Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RTs demonstrate genomic alterations in SMARCB1 (INI1, SNF5, ...BAF47) or, to a lesser extent, SMARCA4 (BRG1) of the SWItch/sucrose nonfermentable chromatin remodeling complex. Recent transcription and methylation profiling studies suggest the existence of molecular subgroups. Thus, at the root of these seemingly enigmatic tumors lies a network of factors related to epigenetic regulation, which is not yet completely understood. While conventional-type chemotherapy may have significant survival benefit for certain patients, it remains to be determined which patients will eventually prove resistant to chemotherapy and thus need novel therapeutic strategies. Elucidation of the molecular consequences of a disturbed epigenome has led to the identification of a series of transduction cascades, which may be targeted for therapy. Among these are the pathways of cyclin D1/cyclin-dependent kinases 4 and 6, Hedgehog/GLI1, Wnt/ß-catenin, enhancer of zeste homolog 2, and aurora kinase A, among others. Compounds specifically targeting these pathways or agents that alter the epigenetic state of the cell are currently being evaluated in preclinical settings and in experimental clinical trials for AT/RT.
Introduction
The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread ...cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3‐45 Study (BAN2401‐G000‐303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3‐45 Study is conducted as a Public‐Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc.
Methods
The AHEAD 3‐45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET‐imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial‐Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC‐PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J‐TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results.
Result
The focus of this article is on the innovative design of the study.
Discussion
The AHEAD 3‐45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma‐based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.
Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids
. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ...ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols
. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions
, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death
. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines
, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q
(CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents.
Donald K. Routh (1937-2021) Roberts, Michael C.
The American psychologist,
10/2021, Letnik:
76, Številka:
7
Journal Article
Recenzirano
Memorializes Donald K. Routh (1927-2021). He received a BA in English from the University of Oklahoma (1962), followed by a MS (1965) and PhD (1967) in psychology from the University of Pittsburgh. ...He completed his clinical internship at the Oklahoma Health Science Center (1967). Routh was board certified in clinical psychology by the American Board of Professional Psychology (1975). Pursuing an academic career, he rose through the ranks at the University of Iowa (1967-1970, 1977-1985), Bowling Green University (1970-1971), the University of North Carolina at Chapel Hill (1971-1977), and the University of Miami (1985-2002) where he served as Director of the clinical psychology program. He was a Fellow of APA and the Association for Psychological Science. Throughout his career, Don emphasized historical foundations of psychology as a scientific discipline and profession. He also affirmed the importance of advocacy for children, families, and those with developmental disabilities and chronic conditions. Two of his books were particularly important contributions: his edited
(1988) covered a field where he was a pioneer, and
since 1917 (1994) demonstrated his prowess as historian. He was elected President of the Society of Pediatric Psychology (now Division 54), the Section on Clinical Child Psychology (now Division 53), Division 37, Division 12, and Division 33. He chaired the Behavioral Medicine Study Section of the National Institutes of Health (1983-1985) and performed a multitude of American Psychological Association accreditation site visits. In 1998 he founded the International Society of Clinical Psychology. He was a Fellow of APA and the Association for Psychological Science. In recognition of his career contributions, he received Presidential Awards from Division 54 (1981), the Academy on Mental Retardation (2001), and the American Association on Mental Retardation (2002) as well as an APA Presidential Citation (2002), the Nicholas Hobbs Award from Division 37 (1996), and the Edgar A. Doll Award from Division 33 (2001). Postretirement, as further evidence of his scholarly curiosity, Don earned BA (2008) and MA (2011) degrees in History from the Florida Gulf Coast University. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Studies report high in-hospital and post-discharge mortality of chronic obstructive pulmonary disease (COPD) exacerbations varying depending upon patient characteristics, hospital resources and ...treatment standards. This study aimed to investigate the patient, resource and organisational factors associated with in-hospital and 90-day post-discharge mortality and readmission of COPD exacerbations within the European COPD Audit. The audit collected data of COPD exacerbation admissions from 13 European countries.On admission, only 49.7% of COPD patients had spirometry results available and only 81.6% had blood gases taken. Using logistic regression analysis, the risk associated with in-hospital and post-discharge mortality was higher age, presence of acidotic respiratory failure, subsequent need for ventilatory support and presence of comorbidity. In addition, the 90-day risk of COPD readmission was associated with previous admissions. Only the number of respiratory specialists per 1000 beds, a variable related to hospital resources, decreased the risk of post-discharge mortality.The European COPD Audit identifies risk factors associated with in-hospital and post-discharge mortality and COPD readmission. Addressing the deficiencies in acute COPD care such as making spirometry available and measuring blood gases and providing noninvasive ventilation more regularly would provide opportunities to improve COPD outcomes.
The advantages of SMRT sequencing Roberts, Richard J; Carneiro, Mauricio O; Schatz, Michael C
GenomeBiology.com,
01/2013, Letnik:
14, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Of the current next-generation sequencing technologies, SMRT sequencing is sometimes overlooked. However, attributes such as long reads, modified base detection and high accuracy make SMRT a useful ...technology and an ideal approach to the complete sequencing of small genomes.
Understanding how European care of chronic obstructive pulmonary disease (COPD) admissions vary against guideline standards provides an opportunity to target appropriate quality improvement ...interventions. In 2010–2011 an audit of care against the 2010 ‘Global initiative for chronic Obstructive Lung Disease’ (GOLD) standards was performed in 16 018 patients from 384 hospitals in 13 countries. Clinicians prospectively identified consecutive COPD admissions over a period of 8 weeks, recording clinical care measures on a web-based data tool. Data were analysed comparing adherence to 10 key management recommendations. Adherence varied between hospitals and across countries. The lack of available spirometry results and variable use of oxygen and non-invasive ventilation (NIV) are high impact areas identified for improvement.
Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how ...loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our genome-wide findings for the chromatin states. Additional generation of ChIP-seq data for SWI/SNF and Polycomb group proteins and the transcriptional repressor protein REST determined differential dependencies of SWI/SNF and Polycomb complexes in regulation of diverse gene sets in ATRTs.
•ATRT epigenomes display a global depletion of H3K27ac and H3K27me3•Neuronal genes bound by SMARCB1 in normal brain are repressed by EZH2 in ATRT•ATRT harbor many active genes occupied by EZH2 but without occupancy of H3K27me3•Residual SWI/SNF occupancy maintains genes active in the presence of Polycomb complex
Erkek et al. show that in atypical teratoid rhabdoid tumors (ATRT), which often lack the SWI/SNF complex component SMARCB1, a large fraction of SMARCB1 binding loci in normal brain is bound by EZH2 but without H3K27me3 and remains in an active state, and some of these genes are essential for ATRT survival.
Adverse childhood experiences (ACEs) detrimentally affect health outcomes in childhood, adolescence, and adulthood. Over the past 2 decades, the recognition of ACEs by scientists and professionals ...across disciplines, policymakers, and the public has evolved and expanded. Although the initial articulation of ACEs in Felitti et al.'s landmark study has formed the basis of subsequent investigations on the long-term impact of childhood adversities on health and health risk behaviors, a wider public health framework, inclusive of psychology and other social sciences, also shapes current conceptualizations, research, practice, and policies. This article provides an overview of the special issue Adverse Childhood Experiences: Translating Research to Action. Given the rapid expansion and widespread application of ACEs, this special issue was developed to articulate critical concepts, to demonstrate the significance and relevance of psychological research and practice, and to catalyze further efforts to develop effective programs and policies informed by science. The 15 articles included reflect the continuum of critical work being conducted in research, practice, intervention and prevention programs, and public policy and serve to synthesize the growing body of empirical evidence. The overarching themes that emerged are framed as 3 essential questions: (a) How broadly should ACEs be defined?, (b) How should ACEs be assessed?, and (c) How can ACEs science translate into high quality services? As illustrated in these articles, policy and practice applications deriving from psychology as a hub science can substantially benefit the health and mental health of children, adolescents, and adults.
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