The inhibitory effects of macrolide antibiotics including clarithromycin (CAM) on autophagy flux have been reported. Although a macrolide antibiotic exhibits no cytotoxicity, its combination with bortezomib (BZ), a proteasome inhibitor, for the simultaneous blocking of the ubiquitin (Ub)-proteasome and autophagy-lysosome pathways leads to enhanced multiple myeloma (MM) cell apoptosis induction via stress overloading of the endoplasmic reticulum (ER). As misfolded protein cargo is recruited by histone deacetylase 6 (HDAC6) to dynein motors for aggresome transport, serving to sequester misfolded proteins, we further investigated the cellular effects of targeting proteolytic pathways and aggresome formation concomitantly in MM cells. Pronounced apoptosis was induced by the combination of vorinostat [suberoylanilide hydroxamic acid (SAHA); potently inhibits HDAC6] with CAM and BZ compared with each reagent or a 2-reagent combination. CAM/BZ treatment induced vimentin positive-aggresome formation along with the accumulation of autolysosomes in the perinuclear region, whereas they were inhibited in the presence of SAHA. The SAHA/CAM/BZ combination treatment maximally upregulated genes related to ER stress including C/EBP homologous protein (CHOP). Similarly to MM cell lines, enhanced cytotoxicity with CHOP upregulation following SAHA/CAM/BZ treatment was shown by a wild-type murine embryonic fibroblast (MEF) cell line; however, a CHOP-deficient MEF cell line almost completely canceled this pronounced cytotoxicity. Knockdown of HDAC6 with siRNA exhibited further enhanced CAM/BZ-induced cytotoxicity and CHOP induction along with the cancellation of aggresome formation. Targeting the integrated networks of aggresome, proteasome, and autophagy is suggested to induce efficient ER stress-mediated apoptosis in MM cells.

Impalement brain injury is rare, and the initial management of this condition is not well-established. We present a case of a well-managed brain injury caused by impalement with a metal bar. A 29-year-old man whose head had been impaled by a metal bar was transferred to our hospital. Upon arrival, he was agitated, with an unsteady gait and prominent odor of alcohol on his breath. He exhibited normal vital signs and neurological findings, except for his level of consciousness. To address the risk of secondary brain injury caused by movement of the foreign body, we immediately administered a sedative agent and muscle relaxant after the initial neurological evaluation. The imaging evaluation revealed the insertion of a metal bar into the right frontal lobe at a depth of >100 mm through the frontal bone; however, there was no apparent major vessel injury-related complication. Three hours after arrival at the hospital, a craniotomy was performed to remove the foreign body. The patient's postoperative course was uneventful, and he was discharged after rehabilitation without any neurological deficits. The strategy of immediate immobilization to prevent the secondary brain injury is important in the initial management of a patient who has survived an impalement brain injury and presented to an emergency department.

No abstract