Annals of the New York Academy of Sciences
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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. · 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. · 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
What is wrong with the tenets underpinning current management of severe traumatic brain injury?
The results of a recent randomized controlled trial comparing intracranial pressure (ICP) monitor-based treatment of severe traumatic brain injury (sTBI) to management without ICP monitoring prompt this skeptical reconsideration of the scientific foundation underlying current sTBI management. Much of current practice arises from research performed under conditions that are no longer relevant today. The definition of an episode of intracranial hypertension is incomplete, and the application of a fixed, universal ICP treatment threshold is poorly founded. ⋯ Similar concerns also apply to manipulation of cerebral perfusion with respect to maintaining universal thresholds for contrived variables rather than tailoring treatment to monitored processes. As such, there is a failure to either optimize management approaches or minimize associated treatment risks for individual sTBI patients. The clinical and research TBI communities need to reassess many of the sTBI management concepts that are currently considered well established.