Objective To mine and analyze cutaneous adverse drug event(ADE)of eight antibody-drug conjugates(ADC),and to ensure the safe clinical use of ADC drugs.Methods The data was obtained from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)for the period from the third quarter of 2011 to the fourth quarter of 2023.The cutaneous ADE associated with 8 eight ADC drugs were identified through the process of specification and standardization of nomenclature.The potential ADE signals were detected using the reporting odds ratio and Bayesian confidence propagation neural network methods.Results A total of 124 234 ADE reports were identified with the 8 ADC drugs as the first suspected drugs,including 5 184 reports of cutaneous ADEs adverse reactions,involving 3 225 patients.A total of 72 preferred term signals were detected for the 8 ADC drugs.The highest number of signals were detected for enfortumab vedotin,followed by ado-trastuzumab emtansine and brentuximab vedotin.Except for detrolizumab,the first-day incidence of cutaneous ADEs associated with the remaining 7 ADC drugs was less than 30％.The median time of occurrence for the 7 drugs,excluding brentuximab vedotin,was within one course of treatment(21 d).Conclusion The risks of cutaneous ADEs was variable with ADC drugs,occurs early in treatment and poses a potential life-threatening danger.Therefore,clinical vigilance and close monitoring of skin conditions are essential during ADC drug use.

Objective: To investigate the effects of lactoprotein iron chelates on rats with iron deficiency anaemia (IDA), so as to provide insights into developing and utilizing novel iron supplements. Methods: Seventy weaning female SPF-graded rats of the SD strain were randomly divided into the control group (A), model group (B), ferrous sulfate group (C), lactoferrin group (D), lactoferrin iron chelate group (E), Casein oligopeptide iron chelate group (F) and whey protein oligopeptide iron chelate group (G), with 10 rats in each group. The rats in group A were fed with normal diet, and the others were fed with poor iron diet for IDA modeling. The corresponding interventions were given by intragastric administration once a day. The iron ion concentrations of group C, E, F and G were 2.0 mg/kg, and the protein and oligopeptide concentrations of group D, E, F and G were 2 000 mg/kg. Body weight and hemoglobin of rats were measured weekly during 21-day intervention. At the end, peripheral blood samples were collected, and blood routine, iron metabolism and liver function indicators were determined. Results: After the intervention, among blood routine indicators, the rats in group C, E, F and G showed elevated hemoglobin, red blood cell, mean corpuscular volume and hematocrit, and decreased free protoporphyrin and mean corpuscular hemoglobin concentration when compared with the rats in group B (all P<0.05); among iron metabolism indicators, the rats in group C, E and G showed elevated serum ferritin, the rats in group C, E, F and G showed elevated serum iron, the rats in group C, D, E, F and G showed decreased unsaturated iron binding capacity and total iron binding capacity when compared with the rats in group B (all P<0.05); among liver function indicators, the rats in group E and G showed decreased alanine transaminase when compared with the rats in group B (both P<0.05). Conclusions Lactoprotein alone could not completely improve IDA in rats compared with traditional iron supplement (ferrous sulfate). Lactoprotein iron chelate, especially whey protein oligopeptide iron chelate, could significantly improve IDA, iron reserve and liver function damage in rats.

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE^-/-LDLR^-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

Objective:To investigate the clinical features of IgD multiple myeloma (MM) and the effect and prognosis of daratumumab-based combination therapy.Methods:The clinicopathological data of a IgD MM patient with disease progression and extramedullary infiltration treated with daratumumab in the Affiliated Hospital of Qingdao University in December 2019 were retrospectively analyzed.Results:The 74-year-old woman was diagnosed as IgD MM by bone marrow aspiration and immunofixation electrophoresis. The patient was given VD (bortezomib, dexamethasone), RD (lenalidomide, dexamethasone) and ID (ixazomib, dexamethasone) regimens. In June 2020, the patient developed multiple subcutaneous nodules, and she was assessed as progressive disease with extensive extramedullary infiltration. After treated with daratumumab-PAD (liposomal doxorubicin, bortezomib, dexamethasone) regimen, the patient's subcutaneous nodules were significantly reduced and partially disappeared, and the general condition was significantly improved. But the patient was in a cachexia state and finally died of the irregular treatment and disease progression.Conclusions:IgD MM has a low incidence and a short survival period, and there is no uniform standard treatment. The early application of daratumumab combined with proteasome inhibitors, immunomodulators, cytotoxic drugs and hematopoietic stem cell transplantation may improve the overall survival of patients.

Objective:To investigate the clinical efficacy and prognosis of transjugular intrahepatic portosystemic shunt (TIPS) and drug combined with endoscopic treatment in patients with liver cirrhosis and esophagogastric variceal bleeding (EGVB).Methods:From January 2012 to December 2013, at the First Affiliated Hospital of Xi′an Jiaotong University, the data of 147 patients with liver cirrhosis and EGVB undergoing TIPS or drug combined with endoscopic treatment were retrospectively collected, with 87 cases in TIPS treatment group and 60 in drug combined with endoscopic treatment group.The 5 years follow-up data were analyzed, and the overall survival rates, rebleeding-free survival rates and hepatic encephalopathy-free survival rates at 6 weeks, 1 year, 2 years and 5 years after treatment of two groups were compared. Independent sample t test, Mann-Whitney U test, chi-square test, Fisher exact test, Z test, log-rank test and trend test were used for statistical analysis. Results:There were no significant differences in age, gender, etiology, Child-Pugh classification, initial liver function, coagulation function, liver ascites, previous history of hepatic encephalopathy, blood pressure and preoperative blood transfusion history between the TIPS treatment group and combination of drugs and endoscopy treatment group (all P>0.05). Forty-one patients died within 5 years, of which 20 (48.8%) died of rebleeding and 6 (14.6%) died of hepatic encephalopathy. There were no significant differences in 6-week, 1-year and 2-year overall survival rates between the TIPS group and drug combined with endoscopic treatment group (all P>0.05), however the 5-year overall survival rate of the TIPS treatment group was higher than that of the drug combined with endoscopic treatment group (78.4% vs. 63.2%), and the difference was statistically significant ( Z=2.06, P=0.048). The 6-week, 1-year, 2-year, 5-year rebleeding-free survival rates of the TIPS group were 97.7%, 96.5%, 88.9% and 70.9%, respectively, which were all higher than those of the drug combined with endoscopic treatment group (86.7%, 53.3%, 43.3% and 27.1%), and the differences were statistically significant ( Z=2.35, 6.39, 6.26 and 4.80, all P<0.05). There were no significant differences in hepatic encephalopathy-free survival rates at 6 weeks, 1 year and 2 years after treatment between the TIPS group and drug combined with endoscopic treatment group (all P>0.05), however the 5-year hepatic encephalopathy-free survival rate of the TIPS treatment group was lower than that of the drug combined with endoscopic treatment group (67.7% vs. 86.7%), and the difference was statistically significant ( Z=2.28, P=0.030). The lower the Child-Pugh classification, the higher the cumulative 5-year survival rate ( χ2=6.75, P<0.01). There was no statistically significant difference in the 5-year overall survival rate in patients with the same Child-Pugh classification between the TIPS group and the drug combined with endoscopic treatment group (all P>0.05). Conclusions:The efficacy of TIPS is better than that of the drug combined with endoscopic treatment in treating EGVB. Even the long-term risk of hepatic encephalopathy of TIPS is higher, the short-term, middle-term and long-term rebleeding rate are decreased. Patients with Child-Pugh grade C do not need to avoid TIPS when choosing the treatment, the earlier the TIPS used, the better survival benefit will be obtained.

Neoadjuvant therapy has become the first choice for locally advanced esophageal carcinoma. Patients with post-neoadjuvant positive lymph node staging (ypN+) have poor prognosis, and there is no effective adjuvant therapy. Programmed death protein-1 (PD-1) antibody can obtain better clinical efficacy in the treatment of advanced esophageal cancer. The authors designed a multicenter, prospective, randomized controlled clinical trial of Toripalimab (PD-1 antibody) adjuvant therapy on esophageal squamous cell carcinoma patients with ypN+ after the treatment of neoadjuvant chemotherapy combined with surgical resection, in order to provide clinical practices for the adjuvant treatment of ypN+ patients.

Despite recent studies, relatively few are known about the diversity of fungal communities in the deep Atlantic Ocean. In this study, we investigated the diversity of fungal communities in 15 different deep-sea sediments from the South Atlantic Ocean with a culturedependent approach followed by phylogenetic analysis of ITS sequences. A total of 29fungal strains were isolated from the 15 deep-sea sediments. These strains belong to four fungal genera, including Aspergillus, Cladosporium, Penicillium, and Alternaria. Penicillium, accounting for 44.8% of the total fungal isolates, was a dominant genus. The antiaflatoxigenic activity of these deep-sea fungal isolates was studied. Surprisingly, most of the strains showed moderate to strong antiaflatoxigenic activity. Four isolates, belonging to species of Penicillium polonicum, Penicillium chrysogenum, Aspergillus versicolor, and Cladosporium cladosporioides, could completely inhibit not only the mycelial growth of Aspergillus parasiticus mutant strain NFRI-95, but also the aflatoxin production. To our knowledge, this is the first report to investigate the antiaflatoxigenic activity of culturable deep-sea fungi. Our results provide new insights into the community composition of fungi in the deep South Atlantic Ocean. The high proportion of strains that displayed antiaflatoxigenic activity demonstrates that deep-sea fungi from the Atlantic Ocean are valuable resources for mining bioactive compounds.

Despite recent studies, relatively few are known about the diversity of fungal communities in the deep Atlantic Ocean. In this study, we investigated the diversity of fungal communities in 15 different deep-sea sediments from the South Atlantic Ocean with a culturedependent approach followed by phylogenetic analysis of ITS sequences. A total of 29fungal strains were isolated from the 15 deep-sea sediments. These strains belong to four fungal genera, including Aspergillus, Cladosporium, Penicillium, and Alternaria. Penicillium, accounting for 44.8% of the total fungal isolates, was a dominant genus. The antiaflatoxigenic activity of these deep-sea fungal isolates was studied. Surprisingly, most of the strains showed moderate to strong antiaflatoxigenic activity. Four isolates, belonging to species of Penicillium polonicum, Penicillium chrysogenum, Aspergillus versicolor, and Cladosporium cladosporioides, could completely inhibit not only the mycelial growth of Aspergillus parasiticus mutant strain NFRI-95, but also the aflatoxin production. To our knowledge, this is the first report to investigate the antiaflatoxigenic activity of culturable deep-sea fungi. Our results provide new insights into the community composition of fungi in the deep South Atlantic Ocean. The high proportion of strains that displayed antiaflatoxigenic activity demonstrates that deep-sea fungi from the Atlantic Ocean are valuable resources for mining bioactive compounds.

OBJECTIVE： To study the mechanism of analgesic effect of 8-O-acetyl-safalinoside （8-OaS） on chronic inflammatory pain model rats. METHODS ：Totally 30 male SD rats were divided into sham operation group （normal saline ）， model group （normal saline ），8-OaS low-dose ，medium-dose and high-dose groups （3，10，30 μg/kg），with 6 rats in each group. Except for sham operation group ，other groups were given planter injection of Freund ’s complete adjuvant to induce chronic inflammatory pain model. After successful modeling ，the rats in each group were given corresponding drugs intrathecally ，once a day，for 7 consecutive days. Then Von-Frey filaments were used to detect the planter pain threshold of the rats in each group ；the area under the planter pain threshold curve of each group and the half effective dose （ED50）of 8-OaS were calculated. Another 36 male SD rats were divided into sham operation group （normal saline ），model group （normal saline ）and 8-OaS group （dose of ED50），and the modeling method and administration route were the same as above. Immunofluorescence histochemical staining was used to observe the positive expression of ionized calcium binding adapter molecule 1（Iba-1）and signal molecule phosphorylated p38 mitogen-activated protein kinase （p-p38 MAPK）；Western blotting assay was used to determine the expression of Iba- 1，p-p38 MAPK，IL-1β，IL-6 and TNF-α in spinal dorsal horn of rats. RESULTS：Compared with sham operation group ，plantar pain threshold and area under the curve in model group were reduced significantly （P＜0.01）. Compared with model group ，plantar pain threshold increased significantly after 5，6，7 days of administration in 8-OaS low-dose group （P＜0.05），plantar pain threshold and area under the curve in 8-OaS medium-dose and high-dose groups were increased significantly （P＜0.05 or P＜0.01）. Most of above indexes in each dose group of 8-OaS were signifficantly different ，and ED 50 of 8-OaS was 18.87 μ g/kg. Results of immunohistochemistry staining and Western blotting showed that p-p 38 MAPK was mainly expressed in Iba- 1 positive cells. Compared with sham operation group ，the fluorescence density of Iba- 1 and p-p 38 MAPK in spinal dorsal horn ，the expression of Iba-1，p-p38 MAPK，IL-6，IL-1β and TNF-α were significantly increased in model group（P＜0.05 or P＜0.01）. Compared with model group ，the fluorescence density of Iba- 1 and p-p 38 MAPK in spinal dorsal horn ，the expression of Iba- 1，p-p38 MAPK， IL-6，IL-1β and TNF-α were decreased significantly in 8-OaS group （P＜0.05）. CONCLUSIONS ：Intrathecal administration of 8-OaS can effectively alleviate chronic inflammatory pain in rats. The mechanism may be related to the inhibition of the phosphorylation of p 38 MAPK and the expression of IL- 6，IL-1β and TNF-α.

Objective: To investigate the changes and clinical significance of Caveolin-1, matrix metalloproteinase-9(MMP-9) and interleukin-1β(IL-1β)in cerebrospinal fluid of children with bacterial meningitis or viral encephalitis. Methods: Thirty-six cases of children with bacterial meningitis, 42 cases of children with viral encephalitis, and 20 cases of children with non-nervous system infection were selected from September 2016 to June 2018 at the Third Affiliated Hospital of Zhengzhou University.The levels of Caveolin-1, MMP-9 and IL-1β in cerebrospinal fluid were detected by using enzyme linked immunosorbent assay(ELISA). Results: Cerebrospinal fluid Caveolin-1, MMP-9 , IL-1β levels in the acute phase of bacterial meningitis were(49.06±8.96) ng/L, (134.79±18.88) μg/L, (100.02±14.67) μg/L, respectively, and (29.13±7.25) ng/L, (18.69±7.23) μg/L, (47.57±8.95) μg/L in recovery phase, which were higher than those of the controls[(11.18±2.24) ng/L, (11.53±3.54) μg/L, (39.75±7.08) μg/L)], and the differences were significant (all P<0.05). Cerebrospinal fluid Caveolin-1, MMP-9, IL-1β levels in the acute phase of viral encephalitis were (42.71±10.48) ng/L, (62.78±17.39) μg/L, (57.97±11.28) μg/L, respectively, and (29.13±7.25) ng/L, (18.69±7.23) μg/L, (47.57±8.95) μg/L in recovery phase, which were higher than those of controls, and the differences were significant (all P<0.05). The levels of Caveolin-1, MMP-9 and IL-1β in cerebrospinal fluid of bacterial meningitis group and viral encephalitis group were significantly higher than those of convalescent group (all P<0.05). The levels of Caveolin-1, MMP-9, IL-1β in cerebrospinal fluid of bacterial meningitis group were significantly higher than those in viral encephalitis group (all P<0.05) in the acute phase, and no significant difference was found in the recovery phase(all P>0.05). Cerebrospinal fluid Caveolin-1, MMP-9, IL-1β showed no significant difference among children with different severity of intracranial infection.Correlation analysis showed that there was a positive correlation between Caveolin-1, MMP-9 and IL-1 β levels in cerebrospinal fluid of acute in bacterial meningitis group and viral encephalitis group(Caveolin-1 and MMP-9: R²=0.239, P<0.05; MMP-9 and IL-1β: R²=0.766, P<0.01; Caveolin-1 and IL-1β: R²=0.245, P<0.05). Conclusions Caveolin-1, MMP-9 and IL-1 β involved in the pathogenesis of intracranial infection in children, and the effects of different pathogens on intracranial infection were different.