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Biomedical subjects

C Sakai

Publications and source records attributed to C Sakai.

At least 37 records · Page 2Linked to original sources
PubMed1998

Human tyrosinase related protein-1 (TRP-1) does not function as a DHICA oxidase activity in contrast to murine TRP-1.

Tyrosinase related protein-1 is a melanocyte specific protein and a member of the tyrosinase gene family which also includes tyrosinase and TRP 2 (DOPAchrome tautomerase). In murine melanocytes, TRP-1 functions as a 5,6-dihydroxyindole-2-carboxylic acid [DHICA] oxidase during the biosynthetic conversion of tyrosine to eumelanin and mutations affecting TRP-1 result in the synthesis of brown rather than black pelage coloration. In this study, we examined the putative DHICA oxidase activity of TRP-1 in human melanocytes using several approaches. We first utilized a line of cultured melanocytes established from a patient with a form of oculocutaneous albinism completely lacking expression of TRP-1 (OCA3). This line of melanocytes endogenously exhibited the same amount of DHICA oxidase activity as control melanocytes expressing TRP-1. In other experiments, cultured human fibroblasts were transfected with a cDNA for TRP-1, in either the sense or antisense direction, or with the retroviral vector alone. TRP-1 expression was induced in fibroblasts transfected with the TRP-1 cDNA in the sense direction only. Although TRP-1 was expressed by sense-transfected cells, there was no significant DHICA oxidase activity above controls. These results demonstrate that human TRP-1 does not use DHICA as a substrate for oxidation.

Animals↗
PubMed1998

Histiocytic sarcoma of the spleen associated with hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia as a possibly unique clinical entity--report of three cases.

We report three patients with histiocytic sarcoma of the spleen associated with severe hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia. After the clinical diagnosis of splenic tumor of unknown origin was made, all three patients underwent splenectomy. The histiocytic origin of the tumor was confirmed histopathologically and immunohistochemically using a panel of antibodies. In contrast to malignant histiocytosis (MH), which typically reveals severe generalized clinical manifestations and a rapidly fatal course caused by the disseminated proliferation of neoplastic histiocytes, these patients were asymptomatic or showed only mild clinical symptoms for a long period of time until the recurrence was detected by which time the tumor cells had already spread to other organs. All three cases were characteristically associated with hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia, which returned to normal after splenectomy. Splenic histiocytic sarcoma with the features described here may represent a unique clinical entity, distinct from MH.

Adult↗
PubMed1998

[Successful treatment with CPT-11 and adriamycin for hemophagocytic syndrome associated with intravascular lymphomatosis].

A 75-year-old man was admitted because of non-Hodgkin's lymphoma (histology undetermined) of the rib. A complete remission was achieved after CHOP therapy and irradiation. One year later, high fever, thrombocytopenia and liver dysfunction developed. Bone marrow aspirate revealed a hypoplastic marrow with hemophagocytic histiocytes, and a diagnosis of hemophagocytic syndrome (HPS) was made. Although no lymphomatous lesions were detected, HPS due to relapsed lymphoma was strongly suspected. The patient received MEVP therapy including etoposide and prednisolone, but without any improvement. Soon after the initiation of CPT-11 and adriamycin (ADM) therapy, all symptoms of HPS disappeared. This combination chemotherapy was repeated over a three-week span, and the patient remained in partial remission for the next 10 months. In November 1997, a tumor developed in the paranasal sinus, and the patient died three months later. The autopsy disclosed many B lymphoma cells filling the small vessels of almost all organs, and a final diagnosis of intravascular lymphomatosis (IVL) was made. These findings indicate that combination CPT-11 and ADM therapy is effective for cases of IVL accompanied by HPS that are refractory to conventional chemotherapies.

Aged↗
PubMed1997

Modulation of murine melanocyte function in vitro by agouti signal protein.

Molecular and biochemical mechanisms that switch melanocytes between the production of eumelanin or pheomelanin involve the opposing action of two intercellular signaling molecules, alpha-melanocyte-stimulating hormone (MSH) and agouti signal protein (ASP). In this study, we have characterized the physiological effects of ASP on eumelanogenic melanocytes in culture. Following exposure of black melan-a murine melanocytes to purified recombinant ASP in vitro, pigmentation was markedly inhibited and the production of eumelanosomes was decreased significantly. Melanosomes that were produced became pheomelanosome-like in structure, and chemical analysis showed that eumelanin production was significantly decreased. Melanocytes treated with ASP also exhibited time- and dose-dependent decreases in melanogenic gene expression, including those encoding tyrosinase and tyrosinase-related proteins 1 and 2. Conversely, melanocytes exposed to MSH exhibited an increase in tyrosinase gene expression and function. Simultaneous addition of ASP and MSH at approximately equimolar concentrations produced responses similar to those elicited by the hormone alone. These results demonstrate that eumelanogenic melanocytes can be induced in culture by ASP to exhibit features characteristic of pheomelanogenesis in vivo. Our data are consistent with the hypothesis that the effects of ASP on melanocytes are not mediated solely by inhibition of MSH binding to its receptor, and provide a cell culture model to identify novel factors whose presence is required for pheomelanogenesis.

Agouti Signaling Protein↗
PubMed1997

Melanosomal proteins as melanoma-specific immune targets.

Pigmentation of our skin, hair and eyes is essential for photoprotection, embryological development, detoxification and protective/cosmetic coloration. A number of proteins important to the production of melanin within melanosomes have now been identified including enzymatic and structural proteins encoded at the murine albino, brown, pinkeyed-dilution, MART1, slaty and silver loci. Interestingly, many of those melanosomal proteins (including epitopes derived from tyrosinase, TRP1/gp75, silver/gp100 and MART1/melan-A) function in vivo as targets of humoral and cellular autoimmune responses directed specifically against normal or transformed melanocytes. These findings have provided new impetus to research on immune responses to melanoma and, perhaps more importantly, examining why they are insufficient to provide protection against tumour growth and what type of immune therapy can be designed to correct that. The melanosome must now be considered beyond its function in pigmentation, and assumes the role of a valuable source for specific immune targets for malignant melanoma.

Amino Acid Sequence↗
PubMed1997

[Acute respiratory failure associated with G-CSF-induced leukocyte recovery in three patients with preceding infection].

Acute respiratory failure (ARF) occurred at the time of leukocyte recovery promoted by granulocyte colony-stimulating factor (G-CSF) in three patients with the preceding infection (S. aureus pneumonia, varicella zoster, and P. aeruginosa bacteremia, respectively) which had developed during leukopenia after cancer chemotherapy. G-CSF was used for 4 to 6 days, and the leukocyte counts at onset of ARF were 19,300/microliter, 11,300/microliter, and 4,100/microliter, respectively. All of the three patients received high-dose methylprednisolone and the artificial respiration was used in two. Consequently two patients responded well and survived, but one died of respiratory failure 2 weeks after occurrence of ARF. Autopsy of the dead case revealed mild interstitial pneumonia in the both lungs together with bacterial pneumonia in the right lobe. These cases indicate that G-CSF-induced leukocyte recovery can cause severe ARF in patients with precending infection. Therefore, G-CSF should be administered very carefully to granulocytopenic patients with infection.

Acute Disease↗
PubMed1997

Impact of a laryngectomy on quality of life: perspective of the patient versus that of the health care provider.

This study retrospectively assesses the impact of laryngectomy on the quality of life of 46 patients as compared to the perception of the impact of laryngectomy of 13 health care providers (HCPs). Employing the "time trade-off" methodology, we assessed patient and HCP preferences and calculated estimated utilities. We found that 20% of patients would be willing to compromise anticipated life expectancy to preserve voice or preoperative quality of life. By comparison, 46% of the HCPs perceived that their patients would be willing to accept a reduced life span in order to preserve their larynx and quality of life. In conclusion, the percentage of HCPs who believed their patients would compromise survival was substantially higher than the percentage of actual patients who expressed this preference. This perception may influence physicians' attitudes toward recommending laryngeal preservation therapy for their patients. For most laryngectomy patients, treatments attempting laryngeal preservation, particularly if associated with compromised survival, may not be warranted.

Adult↗
PubMed1997

[Treatment of acute lymphoblastic leukemia of young adults (15-22 years of age): results of co-operative study with internal medicine and pediatrics].

Ten young adults (15-22 years of age) with acute lymphoblastic leukemia were treated with the protocol of internal medicine and pediatrics co-operative study group since 1989. All patients had complete remission within 5 weeks. Four of 6 patients of low risk group (less than 30,000/microliter of WBC count at diagnosis) and 1 of 4 patients of high risk group have continued the complete remission. Three patients relapsed in bone marrow (BM), and 2 patients in both BM and central nervous system (CNS). All patients could be treated without serious complications except for infection. We obtained the good results of treatment for the low risk group, but did not for the high risk group in this study. Little is known about acute lymphoblastic leukemia in young adults because these individuals are at the borderline age between internal medicine and pediatrics. Taken together with the psychologically distinct age of these patients, it is necessary to establish a closer relationship between internal medicine and pediatrics.

Adolescent↗
PubMed1996

Primary meningeal lymphoma presenting solely with blindness: a report of an autopsy case.

A 64-year-old woman was admitted because of progressive paraplegia. She had a history of unexplained blindness which had developed gradually 1 year earlier. The contrast-enhanced CT showed a small mass at the sella turcica. The funduscopy showed merely atrophic discs. The lumbar puncture revealed marked pleocytosis (cell count: 10.4 x 10(9)/l) and a diagnosis of meningeal lymphoma was made by the cytology of the cerebrospinal fluid. No lymphomatous lesions were detected outside of the central nervous system (CNS) and the patient received whole brain irradiation together with intrathecal chemotherapy. However, there was no improvement in vision or other neurological activities. Eventually the patient died of interstitial pneumonia 2 months after admission. The autopsy revealed a residual B-cell lymphoma existing only in the leptomeninges of medulla oblongata. The optic nerves were atrophic macroscopically and massive gliosis was seen microscopically. In addition, cytomegalovirus infection was observed in the lungs and adrenal glands but not in the CNS. This patient must have had a primary meningeal lymphoma. The mechanism of the visual loss of this patient is discussed.

Atrophy↗
PubMed1996

Inhibitory effect of magnesium L-ascorbyl-2-phosphate (VC-PMG) on melanogenesis in vitro and in vivo.

BACKGROUND: An inhibitory effect of ascorbic acid (AsA) on melanogenesis has been described. However, AsA is quickly oxidized and decomposed in aqueous solution and thus is not generally useful as a depigmenting agent. OBJECTIVE: Our purpose was to examine the effect on pigmentation of magnesium-L-ascorbyl-2-phosphate (VC-PMG), a stable derivative of AsA. METHODS: Percutaneous absorption of VC-PMG was examined in dermatomed human skin, and its effect on melanin production by mammalian tyrosinase and human melanoma cells in culture was also measured. A 10% VC-PMG cream was applied to the patients. RESULTS: VC-PMG suppressed melanin formation by tyrosinase and melanoma cells. In situ experiments demonstrated that VC-PMG cream was absorbed into the epidermis and that 1.6% remained 48 hours after application. The lightening effect was significant in 19 of 34 patients with chloasma or senile freckles and in 3 of 25 patients with normal skin. CONCLUSION: VC-PMG is effective in reducing skin hyperpigmentation in some patients.

Ascorbic Acid↗
PubMed1996

The interaction of agouti signal protein and melanocyte stimulating hormone to regulate melanin formation in mammals.

Important regulatory controls of melanogenesis that operate at the subcellular level to modulate the structural and/or the functional nature of the melanins and melanin granules produced in melanocytes are reviewed. Melanocyte stimulating hormone and agouti signal protein have antagonistic roles and possibly opposing mechanisms of action in the melanocyte. In the mouse, melanocyte stimulating hormone promotes melanogenic enzyme function and elicits increases in the amount of eumelanins produced, while agouti signal protein reduces total melanin production and elicits the synthesis of pheomelanin rather than eumelanin. We are now beginning to understand the complex controls involved in regulating this switch at the molecular and biochemical levels. The quality and quantity of melanins produced by melanocytes have important physiological consequences for melanocyte function and undoubtedly play important roles in the various functions of the melanins per se, including hair and skin coloration and photoprotection.

Agouti Signaling Protein↗
PubMed1995

Changes in expression of putative antigens encoded by pigment genes in mouse melanomas at different stages of malignant progression.

Cutaneous melanomas of Tyr-SV40E transgenic mice (mice whose transgene consists of the tyrosinase promoter fused to the coding regions of simian virus 40 early genes) strikingly resemble human melanomas in their development and progression. Unlike human melanomas, the mouse tumors all arise in genetically identical individuals, thereby better enabling expression of specific genes to be characterized in relation to advancing malignancy. The products of pigment genes are of particular interest because peptides derived from these proteins have been reported to function as autoantigens with immunotherapeutic potential in some melanoma patients. However, the diminished pigmentation characteristic of many advanced melanomas raises the possibility that some of the relevant products may no longer be expressed in the most malignant cells. We have therefore investigated the contributions of several pigment genes in melanotic vs. relatively amelanotic components of primary and metastatic mouse melanomas. The analyses reveal marked differences within and among tumors in levels of mRNAs and proteins encoded by the wild-type alleles at the albino, brown, slaty, and silver loci. Tyrosinase (the protein encoded by the albino locus) was most often either absent or undetectable as melanization declined. The protein encoded by the slaty locus (tyrosinase-related protein 2) was the only one of those tested that was clearly present in all the tumor samples. These results suggest that sole reliance on targeting tyrosinase-based antigens might selectively favor survival of more malignant cells, whereas targeting the ensemble of the antigens tested might contribute toward a more inclusive and effective antimelanoma strategy.

Animals↗
PubMed1995

T cell-rich B cell lymphoma bearing Epstein-Barr virus in tumor cells: a case of IBL-T-like lesion following Lennert's lesion.

A case of T cell-rich B cell lymphoma (TCRBCL) with Epstein-Barr virus (EBV) infection in tumor cells is reported. A 50 year old male developed right cervical lymph node swelling in July 1988. Initial biopsy in April 1989 demonstrated many scattered Hodgkinoid atypical cells with Lennert's lesion. After partial remission following chemotherapy, the lymph nodes enlarged again, and a second biopsy in February 1991 showed an IBL-T-like lesion. Only a small number of Hodgkinoid atypical cells were still observed. After apparently, complete remission, the lesion soon recurred and the patient died in November 1992. Immunohistochemically the Hodgkinoid cells were positive for L26, but negative for LN2, LN3, UCHL-1, MT1, lysozyme, Ber-H2 and Leu-M1. Reactivity for immunoglobulins showed false-positive because of polyclonal staining. IgH monoclonality was detected by the polymerase chain reaction method in the first biopsied specimen, and by Southern blotting in the second biopsied snap-frozen specimen. Monoclonal TCR beta rearrangement was not detected. The Hodgkinoid atypical cells were positive for EBV-encoding RNA by in situ hybridization, and LMP-1 by immunostaining. Occasionally, EBV-bearing immunoblastic, medium sized, or small lymphocytic cells were also observed. This case indicates the possibility that EBV is related to the pathogenesis of TCRBCL.

Blotting, Southern↗
PubMed1995

The expression of tyrosinase, tyrosinase-related proteins 1 and 2 (TRP1 and TRP2), the silver protein, and a melanogenic inhibitor in human melanoma cells of differing melanogenic activities.

The expression of various melanogenic proteins, including tyrosinase, the tyrosinase-related proteins 1 (TRP1) and 2 (TRP2/DOPAchrome tautomerase), and the silver protein in human melanocytes was studied in six different human melanoma cell lines and compared to a mouse derived melanoma cell line. Analysis of the expression of tyrosinase, TRP1, TRP2, and the silver protein using flow cytometry revealed that in general there was a positive correlation between melanin formation and the expression of those melanogenic enzymes. Although several of the melanoma cell lines possessed significant activities of TRP2, the levels of DOPAchrome tautomerase in extracts of human cells were relatively low compared to those in murine melanocytes. Melanins derived from melanotic murine JB/MS cells, from melanotic human Ihara cells and HM-IY cells, from sepia melanin, and from C57BL/6 mouse hair were chemically analyzed. JB/MS cells, as well as Ihara cells and HM-TY cells, possessed significant amounts of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derived melanins, this being dependent on the activity of TRP2. Kinetic HPLC assays showed that 5,6-dihydroxyindole (DHI) produced during melanogenesis was metabolized quickly to melanin in pigmented KHm-1/4 cells, whereas DHI was stable in amelanotic human SK-MEL-24 cells. A melanogenic inhibitor that has been purified from SK-MEL-24 cells that suppressed oxidation of DHI in the presence or absence of tyrosinase, but had no effect on DHICA oxidation. The sum of these results suggests that the expression of melanogenic enzymes as well as the activity of a melanogenic inhibitor are critical to the production of melanin synthesis in humans.

Animals↗
PubMed1995

Comparative analysis of melanins and melanosomes produced by various coat color mutants.

Pigmentation in the skin, hair, and eyes of animals is influenced by a number of genes that modulate the activity of melanocytes, the intervention of enzymatic controls at different stages of the melanogenic process, and the physico-chemical properties of the final pigment. The results of combined phenotypic, ultrastructural, biochemical, and chemical analyses of hairs of a variety of defined genotypes on a common genetic background performed in this study are consistent with the view that pigmentation of dark to black hairs results from the incorporation of eumelanin pigments whereas that of yellow hairs results from the incorporation of eu- and pheomelanins. It is also clear that relatively minor differences in melanin content can have dramatic effects on visible hair color. A good correlation was found for expression of (and enzyme activities associated with) TRP1 and TRP2 with eumelanin synthesis and eumelanosome production.

Animals↗