bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 127: Induction of miR-21 Increases Fibrous Cap Stability in Vulnerable Atherosclerotic Lesions
Authors: Jin Hong , Li Yuhuang , Bäcklund Alexandra , Busch Albert , Eken Suzanne M , Chernogubova Ekaterina , Gustafsson Peter , Perisic Ljubica , Schellinger Isabel , Raaz Uwe , Tsao Philip S , Hansson Göran K , Paulsson- Berne Gabrielle , Hedin Ulf , Maegdefessel Lars 
Published: June 2021

The aim of the present study was to explore the role of miRNAs as potential regulators in patients with carotid artery stenosis and concordant vulnerable atherosclerotic plaques.
A pre-determined miRNA-array of laser captured micro-dissected (LCM) tissue specimen from fibrous caps of 10 symptomatic patients (stroke or TIA within > 14 days and histo-morphologically identified ruptured lesion) compared to fibrous caps from 10 asymptomatic patients (stable lesions; high grade stenosis) discovered miR-21 as one of the two miRNAs (miRs-21 and -210) being substantially down-regulated in symptomatic patients.

To functionally evaluate the contribution of miR-21 to plaque vulnerability, we created

miR21
-/-

/

ApoE
-/-

mice on a C57BL/6 background. We explored the phenotype of these newly developed

miR21
-/-
/ApoE
-/-

mice in experimental models of vascular remodelling and plaque vulnerability. First,

miR21
-/-

mice revealed a complete lack of SMC proliferation in response to carotid ligation injury. In the second inducible plaque rupture model, using incomplete ligation of the common carotid artery with consecutive cuff placement proximal to the ligated region indicated that all

miR21
-/-
/ApoE
-/-

mice (
n
=10) presented atherothombotic events and signs of severe plaque instability. The rupture rate in control

miR21
+/+
/ApoE
-/-

mice was significantly lower at 56% (
n
=9). In addition,

miR21
-/-
/ApoE
-/-

showed an increase in lesion area in the aortic root and substantially higher levels of macrophage infiltration in injured carotid arteries. Dynamic live cell imaging, using isolated aortic SMCs and peritoneal macrophages from

miR21
-/-
/ApoE
-/-

vs.

miR2
+/+
/ApoE
-/-

mice displayed substantial lower cellular proliferation and survival rates (for SMCs), and distinct advanced inflammatory activity upon oxidized LDL (oxLDL) stimulation of macrophages.

In the present study we identified miR-21 as a key modulator of pathologic processes in atherosclerosis-related vascular remodelling. Targeted, lesion-site specific overexpression of miR-21 could be a novel and powerful future strategy to stabilize vulnerable plaques by inducing pro-proliferative mechanisms in SMC-enriched fibrous caps.
Abstract 135: Endothelial Dysfunction in Acute Graft-versus-host Disease After Allogeneic Hematopoietic Cell Transplantation.
In vitro
Evidence of the Protective Effect of Defibrotide
Authors: Mir Enrique , Palomo Marta , Carreras Enric , Diaz-Ricart Maribel , Rovira Montse , Escolar Ginés 
Published: June 2021

Acute Graft-Versus-Host Disease (aGVHD) is the most common early complication after allogeneic Hematopoietic Cell Transplantation (allo-HCT). We demonstrated endothelial dysfunction (ED) in association with allo-HCT. According to this data, aGVHD has been linked to an inflammatory process that may affect the endothelium.
To investigate the differential degree of endothelial damage in patients developing or not aGVHD, to identify potential biomarkers, and to explore the protective effect of defibrotide (DF) in this scenario. DF has orphan designation for GVHD prevention.

Patients blood samples were collected before allo-HCT, at day 0, and every week till day 28 after HCT. Plasma proteins (sTNFR1, sVCAM-1, VWF and ADAMTS-13) were measured as biomarkers of ED in individual samples from patients developing (GVHD, n=24), or not (NoGVHD, n=13), aGVHD. In
in vitro
assays, endothelial cells (EC) in culture were exposed to media containing pooled sera from patients to evaluate changes in the: a) expression of VCAM-1 and ICAM-1 on cell surfaces; b) presence of VWF on the extracellular matrix (ECM) and c) reactivity of the ECM towards platelets, under flow. The effect of DF was explored in the
in vitro
experiments by previous exposure of the EC (for 24h) followed by continuous incubation (100 μg/ml, added every 24h).

Levels of sTNFRI, sVCAM-1 and VWF in samples from group GVHD were significantly higher than in NoGVHD (increases of 100, 37 and 150% respectively, at diagnose, p<0.01). ADAMTS-13 activity and VWF levels were inversely related. In
in vitro
studies, cell surface expression of VCAM-1 and ICAM-1, presence of VWF and platelet adhesion on the ECM in response to GVHD samples were always superior (increases
vs
NoGVHD of 80, 40, 100 and 21%, respectively, at diagnose).
In vitro
exposure of EC to DF attenuated signs of endothelial injury reducing significantly (p<0.05) the expression of VCAM-1, ICAM-1 and VWF (reductions of 22, 30 and 30%, respectively) in the GVHD condition.

Our results demonstrate endothelial damage in association with aGVHD, as evidenced by elevated plasma levels of several biomarkers. The
in vitro
approach showed a marked proinflammatory and prothrombotic phenotype in association with aGVHD, which could be significantly prevented by defibrotide.
Abstract 30: ApoE and ApoCIII Interact to Modulate the Metabolism of HDL ApoA-I in Humans
Authors: Morton Allyson , Mendivil Carlos O , Wang Liyun , Furtado Jeremy D , Sacks Frank M 
Published: June 2021

ApoE has potential roles in HDL metabolism by promoting enlargement and clearance, and apoCIII could delay apoE-mediated clearance by the liver as it does for VLDL metabolism. To determine whether apoE and apoCIII modulate the kinetics of apoA-I HDL, we compared the metabolism of apoA-I in HDL subspecies that have apoE, apoCIII, both, or neither. We recruited 10 participants (4M, 6F) with low HDL-C (range 24-54 mg/dl) and BMI between 25-35 kg/m
2
. They were given an IV bolus of d3-leucine and blood collected up to 46hr. HDL was isolated from plasma by anti-apoA-I immunoaffinity chromatography, separated by sequential anti-apoE and anti-apoCIII chromatography, and size-separated using NDPAGE into alpha-1, alpha-2, alpha-3, and prebeta-1 HDL. ApoA-I was purified from HDL subspecies on SDS-PAGE, and pool size of apoA-I was determined from the protein bands, adjusted to plasma total apoA-I. D3-leucine enrichment was measured by GC-MS. We used SAAM-II modeling software to compute apoA-I fractional catabolic rates (FCR) and fluxes for each HDL subspecies using a published multicompartmental model. The main findings from our preliminary model investigation are:

- The liver secretes a range of HDL sizes for each of these HDL subspecies. About 2-6% of plasma HDL apoA-I is associated with apoE and/or apoCIII. Regardless of size, apoE- and apoCIII-containing HDL are detectable in the circulation slightly earlier after tracer administration than HDL containing neither apoE nor apoCIII.
- HDL that contains apoE but not apoCIII is especially active in size conversions, such as generating prebeta-1 HDL. Prebeta-1 HDL types are not a universal precursor of larger size HDL.
- HDL that contains apoE but not apoCIII has about a 4-fold increased FCR (range 1.3-8.8) across all sizes of HDL compared to other HDL subspecies, consistent with the role of apoE as a liver receptor ligand. When coexisting with apoE, apoCIII abolished the apoE-accelerated clearance, making the FCR similar to that of HDL that does not have apoE. But, when apoCIII is present on HDL that does not have apoE, there is no reduction in clearance compared to HDL containing neither apolipoprotein.
In conclusion, these results suggest that apoE accelerates the metabolism of HDL apoA-I, whereas apoCIII impedes this process.
Abstract 312: Macrophage Metabolic Adaptation to Heme
Authors: Bories Gaël F 
Published: June 2021

Free heme is a very deleterious compound that promotes oxidation, inflammation and cell death, which contributes to numerous vascular pathologies including stroke, thrombosis and atherosclerosis. Rupture of red blood cells (RBC), also known as hemolysis, leads to the release of hemoglobin, which upon oxidation, readily releases free heme into the circulation. Due to their ability to clear heme and fight against heme-induced oxidative damage, macrophages limit tissue damage induced by hemolysis. Inside macrophages, heme is degraded by the inducible heme oxygenase 1 (Hmox-1), producing carbon monoxide (CO), iron and biliverdin. Macrophages respond to changes in their environment; they require a constant metabolic adaptation to sustain the bio-energetic demand. The pentose phosphate pathway (PPP) is the major source of NADPH, which is generated by glucose-6-phosphate dehydrogenase (G6PD) and phospho-gluconate dehydrogenase (PGD). NADPH provides reducing equivalents for numerous, Nrf2 (nuclear factor erythroid 2)-dependent anti-oxidant systems such as glutathione reductase and Hmox-1 itself. Here we show that intracellular free heme induces a specific metabolism in macrophages, characterized by increased glucose uptake, with no change in glycolysis, but a polarization towards the PPP. Pharmacologic inhibition of the PPP demonstrated that this metabolic shift is essential for macrophages to degrade heme efficiently. We also show that the metabolic adaptation to heme is dependent on Hmox activity, involving the upregulation of the glucose transporter (GLUT) 1, G6PD, and PGD. This suggests that CO is involved in the macrophage metabolic adaptation to heme. Finally we show that the PPP is increased in the liver of sickle-cell disease (SCD) mice, an accepted model of chronic intra-vascular hemolysis.
This study provides a new understanding of macrophage metabolic adaptation to efficient heme clearance, opening the field for novel therapies for hemolysis-associated diseases.
Abstract 356: IFN-γ-Dependent TET2 Repression in Coronary Allograft Vasculopathy
Authors: Ostriker Allison , Leslie Kristen , Martin Kathleen 
Published: June 2021

Coronary allograft vasculopathy (CAV) occurs in 50% of heart transplant recipients at 10 years after surgery. Allograft failure secondary to CAV accounts for 30% of deaths in transplant recipients. CAV is characterized by concentric neointimal hyperplasia (NIH) in the graft vasculature results in ischemic injury. T cell-derived INF-γ is a well-established driver of NIH in CAV. The molecular mechanisms engaged by IFN-γ in vascular smooth muscle cells (VSMCs) in CAV are not fully elucidated.
Our group recently showed that TET methylcytosine dioxygenase 2 is a regulator of VSMC phenotype. We hypothesized, therefore, that IFN-γ modulates TET2 expression and/or function in VSMCs. We found, using a single minor histocompatibility mismatch aorta interposition graft model of CAV, that TET2 expression was decreased in vivo in the graft neointima as compared to in control tissue. Further, we found that IFN-y was sufficient to repress TET2 gene transcription in human VSMC in vitro, and this repression was not reversed by mTOR inhibition. We then sought to determine if repression of TET2 is sufficient to exacerbate neointimal hyperplasia in the aorta graft model. We found that NIH was exacerbated in aorta grafts from VSMC-specific, inducible, TET2 knockout (iKO) donors versus controls. Neither T cell recruitment, nor STAT1 activation, was increased in the iKO grafts versus controls; while time course analysis showed that neointimal cells were primarily recipient-derived, suggesting a non-cell autonomous mechanism. Western blot analysis of VSMCs stimulated with IFN-γ for 0-120 minutes suggested that, in addition to STAT1 activation, IFN-γ decreases β-catenin signaling. ChIP-PCR studies showed that STAT1, but not LEF1 (a β-catenin coactivator), occupancy increased at the TET2 promotor following INF-γ stimulation.
Studies are ongoing to further elucidate the requirement for STAT1 and/or β-catenin in IFN-γ-dependent repression of TET2 in VSMCs and the non-autonomous role of TET2 on mediating NIH progression in CAV. Since IFN-y-dependent repression of TET2 is not reversed by rapamycin, elucidating this pathway represents an opportunity for developing complementary therapies to mTOR inhibition that may result in improved outcomes and fewer side effects.
Abstract 357: Antioxidant and Anti-inflammatory Strategies Prevent Endothelial Dysfunction in Chronic Kidney Disease
Authors: Palomo Marta , Martin-Rodriguez Susana , Vera Manel , Cruzado Josep Maria , Rivera Jose , Cases Aleix , Escolar Ginés , Diaz-Ricart Maribel 
Published: June 2021

Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by the development of endothelial dysfunction (ED), with development of a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. The effect of anti-inflammatory and antioxidant strategies on the endothelium has been evaluated in an
in vitro
model of ED in uremia.

Endothelial cells (ECs) were pretreated with the antioxidant enzyme mimetics ebselen, EUK-134 and EUK-118; the flavonoids apigenin, genistein and quercetin, with both antioxidant and anti-inflammatory potential; and two commercially available compounds: N-acetylcysteine (NAC) and defibrotide (DF). There is increasing evidence demonstrating that both NAC and DF exhibit both properties. ECs were exposed to medium containing serum from patients on dialysis (n=10) or from healthy donors (n=15). Changes in the expression of the adhesion receptor ICAM-1 and the production of intracellular reactive oxygen species (ROS) were assessed. Activation of inflammation-related proteins p38 MAPK and NFkappaB (NFκB) were also evaluated.
Exposure of ECs to uremic media resulted in a significantly increased expression of ICAM-1, overproduction of ROS and activation of p38MAPK and NFκB compared to control ECs (p<0.05). Ebselen, EUK 134, and EUK118 inhibited ICAM-1 expression and ROS generation in the uremic condition (p<0.01). Regarding flavonoids, only quercetin showed a moderated but significant inhibitory effect on both parameters (p<0.05). NAC and DF exhibited a protective effect on ECs exposed to the uremic insult (p<0.05 for ICAM-1 expression and ROS generation). All the compounds reduced p38MAPK activation (p<0.05). The antioxidant-enzyme mimetics and NAC were able to inhibit the activation of NFκB induced by the uremic media (p<0.05).
Endothelial dysfunction associated with CKD is considered to be the first step in the progression of atherosclerosis. Our results indicate that the antioxidant enzyme mimetics, NAC and DF exhibit not only antioxidant but also anti-inflammatory effects on the endothelium. Therefore, further research on the protective effects of these compounds may provide new strategies for the prevention of the cardiovascular complications in uremia.
Monotherapy Anticoagulation to Expedite Home Treatment of Patients Diagnosed With Venous Thromboembolism in the Emergency Department: A Pragmatic Effectiveness Trial
Authors: Kline Jeffrey A. , Adler David H. , Alanis Naomi , Bledsoe Joseph R. , Courtney Daniel M. , d’Etienne James P. , Diercks Deborah B. , Garrett John S. , Jones Alan E. , Mackenzie David C. , Madsen Troy , Matuskowitz Andrew J. , Mumma Bryn E. , Nordenholz Kristen E. , Pagenhardt Justine , Runyon Michael S. , Stubblefield William B. , Willoughby Christopher B. 
Published: June 2021

Background:
The objective was to test if low-risk emergency department patients with vitamin K antagonist (venous thromboembolism [VTE]; including venous thrombosis and pulmonary embolism [PE]) can be safely and effectively treated at home with direct acting oral (monotherapy) anticoagulation in a large-scale, real-world pragmatic effectiveness trial.

Methods:
This was a single-arm trial, conducted from 2016 to 2019 in accordance with the Standards for Reporting Implementation Studies guideline in 33 emergency departments in the United States. Participants had newly diagnosed VTE with low risk of death based upon either the modified Hestia criteria, or physician judgment plus the simplified PE severity index score of zero, together with nonhigh bleeding risk were eligible. Patients had to be discharged within 24 hours of triage and treated with either apixaban or rivaroxaban. Effectiveness was defined by the primary efficacy and safety outcomes, image-proven recurrent VTE and bleeding requiring hospitalization >24 hours, respectively, with an upper limit of the 95% CI for the 30-day frequency of VTE recurrence below 2.0% for both outcomes.

Results:
We enrolled 1421 patients with complete outcomes data, including 903 with venous thrombosis and 518 with PE. The recurrent VTE requiring hospitalization occurred in 14/1421 (1.0% [95% CI, 0.5%–1.7%]), and bleeding requiring hospitalization occurred in 12/1421 (0.8% [0.4%–1.5%). The rate of severe bleeding using International Society for Thrombosis and Haemostasis criteria was 2/1421 (0.1% [0%–0.5%]). No patient died, and serious adverse events occurred in 2.5% of venous thrombosis patients and 2.3% of patients with PE. Medication nonadherence was reported by patients in 8.0% (6.6%–9.5%) and was associated with a risk ratio of 6.0 (2.3–15.2) for VTE recurrence. Among all patients diagnosed with VTE in the emergency department during the period of study, 18% of venous thrombosis patients and 10% of patients with PE were enrolled.

Conclusions:
Monotherapy treatment of low-risk patients with venous thrombosis or PE in the emergency department setting produced a low rate of bleeding and VTE recurrence, but may be underused. Patients with venous thrombosis and PE should undergo risk-stratification before home treatment. Improved patient adherence may reduce rate of recurrent VTE.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03404635
The relationship between bite force, morphology, and diet in southern African agamids
Authors: Tan W. C. , Measey J. , Vanhooydonck B. , Herrel A. 
Published: June 2021

AbstractBackgroundMany animals display morphological and behavioural adaptations to the habitats in which they live and the resources they exploit. Bite force is an important whole-organism performance trait that allows an increase in dietary breadth, the inclusion of novel prey in the diet, territory and predatory defence, and is important during mating in many lizards.MethodsHere, we study six species of southern African agamid lizards from three habitat types (ground-dwelling, rock-dwelling, and arboreal) to investigate whether habitat use constrains head morphology and bite performance. We further tested whether bite force and head morphology evolve as adaptations to diet by analysing a subset of these species for which diet data were available.ResultsOverall, both jaw length and its out-lever are excellent predictors of bite performance across all six species. Rock-dwelling species have a flatter head relative to their size than other species, possibly as an adaptation for crevice use. However, even when correcting for jaw length and jaw out-lever length, rock-dwelling species bite harder than ground-dwelling species. Diet analyses demonstrate that body and head size are not directly related to diet, although greater in-levers for jaw closing (positively related to bite force) are associated to an increase of hard prey in the diet. Ground-dwelling species consume more ants than other species.ConclusionsOur results illustrate the role of head morphology in driving bite force and demonstrate how habitat use impacts head morphology but not bite force in these agamids. Although diet is associated with variation in head morphology it is only partially responsible for the observed differences in morphology and performance.
Place4Carers: a multi-method participatory study to co-design, piloting, and transferring a novel psycho-social service for engaging family caregivers in remote rural settings
Authors: Graffigna Guendalina , Gheduzzi Eleonora , Morelli Niccolò , Barello Serena , Corbo Massimo , Ginex Valeria , Ferrari Roberta , Lascioli Andrea , Feriti Carolina , Masella Cristina 
Published: June 2021

AbstractBackgroundFamily caregivers are key actors in the ageing society. They are mediators between practitioners and patients and usually provide also essential daily services for the elders. However, till now, few services have been deployed to help caregivers in their care tasks as in improving their mental health which can experience sever burden due to caregiving duties. The purpose of the study is to implement a community-based participatory research project to co-design an innovative organizational model of social services for family caregivers of elderly health consumers living in remote rural areas in Italy.MethodsThis is a community-based participatory research project in the remote area of Vallecamonica involving four main phases. These included a quantitative analysis of caregiver needs, a scoping review on existing services for caregivers, co-design workshops with local stakeholders and caregivers to create a novel service the piloting and a first implementation of the service and the assessment of project transferability to other contexts.ResultsAs the hours dedicated to elder care increases, both objective and developmental caregiver’s burden significantly increases. Conversely, higher levels of engagement were associated with lower physical and emotional burden, and caregiver engagement was positively correlated with their perceived self-efficacy in managing disruptive patient behaviours. Based on these preliminary results, four co-design workshops with caregivers were conducted and led to the definition of the SOS caregivers service, built on four pillars structured upon the previous need analysis: a citizens’ management board, training courses, peer-to-peer meetings, and project and service information. We found that co-design is an effective means of creating new services for family caregivers, whose experiential knowledge proved to be a key resource for the project team in delivering and managing services. Less positively, the transferability analysis indicated that local municipalities remain reluctant to acknowledge caregivers’ pivotal role.ConclusionsA dedicated support service for caregivers can ameliorate caregiving conditions and engagement levels. The service has resulted a successful co-productive initiative for a psycho-social intervention for family caregivers. For the future, we suggest that family caregiver should be considered an active partner in the process of designing novel psycho-social services and not just as recipients to enhance a better aging-in-place process.
Healthcare-induced trauma in correctional facilities: a qualitative exploration
Authors: Elumn Johanna E. , Keating Layne , Smoyer Amy B. , Wang Emily A. 
Published: June 2021

Abstract
Background
While incarcerated people are known to experience trauma at higher rates than the general population, little is known about how the correctional health system contributes to trauma rates.

Methods
We conducted 20 semi-structured qualitative interviews with men who were recently released from a correctional system to understand their experiences with healthcare systems and medical staff during incarceration. Using reflexive thematic analysis within a critical realist framework, we coded and analyzed the data iteratively to refine and unify emerging themes.

Results
The unanticipated concept of healthcare-induced trauma emerged and was revealed in three overall themes: (1) healthcare leading to fear of serious illness or death, (2) healthcare leading to fear of people, including healthcare providers, correctional staff, and other incarcerated people, and (3) the correctional institutional, social, and physical environment leads to fear of place.

Conclusions
Healthcare in correctional settings has the potential to induce trauma, even when the medical conditions addressed are not life-threatening. Future research should examine the factors contributing to the development of healthcare-induced trauma in correctional settings and develop interventions to prevent and address this phenomenon.