To systematically synthesize evidence on multiple KRAS G12C inhibitors(KRAS G12C inhibitors, KRAS G12Ci) as monotherapy within a unified population and recommended-dose framework, establish a comparable benchmark range of efficacy and safety for previously treated patients with advanced or metastatic KRAS G12C-mutant non-small cell lung cancer(NSCLC), and explore potential effect modifiers.

Objective To gain insights into the biological characteristics of different populations of Culex tritaeniorhynchus within and around the Yellow Sea wetland from the perspective of the occurrence of resistance, we investigated the levels of resistance to deltamethrin and kdr gene mutation in the wetland and its peripheral areas. Methods Specimens were collected from Cx. tritaeniorhynchus populations at two monitoring sites in the Rare Bird National Nature Reserve and Tiaozi Ni Wetland Scenic Area, and also from two populations in Yancheng City and the Liuhe District of Nanjing, and the resistance of these mosquitoes to deltamethrin was determined using the CDC biotest bottle method. For each concentration of deltamethrin assessed, a random subset of exposed specimens was selected for amplification of the kdr gene fragment, followed by Sanger sequencing to identify and analyze resistance-associated mutations. Results The LC50 levels of deltamethrin among mosquitoes from the four populations in Luhe, Yancheng, the Rare Bird National Nature Reserve and the Tiaozi Ni Wetland Scenic Area were 2.048 5, 7.798 2, 3.473 3, and 17.695 5 mg/mL, respectively, with corresponding concentrations of deltamethrin ranging from 0.005 to 5.000,0.050 to 50.000,0.050 to 25.000 and 0.050 to 50.000 mg/mL, respectively. Furthermore, the ranges of the KT50 values were 11.76-107.43, 67.05-216.30,29.77-107.43 and 28.40-329.51 min; the 1-h knockdown rates were 34.58%-99.15%, 9.52%-43.80%, 55.09%-73.01%, and 10.09%-68.07%; and the 24-h mortality rates were 12.15%-67.52%,9.52%-79.56%,13.17%-82.21%, and 11.01%-78.99%, respectively. With respect to kdr gene mutation, we assayed a total of 63,70,59, and 57 mosquitoes for the four populations, for which we detected L1014F mutation frequencies of 14.29%, 35.00%, 20.34%, and 31.58%, respectively, with a majority of these mutations being heterozygous for resistance. In addition, five adult mosquitoes were identified has having synonymous mutations at site 1011[i. e. , AAT(asparagine)mutation to AAC(asparagine)]. Conclusions Our findings revealed the clear resistance of Cx. tritaeniorhynchus to deltamethrin in the Yancheng region of the Yellow Sea wetland, and the resistance phenotype and kdr frequency of Cx. tritaeniorhynchus in the wetland environment were comparable to those of Cx. tritaeniorhynchus in the wetland environment, thereby indicating that the resistance of different populations of Cx. tritaeniorhynchus was homogeneous under the pressure of different insecticide selection within and around the wetland. However, the underlying mechanisms need to be further studied.

Objective:To analyze the genetic characteristics of the VWF gene c.7332G＞A nonsense mutation and explore its molecular pathogenesis.Methods:Phenotypic diagnosis of the proband was performed using VWF:Ag,VWF:RCo,FⅧ:C and multimeric analysis.The probands were genotyped by NGS whole-exome sequencing,and the sequencing results were validated by sanger sequencing.The family members were genotyped by Sanger sequencing.The VWF gene c.7332G＞A nonsense mutant plasmid was constructed.After transfection,the function of VWF gene c.7332G＞A mutant plasmid was verified at cell level in vitro.The mRNA level was detected by qRT-PCR,and the expression level of protein was detected by Western blot,the function of multimerization was verified by the multimeric analysis.Results:VWF:Ag and VWF:RCo were all less than 3％in the proband,and the multimeric analysis showed multimer deficiency.The proband was diagnosed as type 3 VWD.The homozygous nonsense mutation of VWF gene c.7332G＞A was detected by gene sequencing.The VWF mRNA level of the mutant plasmid was decreased,and the VWF protein expression in the cell supernatant was decreased,the mutant protein was truncated and the function of VWF multimerization was impaired.Conclusion:A homozygous mutation in exon 43 of VWF gene,c.7332G＞A,was responsible for the probands type 3 VWD in the proband.The mutation caused a decrease in the relative level of VWF mRNA and protein,and impaired the function of VWF multimerization.

Objective To observe the efficacy of self-guided attention network for detecting responsible lesions related to cerebral palsy(CP)in children with periventricular white matter injury(PVWMI).Methods Totally 383 children with PVWMI were retrospectively enrolled and divided into CP group(n=243)and non-CP group(n=140),while 214 children without obvious brain abnormality on brain MRI were taken as control group.ROI of 4 key anatomical structures related to CP,i.e.centrum semiovale,posterior limb of internal capsule,cerebral peduncle and thalamus were delineated on T1WI,while responsible lesions related to CP within the key anatomical structures were labeled on T2WI,and the images were then registrated and used as input of the networks.ResNet34 network was adopted combined with attention and self-guided networks to train the network for detecting responsible lesions related to CP in children with PVWMI,and their efficacies were evaluated.The optimal network was screened,and its efficacy for segmenting the key anatomical structures was evaluated.Results Self-guided attention network was the optimal network,its area under the curve(AUC)for detecting lesions was 0.794-0.914,and the Dice similarity coefficient for segmenting the key anatomical structures was 0.702-0.764.Conclusion Self-guided attention network could be used for preliminarily detecting responsible lesions related to CP in children with PVWMI.

Objective:To investigate the clinical characteristics and cardiac magnetic resonance (CMR) features of cardiac sarcoidosis (CS).Methods:This retrospective study included 8 consecutive patients with pathologically confirmed CS by endomyocardial biopsy from Fuwai Hospital, Chinese Academy of Medical Sciences, between January 2012 and September 2024. All patients underwent comprehensive CMR examinations including cine imaging and late gadolinium enhancement (LGE) imaging. Clinical data, including electrocardiographic findings, were collected. CMR phenotyping was performed based on imaging characteristics, and cardiac structure and function parameters were evaluated. LGE analysis was conducted using the American Heart Association 17-segment model to assess the distribution patterns and involvement sites.Results:The most common clinical symptoms were chest tightness (4 patients), palpitations (4 patients), and shortness of breath (6 patients). Electrocardiographic abnormalities included atrioventricular block in 4 patients, right bundle branch block in 2 patients, left bundle branch block in 2 patients, frequent premature ventricular contractions in 4 patients, and non-sustained ventricular tachycardia in 5 patients. CMR phenotyping revealed hypertrophic cardiomyopathy pattern in 3 patients, with 2 patients maintaining normal biventricular function and 1 patient showing significantly reduced biventricular systolic function. Dilated cardiomyopathy pattern was identified in 4 patients, all demonstrating significantly impaired biventricular systolic function. One patient exhibited another phenotype with preserved biventricular systolic function. LGE analysis demonstrated that the anterior wall and anterior septum (segments 1, 2, 7, 8) were the most frequently involved regions, followed by the lateral and inferior walls (segments 5, 6, 11, 12). Subepicardial involvement was the predominant pattern of myocardial enhancement.Conclusions:Cardiac sarcoidosis exhibits diverse clinical manifestations and heterogeneous imaging characteristics. CMR not only provides a comprehensive assessment of cardiac structure and function but also reveals distinctive myocardial tissue characteristics, particularly the extent and distribution patterns of LGE involvement. These findings have significant reference value for early identification of CS and differential diagnosis from other cardiomyopathies.

Objective:To explore the feasibility and effectiveness of full free-breathing cardiac magnetic resonance (CMR) in clinical practice.Methods:The study prospectively included patients who underwent full free-breathing CMR and traditional breath-holding cine imaging between June 1 and June 30, 2024. An analysis and comparison were conducted on the image acquisition time, image quality, and left ventricular function parameters under two scanning methods, including left ventricular ejection fraction (LVEF), left ventricular cardiac output (LVCO),left ventricular end diastolic volume (LVEDV), left ventricular end diastolic volume index (LVEDVI), left ventricular end systolic volume (LVESV), left ventricular end systolic volume index (LVESVI), left ventricular stroke volume (LVSV), and left ventricular mass (LVM). In addition, the study conducted both quantitative and qualitative analyses of other sequences in full free-breathing CMR, including T 1 mapping, T 2 mapping, flow imaging, and late gadolinium enhancement (LGE). Group comparisons were performed using the Wilcoxon signed-rank test or paired t-test. Consistency assessments included Bland-Altman analysis, intraclass correlation coefficient ( ICC), and linear regression analysis. Results:Totally, 150 patients were recruited into the study. The average acquisition time of full free-breathing CMR was (22.1±3.1) min, with an average short axis cine sequence examination time of (2.7±0.4) min; The average acquisition time of short axis images in a breath-holding state was (4.9±1.4) min, which was significantly longer than the cine scan in the free-breathing state ( P0.001). The cine and LGE images quality scores obtained from full free-breathing CMR were 4 (4, 4) points and 5 (4, 5) points, respectively, while the cine image quality score obtained in a breath-holding state was 5 (4, 5) points. Compared with traditional breath-hold CMR, free-breathing CMR measurements showed slightly higher LVESV, and LVESVI, while LVEDV, LVEDVI, LVSV, LVCO, LVEF, and LVM were slightly lower, except for LVSV and LVCO, which showed no statistically significant difference, the differences in other cardiac function parameters were statistically significant ( P0.05). However, the two methods demonstrated good consistency( ICC0.947) and correlation (0.808 r0.993, P0.001). The Bland-Altman analysis showed that the bias for all cardiac function parameters was within 8.0%. The Native T 1 and T 2 values for free-breathing CMR were (1 277.5±57.0) ms and 40.1 (38.5, 41.4) ms, respectively, and the results of flow imaging and echocardiography were basically consistent. Conclusions:Free-breathing CMR is feasible and effective in clinical practice, showing a high level of consistency with left ventricular functional parameters obtained from traditional breath-hold scanning. It significantly shortens examination time and holds great clinical value for the promotion and widespread use of CMR.

BACKGROUND:In the preparation of injectable extracellular matrix materials,most of the materials require pepsin digestion followed by combination with other matrix components like hydrogels for pulp tissue regeneration,which also means the destruction of the microenvironment retained by natural extracellular matrix materials.OBJECTIVE:To investigate the effect of injectable dental pulp extracellular matrix prepared by grinding treatment on the regeneration of dental pulp tissue.METHODS:(1)The dental pulp tissue from pig teeth was prepared into acellular dental pulp matrix materials after acellular treatment.After freezing in liquid nitrogen and high-speed grinding,the injectable dental pulp extracellular matrix was prepared.Then,the differences in cell adhesion efficiency and microstructure between the injectable dental pulp extracellular matrix and natural dental pulp extracellular matrix were compared.Immunohistochemical analysis was used to analyze extracellular matrix protein components in injectable dental pulp extracellular matrix.(2)Injectable dental pulp extracellular matrix material inoculated with dental pulp stem cells was injected into the dental pulp cavity constructed from the dentin matrix material.The samples were obtained after 1,3,and 5 weeks of subcutaneous implantation in nude mice to observe the in vivo conversion rate of injectable dental pulp extracellular matrix materials and the regeneration ability of ectopic dental pulp tissue under the skin of nude mice.RESULTS AND CONCLUSION:(1)Compared with the dental pulp extracellular matrix,the injectable dental pulp extracellular matrix significantly improved the cell adhesion rate and retained the porous collagen structure similar to that of natural dental pulp extracellular matrix.(2)Compared with the natural dental pulp extracellular matrix,immunohistochemical staining showed that there was no significant difference in the expression of fibronectin,collagen type Ⅰ,and integrin β1 in the injectable dental pulp extracellular matrix,while the expression of fibronectin was significantly decreased.(3)In vivo experiments show that the injectable dental pulp extracellular matrix has excellent angiogenesis ability and promotes the formation of pulp-like tissues.The results exhibit that the milled injectable dental pulp extracellular matrix can still be used as an effective scaffold for the regeneration of dental pulp.

Objective To investigate whether successful percutaneous coronary intervention(PCI)could improve symptoms and quality of life(QOL)in left main disease and/or 3-vessel disease patients with diabetes.Methods Patients with left main disease and/or 3-vessel disease who underwent PCI in the First Affiliated Hospital of Air Force Medical University from April 2018 to May 2021 were consecutively enrolled and subdivided into 2 groups:diabetes and no diabetes.Detailed baseline characteristics,symptoms,including dyspnea and angina,assessed with the Rose dyspnea scale(RDS),Seattle angina questionnaire(SAQ),the European quality of life-5 dimensions(EQ-5D)and 12-item short-form health survey(SF-12)questionnaire respectively,procedural details,and 1 month and 1 year follow-up data were collected.Results Among 440 left main disease and/or 3-vessel disease patients,disease was present in 176(40.00％),who had more hypertension,peripheral artery disease,and LCX lesion(all P＜0.05).The incidence of major adverse cardiovascular events(MACE)and all-cause mortality were similar between the two groups(both P＞0.05)at 1 month follow-up,while all-cause mortality in diabetes patients was significantly higher than those without diabetes at 1 year follow-up(P=0.013).Low left ventricular ejection fraction was an independent risk factor for MACE and all-cause mortality at 1 month and 1 year follow-up after successful revascularization(all P＜0.05).Most importantly,symptoms,including dyspnea and angina,and QOL were markedly improved regardless of diabetes both at 1 month and 1 year follow-up(all P＜0.05).Diabetes patients showed improved dyspnea and QOL at similar degree to the non-diabetes patients(all P＞0.05)and a more significantly relieved angina(P=0.013).Additionally,the number of chronic total occlusion(CTO)per patient was identified as an independent risk factor of dyspnea(OR 0.723,95％CI 0.525～0.997,P=0.048)and angina relief(OR 0.686,95％CI 0.473～0.995,P=0.047),and the contrast volume(OR 0.995,95％CI 0.992～0.999,P=0.008)as an independent risk factor of QOL improvement in diabetic patients.Conclusions Successful PCI is beneficial for relieving symptoms and improving quality of life in patients with diabetes who have left main disease and/or 3-vessel disease.

AIM To study the chemical constituents from Asteris Radix et Rhizoma and their anti-inflammatory activities.METHODS The extract from Asteris Radix et Rhizoma was isolated and purified by column chromatography and high performance liquid chromatography,then the structures of obtained compounds were identified by physicochemical properties and spectral data.Their anti-inflammatory activities were evaluated by RAW264.7 model.RESULTS Thirteen compounds were isolated and identified as(Z)-9,10,11-trihydroxy-12-octadecenoic acid(1),tianshic acid(2),6,6-dimethyl-2-methlenebicyclo[3.1.1]hept-3-O-(6-O-apiofuranosyl)-β-D-glucopyranoside(3),ent-16β,17-dihydroxy-kauran-19-oic acid(4),ent-17-hydroxy-19-kauranoic acid(5),7β,17-dihydroxy-16α-ent-kauran-19-oic acid 19-O-β-D-glucopyranoside ester(6),paniculoside Ⅳ(7),thomimarine A(8),cyclo-(S-Pro-R-Leu)(9),4,5-di-O-caffeoylquinic acid 1-methyl ether(10),methyl 3,5-di-O-caffeoyl quinate(11),5-acetyl-3β-hydroxy-2β-(1-hydroxyisopropyl)-2,3-dihydrobenzofurane(12),4-ally-2,6-dimethoxyphenyl glucoside(13).Compounds 1 and 3-12 had inhibition on the release of NO in RAW264.7 cells,and 4-6,8,10-12 were better than the positive control.CONCLUSION Compounds 1,6,8-9 are isolated from Compositae family for the first time,and 2-5,7,10 and 11-13 are first isolated from this plant.Compounds 1,3-12 have anti-inflammatory activities.

Background and purpose:China is a country with high incidence rate and mortality of liver cancer.In 2022,there were approximately 368 000 cases of liver cancer and 317 000 deaths in China.Extending the survival period of liver cancer patients is an urgent issue that we need to address.In recent years,tyrosine kinase inhibitor(TKI)alone or in combination with immune checkpoint inhibitors have achieved good results in the treatment of primary liver cancer.However,most studies did not include the combination of transcatheter arterial chemoembolization(TACE)treatment.We speculate that combining TKI drugs with immune checkpoint inhibitors and TACE therapy may provide greater benefits to liver cancer patients.Therefore,this study aimed to evaluate the short-term efficacy and safety of TACE combined with anlotinib and sintilimab in the treatment of liver cancer.Methods:This study is a single arm phase Ⅱ clinical trial approved by the ethics committee of The Third People's Hospital of Yibin(ethical approval numbers:2022009).Inclusion criteria:① Age 18-70 years;② Primary liver cancer confirmed by clinical diagnosis or histopathology;③ Eastern Cooperative Oncology Group(ECOG)performance status score of 0-1;④ China Liver Cancer Staging(CNLC)stage Ⅱb-Ⅲb;⑤ Adequate cardiopulmonary function;⑥ Child-Pugh score≤8 points;⑦ At least one measurable tumor lesion according to the modified Response Evaluation Criteria in Solid Tumors(mRECIST)version 1.1.From November 1,2021 to March 1,2024,we recruited 61 patients,of whom 39 met the criteria.Firstly,all enrolled patients received TACE treatment.Approximately one week after the initial TACE procedure,12 mg of anlotinib(adjusted according to tolerance)was administered orally on days 1-14,every 3 weeks;Simultaneously 200 mg of sintilimab was administered intravenously on day 1,every 3 weeks.After completing 2 cycles of treatment,efficacy evaluation was conducted according to the modified Response Evaluation Criteria in Solid Tumors(mRECIST)1.1.The primary observation indicators of the study were objective response rate(ORR),and the secondary observation indicators were median progression-free survival(mPFS),disease control rate(DCR)and safety.Results:The ORR of this study was 76.9%,DCR was 94.9%,and mPFS was 9.2 months(95%CI:2.317-16.083).39 cases(100%)had grade 1-2 adverse reactions,15 cases(38.5%)had grade 3 adverse reactions,5 cases(12.8%)had grade 4 adverse reactions,and 1 patient died due to upper gastrointestinal bleeding.In the stage mainly treated with TACE combined with TKI and immunotherapy,the incidence of grade 3-4 adverse reactions was higher compared with the stage mainly treated with anlotinib combined with sintilimab.The vast majority of adverse reactions can be recovered through conventional treatment methods.Conclusion:TACE combined with anlotinib and sintilimab has a definite therapeutic effect and overall safety and controllability in the treatment of CNLC stage Ⅱb-Ⅲb liver cancer.This combination therapy may provide a new treatment model for CNLC stage Ⅱb-Ⅲb liver cancer patients.However,further exploration is needed to address the pain,vomiting,decreased appetite,liver function damage,upper gastrointestinal bleeding,and other issues caused by this treatment mode.