Background::Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1), the most frequently altered proto-oncogene in hepatic neoplasms. Methods::Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( β-cateninΔ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-cateninΔ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro. Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV); β-cateninlox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer. Results::MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV; β-cateninlox(ex3)/+ mice, which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer. Conclusion::MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.

Objective To establish a scientific training program that takes into account both anaerobic and aerobic training for pilots,and to explore the appropriate ratio of aerobic and anaerobic training.Methods According to the physical examination standards for pilots,a total of 16 healthy subjects aged 18-24 were selected from two batches.The two batches of subjects were trained with different aerobic and anaerobic ratios.Training period was 3 months.The changes in cardiopulmonary function of the subjects before and after training were evaluated using the cardiopulmonary function exercise testing system(CPET),and the changes in anaerobic capacity were evaluated using changes in strength as an indicator.Results After training,the weight load of the subjects in the two training programs,including barbell squats,leg flexion and hard pull,and barbell under 10RM and 3RM,was significantly increased(P<0.001),and there was no statistically significant difference in anaerobic strength growth between the two groups.The results of CPET showed that the maximum load,maximum heart rate,and respiratory quotient in the two groups were significantly increased after than before the training(P<0.01).The maximum load(Experiment group 1:29.12±19.69,Experiment group 2:72.00±46.24)and respiratory quotient(Experiment grouop 1:0.11±0.09,Experiment group 2:0.28±0.16)of the subjects in experiment group 2 before and after training were greater than those in experiment group 1.The difference was statistically significant(P<0.05).Conclusion The anaerobic and aerobic capacities of the subjects in the experiment group 2 are effectively improved,indicating that ratio of aerobic and anaerobic of the training scheme is better.

Objective:To investigate the neuroprotective effect of histone deacetylase 3 (HDAC3) specific inhibitor RGFP966 on traumatic brain injury (TBI) and its mechanism in rats.Methods:Forty-eight SD rats were randomly divided into sham-operated group, TBI group, TBI+vehicle group and TBI+RGFP966 group ( n=12). Rats in the later 3 groups accepted hydraulic impact brain injury to establish TBI models; and then, RGFP966 (dissolved in 1% DMSO at a dose of 10 mg/kg) was injected intraperitoneally 30 min after modeling, twice a day for 3 d, in TBI+RGFP966 group; same amount of DMSO was injected into TBI+vehicle group at the same time. Three d after modeling, neurological function was tested by modified neurological severity score (mNSS), water content of brain tissues was detected by dry-wet weight method, proportion of injured neurons at the frontal cortical tissues on the affected side was detected by Nissl staining, expressions of HDAC3 and pyroptosis related proteins were detected by immunohistochemical staining and Western blotting, and serum content of inflammatory factors was detected by ELISA. Results:Three d after modeling, compared with the TBI+vehicle group, the TBI+RGFP966 group had significantly decreased mNSS scores (9.83±0.75 vs. 6.67±0.82), water content of the injured cerebral cortex (82.73%±0.36% vs. 80.92%±0.66%), proportion of damaged neurons (75.60%±7.44% vs. 55.87%±4.10%), and HDAC3 protein expression (0.67±0.09 vs. 0.51±0.07), and significantly increased acetylated H3 (Ace-H3) and acetylated H4 (Ace-H4) protein expressions (0.81±0.02 vs. 1.22±0.02; 0.74±0.01 vs. 1.07±0.02), and statistically decreased protein expressions of nuclear factor-κB (NF-κB, 1.20±0.05 vs. 0.94±0.04), NOD-like receptor thermal protein domain associated protein 3 (NLRP3, 0.72±0.02 vs. 0.40±0.03), Caspase-1 containing cysteine (Caspase-1), dermatin D N-terminal fragment (GSDMD-N, 0.71±0.03 vs. 0.52±0.01), significantly decreased NF-κB and NLRP3 immunohistochemical staining scores, and significantly decreased serum contents of tumor necrosis factor-α, interleukin(IL)-1β and IL-18 ( P<0.05). Conclusion:Early intervention with RGFP966 after TBI can reduce the pyroptosis and inflammatory reaction of nerve cells and play neuroprotective role, whose mechanism may be related to inhibited activation of NF-κB/NLRP3/GSDMD pathway.

Objective : To explore the relationship between the methylation level of RABL6 in peripheral blood and early lung cancer (LC) with a case-control study in the Chinese population． Methods : The methylation levels of 7 CpG sites in RABL6 gene in peripheral blood of samples from 275 LC patients (81．5% at stage I) ，and age- and gender-matched 185 benign lung nodule cases and 267 matched healthy controls were measured by matrix-assisted laser desorption ionization time-of-flight mass spectrometry．Multinomial Logistic regression adjusted for covariates was used to analyze the association between the RABL6 methylation and LC．Mann-Whitney U test was applied for the comparisons of RABL6 methylation levels between clinical characteristics subgroups of LC. Results : Compared to the healthy controls，the methylation of RABL6 _CpG_ 17 was inversely associated with LC in females ( per - 10% methylation : OR = 2. 47，95% CI = 1. 19－5. 13，P = 0. 016) ，but positively associated with LC in males (per - 10% methylation : OR = 0. 52，95% CI = 0. 29－0. 94，P = 0. 030) ．In addition，hypermethylation of RABL6_CpG _2 and RABL6_CpG_5 was significantly associated with LC in the subjects older than 55 years (for RABL6_CpG_ 2 : per －10% methylation : OR = 0. 77，95% CI = 0. 60－0. 99，P = 0. 038 ; for RABL6_CpG_5 : OR = 0. 58，95% CI = 0. 34－0. 97，P = 0. 038) ． Conclusion The study reveals an association between peripheral blood-based RABL6 methylation levels and early LC，providing a new clue for developing peripheral blood-based DNA methylation as a potential marker for the evaluation of LC risk.

ObjectiveTo clarify the accumulation and distribution characteristics of dry matter and mineral elements in Artemisia argyi var. argyi cv. Qiai， and to provide technical support for the high yield of and efficient utilization of nutrients in this medicinal species. MethodTwo cultivars of this species， Qiqing 1 and Qihuang 1 were selected， and the composition of dry matter in different organs， the content， accumulation， and distribution of mineral elements in each organ of the two cultivars， and the dynamic changes of volatile oil content and index components eucalyptol and borneol in leaves of the two cultivars were monitored at different growth stages. ResultThe period from February to March marked the early growth stage of Qiai， and the dry matter was mainly distributed in the leaves. It accelerated the growth in April， and the period from April to mid-June witnessed the vigorous vegetative growth of Qiai， during which the dry matter was mainly found in the stems and leaves. It began the reproductive growth from late June and the dry matter was mainly distributed in the stems. In the flowering stage in August， no dry matter accumulation occurred. As for the volatile oil， the content was high （> 1.10%） at the vigorous vegetative growth stage and peaked on June 14 （1.33% in Qiqing 1， and 1.23% in Qihuang 1）. The relative mass fraction of eucalyptol was the maximum at the vegetative growth stage （8.67% in Qiqing 1， and 13.07% in Qihuang 1）. The relative mass fraction of borneol peaked at the early growth stage （2.63% in Qiqing 1， and 5.94% in Qihuang 1）. The content of nitrogen， phosphorus， potassium， and zinc in leaves was in significantly positive correlation with the content of volatile oil and the relative content of eucalyptol and borneol. The content of macroelements nitrogen， phosphorus， potassium， and calcium and trace elements iron and zinc peaked at the early growth stage， and the content was the highest in stem and leaf. The content of macroelement magnesium and trace elements manganese and copper was the highest at vegetative growth stage when the content of other elements decreased and the nutrients were gradually transferred to the buds， flowers and other organs. In the whole growth period， the distribution of potassium， calcium， and zinc was in the order of leaf > stem > root， and the distribution of nitrogen， phosphorus， copper， magnesium， and manganese followed the order of leaf > root > stem. The distribution of iron was in the order of root > leaf > stem. There was a significantly positive correlation between the total amount of dry matter and the absorption of nutrients in 'Qiai'. The absorption of macroelements by Qiai was in the order of potassium > nitrogen > calcium > phosphorus > magnesium， and the ratio of absorbed elements was about 2.66∶2.51∶0.6∶0.11∶0.04. The absorption of trace elements followed the order of manganese > iron > zinc > copper， and the ratio of absorbed elements was about 0.25∶0.17∶0.05∶0.04. In terms of the production of medicinal materials， 'Qiai' needed about 4.11 kg potassium， 3.58 kg nitrogen， 0.91 kg phosphorus， 0.18 kg calcium， 0.06 kg magnesium， about 6.64 g manganese， 2.56 g iron， 1.30 g zinc， and 0.92 g copper to produce 100 kg medicinal materials. ConclusionEnough organic fertilizer and phosphorus and potassium fertilizers should be applied as base fertilizers for Qiai. The vegetative growth stage （April-June） marks the high accumulation of dry matter and large demand of nutrients， during which topdressing should be conducted timely and early， especially nitrogen fertilizer， and appropriate amount of micro-element fertilizer should be added. Qiai needs a large amount of calcium and magnesium fertilizers from the mid-vegetative growth stage， and they should be applied in time in the late stage to ensure the vegetative growth of the plants for seeds and the quality of the medicinal material of Qiai.

Patients with small-cell lung cancer (SCLC) relapse within months after completing previous therapies. This study aimed to investigate the efficacy and safety of anlotinib as third- or further-line therapy in patients with short-term relapsed SCLC from ALTER1202. Patients with short-term relapsed SCLC (disease progression within 3 months after completing ⩾ two lines of chemotherapy) in the anlotinib (n = 67) and placebo (n = 34) groups were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, objective response rate (ORR), disease control rate, and safety. Anlotinib significantly improved median PFS/OS (4.0 vs. 0.7 months, P < 0.0001)/(7.3 vs. 4.4 months, P = 0.006) compared with placebo. The ORR was 4.5%/2.9% in the anlotinib/placebo group (P = 1.000). The DCR in the anlotinib group was higher than that in the placebo group (73.1% vs. 11.8%, P < 0.001). The most common adverse events (AEs) were hypertension (38.8%), loss of appetite (28.4%), and fatigue (22.4%) in the anlotinib group and gammaglutamyl transpeptidase elevation (20.6%) in the placebo group. No grade 5 AEs occurred. For patients with short-term relapsed SCLC, third- or further-line anlotinib treatment was associated with improved survival benefit. Further studies are warranted in this regard.
Humans ; Lung Neoplasms/drug therapy* ; Treatment Outcome ; Neoplasm Recurrence, Local/chemically induced* ; Quinolines/adverse effects*

Objective : To investigate the effect of hypoxic preconditioning (HPC) on mitochondrial energy metabolism in mouse hippocampal HT22 cells and its possible mechanism. Methods : In this paper, mouse hippocampal nerve cells HT22 were divided into control group, hypoxia group, HPC group, and the levels of adenosine triphosphate (ATP) and reactive oxygen species (ROS) in each group were measured for observing the effect of HPC on cell mitochondrial metabolism. Western blot was used to detect the expression of target of rapamycin ( mTOR), phosphorylated mTOR protein and autophagy substrate P62 protein; cellular immunofluorescence was used to detect phosphorylated mTOR, and LysoTrackerTM probe was used to detect lysosomes. Results : Compared with the control group, the ATP level was significantly decreased and the ROS level was increased in the hypoxia group. Exposed to HPC, the ATP level was increased and the ROS level was decreased. Compared with the control group, the expression of phosphorylated mTOR was down⁃regulated and the expression of autophagy substrate P62 was down⁃regulated in the HPC group. Conclusion HPC may affect the energy metabolism of HT22 cells through the mTOR/autophagy signaling pathway, thereby exerting a protective effect on the HT22 cells.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts' discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs.
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Objective:To investigate the effects of positive end-expiratory pressure (PEEP) setting of mechanical ventilation guided by esophageal pressure in the treatment of patients with traumatic craniocerebral injury combined with acute respiratory distress syndrome (ARDS).Methods:The retrospective cohort study was conducted. From June 2016 to June 2018, 55 patients with traumatic craniocerebral injury combined with ARDS who met the inclusion criteria were admitted to Zhengzhou Central Hospital Affiliated to Zhengzhou University. According to PEEP setting method, 28 patients were allocated to esophageal pressure group (17 males and 11 females, aged (40±13) years) and 27 patients were allocated to PEEP-fractional concentration of inspired oxygen (FiO 2) table group (18 males and 9 females, aged (38±10) years). Patients in the 2 groups were treated with mechanical ventilation guided by lung protective ventilation strategy, and the optimal PEEP at 0 (immediately), 24, 48, and 72 h after treatment was determined according to esophageal pressure and PEEP-FiO 2 table, respectively. The mechanical ventilation parameters in the 2 groups were adjusted according to the optimal PEEP. The transpulmonary end-expiratory pressure, pulmonary compliance, oxygen index, central venous pressure, mean arterial pressure, and intracranial pressure at 24, 48, and 72 h after treatment were recorded. Data were statistically analyzed with analysis of variance for repeated measurement, chi-square test, independent sample t test, and Bonferroni correction. Results:The optimal PEEP of patients in esophageal pressure group at 0, 24, 48, and 72 h after treatment was (12.4±3.9), (11.2±3.5), (13.4±2.6), and (13.2±3.6) cmH 2O (1 cmH 2O=0.098 kPa), respectively, which was significantly higher than (8.2±2.5), (7.4±2.2), (8.3±2.3), and (8.5±2.5) cmH 2O in PEEP-FiO 2 table group, respectively ( t=4.702, 4.743, 7.849, 5.623 , P<0.01). The transpulmonary end-expiratory pressure and pulmonary compliance at 24, 48, and 72 h after treatment and oxygen index at 48 and 72 h after treatment of patients in esophageal pressure group were significantly higher than those in PEEP-FiO 2 table group ( t=17.852, 20.586, 19.532, 4.752, 5.256, 7.446, 2.342, 4.178, P<0.05 or P<0.01). The central venous pressure of patients in esophageal pressure group at 24, 48, and 72 h after treatment was significantly higher than that in PEEP-FiO 2 table group ( t=12.632, 5.247, 8.994, P<0.01), and there was no statistically significant difference in mean arterial pressure of patients between the 2 groups at 24, 48, and 72 h after treatment ( P>0.05). The intracranial pressure of patients in esophageal pressure group was higher than that in PEEP-FiO 2 table group at 24, 48, and 72 h after treatment, but there was no statistically significant difference between the 2 groups ( P>0.05). Conclusions:For patients with traumatic craniocerebral injury combined with ARDS, the optimal PEEP can be set under the guidance of esophageal pressure method, and the mechanical ventilation parameters adjusted according to the optimal PEEP can improve lung compliance and accelerate recovery of lung function more effectively, with no adverse effect in mean arterial pressure and intracranial pressure.

Objective:To investigate the value of growth differentiation factor-15 (GDF-15) and extravascular lung water index (EVLWI) in severity grading and prognosis prediction of patients with acute respiratory distress syndrome (ARDS).Methods:Patients with ARDS aged 18-75 years admitted to the department of respiratory intensive care unit (RICU) of Zhengzhou Central Hospital Affiliated to Zhengzhou University from January 2019 to February 2020 were enrolled. All patients were treated with conventional therapies such as mechanical ventilation, anti-infection, stabilization of water, electrolytes and acid-base environment, blood purification and nutritional support according to their conditions. Besides, the pulse-indicated continuous cardiac output (PiCCO) was performed after admission to the department, and EVLWI before treatment and at 24, 48 and 72 hours of treatment were recorded. Serum GDF-15 level was measured by enzyme linked immunosorbent assay (ELISA) during the same period. Patients were classified as mild, moderate, and severe degree according to the 2012 Berlin Definition of ARDS, and EVLWI and GDF-15 levels in patients with different disease levels before and after treatment were compared. In addition, the length of intensive care unit (ICU) stay, ICU mortality, and 28-day mortality of patients with different GDF-15 or EVLWI levels were analyzed comparatively, with the GDF-15 3 458 ng/L and EVLWI 15 mL/kg as the cut point.Results:A total of 82 patients with ARDS were enrolled, including 22 patients with mild ARDS, 28 patients with moderate ARDS, and 32 patients with severe ARDS. The GDF-15 and EVLWI levels in patients with moderate and severe ARDS at each time point before and after treatment were higher than those in patients with mild ARDS. Both GDF-15 and EVLWI levels in patients with severe ARDS were higher than those in the patients with moderate ARDS. The differences were statistically significant at all the time points except for the difference of GDF-15 levels at 24 hours after treatment (ng/L: 3 900.41±546.43 vs. 3 695.66±604.73, P > 0.05). [GDF-15 (ng/L): 3 786.11±441.45 vs. 3 106.83±605.09 before treatment, 3 895.48±558.96 vs. 3 333.29±559.66 at 48 hours, 3 397.33±539.56 vs. 3 047.53±499.57 at 72 hours; EVLWI (mL/kg): 19.06±1.91 vs. 14.31±1.50 before treatment, 18.56±2.23 vs. 13.26±1.69 at 24 hours, 17.23±1.76 vs. 12.45±1.36 at 48 hours, 15.47±1.81 vs. 11.13±2.19 at 72 hours, all P < 0.05]. According to the cut-off value, there were 23 patients with GDF-15 ≥ 3 458 ng/L and GDF-15 < 3 458 ng/L respectively and there were 23 patients with EVLWI ≥ 15 mL/kg and EVLWI < 15 mL/kg respectively. The length of ICU stay and 28-day mortality in patients with high GDF-15 were significantly higher than those in patients with low GDF-15 [length of ICU stay (days): 21.22±2.69 vs. 15.37±3.14, 28-day mortality: 56.5% vs. 21.7%, both P < 0.05]. The length of ICU stay and 28-day mortality in patients with high EVLWI were also significantly higher than those in patients with low EVLWI [length of ICU stay (days): 18.45±2.61 vs. 14.98±2.75, 28-day mortality: 47.8% vs. 17.4%, both P < 0.05]. Conclusion:To some extent, GDF-15 and EVLWI levels reflect the severity of patients with ARDS, and high GDF-15 and EVLWI levels are significantly associated with poor prognosis in patients with ARDS.