PARP1 as an Epigenetic Modulator: Implications for the Regulation of Host-Viral Dynamics.

The principal understanding of the Poly(ADP-ribose) polymerase (PARP) regulation of genomes has been focused on its role in DNA repair; however, in the past few years, an additional role for PARPs and PARylation has emerged in regulating viral-host interactions. In particular, in the context of DNA virus infection, PARP1-mediated mechanisms of gene regulations, such as the involvement with cellular protein complexes responsible for the folding of the genome into the nucleus, the formation of chromatin loops connecting distant regulatory genomic regions, and other methods of transcriptional regulation, provide additional ways through which PARPs can modulate the function of both the host and the viral genomes during viral infection. In addition, potential viral amplification of the activity of PARPs on the host genome can contribute to the pathogenic effect of viral infection, such as viral-driven oncogenesis, opening the possibility that PARP inhibition may represent a potential therapeutic approach to target viral infection. This review will focus on the role of PARPs, particularly PARP1, in regulating the infection of DNA viruses.

PARP1 Inhibition Halts EBV+ Lymphoma Progression by Disrupting the EBNA2/MYC Axis.

PARP1 has been shown to regulate EBV latency. However, the therapeutic effect of PARP1 inhibitors on EBV+ lymphomagenesis has not yet been explored. Here, we show that PARPi BMN-673 has a potent anti-tumor effect on EBV-driven LCL in a mouse xenograft model. We found that PARP1 inhibition induces a dramatic transcriptional reprogramming of LCLs driven largely by the reduction of the MYC oncogene expression and dysregulation of MYC targets, both in vivo and in vitro. PARP1 inhibition also reduced the expression of viral oncoprotein EBNA2, which we previously demonstrated depends on PARP1 for activation of MYC. Further, we show that PARP1 inhibition blocks the chromatin association of MYC, EBNA2, and tumor suppressor p53. Overall, our study strengthens the central role of PARP1 in EBV malignant transformation and identifies the EBNA2/MYC pathway as a target of PARP1 inhibitors and its utility for the treatment of EBNA2-driven EBV-associated cancers.

The Clinical Problem of Pelvic Venous Disorders.

Pelvic venous disorders are inter-related pathologic conditions caused by reflux and obstruction in the pelvic veins. It can present a spectrum of clinical features based on the route of transmission of venous hypertension to either distal or caudal venous reservoirs. Imaging can help to visualize pelvic vascular and visceral structures to rule out other gynecologic, gastrointestinal, and urologic diseases. Endovascular treatment, owing to its low invasive nature and high success rate, has become the mainstay in the management of pelvic venous disorders. This article reviews the pathophysiology, clinical presentations, and diagnostic and therapeutic approaches to pelvic venous disorders.

CT-Overlay Hybrid Imaging to Facilitate Sentinel Cerebral Protection System Deployment in the Presence of an Anomalous Vertebral Artery Originating From the Aortic Arch During Transcatheter Aortic Valve Implantation.

Stroke remains an important risk during transcatheter aortic valve implantation (TAVI). Though the use of the double-filter Sentinel cerebral protection system (Boston Scientific, Marlborough, MA, USA) may lower the stroke risk, the deployment of this device requires manipulation within the aortic arch and cranial arch vessels potentially causing dislodgment of atherosclerotic debris in the process thereby possibly offsetting its benefit with regards to reducing cerebral embolization. Apart from patient selection, minimizing maneuvering during deployment may improve the safety of device deployment. In this context, we illustrate a case using three-dimensional computed tomography (CT) - overlay to facilitate Sentinel cerebral protection system deployment during TAVI. Emphasis in this case rests on demonstration of how aforementioned periprocedural imaging may facilitate negotiation of anatomical variants and avoid inadvertent cannulation of an anomalous left vertebral artery originating from the aortic arch. Imaging guidance with this concept may minimize device manipulation and reduce the risk of cerebral embolization. Further systematic evaluation is needed to demonstrate whether this approach improves clinical outcomes.

Transcatheter aortic valve implantation in the presence of an anomalous left circumflex coronary artery: a case report.

This is a case of an anomalous left circumflex coronary artery (LCX) originating from the right coronary cusp with a retroaortic course in a patient with severe aortic valve stenosis requiring transcatheter aortic valve implantation (TAVI). In the context of TAVI, an anomalous LCX has been described only in a few case reports. In some, the LCX remains unaffected. However, occlusion after TAVI valve deployment has been described. We report pre-procedural imaging and procedural precautions prior to valve deployment in our case in which the LCX remained unaffected by the TAVR valve. More case reports or series are needed to help assess which characteristics are associated with an increased risk of anomalous LCX obstruction.

Selective vs. Global Renal Denervation: a Case for Less Is More.

PURPOSE OF REVIEW: Review the renal nerve anatomy and physiology basics and explore the concept of global vs. selective renal denervation (RDN) to uncover some of the fundamental limitations of non-targeted renal nerve ablation and the potential superiority of selective RDN. RECENT FINDINGS: Recent trials testing the efficacy of RDN showed mixed results. Initial investigations targeted global RDN as a therapeutic goal. The repeat observation of heterogeneous response to RDN including non-responders with lack of a BP reduction, or even more unsettling, BP elevations after RDN has raised concern for the detrimental effects of unselective global RDN. Subsequent studies have suggested the presence of a heterogeneous fiber population and the potential utility of renal nerve stimulation to identify sympatho-stimulatory fibers or "hot spots." The recognition that RDN can produce heterogeneous afferent sympathetic effects both change therapeutic goals and revitalize the potential of therapeutic RDN to provide significant clinical benefits. Renal nerve stimulation has emerged as potential tool to identify sympatho-stimulatory fibers, avoid sympatho-inhibitory fibers, and thus guide selective RDN.