Objective: To assess the immunosuppressive effect of R-CHOP in patients with B-cell lymphoma at 2 years. Methods: Parameters of humoral and cell-mediated immunity were assessed in 89 patients with diffuse large B-cell lymphoma or follicular lymphoma before and after 6-8 cycles of R-CHOP-14 or R-CHOP-21 regimen. Results: Data on pre- and posttreatment serum IgG (sIgG) levels were available for all 89 patients, while the corresponding data on serum CD20+, CD3+, CD4+, and CD8+ lymphocyte counts were available in only 43. Median sIgG levels significantly decreased from 1,221 mg/dl (baseline) to 733 mg/dl (after chemotherapy) (p < 0.001). Although CD20+ and CD4+ cell counts decreased (p < 0.001), no significant effect of chemotherapy on CD3+ and CD8+ cell counts was observed. CD20+ cell counts were restored to baseline levels at the 12-month follow-up. sIgG levels and CD4+ cell counts were not completely restored at 24 months, indicating a sustained immunosuppressive effect of R-CHOP in these patients. The incidence of infections over the 2-year period was 16.3-23.6%. Conclusion: The immunosuppressive effect of R-CHOP in newly diagnosed cases of B-cell lymphoma tends to persist for >2 years, although sIgG levels were restored more quickly than CD4+ cell counts.

Bendamustine is an agent that contains a nitrogen mustard group and a purine-like benzimidazole ring, thus combining alkylating and antimetabolic properties. It is highly active against relapsed or refractory low-grade B-cell lymphoma and m ande cell lymphoma, especially when used in combi nation with rituximab (hereafter referred to as RB therapy) [1,2]. Although bendamustine has a favorable safety pro file, myelosuppression including lymphocytopenia occurs relatively frequendy [1][2][3][4][5], which may cause severe and prolonged immunodeficiency. Given the adverse effect of rituximab on immune function [6], it is a major concern that the combined use of rituximab and bendamustine may enhance immunosuppression. However, to date little is known about whether and to what extent RB therapy affects the immune system. With the aim of providing insights into this issue, we conducted a retrospective analysis of serial blood lymphocyte subset counts and serum immuno globulin (Ig) levels in patients with relapsed or refractory low-grade B-cell lymphoma or mantle cell lymphoma who received RB therapy at our hospital. The study was approved by the Institutional Review Board of the Fujita Health Uni versity School of Medicine.Between January 2011 and January 2013, RB therapy was administered to 21 patients with relapsed or refractory lowgrade B-celi lymphoma or mantle cell lymphoma. Of these 21 patients, 13 with serial measurement of blood lymphocyte subset counts and serum Ig levels were included in the study. The characteristics of the 13 patients are summarized in Table I and Supplementary Table I available online at http:// inform ahealthcare.com/doi/abs/10.3109/10428194.2014. 921298. RB therapy consisted of intravenous infusion of rituximab at a dose of 375 m g/m 2 on day 1, followed by intravenous infusion of bendamustine at a dose of 60, 90 or 120 m g/m 2 on days 2 and 3 for the first cycle and on days 1 and 2 for the second and subsequent cycles. RB therapy was repeated at intervals of 3-4 weeks for a total of 3-8 cycles.During RB therapy, all patients received sulfamethoxazole (400 mg/day)-trimethoprim (80 mg/day) and acyclovir (200 mg/day) prophylactically. To assess immune function, blood counts of lymphocyte subsets (CD4-positive [CD4+], CD8+, and CD20 + cells) were measured using a Cytomics FC500 (Beckman Coulter, Inc., CA), and serum IgG, IgA and IgM levels using a JCA-BM6010 (JEOL Ltd., Tokyo, Japan). Data were obtained before and after RB therapy, and at approximately 3, 6, 9 and 12 months after completion of treatment. For the follow-up samples, only those collected within 1 month of each defined time point were used in the analyses. Descriptive statistics were reported as median and range for continuous variables, and as frequencies and pro portions for categorical variables. The Wilcoxon signed-rank test was used to assess the changes in lymphocyte subset counts and serum Ig levels before and after RB therapy. Figure 1(A) shows the kinetics of the CD4 + cell counts for each individual patient. The median...

Cu, Zn-superoxide dismutase (SOD1), an enzyme implicated in the progression of familial amyotrophic lateral sclerosis (fALS), forms amyloid fibrils under certain experimental conditions. As part of our efforts to understand ALS pathogenesis, in this study we found that reduction of the intramolecular disulfide bond destabilized the tertiary structure of metal free wildtype SOD1 and greatly enhanced fibril formation in vitro. We also identified fibril core peptides that are resistant to protease digestion by using mass spectroscopy and Edman degradation analyses. Three regions dispersed throughout the sequence were detected as fibril core sequences of SOD1. Interestingly, by using three synthetic peptides that correspond to these identified regions, we determined that each region was capable of fibril formation, either alone or in a mixture containing multiple peptides. It was also revealed that by reducing the disulfide bond and causing a decrease in the structural stability, the amyloid fibril formation of a familial mutant SOD1 G93A was accelerated even under physiological conditions. These results demonstrate that by destabilizing the structure of SOD1 by removing metal ions and breaking the intramolecular disulfide bridge, multiple fibril-forming core regions are exposed, which then interact with each another and form amyloid fibrils under physiological conditions.

Patients with myelodysplastic syndrome (MDS) often require blood transfusion and anticancer therapy; however, elderly patients are intolerant to the associated side effects of anticancer therapy. Because L-leucine can be used to treat Diamond-Blackfan anemia, which is caused by defects in ribosomal protein (RP) genes, resulting in increased in vivo hemoglobin synthesis, it is possible that some MDS patients who have aberrations in their RP genes could also be effectively treated with L-leucine. In the present study, we investigated the effects of L-leucine on hematopoietic function (reticulocyte count), red blood cell count, and hemoglobin level in MDS patients. We administered L-leucine (1.8 g, twice daily, 3 d/week) with oral vitamin B6 supplements to a final cohort of eight MDS patients for 15 (interquartile range: 11-18) weeks. We assessed the patients at 10 2 weeks after therapy initiation. Only the absolute reticulocyte count was affected, improving in 6/8 (75%) patients. The median absolute reticulocyte count was 3.5 10 4 (range: 2.7-6.4 10 4) cells/µL, an increase of 0.5 10 4 (range: 0.2-0.7 10 4) cells/µL. At 10 weeks, there was only one case of an improved hemoglobin level. Non-hematological adverse events of grade 3 were observed one raised triglycerides. These data suggest that L-leucine has little effect on MDS. However, it may contribute to the recovery of hematopoietic function, futher study be desired.