May 25, 2012
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Most people take for granted that given a little resolve at the gym they can induce their muscles to grow, however, most people have probably not considered the complexity of the underlying cellular and biochemical processes. In response to exercise or injury, normally quiescent muscle satellite cells are activated and divide to produce progeny myogenic precursor cells that will themselves undergo multiple rounds of division before differentiating and fusing to the multinucleated muscle myofiber, thereby increasing the size and strength of the muscle. Key to the regulation of the satellite cell function is expression of the paired box transcription factors Pax3 and Pax7. These transcription factors are highly related (>85% sequence identity) and play overlapping, but mostly nonredundant roles in the specification and progression of the adult satellite cell lineage. Lineage tracing has suggested that Pax3 is required in cells that contribute to embryonic myoblasts and to the endothelial lineage, but Pax7 cells contribute to fetal myoblasts.
Given their sequence similarity, researchers at the University of Ottawa investigated how the functional differences were achieved. By profiling the global gene expression of satellite cell-derived myoblasts, alongside determining the genome-wind binding sites of Pax3 and Pax7, they showed that Pax3 and Pax7 have intrinsic differences in DNA binding and it is the differential binding that drives the differential downstream gene activation. Specifically, they showed that Pax3 and Pax7 are both able to activate gene expression by binding to combined prd/hbox motifs, but Pax7 can also activate gene expression by binding to the hbox motif alone. Due to this difference in binding ability, over 400 genes are regulated by Pax7, that are not subject to regulation by Pax3 and these genes have diverse functions from cell adhesion to muscle cell differentiation. This work adds to the transcriptional network underpinning muscle cell differentiation and also cautions us by showing how large functional differences can occur in transcription factors with only small differences in sequence.
- Hyperphosphorylation and cleavage at d421 enhance tau secretion. PLoS One. Université de Montréal
- Structural basis for substrate specificity and catalysis of human histone acetyltransferase 1. PNAS. Structural Genomics Consortium, Toronto
- Muramyl Dipeptide Induces NOD2-Dependent Ly6C(high) Monocyte Recruitment to the Lungs and Protects Against Influenza Virus Infection. PLoS One. Laval University
May 24, 2012
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Investors are looking for positive events, share price increases and yield from their various Canadian healthcare investments. This quarter’s review looks at delivery on these objectives during Q1 2012. Click here to download the 2012 Q1 Equicom Healthcare Review (pdf).
May 18, 2012
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The development and application of large scale studies of pathways, metabolites and interactions is clearly hugely important for biomedical advances and today’s paper from the University of Toronto and the University of Ottawa is concerned with acetylomics (a relatively recent addition to the rapidly growing omeome).
Lysine acetylation of histones has long been known to be involved in regulation of gene expression. However, acetylation has only recently come to be appreciated as having a wider role outside of histones and may be as extensive a post-translational modification as phosphorylation, with over 2500 mammalian proteins being subject to acetylation. Normal cell proliferation, growth, and differentiation requires the function of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) to maintain the appropriate levels of histone acetylation and abnormal function of these proteins is found in cancer. Therapeutically, KDACs are the targets of the histone deacetylase inhibitors (e.g. Vorinostat) and also include Sirtuin-1, the proposed target for the much hyped Resveratrol.
In their study, the Andrews lab and collaborators determined a network of 463 synthetic dosage lethal interactions for two classes of KDACs in budding yeast, thereby identifying which cellular pathways were subject to regulation by the different KDACs. The identified genes were enriched for diverse cellular processes, indicating that acetylation has a wide, and currently under-appreciated, role within cells that means we should hope to hear a lot more from acetylomics in the future (whether you be a fan of that particular neologism or not).
- TLR Tolerance Reduces IFN-Alpha Production Despite Plasmacytoid Dendritic Cell Expansion and Anti-Nuclear Antibodies in NZB Bicongenic Mice. PLoS One. Toronto Western Research Institute
- Translational Homeostasis via the mRNA Cap-Binding Protein, eIF4E. Molecular Cell. McGill University
- Multiple roles of integrin-linked kinase in epidermal development, maturation and pigmentation revealed by molecular profiling. PLoS One. University of Western Ontario
May 14, 2012
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Welcome to your Monday Biotech Deal Review for May 14, 2012. Highlights from the previous week include the $5 million private placement announced by Lorus Therapeutics and other equity financing announcements, but otherwise the week has generally been a slow one. Read on to learn more. Read more of this post
May 11, 2012
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The tumour suppressor p15ink4b is a cyclin-dependent kinase (cdk) inhibitor, which functions to cause cell cycle arrest and whose functional presence in tumour cells is often lost through mutation or deletion. The expression of p15ink4b can be rapidly induced by transforming growth factor beta (TGF-β) and regulation of p15ink4b levels occurs primarily at the level of transcription. DNA methylation is one of the mechanisms known to repress transcription of p15ink4b, however, the mechanism by which DNA methylation is reversed for the regulation of transcription is relatively poorly understood. In this week’s Molecular Cell paper, the Torchia lab at the University of Western Ontario sought to determine the mechanism of DNA methylation and demethylation of the p15ink4b in response to TGF-β.
Using chromatin immunoprecipitation-sequencing (ChIP-seq), they showed that the p15ink4b gene is a target for the ZNF217/CoREST complex and that along with the action of specific DNA (cytosine-5)-methyltransferase enzymes e.g. DNMT3A, the p15ink4b gene is hypermethylated and repressed. Overcoming the repression in response to TGF-β induced signaling was shown to require removal of the DNMT3A/ZNF217/CoREST complex and replacement by SMAD2/3, the CBP acetyltransferase, and TDG or MBD4. Base excision repair then occurred, demethylating the DNA and thereby removing the transcriptional repression. They further showed that ZNF217 overexpression, a feature of some cancers, was shown to inhibit recruitment of the demethylation complex.
While focused on the specific regulation of p15ink4b, these results add more generally to our knowledge of methylation-based epigenetic regulation and the important association of abnormal DNA methylation patterns with malignant transformation.
- Monomeric site-specific nucleases for genome editing. PNAS. University of Western Ontario
- TRADD contributes to tumour suppression by regulating ULF-dependent p19(Arf) ubiquitylation. Nature Cell Biology. University of Toronto
[Ed. This is the eighteenth part in Wayne's series. You can access the whole thing by clicking here. Please leave comments or questions on the blog and Wayne will address them in future posts in this series.]
Assuming that a partnering deal is signed, what are the usual financial components?
- Up-front cash usually has no conditions and is a non-dilutive financing. Big pharma generally does not want equity as it just clutters up their balance sheets and is an even bigger problem if the partnership gets terminated.
- Clinical and regulatory milestone payments are fairly standard. The basic milestones are the initial U.S. and E.U. approvals but may include approvals of additional indications if they increase the market potential.
- Sales milestone payments have become more common in the last decade. If the pharma partner does not believe the market potential, milestones can be included for reaching certain annual or cumulative sales milestones.
- Royalties on sales are generally no longer a simple X% on net sales. They can be tiered, increasing after annual or cumulative sales milestones are reached.
- If there is an R&D program, who conducts it and who pays for it?
- Who executes and pays for the clinical and regulatory programs?
- Some companies would like to retain or have an option on some sales and marketing rights in specific territories. These rights may cease to exist if there is a change of control at the smaller company.
The only way to learn about deal structures is to create a fictional deal, make the spread sheet and start looking at the impact of structural changes on the product NPV. The following assumptions have been used to create the attached Excel workbook. Read more of this post
Welcome to your Monday Biotech Deal Review for May 7, 2012. Highlights from the previous week include the announcement by Valeant of its agreement to acquire assets from University Medical Pharmaceuticals Corp. for approximately $64M as well as the announcement of Merus’ $10M bought deal private placement and the completion of Allon Therapeutics’ $10M brokered private placement. Read on to learn more. Read more of this post
The innate immune system is the first line of defense against infection of the host organism by pathogens and in this system, type I interferons are a critical component in limiting viral replication. Indeed, type I interferons are already marketed or in development for their anti-viral and immune modulating activities.
Levels of type I interferons are subject to control and rapid induction in response to the recognition of a pathogen by the host organism’s pattern-recognition receptors (e.g. Toll-like receptors – topically a struggling area of development with Idera’s recent phase II failure of a TLR9 inhibitor for advanced head and neck cancer). Production of the type I interferons is rapidly stimulated through a cascade that includes regulation of both transcription and translation, with the transcriptional activator NF-kB being an important site of regulation. A paper in Nature Immunology from a international consortium of researchers led by the Sonenberg lab at McGill University presents data showing that phosphorylation of the translation factor eIF4E is a key mechanism in regulating NF-kB’s ability to activate type I interferon production. Using mice in which the Ser209 phosphorylation site in eIF4E is removed, they showed indirect enhancement of NF-kB activity through decreased translation of NF-kB’s inhibitor IkBa. Furthermore, they showed that in these mice the replication of three different RNA viruses was impaired and that the mice were more resistant vesicular stomatitis virus (VSV) infection associated neurological damage.
Currently Mnk1 and Mnk2 are the only known kinases to phosphorylate eIF4E in mice, with Mnk2 being constitutively active and Mnk1 being activated in response to mitogens, growth factors and hormones, which places Mnk1 in the cascade initiating response to pathogen detection. Earlier this year researchers at the Child and Family Research Institute at the University of British Columbia identified Mnk1 as mediating Trastuzumab (Herceptin) resistance in HER2-positive breast cancers, which excitingly identifies Mnk1 as an unexploited potential target for multiple therapeutic categories, including cancer, viral infections and immune modulation.
- A programmable droplet-based microfluidic device applied to multiparameter analysis of single microbes and microbial communities. PNAS. University of British Columbia
- Innate immune response to rift valley Fever virus in goats. PLoS Negl Trop Dis. National Center for Foreign Animal Disease, Canadian Food Inspection Agency
- Trappin-2/Elafin Modulate Innate Immune Responses of Human Endometrial Epithelial Cells to PolyI∶C. PLoS One. McMaster University
- Inflammation-Driven Reprogramming of CD4(+)Foxp3(+) Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo. PLoS One. McGill University
- Co-Expression of α9β1 Integrin and VEGF-D Confers Lymphatic Metastatic Ability to a Human Breast Cancer Cell Line MDA-MB-468LN. PLoS One. University of Western Ontario
- Early steps in oxidation-induced SOD1 misfolding: Implications for non-amyloid protein aggregation in familial ALS. J. Mol. Biol. University of Toronto
Following the release of the new U.S. bioeconomy strategy, and as we head toward this year’s BIO Convention in Boston, Deloitte is presenting a webcast that may be of interest on how the U.S. healthcare system will deal with an aging population and increasing cost pressures:
Health Sciences Consolidation: Industry’s Response to the New Normal
The webcast will discuss factors driving the future of consolidation in the following sectors:
- Biotech and Pharmaceutical Manufacturers
- Commercial Health Insurance
Click here to register for the webcast.