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Multiple Myeloma (MM) is a common hematologic malignancy of plasma cells representing an excellent model of epigenomics dysregulation in human disease. Importantly, these findings, in addition to providing a better understanding of the underlying molecular changes leading to this malignance, furnish the basis for an innovative therapeutic approach. Histone deacetylase inhibitors (HDACIs), including Vorinostat and Panobinostat, represent a novel class of drugs targeting enzymes involved in epigenetic regulation of gene expression, which have been evaluated also for the treatment of multiple myeloma. Although the clinical role in this setting is evolving and their precise utility remains to be determined, to date that single-agent anti-MM activity is modest. More importantly, HDACIs appear to be synergistic both in vitro and in vivo when combined with other anti-MM agents, mainly proteasome inhibitors including bortezomib. The molecular basis underlying this synergism seems to be multifactorial and involves interference with protein degradation as well as the interaction of myeloma cells with microenvironment. Here we review molecular events underling antitumor effects of HDACIs and the most recent results of clinical trials in relapsed and refractory MM.

The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade® ) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique -lactone--lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstroms macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid® ), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.

We present the results of a series of molecular dynamics simulations of a melt of flexible bead−spring polymer chains with a single static cylindrical inclusion with diameter equal to the polymer beads. Chains of length N = 10, 25, 50, 100 and polymer/inclusion interactions, which are attractive with well depths of 1, 4, and 10 ε, and athermal, are considered. We show that the distribution in winding number of a polymer chain about the inclusion may be approximated by Belisle's probability distribution for the winding of a random walk about a point. The degree of winding per chain increases as the polymer/inclusion attraction increases because of the larger number of monomers pulled into runs of sequential monomers at the inclusion. Runs accumulate more winding than do loops or tails, and the amount of winding a given run accumulates increases with increasing polymer/inclusion attraction due to increased likelihood of perpendicular bond orientation with respect to the inclusion. The probability of winding depends on monomer distance from the inclusion in an apparently universal manner when distance is scaled by the unperturbed chain radius of gyration. Our results bear direct relevance to understanding the nature of enhancing toughness of polymeric materials by adding filler particles which increase the degree of entanglement.

The methods of formal matched asymptotics are used to investigate the motion of a vortex in shallow inviscid fluid of varying depth and zero Froude number in the limit as the vortex core radius tends to zero. To leading order the vortex is driven by local gradients in the logarithm of the depth along an isobath (or depth contour). A further term in the vortex velocity is calculated in which effects arising from the global bottom topography, other vortices and the vortex core structure appear. The evolution of the vortex core structure is then calculated. A point-vortex model is formulated which describes the motion of a number of small vortices in terms of the bottom topography, the inviscid flows around the vortices and their evolving core structure. A numerical method for solving this model is discussed and finally some numerical simulations of the motion of vortex pairs over a varying bottom topography are presented.

Purpose. To examine whether secondhand smoke (SHS) exposure is associated with restless sleep and/or nighttime sleep duration among adolescents. Methods. Data were analyzed from 1,592 adolescents who completed an internet-delivered survey as part of the British Columbia Adolescent Substance Use Survey cohort study. Ordinal logistic and linear regression models were used to examine associations between frequency of SHS exposure in the past month and frequency of restless sleep and nighttime sleep duration, respectively. Results. SHS exposure was significantly positively associated with restless sleep and significantly negatively associated with sleep duration. In fully adjusted models, compared with students who reported never being exposed to SHS in the past month, students who reported a low, medium, or high frequency of SHS exposure were 1.53, 1.76, and 2.51 times as likely, respectively, to report more frequent restless sleep (OR=1.53, 95% CI 1.08–2.16; OR=1.76, 95% CI 1.22–2.53; OR=2.51, 95% CI 1.59–3.98). With regard to sleep duration, as frequency of SHS exposure increased by one category, nighttime sleep duration during the week and weekend decreased by 4 minutes (B=-0.06, 95% CI=-0.01–-0.11) and 6 minutes (B=-0.09, 95% CI=-0.03–-0.14), respectively. Conclusions. This study suggests that frequency of SHS exposure has a significant dose-response relationship with restless sleep and sleep duration in adolescents.

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