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
Hypertonic saline for the management of raised intracranial pressure after severe traumatic brain injury.
Hyperosmolar agents are commonly used as an initial treatment for the management of raised intracranial pressure (ICP) after severe traumatic brain injury (TBI). They have an excellent adverse-effect profile compared to other therapies, such as hyperventilation and barbiturates, which carry the risk of reducing cerebral perfusion. The hyperosmolar agent mannitol has been used for several decades to reduce raised ICP, and there is accumulating evidence from pilot studies suggesting beneficial effects of hypertonic saline (HTS) for similar purposes. ⋯ To date, no large clinical trial has been performed to directly compare the two agents. The best current evidence suggests that mannitol is effective in reducing ICP in the management of traumatic intracranial hypertension and carries mortality benefit compared to barbiturates. Current evidence regarding the use of HTS in severe TBI is limited to smaller studies, which illustrate a benefit in ICP reduction and perhaps mortality.