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Biomedical subjects

A Hsu

Publications and source records attributed to A Hsu.

At least 73 records · Page 4Linked to original sources
PubMed1992

L-696,474, a novel cytochalasin as an inhibitor of HIV-1 protease. III. Biological activity.

L-696,474, an inhibitor of the HIV-1 protease, was discovered in extracts of the fungal culture Hypoxylon fragiforme (MF5511; ATCC 20995). L-696,474 is a novel cytochalasin with a molecular weight of 477 and an empirical formula of C30H39NO4. L-696,474 inhibited HIV-1 protease activity with an IC50 of 3 microM and the mode of inhibition was competitive with respect to substrate (apparent Ki = 1 microM). Furthermore, L-696,474 was not a slow-binding inhibitor. The inhibition due to L-696,474 was also independent of the HIV-1 protease concentration. L-696,474 was inactive against pepsin, another aspartyl protease; stromelysin, a zinc-metalloproteinase; papain, a cysteine-specific protease or human leucocyte elastase, a serine-specific protease. Two other novel cytochalasins (L-697,318 and L-696,475) isolated from the same culture were inactive against the HIV-1 protease. Commercially available cytochalasins B, C, D, E, F, H and J were inactive while cytochalasin A was as active as L-696,474 against the HIV-1 protease.

Cytochalasins↗
PubMed1991

HIV-1 protease inhibitory activity of L-694,746, a novel metabolite of L-689,502.

L-689,502 is a potent inhibitor of HIV-1 protease activity in vitro. Microbial biotransformations of L-689,502 by cultures belonging to the genus Streptomyces sp. were performed. Extracts of culture broths were examined for the production of metabolites of L-689,502 that could inhibit HIV-1 protease activity. One culture, MA 6804 (Streptomyces lavendulae, ATCC 55095), produced L-694,746 that, while being structurally related to L-689,502, is a novel metabolite and a potent inhibitor of HIV-1 protease.

Amino Acid Sequence↗
PubMed1991

Fixed drug eruptions: evidence for a cytokine-mediated process.

Fixed drug eruptions (FDE) are immunologic reactions to drugs which produce erythematous plaques or blisters that characteristically recur at the same cutaneous sites with repeated antigenic challenges. While a detailed pathogenesis of these lesions remains obscure, T-lymphocyte infiltration has been documented repeatedly. In this study, we tried to determine if FDE were mediated, at least in part, by cytokines, such as gamma-interferon. We examined biopsies from 6 cases of clinically well-documented FDE with an HLA-DR antibody, LN3, and an antibody to gamma IP-10 (IP-10), a protein expressed by keratinocytes, monocytes, lymphocytes and endothelial cells following exposure to gamma-interferon. We found staining of the dermal lymphocytes with anti-HLA-DR antibody in all 6 cases examined. Keratinocytes and endothelial cells showed only focal staining at the antibody concentrations used. In addition, there was keratinocyte staining with the IP-10 antibody at all levels of the epidermis, with accentuation in areas of blister formation. There was more intense staining of keratinocytes with the IP-10 antibody in cases with accumulations of HLA-DR positive lymphocytes in the dermis. We believe that these findings are consistent with the hypothesis that FDE represent cell-mediated immunologic responses to a variety of antigens, and further, that the histologic alterations can be explained, at least in part, by a cytokine-mediated process.

Adult↗
PubMed1991

HMB-45 monoclonal antibody recognizes an inducible and reversible melanocyte cytoplasmic protein.

HMB-45 is a monoclonal antibody directed against human melanoma cells and which stains epidermal and dermal melanoma cells, the junctional components of common and dysplastic melanocytic nevi, and melanocytes in fetal skin. In addition, melanocytes in a variety of reactive conditions have been shown to label with HMB-45, as have dermal melanocytes within Spitz and dysplastic nevi. No melanocytes in normal adult epidermis or in the dermis of common nevi have stained with HMB-45. In order to better understand the properties of this antibody, and of the melanocytes that react with it, we stained cultured human melanocytes grown in a variety of conditions. Melanocytes from human foreskins were grown for 2-3 weeks in MCDB 153 medium supplemented with insulin, epidermal growth factor, and bovine pituitary extract as a mixed population of keratinocytes and melanocytes. Some cells were transferred to basal medium MCDB 153 (unsupplemented) for periods ranging from 3-5 days, and a subset of these were returned to growth-factor supplemented medium. In all cases, S100 staining was used to confirm the presence of melanocytes. Melanocytes grown in complete medium showed strong granular cytoplasmic staining with HMB-45. Cells transferred to basal medium showed a markedly diminished staining intensity which was reversible within 3 days upon return of the cells to complete medium. The findings suggest that expression of the protein recognized by HMB-45 may be related to a growth factor present in complete medium, but missing from basal MCDB 153.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1991

Effect of 1,25-dihydroxyvitamin D3 on mesangial cell proliferation.

We have studied the effect of 1,25-dihydroxyvitamin D3 (1,25, (OH)2D3) on mesangial cell growth. Previous studies have shown that the monocyte-macrophage is the principal effector cell in immune-mediated nephritis; this cell infiltrates the glomerular mesangium, and its products may have important effects on the physiology of the mesangial cell. One of the substances produced by the activated macrophage is 1,25,(OH)2D3. We have investigated the effect of 1,25,(OH)2D3 on mesangial cell growth and found that this vitamin D metabolite suppresses the proliferation of mouse mesangial cells as assessed by mesangial cell tritiated thymidine uptake and by cell counts; this substance also antagonizes the mitogenic effect of epidermal growth factor on mesangial cell growth. By comparison, the vitamin D metabolite 25 hydroxyvitamin D3 has no significant suppressive effect on the proliferation of mesangial cells. It has also been possible to demonstrate that 1,25,(OH)2D3 could suppress the growth of mesangial cells that had been committed to proliferate by the prior addition of epidermal growth factor. The results of these studies are relevant to our understanding of the pathogenesis of the cellular abnormalities that occur in immune-mediated nephritis, and especially in subjects who have concurrent hypertension, because a segment of subjects with hypertension have demonstrable abnormalities in the levels of circulating 1,25,(OH)2D3.

Animals↗
PubMed1990

Neurofibromas and neurotized melanocytic nevi are immunohistochemically distinct neoplasms.

Neurofibromas are often clinically, as well as histologically, indistinguishable from completely neurotized melanocytic nevi. We tested the hypothesis that immunologic markers would differentiate the perineural fibroblasts and Schwann cells of neurofibromas from the neurotized cells of melanocytic origin. We examined eight partially neurotized acquired melanocytic nevi, three partially neurotized congenital melanocytic nevi, and five neurofibromas, with antibodies directed against S-100 protein, Leu-7(HNK-1), glial fibrillary acid protein (GFAP), and myelin-basic protein (MBP). A histologic diagnosis of neurofibroma was based on identification of a dermal proliferation of spindle-shaped cells with wavy nuclei, in a background of loose reticulated collagen. Neurotized nevi were diagnosed upon recognition of scattered nests of type A or B nevus cells, surrounded by basement membrane, present in the papillary dermis of lesions otherwise indistinguishable from neurofibromas. The congenital nevi were all large melanocytic nevi known to be present at birth. S-100 stained the majority of neoplastic cells in all neurofibromas, neurotized acquired nevi, and neurotized congenital nevi. Neurofibromas showed focal staining for Leu-7, GFAP, and MBP. In contrast, neurotized acquired and congenital nevi failed to express these markers. We believe that Leu-7, GFAP, and MBP may be helpful in differentiating neurofibromas from completely neurotized melanocytic nevi. The differences in the immunohistochemical profiles of neurofibromas and neurotized nevi support the concept that these neoplasms are histogenically distinct, despite their similar histologic appearance.

Antigens, Differentiation↗
PubMed1990

Recessive dystrophic epidermolysis bullosa skin displays a chronic growth-activated immunophenotype. Implications for carcinogenesis.

Epidermolysis bullosa represents a grouping of inherited skin diseases characterized by epidermal fragility and frequently wounded skin. The recessive dystrophic subtype of epidermolysis bullosa (RDEB) is characterized by extensive dermal scarring after healing of repeated epidermal injuries and by an unusually high incidence of squamous cell carcinoma occurring in chronically wounded skin. In contrast, the simplex form of epidermolysis bullosa usually heals without scarring and does not predispose to malignant neoplasms of the skin. The differences in scarring and the neoplastic potential of these two forms of epidermolysis bullosa prompted us to investigate growth activation and differentiation characteristics in epidermal keratinocytes in individuals with these disorders. The expression of filaggrin, involucrin, cytokeratins, and the growth activation marker psi-3 was examined by immunohistochemistry in skin biopsy specimens from four individuals with epidermolysis bullosa simplex and six individuals with RDEB. Previous experiments using this technique have demonstrated that these antibodies are good markers for identifying growth-activated keratinocytes in wounded and hyperplastic epidermis. All biopsy specimens of healed wounds in skin from patients with RDEB showed epidermis that reacted with antibodies to filaggrin, involucrin, specific cytokeratins, and psi-3 in a growth-activated pattern. This growth-activated phenotype was maintained in keratinocytes from previously wounded skin that had been healed for more than 2 years. The RDEB growth-activated phenotype detected by immunohistochemistry was not associated with microscopically detectable epidermal hyperplasia. In contrast, all cases of epidermolysis bullosa simplex examined showed an epidermal phenotype similar to that of keratinocytes in normal skin. Thus, healing with dermal scar formation in RDEB is associated with a persistent growth-activated immunophenotype of epidermal keratinocytes. This chronic growth activation state or failure of cells to differentiate in a normal fashion may be directly linked to the high incidence of squamous cell cancers in individuals with RDEB.

Adolescent↗
PubMed1990

Immunohistochemical demonstration of factor XIIIa expression in neurofibromas. A practical means of differentiating these tumors from neurotized melanocytic nevi and schwannomas.

Neurofibromas, schwannomas, and neurotized melanocytic nevi may closely resemble one another at the light microscopic level. We studied 10 neurofibromas, 10 schwannomas, and 10 partially neurotized melanocytic nevi immunohistochemically using an antibody directed against factor XIIIa to determine if this antibody might provide a useful method of differentiating these lesions. The cases were also stained with S100 protein. All of the neurofibromas stained intensely for factor XIIIa. The proportion of cells staining within the tumors varied from 30% to 70%. In contrast, none of the schwannomas and neurotized nevi studied demonstrated staining of tumor cells with this antibody. S100 protein was expressed by 100% of neurofibromas, schwannomas, and melanocytic nevi. Our findings suggest that factor XIIIa may provide a reliable and practical means of differentiating cutaneous neurofibromas from neurotized nevi and cutaneous schwannomas. Distinguishing between these different tumor types may be important in some clinical situations, particularly with respect to rendering a diagnosis of von Recklinghausen's neurofibromatosis. The differences in the immunohistochemical profiles of neurofibromas and neurotized nevi support the concept that these tumors are histogenetically distinct, despite their similar histologic appearances.

Antigens, Neoplasm↗
PubMed1990

"Activated" keratinocyte phenotype is unifying feature in conditions which predispose to squamous cell carcinoma of the skin.

While some cutaneous squamous cell carcinomas (SCC) arise from predisposing conditions such as burn scars, draining sinuses, and chronic, nonhealing wounds, the vast majority of these tumors arise from actinically damaged epidermis. It has been shown previously that keratinocytes within healing wounds show an "activated" immunophenotype when stained with antibodies to psi-3, involucrin, filaggrin, and cytokeratins. A similar pattern has been seen in keratinocytes from patients with recessive dystrophic epidermolysis bullosa (RDEB), in whom the incidence of cutaneous SCC is markedly increased. We tested the hypothesis that actinic keratoses (AK), recognized as precursors in the development of the majority of SCC, would show a similar activated immunophenotype when stained with the antibody panel described above. We examined 10 AK, biopsied from the facies and extremities of ten patients, ages 60 to 80, with antibodies to psi-3, involucrin, filaggrin, and AE1. All lesions examined had an immunostaining pattern indistinguishable from that seen in keratinocytes from patients with RDEB or within healing wounds. There was suprabasilar staining of keratinocytes with antibodies to psi-3 and AE1. Involucrin and filaggrin was expressed by all keratinocytes above the midstratum spinosum. Within the acrosyringia and acrotrichia, the staining pattern was that of the normal epidermis, i.e., AE1 staining of basal keratinocytes, granular layer staining of involucrin and filaggrin, and absence of psi-3 expression. These data suggest that an activated keratinocyte phenotype is a unifying feature in conditions which predispose to development of cutaneous SCC.

Aged↗
PubMed1990

Detection of the interferon-gamma-induced protein 10 in psoriasiform dermatitis of acquired immunodeficiency syndrome.

Interferon-gamma-induced protein 10 is a 10-kd protein produced by human keratinocytes following an exposure to interferon gamma. Keratinocytes within psoriatic plaques and within delayed-type hypersensitivity reactions have been shown to stain strongly with an affinity-purified rabbit antibody prepared against interferon-gamma-induced protein 10, suggesting a possible role for interferon gamma in the production of the lesions. A psoriasiform eruption has been seen in patients with acquired immunodeficiency syndrome (AIDS). Its severity appears to correlate with the degree of immunodeficiency in the early stages of AIDS. We stained 10 lesions of psoriasiform dermatitis of AIDS with the anti-interferon-gamma-induced protein 10 antibody using immunoperoxidase techniques. As controls, we studied 10 lesions of non-AIDS psoriasis, six lesions of seborrheic dermatitis with psoriasiform hyperplasia, one lesion of lichen simplex chronicus, and four biopsy specimens of normal skin from patients with AIDS. In addition, normal skin specimens taken from patients with AIDS and human immunodeficiency virus-negative patients at time of autopsy were examined. An identical, strong and diffuse staining pattern was seen in all cases of psoriasiform dermatitis of AIDS, non-AIDS psoriasis, seborrheic dermatitis, and lichen simplex chronicus. The specimens of normal skin showed only weak basal layer staining with anti-interferon-gamma-induced protein 10. Thus, the presence of interferon-gamma-induced protein 10 in keratinocytes was associated with psoriasiform hyperplasia and could be detected in both AIDS-associated and classic psoriasis.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Keratinocyte protein expression in rapidly regenerating epidermis following laser-induced thermal injury.

We examined 20 punch biopsies taken from five patients at varying intervals following CO2 laser-induced thermal injury. The regenerating epidermis was studied with monoclonal antibodies AE1 and AE3 (directed against low and high molecular weight keratins), and involucrin, a protein found within the cellular envelope of the most mature keratinocytes. Twenty-four hours following thermal damage, there was extensive spillage of keratins and involucrin into the papillary dermis and disarray of all constituents of the necrotic keratinocytes. Early ingrowth of basaloid keratinocytes weakly expressed AE1. By 1 week, keratinocytes expressed AE1 in varying intensities throughout the epidermis. AE3 was present in its normal distribution, staining all but the most basaloid keratinocytes. Involucrin stained cells deep within the epidermis. Six weeks following the initial injury, the staining pattern within the epidermis had returned to normal. Thus, it appears that the regenerating epidermis produces low molecular weight keratins in cells at all levels and forms premature cellular envelopes, perhaps as a protective measure, before expression of these constituents reverts to the normal pattern. These findings suggest that keratinocyte differentiation in wound-healing following laser-induced thermal injury is similar to that seen in other types of injury. Observed clinical differences may be attributable to differences in keratinocyte proliferative or migratory capabilities.

Adult↗