A5021553427- RNA Interference and Gene Delivery
- Immunotherapy and Immune Responses
- Colorectal Cancer Surgical Treatments
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Colorectal and Anal Carcinomas
- Advanced biosensing and bioanalysis techniques
- MicroRNA in disease regulation
- Pancreatic and Hepatic Oncology Research
- Virus-based gene therapy research
- Immune Response and Inflammation
- RNA Research and Splicing
- Genetic factors in colorectal cancer
- Cancer Immunotherapy and Biomarkers
- Genetic and phenotypic traits in livestock
- Bacteriophages and microbial interactions
- Advanced Radiotherapy Techniques
- Animal Virus Infections Studies
- Animal testing and alternatives
- RNA regulation and disease
- Cardiac, Anesthesia and Surgical Outcomes
- Cancer Research and Treatments
- Reproductive Physiology in Livestock
- Neonatal Respiratory Health Research
- Listeria monocytogenes in Food Safety
University of British Columbia
2003-2023
Canada's Michael Smith Genome Sciences Centre
2005-2009
Arbutus Biopharma (Canada)
2008
Upsher-Smith Laboratories (United Kingdom)
2008
KU Leuven
1996-2002
Universitair Ziekenhuis Leuven
1997
Lipid nanoparticles (LNPs) are the leading nonviral technologies for delivery of exogenous RNA to target cells in vivo. As systemic platforms, these exemplified by Onpattro, an approved LNP-based interference therapy, administered intravenously and targeted parenchymal liver cells. The discovery systemically LNP capable preferential beyond hepatocytes has, however, proven more challenging. Here, preceded comprehensive mechanistic understanding vivo nanoparticle biodistribution bodily...
The transfection potency of lipid nanoparticle (LNP) mRNA systems is critically dependent on the ionizable cationic component. LNP composed optimized lipids often display distinctive mRNA-rich "bleb" structures. Here, it shown that such structures can also be induced for LNPs containing nominally less active by formulating them in presence high concentrations pH 4 buffers as sodium citrate, leading to improved potencies both vitro and vivo. Induction bleb structure type buffer employed, with...
Lipid nanoparticles (LNPs) for delivery of mRNA usually contain ionizable lipid/helper lipid/cholesterol/PEG-lipid in molar ratios 50:10:38.5:1.5, respectively. These LNPs are rapidly cleared from the circulation following intravenous (i.v.) administration, limiting uptake into other tissues. Here, we investigate properties LNP systems prepared with high levels "helper" lipids such as 1,2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC) or N-(hexadecanoyl)-sphing-4-enine-1-phosphocholine...
Lipid nanoparticles (LNPs) are currently the most effective in vivo delivery systems for silencing target genes hepatocytes employing small interfering RNA. Antigen-presenting cells (APCs) also potential targets LNP siRNA. We examined uptake, intracellular trafficking, and gene potency primary bone marrow macrophages (bmMΦ) dendritic of siRNA formulated LNPs containing four different ionizable cationic lipids namely DLinDAP, DLinDMA, DLinK-DMA, DLinKC2-DMA. DLinKC2-DMA were potent...
Leukocytes are central regulators of inflammation and the target cells therapies for key diseases, including autoimmune, cardiovascular, malignant disorders. Efficient in vivo delivery small interfering RNA (siRNA) to immune could thus enable novel treatment strategies with broad applicability. In this report, we develop systemic methods siRNA encapsulated lipid nanoparticles (LNP) durable potent interference (RNAi)-mediated silencing myeloid cells. This work provides first demonstration...
Cross-presentation by dendritic cells (DCs) is a crucial prerequisite for effective priming of cytotoxic T-cell responses against bacterial, viral and tumor antigens; however, this antigen presentation pathway remains poorly defined.In order to develop comprehensive understanding process, we tested the hypothesis that internalization MHC class I molecules (MHC-I) from cell surface directly involved in cross-presentation loading antigenic peptides. Here provide first examination MHC-I DCs...
A wide variety of human carcinomas have low expression tumor-associated antigen presentation in the context MHC class I antigens due to defects pathway. This immune evasion mechanism renders many tumors unrecognizable by host surveillance mechanisms. The present study examines HLA, tapasin, transporter associated with processing 1 (TAP1), and beta2 microglobulin small cell lung carcinoma non-small carcinoma. Immunohistochemical staining showed severe impairment pathway all patients. In order...
Sclerostin is a protein secreted by osteocytes that encoded the SOST gene; it decreases bone formation reducing osteoblast differentiation through inhibition of Wnt signaling pathway. Silencing gene using RNA interference (RNAi) could therefore be an effective way to treat osteoporosis. Here, we investigate utility lipid nanoparticle (LNP) formulations siRNA silence in vitro and vivo. It shown primary mouse embryonic fibroblasts (MEF) provide useful model system which can induced incubation...
TLR9 recognizes CpG motifs present in pathogenic DNA and triggers potent immune responses. It is generally accepted that distinguishes based, part, on methylation status, where binds unmethylated but not methylated CpG. However, we showed induces TLR9-mediated responses when delivered lipid nanoparticles. In this article, report dictates the ability of free to colocalize with late endosomes. nanoparticles, colocalize, regardless status. Therefore, it proposed cells distinguish from mammalian...
Abstract Purpose: Tpn is a member of the MHC class I loading complex and functions to bridge TAP peptide transporter molecules. Metastatic human carcinomas often express low levels antigen-processing components Tapasin display few functional surface As result, are unrecognizable by effector CTLs. The aim this study examine if (Tpn) plays critical role in escape tumors from immunologic recognition. Experimental Design: To test our hypothesis, nonreplicating adenovirus vector encoding (AdhTpn)...
Cross-presentation is now recognized as a major mechanism for initiating CD8 T cell responses to virus and tumor antigens in vivo. It provides an elegant that allows relatively few Dendritic cells (DCs) initiate primary immune while avoiding the consumptive nature of pathogenic infection. play role anti-bacterial responses; however, contribution cross-presentation priming bacteria, vivo, not well established. Listeria monocytogenes (Listeria) causative agent Listeriosis, opportunistic...
Approved drugs for the treatment of osteoporosis can prevent further bone loss but do not stimulate formation. Approaches that improve density in metabolic diseases are needed. Therapies take advantage ability mesenchymal stem cells (MSCs) to differentiate into various osteogenic lineages treat disorders particular interest. Here we examine small interfering RNA (siRNA) enhance osteoblast differentiation and formation by silencing negative suppressor gene GNAS MSCs. Using clinically...
The rapid development of CRISPR genome editing technology has provided the potential to treat genetic diseases effectively and precisely. However, efficient safe delivery editors affected tissues remains a challenge. Here, we developed luminescent ABE (LumA), luciferase reporter mouse model containing R387X mutation (c.A1159T) in gene located Rosa26 locus genome. This eliminates activity but can be restored upon A-to-G correction by SpCas9 adenine base (ABEs). LumA was validated through...
PURPOSE: Colonoscopy with biopsy(ies) is performed in patients colorectal cancer for diagnosis and screening of synchronous lesions. There some fear spreading the disease related to implantation tumor cells at sites mucosal damage or hematogenous lymphatic spread as a result manipulation. METHODS: A total colonoscopy including biopsies, patient because anal blood loss tenesmus, revealed circular, polypoid, ulcerated mass from 1.5 12 cm above verge. After preoperative radiotherapy, was...
Abstract Background Segmental intraluminal instillation of several tumoricidal agents including povidone–iodine has been advocated to prevent anastomotic recurrence after colonic resection for colorectal cancer. The local and systemic effects on-table whole-colon washout using 5 per cent were assessed in patients undergoing elective surgery Methods effect on the mucosa mucosal damage by tumour take was first investigated Fischer 344 rats. In 12 euthyroid non-allergic patients, lavage via...
PURPOSE: Exfoliated or soiled free malignant cells have serious consequences in patients undergoing gastrointestinal cancer surgery. The present study evaluates the toxicity and efficacy of cytotoxic agents prevention cell seeding tumor growth peritoneal cavity an experimental model. METHODS: Mtln3 adenocarcinoma viability was tested vitro using trypan blue exclusion test after incubation with povidone-iodine chlorhexidine. In vivo, Fischer rats were inoculated 105or 106cells followed by...
The trypan blue exclusion test, the MTT test and an immuno-staining for apoptosis were performed before after incubation of SW620 human colonic carcinoma cells with different cytotoxic agents (CTAs) in order to assess tumor cell viability CTA efficacy vitro. A modified using light microscopy was also performed. good correlation found between assay as determined by spectrophotometry. There no ‘overestimation’ measured test. monitoring formazan formation feasible, but not very reliable since...
Abstract Background Tumoricidal agents have been used to kill viable exfoliated tumour cells following colorectal cancer surgery. Recent in vivo experiments thrown some doubt on the tumoricidal activity of povidone–iodine. Methods The cytotoxic effect distilled water and povidone–iodine at 0·04, 0·4, 0·8, 2 4 per cent final concentrations human SW620 colonic presence red blood cells, purified haemoglobin cell (RBC) membranes, plasma, albumin, faeces bacteria was investigated. Cell viability...
We hypothesize that over-expression of transporters associated with antigen processing (TAP1 and TAP2), components the major histocompatibility complex (MHC) class I antigen-processing pathway, enhances antigen-specific cytotoxic activity in response to viral infection. An expression system using recombinant vaccinia virus (VV) was used over-express human TAP1 TAP2 (VV-hTAP1,2) normal mice. Mice coinfected either vesicular stomatitis plus VV-hTAP1,2 or Sendai increased lymphocyte (CTL) by at...
Previously, we have assessed the efficacy of different cytotoxic agents on viability SW620 human colonic carcinoma cells in vitro. In this study, investigated tumoricidal some antiseptic which were subsequently inoculated into severe combined immunodeficient (SCID) mice. An inoculum 5 × 106 suspended 200 μl buffer solution was found to be minimum number needed result tumour growth within 8 weeks after subcutaneous injection SCID The integrity vitro with trypan blue exclusion test 30 min...