The polymerase 1 and transcript release factor (PTRF)-cytoplasmic phospholipase A2 (cPLA2) phospholipid remodeling pathway facilitates tumor proliferation in glioma. Nevertheless, blockade of this pathway leads to the excessive activation of oncogenic receptors on the plasma membrane and subsequent drug resistance. Here, CD26/dipeptidyl peptidase 4 (DPP4) was identified through screening of CRISPR/Cas9 libraries. Suppressing PTRF-cPLA2 signaling resulted in the activation of the epidermal growth factor receptor (EGFR) pathway through phosphatidylcholine and lysophosphatidylcholine remodeling, which ultimately increased DPP4 transcription. In turn, DPP4 interacted with EGFR and prevented its ubiquitination. Linagliptin, a DPP4 inhibitor, facilitated the degradation of EGFR by blocking its interaction with DPP4. When combined with the cPLA2 inhibitor AACOCF3, it exhibited synergistic effects and led to a decrease in energy metabolism in glioblastoma cells. Subsequent in vivo investigations provided further evidence of a synergistic impact of linagliptin by augmenting the sensitivity of AACOCF3 and strengthening the efficacy of temozolomide. DPP4 serves as a novel target and establishes a constructive feedback loop with EGFR. Linagliptin is a potent inhibitor that promotes EGFR degradation by blocking the DPP4-EGFR interaction. This study presents innovative approaches for treating glioma by combining linagliptin with AACOCF3 and temozolomide.

BACKGROUND:The expression efficiency of recombinant adeno-associated virus serotype 9(rAAV9)carrying the macrophage-specific promoter synthetic promoter 146-C1(SP146-C1)and the exogenous gene vascular endothelial growth factor C(VEGFC)in atherosclerosis is uncertain. OBJECTIVE:To investigate the expression efficiency of rAAV9-SP146-C1-VEGFC in atherosclerotic mice and its effect on lymphangiogenesis. METHODS:Thirty ApoE-/-mice were fed high-fat diet for 12 weeks to establish atherosclerosis models and were randomly divided into six groups,five in each group:7-,14-,21-,28-,and 35-day transfection groups and control group.The mice in the transfection groups were transfected with 5.0×1011 vg rAAV9-SP146-C1-VEGFC by caudal vein injection.In the control group,the mice were injected with the same amount of control virus rAAV9-SP146-C1-Scramble.Animals in the first five groups were killed under anesthesia at 7,14,21,28 and 35 days after transfection,respectively,and those in the control group were killed under anesthesia at 7 days.Serum,femur,tibia,heart and aorta tissue samples were collected and retained in each group.The femur and tibia of mice in each group were used to extract bone marrow-derived macrophages.The gene expression of vascular endothelial growth factor C(VEGFC),vascular endothelial growth factor receptor 3(VEGFR3),Podoplanin and lymphatic vessel endothelial hyaluronan receptor-1(LYVE-1)in bone marrow-derived macrophages and the aorta were detected by RT-qPCR.VEGFC protein expression levels in bone marrow-derived macrophages and the aorta were detected by western blot,serum level of VEGFC was detected by ELISA,and VEGFC expression in the aortic sinus and LYVE-1 expression around the aorta and in the myocardium was detected by immunofluorescence. RESULTS AND CONCLUSION:The serum level of VEGFC,the mRNA expression of VEGFC,VEGFR3,Podoplanin,and LYVE-1 in bone marrow-derived macrophages and the aorta,the protein expression of VEGFC in bone marrow-derived macrophages,and the fluorescence intensity of VEGFC in aortic sinus plaques were significantly increased in the 7-day transfection group compared with the control group(P＜0.05,P＜0.01).Serum VEGFC level of mice transfected with rAAV9-SP146-C1-VEGFC gradually increased with time and began to decrease at 28 days.mRNA levels of VEGFC,VEGFR3,Podoplanin and LYVE-1 in mouse aorta and bone marrow-derived macrophages,VEGFC protein level in bone marrow-derived macrophages,VEGFC fluorescence intensity in aortic sinus plaques,LYVE-1 fluorescence intensity around the aortic sinus and in the myocardium gradually increased with time(P＜0.05).In addition,the mRNA level of LYVE-1 in the aorta and the fluorescence intensity of LYVE-1 around the aortic sinus and in the myocardium were the highest at 28 days(P＜0.05),and gradually decreased(P＜0.05).The expression of the other indicators reached the peak at 21 days.To conclude,rAAV9-SP146-C1-VEGFC could effectively transfect bone marrow-derived macrophages and promote lymphatic hyperplasia in atherosclerotic mice.

Objective:To explore the clinical manifestations and characteristics of serum adrenal cortex hormone spectrum in patients with adrenocortical hypercortisolism with different pathological types of adrenal adenoma.Methods:A retrospective analysis was conducted on 68 patients with adrenal Cushing's syndrome who underwent surgical treatment in the Department of Endocrinology and/or Urology, Peking University First Hospital from January 2018 to June 2022. Among them, 12 patients had obvious eosinophilic changes in pathology(eosinophilic group), and 56 patients had no obvious eosinophilic changes(non-eosinophilic group). Among eosinophilic group, one male and 11 females, age(49.83±9.87) years old, body mass index (BMI)(25.86±3.21) kg/m 2, systolic blood pressure (140.25±20.72)mmHg(1 mmHg=0.133 kPa), diastolic blood pressure(91.00±14.87)mmHg, 7 cases were overt Cushing's syndrome. Among non-eosinophilic group, 14 males and 32 females, age(52.91±10.82) years old, BMI (26.06 ± 3.57) kg/m 2; ystolic blood pressure (142.13±16.71) mmHg, diastolic blood pressure (83.63±11.41) mmHg; 16 cases of overt Cushing's syndrome. There was no statistically significant difference in the above indicators between the two groups ( P>0.05).In terms of laboratory tests, 0: 00 cortisol levels in the eosinophilic group and non-eosinophilic groups were 14.95(5.93, 23.2) ng/dl and 6.69(4.07, 11.35) ng/dl ( P=0.044), the cortisol levels after 1mg dexamethasone inhibition test were 20.19(11.29, 26.92) ng/dl and 5.94(2.68, 12.90) ng/dl ( P=0.005), and 8: 00, 16: 00, and 0: 00, ACTH levels were 2.08 (1.02, 2.90) pg/ml and 8.37(2.30, 11.67) pg/ml ( P=0.006), 1.22(1.00, 3.20) pg/ml, and 4.22(1.80, 6.33) pg/ml ( P=0.012), 0.65 (0, 2.63) pg/ml, and 2.76(1.44, 5.57) pg/ml( P=0.023), serum triglyceride were 1.92(1.31, 2.50) mmol/L and 1.31(1.04, 1.80) mmol/L ( P=0.026), and the differences were statistically significant. In terms of target organ damage, there were 6 cases and 10 cases ( P=0.017) in the eosinophilic group and non eosinophilic group with ventricular wall hypertrophy, 1 case and 0 cases( P=0.030) in the aortic dissection group, and 4 cases and 5 cases ( P=0.024) with four or more types of target organ damage, respectively, with statistically significant differences. Two groups of preoperative serum adrenal cortex hormone profiles were detected by liquid chromatography tandem mass spectrometry. The differences in adrenal cortex hormone profiles and hormone ratios between the two groups were compared. Age, gender, and statistically significant indicators were included in a multivariate logistic regression model to analyze the correlation between each indicator and eosinophilic changes. Results:Adrenal cortical hormone profile of the two groups showed that the serum estrone levels in the eosinophilic group and non-eosinophilic group were 20.27(13.49, 39.81) pg/ml and 12.59(8.08, 21.18) pg/ml ( P=0.034), and 11-hydroxyandrostenedione levels were 692.34(536.19, 1 049.66) pg/ml and 1 157.60(710.78, 1 539.30) pg/ml( P=0.026), with statistically significant differences; There were no statistically significant difference in the expression levels of other hormones ( P>0.05). In terms of hormone ratio, the estradiol/testosterone ratios in the eosinophilic and non eosinophilic groups were 0.14(0.08, 0.62) and 0.04(0.01, 0.09)( P=0.008), the estrone/androstenedione ratios were 0.06(0.05, 0.12) and 0.04(0.03, 0.06)( P=0.007), the 11-hydroxyandrostenedione/androstenedione ratios were 2.26(1.30, 2.69) and 4.03(2.48, 5.25)( P=0.008), the estriol/estrone ratios were 0.10(0.03, 0.29) and 0.25(0.12, 0.51)( P=0.016), the estriol/estradiol were 0.22(0.03, 0.30) and 0.33(0.12, 0.73)( P=0.032), and the differences were statistically significant. The results of multivariate analysis showed that estrone ( OR=1.04, 95% CI 1.01-1.07, P=0.009) and estrone/androstenedione ( OR=25 008 670.29, 95% CI 8.45-74 015 852 572 024.10, P=0.025) were independently associated with eosinophilic pathology. Conclusions:Adrenocortical hypercortisolism patients with eosinophilic pathology have higher levels of serum cortisol secretion, more pronounced inhibition of the hypothalamic pituitary adrenal axis, more significant metabolic disorders and target organ damage, and higher production of estrone.

Objective:To analyze the prognostic value of the coagulation index in stereotactic radio surgery(SRS)for patients with non-small cell lung cancer(NSCLC)and brain metastases(BMS).Methods:We retrospectively analyzed clinical data from 512 patients diagnosed with NSCLC and BMS,who were treated with SRS at Tianjin Huanhu Hospital from October 2015 to September 2018.The overall survival(OS)and progression-free survival(PFS)rates were analyzed.The Cox model was employed to examine prognostic factors.Subsequently,the receiver operating characteristic(ROC)curve was constructed based on multi-factor analysis usin the Cox model.The area under the ROC curve(AUC)was used to assess the prognostic value of coagulation indexes in patients with NSCLC and BMS who underwent SRS.Results:In 1,2,3,and 4 years,PFS rates were 79.9%,69.9%,56.6%,and 43.2%,respectively,and OS rates were 93.4%,83.2%,69.9%,and 57.6%,respectively.Smoking and average fibrinogen(Fib)levels,prothrombin time(PT),and D-dimer(D-D)levels were correlated with a longer PFS(P<0.05).Av-erage activated partial thromboplastin time(APTT),Fib,and D-D levels were correlated with a longer OS(P<0.05).Smoking and mean Fib and D-D levels were significantly correlated with a longer PFS(P<0.05),while The average levels of Fib and D-D are each significantly associated with longer OS rates(P<0.05).The combined detection of Fib and D-D in predicting the prognosis of NSCLC patients with brain metastases undergoing SRS treatment shows a significantly higher AUC compared to the detection of Fib and D-D individually(P<0.05).Conclusions:Co-agulation indexes have a certain correlation with the prognosis of patients with NSCLC and BMS treated with SRS.Furthermore Fib and D-D are independent risk factors for the prognosis of these patients and can be used to assess their outcomes.The combined evaluation of the indexes provides a more ideal prognostic assessment.

Humans ; Cardiovascular Diseases/chemically induced* ; East Asian People ; Risk Factors ; Heart Disease Risk Factors ; Lipids ; Anticholesteremic Agents/adverse effects* ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Treatment Outcome

ObjectiveTo explore the clinical effect of Tiaoxin formula in the treatment of patients with coronary heart disease and anxiety/depression and its impact on serum levels of 5-hydroxytryptamine （5-HT）， β- thromboglobulin （β-TG） and myeloperoxidase （MPO）. MethodA total of 66 patients with coronary heart disease and anxiety/depression were randomly divided into the Tiaoxin formula group and Deanxit group， 33 cases in each group. Both groups were given fundamental western treatment for coronary heart disease. Additionally， the Deanxit group was treated with flupentixol and melitracen tablets and the Tiaoxin formula group was treated with Tiaoxin Formula. The treatment lasted 8 weeks. Before and after treatment， the changes of clinical efficacy， Patient Health Questionnaire （PHQ-9）， Generalized Anxiety Disorder （GAD-7） scale， Seattle Angina Questionnaire （SAQ）， heart rate variability， and serum 5-HT， β-TG and MPO levels， and incidence of adverse reactions in the two groups were observed. ResultThere was no significant difference in the baseline indexes of patients in the two groups， and thus the two groups were comparable. After treatment for 8 weeks， the total effective rate for traditional Chinese medicine （TCM） syndromes in the Tiaoxin Formula group was 87.88% （29/33） higher than 63.64% （21/33） in the Deanxit group （Z=-2.653， P<0.05）. Compared with those before treatment， the PHQ-9 and GAD-7 scores of the two groups were decreased at week 4 and 8 of treatment （P<0.05）， and there was no statistical difference between two groups. And the SAQ dimension scores of the two groups were increased at week 4 and 8 of treatment （P<0.05）. Compared with the Deanxit group， the Tiaoxin Formula group had elevation in two dimension scores： Physical limitation and angina stability （P<0.05）. Compared with the conditions before treatment， the serum 5-HT level in the two groups were increased， while the β-TG and MPO levels were lowered （P<0.05）， and there was no distinct difference between two groups. In addition， the standard deviation of normal-to-normal intervals （SDNN） and standard deviation of average normal-to-normal intervals （SDANN） of the heart rate variability in the Tiaoxin formula group were elevated after treatment （P<0.05）， which were more significant than those of the Deanxit group （P<0.05）. During the treatment period， the incidence of adverse drug reactions in the Tiaoxin formula group was lower than that in the Deanxit group （P<0.05）， and no adverse events were observed in the two groups. ConclusionTiaoxin formula was effective for the treatment of patients with coronary heart disease accompanied by anxiety and depression， which improved the clinical symptoms， increased serum 5-HT levels， and decreased serum β-TG and MPO levels， and had few adverse reactions and high safety for patients， showing a high clinical value.

OBJECTIVES: To investigate the level and significance of serum γ-glutamyl transferase-to-platelet ratio (GPR) and monocyte count to high-density lipoprotein ratio (MHR) in patients with essential hypertension (EH) and unstable angina (UA). METHODS: A total of 218 patients with coronary angiography aged ≥60 years, who were admitted to the EH hospital of the Department of Cardiac Medicine, Affiliated Hospital of Chengde Medical College, were selected from September 2018 to September 2019. They were divided into an EH+UA group ( RESULTS: Compared with the control group, patients in the EH+UA group and the EH group had higher body mass index (BMI), tyiglyceride (TG), GPR, and MHR, and lower high-density lipoprotein-cholesterol (HDL-C) (all CONCLUSIONS There is a correlation between GPR, MHR and EH combined with UA pectoris, and the combined detection of the two indicators has adjuvant diagnostic value for elderly EH combined with UA.
Aged ; Angina, Unstable ; Cholesterol, HDL ; Coronary Angiography ; Essential Hypertension ; Humans ; Lipoproteins, HDL ; Monocytes

Objective:To observe the functional changes of skeletal muscle in severely burned rats, and to investigate the effects and possible mechanisms of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway inhibitor in skeletal muscle function.Methods:The experiment research method was applied. One hundred and twenty male Wistar rats of 8-week-old were divided into sham injury group, simple burn group, and burn+JAK/STAT3 inhibitor group according to the random number table, with 40 rats in each group. Rats in simple burn group and burn+JAK/STAT3 inhibitor group were inflicted with 50% total body surface area full-thickness scald on the back and abdomen, and rats in sham injury group were sham injured. Rats in burn+JAK/STAT3 inhibitor group were intraperitoneally injected with JAK/STAT3 inhibitor ruxolitinib. On post injury day (PID) 0 (immediately), 1, 4, 7, and 14, 8 rats in each group were used to measure the specific force generated by extensor digitorum longus in optimal length stimulated with pulse frequency of 20, 40, 60, 80, 100, 120, 140, and 160 Hz using a multichannel electrophysiological instrument, and specific force in fatigue period of extensor digitorum longus in optimal length stimulated with pulse frequency of 50 Hz for 0, 10, 20, 30, 60, 120, 180, 240, and 300 s. On PID 0, 1, 4, 7, and 14, carbonyl compound content of extensor digitorum longus was determined by ultraviolet spectrophotometry, and ATP content of extensor digitorum longus was determined by micrometry. Data were statistically analyzed with analysis of variance for repeated measurement, analysis of variance for factorial design, Bonferroni method, and t test. Results:Compared with those of sham injury group, specific forces of extensor digitorum longus of rats in simple burn group were significantly decreased after being stimulated with all the pulse frequency on PID 0, 1, 7, and all the pulse frequency except for 20 Hz on PID 4, and pulse frequency of 20 and 40 Hz on PID 14 ( P<0.05 or P<0.01). Compared with those of simple burn group, specific forces of extensor digitorum longus of rats in burn+JAK/STAT3 inhibitor group were significantly increased after being stimulated with all the pulse frequency except for 20 Hz on PID 1 and all the pulse frequency on PID 4, 7, and 14 ( P<0.05 or P<0.01). Compared with those of sham injury group, specific forces of extensor digitorum longus of rats in simple burn group were significantly decreased in fatigue period at all the time points post injury and stimulation time points except for 240 s on PID 7 ( P<0.05 or P<0.01). Compared with those of simple burn group, specific forces of extensor digitorum longus of rats in burn+JAK/STAT3 inhibitor group were obviously increased in fatigue period at all the stimulation time points except for 60 and 300 s on PID 1 and 240 s on PID 4, and all the stimulation time points on PID 7 and 14 ( P<0.05 or P<0.01). The carbonyl compound content of extensor digitorum longus of rats in simple burn group on PID 0, 1, 4, 7, and 14 was (0.651±0.155), (0.739±0.194), (0.618±0.086), (0.813±0.162), (0.615±0.115) nmol/mg, which were obviously higher than (0.196±0.019), (0.156±0.004), (0.169±0.023) (0.156±0.027), (0.175±0.008) nmol/mg in sham injury group ( t=7.219, 6.491, 10.938, 9.182, 11.589, P<0.01) and (0.538±0.069), (0.369±0.059), (0.273±0.061), (0.334±0.109), (0.318±0.101) nmol/mg in burn+JAK/STAT3 inhibitor group ( t=2.446, 4.689, 8.355, 5.754, 6.097, P<0.05 or P<0.01). The ATP content in extensor digitorum longus of rats in simple burn group on PID 1, 4, 7, and 14 was obviously lower than that in sham injury group ( t=7.159, 7.591, 7.473, 4.026, P<0.01) and burn+JAK/STAT3 inhibitor group ( t=2.295, 2.575, 2.453, 2.997, P<0.05). Conclusions:After severe burn, the specific force of extensor digitorum longus in rats decreased significantly after being stimulated with different pulse frequencies, and the extensor digitorum longus in rats was prone to fatigue. Blocking the JAK/STAT3 signaling pathway can reduce the oxidative stress of muscle protein and increase ATP content, thereby reducing the muscle strength decline caused by burn injury and improving the muscle strength decline during fatigue period.

Objective:To investigate the clinical related factors that affecting peritumoral brain edema (PTBE) and its severity in meningiomas.Methods:A total of 139 patients with meningiomas, admitted to and underwent surgery in our hospital from from January 2017 to October 2020 were chosen; their clinical data were analyzed retrospectively. Meningioma volume and edema volume were calculated from drawn regions of interest on preoperative MRI images by 3D-slicer software. Edema index (EI) was used to evaluate the severity of PTBE. The clinical factors affecting PTBE and EI were determined by statistical methods, and the value of meningioma volume in predicting PTBE was further analyzed.Results:(1) The PTBE incidence was 33.8% (47/139), and average EI was 2.47±0.73. (2) Univariate analysis showed that there was significant difference in percentage of patients with benign/malignant meningiomas, meningioma location, meningioma volume, and Ki-67 index between patients from PTBE group ( n=47) and non-PTBE group ( n=92, P<0.05). Multivariate binary Logistic regression analysis showed that benign/malignant meningiomas and meningioma volumes were independent risk factors for PTBE ( P<0.05). (3) There were significant differences in EI values among patients with different gender, WHO grading, KI-67 index and meningioma volumes ( P<0.05). Multivariate linear regression analysis showed meningioma malignant degrees and meningioma volume were independent risk factors for EI ( P<0.05). (4) Receiver operating characteristic curve showed that the area under curve of meningiomas of the cranial base and non-meningiomas of the cranial base in predicting PTBE was 0.824 and 0.825, respectively, with sensitivity of 0.800 and 0.784, and with specificity of 0.818 and 0.729. Conclusions:(1) Malignant degrees and meningioma volumes are the main factors affecting the incidence of PTBE, and are positively correlated with EI. (2) Meningioma volume has high predictive value in PTBE occurrence.

Objective:To investigate the correlation of the gamma-glutamyl transpeptidase to platelet ratio(GPR)and monocyte count to high-density lipoprotein cholesterol(HDL-C)ratio(MHR)with the severity of coronary artery disease in elderly patients with essential hypertension(EH)combined with unstable angina pectoris(UA).Methods:A total of 218 EH patients aged 60 years and over undergoing coronary arteriography admitted to cardiology department of our hospital were enrolled from September 2018 to September 2019.They were divided into the EH plus UA group(n=113)and the simple EH group(n=105)according to whether UA was combined.In addition, 106 patients with normal coronary angiography who were suspected with coronary heart disease were selected as the healthy group.General data of patients between three groups were compared.Severity of coronary artery disease was evaluated using a Gensini score.The correlation of GPR and MHR with coronary Gensini scores was analyzed in the EH plus UA group.Patients in the EH plus UA group were sub-grouped into the single-, double- and triple-vessel disease groups according to the number of disease branches.Differences in coronary Gensini scores, GPR and MHR were compared among subgroups.A receiver operating characteristic(ROC)curve was used to evaluate the auxiliary diagnostic efficacy of GPR, MHR and the combined GPR and MHR in the EH plus UA group.Results:Compared with the healthy group, both EH plus UA group and EH group showed that the BMI(25.8±3.4 kg/m 2, 25.4±3.6 kg/m 2vs.24.2±2.3 kg/m 2), triglyceride(1.9±1.2, 2.0±1.2 vs.1.5±1.1 mmol/L), and MHR(6.6±1.4, 5.8±1.7 vs.4.9±1.7)were increased, and the HDL-C(1.1±0.2 mmol/L, 1.1±0.3 mmol/L vs.1.3±0.3 mmol/L)were reduced( P<0.05), and only EH plus UA group showed that white blood cells(6.7±1.5×10 9/L vs.6.1±1.8×10 9/L), LDL-C(2.3±0.6 mmol/L vs.2.1±0.6 mmol/L)and GPR(0.3±0.1 vs.0.2±0.1)were higher than in the healthy group( P<0.05). Compared with the EH group, the EH plus UA group showed that the GPR(0.3±0.1 vs.0.2±0.1), and MHR(6.6±1.4 vs.5.8±1.7)were increased( P<0.05). The correlation analysis showed that the levels of GPR and MHR were positively correlated with Gensini scores in the EH plus UA group( r=0.537, 0.333, P<0.05), and the correlation was better along with the increased number of diseased branches( P<0.05). The ROC curve analysis showed that GPR had a high specificity and positive predictive value with the specificity of 68.9% and the area under the ROC curve( AUC)of 0.842, while MHR had a high sensitivity with the sensitivity of 92.9%.The combined detection of GPR and MHR had a higher specificity and positive predictive value with a specificity of 84.0% and the AUC of 0.871. Conclusions:The increase of GPR and MHR can be used as a marker to assist the diagnosis of EH combined with UA, and to assess the severity of coronary artery disease in the elderly.