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Harada T.,Tokushima University | Ozaki S.,Tokushima Prefectural Central Hospital
BioMed Research International | Year: 2014

Multiple myeloma (MM) still remains an incurable disease, at least because of the existence of cell-adhesion mediated drug-resistant MM cells and/or continuous recruitment of presumed MM cancer stem cell-like cells (CSCs). As a new alternative treatment modality, immunological approaches using monoclonal antibodies (mAbs) and/or cytotoxic T lymphocytes (CTLs) are now attracting much attention as a novel strategy attacking MM cells. We have identified that HM1.24 [also known as bone marrow stromal cell antigen 2 (BST2) or CD317] is overexpressed on not only mature MM cells but also MM CSCs. We then have developed a humanized mAb to HM1.24 and defucosylated version of the mAb to adapt to clinical practice. Moreover, we have successfully induced HM1.24-specific CTLs against MM cells. The combination of these innovative therapeutic modalities may likely exert an anti-MM activity by evading the drug resistance mechanism and eliminating presumed CSCs in MM. © 2014 Takeshi Harada and Shuji Ozaki.


Hayashi K.,Tokushima University | Nakamura M.,Tokushima University | Miki H.,Tokushima University | Ozaki S.,Tokushima Prefectural Central Hospital | And 4 more authors.
Advanced Functional Materials | Year: 2014

Physical therapies including photodynamic therapy (PDT) and photothermal therapy (PTT) can be effective against diseases that are resistant to chemotherapy and remain as incurable malignancies (for example, multiple myeloma). In this study, to enhance the treatment efficacy for multiple myeloma using the synergetic effect brought about by combining PDT and PTT, iodinated silica/porphyrin hybrid nanoparticles (ISP HNPs) with high photostability are developed. They can generate both 1O2 and heat with irradiation from a light-emitting diode (LED), acting as photosensitizers for PDT/PTT combination treatment. ISP HNPs exhibit the external heavy atom effect, which significantly improves both the quantum yield for 1O 2 generation and the light-to-heat conversion efficiency. The in vivo fluorescence imaging demonstrates that ISP HNPs, modified with folic acid and polyethylene glycol (FA-PEG-ISP HNPs), locally accumulate in the tumor after 18 h of their intravenous injection into tumor-bearing mice. The LED irradiation on the tumor area of the mice injected with FA-PEG-ISP HNPs causes necrosis of the tumor tissues, resulting in the inhibition of tumor growth and an improvement in the survival rate. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Ozaki S.,Tokushima Prefectural Central Hospital | Shimizu K.,Tokai Central Hospital
BioMed Research International | Year: 2014

High-dose melphalan (200 mg/m2) as conditioning regimen followed by autologous stem cell transplantation (ASCT) rescue has been established as a standard treatment for patients with multiple myeloma (MM) younger than 65 years of age. However, the role of ASCT in elderly patients older than 65 years remains controversial in the era of novel agents such as thalidomide, bortezomib, and lenalidomide. The efficacy and feasibility of ASCT have been shown in elderly patients by reducing the dose of melphalan to 100-140 mg/m 2. Although the clinical benefit of reduced-intensity ASCT in elderly patients has not been clearly established in comparison with that of novel agent-based induction therapy, recent studies have demonstrated that sequential strategies of novel agent-based induction therapy and reduced-intensity ASCT followed by consolidation/maintenance with novel agents translate into better outcome in the management of elderly patients. Thus, ASCT could also be a mainstay in the initial treatment of elderly MM patients, and its indication should be evaluated based on performance status and the presence of complications and/or comorbidities of each elderly patient with MM. © 2014 Shuji Ozaki and Kazuyuki Shimizu.


Uezumi A.,Health Science University | Fukada S.,Osaka University | Yamamoto N.,Aichi University | Ikemoto-Uezumi M.,National Institute for Longevity science | And 7 more authors.
Cell Death and Disease | Year: 2014

Fatty and fibrous connective tissue formation is a hallmark of diseased skeletal muscle and deteriorates muscle function. We previously identified non-myogenic mesenchymal progenitors that contribute to adipogenesis and fibrogenesis in mouse skeletal muscle. In this study, we report the identification and characterization of a human counterpart to these progenitors. By using PDGFR as a specific marker, mesenchymal progenitors can be identified in the interstitium and isolated from human skeletal muscle. PDGFR + cells represent a cell population distinct from CD56 + myogenic cells, and adipogenic and fibrogenic potentials were highly enriched in the PDGFR + population. Activation of PDGFR stimulates proliferation of PDGFR + cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFR + cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. Our results revealed the pathological relevance of PDGFR + mesenchymal progenitors to human muscle diseases and provide a basis for developing therapeutic strategy to treat muscle diseases. © 2014 Macmillan Publishers Limited All rights reserved.


Yagi H.,Tokushima Prefectural Central Hospital
[Rinshō ketsueki] The Japanese journal of clinical hematology | Year: 2013

A 56-year-old male presented with pathological rib fracture and lumbago in 2006. He was diagnosed with multiple myeloma (IgG-lambda type, D&S stage IIIA, ISS 2). He was treated with VAD therapy and tandem auto-PBSCT, and achieved CR in 2007. He was followed without chemotherapy, but relapsed in 2009. He received lenalidomide plus dexamethasone and bortezomib plus dexamethasone and achieved PR which was sustained for 25 months. In 2012, he developed edema of the lower legs and pleural effusion, and was diagnosed as having nephrotic syndrome and heart failure due to AL amyloidosis. He died of renal failure and heart failure 3 months after this diagnosis. Autopsy findings showed amyloid deposition in many organs including the heart, kidneys, liver, spleen, and intestines. Development of rapidly progressive AL amyloidosis is a rare complication of relapse after the achievement of CR, but careful monitoring is needed in patients with multiple myeloma.

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