Pathogenesis and treatment of multiple myeloma bone disease

Multiple myeloma (Plasma cell myeloma), a malignancy of the plasma cells, exhibits tumor expansion preferentially in the bone marrow and the development of bone-destructive lesions. Multiple myeloma is still an incurable disease with changes in the bone marrow microenvironment in favor of the survival and proliferation of multiple myeloma cells and bone destruction. In this review, we described the recent findings on the regulators involved in the development of myeloma bone diseases, and succinctly summarize currently available therapeutic options and the development of novel bone modifying agents for myeloma treatment

Myeloma–Bone Interaction : A Vicious Cycle via TAK1–PIM2 Signaling

Myeloma cells interact with their ambient cells in the bone, such as bone marrow stromal cells, osteoclasts, and osteocytes, resulting in enhancement of osteoclastogenesis and inhibition of osteoblastogenesis while enhancing their growth and drug resistance. The activation of the TAK1–PIM2 signaling axis appears to be vital for this mutual interaction, posing it as an important therapeutic target to suppress tumor expansion and ameliorate bone destruction in multiple myeloma.Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bone-destructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL–NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by factors elaborated in the bone marrow and bone in MM, including the soluble Wnt inhibitors DKK-1 and sclerostin, activin A, and TGF-β, resulting in systemic bone destruction with loss of bone. Osteocytes have been drawn attention as multifunctional regulators in bone metabolism. MM cells induce apoptosis in osteocytes to trigger the production of factors, including RANKL, sclerostin, and DKK-1, to further exacerbate bone destruction. Bone lesions developed in MM, in turn, provide microenvironments suited for MM cell growth/survival, including niches to foster MM cells and their precursors. Thus, MM cells alter the microenvironments through bone destruction in the bone where they reside, which in turn potentiates tumor growth and survival, thereby generating a vicious loop between tumor progression and bone destruction. The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in bone marrow stromal cells and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1–PIM2 pathway plays a critical role in tumor expansion and bone destruction, posing the TAK1–PIM2 pathway as a pivotal therapeutic target in MM

Heat transfer in natural convection with finite-sized particles considering thermal conductance due to inter­particle contacts

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Computational Thermal Sciences following peer review

TPO-RA improved ITP induced by atezolizumab

Immune checkpoint inhibitors (ICIs) have shown impressive anti-tumor effects against multiple types of malignancies. Among the wide variety of immune-related adverse events (irAEs), immune-related thrombocytopenia (ITP) is relatively rare but often clinically significant and life-threatening. However, the appropriate treatment for severe ITP has not been determined. We herein report an 82-year-old male patient with non-small-cell lung cancer who developed severe ITP three weeks after starting the third course of atezolizumab. The initial combination therapy with high-dose prednisolone, intravenous immunoglobulin and platelet transfusion was ineffective. However, additional treatment with eltrombopag, a thrombopoietin receptor agonist, resulted in remarkable improvement in the thrombocytopenia

Aberrant Expression of TFF1, TFF2, and PDX1 and Their Diagnostic Value in Lobular Endocervical Glandular Hyperplasia

Lobular endocervical glandular hyperplasia (LEGH) is a distinct benign glandular lesion expressing gastric gland mucous cell-type mucin (N-acetylglucosaminal -> 4galactose -> R [GlcNAc alpha 1 -> 4Gal -> R]). To investigate histogenesis and diagnostic markers of LEGH, we examined the immunohistochemical expression profile of gastric surface mucous cell (MUC5AC and TFF1), gastric gland mucous cell (MUC6, TFF2, and GlcNAc alpha 1 -> 4Gal -> R), gastric pyloric epithelial cell (PDX1), and endocervical cell (keratan sulfate) markers in normal endocervix samples and benign glandular lesions (nabothian cysts, tunnel clusters, and LEGHs). MUC5AC and MUC6 were expressed in normal endocervical mucosa and benign glandular lesions. TFF1, TFF2, GlcNAc alpha 1 -> 4Gal -> R, and PDX1 were expressed only in LEGH. Keratan sulfate was expressed in normal endocervical mucosa and benign glandular lesions. In LEGH, gastric surface mucous cell and gastric gland mucous cell differentiation were demonstrated, and transdifferentiation from endocervical mucosa into gastric pyloric mucosa was suggested. In addition to GlcNAc alpha 1 -> 4Gal -> R, TFF1, TFF2, and PDX1 are additional useful markers for LEGH.ArticleAMERICAN JOURNAL OF CLINICAL PATHOLOGY. 135(2):253-261 (2011)journal articl

The Observation of Humoral Responses after Influenza Vaccination in Patients with Rheumatoid Arthritis Treated with Japanese Oriental (Kampo) Medicine: An Observational Study

Objective. The efficacy of influenza vaccination in patients treated with Japanese Oriental (Kampo) Medicine is unknown. The objectives of this study were to observe the efficacy of influenza vaccination in RA patients treated with Kampo. Methods. Trivalent influenza subunit vaccine was administered to 45 RA patients who had received Kampo. They were divided into 2 groups: RA patients treated without MTX (“without MTX group”) and treated with MTX (“with MTX group”). Antibody titers were measured before and 4 weeks after vaccination using hemagglutination inhibition assay. Results. Geometric mean titers (GMTs) of anti-influenza antibodies significantly increased for all influenza strains. Response to the influenza vaccination in RA patients treated with Kampo was not lower than that of healthy subjects and the response in the “with MTX group” had a tendency to be higher than that in RA patients treated with MTX in the previous study. There was no significant difference in the GMT after 4 weeks between the “with MTX group” and the “without MTX group.” A decreased efficacy in both seroprotection and seroconversion was not found in the “with MTX group.” Conclusion. These observations may open the way for further clinical trials to establish the efficacy for the influenza vaccination in RA patients treated with Kampo

大動脈瘤形成機序に関する実験的ならびに臨床的研究

取得学位：博士(医学), 学位授与番号：医博乙第1511号，学位授与年月日：平成11年12月15日,学位授与年：199

Oral granuloma with chronic graft-vs-host disease

BACKGROUND Oral mucositis is often observed with graft-versus-host disease (GVHD); however, the occurrence of oral granuloma is rare. The rapid increase in granulomatous lesions should be distinguished from malignant tumors in patients with GVHD because malignant diseases can develop in those patients. This case is the youngest pediatric patient with granuloma associated with GVHD. CASE SUMMARY The patient was a 1-year and 5-mo-old girl who presented to our department for the management of oral nodules. At the age of 5 mo, she was diagnosed with primary immunodeficiency disease, cord blood transplant was performed at 11 mo and bone marrow transplant at 1 year of age. After transplantation, GVHD and oral mucositis developed, and tacrolimus was administered. Interestingly, nodules appeared on the lower lip and buccal mucosa, which spontaneously disappeared. Then, a new nodule appeared on the left lateral border of the tongue. Resection was performed and the histopathological diagnosis was granuloma. The origin of these nodules were considered to be the fibroblasts activated under inflammation caused by GVHD because the calcineurin inhibitor tacrolimus acted on their proliferation. CONCLUSION It is very important to distinguish oral granulomatous lesions from malignancies if GVHD is present at the base and if immunosuppressive agents and steroids are being administered

Mutational analyses of U13 small nucleolar RNA : a guide RNA involved in the acetylation 18S ribosomal RNA.

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