Objective To investigate the protective effect of autophagy inducer rapamycin on acute kidney injury (AKI) induced by sepsis. Methods Twenty-four Sprague-Dawley (SD) male rats were randomly divided into sham group, caecal ligation and puncture (CLP) model group, and rapamycin treatment group (Rap treatment group), with 8 rats in each group. The septic AKI model was reproduced by CLP in rats, and rats in sham group were given appendix isolation without ligation and puncture. The rats in Rap treatment group were given 1.6 mg rapamycin by intraperitoneal injection immediately after model reproduction, and the rats in CLP model group were injected with an equal amount of normal saline. The rats in all groups were sacrificed after collecting peripheral blood specimen at 24 hours after model reproduction, and the levels of blood urea nitrogen (BUN) and serum creatinine (SCr) were determined. The pathomorphology change in renal tissue was observed under light microscope after periodic acid Schiff (PAS) staining. Real-time polymerase chain reaction (real-time PCR, RT-PCR) was used to determine the mRNA expressions of renal tubular autophagy related molecules Atg-5 and Beclin-1. Western Blot was used to detect the expressions of renal tubular autophagy associated protein microtubule labeled protein 1 light chain 3-Ⅱ (LC3-Ⅱ) and Beclin-1 as well as apoptosis protein cytochrome C (Cyt C), Bax and Bcl-2. TdT-mediated dUTP nick-end labeling (TUNEL) assay was used to determine the renal tubular epithelial cell apoptosis. Results Rapamycin could alleviate pathomorphology changes in rats with septic AKI, and decrease the levels of BUN and SCr. Compared with sham group, the expressions of Atg-5, Beclin-1 and LC3-Ⅱ in CLP model group were significantly increased [Atg-5 mRNA (2-ΔΔCt): 2.34±0.04 vs. 1.00±0.03, Beclin-1 mRNA (2-ΔΔCt): 1.40±0.02 vs. 1.00±0.03, LC3-Ⅱ protein (gray value): 0.82±0.03 vs. 0.45±0.04, Beclin-1 protein (gray value): 0.59±0.06 vs. 0.29±0.03, all P < 0.01]. Rapamycin could further up-regulate the expressions of Atg-5, Beclin-1, and LC3 Ⅱ [Atg-5 mRNA (2-ΔΔCt): 3.28±0.19 vs. 2.34±0.04, Beclin-1 mRNA (2-ΔΔCt): 2.38±0.08 vs. 1.40±0.02, LC3-Ⅱ protein (gray value): 1.11±0.07 vs. 0.82±0.03, Beclin-1 protein (gray value): 0.85±0.05 vs. 0.59±0.06, all P < 0.01]. Compared with sham group, the apoptotic cells in CLP model group were increased significantly [(34.49±10.45)% vs. (2.78±1.40)%, P < 0.01], Cyt C and Bax protein expressions were significantly up-regulated (gray value: 0.87±0.02 vs. 0.46±0.03, 1.20±0.06 vs. 0.46±0.01, both P < 0.01), and Bcl-2 expression was significantly down-regulated (gray value: 0.64±0.02 vs. 1.33±0.09, P < 0.01). Rapamycin could effectively inhibit cell apoptosis [(15.44±5.50)% vs. (34.49±10.45)%, P < 0.01] and the protein expressions of Cyt C and Bax (gray value: 0.72±0.03 vs. 0.87±0.02, 0.84±0.03 vs. 1.20±0.06, both P < 0.01), and up-regulate the protein expression of Bcl-2 (gray value: 0.77±0.04 vs. 0.64±0.02, P < 0.01). Conclusion The protective effect of rapamycin on renal tissue of rat with AKI induced by sepsis was depended on cell apoptosis inhibition through inducing and promoting cell autophagy.

Objective To investigate the impact ofα?lipoic acid(ALA)treatment on sepsis?induced acute kidney injury in rats and explore the mechanisms. Methods A total of 32 male SD rats were randomized into 4 groups:normal control group(group A),ALA?treated control group (group B),sepsis group(group C)and sepsis with ALA treated group(group D). Group A and B underwent sham operation,while CLP operations were conducted in group C and D. Rats in both group B and group D were then administered with 200 mg/kg ALA by oral gavage immediately after the surgical procedure. Twenty?four hours after the surgical procedure blood samples were obtained for the evaluation of creatinine,BUN,TNF?α,IL?6 and IL?1β. Rat kidneys were rapidly removed for PAS stain. Western blot was employed to determine the expression of NF?κB. Results Pathologi?cal changes of kidney were induced by sepsis and the level of creatinine,BUN,TNF?α,IL?6 and IL?1βwere significantly increased by 178%,66%, 55%,114%and 110%(P<0.01). respectively;simultaneously the phosphorylation and nuclear expression of NF?κB p65 in kidney tissues were significantly increased by 144%and 102%(P<0.01). Sepsis?induced acute kidney injury also significantly reduced the expression of IκBαby 61%(P<0.01). These changes were significantly suppressed by early ALA treatment. Compared with C group,the level of creatinine,BUN,TNF?α,IL?6 and IL?1βwere significantly decreased by 48%,26%,25%,37%and 40%(P<0.05),respectively,and the relative expression of IκBαwas increased by 103%(P<0.05). Conclusion The present study demonstrated that ALA can suppress the activation of NF?κB,thus ameliorat?ing sepsis?related acute kidney injury.

Objective To retrospectively analyze the prognostic factors for locoregionally recurrent early?stage extranodal nasal?type natural killer/T?cell lymphoma ( NKTCL) . Methods A total of 56 patients with early?stage extranodal nasal?type NKTCL, who had locoregional recurrence after initial treatment and then received salvage treatment from 1995 to 2014, were enrolled as subjects. The effects of salvage treatment on the overall survival ( OS) rate were analyzed after initial treatment and recurrence. Univariate and multivariate prognostic analyses were performed on the OS rate after recurrence. Results The median follow?up time was 35. 9 months after initial treatment and 14. 8 months after recurrence. The 3?year OS rate was 73% after initial treatment and 58% after recurrence. Compared with chemotherapy alone, radiotherapy?containing salvage treatment significantly improved the OS rates after initial treatment and recurrence ( P=0. 040, 0. 009 ) , and re?irradiation also significantly improved the OS rates after initial treatment and recurrence (P=0. 018, 0. 019). Most (84%) of the acute and late adverse reactions after re?irradiation were grade 1?2 ones. The univariate and multivariate analyses showed that the Karnofsky Performance Status score, radiotherapy in initial treatment, and radiotherapy in salvage treatment were influencing factors for the OS rate after recurrence. Conclusions Radiotherapy achieves improved survival and tolerable toxicities, making it indispensable in the treatment of locoregionally recurrent extranodal nasal?type NKTCL.

Objective To analysis the characteristics of thromboelastography and coagulation test in patients with advanced pregnancy combined with severe preeclampsia. Methods A retrospective single?center study was conducted. 35 patients with advanced pregnancy combined with se?vere preeclampsia who were admitted to hospital from January 2012 to December 2014 were analyzed compared to 43 third trimester patients with?out any complication. All the patients were treated based on the routine strategy. Blood sample were taken from the middle elbow vein to test blood cell count,serum biochemistry test,routine coagulation test and thromboelastography. All the results,including R,K,CI,α?angle and MA value, were compared between two groups. Analysis was performed to evaluate the correlation between all parameters of TEG and coagulation test. Re?sults There was no statistical significance between two groups in age ,prothrombin time and activated partial prothrombin time. In the severe pre?eclampsia group,the R value of TEG was increased(5.21±1.20 min vs 6.19±1.55 min,t=-3.144,P=0.002),α?angel was decreased(64.43°± 7.90° vs 60.37°±7.09°,t=2.367,P=0.02),and CI was decreased(0.81±2.27 vs-0.37±1.82,t=2.495,P=0.015). In blood cell count test,the platelets count was decreased in severe preeclampsia group[(217.48±65.68)×109/L vs(166.65±61.39)×109/L,t=3.500,P=0.001]. In routine coagulation test,only thrombin clotting time was increased in severe preeclampsia group(14.59±0.51 s vs 15.28±0.97 s,F=-3.800,P<0.001). In serum biochemistry test,the albumin was decreased in severe preeclampsia group(34.75±3.90 g/L vs 28.77±4.05 g/L,t=6.632,P<0.001),while serum urea nitrogen was increased(2.78±0.87 mmol/L vs 5.98±8.07 mmol/L,F=-2.333,P=0.026). In correlation analysis,thrombin clot?ting time had relationship between R(r=0.290,P=0.010),CI(r=-0.257,P=0.023)andα?angle(r=-0.243,P=0.032). Platelets count cor?related with CI(r=0.383,P=0.001),K(r=-0.409,P<0.001),α?angle(r=0.375,P=0.001)and MA(r=0.512,P<0.001). Conclusion For those who suffered from severe preeclampsia patients with advanced pregnancy,low coagulation function occurs in most of the patients com?pared to those patients without any complications. Thromboelastography may be helpful for those who have high risk factors ,especially with low platelets count and increased thrombin clotting time ,so as to reduce the incidence of bleeding or thromboembolic diseases.

Objective:To compare the effects of sodium butyrate(Sob)on aged and young asthmatic mice.Methods:Male C57BL/6 mice aged 24 months(n=18)and 4 months(n=18)were divided using randomly generated numbers into 3 groups: a control group, a model group(treated with ovalbumin, OVA), and a treatment group(OVA+ Sob), with 6 mice in each group.The control group was given normal saline as the blank control.Two days before the OVA challenge, the treatment group was given 1 mg/g Sob by intraperitoneal injections and the OVA+ Sob group and the control group were given normal saline intervention.Endpoint evaluation was performed 1 day after the last challenge.Differences in airway hyperresponsiveness(AHR), pathological manifestations of lung tissue sections stained with hematoxylin eosin(HE), and inflammatory factors in lung tissues were compared between aged and young mice and the effects of Sob on asthmatic mice of different ages were evaluated.Results:Under the stimulation of methacholine(Mch), AHR of the O-OVA group was significantly higher than that of the Y-OVA group(6.250 g/L: 276.28±113.62 vs.103.02±19.55, t=3.368, P=0.026; 12.500 g/L: 457.5±157.29 vs.114.76±20.28, t=4.338, P=0.022; 25.000 g/L: 1113.16±256.98 vs.567.87±187.34, t=3.538, P=0.009). HE staining revealed that, compared with the Y-control group, the O-control group exhibited a reduced area of alveolar cavity, partial lung consolidation, proliferation of interstitial fibrous connective tissues, alveolar epithelial cells and capillary endothelial cells.Compared with its control group, the O-OVA group had significantly elevated levels of eotaxin( P=0.035), IL-17A( P=0.004)and IL-1β( P=0.001), among the inflammatory factors, whereas the Y-OVA group had elevated levels of eotaxin( P=0.001), IL-17A( P=0.001), IL-4( P=0.004), KC( P=0.012)and IL-1β( P<0.001). Compared with the O-OVA group, the Y-OVA group had increased levels of IL-4( Z=2.882, P=0.004)but decreased levels of IL-1β( t=2.728, P=0.020). As for the effects of Sob on asthmatic mice of different ages, AHR of the O-OVA+ Sob group was significantly alleviated with stimulation of 12.500 g/L Mch( P=0.015)and 25 g/L Mch( P=0.014), compared with the O-OVA group.With stimulation of 3.125 g/L Mch, AHR of the Y-OVA+ Sob group was significantly decreased( P=0.021)and levels of IL-4( P=0.004)and IL-1β( P=0.014)were significantly reduced in the Y-OVA+ Sob group, compared with the Y-OVA group. Conclusions:The severity of asthma in aged mice is greater than in young mice, perhaps as a result of different immunophenotypes; The alleviating effects of Sob on inflammatory factors in young asthmatic mice may be related to mild AHR in young asthmatic mice, compared with aged asthmatic mice.

Objective To evaluate the accuracy of central venous-to-arterial carbon dioxide partial pressure difference (Pcv-aCO2) before and after rapid rehydration test (fluid challenge) in predicting the fluid responsiveness in patients with septic shock. Methods A prospective observation was conducted. Forty septic shock patients admitted to medical intensive care unit (ICU) of Peking Union Medical College Hospital from October 2015 to June 2017 were enrolled. All of the patients received fluid challenge in the presence of invasive hemodynamic monitoring. Heart rate (HR), blood pressure, cardiac index (CI), Pcv-aCO2 and other physiological variables were recorded at 10 minutes before and immediately after fluid challenge. Fluid responsiveness was defined as an increase in CI greater than 10% after fluid challenge, whereas fluid non-responsiveness was defined as no increase or increase in CI less than 10%. The correlation between Pcv-aCO2 and CI was explored by Pearson correlation analysis. Receiver operating characteristic (ROC) curves were established to evaluate the discriminatory abilities of baseline and the changes after fluid challenge in Pcv-aCO2 and other physiological variables to define the fluid responsiveness. The patients were separated into two groups according to the initial value of Pcv-aCO2. The cut-off value of 6 mmHg (1 mmHg = 0.133 kPa) was chosen according to previous studies. The discriminatory abilities of baseline and the change in Pcv-aCO2(ΔPcv-aCO2) were assessed in each group. Results A total of 40 patients were finally included in this study. Twenty-two patients responded to the fluid challenge (responders). Eighteen patients were fluid non-responders. There was no significant difference in baseline physiological variable between the two groups. Fluid challenge could increase CI and blood pressure significantly, decrease HR notably and had no effect on Pcv-aCO2 in fluid responders. In non-responders, blood pressure was increased significantly and CI, HR, Pcv-aCO2 showed no change after fluid challenge. Pcv-aCO2 was comparable in responders and non-responders. In 40 patients, CI and Pcv-aCO2 was inversely correlated before fluid challenge (r = -0.391, P = 0.012) and the correlation between them weakened after fluid challenge (r = -0.301, P = 0.059). There was no significant correlation between the changes in CI and Pcv-aCO2 after fluid challenge (r = -0.164, P = 0.312). The baseline Pcv-aCO2 and ΔPcv-aCO2 could not discriminate between responders and non-responders, with the area under ROC curve (AUC) of 0.50 [95% confidence interval (95%CI) =0.32-0.69] and 0.51 (95%CI = 0.33-0.70), respectively. HR and blood pressure before fluid challenge and their changes after fluid challenge showed very poor discriminative performances. Before fluid challenge, 16 patients had a Pcv-aCO2 > 6 mmHg. Their mean CI was significantly lower and Pcv-aCO2 was significantly higher than that in 24 patients whose Pcv-aCO2 ≤6 mmHg [n = 24; CI (mL·s-1·m-2): 48.3±11.7 vs. 65.0±18.3, P < 0.01; Pcv-aCO2 (mmHg): 8.4±1.9 vs. 2.9±2.8, P < 0.01]. Pcv-aCO2was decreased significantly after fluid challenge in patients with an initial Pcv-aCO2 > 6 mmHg and their ΔPcv-aCO2 was notably different as compared with the patients whose baseline Pcv-aCO2≤6 mmHg (mmHg: -3.8±3.4 vs. 0.9±2.9, P < 0.01). 68.8% (11/16) patients responded to the fluid challenge in patients with an initial Pcv-aCO2 > 6 mmHg. The AUC of the baseline Pcv-aCO2 and ΔPcv-aCO2 to define fluid responsiveness was 0.85 (95%CI = 0.66-1.00) and 0.84 (95%CI = 0.63-1.00), respectively, and the positive predictive value was 1 when the cut-off value was 8.0 mmHg and -4.2 mmHg, respectively. 45.8% (11/24) patients responded to the fluid challenge in patients whose baseline Pcv-aCO2≤6 mmHg. There was no predictive value of baseline Pcv-aCO2 and ΔPcv-aCO2 on fluid responsiveness. Conclusion Pcv-aCO2 and its change cannot serve as a surrogate of the change in cardiac output to define the response to fluid challenge in septic shock patients whose baseline Pcv-aCO2≤6 mmHg, while the predictive values of baseline Pcv-aCO2and the change in Pcv-aCO2 are presented in patients with the initial value of Pcv-aCO2 > 6 mmHg. Clinical Trial Registration Clinical Trials, NCT01941472.

Objective:To explore the effects of short-term particulate matter(PM)exposure and the melatonin receptor 1B(MTNR1B)gene on triglyceride-glucose(TyG)index utilizing data from Fang-shan Family-based Ischemic Stroke Study in China(FISSIC).Methods:Probands and their relatives from 9 rural areas in Fangshan District,Beijing,were included in the study.PM data were obtained from fixed monitoring stations of the National Air Pollution Monitoring System.TyG index was calculated by fasting triglyceride and glucose concentrations.The associations of short-term PM exposure and rs10830963 polymorphism of the MTNR1B gene with the TyG index were assessed using mixed linear models,in which covariates such as age,sex,and lifestyles were adjusted for.Gene-environment inter-action analysis was furtherly performed using the maximum likelihood methods to explore the potential effect modifier role of rs10830963 polymorphism in the association of PM with TyG index.Results:A total of 4 395 participants from 2 084 families were included in the study,and the mean age of the study participants was(58.98±8.68)years,with 53.90％females.The results of association analyses showed that for every 10 μg/m3 increase in PM2.5 concentration,TyG index increased by 0.017(95％CI:0.007-0.027),while for per 10 μg/m3 increment in PM1o,TyG index increased by 0.010(95％CI:0.003-0.017).And the associations all had lagged effects.In addition,there was a positive association between the rs10830963 polymorphism and the TyG index.For per increase in risk allele G,TyG index was elevated by 0.040(95％CI:0.004-0.076).The TyG index was 0.079(95％CI:0.005-0.152)higher in carriers of the GG genotype compared with carriers of the CC genotype.The inter-action of rs10830963 polymorphism with PM exposure had not been found to be statistically significant in the present study.Conclusion:Short-term exposure to PM2.5 and PM10 were associated with higher TyG index.The G allele of rs10830963 polymorphism in the MTNR1B gene was associated with the elevated TyG index.

Objective:To explore the association between polymorphisms of transforming growth factor-β(TGF-β)signaling pathway and non-syndromic cleft lip with or without cleft palate(NSCL/P)among Asian populations,while considering gene-gene interaction and gene-environment interaction.Methods:A total of 1 038 Asian NSCL/P case-parent trios were ascertained from an international consortium,which conducted a genome-wide association study using a case-parent trio design to investigate the genes affec-ting risk to NSCL/P.After stringent quality control measures,343 single nucleotide polymorphism(SNP)spanning across 10 pivotal genes in the TGF-β signaling pathway were selected from the original genome-wide association study(GWAS)dataset for further analysis.The transmission disequilibrium test(TDT)was used to test for SNP effects.The conditional Logistic regression models were used to test for gene-gene interaction and gene-environment interaction.Environmental factors collected for the study in-cluded smoking during pregnancy,passive smoking during pregnancy,alcohol intake during pregnancy,and vitamin use during pregnancy.Due to the low rates of exposure to smoking during pregnancy and al-cohol consumption during pregnancy(＜3％),only the interaction between maternal smoking during pregnancy and multivitamin supplementation during pregnancy was analyzed.The threshold for statistical significance was rigorously set at P=1.46 × 10-4,applying Bonferroni correction to account for multiple testing.Results:A total of 23 SNPs in 4 genes yielded nominal association with NSCL/P(P＜0.05),but none of these associations was statistically significant after Bonferroni's multiple test correction.How-ever,there were 6 pairs of SNPs rs4939874(SMAD2)and rs1864615(TGFBR2),rs2796813(TGFB2)and rs2132298(TGFBR2),rs4147358(SMAD3)and rs1346907(TGFBR2),rs4939874(SMAD2)and rs1019855(TGFBR2),rs4939874(SMAD2)and rs12490466(TGFBR2),rs2009112(TGFB2)and rs4075748(TGFBR2)showed statistically significant SNP-SNP interaction(P＜1.46 × 10-4).In contrast,the analysis of gene-environment interactions did not yield any significant results after being cor-rected by multiple testing.Conclusion:The comprehensive evaluation of SNP associations and interac-tions within the TGF-β signaling pathway did not yield any direct associations with NSCL/P risk in Asian populations.However,the significant gene-gene interactions identified suggest that the genetic architec-ture influencing NSCL/P risk may involve interactions between genes within the TGF-β signaling path-way.These findings underscore the necessity for further investigations to unravel these results and further explore the underlying biological mechanisms.

Lung cancer is the malignant tumor with the highest morbidity and mortality in China. Non-small cell lung cancer (NSCLC) is the main pathological subtype of lung cancer. On April 13, 2023, the National Comprehensive Cancer Network (NCCN) released the third edition of the 2023 NCCN Oncology Clinical Practice Guidelines: Non-small Cell Lung Cancer, which reflects the latest advances in international lung cancer research. This article will interpret the main updated contents of the new edition of the guidelines, and compare it with the third edition of the NCCN guidelines in 2022, so as to provide references about the diagnosis and treatment of NSCLC for clinical medical personnel in China.
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Humans ; Carcinoma, Non-Small-Cell Lung ; China ; Lung Neoplasms ; Thorax

Periodontitis imparting the increased risk of atherosclerotic cardiovascular diseases is partially due to the immune subversion of the oral pathogen, particularly the Porphyromonas gingivalis (P. gingivalis), by inducing apoptosis. However, it remains obscure whether accumulated apoptotic cells in P. gingivalis-accelerated plaque formation are associated with impaired macrophage clearance. Here, we show that smooth muscle cells (SMCs) have a greater susceptibility to P. gingivalis-induced apoptosis than endothelial cells through TLR2 pathway activation. Meanwhile, large amounts of miR-143/145 in P.gingivalis-infected SMCs are extracellularly released and captured by macrophages. Then, these miR-143/145 are translocated into the nucleus to promote Siglec-G transcription, which represses macrophage efferocytosis. By constructing three genetic mouse models, we further confirm the in vivo roles of TLR2 and miR-143/145 in P. gingivalis-accelerated atherosclerosis. Therapeutically, we develop P.gingivalis-pretreated macrophage membranes to coat metronidazole and anti-Siglec-G antibodies for treating atherosclerosis and periodontitis simultaneously. Our findings extend the knowledge of the mechanism and therapeutic strategy in oral pathogen-associated systemic diseases.
Animals ; Mice ; Endothelial Cells ; Toll-Like Receptor 2 ; Macrophages ; Apoptosis ; Atherosclerosis ; Myocytes, Smooth Muscle ; MicroRNAs