The quest for novel therapies to prevent bacterial infections and blood clots (thrombosis) is of utmost importance in biomedical research due to the exponential growth in the cases of thrombosis and blood infections and the emergence of multi-drug-resistant strains of bacteria. Endogenous nitric oxide (NO) is a cellular signaling molecule that plays a pivotal role in host immunity against pathogens, prevention of clotting, and regulation of systemic blood pressure, among several other biological functions. The physiological effect of NO is dose dependent, which necessitates the study of its tunable release kinetics, which is the objective of this study. In the present study, polymer composites were fabricated by incorporating S-nitroso-N-acetylpenicillamine (SNAP) in a medical-grade polymer, Carbosil, and top-coated with varying concentrations of catalytic copper nanoparticles (Cu-NPs). The addition of the Cu-NPs increased the NO release, as well as the overall antimicrobial activity via the oligodynamic effect of Cu. SNAP (10 wt %) composites without Cu-NP coatings showed a NO flux of 1.32 ± 0.6 × 10 mol min cm, whereas Cu-NP-incorporated SNAP films exhibited fluxes of 4.48 ± 0.5 × 10, 4.84 ± 0.3 × 10, and 11.7 ± 3.6 × 10 mol min cm with 1, 3, and 5 wt % Cu-NPs, respectively. This resulted in a significant reduction (up to 99.8%) in both gram-positive and gram-negative bacteria, with very low platelet adhesion (up to 92% lower) as compared to that of the corresponding controls. Copper leachates from the SNAP films were detected using the inductively coupled plasma-mass spectrometry technique and were found to be significantly lower in concentration than the recommended safety limit by the FDA. The cell viability test performed on mouse fibroblast 3T3 cells provided supportive evidence for the biocompatibility of the material in vitro.

Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients.

Although the use of biomedical devices in hospital-based care is inevitable, unfortunately, it is also one of the leading causes of the nosocomial infections, and thus demands development of novel antimicrobial materials for medical device fabrication. In the current study, a multi-defense mechanism against Gram-positive and Gram-negative bacteria is demonstrated by combining a NO releasing agent with a quaternary ammonium antimicrobial that can be covalently grafted to medical devices. Antibacterial polymeric com posites were fabricated by incorporating a nitric oxide (NO) donor, S-nitroso-N-acetyl-penicillamine (SNAP) in CarboSil® polymer and top coated with surface immobilized benzophenone based quaternary ammonium antimicrobial (BPAM) small molecule. The results suggest that SNAP and BPAM have a different degree of toxicity towards Gram-positive and Gram-negative bacteria, and the SNAP-BPAM combination is effective in reducing both types of adhered viable bacteria equally well. SNAP-BPAM combinations reduced the adhered viable Pseudomonas aeruginosa by 99.0% and Staphylococcus aureus by 99.98% as compared to the control CarboSil films. Agar diffusion tests demonstrate that the diffusive nature of NO kills bacteria beyond the direct point of contact which the non-leaching BPAM cannot achieve alone. This is important for potential application in biofilm eradication. The live-dead bacteria staining shows that the SNAP-BPAM combination has more attached dead bacteria (than live) as compared to the controls. The SNAP-BPAM films have increased hydrophilicity and higher NO flux as compared to the SNAP films useful for preventing blood protein and bacterial adhesion. Overall the combination of SNAP and BPAM imparts different attributes to the polymeric composite that can be used in the fabrication of antimicrobial surfaces for various medical device applications.

The PI3K/Akt/mTOR (phosphatidylinositol 3 kinase/ Akt/mammalian target of rapamycin) signalling pathway is an established driver of oncogenic activity in human malignancies. Therapeutic targeting of this pathway holds significant promise as a treatment strategy. Everolimus, an mtor inhibitor, is the first of this class of agents approved for the treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. Everolimus has been associated with significant improvements in progression-free survival; however, it is also associated with increased toxicity related to its specific mechanism of action. Methods: A comprehensive review of the literature conducted using a focused medline search was combined with a search of current trials at http://ClinicalTrials.gov/. Summary tables of the toxicities of the various classes of PI3K/Akt/mTOR inhibitors were created. A broad group of Canadian health care professionals was assembled to review the data and to produce expert opinion and summary recommendations for possible best practices in managing the adverse events associated with these pathway inhibitors. Results: Differing toxicities are associated with the various classes of PI3K/Akt/mTOR pathway inhibitors. The most common unique adverse events observed in everolimus clinical trials in breast cancer include stomatitis (all grades: approximately 60%), noninfectious pneumonitis (15%), rash (40%), hyperglycemia (15%), and immunosuppression (40%). To minimize grades 3 and 4 toxicities and to attempt to attain optimal outcomes, effective management of those adverse events is critical. Management should be interdisciplinary and should use approaches that include education, early recognition, active intervention, and potentially prophylactic strategies. Discussion: Everolimus likely represents the first of many complex oral targeted therapies for the treatment of breast cancer. Using this agent as a template, it is essential to establish best practices involving and integrating multiple disciplines for the management of future PI3K/Akt/mTOR signalling pathway inhibitors.

Ever since the role of endogenous nitric oxide (NO) in controlling a wide variety of biological functions was discovered approximately three decades back, multiple NO-releasing polymeric materials have been developed. However, most of these materials are typically short lived due to the inefficient incorporation of the NO donor molecules within the polymer matrix. In the present study, S-nitroso- N-acetyl penicillamine (SNAP) is covalently attached to poly(dimethylsiloxane) (PDMS) to create a highly stable nitric oxide (NO) releasing material for biomedical applications. By tethering SNAP to the cross-linker of PDMS, the NO donor is unable to leach into the surrounding environment. This is the first time that a sustainable NO release and bacterial inhibition for over 125 days has been achieved by any NO-releasing polymer with supporting evidence of potential long-term hemocompatibility and biocompatibility. The material proves to have very high antibacterial efficacy against Staphylococcus aureus by demonstrating a 99.99% reduction in the first 3 days in a continuous flow CDC bioreactor, whereas a similar inhibitory potential of 99.50% was maintained by the end of 1 month. Hemocompatibility of SNAP-PDMS was tested using a rabbit extracorporeal circuit (ECC) model over a 4 h period. Thrombus formation was greatly reduced within the SNAP-PDMS-coated ECCs compared to the control circuits, observing a 78% reduction in overall thrombus mass accumulation. These results demonstrate the potential of utilizing this material for blood and tissue contacting biomedical devices in long-term clinical applications where infection and unwanted clotting are major issues.