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Yuhong Tang,1,* Jun Cao,1,* Rui Peng,1 Xingkang Mao,1 Bingbing Su,1 Hao Tang,1 Daoyuan Tu,1 Jie Zhou,1 Guoqing Jiang,1 Shengjie Jin,1 Qian Wang,1 Chen Zhang,2 Renjie Liu,1 Chi Zhang,1,3 Dousheng Bai1,3 1Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China; 2The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 3General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dousheng Bai; Chi Zhang, Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Road, Yangzhou, 225000, People’s Republic of China, Email drbaidousheng@yzu.edu.cn; zc17212850@163.comIntroduction: Immune checkpoint therapy (ICIs) effectively improves the prognosis of advanced (stage III/IV) hepatocellular carcinoma (HCC) patients. However, its objective response rate (ORR) is below 20%, significantly limiting ICI use in advanced HCC patients. The level of tumour immune infiltration influences ICI response rate. Recent studies have found ubiquitinase to be an important factor that regulates tumour immune infiltration. Therefore, the aim of this study is to explore the key ubiquitination genes that regulate immune infiltration in advanced HCC and further validate them.Methods: A biotechnological process was performed as a means of classifying 90 advanced HCC patients into three immune subtypes and identifying associations with immune infiltration in the co-expressed modules. Ubiquitination-related genes were then screened with WGCNA. Gene enrichment analysis was performed for the target module and 30 hub genes were screened out by protein–protein interaction network (PPI). ssGSEA, single-gene sequencing and the MCP counter were used for exploring immune infiltration. TIDE score was applied for predicting drug efficacy and GSEA was used for exploring potential pathways. Finally, GRB2 expression in HCC tissue was validated by in vitro experiments.Results: GRB2 expression was found to have a significant correlation with the pathological stage and prognosis of HCC patients and a positive correlation with immune infiltration and tumour mutation burden (TMB). In addition, significant correlations with the efficacy of ICIs, sorafenib and transarterial chemoembolization (TACE) were identified. GRB2 was found to be most significantly associated with the JAK-STAT signalling pathway and cytosolic DNA sensing pathway. Finally, it was found that GRB2 expression is closely related to the prognosis, tumour size and TMN stage.Conclusion: A significant association was observed between the ubiquitinated gene GRB2 and the prognosis and immune infiltration of advanced HCC patients and it may potentially be used for predicting therapy efficacy in advanced HCC patients in the future.Keywords: ubiquitination, growth factor receptor-binding protein 2, liver cancer, tumour-infiltrating immune cells

Zhihan Jiang,1,* Xiaosen Wang,1,* Lijiao Zhang,1,* Drolma Yangzom,2,* Yanping Ning,2 Baiyan Su,3,4 Meijiao Li,5 Meilang ChuTso,2 Yahong Chen,1,6 Ying Liang,1,2,6 Yongchang Sun1,6 1Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Tibet Autonomous Region People’s Hospital, Lhasa, 850000, People’s Republic of China; 3Radiology Department, Peking Union Medical College Hospital, Beijing, 100730, People’s Republic of China; 4Radiology Department, Tibet Autonomous Region People’s Hospital, Lhasa, 850000, People’s Republic of China; 5Radiology Department, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 6Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing, 100083, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying Liang; Yongchang Sun, Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing, People’s Republic of China, Tel +86 138 1096 4766 ; +86 139 1097 9132, Email bysyliangying@126.com; suny@bjmu.edu.cnBackground: COPD patients living in Tibet are exposed to specific environments and different risk factors and probably have different characteristics of COPD from those living in flatlands. We aimed to describe the distinction between stable COPD patients permanently residing at the Tibet plateau and those in flatlands.Methods: We conducted an observational cross-sectional study that enrolled stable COPD patients from Tibet Autonomous Region People’s Hospital (Plateau Group) and Peking University Third Hospital (Flatland Group), respectively. Their demographic information, clinical features, spirometry test, blood routine and high-resolution chest CT were collected and evaluated.Results: A total of 182 stable COPD patients (82 from plateau and 100 from flatland) were consecutively enrolled. Compared to those in flatlands, patients in plateau had a higher proportion of females, more biomass fuel use and less tobacco exposure. CAT score and frequency of exacerbation in the past year were higher in plateau patients. The blood eosinophil count was lower in plateau patients, with fewer patients having an eosinophil count ≥ 300/μL. On CT examination, the proportions of previous pulmonary tuberculosis and bronchiectasis were higher in plateau patients, but emphysema was less common and milder. The ratio of diameters of pulmonary artery to aorta ≥ 1 was more often in plateau patients.Conclusion: Patients with COPD living at Tibet Plateau had a heavier respiratory burden, lower blood eosinophil count, less emphysema but more bronchiectasis and pulmonary hypertension. Biomass exposure and previous tuberculosis were more common in these patients.Keywords: chronic obstructive pulmonary disease, plateau, phenotype, computed tomography, emphysema

Lina Wei,1 Xulei Gou,2 Baoning Su,3 Haiqiong Han,4 Tingting Guo,5 Liang Liu,5 Lei Wang,5 Lina Zhang,3 Weibin Chen6 1Children’s Medical Center, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130021, People’s Republic of China; 2Department of Pediatrics, Beijing Daxing District Maternal and Child Health Care Hospital, Beijing, 102600, People’s Republic of China; 3Department of Pediatrics, Shanghai Jiading Traditional Chinese Medicine Hospital, Shanghai, 201800, People’s Republic of China; 4Department of Rehabilitation Medicine, Community Health Service Center of Jiangqiao Town in Jiading District, Shanghai, 201803, People’s Republic of China; 5Changchun University of Traditional Chinese Medicine, Changchun, 130017, People’s Republic of China; 6Department of Pediatrics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of ChinaCorrespondence: Lina Zhang, Department of Pediatrics, Shanghai Jiading Traditional Chinese Medicine Hospital, No. 222, Bole Road, Jiading District, Shanghai, 201800, People’s Republic of China, Tel +86-18930568760, Email lina1988zhang@163.com Weibin Chen, Department of Pediatrics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 110, Ganhe Road, Hongkou District, Shanghai, 200437, People’s Republic of China, Tel +86-18621863233, Email weibin1965chen@163.comBackground/Purpose: Mahuang decoction (MHD) is a classic famous traditional Chinese medicine and has various pharmacological effects, including anti-inflammation and anti-asthma. In this study, we aimed to investigate the potential protective effect of MHD against asthma and elucidated the underlying mechanism.Materials and Methods: A mouse model of asthma was induced by ovalbumin (OVA) treatment, and then treated with MHD to evaluate its effect on the asthma. Gain- or loss-of-function approaches were performed in SP1 and FGFR3 to study their roles in asthma via measurement of airway inflammation, airway remodeling and airway smooth muscle cell (ASMC) proliferation-related factors.Results: MHD reduced airway inflammation and remodeling. Additionally, MHD contributed to diminished expression of SP1, which was shown to repress airway inflammation and remodeling. Furthermore, SP1 bound to the FGFR3 promoter, resulting in the FGFR3 transcription promotion and ASMC proliferation. Conversely, FGFR3 knockdown abolished airway inflammation and remodeling, the mechanism of which was related to suppression of the PI3K/AKT signaling pathway. Meanwhile, MHD hindered airway inflammation and remodeling following asthma by suppressing the SP1/FGFR3/PI3K/AKT axis.Conclusion: Taken together, MHD may retard airway inflammation and remodeling by suppressing the SP1/FGFR3/PI3K/AKT axis, which contributes to an extensive understanding of asthma and may provide novel therapeutic options for this disease.Keywords: Mahuang decoction, asthma, SP1, FGFR3, PI3K/AKT signaling pathway, airway inflammation, airway remodeling

Heng Fan,1,* Bin-jie Su,2,* Jian-wei Le,1 Jian-hua Zhu1 1Department of Intensive Care Unit, Ningbo First Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 2Department of Intensive Care Unit, Ningbo First Hospital Haishu Branch, Ningbo, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian-hua Zhu, Department of Intensive Care Unit, Ningbo First Hospital, No.59 Liuting Road, Ningbo, Zhejiang Province, 315010, People’s Republic of China, Tel/Fax +86-574-87084625, Email zhujianhua201107@163.comPurpose: To clarify the protective effect and mechanism of salidroside (SLDS) on acute kidney injury (AKI) in septic rats.Methods: We pretreated rats with different doses of SLDS and analyzed the impact of SLDS on the survival of septic rats. We evaluated the levels of inflammatory factors in rats, the expression of NF-ƙB p65 in the kidney, and the apoptosis of kidney tubular epithelial cells (KTECs).Results: SLDS significantly decreased the mortality of septic rats, and it reduced the levels of TNF-α, IL-1β, and IL-17A in plasma and kidneys and decreased the levels of serum creatinine, plasma renal injury molecule-1 and plasma neutrophil gelatin-associated lipocalin. Moreover, SLDS could significantly decrease the expression of NF-ƙB p65 in kidney tissues and the apoptotic number of KETCs, while reducing the mRNA levels of Caspase-3 and Bax mRNA, and increasing the level of Bcl-2 mRNA.Conclusion: SLDS pretreatment protects against AKI in septic rats by inhibiting the inflammation of kidney and the apoptosis of KTECs.Keywords: salidroside, acute kidney injury, sepsis, apoptosis, inflammation

Gangqiang Guo,1,&ast; Huijing Wang,2,&ast; Xinya Tong,1,&ast; Lele Ye,1 Xinyu Shi,1 Su Fang,1 Ya Hu,3 Fei Han,2 Chaosheng Chen,3 Ning Ding,1 Bofeng Su,3 Xiangyang Xue,1 Huidi Zhang3 1Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research & Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens & Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 2Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China; 3Department of Nephrology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bofeng Su; Huidi ZhangDepartment of Nephrology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China, Email 24449681@qq.com; hd_zhang@163.comObjective: Enhancer RNAs (eRNAs), a class of non-coding RNAs, play indispensable roles in regulating target gene transcription and maintaining cell identity in cooperation with promoters. In this study, we investigated the transcriptional landscape and potential functions of eRNAs in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE).Methods: PBMCs from five patients with stable SLE, five patients with active SLE, and ten healthy individuals (HCs) were subjected to RNA-sequencing. Putative regulators, differential expression, and pathways were analyzed. eRNAs that were significantly upregulated were first validated by RT-qPCR in 12 samples. Then, candidate eRNAs were confirmed in a validation cohort of 45 samples. We conducted comprehensive pathway analyses to explore the correlations between the candidate eRNAs and SLE pathology.Results: By analyzing eRNA transcript data from PBMCs from SLE patients and HCs, we identified various eRNAs and functional super-enhancers potentially related with SLE. The SLE-specificity of eRNAs seemed to be largely driven by SLE-specific transcription factors (TFs). A Venn diagram of eRNAs differentially expressed in stable, active, and total SLE vs HCs revealed that 13 and 23 eRNAs were commonly upregulated and downregulated, respectively, in patients with stable SLE and those with active SLE. The commonly upregulated eRNAs participate in regulating SLE-related pathways. Only eRNA TCONS_00034326 was significantly (P < 0.05) upregulated in PBMCs of patients with SLE when compared with those of HCs as indicated by RT-qPCR. The area under the receiver-operating curve of TCONS_00034326 for distinguishing SLE patients from HCs was 0.691. Through its putative SLE-related master TF, TCONS_00034326 is involved in multiple SLE-relevant signaling pathways, especially tumor necrosis factor signaling.Conclusion: This study unraveled the transcriptional landscape of eRNAs, eRNA-related TFs, and super-enhancers in PBMCs from SLE patients and HCs. We identified a panel of SLE-relevant eRNAs, providing potential targets in SLE pathogenesis.Keywords: enhancer RNA, eRNA, systemic lupus erythematosus, SLE, PBMCs, transcription factors, TFs, super-enhancer

Mingxiang Huang,1,&ast; Yaoju Tan,2,&ast; Xuxia Zhang,3,&ast; Yufeng Wang,3 Biyi Su,2 Zhongtan Xue,3 Jingping Wang,4 Yu Pang3 1Department of Clinical Laboratory, Fuzhou Pulmonary Hospital and Fujian Medical University Clinical Teaching Hospital, Fuzhou, People’s Republic of China; 2Department of Clinical Laboratory, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, People’s Republic of China; 3Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 4Clinical Department, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu PangDepartment of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel/Fax +86-10-8950 9359, Email pangyupound@163.comJingping WangClinical Department, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel/Fax +86-10-8950 9029, Email 13641335712@163.comBackground: Correct species identification is essential before initiation of TB treatment, due to substantial drug susceptibility profile differences among mycobacterial species. Given that nontuberculous mycobacteria (NTM) are frequently resistant to first-line anti-tuberculosis drugs, cases with mixed infections with Mycobacterium tuberculosis (MTB) and NTM tend to be diagnosed as multidrug-resistant tuberculosis (MDR-TB) cases. Here we report results of a retrospective multicentre study that was conducted to determine the prevalence of TB-NTM infections in previously diagnosed laboratory-confirmed multidrug-resistant tuberculosis (MDR-TB) patients using phenotypic drug susceptibility testing. The results were then used to identify risk factors associated with susceptibility to mixed infections.Methods: From January 2019 through December 2019, we retrospectively collected MDR-TB isolates from three TB specialised hospitals. Species identifications of isolates were performed using the MeltPro Myco assay.Results: A total of 837 MDR-TB isolates were analysed, of which 22 isolates (2.6%) were found to contain a mixture of NTM and MTB organisms. Significant differences in prevalence rates of mixed infections across regions were observed, with prevalence rates ranging from 0.0% (0/213) in Beijing to 3.4% (12/353) in Fuzhou to 3.7% (10/271) in Guangzhou. Among the 22 patients with NTM-TB mixed infections, a total of five different mycobacterial species were identified, of which the most prevalent species was Mycobacterium intracellulare. Notably, a history of previous TB episodes correlated with higher mixed infection risk.Conclusion: The results reported here demonstrated that mixed infections with MTB and NTM occurred in approximately 3% of suspected MDR-TB patients in China. These findings raise concerns about the accuracy of molecular diagnostics-based species identification tests and draw attention to the possibility that NTM-MTB mixed infections will be misdiagnosed as MDR-TB in high TB burden settings.Keywords: tuberculosis, nontuberculous mycobacteria, multidrug-resistant, China

Ramana K Naidu,1 Rahul Chaturvedi,2 Alyson M Engle,3 Pankaj Mehta,4 Brian Su,1 Krishnan Chakravarthy,5 Kasra Amirdelfan,6 Jeffrey Henn,7 Dawood Sayed,8 Jay Grider,9 Timothy Deer3 1California Orthopedics & Spine, Larkspur, CA, USA; 2School of Medicine, University of California – San Diego, San Diego, CA, USA; 3The Spine & Nerve Centers of the Virginias, Charleston, WV, USA; 4Pain Specialists of America, Killeen, TX, USA; 5Department of Anesthesiology, University of California – San Diego, San Diego, CA, USA; 6Integrated Pain Management, Walnut Creek, CA, USA; 7Joint Implant Surgeons of Florida, Fort Myers, FL, USA; 8Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, USA; 9Department of Anesthesiology, University of Kentucky, Lexington, KY, USACorrespondence: Ramana K Naidu Email ramonaidu@me.comBackground: The discipline of interventional pain management has changed significantly over the past decade with an expected greater evolution in the next decade. Not only have the number of procedures increased, some of the procedures that were created for spine surgeons are becoming more facile in the hands of the interventional pain physician. Such change has outpaced academic institutions, societies, and boards. When a pain physician is in the credentialing process for novel procedure privileges, it can leave the healthcare system in a challenging situation with little to base their decision upon.Methods: This paper was developed by a consensus working group from the American Society of Pain and Neuroscience from various disciplines. The goal was to develop processes and resources to aid in the credentialing process.Results: These guidelines from the American Society of Pain and Neuroscience provide background information to help facilities create a process to appropriately credential physicians on novel procedures. They are not intended to serve as a standard or legal precedent.Conclusion: This paper serves as a guide for facilities to credential physicians on novel procedures.Keywords: interventional pain management, interventional spine care, credentialing, guidelines

Tiansheng Liu,1 Bin Su2 1Department of Joint Surgery, Tianjin Hospital, Tianjin, 300211, People’s Republic of China; 2Department of Research, Characteristic Medical Center of PAP, Tianjin, 300162, People’s Republic of ChinaCorrespondence: Bin SuDepartment of Research, Characteristic Medical Center of PAP, No. 220 Chenglin Road, Dongli District, Tianjin, 300162, People’s Republic of ChinaEmail subin00810@163.comIntroduction: This research was to evaluate the beneficial effects of Styphnolobium japonicum (L.) Schott flower extract (SJF) on the adjuvant-induced arthritis rat model.Methods: Arthritis was evoked by injection of complete Freund’s adjuvant (CFA) in the hind paw. SJF (150 or 300 mg/kg/day) or Celecoxib (5 mg/kg/day) were administered intragastrically from the 0th day to the 28th day. The arthritis symptoms (paw edema, arthritic scores, mechanical hyperalgesia, and thermal hyperalgesia), inflammation biomarkers (RT and CRP), related enzymes (MMP1 and MMP13), oxidative stress markers (CAT, SOD, GPx, and MDA), and inflammatory cytokines (IL-6, IFN-γ, TNF-α, and IL-1β) of SJF-treated CFA rats were evaluated.Results: CFA rats exhibited severe arthritis symptoms, increased oxidative stress, and inflammatory cytokines. Interestingly, SJF treatment relieving arthritis symptoms and restored body weight gain compared with those in the CFA group. SJF treatment decreased the levels of CRP, RF, MMP1, and MMP13 in the CFA group. Besides, SJF treatment increased the activities of antioxidant enzymes and decreased the MDA content and inflammatory cytokines compared with those in the CFA group. Moreover, SJF could increase the mRNA expression of GPx-1 and CAT and inhibit the mRNA expression of IL-6 and TNF-α in the ankle tissue of CFA rats.Keywords: flos sophorae immaturus, arthritis, inflammatory, oxidative stress

Bo Su Department of Endocrinology, Aviation General Hospital, Beijing, 100012, People’s Republic of ChinaCorrespondence: Bo SuDepartment of Endocrinology, Aviation General Hospital, China Medical University, Beijing, 100012, People’s Republic of ChinaTel +8613439927892Email sss_19@163.comPurpose: Timely diagnosis of diabetic retinopathy (DR) can significantly improve the prognosis of patients. In this study, we established a prediction model by analyzing the relationship between diabetic retinopathy and related metabolic and biochemical indicators.Methods: A total of 427 type 2 diabetes mellitus (T2DM) patients were selected from the datadryad website data. Logistic regression (MLR) was used to input layer variables of the model were screened. Then, Tan-Sigmoid was selected as the transfer function of the hidden layer node, and the linear function was used as the output layer function to establish the back propagation artificial neural network (BP-ANN) model. The model was applied to 183 patients with type 2 diabetes mellitus (T2DM) in our hospital to predict DR.Results: A total of 167 patients (39.2%) with DR were obtained from the Datadryad database. Input variables were screened by MLR model, and it was concluded that the age, sex, albumin and creatinine, diabetes course were independently associated with the occurrence of DR. The above variables were used to establish BP-ANN model. The area under receiver operating characteristic curve (AUC) was significantly higher than that of MLR model (0.88 vs 0.74, P< 0.05), the probability threshold of the model was 0.3. Type 2 diabetes mellitus (T2DM) were selected in our hospital, including 92 patients with DR (50.2%). The above BP-ANN model was used to predict the incidence of DR, and the AUC area was significantly higher than that of the MLR model (0.77 vs 0.70, P< 0.05), the probability threshold was 0.7.Conclusion: We established the BP-ANN model and applied it to diagnose DR. Taking diabetic course, age, sex, albumin and creatinine as the inputs of BP-ANN, the existence of DR could be well predicted. Meanwhile, the generalization ability of the model could be improved by selecting different probability thresholds in different ROC curves.Keywords: diabetic retinopathy, type 2 diabetes, probability threshold, BP-ANN

Ying Liang,1,2 Drolma Yangzom,2 Lhamo Tsokyi,2 Yanping Ning,2 Baiyan Su,3,4 Shuai Luo,4 Bian Ma Cuo,2 Meilang ChuTso,2 Yanling Ding,1 Yahong Chen,1 Yongchang Sun1 1Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Tibet Autonomous Region People’s Hospital, Lhasa, 850000, People’s Republic of China; 3Radiology Department, Peking Union Medical College Hospital, Beijing, 100730, People’s Republic of China; 4Radiology Department, Tibet Autonomous Region People’s Hospital, Lhasa, 850000, People’s Republic of ChinaCorrespondence: Yongchang SunDepartment of Respiratory and Critical Care Medicine, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing, People’s Republic of ChinaTel +86 139 1097 9132Fax +86 108 226 6989Email suny@bjmu.edu.cnBackground: COPD at high altitude may have different risk factors and unique clinical and radiological phenotypes. We aimed to investigate the demographic data, clinical and radiological features of COPD patients permanently residing at the Tibet Plateau (≥ 3000 meters above sea level).Methods: We conducted an observational cross-sectional study which consecutively enrolled COPD patients visiting the outpatient of Respiratory Medicine at Tibet Autonomous Region People’s Hospital from January 2018 to March 2021. All patients were Tibetan permanent residents aging ≥ 40 years and met the diagnosis of COPD according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Data including demographic characteristics, altitude of residence, risk factors, respiratory symptoms, comorbidities and medications, as well as computed tomography (CT) measurements were collected.Results: Eighty-four patients with definite COPD were enrolled for analysis. Their mean age was 64.7 (± 9.1) years. All patients lived at ≥ 3000 m above sea level and 34.5% of them lived at ≥ 4000 m. About 8.3% of the patients were current smokers and 44.0% were ex-smokers. Up to 88.1% of the patients reported long-term exposure to indoor biomass fuels. Most of the patients were classified as having mild-to-moderate (GOLD I: 27.4%; GOLD II: 51.2%) COPD, while 89.3% had a CAT score ≥ 10. Only 36.9% of the patients received regular long-term medications for COPD in the past year, in whom ICS/LABA and oral theophylline were the most common used pharmacological therapy. On CT scanning, the majority of our patients (70.7%) showed no or minimal emphysema, while signs of previous tuberculosis were found in 45.1% of the patients.Conclusion: COPD patients living at the Tibet Plateau had a heavy respiratory symptom burden, but most of them did not receive adequate pharmacological treatment. Indoor biomass fuel exposure and previous tuberculosis were prevalent, while the emphysema phenotype was less common in this population.Keywords: chronic obstructive pulmonary disease, high altitude, phenotype, computed tomography

Zeli Huang,1,* Bojin Su,2,* Fang Liu,3,* Ning Zhang,1 Yilong Ye,4 Yang Zhang,1 Zhenghe Zhen,1 Shaoqiang Liang,1 Shaobo Liang,1 Lushi Chen,1 Weijun Luo,1 François X Claret,5,6 Ying Huang,7,8 Tao Xu1 1Department of Radiation Oncology, Cancer Center, First People’s Hospital of Foshan, Foshan 528000, Guangdong Province, People’s Republic of China; 2Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, People’s Republic of China; 3Department of Pathology, First People’s Hospital of Foshan, Foshan 528000, Guangdong Province, People’s Republic of China; 4Department of Infection, First People’s Hospital of Foshan, Foshan 528000, Guangdong Province, People’s Republic of China; 5Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; 6Experimental Therapeutics Academic Program and Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA; 7Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, People’s Republic of China; 8State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying HuangDepartment of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, People’s Republic of ChinaEmail huangying@sysucc.org.cnTao XuDepartment of Radiation Oncology, Cancer Center, First People’s Hospital of Foshan, Foshan 528000, Guangdong Province, People’s Republic of ChinaEmail asian.you@163.comIntroduction: Nasopharyngeal carcinoma (NPC) patients with HBsAg (+) commonly present with high frequencies of distant metastasis and poor survival rate; however, the mechanism has not been elucidated.Materials and Methods: We analyzed the yes-associated protein 1 (YAP1) expression between HBsAg (+) and HBsAg (-) of NPC patients, then analyzed the relationship of YAP1 with survival. We further explored the anti-tumor role in NPC cell lines using YAP1 siRNA technique, and checked whether YAP1 regulatesepithelial–mesenchymal transition ( EMT). The relationship between HBV X protein (HBx) and YAP1 was also tested using Dual-Luciferase reporter assay. Finally, we explored anti-YAP1 to inhibit tumor metastasis using the xenograft mice model.Results: In the current study, we found that YAP1 expression was higher in HBsAg (+) samples than in the HBsAg (-) samples, as a clinical signature, suggesting that YAP1 could be used as a prognostic factor for NPC. Our results showed that the HBx could regulate YAP1, further promoting cellular invasiveness through EMT. Anti-YAP1 can also decrease metastasis in vivo.Conclusion: Our findings suggest that YAP1 is a promising prognostic factor in NPC and could be used as a potential treatment target for NPC with HBV infection.Keywords: YAP1, hepatitis B, HBx, nasopharyngeal carcinoma, metastasis

Rui-huan Gan,1,* Li-song Lin,2,* Jing Xie,3–5,* Li Huang,2,4 Lin-can Ding,2 Bo-hua Su,2 Xian-e Peng,1,5 Da-li Zheng,4,5 You-guang Lu1,3 1Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, Affiliated First Hospital of Fujian Medical University, Fuzhou 350005, People’s Republic of China; 3Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350000, People’s Republic of China; 4Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350004, People’s Republic of China; 5Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350122, People’s Republic of China*These authors contributed equally to this workCorrespondence: You-guang LuDepartment of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, People’s Republic of ChinaTel +86 591 8373 6429Fax +86 591 8372 0599Email fjlyg63@fjmu.edu.cnXian-e PengDepartment of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou 350122, People’s Republic of ChinaTel +86 138 0951 6580Fax +86 591 8372 0599Email fmuxe@163.comPurpose: The Notch signaling pathway plays an oncogenic role in tongue squamous cell carcinoma. The aim of this study was to inhibit the proliferation and self-renewal of tongue cancer cells by applying Notch signaling pathway inhibitor FLI-06 (Selleck, USA) and to lay a foundation for the clinically targeted treatment of tongue cancer for the future.Methods: The mRNA expression level of Notch1 and the overall survival rate of patients with tongue cancer were examined by analyzing the TCGA database. Tongue cancer cells were treated with FLI-06. Cell proliferation, apoptosis, and stem cell self-renewal ability were tested in appropriate ways. A xenograft mouse model was established to observe tumor growth.Results: From the TCGA data, we demonstrated that patients with high expression of Notch1 had a poor prognosis. We observed that the Notch signaling pathway inhibitor FLI-06 can restrain the activation of the Notch signaling pathway, decrease cell proliferation and induce cell apoptosis in vitro. The xenograft experiment indicated that intraperitoneal injection of FLI-06 inhibited tumor growth and increased cell apoptosis. FLI-06 suppressed both the mRNA and protein expression of Notch receptor and Notch targeted genes. We also observed that FLI-06 suppressed the proliferation of tongue cancer stem cells.Conclusion: FLI-06 can block the proliferation and self-renewal of tongue cancer cells. It is inferred that this compound, which inhibits the Notch signaling pathway, may serve as a potential targeted drug for the treatment of tongue cancer in the clinic.Keywords: tongue cancer, Notch signaling pathway, Notch inhibitor, cancer stem cells

Feng Qiu,*,1 Bingsen Su,*,2 Zhao Li,3 Wenke Chen,1 Longbing Cao,1 Fu Chen,4 Dongdong Liu,4 Jingling He,5 Ni Lin31Department of Laboratory Medicine, Nanhai Hospital, Southern Medical University, Foshan, Guangdong 528244, People’s Republic of China; 2Department of Laboratory Medicine, Zhongshan Torch Development Zone Hospital, Zhongshan, Guangdong 528437, People’s Republic of China; 3Department of General Practice Center, Nanhai Hospital, Southern Medical University, Foshan, Guangdong 528244, People’s Republic of China; 4Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, People’s Republic of China; 5Department of Gynecology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, People’s Republic of China*These authors contributed equally to this workBackground: According to the statistics of WHO/IARC, cervical cancer (CC) has become the fourth malignant cancer of female worldwide and it is one of the main causes of death of women in developing countries.Purpose: Potential plasma and metabolic biomarkers for CC precancerous lesions and cervicitis were indicated by LC-MS techniques, and their underlying mechanisms and functions were analyzed.Methods: Plasma samples were selected from healthy people (control), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), CC, and post-treatment patients. All polypeptide types and sequences were detected by LC-MS/MS and the results were normalized by using Pareto-scaling. Potential metabolic biomarkers were screened by applying MetaboAnalyst 4.0 software and XCMS software, and analysis of variance and enrichment analysis were performed. Metabolic pathway analysis and functional enrichment analysis were used to further investigate the significance and pathological mechanisms of potential biomarkers.Results: Compared with healthy people, 9 differentially expressed metabolites were screened, 4 of which were up-regulated and 5 were down-regulated. LSIL group screened 7 differentially expressed metabolites, 5 of which were up-regulated and 2 were down-regulated; CC group screened 12 differentially expressed metabolites were screened, of which 9 were up-regulated and 3 were down-regulated. Eight differentially expressed metabolites were screened in the IF group, of which 5 showed up-regulation and 3 showed down-regulation. In functional enrichment analysis, differential metabolism was found to be associated with addition and coagulation cascades. Among all potential biomarkers, 2-amino-3-methyl-1-butanol, L-carnitine, Asn Asn Gln Arg, Ala Cys Ser Trp, Soladulcidine, Ala Ile Gln Arg, 2-amino-3 -Methyl-1-butanol, L-carnitine, Asn Asn Gln Arg, Ala Cys Ser Trp, Soladulcidine, Ala Ile Gln Arg can be used as predictors of precancerous lesions at different stages of CC. Among all biomarkers, 6α-fluoro-11β1,17-dihydroxypren-4-ene-3,20-dione has higher expression in the CC and HSIL groups and lower expression in the treatment group.Conclusion: By applying molecular markers to assess the progression of the disease, the accuracy and specificity of the diagnosis can be improved, which has certain prospects in clinical applications.Keywords: cervical precancerous lesion, acute cervicitis, LC-MS, metabonomics, serum biomarkers

Tiansheng Liu,1,2 Jinchao Ma,3 Bin Su,4 Hao Wang,3 Qi Wang,3 Xinlong Ma1,2 1Department of Orthopaedic Surgery, The General Hospital of Tianjin Medical University, 2Department of Orthopaedic Surgery, Tianjin Hospital, 3Department of Orthopaedic Surgery, 4Department of Pneumology, the Affiliated Hospital of Logistics University of PAP, Tianjin, People’s Republic of China Objective: To investigate the long-term efficacy of a combination treatment of alendronate, extracorporeal shock and hyperbaric oxygen for osteonecrosis of the femoral head (ONFH) of post-severe acute respiratory syndrome (SARS) patients.Patients and methods: The retrospective study was performed including a total of 37 post-SARS ONFH patients (66 hip joints) in the Department of Orthopedics of the General Hospital of Tianjin Medical University between November 2003 and November 2015, consisting of 6 males (11 hip joints) and 31 females (55 hip joints), with age between 19 and 47 years (average 29.9 years). Visual analog scale (VAS) score, Harris score and Association Research Circulation Osseous (ARCO) stage of imaging examination were compared among those before treatment, and at 1, 3, 6, 9 and 12 years after treatment. Paired t-test was used for statistical analysis of VAS and Harris score before and after treatment. Difference of effective rate on all stages was analyzed with Chi-square test.Results: With 12-year follow-up, significant improvements on VAS (6.81 of pre-treatment vs 3.94 of 12-year post-treatment) and Harris score (74.54 of pre-treatment vs 80.14 of 12-year post-treatment) were observed (all p

Yifeng Sun,1,* Likun Hou,2,* Yu Yang,1 Huikang Xie,2 Yang Yang,1 Zhigang Li,1 Heng Zhao,1 Wen Gao,3 Bo Su4 1Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, 2Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 3Department of Thoracic Surgery, Shanghai Huadong Hospital, Fudan University School of Medicine, Shanghai, 4Central Lab, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: In this study, we investigated the contribution of a gene expression–based signature (composed of BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR) to survival prediction for early-stage lung adenocarcinoma categorized by the new International Association for the Study of Lung Cancer (IASLC)/the American Thoracic Society (ATS)/the European Respiratory Society (ERS) classification. We also aimed to verify whether gene signature improves the risk discrimination of IASLC/ATS/ERS classification in early-stage lung adenocarcinoma. Patients and methods: Total RNA was extracted from 93 patients with pathologically confirmed TNM stage Ia and Ib lung adenocarcinoma. The mRNA expression levels of ten genes in the signature (BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, and SH3BGR) were detected using real-time polymerase chain reaction. Each patient was categorized according to the new IASLC/ATS/ERS classification by accessing hematoxylin–eosin-stained slides. The corresponding Kaplan–Meier survival analysis by the log-rank statistic, multivariate Cox proportional hazards modeling, and c-index calculation were conducted using the programming language R (Version 2.15.1) with the “risksetROC” package. Results: The multivariate analysis demonstrated that the risk factor of the ten-gene expression signature can significantly improve the discriminatory value of TNM staging in survival prediction, but not the value of the IASLC/ATS/ERS classification. Further analysis suggested that only BRCA1 and ERBB3 in the signature were independent risk factors after adjusting for the IASLC/ATS/ERS classification by Cox regression. A new algorithm of the two-gene expression signature containing BRCA1 and ERBB3 was generated. Adding the two-gene signature into the IASLC/ATS/ERS classification model further improved the discriminatory c-statistic from 0.728 to 0.756. Conclusion: The two-gene signature composed of BRCA1 and ERBB3 was an independent risk factor of the IASLC/ATS/ERS classification, which can be used to improve the discriminatory power of prognosis prediction of the IASLC/ATS/ERS classification in early-stage lung adenocarcinoma. The two-gene signature combination with the IASLC/ATS/ERS classification might contribute to better patient stratification for adjuvant chemoradiotherapy or targeted therapy after the surgery. Keywords: molecular biomarker, prognosis, lung, adenocarcinoma

Yongzhu Chen,1 Chengkang Tang,2 Jie Zhang,2 Meng Gong,3 Bo Su,2 Feng Qiu4 1Periodical Press, 2Core Facility of West China Hospital, 3Laboratory of Endocrinology and Metabolism, West China Hospital, 4Laboratory of Anaesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Background: Finding a suitable delivery system to improve the water solubility of hydrophobic drugs is a critical challenge in the development of effective formulations. In this study, we used A6K, a self-assembling surfactant-like peptide, as a carrier to encapsulate and deliver hydrophobic pyrene.Methods: Pyrene was mixed with A6K by magnetic stirring to form a suspension. Confocal laser scanning microscopy, transmission electron microscopy, dynamic light scattering, atomic force microscopy, fluorescence, and cell uptake measurements were carried out to study the features and stability of the nanostructures, the state and content of pyrene, as well as the pyrene release profile.Results: The suspension formed contained pyrene monomers trapped in the hydrophobic cores of the micellar nanofibers formed by A6K, as well as nanosized pyrene crystals wrapped up and stabilized by the nanofibers. The two different encapsulation methods greatly increased the concentration of pyrene in the suspension, and formation of pyrene crystals wrapped up by A6K nanofibers might be the major contributor to this effect. Furthermore, the suspension system could readily release and transfer pyrene into living cells.Conclusion: A6K could be further exploited as a promising delivery system for hydrophobic drugs. Keywords: pyrene, self-assembling peptide, micelles, nanofibers, drug delivery

Michelle Cheng,1,* Samantha Ho,1,* Jun Hwan Yoo,1,2,* Deanna Hoang-Yen Tran,1,* Kyriaki Bakirtzi,1 Bowei Su,1 Diana Hoang-Ngoc Tran,1 Yuzu Kubota,1 Ryan Ichikawa,1 Hon Wai Koon1 1Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 2Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Republic of Korea *These authors share co-first authorship Background: Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. Methods: We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial–mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Results: Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-ß1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation. Conclusion: Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast-supported colon cancer cell proliferation. Keywords: colon cancer, epithelial–mesenchymal transition, fibroblasts

Xiaotong Qi,1 Hong Li,2 Bo Qiao,1 Weichao Li,1 Xinyan Hao,2 Jun Wu,1 Bao Su,1 Dianming Jiang1 1Department of Orthopedics, The First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China; 2School of Physical Science and Technology, Sichuan University, Chengdu, People's Republic of China Abstract: A novel injectable bone cement was developed by integration of nano calcium-deficient hydroxyapatite/multi(amino acid) copolymer (n-CDHA/MAC) and calcium sulfate hemihydrate (CSH; CaSO4 · 1/2H2O). The structure, setting time, and compressive strength of the cement were investigated. The results showed that the cement with a liquid to powder ratio of 0.8 mL/g exhibited good injectability and appropriate setting time and mechanical properties. In vitro cell studies indicated that MC3T3-E1 cells cultured on the n-CDHA/MAC/CSH composite spread well and showed a good proliferation state. The alkaline phosphatase activity of the MC3T3-E1 cells cultured on the n-CDHA/MAC/CSH composite was significantly higher than that of the cells on pure CSH at 4 and 7 days of culture. The n-CDHA/MAC/CSH cement was implanted into critical size defects of the femoral condyle in rabbits to evaluate its biocompatibility and osteogenesis in vivo. Radiological and histological results indicated that introduction of the n-CDHA/MAC into CSH enhanced new bone formation, and the n-CDHA/MAC/CSH cement exhibited good biocompatibility and degradability. In conclusion, the injectable n-CDHA/MAC/CSH composite cement has a significant clinical advantage over pure CSH cement, and may be a promising bone graft substitute for the treatment of bone defects. Keywords: calcium-deficient hydroxyapatite, multi(amino acid) copolymer, calcium sulfate hemihydrate, injectability, biocompatibility, osteogenesis

Background and objectivesObesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis.Materials and methodsMale C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay.ResultsLentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects.ConclusionsCathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.

Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.

Recent genetic association studies have implicated several candidate susceptibility variants for schizophrenia among general populations. Rs1344706, an intronic SNP within ZNF804A, was identified as one of the most compelling candidate risk SNPs for schizo