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Biomedical subjects

F Furukawa

Publications and source records attributed to F Furukawa.

At least 73 records · Page 4Linked to original sources
PubMed1998

Distinct P-cadherin expression in cultured normal human keratinocytes and squamous cell carcinoma cell lines.

Spatially regulated expression of E (epithelial)- and P (placental)-cadherins is crucial for maintaining normal epidermal architecture. In cutaneous squamous cell carcinomas (SCCs), aberrant P-cadherin expression is often observed in "squamoid" cancer cells, whereas E-cadherin expression in cancer cells is generally reduced. Therefore, it is plausible that SCC cells have acquired the ability to express P-cadherin and that P-cadherin plays a role in tumor progression. To address the issue, the in vitro effect of extracellular calcium on differentiation is a good model for investigating P-cadherin in normal and neoplastic skin. With elevations in extracellular calcium, human SCC cell line (DJM-1) cells initiate de novo synthesis of P-cadherin and express P-cadherin on the cell surface, whereas in normal human keratinocytes, P-cadherin expression on the cell surface is enhanced via the translocation from the cytosol to the cell membrane and/or the stabilization of P-cadherin at the cell surface. DJM-1 cells maintain P-cadherin expression on the cell surface at high levels for over 4 days after calcium elevation, whereas normal human keratinocytes cannot sustain cell surface P-cadherin when the cells are cultured in high calcium for more than 2 days. P-cadherin synthesis in DJM-1 cells is regulated at translational levels by extracellular calcium concentrations. SCC cells have the ability to produce P-cadherin by a mechanism not observed in normal keratinocytes, which might relate to the aberrant expression of P-cadherin in SCC of the skin.

Cadherins↗
PubMed1998

Down-regulation of tumoricidal NK and NK T cell activities by MHC Kb molecules expressed on Th2-type gammadelta T and alphabeta T cells coinfiltrating in early B16 melanoma lesions.

We examined whether gammadelta T and alphabeta T cells accumulating in early B16 melanoma lesions regulate NK and NK T cells that attack tumor cells. Freshly isolated and cultured tumor-infiltrating lymphocyte (TIL) populations of NK and NK T cells lysed B16 and produced IFN-gamma, whereas gammadelta T and a large part of alphabeta T cell populations had no substantial cytotoxicity against B16 and secreted Th2 cytokines. Furthermore, the freshly isolated NK1.1+ TIL population exhibited a higher anti-B16 effect than did splenocytes. Gammadelta T and alphabeta T cell populations dramatically inhibited the cytotoxicity of NK and NK T cells in an MHC Kb-dependent manner. Culture supernatant from gammadelta T and alphabeta T cell populations inhibited the proliferation of NK and NK T cell populations but did not affect their cytotoxicity, suggesting that the released Th2 cytokines are merely partly involved in the down-modulation of NK-lineage cells. NK1.1+ cells obtained from TIL of gammadelta T cell-depleted mice significantly lysed B16 cells compared with those from control mice. Finally, anti-Kb Fab mAb injected intralesionally at an early, but not at a late, stage of development of B16 melanoma inhibited tumor growth. These findings suggest that Th2-type gammadelta T and alphabeta T cells infiltrating in early B16 development inhibit the tumoricidal activity of NK-lineage cells using their class I molecules and partly their suppressive cytokines.

Animals↗
PubMed1998

Cross-reactivity in murine fluoroquinolone photoallergy: exclusive usage of TCR Vbeta13 by immune T cells that recognize fluoroquinolone-photomodified cells.

Fluoroquinolone antibacterial agents are well known to elicit photosensitivity as an adverse effect, and their cross-reactivity has been clinically documented. The photoallergenicity of fluoroquinolones is mainly derived from their photohaptenic moiety, and photomodification of skin epidermal cells with fluoroquinolones is thought to be an initial step for this photoallergy. Here we have explored, both in vivo and in vitro, T cell responses to fluoroquinolone-photomodified cells, focusing on their photoantigenic cross-reactivity. Cells were derivatized with fluoroquinolones under exposure to UV-A, and fluoroquinolone photoadducts were detected in photomodified cells by immunostaining, flow cytometry, and cell ELISA using fluoroquinolone-specific mAb. T cell-mediated hypersensitivity induced and elicited by s.c. injection of fluoroquinolone-photomodified epidermal cells was cross-reactive among six fluoroquinolones. In addition, lymph node cells from mice sensitized with fluoroquinolone-photomodified cells proliferated well in vitro not only to Langerhans cell-enriched epidermal cells photoderivatized with corresponding fluoroquinolone, but also to those photomodified with any of five other fluoroquinolones, supporting their cross-reactivity. In three fluoroquinolones tested, Th1 populations that expanded after in vitro photoantigenic stimulation of immune lymph node cells expressed the same Vbeta13 of TCR. The sensitivity could be transferred by the i.v. administration of this Vbeta13+ T cell line into naive recipients, in which a high percentage of Vbeta13+ cells infiltrated at the challenge site. These findings suggest that these fluoroquinolones carry the same photoantigenic epitope, which is recognized by Vbeta13+ T cells, leading to fluoroquinolone photosensitivity and cross-reactivity.

Adoptive Transfer↗
PubMed1998

Regulation of peripheral blood mononuclear cell responses to Dermatophagoides farinae by substance P in patients with atopic dermatitis.

Neuropeptides mediate stress-induced cutaneous inflammation such as atopic dermatitis. The effect of substance P on proliferation and cytokine mRNA expression of peripheral blood mononuclear cells in response to Dermatophagoides farinae (Der f) was studied in atopic dermatitis patients with positive RAST scores to Der f. Upon stimulation with Der f peripheral blood mononuclear cells from patients proliferated in a B7-dependent (CD80- and CD86-dependent) manner, while those from the patients with negative scores, nonatopic eczematous dermatitis patients or normal individuals, did not. Based on the reactivity of normal individuals, atopic dermatitis patients with a stimulation index greater than 1.8 were tentatively defined as high responders, who comprised two-thirds of the patients. Proliferation in high responders was associated with upregulation of IL-2 mRNA expression and induction of IL-5 mRNA expression. Substance p at 10(-10) to 10(-8) M promoted the Der f-induced proliferation when added at the start of culture and upregulated IL-10 MRNA expression while downregulating IL-5 mRNA expression. Our results suggest that substance P modifies immune responses of atopic T cells to Der f by promoting proliferation and altering cytokine profiles, and thus modulates the clinical manifestations of atopic dermatitis.

Adolescent↗
PubMed1998

Recurrent pemphigus vulgaris limited to the surgical area after mastectomy.

A 45-year-old Japanese female presented with bullae and erosions on the trunk in December 1987. The histologic findings revealed a suprabasal cleft and acantholytic cells. Immunofluorescence staining showed IgG autoantibodies in the intercellular spaces. With a working diagnosis of pemphigus vulgaris, she was treated successfully with low dosage prednisolone. Adenocarcinoma of the right breast was found in March 1994, and she received a mastectomy followed by breast reconstruction that used a transverse rectus abdominis muscle flap. Six months later, vesicobullous eruptions developed and were limited to the surgical area (right chest and abdomen). The histopathologic and direct immunofluorescence findings were consistent with pemphigus vulgaris. Although these skin lesions improved with high dosages of prednisolone, she died of multiple metastases due to the breast cancer.

Abdomen↗
PubMed1998

Bullous systemic lupus erythematosus: detection of antibodies against noncollagenous domain of type VII collagen.

A 9-year-old girl with systemic lupus erythematosus developed bullous eruption. Histopathologic examination showed subepidermal blistering and immunoglobulins (IgG, IgM, IgA) and complement components (C1q, C3) deposited linearly at the basement membrane zone. IgG in this patient's serum bound to the dermal side of 1 mol/L sodium chloride-split normal human skin, and a 290 kd protein was identified in the dermal extract. The patient's serum recognized various epitopes on the noncollagenous domain as demonstrated by the use of fusion proteins of type VII collagen. Resolution of the bullous eruption occurred after treatment with dapsone.

Antimetabolites↗
PubMed1998

Roxithromycin down-modulates antigen-presenting and interleukin-1 beta-producing abilities of murine Langerhans cells.

The immunomodulatory effect of the macrolide antibiotic, roxithromycin (RXM) on Langerhans cells (LC) was studied in mice. RXM inhibited the ability of LC to present superantigen and hapten to T cells at 100 microM. The superantigen-presenting activity of LC was more profoundly abrogated by RXM than the hapten-presenting activity. This functional reduction was partly attributed to an RXM-induced decrease in promotion of the expression of major histocompatibility complex class II molecules on LC. On the other hand, RXM down-modulated the production of interleukin-1 beta by LC at a lower concentration of 10 microM than concentrations that inhibited antigen presentation. These results imply that RXM exerts therapeutic effectiveness via not only bacteriocidal action but also inhibitory effect on the LC ability in T-cell-mediated cutaneous diseases that can be exacerbated by skin-colonized Staphylococcus aureus.

Animals↗
PubMed1998

Subcutaneous phaeohyphomycosis caused by Geniculosporium species; a new fungal pathogen.

A 70-year-old Japanese timberworker dealing with imported timber from the U.S.A. and Russia had an asymptomatic subcutaneous nodule with a small fistula on his left knee. Histopathological examination of the nodule revealed brownish hyphal elements in encapsulated pyogranuloma. The fungus isolated from a discharge of the fistula and an excised specimen of the lesion was identified as Geniculosporium sp., which represents a conidial state (anamorph) of several genera such as Anthostomella, Biscogniauxia, Euepixylon, Leprieuria, Nemania, Phylacia and Rosellina in the Xylariaceae. Whereas this dematiaceous hyphomycete is commonly found on decaying wood and bark of various trees, to our knowledge, this is the first case of a phaeomycotic cyst caused by fungi belonging to the genus Geniculosporium.

Aged↗
PubMed1998

Tumour-specific cytotoxic T lymphocyte activity in Th2-type Sézary syndrome: its enhancement by interferon-gamma (IFN-gamma) and IL-12 and fluctuations in association with disease activity.

Sézary syndrome (SzS) is the leukaemic variant of cutaneous T cell lymphoma (CTCL), whose malignant T cells are of the Th2 type in most cases. In this study we investigated the tumouricidal activity of cytotoxic T lymphocytes (CTL) present in peripheral blood of a patient with Th2-type SzS, focusing on the effect of IL-2, IFN-gamma and IL-12 on their cytotoxic activity, and the relationship between their lytic capacity and the patient's clinical course. At four different time points during a 2-month clinical period, CD4+CD7- Sézary cells and CD8+ cells were separated from the patient's circulating cells. CD8+ cells were cultured with chemically attenuated, purified Sézary cells in the presence of IL-2 to develop specific cytotoxicity. The CD8+ cells thus cultured exhibited lytic activity against autologous Sézary cells. Concomitant addition of IFN-gamma or IL-12 exerted a synergistic cytolytic effect with IL-2 on the tumour cells. Cytotoxicity inhibition studies using MoAbs revealed that the cytotoxicity operated in MHC class I-, CD8- and alphabeta T cell receptor-dependent manners. Furthermore, eight CD8+ T cell clones generated from cultured CD8+ cells exhibited a strong cytotoxicity against Sézary cells in an MHC class I-restricted fashion. During the clinical course, the activity of generated CTL and the number of CD8+ cells were inversely correlated with disease activity as assessed by the serum level of lactate dehydrogenase. These findings suggest that CTL down-regulate the growth of malignant T cells in this long-standing disease. Since Th2 cytokines such as IL-4 down-modulate CTL activity, CTL are assumed to be usually suppressed in SzS, whose malignant T cells are of Th2 type. It is likely that the administration of IFN-gamma normalizes this Th2-skewing state, activates CTL, and thus exerts the therapeutic effectiveness in the treatment of CTCL.

Antigens, Neoplasm↗
PubMed1998

Sphingosylphosphorylcholine stimulates proliferation and upregulates cell surface-associated plasminogen activator activity in cultured human keratinocytes.

Of the various sphingolipid metabolites, including sphingosine, sphingosylphosphorylcholine (SPC), dimethylsphingosine, sphingosine-1-phosphate, N-acetylsphingosine, and skin-specific ceramides, only SPC accelerated cutaneous wound healing in full-thickness excision wounds in genetically healing-impaired diabetic (db/db) mice. A histologic examination revealed that SPC promoted not only granulation tissue formation, but also the re-epithelization of epidermal keratinocytes. As the direct effects of SPC on keratinocytes are completely unknown, we investigated the effects of SPC on normal cultured human keratinocytes. SPC concentration-dependently enhanced DNA synthesis in keratinocytes, with an increase in intracellular calcium concentrations due to the release of calcium ions from intracellular stores. SPC upregulated cell surface plasminogen activity, and at the same time increased the cell surface expression of urokinase-type plasminogen activator (uPA) and urokinase-type plasminogen activator-receptor (uPA-R) in keratinocytes. Furthermore, SPC promoted the in vitro wound repair of cultured keratinocytes, which was partially blocked by an anti-uPA monoclonal antibody. Our results suggest that one of the mechanisms responsible for the SPC-mediated promotion of cutaneous wound healing seems to be an enhancement of re-epithelization caused by the direct stimulation of the proliferation of keratinocytes, and an activation of the uPA/uPA-R system, which enhances the migration of keratinocytes.

Animals↗
PubMed1998

Chemopreventive activity of oltipraz against induction of glandular stomach carcinogenesis in rats by N-methyl-N'-nitro-N-nitrosoguanidine.

The modifying effects of oltipraz on induction of glandular stomach carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in a total of 120 male 6-week-old Wistar rats, divided into six groups. Groups 1-3 (30 animals each) were given 100 p.p.m. MNNG in their drinking water for 10 weeks as an initiation treatment for gastric cancer induction and respectively fed diets supplemented with 0.04%, 0.02% and 0% oltipraz for 12 weeks, starting 1 week before and finishing 1 week after the carcinogen exposure. Groups 4-6 (10 animals each) were similarly treated without the application of MNNG. At the end of the 80th experimental week, all surviving animals were autopsied and examined histopathologically for the existence of gastric proliferative lesions. The incidence and multiplicity of adenocarcinomas were significantly (P < 0.01) lower in group 1 than in group 3. In addition, the multiplicity of atypical hyperplasias in the pyloric region was significantly (P < 0.05) decreased in group 1 as compared with the group 3 value. No gastric proliferative lesions were found in groups 4-6. In an additional short-term experiment, oltipraz significantly reduced cell proliferative activity (P < 0.01) and elevated glutathione levels (P < 0.05) in the glandular stomach mucosa of rats treated with MNNG. Thus our results clearly indicate that oltipraz can inhibit induction of proliferative glandular stomach lesions by MNNG in the rat.

Adenocarcinoma↗
PubMed1998

Specific mutational spectrum of dimethylnitrosamine in the lacI transgene of Big Blue C57BL/6 mice.

Dimethylnitrosamine (DMN) produces tumors in mice predominantly in the liver, but also in the kidney and lung. It forms O6-methylguanine adducts in DNA, which induce G:C-->A:T transitions. We have analyzed the spectra of spontaneous and DMN-induced mutations in the lacI transgene of the Big Blue mouse (C57BL/6). In both cases, mutations in the liver, kidney and lung were predominantly base substitutions, among which G:C-->A:T transitions were the most frequent. In contrast, a high incidence of short deletions (2-23 bp) was only found in the liver of treated mice. The deletions often occurred at direct repeat sequences. Single-base deletion incidence was also higher in the liver than in the kidney and lung. These results imply that accumulation of DNA lesions or their repair in liver is different from other organs. Spontaneous and induced base substitutions and deletions appeared to be randomly distributed in the lacI gene and an apparent hotspot was not observed, except for a 4 bp deletion of a (TGGC)3 sequence at positions 621-632. The present data demonstrate, for the first time, that DMN induces short deletions especially in the liver, although the mechanism involved needs further investigation.

Animals↗
PubMed1998

A nevocellular nevus consisting mostly of nevic corpuscles.

A scalp tumor from a 24-year-old male presenting unusual histological finding is described. The tumor was mostly composed of corpuscles resembling Meissner tactile bodies and contained almost no other components. Immunohistochemical studies revealed the tumor cells to be positive for S-100 protein and neuron-specific enolase, so we considered the tumor to be an unusual nevocellular nevus mostly comprised of nevic corpuscles.

Adult↗
PubMed1998

Membranous and soluble forms of Fas antigen in cutaneous lupus erythematosus.

The role of Fas-mediated apoptosis in cutaneous lupus erythematosus (LE) is still unclear, although the Fas/FasL system has been investigated in autoimmune diseases in relation to impaired apoptosis. In order to elucidate the connections between acute cutaneous LE (ACLE) and chronic cutaneous LE (CCLE), we determined the expression of membranous Fas antigen (mFas) on peripheral blood mononuclear cells (PBMC) by flow cytometry and the levels of the soluble form of the Fas antigen (sFas) in sera. The ratio and the mean fluorescence intensity of mFas were much higher in ACLE patients than in others, including patients with CCLE and atopic dermatitis and normal healthy controls. The levels of sFas in ACLE and CCLE patients were also elevated, and there was a significant increase in sFas levels in ACLE patients over that in CCLE patients. Immunohistochemical studies revealed that Fas antigen was predominantly expressed on infiltrating cells around blood vessels and appendages in ACLE and CCLE patients. Based on these findings, it is suggested that the expression of Fas antigen is closely associated with the activation of circulating lymphocytes, especially in ACLE patients, but is not directly associated with keratinocyte damage.

Acute Disease↗
PubMed1998

Enhancing effects of quinacrine on development of hepatopancreatic lesions in N-nitrosobis(2-oxopropyl)amine-initiated hamsters.

The modifying effects of quinacrine administration during the post-initiation phase of carcinogenesis were investigated in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Female Syrian hamsters were given three weekly s.c. injections of BOP at a dose of 10 mg/kg and then 300 or 100 ppm quinacrine in their diet for 37 weeks. Additional groups of animals received the BOP injection alone, or only the 300 ppm quinacrine treatment as BOP-negative controls. At week 40 of the experiment, all surviving animals were killed and development of proliferative lesions was assessed histopathologically. The multiplicity of pancreatic adenocarcinomas and dysplastic lesions per hamster was significantly higher (P<0.01 and P<0.05) in the BOP/Q100 group (1.92 and 1.78) than in the BOP-alone group (1.07 and 0.79). The incidence of hepatocellular adenomas plus carcinomas was also significantly elevated (P<0.05) in the BOP/Q300 and BOP/Q100 groups. In contrast, the multiplicity of lung adenomas plus adenocarcinomas was significantly decreased (P<0.05) by the Q300 treatment. Neither the incidence nor the multiplicity of renal cell tumors (adenomas and carcinomas) or nephroblastomas significantly differed between the BOP-treated groups. Electron microscopic examination revealed an abundance of myeloid lamellar bodies filling the cytoplasm of hepatocytes and pancreatic ductular and acinar cells, and epithelial cells of the gallbladder in the quinacrine-treated animals, the degree being dose-dependent. Our results indicate that quinacrine enhances pancreatic and hepatic carcinogenesis in hamsters induced by BOP.

Animals↗
PubMed1998

Histochemical determination of stereoselectivity of esterases in normal pancreas and pancreatic tubular adenocarcinoma of hamsters.

Esterases in normal hamster pancreas and pancreatic tubular adenocarcinoma of ductal origin induced by N-nitrosobis(2-oxopropyl)amine were stained in cryostat sections with mixtures of a diazonium salt (fast blue RR) and with each of the enantiomers of alpha-naphthyl N-methoxycarbonylalaninate, N-methoxycarbonylvalinate, and N-acetylprolinate. Azo coupling of alpha-naphthol formed by enzymatic hydrolysis with the diazonium salt gives an azo dye that indicates the presence and amount of the enzyme activity in situ. Comparison between the color intensities obtained with each of the enantiomers of a chiral alpha-naphthyl ester shows the stereoselectivity, or enantiomeric preference, of the enzyme. Esterases in acinar cells of the normal pancreas showed slight stereoselectivity for N-methoxycarbonylalaninate, while esterases in fat cells scattered throughout the exocrine pancreas showed high stereoselectivity for (R)-N-acetylprolinate. These esterase activities were not found in the tumor, but another prominent esterase activity with high stereoselectivity for (S)-N-methoxycarbonylvalinate was found. Similar results were obtained by staining after polyacrylamide gel electrophoresis showing that the bands of esterases in the adenocarcinoma stained only with the S enantiomer of the N-methoxycarbonylvalinate. The present method is a valuable tool for designing anticancer prodrugs that are activated by tumor-specific esterases.

Adenocarcinoma↗