Preoperative Imaging in Cochlear Implants.

OBJECTIVE: To determine the utility of computed tomography (CT) and magnetic resonance imaging (MRI) in cochlear implant candidates. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral hospital. PATIENTS: A total of 207 cochlear implanted patients with CT and/or MRI. INTERVENTIONS: N/A. MAIN OUTCOME MEASURES: Age versus abnormal radiologic findings, imaging abnormality versus postoperative outcomes, postoperative outcomes versus electrode design, Cambridge Cochlear Implant Protocol (CCIP) status for imaging abnormalities, sensitivity and specificity of CT and MRI for round-window/cochlear occlusion, and MRI for incomplete partitions. RESULTS: A total of 207 patients with CT, MRI, or both were reviewed retrospectively. Less than half (15.5%) of CT scans had findings that might affect surgical intervention compared with 5.9% of MRI. No significant difference was found between children and adults for relevant imaging abnormalities (grade 4 or higher) with either CT (p = 0.931) or MRI (p = 0.606). CCIP status correlated with cochlear abnormalities (p = 0.040); however, only 46.2% of radiographic abnormalities on CT would be identified by these criteria. For detecting cochlear occlusion requiring surgical intervention, the sensitivity and specificity for CT were 40% (4 of 10; 95% confidence interval [CI], 12.16-73.76) and 95.73% (95% CI, 91.40-98.27), respectively. For MRI, the sensitivity and specificity were 33.33% (1 of 3; 95% CI, 0.84-90.57) and 96.97% (63 of 65; 95% CI, 89.32-99.63), respectively. There was no difference for postoperative AzBio scores for higher-grade imaging abnormalities (p = 0.6012) or for electrode designs (p = 0.3699). CONCLUSIONS: Significant radiographic abnormalities were relatively uncommon in cochlear implant patients on either CT or MRI at our single-center institution. If present, abnormal imaging findings rarely translated to management changes. CCIP status does not reliably predict which patients are likely to have abnormalities. Both MRI and CT have low sensitivity for round-window or cochlear occlusion, but detection likely leads to changes in surgical management.

Predicting the capsid architecture of phages from metagenomic data.

Tailed phages are viruses that infect bacteria and are the most abundant biological entities on Earth. Their ecological, evolutionary, and biogeochemical roles in the planet stem from their genomic diversity. Known tailed phage genomes range from 10 to 735 kilobase pairs thanks to the size variability of the protective protein capsids that store them. However, the role of tailed phage capsids' diversity in ecosystems is unclear. A fundamental gap is the difficulty of associating genomic information with viral capsids in the environment. To address this problem, here, we introduce a computational approach to predict the capsid architecture (T-number) of tailed phages using the sequence of a single gene-the major capsid protein. This approach relies on an allometric model that relates the genome length and capsid architecture of tailed phages. This allometric model was applied to isolated phage genomes to generate a library that associated major capsid proteins and putative capsid architectures. This library was used to train machine learning methods, and the most computationally scalable model investigated (random forest) was applied to human gut metagenomes. Compared to isolated phages, the analysis of gut data reveals a large abundance of mid-sized (T = 7) capsids, as expected, followed by a relatively large frequency of jumbo-like tailed phage capsids (T ≥ 25) and small capsids (T = 4) that have been under-sampled. We discussed how to increase the method's accuracy and how to extend the approach to other viruses. The computational pipeline introduced here opens the doors to monitor the ongoing evolution and selection of viral capsids across ecosystems.

The Missing Tailed Phages: Prediction of Small Capsid Candidates.

Tailed phages are the most abundant and diverse group of viruses on the planet. Yet, the smallest tailed phages display relatively complex capsids and large genomes compared to other viruses. The lack of tailed phages forming the common icosahedral capsid architectures T = 1 and T = 3 is puzzling. Here, we extracted geometrical features from high-resolution tailed phage capsid reconstructions and built a statistical model based on physical principles to predict the capsid diameter and genome length of the missing small-tailed phage capsids. We applied the model to 3348 isolated tailed phage genomes and 1496 gut metagenome-assembled tailed phage genomes. Four isolated tailed phages were predicted to form T = 3 icosahedral capsids, and twenty-one metagenome-assembled tailed phages were predicted to form T < 3 capsids. The smallest capsid predicted was a T = 4/3 ≈ 1.33 architecture. No tailed phages were predicted to form the smallest icosahedral architecture, T = 1. We discuss the feasibility of the missing T = 1 tailed phage capsids and the implications of isolating and characterizing small-tailed phages for viral evolution and phage therapy.

Spatially adaptive unsupervised multispectral nonlocal filtering for improved cerebral blood flow mapping using arterial spin labeling magnetic resonance imaging.

BACKGROUND: Cerebral blood flow (CBF) is an emerging biomarker for normal aging and neurodegenerative diseases. Arterial spin labeling (ASL) perfusion MRI permits noninvasive quantification of CBF. However, high-quality mapping of CBF from ASL imaging is challenging, largely due to noise. NEW METHOD: We demonstrate the ability of the recently introduced nonlocal estimation of multispectral magnitudes (NESMA) filter to greatly improve determination of CBF estimates from ASL imaging data. We evaluated the results of NESMA-ASL for CBF mapping from data obtained on human brain (n = 10) across a wide age range (21-74 years) using a standard clinical protocol. Results were compared to those obtained from unfiltered images or filtered images using conventional and advanced filters. Quantitative analyses for different spatial image resolutions and signal-to-noise ratios, SNRs, were also conducted. RESULTS: Our results demonstrate the potential of NESMA-ASL to permit high-quality high-resolution CBF mapping. NESMA-ASL substantially reduces random variation in derived CBF estimates while preserving edges and small structures, with minimal bias and dispersion in derived CBF estimates. COMPARISON WITH EXISTING METHODS: NESMA-ASL outperforms all evaluated filters in terms of noise reduction and detail preservation. Further, unlike other filters, NESMA-ASL is straightforward to implement requiring only one user-defined parameter, which is relatively insensitive to SNR or local image structure. CONCLUSIONS: In-vivo estimation of CBF in the human brain from ASL imaging data was markedly improved through use of the NESMA-ASL filter. The use of NESMA-ASL may contribute significantly to the goal of high-quality high-resolution CBF mapping within a clinically feasible acquisition time.

Rapid B1 field mapping at 3 T using the 180° signal null method with extended flip angle.

PURPOSE: To extend the null signal method (NSM) for B1 mapping to 3 T magnetic resonance imaging (MRI). BACKGROUND: The NSM operates in the steady state regime and exploits the linearity of the spoiled gradient recalled echo (SPGR) signal around the 180° flip angle (FA). Using linear regression, B1 maps are derived from three SPGR images acquired at different FAs with a short repetition time. While the conventional NSM allows accurate mapping of B1 for moderate B1 variation, we observed that this method fails for the larger B1 variations typical of high-field MRI. METHODS: We analyzed the effect of the FA range of the acquired SPGR images on B1 determination using the NSM for 3 T MRI through extensive numerical and in vivo analyses. B1 maps derived from the extended angle-range NSM (EA-NSM) were calculated and compared to those derived from the conventional, more restricted angle range, NSM, and to those derived from the reference, but much more time-consuming, double angle method (DAM). Furthermore, we investigated the compatibility of EA-NSM B1 mapping and the half-scan and SENSE reconstruction methods for accelerating acquisition time. RESULTS: Our results show that the use of the conventional FA range leads to substantial inaccuracies in B1 determination. Both numerical and in vivo analyses demonstrate that expanding the FA range of the acquired SPGR images substantially improves the accuracy of B1 maps. Furthermore, B1 maps derived from EA-NSM were demonstrated to be quantitatively comparable to those derived from the lengthy DAM protocol. We also found that B1 maps derived from SPGR images using the EA-NSM and imaging acceleration methods were comparable to those derived from images acquired without acceleration. Finally, the use of half scanning combined with SENSE reconstruction permits whole-brain B1 mapping in ~1 min. CONCLUSIONS: The EA-NSM permits accurate, fast, and practical B1 mapping in a 3 T clinical setting.

Anatomic Considerations for Temporomandibular Joint Vascularized Composite Allotransplantation.

Concomitant temporomandibular joint (TMJ) transplantation is an obvious advancement in the reconstructive armamentarium for face transplantation in scenarios involving TMJ ankylosis. This study investigates the fidelity of mandibular morphology and explores the feasibility of bilateral mandibular condyle transfer in facial vascularized composite allotransplantation. Geometric analysis was performed on 100 skeletally mature maxillofacial computed tomography scans. Exclusion criteria included mandibular trauma and dentoalveolar disease. Parameters measured were posterior height, ramus tilt, anterior height, intercondylar widths, condyle height, coronoid height, interglenoid distances, symphyseal and gonial angles, condyle and glenoid volumes, and condyle shapes. Parameters were compared by gender and ethnicity using χ, independent sample t tests, and one-way ANOVA. Correlation with age was assessed using Pearson correlation coefficients. Bilateral measurements were compared using paired-sample t tests. Mean intercondylar width was 102.5 mm (SD 7.0 mm), anterior height 21.5 mm (5.5), and posterior height 65.3 mm (7.7), Males demonstrate larger geometric parameters, for example, intercondylar width (4 mm mean difference, P = 0.005), anterior height (2.3 mm, P = 0.032), posterior height (5 mm, P = 0.001). Asians demonstrated statistically larger intercondylar width (8 mm difference to Caucasians, P < 0.001). Increased age was associated with greater anterior height, gonial angle, and symphyseal angle; decreased glenoid height; and change in condyle shape. Despite significant disparity of laterality measurements within individuals, posterior height, glenoid, and condyle volumes are equivalent. Mandibular morphology is highly variable. However, transplantation of a facial allograft including the mandible and bilateral condyles is technically and anatomically feasible in patients with concomitant TMJ pathology.

CAT-2003: A novel sterol regulatory element-binding protein inhibitor that reduces steatohepatitis, plasma lipids, and atherosclerosis in apolipoprotein E*3-Leiden mice.

CAT-2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT-2003 blocked the maturation of sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9. Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased. In apolipoprotein E*3-Leiden mice fed a cholesterol-containing western diet, CAT-2003 decreased hepatic inflammation and steatosis as evidenced by fewer inflammatory cell aggregates in histopathologic sections, decreased nuclear factor kappa B activity in liver lysates, reduced inflammatory gene expression, reduced intrahepatic cholesteryl ester and triglyceride levels, and decreased liver mass. Plasma PCSK9 was reduced and hepatic low-density lipoprotein receptor protein expression was increased; plasma cholesterol and triglyceride levels were lowered. Aortic root segments showed reduction of several atherosclerotic markers, including lesion size, number, and severity. CAT-2003, when dosed in combination with atorvastatin, further lowered plasma cholesterol levels and decreased hepatic expression of SREBP target genes. Conclusion: SREBP inhibition is a promising new strategy for the prevention and treatment of diseases associated with abnormal lipid metabolism, such as atherosclerosis and nonalcoholic steatohepatitis. (Hepatology Communications 2017;1:311-325).

Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers.

HER2 kinase inhibitors, such as lapatinib, have demonstrated clinical efficacy in HER2-amplified breast cancers. By profiling nearly 700 human cancer cell lines, we identified a subset of non-HER2 amplified cancer cells with striking sensitivity to HER2 kinase inhibition-particularly from head and neck tumors. These cells were found to depend on a neuregulin-1 (NRG1)-mediated autocrine loop driving HER3 activation, which can be disrupted by lapatinib. Elevated NRG1 expression and activated HER3 are strongly associated with lapatinib sensitivity in vitro, and these biomarkers were enriched in a subset of primary head and neck cancer samples. The findings suggest that patients with NRG1-driven tumors lacking HER2 amplification may derive significant clinical benefit from HER2:HER3-directed therapies.

Influence of age on Salvia divinorum use: results of an Internet survey.

An Internet-based survey of Salvia divinorum ("salvia") users was conducted to identify correlates surrounding its use. Salvia-knowledgeable persons were recruited via "social networking Internet websites" (n = 23) where notices were posted on recreational salvia group message boards (n = 69). Data collection included demographics, use circumstances, experiences, and age (current and at first salvia use). A total of 219 surveys were analyzed. Salvia users who were young adults (< or = 21 yrs) at first use favored salvia for fun (OR = 1.94, CI = 1.08-3.49, p = 0.03) or to relieve boredom (OR = 2.06 CI = 1.09-3.91, p = 0.02), while salvia users who were adults (> or = 22 yrs) at first use favored salvia for spiritual effects (OR = 2.63, CI = 1.02-6.75, p = 0.04). Being an adult at first use was associated with higher odds of concurrent marijuana (OR = 2.68, CI = 1.50-4.78, p = 0.0007) or tobacco use (OR = 1.94, CI = 1.05-3.60, p = 0.03). Over half of all respondents reported use reduction or cessation in the past 12 months (114 of 219, 52%), citing dislike of the high (33.3%) or loss of interest in salvia (28.9%). Reports of cessation suggest salvia use may be more attributed to curiosity than continual abuse.

A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.

Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly "drug-tolerant" cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.

Ligand-dependent platelet-derived growth factor receptor (PDGFR)-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors.

Platelet-derived growth factor (PDGF) receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor, c-KIT, and PDGFR, and has shown clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 of 637 tested human tumor-derived cell lines show significant sensitivity to single-agent sunitinib exposure. These two cell lines [a non-small-cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adenosquamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar codependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to gastrointestinal stromal tumors, rare tumors that show PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.

Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma.

Activating BRAF kinase mutations arise in approximately 7% of all human tumors, and preclinical studies have validated the RAF-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-ERK signaling cascade as a potentially important therapeutic target in this setting. Selective RAF kinase inhibitors are currently undergoing clinical development, and based on the experience with other kinase-targeted therapeutics, it is expected that clinical responses to these agents, if observed, will lead to the eventual emergence of drug resistance in most cases. Thus, it is important to establish molecular mechanisms underlying such resistance to develop effective therapeutic strategies to overcome or prevent drug resistance. To anticipate potential mechanisms of acquired resistance to RAF inhibitors during the course of treatment, we established drug-resistant clones from a human melanoma-derived cell line harboring the recurrent V600E activating BRAF mutation, which exhibits exquisite sensitivity to AZ628, a selective RAF kinase inhibitor. We determined that elevated CRAF protein levels account for the acquisition of resistance to AZ628 in these cells, associated with a switch from BRAF to CRAF dependency in tumor cells. We also found that elevated CRAF protein levels may similarly contribute to primary insensitivity to RAF inhibition in a subset of BRAF mutant tumor cells. Interestingly, AZ628-resistant cells demonstrating either primary drug insensitivity or acquired drug resistance exhibit exquisite sensitivity to the HSP90 inhibitor geldanamycin. Geldanamycin effectively promotes the degradation of CRAF, thereby revealing a potential therapeutic strategy to overcome resistance to RAF inhibition in a subset of BRAF mutant tumors.

A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes.

"Oncogene addiction" describes an unexplained dependency of cancer cells on a particular cellular pathway for survival or proliferation. We report that differential attenuation rates of prosurvival and proapoptotic signals in oncogene-dependent cells contribute to cell death following oncogene inactivation. Src-, BCR-ABL-, and EGF receptor-dependent cells exhibit a similar profile of signal attenuation following oncogene inactivation characterized by rapid diminution of phospho-ERK, -Akt, and -STAT3/5, and a delayed accumulation of the proapoptotic effector phospho-p38 MAPK. These findings implicate a transient imbalance in survival and apoptotic oncogenic outputs in the apoptotic response to oncogene inactivation. Moreover, these observations implicate a common profile of signal attenuation for multiple oncogenes and suggest that "addiction" associated with apoptosis reflects an active rather than a passive process.

Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells.

The epidermal growth factor receptor (EGFR) gene is commonly amplified and rearranged in glioblastoma multiforme leading to overexpression of wild-type and mutant EGFRs. Expression of wild-type EGFR ligands, such as transforming growth factor-alpha (TGF-alpha) or heparin-binding EGF (HB-EGF), is also often increased in gliomas resulting in an autocrine loop that contributes to the growth autonomy of glioma cells. Glioblastoma multiformes express a characteristic EGFR mutant (EGFRvIII, de 2-7) that does not bind ligand, signals constitutively, and is more tumorigenic than the wild-type receptor. However, the downstream signals that mediate this increased tumorigenicity are not well understood. We hypothesized that signals induced specifically by EGFRvIII and not the wild-type receptor are more likely to mediate its increased tumorigenic activity and examined the gene expression profiles resulting from inducible expression of comparable levels of either wild-type EGFR or EGFRvIII in a U251-MG glioma cell line. Expression of EGFRvIII resulted in specific up-regulation of a small group of genes. Remarkably, all these genes, which include TGFA, HB-EGF, EPHA2, IL8, MAP4K4, FOSL1, EMP1, and DUSP6, influence signaling pathways known to play a key role in oncogenesis and function in interconnected networks. Increased expression of EGFRvIII-induced genes was validated by real-time PCR. The mutant receptor does not bind ligand, and EGFRvIII-induced expression of TGF-alpha and HB-EGF suggests that EGFRvIII plays a role in generating an autocrine loop using the wild-type EGFR in glioma. It also raises the possibility that EGFRvIII may signal, at least in part, through the wild-type receptor. Indeed, we show that inhibiting the activity of HB-EGF, a potent mitogen, with neutralizing antibodies reduces cell proliferation induced by expression of EGFRvIII. This suggests that the EGFRvIII-HB-EGF-wild-type EGFR autocrine loop plays an important role in signal transduction by EGFRvIII in glioma cells. We also show by immunohistochemistry that HB-EGF expression correlates with the presence of EGFRvIII in glioblastoma multiforme. Thus, our study provides a new insight into oncogenic signaling by EGFRvIII and improves our understanding of how autocrine loops are generated in glioma.