Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways in tumor cells and promote tumor growth, survival, and drug resistance. INCB16562 was developed as a novel, selective, and orally bioavailable small-molecule inhibitor of JAK1 and JAK2 markedly selective over JAK3. The specific cellular activity of the inhibitor was demonstrated by its potent and dose-dependent inhibition of cytokine-dependent JAK/STAT signaling and cell proliferation in the absence of effects on Bcr-Abl-expressing cells. Treatment of myeloma cells with INCB16562 potently inhibited interleukin-6 (IL-6)-induced phosphorylation of STAT3. Moreover, the proliferation and survival of myeloma cells dependent on IL-6 for growth, as well as the IL-6-induced growth of primary bone marrow-derived plasma cells from a multiple myeloma patient, were inhibited by INCB16562. Induction of caspase activation and apoptosis was observed and attributed, at least in part, to the suppression of Mcl-1 expression. Importantly, INCB16562 abrogated the protective effects of recombinant cytokines or bone marrow stromal cells and sensitized myeloma cells to cell death by exposure to dexamethasone, melphalan, or bortezomib. Oral administration of INCB16562 antagonized the growth of myeloma xenografts in mice and enhanced the antitumor activity of relevant agents in combination studies. Taken together, these data suggest that INCB16562 is a potent JAK1/2 inhibitor and that mitigation of JAK/STAT signaling by targeting JAK1 and JAK2 will be beneficial in the treatment of myeloma patients, particularly in combination with other agents.

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The herbicide isoxaflutole has the potential to contaminate drinking water directly, as well as upon hydrolyzing to its active form diketonitrile. Diketonitrile also may impact water quality by acting as a precursor for dichloroacetonitrile (DCAN), which is an unregulated but highly toxic disinfection byproduct (DBP). In this study, we investigated the reaction of diketonitrile with free chlorine and chloramine to form DCAN. We found that diketonitrile reacts with free chlorine within seconds but reacts with chloramine on the time scale of hours to days. In the presence of both oxidants, DCAN was generated at yields up to 100%. Diketonitrile reacted fastest with chlorine at circumneutral pH, which was consistent with base-catalyzed halogenation involving the enolate form of diketonitrile present at alkaline pH and electrophilic hypochlorous acid, which decreases in abundance above its pK a (7.5). In contrast, we found that diketonitrile reacts faster with chloramine as pH values decreased, consistent with an attack on the enolate by electrophilic protonated monochloramine that increases in abundance at acidic pH approaching its pK a (1.6). Our results indicate that increasing isoxaflutole use, particularly in light of the recent release of genetically modified isoxaflutole-tolerant crops, could result in greater occurrences of a high-yield DCAN precursor during disinfection.

In living systems, biomolecule–nanoparticle interactions are mediated by proteins, like those in human serum, and by solutes.

Sex differences on three scales of psychological rigidity were investigated for 250 college students. The size of the intercorrelations among the scales suggested that psychological rigidity is a multidimensional concept. Females were significantly less rigid on two of three scales. The experience by girls of a wider range of approved behavior was suggested as a possible explanation.