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PURPOSE: To evaluate repeatability of ROI sampling strategies for quantifying hepatic proton density fat fraction (PDFF) and to assess error relative to the 9-ROI PDFF. METHODS: This was a secondary analysis in subjects with known or suspected nonalcoholic fatty liver disease who underwent MRI for magnitude-based hepatic PDFF quantification. Each subject underwent three exams, each including three acquisitions (nine acquisitions total). An ROI was placed in each hepatic segment on the first acquisition of the first exam and propagated to other acquisitions. PDFF was calculated for each of 511 sampling strategies using every combination of 1, 2, …, all 9 ROIs. Intra- and inter-exam intraclass correlation coefficients (ICCs) and repeatability coefficients (RCs) were estimated for each sampling strategy. Mean absolute error (MAE) was estimated relative to the 9-ROI PDFF. Strategies that sampled both lobes evenly (“balanced”) were compared with those that did not (“unbalanced”) using two-sample t-tests. RESULTS: The 29 enrolled subjects (23 male, mean age 24 years) had mean 9-ROI PDFF 11.8% (1.1–36.3%). With more ROIs, ICCs increased, RCs decreased, and MAE decreased. Of the 60 balanced strategies with 4 ROIs, all (100%) achieved inter- and intra-exam ICCs>0.998, 55 (92%) achieved intra-exam RC

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD develop refractory epilepsy with multiple seizure types. Management of seizures in CDD remains challenging for clinicians given the highly refractory nature of seizures and the limited number of disease-specific studies that offer a high level of evidence. Epileptic spasms are the most common seizure type in CDD and are more often refractory to standard first-line treatment than are spasms of other etiologies. In other seizure types, the effectiveness of antiseizure medications is limited and wanes over time. Ketogenic diet and palliative surgical treatments have both had mixed results in observational studies. When treating refractory seizures in CDD, we recommend carefully balancing seizure control and treatment-related side effects to optimize each individual's overall quality of life. Clinical trials of medications targeting epilepsy in CDD have been conducted, and additional investigational small molecules, gene therapy, and other disease-modifying therapies are in development for CDD.

Objectives To compare the diagnostic accuracy of US shear wave elastography (SWE) and magnetic resonance elastography (MRE) for classifying fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD). Methods Patients from a prospective single-center cohort with clinical liver biopsy for known or suspected NAFLD underwent contemporaneous SWE and MRE. AUCs for classifying biopsy-determined liver fibrosis stages ≥ 1, ≥ 2, ≥ 3, and = 4, and their respective performance parameters at cutoffs providing ≥ 90% sensitivity or specificity were compared between SWE and MRE. Results In total, 100 patients (mean age, 51.8 ± 12.9 years; 46% males; mean BMI 31.6 ± 4.7 kg/m2) with fibrosis stage distribution (stage 0/1/2/3/4) of 43, 36, 5, 10, and 6%, respectively, were included. AUCs (and 95% CIs) for SWE and MRE were 0.65 (0.54–0.76) and 0.81 (0.72–0.89), 0.81 (0.71–0.91) and 0.94 (0.89–1.00), 0.85 (0.74–0.96) and 0.95 (0.89–1.00), and 0.91 (0.79–1.00) and 0.92 (0.83–1.00), for detecting fibrosis stage ≥ 1, ≥ 2, ≥ 3, and = 4, respectively. The differences were significant for detecting fibrosis stage ≥ 1 and ≥ 2 (p Conclusions In adults with NAFLD, MRE was more accurate than SWE in diagnosing stage ≥ 1 and ≥ 2 fibrosis, but not stage ≥ 3 or 4 fibrosis. Key Points • For detecting any fibrosis or mild fibrosis, MR elastography was significantly more accurate than shear wave elastography. • For detecting advanced fibrosis and cirrhosis, MRE and SWE did not differ significantly in accuracy. • For excluding advanced fibrosis and potentially ruling out the need for biopsy, SWE and MRE did not differ significantly in negative predictive value. • Neither SWE nor MRE had sufficiently high positive predictive value to rule in advanced fibrosis.

Postzygotic (somatic) variants in the mTOR pathway genes cause a spectrum of distinct developmental abnormalities. Accurate classification of somatic variants in this group of disorders is crucial for affected individuals and their families.The ClinGen Brain Malformation Variant Curation Expert Panel was formed to curate somatic variants associated with developmental brain malformations. We selected the genes AKT3, MTOR, PIK3CA, and PIK3R2 as the first set of genes to provide additional specifications to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) sequence variant interpretation guidelines, which currently focus solely on germline variants.A total of 24 of the original 28 ACMG/AMP criteria required modification. Several modifications used could be applied to other genes and disorders in which somatic variants play a role: 1) using variant allele fraction differences as evidence that somatic mutagenesis occurred as a proxy for de novo variation, 2) incorporating both somatic and germline evidence, and 3) delineating phenotype on the basis of variable tissue expression.We have established a framework for rigorous interpretation of somatic mosaic variants, addressing issues unique to somatic variants that will be applicable to many genes and conditions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic of the Coronavirus disease in late 2019 (COVID-19). Vaccine development efforts have predominantly been aimed at 'Extra-viral' Spike (S) protein as vaccine vehicles, but there are concerns regarding ‘viral immune escape’ since multiple mutations may enable the mutated virus strains to escape from immunity against S protein. The ‘Intra-viral’ Nucleocapsid (N-protein) is relatively conserved among mutant strains of coronaviruses during spread and evolution. Herein, we demonstrate novel vaccine candidates against SARS-CoV-2 by using the whole conserved N-protein or its fragment/peptides. Using ELISA assay, we showed that high titers of specific anti-N antibodies (IgG, IgG1, IgG2a, IgM) were maintained for a reasonably long duration (> 5 months), suggesting that N-protein is an excellent immunogen to stimulate host immune system and robust B-cell activation. We synthesized three peptides located at the conserved regions of N-protein among CoVs. One peptide showed as a good immunogen for vaccination as well. Cytokine arrays on post-vaccination mouse sera showed progressive up-regulation of various cytokines such as IFN-γ and CCL5, suggesting that TH1 associated responses are also stimulated. Furthermore, vaccinated mice exhibited an elevated memory T cells population. Here, we propose an unconventional vaccine strategy targeting the conserved N-protein as an alternative vaccine target for coronaviruses. Moreover, we generated a mouse monoclonal antibody specifically against an epitope shared between SARS-CoV and SARS-CoV-2, and we are currently developing the First-in-Class humanized anti-N-protein antibody to potentially treat patients infected by various CoVs in the future.

Under the atmosphere of social inclusion, it becomes the essential goal of trans-disciplines professionals to promote people with intellectual disability (ID) work in community independently. Nevertheless, limitation of cognitive function of people with ID results in their difficulties in learning and insufficient vocational ability. So our team will develop the Virtual reality technology (VRT) system which will allow ID students to learn and adapt to the complex workplace effectively.

ObjectivesThis study assesses the risk of progression of Liver Imaging Reporting and Data System (LI-RADS) categories, and the effects of inter-exam changes in modality or radiologist on LI-RADS categorization.MethodsClinical LI-RADS v2014 CT and MRI exams at our institution between January 2014 and September 2017 were retrospectively identified. Untreated LR-1, LR-2, LR-3, and LR-4 observations with at least one follow-up exam were included. Three hundred and seventy-two observations in 214 patients (149 male, 65 female, mean age 61 ± 10years) were included during the study period (715 exams total). Cumulative incidence curves for progression to malignant LI-RADS categories (LR-5 or LR-M) and to LR-4 or higher were generated for each index category and compared using log-rank tests with a resampling extension. Relationships between inter-exam changes in LI-RADS category and modality or radiologist, adjusted for inter-exam time intervals, were modeled using mixed effect logistic regressions.ResultsMedian inter-exam follow-up interval and total follow-up duration were 123 and 227 days, respectively. Index LR-1, LR-2, LR-3, and LR-4 differed significantly in their cumulative incidences of progression to malignant categories (p&nbsp

The purpose of this study was to (1) evaluate proton density fat fraction (PDFF) distribution across liver segments at baseline and (2) compare longitudinal segmental PDFF changes across time points in adult patients undergoing a very low-calorie diet (VLCD) and subsequent bariatric weight loss surgery (WLS). We performed a secondary analysis of data from 118 morbidly obese adult patients enrolled in a VLCD-WLS program. PDFF was estimated using magnitude-based confounder-corrected chemical-shift-encoded (CSE) MRI in each hepatic segment and lobe at baseline (visit 1), after completion of VLCD (visit 2), and at 1, 3, and 6 months (visits 3–5) following WLS. Linear regressions were used to estimate the rate of PDFF change across visits. Lobar and segmental rates of change were compared pairwise. Baseline PDFF was significantly higher in the right lobe compared to the left lobe (p

PURPOSE:To determine the inter-reader agreement of magnetic resonance imaging proton density fat fraction (PDFF) and its longitudinal change in a clinical trial of adults with nonalcoholic steatohepatitis (NASH). STUDY TYPE:We performed a secondary analysis of a placebo-controlled randomized clinical trial of a bile acid sequestrant in 45 adults with NASH. A six-echo spoiled gradient-recalled-echo magnitude-based fat quantification technique was performed at 3T. Three independent readers measured MRI-PDFF by placing one primary and two additional regions of interest (ROIs) in each segment at both time points. Cross-sectional agreement between the three readers was evaluated using intra-class correlation coefficients (ICCs) and coefficients of variation (CV). Additionally, we used Bland-Altman analyses to examine pairwise agreement between the three readers at baseline, end of treatment (EOT), and for longitudinal change. RESULTS:Using all ROIs by all readers, mean PDFF at baseline, at EOT, and mean change in PDFF was 16.1%, 16.0%, and 0.07%, respectively. The 27-ROI PDFF measurements had 0.998 ICC and 1.8% CV at baseline, 0.998 ICC and 1.8% CV at EOT, and 0.997 ICC for longitudinal change. The 9-ROI PDFF measurements had corresponding values of 0.997 and 2.6%, 0.996 and 2.4%, and 0.994. Using 27 ROIs, the magnitude of the bias between readers for whole-liver PDFF measurement ranged from 0.03% to 0.06% points at baseline, 0.01% to 0.07% points at EOT, and 0.01% to 0.02% points for longitudinal change. CONCLUSION:Inter-reader agreement for measuring whole-liver PDFF and its longitudinal change is high. 9-ROI measurements have only slightly lower agreement than 27-ROI measurements.

Purpose: The purpose of the study is to assess the reader agreement and accuracy of eight ultrasound imaging features for classifying hepatic steatosis in adults with known or suspected hepatic steatosis. Methods: This was an IRB-approved, HIPAA-compliant prospective study of adult patients with known or suspected hepatic steatosis. All patients signed written informed consent. Ultrasound images (Siemens S3000, 6C1HD, and 4C1 transducers) were acquired by experienced sonographers following a standard protocol. Eight readers independently graded eight features and their overall impression of hepatic steatosis on ordinal scales using an electronic case report form. Duplicated images from the 6C1HD transducer were read twice to assess intra-reader agreement. Intra-reader, inter-transducer, and inter-reader agreement were assessed using intraclass correlation coefficients (ICC). Features with the highest intra-reader agreement were selected as predictors for dichotomized histological steatosis using Classification and Regression Tree (CART) analysis, and the accuracy of the decision rule was compared to the accuracy of the radiologists’ overall impression. Results: 45 patients (18 males, 27 females; mean age 56 ± 12 years) scanned from September 2015 to July 2016 were included. Mean intra-reader ICCs ranged from 0.430 to 0.777, inter-transducer ICCs ranged from 0.228 to 0.640, and inter-reader ICCs ranged from 0.014 to 0.561. The CART decision rule selected only large hepatic vein blurring and achieved similar accuracy to the overall impression (74% to 75% and 68% to 72%, respectively). Conclusions: Large hepatic vein blurring, liver–kidney contrast, and overall impression provided the highest reader agreement. Large hepatic vein blurring may provide the highest classification accuracy for dichotomized grading of hepatic steatosis.

Non-membrane bound, hydrogel-like entities, such as RNA granules, nucleate essential cellular functions through their unique physico-chemical properties. However, these intracellular hydrogels have not been as extensively studied as their extracellular counterparts, primarily due to technical challenges in probing these materials in situ. Here, by taking advantage of a chemically inducible dimerization paradigm, we developed iPOLYMER, a strategy for rapid induction of protein-based hydrogels inside living cells. A series of biochemical and biophysical characterizations, in conjunction with computational modeling, revealed that the polymer network formed in the cytosol resembles a physiological hydrogel-like entity that behaves as a size-dependent molecular sieve. We studied several properties of the gel and functionalized it with RNA binding motifs that sequester polyadenine-containing nucleotides to synthetically mimic RNA granules. Therefore, we here demonstrate that iPOLYMER presents a unique and powerful approach to synthetically reconstitute hydrogel-like structures including RNA granules in intact cells.

Author(s): Mamidipalli, Adrija; Hamilton, Gavin; Manning, Paul; Hong, Cheng William; Park, Charlie C; Wolfson, Tanya; Hooker, Jonathan; Heba, Elhamy; Schlein, Alexandra; Gamst, Anthony; Durelle, Janis; Paiz, Melissa; Middleton, Michael S; Schwimmer, Jeffrey B; Sirlin, Claude B | Abstract: PURPOSE:To determine the relationship between hepatic proton density fat fraction (PDFF) and R2* in vivo. MATERIALS AND METHODS:In this Health Insurance Portability and Accountability Act (HIPAA)-compliant, Institutional Review Board (IRB)-approved, cross-sectional study, we conducted a secondary analysis of 3T magnetic resonance imaging (MRI) exams performed as part of prospective research studies in children in whom conditions associated with iron overload were excluded clinically. Each exam included low-flip-angle, multiecho magnitude (-M) and complex (-C) based chemical-shift-encoded MRI techniques with spectral modeling of fat to generate hepatic PDFF and R2* parametric maps. For each technique and each patient, regions of interest were placed on the maps in each of the nine Couinaud segments, and composite whole-liver PDFF and R2* values were calculated. Pearson's correlation coefficients between PDFF and R2* were computed for each MRI technique. Correlations were compared using Steiger's test. RESULTS:In all, 184 children (123 boys, 61 girls) were included in this analysis. PDFF estimated by MRI-M and MRI-C ranged from 1.1-35.4% (9.44 ± 8.76) and 2.1-38.1% (10.1 ± 8.7), respectively. R2* estimated by MRI-M and MRI-C ranged from 32.6-78.7 s-1 (48.4 ± 9.8) and 27.2-71.5 s-1 (42.2 ± 8.6), respectively. There were strong and significant correlations between hepatic PDFF and R2* values estimated by MRI-M (r = 0.874; P l 0.0001) and MRI-C (r = 0.853; P l 0.0001). The correlation coefficients (0.874 vs. 0.853) were not significantly different (P = 0.15). CONCLUSION:Hepatic PDFF and R2* are strongly correlated with each other in vivo. This relationship was observed using two different MRI techniques. LEVEL OF EVIDENCE:2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:418-424.

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA-like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl-tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile-onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease-associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss-of-function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients' clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot-Marie-Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS-associated disease and support that severe early-onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment.

PURPOSE: This study compares splenic proton density fat fraction (PDFF) measured using confounder-corrected chemical-shift-encoded (CSE) MRI to MR spectroscopy in human patients at 3T. METHODS: This was a prospectively designed ancillary study to various previously described single-center studies performed in adults and children with known or suspected nonalcoholic fatty liver disease. Patients underwent magnitude-based MRI (MRI-M), complex-based MRI (MRI-C), high signal-to-noise variants (Hi-SNR MRI-M and Hi-SNR MRI-C), and MR spectroscopy (MRS) at 3T for spleen PDFF estimation. PDFF from CSE-MRI methods were compared to MRS-PDFF using Wilcoxon signed-rank tests. Demographics were summarized descriptively. Spearman’s rank correlations were computed pairwise between CSE-MRI methods. Individual patient measurements were plotted for qualitative assessment. A significance level of 0.05 was used. RESULTS: Forty-seven patients (20 female, 27 male) including 12 adults (median: 55 years old) and 35 children (median: 12 years old). Median PDFF estimated by MRS, MRI-M, Hi-SNR-MRI-M, MRI-C, and Hi-SNR-MRI-C was 1.0%, 2.3%, 1.9%, 2.2%, and 2.0%. The four CSE-MRI methods estimated statistically significant higher spleen PDFF values compared to MRS (p < 0.0001 for all). Pairwise associations in spleen PDFF values measured by different CSE-MRI methods were weak, with the highest Spearman’s rank correlations being 0.295 between MRI-M and Hi-SNR-MRI-M; none were significant after correction for multiple comparisons. No qualitative relationship was observed between PDFF measurements among the various methods. CONCLUSION: Overestimation of PDFF by CSE-MRI compared to MRS and poor agreement between related CSE-MRI methods suggest that non-zero PDFF values in human spleen are artifactual.

OBJECTIVE: We aimed to evaluate the long-term outcome of resective epilepsy surgery in patients with Lennox-Gastaut syndrome (LGS). METHODS: We reviewed the case reports of 90 patients with LGS who had undergone resective surgery between 2003 and 2014 at the Severance Children’s Hospital and managed them for a minimum period of 2 years. RESULTS: At the time of surgery, the patients were between 3.0 and 23.5 years old (mean ± SD: 9.3 ± 4.4). The time from seizure onset to surgery ranged from 0.7 to 20.1 years (7.2 ± 4.3). On postoperative follow-up for an average period of 6.1 ± 2.2 years (range: 2.1–11.4 years), 45 patients (50.0%) had no seizures, and 15 (16.7%) reported infrequent seizures. Seizure-free outcomes were achieved in 15 of the 21 (71.4%) hemispherectomies, 23 of the 51 (45.1%) multilobar resections, and 7 of the 18 (38.9%) single lobar resections. On high-resolution MRIs, 20 patients (22.2%) had negative findings, 8 of whom (40.0%) became seizure-free after resective surgery. Malformation of cortical development was the most common pathologic finding and was noted in 57 patients (63.3%). Seizure-free patients achieved better adaptive behavior and social competence than did patients with persistent seizures at the second (2–3 years after surgery) and third (4–6 years after surgery) follow-ups, as indicated by social quotients (P < .05). CONCLUSIONS: Resective surgery is a viable option in some patients to treat seizures that are associated with LGS, with a high probability of seizure control and better adaptive function.

PURPOSE:Gadoxetate-disodium (Gd-EOB-DTPA)-enhanced 3D T1- weighted (T1w) MR cholangiography (MRC) is an efficient method to evaluate biliary anatomy due to T1 shortening of excreted contrast in the bile. A method that exploits both T1 shortening and T2* effects may produce even greater bile duct conspicuity. The aim of our study is to determine feasibility and compare the diagnostic performance of two-dimensional (2D) T1w multi-echo (ME) spoiled gradient-recalled-echo (SPGR) derived R2* maps against T1w MRC for bile duct visualization in living liver donor candidates. MATERIALS AND METHODS:Ten potential living liver donor candidates underwent pretransplant 3T MRI and were included in our study. Following injection of Gd-EOBDTPA and a 20-min delay, 3D T1w MRC and 2D T1w ME SPGR images were acquired. 2D R2* maps were generated inline by the scanner assuming exponential decay. The 3D T1w MRC and 2D R2* maps were retrospectively and independently reviewed in two separate sessions by three radiologists. Visualization of eight bile duct segments was scored using a 4-point ordinal scale. The scores were compared using mixed effects regression model. RESULTS:Imaging was tolerated by all donors and R2* maps were successfully generated in all cases. Visualization scores of 2D R2* maps were significantly higher than 3D T1w MRC for right anterior (p = 0.003) and posterior (p = 0.0001), segment 2 (p

The insulation failure of multi-turn coils may cause significant damage to hydro generators including both the stator winding and core. A number of stator winding faults have been occurring on hydro generators in the last ten years as result of a turn-to-turn insulation failure. The insulation failure is complex in nature and is attributed to various design and operating factors, thus making the interpretation of the turn insulation condition extremely difficult. The purpose of this paper is to provide typical cases of failure and to share the experience in investigating these turn-to-turn faults, in order to increase knowledge about turn insulation failure. The requirements of insulation design and testing for new stator winding are specified, especially turn insulation. Surge protection to reduce the turn insulation degradation is also presented as the lesson learned from these cases. Some suggestions are also made that may enable utility owners to reduce the risk of multi-turn coil winding failures.

BackgroundClinical trials utilizing proton density fat fraction (PDFF) as an imaging biomarker for hepatic steatosis have used a laborious region-of-interest (ROI) sampling strategy of placing an ROI in each hepatic segment.PurposeTo identify a strategy with the fewest ROIs that consistently achieves close agreement with the nine-ROI strategy.Study typeRetrospective secondary analysis of prospectively acquired clinical research data.PopulationA total of 391 adults (173 men, 218 women) with known or suspected NAFLD.Field strength/sequenceConfounder-corrected chemical-shift-encoded 3T MRI using a 2D multiecho gradient-recalled echo technique.AssessmentAn ROI was placed in each hepatic segment. Mean nine-ROI PDFF and segmental PDFF standard deviation were computed. Segmental and lobar PDFF were compared. PDFF was estimated using every combinatorial subset of ROIs and compared to the nine-ROI average.Statistical testingMean nine-ROI PDFF and segmental PDFF standard deviation were summarized descriptively. Segmental PDFF was compared using a one-way analysis of variance, and lobar PDFF was compared using a paired t-test and a Bland-Altman analysis. The PDFF estimated by every subset of ROIs was informally compared to the nine-ROI average using median intraclass correlation coefficients (ICCs) and Bland-Altman analyses.ResultsThe study population's mean whole-liver PDFF was 10.1 ± 8.9% (range: 1.1-44.1%). Although there was no significant difference in average segmental (P = 0.452) or lobar (P = 0.154) PDFF, left and right lobe PDFF differed by at least 1.5 percentage points in 25.1% (98/391) of patients. Any strategy with ≥4 ROIs had ICC >0.995. 115 of 126 four-ROI strategies (91%) had limits of agreement (LOA) 0.995, and 2/36 (6%) of two-ROI strategies and 46/84 (55%) of three-ROI strategies had LOA

Chronic liver diseases often result in the development of liver fibrosis and ultimately, cirrhosis. Treatment strategies and prognosis differ greatly depending on the severity of liver fibrosis, thus liver fibrosis staging is clinically relevant. Traditionally, liver biopsy has been the method of choice for fibrosis evaluation. Because of liver biopsy limitations, noninvasive methods have become a key research interest in the field. Elastography enables the noninvasive measurement of tissue mechanical properties through observation of shear-wave propagation in the tissue of interest. Increasing fibrosis stage is associated with increased liver stiffness, providing a discriminatory feature that can be exploited by elastographic methods. Ultrasonographic (US) and magnetic resonance (MR) imaging elastographic methods are commercially available, each with their respective strengths and limitations. Here, the authors review the technical basis, acquisition techniques, and results and limitations of US- and MR-based elastography techniques. Diagnostic performance in the most common etiologies of chronic liver disease will be presented. Reliability, reproducibility, failure rate, and emerging advances will be discussed. (©) RSNA, 2018 Online supplemental material is available for this article.

This paper investigates the sustainability of off-grid renewable energy systems (RES) installed in rural communities. Through a solar home system (SHS) case project in Alumar Island, Philippines, the performance of users to sustain their systems was assessed using a novel approach proposed by the authors: the capacity and willingness approach. This approach was an adaptation to advancements in human development theory—the paradigm shift from the traditional resources approach to the capabilities approach, as proposed by A. Sen. The actual financial and technical performances of users were predicted using ordered logit regression analysis. It was found that financial capacity attributes, e.g., income and expenses, were prominent in explaining financial performance; know-how-related attributes, e.g., education, were prominent in explaining technical performance; and willingness-related attributes, i.e., willingness to pay, explained both financial and technical performance. The findings aim to provide developers and communities with better strategies for beneficiary scoping, technology selection, and capacity development.

Fatty liver disease is characterized histologically by hepatic steatosis, the abnormal accumulation of lipid in hepatocytes. It is classified into alcoholic fatty liver disease and nonalcoholic fatty liver disease, and is an increasingly important cause of chronic liver disease and cirrhosis. Assessing the severity of hepatic steatosis in these conditions is important for diagnostic and prognostic purposes, as hepatic steatosis is potentially reversible if diagnosed early. The criterion standard for assessing hepatic steatosis is liver biopsy, which is limited by sampling error, its invasive nature, and associated morbidity. As such, noninvasive imaging-based methods of assessing hepatic steatosis are needed. Ultrasound and computed tomography are able to suggest the presence of hepatic steatosis based on imaging features, but are unable to accurately quantify hepatic fat content. Since Dixon's seminal work in 1984, magnetic resonance imaging has been used to compute the signal fat fraction from chemical shift-encoded imaging, commonly implemented as out-of-phase and in-phase imaging. However, signal fat fraction is confounded by several factors that limit its accuracy and reproducibility. Recently, advanced chemical shift-encoded magnetic resonance imaging methods have been developed that address these confounders and are able to measure the proton density fat fraction, a standardized, accurate, and reproducible biomarker of fat content. The use of these methods in the liver, as well as in other abdominal organs such as the pancreas, adrenal glands, and adipose tissue will be discussed in this review.

Background Proton density fat fraction (PDFF) estimation requires spectral modeling of the hepatic triglyceride (TG) signal. Deviations in the TG spectrum may occur, leading to bias in PDFF quantification. Purpose To investigate the effects of varying six-peak TG spectral models on PDFF estimation bias. Study Type Retrospective secondary analysis of prospectively acquired clinical research data. Population Forty-four adults with biopsy-confirmed nonalcoholic steatohepatitis. Field Strength/Sequence Confounder-corrected chemical-shift-encoded 3T MRI (using a 2D multiecho gradient-recalled echo technique with magnitude reconstruction) and MR spectroscopy. Assessment In each patient, 61 pairs of colocalized MRI-PDFF and MRS-PDFF values were estimated: one pair used the standard six-peak spectral model, the other 60 were six-peak variants calculated by adjusting spectral model parameters over their biologically plausible ranges. MRI-PDFF values calculated using each variant model and the standard model were compared, and the agreement between MRI-PDFF and MRS-PDFF was assessed. Statistical Tests MRS-PDFF and MRI-PDFF were summarized descriptively. Bland–Altman (BA) analyses were performed between PDFF values calculated using each variant model and the standard model. Linear regressions were performed between BA biases and mean PDFF values for each variant model, and between MRI-PDFF and MRS-PDFF. Results Using the standard model, mean MRS-PDFF of the study population was 17.9 ± 8.0% (range: 4.1–34.3%). The difference between the highest and lowest mean variant MRI-PDFF values was 1.5%. Relative to the standard model, the model with the greatest absolute BA bias overestimated PDFF by 1.2%. Bias increased with increasing PDFF (P < 0.0001 for 59 of the 60 variant models). MRI-PDFF and MRS-PDFF agreed closely for all variant models (R2 = 0.980, P < 0.0001). Data Conclusion Over a wide range of hepatic fat content, PDFF estimation is robust across the biologically plausible range of TG spectra. Although absolute estimation bias increased with higher PDFF, its magnitude was small and unlikely to be clinically meaningful. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017.

Non-membrane bound, hydrogel-like entities, such as RNA granules, nucleate essential cellular functions through their unique physico-chemical properties. However, these intracellular hydrogels have not been as extensively studied as their extracellular counterparts, primarily due to technical challenges in probing these materialsin situ.Here, by taking advantage of a chemically inducible dimerization paradigm, we developed iPOLYMER, a strategy for rapid induction of protein-based hydrogels inside living cells. A series of biochemical and biophysical characterizations, in conjunction with computational modeling, revealed that the polymer network formed in the cytosol resembles a physiological hydrogel-like entity that behaves as a size-dependent molecular sieve. We studied several properties of the gel and functionalized it with RNA binding motifs that sequester polyadenine-containing nucleotides to synthetically mimic RNA granules. Therefore, we here demonstrate that iPOLYMER presents a unique and powerful approach to synthetically reconstitute hydrogel-like structures including RNA granules in intact cells.

Objective To compare cancer detection rates and concordance between magnetic resonance imaging and ultrasound (MRI-US) fusion-guided prostate biopsy cores obtained from axial and sagittal approaches. Patients and Methods Institutional records of MRI-US fusion-guided biopsy were reviewed. Detection rates for all cancers, Gleason ≥3 + 4 cancers, and Gleason ≥4 + 3 cancers were computed. Agreement between axial and sagittal cores for cancer detection, and frequency where one was upgraded the other was computed on a per-target and per-patient basis. Results In all, 893 encounters from 791 patients that underwent MRI-US fusion-guided biopsy in 2007–2013 were reviewed, yielding 4688 biopsy cores from 2344 targets for analysis. The mean age and PSA level at each encounter was 61.8 years and 9.7 ng/mL (median 6.45 ng/mL). Detection rates for all cancers, ≥3 + 4 cancers, and ≥4 + 3 cancers were 25.9%, 17.2%, and 8.1% for axial cores, and 26.1%, 17.6%, and 8.6% for sagittal cores. Per-target agreement was 88.6%, 93.0%, and 96.5%, respectively. On a per-target basis, the rates at which one core upgraded or detected a cancer missed on the other were 8.3% and 8.6% for axial and sagittal cores, respectively. Even with the inclusion of systematic biopsies, omission of axial or sagittal cores would have resulted in missed detection or under-characterisation of cancer in 4.7% or 5.2% of patients, respectively. Conclusion Cancer detection rates, Gleason scores, and core involvement from axial and sagittal cores are similar, but significant cancer may be missed if only one core is obtained for each target. Discordance between axial and sagittal cores is greatest in intermediate-risk scenarios, where obtaining multiple cores may improve tissue characterisation.

Purpose A magnetic resonance imaging-ultrasonography (MRI-US) fusion-guided prostate biopsy increases detection rates compared to an extended sextant biopsy. The imaging characteristics and pathology outcomes of subsequent biopsies in patients with initially negative MRI-US fusion biopsies are described in this study. Materials and methods We reviewed 855 biopsy sessions of 751 patients (June 2007 to March 2013). The fusion biopsy consisted of two cores per lesion identified on multiparametric MRI (mpMRI) and a 12-core extended sextant transrectal US (TRUS) biopsy. Inclusion criteria were at least two fusion biopsy sessions, with a negative first biopsy and mpMRI before each. Results The detection rate on the initial fusion biopsy was 55.3%; 336 patients had negative findings. Forty-one patients had follow-up fusion biopsies, but only 34 of these were preceded by a repeat mpMRI. The median interval between biopsies was 15 months. Fourteen patients (41%) were positive for cancer on the repeat MRI-US fusion biopsy. Age, prostate-specific antigen (PSA), prostate volume, PSA density, digital rectal exam findings, lesion diameter, and changes on imaging were comparable between patients with negative and positive rebiopsies. Of the patients with positive rebiopsies, 79% had a positive TRUS biopsy before referral (P = 0.004). Ten patients had Gleason 3+3 disease, three had 3+4 disease, and one had 4+4 disease. Conclusion In patients with a negative MRI-US fusion prostate biopsy and indications for repeat biopsy, the detection rate of the follow-up sessions was lower than the initial detection rate. Of the prostate cancers subsequently found, 93% were low grade (≤ 3+4). In this low risk group of patients, increasing the follow-up time interval should be considered in the appropriate clinical setting.

Patients with an enlarged prostate and suspicion of prostate cancer pose a diagnostic dilemma. The prostate cancer detection rate of systematic 12-core transrectal ultrasound guided biopsy is between 30% and 40%. For prostates greater than 40 cc this decreases to 30% or less. Magnetic resonance-ultrasound fusion biopsy has shown superior prostate cancer detection rates. We defined the detection rate of magnetic resonance-ultrasound fusion biopsy in men with an enlarged prostate gland.We retrospectively analyzed the records of patients who underwent multiparametric prostate magnetic resonance imaging followed by magnetic resonance-ultrasound fusion biopsy at our institution. Whole prostate volumes were calculated using magnetic resonance imaging reconstructions. Detection rates were analyzed with respect to age, prostate specific antigen and whole prostate volumes. Multivariable logistic regression was used to assess these parameters as independent predictors of prostate cancer detection.We analyzed 649 patients with a mean±SD age of 61.8±7.9 years and a median prostate specific antigen of 6.65 ng/ml (IQR 4.35-11.0). Mean whole prostate volume was 58.7±34.3 cc. The overall detection rate of the magnetic resonance-ultrasound fusion platform was 55%. For prostates less than 40 cc the detection rate was 71.1% compared to 57.5%, 46.9%, 46.9% 33.3%, 36.4% and 30.4% for glands 40 to 54.9, 55 to 69.9, 70 to 84.9, 85 to 99.9, 100 to 114.9 and 115 cc or greater, respectively (p0.0001). Multivariable logistic regression showed a significant inverse association of magnetic resonance imaging volume with prostate cancer detection, controlling for age and prostate specific antigen.Transrectal ultrasound guided and fusion biopsy cancer detection rates decreased with increasing prostate volume. However, magnetic resonance-ultrasound fusion biopsy had a higher prostate cancer detection rate compared to that of transrectal ultrasound guided biopsy in the literature. Magnetic resonance-ultrasound fusion biopsy represents a promising solution for patients with suspicion of prostate cancer and an enlarged prostate.

Radiofrequency ablation (RFA) is a standard treatment for small, unresectable hepatocellular carcinomas (HCCS). However, RFA for larger tumours is less successful, and intravenous lyso-thermosensitive liposomal doxorubicin during RFA is one technique postulated to potentially address that limitation. This drug-plus-device combination therapy was used to completely treat a HCC in a patient who underwent liver transplantation 79 days later.

To determine the relationship between hepatic proton density fat fraction (PDFF) and R2* in vivo.In this Health Insurance Portability and Accountability Act (HIPAA)-compliant, Institutional Review Board (IRB)-approved, cross-sectional study, we conducted a secondary analysis of 3T magnetic resonance imaging (MRI) exams performed as part of prospective research studies in children in whom conditions associated with iron overload were excluded clinically. Each exam included low-flip-angle, multiecho magnitude (-M) and complex (-C) based chemical-shift-encoded MRI techniques with spectral modeling of fat to generate hepatic PDFF and R2* parametric maps. For each technique and each patient, regions of interest were placed on the maps in each of the nine Couinaud segments, and composite whole-liver PDFF and R2* values were calculated. Pearson's correlation coefficients between PDFF and R2* were computed for each MRI technique. Correlations were compared using Steiger's test.In all, 184 children (123 boys, 61 girls) were included in this analysis. PDFF estimated by MRI-M and MRI-C ranged from 1.1-35.4% (9.44 ± 8.76) and 2.1-38.1% (10.1 ± 8.7), respectively. R2* estimated by MRI-M and MRI-C ranged from 32.6-78.7 sHepatic PDFF and R2* are strongly correlated with each other in vivo. This relationship was observed using two different MRI techniques.2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:418-424.

Brainstem syndromes are a common initial presentation of multiple sclerosis. Classic syndromes include internuclear ophthalmoplegia, ataxia, and trigeminal neuralgia. While MRI findings of typical MS lesions in the supratentorial white matter or spinal cord can quickly distinguish demyelinating disease from other pathologies, the MRI pattern of brainstem lesions can sometimes be concerning for alternate diagnoses. These would include infections, stroke, and tumors. This chapter describes two pediatric patients presenting with acute brainstem symptoms, both of whom were subsequently diagnosed with multiple sclerosis. An initial attack of brainstem symptoms in MS may predict a more aggressive disease course, and initiation of disease-modifying therapy with close follow-up is important in such patients.

FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan-Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients.

Renewable energy systems (RES), especially solar PV, are being diffused to rural communities to improve energy access. The sustainability of these systems is, however, becoming increasingly relevant. In this paper, the issues of appropriate match between technology and users capacities were addressed using a holistic multi-tiered approach in energy provision using solar PV systems. A multi-tiered approach pertains to the use of different types of systems that cater appropriately to the different types of users with varying levels of available resources, capacities, and willingness to sustain a system. The recommendations were based on actual solar PV cases from the Philippines.

Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevated PRL-3 mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3+, but not PRL-3–, orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3+ tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become “extracellular oncotargets” that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery.

Ke Guo 1,2 , Jing Ping Tang 1,2 , Li Jie 1,2 , Abdul Qader O. Al-Aidaroos 2 , Cheng William Hong 3 , Cheng Peow Bobby Tan 2 , Jung Eun Park 2 , Leyon Varghese 2 , Zhiwei Feng 4 , Jianbiao Zhou 5 , Wee Joo Chng 6 and Qi Zeng 2,7 1 Denotes equal contribution 2 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, Singapore 138648, Republic of Singapore 3 Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue, Cleveland, OH 44195, USA 4 Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore 637551 5 Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456 6 Department of Haematology-Oncology, National University Cancer Institute, Singapore National University Health System, 5 Lower Kent Ridge Road, S119074 7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Republic of Singapore Received: February 2, 2012; Accepted: February 21, 2012; Published: February 27, 2012; Keywords: PRL-3 monoclonal antibody, PRL-3 mouse/human chimeric antibody, antibody therapy, intracellular oncoprotein Correspondence: Qi Zeng, // // Abstract Antibodies are considered as ‘magic bullets’ because of their high specificity. It is believed that antibodies are too large to routinely enter the cytosol, thus antibody therapeutic approach has been limited to extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are localized within the cell. To explore the possibility of antibody therapies against intracellular targets, we generated a chimeric antibody targeting the intracellular PRL-3 oncoprotein to assess its antitumor activities in mice. Remarkably, we observed that the PRL-3 chimeric antibody could efficiently and specifically reduce the formation of PRL-3 expressing metastatic tumors. We further found that natural killer (NK) cells were important in mediating the therapeutic effect, which was only observed in a nude mouse model (T-cell deficient), but not in a Severe Combined Immunodeficiency’ ( scid ) mouse model (B- and T-cell deficient), indicating the anticancer effect also depends on host B-cell activity. Our study involving 377 nude and scid mice suggest that antibodies targeting intracellular proteins can be developed to treat cancer.

Renewable energy systems (RESs) have been promoted for rural electrification as an answer to the growing energy needs of communities while simultaneously satisfying environmental and resource scarcity problems. These off-grid systems however have several challenges in the perspective of sustainability due to the technically and financially weak recipients and users of the projects. There is still, however, less detailed understanding how the technical and economic aspects of the projects can properly match the social aspects to promote sustainability. This paper aimed to further understand the challenges and social impacts of rural electrification projects using RES through a case study of a centralized off-grid solar plant in the Philippines. The study used multiple correspondence analysis (MCA) to identify essential user attributes which explain the users’ electricity consumption behaviors. The community cooperative had difficulties maintaining the facility in the long term due to financial and capacity related challenges. A holistic approach dealing with the technical, economic and social aspects in developing RES projects promote sustainability.

We here discuss the concept of the magnitude and the intensity of disaster of a storm surge and propose a method of calculation based on the principle of the wind scale and the earthquake magnitude. The magnitude of a storm surge is the quantitative index that describes the scale of the storm surge, and the intensity of disaster of a storm surge is the quantitative index that describes the losses caused by the storm surge.

Este trabalho propõe um método de análise de risco aplicada ao descarrilamento (incidente no qual a roda perde a sustentação provida pelo trilho, podendo ser causado por diversos aspectos como imperfeições na via, falhas no material rodante, obstáculos na via, entre outras que pode acarretar possíveis acidentes e perdas materiais e humanas) de forma a tornar mais seguro o transporte ferroviário, que atualmente não apresenta diminuição da taxa de ocorrência dos descarrilamentos, complementando assim as simulações computacionais e simulações dinâmicas que podem ser aplicadas ao estudo deste evento. Risco pode ser definido como o potencial de perda resultante da exposição a um perigo, sendo relacionado à probabilidade de ocorrência de um evento ou combinação de eventos acarretando em um perigo e a conseqüência deste perigo. Este conceito pode ser utilizado para investigar e avaliar as incertezas associadas com um evento. Já Confiabilidade pode ser definida como a probabilidade de um item executar a sua função sob condições pré-definidas de uso e manutenção por um período de tempo específico. Assim, considerando estes dois conceitos, será apresentada uma metodologia de análise de risco e confiabilidade para análise e discussão do descarrilamento, discorrendo sobre os possíveis parâmetros que podem causar este evento bem como propondo uma alternativa para avaliação da probabilidade de ocorrência do descarrilamento; desta forma permite guiar o gerenciamento da segurança quanto a este evento já que no Brasil não existe a figura da autoridade ferroviária, órgão máximo e responsável final pela regulamentação para a operação de um sistema ferroviário, que poderia determinar o processo que deve ser seguido para a garantia de segurança. Os objetos de estudo serão veículos ferroviários e conseqüentemente os elementos de interface com este tipo de veículo, como por exemplo, os elementos de via. This research proposes a risk analysis method applied to derailment event (characterized by the wheel overlap on the rail, which can be caused by many aspects: rail imperfections, rolling stock failures, obstacles etc and which can cause accidents, material and life loss) to increase the safety level on railway transport that actually does not present decrease of derailment rate. This method also complements computational and dynamic simulations, which can be applied to this event. Risk can be defined as the potential loss due to a hazard exposure, also related with the probability of occurrence of an event or combinations of events leading to a hazard and the consequence of this hazard. This concept can be applied to investigate and to evaluate the uncertainties related with this event. Reliability can be defined as the probability of an item to perform its function under predefined use and maintenance conditions during a specific period of time. Thus, considering these two concepts, it will be presented a risk and reliability analysis to study the derailment event, discoursing about the possible parameters that can cause this event and proposing alternatives to evaluate the derailment occurrence probability in order to guide safety management since a railway authority does not exist in Brazil (body with the overall accountability to a regulator for operation a railway system, that could determines the process to be followed to assure safety levels). This research will cover railway vehicles and consequently the interface, for example, the railroad elements.

In magnetic resonance iimaging- (MRI-) ultrasound (US) guided biopsy, suspicious lesions are identified on MRI, registered on US, and targeted during biopsy. The registration can be performed either by a human operator (visual registration) or by fusion software. Previous studies showed that software registration is fairly accurate in locating suspicious lesions and helps to improve the cancer detection rate. Here, the performance of visual registration was examined for ability to locate suspicious lesions defined on MRI. This study consists of 45 patients. Two operators with differing levels of experience (<1 and 18 years) performed visual registration. The overall spatial difference by the two operators in 72 measurements was 10.6 ± 6.0 mm. Each operator showed a spatial difference of 9.4 ± 5.1 mm (experienced; 39 lesions) and 12.1 ± 6.6 mm (inexperienced; 33 lesions), respectively. In a head-to-head comparison of the same 16 lesions from 12 patients, the spatial differences were 9.7 mm ± 4.9 mm (experienced) and 13.4 mm ± 7.4 mm (inexperienced). There were significant differences between the two operators (unpaired,Pvalue = 0.042; paired,Pvalue = 0.044). The substantial differences by the two operators suggest that visual registration could improperly and inaccurately target many tumors, thereby potentially leading to missed diagnosis or false characterization on pathology.

Prostate biopsies are usually performed by urologists in the office setting using transrectal ultrasound (US) guidance. The current standard of care involves obtaining 10-14 cores from different anatomic sections. Biopsies are usually not directed into a specific lesion because most prostate cancers are not visible on transrectal US. Color Doppler, US contrast agents, elastography, magnetic resonance (MR) imaging, and MR imaging/US fusion are proposed as imaging methods to guide prostate biopsies. Prostate MR imaging and fusion biopsy create opportunities for diagnostic and interventional radiologists to play an increasingly important role in the screening, evaluation, diagnosis, targeted biopsy, surveillance, and focal therapy of patients with prostate cancer.

The diagnostic yield of computed tomography (CT)-guided biopsies is dependent on accurate needle insertion. A laser-assisted angle selection system was custom fabricated and used during a CT-guided lung biopsy. Off-target error was measured comparing standard methods to the laser method while pointing towards the target from the skin. The difference between the planned angle and selected angle using the laser-assisted system was 2°, improved from 12° with the standard method. Although yet to be confirmed, laser-assisted angle selection systems may improve the accuracy of needle placement, which may translate into improved outcomes for certain needle based procedures.

A major challenge in cancer therapy is the lack of specificity for cancer cells. Antibody-based therapies have better specificity and, thus, improved efficacy over standard chemotherapy regimens. Monoclonal antibodies (mAb) constitute the most rapidly growing class of human therapeutics and are proven agents for recognizing and destroying malignant cells. However, the development of antibody therapies has focused only on targeting extracellular (cell-surface or secreted) proteins rather than intracellular targets (within cells, such as phosphatases and/or kinases and transcription factors), because antibodies are generally believed to be too large to enter cells, resulting in a large untapped source of intracellular therapeutic targets. Recently, we presented evidence that suggests that intracellular proteins with high expression in cancer cells are useful targets for mAb-based or vaccination immunotherapies, thus challenging current understanding. Here, we further discuss the concept and future uses of these immunotherapies against a large pool of intracellular oncoproteins for cancer therapy. This line of research has the potential to vastly expand the field of antibody therapy and usher in a new era of cancer vaccines. Cancer Res; 72(15); 3715–9. ©2012 AACR.

Providing clean and sustainable energy for all is an ever elusive challenge, especially encountered in remote and poor rural areas. Cost-effective solutions have been found through renewable energy systems (RES) which, when combined with specialized products like rechargeable lamps using light emitting diodes (LED), can provide the basic energy needs (lighting) of rural homes, while replacing fossil-fuel based energy sources (e.g. kerosene lamps). The investigation presents an LED lamps provision system which circumvents the cost and technical challenges that currently hamper LED lamps diffusion into communities. Based on an actual rural island case (Pangan-an Island, Philippines), a sub-centralized lamp rental and charging system was mathematically modeled and analyzed (analytically and numerically) to identify the optimal states and policies, along with the effects of certain parameters, which promote financial viability and supply sustainability. It was found that a dynamically optimized lamp(s) purchase policy yields better financial returns than a statically optimized policy. Furthermore, it was realized that a sub-centralized lamps rental approach can serve as a complementary energy provision system for rural electrification projects by providing for the lower-tier energy demand market of low income users within a community.

PURPOSE. Corneal collagen cross-linking (CXL) is a method for modifying the natural history of keratoconus and other corneal ectatic diseases. The authors evaluated the use of collagenase for generating an experimental model of ectasia to evaluate the topographic effects of CXL interventions. METHODS. Nine human corneoscleral specimens unsuitable for transplantation were used. After epithelial debridement, mounting, and pressurization on an artificial anterior chamber, a solution of 10 mg/mL collagenase type II with 15% dextran was applied to five corneas for three hours. Three of these corneas subsequently underwent riboflavin/UV-A CXL. Scheimpflug-based tomography was performed before collagenase exposure, after collagenase exposure, and after CXL to evaluate changes in maximum axial curvature of the anterior surface (Kmax) at three IOP levels. Results were compared to four control eyes exposed to dextran alone. RESULTS. A statistically significant increase in Kmax was seen across all IOP levels in the collagenase group compared to the control group (þ6.6 6 1.1 diopters [D] and þ0.3 6 0.8 D, respectively, at physiological IOP). After CXL, Kmax decreased (� 7.6 6 2.0 D at physiological IOP). Anterior corneal aberrations increased after collagenase exposure and decreased after CXL. Light microscopy showed loss of normal stromal collagen architecture and localized edema after collagenase exposure. CONCLUSIONS. A method for generating topographic features of corneal ectasia in human tissue is demonstrated. No significant sensitivity of Kmax to IOP was observed. CXL caused regression of steepening and induced aberrations in this model, consistent with clinical trends. The model may be useful for testing modifications to standard CXL techniques. (Invest Ophthalmol

Antibody-based therapies have better specificity and thus improved efficacy over standard chemotherapy regimens, which result in extended survival and improved quality of life for cancer patients. Because antibodies are viewed as too large to access intracellular locations, antibody therapy has traditionally targeted extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are found within the cell (such as intracellular phosphatases/kinases and transcription factors) and have therefore not been pursued for antibody therapies. Here, we explored the possibility of antibody therapy or vaccination against intracellular proteins. As proofs of concept, we selected three representative intracellular proteins as immunogens for tumor vaccine studies: PRL-3 (phosphatase of regenerating liver 3), a cancer-associated phosphatase; EGFP (enhanced green fluorescent protein), a general reporter; and mT (polyomavirus middle T), the polyomavirus middle T oncoprotein. A variety of tumors that expressed these intracellular proteins were clearly inhibited by their respective exogenous antibodies or by antigen-induced host antibodies (vaccination). These anticancer activities were reproducibly observed in hundreds of C57BL/6 tumor-bearing mice and MMTV-PymT transgenic breast tumor mice. Our in vivo data suggest that immunotherapies can target not only extracellular but also intracellular oncoproteins.