Diffuse Alveolar Hemorrhage Secondary to Ibrutinib Therapy in a Patient With Refractory Mantle Cell Lymphoma.

Ibrutinib is a Bruton tyrosine kinase inhibitor that is approved by the FDA for the treatment of mantle cell lymphoma and other hematological malignancies. Bruton tyrosine kinases promote platelet aggregation, and, therefore, bleeding is a common side effect of ibrutinib. At least half of patients taking ibrutinib experience a bleeding event, and up to 10% may experience major bleeding. Patient-specific factors that predict bleeding events remain unknown. This report describes a case of diffuse alveolar hemorrhage in a 67-year-old male taking ibrutinib for refractory mantle cell lymphoma. He was initially admitted to the hospital for recurrence of mantle cell lymphoma and evidence of tumor lysis syndrome, including acute kidney injury and hyperuricemia. He was taking aspirin prior to being hospitalized and was thrombocytopenic. A deep vein thrombosis was noted following admission, and the patient was started on enoxaparin. Two days after starting ibrutinib as an inpatient, the patient developed diffuse alveolar hemorrhage, which was ultimately fatal. Bronchoscopy with bronchoalveolar lavage ruled out infectious and other etiologies. To our knowledge, this is the first case of diffuse alveolar hemorrhage associated with ibrutinib. Based on the available literature, it is unclear if the patient's recent aspirin use, concurrent enoxaparin, or thrombocytopenia was contributory. Further studies are necessary to clarify these patient-specific risks.

Activation of EphB2 Forward Signaling Enhances Memory Consolidation.

EphB2 is involved in enhancing synaptic transmission and gene expression. To explore the roles of EphB2 in memory formation and enhancement, we used a photoactivatable EphB2 (optoEphB2) to activate EphB2 forward signaling in pyramidal neurons in lateral amygdala (LA). Photoactivation of optoEphB2 during fear conditioning, but not minutes afterward, enhanced long-term, but not short-term, auditory fear conditioning. Photoactivation of optoEphB2 during fear conditioning led to activation of the cAMP/Ca2+ responsive element binding (CREB) protein. Application of light to a kinase-dead optoEphB2 in LA did not lead to enhancement of long-term fear conditioning memory or to activation of CREB. Long-term, but not short-term, auditory fear conditioning memory was impaired in mice lacking EphB2 forward signaling (EphB2lacZ/lacZ). Activation of optoEphB2 in LA of EphB2lacZ/lacZ mice enhanced long-term fear conditioning memory. The present findings show that the level of EphB2 forward signaling activity during learning determines the strength of long-term memory consolidation.

Optogenetic activation of EphB2 receptor in dendrites induced actin polymerization by activating Arg kinase.

Erythropoietin-producing hepatocellular (Eph) receptors regulate a wide array of developmental processes by responding to cell-cell contacts. EphB2 is well-expressed in the brain and known to be important for dendritic spine development, as well as for the maintenance of the synapses, although the mechanisms of these functions have not been fully understood. Here we studied EphB2's functions in hippocampal neurons with an optogenetic approach, which allowed us to specify spatial regions of signal activation and monitor in real-time the consequences of signal activation. We designed and constructed OptoEphB2, a genetically encoded photoactivatable EphB2. Photoactivation of OptoEphB2 in fibroblast cells induced receptor phosphorylation and resulted in cell rounding ------- a well-known cellular response to EphB2 activation. In contrast, local activation of OptoEphb2 in dendrites of hippocampal neurons induces rapid actin polymerization, resulting dynamic dendritic filopodial growth. Inhibition of Rac1 and CDC42 did not abolish OptoEphB2-induced actin polymerization. Instead, we identified Abelson tyrosine-protein kinase 2 (Abl2/Arg) as a necessary effector in OptoEphB2-induced filopodia growth in dendrites. These findings provided new mechanistic insight into EphB2's role in neural development and demonstrated the advantage of OptoEphB as a new tool for studying EphB signaling.