IL-6 and TNFα were significantly increased in the bone marrow aspirate samples of patients with active multiple myeloma (MM) compared to those of normal controls. Furthermore, MM patients with advanced aggressive disease had significantly higher levels of IL-6 and TNFα than those with MM in plateau phase. TNFα increased interleukin-6 (IL-6) production from MM cells. However, the detailed mechanisms involved in signaling pathways by which TNFα promotes IL-6 secretion from MM cells are largely unknown. In our study, we found that TNFα treatments induce MEK and AKT phosphorylation. TNFα-stimulated IL-6 production was abolished by inhibition of JAK2 and IKKβ or by small interfering RNA (siRNA) targeting TNF receptors (TNFR) but not by MEK, p38, and PI3K inhibitors. Also, TNFα increased phosphorylation of STAT3 (ser727) including c-Myc and cyclin D1. Three different types of JAK inhibitors decreased the activation of the previously mentioned pathways. In conclusion, blockage of JAK/STAT-mediated NF-κB activation was highly effective in controlling the growth of MM cells and, consequently, an inhibitor of TNFα-mediated IL-6 secretion would be a potential new therapeutic agent for patients with multiple myeloma.

The World Health Organization (WHO) recently endorsed the proposal for a Decade of Healthy Ageing (2020–2030). The WHO defines “healthy aging” as “the process of developing and maintaining the functional ability that enables wellbeing in older age.” Among the strategies for the Decade of Healthy Ageing, the WHO has suggested enhancing intrinsic capacity, promoting functional ability, and implementing the Integrated Care for Older People (ICOPE) package. The WHO has defined steps for ICOPE evaluation and scale-up and is performing a prospective study in 2–3 countries (low and middle income, high income) to test its feasibility in 2021–2022 and a multinational randomized study to validate its clinical efficacy and effectiveness in 2022–2024. Intrinsic capacity and frailty represent two faces of the same coin, with one indicating the reserves of the individual and the other indicating the deficits that accumulate with age. The Integrated Care of Older Patients with Frailty in Primary Care (ICOOP_Frail) study is the first integrated care program for frailty or functional decline in primary care in Korea. The results suggest that the ICOOP_Frail study can be utilized as a reference for ICOPE studies in Korea or at least to provide important findings for the forthcoming ICOPE implementation study in Korea.

Study DesignCross sectional study.PurposeTo characterize the pattern of injury, describe the current clinical management, and determine the outcomes in traumatic spine injury (TSI) patients presenting to a major government hospital in Phnom Penh, Cambodia.Overview of LiteratureThere is a paucity of literature on epidemiology or current clinical practices for TSIs in Cambodia. The findings from this study can thus serve as a valuable resource for future progress in treating TSIs in low-income countries.MethodsThis study was a cross-sectional study of TSI patients admitted to Preah Kossamak Hospital in Phnom Penh, Cambodia. Demographics, cause of spinal injury, spinal level of injury, surgical procedures and techniques, complications, and American Spinal Injury Association (ASIA) grades were recorded and analyzed.ResultsEighty patients were admitted with TSI between October 2013 and June 2014. Falls from heights were the most common cause of TSI, followed by road traffic accidents. 78% of the admitted patients underwent at least one surgical procedure. Without intraoperative imaging, 4 patients (6%) had wrong level surgery, and 1 patient (2%) had misplacement of pedicle screws. Sacral decubitus ulcers were the most common non-surgically related complication. Antibiotics were administered to >90% of patients. There were no in-hospital mortalities. Of the 60 spinal cord injury (SCI) patients, 32% (19/60) showed improvement in their ASIA grade at the time of discharge, and 52% (31/60) showed no change. At follow-up, 32% (19/60) of SCI patients reported improvement, and 8% (5/60) reported no change. However, 36 SCI patients (60%) were lost to follow-up.ConclusionsDespite technological limitations, outcomes of TSI patients in Cambodia appear favorable with evidence of clinical improvement and low mortality.

Bortezomib has been known as the most promising anti-cancer drug for multiple myeloma (MM). However, recent studies reported that not all MM patients respond to bortezomib. To overcome such a stumbling-block, studies are needed to clarify the mechanisms of bortezomib resistance. In this study, we established a bortezomib-resistant cell line (U266/velR), and explored its biological characteristics. The U266/velR showed reduced sensitivity to bortezomib, and also showed crossresistance to the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation, known as stem-like feature, compared to parental U266 cells. U266/velR showed relatively less inhibitory effect of prosurvival NF-κB signaling by bortezomib. Further analysis of RNA microarray identified genes related to ubiquitination that were differentially regulated in U266/velR. Moreover, the expression level of CD52 in U266 cells was associated with bortezomib response. Our findings provide the basis for developing therapeutic strategies in bortezomib-resistant relapsed and refractory MM patients. [BMB Reports 2014; 47(5): 274-279]

Autophagy is a multiple fusion event, initiating with autophagosome formation and culminating with fusion with endo-lysosomes in a Ca 2+ -dependent manner. The source of Ca 2+ and the molecular mechanism by which Ca 2+ is provided for this process are not known. The intracellular Ca 2+ permeable channel transient receptor potential mucolipin 3 (TRPML3) localizes in the autophagosome and interacts with the mammalian autophagy-related protein 8 (ATG8) homolog GATE16. Here, we show that lipid-regulated TRPML3 is the Ca 2+ release channel in the phagophore that provides the Ca 2+ necessary for autophagy progress. We generated a TRPML3-GCaMP6 fusion protein as a targeted reporter of TRPML3 compartment localization and channel function. Notably, TRPML3-GCaMP6 localized in the phagophores, the level of which increased in response to nutrient starvation. Importantly, phosphatidylinositol-3-phosphate (PI3P), an essential lipid for autophagosome formation, is a selective regulator of TRPML3. TRPML3 interacted with PI3P, which is a direct activator of TRPML3 current and Ca 2+ release from the phagophore, to promote and increase autophagy. Inhibition of TRPML3 suppressed autophagy even in the presence of excess PI3P, while activation of TRPML3 reversed the autophagy inhibition caused by blocking PI3P. Moreover, disruption of the TRPML3–PI3P interaction abolished both TRPML3 activation by PI3P and the increase in autophagy. Taken together, these results reveal that TRPML3 is a downstream effector of PI3P and a key regulator of autophagy. Activation of TRPML3 by PI3P is the critical step providing Ca 2+ from the phagophore for the fusion process, which is essential for autophagosome biogenesis.