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Biomedical subjects

W M Lee

Publications and source records attributed to W M Lee.

At least 163 records · Page 9Linked to original sources
PubMed1990

Cardiomyopathy unrecognized as a cause of hepatic failure.

Two patients with similar symptoms referred for diagnosis and treatment of hepatic failure subsequently proved to have cardiomyopathy as the cause of their hepatic decompensation. Except for fatigue and edema, symptoms of congestive heart failure were absent and no history of dyspnea, orthopnea, or paroxysmal nocturnal dyspnea could be elicited. Hepatomegaly was present in both patients, but neck venous distension and hypotension were not apparent, and both patients were able to lie flat. The diagnosis of cardiomyopathy was made by echocardiogram showing global hypokinesis and low ejection fractions; right atrial pressures were markedly increased. Liver biopsies demonstrated centrilobular necrosis and congestion. Treatment for heart failure led to a prompt response in both patients with rapid return of all hepatic parameters toward normal. Paradoxically, our patients had striking evidence of hepatic failure and a notable absence of symptoms and signs of congestive heart failure. An awareness of this unique presentation may avoid prolonged evaluations in such critically ill patients.

Adult↗
PubMed1990

Acetaminophen hepatotoxicity in the alcoholic.

In a retrospective review from 1987 to 1989, we identified seven alcoholics who had severe acute hepatocellular injury soon after using acetaminophen for therapeutic purposes and who had no suicidal intent. All had markedly elevated serum transaminase values (aspartate aminotransferase greater than 4000 U/L) and prolonged prothrombin times. Three died. Use of acetaminophen by the alcoholic patient is potentially lethal.

Acetaminophen↗
PubMed1990

Domains of human c-myc protein required for autosuppression and cooperation with ras oncogenes are overlapping.

Amino acids 106 to 143 and 354 to 433 of the human c-myc protein (439 amino acids) were shown to be required for the protein to suppress c-myc gene transcription and were found to exactly overlap with those necessary for c-myc to cooperate with ras oncogenes in the transformation of rat embryo fibroblasts. The essential carboxyl-terminal region harbors structural motifs (a basic region, a helix-loop-helix motif, and a "leucine zipper"), which, in other proteins, can mediate dimerization and sequence-specific DNA binding.

Animals↗
PubMed1990

Interferon as treatment for viral hepatitis: a progress report.

Treatment of chronic hepatitis with interferon is in its infancy and it is likely that information that we learn today will markedly improve the treatment that is offered tomorrow. The limitations of interferon treatment at the present time are the lack of complete predictable responses in approximately half the patients and the relatively high relapse rates observed thus far. It is predicted that higher doses will result in better response and lower relapse rates, but this remains to be seen. The cost and the frequency of side effects will likely be significantly increased by escalation of dose, but the chance of eradicating an otherwise untreatable and not benign condition is tempting and will continue to challenge our best efforts.

Hepatitis B↗
PubMed1990

Definition of the activities and properties of c-myc required to inhibit cell differentiation.

Previous studies have shown that high levels of c-myc inhibit cell differentiation. The goal of this study was to define the activities and properties of c-myc that are necessary and/or sufficient for this effect. A series of mutant human c-myc genes were stably transfected into the 3T3-L1 preadipocyte cell line and assayed for their capacity to block differentiation into adipocytes. Results of the differentiation tests were then correlated with other known activities and properties of the mutants. Our studies show that the ability of c-myc to inhibit 3T3-L1 cell differentiation requires its transforming activity, and the ability of c-myc to bind sequence-nonspecific DNA and to form oligomers is not sufficient for this effect. Thus, the ability of c-myc to inhibit cell differentiation may be central to its role as a transforming oncogene.

Adipose Tissue↗
PubMed1990

Hepatic infarction associated with eclampsia.

Pregnancy-related liver diseases are complex in presentation and oftentimes confusing to clinicians, leading to misdiagnoses and unwarranted or delayed therapies. The exact pathogenesis of these disorders and their relationship to pre-eclampsia/eclampsia is unclear, thus making categorization difficult. We present a patient who in the third trimester of pregnancy developed severe abdominal pain, fever and transaminases greater than 30 times normal. The patient's laboratory data, abdominal CT scan, abdominal MRI scan, liver-spleen scan and liver biopsy performed 28 days postpartum subsequently confirmed the diagnosis of hepatic infarction. Hepatic infarction is a rare complication of late pregnancy usually associated with severe eclampsia that has distinctive histologic and laboratory findings. Recognition of infarction as a separate entity among the spectrum of the pregnancy-related liver disorders should help avoid unneeded delay in diagnosis or inappropriate treatment of these critically ill patients.

Adolescent↗
PubMed1989

Nuclear and nucleolar targeting sequences of c-erb-A, c-myb, N-myc, p53, HSP70, and HIV tat proteins.

Protein import into the cell nucleus requires specific binding of nuclear proteins to the nuclear pore complex. Based on amino acid sequence "motifs" of known nuclear targeting signals, we identified peptides within a number of nuclear proteins with likely nuclear targeting potential and tested their function by transfecting into cells fusion genes that produce the cytoplasmic "reporter" protein, pyruvate kinase (PK), joined to the test sequence. Sequences within c-myb (PLLKKIKQ), N-myc (PPQKKIKS), p53 (PQPKKKP), and c-erb-A (SKRVAKRKL) oncoproteins that direct PK hybrids into the nucleus were identified. A peptide (GRKKRRQRRRAP) of the human immunodeficiency virus (HIV) tat protein (Tat), which contains two short basic regions, targets fusion proteins to the nucleolus. The COOH-terminal basic Tat region (QRRRAP) does not target PK hybrid proteins into the nucleus, but mutation of two basic amino acids in this region decreases but does not abolish nucleolar accumulation mediated by the entire Tat nucleolar targeting sequence. Moreover, the c-Myc nuclear targeting sequence fused to the COOH-terminal basic Tat region (PAAKRVKLDQRRRAP) effectively localizes PK hybrids to the nucleus and nucleolus. A similar sequence (FKRKHKKDISQNKRAVRR) in the human heat-shock protein HSP70 also localizes PK to the nucleus and nucleolus.

Amino Acid Sequence↗
PubMed1989

Effects of cellular transformation on expression of plasminogen activator inhibitors 1 and 2. Evidence for independent regulation.

Expression of plasminogen activators (PA) has been reported to be associated with invasive tumor growth and increased metastatic ability. In order to delineate changes in PA and PA inhibitor (PAI) expression that accompany cellular transformation, we studied oncogene-containing variants of the Rat-1 cell line. We report here that transfection of the oncogenes v-src, erbB, c-myc, v-myc, N-myc, and EJras into these cells does not result in detectable PA activity in conditioned media or cell extracts. In addition, Northern blot analysis fails to demonstrate urokinase mRNA in Rat-1 cells or transfectants. Moreover, cells transformed by EJras and v-src but not other oncogenes secrete an active placental-type PAI, PAI-2. Using inducible EJras constructs, we find that increased PAI-2 gene expression is detectable within 6-12 h after treatment with the inducing agent. Peak expression of PAI-2 mRNA is increased 10-15-fold over base line, and high levels are maintained for at least 72 h. In contrast to the results with PAI-2, secretion of endothelial-type PAI-1 into conditioned media is sharply down-regulated by several oncogenes. Thus, we have found that PAI-1 and PAI-2 are independently regulated in transformed variants of Rat-1 cells. The specific induction of PAI-2 in cells transformed by oncogenic ras and src suggests that this protease inhibitor may have a previously unsuspected role in malignancy.

Animals↗
PubMed1989

Involvement of the 'leucine zipper' region in the oligomerization and transforming activity of human c-myc protein.

c-Myc plays a part in the regulation of important cellular processes such as growth, differentiation and neoplastic transformation. Although c-myc gene structure and expression are well characterized, the function and biochemical properties of the protein are less well understood. Human c-myc is a 439-amino acid phosphoprotein which binds DNA in vitro and belongs to a discrete subset of nuclear proteins. Using the human c-myc mutants generated by linker-insertion and deletion mutagenesis, we have defined regions of the protein that are important for its transforming activities and its nuclear localization. Here, we show that human c-myc exists as an oligomer in vitro and use mutant proteins to localize the oligomerization domain to a carboxyl-terminal peptide containing the 'leucine zipper' motif. The 'leucine zipper' describes a structure found in a number of DNA-binding proteins that contains leucines occurring at intervals of every seventh amino acid in a region predicted to be alpha-helical. The 'leucine zipper' might mediate dimerization by intermolecular interdigitation of the leucine side-chains. We show that a c-myc mutant, which is inactive but can oligomerize, dominantly inhibits the cotransforming activity with wild-type c-myc of rat embryo cells, whereas inactive mutants which cannot oligomerize properly because of deletions in the oligomerization domain are recessive.

Animals↗
PubMed1989

The myc family of nuclear proto-oncogenes.

Several members of the myc family of proto-oncogenes have been described, and some (c-, N-, and L-myc) have been characterized in considerable detail. They are united by a common gene structure and nucleotide homologies that were used to identify some of them initially. Their protein products also have scattered regions of amino acid identity or homology. Although the cellular activities of the various proteins are unknown, some members may play a role in regulating cell growth and differentiation. They share the ability to cooperate with an activated ras gene and cotransform embryonic rodent cells. In naturally occurring tumors, the members of the myc family of oncogenes appear to be activated by genetic changes (proviral insertion, chromosomal translocation, and gene amplification) that augment or otherwise disrupt normally regulated expression. The members of this family of genes differ markedly in their tissue specificity and developmental regulation of expression. This may account in part for the frequent appearance of activated c-myc genes in a wide variety of neoplasms and the limited appearance of activated N- and L-myc genes in tumors of embryonic or neural origin. The c-myc gene may be activated in tumors by a variety of mechanisms, whereas N- and L-myc appear to be activated only by gene amplification. Regulation of expression of the different myc genes also appears to occur by different mechanisms. Finally, the products of the different genes differ in may regions of the protein, and this divergence probably reflects their specific and individual functions.

Humans↗
PubMed1989

DNA-binding domain of human c-Myc produced in Escherichia coli.

We have identified the domain of the human c-myc protein (c-Myc) produced in Escherichia coli that is responsible for the ability of the protein to bind sequence-nonspecific DNA. Using analysis of binding of DNA by proteins transferred to nitrocellulose, DNA-cellulose chromatography, and a nitrocellulose filter binding assay, we examined the binding properties of c-Myc peptides generated by cyanogen bromide cleavage, of mutant c-Myc, and of proteins that fuse portions of c-Myc to staphylococcal protein A. The results of these analyses indicated that c-Myc amino acids 265 to 318 were responsible for DNA binding and that other regions of the protein (including a highly conserved basic region and a region containing the leucine zipper motif) were not required. Some mutant c-Mycs that did not bind DNA maintained rat embryo cell-cotransforming activity, which indicated that the c-Myc property of in vitro DNA binding was not essential for this activity. These mutants, however, were unable to transform established rat fibroblasts (Rat-1a cells) that were susceptible to transformation by wild-type c-Myc, although this lack of activity may not have been due to their inability to bind DNA.

Amino Acid Sequence↗
PubMed1989

A procedure for purifying jack bean urease for clinical use.

Urease with a purity meeting the requirements of analytical use was purified from jack bean meal through steps consisting of 20% acetone extraction, heat treatment, acid precipitation, and lyophilization. For extraction of urease, one part of bean meal was mixed with 5 parts of 20% acetone containing 1 mM EDTA and 1 mM 2-mercaptoethanol, and stirred at 20 degrees C for 5 min. Milky substances in the extract were removed by heat treatment. Urease in the clear yellow supernatant was precipitated by adjusting the pH of the solution to 5.4 with citric acid. The acid precipitated urease was neutralized by dissolving in 0.015 M phosphate buffer, pH 8.5 (final pH 6.8 to 7.0) and then lyophilized. By this procedure, the purity of the enzyme was increase 14.7 fold, the recovery of activity was 63%, and the yield was 6.75 g from 1 kg of bean seeds. The specific activity of the preparation was 411 units/mg protein (240 units/mg solid), and the free ammonia content was less than 0.01 microgram per unit. Some other proteins were present in the urease preparation as examined by gel filtration and gradient polyacrylamide gel electrophoresis. The molecular weight of the enzyme estimated by gel filtration was 480,000. However, two urease activity bands with molecular weight of 230,000 and 480,000 were observed in the polyacrylamide gel electrophoregram. From the result of determination of blood urea nitrogen (BUN), this simple purification procedure could be used for practical preparation of urease from jack bean meal for clinical analysis.

Acetone↗
PubMed1989

Effects of c-myc overexpression on the growth characteristics of MCF-7 human breast cancer cells.

Amplification and overexpression of the c-myc protooncogene have been observed in 22 to 32% of primary human breast cancers, yet the exact role of this gene in mammary tumor progression is unclear. We sought to elucidate this role by overexpressing cloned myc genes in the human breast carcinoma cell line MCF-7. We found that augmented myc RNA levels were associated with slower in vitro growth rates, but that estrogen receptor levels, the requirement for estrogen for in vivo growth in castrated athymic nude mice, and sensitivity to the antiestrogen, tamoxifen were not altered. Furthermore, chemosensitivity to the cytotoxic agent, Adriamycin, was not affected. Lastly, overexpression of a transfected myc gene did not suppress endogenous myc levels unlike the findings in lymphoma cells. Thus our data suggest that the effect of augmented myc expression in human breast cancer cells is complex and may not induce more malignant patterns of growth as has been suggested for other human cancers.

Animals↗
PubMed1989

Alterations in Gc levels and complexing in septic shock.

Septic shock involves increased generation of eicosanoids from arachidonic acid. Gc (vitamin D-binding protein) has been recently found to bind the parent molecule arachidonic acid but can also complex actin released as a result of tissue damage which causes displacement of bound arachidonic acid. Possible changes in serum levels of Gc and extent of complexing were therefore investigated in patients with gram-negative sepsis. As compared to healthy controls, serum levels of Gc were significantly decreased in patients with septic shock (P less than 0.01). Moreover, the percentages of Gc circulating in complexed form were significantly increased (P less than 0.01) and correlated strongly with disease severity, with levels often greater than 90% in patients who died (normal mean 8% +/- 3). These results suggest a hitherto unsuspected role for Gc in septic shock syndrome.

Actins↗
PubMed1988

Estrogen-induced post-transcriptional modulation of c-myc proto-oncogene expression in human breast cancer cells.

The effects of estradiol (E2) on c-myc proto-oncogene expression were studied in the estrogen receptor (ER)-positive human breast cancer cell line, MCF-7. A biphasic modulation in c-myc mRNA levels occurs during the first 24 h of E2 (1 nM) exposure and in the absence of changes in MCF-7 culture growth, with transcript levels rising 4-6-fold within 1 h, returning to near base-line level after 3-6 h, and increasing again after 24 h of exposure. In contrast, the growth-inhibiting antiestrogen, tamoxifen (1 microM), reduces c-myc to 20% of the pretreatment level within 3-6 h of exposure, and this early decline is followed by a gradual return toward base-line level after continuous 72-h treatment. In ER-negative cells there is no change in c-myc expression following E2 exposure. MCF-7 nuclear runon assays show that c-myc transcription rates remain unchanged from base line for 24 h after E2 administration; as well, cycloheximide inhibition of protein synthesis superinduces c-myc expression and prevents E2 modulation of transcript levels. These results indicate that post-transcriptional modulation of c-myc by E2 is mediated by a labile degradative protein or otherwise dependent on active protein synthesis. We also developed MCF/nm and MCF/dm sublines by transfecting normal cells with human c-myc exons 2-3, transcriptionally driven by a retroviral long terminal repeat. Expression of the transfected c-myc genes in these sublines remains constant and elevated 10-fold, while transcript levels from the endogenous proto-oncogene continue to be modulated by E2. These findings suggest that in ER-positive breast cancer cells, E2 can modulate c-myc mRNA levels by a post-transcriptional mechanism that depends on gene sequences upstream from c-myc exon 2.

Breast Neoplasms↗