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J L Fink

Publications and source records attributed to J L Fink.

At least 19 recordsLinked to original sources
PubMed2001

Temporal gene regulation during HIV-1 infection of human CD4+ T cells.

CD4(+) T-cell depletion is a characteristic of human immunodeficiency virus type 1 (HIV-1) infection. In this study, modulation of mRNA expression of 6800 genes was monitored simultaneously at eight time points in a CD4(+) T-cell line (CEM-GFP) during HIV infection. The responses to infection included: (1) >30% decrease at 72 h after infection in overall host-cell production of monitored mRNA synthesis, with the replacement of host-cell mRNA by viral mRNA, (2) suppression of the expression of selected mitochondrial and DNA repair gene transcripts, (3) increased expression of the proapoptotic gene and its gene p53-induced product Bax, and (4) activation of caspases 2, 3, and 9. The intense HIV-1 transcription resulted in the repression of much cellular RNA expression and was associated with the induction of apoptosis of infected cells but not bystander cells. This choreographed host gene response indicated that the subversion of the cell transcriptional machinery for the purpose of HIV-1 replication is akin to genotoxic stress and represents a major factor leading to HIV-induced apoptosis.

CD4-Positive T-Lymphocytes↗
PubMed2000

Emma & the med error.

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Adaptation, Psychological↗
PubMed1997

Human epidermal melanocyte and keratinocyte melanotropin receptors: visualization by melanotropic peptide conjugated macrospheres (polyamide beads).

The objectives of this research were to determine whether melanotropin receptors are characteristic membrane markers of human epidermal melanocytes. Methodologies were developed to visualize these receptors by light microscopy. Multiple copies (up to a thousand) of [Nle4,D-Phe7] alpha-MSH, a superpotent analog of alpha-melanocyte stimulating hormone (alpha-MSH), were conjugated to a macromolecular carrier, large polyamide beads (macrospheres). Incubation in the presence of the I conjugated macrospheres resulted in binding of human epidermal melanocytes to the macrospheres. Specificity of the binding of melanocytes to the melanotropin-conjugated macrospheres was demonstrated by several studies: (i) Binding of melanocytes to the conjugate was specific since it could be blocked by prior incubation of the cells in the presence of the unconjugated hormone analog; (ii) The macrospheres after removal of the bound ligand did not bind to the melanocytes; (iii) Another peptide hormone ligand (e.g., a substance-P analog) attached to the macrospheres failed to bind to the melanocytes; (iv) B16/F10 mouse melanoma cells known to express melanotropin receptors bound to the macrospheres; (v) Cells of nonmelanocyte origin (e.g., mammary cancer cells, lung cancer cells, fibroblasts) did not bind to the macrospheres. One exception was that human epidermal keratinocytes also expressed melanotropin receptors as determined by all the criteria established for epidermal melanocytes. Thus, cell specific melanotropin receptors appear to be characteristic cell surface markers of epidermal melanocytes and keratinocytes.

Animals↗
PubMed1997

Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells.

Loss of DNA mismatch repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in mismatch repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA mismatch repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Melanotropic peptide receptors: membrane markers of human melanoma cells.

The objectives of this research were to determine whether melanotropin receptors are characteristic (constant) membrane markers of human melanoma cells. Methodologies were developed to visualize these receptors by fluorescence microscopy. Multiple copies (10-20) of both [Nle4,D-Phe7]alpha-MSH, a superpotent analog of alpha-melanocyte stimulating hormone (alpha-MSH), and a fluorophore, were conjugated to polyvinyl alcohol (PVA). Incubation in the presence of the multivalent macromolecular conjugate (FITC-PVA-MSH) resulted in binding of human epidermal melanocytes and keratinocytes and human melanoma cells (both melanotic and amelanotic) to the fluorescent conjugate. Binding of the conjugate to the cells exhibited a unique cluster pattern (capping) suggesting a receptor internalization related phenomenon. Most importantly, every cell of every melanoma cell line, melanotic or amelanotic, possessed receptors as visualized by fluorescence microscopy. Since the cells were not synchronized, some binding apparently took place during all phases of the cell cycle. Therefore, receptor expression appears not to be cell-cycle dependent. Specificity of binding of FITC-PVA-MSH was demonstrated by several studies. (i) Binding of the conjugate to melanoma cells could be blocked by prior incubation of the cells in the presence of the unconjugated hormone analog; [Nle4,D-Phe7]alpha-MSH. (ii) The macromolecular conjugate lacking bound ligand (FITC-PVA) did not bind to the melanoma cells. (iii) Another peptide, a substance-P analog, attached to the substrate (FITC-PVA-SP) failed to bind to the cells. (iv) With the exception of keratinocytes, other cells of nonmelanocyte origin (e.g., fibroblasts, spleen, liver, kidney cells, and mammary cancer cells, lung cancer cells) did not bind to the conjugate. Thus, cell-specific melanotropin receptors appear to be characteristic cell surface markers of epidermal melanocytes, keratinocytes, and melanoma cells. In several human melanoma cell lines these receptors appeared to be functional since [Nle4,D-Phe7]alpha-MSH stimulated tyrosinase activity. Fluorescent melanotropin conjugates might prove useful in determining whether all human melanoma (primary and metastatic) tumors possess such receptors. These receptors might then provide targets for melanotropic peptides for the identification, localization, and chemotherapy of melanoma.

Animals↗
PubMed1996

Melanocortin receptors: identification and characterization by melanotropic peptide agonists and antagonists.

Hormones are chemical messengers released from cells to act on and control the activity of other cells. Hormonal ligands initiate their actions by interacting with receptive substances (Langley, 1906) of the target cells. These receptors are proteins that are either integral components of the cell membrane or are localized cytoplasmically within cells. Ligand-receptor interaction results in either the stimulation or inhibition of cellular activity. Since most hormones bind rather specifically to receptors possessed by their target cells, labeling of hormonal ligands can be utilized to identify and localize cells within an animal. In this report we discuss what is presently known about melanocortin receptors (MCRs) as studied by the use of labeled melanotropic peptide ligands.

Amino Acid Sequence↗
PubMed1996

Human epidermal melanocyte and keratinocyte melanocortin receptors: visualization by melanotropic peptide conjugated microspheres (latex beads).

The objectives of this research were to determine whether melanocortin receptors are characteristic (constant) membrane markers of human epidermal melanocytes. Methodologies were developed to visualize melanotropin receptors by scanning electron microscopy (SEM). Multiple copies (up to a hundred) of [Nle4,D-Phe7]alpha-MSH, a superpotent analog of alpha-melanocyte stimulating hormone (alpha-MSH), were conjugated to a macromolecular carrier (latex beads: microspheres). Incubation in the presence of the melanotropin-conjugated microspheres resulted in binding of human normal epidermal melanocytes to the beads. Almost every (possibly all) melanocyte possesses melanocortin receptors as visualized by SEM. Specificity of binding of the macromolecular conjugate was demonstrated by several studies: 1) Binding of melanocytes to the microspheres was specific since it could be blocked by prior incubation of the cells in the presence of the unconjugated hormone analog; 2) microspheres lacking bound ligand did not bind to the melanocytes; 3) microspheres that were first treated with reducing agents (e.g., dithiothreitol) did not subsequently bind to melanocytes; 4) another peptide hormone ligand (e.g., a substance-P analog) attached to the latex beads failed to bind to the cells; 5) B16/F10 mouse melanoma cells known to express melanocortin receptors bound to the microspheres; and 6) cells of nonmelanocyte origin (e.g., mammary cancer cells, small-cell lung cancer cells, fibroblasts) did not bind to the macromolecular conjugate. One exception was that human epidermal keratinocytes also expressed melanocortin receptors as determined by all the criteria established above for epidermal melanocytes. Thus, cell specific melanocortin receptors appear to be characteristic cell surface markers of epidermal melanocytes and keratinocytes.

Cells, Cultured↗
PubMed1995

The melanotropic peptide, [Nle4,D-Phe7] alpha-MSH, stimulates human melanoma tyrosinase activity and inhibits cell proliferation.

Seventeen human melanoma cell (HMC) lines, both melanotic and amelanotic, were incubated in the continuous presence of a potent melanotropic peptide hormone analog, [Nle4,D-Phe7] alpha-MSH, for 72 hr with daily changes of medium. Only one cell line (HD, melanotic) consistently responded to the hormone analog by increased tyrosinase activity. Three (one melanotic, two amelanotic) of the HMC lines also failed to respond to the peptide by either increased or decreased enzyme activity when incubated continuously in the presence of the peptide for longer periods of time (6,15,27,43 days). The HD cell line, however, again responded with increasingly enhanced basal enzyme activity the longer the cells were incubated in the presence of the melanotropin. One amelanotic cell line (C8161) responded with enhanced enzyme activity when grown to confluency in the continuous presence of the peptide. Basal tyrosinase activity of the C8161 cell line may have increased as cell density in the flasks increased. These results suggest that under conditions of increased cell number, phenotypic expression of tyrosinase activity in so called "amelanotic" (tyrosinase-negative) cells is increased and can be enhanced further by stimulation with a melanotropic peptide. Under conditions of increased cell number, the presence of [Nle4,D-Phe7] alpha-MSH caused morphological differentiation (shape change); the cells became enlarged and very dendritic. The number of cells in monolayer (surface of the flask) and in the medium were drastically reduced in both melanotic and "amelanotic" cell lines incubated with [Nle4,D-Phe7] alpha-MSH. The data support other published reports that melanotropic peptides inhibit human melanoma cell growth (proliferation) in vitro, most likely through a cytostatic mechanism. [Nle4,D-Phe7] alpha-MSH also exhibited a prolonged (residual) inhibitory action on HD cell proliferation. In other words, inhibition of cell growth (proliferation) of the HMCs was evident even several days after removal of the melanotropic peptide from the incubation medium.

Animals↗
PubMed1991

Legal issues--1991.

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Pharmacy Service, Hospital↗
PubMed1989

Legal issues associated with pharmacokinetic software.

Legal issues associated with the use of pharmacokinetic computer software are discussed. One issue involves the physician's reliance on the pharmacist, as a drug therapy expert, to provide consultation on drug dosages. Another issue is the problem of liability associated with the software and how this relates to the physician, the pharmacist, and those who designed, manufactured, and sold the software. The legal concept of negligence as it relates to medical computer software is discussed. Although the programmer and the manufacturer are responsible for verifying that the program does what it purports to do, the user must exercise due care in identifying any program limitations that might influence the accuracy of a consultation. Clinical perspective, effective validation techniques, and critical selection will help to ensure that pharmacokinetic computer software is developed, purchased, and used safely and effectively.

Drug Therapy, Computer-Assisted↗