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We study parton energy-momentum exchange with the quark gluon plasma (QGP) within a multistage approach composed of in-medium DGLAP evolution at high virtuality, and (linearized) Boltzmann Transport formalism at lower virtuality. This multistage simulation is then calibrated in comparison with high $p_T$ charged hadrons, D-mesons, and the inclusive jet nuclear modification factors, using Bayesian model-to-data comparison, to extract the virtuality-dependent transverse momentum broadening transport coefficient $\hat{q}$. To facilitate this undertaking, we develop a quantitative metric for validating the Bayesian workflow, which is used to analyze the sensitivity of various model parameters to individual observables. The usefulness of this new metric in improving Bayesian model emulation is shown to be highly beneficial for future such analyses., 24 pages, 16 figures

We utilize event-by-event Monte Carlo simulations within the JETSCAPE framework to examine scale-dependent jet-medium interactions in heavy-ion collisions. The reduction in jet-medium interaction during the early high-virtuality stage, where the medium is resolved at a short distance scale, is emphasized as a key element in explaining multiple jet observables, particularly substructures, simultaneously. By employing the MATTER+LBT setup, which incorporates this explicit reduction of medium effects at high virtuality, we investigate jet substructure observables, such as Soft Drop groomed observables. When contrasted with existing data, our findings spotlight the significant influence of the reduction at the early high-virtuality stages. Furthermore, we study the substructure of gamma-tagged jets, providing predictive insights for future experimental analyses. This broadens our understanding of the various contributing factors involved in modifying jet substructures., 6 pages, 4 figures, contribution to the Hard Probes 2023 proceedings

The distribution of fitness effects (DFE) of new mutations has been of interest to evolutionary biologists since the concept of mutations arose. Modern population genomic data enable us to quantify the DFE empirically, but few studies have examined how data processing, sample size and cryptic population structure might affect the accuracy of DFE inference. We used simulated and empirical data (from Arabidopsis lyrata) to show the effects of missing data filtering, sample size, number of single nucleotide polymorphisms (SNPs) and population structure on the accuracy and variance of DFE estimates. Our analyses focus on three filtering methods-downsampling, imputation and subsampling-with sample sizes of 4-100 individuals. We show that (1) the choice of missing-data treatment directly affects the estimated DFE, with downsampling performing better than imputation and subsampling; (2) the estimated DFE is less reliable in small samples (

As an extension of the pairwise spike-timingdependent plasticity (STDP) learning rule, the triplet STDP is provided with greater capability in characterizing the synaptic changes in the biological neural cell. In this work, a novel mixedsignal circuit scheme, called multiple-step quantized triplet STDP, is designed to provide a precise and flexible implementation of coactivation triplet STDP learning rule in memristive synapse spiking neural network. The robustness of the circuit is greatly improved through the utilization of pulse-width encoded weight modulation signals. The circuit performance is studied through the simulations which are carried out in MATLAB Simulink & Simscape, and assessment is given by comparing the results of circuits with the algorithmic approaches., 5 pages, 10 figures

Yeast cultures (YCs) are defined as promising feed additives that maintain the health of birds and improve growth performance by modulating gut microbiota. YCs contain effective metabolites such as glycine, fructose, inositol, galactose, and sucrose. This study investigated the effects of YCs and their effective metabolites on carcass traits and cecal microflora in broilers. A total of 280 one-day-old mixed-sex Arbor Acres broilers were randomly allocated to seven groups. The basal diet (control DZ) was supplemented with various proportions of glycine, fructose, inositol, galactose, and sucrose (Groups A, B, and C), 24-hour grown Saccharomyces cerevisiae cultures (Group D) (YC), and a commercial yeast culture product (SZ) at concentrations of 0.1% and 1% (Groups E and F). Bodyweight of broilers was correlated positively with proportions of Proteobacteria in Group C and Lactobacillus and Roseburia in Group B (P

Shower development dynamics for a jet traveling through the quark-gluon plasma (QGP) is a multiscale process, where the heavy flavor mass is an important scale. During the high virtuality portion of the jet evolution in the QGP, emission of gluons from a heavy flavor is modified owing to heavy quark mass. Medium-induced radiation of heavy flavor is sensitive to microscopic processes (e.g. diffusion), whose virtuality dependence is phenomenologically explored in this study. In the lower virtuality part of shower evolution, i.e. when the mass is comparable to the virtuality of the parton, scattering and radiation processes of heavy quarks differ from light quarks. The effects of these mechanisms on shower development in heavy flavor tagged showers in the QGP is explored here. Furthermore, this multiscale study examines dynamical pair production of heavy flavor (via virtual gluon splittings) and their subsequent evolution in the QGP, which is not possible otherwise. A realistic event-by-event simulation is performed using the JETSCAPE framework. Energy-momentum exchange with the medium proceeds using a weak coupling recoil approach. Using leading hadron and open heavy flavor observables, differences in heavy versus light quark energy-loss mechanisms are explored, while the importance of heavy flavor pair production is highlighted along with future directions to study., Comment: 6 pages, 3 figures, contribution to the Hard Probes 2023 proceedings

The Leaf Area Index (LAI) is vital for predicting winter wheat yield. Acquisition of crop conditions via Sentinel-2 remote sensing images can be hindered by persistent clouds, affecting yield predictions. Synthetic Aperture Radar (SAR) provides all-weather imagery, and the ratio between its cross- and co-polarized channels (C-band) shows a high correlation with time series LAI over winter wheat regions. This study evaluates the use of time series Sentinel-1 VH/VV for LAI imputation, aiming to increase spatial-temporal density. We utilize a bidirectional LSTM (BiLSTM) network to impute time series LAI and use half mean squared error for each time step as the loss function. We trained models on data from southern Germany and the North China Plain using only LAI data generated by Sentinel-1 VH/VV and Sentinel-2. Experimental results show BiLSTM outperforms traditional regression methods, capturing nonlinear dynamics between multiple time series. It proves robust in various growing conditions and is effective even with limited Sentinel-2 images. BiLSTM's performance surpasses that of LSTM, particularly over the senescence period. Therefore, BiLSTM can be used to impute LAI with time-series Sentinel-1 VH/VV and Sentinel-2 data, and this method could be applied to other time-series imputation issues.

Multi-antenna global navigation satellite systems (GNSS) can provide attitude measurement information for GNSS/INS integrated system. However, once the wrong attitude measurement is used in the tight coupled model, it is easy to lead to filtering divergence. Therefore, fault detection and exclusion (FDE) is very important for multi-antenna attitude determination. Because the baseline length information is often used as prior information in attitude determination, it cannot be used as the statistic of FDE again. In this paper, we propose a new statistic for attitude FDE, differential inter-system biases (DISB), and jointly use DISB, baseline length, standard deviation, and ratio to perform FDE for multi-antenna GNSS attitudes. The obtained attitudes with high reliability is added to the GNSS/INS tight coupled positioning model for measurement update. A set of urban vehicular data is used to verify the method. The results show that the DISB has FDE capabilities comparable to the baseline length information, which will be a powerful supplement when the baseline length information cannot be used. Compared to the single-antenna GNSS/INS tight coupled model, The accuracy of yaw,pitch and roll of the RTK/INS tightly coupled model with multi-antenna attitude measurement is improved by 57-64%,26-29% and 26-32% respectively, and the accuracy of the PPP/INS tightly coupled model with multi-antenna attitude measurement is improved by 60-61%,51-53% and 41-44% respectively., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

In this study, a 72-h neutral salt spray test was conducted on two low-carbon alloy steels and their corrosion kinetic equations were constructed, and tensile tests were conducted on specimens with different corrosion cycles to evaluate the mechanical properties of the two experimental steels. The test results showed that the corrosion resistance of TZ750MS was better than that of H750MS during the whole test cycle; however, the predicted results of the corrosion kinetic equation showed that the corrosion resistance of TZ750MS was lower than that of H750MS after 144 h. The tensile test results showed that the strength of both steels did not change substantially after corrosion, and the tensile stress-strain diagram showed that the specimens would fracture earlier after passing through the plastic deformation zone .

Memristors have been widely studied as artificial synapses in neuromorphic circuits, due to their functional similarity with biological synapse, low operating power, and high integration density. In this work, a memristor bridge synapse for SNN with excellent linearity and soft-bound synaptic plasticity is designed and utilized for a neuron circuit implementing the robust spike-timing dependent plasticity (STDP) learning. This is the first of its kind demonstrating successful pulse width encoded multiple-step quantized STDP, with mixed-signal neuron possessing linear weight update. Physical models are employed to study the performance of proposed synapse and circuit, and simulations are carried out based on the MATLAB Simulink and Simscape. An improved memristor model which exhibits balanced flexibility, efficiency, convergence, and emulation performance, is developed though including the nonlinear Joule effect and weak signal effect. By using the improved memristor model in pattern learning, the influence of weak signal induced weight variation on circuit performance can be rigorously assessed. Moreover, the robustness and compatibility of the neuron circuit are greatly enhanced by employing the clock-based square-wave pulsed to process and program the synaptic weight. This proposed circuit could give an inspiration for combining the analog memristive synapse and leaky integrate-and-fire neuron with digital control units, prompting their development as edge computing devices., Comment: 10 pages, 25 figures

The effect of hydrostatic pressure up to 27 GPa on the Raman scattering (RS) in bulk HfS$_2$ is investigated. There are two transformations of RS spectra, which take place during compression at pressure between 5.7 GPa and 9.8 GPa as well as between 12.8 GPa and 15.2 GPa. Seven vibrational modes can be observed after the transformation, as compared to four modes before the transformation. The observed change suggests structural change in the material of yet unknown nature. The frequencies of the RS modes observed above the transformation change linearly with pressure and corresponding pressure coefficients have been determined. The other transition manifests itself as a change in the RS lineshape. While a series of well-defined RS modes are observed under pressure below the transition, broad spectral bands can be seen at higher pressure. The overall lineshape of the spectra resembles that of disordered materials. The lineshape does not change during decompression, which suggests permanent nature of the high-pressure transition., 4 pages, 4 figures

Yan-Fen Tang,1,2,&ast; Yu Wang,1,2,&ast; Tian-Jiao Xue,1,2 Gang Liu,1,2 Qi Chen,1,2 Wen Zhao,1,2 Yan-Yan Liu,1,2 Rong-Qian Chen,1,2 Li Chen,1,2 Jing Liu1,2 1Department of Respiratory, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 2Clinical Key Department of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan-Fen TangDepartment of Respiratory, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun Dongjie, Chaoyang District, Beijing, 100015, People’s Republic of ChinaTel +86 10 84322963Fax +86 10 84322146Email yanfenttang@163.comObjective: This study aims to analyze the clinical characteristics of HIV-infected patients complicated with venous thromboembolism (VTE).Methods: Seventy HIV-infected patients complicated with VTE were enrolled from Beijing Ditan Hospital Capital Medical University from October 2009 to December 2020 and divided into two groups according to CD4+. The clinical data of 70 patients were observed, including general conditions, laboratory indexes, viral load, antiretroviral therapy (ART) before the diagnosis of VTE, and thrombus treatment.Results: The patients were divided into two groups according to the CD4+ T lymphocyte count. There were 27 patients with a CD4+ T lymphocyte count ≥ 200 cells/ul, classified as group A (27/70, 38.6%), and there were 43 patients with a CD4+ T lymphocyte count < 200 cells/ul, classified as group B (43/70, 61.4%). In group B, these patients included 37 males and 6 females. The average age was 47.1± 12.1 years old. The average levels of the following indexes were: D-dimer, 3.5 mg/L (0.7, 6.9); total cholesterol, 4.4 mmol/L (3.3, 5.5); triglycerides, 1.4 mmol/L (0.9, 2.0); low density lipoprotein, 1.9 mmol/L (1.5,2.5); albumin, 31.8± 6.4 g/L; CD4+, 66 cells/ul (18, 127); viral load, 12347 copies/mL (27, 203936). Sixty-three patients (63/70, 90%) had started highly active ART (HAART) before VTE was diagnosed, 37 patients (37/70, 52.9%) were complicated with bacterial pneumonia, 16 patients had Mycobacterium tuberculosis (16/70, 22.9%), 13 patients had Pneumocystis carinii pneumonia (PCP) (13/70, 18.6%), and eight patients were complicated with cytomegalovirus (CMV) infection (8/70, 11.4%). Twenty-four patients had tumors, and 15 patients had HIV-related tumors (15/70, 21.4%). There were significant differences between the two groups in the time from the diagnosis of HIV to the discovery of thrombosis, the time from ART to the discovery of thrombosis and bacterial pneumonia, and the differences in WBC, PLT, Hb, CRP, PTA, INR, TCHO, LDL-C, ALB, and viral load were statistically significant.Conclusion: The prevalence of VTE in HIV-infected people in the last 11 years was 1.4%. In patients with a high viral load, CRP, D-dimer levels, and low CD4+ and albumin levels, 11.4– 22.9% were complicated with an opportunistic infection, and 21.4% had HIV-related tumors. There were significant differences between the two groups in high viral load, CRP, D-dimer, and low albumin.Keywords: HIV-infected persons, venous thromboembolism, CD4+ T lymphocytes, disease characteristics

Contains fulltext : 287159.pdf (Publisher’s version ) (Closed access) Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well-designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state-of-the-art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.

Wei Zhao,* Xiaoqing Zhang,* Feng Zhu, Xiufeng Jiang Department of Respiratory and Critical Care Medicine, Wuxi Fifth People’s Hospital, Wuxi, 214000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng Zhu; Xiufeng JiangDepartment of Respiratory and Critical Care Medicine, Wuxi Fifth People’s Hospital, Wuxi, 214000, People’s Republic of ChinaTel +86-13914135026;+86-13013630369, Email 181515688@qq.com; jiangxiufeng69@163.comBackground: To investigate the liver function indexes and dynamic changes in patients with different clinical types of new coronavirus pneumonia (COVID-19).Methods: A retrospective analysis of 170 COVID-19 patients hospitalized in the Wuxi Fifth People’s Hospital was divided into asymptomatic group (13 cases), mild-common group (142 cases) and seriously-critically ill group (15 cases), the clinical data and liver function indexes of the three groups were compared.Results: A total of 170 patients included 94 males and 76 females, with an average age of 44.7 ± 17.8 years. Seriously-critically ill group was older, and the proportion of patients with diabetes and liver injury at admission was also higher. As the hospitalization time increased, the changes of alanine aminotransferase (ALT) levels in asymptomatic group and mild-common group were not significant (all P > 0.05), while the ALT levels of seriously-critically ill group showed a curve that first flattened and then decreased (degree of freedom: 1.809, P = 0.002). Compared with the mild-common group, the daily decrease of ALT was 1.220U/L more in the seriously-critically ill group (P< 0.001). The aspartate aminotransferase (AST) in asymptomatic group and seriously-critically ill group did not decrease significantly (all P > 0.05), while the AST in mild-common group decreased significantly (regression coefficient: − 10.507, P = 0.008). There was no significant difference in AST changes between the three groups (P = 0.250– 0.904).Conclusion: Liver injury is common in COVID-19 patients, especially for severe patients; the dynamic change pattern of liver function indicators may be helpful to judge liver injury and evaluate treatment effects in patients with different clinical types.Keywords: COVID-19, liver injury, ALT, AST

Shuoning Song,1 Yuemei Zhang,2 Xiaolin Qiao,3 Yanbei Duo,1 Jiyu Xu,4 Zhenyao Peng,5 Jing Zhang,6 Yan Chen,3 Xiaorui Nie,3 Qiujin Sun,7 Xianchun Yang,7 Ailing Wang,8 Zechun Lu,8 Wei Sun,4 Yong Fu,1 Yingyue Dong,1 Tao Yuan,1 Weigang Zhao1 1Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Obstetrics, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 3Department of Obstetrics, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 4Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Dean’s Office, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 6Department of Laboratory, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 7Department of Clinical Laboratory, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 8National Center for Women and Children’s Health, China CDC, Beijing, People’s Republic of ChinaCorrespondence: Tao Yuan; Weigang ZhaoDepartment of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel/Fax +86 1069155073Email t75y@sina.com; xiehezhaoweigang@163.comObjective: This study aimed to find the association between alanine transaminase-to-aspartate aminotransferase ratio (ALT/AST) and the incidence of gestational diabetes mellitus (GDM).Methods: A total of 1128 pregnant women were included in this prospective, double-center, observational cohort study. ALT, AST and total bilirubin (TBil) were tested during 6– 12 weeks of gestation and 75-g oral glucose tolerance test (OGTT) was conducted during 24– 28 weeks of gestation to screen GDM. The association between ALT/AST and glucose concentration during OGTT was analyzed by linear regression model. The OR with 95% CI for incidence of GDM associated with ALT/AST was estimated by binary logistic regression. The discriminatory values of ALT/AST and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) for GDM were calculated by the area under the receiver operating characteristic curve (ROC-AUC).Results: The incidence of GDM was 22.07% (249/1128). ALT/AST was higher in GDM group than in NGT group (0.92 [0.75, 1.18] vs 0.80[0.65, 1.02], P < 0.001). ALT/AST had positive correlations with fasting blood glucose, 1-hour and 2-hour blood glucose concentration during OGTT (0.089 [95% CI: 0.034, 0.163], 0.176 [95% CI: 0.052, 0.104], and 0.115 [95% CI: 0.199, 0.609], respectively). The OR of ALT/AST for incidence of GDM was 1.603 (95% CI:1.097, 2.344). The ROC-AUC of ALT/AST and TG/HDL-C reached 0.615 (95% CI: 0.575, 0.655) and 0.619 (95% CI: 0.580, 0.659), respectively.Conclusion: ALT/AST in early pregnancy was an independent risk factor of GDM. The predictive ability of ALT/AST was similar to TG/HDL-C for GDM.Keywords: gestational diabetes mellitus, type 2 diabetes mellitus, alanine transaminase, aspartate aminotransferase, triglyceride

Xuechun Wang,1,&ast; Jia Jia,2,&ast; Xuehong Gu,3 Wei-wei Zhao,4 Caiping Chen,5 Wanxin Wu,6 Jiayuan Wang,1 Midie Xu7 1Department of Laboratory, Jiaxing First Hospital, Jiaxing, 314000, People’s Republic of China; 2Shanghai Center for Bioinformation Technology, Shanghai, 201202, People’s Republic of China; 3Department of Nursing, Jiaxing First Hospital, Jiaxing, 314000, People’s Republic of China; 4Department of Rehabilitation Medicine, Jiaxing First Hospital, Jiaxing, 314000, People’s Republic of China; 5Department of Breast Surgery, Jiaxing First Hospital, Jiaxing, 314000, People’s Republic of China; 6Department of Pathology, Jiaxing First Hospital, Jiaxing, 314000, People’s Republic of China; 7Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuehong GuDepartment of Nursing, Jiaxing First Hospital, No. 1882 of Central South Road, Jiaxing, 314000, People’s Republic of ChinaTel +86 13957368443Fax +86 573-83599079Email guxuehong145@163.comObjective: Breast cancer has become a fatal disease for women world-wide. Its incidence in China has been increasing yearly, and the identification of early-stage biomarkers is urgently required.Methods: ANOVA was carried out in the case of a primary tumor, adjacent normal tissue, and tumor metastasis of breast cancer, and on pan-cancer samples using the genome-wide methylation data of 31 solid tumor Illumina Methylation 450K chips downloaded from The Cancer Genome Atlas (TCGA) website in September 2018. Methylation sites showing a significant difference (P ≤ 0.05) were screened and compared with the whole-genome methylation data of 31 other solid tumor species in the TCGA database using t-tests in order to screen the methylation sites of breast cancer-specific expression. The expression of the screened methylation sites was confirmed through pyrosequencing in 45 cases of breast cancer, lung cancer, gastric cancer, and colorectal cancer.Results: A total of 10 specific breast cancer methylation sites (cg13683194, cg07996594, cg21646032, cg07671949, cg21185686, cg03625109, cg16429070, cg23601468, cg24818566, and cg01240931) were analyzed; nine genes (C9orf125, RARB, ESR1, RUNX3, PCDHGB7, DBC1, PDGFRB, TIMP3, and APC) were involved. The overall effect was excellent; a total of 4 methylation sites (2 in the DBC1 gene [cg03625109 and cg24818566], 1 in the C9orf125 gene [cg13683194], and 1 in the PDGFRB gene [cg16429070]) could effectively distinguish breast cancer from 31 other cancer species. The pyrosequencing results revealed that 7 screened methylation sites could significantly distinguish between breast cancer, lung cancer, gastric cancer, and colorectal cancer samples; these sites could also specifically distinguish between luminal A, luminal B, HER2, and Basal-like types of breast cancer.Conclusion: The 10 breast cancer methylation sites screened in the present study can effectively distinguish breast cancer from 31 other solid tumors, and they are expected to be used as biomarkers for early screening of breast cancer.Keywords: breast cancer, Basal-like breast cancer, methylation, biomarker, TCGA, ANOVA

Chao Jiang,1,2,&ast; Si Yin,1,&ast; Jianmin Wei,3,&ast; Weigong Zhao,1 Xiaohui Wang,1,2 Yongyuan Zhang,1,2 Dingjun Hao,2 Heng Du1 1Department of Orthopaedics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Department of Spine Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Spine Surgery, Baoji City Hospital of Traditional Chinese Medicine, Baoji, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Heng DuDepartment of Orthopaedics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaEmail drdu18@126.comObjective: The purpose of this study was to introduce and evaluate the early clinical outcomes of the full-endoscopic posterior lumbar interbody fusion (Endo-PLIF) technique with epidural anesthesia (EA) for single-segment lumbar degenerative diseases.Methods: In this retrospective case series study, we explored the feasibility and effectiveness of the Endo-PLIF with EA for single-segment lumbar degenerative diseases. Between March 2018 and January 2019, a series of 24 patients with single-segment lumbar degenerative diseases underwent Endo-PLIF surgery and were followed up for a minimum of 12 months (15.21± 2.27 months). Clinical outcomes including visual analog scale (VAS) scores for back and leg pain, Oswestry Disability Index (ODI) scores, and the Short Form-36 health survey questionnaire (SF-36) were evaluated preoperatively, and postoperatively at 3 days and at 3, 6, and 12-months.Results: All patients underwent successful single-segment Endo-PLIF surgery. The mean operation time was 209.17± 39.49 min, and average amount of bleeding was 43.33± 14.87 mL. The VAS for lower extremity pain and back pain significantly improved at 3 days, and at 3, 6, 12 months compared with preoperative, respectively. The ODI scores decreased from 42.04± 3.96 to 12.75± 2.71 (P< 0.001) at preoperative and 12 months postoperatively, respectively. The SF-36 Physical Component Scores (PCS) improved from 34.96± 4.63 preoperatively to 52.08± 6.05 (P< 0.001) at 12 months postoperatively. Additionally, the SF-36 Mental Component Scores (MCS) improved from 39.38± 5.70 at preoperative to 53.13± 5.97 (P< 0.001) at 12 months postoperatively. Two patients experienced dysesthesia, and one patient had a wound infection.Conclusion: Endo-PLIF with EA is a feasible and valuable technique for the treatment of single-segment lumbar degenerative diseases in selected patients.Keywords: full-endoscopic posterior lumbar interbody fusion, lumbar degenerative disease, lumbar fusion, clinical outcome

Fengjing Liu, Si Chen, Weijing Zhao, Mingyun Chen, Jiangfeng Ke, Zhihui Zhang, Junxi Lu, Lianxi Li Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, People’s Republic of ChinaCorrespondence: Lianxi LiDepartment of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, People’s Republic of ChinaTel +86 21 64369181x58337Email lilx@sjtu.edu.cnPurpose: We aimed to investigate whether urine uric acid excretion (UUAE) levels are associated with obesity and abdominal obesity in patients with type 2 diabetes (T2D).Methods: There were 2785 type 2 diabetic patients in this cross-sectional study. Obesity was defined as BMI ≥ 25 kg/m2, and abdominal obesity was defined as waist circumference (WC) ≥ 90 cm for men and WC ≥ 80 cm for women based on World Health Organization (WHO) recommendations for Asians. Chronic kidney disease (CKD) was defined as the estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 and/or urinary albumin excretion (UAE) ≥ 300 mg/24h. 24-h UUAE was determined enzymatically using a single 24-hour urine collection. All the subjects were stratified into quartiles based on UUAE levels. Both obesity and abdominal obesity were compared among the UUAE quartile groups, respectively. Furthermore, the associations of UUAE with obesity and abdominal obesity were analyzed in both CKD and non-CKD patients, respectively.Results: There was an obvious increased trend in both obesity prevalence (36.2%, 41.5%, 46.3%, and 63.4%, respectively, p < 0.001 for trend) and abdominal obesity prevalence (58.1%, 61.2%, 64.7%, and 75.8%, respectively, p < 0.001 for trend) in patients with T2D across the UUAE quartiles after controlling for age, sex and diabetes duration. Multiple logistic regression analyses revealed independent associations between UUAE quartiles and obesity (p < 0.001) and abdominal obesity (p < 0.001) in all patients. However, UUAE was significantly associated with obesity and abdominal obesity only in the T2D patients without CKD (p < 0.001 in model 1, model 2, model 3 and model 4, respectively).Conclusion: Increased UUAE levels were significantly associated with the presence of obesity, especially abdominal obesity in T2D patients without CKD.Keywords: urine uric acid excretion, type 2 diabetes, obesity, abdominal obesity, chronic kidney disease

Lu Gao, Wei Zhao, Qi Liu, Mingzhao Qin Department of Geriatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Lu Gao Email audreygao@qq.comBackground: Peripheral artery disease (PAD) is a manifestation of atherosclerotic cardiovascular disease (ASCVD) and significantly increases the risk of myocardial infarction and stroke. As most patients with PAD are asymptomatic, this condition is largely neglected in clinical practice. Type 2 diabetes (T2DM) patients have higher prevalence of PAD. Therefore, early detection and intervention of diabetic PAD are very important. Metabolic syndrome (MetS) is a group of interrelated metabolic risk factors, a predictor of poor prognosis in elderly patients with ASCVD. Recently, many of the metabolic risk factors as well as the overall concept of MetS itself have sparked a great deal of debate regarding their precise roles in PAD.Objective: To evaluate the relationship between metabolic syndrome (MetS) and peripheral arterial disease (PAD) in elderly patients with type 2 diabetes (T2DM).Methods: Two hundred and eighty-one elderly T2DM patients admitted to Beijing Tongren Hospital from October 2016 to December 2017 were divided into PAD group (n=136) and non-PAD (NPAD) group (n=145). Their medical records, physical examination parameters and laboratory testing parameters were later recorded and analyzed by multivariate logistic regression analysis.Results: No significant difference was detected in general clinical data and laboratory testing parameters between the two groups (P> 0.05). The incidence of MetS was significantly higher in PAD group than in NPAD group (88.2% vs 70.3%, P=0.001). Multivariate logistic regression analysis showed that the risk of PAD was 1.762-fold higher in MetS patients after adjustment for age, sex, history of smoking and alcohol consumption, WC, SBP, serum TC and HbA1c level, eGFR and duration of DM (95% CI: 1.205– 6.330, P=0.016).Conclusion: MetS closely correlates with PAD in elderly T2DM patients, though no significant difference has been detected in their metabolic indicators.Keywords: elderly, type 2 diabetes, metabolic syndrome, peripheral arterial disease

Shuoning Song,1 Yanbei Duo,1 Yuemei Zhang,2 Xiaolin Qiao,3 Jiyu Xu,4 Jing Zhang,5 Zhenyao Peng,6 Yan Chen,3 Xiaorui Nie,3 Qiujin Sun,7 Xianchun Yang,7 Ailing Wang,8 Wei Sun,4 Yong Fu,1 Yingyue Dong,1 Zechun Lu,8 Tao Yuan,1 Weigang Zhao1 1Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Obstetrics, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 3Department of Obstetrics, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 4Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Laboratory, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 6Department of Dean’s Office, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 7Department of Clinical Laboratory, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 8National Center for Women and Children’s Health, China CDC, Beijing, People’s Republic of ChinaCorrespondence: Tao Yuan; Weigang Zhao Email t75y@sina.com; xiehezhaoweigang@163.comObjective: To evaluate the association of hepatic steatosis index (HSI) in the first trimester and the risk of gestational diabetes mellitus (GDM) as well as large for gestational age (LGA) infant in Chinese women.Methods: A total of 1082 pregnant women were included in this study. Maternal basic laboratory data, including ALT, AST, FBG, insulin, TG, and HDL-C, were tested during 6– 12 weeks of gestation and anthropometric characteristics were monitored during gestation. A 75-g oral glucose tolerance test (OGTT) was conducted at 24– 28 weeks of gestation. HSI, nonalcoholic fatty liver disease (NAFLD) liver fat score, triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) and triglyceride-glucose (TyG) index were calculated. Odds ratio with 95% confidence interval for subsequent risk of GDM and LGA by HSI quartiles were assessed by binary logistic regression model. The predictive ability of HSI for GDM and LGA was evaluated by the receiver operating characteristic (ROC) curve analysis and was compared with other indices.Results: The incidence of GDM and LGA were 22.09% (239/1082) and 10.53% (87/826). HSI was higher in GDM group than in NGT group (median, interquartile range: 30.67, 27.20– 35.10 vs 27.98, 25.70– 30.82, P< 0.001). Incidence of GDM was gradually increased with increasing HSI values. Women in the highest HSI quartile had significantly higher risk of LGA delivery than those in the lowest HSI quartile (P< 0.05). The area under the ROC curves of HSI for GDM and LGA were higher than other indices, reaching 0.646 (95%CI: 0.605– 0.686) and 0.600 (95%CI: 0.541– 0.660), respectively.Conclusion: Higher HSI was independently associated with higher risk of GDM and LGA in Chinese women. HSI in the first trimester can predict the risk of GDM and LGA.Keywords: hepatic steatosis index, nonalcoholic fatty liver disease, gestational diabetes mellitus, large for gestational age infant

Luyao Zhang,&ast; Shujuan Dong,&ast; Wenbo Zhao, Jingchao Li, Luqian Cui, Yongmei Han, Yingjie Chu Department of Cardiology, Henan Provincial People’s Hospital, Zhengzhou, Henan Province, 450003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingjie Chu Email Chuyingjie59@163.comBackground: This study determined the ischaemic J wave pattern associated with ventricular fibrillation (VF).Methods: A total of 262 patients diagnosed with ST-elevation myocardial infarction (STEMI) were recruited from October 2017 to September 2020. All data were collected and analysed, including baseline characteristics, electrocardiogram (ECG), coronary angiography (CAG), and examination outcomes.Results: There were 193 STEMI patients with J wave elevation but without an ischaemic J wave (NJ group) and 69 patients with an ischaemic J wave; the latter were then subgrouped into early repolarization pattern (ERP; n=62) and Brugada pattern groups (BrP [anteroseptal ERP]; n=7). Univariate and multivariate logistic regression analyses were used to clarify high-risk factors and characteristics of ischaemic J waves. Multivariate logistic regression analysis revealed that an ischaemic J wave (odds ratio [OR], 9.708; 95% CI, 2.570– 36.664; P=0.01) independently predicted VF. In the subgroup analysis, BrP (OR, 31.214; 95% CI, 3.949– 246.742; P=0.001), slur morphology of the ERP (OR, 8.15; 95% CI, 1.563– 42.558; P< 0.05), and the number of leads with an ischaemic J wave > 3 (OR, 16.174; 95% CI, 3.064– 85.375; P=0.001) were significantly associated with VF occurrence after adjusting for multiple variables.Conclusion: An ischaemic J wave is an independent risk factor for VF in STEMI patients. BrP, slur morphology, and > 3 leads with an ischaemic J wave could increase the incidence of VF.Keywords: STEMI, ischaemic J wave, classification, predictor, ventricular fibrillation

Yan Du,1,&ast; Xueru Duan,1,&ast; Murui Zheng,2,&ast; Wenjing Zhao,3,&ast; Jun Huang,4 Lixian Lao,5 Fan Weng,6 Dan-Er Lin,7 Zhenxiao Yang,1 Haiyi Li,1 Xudong Liu,1 Hai Deng5 1Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Guangzhou Center for Disease Control and Prevention, Guangzhou, People’s Republic of China; 3Department of Public Health, Faculty of Medicine, Hokkaido University, Sapporo, Japan; 4Department of Geriatrics, Institute of Geriatrics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Science, Guangzhou, People’s Republic of China; 5Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Science, Guangzhou, People’s Republic of China; 6Guangzhou Yuexiu District Center for Disease Control and Prevention, Guangzhou, People’s Republic of China; 7Guangzhou Baiyun District Center for Disease Control and Prevention, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xudong Liu; Hai Deng Tel +86-20-87330619; +86-20-83827812-10263Email liuxudong@mail.sysu.edu.cn; doctordh@hotmail.comObjective: The effect of dietary factors on OSA remains unclear. This study was to investigate the association of obstructive sleep apnea (OSA) with individual and overall effects of eating habits among adult Chinese.Methods: A total of 9733 participants were selected from the baseline survey of the Guangzhou Heart Study. OSA was ascertained by Berlin Questionnaire. Food consumption was collected using a food frequency questionnaire, and eating patterns were extracted by principal component analysis. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated by the logistic regression model.Results: After adjustment for confounders, fried food intake with ≥ 1/week was associated with an increased risk of OSA (OR: 1.77, 95% CI: 1.37– 2.27), while fruit consumption of ≥ 1/day was associated with a 26% reduced risk of OSA (OR: 0.74, 95% CI: 0.62– 0.88). Three eating patterns were defined and labeled as pattern I, II, and III. Eating pattern III which had higher factor loadings of animal innards, fried food, salted food, carbonate, and non-carbonated beverages was associated with an increased risk of OSA (OR: 1.30, 95% CI: 1.09– 1.55) when comparing the highest with the lowest tertile of pattern score, after adjusting for confounders; every 1-unit increment of pattern III score was associated with an increased risk of OSA (OR: 1.09, 95% CI: 1.04– 1.14). Neither pattern I nor pattern II was observed to be associated with OSA risk.Conclusion: A higher frequency intake of fruits was associated with a reduced OSA risk and a diet with higher levels of consumption of animal innards, fried food, salted food, carbonated beverages, and non-carbonated beverages may increase the risk of OSA.Keywords: obstructive sleep apnea, eating habits, diet, fruits, fried food

Mi Zhang,1 Wei Zhao,2 Shanshan Liu,1 Haichuan Liu,1 Liang Liu,2 Qiling Peng,2 Chengyou Du,1 Ning Jiang3 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2School of Basic Medical Science, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Department of Pathology, Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Chengyou Du; Ning Jiang Email duchengyou@126.com; jiangning@cqmu.edu.cnBackground: The H/ACA small nucleolar ribonucleoprotein (snoRNP) gene family, including GAR1 ribonucleoprotein (GAR1), NHP2 ribonucleoprotein (NHP2), NOP10 ribonucleoprotein (NOP10), and dyskerin pseudouridine synthase 1 (DKC1), play important roles in ribosome biogenesis. However, the potential clinical value of the H/ACA snoRNP gene family in hepatocellular carcinoma (HCC) has not yet been reported.Methods: Bioinformation databases were used to analyze the expression and roles of the H/ACA snoRNP gene family in HCC. Survival analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment pathway (KEGG) analyses were performed using R software. Tumor Immune Estimation Resource (TIMER) was used to analyze the correlation between the expression of the H/ACA snoRNP gene family and immune infiltration in HCC. Finally, immunohistochemistry and Western blotting were performed to verify the protein expression of the H/ACA snoRNP gene family in HCC tissues and adjacent tissues.Results: The expression of the H/ACA snoRNP gene family was significantly increased in HCC samples compared to normal tissues, and the area under the curve (AUC) of GAR1, NHP2, NOP10, and DKC1 was 0.898, 0.962, 0.884, and 0.911, respectively. Increased expression of the H/ACA snoRNP gene family was associated with poor prognosis in HCC patients (Hazard Ratio, HR = 1.44 [1.02– 2.04], 1.70 [1.20– 2.40], 1.53 [1.09– 2.17], and 1.43 [1.02– 2.03], respectively; log-rank P = 0.036, 0.003, 0.014, 0.039, respectively). GO and KEGG analyses showed that co-expressed genes were primarily enriched in ribosome biogenesis. In addition, upregulated expression of H/ACA snoRNP gene family was related to the infiltration of various immune cells and multiple T cell exhaustion markers in HCC patients. Immunohistochemical analysis and Western blotting showed that the protein expression of H/ACA snoRNP gene family was higher in HCC tissues than in adjacent tissues of clinical samples.Conclusion: H/ACA snoRNP gene family expression was higher in HCC tissues than in normal or adjacent tissues and was highly associated with poor prognosis of HCC patients and, therefore, has the potential to serve as diagnostic and prognostic biomarkers for HCC.Keywords: hepatocellular carcinoma, H/ACA snoRNP gene family, diagnosis, prognosis, biomarker

Parallel title: Linchan huaxue yu gongye Fir bark-based activated carbon with high surface area and porosity was prepared from by a two-step method of low-temperature carbonization and KOH high-temperature activation using forestry waste fir bark as precursor, and applied as supercapacitor electrode materials. The central composite design(CCD) and response surface analysis were carried out using alkali carbon ratio and activation temperature as the experimental factors, and the mass specific capacitance at a current density of 0.5 A/g as the response value. The results showed that the specific surface area of fir bark-based activated carbon could reach 1 522 m2/g, and the maximum pore volume could reach 0.84 cm3/g. At the same time, the average pore size was 1.12 nm, and a large number of mesopores and micropores was coexisted. The interaction between the alkali carbon ratio and the activation temperature had significant impact on the capacitance. The optimal preparation process of Chinese fir bark activated carbon was obtained by response surface methodology: alkali carbon ratio of 3, and activation temperature of 605 ℃. The specific capacitance of the carbon material under this condition was 185.7 F/g. The electrochemical performance test of the activated carbon prepared under the optimized conditions indicated that the maximum specific capacitance could reach 188 F/g at 0.5 A/g, and it had a good rate capability(85.1%).

Wenjun Zhao,1 Gang Wang,2 Ping Xu,3 Tingting Wu,3 Binjuan Chen,3 Haijun Ren,2 Xingjie Li1 1Department of Ultrasound, Imaging, Healthy Management Centre, The Second Hospital of Lanzhou University, Lanzhou City, 730000, Gansu Province, People’s Republic of China; 2Department of Neurosurgeon, Neurology, Neurologist, The Second Hospital of Lanzhou University, Lanzhou City, 730000, Gansu Province, People’s Republic of China; 3Department of Ultrasound, Imaging, Ultrasound Centre, The Second Hospital of Lanzhou University, Lanzhou City, 730000, Gansu Province, People’s Republic of ChinaCorrespondence: Xingjie LiDepartment of Ultrasound, Imaging, Healthy Management Centre, The Second Hospital of Lanzhou University, Landa 2 Yard, No. 82, Cuiying Gate, Chengguan District, Lanzhou City, 730000, Gansu Province, People’s Republic of ChinaTel +86-9318942555; +86-13609337887Email LiXingjie723723@163.comObjective: To determine the risk factors associated with the progress of subaneurysmal aorta (SAA) to abdominal aortic aneurysm (AAA) and provide a reference for the prevention of AAA in rural areas.Methods: A total of 747 SAA patients screened by the Health Management Center of the Second Hospital of Lanzhou University from January 2015 to January 2016 were recruited. The ratio of SAA progressing to AAA was observed through 5 years of follow-up. Logistic stepwise regression analysis was performed to analyze the high-risk factors. The relevant clinical prediction model score table (Nom) was made and the C-index and calibration chart were used to verify the prediction ability of the model.Results: Of the 747 patients diagnosed with SAA, 260 developed to AAA, with an incidence of 34.8%. Univariate analysis showed that age (62– 65 years old), abdominal aorta diameter greater than 2.7 cm, smoking after 30 years old, moderate to severe hypertension, and blood pressure variability were the important high-risk factors of SAA progressing to AAA. Logistic regression analysis showed that these factors were statistically significant. The nomogram of clinical prediction model score showed that when 50– 60% of SAA developed to AAA, the score was 189– 201 and the C-index was 0.883, verifying the moderate predictive ability of this model.Conclusion: Age, smoking habit, degree of hypertension, and control situation were high-risk factors associated with the progression of SAA to AAA. The control of the above high-risk factors was imperative for the prevention of AAA in rural areas without sufficient medical resources.Keywords: abdominal aortic aneurysm, high-risk factors, abdominal aorta dilation, rural areas

Yiwen Guo,1– 3,&ast; Weixin Luo,1– 3,&ast; Shanzhou Huang,4,&ast; Wenting Zhao,5 Huadi Chen,1– 3 Yihao Ma,1– 3 Maodong Ye,1– 3 Yu Nie,1– 3 Yixi Zhang,6 Changjun Huang,1– 3 Qi Zhou,7,8 Xiaoshun He,1– 3 Maogen Chen1– 3 1Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, People’s Republic of China; 3Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, People’s Republic of China; 4Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 5School of Traditional Chinese Medicine, Southern Medical University, Guangdong, Guangzhou, 510515, People’s Republic of China; 6Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100005, People’s Republic of China; 7Department of General Surgery, Hui Ya Hospital of The First Affiliated Hospital, Sun Yat-sen University, Huizhou, Guangdong, 516081, People’s Republic of China; 8Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Maogen Chen; Xiaoshun HeOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, People’s Republic of ChinaTel +86-18122731962; +86-20-87306082Fax +86-20-87306082Email gdtrc@163.com; chenmg3@mail.sysu.edu.cnIntroduction: Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Identifying specific molecular markers that can predict HCC prognosis is extremely important. The protein deoxythymidylate kinase (DTYMK) has been reported to contribute to unfavorable prognosis in non-small cell lung cancer patients, but its role in the prediction of HCC patient prognosis has not been clarified.Methods: Samples from the TCGA and GEO databases were consecutively enrolled for gene expression analysis, clinicopathology analysis, immune microenvironment analysis and chemotherapeutic response prediction. The results were validated using 86 samples from the First Affiliated Hospital of Sun Yat-sen University. Cox regression analysis was used to analyze the effect of DTYMK on progression-free survival (PFS) and overall survival (OS). Functional enrichment analysis was used to describe the marker pathways that were significantly related to DTYMK. TIMER (Tumor Immune Estimation Resource), TISIDB (Tumor and Immune System Interaction DataBase) and CIBERSORT (Cell type Identification By Estimating Relative Subsets Of RNA Transcripts) were used to explore the immune microenvironment.Results: We found that DTYMK expression upregulation is associated with poor prognosis in HCC patients and tightly related to the pathways regulating the cell cycle and acid metabolism. Our findings revealed that hepatocellular carcinoma cell lines with high DTYMK expression were more sensitive to sorafenib and many other chemotherapeutic drugs. We also found an inhibiting effect of DTYMK on the immune microenvironment in the process of tumorigenesis.Discussion: We found that DTYMK has potential as a new prognostic and chemotherapeutic response biomarker for HCC patients and correlates with the immune microenvironment in HCC. However, there are some deficiencies in our study. First, this is a retrospective study that may lead to selection bias. Second, the protein expression of DTYMK was investigated via immunohistochemical analysis. Finally, we did not explore the exact underlying molecular mechanisms of DTYMK in tumorigenesis in this study, which is needed to be clarified in future research.Keywords: hepatocellular carcinoma, DTYMK, cell cycle, immune infiltration, TCGA

Hu Lin,1,&ast; Qin Wang,1,2,&ast; Fangfang Tian,1 Rui Zhang,1 Mi Mu,1 Weiguo Zhao,1 Pengtao Bao1,2 1Department of Pulmonary and Critical Care Medicine, The Eighth Medical Center of Chinese PLA General Hospital, Pulmonary and Critical Care Medicine College, Chinese PLA General Hospital, Beijing, 100093, People’s Republic of China; 2Graduate School, Department of Clinical Medicine, Hebei North University, Zhangjiakou, 075000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pengtao Bao; Weiguo ZhaoDepartment of Pulmonary and Critical Care Medicine, The Eighth Medical Center of Chinese PLA General Hospital, Pulmonary and Critical Care Medicine College, Chinese PLA General Hospital, 17th, Heishanhu Road, Haidian District, Beijing, 100093, People’s Republic of ChinaTel +86-105-5473141Fax +86-105-5473181Email pangye846574808@163.com; gulie998516@163.comBackground: We aimed to explore the efficacy and tolerance of drug-eluting beads bronchial arterial chemoembolization (DEB-BACE) treatment in relapsed/refractory small cell lung cancer (SCLC) patients.Methods: Eleven relapsed/refractory SCLC patients were enrolled and treated with DEB-BACE. Then, treatment response and tumor marker levels were assessed at the first, second and sixth month post treatment. Quality of life was assessed by the EORTC QLQ-C30 scale. Progression-free survival (PFS) and overall survival (OS) were also evaluated.Results: At the first, second and sixth month post treatment, the objective response rates were 63.6%, 54.5%, and 36.4%, respectively; and the disease control rates were 90.9%, 90.9% and 54.5%, respectively. In addition, the neuron-specific enolase (NSE) and progastrin-releasing peptide levels were reduced at the second and sixth month. Quality of life assessed by EORTC QLQ-C30 scale, which included subscales of general health status, functional domains, symptom domains, and single domains except for financial difficulty, was markedly improved at second month post treatment. Median values of PFS and OS were 5.1 (95% CI: 4.1– 5.9) months and 9.0 (95% CI: 6.0– 12.0) months, respectively. The ECOG score and preoperative NSE level were independent predictive factors for PFS, and age as well as lesion location were independent predictive factors for OS. Adverse events were all mild and manageable with chest pain and chest stuffiness the most common ones.Conclusion: DEB-BACE could be a therapeutic option for relapsed/refractory SCLC patients regarding its favorable treatment response, quality of life, survival benefit and safety profile.Keywords: small cell lung cancer, drug-eluting beads bronchial arterial chemoembolization, treatment response, survival, adverse events

Yi Zheng,1 Pan-Pan Ye,2 Yue Zhou,1 Su-Ying Wu,3 Xi-Ting Liu,1 Bin Du,1 Bo-Hao Tang,1 Min Kan,1 Ai-Qing Nie,1 Rui Yin,1 Meng Wang,1 Guo-Xiang Hao,1 Lin-Lin Song,2 Xin-Mei Yang,2 Xin Huang,2 Le-Qun Su,2 Wen-Qi Wang,2 John van den Anker,4– 6 Wei Zhao1,2 1Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China; 2Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, 250014, People’s Republic of China; 3Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 4Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC, USA; 5Departments of Pediatrics, Pharmacology & Physiology, Genomics & Precision Medicine, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA; 6Department of Paediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, University of Basel, Basel, SwitzerlandCorrespondence: Wei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of ChinaEmail zhao4wei2@hotmail.comPurpose: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis.Methods: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9– 42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2.Results: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age.Conclusion: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.Keywords: CYP3A activity, ontogeny, inflammation, pharmacokinetic, mice

Wenjuan Yan,1,&ast; Qi Zhang,1,&ast; Yingjie Zhu,1 Nan Jing,1 Youhua Yuan,1 Yi Zhang,2 Siying Ren,3 Dongmei Hu,4 Wenmin Zhao,5 Xiaojuan Zhang,6 Caiqin Shi,7 Meiyun Wang,8 Yi Li1 1Department of Clinical Microbiology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, People’s Republic of China; 2Department of Clinical Laboratory, Zhengzhou Central Hospital, Affiliated to Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Clinical Laboratory, Kaifeng People’s Hospital, Kaifeng, Henan, People’s Republic of China; 4Department of Clinical Laboratory, Zhumadian First People’s Hospital, Zhumadian, People’s Republic of China; 5Department of Clinical Laboratory, Kaifeng Central Hospital, Kaifeng, Henan, People’s Republic of China; 6Department of Clinical Laboratory, Gongyi People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 7Department of Microbiology Laboratory, KingMed Diagnostics, Zhengzhou, Henan, People’s Republic of China; 8Department of Medical Imaging, Henan Provincial People’s Hospital & the People’s Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi LiDepartment of Clinical Microbiology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, People’s Republic of ChinaTel +86 159 39039006Email liyilabmed@henu.edu.cnPurpose: To evaluate polymyxin-resistant Klebsiella pneumoniae and Escherichia coli prevalence and characteristics in the Henan province, China.Materials and Methods: A total of 2301 bacterial isolates collected at six hospitals were assessed. Their response to polymyxin was evaluated by minimum inhibitory concentration (MIC) analysis, and the mobilized colistin resistance (mcr) and carbapenemase gene were explored. Mutations on mgrB, phoPQ, pmrAB, and crrAB in polymyxin-resistant K. pneumoniae were detected by PCR. phoP, phoQ, pmrK, pmrA, pmrB, and pmrC transcriptional levels were quantified by RT-qPCR. Pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing were performed to determine the phylogenetic relationship between the polymyxin-resistant isolates.Results: Of the E. coli and K. pneumoniae isolates identified, 0.3% and 1.4% were polymyxin-resistant, respectively, with MICs of 4– 64 μg/mL. All polymyxin-resistant isolates were susceptible to tigecycline. Four E. coli isolates were mcr-1-positive and one was carbapenem-resistant, carrying blaNDM-5 and mcr-1. One K. pneumoniae isolate was mcr-1-positive and nine were carbapenem-resistant (PRCRKP), carrying blaKPC-2 but not mcr-1. The five E. coli isolates belonged to four sequence types (ST2, ST132, ST632, and ST983). All PRCRKP isolates belonged to ST11. However, all 16 isolates belonged to different PFGE types with < 95% genetic similarity. Insertion sequences in mgrB were detected in nine (81.8%) polymyxin-resistant K. pneumoniae samples. Colistin resistance was linked with pmrHFIJKLM operon upregulation, with phoP, phoQ, and pmrK being overexpressed in all but one of the polymyxin-resistant K. pneumoniae samples. Furthermore, 33.3% of patients carrying polymyxin-resistant isolates had previously used polymyxin, and 66.7% patients displayed good clinical outcomes.Conclusion: The K. pneumoniae polymyxin resistance rate was slightly higher than that of E. coli and mcr-1 was more common in E. coli than in K. pneumoniae. Moreover, the insertion of ISkpn14 into mgrB may be the main contributor to polymyxin-resistance in K. pneumoniae in Henan.Keywords: polymyxin, Escherichia coli, Klebsiella pneumoniae, mcr, Henan province

Although the concept of Luttinger liquid (LL) that describes a one-dimensional (1D) interacting fermion system collapses in higher dimensions, it has been proposed to be closely related to many mysteries including the normal state of cuprate superconductor, unconventional metal, and quantum criticality. Therefore, the generalization of LL model to higher dimensions has attracted substantial research attention. Here we systematically investigate the electronic structure of a quasi-2D compound {\eta}-Mo4O11 using high-resolution angle-resolved photoemission spectroscopy and ab-initio calculation. Remarkably, we reveal a prototypical LL behavior originating from the crossing quasi-1D chain arrays hidden in the quasi-2D crystal structure. Our results suggest that {\eta}-Mo4O11 materializes the long sought-after crossed LL phase, where the orthogonal orbital components significantly reduce the coupling between intersecting quasi-1D chains and therefore maintain the essential properties of LL. Our finding not only presents a realization of 2D LL, but also provides a new angle to understand non-Fermi liquid behaviors in other 2D and 3D quantum materials.

Haibo Zhang, Wei Zhao Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Haibo Zhang Email zhb840211@163.comObjective: Epithelial ovarian cancer (EOC) is one of the leading causes of death worldwide. The aim of this study was to explore the prognostic significance of prolyl-4-hydroxylase α subunit 2 (P4HA2) in patients with EOC.Patients and Methods: A total of 217 clinical samples (EOC tissues, 167 cases; normal ovarian, 50 cases) were collected and pathologically confirmed using hematoxylin and eosin (H&E) staining. P4HA2 expression in clinical samples was stained by immunohistochemistry (IHC). Relationship between P4HA2 expression and clinicopathological characteristics of EOC patients were analyzed using chi-square test. The differential expression of targets was analyzed in Oncomine database. The prognostic value of P4HA2 was investigated in clinical EOC patients and Kaplan–Meier (KM) Plotter database.Results: IHC staining showed that P4HA2 was significantly up-regulated in EOC tissues, compared to the normal tissues. Two databases retrieved from Oncomine database further confirmed the up-regulation P4HA2 in EOC. Chi-square test demonstrated that P4HA2 expression was associated with clinical stage (p=0.036), tumor grade (p< 0.001), and residual disease (p=0.022). Both in clinical samples and KM Plotter database, high P4HA2 expression was significantly associated with worse progression-free survival (PFS) and overall survival (OS). Cox’s proportional hazards regression analysis suggested that high P4HA2 expression were independent risk factors for the survival of EOC patients. Besides, we confirmed the positive correlation between P4HA2 and COL1A1 expression. Moreover, COL1A1 was found to be up-regulated in EOC and also associated with short PFS and OS.Conclusion: The present study preliminarily proved that P4HA2 expression was associated with clinical outcome in EOC patients. P4HA2 might be a prognostic factor for EOC progression, and has the potential to be a valuable therapeutic target for EOC.Keywords: P4HA2, prognosis, epithelial ovarian cancer, extracellular matrix, collagen

Huixian Zhang,1– 3 Wencheng Zhao,1,2 Xingya Li,3 Yayi He1,2 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Tongji University, Shanghai, 200433, People’s Republic of China; 3Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, 450052, People’s Republic of ChinaCorrespondence: Yayi HeDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of ChinaTel +86-13818828623Email 2250601@qq.comXingya LiDepartment of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, 450052 Tel +86-13838253946Email fcclixy1@zzu.edu.cnAbstract: Checkpoint-based immunotherapies, such as programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors, have shown promising clinical outcomes in many types of cancers. Unfortunately, the response rate of immune checkpoint inhibitors is low. It is very important to discover novel therapeutic targets and prognostic biomarkers. Cholesterol metabolism has been demonstrated to be related to the occurrence and development of a variety of tumors and may provide a new breakthrough in the development of immunotherapy. First of all, cholesterol metabolism in the tumor microenvironment affects the function of tumor-infiltrating immune cells. In addition, intracellular cholesterol homeostasis is an important regulator of immune cell function. Furthermore, drugs that act on cholesterol metabolism affect the efficacy of immunotherapy. What is more, peripheral blood cholesterol level can be a biomarker to predict the efficacy of immunotherapy. In this review, we aimed to explore the potential role of cholesterol metabolism on immunotherapy. By summarizing the major findings of recent preclinical and clinical studies on cholesterol metabolism in immunotherapy, we suggested that cholesterol metabolism could be a potential therapeutic target and a prognostic biomarker for immunotherapy.Keywords: cholesterol metabolism, immunotherapy, immune cell, therapeutic target, biomarker

Xiangqian Guan, Yuyan Lu, Heping Zhu, Shuqi Yu, Wenxiu Zhao, Xiaoqin Chi, Chengrong Xie, Zhenyu Yin Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, People’s Republic of ChinaCorrespondence: Chengrong Xie; Zhenyu YinDepartment of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, 209 South Hubin Road, Xiamen, Fujian Province, 361004, People’s Republic of ChinaEmail eason_xiecr@126.com; yinzy@xmu.edu.cnBackground: Emerging evidences have highlighted the roles of neutrophils, as the major host microenvironment component, in the development of hepatocellular carcinoma (HCC). Neutrophils extracellular traps (NETs) produced in the infection can strengthen the behavior of cancer metastasis. Here, we investigatedthe roles of NETs in HCC metastasis and further explore the underlying mechanism of how NETs interact with cancer.Methods: The neutrophils were isolated from whole blood of HCC patients and used to evaluate the formation of NETs. NET markers were detected in tissue samples, plasma and cell climbing slice. Mouse models were used to evaluate the roles of NETs in HCC metastasis in vivo, and the corresponding mechanisms were explored using in vivo and in vitro assays.Results: An increase in the release of NETs in patients with HCC, particularly those with portal vein tumor thrombosis (PVTT). The presence of NETs in HCC tumor tissues closely correlated with a poor prognosis. Functionally, the invasion ability of HCC cells was enhanced by co-culture with HCC neutrophils, through NETs formation, while the neutrophils from a healthy donor (HD) exhibited the inhibition of the invasion ability. Furthermore, we observed an enhanced ability of forming NETs in neutrophils from HCC patients in vitro, especially patients with PVTT or extra-hepatic metastasis. An in-vivo animal study demonstrated that neutrophils of HCC facilitated the metastatic behavior towards the lung. The further mechanistic investigation unveiled that HCC cells-derived cytokine IL-8 triggered NETs formation in an NADPH oxidase-dependent manner, and NETs-associated cathepsin G (cG) promoted HCC metastasis in vitro as well as vivo. Clinically, the expression of the cG protein in tumor tissues displayed a close correlation with the disease prognosis of HCC patients.Conclusion: Our findings implicated that the induction of NETs by HCC cells is a critical metastasis-supporting cancer–host interaction and that NETs may serve as an immune-based potential therapeutic target against HCC progression.Keywords: hepatocellular carcinoma, neutrophils extracellular traps, cathepsin G, IL-8, E-cadherin, metastasis, NADPH

Yue Zhou,1 Ai-Qing Nie,1 Shang Chen,2 Meng-Meng Wang,1 Rui Yin,1 Bo-Hao Tang,1 Yue-E Wu,1 Fan Yang,1 Bin Du,1 Hai-Yan Shi,3 Xin-Mei Yang,3 Guo-Xiang Hao,1 Xiu-Li Guo,4 Qiu-Ju Han,5 Yi Zheng,1,* Wei Zhao1,3,* 1Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Institute of Biochemical and Biotechnological Drug, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 4Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 5Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Zheng; Wei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, No. 44, Wenhua West Road, Jinan, Shandong Province, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhengyi@sdu.edu.cn; zhao4wei2@hotmail.comPurpose: Considering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL.Subjects and Methods: ALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).Results: Plasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway.Conclusion: Inflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments.Keywords: disease-induced pharmacokinetic change, renal transporters, inflammatory cytokines, clearance

Hao Wang,1,2 Shanhao Chen,1 Die Meng,1,2 Chunyan Wu,3 Junjie Zhu,4 Minlin Jiang,1,2 Jing Ning,1,2 Shengyu Wu,1,2 Lijia Wu,5 Jingjie Li,5 Bin Chen,1 Sha Zhao,1 Wei Li,1 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Yayi He,1 Caicun Zhou1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 2Medical School, Tongji University, Shanghai, 200433, People’s Republic of China; 3Pathology Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 4Surgery Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 5Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, 214104, People’s Republic of ChinaCorrespondence: Yayi He; Caicun ZhouDepartment of Medical Oncology, Shanghai Pulmonary Hospital, No. 507 Zhengmin Road, Shanghai, People’s Republic of ChinaTel +86 13818828623; Tel +86 13818828623Email 2250601@qq.com; caicunzhoudr@126.comIntroduction: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies.Methods: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics.Results: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes.Conclusion: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.Keywords: lung adenocarcinoma, EGFR mutation, tumor mutation burden, immune phenotype, immune checkpoint blockade

Qingpeng Song,1,* Bin Zhu,2,* Wenkui Zhao,3,* Chen Liang,3 Bao Hai,1 Xiaoguang Liu1 1Department of Orthopaedics, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Pain Medicine Center, Peking University Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoguang LiuDepartment of Orthopedics, Peking University Third Hospital, Beijing, People’s Republic of ChinaEmail liuxgspine@126.comPurpose: Compare the efficacy of full-endoscopic lumbar decompression surgery (FELDS) and open decompression and fusion surgery (ODFS) for lumbar spinal stenosis (LSS).Patients and Methods: A retrospective analysis of 358 LSS patients treated by FELDS (“FELD” group) or ODFS (“open” group) was undertaken. There were 177 patients in the FELDS group with a mean age of 65.47± 9.26 years and 181 patients in the open group with a mean age of 64.18± 10.24 years. Duration of follow-up was 38.63± 11.88 months in the FELDS group and 38.56± 12.29 months in the open group. Visual analog scale (VAS) score, Oswestry Disability Index (ODI), and Modified MacNab criteria were used to access clinical outcomes. Surgical outcomes (duration of surgical procedure, blood loss, complications, duration of postoperative hospital stay (DOPHS), prevalence of revision procedures) were evaluated. Magnetic resonance imaging was used to evaluate the change in the Pfirrmann grade at adjacent segments.Results: VAS score (leg and back) and ODI improved significantly in both groups (P< 0.001). Success rate reached 86.55% and 90.60% in the FELDS group and open group (P> 0.05), respectively. Procedure duration (84.12 vs 112.08 min), blood loss (7.97 vs 279.67 mL), and DOPHS (2.68 vs 4.78 days) of the FELDS group were significantly better than those of the open group (P< 0.05). Total prevalence of complications and procedure revisions was 14.69% and 10.73% in the FELD group, respectively, but did not show a significant difference with that in the open group (12.15% and 9.39%, respectively). The Pfirrmann grade increased in 13.04% of adjacent segments in the FELDS group, significantly better than that in the open group (32.67%) (P< 0.05).Conclusion: FELDS had the same efficacy as ODFS for LSS treatment. FELDS had the advantages of minimal invasiveness, less surgical trauma, rapid recovery, and lower risk of degeneration of adjacent segments compared with that of ODFS.Keywords: lumbar spinal stenosis, full-endoscopic lumbar decompression, fusion, clinical outcome, adjacent segments degeneration

Li Zhang,1,* Xin-Mei Yang,2,* Jing Chen,3 Lei Hu,4 Fan Yang,5 Yue Zhou,5 Bei-Bei Zhao,1 Wei Zhao,2,5,* Xiao-Fan Zhu1,* 1Department of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People’s Republic of China; 2Department of Clinical Pharmacy, Clinical Trial Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People’s Republic of China; 3Pediatric Hematology & Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin, People’s Republic of China; 5Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Fan ZhuDepartment of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People’s Republic of ChinaTel/Fax +86 22 2390 9001Email xfzhu@ihcams.ac.cnWei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, No. 44, Wenhua West Road, Jinan, Shandong Province, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhao4wei2@hotmail.comBackground: An oral tetra-arsenic tetra-sulfide (AS4S4) formula has been recommended as an outpatient post-remission treatment for Chinese adults with acute promyelocytic leukemia (APL) but limited data are available for children. In this exploratory study, we aimed to evaluate the pharmacokinetics and safety of the AS4S4 formula in children.Methods: Eleven newly diagnosed and one relapsed pediatric patient (4– 14 years of age) treated with the AS4S4 formula were included. Blood samples were collected from 12 children, and drug concentrations were quantified by ICP-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM software. Toxic effects were graded according to the NCI-CTCAE, Version 3.Results: A total of 107 arsenic concentrations (0.1– 75.0 μg L− 1) were used for population pharmacokinetic analysis. The median (range) of estimated weight-normalized CL and volume distribution at steady-state were 45.26 (35.63– 82.18) L h− 1 kg− 1 and 230.37 (85.96– 495.68) L kg− 1, respectively. No patients discontinued AS4S4 treatment owing to adverse events, and there were no drug-related adverse events over grades 3– 4. All newly diagnosed APL patients were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%.Conclusion: The pharmacokinetics and safety oral AS4S4 formula was evaluated for the first time in pediatric APL. The pharmacokinetic assessment demonstrated that the dosing regimen of 60 mg/kg/d TID resulted in a higher steady-state through concentration in children than that which was achieved in adults. The results of this study indicate that the AS4S4 formula is safe in newly diagnosed pediatric APL patients.Keywords: acute promyelocytic leukemia, Realgar-Indigo Naturalis Formula, pediatric, safety, population pharmacokinetics

The interaction between localized f and itinerant conduction electrons is crucial in the electronic properties of heavy fermion and valence fluctuating compounds. Using high-resolution angle-resolved photoemission spectroscopy, we systematically investigate the electronic structure of the archetypical valence fluctuating compound EuNi2P2 that hosts multiple f electrons. At low temperatures, we reveal the hybridization between Eu 4f and Ni 3d states, which contributes to the electron mass enhancement, consistent with the periodic Anderson model. With increasing temperature, interestingly, we observe opposite temperature evolution of electron spectral function above and below the Kondo coherence temperature near 110 K, which is in contrast to the monotonic valence change and beyond the expectation of the periodic Anderson model. We argue that both f-d hybridization and correlation are imperative in the electronic properties of EuNi2P2. Our results shed light on the understanding of novel properties, such as heavy fermion behaviors and valence fluctuation, of rare-earth transition-metal intermetallic compounds with multiple f electrons.

In this paper, the main aim is to consider the boundedness of the fractional maximal commutator $M_{\alpha,b}$ and the nonlinear commutator $[b, M_{\alpha}]$ on the Lebesgue spaces over some stratified Lie group $\mathbb{G}$ when $b$ belongs to the Lipschitz space, by which some new characterizations of the Lipschitz spaces on Lie group are given., Comment: arXiv admin note: substantial text overlap with arXiv:2205.06529

Recently, many pre-trained language models for source code have been proposed to model the context of code and serve as a basis for downstream code intelligence tasks such as code completion, code search, and code summarization. These models leverage masked pre-training and Transformer and have achieved promising results. However, currently there is still little progress regarding interpretability of existing pre-trained code models. It is not clear why these models work and what feature correlations they can capture. In this paper, we conduct a thorough structural analysis aiming to provide an interpretation of pre-trained language models for source code (e.g., CodeBERT, and GraphCodeBERT) from three distinctive perspectives: (1) attention analysis, (2) probing on the word embedding, and (3) syntax tree induction. Through comprehensive analysis, this paper reveals several insightful findings that may inspire future studies: (1) Attention aligns strongly with the syntax structure of code. (2) Pre-training language models of code can preserve the syntax structure of code in the intermediate representations of each Transformer layer. (3) The pre-trained models of code have the ability of inducing syntax trees of code. Theses findings suggest that it may be helpful to incorporate the syntax structure of code into the process of pre-training for better code representations., Accepted by ICSE 2022 (The 44th International Conference on Software Engineering)

Yuejie Xu,1,* Lei Xu,1,* Weijing Zhao,1 Qing Li,1 Ming Li,1 Wei Lu,1 Hui Zeng,1 Jinhua Yan,2 Daizhi Yang,2 Wei Wu,3 Jianping Weng,2 Jiemin Pan,1 Fang Liu1 1Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, 200233, People’s Republic of China; 2Department of Endocrinology and Metabolic Disease, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China; 3Department of Pediatrics, Tongji Hospital, Wuhan Tongji Medical University, Wuhan, Hubei, 430030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiemin Pan; Fang LiuDepartment of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, 600 Yishan Road, Xuhui District, Shanghai, 200233, People’s Republic of ChinaTel +86-18930173803Email lilypjm@hotmail.com; f-liu@sjtu.edu.cnPurpose: Smartphones have received increasing attention and achieved positive outcomes in diabetes intervention. The widespread use of WeChat in China provides an opportunity for self-management practices in patients with diabetes. Nevertheless, how to combine the strengths of the WeChat platform with traditional medical strategy remains to be explored. This study aimed to evaluate the efficacy of a novel flash glucose monitoring device combined with the WeChat platform in juvenile type 1 diabetes management.Patients and Methods: A total of 60 juvenile patients with type 1 diabetes were randomly assigned into three groups: a blood glucose self-monitoring group (group A), a flash glucose monitoring (group B), and a flash glucose monitoring combined WeChat-interactive management group (group C). The intergroup differences in demographics, biochemical indicators, and questionnaire scores of the Diabetes Monitoring and Treatment Satisfaction Questionnaire and Diabetes Specific Quality of Life assessment were compared at the baseline and after 6 months.Results: After the 6-month intervention, groups B and C showed significantly lower glycated hemoglobin A1c (HbA1c) levels compared to those observed at baseline (both P < 0.05), with the largest decrease observed in group C (group B vs group C, P =0.04). Hypoglycemic episodes per month decreased from baseline in groups B and C (both P < 0.05) and were more significant in group C (P < 0.001). In addition, the DMTSQ scores increased in the 6th month in all groups (all P < 0.05), and the largest rise in scores was found in group C, followed by groups B and A. The DQOL scores in groups B and C decreased significantly from the baseline (both P < 0.05), with no change in group A.Conclusion: Flash glucose monitoring combined with the WeChat-interactive system may help achieve sustained glycemic control and higher satisfaction in patients with juvenile type 1 diabetes.Trial Registration: This study was registered at chictr.org.cn, number ChiCTR1900025495. Registered 29 August 2019.Keywords: WeChat, type 1 diabetes, self-management, glycated hemoglobin A1c

Hao Wang,1,2 Die Meng,1,2 Haoyue Guo,1,2 Chenglong Sun,1,2 Peixin Chen,1,2 Minlin Jiang,1,2 Yi Xu,1,2 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Shengyu Wu,1,2 Sha Zhao,1 Wei Li,1 Bin Chen,1 Lei Wang,1 Yayi He1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Tongji University, School of Medicine, Shanghai, 200433, People’s Republic of ChinaCorrespondence: Yayi HeDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People’s Republic of ChinaTel +86 13818828623Email 2250601@qq.comAbstract: Single-cell sequencing (SCS) which has an unprecedentedly high resolution is an advanced technique for cancer research. Lung cancer still has a high mortality and morbidity. For further understanding the lung cancer, SCS is also been applied to lung cancer research to investigate its heterogeneity, metastasis, drug resistance, tumor microenvironment and many other issues. In this review, we summarized lung cancer research using SCS and their research achievements.Keywords: single-cell sequencing, lung cancer, intratumoral heterogeneity, tumor microenvironment, lung cancer therapy

Weizhu Zhao,1,2 Haiying Yang,3 Jie Chai,4 Ligang Xing1 1Department of Radiology, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, Jinan, 250117, People’s Republic of China; 2Department of Oncology, Binzhou People’s Hospital, Binzhou, 256610, People’s Republic of China; 3Department of Nursing, Binzhou People’s Hospital, Binzhou, 256610, People’s Republic of China; 4Department of Gastrointestinal Surgery, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, Jinan, 250117, People’s Republic of ChinaCorrespondence: Jie ChaiDepartment of Gastrointestinal Surgery, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, No. 440, Jiyan Road, Jinan, 250117, People’s Republic of ChinaTel +86 18678867800Email gu421720jing@163.comLigang XingDepartment of Radiology, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, No. 440 Jiyan Road, Jinan, 250117, People’s Republic of ChinaTel +86 15553181309Email xinglg@medmail.com.cnAbstract: The transcription factor runt-related protein 2 (RUNX2) has an important impact on the transformation of bone marrow mesenchymal stem cells to osteoblasts. Further studies have shown that RUNX2 plays a key role in the invasion and metastasis of cancers. RUNX2 is a “key” molecule in the regulatory network comprised of multiple signaling pathways upstream and its target downstream molecules. Due to the complex regulatory mechanisms of RUNX2, the specific mechanism underlying the occurrence, development and prognosis of malignant tumors has not been fully understood. Currently, RUNX2 as a promising therapeutic target for cancers has become a research hotspot. Herein, we reviewed the current literature on the modulatory functions and mechanisms of RUNX2 in the development of malignant tumors, aiming to explore its potential clinical application in the diagnosis, prognosis and treatment of tumors.Keywords: RUNX2, malignant tumor;, research progress

Xin Jiang,1,* Wenqi Zhao,1,* Tiantian Zhao,2,* Mei Yang,1 Hongbin Yuan,1 Jun Qian,2 Zhenghua Xiang3 1Department of Anesthesiology, Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of General Surgery, Affiliated Xinchang Hospital of Shaoxing University, Zhejiang, People’s Republic of China; 3Department of Neurobiology, Key Laboratory of Molecular Neurobiology, Ministry of Education, Naval Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenghua XiangDepartment of Neurobiology, Key Laboratory of Molecular Neurobiology, Ministry of Education, Naval Medical University, No. 800 Xiangyin Road, Shanghai, 200433, People’s Republic of ChinaTel +86 21 81871044Fax +86 21 81885822Email xiang-zhenghua@163.comJun QianDepartment of General Surgery, Affiliated Xinchang Hospital of Shaoxing University, No. 117 Middle Gushan Road, Xinchang, Zhejiang, 312500, People’s Republic of ChinaTel +86 575 8638079Email qianj001@163.comPurpose: To detect the spatio-temporal expression of S100A4 in a spinal nerve ligation (SNL) rat model. Also to figure out which other molecules directly interact with S100A4 to explore the possible mechanisms which might be involved in neuropathic pain.Methods: Seven-week-old male SD rats were used for the SNL model construction. Immunofluorescence and Western blotting were used to detect the spatio-temporal expression of S100A4 in the model. S100A4 was co-labeled with a number of related molecules and marker molecules that can distinguish between cell types. After intrathecal injection of S100A4 neutralizing antibody, the behavioral changes of SNL rats were recorded, and molecular changes compared. The direct interaction between S100A4 and other related molecules was verified by co-immunoprecipitation (co-IP) to explore its possible mechanism.Results: After spinal nerve ligation, the content of S100A4 in the dorsal root ganglion (DRG) and spinal dorsal horn increased significantly. Intrathecal injection of S100A4 neutralizing antibody could effectively relieve the mechanical pain in rats. co-IP revealed a direct interaction between S100A4 and RAGE.Conclusion: The content of S100A4 in the DRG and spinal dorsal horn of SNL rats increased, compared with that of the control group. Intrathecal injection of S100A4 neutralizing antibody could effectively relieve the mechanical pain in SNL rats. S100A4 may be involved in the production of neuropathic pain through RAGE or other ways, but the specific mechanism needs to be further studied.Keywords: neuropathic pain, S100 calcium binding protein A4, receptor for advanced glycation end products, spinal nerve ligation model

Yali Hu,1,2,* Kunpeng Zhang,1,* Xingyao Zhu,1,* Xiuyan Zheng,1 Chao Wang,1 Xiao Niu,1 Teng Jiang,1 Xinhua Ji,1 Weilin Zhao,1 Lijuan Pang,1 Yan Qi,1 Feng Li,1,3 Li Li,4 Zhiping Xu,4 Wenyi Gu,4 Hong Zou1 1Department of Pathology, The First Affiliated Hospital, School of Medicine, Shihezi University, Key Laboratory of Xinjiang Endemic and Ethnic Diseases of the Ministry of Education of China, Xinjiang, 832002, People’s Republic of China; 2Department of Oncology, Yongcheng People’s Hospital, Henan, 476600, People’s Republic of China; 3Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 10000, People’s Republic of China; 4Australian Institute of Bioengineering and Nanotechnology, University of Queensland, Queensland, 4072, Australia*These authors contributed equally to this workCorrespondence: Hong Zou; Wenyi Gu Tel +86 13899528366; +61733464168Email zouhong_patho@163.com; w.gu@uq.edu.auBackground: Colon cancer is a top lethal cancer in man and women worldwide and drug resistance is the major cause of cancer-related death. Combinational therapy and drug delivery with nanoparticles have been shown to effectively overcome drug resistance in many cancers. We previously reported that nanoemulsion (NE) loaded paclitaxel (PTX) and BEZ235 could synergistically inhibit colon cancer cell growth.Purpose: To investigate whether NE loaded PTX and BEZ235 can overcome drug resistance and synergistically inhibit drug-resistant colon cancer cell growth in vitro and in vivo.Methods: The in vitro treatment effect on cell viability was assayed using CCK8 kit, cell morphological change was detected by β-tubulin immunofluorescence staining, drug resistance-related proteins were analyzed by Western blotting, and in vivo tumor growth test was performed in nude mice xeno-transplanted with 2 drug-resistant colon cancer cell lines HCT116-LOHP and HT29-DDP.Results: Both cell lines were sensitive to PTX but relatively insensitive to BEZ235. PTX combined with BEZ235 synergistically inhibited the proliferation of both cell lines. Nanoemulsion loaded PTX (NE-PTX) reduced the IC50 of PTX to approximately 2/5 of free PTX, indicating a high inhibitory efficacy of NE-PTX. When NE-PTX combined with a low concentration of BEZ235 (50 nM), the IC50 was decreased to approximately 2/3 of free PTX. Moreover, NE-PTX+BEZ235 treatment increased apoptosis, decreased Pgp and ABCC1 expression, and reduced tumor weights compared to the single drug treatment and the control group. These results suggest that nanoemulsion loaded PTX+BEZ235 can overcome drug resistance and improve the inhibitory effect on cancer cell proliferation and tumor growth.Conclusion: Our study thus provides a possible new approach to treat colon cancer patients with drug resistance.Keywords: colon cancer, nanoemulsion, paclitaxel, BEZ235, drug-resistance

Danlei Yu,1,2,* Wen Zhao,2,3,* Karin A Vallega,2 Shi-Yong Sun2 1Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA; 3Department of Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shi-Yong SunDepartment of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, 1365-C Clifton Road, C3088, Atlanta, GA, 30322, USATel +1 (404) 778-2170Fax +1 (404) 778-5520Email ssun@emory.eduAbstract: Although epidermal growth factor receptor (EGFR)-targeted therapy has improved clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) carrying activating EGFR mutations, the development of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), including the promising third-generation ones, results in disease progression and has become an unavoidable problem that limits patient long-term benefit. The third-generation EGFR-TKIs, osimertinib and almonertinib, are now approved for the treatment of advanced NSCLC patients harboring activating EGFR mutations (first-line) and/or the resistant T790M mutation (second-line). Clinically, appropriate management of acquired resistance to third-generation EGFR-TKIs will substantially improve their long-term efficacy against EGFR-mutant NSCLC. Recent preclinical and clinical studies suggest that activation of the Ras/Raf/MEK/ERK signaling pathway may be an important resistance mechanism and accordingly co-targeting this pathway effectively overcomes and abrogates acquired resistance to third-generation EGFR-TKIs. This review focuses on discussing the scientific rationale for and potential of co-targeting MEK/ERK signaling in delaying and overcoming acquired resistance to third-generation EGFR-TKIs, particularly osimertinib.Keywords: acquired resistance, EGFR inhibitors, osimertinib, MEK/ERK, lung cancer

Zhen Wu,1 Wei Zhao,1 Zhen Yang,1 Yue Ming Wang,2 Yu Dai,1 Liang-An Chen1,2 1Respiratory Department of Chinese PLA General Hospital, Beijing, People’s Republic of China; 2School of Medicine, Nankai University, Tianjin, People’s Republic of ChinaCorrespondence: Liang-An Chen IMB 16th Floor, Room 16-104, 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of ChinaTel +86 10-66936184Email chenliangan301@163.comPurpose: Molecular-based targeted therapy has improved life expectancy for advanced non-small cell lung cancer (NSCLC). However, it does not have to be inevitable that patients receiving third-generation EGFR-TKIs become drug resistant. EGFR C797S and MET amplification are common mechanisms of osimertinib. However, a large part of these potential drug mechanisms remains unknown, and further research is needed.Methods: Tumour and blood samples from forty advanced NSCLC patients were identified as acquired drug resistant to osimertinib. The NGS panel was applied to detect EGFR C797S and MET amplification in tumour tissues or plasma samples. Whole-exome sequencing was conducted in five pairs of tumour tissues obtained before osimertinib administration and after osimertinib resistance in patients without C797S/cMET amplification.Results: The overall C797S mutation rate was 20%, and MET amplification was detected in six out of sixteen C797S-negative samples. PDGFRA in the PI3K-AKT-mTOR signalling pathway, RASAL2, RIN3 and SOS2 in the RAS-Raf-ERK signalling pathway, PTK2 in the ERBB signalling pathway and ABCC1 and ABCB5 in the ABC membrane pump system were identified as candidate crucial genes of drug resistance to osimertinib.Conclusion: EGFR C797S mutation and MET amplification are leading mechanisms for osimertinib resistance in lung cancer. The crucial potential mutated genes defined in our present study may need further validation in a considerable number of lung cancer patients.Keywords: osimertinib, drug resistance, whole-exome sequencing, lung cancer, targeted therapy

Wancheng Zhao, Qing Yang Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Qing Yang Email Yangqing_sj@126.comObjective: To explore the relationship between laparoscopic radical hysterectomy (LRH) and cervical cancer lymph-vascular space invasion (LVSI) by comparing the prevalence of LVSI in cervical cancer patients who underwent LRH versus open radical hysterectomy (ORH).Methods: The study participants were 1087 cervical cancer patients (FIGO 2009 stages IA2-IIA2) with pathologically confirmed with or without LVSI who underwent radical hysterectomy at Shengjing Hospital of China Medical University from 2013 through 2018. The patients were divided according to the type of surgical procedure into an LRH group (n=148) and an ORH group (n=939).Results: In the LRH group, 31.76% of patients (47/148) had LVSI-positive tumors compared to 33.23% of patients (312/939) in the ORH group; the difference was not significant (p=0.724). No between-group differences in LVSI prevalence according to lymph node metastasis, interstitial infiltration depth, differentiation degree, and parametrial infiltration were found. However, the number of LVSI-positive patients whose cervical cancer lesions > 4 cm (stage I B2 and II A2) was significantly higher in the LRH group than in the ORH group (Odds Ratio [OR] 0.333, 95% confidence interval [CI] 0.157– 0.706, p=0.005). The 3-Year disease-free survival (DFS) in the LRH group is lower than that in the ORH group (94.75% vs 97.27%), but there was no significance (P=0.187). Furthermore, the percentage of LVSI-positive tumors in patients with lymph node metastases was significantly higher than those without lymph node metastases (OR 2.897, 95% CI 2.129– 3.942, p=0.000). The 3-Year DFS were 98.22% in the LVSI negative patients and 93.78% in the LVSI positive patients, the difference was significant (P=0.002).Conclusion: A higher risk of lymph node metastasis and a lower 3-Year DFS was found in the LVSI-positive patients. In case of LVSI, it would be dangerous to treat patient in laparoscopy, especially in case of cervical cancer lesions > 4cm.Keywords: laparoscopic, cervical cancer, lymph-vascular space invasion, LVSI, radical hysterectomy

Jianping Liu,1 Weihua Zhao,2 Qinghong Gui,1 Ying Zhang,1 Zaiyu Guo,2 Wei Liu3 1Department of Neurology, Tianjin TEDA Hospital, Tianjin 300457, People’s Republic of China; 2Department of Neurosurgery, Tianjin TEDA Hospital, Tianjin 300457, People’s Republic of China; 3Department of Neurology, Tianjin Medical University General Hospital, Tianjin 300052, People’s Republic of ChinaCorrespondence: Zaiyu GuoDepartment of Neurosurgery, Tianjin TEDA Hospital, No. 65, The Third Avenue, Tianjin Economy Development Area, Tianjin 300457, People’s Republic of ChinaTel +86-15302100230Email guozaiyu_teda@163.comWei LiuDepartment of Neurology, Tianjin Medical University General Hospital, No. 154, An Shan Road, Heping District, Tianjin 300052, People’s Republic of ChinaTel +86-2260362255Email liuweithird@126.comPurpose: To investigate the associations between concentrations of Aβ40 and Aβ42 and vascular cognitive impairment (VCI) in cerebral small vessel disease (CSVD) patients and evaluate the value of combination of levels of Aβ40 or Aβ42 and the total CSVD score in predicting VCI.Patients and Methods: A total of 199 CSVD patients were divided into VCI group and non-VCI group according to the criteria of VCI. Demographic data, MRI markers of CSVD, blood pressure, vascular risk factors, laboratory markers, and serum Aβ40 and Aβ42 concentration were collected. Univariate analysis was performed with the Student’s t-test, Mann–Whitney U-test or Chi-square test. Variables with P< 0.10 in univariate analysis were then included in multivariate analysis that used a backward stepwise logistic regression model. The predictive values were assessed with receiver operating characteristic (ROC) curve.Results: VCI was determined in 112 CSVD patients (56.3%). Hyperlipidemia (OR: 1.618, 95% CI: 1.265– 3.049), the total CSVD score (OR: 1.414, 95% CI: 1.213– 2.278) and serum Aβ42 concentration (OR: 1.401, 95% CI: 1.212– 1.946) were independent risk factors for VCI in CSVD patients with adjustment for age, education years, diabetes and fasting blood-glucose (FBG). The area under curves (AUCs) were 0.640 (SE: 0.040, 95% CI: 0.563– 0.718), 0.733 (SE: 0.035, 95% CI: 0.664– 0.802) and 0.827 (SE: 0.030, 95% CI: 0.768– 0.887), respectively, for the total CSVD score, serum Aβ42 concentration and their combination applied in predicting VCI in CSVD patients. Z test demonstrated that the AUC of combination prediction was significantly higher than individual prediction (0.827 vs 0.640, Z=3.740, P< 0.001; 0.827 vs 0.733, Z=2.039, P=0.021).Conclusion: Combination of Aβ42 and total CSVD score could significantly elevate the predictive value of cognitive impairment in CSVD patients.Keywords: Aβ40, Aβ42, vascular cognitive impairment, cerebral small vessel disease, total cerebral small vessel disease score