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Li Wang, Dongling Tang, Pingan Zhang Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaCorrespondence: Pingan Zhang, Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China, Tel +86 13971196429, Email zhangpingan927@163.comPurpose: The glucose metabolic reprogramming is an important pathological mechanism in sepsis, which involves a series of enzymes including Pyruvate kinase M2 (PKM2). The purpose of this study is to explore the diagnostic and prognostic value of serum PKM2 in sepsis patients.Patients and Methods: This study recruited 143 sepsis patients, 91 non-sepsis patients, and 65 physical examiners, divided into sepsis group, non-sepsis group, and control group. Measure the serum PKM2 concentration of subjects, collect and analyze clinical and laboratory indicators of all subjects. Independent risk factors were selected by Logistic regression analysis. The area under curve (AUC) was calculated by plotting the receiver operating characteristic (ROC) curve to determine the diagnostic and prognostic value of biomarkers.Results: Compared with non-sepsis and control groups, the serum PKM2 levels in the sepsis group were significantly increased (both P< 0.001). PKM2 was an independent risk factor for sepsis and had the best diagnostic efficacy when combined with procalcitonin, with the AUC value of 0.9352. Patients with high levels of PKM2 were more likely to experience organ damage and had a higher incidence of septic shock. On the 1st and 3rd days of admission, the serum PKM2 levels in the septic shock group were higher than those in the sepsis group (both P< 0.05), with AUC values of 0.7296 and 0.6247, respectively. On the 3rd and 7th days of admission, the serum PKM2 levels in the non-survival group were significantly higher than those in the survival group (both P< 0.001), with AUC values of 0.7033 and 0.8732, respectively.Conclusion: The serum PKM2 levels in sepsis patients are significantly increased and correlated with disease severity and clinical outcomes. PKM2 may be a new diagnostic and prognostic biomarker for sepsis.Keywords: sepsis, PKM2, glucose metabolic reprogramming, diagnosis, prognosis

We present experimental and computational results for the global drag force on a model Tension-Leg Platform (TLP) in uniform current for various values of the Reynolds number in the subcritical regime (Re = 104 - 1.06×105). The objective of the experiments, which were performed in a towing tank on a representative TLP configuration, was to provide data suitable for validating numerical model predictions. The purpose of the simulations was to determine the extent to which Large-Eddy Simulations (LES), when used as a truly predictive tool, can be relied upon to provide reliable estimates of the total drag force. Thus the simulations were performed only once with no further computations performed in order to bring about closer agreement with the measurements. The dependence of the computed results on the numerical grid was checked using the Grid-Convergence Index (GCI) method applied to results from benchmark flows. These results also served to assess the dependence on the value of the Smagorinsky constant in the model for the sub-grid scale terms. It was found that, at the highest value of Reynolds number considered, the variation between the measured and predicted values of the global drag coefficient was under 10% - a result which is in line with the limitations inherent in both.

Zhengting Jiang,1,&ast; Wenjie Zhang,1,&ast; Jie Zhang,1 Tian Liu,1 Juan Xing,1 Huan Zhang,1 Dong Tang2 1Clinical Medical College, Yangzhou University, Yangzhou, 225000, People’s Republic of China; 2Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong Tang, Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People’s Republic of China, Email 83392785@qq.comAbstract: Cancer immunotherapy, a major breakthrough in cancer treatment, has been successfully applied to treat a number of tumors. However, given the presence of factors in the tumor microenvironment (TME) that impede immunotherapy, only a small proportion of patients achieve a good clinical response. With the ability to increase permeability and cross biological barriers, nanomaterials have been successfully applied to deliver immunotherapeutic agents, thus realizing the anti-cancer therapeutic potential of therapeutic agents. This has driven a wave of research into systems for the delivery of immunotherapeutic agents, which has resulted in widespread interest in nanomaterial-based drug delivery systems. Nanomaterial-based drug delivery systems are able to overcome the challenges from TME and thus achieve good results in cancer immunotherapy. If it can make a breakthrough in improving biocompatibility and reducing cytotoxicity, it will be more widely used in clinical practice. Different types of nanomaterials may also have some subtle differences in enhancing cancer immunotherapy. Moreover, delivery systems made of nanomaterials loaded with drugs, such as cytotoxic drugs, cytokines, and adjuvants, could be used for cancer immunotherapy because they avoid the toxicity and side effects associated with these drugs, thereby enabling their reuse. Therefore, further insights into nanomaterial-based drug delivery systems will provide more effective treatment options for cancer patients.Keywords: drug repurposing, delivery system, immunotherapy, tumor microenvironment, nanomaterial

Dijiao Tang,1 Yuetong Guo,1 Yi Tang,2 Hongxu Wang1 1Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Pathology, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Hongxu Wang, Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel/Fax +86 23 89012513, Email wanghx502@163.comBackground: Castleman disease (CD) is a rare and heterogeneous lymphoproliferative disorder with a spectrum of characteristic pathological abnormalities of lymph node. Furthermore, its clinical diagnosis is very challenging until pathological results are available. This study aimed to investigate the clinical presentations, treatment and prognosis of CD, thereby improving the understanding and diagnosis of CD.Methods: This study retrospectively analyzed the clinical data of 31 patients with CD admitted to the First Hospital Affiliated Hospital of Chongqing Medical University January 2013 to December 2020. The chi-square test and the Mann–Whitney rank sum test were employed to calculate between-group differences for categorical and quantitative data, respectively.Results: Clinically, patients with unicentric CD (UCD) usually present with lymphadenopathy. However, the clinical presentation of patients with multicentric CD (MCD) ranged from mild lymphadenopathy with B-symptoms (5/8, 62.5%) to intense inflammation, vascular leak syndrome (3/8, 37.5%), hepatosplenomegaly (3/8, 37.5%), organ insufficiency (3/8, 37.5%), and even death (2/8, 25.0%). Compared with UCD patients, patients with MCD had significantly lower levels of hemoglobin (104 (90,129) vs 137 (120,149), p=0.018) and plasma albumin (31.5 (27.0,37.0) vs 45.0 (40.0,46.5), p=0.001), but IgG levels were significantly increased. Patients with UCD were mainly treated with surgical resection alone, with a five-year survival rate of 95.65%. When siltuximab is not an option, steroid plus rituximab-based chemotherapy and specific supportive care are common options for MCD. Except for 2 deaths, the remaining MCD patients have stable disease or partial remission.Conclusion: CD describes a heterogeneous group of disorders characterized by morphologically benign lymphoid hyperplasia. Notably, patients with MCD present varying degrees of inflammation responses, even involving multiple systems. Surgery is a direct and effective way to diagnose and treat UCD. In the absence of IL-6 antagonists, anti-inflammatory and immunosuppressive therapeutic strategies, and cytotoxic clearance of cells responsible for hypercytokinemia could be adopted.Keywords: Castleman disease, unicentric, multicentric, heterogeneity

Di Tang,1,&ast; Duo Zhang,1,&ast; Yu Heng,1 Xiao-Ke Zhu,1 Han-Qing Lin,1 Jian Zhou,1 Lei Tao,1 Li-Ming Lu2 1Department of Otorhinolaryngology and ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Ming Lu, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, People’s Republic of China, Tel +86-13916235624, Fax +86-021-63846383, Email lulunew2003@163.com Lei Tao, ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, People’s Republic of China, Tel +86-13916944810, Email doctortaolei@163.comPurpose: Chronic inflammation contributes to tumor initiation, progression, and immune escape. Neutrophils are the major component of inflammatory response and participate in the tumorigenesis process. However, compared to other immune cells in the tumor microenvironment of laryngeal squamous cell carcinoma (LSCC), neutrophils, especially the tumor-associated neutrophils (TANs), have not yet been comprehensively explored. The mechanism for regulating the crosstalk between TANs and tumor cells still remains unclear.Materials and Methods: The distribution profiles and phenotypic features of neutrophils and other inflammatory immune cell populations from a large LSCC patient cohort were systemically analyzed. Co-culturing of peripheral blood associated neutrophils (PANs) and TANs with PBMCs was performed, and the immunosuppression effect on T-cells was examined.Results: LSCC microenvironment is highly inflammatory with remarkable TANs infiltration, which is often associated with unfavorable prognosis and advanced clinical stage. We find that TANs in LSCC display morphologically immature and lower apoptosis, exhibit distinctively immunosuppressive phenotype of high PD-L1, and suppress CD8+ T lymphocytes proliferation and activation. We subsequently discover that PD-L1+TANs induced by LSCC-derived GM-CSF potently impair CD8+ T-cells proliferation and cytokines production function, which are partially blocked by a PD-L1-neutralizing antibody. Clinical data further support GM-CSF as an unfavorable prognostic biomarker and reveal a potential association with inflammatory immune cell infiltration, in particular neutrophils.Conclusion: Tumor-infiltrating PD-L1+ neutrophils induced by LSCC-derived GM-CSF suppress T cell proliferation and activation in the inflammatory microenvironment of LSCC and predict unfavorable prognosis. These TANs cripple antitumor T cell immunity and promote tumor progression. Our findings provide a basis for targeting PD-L1+TANs or GM-CSF as a new immunotherapeutic strategy for LSCC.Keywords: laryngeal squamous cell carcinoma, LSCC, tumor-associated neutrophils, TANs, PD-L1, inflammatory microenvironment, immune suppression, granulocyte-macrophage colony stimulating factor, GM-CSF

Jing-Xiao Li,1 Jin-Shu Pang,2 Bin-Tong Yin,1 Gang Chen,1 Jun-Hong Chen,1 Jia-Yuan Luo,1 Xia Yang,1 Li-Ting Qin,1 Jiang-Hui Zeng,3 Peng Chen,4 Jia-Bo Chen,4 Deng Tang1 1Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3Department of Clinical Laboratory, The Third Affiliated Hospital of Guangxi Medical University/Nanning Second People’s Hospital, Nanning, Guangxi Zhuang Autonomous Region, 530031, People’s Republic of China; 4Department of Pediatric Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530031, People’s Republic of ChinaCorrespondence: Deng TangDepartment of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaTel +86-7715356534Email tdnever@163.comPurpose: The molecular mechanisms and signal pathways of ferroptosis in hepatoblastoma (HB) have not yet been clarified. In previous studies, activating transcription factor 3 (ATF3) was reported to be correlated with several tumors, but the clinical significance of ATF3 has never been determined. Herein, we investigated the clinicopathological value and mechanisms of ATF3 in regulating ferroptosis in HB.Methods: The mRNA microarray and RNA-sequencing data of 402 samples from our hospital and public databases were used to estimate ATF3 expression and assess its clinical role in HB. The standard mean difference (SMD) and summary receiver operating characteristic curves were utilized to judge the discrimination ability of ATF3 between HB and non-HB liver tissues. We examined the expression variation of ATF3 in HB cells after the treatment with erastin. We also predicted the target genes of ATF3 as a transcriptional factor from public Chromatin Immunoprecipitation-sequencing data and selected the ferroptosis-related genes for a signaling pathway analysis.Results: In ten series, the pooled SMD for ATF3 was − 0.91, demonstrating that ATF3 expression was predominantly lower in HB than in non-HB liver tissues. ATF3 down-regulation showed moderate potential to distinguish HB from non-HB liver tissues (area under curves = 0.83, 95% confidence interval = 0.79– 0.86). Altogether, 4855 putative targets of ATF3 as a transcriptional factor were collected, among which, 60 genes were ferroptosis-related.Conclusion: The down-regulated ATF3 expression may play a vital role in the occurrence of HB possible partially by regulating ferroptosis.Keywords: transcription factor, ATF3, hepatoblastoma, ferroptosis

Ding Tang,1 Xufen Zhang,1 Yani Xu,1 Linglin Dai,1 Jianlan Sun,1 Hantong Hu,2 Huangwei Jiang,3 Ping Jin,3 Lifang Chen,2 Jianqiao Fang4 1The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Acupuncture, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Radiological, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4The Third Clinical Medical College of Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Lifang ChenDepartment of Acupuncture, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, XiHu District, Hangzhou, Zhejiang, 310005, People’s Republic of ChinaEmail clfang@163.comJianqiao FangZhejiang Chinese Medical University, NO. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang, 310053, People’s Republic of ChinaEmail fangjianqiao7532@163.comObjective: To verify the efficacy of electroacupuncture (EA) on classical trigeminal neuralgia (CTN), and to observe the brain functional status of patients with CTN and the intervention effects of EA on brain function by resting-state functional magnetic resonance imaging (rs-fMRI).Methods and Analysis: Thirty CTN patients will be randomly divided into EA combined with carbamazepine group and carbamazepine group in 2:1 ratio by using a random number table. Patients in EA combined with carbamazepine will receive EA treatment and carbamazepine for four weeks. The carbamazepine group will only receive carbamazepine treatment. VAS (visual analogue scale), HAMA (Hamilton Anxiety Scale), HAMD (Hamilton Depression Scale) and SF-36 (short form 36 health survey) will be performed before, after four-week treatments and at three-month follow-up in CTN patients. Six CTN patients will be randomly selected from EA combined with carbamazepine group and carbamazepine group, respectively, before treatment, and twelve paired healthy participants will be recruited at the same time. The twelve CTN patients will be scanned by rs-fMRI before and after treatment, and the healthy participants will be scanned by rs-fMRI only at baseline. Regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) analysis will be carried out to compare the dysfunctional brain regions between CTN patients and healthy participants, as well as the differences between two groups of patients with CTN after treatment.Trial Registration: ChiCTR-1900027873.Keywords: electroacupuncture, trigeminal neuralgia, pre-experimental, fMRI, randomized controlled trial, protocol

Huan Li, Juanjuan Chen, Yuanhui Hu, Xin Cai, Dongling Tang, Pingan Zhang Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of ChinaCorrespondence: Pingan Zhang Email zhangpingan927@163.comObjective: To explore the clinical application value of serum complement component C1q levels in sepsis.Methods: The clinical data and laboratory examination data of 320 research subjects (including 132 cases as sepsis group, 93 cases as nonsepsis group and 95 cases as control group) who were diagnosed and treated in Renmin Hospital of Wuhan University from July 2020 to March 2021 were collected. We compared the levels of each index among the three groups and further analyzed the C1q levels of different severity subgroups and different outcome subgroups of sepsis. Afterwards, we explored the correlation between C1q levels and SOFA score, organ damage indexes and coagulation indexes. Finally, the receiver operating characteristic curve (ROC) was used to analyze the prognostic value of C1q in patients with sepsis.Results: C1q levels were significantly reduced in the serum of patients with sepsis; the level of C1q in the death group was lower than that in the survival group (127.1 mg/L vs 153.2 mg/L, P < 0.05), and the mortality in the C1q decreased group was higher when compared with C1q normal group; in addition, serum C1q levels were correlated with SOFA score, organ damage indexes and coagulation indexes; C1q had a high area under the curve (AUC) for the prognosis of sepsis, and the combination of other indexes can further improve the prognostic value.Conclusion: Serum C1q levels have potential clinical value for the condition and prognosis of sepsis.Keywords: C1q, sepsis, infection, organ damage, prognosis

Xishuai Wang,1,2 Zhiqing Wang,1 Donghui Tang1 1Department of College of P.E and Sport, Beijing Normal University, Beijing, People’s Republic of China; 2Department of Animal Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, People’s Republic of ChinaCorrespondence: Donghui Tang; Xishuai WangDepartment of College of P.E and Sport, Beijing Normal University, No. 19, Xinjiekouwai St, Haidian District, Beijing, 100875, People’s Republic of ChinaEmail 201831070001@mail.bnu.edu.cn; 630200346@qq.comBackground: Chronic inflammation, oxidative stress, and apoptosis play critical roles in chronic obstructive pulmonary disease (COPD) pathogenesis. Here, we attempted to determine whether aerobic exercise (AE) could improve COPD by counteracting the COPD-associated inflammatory response, oxidative stress, and apoptosis in mice.Methods: Thirty male ICR mice were assigned into one of three groups: control (Con), COPD, and COPD + AE. COPD was simulated by intratracheal injection of lipopolysaccharide (LPS) for 4 weeks. Low-intensity AE was performed for 4 weeks. Bronchoalveolar lavage fluid (BALF) cell counts and the levels of inflammatory cytokine in BALF and serum were detected. Hematoxylin and eosin (HE), Masson trichrome, and Sirius Red staining as well as terminal deoxynucleotidyl transferase dUTP nick end labeling were performed to identify the degree of pulmonary emphysema, bronchial mucus cell hyperplasia, pulmonary fibrosis, and cell apoptosis. Oxidative stress parameters were measured. Furthermore, gene expression levels for the CXCL1, IL-1β, IL-10, IL-17, matrix metalloproteinase (MMP)9, TGF-β, TNF-α, and silent information regulator (sirt)1 were detected in mice lung tissues.Results: AE improved LPS-induced emphysema, pulmonary fibrosis, bronchial mucus cell hyperplasia, bronchoconstriction, and cell apoptosis. AE prevented an LPS-induced increase in the total cell, neutrophil, and macrophage counts. AE decreased malondialdehyde (MDA) and myeloperoxidase (MPO) levels but increased glutathione (GSH) and superoxide dismutase (SOD) levels. AE decreased BALF levels of IL-1β, TNF-α, and TGF-β but increased BALF IL-10 levels. AE suppressed the gene expression levels of pro-inflammatory factors CXCL1, IL-1β, IL-17, and TNF-α and profibrotic factors MMP-9 and TGF-β but activated those of anti-inflammatory factor IL-10 and lung-protective factor sirt1.Conclusion: AE is a potential therapeutic approach for COPD. AE improved emphysema, bronchial mucus cell hyperplasia, and pulmonary fibrosis in mice with COPD by alleviating the inflammatory response, oxidative stress injury, and cell apoptosis as well as activating sirt1.Keywords: exercise, COPD, pulmonary fibrosis, emphysema, pulmonary inflammation, oxidative stress injury

Cheng Wang,1 Hong Wang,2 Luming Dai,1 Jianqing Zhang,1 Lizhou Fang,1 Ling Liu,1 Weiping Fu,1 Dang Tang3 1Second Department of Respiratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China; 2Department of Burns Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People’s Republic of China; 3First Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of ChinaCorrespondence: Dang Tang Email tangdangdemao@126.comBackground: Chronic obstructive pulmonary disease (COPD) is often combined with type 2 diabetes mellitus (T2DM) in clinical, and with poor prognosis. In recent years, research shows that inflammation is a common characteristic of COPD and T2DM. T-helper 17 cell (Th17)/regulatory T-cell (Treg) balance controls inflammation and may be important in the pathogenesis of COPD combined with T2DM patients. This study investigated the characteristics of Th17, Treg and related inflammatory factors in COPD combined with T2DM patients and the potential mechanism.Methods: Application of flow cytometry technology, real-time fluorescent quantitative PCR and ELISA to detect the changes in peripheral blood of Th17 and Treg number and the expression of key transcription factors and related cytokines in COPD combined T2DM patients were performed.Results: Patients with COPD combined with T2DM revealed significant increase in peripheral Th17, Th17 related cytokines (IL-17A, IL-17F, IL-21, IL-23, IL-6) and transcription factor (RORγt) levels and significant decrease in Treg, Treg-related cytokines (IL-10, TGFβ 1) and transcription factor (Foxp3) as compared with patients with COPD, T2DM and healthy controls.Conclusion: Th17/Treg functional imbalance exists in patients with COPD combined with T2DM, indicating a potential role of Th17/Treg imbalance in the formation and progression of COPD combined with T2DM.Keywords: COPD combined with T2DM, Th17/Treg, cytokine, transcription factor

Dongfang Tang,1 Tao Huang,2 Qilong Tian,2 Julei Wang2 1Department of Neurosurgery, Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Neurosurgery, The Second Affiliated Hospital of Air Force Military Medical University, Xi’an City, People’s Republic of ChinaCorrespondence: Julei WangDepartment of Neurosurgery, The Second Affiliated Hospital of Air Force Military Medical University, No. 569 Xinsi Road, Baqiao District, Xi’an City, Shaanxi Province, 710038, People’s Republic of ChinaTel +86-29-84777777Email wangjulei_wjl@163.comBackground: The role of Hydroxysafflor Yellow A (HSYA) in glioma is less studied, this research determined the effect of HSYA on glioma cells.Methods: The expressions of MYC and NBS1 in glioma tissues were detected by bioinformatics analysis and verified by RT-qPCR. The target relationship between MYC and NBS1 was predicted by bioinformatics. After treating the cells with HSYA, silenced MYC, or overexpressed NBS1, the viability, apoptosis, proliferation, invasion, migration, and DNA damage of the glioma cells were detected by MTT, flow cytometry, colony formation, transwell, wound healing, and γH2AX immunofluorescence assays, respectively. IC50 of HSYA in glioma cells was analyzed by Probit regression analysis. The expressions of MYC, NBS1, factors related to migration, invasion, apoptosis, and DNA damage of the glioma cells were determined by Western blot or RT-qPCR.Results: MYC and NBS1 were high-expressed in glioma, and NBS1 was targeted by MYC. HSYA and siRNA targeting MYC inhibited the cell viability, proliferation, invasion, migration, and induced the cell apoptosis of glioma cells. HSYA upregulated the expressions of MYC, γH2AX, E-Cadherin, Bax, and Cleaved-PARP1, stimulated the activation of NBS1, MRE11, RAD50, and ATM, and downregulated the expressions of N-Cadherin and Bcl2 in glioma cells. SiMYC decreased the IC50 of HSYA in the glioma cells, enhanced the sensitivity of glioma cells to HSYA, and inhibited the activation of NBS1 and ATM. NBS1 overexpression reversed the effect of siRNA targeting MYC on glioma cells.Conclusion: MYC silencing inhibited the DNA damage response via regulation of NBS1, leading to DNA repair deficiency, and subsequently enhanced the sensitivity of glioma cells to HSYA.Keywords: glioma, hydroxysafflor yellow A, MYC, NBS1, drug sensitivity, DNA repair

Ying Cao,1,* Du Tang,1,* Yining Xiang,1 Li Men,2 Chao Liu,1 Qin Zhou,1 Jun Wu,3 Lei Huo,3 Tao Song,3 Ying Wang,4 Zhanzhan Li,1 Rui Wei,1 Liangfang Shen,1 Zhen Yang,1 Jidong Hong1 1Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jidong HongDepartment of Oncology, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, Hunan, 410008, People’s Republic of ChinaTel +86 731 8975 3733Fax +86 731 8975 3336Email hongjidong1966@126.comPurpose: To investigate the appropriate timing of adaptive radiotherapy (ART) for high-grade glioma.Methods: Ten patients with high-grade gliomas were selected and underwent CT/MRI (CT1/MRI1, CT2/MRI2, CT3/MRI3, and CT4/MRI4) scans before RT and during 10-, 20- and 30-fraction RT, and the corresponding RT plans (plan1, plan2, plan3 and plan4) were made. The dose of the initial plan (plan1) was projected to CT2 and CT3 using the image registration technique to obtain the projection plans (plan1– 2 and plan1– 3) and by superimposing the doses to obtain the ART plans (plan10+20 and plan20+10), respectively. The dosimetric differences in the target volume and organs at risk (OARs) were compared between the projection and adaptive plans. The tumor control probability (TCP) for the planning target volume (PTV) and normal tissue complication probability (NTCP) for the OARs were compared between the two adaptive plans.Results: Compared with the projection plan, the D2 to the PTV of ART decreased, the conformity index (CI) to the PTV increased, and the D2/Dmean to the brainstem, optic chiasm and pituitary, as well as the V20, V30, V40 and V50 to the normal brain decreased. The D2 to the pituitary and optic chiasm as well as the V20, V30, V40 and V50 to the normal brain in plan10+20 were lower than those in plan20+10, while the CI to the PTV was higher than that in plan20+10. The TCP of the PTV in plan10+20 was higher than that in plan20+10.Conclusion: ART can improve the precision of target volume irradiation and reduce the irradiation dose to the OARs in high-grade glioma. The time point after 10 fractions of RT is appropriate for ART.Keywords: adaptive radiotherapy, high-grade glioma, dosimetry, biophysical model

Dan Tang,1,2,* Haihai Luo,1,* An Xie,3 Zhichun He,1 Bin Zou,4 Fei Xu,1 Wei Zhang,1 Xinping Xu1 1Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of General Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 3Jiangxi Institute of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 4Department of Thoracic Surgery, Jiangxi Cancer Hospital, Nanchang, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinping Xu; Wei ZhangJiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai St, Nanchang, Jiangxi, 330006, People’s Republic of ChinaEmail xinpingxu@ncu.edu.cn; zhangweiliuxin@163.comPurpose: Lung cancer has been recognized as the most fatal malignant tumor with the highest morbidity and mortality in recent years.Materials and Methods: In this study, we found that LMNB1, which is an important component protein of the nuclear skeleton, was significantly upregulated in lung adenocarcinoma (LUAD) and correlated with the pathological stage as well as lymphatic metastasis.Results: In vitro loss-of-function study utilizing LMNB1 knockdown LUAD cell lines demonstrated that depletion of LMNB1 inhibited development of LUAD through regulating cell proliferation, cell apoptosis, cell cycle and cell motility. Decreased tumorigenesis of LMNB1 knockdown LUAD cells was proved in mice xenograft models. Moreover, the mechanism by which LMNB1 promotes LUAD was explored through the expression evaluation of apoptosis-related proteins and cancer-related signaling pathways.Conclusion: In conclusion, our study identified LMNB1 as a tumor promotor and a potential therapeutic target in LUAD.Keywords: lung cancer, lung adenocarcinoma, LMNB1, cell proliferation, cell apoptosis

The reduction of copper content in converting slag using process control is significant to copper smelter. In this study, the slags produced from the Ausmelt Converting Process for copper matte was analyzed using X-ray diffraction and chemical analysis. Thermodynamic calculation and effects of various conditions including the lance submerging depth in molten bath, the molten bath temperature, the addition of copper matte, and airflow rate were carried out to lower the content in the slag. Thermodynamic analysis indicated that the decrease of copper content was achieved by reducing Fe3O4, CuFe2O4, and Cu2O in the slag, decreasing the magnetism of slag and lowering the viscosity of slag, which was feasible at the operating temperature of the molten bath. Experiments showed that the optimal combination of operating conditions were found to be the addition of copper matte between 5,000 – 7,000 kg/h, a lance airflow rate of 13,000-14,000 Nm3/h, and a lance submergence depth into the molten bath of 700-900 mm, in which the copper content in the slag was effectively reduced from 22.74 wt. % to 7.70 wt. %. This study provides a theoretical support and technical guidance for promoting the utilization of slags from the Ausmelt Converting Process.

Liang Deng,1,* Shan Huang,2,* Bin Chen,3 Yajun Tang,1 Fei Huang,1 Dong Li,1 Di Tang1 1Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, People’s Republic of China; 2Department of Oncology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, People’s Republic of China; 3Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510800, People’s Republic of China*These authors contributed equally to this workCorrespondence: Di TangDepartment of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Xinhu Street, Guangming District, Shenzhen, Guangdong 518107, People’s Republic of ChinaTel +86 18929343913Email tangdi@126.comBackground: The role of high mobility group A2 (HMGA2) in the progression of hepatocellular carcinoma (HCC) is yet to be investigated, though tumor-associated macrophages (TAMs) are known to mediate the process.Methods: Immunohistochemistry (IHC), Western blot, and real-time PCR assays were performed to identify HMGA2 and TAMs markers. The TAMs-like macrophages (TAMs-M&phis;s) were triggered with the help of 25 ng/mL hM-CSF and 50% NBCM. EdU assay wound healing assay, transwell assay, and TUNEL assay, as well as flow cytometry, were carried out to study the effect of HMGA2 or TAMs on the functioning of HCC cells.Results: HCC tumor tissues were detected with upregulated HMGA2 and TAMs markers (CD68, CD163, and CD204); in addition, HMGA2 was positively correlated with TAMs markers. The proliferation, migration, and invasion of HepG2 cells were also observed to be stimulated by HMGA2. Remarkably, cell apoptosis was not affected by upregulated HMGA2, but HMAG2 inhibition was observed to intensify it. Also, the release of CSF1 was observed to be amplified by HMGA2. HMGA2-overexpressed-HepG2 cells promoted the migrating abilities of both M0-M&phis;s and TAMs-M&phis;s but were suppressed by HMGA2 down-regulated HepG2 cells. In addition, TAMs-M&phis;s supernatant regulated the CCAT1/let-7b/HMGA2 signaling pathway by intensifying the malignant biological behaviors.Conclusion: HMGA2 stimulated TAMs-induced HCC progression, mediated by the CCAT1/let-7b/HMGA2 signaling pathway, TAMs aggravated HCC development.Keywords: HMGA2, hepatocellular carcinoma, TAMs, LncRNA CCAT1, let-7b

Jianlong Zhou,1,2,* Dingxue Wang,3,* Dongxin Tang,3 Wenhua Huang1 1Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Oncology, The Affiliated Xinhui Hospital, Southern Medical University, Xinhui, People’s Republic of China; 3Department of Oncology, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongxin TangThe First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, No. 71 Baoshanbei Road, Guiyang 550000, People’s Republic of ChinaEmail tangdongxin@sina.comWenhua HuangDepartment of Oncology, Zhujiang Hospital, Southern Medical University, No.253 Gongye Middle Avenue, Guangzhou 510280, People’s Republic of ChinaEmail huangwenhua88888@outlook.comBackground: Lung tumors and normal lung tissues show large differences in epigenetic modification which can affect the chromosome structure and expression of genes. However, the epigenetic reprogramming in lung adenocarcinoma remains unclear.Methods and Results: With the bioinformatics analysis, we found that some activated super-enhancers (SEs) only appear in lung adenocarcinoma cells, and 781 abnormal activated super-enhancers (AASEs) were found. Not only are the traditional oncogenes found to be activated by AASEs, such as MET and SLC2A1, but also some new genes were activated by AASEs, which probably contributes to the carcinogenic process in lung cancer. The enrichment analysis of the genes activated by AASEs shows that the glycolysis process and cell proliferation were enhanced and the apoptotic process was negatively regulated. Two AASEs were separately knockout by CRISPR/Cas9 in A549, PC-9, and H1299 cell lines and the expression of target genes decreased. The motif of CTCF, SMARCA1, SOX4, FOXM1, IRF3, IRF7, and STAT2 was enriched in AASEs, supporting that the chromosome structure changed and these transcription factors would be the master regulators on the formation of AASEs.Conclusion: This study provided comprehensive insight into the mechanisms of SEs, as well as a potential therapeutic target for lung cancer.Keywords: lung adenocarcinoma, epigenetic, super-enhancer, transcription factors

Yulu Zhang,1,* Songyu Liu,1,* Jinyan Wan,1,* Qiyue Yang,2 Yan Xiang,1 Li Ni,1 Yu Long,1 Mingquan Cui,1 Zhimin Ci,1 Donglei Tang,1 Nan Li1 1College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, People’s Republic of China; 2Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Nan LiCollege of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166, Liutai Avenue, Chengdu 611137, People’s Republic of ChinaTel +86-28-61801001Email 55743198@qq.comPurpose: Baicalin (BA) has a good neuroprotective effect, but it is eliminated quickly in the body and does not easily reach the brain. In this experiment, borneol (BO) was used as an auxiliary drug to prepare borneol-baicalin-liposomes (BO-BA-LP) to prolong the efficacy time of BA, synergistically synergize, introduce drugs into the brain, and better exert the therapeutic effect on cerebral ischemia-reperfusion (I/R) injury.Methods: Through single-factor inspection and response surface optimization analysis, obtained the best preparation process of BO-BA-LP and characterized by various analytical techniques. Validated the long-term effectiveness of BA-BO-LP through pharmacokinetic studies and conducted pharmacodynamic studies on the middle cerebral artery occlusion (MCAO) rat model to verify the therapeutic effect of BO-BA-LP on cerebral I/R injury.Results: The optimum preparation conditions of BO-BA-LP were as follows: the dosage of BO was 9.55 mg, the ratio of phospholipid to drug was 4.02:1, the ratio of phospholipid to cholesterol was 7.25:1, the entrapment efficiency (EE) was 41.49%, and the drug loading (DL) was 4.29%. The particle size range of the liposomes was 167.1 nm, and the polydispersity index (PDI) range was 0.113. The results of pharmacokinetic experiments showed that the combination of BA and BO liposomes effectively improved the pharmacokinetic parameters of BA and prolonged the half-life of BA. Pharmacodynamic studies have found that, compared with BA-LP, BO-BA-LP can significantly improve neurological deficits, cerebral infarction volume, and brain pathological states on MCAO rats.Conclusion: These results demonstrated that BO-BA-LP can improve the circulation of drugs in the blood, and the addition of BO can enhance the therapeutic effect of BA and effectively improve cerebral I/R.Keywords: borneol-baicalin-liposome, pharmacokinetics, pharmacodynamics, MCAO

Guo-feng Xie,1,* Luo-dan Zhao,2,3,* Qiang Chen,4,* Dong-xiao Tang,4 Qiong-yu Chen,4 Hong-fei Lu,4 Jia-rong Cai,5 Zheng Chen4 1Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province 510095, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China; 3Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangzhou Higher Education Institutes, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China; 4Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, People’s Republic of China; 5Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia-rong CaiDepartment of Urology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, Guangdong Province, People’s Republic of ChinaTel +86-20-82179727Fax +86-20-85253336Email caijiar@mail.sysu.edu.cnZheng ChenDepartment of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, Guangdong Province, People’s Republic of ChinaFax +86-20-85253336Email chenzh68@mail.sysu.edu.cnPurpose: Oral squamous cell carcinoma (OSCC) is a common malignancy of the oral cavity. As the survival rate of OSCC patients is low, it is crucial to explore new markers and therapeutic targets for early diagnosis of the disease. A high level of actinin alpha 1 (ACTN1) in patients could serve as an independent prognostic factor of acute myeloid leukemia. However, the role of ACTN1 in OSCC remains unclear. In the present study, we aimed to investigate the role of ACTN1 in OSCC.Methods: ACTN1 protein levels in tissues were determined by immunohistochemical (IHC) staining. The correlation of ACTN1 expression with clinicopathological features and prognosis was analyzed. Univariate and multivariate analyses were performed. The effect of ACTN1 knockdown on cell proliferation, migration, invasion, apoptosis, epithelial-mesenchymal transition (EMT), and the cell cycle was evaluated using Western blotting, Cell Counting Kit‑8 (CCK8) assays, flow cytometry analysis, transwell assays, wound-healing assays, and nude mouse models of subcutaneous xenograft and pulmonary metastasis.Results: Based on the total score of ACTN1 IHC staining analysis, ACTN1 expression was found to be low in 10 normal mucosal tissues, 48 normal mucosal tissues adjacent to OSCC, and 19 OSCC tissues, but high in 29 OSCC tissues. ACTN1 protein levels were significantly associated with the clinical stage and node metastasis, and a high ACTN1 protein level indicated poor prognosis. Moreover, ACTN1 expression was an independent predictor of poor prognosis of OSCC. Using in vitro assays, we found that ACTN1 knockdown could induce cell cycle arrest, promote apoptosis, and inhibit EMT and cell proliferation, migration, and invasion in the OSCC cell lines, SCC-15 and HSC-3. Moreover, ACTN1 knockdown inhibited subcutaneous tumor growth and pulmonary metastasis in vivo.Conclusion: ACTN1 levels were significantly associated with the clinical stage and node metastasis, and a high ACTN1 protein level indicated poor prognosis. Moreover, ACTN1 knockdown could suppress cell proliferation and metastasis of OSCC. Our results suggested that ACTN1 may serve as a diagnostic and prognostic marker of OSCC.Keywords: actinin alpha 1, poor prognosis, oral squamous cell carcinoma, knockdown, proliferation, metastasis

Genome-wide gene expression measurements have enabled comprehensive studies that integrate the changes of gene expression and phenotypic information to uncover their novel associations. Here we reported the association analysis between psychophysical phenotypes and genome-wide gene expression changes in human adaptation to one of the most extreme climates on Earth, the Antarctic Dome Argus. Dome A is the highest ice feature in Antarctica, and may be the coldest, driest and windiest location on earth. It is considered unapproachable due to its hostile environment. In 2007, a Chinese team of 17 male explorers made the expedition to Dome A for scientific investigation. Overall, 133 psychophysical phenotypes were recorded, and genome-wide gene expression profiles from the blood samples of the explorers were measured before their departure and upon their arrival at Dome A. We found that mood disturbances, including tension (anxiety), depression, anger and fatigue, had a strong, positive, linear relationship with the level of a male sex hormone, testosterone, using the Pearson correlation coefficient (PCC) analysis. We also demonstrated that significantly lowest-level Gene Ontology groups in changes of gene expression in blood cells with erythrocyte removal were consistent with the adaptation of the psychophysical characteristics. Interestingly, we discovered a list of genes that were strongly related to significant phenotypes using phenotype and gene expression PCC analysis. Importantly, among the 70 genes that were identified, most were significantly related to mood disturbances, where 42 genes have been reported in the literature mining, suggesting that the other 28 genes were likely novel genes involved in the mood disturbance mechanism. Taken together, our association analysis provides a reliable method to uncover novel genes and mechanisms related to phenotypes, although further studies are needed.

Dianjun Tang,*,1,2 Yanshuo Han,*,3 Yu Lun,1 Han Jiang,1 Shijie Xin,1 Zhiquan Duan,1 Jian Zhang11Department of Vascular Surgery, The First Hospital of China Medical University, Key Laboratory of Pathogenesis, Prevention and Therapeutics of Aortic Aneurysm Liaoning Province, Shenyang, People’s Republic of China; 2Department of Vascular Surgery, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 3Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China*These authors contributed equally to this workPurpose: Abdominal aortic aneurysm (AAA) demonstrates many features of autoimmune diseases. Y chromosome, sex-determining region of the Y chromosome (SRY) gene, androgen receptor (AR) gene, and androgen appear as potential candidates for influence of the male immune function. This study investigated Y chromosome numbers, SRY gene, AR gene, and androgen levels in male AAAs. We also investigated the correlation between Y chromosome loss (LOY) ratio, SRY expression, androgen levels, and age.Patients and methods: We investigated LOY by fluorescence in situ hybridization (FISH) in 37 AAAs and compared with 12 patients with abdominal aortic atherosclerotic occlusive disease (AOD) and 91 healthy controls (HC). We investigated SRY and AR expression at mRNA level by real-time PCR in peripheral T lymphocytes in AAA compared with AOD and HC, and AR protein levels by immunohistochemistry (IHC) in AAA. LOY, SRY expression, androgen levels, and age were examined for correlations using the Spearman’s rank correlation coefficient.Results: LOY ratio in peripheral T lymphocytes was significantly higher in the AAA group compared with the HC (9.11% vs 5.56%, P

Defeng Tang,1,2 Tianlong Lin,1 Yangyang Wang,1 Hui Cao11Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, People’s Republic of China; 2Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, People’s Republic of ChinaPurpose: The aim of this study was to elucidate the prognostic value of proenkephalin (PENK) in gastrointestinal stromal tumors (GISTs).Patients and methods: We collected data on 268 eligible postoperative patients diagnosed with GIST between January 1, 2002, and December 31, 2011. PENK expression was detected in GIST tissues classified using the United States National Institutes of Health (NIH) risk classification system. The associations between high PENK expression and the clinicopathological characteristics were assessed. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan–Meier analysis, and the log-rank test was used to compare the differences between groups. Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of PENK in GIST patients.Results: High PENK expression was more common in the low- and intermediate-risk GIST groups compared with the high-risk group (P

Background: Apoptosis caused by endoplasmic reticulum (ER) stress contributes to atherothrombosis, the underlying cause of cardiovascular disease (CVD). T-cell death-associated gene 51 (TDAG51), a member of the pleckstrin homology-like domain gene family,

Xiaolan You,1,2 Yuanjie Wang,2 Jian Wu,2 Qinghong Liu,2 Dehu Chen,2 Dong Tang,3 Daorong Wang3 1Department of Integrated Traditional Chinese and Western Medicine, Medical College of Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China; 2Department of Gastrointestinal Surgery, Taizhou People’s Hospital, Taizhou, Jiangsu Province, People’s Republic of China; 3Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University (Subei People’s Hospital of Jiangsu Province), Yangzhou, Jiangsu Province, People’s Republic of China Introduction: We evaluated the expression of galectin-1 (Gal-1) and vasculogenic mimicry (VM) in gastric cancer (GC) and investigated their relationships with the clinicopathological factors and prognostic significance in GC.Materials and methods: Immunohistochemical (IHC) staining and CD34–periodic acid-Schiff double stain were used to investigate Gal-1 expression and VM in paraffin-embedded sections from 127 patients with GC of all tumor stages. The relationships between Gal-1 expression and VM, clinicopathological variables, and survival were analyzed. P < 0.05 was considered statistically significant.Results: Among the 127 cases, 86 (67.7%) were positive for Gal-1; VM was detected in 29 cases (22.8%). There was a significant association between VM and the Gal-1 IHC staining; all cases with VM were positive for Gal-1 staining. Gal-1 expression and VM in primary GC tissue were associated with tumor size, differentiation, depth of tumor invasion, stage, lymph node metastases, and tumor emboli in microvessels (all, P < 0.05). Kaplan–Meier analysis revealed that the overall survival time was 52.56 ± 2.44 months (95% confidence interval [CI]: 47.77–57.35) for patients with Gal-1-negative and VM-negative primary GC tissue, 43.83 ± 2.17 months (95% CI: 39.58–48.08) for patients with Gal-1-positive but VM-negative primary GC tissue, and 23.97 ± 2.44 months (95% CI: 19.18–28.76) for patients with Gal-1-positive and VM-positive primary GC tissue (χ2 = 60.21, P < 0.01). Gal-1 expression was positively associated with VM in primary GC tissue.Conclusion: Both Gal-1 expression and VM in primary GC tissue are indicators of poor prognosis for GC after gastrectomy, and Gal-1 may be a novel target for treating VM in GC. Keywords: galectin-1, vasculogenic mimicry, gastric cancer, prognosis

Qian Mu,1,2,* Miao Jiang,1,* Yuzhu Zhang,1 Fei Wu,1 Hui Li,1 Wen Zhang,1 Fang Wang,1 Jiang Liu,1 Liang Li,1 Dongshan Wang,3 Wenjuan Wang,1 Shiwu Li,1 Haibo Song,4 Dongqi Tang1 1Gene and Immunotherapy Center, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Health Management Center, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 4Central Research Laboratory, Zibo Maternal and Child Health Hospital, Affiliated to Shandong Academy of Medical Science, Zibo, People’s Republic of China *These authors contributed equally to this work Background: CD19-chimericantigen receptor (CAR) modified T cells (CD19-CAR T cells) have been well documented to possess potent anti-tumor properties against CD19-expressingleukemia cells. As a traditional medicine, metformin has been widely used to treat type II diabetes mellitus and more recently has become a candidate for the treatment of cancer. However, no report has revealed the direct effect of metformin on CD19-CAR T cell biological function and its underling mechanisms. Purpose: The purpose of this research was to explore the effect of metformin on CD19-CAR T cell biological function and the mechanisms involved. Methods: CD19-CAR T cells proliferation, apoptosis and cytotoxicity were mainly tested by CCK-8 assay, flow cytometry and ELISA. The detection of mechanism primarily used western blot. Bioluminescence imaging is the main application technology of animal studies. Results: In the current study, it was found that metformin inhibited CD19-CAR T cell proliferation and cytotoxicity and induced apoptosis. Furthermore, our study revealed that metformin activated AMPK and suppressed mTOR and HIF1α expression. By using an AMPK inhibitor, compound C, we demonstrated the crucial roles of AMPK in CD19-CAR T cells when they were treated with metformin. Finally, we verified that metformin suppressed the cytotoxicity of CD19-CAR T cell in vivo. Conclusion: Taken together, these results indicated that metformin may play an important role in modulating CD19-CAR T cell biological functions in an AMPK-dependent and mTOR/HIF1α-independent manner. Keywords: Chimeric antigen receptor, metformin, proliferation, apoptosis, cytotoxicity, AMPK

Cheng Wang,1 Jun-Xiong Li,1 Dang Tang,2 Jian-Qing Zhang,1 Li-Zhou Fang,1 Wei-Ping Fu,1 Ling Liu,1 Lu-Ming Dai1 1Second Department of Respiratory Medicine, 2First Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China Background: Metabolomics is the global unbiased analysis of all the small-molecule metabolites within a biological system. Metabolic profiling of different high-resolution computed tomography (HRCT) phenotypes of COPD patients before and after treatment may identify discriminatory metabolites that can serve as biomarkers and therapeutic agents. Patients and methods: 1H nuclear magnetic resonance spectroscopy (1H-NMR)-based metabolomics was performed on a discovery set of plasma samples from 50 patients with stable COPD. Patients were assigned into two groups on the basis of HRCT findings including phenotype E (n=22) and phenotype M (n=28). After budesonide–formoterol treatment (160/4.5 µg ×2 inhalations twice daily for 3 months), clinical characteristics and metabolites were then compared between phenotype E pretreatment and posttreatment, phenotype M pretreatment and posttreatment, phenotype E pretreatment and phenotype M pretreatment, and phenotype E posttreatment and phenotype M posttreatment. Results: Inhaled budesonide–formoterol therapy for both phenotype E (emphysema without bronchial wall thickening) and phenotype M (emphysema with bronchial wall thickening) was effective. However, phenotype E and phenotype M were different in response to therapy. Patients with phenotype M in response to therapeutic effects were significantly greater compared with phenotype E. Certain metabolites were identified, which were closely related to the treatment and phenotype. Metabolic changes in phenotype E or phenotype M after treatment may be involved with adenosine diphosphate (ADP), guanosine, choline, malonate, tyrosine, glycine, proline, l-alanine, l-valine, l-threonine leucine, uridine, pyruvic acid, acetone and metabolism disturbance. Metabolic differences between phenotype E and phenotype M in pretreatment and posttreatment covered glycine, D-glucose, pyruvic acid, succinate, lactate, proline, l-valine and leucine. Conclusion: Bronchial wall thickening in COPD may be an indicator for predicting the better response to the treatment with bronchodilator and corticosteroid. The identification of metabolic alterations provides new insights into different HRCT phenotypes and therapeutic assessment of COPD. Keywords: COPD, metabolomics, budesonide–formoterol, HRCT

Eggs are suitable for the processing of set yoghurt as milk replacements, but there is no yoghurt mainly made from eggs. In the present work, production formula was designed and optimised for high-quality egg-based yoghurt processing by improving water holding capacity, aroma, texture, and taste using single factor experiment and D-optimal mixture design. Results showed that with optimised formula (whole liquid egg, 100 g; water, 180 g; sucrose, 30.89 g; diacetyl tartaric acid ester of mono(di)glycerides, 0.28 g; gelatine, 0.112 g; gellan gum, 0.14 g; and ß-cyclodextrin, 0.56 g), the product showed high sensory evaluation score, fine viscosity, as well as preferable hardness and suitable fracturability. SDS-PAGE electrophoretogram indicated that the proteins in egg-based yoghurt was degraded during fermentation, which might have contributed to the improvement of gel structure and taste. Based on the SEM images, the prepared egg-based yoghurt had smoother, stronger, and more compact gel network microstructure when compared with milk-based yoghurt. [ABSTRACT FROM AUTHOR]

The frequency of the Robertonian (ROB) translocation in newborn babies is approximately one in 1000. Robertsonian translocation is an unusual type of chromosome rearrangement caused by two particular chromosomes joining together. The aim of the study was to analyze the segregation of the ROB translocations in 13 male carriers, and to verify a possible inter-chromosomal effect (ICE) of the ROB translocation on chromosomes 18, X, and Y. Thirteen male patients were included in the study. Multicolor fluorescent in situ hybridization (FISH) was used to analyze chromosomes 13, 14, 15, 21, 22, 18, X and Y in sperm. Among the heterozygous ROB translocation carriers, the frequency of normal/balanced spermatozoa resulting from alternate segregation varied between 70.4 and 85.2%. The frequency of unbalanced spermatozoa resulting from adjacent segregation varied between 14.8 and 29.6%. Increased frequencies of aneuploidy for a sex chromosome were found in 10 ROB translocation carriers (P2-P8, P10-P12). Increased frequencies of aneuploidy for chromosome 18 were found in10 ROB translocation carriers (P3-P9, P11-P13). In addition, increased frequencies of diploid were found in 11 ROB translocation carriers (P2-P9, P11-P13). Among the homozygous ROB translocation carriers, the rate of balanced spermatozoa was 99.7% and the frequency of unbalanced spermatozoa was 0.3%. However, the frequencies of aneuploidy for a sex chromosome and chromosome 18 were normal. Despite the high number of normal/balanced frequencies, there remained many unbalanced spermatozoa resulting from alternate segregation. The ROB translocation carriers may be at an increased risk for ICE. Robertsonian translocation homozygosity could be seen as a potential speciation in humans with 44 chromosomes.