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Haohua Yuan,1 Huan Gui,1 Shuanghui Chen,1 Lan Zhu,1 Chenglv Wang,1 Qianyu Jing,2 Hang Lv,1 Quan Wan,2 Shuyi Wang,1 Shengwen Zhou,1 Xiaodong Ren,1 Yingjie Nie,1,3 Linzhao Li1 1Medical College, Guizhou University, Guizhou Province, 550025, People’s Republic of China; 2School of Preclinical Medicine of Zunyi Medical University, Zunyi, Guizhou Province, 563000, People’s Republic of China; 3NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, 550002, People’s Republic of ChinaCorrespondence: Yingjie Nie; Linzhao Li, Medical College of Guizhou University, Guiyang, Guizhou Province, 550025, People’s Republic of China, Tel +86-085188274013; +86-085188274016, Email nienyj@hotmail.com; lzli@gzu.edu.cnPurpose: This study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (R848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-HP-β-CD).Methods: R848-loaded PLGA nanoparticles modified with 2-HP-β-CD (CD@R848@NPs) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with IR-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of CD@R848@NPs in combination with an anti-TNFR2 antibody were investigated using an MC-38 colon adenocarcinoma model in vivo.Results: The average size of the CD@R848@NPs was 376 ± 30 nm, and the surface charge was 21 ± 1 mV. Through this design, the targeting ability of 2-HP-β-CD can be leveraged and R848 is delivered to tumor-supporting M2-like macrophages in an efficient and specific manner. Moreover, we used an anti-TNFR2 antibody to reduce the proportion of Tregs. Compared with plain PLGA nanoparticles or R848, CD@R848@NPs increased penetration in tumor tissues, dramatically reprogrammed M1-like macrophages, removed tumors and prolonged patient survival.Conclusion: The new nanocapsule system is a promising strategy for targeting tumor, reprogramming tumor -associated macrophages, and enhancement immunotherapy.Keywords: R848, 2-HP-β-CD, anti-TNFR2, TIME, immunotherapy

Yong Zhang,1 Kaisa Cui,2 Yaoxiang Yang,3 Bingxin Liu,4 Minzheng Zhu,1 Hanqing Chen,1 Chong Zhao,1 Youlian Zhou,1 Yuqiang Nie1 1Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, People’s Republic of China; 2Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, People’s Republic of China; 3Department of Pathology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, People’s Republic of China; 4The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, People’s Republic of ChinaCorrespondence: Yuqiang Nie; Youlian Zhou, Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Panfu Road 1, Yuexiu District, Guangzhou, Guangdong, 510006, People’s Republic of China, Tel/Fax +86 20 81048888, Email eynieyuqiang@scut.edu.cn; eyyoulianzhou@scut.edu.cnIntroduction: Immune checkpoint (IC) inhibitor-related immunotherapies have attracted considerable attention in hepatocellular carcinoma (HCC). High IC expression and high tumor infiltrating lymphocyte levels are the current indicators of sensitivity to IC inhibitors. Thus, it is imperative to apply precision medicine strategies for patient selection.Methods: Six independent HCC cohorts were used for analysis at the single-cell and tissue levels. Multiplex immunofluorescence and immunochemistry staining assays were used to validate our results. A series of methodologies were used for immune-related evaluations.Results: Herein, we uncovered a unique CD8+CD274+ cell subpopulation that is associated with tumor progression and poor survival in HCC at the single-cell level. We assessed this subset at the tissue level and found that the prognostic significance of CD274 is dependent on CD8A expression in HCC. Subsequently, we identified a unique high-risk subpopulation that showed high CD8A expression coupled with intense CD274 expression in multiple HCC cohorts. CD8AHighCD274High* subgroup was correlated with malignant indexes and remained an independent prognostic factor when considering the influence of these indexes. Molecular characteristic analyses showed that the CD8AHighCD274High* subgroup harbored more mutations, had higher immune response activity and presented enrichment of cancer-related biological processes. Moreover, this high-risk subpopulation in HCC was characterized by high immune cell infiltration, low tumor purity, and enrichment of cancer-related signatures. Finally, cases with this phenotype demonstrated higher immunomodulator and IC levels and greater sensitivity to IC inhibitors.Conclusion: Our findings illustrate that some HCC patients may have a poor prognosis despite high CD8+ T-cell infiltration. These patients would probably benefit from IC inhibitor-based combination treatment.Keywords: hepatocellular carcinoma, CD8A, CD274, molecular subtype, tumor microenvironment, immune overdrive

Jing Wang,1 Shuanghu Fang,1 Chunying Yang,2 Xiaobin Tang,3 Luosha Zhu,3 Yu Nie4 1School of Educational Science, Anhui Normal University, Wuhu, People’s Republic of China; 2School of Special Education, Zhengzhou Normal University, Zhengzhou, People’s Republic of China; 3School of Marxism, Anhui Normal University, Wuhu, People’s Republic of China; 4Office of Student Affairs, Anhui Normal University, Wuhu, People’s Republic of ChinaCorrespondence: Shuanghu Fang, Email fsh9075@163.comPurpose: To explore the potential classification of psychological flexibility (PF) among Chinese college students, analyze whether there is group heterogeneity in PF, and discuss the differences in the latent profile of PF in the negative emotions of depression, anxiety, and stress.Methods: A total of 1769 college students were investigated using the Psychological Flexibility Questionnaire and Depression-Anxiety-Stress Self-rating Scale, and heterogeneity was tested by latent profile analysis.Results: The PF of college students can be divided into three latent profiles: self-contradiction group (19.2%), high PF group (34.1%), and low PF group (46.7%). The scores of depression, anxiety, and stress are significantly different among the groups.Conclusion: There is obvious group heterogeneity in the PF of college students, and they can be divided into the self-contradiction group, the high PF group, and the low PF group. The self-contradiction and low PF groups score significantly higher on the negative emotions of depression, anxiety, and stress than the high PF group.Keywords: acceptance and commitment therapy, psychological flexibility, negative emotions, latent profile analysis

Jingyu Zhang,1,* Yinxia Zhan,2,* Jiaojiao Chen,2 Dan Kang,2 Rumei Xiang,2 Ruoyi Zhang,2 Yubo Zhang,1 Yang Pu,2 Jiayuan Zhang,1 Lijun Zhang,2 Yanyan Huang,2 Ruoyan Gong,2 Xueyao Su,2 Yuxian Nie,1 Qiuling Shi1,2 1State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, People’s Republic of China; 2School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiuling Shi, State Key Laboratory of Ultrasound in Medicine and Engineering, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-18290585397, Email qshi@cqmu.edu.cnBackground: Patients with hepatobiliary or pancreatic cancers often experience severe symptoms, resulting in a sharp decline in functioning, poor quality of life, and increased mortality risk. Early and effective management of symptoms allows a better quality of life and reduced mortality, depending on the selection of appropriate assessment of specific symptoms for a defined purpose. We aimed to develop a symptom measurement item bank for hepatobiliary or pancreatic cancers.Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was applied to organize this systematic review. The articles validated patient-reported outcome measures (PROMs) for hepatobiliary or pancreatic cancer and published before December 2021 were retrieved from the Web of Science, PubMed, Embase databases and Cochrane Library. Items from the existing PROMs were selected and classified into different patient-reported symptoms based on the concepts and specific underlying constructs of the objects measured.Results: Sixteen unique PROMs were identified across the 29 eligible studies included in our analysis. Items from the literature review (14 PROMs with 421 items for which information was obtained) were selected and classified. As a result of this study, we developed a symptom item bank with 40 patient-reported symptoms and 229 assessment items for hepatobiliary or pancreatic cancer, and fatigue, pain and nausea were the most common symptom items.Conclusion: We developed an item bank to assess the patient-reported symptoms of hepatobiliary or pancreatic cancer. This item bank could allow researchers to select appropriate measures of symptom and provide a basis for the development of a single-item symptom-measurement system.Keywords: patient-reported outcome measures, symptom, item bank, pancreatic carcinoma, hepatocellular carcinoma, cholangiocarcinoma, systematic review

Weiquan Liang,1,* Yiyu Lu,2,* Xingxi Pan,2,* Yunxiang Zeng,1 Weiqiang Zheng,1 Yiran Li,1 Yuanhang Nie,1 Dongbing Li,3 Dongliang Wang3 1Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Foshan (Affiliated Foshan Hospital of Southern Medical University), Foshan, 528200, People’s Republic of China; 2Department of Oncology, The Sixth Affiliated Hospital, South China University of Technology, Foshan, 528200, People’s Republic of China; 3ChosenMed Technology Beijing Co., Ltd, Beijing, 100853, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiquan Liang, Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Foshan (Affiliated Foshan Hospital of Southern Medical University), Weiguo Lu 78, Foshan, Guangdong, 528200, People’s Republic of China, Email ribby8@126.comBackground: There is no clear information regarding the role of FAM181A antisense RNA 1 (FAM181A-AS1) in lung adenocarcinoma (LUAD). We explored the relationship between FAM181A-AS1 and LUAD using bioinformatics analysis and experimental validation in this study.Methods: Statistics and databases were used to evaluate the relationship between clinical features in LUAD patients and FAM181A-AS1 expression, prognostic factors, regulation network, and immune infiltration of FAM181A-AS1 in function. LUAD cell lines were tested for FAM181A-AS1 expression using qRT-PCR.Results: FAM181A-AS1 showed significantly low expression in LUAD patients. Low FAM181A-AS1 expression predicted a poorer overall survival (OS) (HR: 0.66; 95% CI: 0.49– 0.88; P=0.005) and disease specific survival (DSS) (HR: 0.64; 95% CI: 0.44– 0.92; P=0.017) of LUAD patients. There was also an independent correlation between low FAM181A-AS1 expression (HR: 0.547; 95% CI: 0.350– 0.857; P=0.008) and OS in LUAD patients. The FAM181A-AS1 high-expression phenotype was differentially enriched for M phase, cellular senescence, cell cycle checkpoints, chromatin modifying enzymes, ESR-mediated signaling, DNA repair, G2/M checkpoints, HCMV infection, and DNA double-strand break repair. A correlation was found between the expression of FAM181A-AS1 and immune infiltrating cells. A significant decrease in FAM181A-AS1 expression was observed in LUAD cell lines compared to Beas-2B.Conclusion: There was a significant association between low FAM181A-AS1 expression in LUAD patients and poor survival and immune infiltration. The FAM181A-AS1 gene may provide a useful biomarker for LUAD prognosis and immunotherapy response.Keywords: lung adenocarcinoma, FAM181A-AS1, prognosis, immune infiltration, biomarker

Yuanliu Nie,1 Guangyue Yao,1 Liang Li,2 Alei Feng,3 Wentao Zhang,4 Xiaoying Xu,5 Qiang Li,1,3 Zhe Yang1,3 1Tumor Research and Therapy Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, People’s Republic of China; 2Department of Thoracic Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, People’s Republic of China; 3Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 4Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 5Shandong First Medical University, College of Basic Medicine, Shandong First Medical University-Shandong Academy of Medical Sciences, Jinan, Shandong, 250000, People’s Republic of ChinaCorrespondence: Qiang Li; Zhe Yang, Tumor Research and Therapy Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, People’s Republic of China, Tel +86 15053162586; +86 13791089059, Email lq1211@126.com; sdslyyyz@sina.comPurpose: The present study assessed the effects of radiotherapy on overall survival (OS) and progression-free survival time (PFS) in patients with stage II or higher esophageal cancer receiving immunotherapy; evaluated factors independently prognostic of OS and PFS in these patients; and utilized these factors to establish a prognostic nomogram.Patients and Methods: This study enrolled 134 patients with stage II or higher esophageal cancer treated with chemotherapy (platinum-based agents plus paclitaxel or fluorouracil) and immunotherapy. These patients were divided into two groups, a radiotherapy (RT) group (n = 55) and a non-radiotherapy (non-RT) group (n = 79). Following 1:1 propensity score matching, OS and PFS were compared by the Kaplan–Meier method, and factors associated with survival were determined by univariate and multifactorial Cox regression analyses. These factors were used to construct a prognostic nomogram.Results: After propensity matching, all covariates were well balanced in the two groups (all P > 0.05). After matching, both median PFS (15.70 months [95% confidence interval (CI) 8.68– 22.72 months] vs 5.70 months [95% CI 3.38– 8.02 months], P = 0.002) and median OS (15.72 months [95% CI 12.94– 18.46 months] vs 12.06 months [95% CI 9.91– 14.20 months], P = 0.036) were significantly longer in the RT than in the non-RT group. Univariate and multifactorial analyses showed that RT, neutrophil-lymphocyte ratios, and tumor differentiation were independently prognostic of OS, with all hazard ratios (HRs) < 1 and all P-values < 0.05. A nomogram based on these factors was constructed, and its accuracy was verified.Conclusion: Immunotherapy plus RT resulted in better survival outcomes than immunotherapy alone. A nomogram based on prognostic factors can guide personalized treatment and monitor prognosis.Keywords: prognosis, combination therapy, survival, neutrophil-lymphocyte ratio, NLR

Scanning tunneling microscopy (STM) at 5 K is used to study WSe2 layers grown on epitaxial graphene which is formed on Si-terminated SiC(0 0 0 1). Specifically, a partial hydrogenation process is applied to intercalate hydrogen at the SiC-graphene interface, yielding areas of quasi-free-standing bilayer graphene coexisting with bare monolayer graphene. We find that an abrupt and structurally perfect homojunction (band-edge offset ∼0.25 eV) is formed when WSe2 overgrows a lateral junction between adjacent monolayer and quasi-free-standing bilayer areas in the graphene. The band structure modulation in the WSe2 overlayer arises from the varying work function (electrostatic potential) of the graphene beneath. Scanning tunneling spectroscopy measurements reveal that this effect can be also utilized to create WSe2 quantum dots that confine either valence or conduction band states, in agreement with first-principles band structure calculations.

Multiple second heart field (SHF) transcription factors are involved in cardiac development. In this article we evaluate the relationship between SHF transcription factor polymorphisms and congenital heart disease (CHD). Ten polymorphisms were used for genotyping, and three of these were used for the luciferase assay. The risk of CHD was increased 4.31 times and 1.54 times in the C allele of GATA5: rs6061243 G>C and G allele of TBX20: rs336283 A>G, respectively. The minor alleles of SMYD1: rs1542088 T>G, MEF2C: rs80043958 A>G and GATA5: rs6587239 T>C increased the risk of the simple types of CHD. The minor alleles of GATA5: rs41305803 G>A and MEF2C: rs304154 A>G increased the risk of tetralogy of Fallot (TOF). The minor alleles of TBX20: rs336284 A>G and SMYD1: rs88387557 T>G only increased the risk of a single ventricle (SV). Luciferase assays revealed that the minor alleles of rs304154 and rs336284 decreased the transcriptional levels of MEF2C and TBX20, respectively (p

Qingsong Yu,1 Hongfan Yu,1 Wei Xu,1 Yang Pu,1 Yuxian Nie,2 Wei Dai,3 Xing Wei,3 Xin Shelley Wang,4 Charles S Cleeland,4 Qiang Li,3 Qiuling Shi1,2,5 1School of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of China; 2State Key Laboratory of Ultrasound in Medicine and Engineering, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Thoracic Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 4Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Center for Cancer Prevention Research, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Qiuling Shi, School of Public Health and Management, Chongqing Medical University, No. 1, Medical School Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-18290585397, Fax +86-28-85420116, Email qshi@cqmu.edu.cnPurpose: Patient-reported outcome (PRO)-based symptom assessment with a threshold can facilitate the early alert of adverse events. The purpose of this study was to determine whether shortness of breath (SOB) on postoperative day 1 (POD1) can inform postoperative pulmonary complications (PPCs) for patients after lung cancer (LC) surgery.Methods: Data were extracted from a prospective cohort study of patients with LC surgery. Symptoms were assessed by the MD Anderson Symptom Inventory-lung cancer module (MDASI-LC) before and daily after surgery. Types and grades of complications during hospitalization were recorded. SOB and other symptoms were tested for a possible association with PPCs by logistic regression models. Optimal cutpoints of SOB were derived, using the presence of PPCs as an anchor.Results: Among 401 patients with complete POD1 MDASI-LC and records on postoperative complications, 46 (11.5%) patients reported Clavien–Dindo grade II-IV PPCs. Logistic regression revealed that higher SOB score on POD1 (odds ratio [OR]=1.13, 95% CI=1.01– 1.27), male (OR=2.86, 95% CI=1.32– 6.23), open surgery (OR=3.03, 95% CI=1.49– 6.14), and lower forced expiratory volume in one second (OR=1.78, 95% CI=1.66– 2.96) were significantly associated with PPCs. The optimal cutpoint was 6 (on a 0– 10 scale) for SOB. Patients reporting SOB < 6 on POD1 had shorter postoperative length of stay than those reporting 6 or greater SOB (median, 6 vs 7, P =0.007).Conclusion: SOB on POD1 can inform the onset of PPCs in patients after lung cancer surgery. PRO-based symptom assessment with a clinically meaningful threshold could alert clinicians for the early management of PPCs.Keywords: lung cancer, surgery, postoperative pulmonary complications, patient-reported outcomes, shortness of breath

Yanwu Nie,1,&ast; Chenchen Wang,2,&ast; Lei Yang,3 Zhen Yang,4 Yahong Sun,4 Maozai Tian,5,6 Yuhua Ma,7,8 Yuxia Zhang,9 Yimu Yuan,10 Liping Zhang6 1State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, School of Public Health, Xinjiang Medical University, Urumqi, 830017, People’s Republic of China; 2Center for Disease Control and prevention of Xinjiang Uygur Autonomous Region, Urumqi, 830017, People’s Republic of China; 3School of Nursing, Xinjiang Medical University, Urumqi, 830017, People’s Republic of China; 4School of Public Health, Xinjiang Medical University, Urumqi, 830017, People’s Republic of China; 5Center for Applied Statistics, School of Statistics, Renmin University of China, Beijing, 100872, People’s Republic of China; 6College of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, 830017, People’s Republic of China; 7Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People’s Republic of China; 8Department of Pathology, Karamay Central Hospital of XinJiang Karamay, Karamay, Xinjiang Uygur Autonomous Region, 834000, People’s Republic of China; 9Department of Clinical Nutrition, Urumqi Maternal and Child Health Institute, Urumqi, 830001, People’s Republic of China; 10Department of General Practice Medicine, Xinjiang Corps Hospital, Urumqi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liping Zhang, Email zhanglp1219@163.comPurpose: The role of inorganic arsenic (iAs) in the risk of metabolic syndrome (MetS) remains unclear. This investigation focused on the effect of iAs exposure on MetS and whether the results are consistent in different subgroups.Patients and Methods: The present study was conducted on 629 men and 616 women aged 35– 70 years and living in Xinjiang Uygur Autonomous Region, China. The 1:1 propensity score matching (PSM) was adopted to regulate the confounding factors, and the multivariate logistic regression was performed to assess the relationship between urinary iAs and MetS.Results: The median content of urinary iAs was examined as 2.20 μg/dL (interquartile range: 1.30– 3.20 μg/dL), and the MetS prevalence reached 23.69% (295 cases/950 participants). After the confounding factors were adjusted, the ORs (95% CIs) for MetS from the minimal to the maximum urinary iAs quartiles reached 1.171 (0.736,1.863), 1.568 (1.008, 2.440) and 2.011 (1.296, 3.120), respectively (referencing 1.00) (P for trend=0.001). After the PSM, the urinary iAs content still plays a potential prediction role in MetS (P for trend=0.011). In addition, as revealed from the subgroup analysis, the urinary iAs content was a predictor of MetS in the female patients, whereas it did not serve as a significant predictor of MetS in the male patients (P for interaction< 0.05).Conclusion: The increased urinary iAs content was associated with the increased prevalence of MetS in Chinese population. More attention should be paid to female urinary iAs content to avoid the high prevalence of MetS.Keywords: metabolic syndrome, urinary inorganic arsenic, propensity score matching, subgroup analysis

Creating oxide interfaces with precise chemical specificity at the atomic layer level is desired for the engineering of quantum phases and electronic applications, but highly challenging, owing partially to the lack of in situ tools to monitor the chemical composition and completeness of the surface layer during growth. Here we report the in situ observation of atomic layer-by-layer inner potential variations by analysing the Kikuchi lines during epitaxial growth of strontium titanate, providing a powerful real-time technique to monitor and control the chemical composition during growth. A model combining the effects of mean inner potential and step edge density (roughness) reveals the underlying mechanism of the complex and previously not well-understood reflection high-energy electron diffraction oscillations observed in the shuttered growth of oxide films. General rules are proposed to guide the synthesis of atomically and chemically sharp oxide interfaces, opening up vast opportunities for the exploration of intriguing quantum phenomena at oxide interfaces.

Yanting Nie, Yiling Ding, Mengyuan Yang Department of Obstetrics and Gynecology, Second Xiangya Hospital of Central South University, Changsha, People’s Republic of ChinaCorrespondence: Mengyuan Yang Email yangmengyuan_xy@csu.edu.cnBackground: GRHL2 has been shown to function in ovarian carcinogenesis. However, the relationship between GRHL2 and cisplatin (DDP) resistance in serous ovarian cancer (SOC) is not clear. The purpose of this study was to elucidate the function and mechanism of GRHL2 in DDP resistance of SOC.Materials and Methods: Immunohistochemistry (IHC) was utilized to identify GRHL2 protein expression in DDP resistant and sensitive SOC tissues. GRHL2 mRNA and protein levels were identified using quantitative real-time PCR (qRT-PCR) and Western blotting in SKOV3/DDP and SKOV3 cell lines. We conducted loss- and gain-of-function experiments to uncover the consequence of GRHL2 knockdown or overexpression on the sensitivity of ovarian cancer cells to DDP in vitro and in vivo and the underlying mechanism.Results: It was observed that expression of GRHL2 was higher in DDP resistant SOC tissues relative to DDP sensitive SOC tissues. In addition, the increased expression of GRHL2 led to shorter progression-free survival (PFS) and overall survival (OS). Meanwhile, the GRHL2 transcript and protein levels in SKOV3/DDP were also higher than SKOV3. Small hairpin RNA (shRNA)-facilitated GRHL2 gene knockdown considerably heightened the sensitivity of SKOV3/DDP cells to DDP by inhibiting proliferation and promoting apoptosis, while up-regulation of GRHL2 significantly reduced the sensitivity of SKOV3 cells to DDP by promoting proliferation and decreasing apoptosis. In addition, GRHL2 promotes DDP resistance of SOC through activation of ERK/MAPK signaling pathways.Conclusion: Our results suggest that GRHL2 up-regulation predicts a poor prognosis and promotes the resistance of SOC to DDP. Therefore, GRHL2 may be a possible treatment target for cisplatin-resistant serous ovarian cancer.Keywords: serous ovarian cancer, SOC, GRHL2, cisplatin resistance, ERK/MAPK

Fei Pei,1,2,* Guan-Rong Zhang,3,* Li-Xin Zhou,4 Ji-Yun Liu,5 Gang Ma,6 Qiu-Ye Kou,7 Zhi-Jie He,8 Min-Ying Chen,1 Yao Nie,1 Jian-Feng Wu,1,2 Xiang-Dong Guan1 On behalf of the China Critical Care Immunotherapy Research Group1Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People’s Republic of China; 2Clinical Trial Unit, The First Affiliated Hospital, Sun Yat-sen University & The University of Birmingham, Guangzhou 510080, People’s Republic of China; 3Information and Statistics Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, People’s Republic of China; 4Department of Critical Care Medicine, Foshan First Municipal People’s Hospital, Foshan 528000, People’s Republic of China; 5Department of Critical Care Medicine, Guangzhou First Municipal People’s Hospital, Guangzhou 510180, People’s Republic of China; 6Department of Critical Care Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou 510060, People’s Republic of China; 7Department of Critical Care Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, People’s Republic of China; 8Department of Critical Care Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian-Feng Wu Email wujianf@mail.sysu.edu.cnXiang-Dong Guan Email guanxiangdong1962@163.comPurpose: Although immune dysfunction has been investigated in adult septic patients, early immune status remains unclear. In this study, our primary aim was to assess early immune status in adult patients with sepsis stratified by age and its relevance to hospital mortality.Patients and Methods: A post hoc analysis of a multicenter, randomized controlled trial was conducted; 273 patients whose immune status was evaluated within 48 hours after onset of sepsis were enrolled. Early immune status was evaluated by the percentage of monocyte human leukocyte antigen-DR (mHLA-DR) in total monocytes within 48 hours after onset of sepsis and it was classified as immunoparalysis (mHLA-DR ≤ 30%) or non-immunoparalysis (> 30%). Three logistic regression models were conducted to explore the associations between early immunoparalysis and hospital mortality. We also developed two sensitivity analyses to find out whether the definition of early immune status (24 hours vs 48 hours after onset of sepsis) and immunotherapy affect the primary outcome.Results: Of the 181 elderly (≥ 60yrs) and 92 non-elderly (< 60yrs) septic patients, 71 (39.2%) and 25 (27.2%) died in hospital, respectively. The percentage of early immunoparalysis in the elderly was twice of that in the non-elderly patients (32% vs 16%, p=0.006). For the elderly, hospital mortality was higher in the immunoparalysis ones than the non-immunoparalysis ones (53.4% vs 32.5%, p=0.009). But there was no significant difference in hospital mortality between immunoparalysis non-elderly patients and non-immunoparalysis non-elderly ones (33.5% vs 26.0%, p=0.541). By means of logistic regression models, we found that early immunoparalysis was independently associated with increased hospital mortality in elderly, but not in non-elderly patients. Sensitivity analysis further confirmed the definition of early immune status and immunotherapy did not affect the outcomes.Conclusion: The elderly were more susceptible to early immunoparalysis after onset of sepsis. Early immunoparalysis was independently associated with poor prognosis in elderly, but not in non-elderly patients.Keywords: early immune status, elderly, mHLA-DR, immunosuppression, immunoparalysis, sepsis