Identifying professional education gaps and barriers in multiple myeloma patient care: findings of the Managing Myeloma Continuing Educational Initiative Advisory Committee.

Advances in the past decade and a half have led to unprecedented improved outcomes for patients with multiple myeloma (MM), and this disease appears to be transitioning to one more characteristic of a chronic disease in large part due to rapid translation of clinical insights into practice at the community level. Although evidence-based guidelines and consensus recommendations remain an important resource for managing cancer patients, they do not fill the gap between the principles of disease management today and the translation of tailoring treatment for individual patient needs. Thus, there is a continuing need for concise, focused educational activities and resources that facilitate improved knowledge and understanding of appropriate, individualized therapeutic strategies for assessing and caring for patients with MM. The next several years will truly be a time of shifting paradigms in the treatment of MM in which new agents will be approved, response criteria will be updated, and new approaches to risk assessment and monitoring minimal residual disease will evolve and enter practice. New groundbreaking therapeutic approaches, such as immunotherapy, might result in significant changes in how MM is treated and managed over the entire life cycle of the disease. Even the definition of the disease might be further amended as insights grow regarding who should be treated and who might benefit more from observation. As such, oncology clinicians will have to carefully review and update their management approaches accordingly even as they begin to focus even more on the survivorship needs of their MM patients.

G protein-induced trafficking of voltage-dependent calcium channels.

Calcium channels are well known targets for inhibition by G protein-coupled receptors, and multiple forms of inhibition have been described. Here we report a novel mechanism for G protein-mediated modulation of neuronal voltage-dependent calcium channels that involves the destabilization and subsequent removal of calcium channels from the plasma membrane. Imaging experiments in living sensory neurons show that, within seconds of receptor activation, calcium channels are cleared from the membrane and sequestered in clathrin-coated vesicles. Disruption of the L1-CAM-ankyrin B complex with the calcium channel mimics transmitter-induced trafficking of the channels, reduces calcium influx, and decreases exocytosis. Our results suggest that G protein-induced removal of plasma membrane calcium channels is a consequence of disrupting channel-cytoskeleton interactions and might represent a novel mechanism of presynaptic inhibition.

N-type Ca2+ channels as scaffold proteins in the assembly of signaling molecules for GABAB receptor effects.

An emerging concept in signal transduction is the organization of neuronal receptors and channels into microdomains in which signaling proteins are brought together to regulate functional responses. With the multiplicity of potential protein-protein interactions arises the need for the regulation and timing of these interactions. We have identified N-type Ca(2+) channel-signaling molecule complexes formed at different times upon activation of gamma-aminobutyric acid, type B, receptors. The first type of interaction involves pre-association of signaling proteins such as Src kinase with the Ca(2+) channel, because it is rapidly activated by the receptors and regulates the magnitude of the inhibition of the Ca(2+) channel. The second type of interaction involves signaling molecules that are recruited to the channel by receptor activation and control the rate of the channel response. Recruitment of members of the Ras pathway has two effects as follows: 1) modulation of the rate of onset of the gamma-aminobutyric acid-mediated inhibition of Ca(2+) current, and 2) activation of MAP kinase. Our results suggest that the Ca(2+) channel alpha(1) subunit functions as a dynamic scaffold allowing assembly of intracellular signaling components that alter channel activity and route signals to the MAP kinase pathway.