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Biotechnology, Health and Business in Canada, the United States and Worldwide

Category Archives: News

Monday Deal Review: October 29, 2012

Welcome to your Monday Biotech Deal Review for October 29, 2012.  Last week, we saw Warnex agree to sell their Bioanalytics Division, which specializes in bioavailability and bioequivalence analysis for pre-clinical and clinical studies, to France-based Biotrial Research. Calyx Bio-Ventures also had a busy week, not only announcing their intent to raise up to $5 million through provate placement, but also that they will be increasing their existing minority stake in Agrisoma Biosciences. For more detail on these stories as well as many more, read on!   
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Monday Deal Review: October 22, 2012

Welcome to your Monday Biotech Deal Review for October , 2012.  A busy week on the licensing front saw commercial deals involving ProMetic Life Sciences, Abbatis Bioceuitcals and Paladin Labs.  In addition, Aeterna Zenatris closed their $15.2 million USD  public offering, which we covered last week.  Get the whole story on this week’s biotechnology news by clicking through. 
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Q3 2012 in Canadian Healthcare Financing: Slow As Expected

The third quarter has always been the slowest for financing public Canadian healthcare companies and 2012 followed this pattern. Gross proceeds of equity and convertible debt financings closed in Q3 totaled only $69 million. Only three companies closed financings over $10 million in Q3 2012:

  • Trimel Pharmaceuticals       $13.2 million (equity – announced in Q2);
  • Centric Health                          $27.5 million (convertible debt); and
  • Resverlogix                               $25.0 million (debt).

During the first 9 months of 2012, decliners outnumbered gainers by 61 to 37 and 43% of the companies had share price changes of 40% or more in a group of 98 Canadian healthcare companies being assessed for share price performance. A good flow of positive product and company news has been balanced by negative news from some of the well-known companies in the sector, including Aeterna Zentaris, Cardiome Pharma, Theratechnologies and Nordion.

The Canadian sector has also not had that major perception-changing event in 2012, such as a licensing deal by a Canadian company with a major pharma partner and a big dollar up-front payment. While the timing of licensing deals and acquisitions is not predictable, companies expecting to report late stage clinical data in Q4 include:

  • Allon Therapeutics – pivotal clinical trial evaluating davunetide for PSP; and
  • Trimel Pharmaceuticals – Phase 3 clinical trial evaluating CompleoTRT™ in patients with male hypogonadism.

[The data in this post was compiled for the upcoming Q3 2012 Canadian Healthcare Review, co-authored by myself and Ross Marshall, Senior Vice President, The Equicom Group Inc., a wholly-owned subsidiary of TMX Group Inc.]

Monday Deal Review: October 15, 2012

Welcome to your Monday Biotech Deal Review for October 15, 2012.  Thanks to Thanksgiving for the Canadians and Columbus day for the Americans out there, this week’s post covers the last two weeks of activity.  Biggest of the weeks’ stories, however, is Aeterna Zentaris Inc.’s $15 million public offering, closing in mid October.  Read onwards to see just how busy this fall the market is shaping up to be. 
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Monday Deal Review: September 31, 2012

Welcome to your Monday Biotech Deal Review for September 31, 2012. This week’s big news is yet another acquisition by Valeant, this time for the U.S rights and inventory of an age-related macular degeneration treatment from QLT Inc. Find more details on this story and others by clicking through.
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Monday Deal Review: September 24, 2012

Welcome to your Monday Biotech Deal Review for September 24, 2012. A busy week in investment stories includes Valeant’s launch of unsecured notes through its subsidiary VPI Escrow Corp, and MedX Health Corp.’s plans to offer 15,000,000 in common shares. Read on to learn more.
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Friday Science Review: September 21, 2012

Left-sided congenital heart disease (LS-CHD) is one of the most commonly seen forms of cardiac malformations. Affected individuals suffer from a spectrum of cardiac issues that include bicuspid aortic valves, aortic valve stenosis, narrowing of the aorta  and underdevelopment of the left side of the heart (hypoplastic left heart syndrome). Several lines of evidence indicate that LS-CHD is due to genetic factors, but the specific genetic causes are not currently known. An international collaboration, headed by the Andelfinger lab at the Université de Montréal, set out to explore the role of structural genomic variations by searching for copy number variants present in only affected individuals and not other family members.

Their study, reported in PLOS Genetics, revealed 25 new candidate genes for LS-CHD. The genes had diverse functions and included the SMC1A gene, involved in sister chromatid cohesion, MFAP4, believed to be involved in in cell adhesion or intercellular interactions, and CTHRC1, which is involved in vascular remodelling. Together it builds a picture that suggests broad alterations in angiogenesis may be the root cause of at least some of the incidences of LS-CHD. This work is part of the first steps in determining the detailed molecular pathophysiological mechanism of LS-CHD, an important part of understanding the diversity of patient outcomes and of developing therapies.

Monday Deal Review: September 17, 2012

Welcome to your Monday Biotech Deal Review for September 17, 2012. This week’s big news includes Valeant’s plans to syndicate an additional $1,000,000,000 of incremental term B loans, and Cangene’s sale of 3 plasma centres to U.S-based Grifols.  Read on to learn more.
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Monday Deal Review: September 10, 2012

Welcome to your Monday Biotech Deal Review for September 10, 2012. This week’s highlights include Zymeworks Inc.’s completion of a common share offering, as well as their achievement of a major research milestone with Merck.  Read on for more.
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Monday Deal Review: September 3, 2012

Welcome to your Monday Biotech Deal Review for September 3, 2012.  A slow week was capped by today’s announcement that Valeant Pharmaceuticals International Inc. will acquire dermatology specialist Medicis Pharmaceuticals Corporation.  The deal, which pushes Valeant’s total 2012 acquisition spending to over $3.5 billion, continues Valeant CEO Michael Pearson’s strategy of “using M&A as a surrogate for R&D.” Read on to learn more.
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Monday Deal Review: August 27, 2012

Welcome to your Monday Biotech Deal Review for August 27, 2012.  Highlights from the previous two weeks include Miraculins Inc’s grant of stock options and distribution agreement with London Drugs, Microbix Biosyetem’s licensing of a thrombolytic biopharmaceutical to Zydus Cadila, and BIOREM’s closing of its private placement.  The Monday Deal Review for August 13, 2012 also marked the last Review authored by Jacob Cawker.  We’d like to thank Jacob for his hard work and years of service! For more about me, please see my Bio, here.  Read on to learn more. Read more of this post

Financings by Public Canadian Healthcare Companies in H1 2012

Public Canadian healthcare companies raised over $1 billion in equity and convertible debt financings in the first half of 2012. Before anybody wonders whether another biotech boom has suddenly appeared, a closer look at the details shows a different reality.

Large equity and convertible debt financings by profitable Canadian healthcare service companies in the first half of 2012 totaled $1,048 million. These are profitable companies, three of which do monthly distributions to shareholders. These companies fit the current risk profile of many investors, who are looking for profits, value and yield.

  • SXC Health Solutions                                      $541.8 million
  • Chartwell Seniors Housing REIT                $339.3 million (equity and convertible debt)
  • HealthLease Properties REIT                      $110.0 million (IPO)
  • Leisureworld Senior Care                             $  56.4 million

The total for the rest of the sector was about $288 million for equity and convertible debt deals closed in H1 2012. A financing over $10 million indicates that a company, especially one developing a novel therapeutic, may have a chance to plan its future, as opposed to just survive. This list includes:

  • YM BioSciences                            $80.5 M
  • Novadaq Technologies              $40.3 M
  • Oncolytics Biotech                      $21.3 M
  • Bioniche Life Sciences               $20.0 M (debt)
  • BELLUS Health                              $17.3 M (includes plan of arrangement proceeds)
  • Merus Labs                                     $17.3 M (equity plus debt)

Removing these large financings leaves about $127 million for the remaining over 100 companies in the sector to share. A small amount of additional funding came from exercise of warrants, government grants and milestone payments from partners.

The financing numbers in this post were compiled from the Q2 2012 Canadian Healthcare Review (pdf), co-authored by myself and Ross Marshall, Senior Vice President, The Equicom Group Inc., a wholly-owned subsidiary of TMX Group Inc. 

Friday Science Review: July 13, 2012

Oncolytic viruses are a promising therapeutic approach that may finally be approaching the market; Amgen’s recently acquired OncoVEX GM-CSF is in phase III for melanoma with results expected in 2013 and Canada’s own Oncolytics has recently completed the first stage of its phase III trial for the treatment of platinum-refractory head and neck cancers.

For tumour types that are permissive to these viruses much of the promise arises from the specific replication in cancer cells and subsequent lysis. However, another activity that can help improve complete responses and prevent recurrence even when the virus has been cleared from the patient is the induction of antitumor immunity. This immunity is greatly stimulated by the viral replication and lysis process. Aiming to harness this effect, the recent paper in Molecular Therapy by researchers at the University of Ottawa describes an approach to generate a broad anti-tumour immunity against a multitude of tumour antigens through the use of an infected cell vaccine (ICV) platform, which is even applicable for tumours that are not permissive to oncolytic viruses.

The oncolytic VSV-Δ51 virus is able to induce a strong anti-tumour immunity in tumour cell lines, but only when viral replication occurs in the tumour cells. To overcome this, the researchers chose an ex vivo approach, whereby infection of isolated tumour cells with their oncolytic virus construct (the VSV-Δ51 virus, but expressing GM-CSF similar to the BioVEX approach) could be ensured in vitro by a high multiplicity of infection. A vaccine could then be prepared from this population of infected cells. With this approach mice were protected from subsequent tumour challenge and the induced innate and adaptive immune response was robust enough to control the growth of established tumours.

This approach offers a personalized vaccine comprising the full range of a patient’s tumour-specific antigens improving the hope for complete response and effective control of recurrence, albeit with a significant commercialization challenge arising from the inherently unscalable manufacturing, operational complexity and high production costs that is currently being faced by Dendreon’s Provenge.

U.S. Bioscience Industry – Status and Trends

On the heels of the U.S. government’s recent report: National Bioeconomy Blueprint , Battelle and BIO have released: State Bioscience Industry Development 2012.

 The report highlights how the bioscience industry has excelled in terms of job growth. Even during tough economic times and an uneven recovery of the global economy, the industry has generally been an employment generator, well above the U.S. national average.

 The report goes on to examine the bioscience industry by state. To read the report, click here

BIO 2012 by the numbers

BIO 2012 is over and the numbers are in:

 Total attendees: >15,000*

International attendees: 5,000

States represented: 48

Countries represented: 65

 Companies participating in the business forum: 2,800

Partnering meetings: 25,000+

Company presentations: 190

 Exhibition space: 180,000 square feet

Exhibiting companies: 2,000

 *Washington, DC/2011 final registration number was 15,626 and there were more than 21,138 partnering meetings

 Next Convention: Chicago, IL, April 22-25

Cross Border Biotech – Now on Video

As an official blog site for BIO 2012, Cross Border Biotech had the opportunity to participate in a fantastic new program known as the “BIO Buzz Center” which enables official bloggers to do webcasts over BIO’s website.  During the convention, traffic to BIO’s websites surges – with the audience increasing by 2-3 times the normal size therefore increasing visibility.

Not being shy of the camera I jumped at the opportunity and had the privilege of interviewing Mr. Sanj Singh, President and CEO of Ade Therapeutics

Aside from the fact that my mike level was a bit low and I probably should have hit the makeup chair before taping, the 4 minute interview went very well.

A big thank-you to Sanj, Tracy Wemett and Gayle Kansagor for making this happen.

More on Ade Therapeutics

Early stage bio and tech tax credits – Maryland style

In light of the Canadian government’s review of the R+D tax credit regime in Canada and the hand wringing around the fallout should the recommendations from the Jenkins report be implented, it was refreshing to hear about the State of Maryland’s approach.

The Maryland government decided to create a unique approach to tax credits for early stage bio and tech companies resulting in “InvestMaryland”. The program has been highlighted in the “BIOtechNOW” event daily : BIOtech_Issue1_17 (2)  from the BIO 2o12 convention.

The state program has been well received and local governments like Montgomery county have stepped up to provide additional support .

 For further details click here

 

 

 

Greetings from BIO 2012!

BIO 2012 has officially kicked off in the beautiful city of Boston.

Social Media has moved front and centre during the convention with a full range of bloggers and tweeters. This year BIO is re-broadcasting blog posts via: http://convention.bio.org/ . Cross Border  Biotech is listed as an official blog site so please check back for the latest updates and news from the convention floor. Speaking of convention floor, the Canadian Pavilion (booth 735) occupies a very large piece of real estate (7200 sq. ft.) and although not officially open is attracting a steady flow of people. The Pavilion houses companies from every province looking to promote, connect and partner.

Also check out the BIOchannel:  http://www.youtube.com/user/BIOchannel/videos  to see the latest in interviews and bio related presentations.

Bloom Burton & Co. Open the TSX

Leading up to their inaugural healthcare conference later this week, Bloom Burton & Co opened trading on the TSX this morning. In a feat of multimedia wizardry, the moment was captured on film:

Friday Science Review: June 15, 2012

Cisplatin was the first platinum based chemotherapy and remains the most widely used. Through an alkylating-like mechanism of action, cisplatin kills cells by binding, cross linking and damaging their DNA, thereby stimulating apoptosis through failed DNA repair attempts.

Platinum based chemotherapy is a standard first line therapy following surgery for many of the most common cancers (e.g. lung, ovarian, cervical). While cisplatin is able to produce positive responses in many patients, with time many will suffer from disease progression due to the development chemoresistance. While targeting cancer stem cells may prove to be a successful (and topical) approach, other approaches that seek to overcome the mechanisms of chemoresistance are important. These mechanisms will depend upon the agent to which resistance is conferred, but include increased efflux, mutation in the therapeutically target enzyme, decreased drug activation, increased drug metabolism, drug inactivation, enhanced DNA repair and mutation of the apoptosis pathway.

In this weeks post, the Lu lab at the University of Waterloo sought to boost the DNA-damaging activity of cisplatin. Based upon the authors’ previous studies, where they demonstrated the importance of a dissociative electron-transfer mechanism for reductive DNA damage by cisplatin, the authors proposed that addition of a biological electron donor to cisplatin treatment would increase its activity and potentially overcome resistance. N,N,N’,N’-tetramethyl-p-phenlenediamine (TMPD) is one such donor and in combination with cisplatin it was shown to increase plasmid DNA double strand breaks (a simple measure for DNA-damage activity); increase cisplatin sensitivity in both HeLa cells and in the cisplatin resistant ovarian cancer cell line NIH:OVCAR-3. A key feature of the combination is that it led to synergistic rather than additive effects. Furthermore, the authors proposed that the presence of TMPD actually suppressed the mechanism conferring cisplatin resistance to the NIH:OVCAR-3 cells, however, demonstration of that will require further work.

Indeed, much remains to be done to demonstrate the broad applicability and robustness of the results, but cisplatin’s immense importance in the formulary and its frontline use in a wide range of cancers means that the rapid development of a TMPD adjunctive therapy is one to be hoped for.

Q1 2012 in Canadian Healthcare

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).

Friday Science Review: May 18, 2012

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).

Other publications:

  • 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

Friday Science Review: May 11, 2012

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.

Other publications:

  • 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

Friday Science Review: April 13, 2012

Intrinsically disordered proteins, i.e. proteins or regions of proteins that do not adopt defined structural folds, but rather exist as a dynamic ensemble of structures, are a fascinating and important area of biology. Members of this class of proteins are enriched in cell signaling, transcription and translation, where their lack of fixed structure must be conferring a functional advantage.  Often involved in multiple interactions and subject to complex control through post-translational modification, these proteins have immense biomedical relevance, however, their very nature and complexity complicates attempts to characterize them.

Results reported in PNAS by researchers from the Ontario Cancer Institute are gradually filling in the details for one such protein, FOXO3a. This ubiquitously expressed protein activates transcription of genes responsible for differentiation, DNA repair, cell cycle regulation, stress resistance and apoptosis, which it achieves by binding to specific elements in DNA, followed by recruitment of the coactivator CBP/p300. Using nmr on peptides from the intrinsically disordered region of FOXO3a in the presence of the cognate binding partner domain from CBP/p300, they confirmed that two regions of FOXO3a are involved in the interaction, but unexpectedly that the complex is dynamic and exists in two conformationally distinct states. Furthermore, recruitment of CBP/p300 is promoted by interactions with other domains of CBP/p300 and the interaction can be further enhanced by phosphorylation at a specific position within the disordered CBP/p300 binding region of FOXO3a.

These findings help to build a model of the dynamic, promiscuous and multivalent interactions that underlie the functions of intrinsically disordered proteins and can help us to understand why an intrinsic lack of structure can have advantages in both recruiting binding partners and providing mechanisms to modulate those interactions.

Other Publications:

  • Critical Evaluation of Imprinted Gene Expression by RNA-Seq: A New Perspective. PLoS Genetics. University of Toronto
  • Blockade of Fatty Acid synthase triggers significant apoptosis in mantle cell lymphoma. PLoS One. University of Alberta and Cross Cancer Institute
  • EGF-Induced EMT and Invasiveness in Serous Borderline Ovarian Tumor Cells: A Possible Step in the Transition to Low-Grade Serous Carcinoma Cells? PLoS One. University of British Columbia
  • Real-time visualization and quantitation of vascular permeability in vivo: implications for drug delivery. PLoS One. Innovascreen, Inc.
  • Lentivector Transduction Improves Outcomes Over Transplantation of Human HSCs Alone in NOD/SCID/Fabry Mice. Molecular Therapy. University Health Network, Toronto

Friday Science Review: April 6, 2012

Mutations in the CFTR gene, which encodes a chloride channel expressed on the apical membranes of surface epithelial cells, can lead to dysregulation of ion conduction and solute trafficking in these cells. This dysregulation manifests as the accumulation of thicker than normal mucus in the lungs, digestive tract and other areas and it is the inability to clear this mucus that leads to the health consequences for cystic fibrosis (CF) patients.

Over 1900 different mutations and sequence variations in the CFTR gene have been identified and this increase in understanding will allow the development of treatments that target the underlying molecular defect, as demonstrated by the recent approval of Vertex Pharmaceuticals’ Kalydeco, a CFTR potentiator, which increases chloride flux through CFTR channels containing the G551D mutation found in ~4% of CF patients.

However, even in individuals that share the same molecular change to the CFTR gene, there are substantial variations in the disease severity and in the organs affected. The disease pathophysiology is therefore being modulated by variations in other genes. Researchers at the Biostatistics division of the Dalla Lana School of Health and the Department of Statistics of the University of Toronto sought to identify the variations that are associated with meconium ilius (MI), a severe intestinal obstruction at birth that is highly indicative of CF, by carrying out genome wide association studies. Using SNP’s from thousands of CF sufferers born with MI they found associations with variations in three genes that encode members of the solute carrier family of secondary transporter proteins (SLC6A14, SLC26A9, and SLC9A3) and association of MI with multiple other genes that are constituents of the apical plasma membrane.

Identification of these genes helps further develop understanding of the molecular mechanism of the disease i.e. how is the system level function perturbed by the altered chloride levels, as well as opening up new avenues for treating CF by pharmacological modulation of the epithelium as a whole.

Other publications:

  • Differences in the Mechanisms of Proapoptotic BH3 Proteins Binding to Bcl-XL and Bcl-2 Quantified in Live MCF-7 Cells. Molecular Cell. McMaster University
  • PARP1 Parylation Promotes Silent Locus Transmission in the Nucleolus: The Suspicion Confirmed. Molecular Cell. Centre de recherche du CHUQ-Pavillon CHUL
  • Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+:ERα- breast cancer. PNAS. Toronto General Research Institute

Friday Science Review: March 23, 2012

When the human genome was sequenced there was surprise that only 23 thousand protein-encoding genes were found. However, it was followed by an added emphasis on the other mechanisms used by eukaryotic organisms to generate proteome diversity and especially the creation of different protein isoforms through alternative splicing of exons in precursor mRNA transcripts. Indeed, in humans it is estimated that 95% of genes containing more than one exon are subject to alternative splicing and splicing of the same gene varies by tissue type.

Given its importance, characterizing the molecular mechanism by which tissue specific splicing occurs and its effect on downstream function is therefore an important area of research and the study carried out by researchers from McGill University and Laval University is helping to fill some of the current gaps. Alternative splicing is regulated by RNA binding proteins, one of which is Sam68, a member of the signal transduction activator of RNA (STAR) family. Sam68-/- mice are leaner than normal mice and are protected from obesity, insulin resistance and glucose intolerance. In their paper published in Molecular Cell, they explored the alternative splicing events regulated by Sam68 to explain its unexpected physiological roles.

By carrying out genome-wide exon usage profiling in the white adipose tissue, they were able to show that Sam68-/- mouse cells had lower levels of mTOR, which resulted from the introduction of a premature termination codon due to intron 5 from the mTOR gene not being excised. The lower levels of mTOR had downstream consequences, including reduced insulin-stimulated S6 and Akt phosphorylation, which reduced adipogenesis.

mTOR inhibitors are of course in the clinic (and in multiple clinical trials) for use in immune suppression and cancer, but is weight loss about to be added to that list? A recent paper from the University of Geneva shows that the chronic exposure to the mTOR inhibitor rapamycin does result in reduced specific fat mass in rats, but at the cost of rather serious systemic consequences including skeletal muscle insulin resistance.

While probably not initiating the rush for development of the new perfect diet pill, this research on tissue specific gene-splicing continues to add to our understanding of the various levels at which signaling pathways are regulated and their tissue dependence.

Gairdner Awards

This week also saw the announcement of the 2012 Canada Gairdner Awards, which recognized contributions to our understanding of the genetic control of circadian rhythms; of how sensory and motor neurons communicate; and the role of Fc receptors in immune response and autoimmune diseases. The awards also recognized the efforts of two scientists for their role in reducing the toll of infectious diseases. Details can be seen on the Gairdner website here.

Other Publications:

  • Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nature Medicine. University of Calgary
  • Cell-Surface Proteomics Identifies Lineage-Specific Markers of Embryo-Derived Stem Cells. Developmental Cell. University of Toronto
  • Direct observation of multiple misfolding pathways in a single prion protein molecule. PNAS. University of Alberta

Friday Science Review: March 16, 2012

I have spent much of this week looking into cancer metabolism, where the recent partnership successes of Forma and fund raising by Agios have shown how hot this area has become. Many cancer cells it turns out switch their metabolism to aerobic glycolysis, a phenomenon known as the Warburg effect. An important regulator of the switch to glycolytic metabolism is the transcription factor HIF-1 (hypoxia inducible factor 1), which, in response to low oxygen conditions or cytokines, growth factors and ROS amongst others up-regulates a whole host of elements involved in stimulating glycolytic flux, including the glycolysis enzymes and regulators, as well as glucose transporters etc.

The cellular rationale above seems clear, in low oxygen conditions cells up-regulate their ability to carry out anaerobic energy production. However, coincidentally, the recent research led by Dr Michael Ohh at the University of Toronto, reveals an interesting new facet to the adaptations: HIF-1 also increases the expression of Caveolin-1 (CAV1), a structural component of caveolae – small flask shaped invaginations in the plasma membrane that have roles in cell signaling and endocytosis. Their research shows that the HIF-1 induced CAV-1 expression leads to increased caveolae on the cell surface and significantly, as a result, increased activation of the EGF signaling pathway even in the absence of ligand due to dimerization of EGF receptors within the caveolae. HIF-1 dependent up-regulation of CAV-1 thereby enhanced the oncogenic potential of tumour cells and increased tumour cell proliferation.

HIF-1 over-expression is commonly seen in tumors, either due to hypoxic tumor conditions, or due to aberrant regulation resulting from mutations in upstream tumor suppressors such as TSC2, PTEN, p53, and VHL and this new finding emphasizes the complexity of the changes seen in cancer signaling and metabolism. The enhancement of glycolysis and the increase in oncogenic potential from ligand independent EGF signaling are related, but how does one attempt to integrate these very different changes? Are changes like the ligand independent EGF signaling encouraging the switch to glycolysis, or is it glycolysis itself that is favorable (for which there are multiple opinions on the possible cellular rationale)?

Other publications:

  • Lung adenocarcinoma of never smokers and smokers harbor differential regions of genetic alteration and exhibit different levels of genomic instability. PLoS One. British Columbia Cancer Research Centre
  • Mechanistic Insight into the Microtubule and Actin Cytoskeleton Coupling through Dynein-Dependent RhoGEF Inhibition. Molecular Cell. University of Toronto
  • Cell-Type Specific Roles for PTEN in Establishing a Functional Retinal Architecture. PLoS One. University of Calgary
  • HIV-1 Promotes Intake of Leishmania Parasites by Enhancing Phosphatidylserine-Mediated, CD91/LRP-1-Dependent Phagocytosis in Human Macrophages. PLoS One. Université Laval

Friday Science Review: March 9, 2012

An accidental neural theme for this weeks Canadian life science research highlights, beginning with…

…higher-order gyrenphalic non-human primates…

Stroke is currently the second leading cause of death here in the West and might surpass heart disease to become the number one killer. In ischemic stroke, the treatment is focused on restoring the restricted blood flow through the use of surgical or pharmacological removal of the causative blood clot. Ischemia causes neuronal damage through initiation of the ischemic cascade, a series of biochemical events that ultimately leads to neuronal death. A promising therapeutic avenue is therefore to block events in this cascade, thereby eliciting a neuroprotective effect.

However, despite promising data in cell and rodent models, a shocking number – over 100 in fact – experimental approaches have failed to demonstrate a neuroprotective effect in clinical trials. While part of this failure rate can be attributed to the poor selection of candidates to advance (from the >1000 reported pre-clinical experimental approaches), poor pre-clinical studies and poor trial design, it has resulted in a general sentiment that neuroprotection in humans is not possible.

However, research by the Tymianski lab at Toronto Western Hospital Research Institute, reported in Nature should help reinstil some much needed optimism. Rather than a rodent model, Cook and colleagues conducted their study in cynomolgus macaques, a higher-order gyrenphalic non-human primate i.e. an animal that possesses a brain more similar to that of humans. Using two experimental models of ischemia, they demonstrated the neuroprotective ability of a PSD-95 inhibitor using a broad set of measures including MRI assessed infarct volumes, retention of transcriptional ability (normally lost in ischemic cells) and retention of neurological function in neurobehavioral assays.

The target PSD-95 is a synaptic scaffolding protein that links NMDA receptors to neurotoxic signaling pathways and while their peptide based inhibitor Tat-NR2B9c had already been shown to be neuroprotective in rats, it is the first time that neuroprotection has been demonstrated in a species so close in complexity to humans. Hopefully with this model there will finally be a path to clinical success and the long sought-after realization of neuroprotection as a treatment modality for ischemic stroke.

Other publications:

  • Developmental transcriptional networks are required to maintain neuronal subtype identity in the mature nervous system. PLoS Genetics. University of British Columbia
  • Ex vivo and in vivo neuroprotection induced by argon when given after an excitotoxic or ischemic insult. PLoS One. Université Laval

Some Top-Line Numbers From 2011 For Public Canadian Healthcare Companies

The numbers have been crunched in preparation for the 2011 Canadian Healthcare Annual Review, which I co-author with Ross Marshall, Senior Vice President at The Equicom Group. Prior to its publication later this month, we are going to give you a look at some of the top-line numbers.

The biggest concern in the sector is financing, both in Canada and globally. Two groups of numbers are shown below for our universe of public Canadian healthcare companies (132 companies to start 2011) – total equity and convertible debt financings by the group, and financings by development stage companies only (shown in millions of dollars). The 2011 total for the development stage companies is about the same at it was for the prior two years but is less than half of the average raised in 2005-2007.

Another major concern for both companies and shareholders is share price performance. We monitor share prices of a group of companies which started 2011 with a share price of $0.10 or higher and also look at two sub-groups. There were 104 companies in this group to start 2011 but only 97 companies actively trading as healthcare companies at the end.

The Equicom 2011 Canadian Healthcare Annual Review will look more closely at these numbers and the events from 2011, and discuss the results of its recent investor survey.

Friday Science Review: September 16, 2011

Novel Genetically Encoded Calcium Indicators

University of Alberta ♦ Hokkaido University ♦ Kyushu University

Published in Science, September 8, 2011

Calcium transport is critical to normal physiology having an essential role in processes like neural communication and muscle contraction. As a result, the element has been at the centre of a large body of physiological research. Over the years researchers have attempted to trace calcium to monitor physiological reactions, such as neurotransmitter release from neurons or the contraction of cardiac cells. Fluorescent indicator proteins are one means in which to do this. When calcium is present in a system that contains a fluorescent indicator it becomes bound to the indicator causing it to emit a characteristic energy that can be observed using fluorescence microscopy. Although this technology has been around for decades, continuing advances in microscopy have placed new fluorescent indicators in demand. Researchers at the University of Alberta have constructed not just one, but a cassette, of calcium reporters for research use. This cassette is composed of indicators that fluoresce in one of three colours — blue, green, or red; a step up from previous indicators that could only weakly fluoresce in a green hue. These novel proteins are expected to advance our understanding of calcium’s contribution to physiology and allow researchers to complete experiments that were previously impractical to approach.

At the Interface

Holland Bloorview Kids Rehabilitation Hospital ♦ University of Toronto ♦ University of Pittsburgh ♦ Hospital for Sick Children

Published in PLoS ONE, September 7, 2011

Brain computer interface (BCI) technology may one day revolutionize the way humans control devices. Researchers are currently investigating BCIs as a means to translate mental thought to signals that can control external devices. If commercialized, the technology could be useful in areas such as virtual reality, wheelchair control, and speech in individuals that lack muscle control. Several different modalities have been developed to register thought, including electroencephalography, functional magnetic resonance imaging, and magnetoencephalography. However, these methods still have shortcomings that limit their practicality. A technique known as transcranial Doppler ultrasound (TCD), which measures cerebral blood flow velocity in the brain, has shown promise as a new paradigm for BCI systems. Using TCD, researchers were able to measure changes in the velocity of cerebral blood flow in response to a word generation task and a mental rotation task. The system was able to decipher between the two with high accuracy suggesting that TCD could one day be useful for the more complex tasks that BCI will demand.

Also checkout this review on the use of encapsulation technology for applying biofertilizers and biocontrol agents, and this review on extracting polyphenols from plants for analysis in the lab; both papers published in Critical Reviews in Biotechnology.

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