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Precision or personalized medicine through clinical genome and exome sequencing has been described by some as a revolution that could transform healthcare delivery, yet it is currently used in only a small fraction of patients, principally for the diagnosis of suspected Mendelian conditions and for targeting cancer treatments. Given the burden of illness in our society, it is of interest to ask how clinical genome and exome sequencing can be constructively integrated more broadly into the routine practice of medicine for the betterment of public health. In November 2014, 46 experts from academia, industry, policy and patient advocacy gathered in a conference sponsored by Illumina, Inc. to discuss this question, share viewpoints and propose recommendations. This perspective summarizes that work and identifies some of the obstacles and opportunities that must be considered in translating advances in genomics more widely into the practice of medicine.

Abstract ApoEε4 is a major genetic risk factor for Alzheimer’s disease (AD), a disease hallmarked by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoEε4 allele is associated with increased Aβ deposition and a role for ApoEε4 in the potentiation of tau pathology has recently emerged. This study focused on comparing the effects of adeno-associated virus (AAV)-mediated overexpression of the three predominant human ApoE isoforms within astrocytes. The isoform-specific effects of human ApoE were evaluated within in vitro models of tau pathology within neuron/astrocyte co-cultures, as well as in a transgenic tau mouse model. Tau aggregation, accumulation, and phosphorylation were measured to determine if the three isoforms of human ApoE had differential effects on tau. Astrocytic overexpression of the human ApoEε4 allele increased phosphorylation and misfolding of overexpressed neuronal tau in multiple models, including the aggregation and accumulation of added tau oligomers, in an isoform-specific manner. The ability of ApoEε4 to increase tau aggregation could be inhibited by an ApoEε4-specific antibody. This study indicates that astrocytic expression of ApoEε4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoEε4 on tau.

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)+ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8+ T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them. [ABSTRACT FROM AUTHOR]

Introduction In myocardial infarction (MI), infarct size is the most determinant cause of morbidity and mortality (1). Although early reperfusion is of unequivocal benefit, this treatment is inherently complicated by [...], Mechanisms mediating the cardioprotective actions of glucagon-like peptide 1 (GLP-1) were unknown. Here, we show in both ex vivo and in vivo models of ischemic injury that treatment with GLP-1(28-36), a neutral endopeptidase-generated (NEP-generated) metabolite of GLP-1, was as cardioprotective as GLP-1 and was abolished by scrambling its amino acid sequence. GLP-1(28-36) enters human coronary artery endothelial cells (caECs) through macropinocytosis and acts directly on mouse and human coronary artery smooth muscle cells (caSMCs) and caECs, resulting in soluble adenylyl cyclase Adcy10-dependent (sAC-dependent) increases in cAMP, activation of protein kinase A, and cytoprotection from oxidative injury. GLP-1(28-36) modulates sAC by increasing intracellular ATP levels, with accompanying cAMP accumulation lost in [sAC.sup.-/-] cells. We identify mitochondrial trifunctional protein-[alpha] (MTP[alpha]) as a binding partner of GLP-1(28-36) and demonstrate that the ability of GLP-1(2836) to shift substrate utilization from oxygen-consuming fatty acid metabolism toward oxygen-sparing glycolysis and glucose oxidation and to increase cAMP levels is dependent on MTP[alpha]. NEP inhibition with sacubitril blunted the ability of GLP-1 to increase cAMP levels in coronary vascular cells in vitro. GLP-1(28-36) is a small peptide that targets novel molecular (MTP[alpha] and sAC) and cellular (caSMC and caEC) mechanisms in myocardial ischemic injury.

A collection of results is given regarding whether a prime can be the sum or difference of two polyhedral numbers, as well as some primality restrictions on several sequences.

The Ministry of Transportation of Ontario was interested in a rehabilitation strategy that could be used to address deep-seated rutting issues encountered on its 400-series highways. A precast concrete inlay panel (PCIP) rehabilitation design was developed and constructed involving the installation of precast panels into partially-milled asphalt pavement. Sub- surface instrumentation was installed at the PCIP-asphalt interface including earth pressure cells and moisture sensors installed in six instrumentation clusters. This instrumentation has been monitored to gather information regarding the PCIP trial installation. Readings from the moisture sensors indicate that water penetrates beneath the PCIPs in precipitation events, though these moisture levels recede under dry conditions, indicating that the water can exit the sub-slab area. Static load testing using a fully-loaded gravel truck was used to determine the different support reactions caused by different loading configurations. Higher loads were generally found beneath the joints in the two loading situations studied. Le ministere des Transports de l'Ontario s'est penche sur une strategie de refection qui pourrait etre utilisee pour regler les problemes d'ornierage profondement enracines sur ses routes de la serie 400. La conception pour la refection au moyen de panneaux d'incrustation en beton prefabrique (PIBP) a ete developpee et realisee par l'installation de panneaux prefabriques dans un revetement d'asphalte partiellement broye. Une instrumentation enfouie a ete installee a l'interface PIBP- asphalte y compris des cellules manometriques et des sondes d'humidite installees en six regroupements d'instrumentation. Cette instrumentation a fait l'objet d'un controle afin de rassembler des informations quant a l'installation des PIBP d'essai. Les lectures des sondes d'humidite indiquent que l'eau penetre au-dessous des PIBP lors d'evenements de precipitation, quoique ces niveaux d'humidite s'estompent dans des conditions seches, indiquant que l'eau s'evacue de la zone sous les dalles. On a eu recours a un essai de charge statique avec un camion de gravier charge a capacite afin de determiner, au niveau de la portance, les diverses reactions causees par differentes configurations de chargement. Les charges plus elevees se trouvaient generalement au- dessous des joints dans les deux situations de chargement etudiees. [Traduit par la Redaction] Mots-cles : beton prefabrique, refection des chaussees, panneau de beton prefabrique incruste, reparation de routes a forte circulation., Introduction Precast concrete panels (PCPs) have been used as a paving material since as early as 1931 in the Soviet Union (Rollings and Chou 1981); however, their use has only [...]