Byung-Su Kim

Curcumin in combination with bortezomib synergistically induced apoptosis in human multiple myeloma U266 cells

Growth of multiple myeloma cells is controlled by various factors derived from host bone marrow microenvironments. Interaction between multiple myeloma cells and bone marrow stromal cells (BMSCs) plays an important role in the expression of adhesive molecules and secretion of growth factors involved in multiple myeloma (MM) cell growth, survival, and resistance to anticancer drugs. Recently, the possibility of developing novel anti‐cancer therapeutic strategies targeting both MM cells and MM cell–BMSC interactions has been discussed. Here we present data showing that curcumin, a major constituent of turmeric compounds extracted from the rhizomes of the plant Curcuma longa, effectively reduced the growth of MM cells and BMSCs. Upon treatment with curcumin, IL‐6/sIL‐6R‐induced STAT3 and Erk phosphorylation was dramatically reduced in the co‐cultured cells. In addition, curcumin inhibited the production of pro‐inflammatory cytokines and VEGF, factors that are associated with the progression of multiple myeloma, from both MM cells and BMSCs. In a combination treatment with curcumin and bortezomib, IL‐6/sIL‐6R‐induced STAT3 and Erk phosphorylation was effectively inhibited. Moreover, this combination treatment synergistically inhibited the growth of MM cells co‐cultured with BMSCs as compared to controls. Taken together, these results indicate that curcumin potentiates the therapeutic efficacy of bortezomib in MM suggesting this combination therapy to be of value in the clinical management of MM.

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

The paucity of regulatory T cells (Tregs) limits clinical translation to control aberrant immune reactions including graft-versus-host disease (GVHD). Recent studies showed that the agonistic antibody to DR3 (αDR3) expanded CD4(+)FoxP3(+) Tregs in vivo. We investigated whether treating donor mice with a single dose of αDR3 could alleviate acute GVHD in a MHC-mismatched bone marrow transplantation model. αDR3 induced selective proliferation of functional Tregs. CD4(+) T cells isolated from αDR3-treated mice contained higher numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from αDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4(+) T cells were maintained, resulting in improved survival. Conventional T cells derived from αDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNγ, IL-1β, and TNFα) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from αDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of αDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg-based therapies.

Donor Requirements for Regulatory T Cell Suppression of Murine Graft-versus-Host Disease

Adoptive transfer of freshly isolated natural occurring CD4+CD25+Foxp3+ regulatory T cells (Treg) prevents graft-versus-host disease (GVHD) in several animal models and following hematopoietic cell transplantation (HCT) in clinical trials. Donor-derived Treg have been mainly used, as they share the same MHC with CD4+ and CD8+ conventional T cells (Tcon) that are primarily responsible for GVHD. Third party–derived Treg are a promising alternative for cellular therapy, as they can be prepared in advance, screened for pathogens and activity, and banked. We explored MHC disparities between Treg and Tcon in HCT to evaluate the impact of different Treg populations in GVHD prevention and survival. Third-party Treg and donor Treg are equally suppressive in ex vivo assays, whereas both donor and third-party but not host Treg protect from GVHD in allogeneic HCT, with donor Treg being the most effective. In an MHC minor mismatched transplantation model (C57BL/6 → BALB/b), donor and third-party Treg were equally effective in controlling GVHD. Furthermore, using an in vivo Treg depletion mouse model, we found that Treg exert their main suppressive activity in the first 2 d after transplantation. Third-party Treg survive for a shorter period of time after adoptive transfer, but despite the shorter survival, they control Tcon proliferation in the early phases of HCT. These studies provide relevant insights on the mechanisms of Treg-mediated protection from GVHD and support for the use of third-party Treg in clinical trials.

Adenocarcinoma has an excellent outcome with pemetrexed treatment in Korean patients: a prospective, multicenter trial.

OBJECTIVEnThis prospective multicenter study conducted by the Korean Cancer Study Group evaluated the efficacy and safety of pemetrexed in Korean patients with advanced non-small cell lung cancer (NSCLC) who had prior chemotherapy.nnnPATIENTS AND METHODSnPatients with stage IIIB or IV NSCLC in whom prior chemotherapy failed received pemetrexed 500 mg/m(2) every 3 weeks with folic acid and vitamin B12 supplementation until disease progression or the development of intolerable toxicity. Eighty-one patients were enrolled.nnnRESULTSnThe overall response rate for 78 evaluable patients was 5.1% [95% confidence interval (CI) 1.4-12.6; partial response 4/78, no complete response]. The disease control rate including complete, partial response and stable disease was 46.2% (36/78, 95% CI 34.8-57.8). With a median 8.7 months follow-up, the median time to progression was 3.1 months (95% CI 1.17-5.03) and the median overall survival (OS) was 7.8 months (95% CI 5.19-10.35). The median OS for patients with adenocarcinoma histology was 18.7 months compared to 6.1 months for non-adenocarcinoma. In a multivariate analysis, Eastern Cooperative Oncology Group performance status 0-1 [hazards ratio (HR)=0.331, 95% CI 0.135-0.814] and adenocarcinoma (HR=0.504, 95% CI 0.283-0.899) were independent factors for prolongation of overall survival.nnnCONCLUSIONSnPemetrexed monotherapy has promising efficacy in patients with advanced NSCLC as a second-line therapy with less hematologic and non-hematologic toxicity, especially in those with adenocarcinoma histology.

Recombinant human epidermal growth factor on oral mucositis induced by intensive chemotherapy with stem cell transplantation

Oral mucositis (OM) is one of the most common and debilitating complications in patients undergoing intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for OM induced by intensive chemotherapy followed by HSCT. Patients were randomly assigned to either the rhEGF group or placebo group. The severity of OM and self‐reported quality of life (QOL) were assessed daily. A total of 58 patients were analyzed. Baseline characteristics were similar between the two groups. The incidence of NCI grade ≥2 OM was higher in the rhEGF group (78.6% vs. 50%, P = 0.0496). However, the duration of OM in patients with NCI grade ≥2 tended to be shorter in the rhEGF group (8.5 days vs. 14.5 days, P = 0.262). The QOL analysis in patients with World Health Organization (WHO) grade ≥3 OM showed that rhEGF significantly reduced limitations in swallowing (P = 0.039) and drinking (P = 0.042). The duration of hospitalization (P = 0.047), administration of total parenteral nutrition (P = 0.012), and the usage of opioid analgesics (P = 0.018) were significantly shorter in the rhEGF group with WHO grade ≥3 OM. Adverse events were mild and similar between the two groups. In conclusion, this analysis showed that rhEGF did not reduce the incidence of NCI grade ≥2 OM. However, the patients with WHO grade ≥3 OM in the rhEGF group showed better results compared to the placebo group for several secondary endpoints. Am. J. Hematol. 88:107–112, 2013.

A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant

A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2-deoxy-2-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893-902. ©2017 AACR.

Thermoelectric power of MgB2

Abstract Thermoelectric power (TEP) of MgB 2 and its changes with the superconducting transition temperature ( T c ) have been investigated. MgB 2 samples synthesized with different techniques––sample 1 by the encapsulation method and sample 2 by the high pressure and high temperature technique––showed different T c ( T c of sample 1= 38.7 K, and T c of sample 2 = 40.4 K). The characteristic features of the TEP of these samples––low temperature linear behavior, deviation from the low temperature linear behavior at a certain temperature, and an almost saturating value at ∼300 K––were found to vary systematically with T c , consistent with the previously reported TEP changes in Mg 1− x Al x B 2 . These changes of the TEP behaviors with T c in the superconducting diborides system are discussed in comparison with those of high T c cuprates and bismuthates. The common feature of the saturating TEP at high temperatures suggests the importance of an anharmonic electron–phonon interaction.

Allogeneic stem cell transplantation in patients with non-Hodgkin lymphoma who experienced relapse or progression after autologous stem cell transplantation

There are few treatment options for patients with non-Hodgkin lymphoma (NHL) who experienced progression after high-dose chemotherapy (HDC) with autologous stem cell transplantation (auto-SCT). The role of allogeneic stem cell transplantation (allo-SCT) in these patients has not been clarified yet. In this study, we report clinical outcomes of allo-SCT in patients with NHL who experienced progression after HDC with auto-SCT. Patients were enrolled from seven hospitals in Korea. A total of 38 patients were included: 18 patients (47.4%) underwent myeloablative conditioning and 20 patients (52.6%) reduced intensity conditioning. Overall response rate was 73.3%. Median event-free survival was 6.3xa0months. Median overall survival (OS) was 19.0xa0months. Estimated 5-year survival rate was 35.0%. Acute graft-versus-host disease developed in 13 patients (34.2%). Transplant-related mortality (TRM) was 21.1% (eight patients). Ann Arbor stage (pu2009=u20090.022), performance status (pu2009<u20090.001), and baseline serum albumin level (pu2009=u20090.010) were significant risk factors for OS. Performance status (pu2009=u20090.022) was a significant risk factor for TRM. Eight patients with persistent or progressive disease received donor lymphocyte infusion, and two of them achieved complete remission. In conclusion, despite high TRM, allo-SCT is a viable option for patients with NHL who underwent progression after HDC with auto-SCT.