N-type calcium channel blockers: Novel therapeutics for the treatment of pain

Highly selective Cav2.2 voltage-gated calcium channel (VGCC) inhibitors have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Cone snail venoms provided the first drug in class with FDA approval granted in 2005 to Prialt (ω-conotoxin MVIIA, Elan) for the treatment of neuropathic pain. Since this pioneering work, major efforts underway to develop alternative small molecule inhibitors of Cav2.2 calcium channel have met with varied success. This review focuses on the properties of the Cav2.2 calcium channel in different pain states, the action of ω-conotoxins GVIA, MVIIA and CVID, describing their structure-activity relationships and potential as leads for the design of improved Cav2.2 calcium channel therapeutics, and finally the development of small molecules for the treatment of chronic pain.

In-Vivo Corrosion and Fretting of Modular TI-6AL-4V/CO-CR-MO Hip Prostheses: The Influence of Microstructure and Design Parameters

The purpose of this study was to evaluate the incidence of corrosion and fretting in 48 retrieved titanium-6aluminum-4vanadium and/or cobalt-chromium-molybdenum modular total hip prosthesis with respect to alloy material microstructure and design parameters. The results revealed vastly different performance results for the wide array of microstructures examined. Severe corrosion/fretting was seen in 100% of as-cast, 24% of low carbon wrought, 9% of high carbon wrought and 5% of solution heat treated cobalt-chrome. Severe corrosion/fretting was observed in 60% of Ti-6Al-4V components. Design features which allow for fluid entry and stagnation, amplification of contact pressure and/or increased micromotion were also shown to play a role. 75% of prosthesis with high femoral head-trunnion offset exhibited poor performance compared to 15% with a low offset. Large femoral heads (>32mm) did not exhibit poor corrosion or fretting. Implantation time was not sufficient to cause poor performance; 54% of prosthesis with greater than 10 years in-vivo demonstrated none or mild corrosion/fretting.

Genetic-epidemiologic analysis of X-inactivation skewing in human females : suggestive evidence for two distinct traits

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Genetic-epidemiologic analysis of X-inactivation skewing in human females : suggestive evidence for two distinct traits

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating interest in the clinical utility of the oligonucleotide therapeutic class. This is strongly supported through recent advances in nucleic acids chemistry, synthetic oligonucleotide delivery and viral gene therapy that have succeeded in bringing to market at least three nucleic acid-based drugs. As a consequence, multiple new candidates such as RNA interference modulators, antisense, and splice switching compounds are now progressing through clinical evaluation. Here, manipulation of RNA for the treatment of lung disease is explored, with emphasis on robust pharmacological evidence aligned to the five pillars of drug development: exposure to the appropriate tissue, binding to the desired molecular target, evidence of the expected mode of action, activity in the relevant patient population and commercially viable value proposition.

CaV channels and cancer: canonical functions indicate benefits of repurposed drugs as cancer therapeutics

The importance of ion channels in the hallmarks of many cancers is increasingly recognised. This article reviews current knowledge of the expression of members of the voltage-gated calcium channel family (CaV) in cancer at the gene and protein level and discusses their potential functional roles. The ten members of the CaV channel family are classified according to expression of their pore-forming α-subunit; moreover, co-expression of accessory α2δ, β and γ confers a spectrum of biophysical characteristics including voltage dependence of activation and inactivation, current amplitude and activation/inactivation kinetics. CaV channels have traditionally been studied in excitable cells including neurones, smooth muscle, skeletal muscle and cardiac cells, and drugs targeting the channels are used in the treatment of hypertension and epilepsy. There is emerging evidence that several CaV channels are differentially expressed in cancer cells compared to their normal counterparts. Interestingly, a number of CaV channels also have non-canonical functions and are involved in transcriptional regulation of the expression of other proteins including potassium channels. Pharmacological studies show that CaV canonical function contributes to the fundamental biology of proliferation, cell-cycle progression and apoptosis. This raises the intriguing possibility that calcium channel blockers, approved for the treatment of other conditions, could be repurposed to treat particular cancers. Further research will reveal the full extent of both the canonical and non-canonical functions of CaV channels in cancer and whether calcium channel blockers are beneficial in cancer treatment.

Evaluation of strontium-site-deficient Sr2Fe1.4Co0.1Mo<sub>0.5O6-δ-based perovskite oxides as intermediate temperature solid oxide fuel cell cathodes

In this paper strontium-site-deficient Sr₂Fe_1.4Co_0.1Mo<sub>0.5O_6-δ-based perovskite oxides (S_xFCM) were prepared and evaluated as the cathode materials for intermediate temperature solid oxide fuel cells (IT-SOFCs). All samples exhibited a cubic phase structure and the lattice shrinked with increasing the Sr-deficiency as shown in XRD patterns. XPS results determined that the transition elements (Co/Fe/Mo) in S_xFCM oxides were in a mixed valence state, demonstrating the small polaron hopping conductivity mechanism existed. Among the samples, S_1.950FCM presented the lowest coefficient of thermal expansion of 15.62 × 10^-6 K^-1, the highest conductivity value of 28 S cm^-1 at 500 °C, and the lowest interfacial polarization resistance of 0.093 Ω cm² at 800 °C, respectively. Furthermore, an anode-supported single cell with a S_1.950FCM cathode was prepared, demonstrating a maximum power density of 1.16 W cm^-2 at 800 °C by using wet H₂ (3% H₂O) as the fuel and ambient air as the oxidant. These results indicate that the introduction of Sr-deficiency can dramatically improve the electrochemical performance of Sr₂Fe_1.4Co_0.1Mo<sub>0.5O_6-δ, showing great promise as a novel cathode candidate material for IT-SOFCs.

Improved electrochemical performance of Sr2Fe1.5Mo<sub>0.4Nb0.1O6-δ -Sm0.2Ce0.8O2-δ composite cathodes by a one-pot method for intermediate temperature solid oxide fuel cells

In this paper, Sr₂Fe_1.5Mo<sub>0.4Nb_0.1O_6-δ (SFMNb)-xSm_0.2Ce_0.8O_2-δ (SDC) (x = 0, 20, 30, 40, 50 wt%) composite cathode materials were synthesized by a one-pot combustion method to improve the electrochemical performance of SFMNb cathode for intermediate temperature solid oxide fuel cells (IT-SOFCs). The fabrication of composite cathodes by adding SDC to SFMNb is conducive to providing extended electrochemical reaction zones for oxygen reduction reactions (ORR). X-ray diffraction (XRD) demonstrates that SFMNb is chemically compatible with SDC electrolytes at temperature up to 1100 °C. Scanning electron microscope (SEM) indicates that the SFMNb-SDC composite cathodes have a porous network nanostructure as well as the single phase SFMNb. The conductivity and thermal expansion coefficient of the composite cathodes decrease with the increased content of SDC, while the electrochemical impedance spectra (EIS) exhibits that SFMNb-40SDC composite cathode has optimal electrochemical performance with low polarization resistance (R_p) on the La_0.9Sr_0.1Ga_0.8Mg_0.2O₃ electrolyte. The R_p of the SFMNb-40SDC composite cathode is about 0.047 Ω cm² at 800 °C in air. A single cell with SFMNb-40SDC cathode also displays favorable discharge performance, whose maximum power density is 1.22 W cm^-2 at 800 °C. All results indicate that SFMNb-40SDC composite material is a promising cathode candidate for IT-SOFCs.