"Infectious tolerance" develops after the spontaneous acceptance of Lewis-to-Dark Agouti rat liver transplants

BACKGROUND: After monoclonal antibody or donor-specific transfusion treatment, infectious tolerance to rat or mouse heart or skin transplants can be passed on to naive recipients by adoptive transfer of tolerant lymphocytes. We examined whether similar regulatory cells develop after the spontaneous acceptance of Lewis-to-Dark Agouti (DA) rat liver transplants without immunomodulating agents. METHODS: After Lewis-to-DA rat liver transplantation, 100 x 10(6) splenocytes were harvested and adoptively transferred into a 450 rad-irradiated naive DA rat 24 hours before Lewis heart transplantation. Adoptive transfer of CD4+ or CD8+ T cells was also examined. In some experiments, splenocytes from recipients with long-term accepted Lewis hearts induced by adoptive transfer were serially transferred to multiple generations of recipients before Lewis rat heart transplantation. In vitro mixed lymphocyte culture response and cytotoxic T lymphocyte generation were measured. RESULTS: When splenocytes from a DA rat recipient >60 days after Lewis rat liver acceptance were transferred into irradiated DA rat recipients, all Lewis rat hearts were accepted, whereas third-party Brown-Norway rat hearts were rejected. However, splenocytes from DA rat recipients 30 days after liver transplantation did not prolong Lewis rat heart survival. Adoptive transfer of 40 x 10(6) CD4+, 10 x 10(6) CD4+ or 10 x 10(6) CD8+ cells from a DA rat bearing Lewis rat liver >60 days resulted in acceptance of 88%, 80%, or 57% acceptance of Lewis rat hearts, respectively. Serial second and third adoptive transfer of long-term survivor splenocytes resulted in the acceptance of all Lewis rat hearts. In mixed lymphocyte culture, splenocytes from a naive DA rat and a DA rat accepting a Lewis rat liver transplant for >60 days showed similar proliferative responses to both Lewis and Brown-Norway rat stimulators. An equivalent level of indirect cytotoxic T lymphocyte activity was exhibited by splenocytes from both a naive DA and a DA rat accepting a Lewis rat liver transplant for >60 days. CONCLUSIONS: Regulatory cells developing after the spontaneous acceptance of a Lewis to DA liver transplant can serially adoptively transfer the acceptance of a Lewis rat cardiac graft in spite of the presence of in vitro antidonor reactivity. Both CD4+ and CD8+ populations have this regulatory activity, although the CD4+ population plays the dominant role.     

Monocyte-derived microparticles may be a sign of vascular complication in patients with lung cancer

We measured and compared the levels of plasma monocyte-derived microparticles (MDMP) and platelet activation markers [plasma platelet-derived microparticles (PDMP), CD62P binding to platelets; plt-CD62P, CD63 binding to platelets; plt-CD63], to develop a better understanding of their potential contribution to vascular complications of lung cancer. The concentrations of MDMP and PDMP in lung cancer patients were significantly higher (P < 0.01) than those in normal subjects. Levels of plt-CD62P and plt-CD63 were significantly higher (P < 0.001 for each) in lung cancer patients than in controls. Levels of sE-selectin were also higher in lung cancer patients than in control subjects. MDMP correlated positively with plt-CD62P, plt-CD63, and PDMP with its relation to PDMP being particularly significant. The number of MDMPs and PDMPs are patients who are non-small cell lung cancer were significantly higher than that in small cell lung cancer patients. In addition, levels of sE-selectin were higher in non-small cell lung cancer than in small cell lung cancer patients. These findings suggest that elevated MDMPs may be a sign of vascular complication in lung cancer patients, particularly those who suffer from non-small cell lung cancer.     

Effect of nedaplatin, 5-FU,and leucovorin combined with radiation therapy in unresectable esophageal carcinoma

A 51-year-old male was assessed as having esophageal squamous cell carcinoma with trachea invasion and cervical lymph node metastasis. After one course of chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU) and Leucovorin (LV), the patient had progressive disease (PD) of the primary lesion and metastatic lymph nodes, and a side effect of severe nausea. One course of nedaplatin, 5-FU and LV combined with radiation was performed alternatively. The effect was evaluated as a partial response (PR) of the primary lesion and metastatic lymph nodes. There were no adverse side effects such as nausea or renal dysfunction except for pancytopenia of grade 2. Increased serum levels of vascular endothelial growth factor (s-VEGF) decreased after the chemoradiotherapy and increased again during continued radiotherapy alone. More information is needed as to whether changes in s-VEGF relate to the clinical effects of the treatment.     

Differential gene expression screening between parental and highly metastatic pancreatic cancer variants using a DNA microarray

To clarify the difference in genes expressed in hematogenous metastasis and peritoneal dissemination, a broad analysis of differential gene expression analysis between parental cell lines and established metastatic sublines was performed. Using an oligonucleotide array (Gene Chip, Affymetrix), approximately 2,000 genes involved in cancer were analyzed for each of the cell lines. HPC-4H4 (highly metastatic lines to the liver) compared with HPC-4 (low metastatic parental lines), in which 20 overexpressed genes and 5 underexpressed genes were recognized. HPC-4P4a (highly metastatic to the peritoneum) compared with HPC-4, in which 12 overexpressed genes and 15 underexpressed genes were also recognized. Analysis of HPC-4H4 and HPC-4P4a showed comparative up-regulation of 20 genes and down-regulation of 13 in the former, HPC-4H4. Further studies are needed to validate our hypothesis that some of the resulting differentially expressed genes might be implicated in the development of metastasis in pancreatic cancer. In conclusion, this genome-wide expression analysis will help to clarify the molecular mechanisms of cancer metastasis and of the different levels of gene expression in a variety of metastatic potentials in pancreatic cancer.     

Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancer

Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 +/- 17% (p = 0.33) and 21 +/- 11% (p = 0.060), respectively. Multivariate analysis using Cox's proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 +/- 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 +/- 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I - IIIA breast cancer for the prolongation of the recurrence-free survival period.     

A novel geranylated derivative,ethyl 3-(4'-geranyloxy-3'-methoxyphenyl)-2-propenoate,synthesized from ferulic acid suppresses carcinogenesis and inducible nitric oxide synthase in rat tongue

OBJECTIVES: We have previously observed the inhibitory effect of ferulic acid on rat tongue carcinogenesis. In this study, we investigated the modifying effects of a novel geranylated derivative, ethyl 3-(4'-geranyloxy-3'-methoxyphenyl)-2-propenoate (EGMP), synthesized from ferulic acid on tongue carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO). METHODS: F344 male rats except those treated with EGMP alone and untreated rats were given 20 ppm 4-NQO in drinking water for 9 weeks to induce tongue neoplasms. Starting 1 week after the cessation of exposure to 4-NQO, the experimental groups given 4-NQO and a basal diet were fed the experimental diets containing EGMP (0.2% and 2%) for 20 weeks. The activities of glutathione S-transferase (GST) and quinone reductase (QR), the expression of proliferating cell nuclear antigen, polyamine content and ornithine decarboxylase activity in the tongue were examined for mechanistic analysis of modifying effects of EGMP on carcinogenesis. The expression of inducible nitric acid synthase (iNOS) was also assessed immunohistochemically. RESULTS: At week 30, the incidence and multiplicity of tongue squamous cell carcinoma were significantly reduced by feeding of a 2% EGMP diet. EGMP feeding (2% in diet) elevated tongue GST activity and lowered QR activity in the tongue. Dietary EGMP decreased the expression of cell proliferation biomarker expression. Interestingly, EGMP feeding altered iNOS expression in the invasive parts of carcinoma. CONCLUSIONS: These results suggest that EGMP, when given at the 2% dose level during the promotion phase, exerts a chemopreventive action against tongue tumorigenesis through modification of cell proliferation activity and/or detoxifying enzymatic activity.     

Rapid shrinkage of remnant central neurocytoma after gamma knife radiosurgery: a case report

Central neurocytomas are typically benign tumors that have high local control rates after gross total resection. Radiotherapy for residual or recurrent central neurocytomas is controversial.We report a 30-year-old male with a central neurocytoma in the lateral ventricle. The tumor was subtotally resected through a transcallosal approach, and subsequently treated with gamma knife radiosurgery. The tumor had shrunken markedly by 2 months after radiosurgery and remained unchanged during the one year follow-up period.Gamma knife radiosurgery may be an option for effective treatment of patients with residual or recurrent central neurocytomas.     

IL-6 is a key factor in growth inhibition of human myeloma cells induced by pravastatin,an HMG-CoA reductase inhibitor

Although recent developments in initial chemotherapeutic regimens and stem cell transplantation have achieved improvements of initial remission for myeloma patients, relapse and recurrence are still major problems. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been developed for treating hyperlipidemia. Recently, there have been several reports concerning the effects of statins on cancer cells including liver, colon, leukemia, malignant B, stomach, and breast cells. In this study, the in vitro effects of pravastatin on human myeloma cells and the factors closely related to its growth inhibitory effects were examined. Although concentrations were higher than those used clinically, 4 out of 10 myeloma lines showed growth inhibition by pravastatin. The study of factors related to the inhibition indicated IL-6 is important. Indeed, rhIL-6 abolished pravastatin-induced growth inhibition in KMS-21BM cells which did not express IL-6. Statins may be useful in maintenance therapy for myeloma after the screening of IL-6 status.     

Studies on novel bacterial translocase I inhibitors,A-500359s. I. Taxonomy,fermentation, isolation,physico-chemical properties and structure elucidation of A-500359 A,C, D and G

In the course of our screening for bacterial phospho-N-acetylmuramyl-pentapeptide-translocase (translocase I: EC 2.7.8.13) inhibitors, we found inhibitory activity in the cultured broth of the strain identified as Streptomyces griseus SANK 60196. The strain produced capuramycin and four novel capuramycin derivatives designated as A-500359 A, C, D and G. Purification and structural analysis were performed, and the structures of A-500359 A, C, D and G were elucidated as 6'-methylcapuramycin, 3'-demethyl-6'-methylcapuramycin, 2'-deoxy-6'-methylcapuramycin and 3'-demethylcapuramycin, respectively.     

Pradimicin-resistance of yeast is caused by a point mutation of the histidine-containing phosphotransfer protein Ypd1

Pradimicin is an antifungal antibiotic which induces apoptosis like cell death in the yeast Saccharomyces cerevisiae. Pradimicin-resistant mutants were isolated from the S. cerevisiae and the mutation points were analyzed. A point mutation of YPD1 that led to a substitution of the 74th glycine (Gly74) to cysteine (Cys) was identified in a mutant strain NH1. In S. cerevisiae, Ypd1 transfers a phosphoryl group from the sensor kinase Slnl to the response regulator Sskl which regulates a downstream MAP kinase in response to hyperosmotic stress. Gly74 is located in a three-residue reverse turn domain that connects two alpha-helices, one of which contains a histidine residue which is phosphorylated. In the reverse turn, glycine (relative position +10 to the active-site histidine) is highly conserved in Ypd1 and other histidine-containing phosphotransfer proteins. It was therefore suggested that the substitution of Gly74 to Cys altered the Ypd1 structure, which resulted in the resistance to pradimicin.