sorghum in nitrogen utilization.
Nitrate Transporters ; Nitrates/metabolism* ; Sorghum/metabolism* ; Anion Transport Proteins/metabolism* ; Phylogeny ; Protein Sorting Signals/genetics* ; Nitrogen/metabolism* ; DNA ; Gene Expression Regulation, Plant ; Plant Proteins/metabolism*

Objective:To investigate the predictive value of MRI radiologic extranodal extension (rENE) for distant metastasis of prostate cancer (PCa).Methods:The data of 107 patients of initial visit with clinically diagnosed N1 PCa who underwent MRI and 68Ga-prostate specific membrane antigen (PSMA) PET/CT examinations were retrospectively analyzed at Xijing Hospital, Air Force Medical University from January 2017 to April 2022. The rENE was evaluated with MRI. According to the results of 68Ga-PSMA PET/CT, the patients were divided into the distant metastasis group (group M1, 87 cases) and the non-distant metastasis group (group M0, 20 cases). Independent sample t test, Mann-Whitney U test or χ 2 test were used to compare the differences in clinical indicators and rENE between the two groups. The multivariate logistic regression analysis was used to screen the independent risk factors affecting distant metastasis. The receiver operating characteristic (ROC) curve was used to evaluate the predictive efficacy of independent risk factors for PCa distant metastasis. Results:In group M1, 72 cases (82.8%) were rENE positive and 15 cases (17.2%) were rENE negative, and in group M0, 7 cases (35.0%) were rENE positive and 13 cases (65.0%) were rENE negative, and there was a statistically significant difference in rENE between the two groups (χ 2=19.20, P<0.001). There were significant differences in total prostate specific antigen level, International Society of Urological Pathology grade and T stage between the group M1 and the group M0 ( P<0.05). Multivariate logistic regression analysis showed that rENE (OR=6.248, 95%CI 1.807-21.600, P=0.004) was an independent risk factor for distant metastasis of PCa, and the area under the ROC curve of rENE in the diagnosis of distant metastasis of PCa was 0.739 (95%CI 0.607-0.871), the sensitivity was 82.8%, and the specificity was 65.0%. Conclusion:rENE is an independent predictor of distant metastasis of PCa, which has a high efficacy. Compared with patients with rENE negative, PCa patients with rENE positive have a higher degree of invasion and are more likely to have distant metastasis.