OBJECTIVE To investigate the effects of calcitriol on sepsis-induced immunosuppression and its potential mechanism. METHODS A sepsis-induced immunosuppression mice model was established using cecal ligation and puncture （CLP）. The 7-day survival rate， serum levels of tumor necrosis factor- α （TNF- α）， interleukin-6 （IL-6）， and IL-1β were determined in sham operation group， CLP group and calcitriol group （1 μg/kg）； the morphological changes of lung tissue in mice were observed. Lipopolysaccharide （LPS） tolerance macrophage models （representing sepsis-induced immunosuppression） were established using mice macrophage cell line RAW264.7 cells. The levels of TNF-α and IL-6 in cell supernatants as well as mRNA expressions of IL-1β， nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 （NLRP3）， IL-18 and caspase-1 were assessed in culture medium group， LPS group， LPS tolerance group， and calcitriol （5 μmol/L） group. The following parameters were measured： propidium iodide （PI）-positive cell ratio， caspase-1 activity， lactate dehydrogenase （LDH） release， and Ca2+ levels. RESULTS Compared with CLP group， 7-day survival rate and serum levels of TNF-α， IL-6 and IL-1β were increased significantly in calcitriol group （P＜0.05）. Additionally， pulmonary tissue damage was markedly attenuated in calcitriol group. Compared with LPS tolerance group， the levels of TNF-α and IL-6 in cell supernatants， mRNA expressions of IL- 1β， NLRP3， IL-18 and caspase-1， PI-positive cell ratio， caspase-1 activity， LDH release， and Ca2+ levels were all increased significantly in calcitriol group （P＜0.05）. CONCLUSIONS Calcitriol can reverse sepsis-induced immunosuppression， and the mechanism of action may be E-mail：yarfwy@163.com achieved by the binding of calcitriol to vitamin D receptor，which promotes the release of Ca2+ from the endoplasmic reticulum， thereby driving the NLRP3/caspase-1-mediated pyroptosis pathway.

Objective To investigate the risk factors of drug resistance in patients with ischemic stroke by clopidogrel therapy and provide references for promoting clinical individualized drug therapy. Methods A total of 202 inpatients diagnosed with ischemic stroke were admitted and given dual anti-treatment (aspirin+clopidogrel). CYP2C19 genotype was detected by microarray hybridization during hospitalization, and CYP2C19 gene polymorphisms were classified into fast metabolism group, medium metabolism group and slow metabolism group according to the type of drug metabolism. Patients were tested for platelet inhibition induced by adenosine diphosphate (ADP) according to thromboelastographic (TEG) on 7~14 d of drug administration. ADP <30% was classified as clopidogrel drug resistance group and ADP ≥30% as non-resistance group. Logistic regression analysis was used to study the risk factors for the development of clopidogrel resistance. Results Among 202 patients with ischemic stroke, 87 were in the resistant group and 115 in the non-resistant group. The proportion of patients with clopidogrel resistance combined with diabetes and the level of white blood cell count were higher than that in the non-resistant group, and the differences were statistically significant (P<0.05).The proportion of patients with clopidogrel resistance in the CYP2C19 intermediate metabolism group was significantly higher than that in the fast metabolism group, and the rate of platelet inhibition was also significantly lower than that in the fast metabolism group, all with statistically significant differences (P<0.05). Conclusion Combined diabetes mellitus, high white blood cell count levels and CYP2C19 mid-metabolic phenotype are independent risk factors for the development of clopidogrel resistance in patients with ischemic stroke.

Tacrolimus is a commonly used medication for the treatment of nephrotic syndrome.Due to its narrow therapeutic window and significant pharmacokinetic differences among individuals,therapeutic drug monitoring is required during its clinical use.In the process of therapeutic drug monitoring,machine learning-based personalized dosing prediction models for tacrolimus can excavate medication patterns from a large amount of clinical data,assist in clinical decision-making,and achieve individualized precise medication.Machine learning models,the application progress of machine learning in personalized administration of tacrolimus for patients with nephrotic syndrome,modeling points of machine learning prediction models,and the limitations of current prediction models were reviewed in this paper,which could provide references for future research in this field.

Objective To evaluate the second catalog of the key monitoring and rational use drugs(KMRUD),and to provide a reference framework for medical institutions to develop their own KMRUD catalogs and management policies.Methods A comprehensive search on official websites of national and provincial health administrative departments was conducted using the keywords"key monitoring","rational drug use",and"the second catalog".Announced catalogs and related policy documents pertaining to KMRUD use were collected and systematically organized.Comparative analyses were performed between the national KMRUD catalogs of the first and second batches,as well as between the second batch of provincial KMRUD catalogs and the national standard.Additionally,the adoption and variation of national KMRUD drug management policies across provinces,as well as the uniformity and divergence of provincial KMRUD management policies,were examined.Results The second national KMRUD catalog maintained 7 drug varieties from the first batch,eliminated 13,and introduced 23 new varieties.Of the 24 surveyed provinces,9 modified their provincial catalogs relative to the national second batch KMRUD catalog,resulting in alterations to 66 drug varieties within 10 Anatomical Therapeutic Chemical(ATC)classes,primarily systemic anti-infectives.Several provinces,including Xinjiang,Inner Mongolia,Liaoning,Shanghai,and Qinghai,implemented additional management measures such as the establishment of clinical application guidelines and the clarification of application conditions and principles.Moreover,provinces like Inner Mongolia,Shandong,Jilin,and Heilongjiang expanded their KMRUD management toolbox by developing drug monitoring indicators.The revision of inclusion rules from the first to the second KMRUD catalog has led to the incorporation of numerous essential clinical drugs.The prior protocol of medical institutions excluding drugs unilaterally is no longer viable,as it may disrupt the standard medication supply,potentially raising treatment costs.Conclusion Medical institutions ought to assimilate the updated implications of KMRUD use,draw on established provincial monitoring and management methodologies,enhance clinical application guidelines,and articulate conditions and principles for clinical use.Furthermore,by employing prescription review mechanisms,in-hospital monitoring,evaluation,and advanced warning systems,medical institutions can strategically oversee KMRUD use.

Objective To understand the clinical features and therapeutic methods for calcineurin inhibitor-induced pain syndrome (CIPS) in kidney transplant recipients. Methods The related articles or abstracts from January 1991 to December 2020 were obtained by searching PubMed, Google Scholar, CNKI, Wanfang and VIP databases. The reviews, duplicate literatures and the articles involved in non-kidney transplant recipients were excluded. 11 full papers were included with 15 case reports. Results The average age of patients at the time of diagnosis of CIPS was (44.6±8.31) years, and the 53.3% of the patients was male. The average appearance time of CIPS was (2.42±3.07) months after kidney transplantation. CIPS mainly affected bilateral hands, elbows, wrists, knees, ankles, feet and back. The patients had normal or elevated trough concentrations of calcineurin inhibitors (CNIs) when CIPS occurred. Some patients had elevated alkaline phosphatase, parathyroid hormone, blood calcium, C-reactive protein levels, and abnormal phosphorus levels, while rheumatoid factor and uric acid levels were normal. CIPS symptoms in most patients disappeared with dose reduction of CNIs, change to different class of CNIs, pamidronate IV injection, pregabalin, calcium channel antagonists, etc. The average recovery time was (4.43±3.31) months. Conclusion The most effective treatment for CIPS is to reduce the dose of CNIs and replace immunosuppressants. Other treatments include GABA analogs, intravenous pamidronate, calcium channel blockers and conservative therapy.

Objective:To evaluate narrow band imaging-magnifying endoscopy (NBI-ME) for the further assessment of lesions of low-grade intraepithelial neoplasia (LGIN) in the gastric biopsy.Methods:Data of 180 patients who underwent NBI-ME before endoscopic submucosal dissection (ESD) for biopsy of gastric LGIN at the First Affiliated Hospital of Soochow University from January 2017 to October 2020 were analyzed retrospectively. Taking the pathological results after ESD as the gold standard, the sensitivity, the specificity, the positive predictive value, the negative predictive value, and the accuracy of NBI-ME in predicting the pathological upgrading of gastric LGIN lesions after ESD were calculated, and the receiver operator characteristic (ROC) curve was drawn.Results:Among 180 gastric LGIN lesions, 115 (63.89%) were pathological upgraded and 65 (36.11%) were not after ESD. There were 10 missed diagnoses, 19 misdiagnoses, and 151 correct diagnoses in NBI-ME examination before ESD. The sensitivity, the specificity, the positive predictive value, the negative predictive value, and the accuracy of NBI-ME in predicting the pathological upgrading of gastric LGIN lesions after ESD were 91.3% (105/115), 70.8% (46/65), 84.7% (105/124), 82.1%(46/56) and 83.9% (151/180), respectively. The area under the ROC curve was 0.810 (95% CI: 0.737-0.883). Conclusion:Further NBI-ME examination of gastric LGIN lesions diagnosed by biopsy pathology can accurately predict whether the lesions have pathological upgrading after ESD, which is of important guiding significance for the patients to choose the treatment strategy of further follow-up or endoscopic resection.

Tumor neoantigens generated from somatic mutations can be presented by major histo-compability complex (MHC) molecules and elicit specific immune response against cancer. Therapeutic vac-cines and specific T cells targeting tumor neoantigens will realize the potential of precision immunotherapy in cancer treatment. Along with the development of methods for predicting neoantigens, individualized cancer immunotherapy strategies will be widely adopted. In the present review, we discuss the current state of the prediction approaches and clinical applications of neoantigens, as well as the challenges that remain to be ad-dressed in order to improve immunotherapy targeting neoantigens.

Objective: To investigate the association between ABCC2 gene polymorphisms and cyclosporine-induced liver injury in re-nal transplant recipients. Methods: The renal transplant recipients were divided into the liver injury group and the control group. Five single nucleotide polymorphisms ( rs4919395, rs2804398, rs4148394, rs4148397 and rs3740065) of ABCC2 were detected by high-throughput technique. The genotypes and haplotypes were analyzed between the groups. Results: There were 35 patients and 182 patients respectively in the liver injury group and the control group. No significant differences in alleles and genotypes were found between the groups (P>0. 05), and the SNP haplotypes showed no significant difference between the groups (P>0. 05). Conclusion: There is no association of ABCC2 polymorphisms (rs4919395, rs2804398, rs4148394, rs4148397 and rs3740065) with the liver injury induced by cy-closporine.

Objective: To investigate the regulation of CYP3A4 and P-gp by berberine hydrochloride ( BBR) via pregnane X re-ceptor (PXR) pathway. Methods: pLKO. 1-PXR vector, a lentivirus plasmid expressing PXR shRNA, was packaged into 293T cells. Human hepatoma (HepG2) cells were infected with the lentivirus and the cell clones stably expressing PXR shRNA were selected by puromycin according to pLKO. 1 vector characteristics. Real-time RT-PCR and Western blot were used to evaluate CYP3A4 and P-gp mRNA and protein in berberine treated HepG2 cells and PXR-silenced HepG2 cells. Results: The PXR expression in PXR silenced cells significantly decreased (P<0.01) when compared with that in HepG2 cells, while there was no significant difference (P >0. 05) in the expression of CYP3A4 and P-gp between the groups. Compared with that in HepG2 cells, the inhibition of berberine on the mRNA and protein expression of CYP3A4 and P-gp in PXR-silenced HepG2 cells was weakened (P<0. 05 or P<0. 01). Conclu-sion: Berberine can regulate the expression of CYP3A4 and P-gp via PXR signaling pathway, while it is not the only one.

OBJECTIVE:To investigate the association of synergistic effects of Wuzhi capsules on tacrolimus with CYP3A5*3 (6986A>G,rs776746) gene polymorphisms. METHODS:One hundred and severty patients underwent renal transplantation receiving tacrolimus maintenance therapy after surgery were selected from our hospital during Jan. 1997-Dec. 2015,and then divided into Wuzhi capsules(+)group(74 cases)and Wuzhi capsules(-)group(96 cases)according to the use of Wuzhi capsules. Both groups received tacrolimus+mycophenolate mofetil+prednisone;Wuzhi capsules (+)group was additionally given Wuzhi capsules,one capsule each time,bid,for more than 12 months. Trough concentration of tacrolimus was detected by CMIA 0,1,3,6,12 months after medica-tion,and the blood concentrations(C0/D)were calculated at different time points after correcting daily dose. CYP3A5*3 gene polymor-phisms was detected by PCR-RFLP. The association of C0/D value with gene polymorphism was investigated by analysis of covariance. RESULTS:Among 170 patients,there were 65 cases of CYP3A5 GG genotype,83 cases of AG genotype and 22 cases of AA geno-type;genotype frequencies were 38.2%,48.8% and 12.9%,which was in line with Hardy-Weinberg balance (P>0.05). There was statistical significance in the distribution frequencies of GG,AG+AA genotype between Wuzhi capsules(+)group and Wuzhi capsules (-)group (P<0.05). After 1 month of medication,C0/D of tacrolimus in GG genotype was significantly higher in Wuzhi capsules (+)group than in Wuzhi capsules(-)group. After 1,3,6,12 months of medication,C0/D of tacrolimus in AG+AA genotype was sig-nificantly higher in Wuzhi capsules(+)group than in Wuzhi capsules(-)group,with statistical significance(P<0.05). There was no statistical significance in C0/D of tacrolimus in GG genotype between 2 groups after 3,6,12 months of treatment(P>0.05). CON-CLUSIONS:Wuzhi capsules can increase C0/D of tacrolimus in CYP3A5*3 AG+AA genotype,but have no significant effect on C0/D of tacrolimus in GG genotype;CYP3A5*3 genotype should be considered when using Wuzhi capsules as synergist of tacrolimus.