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*

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective:To investigate the impact of bundled management of late-pregnancy induction strategies on induction time and maternal and perinatal clinical outcomes.Methods:This was a historical control study, including 61 pregnant women before the implementation of the bundled management strategies for induction protocol in September 2024, and 78 pregnant women after the implementation in December 2024, who received regular prenatal check-ups and finally admitted to Peking University Third Hospital for elective induction of labor at term. The rate of successful induction, the rate of reaching active phase, induction to labor length, duration of labor, hospital stay, and adverse maternal and preinatal outcomes and other information were compared between two groups. Logistic regression model was used to analyze the factors affecting the rates of successful labor induction and reaching active phase. Kaplan-Meier survival curves were plotted for induction to labor length and duration of labor, and the Cox proportional hazards regression model was used to analyze the impact of the bundled management strategies for induction strategies on the above indicators.Results:(1) Compared with the group before implementation, the group after implementation had a shorter induction to labor length (median: 47.4 vs 35.1 h), a shorter duration of labor (median: 14.0 vs 10.5 h), and a shorter hospital stay (median: 6 vs 4 d). The rate of successful induction increased [87% (53/61) vs 97% (76/78)], and the rate of reaching active phase increased [70% (43/61) vs 86% (67/78)]; the differences were statistically significant (all P<0.05). (2) Multivariate logistic regression analysis showed that the implementation of the bundled management strategies promoted successful induction ( OR=7.299, 95% CI: 1.189-44.800; P=0.032) and reaching active phase ( OR=2.640, 95% CI: 1.003-6.951; P=0.049). A pre-pregnancy body mass index<18.5 kg/m2 promoted successful induction ( OR=9.142, 95% CI: 1.154-72.423; P=0.036). (3) Kaplan-Meier curve analysis indicated that compared with the group before the implementation, the group after the implementation had a significantly shorter induction to labor length ( χ2=13.883, P<0.001) and a shorter duration of labor ( χ2=5.72, P=0.017). Cox proportional hazards regression analysis showed that the implementation of the bundled management strategies for induction protocol was a protective factor for shortening induction to labor length ( HR=1.806, 95% CI: 1.186-2.749; P=0.006) and duration of labor ( HR=1.677, 95% CI: 1.066-2.637; P=0.025). A cervical Bishop score >3 at admission was a protective factor for shortening the induction to labor length ( HR=1.627, 95% CI: 1.110-2.384; P=0.013), and parity was a protective factor for shortening the duration of labor ( HR=3.370, 95% CI: 1.806-6.288; P<0.001). Conclusions:By the implementation of the bundled management strategies for induction protocol, it is possible to promote successful induction of labor and reaching the active phase for pregnant women undergoing induction. This approach also shortens induction to labor length and the duration of labor, without increasing the risk of maternal and perinatal complications.

Research on immune checkpoints such as programmed death protein-1(PD-1)and cytotoxic T lymphocyte antigen-4(CTLA-4)has provided new directions for tumor treatment.V-domain immunoglobulin suppressor of T-cell activation(VISTA)is an emerging immune checkpoint within the B7 family.Functioning as both a ligand and a receptor,VISTA is an inhibitory immune checkpoint molecule expressed in tumor cells,myeloid cells and T lymphocytes.It plays a crucial role in regulating autoimmunity,inflammatory response and tumor immunity.The non-redundant interactions between VISTA and other immune checkpoints,such as PD-1,may offer new therapeutic strategies and serve as a new target for overcoming immunotherapy resistance.This review summarizes the recent research progress on VISTA in hematological tumors,aiming to provide new insights into its application in the treatment of these malignancies.

Objective To investigate the postoperative efficacy of laparoscopic hiatal hernia repair(LHHR)combined with Toupet or Dor fundoplication for the treatment of esophageal hiatal hernia(HH).Methods A retrospective analysis was conducted on the case data of HH patients who underwent LHHR combined with Toupet(Toupet group,n=53)and Dor(Dor group,n=53)fundoplication between December 2018 and December 2022 in Department of General Surgery of Gansu Provincial Hospital.Intraoperative and postoperative recovery outcomes of both groups were observed.We analyzed and compared the incidence of dysphagia and gastroesophageal reflux disease questionnaire(GERD-Q)scores at preoperative and postoperative intervals of 1 month,6 months,and 1 year.The incidence of postoperative complications and the 1-year recurrence rate were compared between the two groups.Additionally,factors influencing postoperative dysphagia within the first month were examined.Results The differences between the two groups in operation time,intraoperative bleeding,postoperative ventilation time,postoperative extubation time and hospitalization time were not statistically significant(P>0.05).There was no significant difference in the incidence of immediate postoperative dysphagia in two groups(P>0.05).Furthermore,the differences between the two groups in the incidence of postoperative complications,such as bloating,abdominal pain and diarrhea,were not statistically significant(P>0.05).The incidence of dysphagia in Toupet group was higher than that in Dor group at 1 month postoperatively,and the difference was statistically significant(P=0.017);but the difference in the incidence of dysphagia between the two groups at 6 months and 1 year postoperatively was not statistically significant(P=0.767,1.000).The results of binary logistic regression analysis showed that both surgical procedure(OR=2.613,95%CI 1.141-5.983,P=0.023)and esophageal contractile reserve function(OR=2.921,95%CI 1.203-7.095,P=0.018)were independent risk factors for the incidence of dysphagia in patients with HH at 1 month after surgery.Compared with the preoperative period,the GERD-Q symptom scores were lower in both groups at 1 month,6 months,and 1 year postoperatively,and the difference was statistically significant(P<0.05);but there was no statistically significant difference between the groups at the same time point(Fintergroup=0.334,P=0.565).The difference between the two groups in 1-year postoperative recurrence rates was not statistically significant(P>0.05).Conclusions LHHR combined with Toupet or Dor fundoplication are both safe and effective surgical procedures for the treatment of HH,with excellent reflux control,fewer complications and lower recurrence rates,but Toupet fundoplication is more likely to have postoperative short-term dysphagia than Dor fundoplication.

Aim To explore the mechanism of Jiawei Shaofu Zhuyu decoction in antagonizing endometriosis fibrosis by regulating mitophagy.Methods After the animal model was constructed,the syndrome was evalu-ated by general condition,organ water content and ther-mal imaging.The curative effect was evaluated by the weight of ectopic focus and the degree of adhesion.The pathological changes were compared using HE stai-ning,transmission electron microscopy,Masson and Sir-ius red staining.The expression of PINK1 and Parkin was detected by immunohistochemistry.The expression of mRNA and protein was determined by qPCR and Western blot,and the level of serum ROS was detected by ELISA.Results The autonomic activity of model mice was weakened,the water content of organs rose,and the temperature of limbs and lower abdomen was reduced by thermal imaging.HE staining showed obvi-ous hyperplasia of ectopic epithelium and glands.Transmission electron microscopy showed mitochondrial and endoplasmic reticulum structure damage,and nor-mal autophagy structure disappeared.Masson and Siri-us red staining showed increased collagen deposition;immunohistochemistry showed decreased expression of PINK1 and Parkin in ectopic foci.qPCR and Western blot showed that the expression of PINK1,Parkin,Bec-lin1,LC3 mRNA and protein in ectopic foci of model mice decreased,the expression of p62 mRNA and pro-tein increased,and serum ROS increased.The syn-drome performance of model mice was improved after the intervention of Jiawei Shaofu Zhuyu decoction;the inflammatory infiltration of ectopic foci was relieved,the morphology of mitochondria and endoplasmic retic-ulum was restored,and normal autophagy structure ap-peared.The degree of collagen deposition and fibrosis was reduced;the mRNA and protein expression of PINK1,Parkin,Beclin1 and LC3 increased.The ex-pression of p62 mRNA and protein decreased,and the level of ROS decreased.Conclusions Jiawei Shaofu Zhuyu decoction can improve the fibrosis of ectopic le-sions in mice with endometriosis of cold-dampness sta-sis syndrome,which may be related to the regulation of mitophagy.

Aim To investigate the intervention effect of Rehmannia radix water extract on bleomycin(BLM)-induced pulmonary fibrosis in mice combined with metabolomics and to reveal the potential mechanism,in order to provide new ideas for clinical treatment of pul-monary fibrosis.Methods Male C57BL/6N mice were randomly divided into the control group,model group,pirfenidone group(positive control,PFD,270 mg·kg-1),and low dose(DH-L,4.55 g·kg-1)group,medium dose(DH-M,9.1 g·kg-1)group and high dose(DH-H,18.2 g·kg-1)group of Rehman-nia.Except for the control group,BLM(5 mg·kg-1)was instilled into the trachea to establish the model of pulmonary fibrosis in the other groups.The survival rate,lung index and blood oxygen saturation of mice in each group were evaluated.HE and Masson staining were used to observe the pathological changes of lung tissue.WBP was used to detect lung function.Flow cytometry was used to detect the apoptosis of primary lung cells,ROS and immune cells.ELISA was used to detect the levels of fibrosis markers and inflammatory factors(α-SMA,collagen Ⅰ,collagen Ⅲ,TGF-β1,TNF-α,IL-1 β,and IL-6).Biochemical method was employed to detect the contents of GSH-Px,T-SOD and MDA.Liquid chromatograph mass spectrometer(LC-MS)metabolomics was used to analyze the changes of serum metabolic profile.Results Water extract of Re-hmannia significantly increased the survival rate,oxy-gen saturation and lung function of mice with pulmona-ry fibrosis,reduced the lung coefficient,ameliorated pathological damage and collagen deposition in lung tissue,reduced the levels of apoptosis and oxidative stress,and down-regulated the levels of inflammatory factors in lung tissue.It regulated the levels of metabo-lites such as bile acid metabolism,sphingolipid metabo-lism,and unsaturated fatty acid metabolism.Conclu-sions Water extract of Rehmannia inhibits lung injury and collagen deposition in mice with pulmonary fibrosis by inhibiting inflammatory response,which may be a-chieved by regulating the levels of inflammatory factors through the metabolic pathways of bile acid and sphin-golipid.

Objective·To investigate the predictive value of the geriatric nutritional risk index(GNRI)for the occurrence of lung infection in hospitalized elderly patients with type 2 diabetes mellitus(T2DM).Methods·Elderly T2DM patients who were admitted to the Geriatric Department of Shanghai Tongren Hospital between June 2022 and June 2024 were retrospectively and consecutively enrolled.They were divided into infected and non-infected groups according to whether lung infection occurred during hospitalization.Baseline data(gender,age,height,weight,duration of diabetes,comorbidities,etc.)were collected and GNRI was calculated.A multivariate Logistic regression model was used to screen the independent risk factors for pulmonary infections,and the predictive value of GNRI for pulmonary infections in T2DM patients was analysed using receiver operating characteristic(ROC)curves.Results·A total of 264 elderly T2DM patients were enrolled,among whom 154 developed pulmonary infections.Significant differences were observed between the infected and non-infected groups in GNRI,albumin,leukocyte count,neutrophil ratio,lymphocyte ratio,glycated hemoglobin,fasting glucose,interleukin-6,C-reactive protein,and procalcitonin levels(P<0.05).Multivariate Logistic regression analysis showed that a lower GNRI was an independent risk factor for lung infection(OR=0.798,95%CI 0.712?0.894;P<0.001).Correlation analysis showed that GNRI was negatively correlated with C-reactive protein and calcitoninogen.ROC curve analysis showed that GNRI predicted pulmonary infection with an area under the curve of 0.828,a sensitivity of 77.9%,and a specificity of 76.6%.Conclusion·A lower GNRI is an independent risk factor for pulmonary infections in elderly T2DM patients,and also has a good predictive value for the occurrence of pulmonary infections.

Objective:To investigate the impact of bundled management of late-pregnancy induction strategies on induction time and maternal and perinatal clinical outcomes.Methods:This was a historical control study, including 61 pregnant women before the implementation of the bundled management strategies for induction protocol in September 2024, and 78 pregnant women after the implementation in December 2024, who received regular prenatal check-ups and finally admitted to Peking University Third Hospital for elective induction of labor at term. The rate of successful induction, the rate of reaching active phase, induction to labor length, duration of labor, hospital stay, and adverse maternal and preinatal outcomes and other information were compared between two groups. Logistic regression model was used to analyze the factors affecting the rates of successful labor induction and reaching active phase. Kaplan-Meier survival curves were plotted for induction to labor length and duration of labor, and the Cox proportional hazards regression model was used to analyze the impact of the bundled management strategies for induction strategies on the above indicators.Results:(1) Compared with the group before implementation, the group after implementation had a shorter induction to labor length (median: 47.4 vs 35.1 h), a shorter duration of labor (median: 14.0 vs 10.5 h), and a shorter hospital stay (median: 6 vs 4 d). The rate of successful induction increased [87% (53/61) vs 97% (76/78)], and the rate of reaching active phase increased [70% (43/61) vs 86% (67/78)]; the differences were statistically significant (all P<0.05). (2) Multivariate logistic regression analysis showed that the implementation of the bundled management strategies promoted successful induction ( OR=7.299, 95% CI: 1.189-44.800; P=0.032) and reaching active phase ( OR=2.640, 95% CI: 1.003-6.951; P=0.049). A pre-pregnancy body mass index<18.5 kg/m2 promoted successful induction ( OR=9.142, 95% CI: 1.154-72.423; P=0.036). (3) Kaplan-Meier curve analysis indicated that compared with the group before the implementation, the group after the implementation had a significantly shorter induction to labor length ( χ2=13.883, P<0.001) and a shorter duration of labor ( χ2=5.72, P=0.017). Cox proportional hazards regression analysis showed that the implementation of the bundled management strategies for induction protocol was a protective factor for shortening induction to labor length ( HR=1.806, 95% CI: 1.186-2.749; P=0.006) and duration of labor ( HR=1.677, 95% CI: 1.066-2.637; P=0.025). A cervical Bishop score >3 at admission was a protective factor for shortening the induction to labor length ( HR=1.627, 95% CI: 1.110-2.384; P=0.013), and parity was a protective factor for shortening the duration of labor ( HR=3.370, 95% CI: 1.806-6.288; P<0.001). Conclusions:By the implementation of the bundled management strategies for induction protocol, it is possible to promote successful induction of labor and reaching the active phase for pregnant women undergoing induction. This approach also shortens induction to labor length and the duration of labor, without increasing the risk of maternal and perinatal complications.

Objective·To investigate the predictive value of the geriatric nutritional risk index(GNRI)for the occurrence of lung infection in hospitalized elderly patients with type 2 diabetes mellitus(T2DM).Methods·Elderly T2DM patients who were admitted to the Geriatric Department of Shanghai Tongren Hospital between June 2022 and June 2024 were retrospectively and consecutively enrolled.They were divided into infected and non-infected groups according to whether lung infection occurred during hospitalization.Baseline data(gender,age,height,weight,duration of diabetes,comorbidities,etc.)were collected and GNRI was calculated.A multivariate Logistic regression model was used to screen the independent risk factors for pulmonary infections,and the predictive value of GNRI for pulmonary infections in T2DM patients was analysed using receiver operating characteristic(ROC)curves.Results·A total of 264 elderly T2DM patients were enrolled,among whom 154 developed pulmonary infections.Significant differences were observed between the infected and non-infected groups in GNRI,albumin,leukocyte count,neutrophil ratio,lymphocyte ratio,glycated hemoglobin,fasting glucose,interleukin-6,C-reactive protein,and procalcitonin levels(P<0.05).Multivariate Logistic regression analysis showed that a lower GNRI was an independent risk factor for lung infection(OR=0.798,95%CI 0.712?0.894;P<0.001).Correlation analysis showed that GNRI was negatively correlated with C-reactive protein and calcitoninogen.ROC curve analysis showed that GNRI predicted pulmonary infection with an area under the curve of 0.828,a sensitivity of 77.9%,and a specificity of 76.6%.Conclusion·A lower GNRI is an independent risk factor for pulmonary infections in elderly T2DM patients,and also has a good predictive value for the occurrence of pulmonary infections.