BACKGROUND: Pre-transplant exposure to immune checkpoint inhibitors (ICIs) significantly increases the risk of allograft rejection after liver transplantation (LT); however, whether ICI-related rejection leads to increased graft loss remains controversial. Therefore, this study aimed to investigate the association between ICI-related allograft rejection and perioperative graft loss. METHODS: This was a retrospective analysis of adult liver transplant recipients with early biopsy-proven T-cell-mediated rejection (TCMR) at Liver Transplantation Center of Sun Yat-sen Memorial Hospital from June 2019 to September 2024. The pathological features, clinical characteristics, and perioperative graft survival were analyzed. RESULTS: Twenty-eight patients who underwent early TCMR between June 2019 and September 2024 were included. Based on pre-LT ICI exposure, recipients were categorized into ICI-related TCMR (irTCMR, n = 12) and conventional TCMR (cTCMR, n = 16) groups. Recipients with irTCMR had a higher median Banff rejection activity index (RAI) (6 vs . 5, P = 0.012) and more aggressive tissue damage and inflammation. Recipients with irTCMR showed higher proportion of treatment resistance, achieving a complete resolution rate of only 8/12 compared to 16/16 for cTCMR. Graft loss occurred in 5/12 of irTCMR recipients within 90 days after LT, with no graft loss in cTCMRs recipients. Cox analysis demonstrated that irTCMR with an ICI washout period of <30 days was an independent risk factor for perioperative graft loss (hazard ratio [HR], 6.540; 95% confidence interval [CI], 1.067-40.067, P = 0.042). CONCLUSION IrTCMR is associated with severe pathological features, increased resistance to treatment, and higher graft loss in adult liver transplant recipients.
Humans ; Liver Transplantation/adverse effects* ; Male ; Female ; Middle Aged ; Retrospective Studies ; Graft Rejection/immunology* ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; T-Lymphocytes/drug effects* ; Graft Survival/immunology* ; Aged

Objective: To screen and identify the key active molecules, signaling pathways, and therapeutic targets of Shuxuening (SXN) injection for treating liver cirrhosis (LC) and to evaluate its therapeutic potential using a mouse model. Methods: Target genes of SXN and LC were retrieved from public databases, and enrichment analysis was performed. A protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and hub genes were identified using Molecular Complex Detection (MCODE). LC was induced in rats and mice via intraperitoneal injections of diethylnitrosamine and carbon tetrachloride (CCl4) for 12 weeks. Starting at week 7, SXN was administered intraperitoneally to the mice in the treatment group. Serum and liver tissues of the mice were collected for the detection of indicators, pathological staining, and expression analysis of hub targets using quantitative real-time polymerase chain reaction (qRT-PCR). Results: We identified 368 overlapping genes (OLGs) between SXN and LC targets. These OLGs were subsequently used to build a PPI network and to screen for hub genes. Enrichment analysis showed that these genes were associated with cancer-related pathways, including phosphoinositide-3-kinase/Akt and mitogen-activated protein kinase signaling and various cellular processes, such as responses to chemicals and metabolic regulation. In vivo experiments demonstrated that SXN treatment significantly improved liver function and pathology in CCl4-induced LC mice by reducing inflammation and collagen deposition. Furthermore, qRT-PCR demonstrated that SXN regulated the expression of MAPK8, AR and CASP3 in the livers of LC mice. Conclusion This study highlighted the therapeutic effects of SXN in alleviating LC using both bioinformatics and experimental methods. The observed effect was associated with modulation of hub gene expression, particularly MAPK8, and CASP3.

Resection of oral and maxillofacial tumors is often accompanied by the inferior alveolar nerve neurectomy, resulting in abnormal sensation in lower lip. It is generally believed that spontaneous sensory recovery in this nerve injury is difficult. However, during our follow-up, patients with inferior alveolar nerve sacrifice showed different degrees of lower lip sensory recovery. In this study, a prospective cohort study was conducted to demonstrate this phenomenon and analyze the factors influencing sensory recovery. A mental nerve transection model of Thy1-YFP mice and tissue clearing technique were used to explore possible mechanisms in this process. Gene silencing and overexpression experiments were then conducted to detect the changes in cell morphology and molecular markers. In our follow-up, 75% of patients with unilateral inferior alveolar nerve neurectomy had complete sensory recovery of the lower lip 12 months postoperatively. Patients with younger age, malignant tumors, and preservation of ipsilateral buccal and lingual nerves had a shorter recovery time. The buccal nerve collateral sprouting compensation was observed in the lower lip tissue of Thy1-YFP mice. ApoD was demonstrated to be involved in axon growth and peripheral nerve sensory recovery in the animal model. TGF-β inhibited the expression of STAT3 and the transcription of ApoD in Schwann cells through Zfp423. Overall, after sacrificing the inferior alveolar nerve, the collateral compensation of the ipsilateral buccal nerve could innervate the sensation. And this process was regulated by TGF-β-Zfp423-ApoD pathway.
Mice ; Animals ; Lip/innervation* ; Prospective Studies ; Mandibular Nerve/pathology* ; Sensation/physiology* ; Trigeminal Nerve Injuries/pathology*

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

OBJECTIVES: To study the early clinical efficacy of combined therapy of stage 4 neuroblastoma. METHODS: A retrospective analysis was performed on the medical data and follow-up data of 14 children with stage 4 neuroblastoma who were diagnosed in Hong Kong University-Shenzhen Hospital from January 2016 to June 2021. RESULTS: The median age of onset was 3 years and 7.5 months in these 14 children. Among these children, 9 had positive results of bone marrow biopsy, 4 had N-Myc gene amplification, 13 had an increase in neuron-specific enolase, and 7 had an increase in vanilmandelic acid in urine. Based on the results of pathological examination, differentiated type was observed in 6 children, undifferentiated type in one child, mixed type, in one child and poorly differentiated type in 6 children. Of all the children, 10 received chemotherapy with the N7 regimen (including 2 children receiving arsenic trioxide in addition) and 4 received chemotherapy with the Rapid COJEC regimen. Thirteen children underwent surgery, 14 received hematopoietic stem cell transplantation, and 10 received radiotherapy. A total of 8 children received Ch14.18/CHO immunotherapy, among whom 1 child discontinued due to anaphylactic shock during immunotherapy, and the other 7 children completed Ch14.18/CHO treatment without serious adverse events, among whom 1 child was treated with Lu177 Dotatate 3 times after recurrence and is still undergoing chemotherapy at present. The median follow-up time was 45 months for all the 14 children. Four children experienced recurrence within 2 years, and the 2-year overall survival rate was 100%; 4 children experienced recurrence within 3 years, and 7 achieved disease-free survival within 3 years. CONCLUSIONS Multidisciplinary combined therapy is recommended for children with stage 4 neuroblastoma and can help them achieve better survival and prognosis.
Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child ; Child, Preschool ; Combined Modality Therapy ; Humans ; Infant ; Neuroblastoma/drug therapy* ; Positron-Emission Tomography ; Radionuclide Imaging ; Retrospective Studies ; Treatment Outcome

The ongoing outbreak of the coronavirus disease 2019 (COVID-19) as named by the World Health Organization has millions of confirmed cases around the world and has claimed hundreds of thousands of lives. The virus was named SARS-CoV-2 in February by International Committee on Taxonomy of Viruses. COVID-19 presents as fever, dry cough, dyspnea, headache and pneumonia. In a small subset of severe cases, the disease quickly progresses to respiratory failure and even death. Since the 21st century, there have been three major outbreaks caused by human coronaviruses, including the severe acute respiratory syndrome (SARS) that broke out in 2003, the Middle East respiratory syndrome (MERS) in 2012, and the recent pandemic of COVID-19. Since 2003, significant progress has been made in the study of SARS-CoV and MERS-CoV concerning their natural origins, pathogenesis, antiviral development and vaccine design. Since SARS-CoV-2 and SARS-CoV are closely related, previous findings on SARS-CoV are highly relevant to a better understanding as well as diagnosis, treatment, prevention and control of SARS-CoV-2. In this review, we highlight recent progresses in the field; compare the biological characteristics of SARS-CoV and SARS-CoV-2; summarize the urgently-needed diagnostic, treatment, prevention and control options; and provide future perspectives for the outcome of the outbreak and research questions to be answered, including some of the difficulties in vaccine development. Hopefully, our comments and suggestions would prove useful for the control of the SARS-CoV-2 epidemic in China and the world.
Antiviral Agents ; pharmacology ; therapeutic use ; Betacoronavirus ; drug effects ; immunology ; pathogenicity ; Coronavirus Infections ; diagnosis ; prevention & control ; therapy ; virology ; Humans ; Middle East Respiratory Syndrome Coronavirus ; drug effects ; immunology ; pathogenicity ; Pandemics ; prevention & control ; Pneumonia, Viral ; diagnosis ; prevention & control ; therapy ; virology ; SARS Virus ; drug effects ; immunology ; pathogenicity ; Severe Acute Respiratory Syndrome ; diagnosis ; prevention & control ; therapy ; virology ; Viral Vaccines

BACKGROUNDTat-interacting protein 30 (TIP30) has been reported to be a tumor suppressor, with reduced or absent expression in various tumors. However, its role in bladder urothelial cancer (BUC) has not been investigated. Therefore, herein, we investigated the expression of TIP30 protein in BUC and normal bladder mucosa and the clinical significance of TIP30 expression in the prognosis of BUC.

METHODSWe reviewed data from 79 cases of BUC and 15 adjacent tissue samples from 79 patients treated at our institution between 2004 and 2007. TIP30 expression was examined by immunohistochemistry. The relationship between TIP30 expression and tumor stage, histological grade, and survival was analyzed. Differences between groups were evaluated using the t-test or matched-pairs test, and differences in the survival rates were analyzed with the log-rank test.

RESULTSTIP30 protein expression was significantly reduced in BUC tissue (t = -6.91, P < 0.05) compared with normal tissue samples, and in invasive bladder cancer (t = 10.89, P < 0.05) compared with superficial bladder cancer. TIP30 protein expression differed significantly among different differentiated groups classified either according to the World Health Organization (2004, F = 17.48, P < 0.01) or World Health Organization (1973, F = 10.68, P < 0.01). TIP30 protein expression was significantly reduced in high-grade papillary urothelial carcinoma compared with papillary urothelial neoplasm of low malignant potential (P < 0.05) and low-grade papillary urothelial carcinoma (P < 0.05). Meanwhile, TIP30 protein expression was significantly reduced in Grade III BUC, compared with Grade I (P < 0.05) and Grade II (P < 0.05). Patients with low TIP30 expression showed a higher incidence of disease progression than those with high TIP30 expression (t = 2.63, P < 0.05). Kaplan-Meier survival analysis showed a strong positive relationship between TIP30 expression and overall survival (OS) (χ2 = 17.29, P < 0.05).

CONCLUSIONSTIP30 expression was associated with clinical tumor stage in BUC, suggesting that it might play an important role in disease progression. Furthermore, TIP30 might predict postoperative OS. Thus, its evaluation might be useful for predicting prognosis.

BACKGROUNDSpine surgery using computer-assisted navigation (CAN) has been proven to result in low screw misplacement rates, low incidence of radiation exposure and excellent operative field viewing versus the conventional intraoperative image intensifier (CIII). However, as we know, few previous studies have described the learning curve of CAN in spine surgery.

METHODSWe performed two consecutive case cohort studies on pedicel screw accuracy and operative time of two spine surgeons with different experience backgrounds, A and B, in one institution during the same period. Lumbar pedicel screw cortical perforation rate and operative time of the same kind of operation using CAN were analyzed and compared using CIII for the two surgeons at initial, 6 months and 12 months of CAN usage.

RESULTSCAN spine surgery had an overall lower cortical perforation rate and less mean operative time compared with CIII for both surgeon A and B cohorts when total cases of four years were included. It missed being statistically significant, with 3.3% versus 4.7% (P = 0.191) and 125.7 versus 132.3 minutes (P = 0.428) for surgeon A and 3.6% versus 6.4% (P = 0.058), and 183.2 versus 213.2 minutes (P = 0.070) for surgeon B. In an attempt to demonstrate the learning curve, the cases after 6 months of the CAN system in each surgeon's cohort were compared. The perforation rate decreased by 2.4% (P = 0.039) and 4.3% (P = 0.003) and the operative time was reduced by 31.8 minutes (P = 0.002) and 14.4 minutes (P = 0.026) for the CAN groups of surgeons A and B, respectively. When only the cases performed after 12 months using the CAN system were considered, the perforation rate decreased by 3.9% (P = 0.006) and 5.6% (P < 0.001) and the operative time was reduced by 20.9 minutes (P < 0.001) and 40.3 minutes (P < 0.001) for the CAN groups of surgeon A and B, respectively.

CONCLUSIONSIn the long run, CAN spine surgery decreased the lumbar screw cortical perforation rate and operative time. The learning curve showed a sharp drop after 6 months of using CAN that plateaued after 12 months; which was demonstrated by both perforation rate and operative time data. Careful analysis of the data showed CAN is especially useful for less experienced surgeon to reduce perforation rate and intraoperative time, although further comparative studies are anticipated.

Cohort Studies ; Humans ; Spine ; surgery ; Surgery, Computer-Assisted ; methods

OBJECTIVETo investigate the relationship between the genetic polymorphisms of CYP3A5 and the clinical effectiveness of Bicyclol on patients with chronic hepatitis B to make individual medication possible.

METHODS34 cases of chronic hepatitis B were treated by bicyclol tablets for 24 weeks. Liver function indexes (ALT and AST) were determined before and after treatment. Blood CYP3A5 genotyping of each patient was determined by the PCR-RFLP analysis.

RESULTSAll subjects were genotyped for the CYP3A5*3 gene and divided into different group. The groups comprised subjects with CYP3A5*3 carriers (n=18) and CYP3A5*1 carriers (n=16) which include CYP3A5*1/*1 (n=2) and CYP3A5*1/*3 (n=14). Compared with pre-treatment, the serum ALT and AST levels were decreased obviously in all patients. The mean percentage reduction of serum ALT and AST levels were significantly greater in subjects with CYP3A5*3 carriers (79.73% and 74.76%) than in those with CYP3A5*1 carriers (65.90% and 49.63%; P < 0.05) The recovery rates of ALT and AST were significantly highter in CYP3A5*3 carriers than those in CYP3A5*1 carriers (P < 0.05).

CONCLUSIONCYP3A5 genotype has an impact on the therapeutic effects of Bicyclol. The subjects with CYP3A5*3 carriers is more effective than the subjects with CYP3A5*1 carriers. CYP3A5 genotyping may be helpful in predicting therapeutic effects of Bicyclol especially in the terms of decreasing ALT and AST.

Adolescent ; Adult ; Alanine Transaminase ; blood ; Biphenyl Compounds ; pharmacology ; therapeutic use ; Cytochrome P-450 CYP3A ; genetics ; Female ; Genotype ; Hepatitis B, Chronic ; blood ; drug therapy ; genetics ; physiopathology ; Humans ; Liver ; drug effects ; enzymology ; physiopathology ; Male ; Middle Aged ; Polymorphism, Genetic

Objective To determine the value and the optimal cutoff point of waist circumference (WC) in screening diabetes mellitus (DM) and to provide evidence for DM prevention and identifying population at risk in mid-western rural areas of Shandong province.Methods A sample consisting 16 341 rural residents was selected and studied.All participants were physically examined on height,weight,WC and fasting plasma glucose (FPG).Oral glucose tolerance test (OGTT) was performed for subjects with FPG valued from 6.1 to 7.0 mmol/L.DM was defined according to the criteria set by WHO in 1999.Area under the curve (AUC),sensitivity,specificity and Youden index were computed based on the receiver operating characteristic (ROC) curve analysis.Optimal cutoff point was determined by the maximum of Youden index.Results The prevalence rates of DM for males and females increased along with the rise of WC (trend test X2=72.01,122.65,P＜0.01 ).It appeared significantly higher in those with WC 85 cm in females and≥80 cm in males,with those WC ＜85 cm for females and ＜80 cm for males,in particular.AUCs were 0.639 and 0.655 for males and females respectively and both had significant differences (t=7.22,11.07,P ＜0.01 ).However,the AUCs did not show significant difference (t=0.70,P ＞ 0.05) between males and females.The Youden index reached maximum when WC approached 85 cm for females (24.90%) and 80 cm for males (24.39%).The sensitivity and specificity were 58.04%and 66.86%for males,and 67.08%and 57.31%for females.Conclusion WC seemed to be an effective indicator for screening the DM.The optimal cutoff point of WC would be 85 cm for females and 80 cm for males in screening DM and defining the population at risk in this area.