Decreased portal vein attenuation and liver enhancement with reduced intravenous contrast dosage during the national iodinated contrast shortage of 2022.

Objectives: The worldwide shortage of intravenous (IV) Omnipaque iodinated contrast (Iohexol, GE Healthcare; Milwaukee, WI, USA) forced institutions to adopt various policies regarding contrast allocation. We sought to evaluate the impact of our hospital's response to the shortage, which was to decrease the dose of IV contrast from 100 mL to 75 mL for patients weighing between 45.4 and 136 kg (100-300 lbs) undergoing abdominal computed tomography (CT) examinations. The main objective was to assess for any differences in liver attenuation and enhancement between contrast dosages. Secondary outcomes included assessing differences in aortic and portal vein attenuation, the variance in attenuation measurements, and whether radiology reports included the correct IV contrast dose. Material and Methods: Consecutive CT abdomen or CT abdomen and pelvis examinations without and with contrast were analyzed for the 3 months before the contrast shortage and for 3 months during the contrast shortage. Attenuation in Hounsfield units (HUs) was measured in the liver on pre-contrast and portal venous phase images. Vessel attenuation was measured in the aorta (arterial phase) and main portal vein (portal venous phase). Standard deviation of liver attenuation measurements was recorded as an indicator of signal-to-noise. Liver enhancement was calculated as the difference between liver portal venous phase attenuation and pre-contrast attenuations. Results: Thirty-nine fixed dose (100 mL) and 36 reduced dose (75 mL) consecutive CT studies were included in the study. There were no significant differences between the two groups with respect to baseline characteristics such as age, weight, body mass index, and gender. There was no significant difference in pre-contrast liver attenuation between groups, but there was statistically significant greater liver attenuation (99.6 vs. 91.2 HU, P = 0.04) and liver enhancement (51.5 vs. 39.1 HU, P < 0.0001) during the portal venous phase for the fixed-dose group compared to the reduced dose group. There was significantly greater main portal vein opacification during the portal venous phase for the fixed dose group (146.6 vs. 122.2 HU, P < 0.0001). No significant difference was found in aortic opacification during the arterial phase (245 vs. 254 HU, P = 0.52). There was no difference in the standard deviation of liver attenuation measurements on the portal venous phase between the groups. The dose was reported correctly in all the patients receiving the fixed dose and in 92% of patients receiving the reduced dose, which was not statistically significant (P = 0.11). Conclusion: Reducing the IV contrast dose from 100 mL to 75 mL Omnipaque 350 in patients weighing 45.4-136 kg (100-300 lbs) undergoing an abdominal CT examination resulted in significantly decreased portal vein opacification and liver enhancement. In particular, liver enhancement and calculated iodine concentrations fell below suggested thresholds for adequate conspicuity of liver lesions. The change in contrast administration protocol also led to more errors in contrast dose reporting in the radiologist's report. These findings are broadly applicable to many practice settings and can help inform strategies in response to any potential future-iodinated contrast shortage.

Cereblon influences the timing of muscle differentiation in Ciona tadpoles.

Thalidomide has a dark history as a teratogen, but in recent years, its derivates have been shown to function as potent chemotherapeutic agents. These drugs bind cereblon (CRBN), the substrate receptor of an E3 ubiquitin ligase complex, and modify its degradation targets. Despite these insights, remarkably little is known about the normal function of cereblon in development. Here, we employ Ciona, a simple invertebrate chordate, to identify endogenous Crbn targets. In Ciona, Crbn is specifically expressed in developing muscles during tail elongation before they acquire contractile activity. Crbn expression is activated by Mrf, the ortholog of MYOD1, a transcription factor important for muscle differentiation. CRISPR/Cas9-mediated mutations of Crbn lead to precocious onset of muscle contractions. By contrast, overexpression of Crbn delays contractions and is associated with decreased expression of contractile protein genes such as troponin. This reduction is possibly due to reduced Mrf protein levels without altering Mrf mRNA levels. Our findings suggest that Mrf and Crbn form a negative feedback loop to control the precision of muscle differentiation during tail elongation.

SARS-CoV-2 infections in patients enrolled on the Children's Oncology Group standard-risk B-cell acute lymphoblastic leukemia trial, AALL1731.

Hematologic malignancy is a risk factor for severe coronavirus disease 2019 (COVID-19) in adults; however, data specific to children with leukemia are limited. High-quality infectious adverse event data from the ongoing Children's Oncology Group (COG) standard-risk B acute lymphoblastic leukemia/lymphoma (ALL/LLy) trial, AALL1731, were analyzed to provide a disease-specific estimate of SARS-CoV-2 infection outcomes in pediatric ALL. Of 253 patients with reported infections, the majority (77.1%) were asymptomatic or mildly symptomatic (CTCAE grade 1/2) and there was a single COVID-19-related death. These data suggest SARS-CoV-2 infection does not confer substantial morbidity among young patients with B-lymphoblastic leukemia/lymphoma (B-ALL/LLy).

Incidental detection of benign metastasizing leiomyoma in asymptomatic female.

Benign metastasizing leiomyoma (BML) is a rare finding of histologically benign smooth muscle tumors in extrauterine locations, most commonly the lungs. We report a case of BML found incidentally on pre-operative imaging in a 42-year-old patient. BML is found in premenopausal women with a history of leiomyoma and, often, hysterectomy. As in our case, the metastatic pulmonary nodules are not hypermetabolic on 18F-fluorodeoxyglucose Positron emission tomography/computed tomography. BML may be clinically malignant or asymptomatic. Since the imaging appearance of BML simulates metastatic disease of more malignant etiology, awareness of its multimodality imaging appearance and presentation can aid in diagnosis.

A meta-analytic review of impact of measurement choice on RCTs to reduce appearance internalization.

OBJECTIVE: Prior reviews have shown that interventions targeting internalization of appearance standards are generally efficacious, though there is considerable heterogeneity in estimates across studies. This updated review of the literature evaluates whether efficacy estimates from RCTs systematically vary as a function of three related outcome measures (internalization, awareness, and perceived pressure regarding appearance standards). METHODS: Seven electronic databases were systematically searched from inception to February 8, 2023. The Cochrane Risk of Bias tool assessed each study's risk of bias. Studies included were randomized-controlled trials evaluating body image/eating disorder prevention or intervention programs targeting internalization as a focal point of treatment. Effect sizes were meta-analyzed and meta-regression analyses were conducted investigating the impact of outcome measure choice on study effect size at post-intervention and follow-up. RESULTS: Thirty-seven studies (N = 4809 participants) were included. The meta-analytic findings as expected found interventions efficacious at reducing internalization post-intervention (d = -0.47, 95% CI [-0.60 to -0.34], k = 44), and at follow-up (d = -0.28, 95% CI [-0.39 to -0.17], k = 43), but also highly heterogenous (I2 = 52-67%). Operationalization of internalization moderated results at follow-up but not post-intervention timepoints, with awareness measures (compared with internalization measures) producing weaker effect sizes. Exploratory analyses found bigger effects when internalization was compared with all other measurement categories combined, suggesting possible issues with statistical power in main analyses. DISCUSSION: Mixed present findings suggest need for further evaluation of measurement effects on efficacy, and possible caution in choice of outcome measure for internalization-based interventions. PUBLIC SIGNIFICANCE STATEMENT: This review provides some preliminary evidence that choice of survey measures used in randomized controlled trials can impact our judgments about whether a trial reduces the extent to which participants endorse unrealistic appearance standards. Accuracy in measurement of this efficacy of trials is crucial, given the role that internalized appearance standards play in onset and maintenance of eating disorders.

OBJETIVO: Las revisiones anteriores han demostrado que las intervenciones dirigidas a la internalización de los estándares de apariencia son generalmente eficaces, aunque existe una heterogeneidad considerable en las estimaciones entre los estudios. Esta revisión actualizada de la bibliografía evalúa si las estimaciones de eficacia de los ECA varían sistemáticamente en función de tres medidas de resultado relacionadas (internalización, conciencia y presión percibida con respecto a los estándares de apariencia). MÉTODO: Se realizaron búsquedas sistemáticas en siete bases de datos electrónicas desde su inicio hasta el 8 de febrero de 2023. La herramienta Cochrane Risk of Bias evaluó el riesgo de sesgo de cada estudio. Los estudios incluidos fueron ensayos controlados aleatorios (ECA) que evaluaron la prevención de la imagen corporal/trastornos alimentarios o programas de intervención dirigidos a la internalización como punto focal del tratamiento. Se metanalizaron los tamaños del efecto y se realizaron análisis de metarregresión que investigaron la repercusión de la elección de la medida de resultado sobre el tamaño del efecto del estudio después de la intervención y el seguimiento. RESULTADOS: Se incluyeron treinta y siete estudios (N = 4 809 participantes). Los hallazgos metaanalíticos como era de esperarse encontraron intervenciones eficaces para reducir la internalización después de la intervención (d = -0,47, IC del 95% [-0,60 a -0,34], k = 44) y en el seguimiento (d = -0,28, IC del 95% [-0,39 a -0,17], k = 43), pero también altamente heterogéneas (I2 = 52-67%). La operacionalización de la internalización moderó los resultados en los puntos temporales de seguimiento pero no en posteriores a la intervención, y las medidas de sensibilización (en comparación con las medidas de internalización) produjeron tamaños del efecto más débiles. Los análisis exploratorios encontraron mayores efectos cuando la internalización se comparó con todas las demás categorías de medición combinadas, lo que sugiere posibles problemas con el poder estadístico en los análisis principales. DISCUSIÓN: Los hallazgos actuales mixtos sugieren la necesidad de una evaluación adicional de los efectos de la medición sobre la eficacia, y la posible precaución en la elección de la medida de resultado para las intervenciones basadas en la internalización.

Collaborative team dynamics and scholarly outcomes of multidisciplinary research teams: A mixed-methods approach.

Introduction: Impactful, transdisciplinary scientific discoveries are created by teams of researchers spanning multiple disciplines, but collaboration across disciplines can be challenging. We examined how team dynamics and collaboration are related to successes and barriers faced by teams of researchers from multiple disciplines. Methods: A mixed-methods approach was used to examine 12 research teams granted multidisciplinary pilot awards. Team members were surveyed to assess their team dynamics and individual views about transdisciplinary research. Forty-seven researchers (59.5%) responded, including two to eight members from each funded team. Associations were examined between collaborative dynamics and scholarly product outcomes, including manuscripts, grant proposals, and awarded grants. One member from each team was selected for an in-depth interview to contextualize and extend information about collaborative processes, successes, and barriers to performing transdisciplinary research. Results: Quality of team interactions was positively associated with achievement of scholarly products (r = 0.64, p = 0.02). Satisfaction with team members (r = 0.38) and team collaboration scores (r = 0.43) also demonstrated positive associations with achievement of scholarly products, but these were not statistically significant. Qualitative results support these findings and add further insight into aspects of the collaborative process that were particularly important to foster success on multidisciplinary teams. Beyond scholarly metrics, additional successes from the multidisciplinary teams were identified through the qualitative portion of the study including career development and acceleration for early career researchers. Conclusions: Both the quantitative and qualitative study results indicate that effective collaboration is critical to multidisciplinary research team success. Development and/or promotion of team science-based trainings for researchers would promote these collaborative skills.

Improving infectious adverse event reporting for children and adolescents enrolled in clinical trials for acute lymphoblastic leukemia: A report from the Children's Oncology Group.

Infections cause substantial morbidity for children with acute lymphoblastic leukemia (ALL). Therefore, accurate characterization of infectious adverse events (AEs) reported on clinical trials is imperative to defining, comparing, and managing safety and toxicity. Here, we describe key processes implemented to improve reporting of infectious AEs on two active phase III Children's Oncology Group (COG) ALL trials. Processes include: (a) identifying infections as a targeted toxicity, (b) incorporation of infection-specific case report form questions, and (c) physician review of AEs with real-time data cleaning. Preliminary assessment of these processes suggests improved reporting, as well as opportunities for further improvement.

Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Predicted distribution of a rare and understudied forest carnivore: Humboldt marten (Martes caurina humboldtensis).

BACKGROUND: Many mammalian species have experienced range contractions. Following a reduction in distribution that has resulted in apparently small and disjunct populations, the Humboldt marten (Martes caurina humboldtensis) was recently designated as federally Threatened and state Endangered. This subspecies of Pacific marten occurring in coastal Oregon and northern California, also known as coastal martens, appear unlike martens that occur in snow-associated regions in that vegetation associations appear to differ widely between Humboldt marten populations. We expected current distributions represent realized niches, but estimating factors associated with long-term occurrence was challenging for this rare and little-known species. Here, we assessed the predicted contemporary distribution of Humboldt martens and interpret our findings as hypotheses correlated with the subspecies' niche to inform strategic conservation actions. METHODS: We modeled Humboldt marten distribution using a maximum entropy (Maxent) approach. We spatially-thinned 10,229 marten locations collected from 1996-2020 by applying a minimum distance of 500-m between locations, resulting in 384 locations used to assess correlations of marten occurrence with biotic and abiotic variables. We independently optimized the spatial scale of each variable and focused development of model variables on biotic associations (e.g., hypothesized relationships with forest conditions), given that abiotic factors such as precipitation are largely static and not alterable within a management context. RESULTS: Humboldt marten locations were positively associated with increased shrub cover (salal (Gautheria shallon)), mast producing trees (e.g., tanoak, Notholithocarpus densiflorus), increased pine (Pinus sp.) proportion of total basal area, annual precipitation at home-range spatial scales, low and high amounts of canopy cover and slope, and cooler August temperatures. Unlike other recent literature, we found little evidence that Humboldt martens were associated with old-growth structural indices. This case study provides an example of how limited information on rare or lesser-known species can lead to differing interpretations, emphasizing the need for study-level replication in ecology. Humboldt marten conservation would benefit from continued survey effort to clarify range extent, population sizes, and fine-scale habitat use.

Profiling CELMoD-Mediated Degradation of Cereblon Neosubstrates.

Targeted protein degradation is garnering increased attention as a therapeutic modality due in part to its promise of modulating targets previously considered undruggable. Cereblon E3 Ligase Modulating Drugs (CELMoDs) are one of the most well-characterized therapeutics employing this modality. CELMoDs hijack Cereblon E3 ligase activity causing neosubstrates to be ubiquitinated and degraded in the proteasome. Here, we describe a suite of assays-cellular substrate degradation, confirmation of CELMoD mechanism of action, in vitro ubiquitination, and Cereblon binding-that can be used to characterize CELMoD-mediated degradation of Cereblon neosubstrates. While the assays presented herein can be run independently, when combined they provide a strong platform to support the discovery and optimization of CELMoDs and fuel validation of targets degraded by this drug modality.

Prioritizing studies of COVID-19 and lessons learned.

INTRODUCTION: COVID-19 altered research in Clinical and Translational Science Award (CTSA) hubs in an unprecedented manner, leading to adjustments for COVID-19 research. METHODS: CTSA members volunteered to conduct a review on the impact of CTSA network on COVID-19 pandemic with the assistance from NIH survey team in October 2020. The survey questions included the involvement of CTSAs in decision-making concerning the prioritization of COVID-19 studies. Descriptive and statistical analyses were conducted to analyze the survey data. RESULTS: 60 of the 64 CTSAs completed the survey. Most CTSAs lacked preparedness but promptly responded to the pandemic. Early disruption of research triggered, enhanced CTSA engagement, creation of dedicated research areas and triage for prioritization of COVID-19 studies. CTSAs involvement in decision-making were 16.75 times more likely to create dedicated diagnostic laboratories (95% confidence interval [CI] = 2.17-129.39; P < 0.01). Likewise, institutions with internal funding were 3.88 times more likely to establish COVID-19 dedicated research (95% CI = 1.12-13.40; P < 0.05). CTSAs were instrumental in securing funds and facilitating establishment of laboratory/clinical spaces for COVID-19 research. Workflow was modified to support contracting and IRB review at most institutions with CTSAs. To mitigate chaos generated by competing clinical trials, central feasibility committees were often formed for orderly review/prioritization. CONCLUSIONS: The lessons learned from the COVID-19 pandemic emphasize the pivotal role of CTSAs in prioritizing studies and establishing the necessary research infrastructure, and the importance of prompt and flexible research leadership with decision-making capacity to manage future pandemics.

Musculoskeletal impairments in children receiving intensive therapy for acute leukemia or undergoing hematopoietic stem cell transplant: A report from the Children's Oncology Group.

BACKGROUND: Children receiving intensive chemotherapy for leukemia or undergoing hematopoietic stem cell transplant (HSCT) for solid tumors or leukemia are at risk for musculoskeletal (MSK) impairment from their underlying disease and from treatment. Data are limited on the incidence and nature of these disorders during intensive therapy. This study's objective was to provide a cross-sectional description of MSK impairments in this population. PROCEDURE: Children with acute myeloid leukemia (AML), relapsed acute lymphoblastic leukemia (rALL), or undergoing HSCT were systematically assessed for MSK impairments as part of Children's Oncology Group study ACCL0934. Assessments occurred at study entry, at 2 months, and at 12 months and included evaluation for signs or symptoms of MSK impairment and the type, site, and diagnosis. RESULTS: Six hundred three patients were included. MSK signs or symptoms were present in 48 (8.0%) children at study entry, 64 (13.5%) children at 2 months, and 40 (11.6%) children at 12 months. Arthralgia and/or gait abnormalities were the most common impairments; the knee was the most common site. Arthritis and tendonitis were both rare. Vincristine neuropathy, MSK impacts from central nervous system pathology, and bone or joint pain from underlying cancer were the most common diagnoses. Multivariate analysis demonstrated that having rALL (odds ratio [OR] 2.00, 95% CI 1.07-3.76, p = .03) or obesity (OR 2.10, 95% CI 1.12-3.95, p = .02) were risk factors for MSK impairment at study entry. CONCLUSIONS: MSK impairments are common in this intensively treated patient population, especially in those with rALL and those who are obese.

Cereblon Modulators Target ZBTB16 and Its Oncogenic Fusion Partners for Degradation via Distinct Structural Degrons.

There is a growing interest in using targeted protein degradation as a therapeutic modality in view of its potential to expand the druggable proteome. One avenue to using this modality is via molecular glue based Cereblon E3 Ligase Modulating Drug compounds. Here, we report the identification of the transcription factor ZBTB16 as a Cereblon neosubstrate. We also report two new Cereblon modulators, CC-3060 and CC-647, that promote ZBTB16 degradation. Unexpectedly, CC-3060 and CC-647 target ZBTB16 for degradation by primarily engaging distinct structural degrons on different zinc finger domains. The reciprocal fusion proteins, ZBTB16-RARα and RARα-ZBTB16, which cause a rare acute promyelocytic leukemia, contain these same structural degrons and can be targeted for proteasomal degradation with Cereblon modulator treatment. Thus, a targeted protein degradation approach via Cereblon modulators may represent a novel therapeutic strategy in acute promyelocytic leukemia where ZBTB16/RARA rearrangements are critical disease drivers.

IDH1 mutated acute myeloid leukemia in a child with metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria.

D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) or a single gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2). Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) is a type of D-2-HGA that has been previously reported in ten patients (OMIM 614875), three of whom had somatic mosaicism for R132 variants in isocitrate dehydrogenase 1 (IDH1). We describe a 3-year-old boy with MC-HGA who subsequently developed acute myeloid leukemia (AML) and was found to have an IDH1 R132C mutation in a leukemic bone marrow sample. Further testing revealed presence of somatic mosaicism for IDH1 R132C variant, suggesting an association of IDH1 in inducing myeloid leukemogenesis.

Validation of an Italian version of the Sociocultural Attitudes Towards Appearance Questionnaire-4-Revised (SATAQ-4R) on non-clinical Italian women and men.

Appearance-ideal internalization and appearance pressures are empirically-supported risk factors for body image disturbance and disordered eating in Western countries. Such a relationship has emerged also in the Italian context, where high rates of body dissatisfaction and disordered eating are present. The Sociocultural Attitudes Towards Appearance Questionnaire (SATAQ) and its revisions are among the most commonly used instruments to assess the role of sociocultural influences on body image. Two studies were conducted to examine the psychometric properties of the female (Study 1, N = 732) and male (Study 2, N = 364) Italian versions of the SATAQ-4-Revised (SATAQ-4R-Female, SATAQ-4R-Male). Confirmatory factor analysis (CFA) indicated that the original seven-factor structure was replicated for women and men. The seven subscales (Internalization: Thin/Low Body Fat; Internalization: Muscular; Internalization: General Attractiveness; Pressures: Family; Pressures: Peers; Pressures: Significant Others; and Pressures: Media) showed good internal consistency and 4-week test-retest reliability. Associations between SATAQ-4R subscales and body dissatisfaction, eating disorder symptomatology, drive for muscularity, self-esteem, family influences, and peer influences, suggested good convergent validity among both women and men. The present study provides evidence for the validity and reliability of the male and female Italian versions of the SATAQ-4R.

Internalized weight bias and psychological wellbeing: An exploratory investigation of a preliminary model.

Although a growing body of literature demonstrates negative effects of internalized weight bias (IWB), the relationships between IWB and relevant social, psychological, and behavioral variables have not yet been evaluated systematically. The purpose of the present study was to create and assess a model of hypothesized risks and outcomes of IWB. In an online survey, 650 adult males and females completed self-report measures of IWB, self-esteem, weight-related stigma experiences, body-related shame, body satisfaction, societal influence on body image, appearance comparisons, binge eating, distress, and weight-related quality of life. The originally hypothesized model did not provide an adequate fit to the data. Iterative modifications were undertaken, and the resulting model, in which social factors were associated with IWB and body image-related constructs which were in turn associated with psychological and behavioral outcomes, provided excellent fit to the data (CFI > .99, SRMR = .02, and RMSEA = .03). Most model paths were similar for underweight or normal weight participants versus participants with overweight or obesity. This study represents an initial effort at constructing a comprehensive model of IWB that can be further refined in future research and used to help guide the development of related interventions.

Serum Amyloid A Is an Exchangeable Apolipoprotein.

Objective- SAA (serum amyloid A) is a family of acute-phase reactants that have proinflammatory and proatherogenic activities. SAA is more lipophilic than apoA-I (apolipoprotein A-I), and during an acute-phase response, <10% of plasma SAA is found lipid-free. In most reports, SAA is found exclusively associated with high-density lipoprotein; however, we and others have reported SAA on apoB (apolipoprotein B)-containing lipoproteins in both mice and humans. The goal of this study was to determine whether SAA is an exchangeable apolipoprotein. Approach and Results- Delipidated human SAA was incubated with SAA-free human lipoproteins; then, samples were reisolated by fast protein liquid chromatography, and SAA analyzed by ELISA and immunoblot. Both in vitro and in vivo, we show that SAA associates with any lipoprotein and does not remain in a lipid-free form. Although SAA is preferentially found on high-density lipoprotein, it can exchange between lipoproteins. In the presence of CETP (cholesterol ester transfer protein), there is greater exchange of SAA between lipoproteins. Subjects with diabetes mellitus, but not those with metabolic syndrome, showed altered SAA lipoprotein distribution postprandially. Proteoglycan-mediated lipoprotein retention is thought to be an underlying mechanism for atherosclerosis development. SAA has a proteoglycan-binding domain. Lipoproteins containing SAA had increased proteoglycan binding compared with SAA-free lipoproteins. Conclusions- Thus, SAA is an exchangeable apolipoprotein and increases apoB-containing lipoproteins' proteoglycan binding. We and others have previously reported the presence of SAA on low-density lipoprotein in individuals with obesity, diabetes mellitus, and metabolic syndrome. We propose that the presence of SAA on apoB-containing lipoproteins may contribute to cardiovascular disease development in these populations.

PAR2 (Protease-Activated Receptor 2) Deficiency Attenuates Atherosclerosis in Mice.

OBJECTIVE: PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. APPROACH AND RESULTS: PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively. To determine the effect of PAR2 deficiency on atherosclerosis, male and female low-density lipoprotein receptor-deficient (Ldlr-/-) mice (8-12 weeks old) that were Par2+/+ or Par2-/- were fed a fat- and cholesterol-enriched diet for 12 or 24 weeks. PAR2 deficiency attenuated atherosclerosis in the aortic sinus and aortic root after 12 and 24 weeks. PAR2 deficiency did not alter total plasma cholesterol concentrations or lipoprotein distributions. Bone marrow transplantation showed that PAR2 on nonhematopoietic cells contributed to atherosclerosis. PAR2 deficiency significantly attenuated levels of the chemokines Ccl2 and Cxcl1 in the circulation and macrophage content in atherosclerotic lesions. Mechanistic studies using isolated primary vascular smooth muscle cells showed that PAR2 deficiency is associated with reduced Ccl2 and Cxcl1 mRNA expression and protein release into the supernatant resulting in less monocyte migration. CONCLUSIONS: Our results indicate that PAR2 deficiency is associated with attenuation of atherosclerosis and may reduce lesion progression by blunting Ccl2- and Cxcl1-induced monocyte infiltration.

Serum amyloid A3 is pro-atherogenic.

BACKGROUND AND AIMS: Serum amyloid A (SAA) predicts cardiovascular events. Overexpression of SAA increases atherosclerosis development; however, deficiency of two of the murine acute phase isoforms, SAA1.1 and SAA2.1, has no effect on atherosclerosis. SAA3 is a pseudogene in humans, but is an expressed acute phase isoform in mice. The goal of this study was to determine if SAA3 affects atherosclerosis in mice. METHODS: ApoE-/- mice were used as the model for all studies. SAA3 was overexpressed by an adeno-associated virus or suppressed using an anti-sense oligonucleotide approach. RESULTS: Over-expression of SAA3 led to a 4-fold increase in atherosclerosis lesion area compared to control mice (p = 0.01). Suppression of SAA3 decreased atherosclerosis in mice genetically deficient in SAA1.1 and SAA2.1 (p < 0.0001). CONCLUSIONS: SAA3 augments atherosclerosis in mice. Our results resolve a previous paradox in the literature and support extensive epidemiological data that SAA is pro-atherogenic.