LPS-CXCL10 Predicts Responses to Bortezomib in Myeloma Patients

To identify predictive biomarkers for clinical responses to bortezomib treatment, 0.06 mL of each whole blood without any cell separation procedures was stimulated ex vivo using five agents, and eight mRNAs were quantified. In six centers, heparinized peripheral blood was prospectively obtained from 80 previously treated or untreated, symptomatic multiple myeloma (MM) patients with measurable levels of M-proteins. The blood sample was procured prior to treatment as well as 2-3 days and 1-3 weeks after the first dose of bortezomib, which was intravenously administered biweekly or weekly, during the first cycle. Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests. Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose. Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients

Combined Single Nucleotide Variants of ORAI1 and BLK in a Child with Refractory Kawasaki Disease

Kawasaki disease (KD) is a systemic vasculitis with an unknown etiology affecting young children. Although intravenous immunoglobulin (IVIG) plus acetylsalicylic acid is effective in most cases, approximately 10–20% of patients do not respond to this therapy. An 8-month-old boy was admitted to a local hospital with the presumptive diagnosis of KD. He received IVIG twice and four series of methylprednisolone pulse therapy from the third to the tenth day of illness. Despite these treatments, his fever persisted with the development of moderate dilatations of the coronary arteries. A diagnosis of refractory KD was made, and infliximab with oral prednisolone was administered without success. Defervescence was finally achieved by cyclosporine A, an inhibitor of the signaling pathway of the calcineurin/nuclear factor of activated T cells (NFAT). Whole-genome sequencing of his deoxyribonucleic acid samples disclosed two single nucleotide variants (SNVs) in disease-susceptibility genes in Japanese KD patients, ORAI1 (rs3741596) and BLK (rs2254546). In summary, the refractory nature of the present case could be explained by the presence of combined SNVs in susceptibility genes associated with upregulation of the calcineurin/NFAT signaling pathway. It may provide insights for stratifying KD patients based on the SNVs in their susceptibility genes

Four hepatosplenic T-cell lymphoma cases of Japanese patients

Hepatosplenic T-cell lymphoma (HSTCL), a rare type of γδ T-cell lymphoma, is characterized by hepatosplenomegaly and cytopenias. It is associated with immunodeficiency and its age of onset is reportedly between the 20s and 30s. We herein report 4 Japanese HSTCL cases. Three of them, including an elderly case that was 74 years of age, were not at adolescence. No cases had a history of immunodeficiency. All other disease phenotypes were similar to the typical HSTCL cases. These findings suggest that there are a certain proportion of HSTCL patients who presented after middle age

Lactobacillus gasseri SBT2055 induces TGF-β expression in dendritic cells and activates TLR2 signal to produce IgA in the small intestine.

Probiotic bacteria provide benefits in enhancing host immune responses and protecting against infection. Induction of IgA production by oral administration of probiotic bacteria in the intestine has been considered to be one reason for this beneficial effect, but the mechanisms of the effect are poorly understood. Lactobacillus gasseri SBT2055 (LG2055) is a probiotic bacterium with properties such as bile tolerance, ability to improve the intestinal environment, and it has preventive effects related to abdominal adiposity. In this study, we have found that oral administration of LG2055 induced IgA production and increased the rate of IgA(+) cell population in Peyer's patch and in the lamina propria of the mouse small intestine. The LG2055 markedly increased the amount of IgA in a co-culture of B cells and bone marrow derived dendritic cells (BMDC), and TLR2 signal is critical for it. In addition, it is demonstrated that LG2055 stimulates BMDC to promote the production of TGF-β, BAFF, IL-6, and IL-10, all critical for IgA production from B cells. Combined stimulation of B cells with BAFF and LG2055 enhanced the induction of IgA production. Further, TGF-β signal was shown to be critical for LG2055-induced IgA production in the B cell and BMDC co-culture system, but TGF-β did not induce IgA production in a culture of only B cells stimulated with LG2055. Furthermore, TGF-β was critical for the production of BAFF, IL-6, IL-10, and TGF-β itself from LG2055-stimulated BMDC. These results demonstrate that TGF-β was produced by BMDC stimulated with LG2055 and it has an autocrine/paracrine function essential for BMDC to induce the production of BAFF, IL-6, and IL-10

Lipopolysaccharide-Induced CXCL10 mRNA Level and Six Stimulant-mRNA Combinations in Whole Blood: Novel Biomarkers for Bortezomib Responses Obtained from a Prospective Multicenter Trial for Patients with Multiple Myeloma.

To identify predictive biomarkers for clinical responses to bortezomib treatment, 0.06 mL of each whole blood without any cell separation procedures was stimulated ex vivo using five agents, and eight mRNAs were quantified. In six centers, heparinized peripheral blood was prospectively obtained from 80 previously treated or untreated, symptomatic multiple myeloma (MM) patients with measurable levels of M-proteins. The blood sample was procured prior to treatment as well as 2-3 days and 1-3 weeks after the first dose of bortezomib, which was intravenously administered biweekly or weekly, during the first cycle. Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests. Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose. Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients