Publications by authors named "Michael Cancilla"

5 Publications

  • Page 1 of 1

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice.

J Endocrinol 2016 Jan 22;228(1):61-73. Epub 2015 Oct 22.

Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.

Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with β-cell dysfunction. A genome-wide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a ∼211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucose-mediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving β-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to β-cell dysfunction in T2D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/JOE-15-0290DOI Listing
January 2016

Making Safe Surgery Affordable: Design of a Surgical Drill Cover System for Scale.

J Orthop Trauma 2015 Oct;29 Suppl 10:S29-32

*Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada; †Arbutus Medical, Vancouver, British Columbia, Canada; ‡Department of Mechanical Engineering, Stanford University, Stanford, CA; and §Department of Pediatric Orthopaedics and Trauma, Loma Linda University Medical Centre, Loma Linda, CA.

Many surgeons in low-resource settings do not have access to safe, affordable, or reliable surgical drilling tools. Surgeons often resort to nonsterile hardware drills because they are affordable, robust, and efficient, but they are impossible to sterilize using steam. A promising alternative is to use a Drill Cover system (a sterilizable fabric bag plus surgical chuck adapter) so that a nonsterile hardware drill can be used safely for surgical bone drilling. Our objective was to design a safe, effective, affordable Drill Cover system for scale in low-resource settings. We designed our device based on feedback from users at Mulago Hospital (Kampala, Uganda) and focused on 3 main aspects. First, the design included a sealed barrier between the surgical field and hardware drill that withstands pressurized fluid. Second, the selected hardware drill had a maximum speed of 1050 rpm to match common surgical drills and reduce risk of necrosis. Third, the fabric cover was optimized for ease of assembly while maintaining a sterile technique. Furthermore, with the Drill Cover approach, multiple Drill Covers can be provided with a single battery-powered drill in a "kit," so that the drill can be used in back-to-back surgeries without requiring immediate sterilization. The Drill Cover design presented here provides a proof-of-concept for a product that can be commercialized, produced at scale, and used in low-resource settings globally to improve access to safe surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BOT.0000000000000403DOI Listing
October 2015

Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors.

Cancer Cell 2005 Apr;7(4):325-36

Exelixis Inc., 170 Harbor Way, South San Francisco, California 94083, USA.

A chemical genetics approach identified a cellular target of several proapoptotic farnesyl transferase inhibitors (FTIs). Treatment with these FTIs caused p53-independent apoptosis in Caenorhabditis elegans, which was mimicked by knockdown of endosomal trafficking proteins, including Rab5, Rab7, the HOPS complex, and notably the enzyme Rab geranylgeranyl transferase (RabGGT). These FTIs were found to inhibit mammalian RabGGT with potencies that correlated with their proapoptotic activity. Knockdown of RabGGT induced apoptosis in mammalian cancer cell lines, and both RabGGT subunits were overexpressed in several tumor tissues. These findings validate RabGGT, and by extension endosomal function, as a therapeutically relevant target for modulation of apoptosis, and enhance our understanding of the mechanism of action of FTIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccr.2005.03.024DOI Listing
April 2005

Caspase activation by granzyme B is indirect, and caspase autoprocessing requires the release of proapoptotic mitochondrial factors.

Immunity 2003 Mar;18(3):319-29

Cancer Immunology Program, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, 8006, Melbourne, Australia.

Apoptosis in response to granzyme B involves activation of caspase-dependent target cell death pathways. Herein, we show that granzyme B initiates caspase processing but cannot fully process procaspase-3 in intact Jurkat T leukemia or NT2 neuronal cells. Rather, the release from mitochondria of proapoptotic mediators cytochrome c, Smac/Diablo, and HtrA2/Omi facilitates full activation of caspases that results from autoprocessing. Bcl-2 overexpression in mitochondria suppresses the release of these proapoptotic molecules, resulting in cell survival despite partial procaspase processing by granzyme B. We propose that binding of inhibitor of apoptosis (IAP) proteins to partially processed procaspases inhibits cell death unless mitochondrial disruption also occurs in response to granzyme B or activated BH3-domain proteins such as truncated Bid.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s1074-7613(03)00050-5DOI Listing
March 2003

High-throughput gene mapping in Caenorhabditis elegans.

Genome Res 2002 Jul;12(7):1100-5

Exelixis, Inc., South San Francisco, California 94083-0511, USA.

Positional cloning of mutations in model genetic systems is a powerful method for the identification of targets of medical and agricultural importance. To facilitate the high-throughput mapping of mutations in Caenorhabditis elegans, we have identified a further 9602 putative new single nucleotide polymorphisms (SNPs) between two C. elegans strains, Bristol N2 and the Hawaiian mapping strain CB4856, by sequencing inserts from a CB4856 genomic DNA library and using an informatics pipeline to compare sequences with the canonical N2 genomic sequence. When combined with data from other laboratories, our marker set of 17,189 SNPs provides even coverage of the complete worm genome. To date, we have confirmed >1099 evenly spaced SNPs (one every 91 +/- 56 kb) across the six chromosomes and validated the utility of our SNP marker set and new fluorescence polarization-based genotyping methods for systematic and high-throughput identification of genes in C. elegans by cloning several proprietary genes. We illustrate our approach by recombination mapping and confirmation of the mutation in the cloned gene, dpy-18.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.208902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC186621PMC
July 2002