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

Chloropicrin is a commonly used pesticide in agricultural production. The clinical manifestations of oral poisoning patients are complex, and the lesions involve multiple organs. At present, the specific pathogenic mechanism of such poisoning is not clear, and the treatment experience is insufficient, so there are certain difficulties in clinical diagnosis, treatment and treatment. In this paper, the data of a patient with oral chloropicrin poisoning treated in Yidu Central Hospital of Weifang City in April 2023 were summarized. The patient was admitted to our hospital for treatment in time, and his condition improved after Hemopurification, methylene blue reduction, organ support, infection prevention as well as other symptomatic support. Oral chlorophenol can cause lung damage, skin and mucous membrane damage, and may have certain effects on the nervous system and kidney. Early intervention, especially blood purification, is effective.

Chloropicrin is a commonly used pesticide in agricultural production. The clinical manifestations of oral poisoning patients are complex, and the lesions involve multiple organs. At present, the specific pathogenic mechanism of such poisoning is not clear, and the treatment experience is insufficient, so there are certain difficulties in clinical diagnosis, treatment and treatment. In this paper, the data of a patient with oral chloropicrin poisoning treated in Yidu Central Hospital of Weifang City in April 2023 were summarized. The patient was admitted to our hospital for treatment in time, and his condition improved after Hemopurification, methylene blue reduction, organ support, infection prevention as well as other symptomatic support. Oral chlorophenol can cause lung damage, skin and mucous membrane damage, and may have certain effects on the nervous system and kidney. Early intervention, especially blood purification, is effective.

Background::A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI.Methods::In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints.Results::From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA ( n = 384) or rt-PA ( n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a –15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: –3.4%; 95% confidence interval [CI]: –11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: –0.5%; 95% CI: –5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. Conclusion::rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI.Trial registration::www.ClinicalTrials.gov (No. NCT02835534).

Objective: To investigate the relationship between total homocysteine (tHcy) levels and sarcopenia among the elderly, so as to provide insights into the prevention and treatment of sarcopenia. Methods: The elderly aged 65 years and older who participated in the physical examination of Shibantan Township Health Center in Xindu District, Chengdu City from April to June 2021 was selected as the study subjects. The elderly with sarcopenia (diagnosed according to the diagnostic criteria of the Asian Sarcopenia Working Group in 2019) and non-sarcopenia were matched 1︰1 by gender and age (±2 years). Demographic information, skeletal muscle mass, skeletal muscle strength and tHcy were collected through questionnaire surveys, physical examination and laboratory testing. Multivariable conditional logistic regression model was used to explore the relationship between tHcy and sarcopenia. Results: A total of 320 individuals, including 160 sarcopenia patients and 160 non-sarcopenia individuals, were investigated. There were 138 males (43.13%) and 182 females (56.87%), with a median age of 71.00 (interquartile range, 6.00) years. There were 57 drinkers (17.81%), 78 smokers (24.37%), 173 cases of hypertension (54.06%) and 124 cases of hyperhomocysteinemia (38.80%). Multivariable conditional logistic regression analysis showed that elevated tHcy was associated with an increased risk of sarcopenia (OR=1.107, 95%CI: 1.024-1.197), after adjusting for smoking, alcohol consumption, hypertension, waist circumference, neck circumference, body mass index, platelet count and high density lipoprotein cholesterol. Conclusion Elevated tHcy is associated with sarcopenia, and intervention should be carried out for the elderly with higher tHcy.

Idiopathic oligoasthenospermia （IO） has been increasingly emphasized in the diagnosis and treatment of male infertility. Oxidative stress damage directly affects sperm quality and spermatogenesis， constituting a major causative factor of IO. Firstly， due to its high content of polyunsaturated fatty acids， the sperm plasma membrane is highly sensitive to reactive oxygen species （ROS）， leading to lipid peroxidation accumulation and even inducing ferroptosis. Secondly， deficient downstream key proteins in the base excision repair pathway render sperm unable to repair extensive DNA oxidative damage under oxidative stress. Simultaneously， under oxidative stress， the apoptotic pathway of sperm is cascade-activated， causing rapid loss of motility. ROS further disrupts the hypothalamic-pituitary-gonadal axis， inhibiting testosterone production and ultimately affecting spermatogenesis. Wuzi Yanzongwan，in line with traditional Chinese medicine theory of treating IO through "nourishing kidney essence and harmonizing Yin and Yang"， clinically demonstrates its ability to improve sperm morphology， count， and motility， thereby enhancing male fertility. The research on the pharmacological constituents of Wuzi Yanzongwan primarily involves establishing a characteristic spectrum of Chinese medicine to achieve quality control and exploring the pharmacology of effective components. Studies have found that its main active ingredients consist of flavonoids and phenylpropanoids. Specifically， compounds such as hyperin， acteoside， kaempferol， and schisandrin A are identified as the primary active substances and quality control components. These compounds exhibit strong antioxidant activity and have been partly applied in research related to reproductive endocrine disorders. Tripterygium glycoside is primarily used for modeling of oxidative stress-induced IO. It leads to the accumulation of various lipid peroxides in testicular tissues and concurrently compromises the body's antioxidant capacity. Mechanistic studies have found that Wuzi Yanzongwan can inhibit elevated ROS levels in IO models and enhance the body's antioxidant capacity， thereby ameliorating inflammation， suppressing cell apoptosis， promoting testosterone production， and ultimately alleviating the decline in sperm quality and spermatogenesis caused by oxidative stress.

Objective:To evaluate the cervical elasticity in pregnant women with singleton pregnancies exhibiting symptoms of threatened preterm labor using E-cervix elastography, and provide a basis for assessing the risk of preterm birth.Methods:This prospective cohort study included pregnant women with singleton pregnancies between 20 +0 and 32 +6 weeks of gestation and no history of preterm birth who developed symptoms of threatened preterm labor and attended the obstetrics outpatient clinic of the Hunan Provincial Maternal and Child Health Care Hospital from May 2022 to May 2023. Several cervical elastography data, including cervical length (CL), hardness ratio (HR), internal ostium (IOS), and external ostium (EOS), were obtained using E-cervix technology, and the differences in these data were compared between women with different pregnancy outcomes (preterm or full-term birth) or different CLs. Statistical analysis was performed using covariance analysis (adjusted for gestational age), Chi-square test or corrected Chi-square test, and Pearson correlation analysis. Results:A total of 120 pregnant women were included, with 39 (32.5%) in the preterm group and 81 (67.5%) in the full-term group. There were 41 women (34.2%) with CL≤25 mm and 79 (65.8%) with CL>25 mm. Among the 41 women with CL≤25 mm, 26 had preterm birth and 15 delivered at term. Compared with the full-term group, the preterm group had a lower cervical HR [(35.75±8.94)% vs. (61.30±10.69)%, F=156.88], but higher IOS and EOS (0.47±0.13 vs. 0.31±0.09, F=54.99; 0.45±0.11 vs. 0.34±0.08, F=34.57) (all P<0.001). The patients with CL≤25 mm had a lower cervical HR [(43.17±14.32)% vs. (58.09±13.94)%, F=26.03], but higher IOS and EOS (0.46±0.14 vs. 0.32±0.08, F=38.71; 0.44±0.12 vs.0.34±0.08, F=21.36) as compared with those with CL>25 mm, with all differences being statistically significant (all P<0.001). Among the women with CL≤25 mm, preterm birth cases had lower cervical HR but higher IOS and EOS than those delivered at term (all P<0.001). In both CL≤25 mm and CL>25 mm groups, the preterm birth rate was higher in patients with HR<50% than in those with HR≥50% [95.5% (21/22) vs. 5/19, χ2=21.01, P<0.001; 61.9% (13/21) vs. 0.0% (0/58), corrected χ2=38.59, P<0.001]. Besides, an increased preterm birth rate was also observed in patients with HR<40% as compared with those with HR≥40% regardless of the CL [CL≤25 mm: 18/18 vs. 34.8% (8/23), χ2=18.51, P<0.001; CL>25 mm: 11/14 vs. 3.1% (2/65), corrected χ2=42.42, P<0.001]. Pearson correlation analysis showed that there was a significant positive correlation between CL and HR ( r=0.51, P<0.001). Conclusion:E-cervix elastography can quantify the hardness of cervical tissue, and identify truly "soft" cervices that are associated with high risk of preterm birth, showing great potential as a more efficient new technology for predicting preterm birth.

This study aims to investigate the protective effect of resveratrol against liver injury in hindlimb unloading rats. Thirty 2-month-old male SD rats were randomly divided into normal group (Control), hindlimb unloading model group (Model), and hindlimb unloading+resveratrol administration group (Model+Res). The Model + Res group was injected intraperitoneally with 30 mg/kg of resveratrol, and the Control and Model groups were injected intraperitoneally with an equal volume of 0.9% NaCl. Liver tissues were collected after 28 days and analyzed for oxidative stress, inflammatory factors, energy metabolism indices, Na ⁺-K ⁺-ATPase and Ca ²⁺-Mg ²⁺-ATPase activity, and morphological changes were observed by hematoxylin-eosin staining. The protein expression levels of Bax, Bcl-2, p-PI3K, PI3K, p-AKT, and AKT were detected by Western blotting. Compared with the Control group, hepatocytes in the Model group showed swelling, abnormal morphology, nuclear consolidation, and cell membrane disruption. Oxidative stress, inflammatory factor levels, hepatic glycogen accumulation, and energy metabolism were increased in the liver tissues of the Model group, while resveratrol treatment significantly reversed these changes. The results of Western blotting showed that resveratrol significantly reduced the expression of Bax and increased the expression levels of Bcl-2, and the proteins of p-PI3K/PI3K and p-AKT/AKT expression levels. It is suggested that 28 days of hindlimb unloading treatment could lead to liver tissue injury in rats, which is manifested as oxidative stress, inflammatory response, energy metabolism disorder and increased apoptosis level, and resveratrol has a certain mitigating effect on this.
Animals ; Resveratrol ; Male ; Liver/pathology* ; Rats, Sprague-Dawley ; Rats ; Hindlimb Suspension ; Oxidative Stress/drug effects* ; Phosphatidylinositol 3-Kinases/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Stilbenes/pharmacology* ; bcl-2-Associated X Protein/metabolism* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Apoptosis/drug effects*

The dynamic tracking of antibody‒drug conjugates (ADCs) in serum is crucial. However, a versatile bioanalytical platform is lacking due to serious matrix interferences, the heterogeneity and complex biotransformation of ADCs, and the recognition deficiencies of traditional affinity technologies. To overcome this, a multiepitope recognition technology (MERT) was developed by simultaneously immobilizing CDR and non-CDR ligands onto MOF@AuNPs. MERT's excellent specificity, ultrahigh ligand density, and potential synergistic recognition ability enable it to target the different key regions of ADCs to overcome the deficiencies of traditional technologies. The binding capacity of MERT for antibodies is ten to hundred times higher than that of the mono-epitope or Fc-specific affinity technologies. Since MERT can efficiently capture target ADCs from serum, a novel bioanalytical platform based on MERT and RPLC‒QTOF-MS has been developed to monitor the dynamic changes of ADCs in serum, including the fast changes of drug-to-antibody ratio from 3.67 to 0.22, the loss of payloads (maytansinol), and the unexpected hydrolysis of the succinimide ring of the linker, which will contribute to clarify the fate of ADCs and provide a theoretical basis for future design. In summary, the MERT-based versatile platform will open a new avenue for in-depth studies of ADCs in biological fluids.

Dynamic tracking analysis of monoclonal antibodies (mAbs) biotransformation in vivo is crucial, as certain modifications could inactivate the protein and reduce drug efficacy. However, a particular challenge (i.e. immune recognition deficiencies) in biotransformation studies may arise when modifications occur at the paratope recognized by the antigen. To address this limitation, a multi-epitope affinity technology utilizing the metal organic framework (MOF)@Au@peptide@aptamer composite material was proposed and developed by simultaneously immobilizing complementarity determining region (CDR) mimotope peptide (HH24) and non-CDR mimotope aptamer (CH1S-6T) onto the surface of MOF@Au nanocomposite. Comparative studies demonstrated that MOF@Au@peptide@aptamer exhibited significantly enhanced enrichment capabilities for trastuzumab variants in comparison to mono-epitope affinity technology. Moreover, the higher deamidation ratio for LC-Asn-30 and isomerization ratio for HC-Asn-55 can only be monitored by the novel bioanalytical platform based on MOF@Au@peptide@aptamer and liquid chromatography-quadrupole time of flight-mass spectrometry (LC-QTOF-MS). Therefore, multi-epitope affinity technology could effectively overcome the biases of traditional affinity materials for key sites modification analysis of mAb. Particularly, the novel bioanalytical platform can be successfully used for the tracking analysis of trastuzumab modifications in different biological fluids. Compared to the spiked phosphate buffer (PB) model, faster modification trends were monitored in the spiked serum and patients' sera due to the catalytic effect of plasma proteins and relevant proteases. Differences in peptide modification levels of trastuzumab in patients' sera were also monitored. In summary, the novel bioanalytical platform based on the multi-epitope affinity technology holds great potentials for in vivo biotransformation analysis of mAb, contributing to improved understanding and paving the way for future research and clinical applications.