BACKGROUND: This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate. RESULTS: A total of 409 patients, 65.0% ( n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% ( n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 10 9 /L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 10 9 /L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs. CONCLUSIONS A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Lung Neoplasms/metabolism* ; Aged ; B7-H1 Antigen/metabolism* ; Programmed Cell Death 1 Receptor/metabolism* ; Adult ; Aged, 80 and over ; Immune Checkpoint Inhibitors/therapeutic use*

Objective : To pathological changes and inducible nitric oxide synthase(iNOS), phosphorylated insulin receptor substrate 1 serine 307(p-IRS1ser 307), phosphorylated protein kinase B serine 473(p-AKTser 473), glycogen synthase kinase-3β(GSK-3β), and gluconeogenic synthase(GS) proteins were observed in the liver of rats under the condition of chronic intermittent hypoxia-replicated oxygen in control. And to explore the role of iNOS/IRS1/AKT/GSK-3β signaling pathway in chronic intermittent hypoxia-induced insulin resistance. Methods : Forty SD rats were randomly divided into a control group(NC group) and an experimental group(CIH group), with 20 rats in each group. The NC group was placed in a normoxic environment for 12 weeks, while the CIH group was first subjected to intermittent hypoxia for 8 weeks, and then resumed normoxic rearing until the 12th week. Fasting blood glucose(FBG) and fasting insulin(FINS) were measured at baseline, week 8 and week 12, and liver tissues were taken for pathology and measurement of iNOS, p-IRS1ser 307, p-AKTser 473, GSK3β and GS levels, to compare the differences between groups. Results: t baseline, there was no significant difference in liver pathology between the two groups, and the observed indexes were not statistically significant(P>0.05); at 8 weeks, compared with the NC group, liver pathology in the CIH group showed significant disorganization of hepatic blood sinusoids and hepatocyte cords, obvious hepatocyte edema, smaller nuclei, increased lymphocyte infiltration, and a small number of fat vacuoles, significantly higher levels of FBG, FINS, insulin resistance index(HOMA-IR), iNOS mRNA, p-IRS1ser 307 protein, GSK-3β protein levels, and decreased p-AKTser 473 protein and GS protein levels, all of which were statistically significant(allP<0.05). IRS1ser 307 protein, GSK-3β protein levels were increased, p-AKTser 473 protein and GS protein levels were decreased, and the differences were statistically significant(allP<0.05); at 12 weeks, no lymphocyte infiltration was seen in the CIH group compared with that of the NC group and fat vacuoles significantly increased, and there was no improvement in the other pathological damage that had already occurred, and the levels of p-AKTser 473 protein significantly increased. AKTser 473 protein level significantly increased, p-IRS1ser 307 protein and GS protein levels were significantly reduced, all of which were statistically significant(allP<0.05), and the rest of the observational indexes were not statistically significant. Pearson′s correlation analysis showed that HOMA-IR of CIH group was significantly positively correlated with the levels of iNOS mRNA, p-IRS1ser 307 protein, and GSK-3β protein at 8 weeks(r=0.874, 0.817,0.872;allP<0.05), and significantly negatively correlated with the levels of p-AKTser 473 protein and GS protein(r=-0.886,-0.879;allP<0.05). Conclusion Chronic intermittent hypoxia can lead to hepatic pathological damage that cannot be reversed even by reoxygenation interventions and may mediate the development of insulin resistance by upregulating the IRS1/AKT/GSK-3β signaling pathway through the upregulation of iNOS mRNA expression.

Objective To investigate the effects of chronic intermittent hypoxia(CIH)and reoxygenation on insulin resistance(IR)and expressions of miR-27a-3p/PPARγ/IRS1/PI3K/AKT in rat skeletal muscle.Methods GEO database was used for screening the differentially expressed miRNAs in CIH,and their target genes were subjected to GO and KEGG enrichment analysis followed by construction of the miRNA-mRNA-pathway regulatory network using Cytoscape.In the animal experiment,48 male SD rats were randomly divided into normoxia group and CIH group(8 weeks of CIH followed by 4 weeks of normoxic recovery).Blood and skeletal muscle samples were collected at baseline,8 weeks,and 12 weeks to evaluate the changes in fasting blood glucose(FBG)and fasting insulin(FINS)levels and muscular pathology.RT-qPCR and Western blotting were used to detect the changes in the expressions of miR-27a-3p,PPARγ,GLUT4,IRS1,p-IRS1,PI3K,p-AKT and AKT in the muscular tissues.Results No muscular miRNA datasets for CIH were available in GEO database,from which only a kidney-related dataset(GSE202480)was obtained,based on which a total of 165 differentially expressed miRNAs were identified.GO/KEGG analysis suggested that these miRNAs were involved in muscular regulation and insulin signaling.The miRNA-mRNA-pathway network highlighted miR-27a-3p as a crucial regulator in the PPAR and PI3K/AKT pathway.In the animal experiment,the rats subjected to CIH for 8 weeks showed significantly increased FBG,FINS,HOMA-IR,and PPARγ levels,loose muscle fiber arrangement,decreased cross-sectional area of the muscle fibers,and lowered expressions of miR-27a-3p,p-IRS1/IRS1,PI3K,and p-AKT/AKT in the skeletal muscles.Conclusion CIH increases IR,causes skeletal muscle pathology,downregulates miR-27a-3p expression,upregulates PPARγ expression,and inhibits IRS1/PI3K/AKT insulin signaling in the skeletal muscles of rats,and these changes can be reversed by reoxygenation.MiR-27a-3p may participate in CIH-induced IR by modulating the PPAR γ/IRS1/PI3K/AKT signaling pathway.

Objective To investigate the effects of chronic intermittent hypoxia(CIH)and reoxygenation on insulin resistance(IR)and expressions of miR-27a-3p/PPARγ/IRS1/PI3K/AKT in rat skeletal muscle.Methods GEO database was used for screening the differentially expressed miRNAs in CIH,and their target genes were subjected to GO and KEGG enrichment analysis followed by construction of the miRNA-mRNA-pathway regulatory network using Cytoscape.In the animal experiment,48 male SD rats were randomly divided into normoxia group and CIH group(8 weeks of CIH followed by 4 weeks of normoxic recovery).Blood and skeletal muscle samples were collected at baseline,8 weeks,and 12 weeks to evaluate the changes in fasting blood glucose(FBG)and fasting insulin(FINS)levels and muscular pathology.RT-qPCR and Western blotting were used to detect the changes in the expressions of miR-27a-3p,PPARγ,GLUT4,IRS1,p-IRS1,PI3K,p-AKT and AKT in the muscular tissues.Results No muscular miRNA datasets for CIH were available in GEO database,from which only a kidney-related dataset(GSE202480)was obtained,based on which a total of 165 differentially expressed miRNAs were identified.GO/KEGG analysis suggested that these miRNAs were involved in muscular regulation and insulin signaling.The miRNA-mRNA-pathway network highlighted miR-27a-3p as a crucial regulator in the PPAR and PI3K/AKT pathway.In the animal experiment,the rats subjected to CIH for 8 weeks showed significantly increased FBG,FINS,HOMA-IR,and PPARγ levels,loose muscle fiber arrangement,decreased cross-sectional area of the muscle fibers,and lowered expressions of miR-27a-3p,p-IRS1/IRS1,PI3K,and p-AKT/AKT in the skeletal muscles.Conclusion CIH increases IR,causes skeletal muscle pathology,downregulates miR-27a-3p expression,upregulates PPARγ expression,and inhibits IRS1/PI3K/AKT insulin signaling in the skeletal muscles of rats,and these changes can be reversed by reoxygenation.MiR-27a-3p may participate in CIH-induced IR by modulating the PPAR γ/IRS1/PI3K/AKT signaling pathway.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective To investigate the prevalence of obstructive sleep apnea-hypopnea syndrome(OSAHS)combined with metabolic syndrome(MS),and analyze the related factors affecting OSAHS combined with MS.Methods Totally 290 patients with OSAHS hospitalized in the First Affiliated Hospital of Baotou Medical College and diagnosed as OSAHS were collected from August 2020 to October 2022.According to whether the patients were complicated with MS,they were divided into OSAHS combined with MS group and simple OSAHS group.According to apnea hypopnea index(AHI),the patients of OSAHS combined with MS group were divided into three subgroups:mild group,moderate group and severe group.The general condition,biochemical indicators and sleep parameters of patients were recorded,and the relevant factors affecting OSAHS with MS were determined by logistic regression analysis.Results(1)Among the 290 patients with OSAHS,the incidence of MS was 51.7%,male patients were more than female patients,and the peak of OSASH with MS was between 50 and 59 years old.(2)body mass index(BMI),systolic blood pressure,hypertension history,diabetes history,AHI,fasting blood glucose(FBG),triglyceride(TG),high density lipoprotein-cholesterol(HDL-C),uric acid(UA)were statistically different between the two groups(P<0.05);Logistic regression analysis showed that BMI,FBG,TG,HDL-C,UA,history of hypertension and history of diabetes were independent risk factors for OSAHS with MS(P<0.05).(3)There were statistically significant differences in gender,age,BMI,AHI,TG,HDL-C and UA among the three groups of OSAHS with MS with different severity(P<0.05).Logistic regression analysis showed that BMI,TG and HDL-C were independent risk factors affecting OSAHS with MS with different severity(P<0.05).Conclusion(1)The inpatients with OSAHS have a high incidence of MS.(2)OSAHS combined with MS is related to BMI,blood pressure,blood glucose,blood lipid,blood uric acid level and other factors.(3)Overweight and dyslipidemia play an important role in the process of inducing disease aggravation.

Objective : By observing the changes of interleukin-22 ( IL-22) ，signal transduction and transcriptional activator 3 (STAT3) ，fasting blood glucose ( FBG) and fasting insulin ( FINS) of rats under the circumstance of chronic intermittent hypoxia and reoxygenation，to explore the role of IL-22 / STAT3 pathway in insulin resistance in- duced by chronic intermittent hypoxia． Methods : 4 SD rats were randomly divided into control group (NC group) and intermittent hypoxia group ( CIH group) ，with 12 rats in each group．NC group was placed in normoxia environment for 12 weeks，while CIH group was first given intermittent hypoxia for 8 weeks and then resumed normoxia feeding until 12 weeks．FBG，FINS，IL-22 and p-STAT3 / STAT3 levels were measured at baseline，week 8 and week 12 in both groups，and insulin resistance index (HOMA-IR) was calculated．The differences between the two groups were compared. Results : ① There was no significant difference of the observation indexes between the two groups at baseline (P＞0. 05) ．At 8 weeks，the levels of FBG，FINS and HOMA-IR in CIH group were higher than those in NC group (P＜0. 05) ，and the levels of IL-22 were lower than those in NC group (P ＜0. 05) ．p-STAT3 / STAT3 showed a decreasing trend，but not statistically significant．At 4 weeks of reoxygenation，there were no significant differences in FBG，FINS，HOMA-IR and IL-22 levels between the two groups (P ＞0. 05 ) ．p-STAT3 / STAT3 in CIH group was significantly higher than that in NC group ( P ＜0. 05 ) . ② Spearman rank correlation analysis showed that HOMA-IR was negatively correlated with IL-22 and p-STAT3 / STAT3 ( all P ＜0. 05) ． Conclusion Chronic intermittent hypoxia can inhibit the expression of IL-22 / STAT3 signaling pathway，IL-22 / STAT3 signaling pathway may mediate insulin resistance induced by chronic intermittent hypoxia.

OBJECTIVES: Fluorouracil chemotherapeutic drugs are the classic treatment drugs of gastric cancer. But the problem of drug resistance severely limits their clinical application. This study aims to investigate whether hypoxia microenvironment affects gastric cancer resistance to 5-fluorouracil (5-FU) and discuss the changes of gene and proteins directly related to drug resistance under hypoxia condition. METHODS: Gastric cancer cells were treated with 5-FU in hypoxia/normoxic environment, and were divided into a Normoxic+5-FU group and a Hypoxia+5-FU group. The apoptosis assay was conducted by flow cytometry Annexin V/PI double staining. The real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect the expression level of hypoxia inducible factor-1α (HIF-1α), multidrug resistance (MDR1) gene, P-glycoprotein (P-gp), and vascular endothelial growth factor (VEGF) which were related to 5-FU drug-resistance. We analyzed the effect of hypoxia on the treatment of gastric cancer with 5-FU. RESULTS: Compared with the Normoxic+5-FU group, the apoptosis of gastric cancer cells treated with 5-FU in the Hypoxia+5-FU group was significantly reduced (P<0.05), and the expression of apoptosis promoter protein caspase 8 was also decreased. Compared with the the Normoxic+5-FU group, HIF-1α mRNA expression in the Hypoxia+5-FU group was significantly increased (P<0.05), and the mRNA and protein expression levels of MDR1, P-gp and VEGF were also significantly increased (all P<0.05). The increased expression of MDR1, P-gp and VEGF had the same trend with the expression of HIF-1α. CONCLUSIONS Hypoxia is a direct influencing factor in gastric cancer resistance to 5-FU chemotherapy. Improvement of the local hypoxia microenvironment of gastric cancer may be a new idea for overcoming the resistance to 5-FU in gastric cancer.
Humans ; Fluorouracil/therapeutic use* ; Vascular Endothelial Growth Factor A/metabolism* ; Stomach Neoplasms/drug therapy* ; Drug Resistance, Multiple ; Vascular Endothelial Growth Factors/metabolism* ; Hypoxia ; ATP Binding Cassette Transporter, Subfamily B/genetics* ; ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics* ; Cell Line, Tumor ; Cell Hypoxia ; RNA, Messenger/metabolism* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Tumor Microenvironment

Objective : To investigate the role of endoplasmic reticulum stress in hepatic insulin resistance induced by intermittent hypoxia in rats． Methods : Twenty-four SD rats were randomly divided into control group ( NC group) and intermittent hypoxia group ( CIH group) ．The NC group was placed in a normoxia environment for 12 weeks，and the CIH group was given intermittent hypoxia for 8 weeks，and then returned to normoxia until the 12th week．In both groups，fasting blood glucose (FBG) ，fasting insulin (FINS) ，and liver inositol-requiring enzyme- 1 α(IRE1 α) ，X-box binding protein 1s(XBP1s) ，forkhead box transcription factor O1 (FoxO1) ，activating transcription factor-6(ATF6) ，cAMP-response element binding protein( CREB) ，CREB-regulated transcription coacti- vator-2( CRTC2) ，double-stranded RNA-dependent protein kinase-like ER kinase ( PERK) ，eukaryotic initiation factor 2 α(eIF2 α) ，protein kinase B ( AKT) ，phosphoenolpyruvate carboxykinase ( PEPCK) ，glucose-6-phosphat- ase( G6Pase) mRNA were measured at baseline，week 8，and week 12 . Results : There was no significant differ- ence in each observation index between the two groups at baseline ; at 8 weeks，the levels of FBG，FINS and the mRNA levels of IRE1α , XBP1s，ATF6，PERK，eIF2 α , PEPCK and G6Pase in the CIH group were higher than those in the NC group (P＜0. 05) ，while the mRNA levels of CREB，CRTC2 and AKT were lower than those in the NC group (P＜0. 05) ; at 12 weeks，there was no significant difference in each observation index between the two groups．Pearson correlation analysis showed(8th week of intermittent hypoxia group) : homeostasis model as- sessment-insulin resistance(HOMA-IR) was positively correlated with FoxO1，CREB，CRTC2 and PERK，eIF2 α mRNA levels (r = 0. 172，0. 595，0. 183，0. 702，0. 608 ; P＜0. 05) while it was negatively correlated with IRE1α , XBP1s，ATF6，AKT mRNA levels (r = －0. 422 ，－0. 327 ，－0. 309 ，－0. 399 ; P＜0. 05) ． Conclusion Intermittent hypoxia can lead to insulin resistance，and endoplasmic reticulum stress may mediate this effect.

Objective To investigate the effects of precautionary high-flow oxygen therapy on preventing hypoxemia in patients with Stanford type A aortic dissection after intubation.Methods Totally 90 hospitalized patients with Stanford type A aortic dissection in our hospital were enrolled in this study.Forty-five patients were recruited in the control group from January to April 2017,and the common mask-type nebulizer was used for oxygen inhalation.From May to October in 2017,45 patients were recruited in the experimental group.The parameters of highflow oxygen therapy in the experimental group were set as oxygen concentration (FiO2) 40％～60％,oxygen flow rate 35～60 L/min.Then after 72h's therapy,normal mask oxygen therapy was provided as replacement therapy.Results Oxygenation index and oxygen partial pressure were increased in the experimental group than those in the control group,the rate of respiration and carbon dioxide partial pressure were decreased than those in the control group,and the differences were statistically significant(P＜0.05).The scores of oral nasal dryness symptom and sore throat symptom in the experimental group were lower than those in the control group in 24 h,48 h,72 h during therapy,and the differences were statistically significant (P＜0.05).The incidence of hypoxemia and the incidence of secondary intubation were lower in the experimental group than those in the control group(P＜0.05).Conclusion Precautionary high-flow oxygen therapy for patients with Stanford type A aortic dissection can increase PaO2/FiO2,PaO2,reduce PaCO2,respiratory rate,reduce respiratory symptoms,reduce the incidence of hypoxemia,and secondary intubation.