Faculty Bibliography

Synaptic dysfunction and loss are core pathological features in Alzheimer disease (AD). In the vicinity of amyloid-β plaques in animal models, synaptic toxicity occurs and is associated with chronic activation of the phosphatase calcineurin (CN). Indeed, pharmacological inhibition of CN blocks amyloid-β synaptotoxicity. We therefore hypothesized that CN-mediated transcriptional changes may contribute to AD neuropathology and tested this by examining the impact of CN over-expression on neuronal gene expression in vivo. We found dramatic transcriptional down-regulation, especially of synaptic mRNAs, in neurons chronically exposed to CN activation. Importantly, the transcriptional profile parallels the changes in human AD tissue. Bioinformatics analyses suggest that both nuclear factor of activated T cells and numerous microRNAs may all be impacted by CN, and parallel findings are observed in AD. These data and analyses support the hypothesis that at least part of the synaptic failure characterizing AD may result from aberrant CN activation leading to down-regulation of synaptic genes, potentially via activation of specific transcription factors and expression of repressive microRNAs.

The cannabinoid CB1 receptor (CB1R) is an abundant metabotropic G-protein-coupled receptor that has been difficult to address therapeutically because of CNS side effects exerted by orthosteric drug candidates. Recent efforts have focused on developing allosteric modulators that target CB1R. Compounds from the recently discovered class of mixed agonistic and positive allosteric modulators (Ago-PAMs) based on 2-phenylindoles have shown promising functional and binding properties as CB1R ligands. Here, we identify binding modes of both the CP 55,940 agonist and GAT228, a 2-phenylindole allosteric modulator, by using our metadynamics simulation protocol, and quantify their affinity and cooperativity by atomistic simulations. We demonstrate the involvement of multiple adjunct binding sites in the Ago-PAM characteristics of the 2-phenylindole modulators and explain their ability to compete with orthosteric agonists at higher concentrations. We validate these results experimentally by showing the contribution of multiple sites on the allosteric binding of ZCZ011, another homologous member of the class, together with the orthosteric agonist.

The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site. This binding mode was confirmed in subsequent metadynamics simulations, which gave an affinity for human hMC4R that matches the experimentally determined value. Extending our simulations of MCL0129 binding to hMC1R and hMC3R, we find that receptor subtype selectivity for hMC4R depends on few amino acids located in various structural elements of the receptor. These insights may support rational drug design targeting the melanocortin systems.

PURPOSE: Transjugular liver biopsy (TJLB) is commonly performed for staging of liver fibrosis and cirrhosis among patients with coagulopathy and/or ascites. We hypothesized that device orientation during needle firing influences hepatic tissue apposition with the specimen notch and specimen quality. METHODS: Needle biopsies were performed in ex vivo bovine livers with specimen notch of the biopsy device oriented at cranial, caudal, or lateral directions with respect to the guiding metal cannula. Biopsy specimen length was measured and evaluated for fragmentation using light microscopy. In addition, a consecutive cohort of patients (n = 50) who underwent TJLB with random (n = 22) or caudal (n = 28) needle orientation was retrospectively reviewed. The number of needle passes was documented, and pathology specimen adequacy was graded using an ordinal scale. RESULTS: A total of 400 biopsies were performed (100 in each orientation) in ex vivo bovine livers. Longer specimens were obtained with caudal orientation of the needle specimen notch (p < 0.0001, ANOVA and Kruskal-Wallis tests). There was no difference in the degree of fragmentation. In the retrospective clinical study, specimen adequacy was significantly higher among patients in the caudal orientation group (p = 0.0002, Mann-Whitney U test). CONCLUSION: Caudal orientation of the needle specimen notch of the biopsy device during TJLB produces superior core biopsy specimens. This simple technical modification may assist in obtaining higher-quality biopsy specimens during TJLB.

Renal angiomyolipoma (AML) is a benign neoplasm with a propensity to bleed among patients with tumors exceeding 4 cm in diameter but can be effectively treated with transarterial embolization to arrest or prevent hemorrhage. We report the use of transradial approach to embolize a bleeding AML in a pregnant patient in order to minimize pelvic radiation. This case illustrates the utility of transradial access as an access approach for performing superselective visceral embolization when a femoral approach is undesirable or not possible

PURPOSE: To determine if pretreatment apparent diffusion coefficient (ADC) of leiomyomas could predict volumetric response (VR) following uterine artery embolization (UAE). MATERIALS AND METHODS: We retrospectively studied 11 women who underwent pelvic MRI before and >120 days following UAE. MRI included conventional and diffusion weighted imaging sequences. Percentage change in leiomyoma volume was determined by multiplanar T2-weighted imaging. A Pearson correlation coefficient was calculated between leiomyoma VR following UAE and the following pre-embolization parameters: initial volume, relative enhancement, relative T2 signal intensity (SI) and ADC. Receiver operating characteristic (ROC) curve analysis was used to determine the sensitivity and specificity of ADC for predicting volumetric response. RESULTS: Twenty-eight leiomyomas were included with a mean interval from UAE to follow-up MRI of 207 days. The preprocedural volume of the leiomyomas ranged from 18 to 182 cm(3) (median 47 cm(3)). and ADC ranged from 0.37 to 1.71 mm(2)/s (mean 0.80 mm(2)/s). All leiomyomas were 100% necrotic following UAE. Leiomyoma VR following UAE was 48% +/- 3.5%. with significant correlation between VR and ADC (r = 0.41; P = 0.017) but no correlation with initial leiomyoma volume, relative T2 SI, or relative enhancement. Using a threshold of 0.875 x 10(-3) mm(2)/s, ADC could predict > 50% VR with sensitivity and specificity of 70% and 83%, respectively. CONCLUSION: Pre-UAE ADC of leiomyomas correlated significantly with percent VR following UAE. In contrast, no correlation was seen between VR post-UAE and conventional imaging findings. This suggests that VR following UAE depends on leiomyoma histology reflected in DWI rather than features revealed by conventional MRI

Cryoablation refers to all methods of destroying tissue by freezing. Cryoablation causes cellular damage, death, and necrosis of tissues by direct mechanisms, which cause cold-induced injury to cells, and indirect mechanisms, which cause changes to the cellular microenvironment and impair tissue viability. Cellular injury, both indirect and direct, can be influenced by four factors: cooling rate, target temperature, time at target temperature, and thawing rate. In this review, the authors describe the mechanisms of cellular injury that occur with cryoablation, the major advantages and disadvantages of cryoablation compared with other thermal ablation techniques, and the current commercially available cryoablation ablation systems.

PURPOSE: To assess the diagnostic accuracy of image subtraction compared with nonsubtracted images obtained with contrast-enhanced T1-weighted imaging (CE T1WI) for the diagnosis of hepatocellular carcinoma (HCC) necrosis after transarterial chemoembolization (TACE), using liver explant as the reference standard. MATERIALS AND METHODS: Thirty-four patients who underwent TACE within 90 days of liver transplantation and CE MRI scans were assessed by two independent observers who determined the percentage of tumor necrosis using nonsubtracted and subtracted postcontrast phases. Histopathologic percentage of necrosis was retrospectively determined by an experienced pathologist. Spearman rank correlation test was used to correlate the percentages of necrosis from MR evaluation and from pathology. Receiver operating characteristics curve analysis was performed to determine the performance of subtracted versus nonsubtracted datasets for the diagnosis of complete tumor necrosis. RESULTS: There were 57 HCCs (mean size, 2.4 cm; range, 1.2-4.2 cm) diagnosed at explant and identified on MRI, including 16 completely necrotic HCCs. Subtraction demonstrated better interobserver agreement than nonsubtraction dataset for the diagnosis of tumor necrosis. There was a strong correlation between image subtraction and histopathologic assessment of necrosis (r = 0.80-0.86, depending on the phase, P < 0.0001). Subtraction demonstrated significantly higher sensitivity and accuracy for the diagnosis of complete tumor necrosis compared with nonsubtracted dataset. CONCLUSION: Image subtraction enables accurate assessment of necrosis of HCC after TACE with the best accuracy observed at the arterial phase