ADNI Private Partners Scientific Board (PPSB) Diversity, Equity, and Inclusion (DE&I) Working Group: A new collaboration that crosses boundaries for industry, academia, and under-represented patients.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) Diversity, Equity, and Inclusion Working Group (DE&I WG) was established to work with the ADNI3 Diversity Task Force to provide an industry perspective on increasing the representation of diverse participants in ADNI3 and to build precompetitive cross-industry knowledge in engagement and recruitment of under-represented participants (URPs). In this article, we review and highlight the role and ongoing activities within the ADNI PPSB DE&I WG and provide a cross-industry perspective on areas where precompetitive collaboration can improve the inclusiveness in clinical trials, drawing on examples from ADNI4. HIGHLIGHTS: New collaboration crosses boundaries to allow PPSB DE&I WG members to work together in a preproprietary way.

Diversity of CFTR variants across ancestries characterized using 454,727 UK biobank whole exome sequences.

Background: Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF.

The Alzheimer's Disease Neuroimaging Initiative and the role and contributions of the Private Partners Scientific Board (PPSB).

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non-profit organizations that have until recently been managed by the Foundation for the National Institutes of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer's disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond.

PINNED: identifying characteristics of druggable human proteins using an interpretable neural network.

The identification of human proteins that are amenable to pharmacologic modulation without significant off-target effects remains an important unsolved challenge. Computational methods have been devised to identify features which distinguish between "druggable" and "undruggable" proteins, finding that protein sequence, tissue and cellular localization, biological role, and position in the protein-protein interaction network are all important discriminant factors. However, many prior efforts to automate the assessment of protein druggability suffer from low performance or poor interpretability.

Novel Alzheimer's disease locus identified by genome-wide association analysis of cerebral tau deposition on PET.

Determining the genetic architecture of Alzheimer's disease (AD) pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we performed a genome-wide association study of cortical tau quantified by positron emission tomography in 3,136 participants from 12 independent studies. The locus was associated with tau deposition.

Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease.

Introduction: The acceleration of biological aging is a risk factor for Alzheimer's disease (AD). Here, we performed weighted gene co-expression network analysis (WGCNA) to identify modules and dysregulated genesinvolved in biological aging in AD.

Methods: We performed WGCNA to identify modules associated with biological clocks and hub genes of the module with the highest module significance.

Association of peripheral blood DNA methylation level with Alzheimer's disease progression.

Background: Identifying biomarkers associated with Alzheimer's disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between peripheral blood DNA methylation profiles measured using Infinium® MethylationEPIC BeadChip and AD progression in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

Harnessing peripheral DNA methylation differences in the Alzheimer's Disease Neuroimaging Initiative (ADNI) to reveal novel biomarkers of disease.

Background: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer's disease Neuroimaging Initiative (ADNI) consortium.

Reduced ITPase activity and favorable IL28B genetic variant protect against ribavirin-induced anemia in interferon-free regimens.

Background: Genetic variants of inosine triphosphatase (ITPA) that confer reduced ITPase activity are associated with protection against ribavirin(RBV)-induced hemolytic anemia in peginterferon(IFN)/RBV-based treatment of hepatitis C virus (HCV). Patients with reduced ITPase activity showed improved treatment efficacy when treated with IFN/RBV. In addition, a genetic polymorphism near the IL28B gene is associated with an improved response to IFN/RBV treatment.

Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice.

BRCA1 is critical for maintenance of genomic stability and interacts directly with several proteins that regulate hematopoietic stem cell function and are part of the Fanconi anemia (FA) double-strand break DNA repair pathway. The effects of complete BRCA1 deficiency on bone marrow (BM) function are unknown. To test the hypothesis that Brca1 is essential in hematopoiesis, we developed a conditional mouse model with Mx1-Cre-mediated Brca1 deletion.

Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation.

Epigenetic alterations play a central role in the control of normal and malignant blood cell development. We demonstrate here that expression of a truncated DNA methyltransferase 3B isoform DNMT3B7, which has been shown to alter cellular epigenetic patterns, decreases the overall number of hematopoietic stem and progenitor cells (HSPCs), and markedly diminishes blood cell reconstitution within the female hormonal microenvironment. Gene expression profiling of HSPCs isolated from DNMT3B7 transgenic embryos identified Apolipoprotein E (Apoe) as overexpressed.

DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID.

Changes in DNA methylation are required for the formation of germinal centers (GCs), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCBs) isolated from wild-type (WT) and AID-deficient (Aicda(-/-)) mice.

TET2 Mutations Affect Non-CpG Island DNA Methylation at Enhancers and Transcription Factor-Binding Sites in Chronic Myelomonocytic Leukemia.

TET2 enzymatically converts 5-methylcytosine to 5-hydroxymethylcytosine as well as other covalently modified cytosines and its mutations are common in myeloid leukemia. However, the exact mechanism and the extent to which TET2 mutations affect DNA methylation remain in question. Here, we report on DNA methylomes in TET2 wild-type (TET2-WT) and mutant (TET2-MT) cases of chronic myelomonocytic leukemia (CMML).

5-hydroxymethylcytosine in cancer: significance in diagnosis and therapy.

Emerging data have demonstrated that 5-methylcytosine (5-mC) and its oxidized products 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-CaC) play unique roles in several biological processes, including the control of gene expression and in the pathogenesis of cancer. In this review, we focus on 5-hmC and the disruption of its distribution in several cancers, including hematological malignancies and solid tumors. We present an outline of how 5-hmC is closely associated with metabolic pathways and may be the missing link connecting epigenetics with metabolism in the context of cancer cells.

DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia.

Somatic mutations in IDH1/IDH2 and TET2 result in impaired TET2-mediated conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The observation that WT1 inactivating mutations anticorrelate with TET2/IDH1/IDH2 mutations in acute myeloid leukemia (AML) led us to hypothesize that WT1 mutations may impact TET2 function. WT1 mutant AML patients have reduced 5hmC levels similar to TET2/IDH1/IDH2 mutant AML.

TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma.

The ten-eleven-translocation 5-methylcytosine dioxygenase (TET) family of enzymes catalyzes the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), a modified cytosine base that facilitates gene expression. Cells respond to hypoxia by inducing a transcriptional program regulated in part by oxygen-dependent dioxygenases that require Fe(II) and α-ketoglutarate. Given that the TET enzymes also require these cofactors, we hypothesized that the TETs regulate the hypoxia-induced transcriptional program.

On the origin of leukemic species.

Recent studies (Shlush et al., 2014; Corces-Zimmerman et al., 2014) have demonstrated that leukemias develop from hematopoietic stem cells that acquire preleukemic mutations, allowing clonal expansion and subsequent acquisition of mutations leading to cancer.

Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis.

Hematopoietic stem cell differentiation involves the silencing of self-renewal genes and induction of a specific transcriptional program. Identification of multiple covalent cytosine modifications raises the question of how these derivatized bases influence stem cell commitment. Using a replicative primary human hematopoietic stem/progenitor cell differentiation system, we demonstrate dynamic changes of 5-hydroxymethylcytosine (5-hmC) during stem cell commitment and differentiation to the erythroid lineage.

Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma.

Unlabelled: Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemoresistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTI) reprogrammed chemoresistant cells to become doxorubicin sensitive without major toxicity in vivo.

Genome-wide hydroxymethylation tested using the HELP-GT assay shows redistribution in cancer.

5-hydroxymethylcytosine (5-hmC) is a recently discovered epigenetic modification that is altered in cancers. Genome-wide assays for 5-hmC determination are needed as many of the techniques for 5-methylcytosine (5-mC) determination, including methyl-sensitive restriction digestion and bisulfite sequencing cannot distinguish between 5-mC and 5-hmC. Glycosylation of 5-hmC residues by beta-glucosyl transferase (β-GT) can make CCGG residues insensitive to digestion by MspI.