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An acute leukemia with an unusual immunophenotype developed in a 17-year-old girl. At the initial presentation, extramedullary involvement was not evident, but with advancing disease, massive splenomegaly and an osteolytic rib tumor developed. The disease was aggressive and refractory to intensive chemotherapeutic regimens for myeloid and lymphoid malignancies, and the patient died 3 months after the initial presentation. The leukemic cells were of irregular shape and variable size; they had deeply indented or bi-lobed nuclei and relatively fine, azurophilic granules in their cytoplasm. They were positive for acid phosphatase and beta-glucuronidase in granular staining, but they were negative for myeloperoxidase. The leukemic cells had a unique immunophenotype: it was positive for T-cell antigens (CD1a, CD2, cytoplasmic CD3, CD4), myeloid antigens (CD13 and CD33), NK-cell antigen (CD56), CD19 and CD30. DNA analysis revealed no gene rearrangement in the T-cell receptor beta, gamma and delta, or immunoglobulin heavy chain genes. The leukemic cells of our patient are thought to have arisen from the transformation of a putative precursor cell common to both the T- and NK-cell lineage in the bone marrow. The current literature on precursor NK-cell malignancy is reviewed, and its clinicopathological feature is discussed. [ABSTRACT FROM AUTHOR]

In cases of adult T cell leukaemia neoplastic T cell infiltration in the skin was accompanied by an increase in Langerhans cells. This is in keeping with the view that Langerhans cells may induce antigen-specific and allogenic T cell activation. [ABSTRACT FROM PUBLISHER]

Background: A small percentage of patients with foreign body ingestion develop complications, which have a variety of clinical presentations. Less than 1% of cases require surgical intervention. We present a patient with an abdominal wall abscess resulting from a fish bone that pierced the cecum. The patient was treated laparoscopically., Case Presentation: A 55-year-old Japanese man presented to our hospital with a complaint of right lower abdominal pain. A physical examination revealed tenderness, swelling, and redness at the right iliac fossa. Computed tomography showed a low-density area with rim enhancement in his right internal oblique muscle and a hyperdense 20 mm-long pointed object in the wall of the adjacent cecum. Based on the findings we suspected an abdominal wall abscess resulting from a migrating ingested fish bone. He was administered antibiotics as conservative treatment, and the abscess was not seen on subsequent computed tomography. Two months after the initial treatment, he presented with the same symptoms, and a computed tomography scan showed the foreign body in the same location as before with the same low-density area. We diagnosed the low-density area as recurrence of the abdominal wall abscess. He underwent laparoscopic surgery to remove the foreign body. His appendix, and part of his cecum and the parietal peritoneum that included the foreign body, were resected. He had an uneventful postoperative course, and at 1 year after the surgery, the abdominal wall abscess had not recurred., Conclusions: An abdominal wall abscess developed in association with the migration of an ingested fish bone. We suggest that a laparoscopic surgical resection of the portion of the bowel that includes the foreign body is a useful option for selected cases.

Hepatic carcinosarcoma (HCS) generally presents in advanced stages, demonstrates aggressive behavior, and has a poor prognosis. Other than curative primary resection, no effective treatment options exist. We present a case of resected HCS with four repeat resections for solitary lymph node recurrence followed by chemoradiotherapy with doxorubicin and ifosfamide. A 67-year-old Japanese man was admitted to our hospital for evaluation of an asymptomatic hepatic tumor. The patient underwent right hepatectomy with a presumptive preoperative diagnosis of atypical hepatocellular carcinoma. Based on histopathological and immunohistochemical findings, the tumor was diagnosed as HCS containing osteosarcoma and chondrosarcoma components. After the initial surgery, the patient underwent four additional resections for solitary lymph node HCS recurrence, and then underwent chemoradiotherapy with doxorubicin and ifosfamide for an unresectable lymph node recurrence. Chemotherapy was stopped after two cycles because of severe adverse events, although chemoradiotherapy markedly reduced the size of the lymph node recurrence and provided a progression-free survival of 12 months. Thirty-seven months after the initial surgery, the patient died of cardiac invasion of multiple mediastinal lymph node metastases. The clinical course outlined in this case report suggests that chemoradiotherapy with doxorubicin and ifosfamide for metastatic HCS may prolong survival in patients with unresectable lesions.

Mesenchymal stem cells (MSCs) are pluripotent cells that can differentiate into multilineage cell types, including adipocytes and osteoblasts. Mechanical stimulus is one of the crucial factors in regulating MSC differentiation. However, it remains unknown how mechanical stimulus affects the balance between adipogenesis and osteogenesis. Low intensity pulsed ultrasound (LIPUS) therapy is a clinical application of mechanical stimulus and facilitates bone fracture healing. Here, we applied LIPUS to adipogenic progenitor cell and MSC lines to analyze how multilineage cell differentiation was affected. We found that LIPUS suppressed adipogenic differentiation of both cell types, represented by impaired lipid droplet appearance and decreased gene expression of peroxisome proliferator-activated receptor γ2 (Pparg2) and fatty acid-binding protein 4 (Fabp4). LIPUS also down-regulated the phosphorylation level of peroxisome proliferator-activated receptor γ2 protein, inhibiting its transcriptional activity. In contrast, LIPUS promoted osteogenic differentiation of the MSC line, characterized by increased cell calcification as well as inductions of runt-related transcription factor 2 (Runx2) and Osteocalcin mRNAs. LIPUS induced phosphorylation of cancer Osaka thyroid oncogene/tumor progression locus 2 (Cot/Tpl2) kinase, which was essential for the phosphorylation of mitogen-activated kinase kinase 1 (MEK1) and p44/p42 extracellular signal-regulated kinases (ERKs). Notably, effects of LIPUS on both adipogenesis and osteogenesis were prevented by a Cot/Tpl2-specific inhibitor. Furthermore, effects of LIPUS on MSC differentiation as well as Cot/Tpl2 phosphorylation were attenuated by the inhibition of Rho-associated kinase. Taken together, these results indicate that mechanical stimulus with LIPUS suppresses adipogenesis and promotes osteogenesis of MSCs through Rho-associated kinase-Cot/Tpl2-MEK-ERK signaling pathway.

LPS signaling is mediated through MyD88-dependent and -independent pathways, activating NF-?B, MAP kinases and IRF3. Cot/Tpl2 is an essential upstream kinase in LPS-mediated activation of ERKs. Here we explore the roles of MyD88 and Cot/Tpl2 in LPS-induced chemokine expression by studying myd88(-/-) and cot/tpl2(-/-) macrophages. Among the nine LPS-responsive chemokines examined, mRNA induction of ccl5, cxcl10, and cxcl13 is mediated through the MyD88-independent pathway. Notably, Cot/Tpl2-ERK signaling axis exerts negative effects on the expression of these three chemokines. In contrast, LPS-induced gene expression of ccl2, ccl7, cxcl2, cxcl3, ccl8, and cxcl9 is mediated in the MyD88-dependent manner. The Cot/Tpl2-ERK axis promotes the expression of the first four and inhibits the expression of the latter two. Thus, LPS induces expression of multiple chemokines through various signaling pathways in macrophages., (Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Although several murine mAbs that have been humanized became useful therapeutic agents against a few malignancies, therapeutic Abs are not yet available for the majority of the human cancers because of our lack of knowledge of which antigens (Ags) can become useful targets. In the present study we established a procedure for comprehensive identification of such Ags through the extensive isolation of human mAbs that may become therapeutic. Using the phage-display Ab library we isolated a large number of human mAbs that bind to the surface of tumor cells. They were individually screened by immunostaining, and clones that preferentially and strongly stained the malignant cells were chosen. The Ags recognized by those clones were isolated by immunoprecipitation and identified by MS. We isolated 2,114 mAbs with unique sequences and identified 21 distinct Ags highly expressed on several carcinomas. Of those 2,114 mAbs 356 bound specifically to one of the 21 Ags. After preparing complete IgG(1) Abs the in vitro assay for Ab-dependent cell-mediated cytotoxicity (ADCC) and the in vivo assay in cancer-bearing athymic mice were performed to examine antitumor activity. The mAbs converted to IgG(1) revealed effective ADCC as well as antitumor activity in vivo. Because half of the 21 Ags showed distinct tumor-specific expression pattern and the mAbs isolated showed various characteristics with strong affinity to the Ag, it is likely that some of the Ags detected will become useful targets for the corresponding carcinoma therapy and that several mAbs will become therapeutic agents.

Objective: To examine 10 cases with primary cutaneous CD30-positive anaplastic large cell lymphoma (ALCL), analyze their clinical manifestations and pathological and immunohistochemical features, and improve early diagnosis of this disease., Methods: We studied the morphological characteristics of primary cutaneous CD30-positive ALCL using histopathological methods. Leukocyte common antigen (LCA), CD20, CD30, CD45RO, CD68, epithelial membrane antigen (EMA), cytokeratin (CK) and HMB45 antibodies were used to determine the expression of their respective antigens from routine paraffin samples of the patients., Results: Ten patients (7 men and 3 women, aged 31 to 84 years) complained of subcutaneous masses or papular eruptions over their lower trunks and extremities. Histopathologically, the lesions were composed of numerous large round or oval pleomorphic cells. The cytoplasm was usually abundant, amphophilic or basophilic, and finely vacuolated. Nuclei were commonly eccentrically localized and lobated or horseshoed in shape, and multinucleated giant cells and Reed-Sternberg-like cells were seen. Nucleoli were generally multiple and large. Of the 10 patients, tumor cells displayed positive antigen expression of CD30 in all cases, positive CD45RO in 6 cases, positive CD20 in only 1 case, but negative CD45RO and CD20 expressions in 3 cases. Two patients died at 7 weeks and 3.4 years of follow-up, respectively., Conclusion: Our study highlights the importance of histopathologic features and positive CD30 staining for differentiation of this disease from other malignant skin tumors.

The restriction endonuclease SmaI has been used for the diagnosis of neurogenic muscle weakness, ataxia and retinitis pigmentosa disease or Leigh's disease, caused by the Mt8993T-->G mutation which results in a Leu156Arg replacement that blocks proton translocation activity of subunit a of F(0)F(1)-ATPase. Our ultimate goal is to apply SmaI to gene therapy for this disease, because the mutant mitochondrial DNA (mtDNA) coexists with the wild-type mtDNA (heteroplasmy), and because only the mutant mtDNA, but not the wild-type mtDNA, is selectively restricted by the enzyme. For this purpose, we transiently expressed the SmaI gene fused to a mitochondrial targeting sequence in cybrids carrying the mutant mtDNA. Here, we demonstrate that mitochondria targeted by the SmaI enzyme showed specific elimination of the mutant mtDNA. This elimination was followed with repopulation by the wild-type mtDNA, resulting in restoration of both the normal intracellular ATP level and normal mitochondrial membrane potential. Furthermore, in vivo electroporation of the plasmids expressing mitochondrion-targeted EcoRI induced a decrease in cytochrome c oxidase activity in hamster skeletal muscles while causing no degenerative changes in nuclei. Delivery of restriction enzymes into mitochondria is a novel strategy for gene therapy of a special form of mitochondrial diseases., (Copyright 2002 National Science Council, ROC and S. Karger AG, Basel)

We examined the modifying effects of heated garlic (Allium sativum L.) on N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)-induced duodenal and jejunal carcinogenesis in mice. Heated garlic powder used in this study was prepared as follows: unpeeled garlic bulbs were blanched in boiling water for 6 min, and then peeled, the cloves being crushed, homogenized, and finally freeze-dried. The garlic powder had almost undetectable alliinase activity and was rich in alliin (the main sulfur compound of heated garlic; 22.1 &mgr;/g dry weight). Male C57BL/6 mice were given ENNG (100 &mgr;/l) in drinking water for the first 4 weeks, and then basal diet (Group 1), or 10% (Group 2), 3% (Group 3) or 1% (Group 4) heated garlic in the diet for 30 weeks. At the termination of the experiment, the incidences of duodenal tumors in Groups 1-3 were significantly lower than those in Group 1, and the multiplicities in Group 2 were significantly lower than those in Group 1. Additionally, the incidences and/or multiplicities of the jejunal tumors in Groups 2 and 4 were also significantly lower than those in Group 1. In this study, we also examined changes in erythrocyte polyamine levels. Values for Group 1 were significantly greater than those in the control group, and this elevation in Group 1 were significantly inhibited by dietary heated garlic (10% in the diet; Group 2). These results indicated that the post-initiation-stage feeding of heated garlic, especially at 10% in the diet, inhibits ENNG-induced duodenal and jejunal carcinogenesis in mice.

We examined the modifying effects of freeze-dried whole-leaf Aloe arborescens Miller var. natalensis Berger (designated as 'ALOE') on N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)-induced duodenal tumorigenesis in C57BL/6 mice. Experiment 1: Male mice were given ENNG in drinking water for the first 4 weeks, and then 10% ALOE in basal diet for 16 weeks. Experiment 2: Female mice were given ENNG for 5 weeks, and then 5%, 1% or 0.2% ALOE in the diet were given for 15 weeks. In Experiment 1, the tumor incidence and tumor multiplicity (tumors per mouse) of the duodenum in the ENNG + 10% ALOE group were significantly decreased compared with that in the ENNG alone group. Erythrocyte polyamine levels in the ENNG + 10% ALOE group were also significantly decreased. In Experiment 2, the incidence of duodenal tumors in the ENNG + 5% ALOE group were significantly decreased compared with that in the ENNG alone group. These results indicated that ALOE, especially at 10% in the diet, inhibits ENNG-induced duodenal tumorigenesis in mice.

For gene therapy of human malignant glioma, we adopted positively charged multilamellar liposomes entrapping the human interferon beta (hIFN-beta) gene. One week after the transplantation of human malignant glioma U251-SP cells to produce glioma in nude mouse brain, the liposomes entrapping the gene (500 ng of DNA per 25 nmol of lipids per 2 microl) were injected into the same site of the cell transplantation once every second day for a total of five injections; and by this means the tumor completely disappeared. To confirm the antiproliferative effect of hIFN-beta, we performed an in vitro study using a plasmid containing a secretion signal sequence-deleted hIFN-beta gene and one containing the hIFN-beta gene inserted in reverse. In both cases, there was no hIFN-beta release into the medium and no growth inhibition effect. On addition of anti-hIFN-beta antibody to the medium, the growth inhibition effect was abolished. As this cell line expresses IFN-alpha/beta receptor, the hIFN-beta produced in the transfected cells could be released and acted in a paracrine manner. For 120 days the body weight change of normal mice treated by the same procedure as used in the curing experiment was not significant among the groups injected with empty liposomes, plasmid only, and liposomes entrapping the gene. In all of these three groups, death, abnormal behavior, and significant histological changes were not observed.

We report a familial case of macrothrombocytopenia without inclusion bodies in polymorphonuclear cells or any congenital abnormalities. The results of the hemostatic and platelet function tests were all normal except for the platelet retention rate. The number of megakaryocytes increased slightly and some were relatively small. Electron microscopic studies revealed a unique morphological abnormality of the platelets' mitochondria.

The localization of Tac antigen in adult T-cell leukemia-associated antigen (ATLA)-positive lymphomas was studied ultrastructurally with the use of the immunoperoxidase technique. The antigen was observed on the plasma membranes of a portion of the characteristic cells with convoluted nuclei and a majority of the cells with less irregular nuclei, which were larger than the former. In addition, the cisternae of the rough endoplasmic reticulum, perinuclear cisternae, and Golgi cisternae of the latter cells were also positively stained with anti-Tac antibody. It is thought that the positive reaction of the plasma membranes may correspond to interleukin 2 (IL 2) receptors, the cytoplasmic and perinuclear reaction sites may well correspond to the precursor of IL 2 receptors, and Tac antigen may be produced in the cytoplasm of the ATLA-positive lymphoma cells.

The effect of ascorbate in reducing Adriamycin toxicity has been examined in mice and guinea pigs. Ascorbate had no effect on the antitumor activity of Adriamycin in mice inoculated with leukemia L1210, but it significantly prolonged the life of mice and guinea pigs treated with Adriamycin. Adriamycin elevated lipid peroxide levels in serum and liver, and ascorbate prevented the elevation. The significant prevention of Adriamycin-induced cardiomyopathy by ascorbate was proved by means of electron microscopy. The earliest alterations of dilation of the sarcoplasmic reticulum and transverse tubular system and the appearance of a large number of cytoplasmic fat droplets, which were seen in cardiac tissue from guinea pigs receiving Adriamycin, were apparently reduced in animals that were treated with ascorbate.

The correlation between the content of individual glycosaminoglycans and the histological patterns are studied on breast tumor tissues. The myxomatous stroma of intracanalicular fibroadenoma contained a large amount of glycosaminoglycans, which were mainly hyaluronic acid. The chondroitin 4- and 6-sulfate level was also high. As the supporting stroma of this tumor became denser and more fibrous, the level of hyaluronic acid content was reduced. In the case of pericanalicular fibroadenoma, glycosaminoglycans were small in amount and the levels of hyaluronic acid and chondroitin sulfate were low, but the ratio of dermatan sulfate content was higher. In the case of gynecomastia, the conent was almost the same as that of pericanalicular fibroadenoma. Scirrhous carcinoma tissues contained a relatively large amount of hyaluronic acid and chondroitin sulfate. No remarkable differences in heparan sulfate content were observed in any one of the breast tumors tested. Dermatan sulfate-chondroitin sulfate copolymers were detected in all the tumors. The presence of dermatan sulfate seemed to have an intimate relation with the fibrogenesis in the interstitial stromal element of the tumor tissues.

The effect of 5-S-cysteinyl-L-3,4-dihydroxyphenylalanine (cys-dopa), an intermediate in the pathway from L-3,4-dihydroxyphenylalanine (L-dopa) to pheomelanin, on the growth of eight human tumor cell lines in culture was compared to that of L-dopa. The tumor cell lines tested comprise two neuroblastomas (NB-1 and YT-nu), two amelanotic melanomas (HMV and SEKI), a gastric carcinoma (MKN-28), and three squamous cell carcinomas (HeLa-S3, KB, and a salivary gland carcinoma). Cys-dopa at a concentration of 1 mM inhibited growth of NB-1 (66%), YT-nu (67%), HMV (44%), SEKI (60%), MKN-28 (47%), HeLa-S3 (24%), KB (64%), and salivary gland carcinoma (33%), while L-dopa exhibited similar or even lower degree of inhibition at a concentration of 6 mM. On the other hand, both catechols had little effect on the growth of two fibroblasts derived originally from normal tissues (mouse fibroblast L929 and Chinese hamster fibroblast Don-6). Cys-dopa and L-dopa inhibited DNA and protein synthesis in YT-nu cells, but RNA synthesis was less affected. Treatment with cys-dopa at a dose of 1000 mg/kg i.p. for 7 days prolonged by 50% the life span of mice inoculated with L1210 leukemia. Normal mice given cys-dopa at a dose of 1000 mg/kg for 12 days showed no signs of toxicity. These results suggest the potential of cys-dopa as an antitumor agent.

Morphological observations and biochemical analysis were made on glycosaminoglycans produced by MDCK cells of dog kidney origin growing on a glass surface as a mosaic of epithelium with many multicellular hemishperical vesicles. MDCK cells synthesized glycosaminoglycans, which consisted mainly of heparan sulfate and hyaluronic acid. The majority of the substances were contained in a cell-surface component removable with ethylenediaminetetraacetic acid-trypsin. In the radioautograph of tissue sections, high radioactivity of 35SO4 was observed on the medium-bathed cell surface, where Alcian blue-strained material could be observed. Ultrastructurally, the surface of microvillous processes which were abundant on the cell surface in contact with the medium was stained with ruthenium red. A small amount of chondroitin 4- and 6-sulfates were also synthesized. After 24 hr, the majority of chondrotin [35S] sulfates newly formed were secreted into the cultured medium, whereas haparan [35S] sulfate was released much less, remaining as a cellular component. The biological roles of glyconsaminoglycans produced by epithelial cells are discussed.