An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus

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Tetrahymena thermophila, a unicellular eukaryote with separate germline and somatic genomes

Tetrahymena thermophila is a ciliate - a unicellular eukaryote. Remarkably, every cell maintains differentiated germline and somatic genomes: one silent, the other expressed. Moreover, the two genomes undergo diverse processes, some as extreme as life and death, simultaneously in the same cytoplasm. Conserved eukaryotic mechanisms have been modified in ciliates to selectively deal with the two genomes. We describe research in several areas of Tetrahymena biology, including meiosis, amitosis, genetic assortment, selective nuclear pore transport, somatic RNAi-guided heterochromatin formation, DNA excision and programmed nuclear death by autophagy, which has enriched and broadened knowledge of those mechanisms.     

Differential accumulation of genetic and phenotypic changes in Venezuelan equine encephalitis virus and Japanese encephalitis virus following passage in vitro and in vivo

The requirement to replicate in both vertebrate and invertebrate hosts is thought to limit the introduction of genetic changes into the genome of arboviruses. Serial passage under laboratory conditions will overcome this limitation allowing for genetic changes to be introduced and affecting the virulence of the virus for animals. In the studies detailed here, the consequence of removing the restriction of alternate replication was demonstrated to be different depending on the virus. Passing Venezuelan equine encephalitis virus in tissue culture cells, eggs or mice resulted in up to 11 nucleotide or amino acid changes but no significant change in the virulence of the virus for mice. Passing Japanese encephalitis virus (JEV) under the identical conditions resulted in as many as 22 nucleotide or amino acid changes that often resulted in improved survival probabilities. For JEV, most genetic changes along with the attenuated phenotype were selected within 5 passes.     

PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11-19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.     

Impact of Hyperthermal Rotary Blood Pump Surfaces on Blood Clotting Behavior: An Approach

The influence of heat dissipating systems, such as rotary blood pumps, was investigated. Titanium cylinders as rotary blood pump housing dummies were immersed in porcine blood and constantly tempered at specific temperatures (37–60°C) over a defined period of time. The porcine blood was anticoagulated either by low heparin dosage or citrate. At frequent intervals, samples were taken for blood analysis and the determination of the plasmatic coagulation cascade. Blood parameters do not alter at surface temperatures below 50°C. Hyperthermia-induced hemolysis could be confirmed. The plasmatic coagulation cascade is terminated at surface temperatures exceeding 55°C. The adhesion of blood constituents on surfaces is temperature and time dependent, and structural changes of adhesions and blood itself were detected.     

Canadian Association of University Surgeons Annual Symposium: continuity of care: Toronto,Ontario, Sep. 6, 2007

This 2007 symposium of the Canadian Association of University Surgeons brought together surgeons from a number of jurisdictions to discuss the challenges and opportunities that reduced physician work hours will bring to the care of the surgical patient. Dr. Brian Taylor, president of the association, underscored the need to find a balance between the benefits of diminished workloads/work hours and the loss of continuity of care. He opined that Canada needs to learn from our European colleagues’ experience. Dr. Per-Olof Nyström, professor of surgery, presented the modern Swedish model of surgical care, which had to be developed as a consequence of the European Union’s legal restrictions on the amount of time an individual surgeon may work. Sweden employs a team-based shared-care model driven by the individual surgeon’s expertise rather than the “village factory” model of the multiskilled, multitasking approach of surgical care more prevalent in Canada. Dr. Chris de Gara, secretary treasurer of the association, presented the evidence base for (and against) work-hour restrictions and how well-designed systems can ensure effective continuity of care. Dr. Stewart Hamilton illustrated how one such system for the delivery of the emergency general surgical services has evolved at the University of Alberta Hospital, which demonstrated its effectiveness in providing quality surgical continuity of care. Dr. Debrah Wirtzfeld underscored the importance of trainee lifestyle and how modern Web-based technologies can ensure reduced errors with the implementation of a “sign-out” system.