Alexander Ryan Berg
MD Student, expected graduation Spring 2028
Contact
https://orcid.org/0000-0002-8480-0181All Publications
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Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model.
Nature communications
2023; 14 (1): 6291
Abstract
Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies. Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. CD117-ADC, similarly to busulfan, allows efficient engraftment, gene marking, and vector-derived fetal hemoglobin induction. Importantly, ADC treatment is associated with minimal toxicity, and CD117-ADC-conditioned animals maintain fertility. In contrast, busulfan treatment commonly causes severe toxicities and infertility in humans. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.
View details for DOI 10.1038/s41467-023-41153-5
View details for PubMedID 37828021
View details for PubMedCentralID PMC10570335
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Longitudinal association of epicardial and thoracic adipose tissues with coronary and cardiac characteristics in psoriasis.
Heliyon
2023; 9 (10): e20732
Abstract
Background: s: Psoriasis is a disease of systemic inflammation associated with increased cardiometabolic risk. Epicardial adipose tissue (EAT) and thoracic adipose tissue (TAT) are contributing factors for atherosclerosis and cardiac dysfunction. We strove to assess the longitudinal impact of the EAT and TAT on coronary and cardiac characteristics in psoriasis.Methods: The study consisted of 301 patients with baseline coronary computed tomography angiography (CTA), of which 139 had four-year follow up scans. EAT and TAT volumes from non-contrast computed tomography scans were quantified by an automated segmentation framework. Coronary plaque characteristics and left ventricular (LV) mass were quantified by CTA.Results: When stratified by baseline EAT and TAT volume quartiles, a stepwise significant increase in cardiometabolic parameters was observed. EAT and TAT volumes associated with fibro-fatty burden (FFB) (TAT: rho=0.394, P<0.001; EAT: rho=0.459, P<0.001) in adjusted models. Only EAT had a significant four-year time-dependent association with FFB in fully adjusted models (beta=0.307P=0.003), whereas only TAT volume associated with myocardial injury in fully adjusted models (TAT: OR=1.57 95% CI = (1.00-2.60); EAT: OR=1.46 95% CI = (0.91-2.45). Higher quartiles of EAT and TAT had increased LV mass and developed strong correlation (TAT: rho=0.370, P<0.001; EAT: rho=0.512, P<0.001).Conclusions: Our study is the first to explore how both EAT and TAT volumes associate with increased cardiometabolic risk profile in an inflamed psoriasis cohorts and highlight the need for further studies on its use as a potential prognostic tool for high-risk coronary plaques and cardiac dysfunction.
View details for DOI 10.1016/j.heliyon.2023.e20732
View details for PubMedID 37867905
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The Relationship between Circulating APOA-1 and Atherosclerosis Initiation and Progression in Psoriasis
JOURNAL OF INVESTIGATIVE DERMATOLOGY
2023; 143 (10): 1947-+
Abstract
APOA-1 is central to the high-density lipoprotein function of reverse cholesterol transport measured by cholesterol efflux capacity. Psoriasis is a systemic inflammatory disease associated with poor cholesterol efflux capacity and accelerated noncalcified coronary burden (NCB) as measured by coronary computed tomographic angiography. In this study, we characterized the relationship between APOA-1, cholesterol efflux capacity, and progression of NCB over 4 years. Consecutively recruited participants with psoriasis underwent coronary computed tomographic angiography for NCB quantification (Medis QAngio, Leiden, The Netherlands) at baseline (n = 310) and at four years (n = 124). Blood was assessed for cardiometabolic biomarkers. The lowest quartile of APOA-1 was associated with cardiometabolic blood markers (insulin, homeostatic model assessment for insulin resistance, and cholesterol efflux capacity) and higher NCB (P < 0.001). The low APOA-1 quartile had higher NCB at 4 years (β = -0.36, P = 0.02) in fully adjusted models. Finally, a 10-unit decrease of APOA-1 was associated with a 16% increase in NCB progression over 4 years (OR = 0.83, 95% confidence interval = 0.70-0.99, P = 0.04). In addition to being associated with cardiometabolic disease, low APOA-1 was associated with more NCB over time. These findings show that low APOA-1 is correlated with initiation and progression of coronary artery disease and may have clinical utility in identifying high-risk populations for development of cardiovascular disease.
View details for DOI 10.1016/j.jid.2023.01.044
View details for Web of Science ID 001084521300001
View details for PubMedID 37088280
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Machine learning demonstrates top predictors of lipid-rich necrotic core modulation over 1 year in psoriasis.
Vascular medicine (London, England)
2023; 28 (4): 342-344
View details for DOI 10.1177/1358863X231171948
View details for PubMedID 37158300
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Comparison of the dietary omega-3 fatty acids impact on murine psoriasis-like skin inflammation and associated lipid dysfunction.
The Journal of nutritional biochemistry
2023; 117: 109348
Abstract
Persistent skin inflammation and impaired resolution are the main contributors to psoriasis and associated cardiometabolic complications. Omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are known to exert beneficial effects on inflammatory response and lipid function. However, a specific role of omega-3 PUFAs in psoriasis and accompanied pathologies are still a matter of debate. Here, we carried out a direct comparison between EPA and DHA 12 weeks diet intervention treatment of psoriasis-like skin inflammation in the K14-Rac1V12 mouse model. By utilizing sensitive techniques, we targeted EPA- and DHA-derived specialized pro-resolving lipid mediators and identified tightly connected signaling pathways by RNA sequencing. Treatment with experimental diets significantly decreased circulating pro-inflammatory cytokines and bioactive lipid mediators, altered psoriasis macrophage phenotypes and genes of lipid oxidation. The superficial role of these changes was related to DHA treatment and included increased levels of resolvin D5, protectin DX and maresin 2 in the skin. EPA treated mice had less pronounced effects but demonstrated a decreased skin accumulation of prostaglandin E2 and thromboxane B2. These results indicate that modulating psoriasis skin inflammation with the omega-3 PUFAs may have clinical significance and DHA treatment might be considered over EPA in this specific disease.
View details for DOI 10.1016/j.jnutbio.2023.109348
View details for PubMedID 37044136
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Association of the triglyceride glucose index with insulin resistance and subclinical atherosclerosis in psoriasis: An observational cohort study.
Journal of the American Academy of Dermatology
2023; 88 (5): 1131-1134
View details for DOI 10.1016/j.jaad.2022.08.027
View details for PubMedID 35995090
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Cholesterol efflux capacity is associated with lipoprotein size and vascular health in mild to moderate psoriasis.
Frontiers in cardiovascular medicine
2023; 10: 1041457
Abstract
Psoriasis is a systemic inflammatory condition with poor cholesterol transport measured by cholesterol efflux capacity (CEC) that is associated with a heightened risk of cardiovascular disease (CVD). In psoriasis patients, we sought to characterize the lipoprotein profile by size using a novel nuclear magnetic resonance algorithm in patients with low CEC compared to normal CEC.Lipoprotein profile was assessed using the novel nuclear magnetic resonance LipoProfile-4 deconvolution algorithm. Aortic vascular inflammation (VI) and non-calcified burden (NCB) were characterized via positron emission tomography-computed tomography and coronary computed tomography angiography. To understand the relationship between lipoprotein size and markers of subclinical atherosclerosis, linear regression models controlling for confounders were constructed.Psoriasis patients with low CEC had higher more severe psoriasis (p = 0.04), VI (p = 0.04) and NCB (p = 0.001), concomitant with smaller high-density lipoprotein (HDL) (p < 0.001) and low-density lipoprotein (LDL) particles (p < 0.001). In adjusted models HDL size (β = -0.19; p = 0.02) and LDL size (β = -0.31; p < 0.001) associated with VI and NCB. Lastly, HDL size strongly associated with LDL size in fully adjusted models (β = -0.27; p < 0.001).These findings demonstrate that in psoriasis, low CEC associates with a lipoprotein profile comprised of smaller HDL and LDL particles which correlates with vascular health and may be driving early onset atherogenesis. Further, these results demonstrate a relationship between HDL and LDL size and provide novel insights into the complexities of HDL and LDL as biomarkers of vascular health.
View details for DOI 10.3389/fcvm.2023.1041457
View details for PubMedID 36891247
View details for PubMedCentralID PMC9986595
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Association of S100A8/A9 with Lipid-Rich Necrotic Core and Treatment with Biologic Therapy in Patients with Psoriasis: Results from an Observational Cohort Study.
The Journal of investigative dermatology
2022; 142 (11): 2909-2919
Abstract
Psoriasis is a systemic inflammatory disease with an increased risk of atherosclerotic events and premature cardiovascular disease. S100A7, A8/A9, and A12 are protein complexes that are produced by activated neutrophils, monocytes, and keratinocytes in psoriasis. Lipid-rich necrotic core (LRNC) is a high-risk coronary plaque feature previously found to be associated with cardiovascular risk factors and psoriasis severity. LRNC can decrease with biologic therapy, but how this occurs remains unknown. We investigated the relationship between S100 proteins, LRNC, and biologic therapy in psoriasis. S100A8/A9 associated with LRNC in fully adjusted models (β = 0.27, P = 0.009; n = 125 patients with psoriasis with available coronary computed tomography angiography scans; LRNC analyses; and serum S100A7, S100A8, S100A9, S100A12, and S100A8/A9 levels). At 1 year, in patients receiving biologic therapy (36 of 73 patients had 1-year coronary computed tomography angiography scans available), a 79% reduction in S100A8/A9 levels (‒172 [‒291.7 to 26.4] vs. ‒29.9 [‒137.9 to 50.5]; P = 0.04) and a 0.6 mm2 reduction in average LRNC area (0.04 [‒0.48 to 0.77] vs. ‒0.56 [‒1.8 to 0.13]; P = 0.02) were noted. These results highlight the potential role of S100A8/A9 in the development of high-risk coronary plaque in psoriasis.
View details for DOI 10.1016/j.jid.2022.05.1085
View details for PubMedID 35750149
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Systemic consequences of abnormal cholesterol handling: Interdependent pathways of inflammation and dyslipidemia.
Frontiers in immunology
2022; 13: 972140
Abstract
Metabolic conditions such as obesity and associated comorbidities are increasing in prevalence worldwide. In chronically inflamed pathologies, metabolic conditions are linked to early onset cardiovascular disease, which remains the leading cause of death despite decades of research. In recent years, studies focused on the interdependent pathways connecting metabolism and the immune response have highlighted that dysregulated cholesterol trafficking instigates an overactive, systemic inflammatory response, thereby perpetuating early development of cardiovascular disease. In this review, we will discuss the overlapping pathways connecting cholesterol trafficking with innate immunity and present evidence that cholesterol accumulation in the bone marrow may drive systemic inflammation in chronically inflamed pathologies. Lastly, we will review the current therapeutic strategies that target both inflammation and cholesterol transport, and how biologic therapy restores lipoprotein function and mitigates the immune response.
View details for DOI 10.3389/fimmu.2022.972140
View details for PubMedID 36091062
View details for PubMedCentralID PMC9459038
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PET/CT-Based Characterization of 18F-FDG Uptake in Various Tissues Reveals Novel Potential Contributions to Coronary Artery Disease in Psoriatic Arthritis.
Frontiers in immunology
2022; 13: 909760
Abstract
Psoriasis is a heterogeneous inflammatory disease that involves the skin, joints, liver, heart, and other organs. Psoriatic arthritis (PsA) is associated with cardiovascular disease (CVD), but the relative contributions of inflammatory and metabolic dysregulation to CVD are incompletely understood. We set out to discover novel potential contributors to CVD in PsA patients by comprehensively phenotyping a cohort of PsA patients using these advanced technologies.In this cross-sectional analysis of a cohort study, we investigated associations of systemic inflammation and metabolic dysregulation with Coronary CT angiography (CCTA)-proven coronary artery disease (CAD) in 39 subjects with PsA. We measured traditional CVD risk factors [blood pressure, Body Mass Index (BMI), diabetes, age, sex, smoking], serum markers of systemic inflammation (hsCRP, GlycA) and metabolic dysfunction (cholesterol efflux capacity), and inflammatory cytokines (IL-1β, IL-6, IL-12/IL-23, IL-17A, TNF-α, IFN-γ). We also incorporated radiographic measures of metabolic dysfunction (visceral and subcutaneous adipose volume) and tissue-specific inflammation (positron emission tomography-computed tomography, PET-CT). To quantify relative contributions of FDG (fluorodeoxyglucose) uptake and adiposity to coronary plaque, we performed multiple linear regression, controlling for Framingham risk score (FRS) and FRS + visceral adiposity.Compared with non-psoriatic volunteers, subjects with PsA had elevated markers of metabolic and inflammatory disease, which was more pronounced in subjects with moderate-to-severe skin disease. This included visceral (p = 0.005) and subcutaneous (p = 0.004) adiposity, BMI (p = 0.001), hemoglobin A1C (p = 0.037), high sensitivity C-reactive protein (p = 0.005), IL-6 (p = 0.003), IFN-γ (p = 0.006), and liver FDG uptake (p = 0.03). In subjects with PsA, visceral adiposity correlated significantly with subclinical CAD (standardized β = 0.681, p = 0.002), as did FDG uptake in bone marrow (standardized β = 0.488, p = 0.008), liver (standardized β = 0.619, p < 0.001), spleen (standardized β = 0.523, p = 0.004), and subcutaneous adipose (standardized β = 0.524, p = 0.003).Together, these findings reveal inflammatory and metabolic potential contributors to subclinical CAD in PsA, including adipose inflammation, and suggesting novel targets for CVD prevention and treatment in PsA.
View details for DOI 10.3389/fimmu.2022.909760
View details for PubMedID 35720288
View details for PubMedCentralID PMC9201918
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Updates in the Impact of Chronic Systemic Inflammation on Vascular Inflammation by Positron Emission Tomography (PET).
Current cardiology reports
2022; 24 (4): 317-326
Abstract
In this review, we focus on the clinical and epidemiological studies pertaining to systemic and vascular inflammation by positron emission tomography (PET) in patients with chronic inflammatory conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), human immunodeficiency virus (HIV), and psoriasis to highlight the importance of chronic systemic inflammation on vascular inflammation by PET in these disease states.Recent clinical and translation advancements have demonstrated the durable relationship between chronic systemic inflammation and cardiovascular disease (CVD). In chronic inflammatory states, this relationship is robustly evident in the form of increased vascular inflammation, yet traditional risk estimates often underestimate the subclinical cardiovascular risk conferred by chronic inflammation. PET has emerged as a novel, non-invasive imaging modality capable of both quantifying the degree of systemic and vascular inflammation and detecting residual inflammation prior to cardiovascular events. We begin by demonstrating the role of inflammation in the pathogenesis of atherosclerosis, discussing how PET has been utilized to measure systemic and vascular inflammation and their effect on subclinical atherosclerosis, and finally reviewing recent applications of PET in constructing improved risk stratification for patients at high risk for stroke and CVD.
View details for DOI 10.1007/s11886-022-01651-2
View details for PubMedID 35171444