The prognostic significance of CDKN2A homozygous deletion in IDH-mutant lower-grade glioma and glioblastoma: a systematic review of the contemporary literature

Journal of Neuro-Oncology - The most recent cIMPACT-NOW update highlighted the homozygous deletion of the Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) gene as a clinically important molecular...     

Genomic context sensitivity of insulator function

The specificity of interactions between genomic regulatory elements and potential target genes is influenced by the binding of insulator proteins such as CTCF, which can act as potent enhancer blockers when interposed between an enhancer and a promoter in a reporter assay. But not all CTCF sites genome-wide function as insulator elements, depending on cellular and genomic context. To dissect the influence of genomic context on enhancer blocker activity, we integrated reporter constructs with promoter-only, promoter and enhancer, and enhancer blocker configurations at hundreds of thousands of genomic sites using the Sleeping Beauty transposase. Deconvolution of reporter activity by genomic position reveals distinct expression patterns subject to genomic context, including a compartment of enhancer blocker reporter integrations with robust expression. The high density of integration sites permits quantitative delineation of characteristic genomic context sensitivity profiles and their decomposition into sensitivity to both local and distant DNase I hypersensitive sites. Furthermore, using a single-cell expression approach to test the effect of integrated reporters for differential expression of nearby endogenous genes reveals that CTCF insulator elements do not completely abrogate reporter effects on endogenous gene expression. Collectively, our results lend new insight into genomic regulatory compartmentalization and its influence on the determinants of promoter–enhancer specificity.

A boundary model offers an attractive paradigm for understanding regulatory specificity in mammalian genomes through the delineation of independent regulatory domains. Insulators are a class of genomic regulatory elements that block interaction of enhancers with their cognate promoters (Phillips and Corces 2009). Enhancer blocker activity is canonically defined by a reporter assay that interposes a candidate insulator element between a weak promoter and an enhancer (Chung et al. 1993), while barrier insulators protect transgenes from silencing owing to spreading of heterochromatin (West et al. 2002). Insulators have also been used to counter genotoxicity from transgene enhancer activation of endogenous oncogenes (Li et al. 2009; Liu et al. 2015). Known insulators such as the chicken beta-globin hypersensitive site 4 element or the Igf2/H19 imprinting control region (Bell and Felsenfeld 2000) are composite elements with enhancer blocker, barrier, and other activities (Dickson et al. 2010), and often have secondary functions, such as silencers (Qi et al. 2015).The architectural protein CTCF is the only known vertebrate insulator protein, and its binding can confer a potent enhancer blocking effect (Phillips and Corces 2009). Additionally, binding sites for CTCF colocalize with genomic features such as topologically associated domain boundaries (Dixon et al. 2012), but direct functional analysis of these sites is impeded by the difficulty of genome engineering at the relevant scales. Although binding affinity, DNA methylation, and recognition sequence orientation appear to confer some specificity for CTCF sites involved in domain organization (de Wit et al. 2015; Guo et al. 2015; Sanborn et al. 2015), these factors alone remain inadequate to distinguish true insulator elements impacting expression of nearby genes from the ∼100,000 CTCF sites genome-wide (Maurano et al. 2015; Tycko et al. 2019). Stably integrated reporter assays have shed light on the mechanics of insulator function, but such methods do not assess interaction with the surrounding endogenous genomic elements (Walters et al. 1999). In contrast, integrated barcoded reporter assays (Akhtar et al. 2013; Maricque et al. 2019; Moudgil et al. 2020) offer the potential to directly assess the interaction between novel CTCF sites and the endogenous genomic landscape.Here, we aim to functionally characterize endogenous genomic regulatory elements through their effect on integrated reporters. We describe a high-throughput randomly integrated barcoded reporter platform based on a previously described enhancer blocker construct interposing a potent CTCF insulator element (Liu et al. 2015) between a weak promoter and a potent enhancer. We integrate these reporters, both with and without insulator elements, randomly throughout the genome of K562 erythroleukemia cells using the Sleeping Beauty transposase system. We use the unique reporter barcodes to map individual insertion locations and enable position-specific readout of genomic context effects. Finally, we apply single-cell RNA-seq (scRNA-seq) to detect specific reporter integrations that perturb endogenous gene expression.     

Aphasia in bilinguals and ASL signers: Implications for a theoretical model of neurolinguistic processing based on a review and synthesis of the literature

Abstract

A comprehensive understanding of language organization in the brain, it is argued, necessitates additional research on both language-particular characteristics and the issue of bilingualism. An analysis of current research on aphasia in bilinguals and American Sign Language (ASL) signers is presented. Central to the presentation is the need for future research to be conducted within the framework advocated.     

Onset Patterns Prior to 36 Months in Autism Spectrum Disorders

The present study investigated differences among children with three different patterns of autism symptom onset: regression, plateau, and no loss and no plateau. Cross-sectional data were collected from parents of children aged 3–17 years with an autism spectrum disorder (n = 2,720) who were recruited through a US-based online research database. Parental report of developmental characteristics was assessed through a parent questionnaire, and current autism symptoms were measured via the Social Responsiveness Scale and Social Communication Questionnaire. Multivariate analyses indicated that children with regression had a distinct developmental pattern marked by less delayed early development. However, following regression, these children evinced elevated autism symptom scores and an increased risk for poorer outcomes when compared with the other onset groups.     

Antibiotics are associated with lower relapse rates in outpatients with acute exacerbations of COPD

BACKGROUND: COPD is a complex disease with exacerbations characterized by worsening of symptoms resulting in deteriorating lung function. STUDY OBJECTIVE: To assess predictive factors of relapse for patients with acute exacerbations of COPD (AECB). DESIGN: Retrospective cohort analysis of visits for AECB. SETTING: Veterans Affairs Medical Center. PATIENTS: Three hundred sixty-two visits (173 patients) with documented COPD treated as outpatients for AECB. MEASUREMENTS: Severity of underlying COPD, severity of AECB, comorbid conditions, therapy, and relapse rates (return visit within 14 days with persistent or worsening symptoms). RESULTS: Each visit was analyzed individually (referred to as a patient-visit). One group received antibiotics (270 patient-visits), and the second group (92 patient-visits) did not. Both groups had similar demographics and severity of underlying COPD. The overall relapse rate was 22%. The majority of patient-visits (95%) with severe symptoms at presentation were prescribed antibiotics vs only 40% of those with mild symptoms. Twenty-nine of 92 patient-visits (32%) were followed by relapse in the group that was not given antibiotics, whereas only 50 of 270 (19%) treated with antibiotics relapsed (p < 0.001). Those treated with amoxicillin had an even higher relapse rate (20 of 37 patient-visits, or 54%) than those who did not receive antibiotics (p = 0.006). CONCLUSIONS: Relapse from AECB was not related to the severity of underlying disease or to the severity of the acute exacerbation. Patients treated with antibiotics had significantly lower relapse rates than those who did not receive antibiotics. However, the specific choice of antibiotic is important because those treated with amoxicillin had the highest relapse rates of all groups.     

Optimizing care for African-American HIV-positive patients

The African-American community has been disproportionately affected HIV/AIDS, as noted by higher reported rates of HIV infection, higher proportion of AIDS cases, and more deaths caused by complications of AIDS than whites and other ethnic groups. In addition, epidemiologic trends suggest that African Americans with HIV infection are more often diagnosed later in the course of HIV disease than whites. Numerous reasons account for this disparity, including the lack of perception of risk and knowledge about HIV transmission as well as a delays in HIV testing and diagnosis in the African-American community. Understanding the important considerations in the management of HIV infection in the African-American patient may create awareness among health care professionals and broaden the knowledge of HIV-infected patients within the African-American community.     

Umfrage zur Therapie der tiefen Beinvenenthrombose unter den Mitgliedern der Deutschen Gesellschaft für Gefäßchirurgie

Introduction. In the literature of the past 15 years, deep venous thrombectomy has been rarely described. The only indications reported for thrombectomy seem to be recurrent pulmonary embolisation and phlegmasia coerulea dolens. Many contraindications and severe complications are making decisions concerning thrombolysis very difficult. At present, anticoagulation therapy is preferred over fibrinolysis. There is no conclusive concept for the standardization of treatment for deep venous thrombosis. As a first step towards achieving this, it was necessary to know what therapy is performed in hospitals throughout Germany. Methods. In 1999, we sent letters of enquiry to the members of the “Deutsche Gesellschaft für Gefässchirurgie”. We wrote to 341 members (hospitals), and the information gained by means of a questionnaire was analysed and evaluated. Results. We received answers from 39.9% (n=136) of the members. In all, 69% of the hospitals had an independent vascular department. In 1999, 6,718 patients underwent treatment for deep venous thrombosis, on average, 51 patients per hospital. Overall, 7,665 therapies were performed in one year (15.9% thrombectomy, 18.6% fibrinolysis, and 65.5% only anticoagulation). Only 23.5% of the hospitals had their own data about the outcome of their patients. The patency rate was 71.8% for thrombectomy and 48.9% for fibrinolysis. A severe postthrombotic syndrome was seen in 6.2% after thrombectomy, in 8.1% after fibrinolysis, and in 10.4% after singular anticoagulation. Conclusion. At present, there is still no standardized concept for the treatment of patients with deep venous thrombosis. It seems that there are better results for some indications with thrombectomy than with other methods. For the establishment of a concept of treatment, a prospective randomised study is necessary.