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Biomedical subjects

R Drews

Publications and source records attributed to R Drews.

At least 19 recordsLinked to original sources
PubMed2001

Hodgkin's lymphoma of T-cell type: clonal association with a CD30+ cutaneous lymphoma.

The derivation of Reed-Sternberg cells in Hodgkin's lymphoma has been a subject of great interest. In most cases, Reed-Sternberg cells seem to be derived from germinal center B cells. In few sporadic cases, a T-cell origin has been shown. This article supports the concept of a T-cell derivation for rare cases of Hodgkin's lymphoma and provides evidence of a novel mechanism of pathogenesis from chronic inflammation in the skin.

Base Sequence↗
PubMed2000

SMARCAD1, a novel human helicase family-defining member associated with genetic instability: cloning, expression, and mapping to 4q22-q23, a band rich in breakpoints and deletion mutants involved in several human diseases.

Members of the DEAD/H box-containing helicase superfamily include proteins essential to genome replication, repair, and expression. We report here the cloning and initial characterization of a novel human member of this protein family, designated hHel1 (human helicase 1), now designated SMARCAD1 by HUGO. This DEAD/H box-containing molecule has seven highly conserved sequence regions that allow us to place it in the SNF2 family of the helicase superfamily. Uniquely, though, hHel1 contains two DEAD/H box motifs, a property not reported to be shared by any other SNF2 family members. This defines a new subfamily consisting of hHel1 and its homologues. In addition to these DEAD/H box/ATP-binding motifs, hHel1 has a putative nuclear localization signal and several regions that may mediate protein-protein interactions. Expression analysis indicates that hHel1 transcripts are ubiquitous, with particularly high levels in endocrine tissue. We have mapped the gene for hHel1 to human chromosome 4q22-q23; this region is rich in breakpoints and deletion mutants of genes involved in several human diseases, notably soft tissue leiomyosarcoma, hepatocellular carcinoma, and hematologic malignancies. Our observation that human Hel1 gene overexpression is present in an E1A-expressing cell line with increased capacity for gene reactivation events by genomic rearrangement suggests that human Hel1 may play a role in genetic instability development.

Adenovirus E1A Proteins↗
PubMed2000

Lymphomatoid papulosis and anaplastic large cell lymphomas of the skin.

It is now generally accepted that primary CD30+ cutaneous lymphomas comprise a clinical and morphologic spectrum in which a clear distinction between lymphomatoid papulosis (LyP) and lymphoma cannot always be made. Management varies from observation in patients who have relatively asymptomatic, spontaneously remitting disease (as in LyP) to multiagent chemotherapy regimens with or without autologous stem cell transplantation in patients whose disease has spread to involve extracutaneous sites other than regional lymph nodes (as in disseminated CD30+ lymphoma). Choosing an appropriate management strategy requires correlation of the patient's clinical history (including symptoms) with physical exam and pathologic findings. The importance of clinicopathologic correlation cannot be overemphasized, because lesions with clinically "benign" behavior may appear "malignant" by pathology, and failure to interpret pathologic findings in accordance with the patient's clinical history and physical exam can result in unnecessary, overly aggressive, and potentially harmful treatments. This review highlights integration of clinical and pathologic features of these primary cutaneous CD30+ lymphoproliferative disorders.

Diagnosis, Differential↗
PubMed2000

Distinct effects of CD30 and Fas signaling in cutaneous anaplastic lymphomas: a possible mechanism for disease progression.

Lymphomatoid papulosis is part of a spectrum of CD30+ cutaneous lymphoproliferative disorders characterized by spontaneous tumor regression. The mechanism(s) of regression is unknown. In a recent study, a selective increase in CD30 ligand expression in regressing lesions of lymphomatoid papulosis and cutaneous CD30+ anaplastic large cell lymphoma was shown, suggesting that activation of the CD30 signaling pathway may be responsible for tumor regression, whereas no difference in Fas/Fas ligand expression was found between regressing and nonregressing lesions. Therefore we tested the effects of CD30 and Fas activation on three CD30+ cutaneous lymphoma cell lines (Mac-1, Mac-2 A, JK) derived from nonregressing tumors of two patients who had progressed from lymphomatoid papulosis to systemic anaplastic large cell lymphoma. To evaluate the effects of CD30 signaling, the cell lines were incubated with a CD30 agonistic antibody, HeFi-1. Proliferative responses, mitogen-activated protein kinase, and nuclear factor kappa B activities were determined with and without CD30 activation. Mac-1 and Mac-2 A showed increased proliferative responses to incubation with CD30 activating antibody, HeFi-1. Inhibition of the mitogen-activated protein kinase activity caused growth inhibition of the Mac-1, Mac-2 A, and JK cell lines. Activation of the Fas pathway induced apoptosis in all three cell lines. Taken together, these findings suggest that resistance to CD30-mediated growth inhibition provides a possible mechanism for escape of cutaneous anaplastic large cell lymphoma from tumor regression. Mitogen-activated protein kinase inhibitors are potential therapeutic agents for the treatment of advanced cutaneous anaplastic large cell lymphoma. J Invest Dermatol 115:1034-1040, 2000

Cell Division↗
PubMed1998

Genetic analysis of adenovirus E1A: induction of genetic instability and altered cell morphologic and growth characteristics are segregatable functions.

Single multifunctional oncoproteins contribute to genomic instability development, but relationships between one or more oncoprotein-associated activities and genetic changes accompanying tumor cell progression are uncertain. Using NIH 3T3 derivative EN/NIH 2-20 containing transcriptionally silent neomycin phosphotransferase gene (neo) integrants with undetectable spontaneous reactivations, we studied wild-type (WT) and mutant adenovirus E1A-induced neo reactivation by neo-allelic rearrangement. WT E1A expression, yielding differential splice transcripts 12S and 13S and resulting in altered cell morphologic and growth characteristics, produced neo reactivations in 9 of 21 subclones (median rate per cell, 35 x 10(-6); range, 0.33 x 10(-6) to 936 x 10(-6)). Only 3 of 17 cell lines expressing CTdl976, a '12S' functional equivalent inducing altered cell morphologic and growth characteristics while lacking the 13S trans activation domain, yielded neo reactivations (range, 0.33 x 10(-6) to 0.67 x 10(-6)). One of 21 subclones expressing NTdl646, an E1A mutant retaining the trans domain but lacking p300 binding activity and the ability to alter cell morphologic and growth characteristics, produced neo reactivations (8.7 x 10(-6)). Other E1A mutants, all lacking the ability to alter cell morphologic and growth characteristics while binding pRb but variously lacking the trans domain and binding for p107 and/or p300, displayed undetectable neo-reactivations. 98 EN/NIH 2-20 derivatives coexpressing complementary mutant E1As exhibited altered morphologic and growth features, but only 10 of these produced neo reactivations, and maximum rates (14 x 10(-6)) were substantially lower than those in comparably derived, morphologically altered E1AWT-expressing counterparts (497 x 10(-6)). These findings suggest that maximum rates of gene reactivations by genomic rearrangement require the collective activities of functional domains assembled in single multifunctional proteins (or complexes) while altered cell morphologic and growth characteristics may arise through comparable sets of functional domains distributed across more than one protein (or complex).

3T3 Cells↗
PubMed1997

Secretion of human furin into mouse milk.

We have previously described the expression of the human proprotein convertase furin or paired basic amino acid-cleaving enzyme, in mice transgenic for paired basic amino acid-cleaving enzyme and human Protein C (HPC). Here we show 100-fold or higher expression of furin in the mammary gland, compared with endogenous furin. Furin and recombinant HPC were detected in the same regions of the mammary gland and regulated similar to the endogenous whey acidic protein. In addition to the expected intracellular localization, furin was secreted into the milk as an 80-kDa form lacking the transmembrane and cytoplasmic domains. Furin present at levels of up to 40,000 units/ml milk cleaved the t-butoxycarbonyl-RVRR-AMC substrate with a Km of 32 microM, and processed the recombinant HPC precursor at the appropriate sites. Surprisingly, the expression of an active protease was not toxic to the mammary gland. This is a rare example of an animal model secreting active truncated forms of a processing endoprotease into a bodily fluid.

Animals↗
PubMed1997

DNAzol: a reagent for the rapid isolation of genomic DNA.

In this report, we present DNAzol, a patent-pending DNA isolation reagent containing guanidine thiocyanate and a detergent mixture. It is a complete, nontoxic and ready-to-use reagent for the isolation of genomic DNA from various biological sources. In the DNAzol protocol, a biological sample is homogenized (or lysed) in DNAzol, and the DNA is precipitated with ethanol, washed and dissolved in 8 mM NaOH. Following pH adjustment, the DNA can be used immediately for analysis or stored at 4 degrees C. The entire isolation can be completed in 20-30 min, and a wide range of DNA molecules can be isolated including genomic DNA and DNA fragments down to 0.1 kb in length. If necessary, samples can be stored in DNAzol at room temperature for extended periods of time. The isolated DNA is ready for PCR, Southern blotting and other molecular biology applications without any additional purification.

Animals↗
PubMed1995

Proteolytic maturation of protein C upon engineering the mouse mammary gland to express furin.

Endoproteolytic processing of the human protein C (HPC) precursor to its mature form involves cleavage of the propeptide after amino acids Lys-2-Arg-1 and removal of a Lys156-Arg157 dipeptide connecting the light and heavy chains. This processing was inefficient in the mammary gland of transgenic mice and pigs. We hypothesized that the protein processing capacity of specific animal organs may be improved by the coexpression of selected processing enzymes. We tested this by targeting expression of the human proprotein processing enzyme, named paired basic amino acid cleaving enzyme (PACE)/furin, or an enzymatically inactive mutant, PACEM, to the mouse mammary gland. In contrast to mice expressing HPC alone, or to HPC/PACEM bigenic mice, coexpression of PACE with HPC resulted in efficient conversion of the precursor to mature protein, with cleavage at the appropriate sites. These results suggest the involvement of PACE in the processing of HPC in vivo and represent an example of the engineering of animal organs into bioreactors with enhanced protein processing capacity.

Amino Acid Sequence↗
PubMed1995

Familial adrenocorticotropin unresponsiveness associated with alacrima and achalasia: biochemical and molecular studies in two siblings with clinical heterogeneity.

UNLABELLED: The syndrome of familial adrenocorticotropin (ACTH) unresponsiveness is a rare form of primary adrenal insufficiency, usually without mineralocorticoid deficiency. It is characterized by elevated plasma ACTH concentrations and undetectable plasma cortisol levels not responding to exogenous ACTH. Alacrima and achalasia have also been occasionally associated with adrenal insufficiency (triple A syndrome). Pathogenetic mutations have been identified in the ACTH receptor gene in families with isolated familial ACTH unresponsiveness. Whether the ACTH receptor represents the locus of the defect for the triple A syndrome is not known. Here we report two siblings with familial ACTH unresponsiveness who were discrepant for skin pigmentation and mineralocorticoid function. In addition, achalasia and alacrima were documented only in the older sibling. The boy, studied at the age of 2 years, was hyperpigmented, in contrast to his normally pigmented sister, studied at the age of 9 years; basal plasma alpha-melanocyte stimulating hormone immunureactivity levels were 79 and 38 pg/ml, respectively (normal < 40 pg/ml). Furosemide-induced diuresis resulted in normal rises of plasma renin activity in both patients; however, plasma aldosterone levels increased only in the boy and not in his sister. Screening for abnormalities of the ACTH receptor gene by single strand conformation polymorphism analysis revealed no abnormality. Direct sequencing of the entire coding area of the ACTH receptor gene was also normal. CONCLUSION: The syndrome of familial ACTH unresponsiveness can vary clinically and biologically within the same family.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Diseases↗
PubMed1994

[Indications and techniques for scleral fixation and suturing of intraocular lenses to the posterior surface of the iris].

The concept of suturing posterior chamber lenses to the ciliary body and sclera as the preferred method for a primary or secondary implantation when there is no capsular or even iris support, particularly at the time of penetrating keratoplasty, was pioneered by Enrique Malbran, M.D., Director of the Malbran Ophthalmology Center in Buenos Aires, Argentina (the current President of the Pan American Association of Ophthalmology). The significant interest existing now with this type of procedure is due to the fact that there are a number of eyes being seen for penetrating keratoplasty where either intracapsular surgery or complicated extracapsular surgery was done and an anterior chamber lens implanted. Some of these eyes later developed corneal decompensation. At the time of penetrating keratoplasty it is in the benefit of these patients for the surgeon to place an intraocular lens into the posterior chamber, away from the endothelium of the graft. The long-term experience with such lenses--more than nine years--is very favorable.

Ciliary Body↗
PubMed1991

G proteins in normal rat pituitaries and in prolactin-secreting rat pituitary tumors.

It is still undetermined which GTP-binding (G) protein is involved in the regulation of prolactin (PRL) release and through which effector. This study shows that, when compared to normal pituitary tissue, the levels of alpha o protein were very low in dopamine (DA)-resistant, PRL-secreting pituitary tumors 7315a and MtTW15, while alpha o mRNA was present in the two tumors. In the MtTW15 tumor alpha i1, alpha i2 and alpha i3 levels were decreased while those of alpha s42 and alpha s47 were increased, and in the 7315a tumor alpha i2, alpha i3 and beta levels were decreased and those of alpha s47 increased. In an estrone-induced, DA-sensitive prolactinoma the levels of alpha i3 were greatly reduced. DA was unable to inhibit basal PRL release by 7315a and MtTW15 and basal cAMP accumulation by adenomatous and MtTW15 cells. Vasoactive intestinal peptide (VIP) increased both cAMP accumulation and PRL release by all cell preparations which could be suppressed by DA with adenomatous and 7315a but not with MtTW15 cells. These and previously published results provide circumstantial evidence that alpha o, alpha i1 and alpha i3 are all involved in the transduction of the DA inhibitory message while alpha s47 transduces cAMP activating messages and alpha s42 is responsible for the constitutive activation of L-type Ca2+ channels, adenylate cyclase and baseline PRL release.

Adenoma↗
PubMed1983

Evaluation of thyroxine monodeiodination to reverse triiodothyronine by tissue homogenates in vitro.

Reverse-triiodothyronine (rT3) generated from thyroxine (T4) in vitro at physiological pH (7.4) is very labile and rapidly undergoes further enzymic deiodination to diiodothyronine. The paper describes the procedure in which by different pH optima, T4 to rT3 conversion distinct from T4 to T3 monodeiodination can be traced at pH 9.0, in the presence of dithiothreitol (DTT) as a donor of sulfhydryl groups. The net in vitro production of rT3 from exogenous T4 was thus measured utilizing specific RIA for the hormone, in several pig tissue homogenates (liver, kidney, skeletal muscle, brain, heart). The thyroxine 5-deiodinase activity was found to be several times higher in the kidney and liver than in other tissues. The procedure can be used for observations of changes in T4 to rT3 conversion under various experimental conditions.

Animals↗
PubMed1982

Reciprocal changes in serum 3, 3', 5'-tri-iodothyronine concentration and the peripheral thyroxine inner ring monodeiodination during food restriction in the young pig.

Utilizing the difference in pH optima between two distinct enzyme systems responsible for the thyroxine (T4) inner and outer ring monodeiodination, and a specific radioimmunoassay for iodothyronines, the net T4 conversion to 3, 3', 5'-tri-iodothyronine (rT3) and 3, 5', 3'-tri-iodothyronine (T3) in growing pigs kept under various food restrictions was determined in vitro. It has been found that fasting lowers deiodination of T4 to T3 by liver and kidney homogenates. The conversion of T4 to rT3 was reduced in the liver but not in the kidney, unless the animals were completely fasted. During food restriction serum T4 and T3 decreased whereas rT3 increased, which indicated that the serum rT3 level is not a good reflection of T4 to rT3 converting activity in the liver or kidney. The data suggest that a rise in rT3 reflects a lowered degradation rate of the hormone or an increased secretion by the thyroid gland rather than changes in rT3 neogenesis in the periphery.

Adaptation, Physiological↗