Publications by authors named "Dongfang Yang"

62 Publications

Knockdown of macrophage migration inhibitory factor (MIF), a novel target to protect neurons from parthanatos induced by simulated post-spinal cord injury oxidative stress.

Biochem Biophys Res Commun 2020 03 14;523(3):719-725. Epub 2020 Jan 14.

China Medical University, Shenbei New District, Shenyang City, Liaoning Province, PR China. Electronic address:

Parthanatos is a form of regulated cell death (RCD) that is closely linked to DNA damage, which is a common consequence of oxidative stress due to central nervous trauma, such as spinal cord injury (SCI). The mechanism by which apoptosis-inducing factor (AIF) mediates DNA strand breaks in parthanatos was not clear until the discovery of the nuclease function of MIF. A previous study suggested that observed results may not be reliable if the oxidative stress induced in cells observed under experimental pathological conditions does not accurately replicate the specific pathologies being studied. According to an earlier direct measurement of extracellular oxidative stress in a rat SCI model, post-SCI oxidative stress was approximately the same as exposure to 150 μM HO. However, this concentration has been reported as sublethal oxidative stress in other cell types related to senescence, apoptosis, and parthanatos. Using sublethal HO concentrations to induce oxidative stress is equivocal. Also, different cell types have diverse tolerances and responses to oxidative stress, and, therefore, exposure to HO. To avoid these limitations, the present study explored the mechanism of neuronal death under this simulated post-SCI oxidative stress and determined the effects of MIF knockdown in parthanatos associated with SCI. Immunofluorescence and flow cytometry were used to reveal typical characteristics of parthanatos that were blocked by PARP-1 inhibitors but not caspase inhibitors. In addition to classic features like PARP-1 and caspase-3 cleavage that were absent, we determined that parthanatos instead of apoptosis played a major role in the cell death caused by oxidative stress following SCI. Flow cytometry analysis of cells transfected by adenovirus with MIF-shRNA then exposed to HO showed a significant decrease in cell death for MIF knockdown cells, even after AIF nuclear translocation. The comet assay also displayed significantly fewer DNA strand breaks after MIF knockdown. This is the first study has verified that MIF knockdown enables to protect neurons from parthanatos under a simulated in vivo oxidative stress following SCI. It suggests that MIF knockdown is a promising therapy to rescue neurons suffering from oxidative stress-induced SCI pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2019.12.115DOI Listing
March 2020

Stromal ColXα1 expression correlates with tumor-infiltrating lymphocytes and predicts adjuvant therapy outcome in ER-positive/HER2-positive breast cancer.

BMC Cancer 2019 Nov 1;19(1):1036. Epub 2019 Nov 1.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, 593 Eddy St, APC 12, Providence, RI, 02903, USA.

Background: The breast cancer microenvironment contributes to tumor progression and response to chemotherapy. Previously, we reported that increased stromal Type X collagen α1 (ColXα1) and low TILs correlated with poor pathologic response to neoadjuvant therapy in estrogen receptor and HER2-positive (ER+/HER2+) breast cancer. Here, we investigate the relationship of ColXα1 and long-term outcome of ER+/HER2+ breast cancer patients in an adjuvant setting.

Methods: A total of 164 cases with at least 5-year follow-up were included. Immunohistochemistry for ColXα1 was performed on whole tumor sections. Associations between ColXα1expression, clinical pathological features, and outcomes were analyzed.

Results: ColXα1 expression was directly proportional to the amount of tumor associated stroma (p = 0.024) and inversely proportional to TILs. Increased ColXα1 was significantly associated with shorter disease free survival and overall survival by univariate analysis. In multivariate analysis, OS was lower in ColXα1 expressing (HR = 2.1; 95% CI = 1.2-3.9) tumors of older patients (> = 58 years) (HR = 5.3; 95% CI = 1.7-17) with higher stage (HR = 2.6; 95% CI = 1.3-5.2). Similarly, DFS was lower in ColXα1 expressing (HR = 1.8; 95% CI = 1.6-5.7) tumors of older patients (HR = 3.2; 95% CI = 1.3-7.8) with higher stage (HR = 2.7; 95% CI = 1.6-5.7) and low TILs. In low PR+ tumors, higher ColXα1 expression was associated with poorer prognosis.

Conclusion: ColXα1 expression is associated with poor disease free survival and overall survival in ER+/HER2+ breast cancer. This study provides further support for the prognostic utility of ColXα1 as a breast cancer associated stromal factor that predicts response to chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-6134-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825361PMC
November 2019

High pressure behavior of crystal [2,2'-bi(1,3,4-oxadiazole)]-5,5'-dinitramide: A DFT investigation.

J Mol Graph Model 2019 07 17;90:87-93. Epub 2019 Apr 17.

Key Laboratory of Magnetic Molecules, Magnetic Information Materials Ministry of Education, The School of Chemistry and Material Science, Shanxi Normal University, Linfen, 041004, PR China.

Density functional theory (DFT) computation was carried out to investigate the crystal, molecular and electronic structures of high energy crystal [2,2'-bi(1,3,4-oxadiazole)]-5,5'-dinitramide (BODN) with the pressure 0-120 GPa. The relaxed crystal structure by the GGA/PBE-TS functional matches well with the experimental data at ambient pressure condition. With the intensifying of pressure, the lattice parameters, volumes, bond lengths, H-bond energies, atomic charges, bond populations, band gaps and density of states of crystal BODN change gently. Under the pressure of 48, 104, and 107 GPa, three pressure-induced transformations occurred. The intramolecular six membered rings pose strong affect in stabilizing systems in the pressure range 0-120 GPa. Between O1 and H2 atoms, the H-bond interaction transforms into covalent interaction under the circumstance of 48 GPa. At 104 GPa, structural transformation occurs with the distortion of the intramolecular six membered ring. In addition, O1⋅⋅⋅H2 and O2⋅⋅⋅H1 have the largest H-bond energies in comparison with the others. When the pressure reaches 107 GPa, the H-bond O1⋅⋅⋅H2 is formed again with the deformation and non-coplanarity of two oxadiazoles in crystal BODN. The electrons can be moved easily based on the density of states and energy bands under high pressure. Helpful information will be conveyed by this work in the field of further analysis connected the pressure effect on molecular transformations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmgm.2019.04.005DOI Listing
July 2019

Tailored Polyimide-Graphene Nanocomposite as Negative Electrode and Reduced Graphene Oxide as Positive Electrode for Flexible Hybrid Sodium-Ion Capacitors.

ACS Appl Mater Interfaces 2018 Dec 7;10(50):43730-43739. Epub 2018 Dec 7.

School of Chemical Engineering , The University of Queensland , Brisbane , QLD 4072 , Australia.

Redox-active polyimide materials hold a great promise for electrochemical energy storage applications, especially for flexible energy storage devices. However, the low utilization efficiency due to poor electrical conductivity of the materials remains one of the greatest challenges. In this work, we designed and prepared polyimide-graphene composite materials and tested their electrochemical properties in sodium-ion capacitors. By manipulating the interfacial chemistry and interactions between the polyimide and graphene, composite electrode materials with different polyimide particle sizes and morphologies were obtained. Sodium-ion storage capacity was significantly improved, from ∼50 mAh g for pure polyimide to 225 mAh g for a polyimide-graphene composite. A hybrid sodium-ion capacitor fabricated with freestanding polyimide-graphene composite as the negative electrode and reduced graphene oxide as the positive electrode delivered energy densities of 55.5 and 21.5 Wh kg at power densities of 395 and 3400 W kg, respectively. A flexible sodium-ion capacitor with outstanding mechanical properties was also demonstrated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.8b17171DOI Listing
December 2018

Utility of 15(S)-HETE as a Serological Marker for Eosinophilic Esophagitis.

Sci Rep 2018 09 28;8(1):14498. Epub 2018 Sep 28.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, USA.

The pathogenesis of eosinophilic esophagitis (EoE) involves Th2-mediated eosinophil recruitment and degranulation into the esophagus. However, measuring serum Th2 cytokines, eosinophils, and eosinophil-derived products does not reliably distinguish EoE from control populations. Non-invasive methods to diagnose EoE are lacking. We evaluated the diagnostic value of a novel candidate biomarker of EoE: 15(S)-hydroxyeicosatetraenoic acid (HETE). We used immunoassay to measure 15(S)-HETE and cytokine profiles in patients undergoing endoscopy with known or suspected EoE. 31 subjects were enrolled, 16 with EoE, and 15 with an alternate diagnosis. 15(S)-HETE was elevated in the EoE group compared to non-EoE group. The sensitivity and specificity of 15(S)-HETE to be used as a non-invasive marker is 50% and 80%, respectively. 15(S)-HETE may aid in the diagnosis of EoE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-32944-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162315PMC
September 2018

ColXα1 is a stromal component that colocalizes with elastin in the breast tumor extracellular matrix.

J Pathol Clin Res 2019 01 1;5(1):40-52. Epub 2018 Nov 1.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA.

The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen α-1 (ColXα1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColXα1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColXα1 and elastin, we evaluated the expression of ColXα1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels. Our findings demonstrate that ColXα1 colocalizes with elastin in invasive breast cancer-associated stroma by immunohistochemistry, immunofluorescence, and electron microscopy. In 212 invasive breast carcinomas, this complex was aberrantly and selectively expressed in tumor extracellular matrix in 79% of ER+/HER2-, 80% of ER+/HER2+, 76% of ER-/HER2+, and 58% of triple negative breast cancers. In contrast, ColXα1 was generally absent, while elastin was present perivascularly in normal breast tissue. ColXα1 and elastin were coexpressed in 58% of ductal carcinoma in situ (DCIS) in periductal areas. In mass-forming DCIS with desmoplastic stroma, the complex was intensely expressed in periductal areas as well as within the tumor-associated stroma in all cases. Our data suggest that the breast carcinoma neoplastic process may involve aberrant expression of ColXα1 and elastin in the tumor microenvironment emerging early at the DCIS stage. Enrichment of these complexes in tumor-associated stroma may represent a stromal signature indicative of intrinsic differences between breast cancers. These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cjp2.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317058PMC
January 2019

Alanine-glyoxylate aminotransferase 1 (AGXT1) is a novel marker for hepatocellular carcinomas.

Hum Pathol 2018 10 5;80:76-81. Epub 2018 Jun 5.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903. Electronic address:

Arginase-1 has been demonstrated as a marker for hepatocellular carcinoma (HCC) with higher sensitivity and specificity than HepPar-1 and glypican-3. However, its sensitivity is diminished in moderately and poorly differentiated HCCs. In the current study, we evaluated the utility of AGXT1 as a diagnostic marker. Immunostains for AGXT1 and arginase-1 were performed in tissue microarrays of 139 HCCs and 374 gastrointestinal and nongastrointestinal carcinomas. AGXT1 exhibited granular cytoplasmic immunoreactivity in contrast to the diffuse cytoplasmic staining characteristic of arginase-1 in nonneoplastic and neoplastic hepatocytes. Sensitivities of AGXT1 for all HCCs were 90.0% compared to 87.8% for arginase-1. A small number of tumors expressed only 1 of the 2 markers. Sensitivity increased to 92.1% when the presence of either marker was considered positive. Excepting 5 cases of cholangiocarcinoma, both AGXT1 and arginase-1 were negative in all non-HCC tumors with specificities of 98.7%. Our data support the consideration of AGXT1 as a novel hepatocellular marker with equally high specificity and slightly higher sensitivity as compared to arginase-1. AGXT1 may aid in diagnostic workup especially in conjunction with arginase-1 for HCCs that may otherwise defy conventional immunostaining patterns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2018.05.025DOI Listing
October 2018

TGR5 expression in normal kidney and renal neoplasms.

Diagn Pathol 2018 Apr 2;13(1):22. Epub 2018 Apr 2.

Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 593 Eddy Street, APC 12, Providence, RI, 02903, USA.

Background: The G protein-coupled bile acid receptor (TGR5) is a cell surface receptor which induces the production of intracellular cAMP and promotes epithelial-mesenchymal transition in gastric cancer cell lines. TGR5 is found in a wide variety of tissues including the kidney. However, the patterns of TGR5 expression have not been well characterized in physiologic kidney or renal neoplasms. We explore the expression of TGR5 in benign renal tissue and renal neoplasms and assess its utility as a diagnostic marker.

Methods: Sixty-one renal cortical neoplasms from 2000 to 2014 were retrieved. TGR5 protein expression was examined by immunohistochemistry. TGR5 mRNA was also measured by real-time PCR.

Results: In normal renal tissue, TGR5 was strongly positive in collecting ducts, distal convoluted tubules and thin loop of Henle. Proximal convoluted tubules showed absent or focal weak staining. In clear cell renal cell carcinomas (RCCs), 25 of 27 cases (92%) were negative for TGR5 (p < 0.001). TGR5 mRNA was also significantly decreased in clear cell RCCs, suggesting that decreased TGR5 protein expression may be attributable to the downregulation of TGR5 mRNA in these tumors. All 11 papillary RCCs expressed TGR5 with 45% (5/11) exhibiting moderate to strong staining. All chromophobe RCCs and oncocytomas were positive for TGR5 with weak to moderate staining. TGR5 mRNA expression in these tumors was similar to normal kidney. All urothelial carcinomas of the renal pelvis strongly expressed TGR5 including a poorly differentiated urothelial carcinoma with sarcomatoid features.

Conclusion: TGR5 is strongly expressed in collecting ducts, distal convoluted tubules and thin loop of Henle. TGR5 protein and mRNA expression were notably decreased in clear cell RCCs and may be helpful in differentiating these tumors from other RCCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13000-018-0700-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880016PMC
April 2018

T-complex-associated-testis-expressed 3 (TCTE3) is a novel marker for pancreatobiliary carcinomas.

Hum Pathol 2017 12 24;70:62-69. Epub 2017 Oct 24.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903. Electronic address:

Several markers of pancreatobiliary lineage have been described in the literature. However, none have demonstrated sufficient specificity and sensitivity to warrant diagnostic use. We evaluated the utility of T-complex-associated-testis-expressed 3 (TCTE3) as a pancreatobiliary marker. A set of 247 adenocarcinomas from the gastrointestinal (GI) tract was identified including 18 from the gastroesophageal junction (GEJ), 29 stomach, 17 ampullary, 62 pancreatic, and 16 common bile duct and gallbladder (CBD/GB), 13 non-ampullary small intestine, 32 colon, and 24 rectum. The remainder consisted of 16 cholangiocarcinomas and 20 hepatocellular carcinomas (HCC). Additionally, 163 adenocarcinomas from the breast, gynecologic tract, prostate, urothelium, kidney, and lung were stained for comparison. Immunohistochemistry for TCTE3 and other gastrointestinal markers was performed. Positive expression of TCTE3 was characterized by a strong, well-defined membranous pattern with or without weak cytoplasmic staining. Expression was identified in the normal epithelial cells of pancreatobiliary tree, but staining was absent in normal epithelial cells of esophagus, stomach, and intestine. Hepatocytes, pancreatic acini and islets and other non-epithelial cells were also negative for staining. TCTE3 was expressed in 93.5% of pancreatic ductal adenocarcinomas, 37.5% of CBD/GB adenocarcinomas, 50% of cholangiocarcinomas, 76.4% of ampullary adenocarcinomas, and 33.3% of GEJ adenocarcinomas. Only 3.5% of the gastric, 7.7% of non-ampullary small intestinal and 6.25% of colonic tumors exhibited positive staining. Expression was absent in rectal carcinomas and HCCs. These results suggest that TCTE3 is a useful marker of pancreatobiliary differentiation and may aid in distinguishing these tumors from gastric and intestinal primary tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2017.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757622PMC
December 2017

Pyridine-Based Electron-Transport Materials with High Solubility, Excellent Film-Forming Ability, and Wettability for Inkjet-Printed OLEDs.

ACS Appl Mater Interfaces 2017 Nov 30;9(44):38716-38727. Epub 2017 Oct 30.

Printable Electronics Research Center, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences , 398 Ruoshui Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, People's Republic of China.

Film morphology has predominant influence on the performance of multilayered organic light-emitting diodes (OLEDs), whereas there is little reported literature from the angle of the molecular level to investigate the impact on film-forming ability and device performance. In this work, four isomeric cross-linkable electron-transport materials constructed with pyridine, 1,2,4-triazole, and vinylbenzyl ether groups were developed for inkjet-printed OLEDs. Their lowest unoccupied molecular orbital (∼3.20 eV) and highest occupied molecular orbital (∼6.50 eV) levels are similar, which are mainly determined by the 1,2,4-triazole groups. The triplet energies of these compounds can be tuned from 2.51 to 2.82 eV by different coupling modes with the core of pyridine, where the 2,6-pyridine-based compound has the highest value of 2.82 eV. Film formation and solubility of the compounds were investigated. It was found that the 2,6-pyridine-based compound outperformed the 2,4-pyridine, 2,5-pyridine, and 3,5-pyridine-based compounds. The spin-coated blue OLEDs based on the four compounds have achieved over 14.0% external quantum efficiencies (EQEs) at the luminance of 100 cd m, and a maximum EQE of 12.1% was obtained for the inkjet-printed device with 2,6-pyridine-based compound.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.7b12190DOI Listing
November 2017

Stromal Clusterin Expression Predicts Therapeutic Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer.

Clin Breast Cancer 2018 06 19;18(3):e373-e379. Epub 2017 Aug 19.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI.

Background: Expression of clusterin correlates with tumor progression and therapeutic response in several human malignancies, including breast cancer. However, its predictive value in the neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether clusterin expression in breast cancer correlated with clinical pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy (NAC).

Materials And Methods: We determined the clusterin expression pattern in 72 triple negative breast cancers (TNBC) treated with NAC before surgery. Clusterin expression was evaluated by immunohistochemistry and was correlated with pathologic characteristics and response to NAC using residual cancer burden score.

Results: Immunohistochemistry analysis revealed a differential pattern of expression between tumor and stroma. Clusterin expression in the tumor associated stroma as opposed to expression by the neoplastic epithelium was significantly associated with neoadjuvant-treated TNBC. Low stromal clusterin, low stromal content, and high tumor-infiltrating lymphocytes were associated with a significantly greater likelihood of achieving a good pathologic response as reflected by lower residual cancer burden scores (P = .002, P = .003, and P = .001, respectively). Tumor and/or stromal clusterin expression were not associated with patient age, tumor histologic grade, stage, and lymph node status.

Conculsion: This study suggests a potential role for the assessment of stromal clusterin as a predictive biomarker for response of TNBC to neoadjuvant therapy. Further validation of this biomarker in a large study is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clbc.2017.08.007DOI Listing
June 2018

ZnO-Layered Double Hydroxide@Graphitic Carbon Nitride Composite for Consecutive Adsorption and Photodegradation of Dyes under UV and Visible Lights.

Materials (Basel) 2016 Nov 15;9(11). Epub 2016 Nov 15.

School of Chemical Engineering, The University of Queensland, Brisbane, QLD 4072, Australia.

In this work, a ZnO-layered double hydroxide@graphitic carbon nitride composite (ZnO-LDH@C₃N₄) was synthesized via co-precipitation method with solvothermal treatment. The structure and morphology of ZnO-LDH@C₃N₄ composite were characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopes/transmission electron microscopes (SEM/TEM), N₂ adsorption/desorption, ultraviolet visible diffuse reflectance spectroscopy (UV-Vis-DRS), photoluminescence spectrometer (PL) and electrochemical impedance spectroscopy (EIS). The adsorption and photocatalytic properties of ZnO-LDH@C₃N₄ composite towards the organic dyes: Orange II sodium salt (OrgII, an anionic azo dye) and methylene blue (MB, a cationic azo dye) were investigated. Compared to ZnO-LDH and g-C₃N₄, the ZnO-LDH@C₃N₄ composite displayed an excellent performance in both adsorption and photocatalytic degradation of the organic dyes. Moreover, a combination of ZnO-LDH and g-C₃N₄ significantly improved the photocatalytic performance of ZnO-LDH and g-C₃N₄ under visible-light irradiation. The adsorption and photocatalytic mechanism were also investigated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ma9110927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457221PMC
November 2016

TGR5 expression in benign, preneoplastic and neoplastic lesions of Barrett's esophagus: Case series and findings.

World J Gastroenterol 2017 Feb;23(8):1338-1344

Shivali Marketkar, Dongfang Yang, Weibiao Cao, Department of Pathology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903, United States.

Aim: To examined the bile acid receptor TGR5 expression in squamous mucosa, Barrett's mucosa, dysplasia and esophageal adenocarcinoma (EA).

Methods: Slides were stained with TGR5 antibody. The staining intensity was scored as 1+, 2+ and 3+. The extent of staining (percentage of cells staining) was scored as follows: 1+, 1%-10%, 2+, 11%-50%, 3+, 51%-100%. A combined score of intensity and extent was calculated and categorized as negative, weak, moderate and strong staining. TGR5 mRNA was measured by real time PCR.

Results: We found that levels of TGR5 mRNA were significantly increased in Barrett's dysplastic cell line CP-D and EA cell line SK-GT-4, when compared with Barrett's cell line CP-A. Moderate to strong TGR5 staining was significantly higher in high-grade dysplasia and EA cases than in Barrett's esophagus (BE) or in low-grade dysplasia. Moderate to strong staining was slightly higher in low-grade dysplasia than in BE mucosa, but there is no statistical significance. TGR5 staining had no significant difference between high-grade dysplasia and EA. In addition, TGR5 staining intensity was not associated with the clinical stage, the pathological stage and the status of lymph node metastasis.

Conclusion: We conclude that TGR5 immunostaining was much stronger in high-grade dysplasia and EA than in BE mucosa or low-grade dysplasia and that its staining intensity was not associated with the clinical stage, the pathological stage and the status of lymph node metastasis. TGR5 might be a potential marker for the progression from BE to high-grade dysplasia and EA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3748/wjg.v23.i8.1338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330818PMC
February 2017

Human Papillomavirus Genotyping of Incidental Malignant and Premalignant Lesions on Hemorrhoidectomy Specimens.

Am J Surg Pathol 2017 Mar;41(3):382-388

Departments of *Pathology and Laboratory Medicine, Rhode Island Hospital †Pathology and Laboratory Medicine, Women and Infants Hospital of Rhode Island ‡Pathology and Laboratory Medicine §Pathology and Laboratory Medicine, The Miriam Hospital, Alpert Medical School of Brown University, Providence, RI.

Routine histopathologic examination of hemorrhoidectomy specimens is controversial having been described as not useful and expensive with few of these common cases demonstrating incidental lesions. However, unexpected premalignant and malignant lesions have been detected on excised hemorrhoids. The high-risk human papillomavirus (HR-HPV) types associated with these incidentally identified high-grade lesions are presently unknown. We aimed to identify cases of incidental high-grade anal intraepithelial neoplasia (HG-AIN) and anal squamous cell carcinoma incidentally discovered on hemorrhoidectomy specimens, genotype HR-HPVs from these lesions, and assess p53 and p16 expression by immunohistochemistry to identify risk factors for their development. With institutional approval, cases with associated demographics from 1995 to 2015 were reviewed to identify and confirm incidental HG-AIN or squamous cell carcinoma in hemorrhoidectomy specimens. Genotyping for HR-HPV types and immunohistochemical staining for p53 and p16 was performed. Statistical analysis comparing HPV genotypes, p53 and p16 staining, and potential risk factors by the Fisher exact test was performed. In the largest series of incidental high-grade lesions on hemorrhoidectomy, HPV 16 was the most common HR-HPV detected though multiple-type infections were common including some HPV 16/18-negative cases. By genotyping, HPV 39 was significantly associated with IV-drug abuse history (P=0.0015) and HIV-positive status (P=0.037), whereas HPV 58 detection correlated with chemotherapy-induced immunosuppression (P=0.029). There was frequent overlap between p53 staining and HPV positivity, particularly when HPV 31 was detected. We also identified several mimickers of HG-AIN that may present diagnostic challenges in these specimens. Our data support continued routine examination of hemorrhoidectomy specimens and suggest that adjunctive studies such as immunohistochemistry for challenging cases may be useful.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000000809DOI Listing
March 2017

Collagen type III α1 as a useful diagnostic immunohistochemical marker for fibroepithelial lesions of the breast.

Hum Pathol 2016 11 3;57:176-181. Epub 2016 Aug 3.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI 02903.

Phyllodes tumors (PTs) of the breast constitute an uncommon group of fibroepithelial neoplasms that are classified into benign, borderline, and malignant categories based on a constellation of histologic characteristics including cytologic atypia, mitotic count, degree of stromal cellularity, stromal overgrowth, and microscopic margins. Accurately and reproducibly differentiating these tumors is a long-standing diagnostic challenge. In addition, the distinction between benign PT from cellular fibroadenoma (FA) is especially difficult because of overlapping microscopic features. We have previously shown differential expression of various collagens, including collagen type III α1 (Col3A) in breast carcinomas. In this study, we evaluated clinicopathological characteristics of 95 cases of fibroepithelial lesions including 56 PTs and 39 FAs (25 cellular FA, 14 typical FA) and correlated them with the immunohistochemical staining pattern for Col3A. We found that stromal Col3A expression was significantly increased in PTs when compared with FAs (P < .0001). Among the PT groups, there was significantly increased expression from benign tumors through borderline to malignant tumors. High Col3A expression was associated with PT type, irregular margin status, and high mitotic activity. A distinct periductal cuffing pattern of Col3A staining was unique to PTs and absent in FAs. These findings suggest that Col3A can be a potential adjunct marker for both differentiating FA from PT and assessing malignant potential in PTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2016.07.017DOI Listing
November 2016

Fatty acid-binding protein 1 is preferentially lost in microsatellite instable colorectal carcinomas and is immune modulated via the interferon γ pathway.

Mod Pathol 2017 01 30;30(1):123-133. Epub 2016 Sep 30.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.

Fatty acid-binding protein 1 (FABP1) is an intracellular protein responsible for the transportation of long chain fatty acids. Aside from its functions in lipid metabolism and cellular differentiation, FABP1 also plays a role in inflammation through its interaction with peroxisome proliferator-activated receptors (PPARs). Previously, we compared expression of colonic epithelium genes in a subset of microsatellite instable (MSI) colorectal carcinomas (medullary carcinomas) to normal colonic mucosa and found that FABP1 expression was markedly decreased in the tumors. Further analysis of RNA expression in the colorectal subtypes and The Cancer Genome Atlas data set found that FABP1 expression is decreased in the CMS1 subset of colorectal carcinomas, which is characterized by microsatellite instability. As MSI colorectal carcinomas are known for their robust immune response, we then aimed to link FABP1 to the immune microenvironment of MSI carcinomas. To confirm the gene expression results, we performed immunohistochemical analysis of a cohort of colorectal carcinomas. FABP1 was preferentially lost in MSI carcinomas (123/133, 93%) compared with microsatellite stable carcinomas (240/562, 43%, P<0.0001). In addition, higher numbers of tumor-infiltrating lymphocytes were present in tumors with loss of FABP1 (P<0.0001). Decreased expression of the fatty acid storage and glucose regulator, PPARγ, was associated with the loss of FABP1 (P<0.0001). Colorectal cancer cell lines treated with interferon γ exhibited decreased expression of FABP1. FABP1 expression was partially recovered with the treatment of the cell lines with rosiglitazone, a PPARγ agonist. This study demonstrated that the loss of FABP1 expression is associated with MSI carcinomas and that interferon γ stimulation plays a role in this process via its interaction with PPARγ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2016.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218856PMC
January 2017

Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.

BMC Cancer 2016 Apr 18;16:274. Epub 2016 Apr 18.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA.

Background: The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.

Methods: We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.

Results: Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.

Conclusions: Increased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-016-2302-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835834PMC
April 2016

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment.

Mod Pathol 2016 05 11;29(5):528-41. Epub 2016 Mar 11.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.

Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n=105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (P<0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (P<0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups (P<0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2016.54DOI Listing
May 2016

Peroxidase-like activity of the Co3O4 nanoparticles used for biodetection and evaluation of antioxidant behavior.

Nanoscale 2016 Mar 25;8(11):5938-45. Epub 2016 Feb 25.

Key Laboratory of Micro-Nano Materials for Energy Storage and Conversion of Henan Province, Institute of Surface Micro and Nano Materials, Xuchang University, Xuchang, Henan 461000, P. R. China.

Nanostructured enzyme mimics are of great interest as promising alternatives to artificial enzymes for biomedical and catalytic applications. Studying the chemical interactions between antioxidants and nano-enzymes may result in a better understanding of the antioxidant capability of antioxidants and may help improve the function of artificial enzymes to better mimic natural enzymes. In this study, using Co3O4 nanoparticles (NPs) as peroxidase mimics to catalyze the oxidation of chromophoric substrates by H2O2, we developed a platform that acts as a biosensor for hydrogen peroxide and glucose and that can study the inhibitory effects of natural antioxidants on peroxidase mimics. This method can be applied specifically to glucose detection in real samples. Three natural antioxidants, gallic acid (GA), tannic acid (TA), and ascorbic acid (AA), were compared for their antioxidant capabilities. We found that these three antioxidants efficiently inhibit peroxidase-like activity with concentration dependence. The antioxidants showed different efficiencies, in the following order: tannic acid > gallic acid > ascorbic acid. They also showed distinct modes of inhibition based on different interaction mechanisms. This study serves as a proof-of-concept that nano-enzyme mimics can be used to evaluate antioxidant capabilities and to screen enzyme inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c6nr00860gDOI Listing
March 2016

Composition Directed Generation of Reactive Oxygen Species in Irradiated Mixed Metal Sulfides Correlated with Their Photocatalytic Activities.

ACS Appl Mater Interfaces 2015 Aug 22;7(30):16440-9. Epub 2015 Jul 22.

‡Division of Bioanalytical Chemistry and Division of Analytical Chemistry, Office of Regulatory Science, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland 20740, United States.

The ability of nanostructures to facilitate the generation of reactive oxygen species and charge carriers underlies many of their chemical and biological activities. Elucidating which factors are essential and how these influence the production of various active intermediates is fundamental to understanding potential applications of these nanostructures, as well as potential risks. Using electron spin resonance spectroscopy coupled with spin trapping and spin labeling techniques, we assessed 3 mixed metal sulfides of varying compositions for their abilities to generate reactive oxygen species, photogenerate electrons, and consume oxygen during photoirradiation. We found these irradiated mixed metal sulfides exhibited composition dependent generation of ROS: ZnIn2S4 can generate (•)OH, O2(-•) and (1)O2; CdIn2S4 can produce O2(-•) and (1)O2, while AgInS2 only produces O2(-•). Our characterizations of the reactivity of the photogenerated electrons and consumption of dissolved oxygen, performed using spin labeling, showed the same trend in activity: ZnIn2S4 > CdIn2S4 > AgInS2. These intrinsic abilities to generate ROS and the reactivity of charge carriers correlated closely with the photocatalytic degradation and photoassisted antibacterial activities of these nanomaterials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.5b03626DOI Listing
August 2015

Ontogenic expression of human carboxylesterase-2 and cytochrome P450 3A4 in liver and duodenum: postnatal surge and organ-dependent regulation.

Toxicology 2015 Apr 24;330:55-61. Epub 2015 Feb 24.

Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, Kingston, RI 2881, United States. Electronic address:

Human carboxylesterase-2 (CES2) and cytochrome P450 3A4 (CYP3A4) are two major drug metabolizing enzymes that play critical roles in hydrolytic and oxidative biotransformation, respectively. They share substrates but may have opposite effect on therapeutic potential such as the metabolism of the anticancer prodrug irinotecan. Both CES2 and CYP3A4 are expressed in the liver and the gastrointestinal tract. This study was conducted to determine whether CES2 and CYP3A4 are expressed under developmental regulation and whether the regulation occurs differentially between the liver and duodenum. A large number of tissues (112) were collected with majority of them from donors at 1-198 days of age. In addition, multi-sampling (liver, duodenum and jejunum) was performed in some donors. The expression was determined at mRNA and protein levels. In the liver, CES2 and CYP3A4 mRNA exhibited a postnatal surge (1 versus 2 months of age) by 2.7 and 29 fold, respectively. CYP3A4 but not CES2 mRNA in certain pediatric groups reached or even exceeded the adult level. The duodenal samples, on the other hand, showed a gene-specific expression pattern at mRNA level. CES2 mRNA increased with age but the opposite was true with CYP3A4 mRNA. The levels of CES2 and CYP3A4 protein, on the other hand, increased with age in both liver and duodenum. The multi-sampling study demonstrated significant correlation of CES2 expression between the duodenum and jejunum. However, neither duodenal nor jejunal expression correlated with hepatic expression of CES2. These findings establish that developmental regulation occurs in a gene and organ-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tox.2015.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496585PMC
April 2015

Suppression of the pregnane X receptor during endoplasmic reticulum stress is achieved by down-regulating hepatocyte nuclear factor-4α and up-regulating liver-enriched inhibitory protein.

Toxicol Sci 2015 Apr 22;144(2):382-92. Epub 2015 Jan 22.

Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, Kingston, Rhode Island 02881

Endoplasmic reticulum (ER) stress is recognized as a common theme in the development of metabolic syndrome and other diseases. Chronic liver diseases develop ER stress and also show decreased capacity of drug metabolism. The pregnane X receptor (PXR) is a master regulator of genes involved in drug elimination. This study was performed to determine whether ER stress condition decreases the expression of PXR and whether the decrease alters the induction of cytochrome P450 3A4 (CYP3A4). Human primary hepatocytes and HepG2 cell line (human hepatocellular carcinoma) were treated with brefeldin A and thapsigargin, 2 well-established ER stressors. Without exceptions, both stressors significantly decreased the expression of PXR. The decrease led to reduced induction of CYP3A4. Reporter dissection study, electrophoretic mobility shift assay, and chromatin immunoprecipitation located in the PXR promoter region 2 adjacent elements recognized by hepatocyte nuclear factor-4α (HNF-4α) and cytidine-cytidine-adenosine-adenosine-thymidine enhanced binding proteins (C/EBPs), respectively. Additional studies demonstrated that HNF-4α was down-regulated during ER stress but the expression of C/EBPβ varied depending on a particular form of C/EBPβ. Liver-enriched activator protein (LAP) was down-regulated but liver-enriched inhibitory protein (LIP) was highly induced. Nevertheless, over-expression of HNF-4α or LAP restored the expression of PXR. Interestingly, the very same sequence also responded to interleukin-6 (IL-6), and primary hepatocytes treated with thapsigargin significantly increased the level of IL-6 mRNA. These findings establish a functional interconnection between ER stress and signaling of proinflammatory cytokines in the regulation of PXR expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfv008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372669PMC
April 2015

Comparison of tyrosine kinase receptors HER2, EGFR, and VEGFR expression in micropapillary urothelial carcinoma with invasive urothelial carcinoma.

Target Oncol 2015 Sep 8;10(3):355-63. Epub 2014 Oct 8.

Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA,

Invasive micropapillary urothelial carcinomas (MPUC) emerge at higher stages and follow a more aggressive course than conventional invasive urothelial carcinomas (UC). Little is known about the target therapies using tyrosine kinase inhibitors in MPUC. This study is to investigate potential effectiveness of tyrosine kinase receptor inhibitors by determining expression of epidermal growth factor receptor (EGFR), human epidermal receptor 2 (HER2), and vascular endothelial growth factor receptor 2 (VEGFR) proteins in MPUC and UC. 16 cases of MPUC and 16 stage-matched UC were identified. Immunohistochemistry for EGFR, HER2, and VEGFR2 and HER2 gene amplification by fluorescence in situ hybridization (FISH) were performed. HER2 and EGFR proteins were expressed in MPUC and UC, with significantly higher HER2 expression in MPUC (ratio 1.82, p < 0.01). HER2 gene amplification was identified in 4 of 16 MPUC (25 %). Amplification was limited to cases with 3+ HER2 expression (100% concordance). EGFR expression in MPUC was slightly higher than UC but not statistically significant (ratio 1.57, p = 0.19). EGFR and HER2 coexpression was noted in 75% of MPUC and 37.5% of UC. No VEGFR expression was identified in the urothelium. Strong VEGFR expression was noted in stromal vessels in both MPUC and UC. In conclusion, EGFR and HER2 are potential targets for neoadjuvant chemotherapy in MPUC and UC. There is no direct anti-tumor effect expected for VEGFR inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11523-014-0341-xDOI Listing
September 2015

Combinatorial photothermal and immuno cancer therapy using chitosan-coated hollow copper sulfide nanoparticles.

ACS Nano 2014 Jun 13;8(6):5670-81. Epub 2014 May 13.

Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island , Kingston, Rhode Island 02881, United States.

Near-infrared light-responsive inorganic nanoparticles have been shown to enhance the efficacy of cancer photothermal ablation therapy. However, current nanoparticle-mediated photothermal ablation is more effective in treating local cancer at the primary site than metastatic cancer. Here, we report the design of a near-infrared light-induced transformative nanoparticle platform that combines photothermal ablation with immunotherapy. The design is based on chitosan-coated hollow CuS nanoparticles that assemble the immunoadjuvants oligodeoxynucleotides containing the cytosine-guanine (CpG) motifs. Interestingly, these structures break down after laser excitation, reassemble, and transform into polymer complexes that improve tumor retention of the immunotherapy. In this "photothermal immunotherapy" approach, photothermal ablation-induced tumor cell death reduces tumor growth and releases tumor antigens into the surrounding milieu, while the immunoadjuvants potentiate host antitumor immunity. Our results indicated that combined photothermal immunotherapy is more effective than either immunotherapy or photothermal therapy alone against primary treated and distant untreated tumors in a mouse breast cancer model. These hollow CuS nanoparticles are biodegradable and can be eliminated from the body after laser excitation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/nn5002112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072412PMC
June 2014

Correlation of ALOX15 expression with eosinophilic or reflux esophagitis in a cohort of pediatric patients with esophageal eosinophilia.

Hum Pathol 2014 Jun 6;45(6):1205-12. Epub 2014 Feb 6.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI 02903. Electronic address:

The differential diagnosis between eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) is often challenging. We recently showed that the ALOX15 protein is expressed in 95% of esophageal biopsies from patients with a definitive diagnosis of EoE. Here we correlated ALOX15 expression with the clinical classification of EoE or GERD in a cohort of consecutive pediatric patients (n = 62) with at least 1 esophageal biopsy containing at least 15 eosinophils per high-power field (eos/HPF). The patients were categorized into the following groups: (1) at least 15 eos/HPF in the distal esophagus only (n = 24), (2) at least 15 eos/HPF in the proximal esophagus only (n = 5), and (3) at least 15 eos/HPF in the distal and proximal biopsies (n = 33). Control groups included patients with GERD with biopsies containing 6 to 15 eos/HPF (n = 9), patients with GERD with 5 eos/HPF or less (n = 15), patients with candida esophagitis (n = 15), and patients with normal biopsies (n = 15). ALOX15 was positive in 90.5% of patients with EoE (13/16 in group 1, 4/4 in group 2, 31/33 in group 3) versus 44% of patients with GERD (4/8 in group 1, 0/1 in group 2, and 0/0 in group 3), 2 of 9 (22%) of patients with 6 to 15 eos/HPF, and was negative in all patients with GERD with biopsies containing 5 eos/HPF or less, all patients with candida esophagitis, and all normal controls. In conclusion, ALOX15 is a sensitive marker of EoE; however, subpopulations of patients with GERD with >5 eos/HPF also express ALOX15. Positive ALOX15 expression is more prevalent in EoE than in GERD and may prove to be a useful diagnostic marker in patients with discrepant biopsy findings between the proximal and distal esophagus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2014.01.021DOI Listing
June 2014

Angiotensin receptor blockers and statins could alleviate atrial fibrosis via regulating platelet-derived growth factor/Rac1/nuclear factor-kappa B Axis.

Int J Med Sci 2013 26;10(7):812-24. Epub 2013 Apr 26.

Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Aims: To investigate whether the administration of renin-angiotensin system (RAS) inhibitors and statins could alleviate atrial fibrosis via platelet-derived growth factor (PDGF)/Rac1 /nuclear factor-kappa B (NF-κB) axis.

Methods And Results: In human left atrium, the degree of atrial fibrosis, as well as the expression levels of PDGF, Rac1 and NF-κB increased 1.5 to 2.9 folds in patients with atrial fibrillation compared to that with sinus rhythm, (P<0.0001). There were strongly positive correlations between angiotensin II (Ang II) or procollagen type III-alpha-1 (COL3A1) with PDGF, Rac1, NF-κB, and among PDGF, Rac1 and NF-κB (all P<0.05). At 3 weeks after the transverse aorta constriction (TAC) operation in rat model and with intervention of irbesartan or/and simvastatin, the collagen volume fraction (CVF) and atrial natriuretic peptide (ANP) values respectively increased 6-folds and 3.5-folds in the TAC group compared to SHAM group (P<0.0001), but these levels decreased by 16% to 63% with following drug intervention (all P<0.0001), the combined treatment was the lowest. Accordingly, the expression levels of PDGF (3-folds), Rac1 (1.6-folds), NF-κB (7-folds) and AngII (12-folds) significantly increased in the TAC group compared to the SHAM group, and these levels were also reduced by 25% to 64% with following drug intervention. The highest reduction could be seen after treatment with irbesartan and simvastatin in combination (all P<0.001).There were strongly positive correlations between AngII or CVF with PDGF, Rac1, NF-κB, and among PDGF, Rac1 and NF-κB (all P<0.05).

Conclusions: Irbesartan or/and simvastatin can improve atrial fibrosis by regulating PDGF/Rac1/NF-κB axis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ijms.5931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689874PMC
January 2014

Regulation of carboxylesterase-2 expression by p53 family proteins and enhanced anti-cancer activities among 5-fluorouracil, irinotecan and doxazolidine prodrug.

Br J Pharmacol 2013 Apr;168(8):1989-99

Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, Kingston, RI 02881, USA.

Background And Purpose: For four decades, 5-fluorouracil (5-FU) has been a major anti-cancer medicine. This drug is increasingly used with other anti-cancer agents such as irinotecan. Irinotecan and many others such as PPD (pentyl carbamate of p-aminobenzyl carbamate of doxazolidine) require activation by carboxylesterase-2 (CES2). 5-FU, on the other hand, reportedly induces CES2 in colorectal tumour lines. The aims of this study were to determine the molecular basis for the induction and to ascertain interactive cell-killing activity between 5-FU and ester prodrugs.

Experimental Approach: Colorectal and non-colorectal lines and xenografts were treated with 5-FU and the expression of CES2 was determined. Cell-killing activity of irinotecan and PPD were determined in the presence or absence of CES2 inhibitor. Several molecular experiments were used to determine the molecular basis for the induction.

Key Results: Without exceptions, robust induction was detected in cell lines expressing functional p53. High-level induction was also detected in xenografts. 5-FU pretreatment significantly increased cell-killing activity of irinotecan and PPD. Molecular experiments established that the induction was achieved by both transactivation and increased mRNA stability through p53. Either p63 or p73, functionally related to p53, did not support the transactivation.

Conclusions And Implications: The results in this study suggest that FOLFIRI, a common regimen combining irinotecan and 5-FU, should switch the dosing sequence, namely from 5-FU to irinotecan, to enhance hydrolytic activation of irinotecan. This modified order likely reduces the dose of anti-cancer agents, thus minimizing overall toxicity. The results also conclude that p53 family members act differently in regulating gene expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.12125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623067PMC
April 2013

Carboxylesterase-2 is a highly sensitive target of the antiobesity agent orlistat with profound implications in the activation of anticancer prodrugs.

Biochem Pharmacol 2013 Feb 7;85(3):439-47. Epub 2012 Dec 7.

Department of Biomedical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, Kingston, RI 02881, USA.

Orlistat has been the most used anti-obesity drug and the mechanism of its action is to reduce lipid absorption by inhibiting gastrointestinal lipases. These enzymes, like carboxylesterases (CESs), structurally belong to the α/β hydrolase fold superfamily. Lipases and CESs are functionally related as well. Some CESs (e.g., human CES1) have been shown to hydrolyze lipids. This study was designed to test the hypothesis that orlistat inhibits CESs with higher potency toward CES1 than CES2, a carboxylesterase with little lipase activity. Liver microsomes and recombinant CESs were tested for the inhibition of the hydrolysis of standard substrates and the anticancer prodrugs pentyl carbamate of p-aminobenzyl carbamate of doxazolidine (PPD) and irinotecan. Contrary to the hypothesis, orlistat at 1 nM inhibited CES2 activity by 75% but no inhibition on CES1, placing CES2 one of the most sensitive targets of orlistat. The inhibition varied among some CES2 polymorphic variants. Pretreatment with orlistat reduced the cell killing activity of PPD. Certain mouse but not rat CESs were also highly sensitive. CES2 is responsible for the hydrolysis of many common drugs and abundantly expressed in the gastrointestinal track and liver. Inhibition of this carboxylesterase probably presents a major source for altered therapeutic activity of these medicines if co-administered with orlistat. In addition, orlistat has been linked to various types of organ toxicities, and this study provides an alternative target potentially involved in these toxicological responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2012.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102434PMC
February 2013

[Rapid determination of benzene series in seawater by gas chromatography-mass spectrometry with static headspace extraction].

Se Pu 2012 May;30(5):474-9

First Institute of Oceanography, State Oceanic Administration, Qingdao 266061, China.

A method for the simultaneous determination of 13 benzene series (BTEX) in seawater using gas chromatography-mass spectrometry with static headspace extraction (HS-GC/MS) was developed. To carefully characterize the performance of this method, several factors affecting parameters were studied in detail, such as the type of column, heating procedure, equilibrium temperature, equilibrium time and the volume ratio of gas phase to liquid phase. The optimized conditions were as follows: the polar column of DB-WAX; heating procedure, 40 degrees C kept for 4 min, then raised to 120 degrees C at 10 degrees C/min, to 180 degrees C at 25 degrees C/min; equilibrium temperature, 80 degrees C; equilibrium time, 10 min; and the volume ratio of gas phase to liquid phase, 1:1. Under the optimized conditions, the linear equations were obtained in the concentration range of 0.16-320 microg/L with correlation coefficients greater than 0.999. The limits of detection (S/N = 3) were 0.019-0.033 microg/L. The recoveries at the three spiked levels of 1.6, 16 and 160 microg/L ranged from 81. 25% to 103.73% with the relative standard deviations (RSD, n=6) from 0.3% to 4.4%. The analytical results of the practical seawater samples from Shanghai Huangpu District were satisfactory. The determination of the 13 benzene series can be finished in 12 min. The method is simple, accurate, reliable, efficient and environmental-friendly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3724/sp.j.1123.2011.12042DOI Listing
May 2012

Antioxidant sulforaphane and sensitizer trinitrobenzene sulfonate induce carboxylesterase-1 through a novel element transactivated by nuclear factor-E2 related factor-2.

Biochem Pharmacol 2012 Sep 6;84(6):864-71. Epub 2012 Jul 6.

Department of Biomedical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, Kingston, RI 02881, USA.

Carboxylesterase-1 (CES1), the most versatile human carboxylesterase, plays critical roles in drug metabolism and lipid mobilization. This enzyme is highly induced by antioxidants and sensitizers in various cell lines. These compounds are known to activate nuclear factor-E2 related factor-2 (Nrf2) by reacting to kelch-like ECH-associated protein-1 (Keap1). The aims of this study were to determine whether antioxidant sulforaphane (SFN) and sensitizer trinitrobenzene sulfonate (TNBS) target Keap1 similarly and whether they use the same element for CES1 induction. Cells over-expressing Keap1 were treated with TNBS or SFN and the formation of disulfide bonds among Keap1 molecules were determined. SFN promoted intramolecular disulfide formation whereas TNBS promoted intermolecular disulfide formation of Keap1. Two elements, sensitizing/antioxidant response element (S/ARE) and ARE4, were identified to support Nrf2 in the regulated expression of CES1A1. Both elements were bound by Nrf2, however, the S/ARE element supported, whereas the ARE4 element repressed Nrf2 transactivation. The repression required higher amounts of Nrf2, suggesting that the transactivation through the S/ARE element dominates the trans-repression through the ARE4 element under normal antioxidative condition. These findings conclude that compounds, although triggering the Keap1-Nrf2 pathway, may differ in the mode of reacting with Keap1. These findings also conclude that both positive and negative Nrf2 elements exist even within the same gene, and such opposing mechanisms provide fine-tuning in transcriptional regulation by the Keap1-Nrf2 pathway. High levels of CES1 are linked to lipid retention. Excessive induction of CES1 by antioxidants and sensitizers likely provides a mechanism for potential detrimental effect on human health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2012.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096214PMC
September 2012