Isoliquiritigenin inhibits NLRP3 inflammasome activation with CAPS mutations by suppressing caspase-1 activation and mutated NLRP3 aggregation.

The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome contributes to the development of inflammatory diseases. Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease caused by NLRP3 gene mutations that results in excessive IL-1ß production. We previously identified isoliquiritigenin (ILG), a component of Glycyrrhiza uralensis extracts, as a potent inhibitor of the NLRP3 inflammasome. Here, we aimed to investigate whether ILG inhibits the activation of NLRP3 inflammasome caused by NLRP3 gene mutations. We demonstrated that ILG significantly inhibited NLRP3 inflammasome-mediated lactate dehydrogenase (LDH) release and IL-1ß production in two CAPS model THP-1 cell lines, NLRP3-D303N and NLRP3-L353P, in a dose-dependent manner. Interestingly, the NLRP3 inhibitor MCC950 inhibited LDH release and IL-1ß production in NLRP3-D303N cells, but not in NLRP3-L353P cells. Western blotting and caspase-1 activity assays showed that ILG, as well as caspase inhibitors, including Z-VAD and YVAD, suppressed caspase-1 activation. Notably, ILG prevented cryo-sensitive foci formation of NLRP3 without affecting the levels of intracellular Ca2+. We concluded that ILG effectively prevents the constitutive activation of the inflammasome associated with NLRP3 gene mutations by inhibiting the aggregation of cryo-sensitive mutated NLRP3.

First complete remission favours haploidentical haematopoietic stem cell transplantation with post-transplant cyclophosphamide over cord blood transplantation in acute lymphoblastic leukaemia.

To assess the benefits of HLA-haploidentical haematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) relative to those of umbilical cord blood (UCB) transplantation in acute lymphoblastic leukaemia (ALL), we analysed 1999 patients (PTCy-haplo, 330; UCB, 1669), using the nationwide Japanese registry. PTCy-haplo was associated with a significantly higher relapse rate, but lower non-relapse mortality, which results in overall survival and disease-free survival, comparable to those of UCB. Among patients in CR1, PTCy-haplo showed a significantly higher survival than UCB regardless of the CD34+ cell dose. Our findings provide valuable insights into the donor selection algorithm in allogeneic HSCT for adult patients with ALL.

Secondary central nervous system involvement in patients with diffuse large B-cell lymphoma treated with rituximab combined CHOP therapy - a supplementary analysis of JCOG0601.

Secondary central nervous system involvement (sCNSi) in diffuse large B-cell lymphoma (DLBCL) is fatal. However, its features in patients with sCNSi who are categorized as lower risk by international prognostic index (IPI) or CNS-IPI are not yet fully understood. In the present analysis, we evaluated DLBCL patients who developed sCNSi at their first progression and who participated in JCOG0601, most of whom were lower risk by IPI. Of 409 patients, 21 (5.1%) developed sCNSi during a median follow-up of 4.9 years. Five-year cumulative incidence of sCNSi were 5.1%; and 4.0%, 5.3%, and 11.5% at low, intermediate, and high risk of CNS-IPI, respectively. The most common locations of extranodal lesions at the time of registration in patients with sCNSi were the stomach (n = 4), paranasal cavity (n = 3), and bone marrow (n = 2). In univariable analysis, paranasal cavity lesion was a high-risk factor for sCNSi (subdistribution hazard ratio, 4.34 [95% confidence interval 1.28-14.73]). Median overall survival after sCNSi was 1.3 years, with a 2-year overall survival rate of 39.3%. The incidence of sCNSi in DLBCL patients at lower risk of CNS-IPI was low, as previously reported, but paranasal cavity lesion might indicate high risk for organ involvement. CLINICAL TRIAL REGISTRATION: JCOG0601 was registered in the UMIN Clinical Trials Registry (UMIN000000929, date of registration; December 04, 2007) and the Japan Registry of Clinical Trials (jRCTs031180139, date of registration; February 20, 2019).