Publications by authors named "Yu Lun"

57 Publications

Analysis of the Prognostic Value and Potential Molecular Mechanisms of TREM-1 Overexpression in Papillary Thyroid Cancer Bioinformatics Methods.

Front Endocrinol (Lausanne) 2021 27;12:646793. Epub 2021 May 27.

Department of Vascular and Thyroid Surgery, The First Hospital, China Medical University, Shenyang, China.

Background: Triggering receptor expressed on myeloid cells-1 (TREM-1) has been reported as a biomarker in many cancers. However, the biological function of TREM-1 in papillary thyroid carcinoma (PTC) remains unknown.

Methods: We obtained TREM-1 expression data from The Cancer Genome Atlas (TCGA) database. Enrichment analysis of coexpressed genes and methylation analysis were performed LinkedOmics. The correlations between TREM-1 and immune infiltrates were investigated ESTIMATE, TIMER and TISIDB. We analyzed the association of TREM-1 expression with pan-cancer overall survival Gene Expression Profiling Interactive Analysis (GEPIA).

Results: has lower methylation levels and higher expression levels in PTC tissues compared to normal tissues. TREM-1 expression is significantly associated with poor prognosis, advanced T classification, advanced N classification, and an increased incidence of and mutations. Genes coexpressed with primarily participate in immune-related pathways. TREM-1 expression is positively correlated with immune infiltration, tumor progression and poor overall survival across cancers.

Conclusions: TREM-1 is a good prognostic and diagnostic biomarker in PTC. TREM-1 may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of TREM-1 expression and biological function. Additionally, TREM-1 has broad prognostic value in a pan-cancer cohort.
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http://dx.doi.org/10.3389/fendo.2021.646793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190971PMC
May 2021

CDCP1 on Dendritic Cells Contributes to the Development of a Model of Kawasaki Disease.

J Immunol 2021 Jun 7. Epub 2021 Jun 7.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA;

The etiology and pathology of Kawasaki disease (KD) remain elusive. Cub domain-containing protein 1 (CDCP1), a cell-surface protein that confers poor prognosis of patients with certain solid tumors, was recently identified as one of the most significantly upregulated genes in SARS-CoV-2-infected children who developed systemic vasculitis, a hallmark of KD. However, a potential role of CDCP1 in KD has not previously been explored. In this study, we found that CDCP1 knockout (KO) mice exhibited attenuated coronary and aortic vasculitis and decreased serum water-soluble fraction (CAWS)-specific IgM/IgG2a and IL-6 concentrations compared with wild-type mice in an established model of KD induced by CAWS administration. CDCP1 expression was not detectable in cardiomyocytes, cardio fibroblasts, or coronary endothelium, but constitutive expression of CDCP1 was observed on dendritic cells (DCs) and was upregulated by CAWS stimulation. CAWS-induced IL-6 production was significantly reduced in CDCP1 KO DCs, in association with impaired Syk-MAPK signaling pathway activation. These novel findings suggest that CDCP1 might regulate KD development by modulating IL-6 production from DCs via the Syk-MAPK signaling pathway.
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http://dx.doi.org/10.4049/jimmunol.2001406DOI Listing
June 2021

Low Serum-Free Testosterone Concentration in Chinese Male Patients with Uncomplicated Acute Type B Aortic Dissection.

Ann Vasc Surg 2021 Aug 4;75:324-331. Epub 2021 Feb 4.

Department of Vascular Surgery, The First Hospital, China Medical University, Shenyang, China. Electronic address:

Objective: Although aortic dissection occurs predominantly in men, its association with androgens is unknown. The aim of this study was to evaluate the androgen levels in Chinese male patients with uncomplicated, acute type B aortic dissection.

Study Design: Cross-sectional study.

Materials And Methods: A total of 192 age-matched male patients with uncomplicated, acute type B aortic dissection or essential hypertension were recruited between 2016 and 2018. The demographic and clinical data were analyzed.

Results: Male patients with uncomplicated, acute type B aortic dissection had lower serum total testosterone and free testosterone than male patients with essential hypertension (7.6 ± 3.7 nmol/L vs. 10.9 ± 3.8 nmol/L, P < 0.001; 36.0 ± 19.8 pmol/L vs. 56.4 ± 19.2 pmol/L, P < 0.001). Lower free testosterone level was significantly associated with uncomplicated, acute type B aortic dissection (univariate odds ratio 0.948, P < 0.001; multivariate odds ratio = 0.966, P = 0.002). No statistical difference was observed for free testosterone between younger patient groups (aged < 51 years; aged 51-60 years) and older patient groups (aged 61-70 years; aged >70 years) with uncomplicated, acute type B aortic dissection (33.7 ± 19.8 pmol/L vs. 38.5 ± 19.8 pmol/L, P = 0.239).

Conclusions: Lower free testosterone was independently associated with uncomplicated, acute type B aortic dissection in the Chinese male population with hypertension. Additional studies are needed to clarify whether earlier onset in Chinese patients with aortic dissection is associated with androgen deficiency.
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http://dx.doi.org/10.1016/j.avsg.2021.01.084DOI Listing
August 2021

Use of a Sparse-Response Deep Belief Network and Extreme Learning Machine to Discriminate Alzheimer's Disease, Mild Cognitive Impairment, and Normal Controls Based on Amyloid PET/MRI Images.

Front Med (Lausanne) 2020 18;7:621204. Epub 2021 Jan 18.

Department of PET-CT Center, Chenzhou No.1 People's Hospital, Chenzhou, China.

In recent years, interest has grown in using computer-aided diagnosis (CAD) for Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI). However, existing CAD technologies often overfit data and have poor generalizability. In this study, we proposed a sparse-response deep belief network (SR-DBN) model based on rate distortion (RD) theory and an extreme learning machine (ELM) model to distinguish AD, MCI, and normal controls (NC). We used [F]-AV45 positron emission computed tomography (PET) and magnetic resonance imaging (MRI) images from 340 subjects enrolled in the ADNI database, including 116 AD, 82 MCI, and 142 NC subjects. The model was evaluated using five-fold cross-validation. In the whole model, fast principal component analysis (PCA) served as a dimension reduction algorithm. An SR-DBN extracted features from the images, and an ELM obtained the classification. Furthermore, to evaluate the effectiveness of our method, we performed comparative trials. In contrast experiment 1, the ELM was replaced by a support vector machine (SVM). Contrast experiment 2 adopted DBN without sparsity. Contrast experiment 3 consisted of fast PCA and an ELM. Contrast experiment 4 used a classic convolutional neural network (CNN) to classify AD. Accuracy, sensitivity, specificity, and area under the curve (AUC) were examined to validate the results. Our model achieved 91.68% accuracy, 95.47% sensitivity, 86.68% specificity, and an AUC of 0.87 separating between AD and NC groups; 87.25% accuracy, 79.74% sensitivity, 91.58% specificity, and an AUC of 0.79 separating MCI and NC groups; and 80.35% accuracy, 85.65% sensitivity, 72.98% specificity, and an AUC of 0.71 separating AD and MCI groups, which gave better classification than other models assessed.
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http://dx.doi.org/10.3389/fmed.2020.621204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847932PMC
January 2021

Analysis of the expression and potential molecular mechanism of interleukin-1 receptor antagonist (IL1RN) in papillary thyroid cancer via bioinformatics methods.

BMC Cancer 2020 Nov 25;20(1):1143. Epub 2020 Nov 25.

Department of Vascular and Thyroid Surgery, The First Hospital, China Medical University, Shenyang, China.

Background: Interleukin-1 receptor antagonist (IL1RN) has been reported as a biomarker of many cancers. However, the biological function of IL1RN in papillary thyroid carcinoma (PTC) remains undetermined.

Methods: We obtained IL1RN expression data from The Cancer Genome Atlas (TCGA) database. Enrichment analysis of coexpressed genes and IL1RN methylation analysis were performed via LinkedOmics. The correlations between IL1RN and immune infiltrates were investigated via ESTIMATE, TIMER and TISIDB. We analyzed the association of IL1RN expression with pancancer overall survival (OS) via Gene Expression Profiling Interactive Analysis (GEPIA).

Results: IL1RN showed higher expression levels and lower methylation levels in PTC tissues than in normal tissues. Higher IL1RN expression was significantly associated with shorter progression-free survival (PFS), advanced tumor stage, tumor metastasis, increased incidence of BRAF mutations, and decreased incidence of N-RAS and H-RAS mutations. Genes coexpressed with IL1RN participate primarily in immune-related pathways. IL1RN expression positively correlated with immune infiltration, tumor progression and poor OS for all cancers.

Conclusions: IL1RN is a good prognostic and diagnostic biomarker for PTC. IL1RN may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of IL1RN expression and biological function. Additionally, IL1RN was shown to have broad prognostic value in a pancancer cohort.
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http://dx.doi.org/10.1186/s12885-020-07620-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687764PMC
November 2020

Immune Cell Confrontation in the Papillary Thyroid Carcinoma Microenvironment.

Front Endocrinol (Lausanne) 2020 22;11:570604. Epub 2020 Oct 22.

Department of Vascular and Thyroid Surgery, The First Hospital, China Medical University, Shenyang, China.

Background: Papillary thyroid cancer has been associated with chronic inflammation. A systematic understanding of immune cell infiltration in PTC is essential for subsequent immune research and new diagnostic and therapeutic strategies.

Methods: Three different algorithms, single-sample gene set enrichment analysis (ssGSEA), immune cell marker and CIBERSORT, were used to evaluate immune cell infiltration levels (abundance and proportion) in 10 data sets (The Cancer Genome Atlas [TCGA], GSE3467, GSE3678, GSE5364, GSE27155, GSE33630, GSE50901, GSE53157, GSE58545, and GSE60542; a total of 799 PTC and 194 normal thyroid samples). Consensus unsupervised clustering divided PTC patients into low-immunity and high-immunity groups. Weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA) were used to analyze the potential mechanisms causing differences in the immune response.

Results: Compared with normal tissues, PTC tissues had a higher overall immune level and higher abundance levels and proportions of M2 macrophages, Tregs, monocytes, neutrophils, dendritic cells (DCs), mast cells (MCs), and M0 macrophages. Compared with early PTC, advanced PTC showed higher immune infiltration and higher abundance levels and proportions of M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages. Compared to the low-immunity group, the high-immunity group exhibited more advanced stages, larger tumor sizes, greater lymph node metastases, higher tall-cell PTCs, lower follicular PTC proportions, more BRAF mutations, and fewer RAS mutations. Epstein-Barr virus (EBV) infection was the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for key module genes.

Conclusions: In human PTC, M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages appear to play a tumor-promoting role, while M1 macrophages, CD8+ T cells, B cells, NK cells, and T follicular helper (T) cells (including eosinophils, γδ T cells, and Th17 cells with weak supporting evidence) appear to play an antitumor role. During the occurrence and development of PTC, the overall immune level was increased, and the abundance and proportion of tumor-promoting immune cells were significantly increased, indicating that immune escape had been aggravated. Finally, we speculate that EBV may play an important role in changing the immune microenvironment of PTC tumors.
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http://dx.doi.org/10.3389/fendo.2020.570604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642595PMC
May 2021

Papillary thyroid carcinoma with a high tumor mutation burden has a poor prognosis.

Int Immunopharmacol 2020 Dec 19;89(Pt B):107090. Epub 2020 Oct 19.

Department of Vascular and Thyroid Surgery, The First Hospital, China Medical University, Shenyang, China. Electronic address:

Background: Tumor mutation burden (TMB) as a prognostic marker for immunotherapy has shown prognostic value in many cancers. However, there is no systematic investigation on TMB in papillary thyroid carcinoma (PTC).

Methods: Based on the somatic mutation data of 487 PTC patients from The Cancer Genome Atlas (TCGA), TMB was calculated, and we classified the samples into high-TMB (H-TMB) and low-TMB (L-TMB) groups. Bioinformatics methods were used to explore the characteristics and potential mechanism of TMB in PTC.

Results: High TMB predicts shorter progression-free survival (PFS) (P < 0.001). TMB was positively correlated with age, stage, tumor size, metastasis, the male sex and tall cell PTC. Compared to the L-TMB group, the H-TMB group presented with lower immune cell infiltration, a higher proportion of tumor-promoting immune cells (M0 macrophages, activated dendritic cells and monocytes) and a lower proportion of antitumor immune cells (M1 macrophages, CD8 T cells and B cells). Additionally, the characteristics displayed by different TMB groups were not driven by critical driver mutations such as BRAF and RAS.

Conclusions: PTC patients with high TMB have a worse prognosis. By stratifying PTC patients according to their TMB, advanced PTC patients who are candidates for immunotherapy could be selected.
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http://dx.doi.org/10.1016/j.intimp.2020.107090DOI Listing
December 2020

Bioinformatics analysis of the clinical value and potential mechanisms of AHNAK2 in papillary thyroid carcinoma.

Aging (Albany NY) 2020 Sep 23;12(18):18163-18180. Epub 2020 Sep 23.

Department of Vascular and Thyroid Surgery, The First Hospital, China Medical University, Shenyang, China.

Background: has been recently reported as a biomarker in many cancers. However, a systematic investigation of in papillary thyroid carcinoma (PTC) has not been conducted.

Results: is overexpressed in PTC tissues and could be an independent prognostic factor. expression was significantly high in patients with advanced stage, advanced T classification, lymph node metastasis, increased mutations and decreased mutations. Cell adhesion-, cell junction-, and immune-related pathways were the most frequently noted in gene set enrichment analysis. expression in PTC was positively correlated with immune infiltration and negatively correlated with methylation. expression was significantly positively correlated with tumor progression and poor overall survival (OS) in pan-cancer patients.

Conclusions: is a good biomarker for the diagnosis and prognosis of PTC. may promote thyroid cancer progression through cell adhesion-, cell junction-, and immune-related pathways. Methylation may act as an upstream regulator to inhibit the expression and biological function of . Additionally, has broad prognostic value in pan-cancer.

Methods: Based on The Cancer Genome Atlas (TCGA) data, we screened -related genes through weighted gene coexpression network analysis and explored the clinical value and the potential mechanism of in PTC by multiomics analysis.
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http://dx.doi.org/10.18632/aging.103645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585101PMC
September 2020

Rupture of an infected iliac artery pseudoaneurysm caused by asymptomatic gastrointestinal foreign body perforation.

J Int Med Res 2020 Jul;48(7):300060520942082

Department of Vascular Surgery, The First Hospital, China Medical University, Shenyang, China.

We report a unique case of a ruptured iliac artery pseudoaneurysm caused by asymptomatic gastrointestinal perforation and retroperitoneal abscess formation. A 46-year-old man presented to the Emergency Department of our institution. Angiography showed a ruptured iliac artery pseudoaneurysm caused by retroperitoneal abscess formation. After endovascular repair and surgical drainage, the cause of the abscess was finally identified as a toothpick. Findings from this case show that asymptomatic gastrointestinal foreign body perforation can be a rare, but insidious, cause of an infected pseudoaneurysm. Prompt surgical intervention is sometimes necessary when treating patients with arterial pseudoaneurysm caused by a perivascular abscess.
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http://dx.doi.org/10.1177/0300060520942082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378727PMC
July 2020

Treatment Options for Venous Cystic Adventitial Disease: A Case Report and Literature Review.

Ann Vasc Surg 2020 Apr 24;64:413.e1-413.e4. Epub 2019 Oct 24.

Department of Vascular Surgery, The First Hospital, China Medical University, Shenyang, China.

Venous cystic adventitial disease (CAD) is an uncommon vascular anomaly that most frequently affects the common femoral vein. Transluminal or transadventitial evacuation followed by cyst excision is considered an effective treatment for this condition, although the recurrence rate is relatively high. Herein, we report a case of a 59-year-old man with venous CAD that was successfully treated with saphenous vein patch angioplasty after mucoid evacuation and cyst excision, and we discuss the options for treating venous CAD.
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http://dx.doi.org/10.1016/j.avsg.2019.10.057DOI Listing
April 2020

AEBP1 Promotes the Occurrence and Development of Abdominal Aortic Aneurysm by Modulating Inflammation via the NF-κB Pathway.

J Atheroscler Thromb 2020 Mar 28;27(3):255-270. Epub 2019 Aug 28.

Department of Vascular & Thyroid Surgery, the First Hospital, China Medical University.

Aim: Inflammation plays a significant role in the pathogenesis of human abdominal aortic aneurysm (AAA). AEBP1 can promote activation of the NF-κB pathway, subsequently affecting the expression of NF-κB target genes, including inflammatory cytokines and matrix metalloproteinases (MMPs). Our objective was to examine the role of AEBP1 in the development of AAA and characterize the underlying mechanism.

Methods: ITRAQ, RT-PCR, western blot, immunohistochemistry, and ELISA were used to compare different experimental groups with the controls and to determine the differentially expressed genes. We generated an AAA model using porcine pancreatic elastase in Sprague-Dawley rats and silenced their AEBP1 in vivo by adenoviruses injected intra-adventitially. We also silenced or overexpressed AEBP1 in human vascular smooth muscle cells in vitro in the presence and in the absence of NF-κB inhibitor BAY 11-7082.

Results: Proteome iTRAQ revealed a high expression of AEBP1 in AAA patients, which was verified by qRT-PCR, western blot, immunohistochemistry, and ELISA. The mean expression level of AEBP1 in AAA patients was higher than that in controls. Along with AEBP1 upregulation, we also verified mis-activation of NF-κB in human AAA samples. The in vivo studies indicated that AEBP1 knockdown suppressed AAA progression. Finally, the in vitro studies illustrated that AEBP1 promotes activation of the NF-κB pathway, subsequently upregulating pro-inflammatory factors and MMPs.

Conclusions: Our results indicate a role of AEBP1 in the pathogenesis of AAA and provide a novel insight into how AEBP1 causes the development of AAA by activating the NF-κB pathway.
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http://dx.doi.org/10.5551/jat.49106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113137PMC
March 2020

Y chromosome loss is associated with age-related male patients with abdominal aortic aneurysms.

Clin Interv Aging 2019 23;14:1227-1241. Epub 2019 Jul 23.

Department of Vascular Surgery, The First Hospital of China Medical University, Key Laboratory of Pathogenesis, Prevention and Therapeutics of Aortic Aneurysm Liaoning Province, Shenyang, People's Republic of China.

Purpose: Abdominal aortic aneurysm (AAA) demonstrates many features of autoimmune diseases. Y chromosome, sex-determining region of the Y chromosome () gene, androgen receptor () gene, and androgen appear as potential candidates for influence of the male immune function. This study investigated Y chromosome numbers, gene, gene, and androgen levels in male AAAs. We also investigated the correlation between Y chromosome loss (LOY) ratio, expression, androgen levels, and age.

Patients And Methods: We investigated LOY by fluorescence in situ hybridization (FISH) in 37 AAAs and compared with 12 patients with abdominal aortic atherosclerotic occlusive disease (AOD) and 91 healthy controls (HC). We investigated and expression at mRNA level by real-time PCR in peripheral T lymphocytes in AAA compared with AOD and HC, and AR protein levels by immunohistochemistry (IHC) in AAA. LOY, SRY expression, androgen levels, and age were examined for correlations using the Spearman's rank correlation coefficient.

Results: LOY ratio in peripheral T lymphocytes was significantly higher in the AAA group compared with the HC (9.11% vs 5.56%, <0.001) and AOD groups (9.11% vs 6.42%, =0.029). The SRY mRNA expression in peripheral T lymphocytes was 4.7-fold lower expressed in the AAA group than in the HC group (<0.001). Free plasma testosterone levels were lower in the AAA group compared with the HC group (=0.036), whereas sex hormone-binding globulin levels were higher (=0.020). LOY ratio and expression of mRNA level increased with age in the AAA group (R=0.402 and, R=0.366, respectively). A significant correlation between AR mRNA level (R=0.692) and aortic diameter was detected. Simultaneously, in AAA tissue, the rate of LOY increased with age (R=0.547) and also positively associated with LOY in peripheral blood T lymphocytes (R=0.661).

Conclusion: This study identified a prominent Y chromosome loss in male AAAs, which is correlated to age, lower level of expression and free testosterone, providing a new clue for the mechanisms of AAA.
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http://dx.doi.org/10.2147/CIA.S202188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662525PMC
December 2019

Epigenetic regulation of regulatory T cells in patients with abdominal aortic aneurysm.

FEBS Open Bio 2019 06 14;9(6):1137-1143. Epub 2019 May 14.

Department of Vascular Surgery, The First Hospital, China Medical University, Shenyang, China.

Abdominal arterial aneurysm (AAA) shares many features with autoimmune diseases and appears to be a T-cell-mediated process. In addition, certain epigenetic changes, including DNA methylation, are associated with AAA. In this study, we investigated epigenetic modifications in regulatory T cells (Tregs) from AAA patients. We used flow cytometry to sort FOXP3 CD4 CD25 Tregs from the peripheral blood of AAA patients and from healthy controls (HC), and then detected DNA methylation and histone modifications by ELISA. The DNA methylation rate of Tregs was significantly higher in AAA patients than in the HC group (0.159 ± 0.08% vs 0.098 ± 0.03%, P < 0.05), while the acetylation rates of H3 and H3K9 histones were lower in the AAA than in the HC group. We also examined the expression of mRNA encoding enzymes that catalyze making and removing epigenetic modifications by real-time PCR: we found that mRNA levels of DNA methyltransferase (DNMT) 1 and DNMT3A were higher in the AAA than in the HC group, mRNA levels of methyl-CpG-binding domain protein (MBD) 2 and MBD4 were higher in the AAA than in the HC group (MBD2: 6.21 ± 2.57 vs 3.04 ± 1.45; MBD4: 7.76 ± 3.48 vs 4.97 ± 3.10; both P < 0.05), and mRNA levels of histone deacetylase (HDAC) 1 and HDAC5 were significantly up-regulated in the AAA compared with the HC group (HDAC1: 2.17 ± 1.18 vs 1.51 ± 0.99; HDAC5: 1.35 ± 0.49 vs 0.94 ± 0.76; both P < 0.05). Together, our results reveal that rates of DNA methylation and histone modifications of Tregs are significantly altered in AAA patients.
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http://dx.doi.org/10.1002/2211-5463.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551495PMC
June 2019

Contained rupture of a common iliac aneurysm associated with immunoglobulin G4-related disease.

J Vasc Surg 2018 11;68(5):1564-1565

Department of Vascular Surgery, The First Hospital, China Medical University, Shenyang, China. Electronic address:

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http://dx.doi.org/10.1016/j.jvs.2017.09.023DOI Listing
November 2018

Saphenous vein graft aneurysm formation in a patient with idiopathic multiple aneurysms.

J Vasc Surg Cases Innov Tech 2018 Sep 17;4(3):197-200. Epub 2018 Aug 17.

Department of Vascular Surgery, The First Hospital, China Medical University, Shenyang, China.

True aneurysmal vein graft dilation is rare, and its etiology remains speculative. However, systemic dilation diathesis is regarded as a risk factor. We herein report a case of a rapidly expanding aneurysm in a great saphenous vein graft, resulting in distal malperfusion in a patient who had previously undergone open repair of multiple popliteal artery aneurysms. After an unsuccessful endovascular intervention, the dilated section was eventually replaced by a reversed segment of the contralateral great saphenous vein. Subsequent whole-exome sequencing identified no relevant mutations. This case provides further evidence that aneurysmal disease may be associated with systemic dilation diathesis.
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http://dx.doi.org/10.1016/j.jvscit.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105753PMC
September 2018

[A novel method of optic disk segmentation based on visual saliency and rotary scanning].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2018 04;35(2):229-236

College of Physics and Information Engineering, Fuzhou University, Fuzhou 350116, P.R.China.

Fast optic disk localization and boundary segmentation is an important research topic in computer aided diagnosis. This paper proposes a novel method to effectively segment optic disk by using human visual characteristics in analyzing and processing fundus image. After a general analysis of optic disk features in fundus images, the target of interest could be located quickly, and intensity, color and spatial distribution of the disc are used to generate saliency map based on pixel distance. Then the adaptive threshold is used to segment optic disk. Moreover, to reduce the influence of vascular, a rotary scanning method is devised to achieve complete and continuous contour of optic disk boundary. Tests in the public fundus images database Drishti-GS have good performances, which mean that the proposed method is simple and rapid, and it meets the standard of the eye specialists. It is hoped that the method could be conducive to the computer aided diagnosis of eye diseases in the future.
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http://dx.doi.org/10.7507/1001-5515.201706013DOI Listing
April 2018

Interstitial fibrosis in papillary thyroid microcarcinoma and its association with biological behavior.

Oncol Lett 2018 Apr 2;15(4):4937-4943. Epub 2018 Feb 2.

Department of Vascular and Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Previous studies have revealed that fibrosis may affect the biological behavior of tumors, however associated research on papillary thyroid microcarcinoma (PTMC) is rare. The aim of the present study was to explore the association between interstitial fibrosis (IF) and the biological behavior of PTMC. In the present study, a total of 511 consecutive cases of PTMC were evaluated for the presence of IF and its association with clinical parameters and pathologic biomarkers. IF was identified in 340 of the 511 consecutive cases and it was significantly associated with the age (P=0.033), tumor diameter (P=0.017) and lymphocytic metastasis (P<0.001) of the patient. There were significantly more female in the fibrosis group than in fibrosis-absent group (P=0.024). In the analysis of clinical biomarkers using immunohistochemistical staining, IF was significantly associated with cytokeratin 19 (P=0.008) and galectin-3 (P=0.022). Analysis of patient outcomes indicated that IF was an independent prognostic factor of recurrence (hazard ratio = 2.181; 95% confidence interval = 1.163-4.090; P=0.015). These findings suggest that the combined effect of a patient's age, sex and tumor size may potentially contribute to fibrotic lesions and IF was a factor contributing to poor prognosis in patients with PTMC.
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http://dx.doi.org/10.3892/ol.2018.7928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840693PMC
April 2018

Abnormal acetylation of FOXP3 regulated by SIRT-1 induces Treg functional deficiency in patients with abdominal aortic aneurysms.

Atherosclerosis 2018 04 14;271:182-192. Epub 2018 Feb 14.

Department of Vascular Surgery, The First Hospital of China Medical University, Nanjing Bei Str. 155, Shenyang 110001, China. Electronic address:

Background And Aims: Acetylation levels of FOXP3 could influence its expression level and SIRT1 is a deacetylase, which could regulate the acetylation level of FOXP3. We aimed to investigate the mechanism of Treg dysfunction, which might be caused by abnormal acetylation of FOXP3 regulated by SIRT1 in abdominal aortic aneurysm (AAA) patients.

Methods: Peripheral CD4 T cells from AAA patients, abdominal aortic atherosclerotic occlusive disease (AOD) patients, and healthy donors (HC) were analyzed by flow cytometry to determine the percentage of CD4CD25 Tregs and CD4CD25FOXP3 T cells in CD4 T cells. Expression of FOXP3 and SIRT1 was analyzed by Western Blot. Cultured CD4 T cells were treated with SIRT1 specific inhibitor EX-527 or left untreated. Acetylation expression of FOXP3 in CD4 T cells was analyzed by immunoprecipitation and Western Blot. The suppressive function of Treg was analyzed by CFSE-assay.

Results: AAA patients had significantly lower CD4CD25FOXP3 T cells. Western blot results showed that AAA CD4 T cells had significantly less FOXP3 expression but significantly higher SIRT1 expression. After EX-527 treatment, CD4CD25FOXP3 T cells and FOXP3 expression in the AAA group were significantly increased. FOXP3 acetylation level in the AAA group was lower than in control groups. After EX-527 treatment, it was significantly increased. AAA Tregs exhibited less suppressive activity, EX-527 treatment significantly increased the suppressive activity of AAA Tregs.

Conclusions: Our data demonstrate that reduced FOXP3 expression and Treg function in AAA patients are regulated by SIRT1-induced FOXP3 deacetylation. EX-527 could up-regulate FOXP3 acetylation and increase number and suppressive function of Treg in AAA patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.02.001DOI Listing
April 2018

SIRT1-Regulated Abnormal Acetylation of FOXP3 Induces Regulatory T-Cell Function Defect in Hashimoto's Thyroiditis.

Thyroid 2018 02;28(2):246-256

Department of Vascular Surgery, The First Hospital of China Medical University , Shenyang, P.R. China .

Background: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease characterized by low expression of transcription factor Forkhead Box P3 (FOXP3) and functional deficiency of a cluster of differentiation regulatory T cells (Tregs). This study aimed to investigate the mechanism of Treg dysfunction in HT.

Methods: The number of CD4CD25FOXP3 T cells was determined by flow cytometry. Expression of FOXP3 and Sirtuin type 1 (SIRT1) was evaluated by Western blot analysis. Acetylation of FOXP3 was analyzed by immunoprecipitation and Western blot analysis. The suppressive function of Treg was analyzed by the 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) assay.

Results: The percentage of CD4CD25FOXP3 T cells, expression of FOXP3, and FOXP3 acetylation level in the HT group were significantly lower than in the control groups. Conversely, SIRT1 expression was significantly higher in the HT group than in the other two groups. After Ex-527 treatment, the CD4CD25FOXP3 T cells percentage, FOXP3 expression, and FOXP3 acetylation level in the HT group were significantly increased. HT Tregs exhibited less suppressive activity, but Ex-527 treatment significantly increased their suppressive activity.

Conclusions: The findings demonstrate that the reduced FOXP3 expression level and Treg function defect in HT patients are regulated by SIRT1-mediated abnormal FOXP3 acetylation. Ex-527 may upregulate the FOXP3 acetylation level and subsequently increase the number and suppressive function of Treg cells.
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http://dx.doi.org/10.1089/thy.2017.0286DOI Listing
February 2018

Generation of a Potential Prognostic Matrix for Papillary Thyroid Cancer that Assesses Age, Tumor Size, Transforming Growth Factor-β, and BRAFV600E Mutation.

Oncol Res Treat 2017 12;40(10):586-592. Epub 2017 Sep 12.

Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China.

Background: Papillary thyroid cancer (PTC) is the most common differentiated thyroid cancer and is responsible for 80-90% of thyroid cancer cases. Despite typically excellent prognoses, these subclinical low-risk cancers are often treated aggressively by surgical thyroidectomy. Consequently, the objective of this study was to generate a prognostic matrix to be used prior to PTC intervention.

Methods: In this study, 80 PTC patients were assessed. Following adjustment for sex, logistic regression analysis showed that BRAFV600E mutation, transforming growth factor beta (TGF-β) expression, age, and tumor size are risk factors that can affect tumor clinical stage (p < 0.05). Based on the results of this analysis, we generated a matrix that incorporated 4 variables: patient age, tumor size, BRAFV600E mutation, and TGF-β expression.

Results: We observed that the corresponding area under curve was as high as 0.91. The sensitivity and specificity of the model were 94.74 and 83.61%, respectively. These values are significantly higher than those generated from single indexes.

Conclusion: As a result of this analysis, it is hoped that the resultant matrix can be utilized during clinical diagnosis and treatment prior to thyroid nodule surgery.
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http://dx.doi.org/10.1159/000477909DOI Listing
October 2018

Neuron-derived netrin-1 and netrin-4 proteins are additional effective targets in diabetic retinopathy beyond VEGF.

Int J Clin Exp Pathol 2017 1;10(8):8174-8186. Epub 2017 Aug 1.

Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University Qingdao 266555, Shandong Province, China.

Vascular endothelial growth factor (VEGF) is the typical representative factor of diabetic retinopathy (DR) and is considered to be a key inducer of retinal vascular permeability in DR. Anti-VEGF has been widely used in clinical treatment but every patient is effective, therefore, it is necessary to find other effective factors that participate in the pathology of DR. We provide evidence from both human and animal experiments for the considerable roles of classical neuronal guidance factors, netrin-1 and netrin-4, in indicating and amending the pathology of DR. We reveal that levels of both netrin-1 and netrin-4 are reduced while VEGF increases in DR patients and animal models. We demonstrate through different experimental methods that augmenting netrin-1 and netrin-4 can alleviate vasculopathy and neuropathy which appear in DR. Our findings offer additional effect targets besides VEGF for DR and suggest we should increase the focus on neurovascular crosstalk as DR is a neurovascular disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965419PMC
August 2017

Splenic and Pancreatic Abscesses Associated with In Situ Thrombosis of Splenic Artery.

Ann Vasc Surg 2017 Nov 6;45:265.e9-265.e11. Epub 2017 Jul 6.

Department of Vascular Surgery, The First Hospital, China Medical University, Shenyang, China. Electronic address:

Splenic infarction is rare and occurs when the splenic artery or its branches become occluded, either by an embolus or by in situ thrombosis. In situ thrombosis of splenic artery leading to splenic and pancreatic abscess formation after infarction is rare. We here present a case of a 65-year-old man who was found to have acute complete splenic and distal pancreatic infarction and abscess formation attributable to in situ thrombosis of splenic artery.
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http://dx.doi.org/10.1016/j.avsg.2017.06.130DOI Listing
November 2017

Severe hypertriglyceridemia due to two novel loss-of-function lipoprotein lipase gene mutations (C310R/E396V) in a Chinese family associated with recurrent acute pancreatitis.

Oncotarget 2017 Jul;8(29):47741-47754

Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao, China.

Lipoprotein lipase (LPL) is widely expressed in skeletal muscles, cardiac muscles as well as adipose tissue and involved in the catabolism of triglyceride. Herein we have systematically characterized two novel loss-of-function mutations in LPL from a Chinese family in which afflicted members were manifested by severe hypertriglyceridemia and recurrent pancreatitis. DNA sequencing revealed that the proband was a heterozygote carrying a novel c.T928C (p.C310R) mutation in exon 6 of the LPL gene. Another member of the family was detected to be a compound heterozygote who along with the c.T928C mutation also carried a novel missense mutation c.A1187T (p.E396V) in exon 8 of the LPL gene. Furthermore, COS-1 cells were transfected with lentiviruses containing the mutant LPL genes. While C310R markedly reduced the overall LPL protein level, COS-1 cells carrying E396V or double mutations contained similar overall LPL protein levels to the wild-type. The specific activity of the LPL mutants remained at comparable magnitude to the wild-type. However, few LPL were detected in the culture medium for the mutants, suggesting that both mutations caused aberrant triglyceride catabolism. More specifically, E396V and double mutations dampened the transport of LPL to the cell surface, while for the C310R mutation, reducing LPL protein level might be involved. By characterizing these two novel LPL mutations, this study has expanded our understanding on the pathogenesis of familial hypertriglyceridemia (FHTG).
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http://dx.doi.org/10.18632/oncotarget.17762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564601PMC
July 2017

Fluorescence Dye Loaded Nano-graphene for Multimodal Imaging Guided Photothermal Therapy.

RSC Adv 2016;6(3):1894-1901. Epub 2015 Dec 21.

Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.

Photoacoustic imaging (PA) has emerged as a novel and noninvasive imaging modality owing to its high spatial resolution and high soft tissue contrast. Herein, we loaded a near-infrared (NIR) fluorescence dye (CySCOOH) onto the surface of PEGylated graphene oxide (GO) via π-π stacking to increase the NIR absorbance of GO. The PA imaging proved that PEGylated GO-CysCOOH (GO-PEG-CysCOOH) significantly enhances the PA signal in the tumor site compared with free GO-PEG. We then utilized the strong optical absorbance of GO-PEG-CySCOOH in the NIR region for photothermal therapy, achieving efficient tumor ablation after intravenous injection of GO-PEG-CySCOOH and low-power laser irradiation on the tumor. Our results indicate that this graphene-based nanocomposite can be developed as a promising contrast agent for PA imaging and a thermal agent for imaging guided photothermal therapy.
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http://dx.doi.org/10.1039/C5RA24752GDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987095PMC
December 2015

A Chinese patient with recurrent pancreatitis during pregnancy induced by hypertriglyceridemia associated with compound heterozygosity (Glu242Lys and Leu252VaL) in the lipoprotein lipase gene.

J Clin Lipidol 2016 Jan-Feb;10(1):199-203.e1. Epub 2015 Sep 30.

Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China. Electronic address:

We herein report a novel compound heterozygote of Glu242Lys and Leu252Val in a Chinese patient, characterized by recurrent hypertriglyceridemia-induced acute pancreatitis caused by lipoprotein lipase deficiency. The proband's LPL level after injection of heparin was measured at 184 U/L, considerably lower than the normal controls (382 U/L). Furthermore, LPL activity in the proband was 16.7% of the normal controls. However, the hepatic lipase activity was 80% of the normal controls. These results indicated that the compound mutation was associated with hypertriglyceridemia due to both LPL deficiency and defective LPL function. The LPL deficiency was partially compensated by the roughly normal hepatic lipase, resulting in the apparent normal phenotype of the proband until pregnancy.
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http://dx.doi.org/10.1016/j.jacl.2015.09.010DOI Listing
November 2016

Association Between Tumor Necrosis Factor-α and Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes: a Meta-Analysis.

Mol Neurobiol 2017 03 21;54(2):983-996. Epub 2016 Jan 21.

Department of Endocrinology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.

Tumor necrosis factor-α (TNF-α) is a cell signaling protein involved in systemic inflammation, and is also an important cytokine in the acute phase reaction. Several studies suggested a possible association between TNF-α and diabetic peripheral neuropathy (DPN) in type 2 diabetic patients, but no accurate conclusion was available. A systematic review and meta-analysis of observational studies was performed to comprehensively assess the association between serum TNF-α levels and DPN in type 2 diabetic patients. We searched Pubmed, Web of Science, Embase, and China Biology Medicine (CMB) databases for eligible studies. Study-specific data were combined using meta-analysis. Fourteen studies were finally included into the meta-analysis, which involved a total of 2650 participants. Meta-analysis showed that there were obviously increased serum TNF-α levels in DPN patients compared with type 2 diabetic patients without DPN (standard mean difference [SMD] = 1.203, 95 % CI 0.795-1.611, P < 0.001). There were also obviously increased levels of serum TNF-α in diabetic patients with DPN when compared with healthy controls (SMD = 2.364, 95 % CI 1.333-3.394, P < 0.001). In addition, there were increased serum TNF-α levels in painful DPN patients compared with painless DPN patients (SMD = 0.964, 95 % CI 0.237-1.690, P = 0.009). High level of serum TNF-α was significantly associated with increased risk of DPN in patients with type 2 diabetes (odds ratio [OR] = 2.594, 95 % CI 1.182-5.500, P = 0.017). Increased serum levels of TNF-α was not associated with increased risk of painful DPN in patients with type 2 diabetes (OR = 2.486, 95 % CI 0.672-9.193, P = 0.172). Sensitivity analysis showed that there was no obvious change in the pooled estimates when omitting single study by turns. Type 2 diabetic patients with peripheral neuropathy have obviously increased serum TNF-α levels than type 2 diabetic patients without peripheral neuropathy and healthy controls, and high level of serum TNF-α may be associated with increased risk of peripheral neuropathy independently. Further prospective cohort studies are needed to assess the association between TNF-α and DPN.
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http://dx.doi.org/10.1007/s12035-016-9702-zDOI Listing
March 2017

Integrin (αvβ3) Targeted RGD Peptide Based Probe for Cancer Optical Imaging.

Curr Protein Pept Sci 2016 ;17(6):570-81

School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.

Integrins have an important impact on the regulation of normal and tumor cell migration and survival, especially the integrin αvβ3 and its role in angiogenesis and tumor metastasis. Owing to the role of integrins, non-invasive imaging of αvβ3 expression in diseased tissue will be of great benefit in directing adjuvant therapy for cancer patients. To this end, RGD peptide based probes for optical imaging have emerged as a real-time, sensitive, and noninvasive approach for visualization, localization, and measurement of cancer in vivo. With the advantages of optical imaging such as sensitivity, cost effectiveness, and non-invasion, the past decades have witnessed the rapid development of integrin- targeted optical probes and its wide applications in cancer research. In this review, we present and introduce numerous approaches by the term "RGD motif based optical imaging probes" with respect to their probe design strategies and applications. Additionally, a variety of labels such as QDs, UCLs and near-infrared fluorochrome used in these optical imaging probes are also discussed.
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http://dx.doi.org/10.2174/1389203717666160101124015DOI Listing
February 2017

Protein-based photothermal theranostics for imaging-guided cancer therapy.

Nanoscale 2015 Oct;7(39):16330-6

Department of Radiology, the Third Xiangya Hospital, Central South University, Changsha, 410013, PR China.

The development of imageable photothermal theranostics has attracted considerable attention for imaging guided photothermal therapy (PTT) with high tumor ablation accuracy. In this study, we strategically constructed a near-infrared (NIR) cyanine dye by introducing a rigid cyclohexenyl ring to the heptamethine chain to obtain a heptamethine dye CySCOOH with high fluorescence intensity and good stability. By covalent conjugation of CySCOOH onto human serum albumin (HSA), the as-prepared [email protected] nanoplatform is highly efficient for NIR fluorescence/photoacoustic/thermal multimodality imaging and photothermal tumor ablation. The theranostic capability of [email protected] was systematically evaluated both in vitro and in vivo. Most intriguingly, complete tumor elimination was achieved by intravenous injection of [email protected] (CySCOOH, 1 mg kg(-1); 808 nm, 1.0 W cm(-2) for 5 min) into 4T1 tumor-bearing mice, with no weight loss, noticeable toxicity, or tumor recurrence being observed. This as-prepared protein-based nanotheranostics exhibits high water dispersibility, no off target cytotoxicity, and good biodegradability and biocompatibility, thus facilitating its clinical translation to cancer photothermal theranostics.
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http://dx.doi.org/10.1039/c5nr04428fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599582PMC
October 2015

T-cell immunoglobulin mucin-3 expression in bladder urothelial carcinoma: Clinicopathologic correlations and association with survival.

J Surg Oncol 2015 Sep 11;112(4):430-5. Epub 2015 Aug 11.

Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China.

Background: T cell immunoglobulin mucin-3 (Tim-3) was initially recognized as a pivotal immune checkpoint inhibitor that maintains immune homeostasis and tolerance. Recently, Tim-3 has been demonstrated to play an important role in tumor-associated immune suppression and aberrant Tim-3 expression has been reported in several human malignancies. However, the role of Tim-3 in bladder urothelial carcinoma (BUC) remains largely unknown. The present study aims to investigate Tim-3 expression in BUC and analyze correlations with clinicopathologic outcomes and postoperative survival.

Methods: Tim-3 protein expressions were detected in paraffin embedded sections from 100 patients with BUC by immunohistochemistry. Expressions were correlated with clinicopathologic outcomes and postoperative survival.

Results: Tim-3 protein was over-expressed in bladder cancer cells, tumor infiltrating lymphocytes and endothelial cells from patients with BUC. The expression levels of Tim-3 were significantly correlated with advanced pathological grade and T stage. Moreover, another immune checkpoint molecule programmed death receptor-1(PD-1) was also over- expressed in BUC tissues and had a significant correlation with Tim-3. Multivariate analysis showed that Tim-3 expression, as well as PD-1 expression was both independent predictors of disease-free survival and overall survival in patients with BUC.

Conclusion: Tim-3 over-expression implies adverse clinical outcomes for BUC, which suggests it is a potential prognostic biomarker and a novel therapeutic target in BUC.
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http://dx.doi.org/10.1002/jso.24012DOI Listing
September 2015

Dual-Modality Noninvasive Mapping of Sentinel Lymph Node by Photoacoustic and Near-Infrared Fluorescent Imaging Using Dye-Loaded Mesoporous Silica Nanoparticles.

Mol Pharm 2015 Sep 27;12(9):3119-28. Epub 2015 Jul 27.

School of Pharmaceutical Sciences, Central South University , Changsha, 410013, P. R. China.

The imaging of sentinel lymph nodes (SLNs), the first defense against primary tumor metastasis, has been considered as an important strategy for noninvasive tracking tumor metastasis in clinics. In this study, we developed an imaging contrast system based on fluorescent dye-loaded mesoporous silica nanoparticles (MSNPs) that integrate near-infrared (NIR) fluorescent and photoacoustic (PA) imaging modalities for efficient SLN mapping. By balancing the ratio of dye and nanoparticles for simultaneous optimization of dual-modality imaging (NIR and PA), the dye encapsulated MSNP platform was set up to generate both a moderate NIR emission and PA signals simultaneously. Moreover, the underlying mechanisms of the relevance between optical and PA properties were discovered. Subsequently, dual-modality imaging was achieved to visualize tumor draining SLNs up to 2 weeks in a 4T1 tumor metastatic model. Obvious differences in uptake rate and contrast between metastatic and normal SLNs were observed both in vivo and ex vivo. Based on all these imaging data, it was demonstrated that the dye-loaded MSNPs allow detection of regional lymph nodes in vivo with time-domain NIR fluorescent and PA imaging methods efficiently.
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http://dx.doi.org/10.1021/mp500698bDOI Listing
September 2015
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