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Hao Peng,1,2,* Jixue Li,1,* Xiaoru Zhou,1 Zhewen Nong,1 Ruiying Zhang,1 Pei Lu,1 Shasha Ye,1 Liping Lei,3 Chuang Qin,2 Jiangfa Li1,4,5 1Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, People’s Republic of China; 2Department of Hepatobiliary and Pancreatic Surgery, Liuzhou People’s Hospital, Liuzhou, 545001, People’s Republic of China; 3Department of Geriatric Medicine, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, People’s Republic of China; 4Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China; 5Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chuang Qin, Department of Hepatobiliary and Pancreatic Surgery, Liuzhou People’s Hospital, No. 8, Wenchang Road, Central District, Liuzhou, 545001, People’s Republic of China, Email 382944957@qq.com Jiangfa Li, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, No. 15, Lequn Road, Xiufen District, Guilin, Guangxi, 541001, People’s Republic of China, Email 247546160@qq.comObjective: To explore a more effective and practical comprehensive index for differentiating benign from malignant obstructive jaundice by analyzing the clinical data of patients with benign obstructive jaundice (BJ) group and malignant obstructive jaundice (MJ) group.Methods: A retrospective analysis was conducted on the clinical data of 339 patients with obstructive jaundice. The cases were divided into two data sets: training cohort and validation cohort. The cases were divided into two groups: malignant and benign obstructive jaundice group. Logistic regression analysis was used to build a prediction model for judging the nature of obstructive jaundice, and the prediction model was verified using the validation cohort.Results: Multivariate analysis revealed that CEA, TBIL, and NLR were independent factors in malignant obstructive jaundice. A comprehensive index for differentiating benign from malignant obstructive jaundice was established based on these indicators. The sensitivity, specificity, and receiver operating characteristic curve of this model for differentiating benign from malignant obstructive jaundice were 79.57%, 93.26%, and 0.920, respectively.Conclusion: The prediction model based on the comprehensive index of CEA, TBIL, and NLR has a higher accuracy in differentiating malignant obstructive jaundice.Keywords: obstructive jaundice, comprehensive index, differentiation diagnosis

Xiaobo Li,1,2 Chen Yu,1 Xuewei Liu,3 Yejia Chen,1 Yutian Wang,1 Hongbin Liang,1 ShiFeng Qiu,1 Li Lei,1 Jiancheng Xiu1 1Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Cardiology, Xiangdong Hospital, Hunan Normal University, Liling, Hunan, People’s Republic of China; 3The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Southern Medical University, Dongguan, Guangdong, People’s Republic of ChinaCorrespondence: Jiancheng Xiu, Tel +8613903064940, Email xiujch@163.comObjective: To evaluate the prognostic value of the systemic immune-inflammatory index (SII) for predicting in-hospital major adverse cardiovascular events (MACEs) in patients with acute myocardial infarction (AMI) and establish a relevant nomogram.Methods: This study included 954 AMI patients. We examined three inflammatory factors (SII, platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR)) to see which one predicts in-hospital MACEs better. The predictors were subsequently screened using bidirectional stepwise regression method, and a MACE nomogram was constructed via logistic regression analysis. The predictive value of the model was evaluated using the area under the curve (AUC), sensitivity and specificity. In addition, the clinical utility of the nomogram was evaluated using decision curve analysis. We also compared the nomogram with the Global Registry of Acute Coronary Events (GRACE) scoring system.Results: 334 (35.0%) patients had MACEs. The SII (AUC =0.684) had a greater predictive value for in-hospital MACEs in AMI patients than the PLR (AUC =0.597, P< 0.001) or NLR (AUC=0.654, P=0.01). The area under the curve (AUC) of the SII-based multivariable model for predicting MACEs, which was based on the SII, Killip classification, left ventricular ejection fraction, age, urea nitrogen (BUN) concentration and electrocardiogram-based diagnosis, was 0.862 (95% CI: 0.833– 0.891). Decision curve and calibration curve analysis revealed that SII-based multivariable model demonstrated a good fit and calibration and provided positive net benefits than the model without SII. The predictive value of the SII-based multivariable model was greater than that of the GRACE scoring system (P< 0.001).Conclusion: SII is a promising, reliable biomarker for identifying AMI patients at high risk of in-hospital MACEs, and SII-based multivariable model may serve as a quick and easy tool to identify these patients.Keywords: systemic immune-inflammatory index, major adverse cardiovascular events, inflammation, acute myocardial infarction

Lei Lei, Ke Wang Henan Provincial Chest Hospital, Zhengzhou, 450008, Henan, People’s Republic of ChinaCorrespondence: Ke Wang, Email 13837178129@163.comBackground: Preserving nephrons while avoiding tumor recurrence during the treatment of renal cell carcinoma remains as a challenge in clinic. To achieve desired therapeutic outcome, we developed specific nanozymes based on the tumor microenvironment and evaluated its efficacy in combination with radiotherapy.Methods: Herein, a hybrid nanozyme CeO2@Au-PEG nanocomposite nanoparticle (NPs) was developed for the treatment of renal tumor. It was composed of gold nanozyme decorated CeO2 nanorods and exhibited both glucose-oxidase like by gold nanozyme and peroxidase-like catalytic activities. Due to the high metabolic rate of tumor cells, they take up a huge amount of glucose to survive and proliferate. Therefore, we generated CeO2@Au-PEG NPs, which exhausted glucose in the tumor tissue and generated hydrogen peroxide, depleting the source of energy and causing tumor cell death. Then the generated hydrogen peroxide was degraded by the peroxidase-mimicking properties of CeO2@Au-PEG NPs, elevating oxidative stress and thus enhancing tumor cell death. Moreover, due to the high mass nuclei of gold and cerium, they could further sensitize the tumors to radiotherapy and thus thoroughly eliminate tumors.Results: With enough biocompatibility, CeO2@Au-PEG NPs showed superior ability to deplete glucose as well as enhance oxidative stress by producing reactive oxygen species in RENCA cells under ionizing irradiation. Moreover, CeO2@Au-PEG NPs greatly improved radiotherapy mediated tumor ablation in tumor bearing mice.Conclusion: Systematic experiments demonstrated the synergistic therapeutic effects of the combination of CeO2@Au-PEG NPs and radiotherapy in renal tumor model, which may serve as a promising strategy for treating renal cancer patients in the clinic.Keywords: nanozyme, radiotherapy, glucose consumption, reactive oxygen species, renal cell carcinoma

Liping Lei,1,2,&ast; Jingjing Yang,1,&ast; Hao Peng,1 Ruiyan Huang,1 Lichun Liang,1 Ruifang Liu,1 Jiangfa Li1 1Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, People’s Republic of China; 2Department of Geriatric Medicine, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiangfa Li, Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, People’s Republic of China, Tel +86-7732824373, Email 247546160@qq.comBackground: Abnormal expression of genes causes tumorigenesis, tumor progression, and poor prognosis in hepatocellular carcinoma (HCC). Therefore, the aims of this study were to explore the transcription enhancer domain factor 4 (TEAD4) in patients with liver cancer and its relationship with prognosis.Methods: HTSeq-FPKM data and corresponding clinical data of HCC patients were obtained from The Cancer Genome Atlas (TCGA). Difference in TEAD4 expression between normal and tumor and the correlation with clinical characteristics were analyzed by the chi-squared test based on UALCAN. HepG2 cell lines were used to study the effect of TEAD4 on HCC cell lines. The expression and clinical significance of TEAD4 in HCC were detected in clinical cases.Results: The transcription and post-transcription levels of TEAD4 were higher in HCC tumors than normal illustrated different expressed transcription of TEAD4 in gender, nodal metastasis status, tumor grades, and individual cancer stages. The high TEAD4 expression was significantly associated with tumor grades. The high expression of TEAD4 was significantly correlated to shorter 2– 5 years overall survival. Inhibition of TEAD4 expression in HepG2 cells resulted in significantly decreased cell proliferation and invasion.Conclusion: TEAD4 was identified as an independent prognostic factor, and inhibition of TEAD4 expression in HepG2 cells resulted in significantly decreased cell proliferation and invasion.Keywords: TCGA, TEAD4, hepatocellular carcinoma

Xuan Zhong,1,&ast; Nongping Feng,2,&ast; Binfa Ouyang,1 Dan Zhao,1 Lin Lei,3 Ji Peng,3 Xiaolin Peng1 1Department of Oncology, Injury and Nutrition, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, Guangdong Province, People’s Republic of China; 2Department of Non-Communicable Disease Prevention and Control, Shenzhen Longgang Center for Chronic Disease Control, Shenzhen, Guangdong Province, People’s Republic of China; 3Department of Cancer Prevention and Control, Shenzhen Center for Chronic Disease Control, Shenzhen, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaolin Peng, Department of Oncology, Injury and Nutrition, Shenzhen Nanshan Center for Chronic Disease Control, No. 7, Huaming Road, Nanshan District, Shenzhen, Guangdong Province, People’s Republic of China, Tel +86-0755-26640203, Email 25731738@qq.comAim: The rising incidence and death rate of colorectal cancer (CRC) have posed a severe danger to the lives and health of residents. Individuals at high risk of CRC are drawing growing attention as the majority of the population impacted by CRC. Hence, it is imperative to examine the detection rates and modifiable factors affecting the populations at high risk for CRC in Shenzhen.Methods: The multi-stage stratified cluster sampling method was used to select residents aged 45– 74 years old from September 2020 to December 2021. The community-based CRC screening was attended by a total of 30,921 residents from urban and suburb regions. The association between modifiable risk factors and the detection rate of high-risk groups was analyzed using multinomial logistic regression with the inverse probability treatment weighting (IPTW) based on the propensity score.Results: The cross-sectional analysis included 24,613 people after excluding 6308 people who had missing or invalid fecal occult blood test (FOBT) results. The detection rate for high-risk groups during CRC screening was 28.50%. Higher rate of high-risk groups was detected among those who were male, aged 60 or above, college or above, other marital status, and living in urban (P < 0.05). Demographic characteristics after IPTW showed a weak correlation coefficient with the detection rate of CRC high-risk both in high-risk and general-risk groups (SMD < 0.1), suggesting a balanced group of participants. The results of logistic regression with IPTW indicated that smoking, drinking, obesity, lack of exercise, vegetable or fruit eating infrequently, red meat, processed meat, cereal food and their clustering status were more inclined to be risk indicators of CRC (P < 0.05).Conclusion: The detection rate for high-risk CRC groups was comparatively high in Shenzhen. The distribution characteristics of lifestyle and dietary risk factors of high-risk groups should be given consideration when adopting individualized intervention measures and comprehensive prevention and control strategies.Keywords: modifiable risk factors, colorectal cancer, high-risk group, propensity score method

Reliable estimations of the relative permeability of gas and water in hydrate-bearing sediments (HBS) and the dependency of the relative permeability on hydrate saturation are critical to predict the productivity of a hydrate reservoir. Yet, this remains poorly estimated owing to lack of experimental data associated with difficulties in conducting multiphase flow experiments in HBS. Recognizing the experimental challenges, this study intends to develop and validate a new experimental system and procedure of unsteady-state relative permeability test that can generate reliable and reproducible flow measurements in HBS. Gas hydrate is considered as a part of solid matrix in the sediment, so one of the challenges is to maintain a constant hydrate saturation, which is achieved in this experimental study using tight pressure-temperature (P-T) control near the hydrate stability boundary. The measured differential pressure across the specimen, methane injection flow rate, and volume of displaced brine are used to calculate the relative permeability by adopting a conventional Buckley-Leverett theory-based interpretation method. Residual brine saturation calculated for the hydrate-bearing specimen is higher than that of hydrate-free specimen, presumably due to decrease in pore size, increase in heterogeneity of solid matrix, and increase in size distribution of solid matrix and pore in the presence of hydrates. Further studies are necessary to represent the results of the unsteady-state flow experiment in HBS with a gas hydrate-dependent relative permeability model.

Geologic reservoirs containing gas hydrate occur beneath permafrost environments and within marine continental slope sediments, representing a potentially vast natural gas source. Numerical simulators provide scientists and engineers with tools for understanding how production efficiency depends on the numerous, interdependent (coupled) processes associated with potential production strategies for these gas hydrate reservoirs. Confidence in the modeling and forecasting abilities of these gas hydrate reservoir simulators (GHRSs) grows with successful comparisons against laboratory and field test results, but such results are rare, particularly in natural settings. The hydrate community recognized another approach to building confidence in the GHRS: comparing simulation results between independently developed and executed computer codes on structured problems specifically tailored to the interdependent processes relevant for gas hydrate-bearing systems. The United States Department of Energy, National Energy Technology Laboratory, (DOE/NETL), sponsored the first international gas hydrate code comparison study, IGHCCS1, in the early 2000s. IGHCCS1 focused on coupled thermal and hydrologic processes associated with producing gas hydrates from geologic reservoirs via depressurization and thermal stimulation. Subsequently, GHRSs have advanced to model more complex production technologies and incorporate geomechanical processes into the existing framework of coupled thermal and hydrologic modeling. This paper contributes to the validation of these recent GHRS developments by providing results from a second GHRS code comparison study, IGHCCS2, also sponsored by DOE/NETL. IGHCCS2 includes participants from an international collection of universities, research institutes, industry, national laboratories, and national geologic surveys. Study participants developed a series of five benchmark problems principally involving gas hydrate processes with geomechanical components. The five problems range from simple geometries with analytical solutions to a representation of the world's first offshore production test of methane hydrates, which was conducted with the depressurization method off the coast of Japan. To identify strengths and limitations in the various GHRSs, study participants submitted solutions for the benchmark problems and discussed differing results via teleconferences. The GHRSs evolved over the course of IGHCCS2 as researchers modified their simulators to reflect new insights, lessons learned, and suggested performance enhancements. The five benchmark problems, final sample solutions, and lessons learned that are presented here document the study outcomes and serve as a reference guide for developing and testing gas hydrate reservoir simulators.

Guangda He,1 Runqing Ji,1 Xiqian Huo,1 Xiaoming Su,1 Jinzhuo Ge,1 Wei Li,1 Lubi Lei,1 Boxuan Pu,1 Aoxi Tian,1 Jiamin Liu,1 Lihua Zhang,1 Yongjian Wu2 On behalf of the China PEACE Collaborative Group1National Clinical Research Center for Cardiovascular Diseases, NHC Key Laboratory of Clinical Research for Cardiovascular Medications, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, People’s Republic of China; 2Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Lihua Zhang, National Clinical Research Center for Cardiovascular Diseases, NHC Key Laboratory of Clinical Research for Cardiovascular Medications, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, 167 Beilishi Road, Beijing, 100037, People’s Republic of China, Email zhanglihua@fuwai.com Yongjian Wu, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China, Email wuyongjian@fuwai.comBackground: Inflammation contributes to the progression of heart failure (HF). However, long-term inflammatory trajectories and their associations with outcomes in patients with acute HF remain unclear.Methods: Data was obtained from the China Patient-Centered Evaluative Assessment of Cardiac Events Prospective Heart Failure Study, and high-sensitivity C-reactive protein (hsCRP) was used to reflect the inflammatory level. Only patients who survived over 12-month and had hsCRP data at admission, 1-, and 12-month after discharge were included. The latent class trajectory modeling was used to characterize hsCRP trajectories. Multivariable Cox regression models were used to explore the association between hsCRP trajectories and following mortality.Results: Totally, 1281 patients with a median 4.77 (interquartile range [IQR]: 4.24– 5.07) years follow-up were included. The median age was 64 years (IQR: 54– 73 years); 453 (35.4%) were female. Four distinct inflammatory trajectories were characterized: persistently low (n = 419, 32.7%), very high-marked decrease (n = 99, 7.7%), persistently high (n = 649, 50.7%), and persistently very high (n = 114, 8.9%). Compared with the persistently low trajectory, the all-cause mortality was increased in a graded pattern in the persistently high (hazard ratio [HR]: 1.59, 95% confidence interval [CI]: 1.23– 2.07) and persistently very high (HR: 2.56, 95% CI: 1.83– 3.70) trajectories; nevertheless, the mortality was not significantly increased in very high-marked decrease trajectory (HR: 0.94, 95% CI: 0.57– 1.54).Conclusion: Four distinct inflammatory trajectories were identified among patients with acute HF who survived over 12-month. Patients with persistently high and very high trajectories had significantly higher mortality than those with the persistently low trajectory.Keywords: heart failure, high-sensitivity C-reactive protein, trajectory, latent class trajectory modeling, mortality

Jin-Jin Yang,1,2 Lei Lei,1,2 Di Qiu,1 Sai Chen,1 Li-Ka Xing,1 Jing-Wei Zhao,1 Yuan-Yuan Mao,1,2 Jian-Jun Yang1,2 1Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Henan Province International Joint Laboratory of Pain, Cognition and Emotion, Zhengzhou, People’s Republic of ChinaCorrespondence: Jian-Jun Yang, Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, People’s Republic of China, Tel +8613783537619, Email yjyangjj@126.comBackground: Postoperative delirium is common in older adult patients and associated with a poor prognosis. The use of benzodiazepine was identified as an independent risk factor for delirium, but there is no randomized controlled trial regarding the relationship between remimazolam, a new ultra-short acting benzodiazepine, and postoperative delirium. We designed a randomized controlled trial to evaluate if remimazolam increases the incidence of postoperative delirium compared with propofol in older adult patients undergoing orthopedic surgery with general anesthesia.Patients and Methods: We enrolled 320 patients aged more than 60 with American Society of Anesthesiologists physical status I–III who underwent orthopedic surgery. Patients were randomized to two groups to receive intraoperative remimazolam or propofol, respectively. Our primary outcome was the incidence of delirium within 3 days after surgery. Secondary outcome was emergence quality including the incidence of emergence agitation, extubation time, and length of post-anesthesia care unit (PACU) stay. Adverse events were also recorded.Results: The incidence of postoperative delirium was 15.6% in the remimazolam group and 12.4% in the propofol group (Risk ratio, 1.26; 95% CI, 0.72 to 2.21; Risk difference, 3.2%; 95% CI, − 4.7% to 11.2%; P = 0.42). No significant differences were observed for time of delirium onset, duration of delirium, and delirium subtype between the two groups. Patients in remimazolam group had a lower incidence of hypotension after induction and consumed less vasoactive drugs intraoperatively, but had a longer postoperative extubation time and PACU stay.Conclusion: General anesthesia with remimazolam was not associated with an increased incidence of postoperative delirium compared with propofol in older adult patients undergoing orthopedic surgery.Keywords: benzodiazepines, delirium, older adults, orthopedic surgery, propofol, remimazolam

Gaizhi Li,1,2 Lei Lei,1 Chunxia Yang,1 Zhifen Liu,1 Ke-Rang Zhang1,2 1Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Psychiatry, First Clinical Medical College, Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Zhifen Liu; Ke-Rang Zhang, Department of Psychiatry, First Hospital of Shanxi Medical University, Shanxi Medical University, No. 85 Jiefang Nan Road, Taiyuan, Shanxi, 030001, People’s Republic of China, Tel +86 13703586547 ; +86 18135078183, Email liuzhifen5518@163.com; krzhang_sxmu@vip.163.comObjective: Repetitive transcranial magnetic stimulation (rTMS) is an effective and evidence-based treatment for major depressive disorder (MDD). This retrospective study aimed to explore the efficacy of add-on iTBS treatment in MDD in real-world clinical practice.Methods: One hundred and fifty-nine inpatients with MDD in a general hospital were included in this study. These patients were treated with at least 8 sessions of iTBS, in addition to antidepressants and supportive psychotherapy. Symptoms of depression and anxiety were assessed with the Hamilton Depression Rating Scale (HDRS) and the Hamilton Rating Scale for Anxiety (HAMA) at baseline and after 2– 4 weeks of treatment. The improvement degree of depressive and anxious symptoms was compared between the first-episode MDD (n=107) and recurrent MDD (n=52) groups.Results: Depressive and anxious symptoms were reduced significantly after the add-on iTBS treatment; the response and remission rates in the first-episode MDD group were 55.14% and 28.97%, which were 63.46% and 28.85% for the recurrent MDD group, respectively (P> 0.05). The response rate and remission rate of anxiety in the first-episode MDD group was 64.13% and 57.45% for HAMA, and 66.67% and 62.50% for the recurrent MDD group (P> 0.05).Conclusion: Our findings indicated that antidepressant and anti-anxiety efficacy of add-on iTBS treatment remains equivocal in real-world clinical practice, regardless of a first-episode depression diagnosis or recurrent depression.Keywords: depression, anxious, add-on iTBS, real world, efficacy

Lei Lei,1 Yihua Bai,1 Yang Fan,1 Yaling Li,1 Hongying Jiang,1 Jiaping Wang2 1Department of Nephrology, The Second Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 2Department of Radiology, The Second Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People’s Republic of ChinaCorrespondence: Yihua Bai, Department of Nephrology, The Second Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People’s Republic of China, Email baiyihua@kmmu.edu.cnBackground: Diabetic nephropathy (DN) is a primary driver of end-stage renal disease. Given the heterogeneity of renal lesions and the complex mechanisms of DN, the present-day diagnostic approach remains highly controversial. We aimed to design a diagnostic model by bioinformatics methods for discriminating DN patients from normal subjects.Methods: In this study, transcriptome sequencing was performed on 6 clinical samples (3 from DN patients and 3 from healthy volunteers) from the Second Affiliated Hospital of Kunming Medical University. Construction of a competing endogenous RNA (ceRNA) network based on differentially expressed (DE)-mRNAs and -long noncoding RNAs (lncRNAs). Subsequently, the CytoHubba plugin was used to identify hub genes from DE-mRNAs in the ceRNA network and to perform functional enrichment analysis on them. The least absolute shrinkage and selection operator (LASSO) regression analysis was responsible for screening the diagnostic biomarkers from hub genes and assessing their diagnostic power using ROC curves. The pathways involved in hub genes were revealed by single-gene Gene Set Enrichment Analysis (GSEA). Moreover, we verified the expression levels of diagnostic biomarkers by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot.Results: A total of 10 hub genes were screened from the ceRNA network, which appeared to be associated with the viral infection, kidney development, and regulation of immune and inflammatory responses. Subsequently, LASSO regression analysis established a diagnostic model consisting of DDX58, SAMD9L, and TLR6 with a robust diagnostic potency (AUC = 1). Similarly, single-gene GSEA showed a strong association of these diagnostic biomarkers with the viral infection. Furthermore, PCR and Western blot demonstrated showed that DDX58, SAMD9L, and TLR6 were upregulated in DN patients at both transcriptome and protein levels compared to healthy controls.Conclusion: We confirmed that differentially expressed hub genes may be novel diagnostic biomarkers in DN.Keywords: diabetic nephropathy, DN, diagnosis, ceRNA, biomarker

Describing the pore habit of methane hydrate in sediment matrices is essential for understanding natural distribution of methane hydrate, methane trace (transport and solidification) in the hydrate stability zone, physical properties of hydrate-bearing sediments, and the associated influence on potential gas production. Pore habit visualization in natural media at pore scale even with laboratory synthesized cores has been challenging due to the similar densities of methane hydrate from pore liquid. In this work, we used phase-contrast assisted micro-CT with potassium iodine-doped brine to visualize four phases: sand particles, pore fluid, methane hydrate and methane gas. This study visualizes the pore habit of methane hydrate at various stages including during hydrate formation in excess-gas systems, its evolution after brine injection to replace pore fluid, and hydrate formation in excess-water systems. Hydrate tends to adopt round and smooth surfaces when in contact with water while exhibits relatively angular interfaces when in contact with methane gas. Hydrate formation in excess-gas systems results in a partial cementing and partial mineral-coating pore habit, while hydrate in excess-water systems develops mainly as pore-filling, and locally cementing or mineral-coating where big gas pockets exist at the initial state. Pore liquid replacement from methane gas to brine triggers a shift of hydrate pore habit towards pore-filling. Methane hydrate evolution over time produces bigger hydrate particles but with less contact area with sand particles. The effects of hydrate pore habit become less important as hydrate particle size exceeds the pore size. Additionally, hydrate formation could trap residual methane gas and brine as inclusions.

Yuting Tian,1,&ast; Yue Zhang,1,&ast; Mengjiao Zhang,2 Xianchun Chen,3 Lei Lei,1 Tao Hu1 1State Key Laboratory of Oral Diseases, Department of Preventive Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 2West China School of Pharmacy, Sichuan University, Chengdu, 610041, People’s Republic of China; 3College of Polymer Science and Engineering, Sichuan University, Chengdu, 610065, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xianchun Chen; Tao Hu, Tel +86 13880649396, +86 28-85503486, Email chenxianchun@scu.edu.cn; hutao@scu.edu.cnPurpose: VicR is the essential response regulator related to the synthesis of exopolysaccharide (EPS) – one of the main cariogenic factors of S. mutans. An antisense vicR RNA (ASvicR) could bind to vicR mRNA, hindering the transcription and translation of the vicR gene. We had constructed a recombinant plasmid containing the ASvicR sequence (plasmid-ASvicR) and proved that it could reduce EPS synthesis, biofilm formation, and cariogenicity. However, the recombinant plasmids are supposed to be protected from enzymatic degradation and possess higher transformation efficiency. The principal objective of the present research was to construct an appropriate vector that can carry and protect the plasmid-ASvicR and investigate the effects of the carried plasmids on the cariogenicity of the S. mutans.Methods: Aminated dendritic mesoporous silica nanoparticles (DMSNs-NH2) were synthesized and characterized. The ability of DMSNs-NH2 to carry and preserve the plasmid-ASvicR (DMSNs-NH2-ASvicR) was proved by the loading curve, agarose electrophoresis, DNase I digestion assays, and energy-dispersive spectrometry (EDS) mapping. Transformation assays demonstrated whether the plasmid could enter S. mutans. The effect of DMSNs-NH2-ASvicR on the 12-hour and 24-hour biofilms of S. mutans was evaluated by biofilm formation experiments and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The cytotoxicity of DMSNs-NH2-ASvicR was assessed by CCK-8 and live/dead staining assays. The regulation of DMSNs-NH2-ASvicR on the cariogenicity of S. mutans was also evaluated in vivo.Results: DMSNs-NH2 could load approximately 92% of plasmid-ASvicR at a mass ratio of 80 and protect most of plasmid-ASvicR from degradation by DNase I. The plasmid-ASvicR loaded on DMSNs-NH2 could be transformed into S. mutans, which down-regulated the expression of the vicR gene, reducing EPS synthesis and biofilm organization of S. mutans. DMSNs-NH2-ASvicR exhibited favorable biocompatibility, laying a foundation for its subsequent biomedical application. In addition, DMSNs-NH2-ASvicR led to decreased caries in vivo.Conclusion: DMSNs-NH2 is a suitable vector of plasmid-ASvicR, and DMSNs-NH2-ASvicR can inhibit biofilm formation, reducing the cariogenicity of S. mutans. These findings reveal that DMSNs-NH2-ASvicR is a promising agent for preventing and treating dental caries.Keywords: biofilm, exopolysaccharides, cariogenicity, mesoporous silica nanoparticles, Streptococcus mutans

Jin Teng,1 Lu Xiang,2 Huaicong Long,2 Caiping Gao,3 Lei Lei,3 Yinghui Zhang3 1Department of Cadre Health, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, 610072, People’s Republic of China; 2Department of Geriatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, 610072, People’s Republic of China; 3Department of Digestive Internal Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, 610072, People’s Republic of ChinaCorrespondence: Yinghui ZhangDepartment of Digestive Internal Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, 610072, People’s Republic of ChinaTel +86- 18981838123Email jn2021680@163.comObjective: This study attempted to screen and combine effective biomarkers to analyse the association between these biomarkers and gastrointestinal failure (GIF) in critically ill patients.Methods: A total of 110 critically ill patients with acute gastrointestinal injury (AGI) admitted to ICU were enrolled. The AGI grade was determined by the AGI classification proposed by ESICM. There were 67 patients in gastrointestinal dysfunction (GID) group (AGI grade II), 43 patients in GIF group (AGI grade III–IV), and 41 healthy adults in healthy control (HC) group. APACHE II and SOFA score were used to evaluate the disease severity. Peripheral blood samples of patients were collected within 24 hours of admission to the ICU (prior-treatment) and after the conventional medication therapy for 7 consecutive days (post-treatment). Citrulline serum level was detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method, and D-lactate and lipopolysaccharide (LPS) serum levels were measured by ELISA. Pearson correlation, logistic regression, and ROC curve analysis were used.Results: Patients with GID or GIF had lower serum level of citrulline, while higher levels of D-lactate and LPS than HC. Compared with GID patients, serum level of citrulline was reduced, while D-lactate and LPS were elevated in GIF patients. Correlation analysis displayed that serum levels of citrulline, D-lactate, and LPS were associated with the APACHE II and SOFA score in patients with GID or GIF. Logistics regression analysis showed that citrulline and D-lactate were risk for both GID and GIF. ROC curve analysis exhibited that combination of citrulline and D-lactate had relatively high value to distinguish GID from HC, GIF from GID, and GIF from HC.Conclusion: Serum citrulline and D-lactate were associated with severity of GIF, combination of citrulline and D-lactate improved the diagnostic efficacy to identify GIF in critically ill patients.Keywords: gastrointestinal failure, gastrointestinal dysfunction, citrulline, D-lactate, critically ill patients

Xiaotong Song,1,2 Ning Sun,1– 3 Aixia Zhang,1– 3 Lei Lei,1 Xinrong Li,1 Zhifen Liu,1– 3 Yanfang Wang,1 Chunxia Yang,1– 3 Kerang Zhang1 1Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Mental Health, Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Chunxia Yang; Kerang ZhangDepartment of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of ChinaEmail ychunxia2000@163.com; atomsxmu@vip.163.comObjective: Although the pathogenesis of major depressive disorder (MDD) is still unclear, studies have shown that the dopaminergic system of depressed patients is defective, and that NR4A2 is an important transcription factor affecting the development and maintenance of dopaminergic neurons. As such, NR4A2 levels affected by NR4A2 single nucleotide polymorphisms (SNPs) may be associated with MDD. This study examined whether NR4A2 SNPs are associated with depressive symptoms and antidepressant efficacy.Methods: A total of 441 patients with first-episode depression were enrolled in this study. We analysed three SNPs of NR4A2, using the 17-item Hamilton Depression Rating Scale (HAM-D) and its four factors to obtain scores at baseline and at the end of 6 weeks. UNPHASED software was employed for quantitative character analysis, and SPSS software was adopted for antidepressant efficacy analysis.Results: Patients with rs12803-A exhibited higher scores of retardation symptoms. Patients with the rs834834-C allele and rs834834-CC genotype had higher retardation symptom scores. Patients with rs3769340 exhibited greater antidepressant efficacy.Conclusion: NR4A2 gene polymorphisms are associated with retardation symptoms, somatic symptoms (gastro-intestinal), anxiety-based somatic symptoms, insight, and weight loss in patients with MDD. Additionally, rs3769340 may be a predictor of antidepressant efficacy in patients with major depressive disorder.Keywords: major depressive disorder, NR4A2, single nucleotide polymorphism, antidepressant treatment

Lei Lei,1 Jing Zhao,1 Xue-Qi Liu,1 Juan Chen,1 Xiang-Ming Qi,1 Ling-Ling Xia,2 Yong-Gui Wu1 1Department of Nephropathy, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China; 2Department of Infectious Disease, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of ChinaCorrespondence: Ling-Ling XiaDepartment of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaTel +86 0551 6292 2450Email 13966684365@163.comYong-Gui WuDepartment of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaTel +86 0551 6292 2111Email wuyonggui@medmail.com.cnIntroduction: Kidney tubular epithelial injury is one of the key factors in the progression of diabetic nephropathy (DN). Wogonin is a kind of flavonoid, which has many pharmacological effects, such as anti-inflammation, anti-oxidation and anti-fibrosis. However, the effect of wogonin in renal tubular epithelial cells during DN is still unknown.Materials and Methods: STZ-induced diabetic mice were given doses of wogonin (10, 20, and 40 mg/kg) by intragastric administration for 16 weeks. The metabolic indexes from blood and urine and pathological damage of renal tubules in mice were evaluated. Human tubular epithelial cells (HK-2) were cultured in high glucose (HG) condition containing wogonin (2μM, 4μM, 8μM) for 24 h. Tubular epithelial cell inflammation and autophagic dysfunction both in vivo and in vitro were assessed by Western blot, qRT-PCR, IHC, and IF analyses.Results: The treatment of wogonin attenuated urinary albumin and histopathological damage in tubulointerstitium of diabetic mice. We also found that wogonin down-regulated the expression of pro-inflammatory cytokines and autophagic dysfunction in vivo and in vitro. Molecular docking and Cellular Thermal Shift Assay (CETSA) results revealed that mechanistically phosphoinositide 3-kinase (PI3K) was the target of wogonin. We then found that inhibiting PI3K eliminated the protective effect of wogonin. Wogonin regulated autophagy and inflammation via targeting PI3K, the important connection point of PI3K/Akt/NF-κB signaling pathway.Conclusion: Our study is the first to demonstrate the novel role of wogonin in mitigating tubulointerstitial fibrosis and renal tubular cell injury via regulating PI3K/Akt/NF-κB signaling pathway-mediated autophagy and inflammation. Wogonin might be a latent remedial drug against tubular epithelial injury in DN by targeting PI3K.Keywords: diabetic nephropathy, tubular epithelial cell, wogonin, inflammation, autophagy, PI3K/Akt/NF-κB pathway

Jiahuan Huang,1,2 Lei Lei,1,2 Bo Chen,2,3 Guoqiang Pan,4 Xiaojiao Wang,1,2 Meiyu Fang2,5 1Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, People’s Republic of China; 2Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, People’s Republic of China; 3Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, People’s Republic of China; 4Department of Thoracic Oncology, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 5Department of Medical Oncology of Rare Cancer and Head and Neck Cancer, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Key Laboratory of Head and Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, 310022, People’s Republic of ChinaCorrespondence: Meiyu Fang Department of Medical Oncology of Rare Cancer and Head and Neck CancerCancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Key Laboratory of Head and Neck Cancer Translational Research of Zhejiang Province, Hangzhou, 310022, People’s Republic of ChinaTel +86-571-88122222Email fangmy@zjcc.org.cnXiaojiao WangDepartment of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, People’s Republic of ChinaTel +86-571-88122222Email wxiaojia0803@163.comBackground: Sarcomatoid carcinoma (SaCa) of the palatine tonsil is a rare and aggressive subset of head and neck (H&N) cancer which is characterized by insensitivity to surgery and radiotherapy and a poor prognosis. Immunotherapy has led advances in the treatment of melanoma and H&N cancer, but the combined effects of immunotherapy and chemotherapy have not been sufficiently investigated.Case Presentation: Herein, we report the case of 29-year-old Chinese women with local advanced non-resectable SaCa of the palatine tonsil who exhibited a substantial partial response to toripalimab and chemotherapy followed by radiation therapy. To the best of our knowledge, this is the first report of its successful application in this context.Conclusion: Toripalimab combined with chemotherapy may be an effective approach for locally advanced H&N cancer in rare categories of patients, which was the first application as far as we know.Keywords: chemotherapy, combination therapy, palatine tonsil cancer, PD-1 inhibitor, sarcomatoid carcinoma

Zhi-chao Zheng, Wei Zhu, Lei Lei, Xue-qi Liu, Yong-gui Wu Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Yong-gui WuDepartment of Nephrology, The First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Hefei, Anhui 230032, People’s Republic of ChinaTel +86 0551 6292 2111Email wuyonggui@medmail.com.cnIntroduction: Diabetic nephropathy (DN) has become an increasing threat to health, and inflammation and fibrosis play important roles in its progression. Wogonin, a flavonoid, has been proven to suppress inflammation and fibrosis in various diseases, including acute kidney injury. This study aimed at investigating the effect of wogonin on diabetes-induced renal inflammation and fibrosis.Materials and Methods: Streptozotocin (STZ)-induced diabetic mouse models received gavage doses of wogonin (10, 20, and 40 mg/kg) for 12 weeks. Metabolic indices from blood and urine and pathological damage of glomerulus in the diabetic model were assessed. Glomerular mesangial cells SV40 were cultured in high glucose (HG) medium containing wogonin at concentrations of 1.5825, 3.125, and 6.25 μg/mL for 24 h. Inflammation and fibrosis indices were evaluated by histopathological, Western blotting, and PCR analyses.Results: Wogonin treatment ameliorated albuminuria and histopathological lesions in diabetic mice. Inflammatory cytokines, such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and related signaling pathway NF-κB were downregulated after the administration of wogonin in vivo and in vitro. Furthermore, wogonin reduced the expression of extracellular matrix (ECM), including fibronectin (FN), collagen IV (Col-IV), α-smooth muscle actin (α-SMA), and transforming growth factor-β 1 (TGF-β 1) in the kidneys of diabetic mice and HG-induced mesangial cells. Moreover, the inhibition of TGF-β 1/Smad3 pathway might be responsible for these changes.Conclusion: Wogonin may ameliorate renal inflammation and fibrosis in diabetic nephropathy by inhibiting the NF-κB and TGF-β 1/Smad3 signaling pathways.Keywords: diabetic nephropathy, wogonin, inflammation, fibrosis

Lan Lei, 1, 2 Zhe-Nan Ling, 3 Xiang-Liu Chen, 1 Lian-Lian Hong, 1 Zhi-Qiang Ling 1 1Department of Molecular Oncology, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Gongshu District, Hangzhou, 310022, People’s Republic of China; 2The Second Clinical Medical College of Zhejiang Chinese Medicine University, Hangzhou 310053, People’s Republic of China; 3Department of Clinical Medicine, Medical College, Zhejiang University City College, Hangzhou 310015, People’s Republic of ChinaCorrespondence: Zhi-Qiang LingDepartment of Molecular Oncology, Zhejiang Cancer Institute, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, No.1 Banshan East Road, Gongshu District, Hangzhou 310022, People’s Republic of ChinaEmail lingzq@zjcc.org.cnAbstract: The Golgi apparatus is critical in the compartmentalization of signaling cascades originating from the cytoplasmic membrane and various organelles. Scaffold proteins, such as progestin and adipoQ receptor (PAQR)3, specifically regulate this process, and have recently been identified in the Golgi apparatus. PAQR3 belongs to the PAQR family, and was recently described as a tumor suppressor. Accumulating evidence demonstrates PAQR3 is downregulated in different cancers to suppress its inhibitory effects on malignant potential. PAQR3 functions biologically through the pathological regulation of altered signaling pathways. Significant cell proliferation networks, including Ras proto-oncogene (Ras)/mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), insulin, and vascular endothelial growth factor, are closely controlled by PAQR3 for physiologically relevant effects. Meanwhile, genetic/epigenetic susceptibility and environmental factors, may have functions in the downregulation of PAQR3 in human cancers. This study aimed to assess the subcellular localization of PAQR3 and determine its topological features and functional domains, summarizing its effects on cell signaling compartmentalization. The pathophysiological functions of PAQR3 in cancer pathogenesis, metabolic diseases, and developmental ailments were also highlighted.Keywords: cell signaling, Golgi apparatus, metabolic regulation, metastasis, PAQR3, tumor suppressor