Cancers are able to grow by subverting immune suppressive pathways, to prevent the malignant cells as being recognized as dangerous or foreign. This mechanism prevents the cancer from being eliminated by the immune system and allows disease to progress from a very early stage to a lethal state. Immunotherapies are newly developing interventions that modify the patient's immune system to fight cancer, by either directly stimulating rejection-type processes or blocking suppressive pathways. Extracellular adenosine generated by the ectonucleotidases CD39 and CD73 is a newly recognized "immune checkpoint mediator" that interferes with anti-tumor immune responses. In this review, we focus on CD39 and CD73 ectoenzymes and encompass aspects of the biochemistry of these molecules as well as detailing the distribution and function on immune cells. Effects of CD39 and CD73 inhibition in preclinical and clinical studies are discussed. Finally, we provide insights into potential clinical application of adenosinergic and other purinergic-targeting therapies and forecast how these might develop in combination with other anti-cancer modalities.

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets.

At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-α and related family members leading to activation of NF-κB; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

Molecular Biology of Atherosclerosis

There is nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory-motor nerves, as well as in intracardiac neurons. Centers in the brain control heart activities and vagal cardiovascular reflexes involve purines. Adenine nucleotides and nucleosides act on purinoceptors on cardiomyocytes, AV and SA nodes, cardiac fibroblasts, and coronary blood vessels. Vascular tone is controlled by a dual mechanism. ATP, released from perivascular sympathetic nerves, causes vasoconstriction largely via P2X1 receptors. Endothelial cells release ATP in response to changes in blood flow (via shear stress) or hypoxia, to act on P2 receptors on endothelial cells to produce nitric oxide, endothelium-derived hyperpolarizing factor, or prostaglandins to cause vasodilation. ATP is also released from sensory-motor nerves during antidromic reflex activity, to produce relaxation of some blood vessels. Purinergic signaling is involved in the physiology of erythrocytes, platelets, and leukocytes. ATP is released from erythrocytes and platelets, and purinoceptors and ectonucleotidases are expressed by these cells. P1, P2Y1, P2Y12, and P2X1 receptors are expressed on platelets, which mediate platelet aggregation and shape change. Long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides promote migration and proliferation of vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis, vessel remodeling during restenosis after angioplasty and atherosclerosis. The involvement of purinergic signaling in cardiovascular pathophysiology and its therapeutic potential are discussed, including heart failure, infarction, arrhythmias, syncope, cardiomyopathy, angina, heart transplantation and coronary bypass grafts, coronary artery disease, diabetic cardiomyopathy, hypertension, ischemia, thrombosis, diabetes mellitus, and migraine.

Purinergic Signaling in the Cardiovascular System.

Objective: Antiphospholipid syndrome (APS) is a leading acquired cause of thrombotic events. While antiphospholipid antibodies have been shown to promote thrombosis in mice, the role of neutrophils has not been explicitly studied. Here, we characterized neutrophils in the context of a new model of antiphospholipid antibody-mediated venous thrombosis.

Methods: Mice were administered IgG fractions prepared from patients with APS. At the same time, flow through the inferior vena cava was reduced by a standard stenosis. Resulting thrombi were characterized for size and neutrophil content. Circulating factors and the vessel wall were also assessed.

Results: As measured by both thrombus weight and thrombosis frequency, mice treated with IgG from patients with APS demonstrated exaggerated thrombosis as compared with controls. APS thrombi were enriched for citrullinated histone H3 (a marker of neutrophil extracellular traps/NETs). APS mice also demonstrated elevated levels of circulating cell-free DNA and human IgG bound to the neutrophil surface. In contrast, circulating neutrophil numbers and markers of vessel wall activation were not appreciably different between APS and control mice. Regarding therapy, treatment with either deoxyribonuclease (which dissolves NETs) or a neutrophil-depleting antibody reduced thrombosis in APS mice to the level seen in controls.

Conclusion: These data support a mechanism whereby circulating neutrophils are primed by antiphospholipid antibodies to accelerate thrombosis. This line of investigation suggests new, immunomodulatory approaches for the treatment of APS. This article is protected by copyright. All rights reserved.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.39938

In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody-Mediated Venous Thrombosis.

The formation of atherosclerotic plaques in the large and medium sized arteries is classically driven by systemic factors, such as elevated cholesterol and blood pressure. However, work over the past several decades has established that atherosclerotic plaque development involves a complex coordination of both systemic and local cues that ultimately determine where plaques form and how plaques progress. Although current therapeutics for atherosclerotic cardiovascular disease primarily target the systemic risk factors, a large array of studies suggest that the local microenvironment, including arterial mechanics, matrix remodelling and lipid deposition, plays a vital role in regulating the local susceptibility to plaque development through the regulation of vascular cell function. Additionally, these microenvironmental stimuli are capable of tuning other aspects of the microenvironment through collective adaptation. In this review, we will discuss the components of the arterial microenvironment, how these components cross-talk to shape the local microenvironment, and the effect of microenvironmental stimuli on vascular cell function during atherosclerotic plaque formation.

The arterial microenvironment: the where and why of atherosclerosis

Background:Pelvic incidence (PI) is an important variable in assessing spinopelvic balance that is associated with hip pathology. A lateral radiograph of the pelvis can be used to measure PI, but this view is not routinely performed in the clinical setting during evaluation of hip pain. The false-profile (FP) radiographic view of the hip is commonly obtained to measure acetabular coverage.Purpose:To evaluate the tolerance of PI measurements to pelvic rotation and assess the feasibility of using an FP radiograph to obtain an accurate measurement of PI.Study Design:Cohort study (diagnosis); Level of evidence, 2.Methods:A mathematical model was developed to predict the change in PI with rotation. Fluoroscopic images were obtained of 6 reconstructed cadaveric adult pelvis and femur specimens at varying degrees of rotation, including a perfect lateral and FP image. PI was measured with the midpoint between the centers of the femoral heads as a reference point. The findings were confirmed clinically by retrospe...

Use of the False-Profile Radiographic View to Measure Pelvic Incidence.

BackgroundScapular body fractures generally occur as a result of high-energy, direct trauma to the shoulder sustained in automobile accidents. While such mechanisms have been well described, little...

Scapular Body Fracture in the Athlete: A Systematic Review.

Background: No investigation has analyzed the time from injury to operative intervention and its effect on complications and functional outcomes in distal radius fractures. This investigation aimed to establish whether the time to surgical intervention from injury was associated with the observed rate of complications in distal radius fractures. Methods: A retrospective review of all orthopedic trauma patients who came to our center was conducted from 2008 through 2014. Patients who sustained closed distal radius fractures were included. A postoperative complication following distal radius fracture was defined as reoperation, superficial or deep infection, complex regional pain syndrome, new-onset carpal tunnel syndrome, tendon irritation, and symptomatic hardware. Results: In all, 190 patients were included in the study with a mean age of 48 years (SD ±14.7). According to the AO-Müller/Orthopaedic Trauma Association classification, radiographs revealed 80 A fractures, 15 B fractures, and 95 C fractures. Thirty distal radii were fixed within 0 to 3 days after injury, 91 patients within 4 to 10 days, and 69 patients after 10 days. Overall, 28 complications (14.7%) were identified. There was no statistical difference in the rate of complications between the time interval groups (P = .17). Conclusions: Despite the increased popularity of surgical intervention for distal radius fractures, the optimal parameters to maximize patient outcomes have yet to be clearly defined. Time to intervention did not affect the rate of postoperative complication and range of motion.

Does Time to Operative Intervention of Distal Radius Fractures Influence Outcomes?

Background: Cartilage transplants in the patellofemoral joint have demonstrated lower success rates than in the femoral condyles. This is likely related to the more complex morphology and biomechanics of the joint. While previous studies have evaluated cartilage surface matching and congruence, little work has been done to study the associated subchondral bone congruency in these grafts. Purpose: To determine if differences in patellar morphology play a role in the alignment of the donor patellar osteochondral allograft subchondral bone with the native patellar subchondral bone. Study Design: Controlled laboratory study. Methods: A total of 20 (10 Wiberg I and 10 Wiberg II/III) fresh-frozen human patellae were designated as recipients and size-matched to both a Wiberg I and a Wiberg II/III patellar donor. A 16-mm osteochondral allograft transplant to the central ridge of the patella was performed in random order with each matched donor. Transplanted patellae underwent a nano—computed tomography (nano-CT) scan, were digitally reconstructed, and were superimposed on the initial nano-CT scan of the native recipient patella. MATLAB was used to determine the surface height deviation between the native and donor subchondral bone surfaces. DragonFly 3-dimensional imaging software was used to measure subchondral bone step-off heights at the native-donor interface. Differences between matched and unmatched grafts were compared using a 2-way analysis of variance and the Sidak post hoc test. Results: Subchondral bone surface deviation did not differ between Wiberg matched and unmatched allografts. The step-off height was significantly greater in unmatched (1.38 ± 0.49 mm) compared with matched (1.14 ± 0.52 mm) plugs (P = .015). The lateral quadrant step-off differed between matched (0.89 ± 0.43 mm) and unmatched (1.60 ± 0.78 mm) grafts (P = .007). Conclusion: While unmatched Wiberg patellar osteochondral allograft implantation did not result in significantly different subchondral bone surface height deviations, there was a significant difference in the circumferential subchondral bone step-off height in the lateral quadrant. Further investigation using finite element analysis modeling will help determine the role of subchondral bone surface on shear and compression force distributions in these areas. Clinical Relevance: Given that subchondral bone stiffness and morphology play a role in cartilage health, subchondral bone congruency may play a role in graft survival. Understanding how this congruency plays a role in cartilage force distribution will help surgeons improve the long-term success of osteochondral allograft transplants.

The Effect of Patellar Surface Morphology on Subchondral Bone Alignment When Matching Patellar Osteochondral Allografts to the Central Ridge of the Patella

Abstract 624: Ecto-enzymatic Suppression Of Atherogenesis By CD39

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