Coexistence of double seropositivity for MPO antibody and anti-GBM antibody in ANCA-associated vasculitis concurrent with multiple myeloma: A case report.

RATIONALE: Immune-mediated vasculitis with 2 or more autoantibodies, for example, anti-proteinase-3, combined with anti-myeloperoxidase (MPO) or anti-glomerular basement membrane (GBM) antibodies, is extremely unusual. Furthermore, the coexistence of autoimmune vasculitis and hematological malignancies is uncommon. Herein, we describe a case of double-seropositive anti-neutrophil cytoplasmic antibody (ANCA) vasculitis with multiple myeloma. PATIENT CONCERNS: A 79-year-old Asian man presented with persistent leg edema and kidney dysfunction. His kidney function rapidly decreased, and serologic test results showed higher titers of the anti-MPO antibody (54.7 IU/mL) and anti-GBM antibodies (>200 IU/mL). Additionally, the clinical features showed the possibility of monoclonal gammopathy with anemia and hyperglobulinemia. We performed kidney and bone marrow biopsy. Serum protein electrophoresis and immunofixation revealed no significant differences, but the results of the bone marrow smear were compatible with those of myeloma with 15% plasmacytosis. However, kidney biopsy showed diffuse crescentic glomerulonephritis without deposition of the immune complex or kappa/lambda chain. DIAGNOSES AND INTERVENTIONS: Finally, the patient was diagnosed with double-seropositive ANCA-associated glomerulonephritis and multiple myeloma. Given the patient's performance status, we initiated low-dose steroid pulse therapy, followed by conservative management. OUTCOMES: While the pulmonary lesions showed improvement, the kidney function did not regain its previous state, prompting the initiation of kidney replacement therapy by hemodialysis. There has been a decrease in the levels of anti-GBM and anti-MPO antibodies since the initial diagnosis. LESSONS: This case elucidates the complex interplay between ANCA-associated glomerulonephritis and hematologic malignancy and emphasizes the need for a nuanced treatment strategy considering its multifaceted clinical presentation.

Anti­survival and pro­apoptotic effects of meridianin C derivatives on MV4­11 human acute myeloid leukemia cells.

Meridianin C is a marine natural product with anticancer activity. Several meridianin C derivatives (compounds 7a­j) were recently synthesized, and their inhibitory effects on pro­viral integration site for Moloney murine leukemia virus (PIM) kinases, as well as their antiproliferative effects on human leukemia cells, were reported. However, the anti­leukemic effects and mechanisms of action of meridianin C and its derivatives remain largely unknown. The aim of the present study was to investigate the effects of meridianin C and its derivatives on MV4­11 human acute myeloid leukemia cell growth. The parent compound meridianin C did not markedly affect the viability and survival of MV4­11 cells. By contrast, MV4­11 cell viability and survival were reduced by meridianin C derivatives, with compound 7a achieving the most prominent reduction. Compound 7a notably inhibited the expression and activity of PIM kinases, as evidenced by reduced B­cell lymphoma­2 (Bcl­2)­associated death promoter phosphorylation at Ser112. However, meridianin C also suppressed PIM kinase expression and activity, and the pan­PIM kinase inhibitor AZD1208 only slightly suppressed the survival of MV4­11 cells. Thus, the anti­survival effect of compound 7a on MV4­11 cells was unrelated to PIM kinase inhibition. Moreover, compound 7a induced apoptosis, caspase­9 and ­3 activation and poly(ADP­ribose) polymerase (PARP) cleavage, but did not affect death receptor (DR)­4 or DR­5 expression in MV4­11 cells. Compound 7a also induced the generation of cleaved Bcl­2, and the downregulation of myeloid cell leukemia (Mcl)­1 and X­linked inhibitor of apoptosis (XIAP) in MV4­11 cells. Furthermore, compound 7a increased eukaryotic initiation factor (eIF)­2α phosphorylation and decreased S6 phosphorylation, whereas GRP­78 expression was unaffected. Importantly, treatment with a pan­caspase inhibitor (z­VAD­fmk) significantly attenuated compound 7a­induced apoptosis, caspase­9 and ­3 activation, PARP cleavage, generation of cleaved Bcl­2 and downregulation of Mcl­1 and XIAP in MV4­11 cells. Collectively, these findings demonstrated the strong anti­survival and pro­apoptotic effects of compound 7a on MV4­11 cells through regulation of caspase­9 and ­3, Bcl­2, Mcl­1, XIAP, eIF­2α and S6 molecules.