Growth Promoting Activity of PDGF, EGF and TGF-β on Highly Metastatic Subline of Meth a Cells

The response of a highly metastatic cell line of methylcholanthrene induced A fibrosarcoma (Meth A) to growth factors from platelets was examined. The highly metastatic cell subline (MH) proliferated more rapidly than its parental counterpart cell subline (ML) in a medium containing platelet lysate. However, when the three major growth factors from platelets, ie, platelet-derived growth factor, epidermal growth factor, and transforming growth factor-β(PDGF, EGF, TGF-β), were independently examined for their growth promoting activity, the former 2 growth factors preferentially stimulated the proliferation of ML and the latter growth factor rather suppressed the growth of both cells.

On the other hand, the combined effects of these factors were more marked on MH. This combination effect was supported by the evidence that the number of receptors for EGF (which is probably an essential growth factor for the Meth A cell) was increased by pretreatmenl with PDGF or TGF-β. Thus, the highly metastatic cells of MH were considered to be the most susceptible to growth factors released from platelets. This conclusion is consistent with the concept that platelets may play an important role in the formation of blood-borne metastasis by releasing growth factors to promote the proliferation of tumor cells, following aggregation with tumor cells.     

CD1d expression level in tumor cells is an important determinant for anti-tumor immunity by natural killer T cells

Invariant natural killer T (iNKT) cells are thought to regulate anti-tumor immunity. Human iNKT (i.e. Valpha24+ NKT) cells have been reported to recognize CD1d on target cells and show cytotoxicity directly on the target cells in vitro. However, the anti-tumor effect of mouse iNKT (i.e. Valpha14+ NKT) cells has been repeatedly reported to be dependent on the activity of natural killer (NK) cells via interferon-gamma, with no evidence of direct cytotoxicity. In the present study, we report that in vitro cytolysis of EL-4 mouse lymphoblastic lymphoma cells by Valpha24+ NKT cells and in vivo eradication of these cells are both dependent on the level of CD1d expression on the tumor cell surface. These observations possibly suggest that direct cytotoxicity of tumor cells by iNKT cells is common to both humans and mice, and that the high expression level of CD1d may be a predictor whether the tumor is a good target of iNKT cells.     

Comparison of inhibitory effects of polyanions on nitric oxide production by macrophages stimulated with LPS

In this paper, we investigated the inhibitory mechanism of the production of nitric oxide (NO) by polyanions and liposomes composed of phosphatidylserine (PS-liposomes) focusing on cytokine production and mitogen activated protein kinase (MAP kinase) activation. NO production by macrophages was inhibited by treatment with oxidized lipoprotein (OxLDL), maleylated bovine serum albumin (mBSA), and heparin. No inhibitory effect was exhibited by poly-cytidilic acid (PolyC). To clarify the mechanism of the inhibitory effect of polyanions on NO production, we evaluated the productions of transforming growth factor-beta (TGF-beta) and interleukin (IL)-10 which are known to be anti-inflammatory cytokines. TGF-beta was produced when macrophages were treated with OxLDL as was the case with PS-liposomes. No increase in TGF-beta production was observed for mBSA, heparin, and PolyC. On the other hand, significant production of IL-10 was observed using mBSA. Extracellular signal-regulated kinase (ERK), a member of the MAP kinase superfamily, was activated when macrophages were treated with OxLDL as well as PS-liposomes. In the case of mBSA, the activation of ERK and c-Jun N-terminal kinase (JNK) was observed. No activation of p38 MAP kinase was observed using any of the polyanions. Although heparin had an inhibitory effect on NO production by macrophages, no activation of MAP kinase or production of TGF-beta and IL-10 was observed. The inhibitory effect of these ligands on NO production may be regulated via different signaling pathways.     

Changes in immune responses to mite antigen sensitized through barrier-disrupted skin with CpG-oligodeoxynucleotide in mice

CpG-oligodeoxynucleotide (CpG-ODN) plays a critical role in immunity via the augmentation of Th1 and suppression of Th2 responses. We examined here the effect of CpG-ODN on the immune response to mite antigen sensitized through barrier-disrupted skin of human atopic dermatitis (AD) model mouse. Although sensitization with mite antigen induced Th2-dominant immune response, co-administration of CpG-ODN elicited Th1-predominant immune response. In terms of antigen-specific antibody production, the level of IgG2a was increased by CpG-ODN, but not in IgE. These results suggested that administration of CpG-ODN via skin is a simple strategy for patients with diseases like AD, which is characterized by Th2-dominated inflammation.     

Role of positron emission tomography in decisions on treatment strategies for pancreatic cancer

Background/Purpose The purpose of this study was to estimate the usefulness of positron emission tomography (PET) in deciding on strategies for the treatment of pancreatic cancer. The following two parameters were evaluated: the ability of PET to provide an estimation of the progression of pancreatic cancer, and the ability of PET to predict survival and the effect of chemoradiotherapy. Methods Forty-two patients underwent PET as part of the procedure for making a diagnosis of pancreatic tumors. The maximum standardized uptake value (SUVmax) levels were compared with clinicopathological factors and analyzed. Results PET provided a sensitivity of 87%, a specificity of 67%, and an overall accuracy of 85% for the diagnosis of pancreatic malignancy. Tumors with distant metastases showed significantly higher SUV levels than tumors without metastasis. In the patients who received chemoradiotherapy, the overall survival of the group in which SUVmax was less than 7.0 was better than that of the group in which SUVmax was more than 7.0. Conclusions We conclude that PET is a useful tool for determining pathological status and distant metastasis in pancreatic cancer, and for predicting the prognosis of patients receiving chemoradiotherapy.     

Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia

Idiopathic aplastic anemia (AA) is a common cause of acquired BM failure. Although autoimmunity to hematopoietic progenitors is thought to be responsible for its pathogenesis, little is known about the molecular basis of this autoimmunity. Here we show that a substantial proportion of AA patients harbor clonal hematopoiesis characterized by the presence of acquired copy number-neutral loss of heterozygosity (CNN-LOH) of the 6p arms (6pLOH). The 6pLOH commonly involved the HLA locus, leading to loss of one HLA haplotype. Loss of HLA-A expression from multiple lineages of leukocytes was confirmed by flow cytometry in all 6pLOH(+) cases. Surprisingly, the missing HLA-alleles in 6pLOH(+) clones were conspicuously biased to particular alleles, including HLA-A*02:01, A*02:06, A*31:01, and B*40:02. A large-scale epidemiologic study on the HLA alleles of patients with various hematologic diseases revealed that the 4 HLA alleles were over-represented in the germline of AA patients. These findings indicate that the 6pLOH(+) hematopoiesis found in AA represents "escapes" hematopoiesis from the autoimmunity, which is mediated by cytotoxic T cells that target the relevant auto-antigens presented on hematopoietic progenitors through these class I HLAs. Our results provide a novel insight into the genetic basis of the pathogenesis of AA.     

Successful endovascular treatment of hemosuccus pancreaticus due to splenic artery aneurysm associated with segmental arterial mediolysis

Hemosuccus pancreaticus, which is generally due to the rupture of a splenic artery aneursym into the pancreatic duct, is a rare cause of intermittent upper gastrointestinal hemorrhage. Segmental arterial mediolysis (SAM) is a rare arteriopathy. We report a 53-year-old man with hemosuccus pancreaticus due to a splenic artery aneurysm associated with SAM. The patient, who also had a celiac artery aneurysm affected by SAM, was successfully treated by both coil embolization and aortic stent grafting for complete coverage of the celiac artery. SAM is a very rare cause of hemosuccus pancreaticus, and endovascular treatment may be favorable for hemosuccus pancreaticus.