Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.

Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer

Absence of Serological Evidence of Exposure to Treponema pallidum among Children Suggests Yaws Is No Longer Endemic in Kiribati.

Yaws is a neglected tropical disease targeted for eradication by 2020. Kiribati, a Pacific Island nation, was previously endemic for yaws but lacks recent data from which its current endemicity status could be determined. This study tested antibody responses to Treponema pallidum to determine if transmission of yaws is taking place among children in Kiribati. Using a commercially available T. pallidum particle agglutination kit (Serodia®, Fujirebio Inc., Tokyo, Japan), we tested dried blood spots, collected during population-based trachoma prevalence surveys on Tarawa Atoll and Kiritimati Island, for long-lived treponemal antibodies. Dried blood spots from 1,420 children aged 1-9 years were tested. Only two were positive, suggesting T. pallidum is not being widely transmitted among children in the settings sampled. These data require support from additional surveys to demonstrate the absence of clinical signs of disease and molecular evidence of infection, to confirm that yaws is no longer endemic in Kiribati

Role of Imaging in the Staging and Response Assessment of Lymphoma:Consensus of the International Conference on Malignant Lymphomas Imaging Working Group

This article comprises the consensus reached to update guidance on the use of PET-CT for staging and response assessment for 18F FDG-avid lymphomas in clinical practice and late-phase trials

NS-HGlio: A generalizable and repeatable HGG segmentation and volumetric measurement AI algorithm for the longitudinal MRI assessment to inform RANO in trials and clinics.

BACKGROUND Accurate and repeatable measurement of high-grade glioma (HGG) enhancing (Enh.) and T2/FLAIR hyperintensity/edema (Ed.) is required for monitoring treatment response. 3D measurements can be used to inform the modified Response Assessment in Neuro-oncology criteria. We aim to develop an HGG volumetric measurement and visualization AI algorithm that is generalizable and repeatable. METHODS A single 3D-Convoluted Neural Network, NS-HGlio, to analyze HGG on MRIs using 5-fold cross validation was developed using retrospective (557 MRIs), multicentre (38 sites) and multivendor (32 scanners) dataset divided into training (70%), validation (20%), and testing (10%). Six neuroradiologists created the ground truth (GT). Additional Internal validation (IV, three institutions) using 70 MRIs, and External validation (EV, single institution) using 40 MRIs through measuring the Dice Similarity Coefficient (DSC) of Enh., Ed. ,and Enh. + Ed. (WholeLesion/WL) tumor tissue and repeatability testing on 14 subjects from the TCIA MGH-QIN-GBM dataset using volume correlations between timepoints were performed. RESULTS IV Preoperative median DSC Enh. 0.89 (SD 0.11), Ed. 0.88 (0.28), WL 0.88 (0.11). EV Preoperative median DSC Enh. 0.82 (0.09), Ed. 0.83 (0.11), WL 0.86 (0.06). IV Postoperative median DSC Enh. 0.77 (SD 0.20), Ed 0.78. (SD 0.09), WL 0.78 (SD 0.11). EV Postoperative median DSC Enh. 0.75 (0.21), Ed 0.74 (0.12), WL 0.79 (0.07). Repeatability testing; Intraclass Correlation Coefficient of 0.95 Enh. and 0.92 Ed. CONCLUSION NS-HGlio is accurate, repeatable, and generalizable. The output can be used for visualization, documentation, treatment response monitoring, radiation planning, intra-operative targeting, and estimation of Residual Tumor Volume among others

NS-HGlio: A generalizable and repeatable HGG segmentation and volumetric measurement AI algorithm for the longitudinal MRI assessment to inform RANO in trials and clinics

BACKGROUND Accurate and repeatable measurement of high-grade glioma (HGG) enhancing (Enh.) and T2/FLAIR hyperintensity/edema (Ed.) is required for monitoring treatment response. 3D measurements can be used to inform the modified Response Assessment in Neuro-oncology criteria. We aim to develop an HGG volumetric measurement and visualization AI algorithm that is generalizable and repeatable. METHODS A single 3D-Convoluted Neural Network, NS-HGlio, to analyze HGG on MRIs using 5-fold cross validation was developed using retrospective (557 MRIs), multicentre (38 sites) and multivendor (32 scanners) dataset divided into training (70%), validation (20%), and testing (10%). Six neuroradiologists created the ground truth (GT). Additional Internal validation (IV, three institutions) using 70 MRIs, and External validation (EV, single institution) using 40 MRIs through measuring the Dice Similarity Coefficient (DSC) of Enh., Ed. ,and Enh. + Ed. (WholeLesion/WL) tumor tissue and repeatability testing on 14 subjects from the TCIA MGH-QIN-GBM dataset using volume correlations between timepoints were performed. RESULTS IV Preoperative median DSC Enh. 0.89 (SD 0.11), Ed. 0.88 (0.28), WL 0.88 (0.11). EV Preoperative median DSC Enh. 0.82 (0.09), Ed. 0.83 (0.11), WL 0.86 (0.06). IV Postoperative median DSC Enh. 0.77 (SD 0.20), Ed 0.78. (SD 0.09), WL 0.78 (SD 0.11). EV Postoperative median DSC Enh. 0.75 (0.21), Ed 0.74 (0.12), WL 0.79 (0.07). Repeatability testing; Intraclass Correlation Coefficient of 0.95 Enh. and 0.92 Ed. CONCLUSION NS-HGlio is accurate, repeatable, and generalizable. The output can be used for visualization, documentation, treatment response monitoring, radiation planning, intra-operative targeting, and estimation of Residual Tumor Volume among others

Short-term prognostic implications of serum and urine neutrophil gelatinase-associated lipocalin in acute heart failure:findings from the AKINESIS study

AIMS: Kidney impairment has been associated with worse outcomes in acute heart failure (AHF), although recent studies challenge this association. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel biomarker of kidney tubular injury. Its prognostic role in AHF has not been evaluated in large cohorts. The present study aimed to determine if serum NGAL (sNGAL) or urine NGAL (uNGAL) is superior to creatinine for predicting short-term outcomes in AHF. METHODS AND RESULTS: The study was conducted in an international, multicentre, prospective cohort consisting of 927 patients with AHF. Admission and peak values of sNGAL, uNGAL and uNGAL/urine creatinine (uCr) ratio were compared to admission and peak serum creatinine (sCr). The composite endpoints were death, initiation of renal replacement therapy, heart failure (HF) readmission and any emergent HF-related outpatient visit within 30 and 60 days, respectively. The mean age of the cohort was 69 years and 62% were male. The median length of stay was 6 days. The composite endpoint occurred in 106 patients and 154 patients within 30 and 60 days, respectively. Serum NGAL was more predictive than uNGAL and the uNGAL/uCr ratio but was not superior to sCr (area under the curve [AUC]; admission sNGAL 0.61 [95% confidence interval (CI) 0.55-0.67] and 0.59 [95% CI 0.54-0.65], peak sNGAL 0.60 [95% CI 0.54-0.66] and 0.57 [95% CI 0.52-0.63], admission sCr 0.60 [95% CI 0.54-0.64] and 0.59 [95% CI 0.53-0.64] [area under the curve: admission sNGAL 0.61, 95% confidence interval (CI) 0.55-0.67, and 0.59, 95% CI 0.54-0.65; peak sNGAL: 0.60, 95% CI 0.54-0.66, and 0.57, 95% CI 0.52-0.63; admission sCr: 0.60, 95% CI 0.54-0.64, and 0.59, 95% CI 0.53-0.64, at 30 and 60 days, respectively], peak sCr 0.61 [95% CI 0.55-0.67] and 0.59 [95% CI 0.54-0.64] at 30 and 60 days, respectively). NGAL was not predictive of the composite endpoint in multivariate analysis. CONCLUSIONS: Serum NGAL outperformed uNGAL but neither was superior to admission or peak sCr for predicting adverse events

Cryptic species of cardinalfish with evidence for old and new divergence

Larval dispersal and limited knowledge of physical boundaries challenge our understanding of the processes that drive genetic divergence and potential speciation in the marine environment. Divergence, both within and between populations of marine taxa, is not uncommon, but spatial and temporal stability of observed genetic structure is not well known. Previously, we detected large genetic differences among populations of the cardinalfish species Ostorhinchus doederleini inhabiting adjacent coral reefs. Here, we determined the spatial and temporal persistence of these genetic structures over the course of ten consecutive generations. Using microsatellite markers, we detected large changes (genetic population distance, D (est), ranged from 0.04 to 0.46) in the genetic structure in some years, but some reefs maintained the same populations for nearly all sampling years. As this species' life span does not exceed 1 yr, persistence of distinct reef populations suggests natal homing. Mitochondrial identity based on two mtDNA markers corroborates the nuclear genetic evidence for genetic differences large enough to constitute different clades and even cryptic species in O. doederleini, which, based on gross morphology, was thought to be a single taxon. Habitat specialization was observed in one clade that exclusively inhabited reef lagoons, while all clades could be observed on reef slopes. We suggest that local habitat recognition combined with local population recognition and selection against hybrids can form barriers that maintain a cryptic species complex

ORIGINAL ARTICLE Correcting False Gene Expression Measurements From Degraded RNA Using RTQ-PCR

Abstract: This paper describes a method allowing correcting false gene expression measured on highly degraded RNA using real-time quantitative reverse transcription-polymerase chain reaction (RTQ-PCR). RNA was isolated from different models (in vitro cell lines, in vivo models of human and dog) and different tissue types. In vitro RNA degradation and modeling of in vivo degradation were applied on intact and degraded total RNA. Gene expression (eg, Bcl-2, GAPDH, PGK, PSME3, RAB2, BAX) was measured using RTQ-PCR. 18S rRNA proved to be the most constant house-keeping gene. Less than 10-fold degraded RNA can be quantified correctly when using 18S rRNA for normalization purposes. Higher-fold degraded RNA can be quantified correctly up to a precision that is comparable to RTQ-PCR measurements on intact RNA when simulating the RNA-species and tissue-specific degradation kinetic. Key Words: RNA degradation, RTQ-PCR, correction of false gene expression measurements, house-keeping genes, simulation of RNA degradation (Diagn Mol Pathol 2007;16:38–49) With the advent of molecular biologic methods, it became desirable to apply these potent methods to archival paraffin-embedded tissue samples. Isolation of RNA in particular seemed to be interesting, because expression alterations caused by gene abnormalities like deletions, structural alterations, rearrangements, and amplifications are associated with certain diseases suc