Mechanism of Lian Hua Qing Wen capsules regulates the inflammatory response caused by M1 macrophage based on cellular experiments and computer simulations.

PURPOSE: The polarization of macrophages with the resulting inflammatory response play a crucial part in tissue and organ damage due to inflammatory. Study has proved Lian Hua Qing Wen capsules (LHQW) can reduce activation of inflammatory response and damage of tissue derived from the inflammatory reactions. However, the mechanism of LHQW regulates the macrophage-induced inflammatory response is unclear. Therefore, we investigated the mechanism of LHQW regulated the inflammatory response of M1 macrophages by cellular experiments and computer simulations. METHODS: This study has analysed the targets and mechanisms of macrophage regulating inflammatory response at gene and protein levels through bioinformatics. The monomeric components of LHQW were analyzed by High Performance Liquid Chromatography (HPLC). We established the in vitro cell model by M1 macrophages (Induction of THP-1 cells into M1 macrophages). RT-qPCR and immunofluorescence were used to detect changes in gene and protein levels of key targets after LHQW treatment. Computer simulations were utilized to verify the binding stability of monomeric components and protein targets. RESULTS: Macrophages had 140,690 gene targets, inflammatory response had 12,192 gene targets, intersection gene targets were 11,772. Key monomeric components (including: Pinocembrin, Fargesone-A, Nodakenin and Bowdichione) of LHQW were screened by HPLC. The results of cellular experiments indicated that LHQW could significantly reduce the mRNA expression of CCR5, CSF2, IFNG and TNF, thereby alleviating the inflammatory response caused by M1 macrophage. The computer simulations further validated the binding stability and conformation of key monomeric components and key protein targets, and IFNG/Nodakenin was able to form the most stable binding conformation for its action. CONCLUSION: In this study, the mechanism of LHQW inhibits the polarization of macrophages and the resulting inflammatory response was investigated by computer simulations and cellular experiments. We found that LHQW may not only reduce cell damage and death by acting on TNF and CCR5, but also inhibit the immune recognition process and inflammatory response by regulating CSF2 and IFNG to prevent polarization of macrophages. Therefore, these results suggested that LHQW may act through multiple targets to inhibit the polarization of macrophages and the resulting inflammatory response.

Unique profile on the progress free survival and overall survival in patients with advanced non-small cell lung cancer in the Qujing area, Southwest China.

Background: China's southwestern region, Qujing, harbors a high incidence of non-small cell lung cancer (NSCLC) and related mortality. This study was designed to reveal the impact of an immune-related prognostic signature (IRPS) on advanced NSCLC in the Qujing. Methods: Tissue specimens from an independent cohort of 37 patients with advanced NSCLC were retrospectively evaluated to determine the relationship between the IRPS estimated by next-generation sequencing (NGS) and clinical outcome. To compare the IRPS in tissue and the clinical outcomes between Qujing and non-Qujing populations, we analyzed datasets of 23 patients with advanced NSCLC from The Cancer Genome Atlas (TCGA) database. In addition, an independent cohort (n=111) of blood specimens was retrospectively analyzed to determine the relationship between the IRPS and clinical outcome. Finally, we evaluated the utility of the blood IRPS in classifying 24 patients with advanced NSCLC who might benefit from immunotherapy. Results: In cohort 1, the Qujing population with tTMB-H (≥ 10 mutations/Mb) or KRAS mutations had shorter progression-free survival (PFS) (hazard ratio [HR] 0.37, 0.14 to 0.97, P = 0.04; HR 0.23, 0.08 to 0.66, P < 0.01) and overall survival (OS) (HR 0.05, 0.01 to 0.35, P < 0.01; HR 0.22, 0.07 to 0.66, P < 0.01). In cohort 2 of the Qujing population, bTMB-H (≥ 6 mutations per Mb) and KRAS mutations were related to PFS (HR 0.59, 0.36 to 0.99, P = 0.04; HR 0.50, 0.26 to 0.98, P = 0.04) and OS (HR 0.58, 0.35 to 0.96, P = 0.03; HR 0.48, 0.25 to 0.93, P = 0.03). Notably, the Qujing population with bTMB-H had superior PFS (HR 0.32, 0.09 to 1.09, P = 0.01), OS (HR 0.33, 0.10 to 1.13, P < 0.01) and objective response rates (ORRs) (83.3% vs. 14.3% vs. 20.0%, P <0.01) to immunotherapy than other populations. Conclusions: These findings show that tTMB, bTMB and KRAS mutations appear to be independent validated IRPSs that predict the clinical outcomes of Qujing populations with advanced NSCLC and that bTMB may be used as a reliable IRPS to predict the clinical benefit from anti-PD-1 therapies among populations from Qujing with advanced NSCLC.

Therapeutic effect of captopril combined with phosphocreatine sodium on viral myocarditis.

OBJECTIVE: To analyze the therapeutic effect of captopril combined with phosphocreatine sodium in patients with viral myocarditis. METHODS: A total of 140 patients with infectious myocarditis who received treatment in Hanzhong City People's Hospital from December 2019 to January 2022 were retrospectively enrolled as study subjects. 61 of them were treated with captopril and constituted the control group (CG), and the remaining 79 who received phosphocreatine sodium in addition to captopril were the research group (RG). Variables were observed and compared between the two groups, including clinical efficacy, adverse reactions during treatment, and changes in myocardial enzymes, cardiac function, troponin, and inflammatory factors. According to therapeutic effect, those patients with marked results were categorized as the significant improvement group, and those whose results were just effective or ineffective were the insignificant improvement group. The risk factors affecting the efficacy of the patients were analyzed by logistic regression. RESULTS: Compared to the CG, the RG had greater decreases in aspartate aminotransferase (AST), creatine kinase isoenzyme (CK-MB), creatine kinase (CK), and lactate dehydrogenase (LDH) (all P < 0.05). The left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS), and left ventricular stroke volume (SV) in the RG increased significantly more after treatment (P < 0.05), while the levels of high-sensitivity troponin I (cTnI) and cardiac troponin T (cTnT) decreased more significantly (P < 0.05) compared to the CG. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the RG were more down-regulated (P < 0.05), and they had a higher overall response rate after treatment (P < 0.05). However, there was no significant difference in the incidence of adverse reactions between these two groups (P > 0.05). Multivariate logistic regression analysis showed that CK-MB, LVEF, cTnI, and cTnT were independent factors affecting the efficacy. CONCLUSION: Captopril combined with phosphocreatine sodium can reduce the inflammatory response in patients with infectious myocarditis, improve cardiac function, and improve the therapeutic efficacy.

A splicing variation in NPRL2 causing familial focal epilepsy with variable foci: additional cases and literature review.

NPRL2 (nitrogen permease regulator like 2) is a component of the GATOR1(GAP activity towards rags complex 1) proteins, which is an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. GATOR1 complex variations were reported to correlate with familial focal epilepsy with variable foci (FFEVF). However, FFEVF caused by NPRL2 variants has not been widely explored. Here, we describe a variant, 339+2T>C, in NPRL2 identified by trio whole-exome sequencing (WES) in a family. This splicing variant that occurred at the 5' end of exon 3 was confirmed by minigene assays, which affected alternative splicing and led to exon 3 skipping in NPRL2. Our cases presented multiple seizure types (febrile seizures, infantile spasms, focal seizures, or focal to generalized tonic-clonic seizures). Electroencephalogram (EEG) showed frequent discharges in the left frontal and central regions. A favorable prognosis was achieved in response to vitamin B6 and topiramate when the patient was seven months old. Our study expands the phenotype and genotype spectrum of FFEVF and provides solid diagnostic evidence for FFEVF.

Effects of food on the pharmacokinetics of ensartinib in healthy Chinese subjects.

Ensartinib is a promising, aminopyridazine-based small molecule that potently inhibits anaplastic lymphoma kinase. This random, two-period, crossover study evaluated the effects of food on the pharmacokinetics of ensartinib after a single dose (225 mg) in healthy Chinese subjects. The pharmacokinetic parameters of ensartinib were calculated using non-compartmental analysis. Twenty-four healthy Chinese subjects age 20-44 years were included in this study. The area under the concentration-time curve of ensartinib was ~25% lower after the intake of a high-fat, high-calorie meal before dosing, whereas the maximum plasma concentration was decreased by ~37%, illustrating the statistically significant effect of food on ensartinib pharmacokinetics. In addition, food intake prolonged the absorption phase of ensartinib (median time to maximum plasma concentration, from 4.5 to 6 hours). Population pharmacokinetic (PopPK) analysis was conducted using NONMEM, and the influences of food, age, sex, body weight and body mass index were studied via covariate analysis. In this analysis, ensartinib plasma concentrations were best described by a one-compartment model with Weibull absorption. The final model included food and age as covariates on apparent distribution and apparent clearance. Based on the final PopPK model, food was identified as a significant covariate for apparent clearance, apparent volume of distribution and absorption rate constant, consistent with the results of non-compartmental pharmacokinetic analysis.

Pericardial tamponade after chronic total occlusion revascularization: a case report and literature review.

Pericardial tamponade is a complication of percutaneous coronary intervention (PCI) with extremely high mortality. The rupture of coronary artery causes hypotension and shock, eventually resulting in death due to pericardial tamponade. Because of the complex operation in revascularization of chronic total occlusion (CTO-PCI) lesion, the incidence of pericardial tamponade increases. Usually, we use coronary angiogram to identify the rupture of coronary artery after PCI by the contrast agent. We presented a 67-year-old woman with pericardial tamponade after CTO revascularization. She had chest pain and out of breath for nearly two years. The coronary angiogram showed three branch lesion and CTO lesion of the right coronary artery (RCA). After revascularization of the RCA CTO lesion, the pericardial effusion and low blood pressure occurred, but we didn't find the leak of contrast agents during the final angiography. Then the patient was transferred to cardiac surgery department for emergency thoracotomy. They found the hematoma on the surface of the RCA and finally discharged without any symptoms. Our case approved: (I) there was still the possibility of coronary artery rupture even the coronary angiogram showed no contrast agent leakage from the coronary artery after PCI; (II) the combined use of IVUS and coronary angiogram may improve the accuracy and safety of CTO revascularization procedure.

Blood Tumor Mutational Burden as a Predictive Biomarker in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC).

This study was designed to investigate the impact of blood tumor mutational burden (bTMB) on advanced NSCLC in Southwest China. The relationship between the tTMB estimated by next-generation sequencing (NGS) and clinical outcome was retrospectively analyzed in tissue specimens from 21 patients with advanced NSCLC. Furthermore, the relationship between the bTMB estimated by NGS and clinical outcome was retrospectively assessed in blood specimens from 70 patients with advanced NSCLC. Finally, 13 advanced NSCLC patients were used to evaluate the utility of bTMB assessed by NGS in differentiating patients who would benefit from immunotherapy. In the tTMB group, tTMB ≥ 10 mutations/Mb was related to inferior progression-free survival (PFS) (hazard ratio [HR], 0.30; 95% CI, 0.08-1.17; log-rank P = 0.03) and overall survival (OS) (HR, 0.30; 95% CI, 0.08-1.16; log-rank P = 0.03). In the bTMB group, bTMB ≥ 6 mutations/Mb was associated with inferior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and OS (HR, 0.31; 95% CI, 0.14-0.7; log-rank P < 0.01). In the immunotherapy section, bTMB ≥ 6 mutations/Mb was related to superior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and objective response rates (ORRs) (bTMB < 6: 14.2%; 95% CI, 0.03-1.19; bTMB ≥ 6: 83.3%; 95% CI, 0.91-37.08; P = 0.02). These findings suggest that bTMB is a validated predictive biomarker for determining the clinical outcome of advanced NSCLC patients and may serve as a feasible predictor of the clinical benefit of immunotherapies (anti-PD-1 antibody) in the advanced NSCLC population in Yunnan Province.

Oncogenic Genetic Alterations in Non-Small-Cell Lung Cancer (NSCLC) in Southwestern China.

PURPOSE: To investigate the impact of oncogenic genetic alterations (GAs) on non-small-cell lung cancer (NSCLC) in southwestern China. PATIENTS AND METHODS: We first collected 579 pathologically confirmed NSCLC specimens and then used next-generation sequencing (NGS) to evaluate the DNA samples for GAs. Both the tissue and plasma samples were provided by 28 patients. Furthermore, subgroup analyses based on sample type, concordance, and GA type were carried out. RESULTS: GAs were detected by NGS in 61.8% (358/579) of patients. Two hundred and twenty-nine patients (39.6%) harbored EGFR mutations, 63 (10.9%) harbored KRAS mutations, 13 (2.2%) harbored BRAF mutations, 30 (5.18%) harbored ALK fusions, and 13 (2.2%) had ROS1 fusions. We found that females (p < 0.01), nonsmokers (p < 0.001), adenocarcinoma (p < 0.001), and tissue (p = 0.03) had a relatively high EGFR mutation rate. Notably, NSCLC patients from Xuanwei had a significantly different mutational pattern for EGFR in comparison with that of non-Xuanwei patients (higher G719X + S768I mutations and multiple gene alterations, but fewer exon 19 deletion mutations and single gene alterations). We found that adenocarcinoma (p = 0.02), family history of malignancy (p = 0.03), Xuanwei origin (p < 0.001), and tissue (p = 0.04) were associated with a higher number of KRAS mutations. Subgroup analysis showed that ALK (p < 0.001) and ROS1 (p < 0.05) fusions and rare EGFR mutations (p < 0.001) were associated with non-Han ethnic patients. CONCLUSION: Yunnan NSCLC patients from Xuanwei and non-Han ethnic patients had an obviously unique prevalence of GAs.

[Pharmacology and Clinical Evaluation of Ensartinib Hydrochloride Capsule].

Lung cancer is one of the most common malignancies with the highest incidence rate and mortality rate worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85%. Only 5% NSCLC patients are anaplastic lymphoma kinase (ALK) rearrangement positive NSCLC, but the prognosis of these patients is poor, and treatment is urgent. Ensartinib (X-396), a next-generation ALK tyrosine kinase inhibitor (ALK-TKI), has shown greater potency on inhibiting ALK activity and controlling brain metastases than crizotinib, which is indicated for the treatment of crizotinib-resistant, ALK-positive NSCLC patients. Several phase I to III clinical trials included both healthy volunteers and NSCLC patients have been conducted both in China and abroad. In this review, we briefly summarized the results of these trials, and preliminary efficacy, safety, pharmacology and pharmacokinetics/pharmacodynamics of ensartinib were discussed.

Tumor Mutational Burden and PD-L1 Expression in Non-Small-Cell Lung Cancer (NSCLC) in Southwestern China.

PURPOSE: To explore the impact between the tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression on NSCLC in the Yunnan region of southwestern China. PATIENTS AND METHODS: Seventy-one NSCLC specimens that were pathologically confirmed were collected at first. The TMB and driver genetic alterations were evaluated accordingly by next-generation sequencing (NGS). Afterwards, clinical parameters and tumor PD-L1 expressions were collected. Finally, the relationship between TMB, PD-L1 expression and clinical outcome was evaluated. RESULTS: The median TMB was 5 (0.6-49) mutations/Mb by our NGS panel and the majority of patients (63/71, 88.7%) did not receive immunotherapy. The progression-free survival (PFS) was longer in TMB-low patients versus TMB-high ones (median 18.0 vs. 9.0 months, hazard ratio = 0.34, 95% confidence interval 0.14 to 0.84, p = 0.02) and the cut-off value was 10 mutations/Mb. The overall survival (OS) was longer in TMB-low patients vs. TMB-high ones (median 21.0 vs. 10.0 months, HR = 0.32, 95% CI 0.12 to 0.82, p = 0.02). Notably, our study also found that, excluding the eight patients with immunotherapy, the PFS was longer in patients with TMB-low vs. TMB-high (median 19.0 vs. 8.0 months, HR = 0.11, 95% CI 0.03 to 0.39, p < 0.01) and the OS was longer in TMB-low patients vs. TMB-high (median 21.0 vs 10.0 months, HR = 0.12, 95% CI 0.03 to 0.42, p < 0.01). CONCLUSION: TMB was a valid and independent prognostic biomarker for NSCLC patients' clinical outcome and comprehensive screening of TMB based on NGS is recommended for individualized treatment strategies in Yunnan population.