Selective leukemic-cell killing by a novel functional class of thalidomide analogs

Using a novel cell-based assay to profile transcriptional pathway targeting, we have identified a new functional class of thalidomide analogs with distinct and selective antileukemic activity. These agents activate nuclear factor of activated T cells (NFAT) transcriptional pathways while simultaneously repressing nuclear factor-κB (NF-κB) via a rapid intracellular amplification of reactive oxygen species (ROS). The elevated ROS is associated with increased intracellular free calcium, rapid dissipation of the mitochondrial membrane potential, disrupted mitochondrial structure, and caspase-independent cell death. This cytotoxicity is highly selective for transformed lymphoid cells, is reversed by free radical scavengers, synergizes with the antileukemic activity of other redox-directed compounds, and preferentially targets cells in the S phase of the cell cycle. Live-cell imaging reveals a rapid drug-induced burst of ROS originating in the endoplasmic reticulum and associated mitochondria just prior to spreading throughout the cell. As members of a novel functional class of “redoxreactive” thalidomides, these compounds provide a new tool through which selective cellular properties of redox status and intracellular bioactivation can be leveraged by rational combinatorial therapeutic strategies and appropriate drug design to exploit cell-specific vulnerabilities for maximum drug efficacy

Neuroinflammation and Sjogren’s Syndrome

Sjogren's syndrome (SS) is a chronic organ-specific autoimmune disease mainly involving exocrine glands such as lacrimal and salivary glands. SS may also involve central and peripheral nervous system with variable prevalence due to differences in diagnostic criteria and in time length to reach diagnosis. Clinical features of the central nervous involvement share similarities with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), two major neuroimmune disorders. SS may even coexist with MS or NMOSD. Sensory neuropathy, chronic polyradiculoneuropathy, cranial neuropathies as well as small fibre neuropathy are the main manifestations of the peripheral nervous system involvement. The pathogenic mechanism underlying neuro-SS is unclear even though molecular mimicry and epitope spreading have been hypothesized for central nervous involvement, whereas vasculitis with or without direct damage to nerve could account for peripheral nervous involvement. Treatment is mainly based on immunosuppressive therapies requiring a close cooperation between neurologists and rheumatologists to achieve the best management