Purpose: Rituximab is commonly incorporated into CD20-positive B-cell lymphoma therapy to improve response and prognosis. With increasing use, resistance to rituximab is a continuing concern, but CD20 mutation as a cause of resistance has not previously been reported. Experimental Design: Freshly collected lymphoma cells from 50 patients with previously untreated or relapsed/resistant non-Hodgkin's B-cell lymphomas (diffuse large B cell, n = 22; follicular, n = 7; mucosa associated lymphoid tissue, n = 16; chronic lymphocytic leukemia, n = 2; small lymphocytic lymphoma, n = 1; lymphoplasmacytic, n = 1; mantle cell lymphoma, n = 1) were assessed for CD20 expression by flow cytometry, and CD20 gene sequencing was done on extracted DNA. Results: CD20 mutations were found in 11 (22.0%) of 50 patients and could be grouped as C-terminal deletion (8.0%), early termination (10.0%), and extracellular domain (2.0%) or transmembrane domain (2.0%) mutations. The mean fluorescence intensity of CD20 on fresh lymphoma cells was significantly lower for the C-terminal deletion mutation [3.26; 95% confidence interval (95% CI), 0.09-6.89] compared with wild type (30.8; 95% CI, 22.4-39.2; P < 0.05). In contrast, early termination mutations did not show significant differences in CD20 expression compared with wild type (19.5; 95% CI, 10.7-28.4; P > 0.05).Conclusions: It is possible that C-terminal deletion mutations of CD20 may be related to relapse/resistance after rituximab therapy. These mutations should be examined in patients showing progression of disease after partial remission. . 3), respectively. The rituximab target antigen is the B-cell membrane differentiation antigen CD20, and rituximab has emerged as a useful tool for adjunct cancer therapy (4). Although CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone) therapy leads to median overall survival rates of only 60%, addition of rituximab improves rates by f20% (5).With the need to determine standard first-, second-, and subsequent-line combination therapies using rituximab (6, 7), relapse/resistance to rituximab therapy is an important issue.The mechanisms of action of rituximab are inhibition of proliferation, induction of apoptosis, complement-dependent cytotoxicity, and antibody-dependent cellular cytotoxicity. A few reports indicate that loss of CD20 expression occurs in some patients with non-Hodgkin's lymphoma during rituximab therapy (8 -10), but the relationship between development of resistance to rituximab and changes in rituximab action have not yet been clarified. Heterogeneity of intensity of CD20 expression in replicate analysis of the same sample has been commonly observed by flow cytometric analysis (11). One explanation for this might be the development of resistant subsets of lymphoma cells by mutation. Recently, mutations in the epidermal growth factor receptor have been reported to have a relationship with the differing sensitivity to gefitinib therapy seen in samples from Japanese and American patients (12).Our ex...

Recent studies have shown that metabolites produced by microbes can be considered as mediators of host-microbial interactions. In this study, we examined the production of tryptophan metabolites by Bifidobacterium strains found in the gastrointestinal tracts of humans and other animals. Indole-3-lactic acid (ILA) was the only tryptophan metabolite produced in bifidobacteria culture supernatants. No others, including indole-3-propionic acid, indole-3-acetic acid, and indole-3-aldehyde, were produced. Strains of bifidobacterial species commonly isolated from the intestines of human infants, such as Bifidobacterium longum subsp. longum, Bifidobacterium longum subsp. infantis, Bifidobacterium breve, and Bifidobacterium bifidum, produced higher levels of ILA than did strains of other species. These results imply that infant-type bifidobacteria might play a specific role in host–microbial cross-talk by producing ILA in human infants.

Recently, anti-CD20 (rituximab) and anti-Her2/neu (trastuzumab) antibodies have been developed and applied to the treatment of malignant lymphoma and breast cancer, respectively. However, bulky lymphoma is known to be resistant to rituximab therapy, and this needs to be overcome. Fresh lymphoma cells were collected from 30 patients with non-Hodgkin's lymphoma, the expression of CD20 and CD55 was examined by flow cytometry, and complement-dependent cytotoxicity (CDC) assays were carried out. Susceptibility to CDC with rituximab was decreased in a tumor size-dependent manner (r = -0.895, P < 0.0001), but not in a CD20-dependent manner (r = -0.076, P = 0.6807) using clinical samples. One complement-inhibitory protein, CD55, contributed to bulky lymphoma-related resistance to CDC with rituximab. A decrease in susceptibility to CDC with rituximab was statistically dependent on CD55 expression (r = -0.927, P < 0.0001) and the relationship between tumor size and CD55 expression showed a significant positive correlation (r = 0.921, P < 0.0001) using clinical samples. To overcome the resistance to rituximab by high expression of CD55 in bulky lymphoma masses, small interfering RNA (siRNA) was designed from the DNA sequence corresponding to nucleic acids 1-380 of the CD55 cDNA.

Therapeutic radiation causes bone damage and may increase fracture risks in treatment for head-and-neck cancer and in pelvic irradiation. These properties can also be used for prevention of heterotopic ossification in hip arthroplasty. To evaluate the effects of ionizing radiation on osteoblast differentiation, C2C12 cells were directed into an osteogenic lineage by treatment with a combination of bone morphogenic protein 2 (BMP-2) (100 ng/ml) and heparin (30 mug/ml) 6 h after irradiation (2 and 4 Gy). Osteoblast differentiation was evaluated based on alkali phosphatase (ALP) activity and expression of mRNA encoding ALP and collagen type I. Ionizing radiation suppressed the growth of C2C12 cells and decreased expression of ALP and collagen type I mRNAs with concomitant reduction of the ALP activity. Although further studies are needed to elucidate the molecular mechanism, our findings suggest that ionizing radiation at therapeutic doses interferes with bone formation by reducing ALP activity and expression of mRNA encoding ALP and collagen type I.

Subcutaneous transplantation of macroencapsulated porcine PEC normalized hyperglycemia in diabetic mice. Our results identified a potential for a favorable development of subcutaneous transplantation of porcine PEC as a cure for diabetes.

No abstract

No abstract

No abstract