Citations

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 ( ADCY9 ) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

Abstract Wide-necked bifurcation aneurysms pose technical and anatomical challenges to endovascular treatment, which make the simpler assisted (balloon or single stent) coiling techniques less effective. 1 Consequently, unique endovascular solutions to treat such aneurysms have been devised. 2,3 One such device is PulseRider (Cerenovus, New Brunswick, New Jersey), which is designed to provide neck support for a coil mass while protecting the bifurcation. 3 The device comprises a body or stem that is deployed in the parent artery and a saddle component that sits at the aneurysm neck to keep the coil mass away from the bifurcation. There are several technical nuances involved in successful use of the device during positioning, deployment, and detachment. 3 We present a surgical video detailing the steps of PulseRider-assisted coiling of unruptured basilar bifurcation (or basilar apex) aneurysms. The first case highlights index treatment at diagnosis and the second showcases treatment of a recurrent basilar apex aneurysm. Both patients provided informed consent to the procedure. We also briefly discuss the rationale for treating basilar apex aneurysms. 4,5

Abstract Mechanical thrombectomy as a treatment for large vessel occlusion to achieve rapid revascularization is supported in the literature. 1-3 The presenting symptoms will localize to functions of the ischemic area. The middle cerebral artery (MCA) supplies areas of the frontal, temporal, and parietal cortices, as well as the basal ganglia. Occlusion of the MCA will present with contralateral hemiplegia, sensory loss, and, if the dominant hemisphere is involved, language deficits. We present a right-hand-dominant 79-yr-old female with right MCA syndrome—her last known well time was 1.5 h prior to presentation. Her NIH (National Institutes of Health) Stroke Scale was 16, most notable for left hemiplegia. Although the patient presented early in the clinical time course, as part of our institution protocol, a computed tomography (CT) head, CT perfusion, and CT angiogram (CTA) were performed. CT head did not demonstrate acute hemorrhage, so she received intravenous tissue plasminogen activator. CTA demonstrated a right MCA occlusion and CT perfusion suggested a large area of salvageable tissue, so she was taken to the angiography suite for mechanical thrombectomy. Angiography of the right internal carotid artery (ICA) showed MCA occlusion (insular segment). A thrombectomy device was deployed over the area of occlusion and allowed to engage for 5 min. An aspiration catheter was advanced over the stentriever up against the clot. The stentriever device was withdrawn under continuous aspiration and follow-up angiography showed complete reperfusion. The patient demonstrated improvement and was eventually discharged to an inpatient rehabilitation center. Patient provided consent for photography per university protocol. Institutional review board (IRB) approval was not needed for the single-patient data included in this report.

PURPOSETumor tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the PTEN-PI3K-AKT pathway. However, identifying CNVs in plasma cell–free DNA (cfDNA) has proven to be challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, we profiled PTEN-PI3K-AKT pathway aberrations in patients with mCRPC using a novel cfDNA assay optimized for CNV detection.METHODSA next-generation sequencing–based cfDNA assay was used to profile 231 patients with mCRPC from two independent cohorts (Australian, n = 78; United States, n = 153). PTEN-PI3K-AKT pathway genomic aberrations were correlated with clinical outcomes, including progression-free survival and overall survival (OS).RESULTSPTEN loss and PIK3CA gain were detected in 37% (85 of 231) and 17% (39 of 231) of patients, respectively. Poorer outcomes were observed in patients with PTEN-PI3K-AKT pathway aberrations, including those with dual PTEN loss and PIK3CA gain (hazard ratio 2.3, 95% CI 1.2 to 4.4). Cumulative CNV burden in the PTEN-PI3K-AKT and androgen receptor (AR) pathways was associated with significantly worse clinical outcomes (0 v 1 v ≥ 2 CNVs in Australian cohort: median OS 33.5 v 17.2 v 9.7 months, P < .001; 0 v 1 v ≥ 2 CNVs in US cohort: median OS 35.5 v 14.3 v 9.2 months, P < .001). Notably, 21% (31 of 146) of PTEN-neutral patients harbored alternative PTEN-PI3K-AKT pathway aberrations.CONCLUSIONPTEN-PI3K-AKT pathway CNVs were readily detected using our cfDNA assay, with the prevalence of PTEN loss comparable with tissue-based studies. Additional PTEN-PI3K-AKT pathway aberrations were found in one fifth of PTEN-neutral cases. Concurrent CNVs in the PTEN-PI3K-AKT and AR pathways portended poor survival, and identifying this high-risk patient subset for dual AR/Akt inhibition may optimize precision treatment with Akt inhibitors in mCRPC.

Abstract As capabilities for endovascular treatment of intracranial vascular pathologies continue to expand, the need for access to the distal internal carotid artery with rigid support catheter systems continues to increase. One of the dominant factors limiting this access is patient anatomy, specifically vessel tortuosity. Increased tortuosity of the carotid siphon is a frequently encountered anatomic variant and may complicate endovascular procedures in adults and children. 1,2 Failed attempts to navigate the carotid siphon with a distal access catheter carry a risk of vessel injury and treatment failure. For this reason, techniques that aid in supporting safe advancement of a distal access catheter across a tortuous carotid siphon are essential. 3,4 In this video, we demonstrate 2 ways in which this may be accomplished. The first technique uses a larger diameter microcatheter, such as the AXS Offset catheter (Stryker, Kalamazoo, Michigan), to increase support for the distal access catheter, while the second uses a buddy wire technique to accomplish this increased support. Both of these techniques can help increase the safety of navigating a tortuous carotid siphon and increase the likelihood of successful treatment. The procedures shown were performed with the informed consent of the patients.

Abstract Chromatin immunoprecipitation followed by massively parallel, high throughput sequencing (ChIP-seq) is the method of choice for genome-wide identification of DNA segments bound by specific transcription factors or in chromatin with particular histone modifications. However, the quality of ChIP-seq datasets varies widely, with a substantial fraction being of intermediate to poor quality. Thus, it is important to discern and control the factors that contribute to variation in ChIP-seq. In this study, we focused on sonication, a user-controlled variable, to produce sheared chromatin. We systematically varied the amount of shearing of fixed chromatin from a mouse erythroid cell line, carefully measuring the distribution of resultant fragment lengths prior to ChIP-seq. This systematic study was complemented with a retrospective analysis of additional experiments. We found that the level of sonication had a pronounced impact on the quality of ChIP-seq signals. Over-sonication consistently reduced quality, while the impact of under-sonication differed among transcription factors, with no impact on sites bound by CTCF but frequently leading to the loss of sites occupied by TAL1 or bound by POL2. The bound sites not observed in low-quality datasets were inferred to be a mix of both direct and indirect binding. We leveraged these findings to produce a set of CTCF ChIP-seq datasets in rare, primary hematopoietic progenitor cells. Our observation that the amount of chromatin sonication is a key variable in success of ChIP-seq experiments indicates that monitoring the level of sonication can improve ChIP-seq quality and reproducibility and facilitate ChIP-seq in rare cell types.

Abstract Proton therapy has a distinct dosimetric advantage over conventional photon therapy due to its Bragg peak profile. This allows greater accuracy in dose delivery and dose conformation to the target, however it requires greater precision in setup, delivery and for quality assurance (QA) procedures. The AAPM TG 224 report recommends daily range and spot position checks with tolerance on the order of a millimetre. Daily QA systems must therefore be efficient for daily use and be capable of sub-millimetre precision however few suitable commercial systems are available. In this work, a compact, real-time daily QA system is optimised and characterised for proton range verification using an ad-hoc Geant4 simulation. The system is comprised of a monolithic silicon diode array detector embedded in a perspex phantom. The detector is orientated at an angular offset to the incident proton beam to allow range in perspex to be determined for flat proton fields. The accuracy of the system for proton range in perspex measurements was experimentally evaluated over the full range of clinical proton energies. The mean R 100 , R 90 and R 80 ranges measured with the system were accurate within ±0.6 mm of simulated ranges in a perspex phantom for all energies assessed. This system allows real-time read-out of individual detector channels also making it appropriate for temporal beam delivery diagnostics and for spot position monitoring along one axis. The system presented provides a suitable, economical and efficient alternative for daily QA in proton therapy.

HIV is an independent risk factor for lung disease, including chronic obstructive pulmonary disease (COPD) and emphysema. Angiotensin receptor blockers may be beneficial in COPD and emphysema through pathways that have been implicated in HIV-related lung disease. We performed a randomized comparison of the effects of losartan versus placebo on the plasma concentrations of the pneumoproteins, surfactant protein D (SPD) and club cell secretory protein (CCSP), in people living with HIV (PLWH). A total of 108 PLWH were included (52 assigned to losartan and 56 assigned to placebo). We found no difference in the change from baseline in log 2 concentrations of CCSP or SPD over 1 year of follow-up. For SPD, we found a strong interaction by CD4+ counts, where those with CD4+ counts >350 cells/mm 3 treated with losartan had more reduction (improvement) in SPD concentration than those treated with placebo ( p value for interaction <.001). In conclusion, we did not find a beneficial effect of losartan on pneumoprotein concentrations in PLWH, but PLWH with higher CD4+ counts may have improvement in SPD when treated with losartan.