Annals of the New York Academy of Sciences
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Ann. N. Y. Acad. Sci. · Jun 2016
ReviewRestructuring reward processing with Mindfulness-Oriented Recovery Enhancement: novel therapeutic mechanisms to remediate hedonic dysregulation in addiction, stress, and pain.
Though valuation processes are fundamental to survival of the human species, hedonic dysregulation is at the root of an array of maladies, including addiction, stress, and chronic pain, as evidenced by the allostatic shift in the relative salience of natural reward to drug reward observed among persons with severe substance use disorders. To address this crucial problem, novel interventions are needed to restore hedonic regulatory processes gone awry in persons exhibiting addictive behaviors. ⋯ MORE is innovative and distinct from extant mindfulness-based interventions in that it unites traditional mindfulness meditation with reappraisal and savoring strategies designed to reverse the downward shift in salience of natural reward relative to drug reward, representing a crucial tipping point to disrupt the progression of addiction-a mechanistic target that no other behavioral intervention has been designed to address. Though additional studies are needed, clinical and biobehavioral data from several completed and ongoing trials suggest that MORE may exert salutary effects on addictive behaviors and the neurobiological processes that underpin them.
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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.