Annals of the New York Academy of Sciences
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Ann. N. Y. Acad. Sci. · Nov 2015
ReviewDevelopment of macitentan for the treatment of pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a serious, chronic condition that, without early recognition and treatment, leads to progressive right heart failure and death. The dual endothelin receptor antagonist macitentan was designed through a deliberate discovery process to maximize endothelin-axis blockade while improving adverse-effect profiles compared with previous compounds. Macitentan's efficacy was demonstrated in an event-driven morbidity and mortality study of treatment-naive and background PAH therapy-treated symptomatic patients. ⋯ Furthermore, it significantly improved cardiopulmonary hemodynamics and quality of life, and had a favorable safety and tolerability profile. To date, this was the largest and longest prospective trial for PAH. Macitentan, currently the only approved oral PAH treatment shown to be safe and effective in delaying long-term progression and reducing PAH-related hospitalizations, has changed treatment paradigms from goal-directed to long-term outcome-oriented therapy.
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Ann. N. Y. Acad. Sci. · Nov 2015
ReviewDevelopment of the Bruton's tyrosine kinase inhibitor ibrutinib for B cell malignancies.
Ibrutinib is a first-in-class oral covalent inhibitor of Bruton's tyrosine kinase that has demonstrated clinical benefit for many patients with B cell malignancies. Positive results in initial trials led the U. S. ⋯ Via a unique mechanism of action, ibrutinib inhibits B cell signaling pathways that regulate the survival, proliferation, adhesion, and homing of cancerous cells. This marks a paradigm shift from the conventional cytotoxic chemotherapy approach to treating B cell malignancies. Ibrutinib continues to be evaluated across a range of B cell malignancies, either as single-agent therapy or in combination with other therapies, and continues to transform the lives of these patients.
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Ann. N. Y. Acad. Sci. · Sep 2015
ReviewHow ion channels sense mechanical force: insights from mechanosensitive K2P channels TRAAK, TREK1, and TREK2.
The ability to sense and respond to mechanical forces is essential for life and cells have evolved a variety of systems to convert physical forces into cellular signals. Within this repertoire are the mechanosensitive ion channels, proteins that play critical roles in mechanosensation by transducing forces into ionic currents across cellular membranes. Understanding how these channels work, particularly in animals, remains a major focus of study. ⋯ Structural and functional insights have led to a physical model for mechanical activation of these channels. This model of force sensation by K2Ps is compared to force sensation by bacterial mechanosensitive ion channels MscL and MscS to highlight principles shared among these evolutionarily unrelated channels, as well as differences of potential functional relevance. Recent advances address fundamental questions and stimulate new ideas about these unique mechanosensors.
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Ann. N. Y. Acad. Sci. · Jun 2015
ReviewPersonalized health care beyond oncology: new indications for immunoassay-based companion diagnostics.
Personalized health care (PHC) is an evolving field of medicine aimed at providing the right therapy to the right patient at the right time. This approach often incorporates the use of companion diagnostics (CDx) assays that provide information essential for the safe and effective use of the corresponding drug. In addition to oncology, many other therapy areas, such as cardiovascular, neurological, and infectious and inflammatory diseases, may benefit from PHC, owing to disease complexity and heterogeneity. ⋯ In this review we discuss how the incorporation of biomarker immunoassays into routine diagnostic testing may allow early and definitive detection of Alzheimer's disease and enable population enrichment in clinical trials. In addition, we will describe how biomarker-based CDx immunoassays have potential utility for stratifying patients with asthma based on their potential response to therapy and for selecting treatment according to phenotypic profile. Continued research into the underlying disease pathology and development of accurate and reliable diagnostic assays may ensure that PHC becomes the future standard for many indications.
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Ann. N. Y. Acad. Sci. · May 2015
A conceptual approach to managing severe traumatic brain injury in a time of uncertainty.
Current controversies in the literature suggest that a reassessment of the current management of severe traumatic brain injury (sTBI) is necessary. This article presents a conceptual framework toward individualizing sTBI treatment with respect to targeting thresholds and strategies on the basis of known physiologic processes and available monitors. Intracranial pressure (ICP) is modeled as an epiphenomenon of cerebral compliance and herniation tendency, as well as cerebral ischemia. ⋯ Similarly, by collecting and trending clinical, imaging, and monitoring data on the status of cerebral blood flow, the balance of oxygen consumption and delivery, and the status of cerebral static pressure autoregulation, and analyzing them with respect to measured parameters, such as blood pressure, ICP, and cerebral perfusion pressure, one can attempt to fine-tune these variables as well. Such individualization of management optimizes the possibility of successfully treating demonstrated pathophysiological processes while avoiding unnecessary interventions and treatment toxicity. Monitor values must not be seen as targets but rather as indicators of targetable pathology.