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PERSPECTIVEtheir CoA esters, are available for synthesis of triglycerides, sphingolipids, glycolipids, or phospholipids or for transport from the liver as very low density lipoproteins (VLDL).ACC constitutes the key control enzyme in the fatty acid synthetic pathway. 3 Control is exercised both allosterically and by phosphorylation/dephosphorylation at various serine 5617

Some experimental data, primarily on total force response, are presented for nonlinear lateral sloshing in rigid tanks of various geometries. Some effect of excitation amplitude on liquid swirl boundaries in an open circular cylindrical tank is noted. Data for the circular cylindrical tank are also compared with theoretical predictions. The primary nonlinear effects observed in all tanks were decreasing response frequency with increasing excitation amplitude and jump phenomena.

An experimental study of the vibrations of cantilever plates in air and in water has been conducted, and the results are compared with theoretical predictions based on simple beam theory and thin-plate theory. Both theories are modified to include an apparent mass factor which is derived from chordwise hydrodynamic strip theory. Good theoretical and experimental correlation is achieved upon further including an empirical correction factor which allows for the influence of plate aspect ratio and thickness ratio on the results. Liquid free surface and partial submergence effects are determined experimentally.

The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are the therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development.

Treatment of multiple myeloma (MM), a neoplasm of plasma cells, formerly dependent on alkylating drugs, corticosteroids, and autologous stem cell transplantation, has changed dramatically in the past 20 years because 3 new classes of small molecule drugs (arbitrarily defined as having a molecular weight of < 900 kDa)-immunomodulators, proteasome inhibitors, and histone deacetylase blockers-have been introduced for the disease. Therapeutic options for MM expanded further in 2015 when 2 new monoclonal antibodies (daratumumab and elotuzumab) were approved by the Food and Drug Administration for MM. Although MM remains incurable, the cumulative effect of these advances has resulted in a near-doubling of the 5-year survival rate since the late 1980s. Despite these advances, therapy for MM continues to pose substantial challenges because resistance to therapy frequently develops, and relapse and recurrence are all too common. The present review focused on the pipeline for new small molecules in various stages of development and their associated cellular targets. In addition to newer versions of alkylators, immunomodulators, proteasome inhibitors, and histone deacetylase inhibitors, the present review considered the prospects for adding new classes of small molecules to the MM armamentarium, which offer the potential for oral efficacy, relative simplicity of preparation, and prospects for improvement in the cost-to-benefit ratio. Included are agents that affect myeloma epigenetics and the ubiquitination-proteasome system and the unfolded protein response, apoptotic mechanisms, chromosomal abnormalities, nuclear protein transport, and various kinases involved in cellular signaling pathways.

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