bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 524: Myxomaviral Anti-angiogenesis Protein Serp-1 Inhibits Pancreatic Cancer Growth in Mice
Authors: Zheng Donghang , Chen Hao , Bartee Mee , Davids Jennifer , Lucas Alexandra 
Published: March 2022

Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with a critical role in tumor invasion, growth, angiogenesis, and metastasis. Increased serine proteases in the thrombolytic cascade, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory cell invasion, angiogenesis, cancer growth and invasion. Inflammation in pancreatic cancer is linked with myeloid-derived suppressor cell activity and cancer progression. Myxomavirus is a complex DNA virus encoding highly potent immune modulators such as Serp-1, which inhibits uPA, tPA, plasmin and coagulation factor X. Serp-1 has also been demonstrated to inhibit angiogenesis in a chicken chorioallantoic membrane (CAM) model. To explore the potential use of anti-inflammatory, anti-angiogenesis proteins that target thrombotic and thrombolytic as well as inflammatory pathways, for cancer treatment, severe combined immunodeficient (SCID) mice engrafted with human cancer cells were treated with Serp-1 and neuroserpin, a selective mammalian inhibitor of thrombolytic proteases or control saline. Proteins were tested for efficacy in preventing human pancreatic and breast cancer cell growth in NOD/SCID mice (n=67 total) at 4 weeks after implantation. Serp-1 and neuroserpin inhibited pancreatic cancer Hs766t (n=27; P=0.03 and P=0.01, respectively), but not breast cancer MDA231 growth (n=11) when compared to saline controls (N =5). Serpin inhibition of pancreatic tumor growth was associated with decreased MDSC as shown by flow cytometry analysis of splenocyte (P=0.009). Serpin-mediated anti-inflammatory activity in pancreatic tumor growth was also demonstrated by reduced macrophage infiltration in tumors (P=0.001). Furthermore, RT-PCR array analysis revealed a five-fold decrease in the expression of inducible nitric oxide synthase (iNOS), which has been shown to play important role in tumor angiogenesis.

Conclusions
Anti-inflammatory protease inhibitors, virus-derived Serp-1 and mammalian neuroserpin, may provide new treatment approaches by targeting the angiogenesis and inflammatory responses that support cancer cell growth.
Abstract 526: Angiogenesis and Kallikrein-kinin System Activation after Exercise Training in Rats with Sustained Adrenergic Hyperactivity
Authors: Santana Eduardo T , Serra Andrey J , Manchini Martha T , Antonio Ednei L , Tucci Paulo J , Silva Jose A 
Published: March 2022

Several mechanisms are involved to exercise-related cardioprotection.

Purpose
Kallikrein-kinin system may contribute to this effect inducing endothelial vascular growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression.

Methods
In a model of β-adrenergic hyperactivity, male Wistar rats were assigned into four groups: sedentary non-treated (Con); sedentary isoproterenol-treated (Iso); exercised only (Ex); and exercised isoproterenol-treated (Iso+Ex). Left ventricles were processed for Real time PCR and Western blot analysis in order to quantify the expression of kinins and angiogenic molecules.

Results
In Iso+Ex, a significant increase of tissue kallikrein gene and protein expression was observed (p<0.01). In the same group, an augmented eNOS (p<0.05), VEGF and VEGF receptor mRNA expression (p<0.01) was observed. The expression of angiogenic IL-1 and Il-8 were increased after exercise (p<0.01). Expression of integrin linked kinase (ILK), another angiogenesis promoter, also augmented after training (p<0.01).

Conclusion
Our results represent the first demonstration that exercise increases the tissue kallikrein gene and protein expression in rat myocardium after β-adrenergic hyperactivity. Together with the observed augmented eNOS and VEGF and angiogenesis-related molecules mRNA expression, a feasibly pathway might be drawn to understand the kallikrein-kinin system protective role to avoid the abnormalities developed due excessive catecholaminergic activation as observed in cardiac failure. Our data suggest a strong evidence of beneficial exercise action, particularly related to angiogenesis, in response of myocardium towards β-adrenergic hyperactivity.
Abstract 53: Noninvasive Detection of Inflammation of Murine Stasis Deep Venous Thrombosis (DVT) Using Integrated 18F-FDG PET/CT
Authors: Hara Tetsuya , Truelove Jessica , Jokivarsi Kimmo , Brownell Anna-Liisa , Wojtkiewicz Gregory R , Weissleder Ralph , Tawakol Ahmed , Jaffer Farouc A 
Published: March 2022

Background
Noninvasive imaging of inflammation in DVT could offer new insights into the resolution of deep venous thrombosis (DVT) in living subjects. While a few clinical studies have reported incidental uptake of 18F-FDG PET in a subgroup of DVTs, limited information exists regarding the cellular mechanisms and time dependence of FDG uptake in DVT. Here we investigated whether FDG-PET could enhance murine stasis-induced DVT in acute to subacute DVT, and assessed the inflammatory cell infiltrate within DVT.

Methods
C57BL/6 mice (n=6) underwent ligation of the jugular vein to induce stasis DVT. At DVT timepoints from day 2 to day 7, 18F-FDG PET (25-35 μCi/g) and contrast CT venography was performed. After PET/CT imaging, animals were sacrificed and veins were resected. Gamma-counting and histological analyses of thrombus neutrophils and macrophages were then performed.

Results
PET/CT images demonstrated the FDG signal accumulated in thrombosed jugular veins in acute DVT, and significantly more than in contra-lateral sham veins (SUV = 1.27±0.11 vs. 0.79±0.069, SUVmax = 1.45±0.090 vs. 1.02±0.056, p<0.05, respectively). The %IDGT was significantly higher in thrombosed veins (7.21±0.17% vs. 1.54±0.47% sham vein, p<0.05). The % positive area of neutrophil in thrombus was 25 times higher than macrophages (14.1±2.9% vs. 0.58±0.091%, p<0.0001) in earlier-stage (day2-4) DVT.

Conclusions
Noninvasive FDG-PET/CT can visualize inflammation in experimental DVT. Thrombus neutrophils appear to be the cellular source underlying accumulated FDG signal in earlier-stage DVT. FDG-PET may enable assessment of thrombus age and provide new insights into the resolution of DVT.
Abstract 556: Significant Interaction of Smoking and Metabolic Syndrome for Subclinical Vascular Inflammation
Authors: Jamal Omar , Ali Shozab S , Blaha Michael J , Shaharyar Sameer , Agatston Arthur A , Blumenthal Roger S , Santos Raul D , Nasir Khurram 
Published: March 2022

BACKGROUND
Emerging data suggest an additive interaction of current smoking and metabolic syndrome (MS) on cardiovascular risk. In this study we aim to assess if this increased risk can be explained by an increased risk of subclinical vascular inflammation.

METHODS
We evaluated 6,464 healthy non-diabetic Brazilian subjects (43±10 years, 79% males). Participants were divided into 4 subgroups by MS and smoking status. High-sensitivity C reactive protein (hs-CRP) was measured to assess degree of underlying inflammation. We excluded 945
(14%) individuals with missing hs-CRP levels.

RESULTS
Overall 1,062/5,519 (19%) had hs-CRP≥3 mg/dl. The figures show prevalence of high CRP across smoking and MS status. As compared with never smokers without MS, in multivariate
analysis the adjusted OR’s for elevated hs-CRP were 1.28 (95% CI: 0.98-1.67), 2.09 (95% CI: 1.76-2.48), and 4.24 (95% CI:2.95-6.08) for smokers without MS, nonsmokers with MS, and current
smokers with MS. The interaction for MS and smoking with high hs-CRP was statistically significant(p=0.05) The risk of hsCRP≥3 with smoking was 1.58 (1.00-2.52) fold vs smokers among non MS
individuals.

CONCLUSION
The current study further demonstrates a synergistic interaction of current smoking and MS for vascular inflammation, highlighting those with MS are at higher risk and needed to be
aggressively targeted for smoking cessation.
Abstract 559: Systemic Oxidative Stress is Associated with Myocardial Perfusion in Whites but not in Blacks: The Bogalusa Heart Study
Authors: Fernández Alonso Camilo , Li Shengxu , Blandon Roberto , Srinivasan Sathanur R , Chen Wei , Berenson Gerald S 
Published: March 2022

Central and peripheral vascular damage by oxidative stress-mediated mechanisms has been described in male and female patients with inflammatory pathologies. However, information is scant on the association between oxidative stress and myocardial perfusion in biracial (black-white) asymptomatic young adults.
We assessed the hypothesis that the association between oxidative stress and myocardial perfusion differs among biracial (black-white) asymptomatic young adults.
As a part of the Bogalusa Heart Study, systemic oxidative stress (in terms of urinary creatinine-indexed levels of 8-epi-PGF2alfa -isoprostane-) and non-invasive myocardial perfusion (in terms or Subendocardial Viability Ratio -SEVR) were assessed in 605 asymptomatic individuals aged 29-51 years (mean 43.4; 68.7% white and 54.4% female), along with evaluation of traditional cardiovascular risk factors. The race-specific association of urinary creatinine -indexed 8-epi-PGF2alfa with SEVR was tested through multivariable- adjusted linear regression analyses.
SEVR levels were significantly higher in white and male participants (p<0.001), whereas creatinine-indexed 8-epi-PGF2alfa levels were lower; when compared to their counterparts. In race-specific multivariable-adjusted linear regression analyses, controlling for age, sex, body mass index, smoking, hypertensive and diabetic status; along with traditional cardiovascular risk factors, a significant inverse association was observed between creatinine-indexed 8-epi-PGF2alfa and SEVR in white (B= -0.246, p<0.001) but not in black participants (B= 0.007, p=0.93).
In conclusion, the described observations help support the hypothesis that the impact of oxidative stress on myocardial perfusion (coronary microcirculation) is different among race (black-white) groups. Further, this may aid to emphasize and enhance race-specific risk factor screening and disease evaluation.
Abstract 564: Influence of Coronary Artery Disease-Associated Genetic Variants on Risk of Venous Thromboembolism
Authors: Bruzelius Maria , Strawbridge Rona J , Tregouet David A , Bergendal Annica , Silveira Angela , Gertow Karl , Sundström Anders , Kieler Helle , Syvänen Ann-Christine , Morange Pierre-Emmanuel , Odeberg Jacob , Hamsten Anders 
Published: March 2022

Objective
To determine whether genetic variation robustly associated with coronary artery disease (CAD) also influences risk of venous thromboembolism (VTE) in a well-defined, female case-control study (n=2753) from Sweden (the ThromboEmbolism Hormone Study (TEHS)).

Approach and Results

Single nucleotide polymorphisms associated with CAD in genome-wide association studies were genotyped in TEHS. Association with VTE was assessed by logistic regression (Bonferroni-corrected p-values). A strong association was found between
rs579459
in the
ABO
locus and VTE risk (p=3.8×10
13
). Adjustment for known VTE-associated variants within the
ABO
,
F5
,
F2
,
F11
and
FGG
loci, along with age and body-mass index, identified a further suggestive association for rs1333049 in the
ANRIL
locus (p=0.003). However, replication analysis in 3 French cohorts (total n=5503) failed to confirm the
ANRIL
association with VTE, but indicated that the effect direction is consistent across cohorts. Furthermore, marked variation was found in minor allele and minor allele frequency of the
ANRIL
variant in a survey of studies conducted across Europe.

Conclusions

CAD-associated genetic variants in the
ABO
and
ANRIL
loci appear to influence risk of VTE. Differences in cohort characteristics, including allele frequencies, may account for the failure to replicate the association with rs1333049 in the French cohorts.
Abstract 62: The Effect of ETC-1002 on Low Density Lipoprotein-Cholesterol and Additional Risk Factors in Patients With Type 2 Diabetes
Authors: Rosenberg Noah , MacDougall Diane , Hanselman Jeffrey C , McBride Scott , Strange Poul , Gutierrez Maria , Margulies Janice , Newton Roger 
Published: March 2022

Background
Patients with type 2 diabetes (T2DM) are at high risk for cardiovascular (CV) disease and over half do not achieve LDL-C goal. Statins lower CV risk by reducing LDL-C and inflammation, but have been associated with worsening glycemic control and new onset diabetes, resulting in class label warnings for all statins. ETC-1002 is an oral investigational drug in Phase 2 development to treat dyslipidemia and other cardio-metabolic risk factors through dual adenosine monophosphate-activated protein kinase activation and adenosine triphosphate-citrate lyase inhibition.

Methods
Sixty T2DM patients received either ETC-1002 (80 mg for 2 weeks followed by 120 mg for 2 weeks) or placebo (PBO) for 4 weeks following a 4 week T2DM drug washout and 1 week PBO run-in.

Results

ETC-1002 lowered LDL-C by 43% (PBO corrected mean -39%; p<.0001) and non-HDL-C by 32% (PBO corrected mean -31%; p<.0001). Median reductions in high sensitivity C-reactive protein (hsCRP) were 41% and 11% for ETC-1002 and PBO (p=.0011). Post hoc analyses showed additional benefits of ETC-1002. An LDL-C goal of <100 mg/dL was achieved by 88% of ETC-1002 (21/24) and 4% of PBO subjects (1/24) not at baseline goal (p<.0001 versus PBO). Reductions in post-prandial hyperglycemia following standard meal challenge were observed which were significant in a subgroup of patients with BMI ≥ 30 kg/m
2
(p=.0246 versus placebo). Using continuous glucose monitoring, ETC-1002 treatment resulted in significant peak glycemic reduction between hours 6-12 and a trend between hours 12-18 and 18-24. A weight loss trend was observed with ETC-1002. In patients with 24 hour diastolic ambulatory blood pressure (DBP) > 80 mmHg, a 7 mmHg reduction versus PBO was observed (p=.0474). ETC-1002 was safe and well tolerated with no drop-outs, dose limiting side effects or serious adverse events, and no liver function tests >2 times upper limit normal.

Conclusion
In patients with T2DM and dyslipidemia, ETC-1002 produced statin-like reduction in LDL-C, robust reduction in hsCRP and was associated with modest to significant improvement of blood pressure, glucose control and weight loss. The novel mechanism of action of ETC-1002 may provide unique benefit to these patients.
Abstract 80: Loss of Id3 in B Cells Leads to Increased Adipose Tissue T15-IgM and Protects Against Diet-Induced Glucose Intolerance
Authors: Harmon Daniel B , Oldham Stephanie N , McNamara Coleen A 
Published: March 2022

Background
B1 B cells [[Unable to Display Character: &#8211;]] the major producers of anti-inflammatory natural T15-IgM antibodies that promote tissue homeostasis [[Unable to Display Character: &#8211;]] have been identified in adipose tissue, but their role in adipose tissue response to high-fat diet (HFD)-induced obesity is unclear. Our group and others have shown that the helix-loop-helix protein Id3 is a key regulator of B cell function in disease; mice null for Id3 have increased IgM levels and are protected from HFD-induced obesity. In this study, we test the hypothesis that B cell-specific Id3 deletion protects against the consequences of HFD-induced obesity through increased local production of natural IgM antibodies.

Methods and Results

C57Bl/6 floxed Id3 (Id3fl/fl) and CD19cre/+ mice were crossed to create an Id3fl/fl CD19cre/+ mouse. While these mice had similar body and adipose depot mass as littermate controls after 12 weeks of HFD, they had significantly improved glucose clearance (2hr blood glucose: 314 ± 33 vs. 420 ± 38 mg/dl; n=7-11; p<0.05). At baseline, these mice were found to have significantly more B1b B cell than controls in the peritoneal fluid (3.2E5 ± 0.4E5 vs. 0.9E5 ± 0.4E5 cells; n=5-8; p<0.01), epididymal adipose tissue (4072 ± 923 vs. 1149 ± 652 cells/g fat; n=5-8; p<0.05), and omental adipose tissue. There were no differences in B1a or B2 cells in any compartment, and the mice had similar T cell and macrophage numbers in epididymal adipose tissue. ELISA analysis on whole epididymal adipose tissue revealed significantly higher levels of both total IgM (0.64 ± 0.06 vs. 0.24 ± 0.01 ng/ug protein; n=3-7; p<0.001) and T15-IgM (7.6 ± 1.5 vs. 2.8 ± 0.4 U/ng protein; n=3-7; p<0.05) in mice null for Id3 in B cells compared to controls. No differences were observed in the serum. In addition, omental fat from Id3fl/fl CD19cre/+ mice cultured
ex vivo
secreted significantly more T15-IgM than omental fat from littermate controls (40.0 ± 5.9 vs. 17.5 ± 4.2 U/mg fat; n=3-4; p<0.01).

Conclusions
Loss of Id3 expression in B cells leads to elevated B1b B cells and increased local T15-IgM production in omental adipose tissue, along with improved glucose tolerance in mice fed a HFD, suggesting that T15-IgM may protect against the metabolic dysfunction caused by obesity.
Abstract 113: Screening of MicroRNAs Expressed in Isolated Cells of Human Abdominal Aortic Aneurysm for the Identification of Potential Biomarkers
Authors: Rafaelle Spear , Boytard Ludovic , Blervaque Renaud , Hot David , Vanhoutte Jonathan , Staels Bart , Chwastyniak Maggy , Amouyel Philippe , Haulon Stephan , Pinet Florence 
Published: March 2022

Abdominal aortic aneurysm (AAA) is a vascular asymptomatic disease that is one of the leading causes of death in developed countries. Identifying biomarkers for AAA that can be detected easily in blood, before rupture could be useful.
The aim of this study was to investigate the potentiality of miRNAS as biomarkers of AAA by performing a profiling of miRNAs expressed in major cells present in the human AAA tissue.
The inflammatory cells as macrophages M1 and M2 and smooth muscle cells (SMC) were located by immunohistochemistry in 20 human AAA biopsies, showing a specific distribution towards the aneurysmal aortic wall. The cells were isolated by laser microdissection (LMD) from 20 human AAA biopsies obtained during surgical repair and control SMC from 14 healthy aortic biopsies harvested during organs multiretrieval. RNA extracted from 2 samples of each LMD isolated cells was screened on human miRNAs microarray. MiRNAs were selected with at least a 2-fold change and a detection value threshold corresponding to the value of miR-29b, described in experimental AAA models.
Out of the 850 human miRNAs tested for each sample, 408 were found to be present in AAA. Thirty miRNAs were common to each tested cells. Fifty-three miRNAs were found in SMC, of which 12 were specific to AAA compared to control aortas; 86 miRNAs were found in macrophages, of which 11 were specific to M1 macrophages, 37 to M2 macrophages and 38 common to both subtypes. Ten miRNAs were selected to be validated by quantitative RT-PCR in LMD isolated healthy SMC and aneurysmal SMC, M1 and M2 macrophages. We validated 4 miRNAs to be overexpressed in M1 macrophages and 1 overexpressed in M2 macrophages. Two miRs were validated to be less expressed in aneurysmal SMC compared to SMC from normal aortas. MiR-29b expression was specifically down-regulated in aneurysaml SMC compared to normal SMC.
In conclusion, the analysis of isolated cells allows to discriminate the miRNAs specifically expressed in inflammatory and vascular cells in AAA and to determine other miRNAs than those described in experimental AAA models as potential biomarkers of AAA.
Abstract 212: Genetically Modified Mesenchymal Stem Cells Help Reduce Inflammation and Glucose-Mediated Insulin Response in Obese Diabetic Mouse Models
Authors: Sen Sabyasachi , Yadava Nagendra 
Published: March 2022

MSCs are multipotent cells that differentiate into fat, muscle, bone and cartilage. High Glucose (HG) exposure of bone marrow derived MSCs leads to: increased ROS accumulation both in cytosol and mitochondria ( analysed by FACS using Mitosox Red dye) and increased intra-cellular lipid droplet accumulation. We hypothesized that intra-cellular antioxidant up-regulation specifically mitochondrial (super-oxide dismutase-2), may help reduce superoxide accumulation in mitochondria which will subsequently help reduce fat droplet accumulation and associated cellular inflammation.
We exposed hMSCs to HG (25mM) and normal glucose (NG, 5.5 mM) and interrogated mitochondrial superoxide accumulation and cellular oxygen consumption rate (OCR using Seahorse) and interrogated response to mitochondrial complex I-IV 4 substrate addition. We used AdSOD2 to up-regulate SOD2 prior to HG exposure. HG exposure increased TNF α (Tumor Necrosis Factor, 4 fold) and IL6 (interleukin6, 6-fold) mRNA and increased lipid accumulation (2.5 fold) and led to impaired OCR on SeaHorse and impaired Mitochondrial Complex 1.
With prior SOD2 upregulation in MSCs, TNF α and IL6 mRNA expression was reduced in HG and improved Complex-1 function.
Next we delivered the SOD2 upregulated MSC intra-peritoneally to obese diabetic (db/db) mice. We confirmed homing-in of eGFP labeled MSC, delivered IP, to different fat pockets. The mice that received MSC-SOD2 (experimental) showed reduced adipocyte and systemic inflammation (IL6 and TNF alpha levels) compared the mice that received MSC-Null (control). Interestingly the experimental group showed consistent reduction in fat mass (Echo-MRI), local adipocyte inflammation, systemic inflammation in serum and marked improvement in glucose tolerance tests (GTT).
We conclude that local delivery of mitochondrial superoxide dismutase using stem cells as a gene delivery vehicle reduces inflammation and glucose tolerance tests in vivo. We plan to carry out further glucose clamp studies to consolidate our findings. In conclusion local rather than systemic up-regulation of a mitochondrial anti-oxidant helps in reducing local and systemic inflammation, total fat mass and improves glucose mediated insulin response in obese diabetic mouse models.
Abstract 229: Development of a Conditional Knockout of Cholesterol Synthesis in the Mouse
Authors: Weerasekera Ranjuna , McKenzie Alison , Emmer Joseph , Cai Yanhong , Patel Kriya , Tyshynsky Roman , Patel Shailendra B 
Published: March 2022

Dhcr24 (3β-hydroxysteroid-Δ24 reductase) is responsible for reducing the C24-C25 double bond in sterol intermediates of cholesterol and this step is necessary to synthesize cholesterol. In humans, mutations in the Dhcr24 gene cause desmosterolosis (OMIM #602398), characterized by severe developmental abnormalities and elevated levels of desmosterol in plasma and tissue. The first case was reported in 1998 when a premature infant died shortly after birth, had elevated levels of desmosterol and phenotypic abnormalities. Although initially reported as a ‘cholesterol-free mouse’ in Science, the global Dhcr24 knockout mouse shows neonatal lethality within 10h of birth, a finding reproduced in many different laboratories, despite sharing the original knockout mouse.
We now report a conditional knockout model using the LoxP-cre deletion system and show proof-of-principle by studying effects Dhcr24 deletion in the liver.