OBJECTIVE To explore and analyze the adverse drug event （ADE） signals of darolutamide and provide a reference for its clinical safe use. METHODS ADEs related to darotamide were collected based on the US FDA adverse event reporting system （FAERS） database from the third quarter of 2019 to the third quarter of 2022. Data mining and analysis were conducted by the report odds ratio （ROR） and proportional reporting ratio （PRR） methods. RESULTS A total of 565 ADE reports related to darolutamide were extracted， 356 ADE reports about darolutamide as the primary suspected drug were included， 38 ADE signals with darolutamide as the primary suspected drug were excavated， involving 15 system organ class （SOC）， mainly concentrated in patients over 65 years old. The SOC of darotamide ADE signal mainly focused on various examinations， systemic diseases and various reactions at the administration site， benign/malignant tumors or those with unknown nature （including cystic and polypoid）， kidney and urinary system diseases. A total of 13 ADE signals not mentioned in the instructions included increased prostate-specific antigen， dysphagia， cognitive impairment， erectile dysfunction， rhabdomyolysis， gynecomastia and decreased platelet count， etc. CONCLUSIONS When using darolutamide， in addition to ADE in the drug instruction， we should pay close attention to potential ADE， such as increased prostate-specific antigen， rhabdomyolysis， gynecomastia and decreased platelet count， so as to avoid drug withdrawal or organ damage caused by ADE.

Objective To understand the genotyping of human immunodeficiency virus (HIV) co-infected hepatitis C virus (HCV) patients in Yunnan Province, and to analyze the differences in viral load, biochemical indicators, and blood routine indicators among different genotypes, in order to provide a laboratory basis for the diagnosis and clinical treatment of HIV/HCV co-infected patients. Methods From November 2022 to June 2023, the serum samples and basic information of patients diagnosed with HIV/HCV co-infection were collected in the antiviral outpatient clinic of Yunnan Provincial Hospital of Infectious Diseases. The HCV viral load was detected by one-step qRT-PCR amplification, the positive samples were sequenced, and genotyping was determined based on NS5 gene sequence. The differences in biochemical and blood routine indexes between HIV patients co-infected with different HCV genotypes and low/high viral loads were analyzed. Results A total of 126 HIV/HCV co-infected patients were collected, including 20 HCV genotype 1 (15.9%), 91 HCV genotype 3 (72.2%), and 15 HCV genotype 6 (11.9%). The maximum and minimum viral load of the three HCV genotypes were as follows: HCV type 1 (1.0×108, 4.8×104 IU/mL), HCV type 3 (2.2×108, 2.9×102 IU/mL), and HCV type 6 (8.1×107, 6.8×104 IU/mL). The results showed that there was no significant difference between HIV co-infection with different genotypes of HCV and three HIV treatment schemes, including nucleoside reverse transcriptase inhibitors+integrase strand transfer inhibitors (NRTIs+INSTIs), nucleoside reverse transcriptase inhibitors+non-nucleoside reverse transcriptase inhibitors (NRTIs+NNRTIs) and nucleoside reverse transcriptase inhibitors+protease inhibitor (NRTIs+PLs), and the viral load of patients (P>0.05). The analysis of biochemical indexes such as total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), and blood routine indexes such as white blood cell (WBC), red blood cell (RBC), hemoglobin (HGB), platelet (PLT), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) among different HCV genotypes and low/high viral loads showed that there was no significant difference in biochemical indexes and blood routine indexes between low/high viral loads of HIV co-infected HCV patients (P>0.05); however, the biochemical indicators TBIL, IBIL and MCHC were significantly different statistically between patients with genotype 3 HCV infection and those with genotype 1 HCV infection (P<0.05), while other biochemical and blood routine indexes were not statistically different among different HCV genotypes (P>0.05). Conclusions There are six subtypes of HCV co-infection in HIV patients in Kunming, Yunnan Province, including three genes of genotype 1, 3, and 6. Among them, genotype 3 HCV is the main prevalent genetic virus among HIV co-infected populations. The TBIL, IBIL and MCHC values of HIV patients co-infected with HCV type 3 are different from those infected with HCV type 1.

Objective·To explore EDAR(ectodysplasin A receptor)gene variants that lead to congenital tooth agenesis,and preliminarily analyze the reasons why variants in EDAR can cause both syndromic and non-syndromic tooth agenesis.Methods·Patients with congenital tooth agenesis admitted to the Department of 2nd Dental Center,Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine and their family members were included,and genomic DNA from their peripheral blood was extracted for whole exome sequencing(WES).After preliminary screening,PolyPhen-2,Mutation Taster,and Provean were used to predict the harmfulness of potential variants.The screened variants in patients and their families were verified by Sanger sequencing.Conservation analysis of variants was performed,and Swiss-Model was used to analyze the changes in the three-dimensional structure of EDAR.The teeth and syndromic phenotype of the patients and their family members were investigated.Results·Among the included congenital tooth agenesis patients,five patients with EDAR mutations were found,one with EDAR frameshift mutation c.368_369insC(p.L123fs)and the other four with EDAR missense mutations.Two of these four patients were diagnosed as non-syndromic tooth agenesis(NSTA),resulted from c.77C＞A(p.A26E)homozygous mutation and c.380C＞T(p.P127L)heterozygous mutation,respectively.The other two patients with two variants were diagnosed as hypohidrotic ectodermal dysplasia(HED).One compound heterozygous missense mutation patient carried EDAR c.77C＞T(p.A26V)from her father andEDAR c.1281G＞C(p.L427F)from her mother;the other patient with both EDAR and EDA mutations carried EDAR c.1138A＞C(p.S380R)heterozygous mutation and EDA c.1013C＞T(p.T338M)hemizygous mutation.Both variants were from his mother and were reported to be related with NSTA.Two of these missense mutations,EDAR c.1281G＞C(p.L427F)and EDAR c.77C＞A(p.A26E),had not been reported before.The missense mutations affected the protein's spatial conformation by altering the polarity,charge,or volume of the amino acid residues.The frameshift mutation caused a non-triplet base addition,which probably led to protein truncation or degradation.Conclusion·Two new EDAR missense mutations are discovered.An NSTA patients with EDAR homozygous mutations and an HED patient with both EDA and EDAR mutations are reported.It expands the understanding of pathogenic mechanisms of EDAR mutations causing HED and NSTA.

Objective To investigate the correlation of serum atresia zonule protein 1(ZO-1)and anti-β2-glycoprotein 1 antibody(aβ2-GP1)levels with infarct lesion extent and degree of carotid atherosclerosis in pa-tients with cerebral infarction.Methods A total of 103 patients with cerebral infarction treated in Baoding No.1 Central Hospital from January 2020 to January 2023 were selected as the study group,and 51 healthy subjects in the same hospital during the same period were selected as the control group.Patients with cerebral infarction were divided into large infarction group(infarct lesion extent>50 cm2),middle infarction group(infarct lesion extent as 10-50 cm2),and small infarction group(infarct lesion extent<10 cm2)according to the infarct lesion extent.According to the results of carotid ultrasound,the patients with cerebral infarction were divided into plaque stage group,thickening stage group and normal vessel wall group.Enzyme-linked im-munosorbent assay was used to detect serum ZO-1,aβ2-GP1 levels,and the levels of ZO-1 and aβ2-GP1 in each group were compared.Spearman correlation analysis was used to analyze the correlation between serum ZO-1,aβ2-GP1 levels and the infarct lesion extent and the degree of carotid atherosclerosis in patients with cerebral infarction.Results The study group had a significantly lower serum level of ZO-1 and a significantly higher serum level of aβ2-GP1 than the control group(P<0.05).Among the 103 patients with cerebral in-farction,there were 32 cases in the large infarction group,34 cases in the middle infarction group,and 37 cases in the small infarction group.The small infarction group had a significantly higher level of ZO-1 and a signifi-cantly lower level of aβ2-GP1 than the medium infarction group and large infarction group(P<0.05).The middle infarction group had a significantly higher level of ZO-1 and a significantly lower level of aβ2-GP1 than the large infarction group(P<0.05).Among 103 patients with cerebral infarction,there were 29 cases in the plaque stage group,38 cases in the thickening stage group,6 cases in the normal vessel wall group.The plaque stage group had a significantly lower serum level of serum ZO-1 and a significantly higher level of aβ2-GP1 than the thickening stage group and normal vessel wall group(P<0.05).The thickening stage group had a significantly lower serum level of ZO-1 and a significantly higher serum level of aβ2-GP1 than the normal ves-sel wall group(P<0.05).Spearman correlation analysis showed that the serum level of ZO-1 was negatively correlated with the degree of carotid atherosclerosis and the extent of infarction(P<0.05),and the serum level of aβ2-GP1 was positively correlated with the degree of carotid atherosclerosis and the extent of infarc-tion(P<0.05).Conclusion The levels of serum ZO-1 and aβ2-GP1 in patients with cerebral infarction are significantly correlated with the degree of carotid atherosclerosis and the extent of infarction,which have po-tential value in the diagnosis,treatment and prognosis of patients with cerebral infarction.

N6-Methyladenosine (m⁶A) is the most abundant internal modification in eukaryotic mRNA, playing critical role in various bioprocesses. Like other epigenetic modifications, m⁶A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m⁶A demethylases have been reported, fat mass and obesity-associated protein (FTO) and alkylation protein AlkB homolog 5 (ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5.

Objective: To classify the characteristics of circadian type among clinical nurses and examine their relationships with presenteeism and work-related flow. Methods: Using a cross-sectional design, 568 nurses were recruited through convenience sampling in January 2021 from three hospitals in Shandong Province, China. The data were collected using self-report measures, including the 11-item Circadian Type Inventory, Stanford Presenteeism Scale-6, and Work-Related Flow Inventory. Latent class analysis was performed to identify any clustering of circadian types. One-way analysis was performed to compare the differences between presenteeism and work-related flow in different circadian types. Results: Four latent classes were identified, including high response class (14.4%), high flexible class (20.1%), high languid class (51.1%), and low response class (14.4%). Regarding presenteeism, the high languid class had higher scores than others. Regarding work-related flow, the scores of high flexible class were higher than those of high languid class, while the differences in all three dimensions were statistically significant. Conclusion Although the shift work mode is not expected to change, nursing managers could use circadian type as a predictive index to select and employ individuals for shift work to enhance work performance and provide sufficient support to staff who are intolerant to shift work.

OBJECTIVE: To explore the genetic basis for a pedigree affected with Alport syndrome. METHODS: Next generation sequencing and Sanger sequencing was carried out to detect potential variant of the COL4A5 gene among members from the pedigree and 100 unrelated healthy controls. RESULTS: A novel missense c.3293G>T (p.Gly1098Val) variant was found in the COL4A5 gene among 6 affected members but not the unaffected members of the pedigree or the 100 healthy controls. According to the American College of Medical Genetics and Genomics standards and guidelines, the c.3293G>T variant was classified as pathogenic (PP1-strong+PM1+PM2+PP3+PP4). CONCLUSION By destructing the Gly-X-Y structure of its protein product, the c.3293G>T variant of the COL4A5 gene probably underlies the Alport syndrome in this pedigree. Above finding has enriched the spectrum of COL4A5 variants.

OBJECTIVE: To analyze variant of IDS gene in a pedigree affected with mucopolysaccharidosis type II (MPS II). METHODS: The proband was subjected to next generation sequencing and Sanger sequencing to identify potential variants. Suspected variant was analyzed by its co-segregation with the disease in the pedigree. Its impact on mRNA splicing was analyzed by using reverse transcription PCR (RT-PCR). RESULTS: A hemizygous IVS1-3T>G variant was found in the IDS gene in the proband. RT-PCR results revealed two abnormal cDNA fragments of 600 bp and 300 bp. The 600 bp fragment had inserted 216 nucleotides at the 3' end of intron 1, while the 300 bp fragment had lost 109 nucleotides at the 5' end of exon 2, which resulted in two truncated proteins comprising 38 and 92 amino acids, respectively, instead of the normal product (550 amino acids). The proband and his mother were respectively hemizygous and heterozygous for the variant. The same variant was not found among 100 normal controls. CONCLUSION The IVS1-3T>G variant of the IDS gene probably underlies the MPS II in this pedigree by causing reduction or elimination of the IDS protein.

OBJECTIVES: Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) controls mitochondrial biogenesis, but its role in cardiovascular diseases is unclear. The purpose of this study is to explore the effect of PGC1α on myocardial ischemia-reperfusion injury and the underlying mechanisms. METHODS: The transverse coronary artery of SD rat was ligated for 30 minutes followed by 2 hours of reperfusion. Triphenyltetrazolium chloride (TTC) staining was performed to measure the area of myocardial infarction. Immunohistochemistry and Western blotting were used to detect the PGC1α expression in myocardium. The rat cardiomyocyte H9C2 was subjected to hypoxia/reoxygenation (H/R) with the knockdown of PGC1α or hypoxia- inducible factor 1α (HIF-1α), or with treatment of metformin. Western blotting was used to detect the expression of PGC1α, HIF-1α, p21, BAX, and caspase-3. CCK-8 was performed to detect cell viability, and flow cytometry was used to detect apoptosis and mitochondrial superoxide (mitoSOX) release. RT-qPCR was used to detect the mRNA expression of PGC1α and HIF-1α. Besides, chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter gene assay were applied to detect the transcriptional regulation effect of HIF-1α on PGC1α. RESULTS: After I/R, the PGC1α expression was increased in infarcted myocardium. H/R induced H9C2 cell apoptosis ( CONCLUSIONS After I/R, HIF-1α up-regulates the expression of PGC1α, leading to an increase in ROS production and aggravation of injury. Metformin can inhibit the accumulation of HIF-1α during hypoxia and effectively protect myocardium from ischemia/reperfusion injury.
Animals ; Apoptosis ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Myocardial Reperfusion Injury/genetics* ; Myocytes, Cardiac/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism* ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury

In this study, eight-month-old ectomycorrhizae of Tuber borchii with Corylus avellana were synthesized to explore the influence of T. borchii colonization on the soil properties and the microbial communities associated with C. avellana during the early symbiotic stage. The results showed that the bacterial richness and diversity in the ectomycorrhizae were significantly higher than those in the control roots, whereas the fungal diversity was not changed in response to T. borchii colonization. Tuber was the dominant taxon (82.97%) in ectomycorrhizae. Some pathogenic fungi, including Ilyonectria and Podospora, and other competitive mycorrhizal fungi, such as Hymenochaete, had significantly lower abundance in the T. borchii inoculation treatment. It was found that the ectomycorrhizae of C. avellana contained some more abundant bacterial genera (e.g., Rhizobium, Pedomicrobium, Ilumatobacter, Streptomyces, and Geobacillus) and fungal genera (e.g., Trechispora and Humicola) than the control roots. The properties of rhizosphere soils were also changed by T. borchii colonization, like available nitrogen, available phosphorus and exchangeable magnesium, which indicated a feedback effect of mycorrhizal synthesis on soil properties. Overall, this work highlighted the interactions between the symbionts and the microbes present in the host, which shed light on our understanding of the ecological functions of T. borchii and facilitate its commercial cultivation.
Colon ; Corylus ; Fungi ; Magnesium ; Mycorrhizae ; Nitrogen ; Phosphorus ; Podospora ; Rhizobium ; Rhizosphere ; Soil ; Streptomyces