OCTANE (Ontario-wide Cancer Targeted Nucleic Acid Evaluation): a platform for intraprovincial, national, and international clinical data-sharing.

Cancer is a genetic disease resulting from germline or somatic genetic aberrations. Rapid progress in the field of genomics in recent years is allowing for increased characterization and understanding of the various forms of the disease. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) clinical trial, open at cancer centres across Ontario, aims to increase access to genomic sequencing of tumours and to facilitate the collection of clinical data related to enrolled patients and their clinical outcomes. The study is designed to assess the clinical utility of next-generation sequencing (ngs) in cancer patient care, including enhancement of treatment options available to patients. A core aim of the study is to encourage collaboration between cancer hospitals within Ontario while also increasing international collaboration in terms of sharing the newly generated data. The single-payer provincial health care system in Ontario provides a unique opportunity to develop a province-wide registry of ngs testing and a repository of genomically characterized, clinically annotated samples. It also provides an important opportunity to use province-wide real-world data to evaluate outcomes and the cost of ngs for patients with advanced cancer. The octane study is attempting to translate knowledge to help deliver precision oncology in a Canadian environment. In this article, we discuss the background to the study and its implementation, current status, and future directions.

SHP2 is required for BCR-ABL1-induced hematologic neoplasia.

BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, are essential for BCR-ABL1+, but not WT, pre-B-cell proliferation. The mitogen-activated protein kinase kinase (MEK) / extracellular signal-regulated kinase (ERK) pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.

Effect of topical interferon-γ gene therapy using gemini nanoparticles on pathophysiological markers of cutaneous scleroderma in Tsk/+ mice.

Scleroderma is a chronic disorder manifested by excessive synthesis and deposition of collagen in skin and connective tissue, vascular abnormalities, and autoimmunity. Using microarray and real-time PCR data, we show that intradermally expressed interferon γ (IFN-γ), generated after intradermal injection of IFN-γ-coding plasmid, and non-invasive topical nanoparticle (TNP) treatment with IFN-γ-coding plasmid, decreased collagen synthesis (via the Jak/Stat 1 pathway), upregulated Th1 cytokine levels, and downregulated the profibrotic cytokine Transforming growth factor ß and the Smad pathways in the Tsk/+ (tight-skin scleroderma) mouse model. The TNP gene delivery system was constructed from gemini surfactant 16-3-16 and IFN-γ-coding plasmid. Topical administration of IFN-γ-coding plasmid in TNPs was effective in expressing IFN-γ levels after a 20-day treatment regimen without increased TLR4, CCL2, CCL11 and CCR2 mRNA levels that were observed in injected animals, signs considered to be innate responses to injury. The more uniform transgene IFN-γ expression caused significant (70-72%) collagen reduction, as assessed by reverse transcription real-time PCR. These results demonstrate efficient in vivo transfection using a gemini surfactant-based TNP delivery system able to modulate excessive collagen synthesis in scleroderma-affected skin.

Expanding the capabilities of laboratory instruments using built-in microprocessors and serial interfaces: adapting an LKB Ultrospec II UV spectrophotometer for scanning and enzyme kinetic analyses.

An IBM-compatible microcomputer was used to enable an LKB Ultrospec II UV-Visible spectrophotometer to perform two features which are not available on the basic unit: wavelength scanning and enzyme kinetic analyses. The spectrophotometer was controlled using a simple BASIC program, an RS232c interface and the instrument's own built-in microprocessor. This technique required no special analogue to digital conversion hardware or software and only a rudimentary knowledge of programming. User-designed software permits a greater degree of flexibility in routines and output formats than is offered in most pre-programmed instruments, while offering substantial savings.