The Cross-Border Biotech Blog

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

Monthly Archives: November 2011

Monday Biotech Deal Review: November 28, 2011

Welcome to your Monday Biotech Deal Review for November 28, 2011.  Notable events from the previous week include the announcement of a fully-subscribed brokered private placement by Resverlogix for proceeds of $17.5 million, as well as the announcement by Valeant of an agreement to acquire iNova (Valeant’s appetite for acquisitions continues, unabated), a prescription and OTC seller and distributor operating in the Asia Pacific region and South Africa.  Read on to learn more.  Read more of this post

Friday Science Review: November 25, 2011

Bacterial Response to Starvation Breeds Resilience

McGill University ♦ Published in Science, November 18, 2011

Biofilms are one of the primary mechanisms by which bacteria evade the toxic effect of antibiotics. Using a process known as quorum sensing bacteria can communicate amongst one another to accumulate in unison on a surface, living, synthetic, or natural. The benefits provided to the bacteria in film-formation are two-fold: firstly, the density of the bacteria reduces bacterial exposure to antibiotics, and secondly, a protective layer eventually encases the film as it exudes heavy polymeric substances.

However, there is a consequence to biofilm formation — nutrient deprivation and starvation. One would think this to be a disadvantage, but it actually further increases bacterial resistance to antibiotics. One hypothesis to explain this phenomenon is that starvation induces growth arrest and that this reduces the activity of factors that antibiotics require to kill bacteria. New findings from McGill indicate that there is more to the explanation than the passive resistance created through growth arrest. Researchers have discovered an active response to starvation, the starvation-signaling stringent response (SR), which increases tolerance to antibiotics. During times of starvation the SR mechanism is activated leading to a reduction in the burden of oxidants inside bacterial cells. A key finding in this study was that bacteria could be sensitized to antibiotics, by several orders of magnitude, by interfering with the SF mechanism.

Cystic fibrosis (CF) is a good example of a disease indication where biofilms contribute to morbidity. Aggressive Pseudomonas aeruginosa infections occur in the lungs and airways of CF patients. These infections can be treated during the early stages of the disease, however resistant biofilms lead to bacterial adaptation and chronic infection, which ultimately causes fatal complications. Future therapies for biofilms will likely involve a multi-faceted approach that target the many pathways and signaling mechanisms that lead to their formation.

Repression of Mitochondrial Translation: New Therapeutic Approach for AML

Ontario Cancer Institute ♦ Published in Cancer Cell, November 15, 2011

A chemical screen has identified the small molecule tigecycline as a potent suppressor of acute myeloid leukemia (AML). The screen involved 312 drugs that had already been approved by the FDA, both on-patent and off-patent, and focused on those that were well characterized antimicrobials or metabolic regulators. Tigecycline exhibited cytotoxic effects on two human AML cell lines, while having little effect on their normal hematopoietic counterparts. The molecule also had antileukemic activity in a mouse model of human leukemia. A genome-wide screen in yeast was carried out to elucidate tigecycline’s mechanism of action. The small molecule was found to inhibit a transcription factor. The interesting finding was that inhibition was not cytoplasmic, but instead mitochondrial. Tigecyline likely interacts with the EF-Tu transcription factor in the mitochondria, as researchers found they could mimic tigecycline’s effects by downregulating expression of EF-Tu using shRNAs.

Monday Biotech Deal Review: November 21, 2011

Welcome to your Monday Biotech Deal Review for November 21, 2011.  The week appears to have been dead quiet on the biotech front, with only a handful of items, including the announcement by Response Biomedical of an $8M equity financing by way of a rights offering.  Read on to learn more.  Read more of this post

Friday Science Review: November 18, 2011

NF-κβ1 Restrains Maturation of Dendritic Cells

Ontario Cancer Institute ♦ University of Toronto

Published in Nature Medicine, November 13, 2011

Dendritic cells (DCs) are critical for adaptive immune response, however if their proliferation becomes overzealous or their survival too prolonged they can cause autoimmunity. While most researchers have focused on the factors that stimulate DC maturation and autoimmunity, a group at the Ontario Cancer Institute has taken a different approach, and begged the question as to whether there exist factors that put a damper on DC maturation. Sure enough they recently discovered that NF-κβ1 maintains the resting state of DCs. Unstimulated DCs derived from mice lacking the Nfkb1 gene were able to activate CD8+ T lymphocytes. Injecting Nfkb1-/- DCs into mice could also produce diabetes, an autoimmune disease wherein the host’s immune system slowly eats away at insulin producing cells in the pancreas. NF-κβ1 ensures that DC production of TNF-α is regulated. Without NF-κβ1 the production of TNF-α becomes dysregulated leading to upregulation of granzyme B in T cells, which causes autoimmunity.

Human Spinal Cord-Derived NSPCs Survive Transplantation and Differentiate

Toronto Western Research Institute and Krembil Neuroscience Centre

Published in PLoS ONE, November 2, 2011

Researchers have provided a proof-of-principle that adult neural stem/progenitor cells (NSPCs) from the human spinal column can be successfully transplanted in a spinal cord injury (SCI) setting. The ability of NSPCs to engraft and differentiate in vivo was assessed with a mouse model of SCI. Following transplantation NSPCs differentiated into both neurons and glia. In order to establish NSPC lines, neural tissue samples were taken from the spine of organ transplant donors and grown in an adherent cell culture. NSPCs were selected and expanded in the presence of epidermal growth factor and fibroblast growth factor-2. Cultures can be maintained for at least 9 months and exhibit full multipotentiality in that they can differentiate into all three neural cells types, including neurons, oligodendrocytes, and astrocytes. In 2008, a research group successfully established an NSPC cell line, however was not able to scale the cells up for experimentation. This study is the first that shows NSPCs derived from the human spinal column can be scaled up for therapeutic purposes.

Monday Biotech Deal Review: November 14, 2011

Welcome to your Monday Biotech Deal Review for November 14, 2011, marking the end of its one month hiatus.  The Monday Biotech Deal Review will now be resuming its normal weekly schedule.  Below are summaries of recent transactions over the past month, which includes the acquisition of Afexa by Valeant for $0.85 per Afexa share, in cash.    Read on to learn more.  Read more of this post

Friday Science Review: November 11, 2011

Genetically Modified MSCs for Acute Kidney Injury

McGill University ♦ Published in Molecular Therapy (npg), November issue

A research group has taken mesenchymal stem cells (MSCs) and enhanced them with a gene encoding erythropoietin (Epo) to show that they can be used to treat acute kidney injury (AKI). To generate a mouse model of AKI mice were injected with cisplatin, causing injury to the kidney. Epo-enhanced MSCs were then tested against unmodified MSCs for their capacity to regenerate tissue in the kidney and restore kidney function. Mice that received the Epo-enhanced MSCs exhibited improved survival and significantly better kidney function, as measured by blood levels of urea nitrogen, creatinine, and the enzymes amylase and alanine aminotransferase. Histological sections of recipient kidneys displayed less cell death and higher quantities of proliferating cells. Delivery of the Epo gene to modified MSCs causes the cells to secreate Epo protein, which is a known cytoprotective agent. This factor, in addition to the reparative effects of MSCs, produces a particularly strong regenerative effect upon transplantation.

Link Between p53 and Metabolism

York University ♦ University of Toronto ♦ Princess Margaret Hospital

Published in Molecular Cell, November 4, 2011

The tumour suppressor protein p53 has long been known to be the cell’s guardian. The protein can induce cell cycle arrest to allow for DNA repair, induce cellular senescence, or initiate signaling cascades leading to cell death if stress signals become overbearing. New findings suggest p53 is also involved in regulating metabolism on some level. A recent investigation has identified another link between p53 and metabolism, strengthening this hypothesis. Researchers found that the metabolism-regulating gene Lpin1 is partially under the control of p53. The lipin-1 protein controls the degree of fatty acid oxidation in the cell based on p53-signaling. Under normal glucose conditions, where cells can utilize glucose as a source of energy, the lipin-1 protein suppresses fatty acid oxidation. However, during times of nutritional stress lipin-1 promotes the oxidation of fatty acids to provide energy for cellular processes. In this study mouse myoblasts and human fibroblasts were cultured in conditions that induced nutritional stress. During nutrient deprivation reactive oxygen species (ROS) in the cell amass and a protein known as ATM kinase is activated, which in turn causes the activation of p53 and upregulation of Lpin1.

Friday Science Review: November 4, 2011

Native Microbiota Stave Off Infection

University of British Columbia ♦ Published in PLoS ONE, October 28, 2011

Genetics can contribute to host susceptibility to microbial infection but are there other causes? A growing body of evidence points to the composition of microbial flora in the intestine as a key factor in how mammals respond to foreign pathogens. In this study out of the University of British Columbia researchers investigated the effect that infection with a common pathogen had on a number of different strains of mice with widely varying genetic backgrounds. As would be expected the mice responded differently after oral exposure. Some mice were resistant to infection while others became very sick, or even died. However, it wasn’t only genetics at work. Transplantation of microbial samples from the intestines of resistant mice into those of lethally susceptible mice prolonged microbial colonization and death, illustrating the importance that the microbial ecosystem has in regulating mucosal immunity and intestinal health.

Selection of Cardiomyocytes with SIRPA

McEwen Centre for Regenerative Medicine (UHN) ♦ University of Toronto ♦ Monash University

Published in Nature Biotechnology, October 23, 2011

Gordon Keller’s lab has discovered a protein, known as signal-regulatory protein alpha (SIRPA), that can enrich for embryonic stem cell and iPS cell-derived cardiomyocytes at purities as high as 98%. Keller, who was the first researcher to produce functional heart cells from human embryonic stem (hES) cells, has spent years investigating the developmental path that leads to the cardiac identity. In order to find this specialized protein marker researchers carried out a screen of cardiomyocytes against a panel of some 380 CD antibodies. SIRPA was found to be expressed specifically on cardiomyocytes that were the progeny of hES cells or iPS cells; the protein will allow for rapid and efficient separation of cardiomyocytes from both primitive cell types.

Engineering Therapeutic Viruses for Greater Impact

Children’s Hospital of Eastern Ontario Research Institute ♦ University of Ottawa ♦ Ottawa Hospital Research Institute ♦ OICR ♦ McGill

Published in Cancer Cell, October 18, 2011

Viruses are now being leveraged in order to target and destroy cancer cells in the body. Termed “oncolytic” viruses, these treatments not only infect and burst cancer cells but also alert the host’s immune system to the presence of the tumour ensuring a continued onslaught following administration. In hopes of improving upon oncolytic viruses currently under development, researchers have implemented functional genomics to glean information related to virus-tumour interactions. A genome-wide RNAi screen identified the endoplasmic reticulum (ER) stress response as a mechanism by which tumour cells resist the effects imposed by oncolytic viruses. Inhibiting the ER stress response pathway sensitized resistant tumour cells and increased the efficacy of oncolytic viruses by up to 10,000 fold in some cases.


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