A genomic analysis of chicken cytokines and chemokines.

As most mechanisms of adaptive immunity evolved during the divergence of vertebrates, the immune systems of extant vertebrates represent different successful variations on the themes initiated in their earliest common ancestors. The genes involved in elaborating these mechanisms have been subject to exceptional selective pressures in an arms race with highly adaptable pathogens, resulting in highly divergent sequences of orthologous genes and the gain and loss of members of gene families as different species find different solutions to the challenge of infection. Consequently, it has been difficult to transfer to the chicken detailed knowledge of the molecular mechanisms of the mammalian immune system and, thus, to enhance the already significant contribution of chickens toward understanding the evolution of immunity. The availability of the chicken genome sequence provides the opportunity to resolve outstanding questions concerning which molecular components of the immune system are shared between mammals and birds and which represent their unique evolutionary solutions. We have integrated genome data with existing knowledge to make a new comparative census of members of cytokine and chemokine gene families, distinguishing the core set of molecules likely to be common to all higher vertebrates from those particular to these 300 million-year-old lineages. Some differences can be explained by the different architectures of the mammalian and avian immune systems. Chickens lack lymph nodes and also the genes for the lymphotoxins and lymphotoxin receptors. The lack of functional eosinophils correlates with the absence of the eotaxin genes and our previously reported observation that interleukin- 5 (IL-5) is a pseudogene. To summarize, in the chicken genome, we can identify the genes for 23 ILs, 8 type I interferons (IFNs), IFN-gamma, 1 colony-stimulating factor (GM-CSF), 2 of the 3 known transforming growth factors (TGFs), 24 chemokines (1 XCL, 14 CCL, 8 CXCL, and 1 CX3CL), and 10 tumor necrosis factor superfamily (TNFSF) members. Receptor genes present in the genome suggest the likely presence of 2 other ILs, 1 other CSF, and 2 other TNFSF members.     

Elucidating the associations between sleep disturbance and depression,fatigue, and pain in older adults with cancer

Objectives

Sleep disturbance is prevalent and often coexists with depression, fatigue, and pain in the cancer population. The aim of this study was to describe the prevalence of sleep disturbance with co-existing depression, fatigue, and pain in older patients with cancer. We also examined the associations of several socio-demographic and clinical variables with sleep disturbance.

Targeted agents for HER2-positive breast cancer in older adults: current and future perspectives

ABSTRACT

Introduction: One-third of breast cancer (BC) cases worldwide occur in women aged 65 years and older, with 10 to 15% overexpressing the human epidermal growth factor receptor 2 (HER2). Although several HER2-targeted therapies have been developed, the lack of data regarding their use in older patients hampers evidence-based decision-making for this population.

Areas Covered: We review current evidence on the efficacy and safety of HER2-targeted therapies in older adults with BC, focusing on approved therapies such as trastuzumab, lapatinib, pertuzumab, ado-trastuzumab-emtansine, and neratinib. Additionally, we discuss drugs under development to target the HER2-receptor, and to overcome resistance to existing therapies. Finally, we highlight the cardiotoxicity of HER2-targeted drugs among older adults.

Expert Opinion: Older adults are underrepresented in trials of HER2-targeted therapies in BC. We propose strategies to increase recruitment of older adults in clinical trials in order to increase the evidence base to treat this growing population.     

Feasibility of Ultrasound-Based Computational Fluid Dynamics as a Mitral Valve Regurgitation Quantification Technique: Comparison with 2-D and 3-D Proximal Isovelocity Surface Area-Based Methods

Current Doppler echocardiography quantification of mitral regurgitation (MR) severity has shortcomings. Proximal isovelocity surface area (PISA)-based methods, for example, are unable to account for the fact that ultrasound Doppler can measure only one velocity component: toward or away from the transducer. In the present study, we used ultrasound-based computational fluid dynamics (Ub-CFD) to quantify mitral regurgitation and study its advantages and disadvantages compared with 2-D and 3-D PISA methods. For Ub-CFD, patient-specific mitral valve geometry and velocity data were obtained from clinical ultrasound followed by 3-D CFD simulations at an assumed flow rate. We then obtained the average ratio of the ultrasound Doppler velocities to CFD velocities in the flow convergence region, and scaled CFD flow rate with this ratio as the final measured flow rate. We evaluated Ub-CFD, 2-D PISA and 3-D PISA with an in vitro flow loop, which featured regurgitation flow through (i) a simplified flat plate with round orifice and (ii) a 3-D printed realistic mitral valve and regurgitation orifice. The Ub-CFD and 3-D PISA methods had higher precision than the 2-D PISA method. Ub-CFD had consistent accuracy under all conditions tested, whereas 2-D PISA had the lowest overall accuracy. In vitro investigations indicated that the accuracy of 2-D and 3-D PISA depended significantly on the choice of aliasing velocity. Evaluation of these techniques was also performed for two clinical cases, and the dependency of PISA on aliasing velocity was similarly observed. Ub-CFD was robustly accurate and precise and has promise for future translation to clinical practice.     

Associations of Uncertainty With Psychological Health and Quality of Life in Older Adults With Advanced Cancer

ContextOlder adults with advanced cancer face uncertainty related to their disease and treatment.ObjectivesTo evaluate the associations of uncertainty with psychological health and quality of life (QoL) in older adults with advanced cancer.MethodsSecondary cross-sectional analysis of baseline data from a national clustered geriatric assessment trial. Patients 70 years and older with advanced cancer considering a new line of chemotherapy were recruited. We measured uncertainty using the modified nine-item Mishel Uncertainty in Illness Scale. Dependent variables included anxiety (Generalized Anxiety Disorder-7), depression (Generalized Depression Scale-15), distress (distress thermometer), QoL (Functional Assessment of Cancer Therapy—General), and emotional well-being (Functional Assessment of Cancer Therapy—General subscale). We used multivariate linear regression analyses to evaluate the association of uncertainty with each dependent variable. We conducted a partial least squares analysis with a variable importance in projection (VIP) plot to assess the contribution of individual variables to the model. Variables with a VIP <0.8 were considered less influential.ResultsWe included 527 patients (median age 76 years; range 70–96). In multivariate analyses, higher levels of uncertainty were significantly associated with greater anxiety (β = 0.11; SE = 0.04), depression (β = 0.09; SE = 0.02), distress (β = 0.12; SE = 0.02), as well as lower QoL (β = ?1.08; SE = 0.11) and emotional well-being (β = ?0.29; SE = 0.03); the effect sizes were considered small. Uncertainty items related to disease and treatment were most strongly associated with psychological health and QoL scores (all VIP >0.8).ConclusionUncertainty among older patients with advanced cancer is associated with worse psychological health and QoL. Tailored uncertainty management strategies are warranted.