Description: Electron microscopy is used to determine the form and size of samples from images. Consequently, distortion or error in the images produces incorrect data. This study developed an algorithm to enhance the scanner signal in order to improve the orthogonality of the image. The results of images with poor orthogonality, when observed from the central axis standard, are analogous to those of rotationally transformed images. Therefore, we believe that transmitting enhanced signals with rotationally transformed images will improve the quality of the data.

Description: The utility of 18 F-FDG PET/CT in patients with nasal-type natural killer (NK)/T-cell lymphoma has not been established. Therefore, we evaluated the role of 18 F-FDG PET/CT for determining cancer staging by comparing its results to those of conventional staging methods (CSMs) (physical examination, CT with intravenous contrast, biopsies from primary sites, and bone marrow examinations) in patients with nasal-type NK/T-cell lymphoma. Methods: In this study, 52 consecutive patients (34 men, 18 women; mean age, 49.4 y) with newly diagnosed nasal-type NK/T-cell lymphoma were studied. Anatomic regions ( n = 1,300; 16 nodal and 9 extranodal regions per patient) were assessed with an 18 F-FDG PET/CT scan and with CSMs, and each anatomic region was classified as positive or negative for malignancy. Biopsy and clinical follow-up, including additional imaging studies, were used as the gold standard for diagnosis. Results: Of the 59 nodal and 71 extranodal anatomic regions that were truly positive for malignancy, 18 F-FDG PET/CT detected 58 nodal and 69 extranodal. CSMs, however, detected only 44 of the nodal and 61 of the extranodal anatomic regions that were positive for malignancy (nodal comparison of PET/CT vs. CSMs, P 〈 0.001; extranodal comparison of PET/CT vs. CSMs, P = 0.008). PET/CT scans exhibited a significantly better sensitivity (97.7% vs. 80.7%, P 〈 0.001) than CSMs for the detection of malignant lesions. PET/CT findings altered the original staging category for 12 patients (21.2%) and affected treatment planning in 23 cases (44.2%). Conclusion: Our study demonstrated that 18 F-FDG PET/CT scanning is a valuable modality for staging and treatment planning in patients with nasal-type NK/T-cell lymphoma.

Description: Microsatellite instability (MSI) is a critical mechanism that drives genetic aberrations in cancer. To identify the entire MS mutation, we performed the first comprehensive genome- and transcriptome-wide analyses of mutations associated with MSI in Korean gastric cancer cell lines and primary tissues. We identified 18,377 MS mutations of five or more repeat nucleotides in coding sequences and untranslated regions of genes, and discovered 139 individual genes whose expression was down-regulated in association with UTR MS mutation. In addition, we found that 90.5% of MS mutations with deletions in gene regions occurred in UTRs. This analysis emphasizes the genetic diversity of MSI-H gastric tumors and provides clues to the mechanistic basis of instability in microsatellite unstable gastric cancers.

Description: Background— Chronic kidney disease (CKD) promotes the development of atherosclerosis and increases the risk of cardiovascular disease. The aim of the present study was to compare the coronary plaque characteristics of patients with and without CKD using optical coherence tomography. Methods and Results— We identified 463 nonculprit plaques from 287 patients from the Massachusetts General Hospital (MGH) optical coherence tomography registry. CKD was defined as estimated glomerular filtration rate 〈60 mL/min per 1.73 m 2 . A total of 402 plaques (250 patients) were in the non-CKD group and 61 plaques (37 patients) were in the CKD group. Compared with non-CKD plaques, plaques with CKD had a larger lipid index (mean lipid arc x lipid length, 1248.4±782.8 mm° [non-CKD] versus 1716.1±1116.2 mm° [CKD]; P =0.003). Fibrous cap thickness was not significantly different between the groups. Calcification (34.8% [non-CKD] versus 50.8% [CKD]; P =0.041), cholesterol crystals (11.2% [non-CKD] versus 23.0% [CKD]; P =0.048), and plaque disruption (5.5% [non-CKD] versus 13.1% [CKD]; P =0.049) were more frequently observed in the CKD group. In the multivariate linear regression model, a lower estimated glomerular filtration rate and diabetes mellitus were independent risk factors for a larger lipid index. Conclusions— Compared with non-CKD patients, the patients with CKD had a larger lipid index with a higher prevalence of calcium, cholesterol crystals, and plaque disruption. The multivariate linear regression model demonstrated that a lower estimated glomerular filtration rate was an independent risk factor for a larger lipid index. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01110538.

Description: Although the role of IL-7 and IL-7R has been implicated in the pathogenesis of rheumatoid arthritis (RA), the majority of the studies have focused on the effect of IL-7/IL-7R in T cell development and function. Our novel data, however, document that patients with RA and greater disease activity have higher levels of IL-7, IL-7R, and TNF-α in RA monocytes, suggesting a feedback regulation between IL-7/IL-7R and TNF-α cascades in myeloid cells that is linked to chronic disease progression. Investigations into the involved mechanism showed that IL-7 is a novel and potent chemoattractant that attracts IL-7R + monocytes through activation of the PI3K/AKT1 and ERK pathways at similar concentrations of IL-7 detected in RA synovial fluid. To determine whether ligation of IL-7 to IL-7R is a potential target for RA treatment and to identify their mechanism of action, collagen-induced arthritis (CIA) was therapeutically treated with anti–IL-7 Ab or IgG control. Anti–IL-7 Ab treatment significantly reduces CIA monocyte recruitment and osteoclast differentiation as well as potent joint monocyte chemoattractants and bone erosion markers, suggesting that both direct and indirect pathways might contribute to the observed effect. We also demonstrate that reduction in joint MIP-2 levels is responsible for suppressed vascularization detected in mice treated with anti–IL-7 Ab compared with the control group. To our knowledge, we show for the first time that expression of IL-7/IL-7R in myeloid cells is strongly correlated with RA disease activity and that ligation of IL-7 to IL-7R contributes to monocyte homing, differentiation of osteoclasts, and vascularization in the CIA effector phase.

Description: A deficiency in bone morphogenetic protein receptor type 2 (BMPR2) signaling is a central contributor in the pathogenesis of pulmonary arterial hypertension (PAH). We have recently shown that endothelial-specific Bmpr2 deletion by a novel L1Cre line resulted in pulmonary hypertension. SMAD1 is one of the canonical signal transducers of the BMPR2 pathway, and its reduced activity has been shown to be associated with PAH. To determine whether SMAD1 is an important downstream mediator of BMPR2 signaling in the pathogenesis of PAH, we analyzed pulmonary hypertension phenotypes in Smad1 -conditional knockout mice by deleting the Smad1 gene either in endothelial cells or in smooth muscle cells using L1Cre or Tagln -Cre mouse lines, respectively. A significant number of the L1Cre(+); Smad1 (14/35) and Tagln -Cre(+); Smad1 (4/33) mutant mice showed elevated pulmonary pressure, right ventricular hypertrophy, and a thickening of pulmonary arterioles. A pulmonary endothelial cell line in which the Bmpr2 gene deletion can be induced by 4-hydroxy tamoxifen was established. SMAD1 phosphorylation in Bmpr2 -deficient cells was markedly reduced by BMP4 but unaffected by BMP7. The sensitivity of SMAD2 phosphorylation by transforming growth factor-β1 was enhanced in the Bmpr2 -deficient cells, and the inhibitory effect of transforming growth factor-β1–mediated SMAD2 phosphorylation by BMP4 was impaired in the Bmpr2 -deficient cells. Furthermore, transcript levels of several known transforming growth factor-β downstream genes implicated in pulmonary hypertension were elevated in the Bmpr2 -deficient cells. Taken together, these data suggest that SMAD1 is a critical mediator of BMPR2 signaling pertinent to PAH, and that an impaired balance between BMP4 and transforming growth factor-β1 may account for the pathogenesis of PAH.

Description: Purpose: To investigate the patterns of imaging appearance of hepatocellular carcinoma (HCC) on gadoxetic acid–enhanced magnetic resonance (MR) images and to assess their potential value as prognostic markers of HCC associated with tumor recurrence after surgery. Materials and Methods: The institutional review board approved this retrospective study and informed consent was waived. A total of 216 patients with 304 pathologically proved HCCs underwent gadoxetic acid–enhanced MR imaging prior to surgery and were included in the study. Two reviewers, blinded to the clinical data, evaluated in consensus the imaging patterns of HCC according to enhancement patterns on dynamic phase images and signal intensity on hepatobiliary phase (HBP) images. The association of imaging features with clinical-pathologic findings was evaluated by using the Student t test, 2 test, Mann-Whitney U test, and linear-by-linear association. The dependence of time to tumor recurrence (TTR) after surgery was evaluated by using the Kaplan-Meier method, log-rank test, and Cox proportional hazard model. Results: HCCs with atypical enhancement pattern ( P = .0167, P = .0450, P 〈 .0001, respectively) and iso- to hyperintensity on HBP images ( P = .0001, P = .0002, P 〈 .0001, respectively) had smaller tumor size, lower histologic grade, and worse Child-Pugh class. The log-rank test ( P = .0064) and Cox proportional hazards model (hazard ratio, 5.676; P = .0158) revealed that HCCs with iso- to hyperintensity on HBP images had significantly longer TTR than HCCs with hypointensity on HBP images. Conclusion: HCCs can be classified into several imaging patterns on gadoxetic acid–enhanced MR images, which are associated with tumor aggressiveness and outcome. In addition, iso- to hyperintensity on HBP images may be a useful imaging biomarker to indicate longer TTR after surgery. © RSNA, 2013

Description: Background and Purpose— Diffusion-weighted image fluid-attenuated inversion recovery (FLAIR) mismatch has been considered to represent ischemic lesion age. However, the inter-rater agreement of diffusion-weighted image FLAIR mismatch is low. We hypothesized that color-coded images would increase its inter-rater agreement. Methods— Patients with ischemic stroke 〈24 hours of a clear onset were retrospectively studied. FLAIR signal change was rated as negative, subtle, or obvious on conventional and color-coded FLAIR images based on visual inspection. Inter-rater agreement was evaluated using and percent agreement. The predictive value of diffusion-weighted image FLAIR mismatch for identification of patients 〈4.5 hours of symptom onset was evaluated. Results— One hundred and thirteen patients were enrolled. The inter-rater agreement of FLAIR signal change improved from 69.9% ( k =0.538) with conventional images to 85.8% ( k =0.754) with color-coded images ( P =0.004). Discrepantly rated patients on conventional, but not on color-coded images, had a higher prevalence of cardioembolic stroke ( P =0.02) and cortical infarction ( P =0.04). The positive predictive value for patients 〈4.5 hours of onset was 85.3% and 71.9% with conventional and 95.7% and 82.1% with color-coded images, by each rater. Conclusions— Color-coded FLAIR images increased the inter-rater agreement of diffusion-weighted image FLAIR recovery mismatch and may ultimately help identify unknown-onset stroke patients appropriate for thrombolysis.

Description: Our aim was to examine the impact of TLR5 ligation in rheumatoid arthritis (RA) and experimental arthritis pathology. Studies were conducted to investigate the role of TLR5 ligation on RA and mouse myeloid cell chemotaxis or osteoclast formation, and in addition, to uncover the significance of TNF-α function in TLR5-mediated pathogenesis. Next, the in vivo mechanism of action was determined in collagen-induced arthritis (CIA) and local joint TLR5 ligation models. Last, to evaluate the importance of TLR5 function in RA, we used anti-TLR5 Ab therapy in CIA mice. We show that TLR5 agonist, flagellin, can promote monocyte infiltration and osteoclast maturation directly through myeloid TLR5 ligation and indirectly via TNF-α production from RA and mouse cells. These two identified TLR5 functions are potentiated by TNF-α, because inhibition of both pathways can more strongly impair RA synovial fluid–driven monocyte migration and osteoclast differentiation compared with each factor alone. In preclinical studies, flagellin postonset treatment in CIA and local TLR5 ligation in vivo provoke homing and osteoclastic development of myeloid cells, which are associated with the TNF-α cascade. Conversely, CIA joint inflammation and bone erosion are alleviated when TLR5 function is blocked. We found that TLR5 and TNF-α pathways are interconnected, because TNF-α is produced by TLR5 ligation in RA myeloid cells, and anti–TNF-α therapy can markedly suppress TLR5 expression in RA monocytes. Our novel findings demonstrate that a direct and an indirect mechanism are involved in TLR5-driven RA inflammation and bone destruction.

Description: Hepatitis C virus (HCV) nonstructural protein 5B (NS5B), an RNA-dependent RNA polymerase (RdRp), is the key enzyme for HCV RNA replication. We previously showed that HCV RdRp is phosphorylated by protein kinase C-related kinase 2 (PRK2). In the present study, we used biochemical and reverse-genetics approaches to demonstrate that HCV NS5B phosphorylation is crucial for viral RNA replication in cell culture. Two-dimensional phosphoamino acid analysis revealed that PRK2 phosphorylates NS5B exclusively at its serine residues in vitro and in vivo . Using in vitro kinase assays and mass spectrometry, we identified two phosphorylation sites, Ser29 and Ser42, in the 1 finger loop region that interacts with the thumb subdomain of NS5B. Colony-forming assays using drug-selectable HCV subgenomic RNA replicons revealed that preventing phosphorylation by Ala substitution at either Ser29 or Ser42 impairs HCV RNA replication. Furthermore, reverse-genetics studies using HCV infectious clones encoding phosphorylation-defective NS5B confirmed the crucial role of these PRK2 phosphorylation sites in viral RNA replication. Molecular-modeling studies predicted that the phosphorylation of NS5B stabilizes the interactions between its 1 loop and thumb subdomain, which are required for the formation of the closed conformation of NS5B known to be important for de novo RNA synthesis. Collectively, our results provide evidence that HCV NS5B phosphorylation has a positive regulatory role in HCV RNA replication. IMPORTANCE While the role of RNA-dependent RNA polymerases (RdRps) in viral RNA replication is clear, little is known about their functional regulation by phosphorylation. In this study, we addressed several important questions about the function and structure of phosphorylated hepatitis C virus (HCV) nonstructural protein 5B (NS5B). Reverse-genetics studies with HCV replicons encoding phosphorylation-defective NS5B mutants and analysis of their RdRp activities revealed previously unidentified NS5B protein features related to HCV replication and NS5B phosphorylation. These attributes most likely reflect potential structural changes induced by phosphorylation in the 1 finger loop region of NS5B with two identified phosphate acceptor sites, Ser29 and Ser42, which may transiently affect the closed conformation of NS5B. Elucidating the effects of dynamic changes in NS5B phosphorylation status during viral replication and their impacts on RNA synthesis will improve our understanding of the molecular mechanisms of NS5B phosphorylation-mediated regulation of HCV replication.