Publications by authors named "Jianqing Lin"

66 Publications

Hypoxia-Inducible Factor-2α as a Novel Target in Renal Cell Carcinoma.

J Kidney Cancer VHL 2021 7;8(2):1-7. Epub 2021 Apr 7.

George Washington University Hospital, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.

Hypoxia-inducible factor (HIF), an important mediator of hypoxia response, is implicated in tumorigenesis in the setting of pseudohypoxia, such as in the inactivation of von Hippel-Lindau tumor suppressor protein (pVHL), leading to development and progression of clear cell renal cell carcinoma (ccRCC). Targeting downstream molecules in HIF pathway, such as vascular endothelial growth factor (VEGF), has led to improvement in clinical outcome for patients with advanced ccRCC, but such therapy thus far has been limited by eventual resistance and treatment failure. Following the discovery of HIF-2α playing a key role in ccRCC carcinogenesis, inhibitors targeting HIF-2α have been developed and have demonstrated encouraging efficacy and safety profile in clinical trials. This review discusses HIF-2α as a promising therapeutic target for ccRCC.
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http://dx.doi.org/10.15586/jkcvhl.v8i1.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033537PMC
April 2021

DUSP4 inhibits autophagic cell death in PTC by inhibiting JNK-BCL2-Beclin1 signaling.

Biochem Cell Biol 2021 Feb 23. Epub 2021 Feb 23.

Second Affiliated Hospital of Fujian Medical University, 117889, Quanzhou, China, 362000;

DUSP4 is a prognostic marker and potential target of papillary thyroid carcinoma (PTC). However, the molecular mechanism underlying DUSP4-regulated PTC carcinogenesis is unclear. DUSP4 is a negative regulator of the autophagy promoter, JNK. This study aimed to explore the relationship between DUSP4 and JNK-mediated autophagic cell death in PTC. In this study, we explored the roles of DUSP4 in PTC using gain-of-function and loss-of-function assays. In addition, we further identified the significance of JNK-BCL2-Beclin1-autophagy signaling on DUSP4-regulated PTC carcinogenesis by combining DUSP4 silencing with JNK specific inhibitor (SP600125). We found that DUSP4 silencing promoted the phosphorylation of JNK and BCL2 in PTC cells and enhanced the release of Beclin1 from BCL2-Beclin1 complex. DUSP4 silencing promoted autophagy and death in PTC cells.The death and autophagy enhanced by DUSP4 silencing was reversed by JNK inhibitor. We further extended the in vitro experiments by injecting K1 cells transduced with DUSP4-silencing vector subcutaneously into nude mice. In vivo assays showed that DUSP4 silencing not only inhibited tumor growth, but also promoted JNK and BCL2 phosphorylation and LC3II expression.Overall, DUSP4 inhibits BCL2-Beclin1- autophagy signaling through negatively regulating JNK activity, thus inhibiting PTC oncogenesis.This study provides more potential clues for the prevention and cure of PTC.
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http://dx.doi.org/10.1139/bcb-2020-0636DOI Listing
February 2021

Improved Prognostic Stratification Using Circulating Tumor Cell Clusters in Patients with Metastatic Castration-Resistant Prostate Cancer.

Cancers (Basel) 2021 Jan 13;13(2). Epub 2021 Jan 13.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Liquid biopsy-based biomarkers have advantages in monitoring the dynamics of metastatic castration-resistant prostate cancer (mCRPC), a bone-predominant metastatic disease. Previous studies have demonstrated associations between circulating tumor cells (CTCs) and clinical outcomes of mCRPC patients, but little is known about the prognostic value of CTC-clusters. In 227 longitudinally collected blood samples from 64 mCRPC patients, CTCs and CTC-clusters were enumerated using the CellSearch platform. The associations of CTC and CTC-cluster counts with progression-free survival (PFS) and overall survival (OS), individually and jointly, were evaluated by Cox models. CTCs and CTC-clusters were detected in 24 (37.5%) and 8 (12.5%) of 64 baseline samples, and in 119 (52.4%) and 27 (11.9%) of 227 longitudinal samples, respectively. CTC counts were associated with both PFS and OS, but CTC-clusters were only independently associated with an increased risk of death. Among patients with unfavorable CTCs (≥5), the presence of CTC-clusters signified a worse survival (log-rank = 0.0185). mCRPC patients with both unfavorable CTCs and CTC-clusters had the highest risk for death (adjusted hazard ratio 19.84, = 0.0072), as compared to those with <5 CTCs. Analyses using longitudinal data yielded similar results. In conclusion, CTC-clusters provided additional prognostic information for further stratifying death risk among patients with unfavorable CTCs.
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http://dx.doi.org/10.3390/cancers13020268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828213PMC
January 2021

Relugolix as a promising novel oral GnRH antagonist for prostate cancer treatment.

Asian J Androl 2020 Nov 24. Epub 2020 Nov 24.

The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.

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http://dx.doi.org/10.4103/aja.aja_77_20DOI Listing
November 2020

Respiratory health effects of residential individual and cumulative risk factors in children living in two cities of the Pearl River Delta Region, China.

J Thorac Dis 2020 Oct;12(10):6342-6355

Key Laboratory for Urban Habitat Environmental Science and Technology, School of Environment and Energy, Peking University Shenzhen Graduate School, Shenzhen 518055, China.

Background: Indoor environment is complex, with many factors potentially interacting with each other to affect health. However, previous studies have usually focused on effect of a single factor. Assessment of the combined effects of multiple factors can help with understanding the overall health risk.

Methods: A cross-sectional study was conducted among 2,306 school children in Guangzhou and Shenzhen. Questionnaire data on respiratory symptoms and diseases were collected along with sociodemographic and residential environmental information. A subset of children (N=987) were measured for their lung function. A random forest algorithm was applied to screen the top-ranked indoor environmental exposure variables and to form a composite index for cumulative risk of indoor pollution (CRIP). Logistic regressions were conducted to analyze the independent effect of single indoor environmental risk factors and the combined effect of CRIP on children's respiratory health. Multiple linear regressions were used to examine the independent and combined effects of indoor environmental exposure on lung function.

Results: We found that home dampness and molds as well as environmental tobacco smoke (ETS) were significantly and independently associated with increased prevalence of children's respiratory symptoms and diseases and with reduced lung function. A higher CRIP level was significantly associated with increased risk of cough with cold (OR =1.37, 95% CI: 1.05-1.79) and wheeze (OR =2.71, 95% CI: 1.16-6.34). A higher CRIP level was also associated with reduced lung function measured as FVC, FEV, PEF, FEF, FEF and VC.

Conclusions: In children living in the subtropical region of the Pearl River Delta, home dampness and the presence of mold as well as ETS were individual risk factors for children's respiratory health. The composite CRIP index was associated with respiratory symptoms and lung function, suggesting the utility of this index for predicting the combined effects of multiple risk factors.
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http://dx.doi.org/10.21037/jtd.2020.03.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656417PMC
October 2020

The SiaABC threonine phosphorylation pathway controls biofilm formation in response to carbon availability in Pseudomonas aeruginosa.

PLoS One 2020 6;15(11):e0241019. Epub 2020 Nov 6.

University of Stuttgart, Institute of Biochemistry and Technical Biochemistry, Stuttgart, Germany.

The critical role of bacterial biofilms in chronic human infections calls for novel anti-biofilm strategies targeting the regulation of biofilm development. However, the regulation of biofilm development is very complex and can include multiple, highly interconnected signal transduction/response pathways, which are incompletely understood. We demonstrated previously that in the opportunistic, human pathogen P. aeruginosa, the PP2C-like protein phosphatase SiaA and the di-guanylate cyclase SiaD control the formation of macroscopic cellular aggregates, a type of suspended biofilms, in response to surfactant stress. In this study, we demonstrate that the SiaABC proteins represent a signal response pathway that functions through a partner switch mechanism to control biofilm formation. We also demonstrate that SiaABCD functionality is dependent on carbon substrate availability for a variety of substrates, and that upon carbon starvation, SiaB mutants show impaired dispersal, in particular with the primary fermentation product ethanol. This suggests that carbon availability is at least one of the key environmental cues integrated by the SiaABCD system. Further, our biochemical, physiological and crystallographic data reveals that the phosphatase SiaA and its kinase counterpart SiaB balance the phosphorylation status of their target protein SiaC at threonine 68 (T68). Crystallographic analysis of the SiaA-PP2C domain shows that SiaA is present as a dimer. Dynamic modelling of SiaA with SiaC suggested that SiaA interacts strongly with phosphorylated SiaC and dissociates rapidly upon dephosphorylation of SiaC. Further, we show that the known phosphatase inhibitor fumonisin inhibits SiaA mediated phosphatase activity in vitro. In conclusion, the present work improves our understanding of how P. aeuruginosa integrates specific environmental conditions, such as carbon availability and surfactant stress, to regulate cellular aggregation and biofilm formation. With the biochemical and structural characterization of SiaA, initial data on the catalytic inhibition of SiaA, and the interaction between SiaA and SiaC, our study identifies promising targets for the development of biofilm-interference drugs to combat infections of this aggressive opportunistic pathogen.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241019PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647112PMC
December 2020

Effects of sevoflurane inhalation anesthesia on IL-6, TNF-α and MMP-9 expression and hemodynamics in elderly patients undergoing lobectomy for lung cancer.

Cell Mol Biol (Noisy-le-grand) 2020 Jul 31;66(5):49-53. Epub 2020 Jul 31.

Fuzhou Center for Disease Control and Prevention, Fujian, 350005, China.

Objective of current research was to investigate the effect of sevoflurane inhalation anesthesia on hemodynamics and inflammatory response in elderly patients with lung cancer lobectomy. Methods: A total of 168 patients with lung cancer who underwent lobectomy in our hospital from January 2019 to December 2019 were selected as the study subjects. The patients were divided into an observation group and control group according to the anesthesia program. In the control group, 1 mg/kg propofol intravenous pump induced anesthesia was maintained at 6mg/kg/h. In the observation group, 8% sevoflurane was used to induce anesthesia and 2% sevoflurane was used to maintain anesthesia. Mean artery pressure (MAP), heart rate (HR) and blood oxygen saturation (SpO2) were monitored at the beginning of single-lung ventilation (t1), when single-lung ventilation was changed to double-lung ventilation (t2), and at 30 minutes after double-lung ventilation (t3), respectively. Serum levels of interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and matrix metalloproteinases (MMP-9) were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Assess the patient's adverse reactions. Results: At time t1 and time t2, there was no significant difference in the three hemodynamic indicators between the two groups (P>0.05). However, at t3, both MAP and HR in the observation group were significantly lower than those in the control group, while SpO2 was significantly higher than those in the control group (P<0.05). At t1 and t2, there was no significant difference in IL-6 and TNF- levels between the two groups, but at t3, IL-6 and TNF-α levels in the observation group were significantly lower than those in the control group (P<0.05). Compared with the control group, serum MMP-9 level was significantly decreased in the whole t1 to t3 stage (P<0.05). The incidence of complications in the observation group was significantly higher than that in the control group. It was calculated that Sevoflurane can significantly improve hemodynamics and inflammatory response in elderly patients with lung cancer lobectomy, but the incidence of complications is high.
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July 2020

Crystal structure of the periplasmic sensor domain of histidine kinase VbrK suggests indirect sensing of β-lactam antibiotics.

J Struct Biol 2020 11 2;212(2):107610. Epub 2020 Sep 2.

Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Centre, 138602, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 637551, Singapore. Electronic address:

Bacterial two-component regulatory systems (TCS) play important roles in sensing environmental stimuli and responding to them by regulating gene expression. VbrK/VbrR, a TCS in Vibrio parahaemolyticus, confers resistance to β-lactam antibiotics through activating a β-lactamase gene. Its periplasmic sensor domain was previously suggested to detect β-lactam antibiotics by direct binding. Here, we report a crystal structure of the periplasmic sensing domain of VbrK (VbrK) using sulfur-based single-wavelength anomalous diffraction (S-SAD) phasing. Contrary to most bacterial sensor domains which form dimers, we show that VbrK is a monomer using size exclusion chromatography coupled with multi-angle light scattering. This observation is also supported by molecular dynamics simulations. To quantify the binding affinity of β-lactam antibiotics to VbrK, we performed isothermal titration calorimetry and other biophysical analyses. Unexpectedly, VbrK did not show any significant binding to β-lactam antibiotics. Therefore, we propose that the detection of β-lactam antibiotics by VbrK is likely to be indirect via an as yet unidentified mechanism.
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http://dx.doi.org/10.1016/j.jsb.2020.107610DOI Listing
November 2020

Linkage between Particulate Matter Properties and Lung Function in Schoolchildren: A Panel Study in Southern China.

Environ Sci Technol 2020 08 16;54(15):9464-9473. Epub 2020 Jul 16.

Department of Occupational and Environmental Health, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, P. R. China.

While several scientific studies have linked PM to decreased lung function, there is still some degree of uncertainty regarding which particulate physicochemical properties are most harmful. We followed a panel of 57 healthy schoolchildren (857 person-days) to investigate the associations between a wide variety of PM and lung function in Heshan, China in 2016 for three periods. We monitored the daily concentrations of mass, chemical composition, size, number, surface area, and volume of particulate mixture. Associations of lung function with various particle metrics were estimated using generalized estimating equations and unconstrained distributed lag models. Random forest model was used to compare the relative importance of exposure metrics. Immediate (lag 0) associations of PM and carbonaceous aerosols with reduced FEV and MMEF, and accumulation-mode particles with FEV were found. Slightly delayed (lag 1, 2) effects on PEF were particularly prominent for Aitken-mode particles. Possible cumulative (lags 0-2) effects of PM and carbonaceous aerosols on PEF and Aitken-mode particles on FEV, MMEF, and PEF were observed. This study provides comprehensive evidence that the physicochemical properties of particulate mixtures are associated with reduced lung function in children. Organic carbon (OC) may be an important risk factor for the decreased lung function related to PM exposure.
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http://dx.doi.org/10.1021/acs.est.9b07463DOI Listing
August 2020

Rab7 Is Associated with Poor Prognosis of Gastric Cancer and Promotes Proliferation, Invasion, and Migration of Gastric Cancer Cells.

Med Sci Monit 2020 Jun 27;26:e922217. Epub 2020 Jun 27.

Department of Surgical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China (mainland).

BACKGROUND Rab7 belongs to the Ras oncogene family. Many studies have shown that its dysfunction is associated with many types of malignant tumors, but its effect on the pathogenesis of gastric cancer (GC) is still unknown. Therefore, we investigated the effect and mechanism of Rab7 in GC. MATERIAL AND METHODS The expression of Rab7 in GC and adjacent tissues was detected by immunohistochemistry, Western blot analysis, and qRT-PCR. The relationship of Rab7 with clinicopathological parameters and prognosis was analyzed. The expressions of Rab7, PI3K, and AKT in GC cells were assessed by Western blot. Overexpressed and silenced GC cell lines were constructed and AGS cells were treated with LY294002. The proliferation capacity of GC cells was detected by CCK8 assay, cell cycle changes were detected by flow cytometry, and the invasion and migration abilities of GC cells were assessed by transwell assay. RESULTS The expression of Rab7 was upregulated in the samples and cells, and was positively correlated with lymph node metastasis but negatively correlated with histological differentiation and clinical prognosis. In cell function experiments, overexpression of Rab7 induced the transition from S phase to G2 phase and promoted the proliferation, invasion, and migration of GC cells. Our assessment of the molecular mechanism showed that Rab7 promoted the phosphorylation of PI3K and AKT in GC cells. Incubation with the PI3K inhibitor Ly294002 impaired the enhanced effect of Rab7 overexpression on proliferation, migration, and invasion abilities of GC cells. These results show that the Rab7 affects GC cell progression by modulating the PI3K/AKT pathway. CONCLUSIONS Rab7 could be a prognostic biomarker and therapeutic target of the PI3K/AKT pathway in GC.
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http://dx.doi.org/10.12659/MSM.922217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339976PMC
June 2020

Insights into facile synthesized pomelo biochar adsorbing thallium: potential remediation in agricultural soils.

Environ Sci Pollut Res Int 2020 Jun 22;27(18):22698-22707. Epub 2020 Apr 22.

College of Food and Biological Engineering, Jimei University, Xiamen, 361021, China.

Little information is available on thallium (Tl) adsorption onto fruit-derived biochar. In this study, pomelo peel and waste pomelo were thus chosen to prepare two kinds of biochars recorded as PPB and WPB. The two produced biochars subsequently evaluated their potential remediation of thallium (Tl) contamination in agricultural soils by their Tl adsorption capacity. Results showed that the two pomelo-derived biochars presented obvious microporous structure and rich oxygen-containing functional group, supported by the observant data of specific surface area, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). Furthermore, Langmuir isothermal adsorption model can better fit the adsorption behavior of thallium onto PPB and WPB, and the subsequent maximum adsorption capacity was 4283.9 μg g and 5286.0 μg g, respectively. In addition, the pseudo-second-order kinetic model could well fit the kinetic behavior of thallium adsorption onto PPB and WPB, indicating that the process is accompanied by chemical adsorption. Meanwhile, in agricultural soils, PPB and WPB can be used as environmentally friendly adsorbents to remediate Tl contamination due to their pH increase of the tested soils and their comparable adsorption ability of Tl. The obtained findings can provide insights into comprehensively developed fruit-derived biochar technology to remediate Tl contamination in agricultural soils.
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http://dx.doi.org/10.1007/s11356-020-08595-6DOI Listing
June 2020

Phase I Trial of Weekly Cabazitaxel with Concurrent Intensity Modulated Radiation and Androgen Deprivation Therapy for the Treatment of High-Risk Prostate Cancer.

Int J Radiat Oncol Biol Phys 2020 04 3;106(5):939-947. Epub 2020 Feb 3.

Department of Medical Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania.

Purpose: Cabazitaxel has been demonstrated to improve the overall survival for men with metastatic castrate-resistant prostate cancer. The purpose of this study was to determine the maximum tolerated dose for concurrent cabazitaxel with androgen deprivation and intensity modulated radiation therapy in men with high-risk prostate cancer.

Methods And Materials: Twenty men were enrolled in this institutuional review board-approved phase I clinical trial using a 3 + 3 design. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition.

Results: With a median follow-up time of 56 months, the maximum tolerated dose of concurrent cabazitaxel was 6 mg/m. The 5-year biochemical disease-free survival was 73%, despite 75% of patients having very high risk prostate cancer per the National Comprehensive Cancer Network guidelines. Four patients were unable to complete chemotherapy owing to dose-limiting toxicities (eg, rectal bleeding, diarrhea, and elevated transaminase). There was no significant minimally important difference in Expanded Prostate Index Composite patient-reported outcomes for either the urinary or bowel domains; however, there was a significant decrease in the sexual domain.

Conclusions: This is the first clinical trial of prostate cancer to report on the combination of cabazitaxel and radiation therapy. The maximum tolerated dose of concurrent cabazitaxel with radiation and androgen deprivation therapy was determined to be 6 mg/m. Despite the aggressive nature of the disease, robust biochemical control was observed.
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http://dx.doi.org/10.1016/j.ijrobp.2019.11.418DOI Listing
April 2020

ONECUT2 is a novel target for treatment of castration-resistant prostate cancer.

Expert Opin Ther Targets 2020 02 3;24(2):89-90. Epub 2020 Feb 3.

Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

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http://dx.doi.org/10.1080/14728222.2020.1723080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523780PMC
February 2020

A Pilot Study of Radiation Therapy in Combination With Pembrolizumab in Patients With Metastatic Renal Cell Cancer.

Am J Clin Oncol 2020 02;43(2):82-86

Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.

Objectives: There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors.

Materials And Methods: mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry.

Results: Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92).

Conclusion: Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.
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http://dx.doi.org/10.1097/COC.0000000000000636DOI Listing
February 2020

Racial disparities in late-stage prostate cancer: a SEER analysis 2005-2015.

Can J Urol 2019 10;26(5):9946-9951

Department of Medicine and Surgery, George Washington University, Washington DC, USA.

Introduction: To evaluate the impact of prostate cancer screening guidelines on different racial and ethnic populations.

Materials And Methods: Data was collected from the 2005-2015 Surveillance, Epidemiology, and End Results (SEER) program. Incidence of prostate cancer diagnosis was categorized and analyzed by stage, race/ethnicity, and age group. Appropriate univariate and multivariable statistical analysis was performed.

Results: The odds of being diagnosed with regional-stage prostate cancer in 2013-2015 were 1.3 times higher for black men, 1.3 times higher for Asian American/Pacific Islander (AAPI) men, and 1.2 times higher for white men when compared to 2005-2008. The odds of being diagnosed with distant-stage prostate cancer in 2013-2015 were 1.6 times higher for black men, 1.8 times higher for AAPI men, and 2.1 times higher for white men when compared to 2005-2008. In 2005-2008, 2009-2012, and 2013-2015 respectively, the odds of being diagnosed with distant-stage prostate cancer were 1.8 times higher, 1.7 times higher, and 1.4 times higher for black men compared to white men, and 1.5 times higher, 1.5 times higher, and 1.4 times higher for AAPI men compared to white men (all respective p < .001).

Conclusions: The proportion of late-stage prostate cancer has increased significantly in all US males regardless of race and/or ethnicity. From 2013-2015, all men had a higher chance of being diagnosed with regional or distant stage disease compared to years prior. Newly-diagnosed regional-stage disease increased the most over time in AAPI and black men, while distant prostate cancer increased the most over time in white men.
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October 2019

An NF90/long noncoding RNA-LET/miR-548k feedback amplification loop controls esophageal squamous cell carcinoma progression.

J Cancer 2019 28;10(21):5139-5152. Epub 2019 Aug 28.

Department of Surgical Oncology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian, China.

In our previous study we have found that miR-548k has oncogenic roles in esophageal squamous cell carcinoma (ESCC) via repressing long noncoding RNA (lncRNA)-LET and further upregulating nuclear factor 90 (NF90). However, the upstream factors controlling miR-548k expression are still unknown. In this study, we found NF90 directly binds pri-miR-548k, increases the stability of pri-miR-548k, and upregulates the expression of pri-miR-548k and miR-548k. Therefore, NF90, miR-548k and lncRNA-LET forms a feedback loop. Gain-of-function and loss-of-function assays demonstrated that in accordance with the roles of miR-548k, NF90 also promotes ESCC cell proliferation and migration. Furthermore, we verified the regulatory feedback loop between NF90, miR-548k, and lncRNA-LET. We found NF90 upregulated miR-548k and downregulated lncRNA-LET. miR-548k downregulated lncRNA-LET and upregulated NF90. lncRNA-LET downregulated NF90 and miR-548k. Through the reciprocal regulations between each other, the NF90/miR-548k/lncRNA-LET feedback loop controls the expressions of NF90 targets (HIF-1α and VEGF), miR-548k targets (KLF10 and EGFR), and lncRNA-LET target (p53). Further functional assays demonstrated that activation of the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously overexpressing NF90 and miR-548k and simultaneously depleting lncRNA-LET significantly promotes ESCC cell proliferation and migration and ESCC tumor growth . Targeting the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously depleting NF90 and miR-548k and simultaneously overexpressing lncRNA-LET significantly inhibits ESCC cell proliferation and migration and ESCC tumor growth . In summary, our findings identified a crucial oncogenic NF90/lncRNA-LET/miR-548k feedback amplification loop, which may be promising therapeutic targets for ESCC.
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http://dx.doi.org/10.7150/jca.30816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775607PMC
August 2019

Effect of T-cadherin on the AKT/mTOR signaling pathway, gastric cancer cell cycle, migration and invasion, and its association with patient survival rate.

Exp Ther Med 2019 May 6;17(5):3607-3613. Epub 2019 Mar 6.

Department of Surgical Oncology, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.

Gastric cancer (GC) is among the most common types of human cancer and is associated with recurrence and metastasis, despite comprehensive surgical and medical treatment. Previous studies observed downregulation of T-cadherin expression in GC tissues, suggesting that this protein may act as an oncosuppressor. The current study investigated the activity of T-cadherin in GC tissues. In a follow-up study of 81 patients with GC, a Kaplan-Meier analysis of overall survival revealed a strong association of T-cadherin overexpression with increased overall survival (P<0.01). Furthermore, stable T-cadherin-overexpressing cell lines were established from HGC-27 cells via transfection of a pcDNA3.1-T-cadherin plasmid and growth and cell cycle of these cells were measured using MTT and flow cytometry assays, respectively. MTT assays revealed that proliferation of engineered T-cadherin-overexpressing cells was significantly inhibited and flow cytometry demonstrated that T-cadherin overexpression in HGC-27 cells induced cell cycle arrest in the G/G phase. Transwell assays demonstrated that T-cadherin-overexpressing HGC-27 cells exhibited reduced invasiveness and metastatic potential. Phosphorylated (p)-protein kinase B (AKT) and p-mammalian target of rapamycin (mTOR) protein levels were reduced in T-cadherin overexpressing HGC-27 cells, suggesting that the AKT/mTOR signaling pathway was involved in the gastric tumor inhibitory effect of T-cadherin. Administration of AKT-activator, insulin-like growth factor-1, to T-cadherin-overexpressing HGC-27 cells significantly affected the proliferation phenotype. In conclusion, the current study provided clinical evidence and revealed a potential mechanism supporting that T-cadherin inhibits gastric tumorigenesis through inhibition of the AKT/mTOR signaling pathway.
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http://dx.doi.org/10.3892/etm.2019.7350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447793PMC
May 2019

Pellino1 specifically binds to phospho-Thr18 of p53 and is recruited to sites of DNA damage.

Biochem Biophys Res Commun 2019 06 12;513(3):714-720. Epub 2019 Apr 12.

School of Biological Sciences, Nanyang Technological University, Singapore. Electronic address:

Pellino1 is an E3 ubiquitin ligase that plays a key role in positive regulation of innate immunity signaling, specifically required for the production of interferon when induced by viral double-stranded RNA. We report the identification of the tumor suppressor protein, p53, as a binding partner of Pellino1. Their interaction has a K of 42 ± 2 μM and requires phosphorylation of Thr18 within p53 and association with the forkhead-associated (FHA) domain of Pellino1. We employed laser micro-irradiation and live cell microscopy to show that Pellino1 is recruited to newly occurring DNA damage sites, via its FHA domain. Mutation of a hitherto unidentified nuclear localization signal within the N-terminus of Pellino1 led to its exclusion from the nucleus. This study provides evidence that Pellino1 translocates to damaged DNA in the nucleus and has a functional role in p53 signaling and the DNA damage response.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.095DOI Listing
June 2019

Differential diagnosis of multielements in cancerous and non-cancerous esophageal tissues.

Talanta 2019 May 21;196:585-591. Epub 2018 Dec 21.

Department of Chemistry and the MOE Key Lab of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen 361005, Fujian, China. Electronic address:

It is known that variations in the concentrations of certain elements in humans may be an indication of cancers. In this work, a method for the quantitative analysis of 22 elements in non-tumor and esophageal squamous cell carcinoma (ESCC) tissues from the same individual is reported. Based on the optimized platform combined with multivariate analysis, diagnostic models of ESCC were established using principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), showing excellent classification of cancerous and non-cancerous group by metallomic profiling. Elemental concentrations of 10 elements (Mn, Se, Cu, Ti, Mg, Fe, Co, Zn, Sr, Ca) showed significant difference (p < 0.001) in tumor and non-tumor tissues, in which Mn, Se, Cu and Ti are the top 4 elements of statistical significance and a shift towards higher concentration levels has also been observed in the tumor samples. These results confirm the considerable potential of elemental studies for biomedical purposes. To our knowledge, previous studies on elemental concentration in esophageal cancer were performed in serum or plasma levels; and this is the first study to evaluate the association of tissue elemental concentrations with ESCC.
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http://dx.doi.org/10.1016/j.talanta.2018.12.061DOI Listing
May 2019

Effects of Human Interleukin-10 on Ventilator-Associated Lung Injury in Rats.

Inflammation 2019 Apr;42(2):538-547

Department of Anesthesiology, the First Hospital of Fujian Medical University, Fuzhou, 350005, China.

Ventilator-induced lung injury (VILI) is one of the most serious complications of mechanical ventilation (MV) and can increase the mortality of patients with acute respiratory distress syndrome (ARDS). This work aimed to test the hypothesis that the anti-inflammatory properties of human interleukin-10 (hIL-10) can reduce VILI. Thirty-six healthy male Sprague-Dawley rats were randomly assigned into three groups (n = 12) as follows: a control group, a VILI group, and a hIL-10 group. Lung function was evaluated by oxygenation index and pulmonary edema, and morphological changes associated with lung injury were assessed by HE staining and quantitative histological lung injury score. Malondialdehyde (MDA) and Superoxide dismutase (SOD) were measured, and the levels of various inflammatory cytokines were assessed in BALF and plasma. The oxygenation index in the VILI group decreased significantly relative to the control group and improved substantially in the hIL-10 group (P < 0.01). Compared to the control group, MDA production was stimulated (P < 0.01), and SOD activity rapidly declined (P < 0.01) in the VILI group. After hIL-10, MDA content was lower than that seen in the VILI group (P < 0.01), and SOD activity was enhanced (P < 0.01). The VILI group had the highest cytokine levels, compared to either the hIL-10 group or the control group (P < 0.05). High tidal volume MV can induce VILI. hIL-10 may regulate the inflammatory response in the lung tissue, improve lung tissue oxygenation, and inhibit oxidative stress, therefore reducing VILI in rats. These experiments reveal a potential new treatment option for VILI.
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http://dx.doi.org/10.1007/s10753-018-0911-7DOI Listing
April 2019

Neoadjuvant Dose-dense Gemcitabine and Cisplatin in Muscle-invasive Bladder Cancer: Results of a Phase 2 Trial.

Eur Urol Oncol 2018 May 6;1(1):54-60. Epub 2018 Jun 6.

Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA.

Background: Accelerated (also termed dose-dense, DD) chemotherapy regimens such as accelerated methotrexate, vinblastine, doxorubicin, and cisplatin have shown better efficacy and tolerability in the metastatic setting, and shortened the time to surgery in the neoadjuvant setting compared to standard-schedule regimens. We hypothesized that a DD schedule of gemcitabine and cisplatin (GC) would shorten the time to surgery and yield similar pathologic complete response rates (pT0) in patients with muscle-invasive bladder cancer (MIBC) compared with historical controls with standard GC.

Objective: To determine the safety and efficacy of neoadjuvant DDGC in MIBC.

Design Setting And Participants: Patients with cT2-4a, N0-1, M0 MIBC were eligible and received three 14-d cycles of DDGC with pegfilgrastim support followed by radical cystectomy with lymph node dissection. The primary end point was the pT0 rate. Molecular subtypes were assigned and correlated with survival.

Results And Limitations: Thirty-one patients were evaluable for toxicity and response, of whom 58% had baseline clinical stage >T2N0M0; the median age was 69 yr. Ten patients (32%, 95% confidence interval [CI] 16-49%) achieved ypT0N0 status at cystectomy. Another four patients (13%, 95% CI 1-25%) were downstaged to non-muscle-invasive (
Conclusions: DDGC yielded a similar pT0 rate to that noted retrospectively with standard GC. Vascular events precluded, delayed, or increased the risk of surgery for 23% of patients, resulting in early closure of the study. Additional prospective studies with embedded biomarker correlatives of GC in the neoadjuvant setting are critical to accurately define both the activity and toxicity of this combination in MIBC.

Patient Summary: Neoadjuvant chemotherapy before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC). This prospective phase 2 study tested a dose-dense schedule of gemcitabine and cisplatin in MIBC. The study was closed early because of a higher than expected rate of vascular events. These data suggest that caution is required in using this regimen, particularly when there is better prospective evidence for the safety and efficacy of alternative regimens such as dose-dense or accelerated methotrexate, vinblastine, doxorubicin, and cisplatin.
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http://dx.doi.org/10.1016/j.euo.2018.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226048PMC
May 2018

Severe Hypocalcemia and Hypomagnesemia with Denosumab in Advanced Chronic Kidney Disease: Case Report and Literature Review.

Case Rep Oncol Med 2018 14;2018:2059364. Epub 2018 Oct 14.

Division of Hematology and Oncology, George Washington University School of Medicine, USA.

Background: Denosumab has become the preferred agent over zolendronic acid to help prevent skeletal-related events in patients with metastatic bone disease and multiple myeloma because it is approved for use in those with kidney dysfunction. However, denosumab has been linked to cases of hypocalcemia, particularly in those with advanced kidney disease.

Case Presentation: We present the case of a patient with metastatic prostate cancer and chronic kidney disease due to obstructive nephropathy who developed severe hypocalcemia and hypomagnesemia after denosumab injection, which required intensive care unit admission, aggressive calcium supplementation, and hemodialysis assistance. We reviewed the evidence behind the safety profile of denosumab in chronic kidney disease, and we also looked at additional factors that may precipitate severe hypocalcemia with denosumab in advanced kidney disease.

Conclusion: We believe that denosumab should be avoided in advanced chronic kidney disease due to the potential life-threatening, severe hypocalcemia that has been observed.
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http://dx.doi.org/10.1155/2018/2059364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204163PMC
October 2018

The protein kinase CK2 catalytic domain from Plasmodium falciparum: crystal structure, tyrosine kinase activity and inhibition.

Sci Rep 2018 05 9;8(1):7365. Epub 2018 May 9.

School of Biological Sciences, 60 Nanyang Drive, Nanyang Technological University, Singapore, 637551, Singapore.

Malaria causes every year over half-a-million deaths. The emergence of parasites resistant to available treatments makes the identification of new targets and their inhibitors an urgent task for the development of novel anti-malaria drugs. Protein kinase CK2 is an evolutionary-conserved eukaryotic serine/threonine protein kinase that in Plasmodium falciparum (PfCK2) has been characterized as a promising target for chemotherapeutic intervention against malaria. Here we report a crystallographic structure of the catalytic domain of PfCK2α (D179S inactive single mutant) in complex with ATP at a resolution of 3.0 Å. Compared to the human enzyme, the structure reveals a subtly altered ATP binding pocket comprising five substitutions in the vicinity of the adenine base, that together with potential allosteric sites, could be exploited to design novel inhibitors specifically targeting the Plasmodium enzyme. We provide evidence for the dual autophosphorylation of residues Thr and Tyr of PfCK2. We also show that CX4945, a human CK2 inhibitor in clinical trials against solid tumor cancers, is effective against PfCK2 with an IC of 13.2 nM.
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http://dx.doi.org/10.1038/s41598-018-25738-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943518PMC
May 2018

Abiraterone is effective and should be considered for the treatment of metastatic castrate-naïve prostate cancer.

Expert Opin Pharmacother 2018 Apr 1;19(5):507-509. Epub 2018 Mar 1.

a Division of Hematology/Oncology, Department of Medicine , George Washington University School of Medicine and Health Sciences , Washington , DC , USA.

Introduction: Androgen deprivation therapy (ADT) has been the standard of care for the treatment of newly diagnosed metastatic prostate cancer for the past 70 years. Furthermore, adding docetaxel chemotherapy to ADT significantly improved patient survival, and thus became the new standard for patients with high volume disease. However, recent evidence has called this treatment strategy into question since a published study has shown that the drug abiraterone has a similar benefit to docetaxel in a similar patient population group but with less toxicity. The following article considers this key paper and its implications. Areas covered: In this key paper evaluation, the authors discuss the rational, trial design and results of the LATITUDE trial. Furthermore, the past and current standard of care of metastatic castrate-naïve prostate cancer (mCNPC) is discussed, while the authors also compare abiraterone and docetaxel in terms of benefit, safety profile, and affordability. Expert opinion: Abiraterone is highly effective and has an excellent safety profile for the treatment of metastatic castrate-naïve prostate cancer. It is the authors' opinion that it should now be considered the new standard of care.
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http://dx.doi.org/10.1080/14656566.2018.1444028DOI Listing
April 2018

Mcl-1 inhibitor suppresses tumor growth of esophageal squamous cell carcinoma in a mouse model.

Oncotarget 2017 Dec 28;8(70):114457-114462. Epub 2017 Jun 28.

Department of Medical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.

Esophageal squamous cell carcinoma (ESCC) has a high morbidity in China, accounting for 90% of all esophageal carcinoma cases. Hence, identifying drug targets for prevention and treatment of ESCC is essential. Due to its critical role in the regulation of cell apoptosis, Mcl-1 holds great potential as a target for treatment against ESCC. In current study, we used a 4-nitroquinoline-1-oxide (4-NQO)-induced ESCC mouse model of test whether A-1210477, a Mcl-1 small molecular inhibitor, could repress ESCC development. We showed that A-1210477 treatment decreased ESCC formation and animal weight loss in a dose dependent manner. We detected decreased cellular proliferation in A-1210477-treated ESCC tissue by Ki67 expression. Moreover, A-1210477 treatment increased the number of apoptotic cells in ESCC tissues. Our study clearly demonstrates the contribution of Mcl-1 to ESCC development through promoting cell proliferation and inhibition of apoptosis, and provides a strong evidence for further evaluation of A-1210477 for treating ESCC.
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http://dx.doi.org/10.18632/oncotarget.18772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777705PMC
December 2017

Up-regulated miR-548k promotes esophageal squamous cell carcinoma progression via targeting long noncoding RNA-LET.

Exp Cell Res 2018 01 8;362(1):90-101. Epub 2017 Nov 8.

Department of Surgical Oncology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian, China. Electronic address:

Dysregulated noncoding RNAs have been observed in diverse cancers. MIR458K is frequently amplified in esophageal squamous cell carcinoma (ESCC). However, the expression, clinical significances, and action mechanisms of miR-548k in ESCC are still unclear. In this study, we found that miR-548k is significantly up-regulated in ESCC tissues and cell lines. Up-regulated miR-548k expression is significantly correlated with advanced invasion depth, lymph node metastasis, advanced TNM stage, and poor overall survival. Gain-of- and loss-of-function assays demonstrated that miR-548k promotes the proliferation and migration of ESCC cells in vitro and tumor growth in vivo. Mechanistically, we found that miR-548k directly targets and represses the expression of long noncoding RNA-LET (lncRNA-LET), and further down-regulates p53 and up-regulates NF90. In addition, we found that lncRNA-LET is down-regulated and inversely correlated with miR-548k in ESCC. Down-regulated lncRNA-LET also indicated poor overall survival of ESCC patients. Functional assays demonstrated that lncRNA-LET inhibits the proliferation and migration of ESCC cells, and the effects of miR-548k on ESCC are dependent on the negative regulation of lncRNA-LET. In summary, our data revealed the critical roles of miR-548k-lncRNA-LET regulation axis in ESCC and suggested that the miR-548k-lncRNA-LET regulation axis may be promising prognostic biomarkers and therapeutic targets for ESCC.
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http://dx.doi.org/10.1016/j.yexcr.2017.11.006DOI Listing
January 2018

Upregulation of T-cadherin suppresses cell proliferation, migration and invasion of gastric cancer .

Exp Ther Med 2017 Nov 1;14(5):4194-4200. Epub 2017 Sep 1.

Department of Surgical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.

As a unique member of the cadherin superfamily, T-cadherin (T-cad) has been demonstrated to be associated with gastric cancer (GC) prognosis. To elucidate the function of T-cad in GC , the present study firstly examined T-cad protein expression in normal and gastric cancer tissues and cell lines, and it was demonstrated to be significantly downregulated in gastric cancer samples compared with normal samples. Control and T-cad expression vectors were then transfected into the MGC8-03 and AGS GC cell lines. Utilizing MTT, clonogenic, flow cytometry, wound healing and Transwell invasion assays in addition to Western blotting, the present study demonstrated that the overexpression of T-cad suppressed GC cell growth and colony formation via cell cycle arrest at the G0/G1 phase via downregulating the expression of cyclin dependent kinase 4 and Cyclin D1. In addition, overexpression of T-cad significantly inhibited GC cell migration and invasion by increasing E-cadherin and decreasing Vimentin expression. These findings suggest T-cad may be important in GC cell proliferation and metastasis and serve as a promising target for the treatment of GC in the future.
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http://dx.doi.org/10.3892/etm.2017.5090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658734PMC
November 2017

A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone.

Oncologist 2016 11 24;21(11):1296-1297e. Epub 2016 Oct 24.

Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Lessons Learned: Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone.There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone.

Background: We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone.

Methods: This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1-7 every 21 days) per standard 3+3 design.

Results: Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early.

Conclusion: A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.
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http://dx.doi.org/10.1634/theoncologist.2016-0297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189628PMC
November 2016

Bioconcentration, metabolism, and biomarker responses in marine medaka (Oryzias melastigma) exposed to sulfamethazine.

Aquat Toxicol 2016 Dec 27;181:29-36. Epub 2016 Oct 27.

School of Bioengineering, Jimei University, Xiamen 361021, China.

The antibiotic sulfamethazine (SM) is commonly used in agriculture and livestock for its broad-spectrum antibacterial properties. Due to its widespread application, SM is frequently detected in surface water and sediments. The objective of this study was to investigate the bioconcentration, distribution and biomarker responses of SM and its main metabolite, acetylated sulfamethazine (N-SM) in medaka (Oryzias melastigma). Two treated groups of medaka were exposed to concentrations of 40μg/L and 200μg/L of SM for 24h to simulate the habitual use of those antibiotics in aquiculture activities. SM and its main metabolite, N-SM, were measured in several tissues during the 24h uptake period by UPLC/MS/MS. The bile exhibited the highest SM concentration followed by the liver, gonad, gills, and muscle and the bioconcenration factor (BCF) was 10.69-42.95 in female fish and 2.78-145.36 in male fish. N-SM showed a different distribution pattern from the parent compound, accumulating mainly in the gonad, and its BCF was much higher in the male group. Gender-related differences were also observed in the bioconcentration, transform rate and biomarkers of SM. Biomarkers (SOD, CAT) in the liver changed significantly after 2, 12, and 24h of exposure (P<0.05), and presented a double-peak phenomenon. These results indicated that SM can be absorbed and metabolized through multiple routes by fish in a short time. Interactions between biological systems and SM or its metabolites may induce biochemical disturbances in fish.
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http://dx.doi.org/10.1016/j.aquatox.2016.10.026DOI Listing
December 2016

Hypermethylation of the HIC1 promoter and aberrant expression of HIC1/SIRT1 contribute to the development of thyroid papillary carcinoma.

Oncotarget 2016 Dec;7(51):84416-84427

Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China.

Hypermethylation leading to the loss of hypermethylated in cancer-1 (HIC1) gene expression occurs in many different types of human cancer. HIC1 is a transcriptional repressor that directly binds to the promoter region of NAD-dependent deacetylase sirtuin-1 (SIRT1). SIRT1 functions in cell growth, is anti-apoptotic, protect neurons, functions in senescence, and regulates energy restriction. Epigenetic modification and dysregulation affecting the HIC1/SIRT1 axis is potentially important for the development of malignancies. However, the importance of HIC1 expression in the development of papillary thyroid carcinoma, especially in Chinese patients, is uncertain. Therefore, we assessed the level of methylation in the HIC1 promoter and the mRNA and protein expression levels of HIC1 and SIRT1 in human thyroid papillary carcinoma and tumor adjacent control tissues. The demethylation reagent 5-aza-2'-deoxyctidine (5-aza-dc) and an HIC1 overexpression plasmid were used to manipulate the HIC1/SIRT1 pathway, and the effects on cell senescence, apoptosis, and cell cycle progression were assessed. Compared to normal thyroid tissue, thyroid tumors had lower expression of HIC1 and higher SIRT1 expression. The level of HIC1 methylation was also higher in thyroid carcinoma tissues than adjacent tissues. HIC1 expression was closely correlated with patient age and tumor progression. Restoration of HIC1 expression through an overexpression plasmid or 5-aza-dC treatment reduced SIRT1 expression and cell proliferation, and led to senescence, cell cycle arrest, and apoptosis. Aberrant expression of HIC1/SIRT1 and hypermethylation of the HIC1 promoter may be critical for the development and progression of papillary thyroid cancer.
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http://dx.doi.org/10.18632/oncotarget.12936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356670PMC
December 2016