bluuebunny/crossref_metadata_2025_split huggingface dataset:
E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms
Authors: Jolly Mohit Kumar , Ware Kathryn E. , Xu Shengnan , Gilja Shivee , Shetler Samantha , Yang Yanjun , Wang Xueyang , Austin R. Garland , Runyambo Daniella , Hish Alexander J. , Bartholf DeWitt Suzanne , George Jason T. , Kreulen R. Timothy , Boss Mary-Keara , Lazarides Alexander L. , Kerr David L. , Gerber Drew G. , Sivaraj Dharshan , Armstrong Andrew J. , Dewhirst Mark W. , Eward William C. , Levine Herbert , Somarelli Jason A. 
Published: March 2019

Abstract

CDH1 (also known as E-cadherin), an epithelial-specific cell–cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-to-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-to-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB1 (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell–cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth.

Implications:
We highlight how E-cadherin can restrict aggressive behavior in sarcomas through both biochemical signaling and biomechanical effects.
First photographic record of the Rusty-spotted Cat Prionailurus rubiginosus (I. Geoffroy Saint-Hilaire, 1831) (Mammalia: Carnivora: Felidae) in Horton Plains National Park, Sri Lanka
Authors: Nimalrathna Thilina Sudarshana , Choo Yan Ru , Kudavidanage Enoka P. , Amarasinghe Thakshila Ravindra , Bandara Udamulle Gedara Sumith Indika , Wanninayaka Wanninayaka Aarahchilage Charitha Lakmal , Ravindrakumar Piyal , Chua Marcus Aik Hwee , Webb Edward L 
Published: March 2019

The Rusty-spotted Cat Prionailurus rubiginosus is thought to be present in most forested areas of Sri Lanka. Though it was suggested that the species may occur in montane regions, there was no photographic evidence to date. Here we present the first photographic record of the Rusty-spotted Cat in Horton Plains National Park. Individuals including cubs were photo-captured on 15 separate occasions during a 5,538 camera trap days study. These photo-captures were made both during the day and night, and indicate the presence of a breeding population in this protected area.
Abstract 033: Differential Effects of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Production and Function on Microsomal Triglyceride Transfer Protein
Authors: Huang Cecilia , Miles Joshua , Tavori Hagai , Toth Peter P , Toth Peter P , Fazio Sergio 
Published: March 2019

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that plays a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol levels. PCSK9 binding to the LDL receptor (LDLR) leads to receptor-mediated endocytosis and lysosomal degradation of LDLR. Prior studies have shown that PCSK9 increases production of triglyceride-rich apoB-lipoproteins via up-regulation of lipogenic genes, and that PCSK9 inhibition reduces plasma triglyceride levels. However, the effect of PCSK9 inhibition on hepatic lipogenic genes expression remain unclear.
Using a human hepatocellular carcinoma cell line (HepG2) we show that overexpression of PCSK9 upregulated the expression of several lipogenic genes, including a 1.5-fold increase in ATP citrate lyase (ACLY), a 1.2-fold increase in Fatty Acid Synthase (FAS), a 1.2-fold increase in HMG-CoA-reductase, and a 1.8-fold increase in microsomal triglyceride transfer protein (MTTP), when compared with untransfected HepG2 cells. Overexpression of a gain-of-function mutant of PCSK9 (PCSK9-D374Y) had stronger effects in the same direction: a 2.3-fold increase in ACLY, a 1.8-fold increase in FAS, a 1.6-fold increase in HMG-CoA-reductase, and a 2.1-fold increase in MTTP. In HepG2 cells overexpressing either normal PCSK9 or PCSK9-D374Y, inhibition of PCSK9 function using a monoclonal antibody blocked PCSK9-mediated degradation of LDLR, and reduced expression of SREBP-dependent genes (ACLY, FAS and HMG-CoA-reductase) to levels of untransfected HepG2 cells. Interestingly, while inhibition of PCSK9 function via monoclonal antibody did not affect MTTP gene expression in these cells, inhibition of PCSK9 production via RNA interference reduced MTTP gene expression by 66%.
We conclude that inhibition of PCSK9 production decreases MTTP gene expression, whereas blockade of PCSK9 function (and cellular re-entry) only decreases SREBP-dependent genes expression, but does not affect MTTP gene expression. This study shows that while PCSK9 exerts an influence on genes related to both lipogenesis and lipoprotein assembly, any inhibition of PCSK9 controls SREPB-dependent genes but only inhibiting PCSK9 production controls MTTP gene expression.
Abstract 097: Diagnosis of Atherosclerotic Coronary Heart Disease using Plasma Extracellular Vesicle Proteins
Authors: de Kleijn Dominique P , Waissi Farahnaz , Dekker Mirthe , Bank Ingrid , Schoneveld Arjan , Mosterd Arend , Timmers Leo 
Published: March 2019

Atherosclerosis is the underlying syndrome of Cardiovascular Disease (CVD). Ischemic Heart Disease and Stroke are cardiovascular events both due to atherosclerosis that are the number 1 and 2 cause of death in the world and expect to increase especially in Asia.
Ischemic heart disease (IHD) comprises 3 entities: stable coronary artery disease (SCAD), unstable angina (UA) and myocardial infarction (MI). Despite its large numbers, diagnosis IHD is challenging, as many patients present with atypical symptoms with women have a different symptom sensation than men. Troponins are the main diagnostic tool for detection of MI. Blood biomarkers for SCAD (typically causing stable angina) and UA, however, are not available. These diagnoses frequently require hospital visits/admissions for time-consuming and costly (non)invasive tests.
Extracellular vesicles are composed of a lipid bilayer containing cytosolic, membrane and nuclear molecules derived from the cell and cell compartments of origin and released by the cell into extracellular biofluids. Using proteomics, we identified a plasma extracellular vesicle protein signature of inflammatory and coagulation proteins in different plasma vesicle subpopulations that can identify UA and SCAD patients. This signature was verified for UA in 60 acute chest pain patients (AUC 0.93), and for SCAD in 60 chest pain patients scheduled for heart perfusion imaging (AUC 0.86).
This shows that plasma extracellular vesicle proteins can be used for early diagnosis of SCAD and UA and underlines the biological role for extracellular vesicles in atherosclerosis.
Abstract 211: MKL1 Affects Proliferation/Survival Property of Pro-Atherogenic Macrophages
Authors: An Jianbo , Naruse Taeko K , Kimura Akinori 
Published: March 2019

Coronary artery disease (CAD) is one of the leading causes of death in the most countries. Atherosclerosis of coronary arteries often results in high incidence of vascular occlusion and is recognized as the major cause of CAD. We have previously reported from a genome-wide association study that a promoter SNP in megakaryoblastic leukemia 1 gene (
MKL1
), which conferred higher transcriptional activity, was significantly associated with the susceptibility to CAD as well as coronary atherosclerosis. MKL1 is a Rho-Rock signaling-responsive co-activator of serum response factor, and regulates a variety of cellular functions. We found that MKL1 was highly expressed in activated macrophages in the neointima of atherosclerotic lesions from human and ApoE-knockout (KO) mouse. In addition, the expression level of MKL1 in lesional macrophages was increased during the development of atherosclerosis in ApoE-KO mice.

We have established a transgenic mouse line, MKL1-TgM, in which human
MKL1
was specifically overexpressed in monocyte/macrophage lineage cells. In this study, MKL1-TgM was crossbred onto ApoE-KO background. ApoE-KO/MKL1-TgM fed with normal chow developed severer atherosclerosis and showed poorer survival rate than ApoE-KO mice. Serum level of pro-inflammatory cytokines was increased in ApoE-KO/MKL1-TgM. Interestingly, ApoE-KO/MKL1-TgM also developed hypertriglyceridemia, which was associated with severe lipodystrophy.

We also investigated how MKL1 regulated macrophages function. Recently, local proliferation/accumulation of lesional macrophages was reported to be a crucial event in atherosclerosis. We treated bone marrow-derived macrophages (BMDMs) with stimuli, such as M-CSF or OxLDL, and found that proliferation property of BMDMs from MKL1-TgM was elevated. On the other hand, BMDMs from MKL1-TgM were more resistant to apoptosis. Furthermore, immunohistochemistry analyses of lesional macrophages in ApoE-KO/MKL1-TgM showed enhanced proliferation and mitigated apoptosis.
Taken together, our data indicated that MKL1 would contribute to the development of atherosclerosis by modulating pro-atherogenic functions of macrophages, providing a potential molecular target for the therapy and prevention of atherosclerosis.
Abstract 361: Multifocal Vascular Disorders Due to the Uncommon Anti-phosholipid Antibody Syndrome
Authors: Kawanura Yasutaka , Ai Masato , Nakaki Masafumi 
Published: March 2019

Purpose:
We report three cases with uncommon anti-phosholipid antibody syndrome. The difficulty in diagnosing as well as treatment procedures for multifocal vascular disorders is discussed.

Patients and Methods:
All patients were examined and were initially treated for digestive disorders.

Patient 1, 84-year-old woman, with gastrointestinal bleeding
Patient 2, 76-year-old man, with sudden onset of upper abdominal pain
Patient 3, 54-year-old man, with nausea and vomiting, liver dysfunctionClinical manifestation was superior mesenteric artery (SMA) thrombosis in the patient 1 and 2, and portal vein thrombosis in the patient 3.
Serial CT scans were examined on 64 multidetector-row CT; Hitachi and GE, with bolus injection of contrast media for CT angiography.
Abdominal angiography and coronary angiography with endovascular intervention performed on were performed on Allura; Philips.

Results:
CTA of for patient 1 and 2 showed decreased contrast enhancement of SMA and SMV enhancement. The intestinal enhancement was poor in patient 1 and well preserved in patient 2. A week later, patient 1 died suddenly due to multiple organ failure. Although the symptom improved in patient 2, the follow-up CT revealed the enlargement ofSMA thrombosis. The aspiration and the dissolution of SMA thrombosis were performed and resulted in complete recanalization. Then he felt chest oppression and 75% stenosis of RCA #4, followed by complete spastic occlusion on Acetylcholine loading on the coronary angiography, which recovered perfectly with intracoronary nitroglycerin administration.He discharged our hospital with health, while he developed cerebellar infarction. On patient 3, to resolve portal hypertension, balloon-occluded retrograde transvenous obliteration and splenic arterial embolization were successfully performed.

Discussion and Conclusions:
Acute deterioration encountered in patient 1, the progressive SMA thrombosis with coronary disease and subsequent cerebellar occlusion seen in patient 2, and portal vein thrombosis and portal hypertension without chronic hepatitis, cirrhosis or alcoholic liver damage in the patient 3 were seemed to be unusual. To discover underlining disorders such as uncommon anti-phosholipid antibody syndrome is important to prevent serious vascular diseases in sequence.
Abstract 477: Platelet microRNAs Crosstalk with Vascular Endothelial Cells in Diabetes
Authors: Dangwal Seema , Stratmann Bernd , Ke Xiao , Kleinbongard Petra , Heusch Gerd , Erbel Raimund , Tschoepe Diethelm , Thum Thomas 
Published: March 2019

Platelets are major source of extracellular miRNAs (miRs) constituting the plasma miR-pool. Here we generated miR-profile of leukocyte depleted platelets (LDP) isolated from type-2 diabetic (T2DM) or healthy subjects and investigated mechanism of miRNA mediated vascular crosstalk.
LDPs were obtained by leukocyte filtration of platelet rich plasma isolated from blood withdrawn from T2DM (6 males, age: 54.8±7.6 yr; HbA1c: 8.9±0.6%; BMI: 30.9±2.8kg/m2) and healthy subjects (10 males, age: 49.2±6.8yr; HbA1c: 5.3±0.2%; BMI: 26.6±3.8kg/m2). MiR-profile was generated using total RNA isolated from T2DM or healthy LDPs. Students t-test applied to compare groups and p≤0.05 considered significant.
Among all detected 735 miRs (cutoff<29 Ct), 19.5% miRs were depleted, whereas 7.5% showed >2 fold increase in T2DM-LDPs. Compared to healthy LDPs (n=10), depletion of 14 platelet-enriched miR candidates, including miR-21 and -22, were validated by RTPCR in individual T2DM-LDPs (n=11) irrespective of aspirin intake or presence of coronary heart disease.Ex-vivo thrombin stimulation of washed healthy platelets increased the release of miRNA into cellular-supernatants and confocal microscopy confirmed the cellular uptake of platelet released miRNA-carrying microparticles into human coronary artery endothelial cells (ECs) within 2-24h. In addition, EC overexpression of miR-21 or -22 decreased cell proliferation, whereas miR-22 also attenuated their tube forming capacity. MiR-21 or -22 modulations inversely regulated gene expression of their common predicted target, the cell-cycle regulator gene- CDK-6. MiR concentrations were also measured in particulate debris and plasma derived from coronary aspirates retrieved during stent implantation from 3 T2DM or 4 non-diabetic patients. In line, higher miR-21 or -22 ratios in plasma to particulate debris in T2DM vs non-diabetic aspirates indicated miR release from particulate debris into coronary plasma. This in turn provides relatively richer miR-21 or -22 microenvironment to the vicinal vascular ECs.
T2DM platelets show distinct miR-profile compared to healthy platelets and depletion of miRNAs may represent their active secretion from diabetic platelets. Altered coronary microenvironment may lead to altered cellular responses to injury in diabetic vessels.
Abstract 494: Endothelial Cell Heterogeneity Governs Basal and Inducible Inflammatory Responses Relevant to Allograft Injury
Authors: Zufall Gianna , Valenzuela Nicole 
Published: March 2019

Introduction:
Transplanted organs are not equally susceptible to rejection, suggesting a role for site specialization of vascular endothelial cells (EC). Most studies of leukocyte recruitment employ umbilical vein or aorta EC, and fail to capture physiological differences among EC.

Methods:
EC were left unstimulated or treated with TNFα or IL-1β (0.01-10ng/mL, 4-24hr). Confluent primary human EC from aorta (AEC), coronary artery (CAEC), cardiac microvessel (CMVEC), pulmonary artery (PAEC), lung microvessel (LMVEC), skin blood microvessel (DMVEC), liver sinusoids (LSEC), kidney glomerulus (RGEC) and brain microvessel (HMBVEC) were compared for expression of adhesion molecules and chemokines by Nanostring Human Immunology 594 gene panel, flow cytometry and 38-plex Luminex assay (n=3 donors). A novel adhesion assay enabled immunophenotyping of allogeneic leukocyte subsets (T, B, NK and monocytes) adherent to EC (n=4 PBMC donors).

Results:
>200 immunology-related genes were differentially expressed (fold >1.5, p<0.05) across untreated EC. Microvascular EC expressed higher baseline levels of ICAM-1, E-selectin and VCAM-1. TNFα and IL-1β increased these adhesion molecules, but there were clear differences in the magnitude and kinetics across cells. Most notably, LSEC failed to significantly upregulate E-selectin, and exhibited the lowest adherence of leukocytes. Only LSEC constitutively expressed suppressors of cytokine signaling (SOCS1 and SOCS3).

After stimulation with TNFα and IL-1β, cardiac EC produced more fractalkine than other EC irrespective of vessel size; but large vessel (AEC, PAEC) produced the most IL-6 and G-CSF. AEC were a poor source of RANTES and IP-10, while LSEC did not increase fractalkine or GM-CSF.
IL-1β increased GM-CSF, G-CSF, and GROα and IL-6. TNFα increased RANTES. More NK and B cells were recruited to TNFα than IL-1β activated EC. IL-1β selectively increased the nuclear cofactor NFKBIZ (IκBζ), but TNFα promoted Bcl-3 expression, suggesting different transcriptional programs.

Conclusion:
These findings demonstrate heterogeneity among EC from different vascular beds and organs. SOCS proteins may be potential therapeutic targets to reduce the inflammatory responses of ECs in multiple vascular disease models.
Abstract 722: Evaluation of Peripheral Calcium Score as a Measure of Peripheral Artery Disease Severity
Authors: Lee Sujin , Kalra Kanika , Redpath Benjamin , Little Brent , Bernheim Adam , Brewster Luke , Shaw Leslee , Arya Shipra 
Published: March 2019

The current gold standard for diagnosing PAD is Ankle Brachial Index (ABI). However, vascular calcification can falsely elevate ABI. No studies have compared the diagnostic value of peripheral calcium score (PCS) in lower extremity arteries with ABI.

Primary aim of this study was to describe the association of PCS with continuous ABI values and categories of ABI in a retrospective cohort design. We identified 50 patients who underwent CTA and ABI measurements [ABI categories for PAD severity: severe (<0.5), moderate (0.5-0.9), normal (0.9-1.4), noncompressible (>1.4)]. We evaluated CTAs imaged from abdominal aorta through lower extremities and determined total calcium volume of plaques with density >130 HU and area >1mm
2
from infrarenal abdominal aorta to the foot using TeraRecon by two independent readers (Intra class correlation 99%). We explored the association between ABI and PCS in SAS using multiple linear regression and analysis of covariance adjusting for age, race, smoking status, hypertension, hyperlipidemia, type II diabetes, and chronic kidney disease.

We found that ABI was inversely associated with PCS in linear regression (p<0.01, Figure 1A). Differences in mean PCS were statistically significant across ABI categories [F(3,29)= 5.03, p=0.01, Figure 1B]. Across subgroups, the mean PCS was significantly different for ABIs <0.5 and 0.5-0.9 (p=0.02), <0.5 and >1.4 (p<0.001), 0.5-0.9 and >1.4 (p=0.04), 0.9-1.4 and >1.4 (p=0.05). Proportion of tibial calcium to overall PCS was much lower in ABI<0.5: 0.0003 vs ABI>1.4: 0.357 (p=0.02).
Mean PCS may be a valid measure of PAD severity and percentage of tibial calcium may help quantify PAD burden in non-compressible vessels. Our study serves as proof of concept for a comprehensive PCS system to diagnose and evaluate PAD severity, particularly in high-risk subpopulations where non-invasive studies may be unreliable.
Abstract 726: Intermittent Pneumatic Compression during Hemodialysis to improve Quality of Life in Patients with Peripheral Artery Disease and End Stage Renal Disease
Authors: Paz Rios Luis H , Al-Ogaili Ahmed , Torres Christian , Ayub Muhammad T , Del Cid Fratti Juan , Kolkailah Ahmed A , Ayoub Ali , Golemi Iva , Fuentes Harry E , Hart Peter , Acob Christine , Tafur Alfonso J 
Published: March 2019

Peripheral artery disease (PAD) is a prevalent global problem with increased mortality. Affects about one in four patients with end stage renal disease (ESRD). Intermittent pneumatic compression (IPC) has shown improvement of lower extremity hemodynamics and symptoms and may be implemented during hemodialysis (HD).
We designed a trial to test the utility of IPC in the ESRD population by assessing improvement in quality of life (QOL) and functional limitation from PAD-related symptoms. We aim to present our design and initial results.

Methods:
This is a prospective single cohort study for paired analysis undergoing recruitment of outpatients at the HD unit of John H. Stroger, Jr. Hospital of Cook County. A sample size of 78 yields a power of 80% and alpha of 0.05, assuming an average peak walking time of five minutes and 25% improvement after supervised exercise. PAD is confirmed by ankle-brachial index (ABI) and demographics collected. A baseline Six-minute Walk Test (6MWT), Peripheral Artery Questionnaire (PAQ) and Walking Impairment Questionnaire (WIQ) are administered and will be compared with their performance post intervention. The IPC device (Bio Arterial Plus) will be used for intervention during each HD for two months average. We present continuous variables as mean±SD and categorical variables as percentage.

Results:
From 10 recruited patients in the first month, 60% are men, age 54.6±13.1 years, the majority Hispanic (80%). 70% of ABI were abnormal, all due to non-compressible PAD (1.44±0.20). All patients have HTN, 50% diabetes, 20% hyperlipidemia, 10% had a stroke and 10% revascularization for PAD. At baseline 6MWT, distance walked was 357.7±59.5 m, with 600±52.5 total steps and fatigue as main symptom (30%) and no typical claudication. QOL questionnaires showed WIQ walking distance 68.58±18.04, WIQ walking speed 72.5±26.36, and WIQ stair climbing 50.04±30.04 points; PAQ physical limitation 61±21.4, PAQ symptoms 62.79±18.7, PAQ satisfaction 68.67±27.9, PAQ quality of life 64±13.04, and PAQ social limitation 70±23.13 points.

Conclusion:
Non-compressible PAD is prevalent in ESRD, and QOL seems significantly compromised from it. Our trial will provide insight of an alternative therapy, and optimize the time in HD even further.