The implementation of targeted therapies for acute myeloid leukemia has been challenged by complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here, we report initial findings from the Beat AML program on a cohort of 672 tumor specimens collected from 562 patients. We assessed these specimens using whole exome sequencing, RNA-sequencing, and ex vivo drug sensitivity analyses. Our data reveal Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

AtT-20 cells expressing the wild-type kappa opioid receptor (KOR) increased phospho-p38 MAPK following treatment with the kappa agonist U50,488. The increase was blocked by the kappa antagonist norbinaltorphimine and not evident in untransfected cells. In contrast, U50,488 treatment of AtT-20 cells expressing KOR having alanine substituted for serine-369 (KSA) did not increase phospho-p38. Phosphorylation of serine 369 in the KOR carboxyl terminus by G-protein receptor kinase 3 (GRK3) was previously shown to be required for receptor desensitization, and the results suggest that p38 MAPK activation by KOR may require arrestin recruitment. This hypothesis was tested by transfecting arrestin3-(R170E), a dominant positive form of arrestin that does not require receptor phosphorylation for activation. AtT-20 cells expressing both KSA and arrestin3-(R170E) responded to U50,488 treatment with an increase in phospho-p38 consistent with the hypothesis. Primary cultured astrocytes (glial fibrillary acidic protein-positive) and neurons (␥-aminobutyric acid-positive) isolated from mouse striata also responded to U50,488 by increasing phospho-p38 immunolabeling. p38 activation was not evident in either striatal astrocytes or neurons isolated from KOR knock-out mice or GRK3 knock-out mice. Astrocytes pretreated with small interfering RNA for arrestin3 were also unable to activate p38 in response to U50,488 treatment. Furthermore, in striatal neurons, the kappamediated phospho-p38 labeling was colocalized with arrestin3. These findings suggest that KOR may activate p38 MAPK in brain by a GRK3 and arrestin-dependent mechanism.Kappa opioid receptors are G-protein-coupled receptors (GPCRs) 2 that are widely expressed throughout the brain and are activated by the endogenous opioid peptides derived from prodynorphin (1, 2). Several reports have characterized the signal transduction events initiated by KOR activation. By coupling to the G-protein G␣ i/o , KOR inhibits adenylate cyclase, increases potassium conductance, decreases calcium conductance, and mobilizes intracellular calcium (3). More recently, KOR has been recognized to activate the extracellular signalregulated kinase (ERK 1/2) (4, 5). This activation has been demonstrated to persist for several hours following agonist treatment, suggesting a role for KOR in long term growth and gene regulation. Other studies have demonstrated that KOR can activate c-Jun amino-terminal kinase (6). These studies suggest that KOR can activate multiple signaling pathways that result in the immediate and long term cellular effects of kappa opioids.Sustained agonist exposure causes GPCR phosphorylation and desensitization (7). For the kappa opioid receptor, G-protein receptor kinase 3 (GRK3) phosphorylation of serine 369 in the carboxyl-terminal domain of KOR initiates arrestin-dependent receptor desensitization and internalization (8, 9). Recently, new evidence suggests that the arrestin-bound GPCR is not inactive and instead can recruit MAPK signaling modules (10). For example, for the chem...

Objectives Little is known about how opioid prescriptions for chronic pain are initiated. We sought to describe patterns of prescription opioid initiation, identify correlates of opioid initiation, and examine correlates of receipt of chronic opioid therapy (COT) among veterans with persistent non-cancer pain. Methods Using Veterans Affairs (VA) administrative data, we identified 5,961 veterans from the Pacific Northwest with persistent elevated pain intensity scores who had not been prescribed opioids in the prior 12 months. We compared veterans not prescribed opioids over the subsequent 12 months to those prescribed any opioid and to those prescribed COT (≥90 consecutive days). Results During the study year, 34% of the sample received an opioid prescription, and 5% received COT. Most first opioid prescriptions were written by primary care clinicians. Veterans prescribed COT were younger, had greater pain intensity, and high rates of psychiatric and substance use disorders (SUDs) compared to veterans in the other two groups. Among patients receiving COT, 29% were prescribed long-acting opioids, 37% received one or more urine drug screens, and 24% were prescribed benzodiazepines. Adjusting for age, sex, and baseline pain intensity, major depression (OR 1.24 [1.10–1.39]; 1.48 [1.14–1.93]) and nicotine dependence (1.34 [1.17–1.53]; 2.02 [1.53–2.67]) were associated with receiving any opioid prescription and with COT, respectively. Discussion Opioid initiations are common among veterans with persistent pain, but most veterans are not prescribed opioids long-term. Psychiatric disorders and SUDs are associated with receiving COT. Many Veterans receiving COT are concurrently prescribed benzodiazepines and many do not receive urine drug screening; additional study regarding practices that optimize safety of COT in this population is indicated.

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The calcium-permeable transient receptor potential M2 (TRPM2) ion channel was recently demonstrated to have a sexually dimorphic contribution to ischemic brain injury, with inhibition or knockdown of the channel protecting male brain preferentially. We tested the hypothesis that androgen signaling is required for this male-specific cell-death pathway. Additionally, we tested the hypothesis that differential activation of the enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is responsible for male-specific TRPM2 channel activation and neuronal injury. We observed that administration of the TRPM2 inhibitor clotrimazole (CTZ) 2 hours after onset of ischemia reduced infarct volume in male mice and that protection from ischemic damage by CTZ was abolished by removal of testicular androgens (castration; CAST) and rescued by androgen replacement. Male PARP-1 knockout mice had reduced ischemic damage compared with WT mice and inhibition of TRPM2 with CTZ failed to reduce infarct size. Lastly, we observed that ischemia increased PARP activity in the peri-infarct region of male mice to a greater extent than female mice and the difference was abolished in CAST male mice. Data presented in the current study indicate that TRPM2-mediated neuronal death in the male brain requires intact androgen signaling and PARP-1 activity.