BACKGROUND: Durvalumab after chemoradiotherapy (CRT) failed to bring survival benefits to patients with epidermal growth factor receptor ( EGFR ) mutations in PACIFIC study (evaluating durvalumab in patients with stage III, unresectable NSCLC who did not have disease progression after concurrent chemoradiotherapy). We aimed to explore whether locally advanced inoperable patients with EGFR mutations benefit from tyrosine kinase inhibitors (TKIs) and the optimal treatment regimen. METHODS: We searched the PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases from inception to December 31, 2022 and performed a meta-analysis based on a Bayesian framework, with progression-free survival (PFS) and overall survival (OS) as the primary endpoints. RESULTS: A total of 1156 patients were identified in 16 studies that included 6 treatment measures, including CRT, CRT followed by durvalumab (CRT-Durva), TKI monotherapy, radiotherapy combined with TKI (RT-TKI), CRT combined with TKI (CRT-TKI), and TKI combined with durvalumab (TKI-Durva). The PFS of patients treated with TKI-containing regimens was significantly longer than that of patients treated with TKI-free regimens (hazard ratio [HR] = 0.37, 95% confidence interval [CI], 0.20-0.66). The PFS of TKI monotherapy was significantly longer than that of CRT (HR = 0.66, 95% CI, 0.50-0.87) but shorter than RT-TKI (HR = 1.78, 95% CI, 1.17-2.67). Furthermore, the PFS of RT-TKI or CRT-TKI were both significantly longer than that of CRT or CRT-Durva. RT-TKI ranked first in the Bayesian ranking, with the longest OS (60.8 months, 95% CI = 37.2-84.3 months) and the longest PFS (21.5 months, 95% CI, 15.4-27.5 months) in integrated analysis. CONCLUSIONS: For unresectable stage III EGFR mutant NSCLC, RT and TKI are both essential. Based on the current evidence, RT-TKI brings a superior survival advantage, while CRT-TKI needs further estimation. Large randomized clinical trials are urgently needed to explore the appropriate application sequences of TKI, radiotherapy, and chemotherapy. REGISTRATION PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42022298490.
Humans ; Carcinoma, Non-Small-Cell Lung/therapy* ; ErbB Receptors/genetics* ; Lung Neoplasms/drug therapy* ; Mutation/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Chemoradiotherapy ; Antibodies, Monoclonal/therapeutic use*

Objective To investigate the reproductive and developmental effects of Clothianidin in rats. Methods Clothianidin was administrated by diet to both parental and first filial (F 1) generations of rats at the dosages of 0, 30.51, 110.84 and 304.26 mg/(kg·d) in females, and 0, 26.45, 92.69 and 279.42 mg/(kg·d) in males. Clothianidin was administered through diet to male and female rats for 8 weeks before mating. Clothianidin was administered to female rats in the parental and F1 generations during mating, gestation and lactation periods. During the test, toxicity performance was observed, reproduction index was calculated, and pathological examination was carried out. Results The body weights of rats in the parent and F1 generations in the high-dose group were lower than those in the control group during pre-mating exposure and at various time points during pregnancy and lactation (P<0.05). The pregnancy rates of parental and F1 generations in the high-dose group were lower than those of the control group (48.57% vs 71.43%, 45.71% vs 80.00%, P＜0. 05). Sperm concentration and sperm motility of the parental generation were lower than those of the control group [(42.55±12.87) vs (53.84±7.65) ×106/ml, (58.94±10.59) vs (65.59±6.03), （P＜0.05）]. Sperm concentration and sperm motility of the F1 generation were lower than those of the control group [(41.64±12.42) vs (53.09±9.48), (55.13±9.19) vs (64.53±6.31), (P＜0.05). Conclusion Exposure to clothianidin has reproductive toxicity to Wistar rats, and the no-observed adverse effect level (NOAEL) in the two-generation reproductive toxicity test is 92.69 mg/kg·BW for males and 110.84 mg/kg·BW for females in Wistar rats.

To analyze the treatment strategy for a 78-year-old female patient with mismatch repair deficient (dMMR) gastric cancer who achieved long-term survival. After third-line chemotherapy failed, gene testing showed ARID1A p.Gln748fs, c.2733-1G＞T variation, with PD-L1 TPS 30%, CPS 60%. The nivolumab was employed, and two weeks later, the best response was partial response (PR). During the fourth-line immunotherapy maintenance treatment, progression of left adrenal metastasis was observed. The expression of human epidermal growth factor receptor-2 (HER-2) was positive, and the antibody drug conjugate disitamab vedotin (RC48) was chosen for treatment. After 10 months of treatment with nivolumab combined with RC48, the best efficacy was assessed as stable disease (SD), with a progression free survival (PFS) of up to 12 months. Radiotherapy was employed, and immunotherapy was maintained, allowing the patient to achieve a PFS of 18 months again. During immunotherapy, a clinical pharmacist developed a personalized pharmaceutical care plan for this patient. At the last follow-up, this patient achieved 78 months of long-term survival.

This study predicts the quality markers(Q-markers) for the cough-relieving and phlegm-expelling effects of Kening Granules based on pharmacodynamics, plasma drug chemistry, network pharmacology, and pharmacokinetics. Strong ammonia solution spray and phenol red secretion assays were employed to evaluate the cough-relieving and phlegm-expelling effects of Kening Granules. Twentysix absorbed prototype components of Kening Granules were identified by ultra high performance liquid chromatography coupled with QExactive Plus quadrupole/Orbitrap high resolution mass spectrometry(UHPLC-Q-Exactive Plus Orbitrap HRMS). Through network pharmacology, 11 potential active components were screened out for the cough-relieving and phlegm-expelling effects of Kening Granules. The 11 components acted on 40 common targets such as IL6, TLR4, and STAT3, which mainly participated in PI3K/Akt, HIF-1, and EGFR signaling pathways. Pharmacokinetic quantitative analysis was performed for 7 prototype components. Three compounds including azelaic acid, caffeic acid, and vanillin were identified as Q-markers for the cough-relieving and phlegm-expelling effects of Kening Granules based on their effectiveness, transmissibility, and measurability. The results of this study are of great significance for clarifying the pharmacological substance basis, optimizing the quality standards, and promoting the clinical application of Kening Granules.
Drugs, Chinese Herbal/administration & dosage* ; Network Pharmacology ; Cough/blood* ; Male ; Humans ; Animals ; Rats ; Rats, Sprague-Dawley ; Biomarkers/blood* ; Quality Control ; Chromatography, High Pressure Liquid ; Antitussive Agents/chemistry*

OBJECTIVES: To explore the impact of different treatment attitudes on the survival status of extremely preterm infants (EPIs) and evaluate the mortality and occurrence of severe complications in actively treated infants, as well as their risk factors. METHODS: A retrospective analysis was conducted on perinatal data of EPIs born between January 1, 2016, and December 31, 2023, who were admitted to the neonatal intensive care unit of Nanjing Women and Children's Healthcare Hospital within 24 hours after birth. The analysis focused on the attributable risk of mortality associated with different treatment attitudes in EPIs of varying gestational ages and birth weights. A multivariate logistic regression model was used to analyze the risk factors for mortality and severe complications in the actively treated group. RESULTS: A total of 485 EPIs were included. As gestational age or birth weight increased, the attributable risk of mortality with care withdrawal increased. Active treatment significantly improved the survival status of EPIs born at a gestational age of ≥24 weeks. Multivariate logistic regression analysis indicated that lower gestational age and the need for mechanical ventilation within 72 hours after birth were independent risk factors for mortality or severe complications in EPIs (P<0.05). CONCLUSIONS Active treatment can significantly extend the survival time of EPIs born at a gestational age of ≥24 weeks. Lower gestational age and the need for mechanical ventilation within 72 hours after birth are closely associated with poor survival outcomes in EPIs.
Humans ; Retrospective Studies ; Infant, Extremely Premature ; Risk Factors ; Infant, Newborn ; Female ; Male ; Gestational Age ; Logistic Models ; Birth Weight

Objective:To explore the correlation between serum hepcidin antimicrobial peptide (HAMP), secreted phosphoprotein 1 (SPP1), and regulator of G protein signaling 2 (RGS2) levels and the clinical pathological characteristics of gastric cancer patients, and their predictive value for postoperative recurrence or metastasis.Methods:A total of 92 gastric cancer patients treated at Handan First Hospital from March 2021 to March 2023 were selected as the gastric cancer group, and 92 healthy individuals who underwent physical examinations during the same period were selected as the control group. The serum levels of HAMP, SPP1 and RGS2 were compared between the two groups. According to the mean levels of HAMP, SPP1, and RGS2 in the serum of gastric cancer patients, they were divided into HAMP high level group and HAMP low level group, SPP1 high level group and SPP1 low level group, RGS2 high level group and RGS2 low level group. The clinicopathological characteristics of gastric cancer patients with different levels of HAMP, SPP1 and RGS2 were compared respectively. After a median follow-up of 18 months, gastric cancer patients were divided into a non-recurrence or metastasis group ( n=59) and a recurrence and metastasis group ( n=33) based on whether the tumor recurred or metastasized. The serum levels of HAMP, SPP1, and RGS2 were compared between the two groups of patients. The predictive value of HAMP, SPP1 and RGS2 for postoperative recurrence or metastasis in patients with gastric cancer was analyzed by using the receiver operator characteristic (ROC) curve. Results:Compared with the control group, the gastric cancer group had higher levels of serum HAMP [ (52.28±5.44) ng/ml vs. (31.22±4.18) ng/ml] and SPP1 [ (55.96±6.43) ng/ml vs. (36.99±5.25) ng/ml] ( t=29.44, P<0.001; t=21.92, P<0.001), and lower level of RGS2 [ (3.72±0.66) mg/L vs. (5.11±0.87) mg/L) ] ( t=12.21, P<0.001). There were statistically significant differences in maximum tumor diameter ( χ2=13.07, P<0.001; χ2=6.71, P=0.010; χ2=10.56, P=0.001), TNM staging ( χ2=7.42, P=0.006; χ2=6.36, P=0.012; χ2=5.39, P=0.020), lymph node metastasis ( χ2=23.41, P<0.001; χ2=6.52, P=0.011; χ2=13.11, P<0.001), and differentiation degree ( χ2=9.01, P=0.003; χ2=7.97, P=0.005; χ2=15.29, P<0.001) between the gastric cancer patients in the HAMP high level group ( n=44) and the HAMP low level group ( n=48), the SPP1 high level group ( n=43) and the SPP1 low level group ( n=49), and the RGS2 high level group ( n=50) and the RGS2 low level group ( n=42). Compared with the non-recurrence or metastatic group, the recurrence and metastatic group had higher levels of serum HAMP [ (59.26±5.66) ng/ml vs. (48.37±4.28) ng/ml] and SPP1 [ (62.85±6.36) ng/ml vs. (52.11±5.38) ng/ml] level ( t=10.40, P<0.001; t=8.60, P<0.001), and lower level of RGS2 [ (3.01±0.48) mg/L vs. (4.12±0.69) mg/L] ( t=8.19, P<0.001). ROC curve analysis showed that the area under the curve (AUC) values of serum HAMP, SPP1, and RGS2 levels alone for predicting postoperative recurrence or metastasis in gastric cancer patients were 0.777, 0.813, and 0.778, respectively. The AUC value of the combination of the three indicators for predicting postoperative recurrence or metastasis in gastric cancer patients was 0.871. The predictive efficacy of the combination of the three indicators for predicting postoperative recurrence or metastasis in gastric cancer patients was better than that alone ( Z=2.51, P=0.035; Z=2.61, P=0.032; Z=2.71, P=0.029) . Conclusions:The levels of HAMP and SPP1 in the serum of gastric cancer patients increase, while the level of RGS2 decreases, and the levels of the three are related to the maximum tumor diameter, TNM staging, lymph node metastasis and differentiation degree, and their combined detection has higher predictive value for postoperative recurrence or metastasis in gastric cancer patients.

Objective To investigate the relationship between kinase insert domain receptor(KDR)rs2305948 polymorphism and clopidogrel resistance(CR)in patients with acute coronary syndrome after receiving percutaneous coronary intervention(PCI).Methods A total of 468 patients with acute coronary syndrome,who were admitted to the Zhangjiakou Municipal First Hospital of China from September 2022 to September 2023,were selected as the subjects of study.All patients received PCI treatment and took medication of clopidogrel after the treatment.The occurrence of CR was recorded.The factors influencing the occurrence of CR were analyzed.The clinical significance of KDR rs2305948 polymorphism in predicting CR in patients with acute coronary syndrome after receiving PCI was evaluated.Results Of 468 patients with acute coronary syndrome,116(24.79％)developed CR.Logistic multivariate regression analysis indicated that low-density lipoprotein cholesterol(LDL-C,95％CI=1.420-8.390,OR=3.452),type 2 vascular endothelial growth factor receptor(VEGFR-2,95％CI=1.374-8.118,OR=3.340),KDR rs2305948 T/T genotype(95％CI=1.677-9.905,OR=4.076),and T allele(95％CI=1.390-8.207,OR=3.377)were the independent factors influencing the occurrence of CR inpatients with acute coronary syndrome after receiving PCI(all P＜0.05).Receiver operating characteristic(ROC)curve analysis showed that the sensitivity,specificity,and area under ROC curve(AUC)of the T/T genotype of KDR rs2305948 in predicting CR in patients with acute coronary syndrome after receiving PCI were 75.86％,70.45％,and 0.773(95％CI=0.666-0.880)respectively.Conclusion In patients with acute coronary syndrome after receiving PCI,the risk of developing CR is higher.The KDR rs2305948 polymorphism is correlated with CR in patients with acute coronary syndrome after receiving PCI,and it has a certain predictive value for CR.

Aim To express and purify recombinant hCGH-CTP fusion protein in high-density suspension culture of Chinese hamster ovary cells (CHO-S), and to verify the lipid accumulation effect of rhCGH-CTP on 3T3-L1 mature adipocytes. Methods The recombinant protein expression vector (pcDNA3. 1-rhCGH-CTP) was constructed, achieved by fusing the human glycoprotein hormone beta 5/alpha 2 cDNA with CTP Linker. The expression plasmid was transiently transfected into the suspended CHO-S to express rhCGH-CTP protein and then purified, and the protein biological activity was verified. Intervention with 3T3-L1 mature adipocyte cells for 24 h was performed to detect the changes of intracellular triglyceride (TG) level. Results Western blot results showed that rhCGH-CTP protein was successfully expressed in CHO-S cells, and the yield was up to 715. 4 mg • L~ . The secreted protein was purified by AKTA pure system with higher purity that was up to 90% as identified by SDS-PAGE. In addition, the intracellular cAMP content of mature adipocytes with high expression of TSHR gene significantly increased after intervention with different concentrations of rhCGH-CTP protein by ELISA kit, indicating that rhCGH-CTP protein had biological activity. Oil red 0 staining showed that compared with the control group, the lipid content of mature adipocytes in the intervention groups with different concentrations of rhCGH-CTP protein significantly decreased (P < 0. 05) . Conclusions The rhCGH-CTP protein has been successfully expressed and purified with biological activity, and effectively reduce TG. This research provides an important theoretical basis for further revealing the physiological role of CGH protein and its potential application in clinical practice.

italic>Artemisia argyi is a traditional Chinese medicine in China, which is used as medicine with its leaves. The leaves of A. argyi mainly contain flavonoids, phenolic acids, volatile oils and other compounds, and have a variety of pharmacological activities. AP2/ERF transcription factors are abundant in plants and are mainly involved in plant growth and development, abiotic stress response and secondary metabolite biosynthesis regulation. However, there are few reports on the AP2/ERF gene family and its functions in A. argyi. In this study, we systematically identified the AP2/ERF gene family in A. argyi genome, and analyzed its phylogenetic tree, protein physicochemical properties, subcellular localization, conserved motifs, promoter elements, and expression patterns. The results showed that a total of 204 AP2/ERF transcription factors were identified in A. argyi genome, encoding proteins consisting of 88-483 amino acids with a relative molecular mass of 10-52.94 kDa and a theoretical isoelectric point of 4.62-9.88. Subcellular prediction showed that the majority of AP2/ERFs were located in the nucleus, cytoplasm, and the minority of them is located in the membrane and chloroplasts. According to the Arabidopsis AP2/ERF family classification, A. argyi AP2/ERF proteins were divided into four subfamilies: Soloist, AP2, ERF (B3, B4, B5, B6), and DREB (A1, A2, A4, A5, A6), among which DREB family accounted for the largest proportion, and the same subfamily had similar conserved motifs. cis-Acting element analysis showed that AP2/ERF promoters have a large number of elements responding to light and abiotic stress. Expression pattern analysis showed that most of the genes of the AP2/ERF family were dominantly expressed mainly in roots and stems, of which 19 were dominantly expressed in leaves, 77 would be induced to be expressed by methyl jasmonate, of which 16 genes were both dominantly expressed in leaves and induced to be expressed by methyl jasmonate, and these AP2/ERF genes may be the key regulatory genes for the synthesis of active ingredients in A. argyi leaves.This study lays the foundation for the functional study of AP2/ERF family genes and their regulating roles in the active components biosynthesis in A. argyi leaves.

Objective With the widespread of transcatheter aortic valve replacement(TAVR)in patients with severe symptomatic aortic stenosis(AS),the life-cycle management has become a major determinant of prognosis.Methods A total of 408 AS patients who underwent successfully TAVR from June 2021 to August 2023 were consecutively enrolled in Hospital Valve Intervention Center.Patients were assigned to the Usual Care(UC)group between June 2021 and October 2022,while patients were assigned to the Heart Multi-parameter Monitoring(HMM)group between November 2022 and August 2023.The primary endpoint was defined as composite endpoint within 6 months post-TAVR,including all-cause death,cardiovascular death,stroke/transient ischemic attack,conduction block,myocardial infarction,heart failure rehospitalization,and major bleeding events.Secondary endpoints were the time interval(in hours)from event occurrence to medical consultation or advice and patient satisfaction.Statistical analysis was performed using Kaplan-Meier and multivariable Cox proportional hazards models.Results The incidence of primary endpoint in HMM group was significantly lower than that in UC group(8.9％vs.17.7％,P=0.016),the driving event was the rate of diagnosis and recognition of conduction block.The average time intervals from event occurrence to receiving medical advice were 3.02 h in HHM group vs.97.09 h in UC group(P＜0.001).Using cardiac monitoring devices and smart healthcare platforms provided significant improving in patients long-term management(HR 0.439,95％CI 0.244-0.790,P=0.006).Conclusions The utilization of cardiac monitoring devices and smart healthcare platforms effectively alerted clinical events and improved postoperative quality of life during long-term management post TAVR.