A Novel Molecular Grading Model: Combination of Ki67 and VEGF in Predicting Tumor Recurrence and Progression in Non-invasive Urothelial Bladder Cancer

Chen, Jun-Xing,Deng, Nan,Chen, Xu,Chen, Ling-Wu,Qiu, Shao-Peng,Li, Xiao-Fei,Li, Jia-Ping Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.5

Purpose: To assess efficacy of Ki67 combined with VEGF as a molecular grading model to predict outcomes with non-muscle invasive bladder cancer (NMIBC). Materials: 72 NMIBC patients who underwent transurethral resection (TUR) followed by routine intravesical instillations were retrospectively analyzed in this study. Univariate and multivariate analyses were performed to confirm the prognostic values of the Ki67 labeling index (LI) and VEGF scoring for tumor recurrence and progression. Results: The novel molecular grading model for NMIBC contained three molecular grades including mG1 (Ki67 $LI{\leq}25%$, VEGF $scoring{\leq}8$), mG2 (Ki67 LI>25%, VEGF $scoring{\leq}8$; or Ki67 $LI{\leq}25%$, VEGF scoring > 8), and mG3 (Ki67 LI > 25%, VEGF scoring > 8), which can indicate favorable, intermediate and poor prognosis, respectively. Conclusions: The described novel molecular grading model utilizing Ki67 LI and VEGF scoring is helpful to effectively and accurately predict outcomes and optimize personal therapy.

NEDD8-activating enzyme inhibitor, MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis through up-regulation of ATF-4

Liu, Xiaojun,Jiang, Yanan,Wu, Jianfu,Zhang, Wenjuan,Liang, Yupei,Jia, Lijun,Yu, Jinha,Jeong, L.S.,Li, Lihui Elsevier 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>It has been reported that MLN4924 can inhibit cell growth and metastasis in various kinds of cancer. We have reported that MLN4924 is able to inhibit angiogenesis through the induction of cell apoptosis both in vitro and in vivo models. Moreover, Neddylation inhibition using MLN4924 triggered the accumulation of pro-apoptotic protein NOXA in Human umbilical vein endothelial cells (HUVECs). However, the mechanism of MLN4924-induced NOXA up-regulation has not been addressed in HUVECs yet. In this study, we investigated how MLN4924 induced NOXA expression and cellular apoptosis in HUVECs treated with MLN4924 at indicated concentrations. MLN4924-induced apoptosis was evaluated by Annexin V-FITC/PI analysis and expression of genes associated with apoptosis was assessed by Quantitative RT-PCR and western blotting. As a result, MLN4924 triggered NOXA-dependent apoptosis in a dose-dependent manner in HUVECs. Mechanistically, inactivation of Neddylation pathway caused up-regulation of activating transcription factor 4 (ATF-4), a substrate of Cullin-Ring E3 ubiquitin ligases (CRL). NOXA was subsequently transactivated by ATF-4 and further induced apoptosis. More importantly, knockdown of ATF-4 by siRNA significantly decreased NOXA expression and apoptotic induction in HUVECs. In summary, our study reveals a new mechanism underlying MLN4924-induced NOXA accumulation in HUVECs, which may help extend further study of MLN4924 for angiogenesis inhibition treatment.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MLN4924 triggered NOXA-dependent apoptosis in a dose-dependent manner in HUVECs. </LI> <LI> Inactivation of neddylation caused up-regulation of ATF4, a substrate of CRL. </LI> <LI> NOXA was transactivated by ATF4 and further induced apoptosis. </LI> <LI> Knockdown of ATF-4 significantly decreased NOXA expression and apoptotic induction. </LI> <LI> We revealed a new mechanism underlying MLN4924-induced NOXA accumulation in HUVECs. </LI> </UL> </P>

The Synergism of Human Lactobacillaceae and Inulin Decrease Hyperglycemia via Regulating the Composition of Gut Microbiota and Metabolic Profiles in db/db Mice

Li Peifan,Tong Tong,Wu Yusong,Zhou Xin,Zhang Michael,Liu Jia,She Yongxin,Li Zuming,Li Yongli 한국미생물·생명공학회 2023 Journal of microbiology and biotechnology Vol.33 No.12

This study aimed to evaluate the effects of Limosilactobacillus fermentum and Lactiplantibacillus plantarum isolated from human feces coordinating with inulin on the composition of gut microbiota and metabolic profiles in db/db mice. These supplements were administered to db/db mice for 12 weeks. The results showed that the Lactobacillaceae coordinating with inulin group (LI) exhibited lower fasting blood glucose levels than the model control group (MC). Additionally, LI was found to enhance colon tissue and increase the levels of short-chain fatty acids. 16S rRNA sequencing revealed that the abundance of Corynebacterium and Proteus, which were significantly increased in the MC group compared with NC group, were significantly decreased by the treatment of LI that also restored the key genera of the Lachnospiraceae_NK4A136_group, Lachnoclostridium, Ruminococcus_ gnavus_group, Desulfovibrio, and Lachnospiraceae_UCG-006. Untargeted metabolomics analysis showed that lotaustralin, 5-hydroxyindoleacetic acid, and 13(S)-HpODE were increased while L-phenylalanine and L-tryptophan were decreased in the MC group compared with the NC group. However, the intervention of LI reversed the levels of these metabolites in the intestine. Correlation analysis revealed that Lachnoclostridium and Ruminococcus_gnavus_group were negatively correlated with 5-hydroxyindoleacetic acid and 13(S)-HpODE, but positively correlated with L-tryptophan. 13(S)-HpODE was involved in the "linoleic acid metabolism". L-tryptophan and 5-hydroxyindoleacetic acid were involved in "tryptophan metabolism" and "serotonergic synapse". These findings suggest that LI may alleviate type 2 diabetes symptoms by modulating the abundance of Ruminococcus_gnavus_group and Lachnoclostridium to regulate the pathways of "linoleic acid metabolism", "serotonergic synapse", and" tryptophan metabolism". Our results provide new insights into prevention and treatment of type 2 diabetes.

JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis

Li Xie,Hui Chen,Li Zhang,Yue Ma,Yuan Zhou,Yong-Yu Yang,Chang Liu,Yu-Li Wang,Ya-Jun Yan,Jia Ding,Xiao Teng,Qiang Yang,Xiu-Ping Liu,Jian Wu 대한간학회 2024 Clinical and Molecular Hepatology(대한간학회지) Vol.30 No.2

Background/Aims: Cholestatic liver diseases including primary biliary cholangitis (PBC) are associated with active hepatic fibrogenesis, which ultimately progresses to cirrhosis. Activated hepatic stellate cells (HSCs) are the main fibrogenic effectors in response to cholangiocyte damage. JCAD regulates cell proliferation and malignant transformation in nonalcoholic steatoheaptitis-associated hepatocellular carcinoma (NASH-HCC). However, its participation in cholestatic fibrosis has not been explored yet. Methods: Serial sections of liver tissue of PBC patients were stained with immunofluorescence. Hepatic fibrosis was induced by bile duct ligation (BDL) in wild-type (WT), global JCAD knockout mice (JCAD-KO) and HSC-specific JCAD knockout mice (HSC-JCAD-KO), and evaluated by histopathology and biochemical tests. In situ-activated HSCs isolated from BDL mice were used to determine effects of JCAD on HSC activation. Results: In consistence with staining of liver sections from PBC patients, immunofluorescent staining revealed that JCAD expression was identified in smooth muscle α-actin (α-SMA)-positive fibroblast-like cells and was significantly up-regulated in WT mice with BDL. JCAD deficiency remarkably ameliorated BDL-induced hepatic injury and fibrosis, as documented by liver hydroxyproline content, when compared to WT mice with BDL. Histopathologically, collagen deposition was dramatically reduced in both JCAD-KO and HSC-JCAD-KO mice compared to WT mice, as visualized by Trichrome staining and semi-quantitative scores. Moreover, JCAD deprivation significantly attenuated in situ HSC activation and reduced expression of fibrotic genes after BDL. Conclusions: JCAD deficiency effectively suppressed hepatic fibrosis induced by BDL in mice, and the underlying mechanisms are largely through suppressed Hippo-YAP signaling activity in HSCs.

Expression of Endogenous Hypoxia Markers in Vulvar Squamous Cell Carcinoma

Li, Yu-Zhu,Li, Shu-Ling,Li, Xia,Wang, Li-Jie,Wang, Jiu-Ling,Xu, Jia-Wen,Wu, Zhi-Hong,Gong, Li,Zhang, Xiao-Dan Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.8

Objective: To investigate the expression of endogenous hypoxia-related markers identified as being involved in vulvar squamous cell carcinoma (VSCC). Methods: We performed immunohistochemical staining of hypoxia-inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$), glucose transporter-1 (GLUT-1), carbonic anhydrase 9 (CA-9) and vascular endothelial growth factor (VEGF), on tissue sections of 25 VSCC patients, 10 vulvar intraepithelial neoplasia (VIN) patients and 12 healthy controls. Results: HIF-$1{\alpha}$ expression was found in all sections, with no significant difference between controls, VIN and VSCC sections (all P<0.05). Glut-1 expression was found in 25% of control, 90% of VIN and 100% of VSCC sections. A significant difference between control and VIN or VSCC was observed (all P<0.05), while no difference was found between VIN and VSCC sections (P>0.05). CA-9 expression was negative in control sections, but it was found in 30% of VIN sections and 52% of VSCC sections with strong staining. Similarly, CA-9 expression also showed obvious differences between controls and VIN or VSCC sections (all P<0.05). However, there was no significant difference between VIN and VSCC (P>0.05). There were only 25% of control sections with weak VEGF expression, while strong staining was found in about 60% of VIN sections and 25% of VSCC sections (all P<0.05). In addition, a difference was also found between VIN and VSCC sections (P<0.05). Conclusion: Expression of endogenous hypoxia markers (HIF-$1{\alpha}$, GLUT-1, CA-9 and VEGF) might be involved in the malignant progression of VSCC.

Staged Improvement in Awareness of Disease for Elderly Cancer Patients in Southern China

Li, Xing,Dong, Min,Wen, Jing-Yun,Wei, Li,Ma, Xiao-Kun,Xing, Yan-Fang,Deng, Yun,Chen, Zhan-Hong,Chen, Jie,Ruan, Dan-Yun,Lin, Ze-Xiao,Wang, Tian-Tian,Wu, Dong-Hao,Liu, Xu,Hu, Hai-Tao,Lin, Jia-Yu,Li, Zhu Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.15

Background: In mainland China, awareness of disease of elderly cancer patients largely relies on the patients' families. We developed a staged procedure to improve their awareness of disease. Materials and Methods: Participants were 224 elderly cancer patients from 9 leading hospitals across Southern China. A questionnaire was given to the oncologists in charge of each patient to evaluate the interaction between family and patients, patient awareness of their disease and participation in medical decision-making. After first cycles of treatment, increased information of disease was given to patients with cooperation of the family. Then patient awareness of their disease and participation in medical decision-making was documented. Results: Among the 224 cancer elderly patients, 26 (11.6%) made decisions by themselves and 125 (55.8%) delegated their rights of decision-making to their family. Subordinate family members tended to play a passive role in decision-making significantly. Patients participating more in medical decision-making tended to know more about their disease. However, in contrast to the awareness of disease, patient awareness of violation of medical recommendations was reversely associated with their participation in medical decision-making. Improvement in awareness of diagnosis, stages and prognosis was achieved in about 20% elderly cancer patients. About 5% participated more actively in medical decision-making. Conclusions: Chinese elderly cancer patient awareness of disease and participation in medical decision-making is limited and relies on their family status. The staged procedure we developed to improve patient awareness of disease proved effective.

Tumor-Derived Transforming Growth Factor-β is Critical for Tumor Progression and Evasion from Immune Surveillance

Li, Zheng,Zhang, Li-Juan,Zhang, Hong-Ru,Tian, Gao-Fei,Tian, Jun,Mao, Xiao-Li,Jia, Zheng-Hu,Meng, Zi-Yu,Zhao, Li-Qing,Yin, Zhi-Nan,Wu, Zhen-Zhou Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.13

Tumors have evolved numerous mechanisms by which they can escape from immune surveillance. One of these is to produce immunosuppressive cytokines. Transforming growth factor-${\beta}$(TGF-${\beta}$) is a pleiotropic cytokine with a crucial function in mediating immune suppression, especially in the tumor microenvironment. TGF-${\beta}$ produced by T cells has been demonstrated as an important factor for suppressing antitumor immune responses, but the role of tumor-derived TGF-${\beta}$ in this process is poorly understood. In this study, we demonstrated that knockdown of tumor-derived TGF-${\beta}$ using shRNA resulted in dramatically reduced tumor size, slowing tumor formation, prolonging survival rate of tumor-bearing mice and inhibiting metastasis. We revealed possible underlying mechanisms as reducing the number of myeloid-derived suppressor cells (MDSC) and $CD4^+Foxp3^+$ Treg cells, and consequently enhanced IFN-${\gamma}$ production by CTLs. Knockdown of tumor-derived TGF-${\beta}$ also significantly reduced the conversion of na$\ddot{i}$ve $CD4^+$ T cells into Treg cells in vitro. Finally, we found that knockdown of TGF-${\beta}$ suppressed cell migration, but did not change the proliferation and apoptosis of tumor cells in vitro. In summary, our study provided evidence that tumor-derived TGF-${\beta}$ is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF-${\beta}$ may serve as a potential therapeutic approach for cancer.

Wind tunnel investigation on wind characteristics of flat and mountainous terrain

Jia-Wu Li,Jun Wang,Shucheng Yang,Feng Wang,Guohui Zhao 한국풍공학회 2022 Wind and Structures, An International Journal (WAS Vol.35 No.4

Wind tunnel test is often adopted to assess the site-specific wind characteristics for the design of bridges as suggested by current design standards. To investigate the wind characteristics of flat and mountainous terrain, two topographic models are tested in a boundary layer wind tunnel. The wind characteristics, including the vertical and horizontal mean wind speed distributions, the turbulence intensity, and the wind power spectra, are presented. They are investigated intensively in present study with the discussions on the effect of wind direction and the effect of topography. It is indicated that for flat terrain, the wind direction has negligible effect on the wind characteristics, however, the assumption of a homogenous wind field for the mountainous terrain is not applicable. Further, the non-homogeneous wind field can be defined based on a proposed approach if the wind tunnel test or on-site measurement is performed. The calculated turbulence intensities and wind power spectra by using the measured wind speeds are also given. It is shown that for the mountainous terrain, engineers should take into account the variability of the wind characteristics for design considerations

Framework for Calculating the Vertical Human-Induced Vibration of the Suspension Footbridge Under the Random Pedestrian Flow

Yu Li,Dong-Shuo Yin,Jia-Hao Wang,Jia-Wu Li 한국강구조학회 2022 International Journal of Steel Structures Vol.22 No.5

Currently, the problem of human-induced vibration of suspension footbridges is a research hotspot in bridge engineering. Moreover, on the suspension footbridge deck, the walking parameters of pedestrians, the simulation of random pedestrian fl ow, and the calculation method of human-induced vibration are the keys to solving the above problem. Therefore, in this paper, the following three studies have been carried out: (1) Firstly, the Jiufengshan suspension footbridge was taken as the observation site, and the statistical values of the step frequency ( f ), step length ( l ), and walking velocity ( v ) of pedestrians on the suspension footbridge deck were investigated and obtained. (2) Secondly, by combining the “social force model” with the obtained f , l , and v , a Matlab program was compiled to simulate the random pedestrian fl ow on the suspension footbridge deck. (3) Finally, by combining the above program with the vertical vibration equations of the human–footbridge coupling system, a Matlab program was compiled to calculate the vertical human-induced vibration of the suspension footbridge deck, which then was used to study the infl uence of the random pedestrian fl ow and human–footbridge coupling eff ect on the vertical human-induced vibration of the suspension footbridge deck. So, the above studies can provide a meaningful reference for the design of suspension footbridges.

Patterns of Lymph Node Recurrence after Radical Surgery Impacting on Survival of Patients with pT1-3N0M0 Thoracic Esophageal Squamous Cell Carcinoma

Xiao-li Chen,,Tian-wu Chen,Zhi-jia Fang,Xiao-ming Zhang,Zhen-lin Li,Hang Li,Hong-jie Tang,Li Zhou,Dan Wang,Zishu Zhang 대한의학회 2014 Journal of Korean medical science Vol.29 No.2

The aim of this study was to investigate how patterns of lymph nodes recurrence after radical surgery impact on survival of patients with pT1-3N0M0 thoracic esophageal squamous cell carcinoma. One hundred eighty consecutive patients with thoracic esophageal squamous cell carcinoma underwent radical surgery, and the tumors were staged as pT1-3N0M0 by postoperative pathology. Lymph nodes recurrence was detected with computed tomography 3-120 months after the treatment. The patterns of lymph nodes recurrence including stations, fields and locations of recurrent lymph nodes, and impacts on patterns of survival were statistically analyzed. There was a decreasing trend of overall survival with increasing stations or fields of postoperative lymph nodes involved (all P<0.05). Univariate analysis showed that stations or fields of lymph nodes recurrence, and abdominal or cervical lymph nodes involved were prognostic factors for survival(all P<0.05). Cox analyses revealed that the field was an independent factor (P<0.05, odds ratio=2.73). Lymph nodes involved occurred predominantly in cervix and upper mediastinum (P<0.05). In conclusion, patterns of lymph node recurrence especially the fields of lymph nodes involved are significant prognostic factors for survival of patients with pT1-3N0M0 thoracic esophageal squamous cell carcinoma.