Linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-kB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), and expression of HOIP which parallels LUBAC activity is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-kB activation, and the analysis of human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-kB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-kB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicates that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage-induced cell death, and is a suitable therapeutic target for B-cell lymphomas.

Patient selection criteria of deceased donor liver transplantation for primary biliary cirrhosis (PBC) are almost completely established. The aim of this study was to establish selection criteria for both patients and donors of living donor liver transplantation (LDLT) for PBC. We used univariate and multivariate analyses to examine patient and donor characteristics of our first 50 cases of LDLT for PBC to elucidate factors that significantly impacted patient survival or disease recurrence after LDLT in the univariate and/or multivariate analyses. Multivariate analysis demonstrated that the presence of persistent ascites before LDLT, a higher number of human leukocyte antigen (HLA)-A, -B, and -DR mismatches between donor and recipient, and donor age Ն50 years were factors significantly associated with early posttransplant death. Independent risk factors for PBC recurrence after LDLT were a lower number of HLA mismatches between donor and recipient, and a lower average trough level of tacrolimus within 1 year after LDLT. Specifically, the lower the number of HLA-A, -B, and -DR mismatches or the average trough level of tacrolimus within 1 year after LDLT, the higher the possibility of developing a recurrence of PBC. In conclusion, the absence of persistent ascites before LDLT, a lower number of HLA-A, -B, and -DR mismatches between donor and recipient, and a younger donor (Ͻ50 years) are preferred for gaining acceptable survival outcomes for the transplant. However, a lower number of HLA-A, -B, and -DR mismatches between donor and recipient may be a risk factor for PBC recurrence. Liver Transpl 13: 80-90, 2007.

Hemorrhagic cystitis (HC) is a major complication after allogeneic stem cell transplantation (allo-SCT) and can be life threatening. To analyze risk factors and prognosis, we retrospectively reviewed 249 cases receiving allo-SCT in our institution. Median age was 47 years (13-72 years). Disease status at SCT was progressive in 73 cases. Conditioning was myeloablative (MAC) in 146 cases. Acute graft-versus-host disease (aGVHD) grade II-IV treated with prednisolone occurred in 82 cases, and cytomegalovirus (CMV) was reactivated in 91 cases. HC was reported in 47 cases at a median of 35 days (7-469 days) after SCT, and 34 (72.3%) cases recovered after a median of 19.5 days (2-252 days). In univariate analysis, the identified risk factors for HC included age over 45 years, progressive disease status, MAC, aGVHD treated with prednisolone, and CMV reactivation. In multivariate analysis, older age, MAC, and CMV remained independent predictors (hazard ratios: 2.35, 3.50, and 2.87). In patients with severe HC, percentage recovery was lower (3 in 13 cases; 23.1%) and the median duration was longer (54 days) than in those with moderate HC (31 in 36 cases; 86.1%, 17 days, P < 0.01). Treatment-related mortality was also higher (59.1%, P = 0.03) and overall survival was poorer (16.7%, P < 0.01) at 1 year after SCT. Prospective studies should be started considering prophylactic antiviral administration in high-risk patients such as those identified in this study.

The efficacy of rabbit antithymocyte globulin (ATG) for the prevention of graft-versus-host disease (GVHD) has been evaluated in several randomized control trials, but the results show some discrepancies. Therefore, we performed a systematic review and meta-analysis covering the latest RCTs including six trials (total 845 patients). The incidence of acute and chronic GVHD was significantly lower in the ATG arms (risk ratio, 0.75 and 0.54, respectively). No significant differences were found regarding overall survival, the incidence of relapse, and non-relapse mortality; however, the incidence of cytomegalovirus and Epstein-Barr virus reactivation increased (risk ratio, 1.25 and 1.33), and neutrophil engraftment was significantly delayed (median, 2.66 days). In conclusion, rabbit ATG should be beneficial as a GVHD prophylaxis in addition to conventional regimens, with close monitoring of virus reactivation and enough attention to delayed engraftment. Studies comparing the timing and dosage of ATG are essential to determine the suitable prophylactic regimens.