Publications by authors named "Yali Fan"

22 Publications

  • Page 1 of 1

Highly potent dopamine receptor D2 antagonist ONC206 demonstrates anti-tumorigenic activity in endometrial cancer.

Am J Cancer Res 2021 15;11(11):5374-5387. Epub 2021 Nov 15.

Division of Gynecologic Oncology, University of North Carolina at Chapel Hill Chapel Hill, NC 27599, USA.

Endometrial cancer (EC) is a highly obesity-driven cancer, with limited treatment options. ONC201 is an imipridone that selectively antagonizes the G protein-coupled receptors dopamine receptor D2 and D3 (DRD2/3) and activates human mitochondrial caseinolytic protease P (ClpP). It is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through induction of the integrated stress response (ISR) as well as through stimulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and subsequent induction of apoptosis. ONC201 is being evaluated in Phase II clinical trials for solid tumors and hematological malignancies, including EC. ONC206 is an analog of ONC201 with nanomolar potency in Phase I clinical trials. This study evaluated the anti-tumor efficacy of ONC206 in EC cell lines and the genetically engineered mouse model of endometrioid EC. ONC206 revealed greater potency than ONC201 in the inhibition of proliferation in EC cell lines, with IC50 concentration ranges of 0.21-0.32 µM for ONC026 versus 2.14-3.53 µM for ONC201. ONC206 induced cellular stress, apoptosis and cell cycle G1 arrest, accompanied by inhibition of the AKT/mTOR/S6 pathways in EC cells. Diet-induced obesity accelerated tumor growth in mice. ONC206 inhibited EC tumor size and weight in both obese and lean mice after 4 weeks of treatment. Treatment with ONC206 led to a decrease in expression of Ki67, BCL-XL and phosphorylation of S6, as well as an increase in ClpP in endometrial tumors under both obese and lean conditions. Overall, the pre-clinical efficacy of ONC206 is promising and worthy of further exploration in clinical trials for endometrioid EC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640798PMC
November 2021

Early Gut Microbiota Colonisation of Premature Infants Fed with Breastmilk or Formula with or without Probiotics: A Cohort Study.

Nutrients 2021 Nov 14;13(11). Epub 2021 Nov 14.

Menzies Health Institute Queensland, School of Medicine and Dentistry, Griffith University, Gold Coast, QLD 4215, Australia.

Premature infants have a fragile ecology of the gut microbiota, which is associated with many health problems and may be influenced by formula versus breast feeding. The present study investigated differences in the process of gut microbiota colonisation in preterm infants fed with breastmilk or formula with or without probiotics before 12 weeks. This cohort study recruited 138 premature infants; 31 in the breastmilk (BM) group, 59 in the probiotics formula (PF) group and 48 in the non-probiotics formula (NPF) group, according to the feeding practice they received at birth. Gut bacterial composition was identified with 16S rRNA gene sequencing in faecal samples collected at 1 week, 6 weeks and 12 weeks after birth. The alpha diversity was higher in the PF group compared to the other groups at week 1 and 6 (both < 0.01) but showed no difference at week 12. The beta diversity of the three groups showed a trend towards similarity at the first two stages ( < 0.001 and = 0.009, respectively) and finally showed no difference at week 12. Canonical redundancy analysis showed that feeding type could explain the difference in gut microbiota composition at week one and six (both < 0.01). At genus level, was enriched in the PF group, while the and was enriched in the NPF group. In summary, formula with probiotics feeding after birth can affect gut microbiota colonisation and lead to a bacterial community with less potential pathogens.
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http://dx.doi.org/10.3390/nu13114068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624512PMC
November 2021

Substrate Stiffness Modulates the Growth, Phenotype, and Chemoresistance of Ovarian Cancer Cells.

Front Cell Dev Biol 2021 24;9:718834. Epub 2021 Aug 24.

Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

Mechanical factors in the tumor microenvironment play an important role in response to a variety of cellular activities in cancer cells. Here, we utilized polyacrylamide hydrogels with varying physical parameters simulating tumor and metastatic target tissues to investigate the effect of substrate stiffness on the growth, phenotype, and chemotherapeutic response of ovarian cancer cells (OCCs). We found that increasing the substrate stiffness promoted the proliferation of SKOV-3 cells, an OCC cell line. This proliferation coincided with the nuclear translocation of the oncogene Yes-associated protein. Additionally, we found that substrate softening promoted elements of epithelial-mesenchymal transition (EMT), including mesenchymal cell shape changes, increase in vimentin expression, and decrease in E-cadherin and β-catenin expression. Growing evidence demonstrates that apart from contributing to cancer initiation and progression, EMT can promote chemotherapy resistance in ovarian cancer cells. Furthermore, we evaluated tumor response to standard chemotherapeutic drugs (cisplatin and paclitaxel) and found antiproliferation effects to be directly proportional to the stiffness of the substrate. Nanomechanical studies based on atomic force microscopy (AFM) have revealed that chemosensitivity and chemoresistance are related to cellular mechanical properties. The results of cellular elastic modulus measurements determined by AFM demonstrated that Young's modulus of SKOV-3 cells grown on soft substrates was less than that of cells grown on stiff substrates. Gene expression analysis of SKOV-3 cells showed that mRNA expression can be greatly affected by substrate stiffness. Finally, immunocytochemistry analyses revealed an increase in multidrug resistance proteins, namely, ATP binding cassette subfamily B member 1 and member 4 (ABCB1 and ABCB4), in the cells grown on the soft gel resulting in resistance to chemotherapeutic drugs. In conclusion, our study may help in identification of effective targets for cancer therapy and improve our understanding of the mechanisms of cancer progression and chemoresistance.
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http://dx.doi.org/10.3389/fcell.2021.718834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421636PMC
August 2021

Asparagus officinalis Exhibits Anti-Tumorigenic and Anti-Metastatic Effects in Ovarian Cancer.

Front Oncol 2021 14;11:688461. Epub 2021 Jul 14.

Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Ovarian cancer is one of the leading causes of female cancer death. Emerging evidence suggests that many dietary natural products have anti-tumorigenic activity, including that of asparagus officinalis. The current study aimed to assess the anti-tumorigenic and anti-metastatic effects of asparagus officinalis on serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer. Asparagus officinalis decreased cellular viability, caused cell cycle G1 phase arrest and induced apoptosis in the OVCAR5 and SKOV3 cells. Induction of apoptosis and inhibition of cell proliferation was rescued by the pan-caspase inhibitor, Z-VAD-FMK, implying that its cytotoxic effects were mainly dependent on caspase pathways. Asparagus officinalis increased levels of ROS and decreased mitochondrial membrane potential with corresponding increases in PERK, Bip, Calnexin PDI and ATF4 in both cell lines. Treatment with asparagus officinalis also reduced ability of adhesion and invasion through epithelial-mesenchymal transition and reduction of VEGF expression. The combination of Asparagus officinalis with paclitaxel had synergistic anti-proliferative activity. Furthermore, Asparagus officinalis significantly inhibited tumor growth and reduced serum VEGF in a genetically engineered mouse model of ovarian cancer under obese and lean conditions, accompanied with a decrease in the expression of Ki67, VEGF and phosphorylated S6, and in an increase in phosphorylation of AMPK in the ovarian tumor tissues. Overall, our data provide a pre-clinical rationale for asparagus officinalis in the prevention and treatment of ovarian cancer as a novel natural product.
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http://dx.doi.org/10.3389/fonc.2021.688461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317209PMC
July 2021

Plasma Metabolic Profiling in Patients With Silicosis and Asbestosis.

J Occup Environ Med 2021 09;63(9):787-793

Department of Occupational Medicine and Toxicology, Clinical Center for Interstitial Lung Diseases, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Workers' Stadium South Road, Chao-Yang District, Beijing 100020, China (Zhou, Xue, Fan, Wu, Ma, Ye), Department of Occupational Diseases and Chemical Poisoning, the Fifth People's Hospital of Suzhou, the Affiliated Infectious Hospital of Soochow University, 10 Guangqian Road, Xiang-Cheng District, Suzhou 215131, Jiangsu Province, China (Zhou).

Objectives: To explore the circulating metabolites and related pathways in silicosis and asbestosis exposure to different mineral dust.

Methods: Plasma of 30 silicosis, 30 asbestosis, and 20 healthy controls was analyzed using liquid chromatography-mass spectrometry. Metabolic networks and the relevance of the identified metabolic derangements were explored.

Results: Compared with healthy controls, 37 and 39 dysregulated plasma metabolites were found in silicosis and asbestosis, respectively, of which the levels of 22 metabolites differed. Three major pathways were identified, among which arginine and proline metabolism was identified as the most closely related metabolic pathway.

Conclusions: The types and quantities of up-regulated metabolites including lipids, amino acids, and carnitines differed between silicosis and asbestosis. Pathways inducing lung fibrosis were common to mineral dust exposure, while pathways related to oxidative stress and tumorigenesis differed between silicosis and asbestosis.
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http://dx.doi.org/10.1097/JOM.0000000000002232DOI Listing
September 2021

Distinct metabolic features in the plasma of patients with silicosis and dust-exposed workers in China: a case-control study.

BMC Pulm Med 2021 Mar 17;21(1):91. Epub 2021 Mar 17.

Department of Occupational Medicine and Toxicology, Clinical Centre for Interstitial Lung Diseases, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Workers' Stadium South Road, Chao-Yang District, Beijing, 100020, China.

Background: Silicosis is a progressive pneumoconiosis characterized by interstitial fibrosis following exposure to silica dust. The role of metabolic dysregulation in the pathogenesis of silicosis has not been investigated in detail. This study aimed to identify different metabolic features in the plasma of patients with silicosis and dust-exposed workers without silicosis in metabolomics studies.

Methods: Patients with silicosis, dust-exposed workers (DEWs) without silicosis and age-matched healthy controls were recruited in a case-control study. The metabolomics analyses by ultra-high performance liquid chromatography-mass spectrometry were conducted. Distinct metabolic features (DMFs) were identified in the pilot study and were validated in the validation study. The enriched signalling pathways of these DMFs were determined. The ability of DMFs to discriminate among the groups was analysed through receiver operating characteristic (ROC) curves. The correlations between DMFs and clinical features were also explored.

Results: Twenty-nine DMFs and 9 DMFs were detected and had the same trend in the pilot study and the validation study in the plasma of the DEW and silicosis groups, respectively. Sphingolipid metabolism was the major metabolic pathway in the DEWs, and arginine and proline metabolism was associated with silicosis. Twenty DMFs in the DEWs and 3 DMFs in the patients with silicosis showed a discriminatory ability with ROC curve analysis. The abundance of kynurenine was higher in Stage III silicosis than in Stage I or Stage II silicosis. L-arginine and kynurenine were both negatively correlated with the percentage of forced vital capacity predicted in silicosis.

Conclusions: Distinct metabolic features in the plasma of DEWs and the patients with silicosis were found to be different. Sphingolipid metabolism and arginine and proline metabolism were identified as the major metabolic pathway in the DEW and silicosis groups, respectively. L-arginine and kynurenine were correlated with the severity of silicosis.
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http://dx.doi.org/10.1186/s12890-021-01462-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971960PMC
March 2021

Chemoprotective effect of atorvastatin against benzo(a)pyrene-induced lung cancer via the inhibition of oxidative stress and inflammatory parameters.

Ann Transl Med 2021 Feb;9(4):355

Department of Respiratory, Affiliated Xi'an Central Hospital, The Medical School of Xi'an Jiaotong University, Xi'an, China.

Background: Lung cancer affects approximately 9% of women and 17% of men worldwide, and has a mortality rate of 17%. Previously published studies have suggested that oxidative stress expansion can lead to lung cancer. The aim of the current study was to analyze the possible inhibitory pathway of atorvastatin against lung cancer cells in an model.

Methods: The cytotoxic effects of atorvastatin on lung cancer cell lines H460 and A549 were analyzed, as well as cell cycle arrest and cell morphology. Benzo(a)pyrene (BaP) was used for the induction of lung cancer in experimental rats, and atorvastatin (5, 10, and 20 mg/kg body weight) was used for treatment in a dose-dependent manner. Body weight and lung tumors were calculated at regular intervals. Antioxidants, pro-inflammatory cytokines, phase I and II antioxidant enzymes, polyamine enzymes, and apoptosis markers were determined at end of the experimental study.

Results: Cell cycle arrest occurred at the G2/M phase after atorvastatin treatment. Atorvastatin increased cytochrome C expression and caspase activity in a dose-dependent manner, and increased the activity of antioxidative enzymes, such as GPx, SOD, GST, reduced glutathione, and catalase, and reduced the level of nitrate and LPO. It also altered the xanthine oxidase (XO), Lactic Acid Dehydrogenase (LDH), quinone reductase (QR), UDP-glucuronosyltransferase (UDP-GT), adenosine deaminase (ADA), Aryl hydrocarbon hydroxylase (AHH), 5'-nucleotidase, cytochrome P450, cytochrome B5 and NADPH cytochrome C reductase levels. Atorvastatin was found to modulate polyamine enzyme levels, such as histamine, spermine, spermidine, and putrescine, and significantly (P<0.001) reduced the pro-inflammatory cytokine levels, such as tumor necrosis factor-α. Interleukin (IL)-6 and interleukin-1β (IL-1β) increased caspase-3 and caspase-9 levels in a dose-dependent manner.

Conclusions: Our findings indicate that atorvastatin can inhibit lung cancer through apoptosis.
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http://dx.doi.org/10.21037/atm-20-7770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944302PMC
February 2021

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer.

J Exp Clin Cancer Res 2021 Feb 8;40(1):61. Epub 2021 Feb 8.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Background: ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer.

Methods: Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1p53 mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer.

Results: Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1/p53 mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice.

Conclusion: ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.
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http://dx.doi.org/10.1186/s13046-021-01842-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869513PMC
February 2021

Docosahexaenoic acid (DHA), an omega-3 fatty acid, inhibits tumor growth and metastatic potential of ovarian cancer.

Am J Cancer Res 2020 1;10(12):4450-4463. Epub 2020 Dec 1.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill Chapel Hill, NC, USA.

Omega-3 polyunsaturated fatty acids (PUFAs), such as those found in fish oil, are thought to have anti-tumorigenic effects and may help to treat and prevent cancer, including ovarian cancer. Thus, we aimed to evaluate the potential of docosahexaenoic acid (DHA), an omega-3 PUFA, as a therapeutic agent in ovarian cancer cell lines and a transgenic mouse model of ovarian cancer. DHA significantly inhibited cellular proliferation, induced cell cycle arrest and caused apoptosis in Hey and IGROV-1 cells. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed DHA-induced caspase 3 activity and prevented DHA-reduced cell proliferation. DHA also induced cellular reactive oxygen species (ROS) and inhibited adhesion and invasion in IGROV-1 and Hey cells. Furthermore, treatment with DHA demonstrated anti-tumorigenic and anti-invasive activity in a K18-gT ; p53; Brca1 mouse model of ovarian cancer including downregulation of Ki67 and VEGF expression. The data provide a preclinical rationale for applying DHA for dietary intervention and therapeutic adjunct in patients with ovarian cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783742PMC
December 2020

Telomerase gene variants and telomere shortening in patients with silicosis or asbestosis.

Occup Environ Med 2020 Dec 15. Epub 2020 Dec 15.

Department of Occupational Medicine and Toxicology, Clinical Center for Interstitial Lung Diseases, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Chao-Yang Hospital, Capital Medical University, No.8 Worker's Stadium, Chaoyang District. Beijing, China

Objectives: Telomerase gene variants that lead to accelerated telomere shortening are linked to progressive-fibrosing interstitial lung diseases. However, little is known about their relationships with pneumoconiosis. This study aimed to identify variants and leucocyte telomere lengths (LTL) in patients with silicosis or asbestosis.

Methods: In the present study, Sanger sequencing of variants was performed in 193 Chinese Han patients with pneumoconiosis, including 109 with silicosis and 84 with asbestosis. Quantitative PCR was used to measure LTL in peripheral blood of the patients and 200 age and sex-matched healthy controls.

Results: In total, 7.3% patients with pneumoconiosis had 17 variants. Among which 8.3% of patients with silicosis and 3.6% of patients with asbestosis had variants, respectively. No variants were detected in silicosis, whereas 3.6% of patients with asbestosis had variants. Telomeres were significantly shorter in the patients with pneumoconiosis compared with healthy controls (p<0.001). No significant differences in LTL were found between variant carriers and non-carriers. Exposure to silica dust was associated with the severity of pneumoconiosis after adjusting for covariates (OR 4.92, p=0.002). However, variants and short telomeres were not associated with the severity of pneumoconiosis.

Conclusion: Telomerase gene variants and short telomeres may be identified in the patients with silicosis and asbestosis in response to the exposure to silica or asbestos dust but are not related to disease severity.
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http://dx.doi.org/10.1136/oemed-2020-107046DOI Listing
December 2020

Short-term exposure to ambient particulate matter and outpatient visits for respiratory diseases among children: A time-series study in five Chinese cities.

Chemosphere 2021 Jan 8;263:128214. Epub 2020 Sep 8.

Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China. Electronic address:

There was limited evidence regarding the association between short-term exposure to ambient particulate matter (PM) and respiratory outpatient visits among children at a multicity level. In this study, a time-series study was conducted among children aged 0-14 years in five Chinese cities from 2013 to 2018. City-specific effects of fine particles (PM), inhalable particles (PM) and coarse particles (PM) were estimated for time lags of zero up to seven previous days using the overdispersed generalized additive models after adjusting for time trends, meteorological variables, day of the week and holidays. Meta-analyses were applied to pool the overall effects, while the exposure-response (E-R) curves were evaluated using a cubic regression spline. The overall effects of PM were significantly associated with total and cause-specific respiratory outpatients among children, even at PM and PM levels below the current Chinese Ambient Air Quality Standards (CAAQS) Grade II. Each 10 μg/m increment in PM, PM and PM at lag 07 was associated with a 1.39% (95% CI: 0.38%, 2.40%), 1.10% (95% CI: 0.38%, 1.83%) and 2.93% (95% CI: 1.05%, 4.84%) increase in total respiratory outpatients, respectively. An E-R relationship was observed except for PM in Beijing and PM and PM in Shanghai. The effects of PM were stronger in cold season in 3 southern cities, while it was stronger in transition season in 2 northern cities. In conclusion, short-term PM exposures were dose-responsive associated with increased respiratory outpatient visits among children, even for PM and PM levels below current CAAQS II in certain cities.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128214DOI Listing
January 2021

ONC206, an Imipridone Derivative, Induces Cell Death Through Activation of the Integrated Stress Response in Serous Endometrial Cancer .

Front Oncol 2020 20;10:577141. Epub 2020 Oct 20.

Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

ONC206 (Oncoceutics) is an imipiridone with nanomolar potency and analogue of ONC201, a selective dopamine receptor D2 (DRD2) antagonist currently being investigated in phase II clinical trials for serous endometrial cancer (SEC). This study investigated the anti-proliferative efficacy of ONC206 in SEC cell lines as well as its impact on cellular stress and adhesion/invasion. ONC206 inhibited cellular proliferation in a dose-dependent manner and was more potent than ONC201 in the ARK1 (IC = 0.33µM vs. IC = 1.59uM) and SPEC-2 (IC = 0.24uM vs. IC = 0.81uM) cell lines. Treatment with ONC206 resulted in induction of ROS production and reduction of mitochondrial membrane potential, accompanied by an increase in cleaved caspase-3 and caspase-9 activity (p < 0.01). ONC206 also significantly inhibited cellular adhesion and migration in both cell lines (p < 0.01). Pretreatment with the stress inhibitor N-acetylcysteine (NAC) significantly attenuated the efficacy of ONC206 on cell proliferation, ROS production and cellular invasion. ONC206 demonstrates nanomolar potency for the inhibition of proliferation in SEC cells. Specifically, ONC206 utilizes ISR activation as a significant pathway in the propagation of its anti-proliferative and anti-metastatic effects. Thus, ONC206 may be a promising agent in future SEC clinical trials as was its predecessor ONC201.
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http://dx.doi.org/10.3389/fonc.2020.577141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641618PMC
October 2020

Short term effects of air pollutants on hospital admissions for respiratory diseases among children: A multi-city time-series study in China.

Int J Hyg Environ Health 2021 01 17;231:113638. Epub 2020 Oct 17.

Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China. Electronic address:

Evidence concerning short-term acute association between air pollutants and hospital admissions for respiratory diseases among children in a multi-city setting was quite limited. We conducted a time-series analysis to evaluate the association of six common air pollutants with hospital admissions for respiratory diseases among children aged 0-14 years in 4 cities (Guangzhou, Shanghai, Wuhan and Xining), China during 2013-2018. We used generalized additive models incorporating penalized smoothing splines and random-effect meta-analysis to calculate city-specific and pooled estimates, respectively. The exposure-response relationship curves were fitted using the cubic spline regression. Subgroup analyses by gender, age, season and disease subtype were also performed. A total of 183,036 respiratory diseases hospitalizations were recorded during the study period, and 94.1% of the cases were acute respiratory infections. Overall, we observed that increased levels of air pollutants except O, were significantly associated with increased hospital admissions for respiratory disease. Each 10 μg/m increase in PM, SO and NO at lag 07, PM at lag 03 and per 1 mg/m increase in CO at lag 01 corresponded to increments of 1.19%, 3.58%, 2.23%, 0.51% and 6.10% in total hospitalizations, respectively. Generally, exposure-response relationships of PM and SO in Guangzhou, SO, NO and CO in Wuhan, as well as SO and NO in Xining with respiratory disease hospitalizations were also found. Moreover, the adverse effects of these pollutants apart from PM in certain cities remained significant even at exposure levels below the current Chinese Ambient Air Quality Standards (CAAQS) Grade II. Children aged 4-14 years appeared to be more vulnerable to the adverse effects of PM, SO and NO. Furthermore, with the exception of O, the associations were stronger in cold season than in warm season. Short-term exposure to PM, SO, NO and CO were associated, in dose-responsive manners, with increased risks of hospitalizations for childhood respiratory diseases, and adverse effects of air pollutants except PM held even at exposure levels below the current CAAQS Grade II in certain cities.
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http://dx.doi.org/10.1016/j.ijheh.2020.113638DOI Listing
January 2021

SPR064, a pro-drug of paclitaxel, has anti-tumorigenic effects in endometrial cancer cell lines and mouse models.

Am J Transl Res 2020 15;12(8):4264-4276. Epub 2020 Aug 15.

Division of Gynecologic Oncology, University of North Carolina at Chapel Hill Chapel Hill, NC, USA.

Paclitaxel is one of the most effective and widely used agents in treating a variety of cancers, including endometrial cancer. Because of its poor solubility in water, the current intravenous pharmaceutical paclitaxel is formulated in Cremophor EL and dehydrated in ethanol in equal volumes. Cremophor EL is capable of causing complement activation, which can trigger an immediate hypersensitivity reaction. SPR064 is a pro-drug of paclitaxel which has a much higher solubility as compared to the parent drug; hence, SPR064 can be conveniently formulated in non-cremapor based medium, reducing the risk of cremaphor-related hypersensitivity reactions. The pharmacokinetics and solubility of SPR064 were evaluated in rats. The anti-tumorigenic potential of SPR064 was compared to paclitaxel in endometrial cancer cell lines and a genetically engineered mouse model ( ) of endometrial cancer. Overall, SPR064 exhibited improved solubility and better exposure to drug in rats when compared to paclitaxel. SPR064 and paclitaxel inhibited cell proliferation, induced apoptosis, enhanced cellular stress and caused cell cycle G1 arrest in endometrial cancer cell lines, with similar potency. Both SPR064 and paclitaxel reduced tumor weight in the mouse model under obese and lean conditions compared to their respective controls. Immunohistochemical staining demonstrated that SPR064 and paclitaxel significantly reduced the expression of Ki-67 and BCL-xL in the endometrial tumors of both obese and lean mice. In summary, SPR064 has anti-tumorigenic effects that are equivalent to paclitaxel in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Thus, SPR064 may be a promising therapy for endometrial cancer without the significant risk of hypersensitivity reactions seen with paclitaxel.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476112PMC
August 2020

Association of occupational dust exposure with combined chronic obstructive pulmonary disease and pneumoconiosis: a cross-sectional study in China.

BMJ Open 2020 09 9;10(9):e038874. Epub 2020 Sep 9.

Department of Occupational Medicine and Toxicology, Clinical Center for Interstitial Lung Diseases, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China

Objectives: Occupational dust exposure may induce various lung diseases, including pneumoconiosis and chronic obstructive pulmonary disease (COPD). The features of combined COPD and pneumoconiosis have not been well described, and this may hamper the management. This study aimed to describe the prevalence and characteristics as well as the risk factors of the combined diseases.

Design: A cross-sectional study.

Setting And Participants: 758 patients with pneumoconiosis were recruited at a single-medical centre. Of these, 675 patients with pneumoconiosis, including asbestosis, silicosis, coal workers' pneumoconiosis and other pneumoconiosis, was eligible for analysis.

Primary Outcome Measures: COPD was diagnosed based on clinical features and/or history of exposure to risk factors and post bronchodilator forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC) ratio <0.7. Clinical data were collected from predesigned medical reports. The patients underwent both chest radiograph and high-resolution CT scans. Risk factors for combined COPD and pneumoconiosis were analysed using regression analysis.

Results: COPD prevalence overall was 32.7% (221/675) and was the highest in silicosis (84/221) and coal workers' pneumoconiosis (100/221). COPD prevalence increased with smoking pack-years, dust exposure duration and pneumoconiosis stage. Patients with combined diseases had lower body mass index, higher smoking index and worse pulmonary function. Risk factors for combined diseases included heavy smoking, silica or coal exposure and advanced pneumoconiosis. The interaction between dust exposure and smoking in COPD was also identified. The risk of combined COPD significantly increased with heavy smoking and silica or coal exposure (OR 5.49, 95% CI 3.04 to 9.93, p<0.001).

Conclusions: COPD is highly prevalent in patients with pneumoconiosis, especially patients with silicosis and coal workers' pneumoconiosis. Occupational dust exposure as well as heavy smoking is associated with an increased risk of combined COPD and pneumoconiosis, which demands an effective preventive intervention.
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http://dx.doi.org/10.1136/bmjopen-2020-038874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482476PMC
September 2020

Combining brain-computer interface and virtual reality for rehabilitation in neurological diseases: A narrative review.

Ann Phys Rehabil Med 2021 Jan 2;64(1):101404. Epub 2020 Sep 2.

Yanshan University Library, Yanshan University, Qinhuangdao, China.

Background: The traditional rehabilitation for neurological diseases lacks the active participation of patients, its process is monotonous and tedious, and the effects need to be improved. Therefore, a new type of rehabilitation technology with more active participation combining brain-computer interface (BCI) with virtual reality (VR) has developed rapidly in recent years and has been used in rehabilitation in neurological diseases.

Objectives: This narrative review analyzed and characterized the development and application of the new training system (BCI-VR) in rehabilitation of neurological diseases from the perspective of the BCI paradigm, to provide a pathway for future research in this field.

Methods: The review involved a search of the Web of Science-Science Citation Index/Social Sciences Citation Index and the China National Knowledge Infrastructure databases; 39 papers were selected. Advantages and challenges of BCI-VR - based neurological rehabilitation were analyzed in detail.

Results: Most BCI-VR studies included could be classified by 3 major BCI paradigms: motor imagery, P300, and steady-state visual-evoked potential. Integrating VR scenes into BCI systems could effectively promote the recovery process from nervous system injuries as compared with traditional methods.

Conclusion: As compared with rehabilitation based on traditional BCI, rehabilitation based on BCI-VR can provide better feedback information for patients and promote the recovery of brain function. By solving the challenges and continual development, the BCI-VR system can be broadly applied to the clinical treatment of various neurological diseases.
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http://dx.doi.org/10.1016/j.rehab.2020.03.015DOI Listing
January 2021

Ku80 gene knockdown by the CRISPR/Cas9 technique affects the biological functions of human thyroid carcinoma cells.

Oncol Rep 2019 Dec 1;42(6):2486-2498. Epub 2019 Oct 1.

Department of Pathology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, P.R. China.

In the present study, to evaluate the role of Ku80 in thyroid carcinoma (TC), 86 thyroid tissue samples from patients with a spectrum of thyroid disorders were examined for protein levels of Ku80, nuclear factor‑κB (NF‑κB) and RET/TC by immunohistochemistry. Furthermore, in TC cells, Ku80 mRNA was detected by reverse transcription‑quantitative PCR analysis and silenced using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‑associated protein 9 (Cas9) technique to assess its role. An antibody array was used to identify Ku80‑related regulatory genes. The protein levels of Ku80 in the TC tissues were significantly higher than those in non‑neoplastic adjacent tissue samples (P<0.01). The activation of NF‑kB and expression of RET/TC in the TC group were significantly increased (P<0.05) and were correlated with the protein expression of Ku80 (P<0.05). In papillary TC cells, the mRNA levels of Ku80 were high; Ku80 knockdown resulted in reductions in proliferation, invasion and colony formation, increased apoptosis, and reduced levels of proteins involved in MAPK signaling, cell proliferation and apoptosis. The high expression of Ku80 in TC was found to be associated with the expression of RET/TC and activation of NF‑κB, and Ku80 knockdown decreased the malignancy of TC cells.
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http://dx.doi.org/10.3892/or.2019.7348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826323PMC
December 2019

PCAT1 is a poor prognostic factor in endometrial carcinoma and associated with cancer cell proliferation, migration and invasion.

Bosn J Basic Med Sci 2019 Aug 20;19(3):274-281. Epub 2019 Aug 20.

Department of Obstetrics and Gynecology, The First People's Hospital of Lanzhou city, Lanzhou, Gansu, China.

Long non-coding RNAs (lncRNAs) are emerging as important modulators of cancer progression, among which prostate cancer-associated transcript 1 (PCAT1) has been shown to be an oncogene in several tumors. However, the clinical significance and biological function of PCAT1 in endometrial carcinoma (EC) remain unclear. In this study, we used 89 EC tissues and HEC-1B, Ishikawa, RL95-2 and AN3CA EC cell lines. We found elevated expression levels of PCAT1 in EC tissues and cell lines using reverse transcription qPCR (RT-qPCR). The prognostic value of PCAT1 was determined using Kaplan-Meier survival and Cox regression analysis. The results showed that higher PCAT1 expression was positively correlated with FIGO stage, myometrial invasion, lymph node metastasis, and a shorter overall survival. A series of functional assays showed that the knockdown of PCAT1 by small interfering RNA (siRNA) targeting PCAT1 (siPCAT1) suppressed cell proliferation, migration and invasion, but promoted apoptosis. Western blot analysis further showed that B-cell lymphoma 2 (Bcl-2), vimentin and N-cadherin were downregulated, but E-cadherin and Bcl-2-associated death promoter (Bad) were upregulated in PCAT1-silenced EC cells. Taken together, our results underscore the oncogenic role of PCAT1 in EC and show that PCAT1 may be a potential therapeutic target in EC treatment.
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http://dx.doi.org/10.17305/bjbms.2019.4096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716094PMC
August 2019

Water-induced strong protection against acute exposure to low subzero temperature of adult Aedes albopictus.

PLoS Negl Trop Dis 2019 02 4;13(2):e0007139. Epub 2019 Feb 4.

Sun Yat-sen University-Michigan State University Joint Center of Vector Control for Tropical Diseases, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

As an important vector of dengue and Zika, Aedes albopictus has been the fastest spreading invasive mosquitoes in the world over the last 3-4 decades. Cold tolerance is important for survival and expansion of insects. Ae. albopictus adults are generally considered to be cold-intolerant that cannot survive at subzero temperature. However, we found that Ae. albopictus could survive for several hours' exposure to -9 to -19 oC so long as it was exposed with water. Median lethal time (LT50) of Ae. albopictus exposed to -15 and -19 oC with water increased by more than 100 times compared to those exposed to the same subzero temperature without water. This phenomenon also existed in adult Aedes aegypti and Culex quinquefasciatus. Ae. albopictus female adults which exposed to low subzero temperature at -9 oC with water had similar longevity and reproductive capacity to those of females without cold exposure. Cold exposure after a blood meal also have no detrimental impact on survival capacity of female adult Ae. albopictus compared with those cold exposed without a blood meal. Moreover, our results showed that rapid cold hardening (RCH) was induced in Ae. albopictus during exposing to low subzero temperature with water. Both the RCH and the relative high subzero temperature of water immediate after cold exposure might provide this strong protection against low subzero temperature. The molecular basis of water-induced protection for Ae. albopictus might refer to the increased glycerol during cold exposure, as well as the increased glucose and hsp70 during recovery from cold exposure. Our results suggested that the water-induced strong protection against acute decrease of air temperature for adult mosquitoes might be important for the survival and rapid expansion of Ae. albopictus.
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http://dx.doi.org/10.1371/journal.pntd.0007139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382212PMC
February 2019

Pm62, an adult-plant powdery mildew resistance gene introgressed from Dasypyrum villosum chromosome arm 2VL into wheat.

Theor Appl Genet 2018 Dec 30;131(12):2613-2620. Epub 2018 Aug 30.

College of Agronomy/JCIC-MCP/National Key Laboratory of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Nanjing, 210095, People's Republic of China.

Key Message: Pm62, a novel adult-plant resistance (APR) gene against powdery mildew, was transferred from D. villosum into common wheat in the form of Robertsonian translocation T2BS.2VL#5. Powdery mildew, which is caused by the fungus Blumeria graminis f. sp. tritici, is a major disease of wheat resulting in substantial yield and quality losses in many wheat production regions of the world. Introgression of resistance from wild species into common wheat has application for controlling this disease. A Triticum durum-Dasypyrum villosum chromosome 2V#5 disomic addition line, N59B-1 (2n = 30), improved resistance to powdery mildew at the adult-plant stage, which was attributable to chromosome 2V#5. To transfer this resistance into bread wheat, a total of 298 BCF plants derived from the crossing between N59B-1 and Chinese Spring were screened by combined genomic in situ hybridization and fluorescent in situ hybridization, 2V-specific marker analysis, and reaction to powdery mildew to confirm that a dominant adult-plant resistance gene, designated as Pm62, was located on chromosome 2VL#5. Subsequently, the 2VL#5 (2D) disomic substitution line (NAU1825) and the homozygous T2BS.2VL#5 Robertsonian translocation line (NAU1823), with normal plant vigor and full fertility, were identified by molecular and cytogenetic analyses of the BCF generation. The effects of the T2BS.2VL#5 recombinant chromosome on agronomic traits were also evaluated in the F segregation population. The results suggest that the translocated chromosome may have no distinct effect on plant height, 1000-kernel weight or flowering period, but a slight effect on spike length and seeds per spike. The translocation line NAU1823 has being utilized as a novel germplasm in breeding for powdery mildew resistance, and the effects of the T2BS.2VL#5 recombinant chromosome on yield-related and flour quality characters will be further assessed.
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http://dx.doi.org/10.1007/s00122-018-3176-5DOI Listing
December 2018

Knockdown of POLE2 expression suppresses lung adenocarcinoma cell malignant phenotypes in vitro.

Oncol Rep 2018 Nov 17;40(5):2477-2486. Epub 2018 Aug 17.

Institute of Cancer Research, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

In the present study, we profiled β‑elemene‑regulated gene expression and investigated the effects of the silencing of the DNA polymerase epsilon 2, accessory subunit (POLE2) in lung cancer cells. Differently expressed genes were profiled in A549 cells incubated in the presence or absence of β‑elemene by Affymetrix Human Gene Expression Array. POLE2 shRNA was then constructed to knock down POLE2 expression. Cells were counted and phenotypes were assessed via CCK‑8, colony formation and caspase-3/-7 activity assays. PathScan antibody array analysis was used to identify shPOLE2‑regulated genes. The cDNA microarray identified a total of 721 differentially expressed genes in the A549 cells. Furthermore, knockdown of POLE2 expression inhibited A549 and NCI‑H1299 cell proliferation and apoptosis. The PathScan data indicated that expression levels of p‑Akt (phosphorylated‑protein kinase B, p‑AKT/p‑PKB), p‑Smad2 (phosphorylated mothers against decapentaplegic homolog 2), p‑p38 MAPK (phosphorylated mitogen‑activated protein kinases p38), p‑SAPK/JNK (phosphorylated c‑Jun N‑terminal protein kinase/stress activated protein kinase), cleaved caspase‑7, IκBα (nuclear factor of κ light polypeptide gene enhancer in B‑cell inhibitor, α), p‑Chk1 (phosphorylated checkpoint kinase 1), p‑IκBα, p‑eIF2α (phosphorylated eukayotic translational initiation factor 2α), p‑TAK1 (phosphorylated TGF‑B‑activated kinase 1), survivin and α‑tubulin were significantly lower in shPOLE2 cells than these levels in the shCtrl cells. The PathScan data indicated that the expression levels of p‑p53 (phosphorylated tumor protein 53) were significantly higher in the shPOLE2 cells than these levels in the shCtrl cells. β‑elemene can restrain human lung cancer A549 and NCI‑H1299 cell proliferation and apoptosis by suppressing POLE2 expression.
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http://dx.doi.org/10.3892/or.2018.6659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151888PMC
November 2018

[Penetration moxibustion with different dosage for insomnia of insufficiency of heart and spleen type].

Zhongguo Zhen Jiu 2016 Nov;36(11):1139-1143

College of Acupuncture-Moxibustion and Tuina, Henan University of CM, Zhengzhou 450008, China.

Objective: To observe the clinical efficacy differences between acupuncture combined with 40-min penetration moxibustion and 60-min penetration moxibustion at back- points for insomnia of insufficiency of heart and spleen type.

Methods: Sixty patients of insomnia with insufficiency of heart and spleen type were randomly assigned into a 40-min group and a 60-min group. The two groups were treated with acupuncture at Jueyinshu (BL 14), Xinshu (BL 15), Geshu (BL 17), Pishu (BL 20), Shendao (GV 11) and Zhiyang (GV 9). With moxibustion box, the penetration moxibustion was applied at the back until sweating and redness on the back. The moxibustion was given for 40 min in the 40-min group and 60 min in the 60-min group. The treatment was given once a day, five days per week. Each session was consisted of 5 treatments, with an interval of 2 days between session and totally 4 consecutive weeks were provided. The Pittsburgh sleep quality index (PSQI), TCM symptom scale were observed and recorded before and after treatment in the two groups. The even temperature at raising period, effective period, reducing period, as well as minimum high temperature, comfortable temperature, minimum cold temperature and medication status were compared; also the effect was compared between the two groups.

Results: The total effective rate was 96.6% (28/29) in the 60-min group, which was higher than 89.3% (25/28) in the 40-min group (<0.05). Compared before treatment, the total score of PSQI and sleep quality, sleep time, sleep efficiency, sleep disorder, daytime dysfunction as well as the total TCM symptom score and its drowsiress in the morning, palpitation, amnesia, appetite were reduced after treatment in the 40-min group (all <0.05). After treatment, the total score and each score of PSQI as well as total score and each score of TCM symptom scale were reduced after treatment in the 60-min group (all <0.05). After treatment, the total score and each score of PSQI as well as total score and each score of TCM symptom scale were significantly different between the two groups (all <0.05).

Conclusions: Acupuncture combined with penetration moxibustion can improve the symptomsof insomnia with insufficiency of heart and spleen type, which is more significant in the 60-min group, indicating prolonged time of penetration moxibustion can improve sleep latency.
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http://dx.doi.org/10.13703/j.0255-2930.2016.11.007DOI Listing
November 2016
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