The evolution of health data ecosystems: An international survey.

This paper reports the findings of an international survey of health data ecosystems (HDEs) in 12 countries plus the H3 Africa project using live, structured interviews with senior project team members under the auspices of Canada's All for One Precision Health Initiative. We note the high level of interest in HDEs around the world, as well as in Canada, despite the financial, jurisdictional, and other barriers that continue to hold back widespread data sharing. We present results detailing operational profiles for each of the 13 participants, including whether their healthcare systems are centralized (national) or decentralized (regional), project start date, funding, information technology (IT) infrastructure, and the extent to which participants have implemented a data-sharing mandate.

International Precision Child Health Partnership (IPCHiP): an initiative to accelerate discovery and improve outcomes in rare pediatric disease.

Advances in genomic technologies have revolutionized the diagnosis of rare genetic diseases, leading to the emergence of precision therapies. However, there remains significant effort ahead to ensure the promise of precision medicine translates to improved outcomes. Here, we discuss the challenges in advancing precision child health and highlight how international collaborations such as the International Precision Child Health Partnership, which embed research into clinical care, can maximize benefits for children globally.

Preclinical Evaluation of a Novel SHIP1 Phosphatase Activator for Inhibition of PI3K Signaling in Malignant B Cells.

Purpose: PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of B-cell malignancies.

A study of splicing mutations in disorders of sex development.

The presence of splicing sequence variants in genes responsible for sex development in humans may compromise correct biosynthesis of proteins involved in the normal development of gonads and external genitalia. In a cohort of Brazilian patients, we identified mutations in HSD17B3 and SRD5A2 which are both required for human sexual differentiation. A number of these mutations occurred within regions potentially critical for splicing regulation.

Novel splice-switching oligonucleotide promotes BRCA1 aberrant splicing and susceptibility to PARP inhibitor action.

Tumors carrying hereditary mutations in BRCA1, which attenuate the BRCA1 DNA damage repair pathway, are more susceptible to dual treatment with PARP inhibitors and DNA damaging therapeutics. Conversely, breast cancer tumors with nonmutated functional BRCA1 are less sensitive to PARP inhibition. We describe a method that triggers susceptibility to PARP inhibition in BRCA1-functional tumor cells.

The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia.

B-cell receptor (BCR)-associated kinase inhibitors, such as ibrutinib, have revolutionized the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative, and resistance is already emerging in a proportion of patients. IL4, expressed in CLL lymph nodes, can augment BCR signaling and reduce the effectiveness of BCR kinase inhibitors.

IL-4 enhances expression and function of surface IgM in CLL cells.

Kinase inhibitors targeting the B-cell receptor (BCR) are now prominent in the treatment of chronic lymphocytic leukemia (CLL). We have focused here on interleukin 4 (IL-4), a cytokine that protects normal and malignant B cells from apoptosis and increases surface immunoglobulin M (sIgM) expression on murine splenic B cells. First, we have demonstrated that IL-4 treatment increased sIgM expression in vitro on peripheral blood B cells obtained from healthy individuals.

The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model.

Current treatment strategies for chronic lymphocytic leukemia (CLL) involve a combination of conventional chemotherapeutics, monoclonal antibodies, and targeted signaling inhibitors. However, CLL remains largely incurable, with drug resistance and treatment relapse a common occurrence, leading to the search for novel treatments. Mechanistic target of rapamycin (mTOR)-specific inhibitors have been previously assessed but their efficacy is limited due to a positive feedback loop via mTOR complex 2 (mTORC2), resulting in activation of prosurvival signaling.

A targeted oligonucleotide enhancer of SMN2 exon 7 splicing forms competing quadruplex and protein complexes in functional conditions.

The use of oligonucleotides to activate the splicing of selected exons is limited by a poor understanding of the mechanisms affected. A targeted bifunctional oligonucleotide enhancer of splicing (TOES) anneals to SMN2 exon 7 and carries an exonic splicing enhancer (ESE) sequence. We show that it stimulates splicing specifically of intron 6 in the presence of repressing sequences in intron 7.

BRCA1 exon 11 a model of long exon splicing regulation.

BRCA1 exon 11 is one of the biggest human exons, spanning 3426 bases. This gene is potentially involved in DNA repair as well as cell growth and cell cycle control. Exon 11 is regulated at the splicing level producing three main different combinations of BRCA1 mature transcripts; one including the whole of exon 11 (full isoform), one skipping the entire exon (D11 isoform), and one including only 117 base pairs of exon 11 (D11q isoform).

Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium.

Loss-of-function germline mutations in BRCA1 (MIM #113705) confer markedly increased risk of breast and ovarian cancer. The full-length transcript codifies for a protein involved in DNA repair pathways and cell-cycle checkpoints. Several BRCA1 splicing isoforms have been described in public domain databases, but the physiological role (if any) of BRCA1 alternative splicing remains to be established.

Intron retention in the alternatively spliced region of RON results from weak 3' splice site recognition.

The RON gene encodes a tyrosine kinase receptor for macrophage-stimulating protein. A constitutively active isoform that arises by skipping of exon 11 is expressed in carcinomas and contributes to an invasive phenotype. However, a high proportion of the mRNA expressed from the endogenous gene, or from transfected minigenes, appears to retain introns 10 and 11.

Design principles for bifunctional targeted oligonucleotide enhancers of splicing.

Controlling the patterns of splicing of specific genes is an important goal in the development of new therapies. We have shown that the splicing of a refractory exon, SMN2 exon 7, could be increased in fibroblasts derived from patients with spinal muscular atrophy by using bifunctional targeted oligonucleotide enhancers of splicing (TOES) oligonucleotides that anneal to the exon and contain a 'tail' of enhancer sequences that recruit activating proteins. We show here that there are striking agreements between the effects of oligonucleotides on splicing in vitro and on both splicing and SMN2 protein expression in patient-derived fibroblasts, indicating that the effects on splicing are the major determinant of success.