Assessing the Effects of Geniculate Artery Embolization in a Nonsurgical Animal Model of Osteoarthritis.

PURPOSE: To create a nonsurgical animal model of osteoarthritis (OA) to evaluate the effects of embolotherapy during geniculate artery embolization (GAE). MATERIALS AND METHODS: Fluoroscopy-guided injections of 700 mg of sodium monoiodoacetate were performed into the left stifle in 6 rams. Kinematic data were collected before and after induction. At 10 weeks after induction, Subjects 1 and 4-6 underwent magnetic resonance (MR) imaging with dynamic contrast enhancement (DCE) and Subjects 1, 3, and 4-6 underwent angiography with angiographic scoring to identify regions with greatest disease severity for superselective embolization (75-250-µm microspheres). Target vessel size was measured. At 24 weeks after angiography, DCE-MR imaging, angiography, and euthanasia were performed, and bilateral stifles were harvested. Medial/lateral tibial and femoral condylar, patellar, and synovial samples were cut, preserved, decalcified, and scored using the Osteoarthritis Research Society International criteria. The stifle and synovium Whole-Organ Magnetic Resonance Imaging Score and Multicenter Osteoarthritis Study score were determined. The volume transfer constant (Ktrans) and extracellular volume fraction (ve) were calculated from DCE-MR imaging along the lateral synovial regions of interest. RESULTS: The mean gross and microscopic pathological scores were elevated at 38 and 61, respectively. Mean synovitis score was elevated at 9.2. Mean pre-embolization and postembolization angiographic scores were 5 and 3.8, respectively. Mean superior, transverse, and inferior geniculate artery diameters were 3.1 mm ± 1.21, 2.0 mm ± 0.50, and 1.6 mm ± 0.41 mm, respectively. Mean pre-embolization and postembolization cartilage and synovitis scores were elevated at 35.13 and 73.3 and 5.5 and 9.2, respectively. The Ktrans/ve values of Subjects 4, 5, and 6 were elevated at 0.049/0.38, 0.074/0.53, and 0.065/0.51, respectively. Altered gait of the hind limb was observed in all subjects after induction, with reduced joint mobility. No skin necrosis or osteonecrosis was observed. CONCLUSIONS: A nonsurgical ovine animal knee OA model was created, which allowed the collection of angiographic, histopathological, MR imaging, and kinematic data to study the effects of GAE.

B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis.

RATIONALE: B cells contribute to atherosclerosis through subset-specific mechanisms. Whereas some controversy exists about the role of B-2 cells, B-1a cells are atheroprotective because of secretion of atheroprotective IgM antibodies independent of antigen. B-1b cells, a unique subset of B-1 cells that respond specifically to T-cell-independent antigens, have not been studied within the context of atherosclerosis. OBJECTIVE: To determine whether B-1b cells produce atheroprotective IgM antibodies and function to protect against diet-induced atherosclerosis. METHODS AND RESULTS: We demonstrate that B-1b cells are sufficient to produce IgM antibodies against oxidation-specific epitopes on low-density lipoprotein both in vitro and in vivo. In addition, we demonstrate that B-1b cells provide atheroprotection after adoptive transfer into B- and T-cell deficient (Rag1(-/-)Apoe(-/-)) hosts. We implicate inhibitor of differentiation 3 (Id3) in the regulation of B-1b cells as B-cell-specific Id3 knockout mice (Id3(BKO)Apoe(-/-)) have increased numbers of B-1b cells systemically, increased titers of oxidation-specific epitope-reactive IgM antibodies, and significantly reduced diet-induced atherosclerosis when compared with Id3(WT)Apoe(-/-) controls. Finally, we report that the presence of a homozygous single nucleotide polymorphism in ID3 in humans that attenuates Id3 function is associated with an increased percentage of circulating B-1 cells and anti-malondialdehyde-low-density lipoprotein IgM suggesting clinical relevance. CONCLUSIONS: These results provide novel evidence that B-1b cells produce atheroprotective oxidation-specific epitope-reactive IgM antibodies and protect against atherosclerosis in mice and suggest that similar mechanisms may occur in humans.

N-benzyladriamycin-14-valerate (AD 198) exhibits potent anti-tumor activity on TRAF3-deficient mouse B lymphoma and human multiple myeloma.

BACKGROUND: TRAF3, a new tumor suppressor identified in human non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), induces PKCδ nuclear translocation in B cells. The present study aimed to evaluate the therapeutic potential of two PKCδ activators, N-Benzyladriamycin-14-valerate (AD 198) and ingenol-3-angelate (PEP005), on NHL and MM. METHODS: In vitro anti-tumor activities of AD 198 and PEP005 were determined using TRAF3-/- mouse B lymphoma and human patient-derived MM cell lines as model systems. In vivo therapeutic effects of AD 198 were assessed using NOD SCID mice transplanted with TRAF3-/- mouse B lymphoma cells. Biochemical studies were performed to investigate signaling mechanisms induced by AD 198 or PEP005, including subcellular translocation of PKCδ. RESULTS: We found that AD 198 exhibited potent in vitro and in vivo anti-tumor activity on TRAF3-/- tumor B cells, while PEP005 displayed contradictory anti- or pro-tumor activities on different cell lines. Detailed mechanistic investigation revealed that AD 198 did not affect PKCδ nuclear translocation, but strikingly suppressed c-Myc expression and inhibited the phosphorylation of ERK, p38 and JNK in TRAF3-/- tumor B cells. In contrast, PEP005 activated multiple signaling pathways in these cells, including PKCδ, PKCα, PKCε, NF-κB1, ERK, JNK, and Akt. Additionally, AD198 also potently inhibited the proliferation/survival and suppressed c-Myc expression in TRAF3-sufficient mouse and human B lymphoma cell lines. Furthermore, we found that reconstitution of c-Myc expression conferred partial resistance to the anti-proliferative/apoptosis-inducing effects of AD198 in human MM cells. CONCLUSIONS: AD 198 and PEP005 have differential effects on malignant B cells through distinct biochemical mechanisms. Our findings uncovered a novel, PKCδ-independent mechanism of the anti-tumor effects of AD 198, and suggest that AD 198 has therapeutic potential for the treatment of NHL and MM involving TRAF3 inactivation or c-Myc up-regulation.

Maximizing Educational Engagement and Program Exposure for Recruitment to the Integrated and Independent Interventional Radiology Programs in a Virtual Environment.

Interventional Radiology residency training programs experienced significant impacts secondary to the COVID-19 pandemic. Prospective resident recruitment and resident education were particularly affected due to limitations on in-person gatherings in effort to curb exposure. Finding ways to mitigate the pandemic's effect on recruitment and education was a challenge faced by residency programs across the nation. This article discusses a single Interventional Radiology program's approach to adapting to the reality of limited interpersonal interaction as well as efforts to maintain engagement for resident recruitment and education in a virtual setting.

A Brief Review of Thrombolytics for Venous Interventions.

Anticoagulation continues to be the mainstay of therapy for the management of venous thromboembolism. However, anticoagulation does not lead to the breakdown or dissolving of the thrombus. In an acute pulmonary embolism, extensive thrombus burden can be associated with a high risk for early decompensation, and in acute deep venous thrombosis, it can be associated with an increased risk for phlegmasia. In addition, residual thrombosis can be associated with chronic thromboembolic pulmonary hypertension and postthrombotic syndrome in a chronic setting. Thrombolytic therapy is a crucial therapeutic choice in treating venous thromboembolism for thrombus resolution. Historically, it was administered systemically and was associated with high bleeding rates, particularly major bleeding, including intracranial bleeding. In the last two decades, there has been a significant increase in catheter-based therapies with and without ultrasound, where lower doses of thrombolytic agents are utilized, potentially reducing the risk for major bleeding events and improving the odds of reducing the thrombus burden. In this article, we provide an overview of several thrombolytic therapies, including delivery methods, doses, and outcomes.

Endovascular Management of Malperfusion Syndromes in Aortic Dissection.

Malperfusion Syndrome (MPS) refers to inadequate perfusion of end organs secondary to ongoing arterial obstruction of the aorta and its branches resulting in increased morbidity and mortality. While uncomplicated type B dissection can typically be monitored, type A or type B dissections with malperfusion syndrome are should be considered for hybrid treatment with an endovascular intervention.  In addition to pre-procedure CTA and labs, intra-procedure evaluation of the true lumen, false lumen, and branch vessels is performed with intravascular ultrasound (IVUS) and manometry to delineate static versus dynamic obstruction. Dynamic obstruction of the visceral arteries is typically treated first and can be relieved either with supraceliac dissection flap fenestration or exclusion of the entry tear by thoracic endovascular aortic repair, both of which will restore flow to the true lumen. Static obstruction requires stenting or other branch-artery intervention including branch artery fenestration, suction embolectomy, or thrombolysis. Throughout the procedure, IVUS and manometry are used to evaluate results of interventions with respect to continued hemodynamically significant obstruction. Endovascular intervention should be performed in conjunction with a multi-disciplinary team as patients are often complex and may require further procedures such as bowel resection or open aortic repair.

Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells.

Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations.