Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis

International audienceGlioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is critical for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumour development and prolongs survival. Moreover, we identify TET3 as a potent tumour suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma

Characteristics of Human Brain Activity during the Evaluation of Service-to-Service Brand Extension

Brand extension is a marketing strategy to apply the previously established brand name into new goods or service. A number of studies have reported the characteristics of human event-related potentials (ERPs) in response to the evaluation of goods-to-goods brand extension. In contrast, human brain responses to the evaluation of service extension are relatively unexplored. The aim of this study was investigating cognitive processes underlying the evaluation of service-to-service brand extension with electroencephalography (EEG). A total of 56 text stimuli composed of service brand name (S1) followed by extended service name (S2) were presented to participants. The EEG of participants was recorded while participants were asked to evaluate whether a given brand extension was acceptable or not. The behavioral results revealed that participants could evaluate brand extension though they had little knowledge about the extended services, indicating the role of brand in the evaluation of the services. Additionally, we developed a method of grouping brand extension stimuli according to the fit levels obtained from behavioral responses, instead of grouping of stimuli a priori. The ERP analysis identified three components during the evaluation of brand extension: N2, P300, and N400. No difference in the N2 amplitude was found among the different levels of a fit between S1 and S2. The P300 amplitude for the low level of fit was greater than those for higher levels (p < 0.05). The N400 amplitude was more negative for the mid- and high-level fits than the low level. The ERP results of P300 and N400 indicate that the early stage of brain extension evaluation might first detect low-fit brand extension as an improbable target followed by the late stage of the integration of S2 into S1. Along with previous findings, our results demonstrate different cognitive evaluation of service-to-service brand extension from goods-to-goods

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Palladium-catalysed amination of bromofluorans and an investigation of their thermochromic behaviour

The palladium-catalysed amination of readily accessible bromofluorans and bromobenzo[a]fluorans has been accomplished with a series of anilines and morpholine. The resulting aminofluorans generated intense black shades upon formulation in methyl stearate containing bisphenol A. The route provides an alternative approach to various amino substituted fluorans without the need of a series of individual diphenylamine intermediates

Predictive Modeling of Colonoscopic Findings in a Fecal Immunochemical Test-Based Colorectal Cancer Screening Program.

BackgroundThe fecal immunochemical test (FIT) is the primary modality used by the Los Angeles County Department of Health Services (LADHS) for colorectal cancer (CRC) screening in average-risk patients. Some patients referred for FIT-positive diagnostic colonoscopy have neither adenomas nor more advanced pathology. We aimed to identify predictors of false-positive FIT (FP-FIT) results in our largely disenfranchised, low socioeconomic status population.MethodsWe conducted a retrospective study of 596 patients who underwent diagnostic colonoscopy following a positive screening FIT. Colonoscopies showing adenomas (or more advanced pathology) were considered positive. We employed multiple logistic and linear regression as well as machine learning models (MLMs) to identify clinical predictors of FP-FIT (primary outcome) and the presence of advanced adenomas (secondary outcome).ResultsOverall, 268 patients (45.0%) had a FP-FIT. Female sex and hemorrhoids (odds ratios [ORs] 1.59 and 1.89, respectively) were associated with increased odds of FP-FIT and fewer advanced adenomas (β = - 0.658 and  - 0.516, respectively). Conversely, increasing age and BMI (ORs 0.94 and 0.96, respectively) were associated with decreased odds of FP-FIT and a greater number of advanced adenomas (β = 0.073 and 0.041, respectively). MLMs predicted FP-FIT with high specificity (93.8%) and presence of advanced adenoma with high sensitivity (94.4%).ConclusionIncreasing age and BMI are associated with lower odds of FP-FIT and greater number of advanced adenomas, while female sex and hemorrhoids are associated with higher odds of FP-FIT and fewer advanced adenomas. The presence of the aforementioned predictors may inform the decision to proceed with diagnostic colonoscopy in FIT-positive patients

Machine learning models compared to existing criteria for noninvasive prediction of endoscopic retrograde cholangiopancreatography-confirmed choledocholithiasis

Background and aimsNoninvasive predictors of choledocholithiasis have generally exhibited marginal performance characteristics. We aimed to identify noninvasive independent predictors of endoscopic retrograde cholangiopancreatography (ERCP)-confirmed choledocholithiasis and accordingly developed predictive machine learning models (MLMs).MethodsClinical data of consecutive patients undergoing first-ever ERCP for suspected choledocholithiasis from 2015-2019 were abstracted from a prospectively-maintained database. Multiple logistic regression was used to identify predictors of ERCP-confirmed choledocholithiasis. MLMs were then trained to predict ERCP-confirmed choledocholithiasis using pre-ERCP ultrasound (US) imaging only and separately using all available noninvasive imaging (US/CT/magnetic resonance cholangiopancreatography). The diagnostic performance of American Society for Gastrointestinal Endoscopy (ASGE) "high-likelihood" criteria was compared to MLMs.ResultsWe identified 270 patients (mean age 46 years, 62.2% female, 73.7% Hispanic/Latino, 59% with noninvasive imaging positive for choledocholithiasis) with native papilla who underwent ERCP for suspected choledocholithiasis, of whom 230 (85.2%) were found to have ERCP-confirmed choledocholithiasis. Logistic regression identified choledocholithiasis on noninvasive imaging (odds ratio (OR) = 3.045, P = 0.004) and common bile duct (CBD) diameter on noninvasive imaging (OR=1.157, P = 0.011) as predictors of ERCP-confirmed choledocholithiasis. Among the various MLMs trained, the random forest-based MLM performed best; sensitivity was 61.4% and 77.3% and specificity was 100% and 75.0%, using US-only and using all available imaging, respectively. ASGE high-likelihood criteria demonstrated sensitivity of 90.9% and specificity of 25.0%; using cut-points achieving this specificity, MLMs achieved sensitivity up to 97.7%.ConclusionsMLMs using age, sex, race, presence of diabetes, fever, body mass index (BMI), total bilirubin, maximum CBD diameter, and choledocholithiasis on pre-ERCP noninvasive imaging predict ERCP-confirmed choledocholithiasis with good sensitivity and specificity and outperform the ASGE criteria for patients with suspected choledocholithiasis