This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRAS^G12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFR^L858R and EGFR^Δ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01‍‒‍1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49‍‒‍2.63; P<0.0001), while classical activating mutations with EGFR^T790M showed no difference compared to classical activating mutations without EGFR^T790M in OS (adjusted HR, 0.96; 95% CI, 0.48‍‒‍1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‍‒‍1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32‍‒‍0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38‍‒‍0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75‍‒‍8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88‍‒‍6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRAS^G12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFR^T790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; ErbB Receptors/genetics* ; Extracellular Matrix Proteins/genetics* ; Immune Checkpoint Inhibitors/therapeutic use* ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Proto-Oncogene Proteins p21(ras)/genetics* ; Treatment Outcome

Objective To explore the safety and effectiveness of bridging therapy in elderly patients with acute stroke due to posterior circulation large vessel occlusion.Methods A total of 160 eld-erly patients with acute stroke caused by posterior circulation large vessel occlusion admitted to our department were prospectively recruited and randomly divided into bridging group(n=80)and control group(n=80).The bridging group received thrombolysis treatment and then mechan-ical thrombectomy.The control group received mechanical thrombectomy directly.Prognosis and adverse reactions were compared between the two groups.Results The NIHSS score and BATMAN score after treatment were significantly decreased in both groups(P＜0.01),and the two scores were obviously lower in the bridging group than the control group(6.54±1.23 vs 7.12± 0.98,2.12±0.34 vs 2.87±0.44,P＜0.01).There was no statistical difference in the conversion rate of bleeding after cerebral infarction between the two groups(5.00％vs 3.75％,P＞0.05).The number of intraoperative thrombus removal was significantly lower in the bridging group than the control group(2.43±0.33 vs 2.98±0.41,P＜0.01).Remarkable difference was observed in the mRS score between the two groups after treatment(P＜0.05),with the proportion of mRS score ranging from 0 to 1 larger in the bridging group than the control group(52.50％vs 27.50％,P＜0.05).Conclusion Bridging thrombolysis can significantly improve the neurological function in elderly patients with acute stroke due to posterior circulation occlusion.

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95％ confidence interval (CI), 1.01?1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95％ CI, 1.49?2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95％ CI, 0.48?1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95％ CI, 0.39?1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A (USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95％ CI, 0.32?0.82; P=0.0077), PFS (adjusted HR, 0.51; 95％ CI, 0.38?0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95％ CI, 2.75?8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95％ CI, 1.88?6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12C mutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

Objective:Taking clinical strains of Helicobacter pylori ( H. pylori) with different antimicrobial resistance as the research object, to explore the new genes related to the resistance of H. pylori to clarithromycin (CLA) and levofloxacin (LVX) based on whole-genome sequencing. Methods:From September 1st, 2016 to August 31st, 2019, 1 749 patients with upper gastrointestinal symptoms and positive 13C urea breath test who visited the Department of Gastroenterology and Hepatology, the University of Hong Kong-Shenzhen Hospital were enrolled. After gastric mucosal biopsy, H. pylori was isolated and cultured from gastric mucosa. Ninety H. pylori strains were successfully preserved. According to the results of in vitro drug sensitivity test, a total of 40 strains including 10 strains with single-drug resistance to CLA (CLA group), 10 strains with single-drug resistance to LVX (LVX group), 10 strains with dual-resistance to CLA and LVX (dual resistance group) and 10 strains sensitive to CLA, LVX, amoxicillin, furazolidone, tetracycline and metronidazole (all sensitive group) were screened out. By whole-genome sequencing and comparison to the comprehensive antibiotic research database (CARD), single nucleotide variations (SNV) and indels were analyzed, genes related to H. pylori resistance to CLA and LVX were screened out and the differences of new genes among 4 groups were analyzed. Independent sample t test, one-way analysis of variance, least significant difference method and chi-square test were used for statistical analysis. Results:Among the 4 groups there were no statistically significant differences in the number of SNV (74 952.00±8 755.21, 77 128.10±3 191.35, 78 639.90±601.23 and 77 474.60±2 421.05) and Indels (2 582.20±265.45, 2 653.60±108.37, 2 667.10±43.82 and 2 641.10±80.25) (all P>0.05). Compared to CARD, a total of 223 drug resistance-related genes were detected, of which 19 genes related to CLA mono-resistance in CLA group, 24 genes related to LVX mono-resistance in LVX group, 16 genes related to CLA mono-resistance, 14 genes related to LVX mono-resistance, and 12 dual resistance-related genes in dual resistance group, and 11 genes related to CLA mono-resistance, 17 genes related to LVX mono-resistance, and 13 dual resistance-related genes in all sensitive group. Among the genes related to CLA mono-resistance, the detection rates of erythromycin esterase gene ( ere)B in CLA group, LVX group, dual resistance group and all sensitive group were 0/10, 0/10, 3/10, 0/10, respectively, and the difference was statistically significant( χ2=5.79, P=0.049). The detection rate of erythromycin ribosomal methylase gene ( erm) family in CLA group and dual resistance group was higher than that in LVX group and all sensitive group (45.0%, 9/20 vs. 10.0%, 2/20), and the difference was statistically significant ( χ2=6.14, P=0.013). The detection rates of free methionine-(R)-sulfoxide reductase gene ( msrC) in CLA group, LVX group, dual resistance group and all sensitive group were 10/10, 7/10, 6/10, 4/10, respectively, and the difference was statistically significant ( χ2=8.97, P=0.030). Among the genes related to LVX mono-resistance, the detection rate of quinolone resistance pentapeptide repeat protein gene ( qnr) family in LVX group and dual resistance group was higher than that in CLA group and all sensitive group (60.0%, 12/20 vs. 25.0%, 5/20), and the difference was statistically significant ( χ2=5.01, P=0.025). The detection rates of qnrB4 in CLA group, LVX group, dual resistance group and all sensitive group were 1/10, 3/10, 7/10, 1/10, respectively, and the difference was statistically significant ( χ2=10.17, P=0.010). The number of efflux transporter genes related to CLA mono-resistance in 4 groups were less than those of LVX mono-resistance and dual drug resistance (11 vs. 29 and 11 vs. 23), and the differences were statistically significant ( χ2=11.87, 5.80; P=0.001, 0.016). The detected numbers of LVX resistance-related efflux transport genes in CLA group, LVX group, dual resistance group and all sensitive group were 28, 40, 24 and 27, respectively, and the difference was statistically significant ( χ2=10.26, P=0.016). Conclusions:Erm family and msrC may be important genes that mediate the resistance of H. pylori to CLA, and qnr family is related to mediating the resistance of H. pylori to LVX. Efflux transport genes may play a synergistic role in the process of drug efflux, and are more likely to mediate H. pylori resistance to LVX.

Objective:To evaluate the effects of different pacing modes (unipolar/bipolar) under left bundle branch pacing(LBBP) on ventricular mechanical synchrony and myocardial work using the pressure-strain loop technique.Methods:Twenty-nine patients with LBBP due to symptomatic bradycardia were collected as LBBP group in Sun Yat-sen Memorial Hospital of Sun Yat-sen University from December 2018 to July 2020. Another 29 matched patients with right ventricular pacing (RVP) during the same period were also included as a RVP group. Each LBBP patient was programmed to different pacing modes (uni-/bio-polar) within 1 week after the operation.Under each pacing mode, the inter- and intra-ventricular mechanical synchronization were evaluated. Meanwhile, the global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) were obtained by the left ventricular pressure-strain loops technique.Results:Compared with the RVP group, the mechanical synchrony in the LBBP group was significantly improved (all P<0.05). GWI, GCW, and GWE increased, while GWW decreased, and the differences were statistically significant (all P<0.05), there were no significant differences in ventricular mechanical synchronization, GWI, GCW, GWE, and GWW between unipolar and bipolar pacing in the LBBP group (all P>0.05), there were no significant differences in these parameters when increasing output voltage (all P>0.05). Conclusions:LBBP induces better mechanical synchronization and higher myocardial work efficiency than RVP. Different LBBP pacing modes do not affect ventricular mechanical synchronization and myocardial work efficiency.

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a child with Perlman syndrome. METHODS: Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Whole exome sequencing (WES) was carried out to detect potential variant in the proband. Candidate variant was verified by Sanger sequencing. The pathogenicity of candidate variants was evaluated according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). RESULTS: The results of WES showed that the proband has harbored compound heterozygous variants of the DIS3L2 gene, namely c.2109delC and c.1829.c.1830insC, which were respectively inherited from her mother and father. The results were confirmed by Sanger sequencing. Based on the ACMG guidelines, the two novel variants were both predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION The compound heterozygous variants of the DIS3L2 gene probably underlay the Perlman syndrome in this patient. Above finding has enriched the spectrum of DIS3L2 gene mutations.
Exoribonucleases ; Female ; Fetal Macrosomia ; Genetic Testing ; Genomics ; Humans ; Mutation ; Whole Exome Sequencing ; Wilms Tumor

AlM: The Chinese medicinal herb Hanfangji is dried roots of Stephania tetrandra S. Moore (Family, Menispermaceae). Tetrandrine and fangchinoline are two major constituents of Hanfangji and these bisbenzyltetrahydroisoquinoline alkaloids possess anti - cancer and other pharmacological activities. To facilitate further pharmacodynamic investigation of these compounds, a pharmacokinetic investigation was performed in rats and in vitro. METHODS: Pharmacokinetics of tetrandrine and fangchinoline were characterized in rats p.o. or i.v. dosing an aqueous extract of Hanfangji or the individual compound. Unbound levels of systemic exposure to these two alkaloids were assessed using in vitro studies of plasma protein binding, blood-plasma partition, and lysosomal trapping. All the study samples were analyzed by liquid chromatography/mass spectrometry.RESULTS: We found two pharmacokinetic features of tetrandrine and fangchinoline. First, the two compounds had blood levels of systemic exposure substantially higher than the respective plasma levels of systemic exposure. Second, the two compounds exhibited significantly higher systemic exposure levels after p.o. dosing an aqueous extract of Hanfangji than the respective exposure levels after p.o. dosing the individual compound, at the same compound dose levels and under the same conditions for analytical measurement and the same conditions for animal study. Unbound fractions of tetrandrine and fangchinoline in rat plasma were 2%-5% and the concentrations of the alkaloids in rat erythrocytes were 5-times higher than those in rat plasma. Lysosomal inhibitor could block their trapping in lysosomes and significantly reduce their concentrations in HEK-293 cells. CONCLUSlON: The following pharmacokinetic aspects should be noted in pharmacodynamic investigation of tetrandrine and fangchinoline: extensive binding with plasma proteins, extensive binding with erythrocytes, and trapping by lysosomes of tissue cells substantially reduce the levels of unbound tetrandrine and fangchinoline in the systemic circulation.

Phthalic acid esters (PAEs) are commonly used plasticizers and solvents. Human body is exposed and absorbed mainly through diet, skin and air inhalation. The biological samples such as urine, blood, saliva, semen and breast milk generally contain PAEs and their metabolites, but the concentrations of PAEs metabolites vary in different samples. In the general population, the levels of PAEs are higher in children than in adults, and higher in women than in men; the levels of PAEs are higher in the occupational population than in the general population. In this paper, the research of PAEs related human biomonitoring in the general population and occupational population at home and abroad is reviewed, so as to provide the basis for reducing the exposure of PAEs and related health risk.

T-box transcription factor gene (TBX) interferes with the origin and development of organs, and TBX5 is expressed highest in normal cardiac and pulmonary tissues. Lack of TBX5 may lead to thoracic malformation and abnormal diaphragmatic development, in which ectopic expression and overexpression may induce the apoptosis of cell and inhibit the development of cell. Previous studies demonstrated the potential role of TBX5 in the development and progression of esophageal adenocarcinoma, gastric cancer, colon cancer and breast cancer. We reviewed the association between the expression of TBX2 subfamily and the prognosis, and explore the research progress of TBX5 in regulating the development and progression of lung cancer. Even though the relationshihp the development of lung cancer and TBX5 are not clear, TBX5 could significantly inhibit in vivo tumor growth, and the level of TBX5 was negatively correlated with lung cancer progression. Therefore, the gene expression levels and methylation extent of TBX could be a potential biomarker to reveal the proliferation and metastasis of lung cancer, as well as a therapeutic target for lung cancer.
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