Epidermal growth factor receptor-tyrosine kinase inhibitor （EGFR-TKI） represent a class of small-molecule targeted therapeutics for oncology treatment， and serve as first-line therapy for advanced non-small cell lung cancer （NSCLC） with EGFR- sensitive mutations， with representative agents including gefitinib， dacomitinib， and osimertinib. In clinical practice， dose adjustment of EGFR-TKI may be required for cancer patients under special circumstances such as drug combinations or hepatic/ renal impairment. Physiologically-based pharmacokinetic （PBPK） model， capable of predicting pharmacokinetic （PK） processes in humans， has emerged as a vital tool for clinical dose optimization. This article sorts the modeling methodologies， workflows， and commonly used software tools for PBPK model， and summarizes the current applications of PBPK model in EGFR-TKI precision therapy as of June 30， 2024. Findings demonstrate that PBPK modeling methods commonly employ the “bottom-up” approach and the middle-out approach. The process typically involves four steps： parameter collection， compartment selection， model validation， and model application. Commonly used software for modeling includes Simcyp， GastroPlus， and open-source software such as PK- Sim. PBPK model can be utilized for predicting drug-drug interactions of EGFR-TKI co-administered with metabolic enzyme inducers or inhibitors， acid-suppressive drugs， or traditional Chinese and Western medicines. It can also adjust dosages in conjunction with genomics， predict PK processes in special populations （such as patients with liver or kidney dysfunction， pediatric patients）， evaluate the efficacy and safety of drugs， and extrapolate PK predictions from animal models to humans.

Objective To investigate the expression of pepsin in vocal cord polyps and vocal cord cancer,and to compare the difference of pepsin expression.Methods From May 2020 to December 2021,27 patients with vocal cord polyp,27 patients with vocal cord cancer and 23 healthy volunteers were selected.RSI and RFS scoring scales were used for scoring,pepsin detection kit was used for saliva pepsin detection,and immunohistochemical methods were used to detect the expression of pepsin in vocal cord tissues of patients with vocal cord polyps and vocal cord cancer.Results The RSI score,RFS score and pepsin test kit results of vocal cord polyp group and vocal cord canc-er group were higher than those of non-vocal cord disease group,and the differences of the three indexes were statis-tically significant(P＜0.05).RSI score,pepsin detection kit results and pepsin immunohistochemistry results of vocal cord polyp group showed no significant difference compared with vocal cord cancer group(P＞0.05).The RFS score of vocal cord polyp group was significantly different from that of vocal cord cancer group(P＜0.05).Conclusion Pepsin may be an important pathogenic factor of vocal cord polyp and vocal cord cancer,and play an im-portant role in the occurrence of these two diseases.The difference of pepsin expression in vocal cord polyp and vo-cal cord cancer suggests that pepsin may have different pathogenesis.

OBJECTIVE To investigate the effects of CYP3A5 gene polymorphism and Wuzhi capsule （WZ） on early postoperative tacrolimus exposure and adverse reactions in renal transplant patients. METHODS A total of 132 patients who underwent renal transplantation and received tacrolimus + mycophenolic acids + prednisone after operation in our hospital from September 2021 to September 2023 were selected and divided into four groups according to genotypes （CYP3A5*1 or CYP3A5*3/*3） and with or without WZ （“ +WZ” meant drug combination， “ +NO WZ” meant without combination）. The blood trough concentration/daily dose （c0/D） values of the four groups were analyzed on the 14th day， 1 month and 3 months after renal transplantation. The incidence of acute rejection and the incidence of tacrolimus-related adverse reactions within 3 months after transplantation were compared among 4 groups. RESULTS On the 14th day， 1 month and 3 months after surgery （except for the CYP3A5*1+WZ group）， c0/D values of CYP3A5*1 genotype patients were significantly lower than those of CYP3A5*3/*3 genotype patients regardless of whether they were treated with WZ additionally （P＜0.05）. Within 3 months after surgery， although there was no significant difference in the incidence of acute rejection and tacrolimus-related adverse reactions among the four groups （P＞ 0.05）， the incidence of hyperglycemia in patients with CYP3A5*3/*3 was higher （41.67%）. CONCLUSIONS CYP3A5 gene polymorphism is significantly related to tacrolimus c0/D in kidney transplant patients. Under the premise of c0 monitoring of tacrolimus， patients with CYP3A5*1 genotype should be given WZ as soon as possible after surgery to accelerate tacrolimus to reach the therapeutic concentration range， while CYP3A5*3/*3 genotype is not recommended to be given WZ because of the higher risk of hyperglycemia.

Objective To investigate the antigen presentation characteristics of dendritic cells(DC)and B cells in cardiac grafts.Methods The heart of BALB/c mice was transplanted into the abdominal cavity of C57BL/6J mice.CD45+cells in the heart graft were extracted and sorted by flow cytometry at postoperative 5 d,and single cell RNA sequencing was performed.Taking DC and B cell subsets in cardiac grafts as the main study cells,the changing trend,antigen presenting ability and intercellular communication with T cells after heart transplantation were analyzed by bioinformatics analysis and flow cytometry.Gene ontology(GO)function enrichment difference analysis was adopted to prove the specific function and the reliability annotation of cell subsets.Results Germinal center-like B cell(GC-L B)was the B cell subset with the largest increase in quantity during the acute rejection phase,accounting for 87％.Classical DC(cDC)2 was the only DC subset with a significant increase in quantity during acute rejection of heart transplantation,accounting for 44％of DC subset,and it occupied the highest communication intensity with T cells after heart transplantation.Mononucleated DC(moDC)and memory B cell(MBC)were the main transmitters of T cell input signals in non-transplanted hearts,whereas transformed into cDC2 and GC-L B during the acute rejection phase.Among them,MBC and GC-L B were the main sources of T cell input signals in non-transplanted hearts and heart grafts.Conclusions Compared with DC,B cells occupy a higher number and weight in the intercellular communication with T cells in non-transplanted hearts and heart grafts,prompting that the antigen presenting activity of B cells is more active and stronger than DC in the early stage of acute rejection of heart transplantation.

Objective:To analyze the level and clinical significance of IL-18 and IL-18-binding protein (BP) in the bone marrow of patients with myelodysplastic syndrome (MDS) .Methods:A total of 43 newly diagnosed patients with MDS who were admitted to the Department of Hematology, Tianjin Medical University General Hospital, from July 2020 to February 2021 were randomly selected. The control group consisted of 14 patients with acute myeloid leukemia (AML) and 25 patients with iron-deficiency anemia (IDA). The levels of IL-18 and IL-18 BP in the bone marrow supernatant were measured, and their correlations with MDS severity, as well as the functionality of CD8 + T cells and natural killer cells, was analyzed. Results:The levels of IL-18, IL-18 BP, and free IL-18 (fIL-18) in the bone marrow supernatant of patients with MDS were higher than in the IDA group. The level of fIL-18 was linearly and negatively correlated with the MDS-International Prognostic Scoring System (IPSS) score. IL-18 receptor (IL-18Rα) expression on CD8 + T cells in the MDS group was lower than in the IDA group, and the levels of fIL-18 and IL-18Rα were positively correlated with CD8 + T-cell function in the MDS group. Conclusion:IL-18 BP antagonizes IL-18, leading to a decrease in fIL-18 in the bone marrow microenvironment of patients with MDS, affecting CD8 + T-cell function, which is closely related to MDS severity; therefore, it may become a new target for MDS treatment.

Objective:Progressive bone resorption and destruction is one of the most critical clinical features of middle ear cholesteatoma,potentially leading to various intracranial and extracranial complications.However,the mechanisms underlying bone destruction in middle ear cholesteatoma remain unclear.This study aims to explore the role of parathyroid hormone-related protein(PTHrP)in bone destruction associated with middle ear cholesteatoma. Methods:A total of 25 cholesteatoma specimens and 13 normal external auditory canal skin specimens were collected from patients with acquired middle ear cholesteatoma.Immunohistochemical staining was used to detect the expressions of PTHrP,receptor activator for nuclear factor-kappa B ligand(RANKL),and osteoprotegerin(OPG)in cholesteatoma and normal tissues.Tartrate-resistant acid phosphatase(TRAP)staining was used to detect the presence of TRAP positive multi-nucleated macrophages in cholesteatoma and normal tissues.Mono-nuclear macrophage RAW264.7 cells were subjected to interventions,divided into a RANKL intervention group and a PTHrP+RANKL co-intervention group.TRAP staining was used to detect osteoclast formation in the 2 groups.The mRNA expression levels of osteoclast-related genes,including TRAP,cathepsin K(CTSK),and nuclear factor of activated T cell cytoplasmic 1(NFATc1),were measured using real-time polymerase chain reaction(real-time PCR)after the interventions.Bone resorption function of osteoclasts was assessed using a bone resorption pit analysis. Results:Immunohistochemical staining showed significantly increased expression of PTHrP and RANKL and decreased expression of OPG in cholesteatoma tissues(all P<0.05).PTHrP expression was significantly positively correlated with RANKL,the RANKL/OPG ratio,and negatively correlated with OPG expression(r=0.385,r=0.417,r=-0.316,all P<0.05).Additionally,the expression levels of PTHrP and RANKL were significantly positively correlated with the degree of bone destruction in cholesteatoma(r=0.413,r=0.505,both P<0.05).TRAP staining revealed a large number of TRAP-positive cells,including multi-nucleated osteoclasts with three or more nuclei,in the stroma surrounding the cholesteatoma epithelium.After 5 days of RANKL or PTHrP+RANKL co-intervention,the number of osteoclasts was significantly greater in the PTHrP+RANKL co-intervention group than that in the RANKL group(P<0.05),with increased mRNA expression levels of TRAP,CTSK,and NFATc1(all P<0.05).Scanning electron microscopy of bone resorption pits showed that the number(P<0.05)and size of bone resorption pits on bone slices were significantly greater in the PTHrP+RANKL co-intervention group compared with the RANKL group. Conclusion:PTHrP may promote the differentiation of macrophages in the surrounding stroma of cholesteatoma into osteoclasts through RANKL induction,contributing to bone destruction in middle ear cholesteatoma.

Objective:Middle ear cholesteatoma is a non-tumorous condition that typically leads to hearing loss,bone destruction,and other severe complications.Despite surgery being the primary treatment,the recurrence rate remains high.Therefore,exploring the molecular mechanisms underlying cholesteatoma is crucial for discovering new therapeutic approaches.This study aims to explore the involvement of N6-methyladenosine(m6A)methylation in long non-coding RNAs(lncRNAs)in the biological functions and related pathways of middle ear cholesteatoma. Methods:The m6A modification patterns of lncRNA in middle ear cholesteatoma tissues(n=5)and normal post-auricular skin tissues(n=5)were analyzed using an lncRNA m6A transcriptome microarray.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were conducted to identify potential biological functions and signaling pathways involved in the pathogenesis of middle ear cholesteatoma.Methylated RNA immunoprecipitation(MeRIP)-PCR was used to validate the m6A modifications in cholesteatoma and normal skin tissues. Results:Compared with normal skin tissues,1 525 lncRNAs were differentially methylated in middle ear cholesteatoma tissues,with 1 048 showing hypermethylation and 477 showing hypomethylation[fold change(FC)≥3 or<1/3,P<0.05].GO enrichment analysis indicated that hypermethylated lncRNAs were involved in protein phosphatase inhibitor activity,neuron-neuron synapse,and regulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)receptor activity.Hypomethylated lncRNAs were associated with mRNA methyltransferase activity,secretory granule membrane,and mRNA methylation.KEGG analysis revealed that hypermethylated lncRNAs were mainly associated with 5 pathways:the Hedgehog signaling pathway,viral protein interaction with cytokines and cytokine receptors,mitogen-activated protein kinase(MAPK)signaling pathway,cytokine-cytokine receptor interaction,and adrenergic signaling in cardiomyocytes.Hypomethylated lncRNAs were mainly involved in 4 pathways:Renal cell carcinoma,tumor necrosis factor signaling pathway,transcriptional misregulation in cancer,and cytokine-cytokine receptor interaction.Additionally,MeRIP-PCR confirmed the changes in m6A methylation levels in NR_033339,NR_122111,NR_130744,and NR_026800,consistent with microarray analysis.Real-time PCR also confirmed the significant upregulation of MAPK1 and NF-κB,key genes in the MAPK signaling pathway. Conclusion:This study reveals the m6A modification patterns of lncRNAs in middle ear cholesteatoma,suggests a direction for further research into the role of lncRNA m6A modification in the etiology of cholesteatoma.The findings provide potential therapeutic targets for the treatment of middle ear cholesteatoma.

Clostridium perfringens is a common Gram-positive anaerobic conditioned pathogen,widely existing in nature,which can cause diarrhea,gas gangrene,and other diseases.Antibiotics are used in the clinical treatment of Clostridium perfringens infection,but the bacteria will devel-op resistance through mutation,drug-resistant plasmid transmission,and other ways,so that Clos-tridium perfringens can survive under the environmental pressure of antibiotics.Therefore,it is very important to find and develop new preparations to replace antibiotics or as feed additives to target the removal of Clostridium perfringens from the body or to prevent infection.In this study,a virulent Clostridium perfringens phage vB_CPP_AT was isolated from sewage by double plate method.The morphology of the bacteriophage was observed by transmission electron microscope.The biological characteristics of the bacteriophage were analyzed by lytic spectrum,MOI,pH,and temperature tolerance.The results showed that the vB_CPP_AT belongs to the Podoviridae.It would grow explosively at 60 min with an optimal MOI of 0.1.The vB_CPP_AT only lyse Clos-tridium perfringens and the lytic rate was 40％(8/20).No cleavage reaction occurred with other bacteria tested.The phage had good thermal stability and acid-base tolerance.Genomic analysis re-vealed that the phage had double-stranded DNA with a total length of 16 790 bp,and 20 open read-ing frames.Genomic analysis of vBCPPAT showed that it was a new virulent phage of Clostridi-um perfringens.The results laid a foundation for the clinical treatment of Clostridium perfringens with phage.

Objective To investigate the diagnostic value of CT plain scanning for isolated superior mesenteric artery dissection(ISMAD).Methods This study retrospectively investigated CT plain images of the superior mesenteric artery(SMA)in 45 patients with ISM AD and 45 patients without ISMAD.The imaging manifestations of ISMAD were analyzed,and the sensitivity and specificity of these manifestations were analyzed using receiver operating characteristic(ROC)curve.Results There were statistically significant differences in both the trunk diameter and standardized trunk diameter of the SMA between the two groups(P＜0.001,P=0.001).Additionally,the area under the curve(AUC)for the SMA trunk diameter in diagnosing ISMAD was determined to be 0.988,with a statistically significant P-value of less than 0.001.Furthermore,when the diameter of the SMA trunk reached 8.20 mm,the diagnostic sensitivity was 97.8％and the specificity was 93.3％.The AUC for the standardized diameter of the SMA trunk was determined to be 0.976.Additionally,when the standardized diameter of the SMA trunk reached 70.33％,the diagnostic sensitivity was 95.6％and the specificity was 82.2％.There was no statistically significant difference observed in the luminal CT value and standardized CT value of the SMA between the two groups(P＞0.05).Additionally,the presence of the"crescent sign"and peritubular fat blurring in the SMA demonstrated some level of diagnostic significance.Conclusion CT scanning has the capability to identify the enlarged diameter of the SMA trunk,as well as plain the"crescent sign"and related manifestations.This finding holds significant value in diagnosing ISMAD.Furthermore,it provides the basis for the necessity of subsequent computed tomography angiography(CTA)examinations.

Purpose To investigate the risk factors of severe hypocalcemia after ultrasound-guided thermal ablation for secondary hyperparathyroidism.Materials and Methods A retrospective case-control study was used to study 91 patients with uremia complicated with secondary hyperparathyroidism in the First People's Hospital of Yulin from May 2019 to May 2023.All patients underwent ultrasound-guided thermal ablation and were divided into severe hypocalcemia group(SH)and non-SH group according to postoperative blood calcium levels.The difference of clinical data between the two groups was compared,and the independent risk factors of SH were investigated by multivariate Logistic regression analysis.Results A total of 317 glands were ablated in 49 cases of microwave ablation and 42 cases of radiofrequency ablation.SH occurred in 57 cases(62.64%)after ablation.The comparison of clinical data between the two groups showed that there were significant differences in the preoperative intact parathyroid hormone(iPTH),decline rate of iPTH 1 d,preoperative serum alkaline phosphatase,the proportion of parathyroid glands≥4 and the total gland volume between the two groups(all P<0.05).Receiver operating characteristic curve analysis was used to obtain the best cut-off point of iPTH 1 d decline rate,the result was 74.59%,the area under the curve was 0.866(95%CI 0.787-0.945)(P<0.05),the sensitivity was 84.2%,and the specificity was 78.1%.Multivariate Logistic regression analysis showed that preoperative alkaline phosphatase(OR=1.015,95%CI 1.005-1.025,P=0.030)and decline rate of iPTH 1 d≥74.59%(OR=30.423,95%CI 5.938-155.858,P<0.001)and parathyroid glands≥4(OR=4.355,95%CI 1.027-18.469,P=0.046)were independent risk factors for postoperative SH(all P<0.05).Conclusion Preoperative alkaline phosphatase and decline rate of iPTH 1 d≥74.59%and the number of parathyroid glands≥4 are independent risk factors for SH after thermal ablation.