To clarify the cellular origin of extranodal marginal-zone B-cell lymphoma (EZML) of the mucosa-associated lymphoid tissue (MALT) type in ocular adnexa, the somatic mutation was analyzed in the ...immunoglobulin heavy-chain variable region (VH) gene.
Eight cases of EZML in the orbit and four in the conjunctiva were studied. The VH genes were amplified by a seminested PCR and sequenced directly. These were compared with the closest published VH germline segments to determine the somatic mutation frequency. Intraclonal microheterogeneity, which was termed the ongoing mutation frequency in the current study, was estimated by counting the number of single nucleotide substitutions in individual clones and dividing by the total number of nucleotides analyzed. Nine cases of gastrointestinal EMZL were also examined for comparison.
The somatic mutation frequency varied between 2.0% and 12.7%, with a mean value of 7.9%. Ten cases with intraclonal microheterogeneity showed between one and six further substitutions. The average of ongoing mutation frequency was 0.11%, with a range of 0% to 0.25%. In the gastrointestinal EMZLs, the average of somatic mutation frequency was 8.5% (1.5%-14.2%) and of ongoing mutation frequency was 0.51% (0.25%-0.75%).
The average of ongoing mutation frequency in ocular adnexal EMZL was lower than that in gastrointestinal EMZL. Both ocular adnexal and gastrointestinal EMZLs are derived from postgerminal center memory B cells, but the low ongoing mutation frequencies of ocular adnexal EMZL may result from less antigen stimulation and follicular colonization in the orbit relative to gastrointestinal EMZL.
The genotoxicity of 22 mono-functional alkylating agents (including 9 dialkyl
N-nitrosoamines) and 10 DNA crosslinkers selected from IARC (International Agency for Research on Cancer) groups 1, 2A, ...and 2B was evaluated in eight mouse organs with the alkaline single cell gel electrophoresis (SCGE) (comet) assay. Groups of four mice were treated once intraperitoneally at the dose at which micronucleus tests had been conducted, and the stomach, colon, liver, kidney, bladder, lung, brain, and bone marrow were sampled 3, 8, and/or 24 h later. All chemicals were positive in the SCGE assay in at least one organ. Of the 22 mono-functional alkylating agents, over 50% were positive in all organs except the brain and bone marrow. The two subsets of mono-functional alkylating agents differed in their bone marrow genotoxicity: only 1 of the 9 dialkyl
N-nitrosoamines was positive in bone marrow as opposed to 8 of the 13 other alkylating agents, reflecting the fact that dialkyl
N-nitrosoamines are poor micronucleus inducers in hematopoietic cells. The two groups of mono-functional alkylating agents also differ in hepatic carcinogenicity in spite of the fact that they are similar in hepatic genotoxicity. While dialkyl
N-nitrosoamines produce tumors primarily in mouse liver, only one (styrene-7,8-oxide) out of 10 of the other type of mono-functional alkylating agents is a mouse hepatic carcinogen. Taking into consideration our previous results showing high concordance between hepatic genotoxicity and carcinogenicity for aromatic amines and azo compounds, a possible explanation for the discrepancy might be that chemicals that require metabolic activation show high concordance between genotoxicity and carcinogenicity in the liver. A high percent of the 10 DNA crosslinkers were positive in the SCGE assay in the gastrointestinal mucosa, but less than 50% were positive in the liver and lung. In this study, we allowed 10 min alkali-unwinding to obtain low and stable control values. Considering that DNA crosslinking lesions can be detected as lowering of not only positive but also negative control values, low control values by short alkali-treatment might make it difficult to detect DNA crosslinking lesions. In conclusion, although both mono-functional alkylating agents and DNA crosslinkers are genotoxic in mouse multiple organs, the genotoxicity of DNA crosslinkers can be detected in the gastrointestinal organs even though they were given intraperitoneally followed by the short alkali-treatment.
A design concept of few-mode multicore fiber is presented. Cores with a step-index profile are designed to support two LP modes over the C band and the L band with a large effective area larger than ...110 μm 2 . The pitch of cores is determined regarding the inter-core crosstalk related to the LP 11 mode. The two LP modes multicore fibers with four cores and seven cores show a relative core multiplicity factor (RMCF) of 7.3 and 9.2, respectively. The RCMF of the proposed two LP modes multicore fiber is larger than that of previously reported single-mode multicore fibers.
We examined the role of regulatory myosin light chain (MLC) phosphorylation of myosin II in cell migration of fibroblasts. Myosin light chain kinase (MLCK) inhibition blocked MLC phosphorylation at ...the cell periphery, but not in the center. MLCK-inhibited cells did not assemble zyxin-containing adhesions at the periphery, but maintained focal adhesions in the center. They generated membrane protrusions all around the cell, turned more frequently, and migrated less effectively. In contrast, Rho-associated kinase (ROCK) inhibition blocked MLC phosphorylation in the center, but not at the periphery. ROCK-inhibited cells assembled zyxin-containing adhesions at the periphery, but not focal adhesions in the center. They moved faster and more straight. On the other hand, inhibition of myosin phosphatase increased MLC phosphorylation and blocked peripheral membrane ruffling, as well as turnover of focal adhesions and cell migration. Our results suggest that myosin II activated by MLCK at the cell periphery controls membrane ruffling, and that the spatial regulation of MLC phosphorylation plays critical roles in controlling cell migration of fibroblasts.
Background and Objectives To date there has been no published report on a systematic evaluation of the heat sensitivity of human parvovirus B19 (B19) and the related safety of the plasma‐derived ...fractionated products. In this study, we examined the heat sensitivity of B19 by using the infectivity assay with cultured cells.
Materials and Methods The heat sensitivity of B19 was examined by measuring the reduction in viral infectivity titres after heating liquid containing B19 at 60 °C. Viral infectivity was assayed by detection of viral antigens or viral mRNA in infected cells. As a control, canine parvovirus (CPV) was also heat‐treated.
Results B19 displayed quite different inactivation kinetics to CPV when both were heated in liquid at 60 °C. In sharp contrast to the latter, B19 was rapidly inactivated within 1 h when the virus was suspended in 5% or 25% human serum albumin solution, phosphate‐buffered saline, or complete medium. However, B19 appeared to be resistant to heat inactivation in liquid containing 60% sucrose.
Conclusions The heat sensitivity of B19 in liquid was clearly different from that of CPV. Significantly, the efficiency to inactivate B19 and reduce its infectivity following heating in liquid was mainly affected by the composition of the solutions used for virus suspension.
Previously we reported that TGF-β1-induced growth suppression was associated with a decrease in mutant p53 levels in B-cell lymphoma cells. The goal of the present study was to understand the ...mechanism involved in TGF-β1-mediated down-regulation of mutant p53. In RL and CA46, two B-cell lymphoma cell lines, TGF-β1 treatment caused down-regulation of E2F-1 transcription factor resulting in the down-regulation of both p14(ARF) and mutant p53, leading to growth arrest. Experimental overexpression of E2F-1 increased p14(ARF) level and blocked TGF-β1-induced down-regulation of p14(ARF). Overexpression of p14(ARF) blocked the down-regulation of mutant p53 and prevented growth arrest. p14(ARF) also attenuated TGF-β1-induced p21(Cip1/WAF1) induction, which was reversible by p53 siRNA, indicating the involvement of mutant p53 in controlling the TGF-β1-induced expression of p21(Cip1/WAF1). The interaction observed between phospho-Smad2 and mutant p53 in the nucleus could be the mechanism responsible for blocking the growth-suppressive effects of TGF-β1. In RL cells, p14(ARF) is present in a trimer consisting of mutant p53-Mdm2-p14(ARF) and in a dimer consisting of Mdm2-p14(ARF). Because it is known that Mdm2 can degrade p53, it is possible that, in its trimeric form, p14(ARF) is able to stabilize mutant p53 by inhibiting Mdm2. In its dimeric form, p14(ARF) may be sequestering Mdm2, limiting its ability to degrade p53. Collectively, these data demonstrate a unique mechanism in which the inhibition of TGF-β1-mediated growth suppression by mutant p53 can be reversed by the down-regulation of its stabilizing protein p14(ARF). This work suggests that the high levels of p14(ARF) often found in tumor cells could be a potential therapeutic target.
The extraction of 75 elements by
N,
N,
N′,
N′-tetraoctyl-3-oxapentanediamide (TODGA) from nitric acid to
n-dodecane was investigated and discussed concerning distribution ratios (
D) of metal ions ...and their ionic radii. The extractability for elements depends strongly on their oxidation state. Monovalent and pentavalent ions were not extractable. In divalent metal extraction, Ca(II) (ionic radius: 100
pm) showed the highest
D-value and the
D decreased with increase or decrease of the ionic radius. Trivalent and tetravalent ions with ionic radii of 87–113 and 83–94
pm, respectively, showed the
D over 1000, and the extracted chemical forms were determined to be M(TODGA)
3(NO
3)
n
or M(TODGA)
4(NO
3)
n
(
n
=
3 or 4). The oxonium ions with higher oxidation states than tetravalent one forms the complicated metal-complex with TODGA, and the number of TODGA associated in those extraction reactions was confirmed to be two at most.
Background: The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of oral fludarabine phosphate in relapsed patients with indolent B-cell ...non-Hodgkin's lymphoma (B-NHL).
Patients and methods: Patients received fludarabine phosphate orally for 5 days, for a total of one to three cycles. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria. Efficacy was assessed using the International Workshop Criteria for NHL. Pharmacokinetic samples were taken on day 1 and day 5 of the first treatment cycle.
Results: Twelve patients were enrolled. One patient at 40 mg/m2/day developed grade 4 hyperuricemia. At 50 mg/m2/day, one patient developed grade 3 febrile neutropenia and grade 4 leukopenia, and another patient showed lasting grade 4 neutropenia. Most common toxicities included grade 3 or 4 lymphopenia (83%), leukopenia (50%) and neutropenia (50%). All the toxicities were reversible. The overall response rate was 67%. The AUC0–24h values on day 5 indicated a dose-dependent increase in systemically available 2-fluoro-arabinofuranosyl-adenine (2F-ara-A).
Conclusions: Oral fludarabine phosphate is safe and effective for relapsed patients with indolent B-NHL. The dose of 40 mg/m2/day is recommended for a following pivotal phase II study.
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