Statin-independent prognosis of patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy.

BACKGROUND: A recent laboratory study indicated that statins impaired the antitumor effects of rituximab by inducing conformational changes in CD20. Although these findings raised significant concerns about statin use during rituximab treatment, their clinical significance is unclear. PATIENTS AND METHODS: We conducted a retrospective study investigating the effects of statins on the prognosis of diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). Newly diagnosed DLBCL patients were analyzed (n = 256), including 35 patients taking statins. RESULTS: The 3-year progression-free survival rates were 84% and 73% (P = 0.38), while the overall survival rates were 89% and 78% (P = 0.28) for those patients treated with and without statins, respectively. After adjusting for the International Prognostic Index and serum cholesterol level, statin use was not associated with prognosis. CONCLUSIONS: These results indicate that statins do not influence the clinical prognosis of DLBCL treated with RCHOP. Further studies with larger numbers of patients are warranted to confirm the prognostic significance of statins for patients with DLBCL receiving rituximab-containing chemotherapy.

Bone metastasis and poor performance status are prognostic factors for survival of carcinoma of unknown primary site in patients treated with systematic chemotherapy.

BACKGROUND: Cancer of unknown primary site (CUP) generally has a poor prognosis, and there is no established standard therapy. There have been no reports of a prognostic model for CUP patients treated with a single regimen of systemic chemotherapy. METHODS: Univariate and multivariate prognostic factor analysis for overall survival (OS) were conducted retrospectively in 58 consecutive CUP patients treated with carboplatin plus paclitaxel (Taxol) therapy as a first-line treatment. RESULTS: Univariate prognostic factor analysis revealed baseline performance status (PS) of two or more, low serum albumin level, pleural effusion, bone metastasis, and liver metastasis as adverse prognostic factors. Cox proportional hazards analysis showed that poor PS and bone metastasis had the most powerful adverse impact on survival. We developed a prognostic model using those two variables-a good-risk group (PS 0-1 without bone metastasis) and a poor-risk group (PS > or =2 or bone metastasis). The poor-risk group showed significantly poorer OS than the good-risk group (1 year OS 36.8% versus 67.1%, P = 0.0003). CONCLUSIONS: Poor PS and bone metastasis were identified as independent adverse prognostic factors in CUP. A simple prognostic model was developed and seems useful for decision making as to whether chemotherapy is indicated for CUP patients.

On the origin of visibility contrast in x-ray Talbot interferometry.

The reduction in visibility in x-ray grating interferometry based on the Talbot effect is formulated by the autocorrelation function of spatial fluctuations of a wavefront due to unresolved micron-size structures in samples. The experimental results for microspheres and melamine sponge were successfully explained by this formula with three parameters characterizing the wavefront fluctuations: variance, correlation length, and the Hurst exponent. The ultra-small-angle x-ray scattering of these samples was measured, and the scattering profiles were consistent with the formulation. Furthermore, we discuss the relation between the three parameters and the features of the micron-sized structures. The visibility-reduction contrast observed by x-ray grating interferometry can thus be understood in relation to the structural parameters of the microstructures.

Soluble interleukin-2 receptor retains prognostic value in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP (RCHOP) therapy.

BACKGROUND: Soluble interleukin-2 receptor (SIL-2R) is known to be a prognostic parameter in patients with diffuse large B-cell lymphoma (DLBCL) receiving cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy. However, its prognostic value has not been well known since the introduction of rituximab. PATIENTS AND METHODS: We retrospectively evaluated the prognostic impact of SIL-2R in 228 DLBCL patients, comparing 141 rituximab-combined CHOP (RCHOP)-treated patients with 87 CHOP-treated patients as a historical control. RESULTS: Patients with high serum SIL-2R showed significantly poorer event-free survival (EFS) and overall survival (OS) than patients with low SIL-2R in both the RCHOP group (2-year EFS, 66% versus 92%, P<0.001; OS, 82% versus 95%, P=0.005) and the CHOP group (2-year EFS, 40% versus 82%; OS, 61% versus 90%, both P<0.001). Multivariate analysis including the five parameters of International Prognostic Index (IPI) and two-categorized IPI revealed that SIL-2R was an independent prognostic factor for EFS and OS in the RCHOP group as well as in the CHOP group. CONCLUSIONS: Our results demonstrate that SIL-2R retains its prognostic value in the rituximab era. The prognostic value of SIL-2R in DLBCL patients receiving rituximab-combined chemotherapy should be reassessed on a larger scale and by long-term follow-up.

CD5 expression is potentially predictive of poor outcome among biomarkers in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy.

BACKGROUND: Several biomarkers indicating poor prognosis have been reassessed in patients receiving rituximab combination chemotherapy for diffuse large B-cell lymphoma (DLBCL). However, few studies have investigated outcome in relation to a combination of these biomarkers. In addition, no large-scale studies have reassessed the outcome of patients with CD5-positive DLBCL treated with rituximab. PATIENTS AND METHODS: We conducted a retrospective study and investigated the predictive value of three biomarkers -- BCL2, germinal center (GC) phenotype and CD5 -- in 121 DLBCL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone. RESULTS: CD5-positive patients showed significantly poorer event-free survival (EFS) and overall survival (OS) than CD5-negative patients (2-year EFS, 18% versus 73%, P < 0.001; 2-year OS, 45% versus 91%, P = 0.001). However, no significant difference in outcome according to BCL2 or GC phenotype was observed. Multivariate analysis revealed that CD5 expression was a significant prognostic factor for EFS [hazard ratio 14.2, 95% confidence interval (CI) 4.7-43.2] and OS (hazard ratio 20.3, 95% CI 3.6-114.4). CONCLUSIONS: CD5 expression was the only significant prognostic factor among the biomarkers examined in this study. Further studies with larger numbers are warranted to confirm the prognostic significance of CD5 expression for patients with DLBCL receiving rituximab-containing chemotherapy.

Low absolute peripheral blood CD4+ T-cell count predicts poor prognosis in R-CHOP-treated patients with diffuse large B-cell lymphoma.

The absolute peripheral blood lymphocyte count at diagnosis is known to be a strong prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but it remains unclear as to which peripheral blood lymphocyte population is reflective of DLBCL prognosis. In this cohort, 355 patients with DLBCL treated with R-CHOP from 2006 to 2013 were analyzed. The low absolute CD4+ T-cell count (ACD4C) at diagnosis negatively correlated with the overall response rate and the complete response rate significantly (P<0.00001). An ACD4C<343 × 106/l had a significant negative impact on the 5-year progression-free survival and the overall survival as compared with an ACD4C⩾343 × 106/l (73.7% (95% confidence interval (CI)=66.7-79.5) versus 50.3% (95% CI=39.0-60.6), P<0.00001 and 83.3% (95% CI=77.1-88.0) versus 59.0% (95% CI=47.9-68.5), P<0.00000001, respectively). Multivariate analysis revealed that the ACD4C was an independent prognostic marker (hazard ratio=2.2 (95% CI=1.3-3.7), P<0.01). In conclusion, a low ACD4C at diagnosis served as an independent poor prognostic marker in patients with DLBCL.

NH2-terminal pentapeptide of endothelial interleukin 8 is responsible for the induction of apoptosis in leukemic cells and has an antitumor effect in vivo.

We have reported that endothelial interleukin 8 (IL-8) induces apoptosis in leukemic cells in vitro and in vivo, and that interaction between endothelial cells and leukemic cells causes induction of apoptosis through the release of endothelial IL-8 (Y. Terui et al., Biochem. Biophys. Res. Commun., 243: 407-411, 1998; Y. Terui et al., Blood, 92: 2672-2680, 1998). Here, we examined whether a pentapeptide corresponding to the NH2-terminal region of endothelial IL-8 can induce apoptosis in leukemic cells. The NH2-terminal pentapeptide Ala-Val-Leu-Pro-Arg (AVLPR) was found to significantly induce apoptosis in the leukemic cell lines K562, HL-60, Jurkat, and Daudi, as compared with the COOH-terminal pentapeptide Arg-Glu-Ala-Asn-Ser (REANS). Moreover, the NH2-terminal pentapeptide AVLPR significantly inhibited growth of i.p. and s.c. tumor masses of K562 cells and induced apoptosis in these cells in vivo. The active site of endothelial IL-8 is the NH2-terminal pentapeptide AVLPR, and this may serve as a new therapy for hematological malignancies.

Antitumor effect of beta2-microglobulin in leukemic cell-bearing mice via apoptosis-inducing activity: activation of caspase-3 and nuclear factor-kappaB.

We have reported previously that beta2-microglobulin (beta2m) induces apoptosis in leukemic cells in vitro, and that an interaction between beta2m and HLA class I antigen induces apoptosis. Here we examined whether beta2m can induce apoptosis in leukemic cells in vivo and whether it has an antitumor effect in tumor-bearing mice. Daily administration of 50 or 250 microg of beta2m induced apoptosis and an antitumor effect on K562 leukemia cell-bearing mice in the same manner as tumor necrosis factor-alpha. In tumor tissues in beta2m-treated mice, both caspase-3 and nuclear factor-kappaB (NF-kappaB) were stained more strongly than in control mice by anti-caspase-3 and anti-NF-kappaB p65/Rel A polyclonal antibodies. We also observed the in vivo immunological effects of beta2m on lymphoid and hematopoietic organs, such as thymus, bone marrow, Peyer's patches, liver, and spleen in normal mice. Using antibodies against caspase-3 and NF-kappaB, immunohistochemical staining showed that no specific tissues were damaged or stained in normal mice. We conclude that beta2m stimulates caspase-3 and NF-kappaB pathways to induce apoptosis, making it a useful approach to a new therapy for leukemia.

A novel variant of translation elongation factor-1beta: isolation and characterization of the rice gene encoding EF-1beta2.

A rice gene encoding a novel isoform of translation elongation factor-1beta subunit (termed EF-1beta2) was isolated and characterized. The gene comprises of eight exons, and encodes a 226-amino-acid protein. Expression of EF-1beta2 mRNA is abundant in seeds and cultured cells, but is considerably low in the tissues of the rice seedling. Antiserum raised against an EF-1beta2 synthetic peptide detected a protein with a relative molecular mass of about 32 kDa, indicating the EF-1beta2 gene is actually expressed in rice tissues. EF-1beta2 showed a close similarity to the cognate subunits from plant (beta and beta').

Bcl-x is a regulatory factor of apoptosis and differentiation in megakaryocytic lineage cells.

Differentiation- and lineage-related differences in the expression of two anti-apoptotic molecules, bcl-x and bcl-2, were examined using various human hematopoietic cell lines. Bcl-x was strongly expressed in cell lines with erythroid and megakaryocytic properties (K562, HEL, CMK, and Mo7E), and was moderately expressed in immature myeloid cell lines (KG-1 and KCL-22). Bcl-2 expression was relatively weak in these cells. On the other hand, bcl-x was not expressed in more mature myeloid cell lines (HL-60 and PL-21), but bcl-2 was strongly expressed in these cells and in monocytoid cell lines (U937, THP-1, and JOSK-I). We investigated the biological significance of high levels of bcl-x expression in erythroid and megakaryocytic lineage cells. When K562 cells were specifically differentiated into megakaryocytic lineage by phorbol ester, the amounts of bcl-x increased by 10-fold. In contrast, bcl-x was gradually downregulated during erythroid differentiation induced by cytosine arabinoside. Apoptosis was observed following erythroid differentiation of K562 cells, but it was not associated with megakaryocytic differentiation in consistent with the increase in bcl-x. Moreover, phorbol ester-induced megakaryocytic differentiation was facilitated by the overexpression of bcl-x in K562 cells. Finally, in situ hybridization revealed that bcl-x mRNA expression was strongest in megakaryocytes among normal bone marrow cells. These results suggest that bcl-x is a regulatory factor in the apoptosis and differentiation of megakaryocytes.

Cloning and characterization of the cDNA encoding rice elongation factor 1 beta.

We have cloned and sequenced a cDNA coding for rice elongation factor 1 beta (EF-1 beta). The clone was 1420 bp long and contained an open reading frame coding for 229 amino acids. The overall identity between rice EF-1 beta and rice EF-1 beta' [Matsumoto, S., Oizumi, N., Taira, H. and Ejiri, S. (1992) FEBS Lett. 311, 46-48] is 60% at the amino acid sequence level; a higher percent identical residues (81%) were especially observed in the C-terminal region. Rice EF-1 beta has no conserved phosphorylation site for casein kinase II and no leucine zipper motif, although these motifs are well conserved in EF-1 delta (= beta in plants) subunits of animal EF-1.

Synthesis and 3'-substituent effects of some 7 alpha-methoxy-1-oxacephems on antibacterial activity and alkaline hydrolysis rates.

Relationships between intrinsic antibacterial activity and beta-lactam chemical reactivity of 7 beta-(phenylacetamido)-7 alpha-methoxy-1-oxacephems with various 3'-substituents were studied in order to clarify the effect of the 3'-substituent on the antibacterial activity. The chemical reactivity of the beta-lactam ring estimated by pseudo-first-order rate constants log kobsdNMR of alkaline hydrolysis at pD 10.4 and 35.0 degrees C correlates well linearly with 13C NMR chemical shift differences (delta delta(4-3], infrared stretching frequencies of the beta-lactam carbonyl (vC = O), and sigma I values. Values of log (1/CN), averaged for the MIC values for Escherichia coli, E. coli NIH JC-2, E. coli EC-14, and Klebsiella pneumoniae SRC-1, were taken as an estimation of the intrinsic antibacterial activity. The log (1/CN) values of the compounds without good leaving groups correlated fairly well with log kobsdNMR values. The comparatively high antibacterial activity of compounds with good leaving groups may be attributable to the different course of decomposition of these compounds.

1H NMR study of degradation mechanisms of oxacephem derivatives with various 3'-substituents in alkaline solution.

The degradation process of oxacephems with various 3'-substituents in alkaline solution was examined by 1H NMR spectroscopy, and the structures of two types of degradation products were determined: the hydrolysis products having the cleaved beta-lactam ring and the remaining 3'-substituents, and the exo-methylene compounds having the cleaved beta-lactam ring and the expelled 3'-substituents. The oxacephems were found to decompose, giving the former compounds that subsequently decomposed to the latter compound. Although the ratios of the formation of the exo-methylene compound 15 relative to the other degradation products depended on the leavability of the 3'-substituents, there was little correlation between the relative yields and the beta-lactam reactivity. Thus, the expulsion of the leaving group at the 3'-position was concluded to be not involved in the nucleophilic attack on the beta-lactam carbonyl.

Expression of differentiation-related phenotypes and apoptosis are independently regulated during myeloid cell differentiation.

When human promyelocytic leukemia cell line HL-60 was treated with various differentiation-inducers, apoptosis always occurred after the full appearance of differentiation-related phenotypes. However, the two phenomena could be dissociated when HL-60 cells were treated with PDBu. When HL-60 cells were cultured with PDBu for more than 36 h, apoptosis was induced following differentiation. Apoptosis was not, however, observed when PDBu was removed within 24 h, even though induction of differentiation-related phenotypes, such as NBT-reducing ability and surface marker expression, was the same as that in the control. Northern blot analysis revealed that bcl-2 mRNA was rapidly down-regulated within 6 h of the treatment with PDBu. The amount of bcl-2 mRNA recovered to that of undifferentiated HL-60 cells when PDBu was washed out within 24 h. In contrast, the recovery of bcl-2 was incomplete when the cells were treated with PDBu for more than 36 h, suggesting that bcl-2 is also a critical regulator of the cell fate during myeloid differentiation. This hypothesis was confirmed by experiments using antisense oligonucleotides, i.e., blocking the recovery of bcl-2 mRNA by antisense oligonucleotides could result in the induction of apoptosis in HL-60 cells from which PDBu was removed within 24 h. Moreover, overexpression of BCL-2 in HL-60 cells could block apoptosis during differentiation without any significant effect on differentiation itself. These results strongly suggest that apoptosis is not a simple consequence of differentiation-induction, and that apoptosis and differentiation are regulated independently in myeloid cells.

CAM-cytarabine, aclarubicin plus macrophage colony-stimulating factor in the treatment of acute myelogenous leukemia with trilineage dysplasia: usefulness of in vitro apoptosis in leukemic cells.

A 67-year-old woman was treated for acute myelogenous leukemia with trilineage dysplasia (AML-TLD) by combination chemotherapy with cytarabine, aclarubicin plus macrophage colony-stimulating factor (M-CSF) (referred to as CAM therapy). Complete remission was achieved after two courses of CAM therapy. After coculture of her bone marrow mononuclear cells with M-CSF in vitro, differentiation of leukemic cells into macrophages with apoptotis was observed. This case confirms an earlier report that an effect of M-CSF inducible by differentiation with apoptotic phenomena, against human leukemic cells was shown both in vitro and in vivo when achieving complete remission.

Apoptosis-gene expression in hematopoietic system: normal and pathological conditions (Review).

Gene expression involving apoptosis in the hematopoietic system is reviewed. In normal and hematological disorders, Fas-Fas ligand and tumor necrosis factor-alpha-receptor interaction play a major role in enhancing apoptosis. On the other hand, bcl-2 or certain novel proteins (including FADD, RIP, TRADD and sentrin) prevent apoptosis. Apoptosis is involved in myelodysplastic syndrome and pathogenesis of leukemia. Expression of Fas antigen plays a role in negative regulation of hematopoiesis in the bone marrow as does interferon-gamma.

Structures of agglomerins.

Structures of a series of new antibiotics, agglomerins A, B, C and D, which are active against a variety of anaerobic bacteria, were determined to be 1-acyl-2,3-dihydroxy-1,3-butadiene-1-carboxylic acid, (1----3)-gamma-lactones, i.e., 2-acyl-4-ylidenetetronic acids with different hydrocarbon chains in the acyl group. Their common chromophore exhibited tautomerism in solution. The relationship of their structure to the activity against anaerobes is discussed.

New aureolic acid antibiotics. II. Structure determination.

Structure determination using NMR spectroscopy of new aureolic acid analogues, demethylchromomycins A2 and A3 and demethylolivomycins A and B produced by Streptomyces aburaviensis PA-39856, is described.

The structures of katanosins A and B.

1H and 13C NMR studies on katanosin A confirmed the presence of eight usual amino acid residues which were previously deduced by amino acid analysis and suggested the presence of beta-hydroxyaspartic acid, beta-hydroxyleucine and beta-phenylserine residues. These amino acids were isolated and confirmed, including their stereochemistries, by comparison with the respective authentic specimens. Stereochemistries of the usual amino acids were determined by comparing the L-leucylated amino acids with reference compounds by HPLC. Lithium borohydride reduction and chromic acid oxidation of katanosin A and alkali-treated katanosin A elucidated a lactone linkage between the C-terminal Ser and phenylserine residues. Edman degradation on alkali-treated katanosin A clarified the total amino acid sequence. The difference in katanosins A and B was determined to be replacement of Val in A by Ile in B. Thus, the structures of katanosins A and B were elucidated.

NMR studies of chromomycins, olivomycins, and their derivatives.

Detailed studies on the 13C and 1H NMR spectra of chromomycins A2 and A3, olivomycins A and B, and their derivatives clarified the assignment of many signals which had been unassigned or erroneously reported in the literatures. The revised assignments for chromomycin A3 and olivomycin A include the assignment of a key 13C signal used to discuss the saccharide linkage in question. Structure analyses based on the revised assignments support the alpha,1----3-bond between components of the disaccharide moiety in the molecules. Some general information useful for structure analysis of saccharides is also reported.