Showing papers by "Kettering University published in 1993"
TL;DR: The Hsp70 DnaK and Dna! are a Chaperone Team and the Translocation-Competent State of Precursor Proteins is maintained, and Cells Under Metabolic Stress is studied.
Abstract: 3. HSP70 PROTEINS: CHAPERONES WITH DIVERSE ROLES IN PROTEIN METABOLISM . . .. . . . . . . . . .. . . . . .. . . ... . . . .... . . . . 357 Structure and Function of Hsp70 Chaperones . . . . . . . . . . . . . . . . . . . . . . . 357 Maintenance of the Translocation-Competent State of Precursor Proteins . . . . . . 359 The Hsp70 DnaK and Dna! are a Chaperone Team . . . . . . . . . . . . . . . . . . . 360 Organellar Hsp70s in Membrane Translocation and Folding .. . . . .. . . . . . . 361 Hsp70 in Cells Under Metabolic Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . 362 Hsp70 and Protein Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
1,614 citations
TL;DR: Three-dimensional structures of complexes of the SH2 domain of the v-src oncogene product with two phosphotyrosyl peptides have been determined by X-ray crystallography at resolutions of 1.5 and 2.0 Å.
Abstract: Three-dimensional structures of complexes of the SH2 domain of the v-src oncogene product with two phosphotyrosyl peptides have been determined by X-ray crystallography at resolutions of 1.5 and 2.0 A, respectively. A central antiparallel β-sheet in the structure is flanked by two α-helices, with peptide binding mediated by the sheet, intervening loops and one of the helices. The specific recognition of phosphotyrosine involves amino–aromatic interactions between lysine and arginine side chains and the ring system in addition to hydrogen-bonding interactions with the phosphate.
647 citations
TL;DR: It is proposed that the ectopic c-kit expression in Wsh mice affects early melanogenesis in a dominant fashion and the "sash" or white belt of Wsh/+ animals and some other mutant mice is explained by the varying density of melanoblasts along the body axis of wild-type embryos.
Abstract: The c-kit receptor tyrosine kinase belongs to the PDGF/CSF-1/c-kit receptor subfamily The kit-ligand, KL, also called steel factor, is synthesized from two alternatively spliced mRNAs as transmembrane proteins that can either be proteolytically cleaved to produce soluble forms of KL or can function as cell-associated molecules The c-kit receptor kinase and KL are encoded at the white spotting (W) and steel (Sl) loci of the mouse, respectively Mutations at both the W and the Sl locus cause deficiencies in gametogenesis, melanogenesis and hematopoiesis The c-kit receptor is expressed in the cellular targets of W and Sl mutations, while KL is expressed in their microenvironment In melanogenesis, c-kit is expressed in melanoblasts from the time they leave the neural crest and expression continues during embryonic development and in the melanocytes of postnatal animals In gametogenesis c-kit is expressed in primordial germ cells, in spermatogonia, and in primordial and growing oocytes, implying a role at three distinct stages of gametogenesis Many mutant alleles are known at W and Sl loci and their phenotypes vary in the degree of severity in the different cellular targets of the mutations While many W and Sl alleles severely affect primordial germ cells (PGC), several mild Sl alleles have weak effects on PGCs and exhibit differential male or female sterility Steel Panda (Sl(pan)) is a KL expression mutation in which KL RNA transcript levels are reduced in most tissues analyzed In female Sl(pan)/Sl(pan) mice, ovarian follicle development is arrested at the one layered cuboidal stage as a result of reduced KL expression in follicle cells, indicating a role for c-kit in oocyte growth Wsh is a c-kit expression mutation, which affects mast cells and melanogenesis While the mast cell defect results from lack of c-kit expression, the pigmentation deficiency appears to stem from ectopic c-kit receptor expression in the somitic dermatome at the time of migration of melanoblasts from the neural crest to the periphery It is proposed that the ectopic c-kit expression in Wsh mice affects early melanogenesis in a dominant fashion The "sash" or white belt of Wsh/+ animals and some other mutant mice is explained by the varying density of melanoblasts along the body axis of wild-type embryos
384 citations
TL;DR: It is concluded that membrane-bound ARF confers to Golgi membranes all of the requirements for specific beta-COP binding, and that myristoylated, but not non-myristoylation, ARF is the required species.
340 citations
TL;DR: The data presented here indicate that loss of the carboxyl terminus of RAP1 abolishes position effects at yeast telomeres and diminishes silencing at the HML locus, and it is shown that telomere position effects are highly sensitive to changes in the size (or structure) of the telomeric tract.
Abstract: To investigate the role of the yeast telomere-, silencing-, and UAS-binding protein RAP1 in telomere position effects, we have characterized two sets of mutant cells: (1) a set of rap1 alleles (termed the rap1t alleles) that produce truncated RAP1 proteins missing the carboxy-terminal 144-165 amino acids; and (2) null mutants of the RIF1 gene, encoding a protein capable of interaction with the carboxyl terminus of RAP1. The data presented here indicate that loss of the carboxyl terminus of RAP1 abolishes position effects at yeast telomeres and diminishes silencing at the HML locus. Elimination of position effects in these cells is associated with increased accessibility to the Escherichia coli dam methylase in vivo. Thus, the carboxy-terminal domain of RAP1 is required for telomere position effects. In contrast, rif1 deletion alleles increase the frequency of repressed cells. Using the rap1t alleles to generate wild-type cells differing only in telomere tract lengths, we also show that telomere position effects are highly sensitive to changes in the size (or structure) of the telomeric tract. Longer poly(G1-3T) tracts can increase the frequency of transcriptional repression at the telomere, suggesting that telomeric poly(G1-3T) tracts play an active role in the formation or stability of subtelomeric transcriptional states.
283 citations
TL;DR: In this article, an isolated mammalian nucleic acid molecule encoding a mammalian prostate-specific membrane antigen was used for detecting hematogenous micrometastic tumor cells of a subject performing the polymerase chain reaction (PCR) on samples of the subjet using primers of said antigen.
Abstract: This invention provides for an isolated mammalian nucleic acid molecule encoding a mammalian prostate-specific membrane antigen. This invention provides for nucleic acid probes which specifically hybridize with the nucleic acid molecule encoding said antigen. This invention provides for a method of detecting hematogenous micrometastic tumor cells of a subject performing the polymerase chain reaction (PCR) on samples of the subjet using primers of said antigen. This invention provides for methods to identify ligands which bind to said antigen. This invention provides for the prevention and/or treatment of prostate tumor growth.
266 citations
TL;DR: Investigation of the basis of the phenotype of the Slpan mutation found that a reduced level of KL in Slpan/Slpan ovary arrests ovarian follicle development, while a similar reduction in testes has relatively little effect on spermatogonial development.
216 citations
TL;DR: Diet provides a further therapeutic strategy in active Crohn's disease and clinical improvement in the diet group was associated with significant changes in plasma albumin and alpha 1-antichymotrypsin concentrations and erythrocyte sedimentation rate.
198 citations
TL;DR: It is shown that a 91-kDa protein, first identified as a component of ISGF3, the IFN-alpha-induced transcription complex, is present in at least two of the DNA-protein complexes and suggested that an additional complex may be required for optimal expression and specificity.
Abstract: A 39-nt DNA sequence, the interferon gamma (IFN-gamma) response region (GRR), is necessary for the IFN-gamma-induced transcription of the high-affinity Fc receptor for IgG (Fc gamma RI) and sufficient for the IFN-gamma-induced transcription of transfected plasmids. By using extracts from IFN-gamma-treated cells, three protein complexes will assemble in vitro on a 9-nt core region in the 3' domain of the GRR. The sequence of this core resembles the IFN-gamma-activated sequence (GAS) described for the GBP gene. Mutations in this GAS core region prevent complex assembly and result in the loss of IFN-gamma induction of reporter constructs containing the mutation. In addition to the GAS core region, a 5' region of the GRR is necessary for optimal IFN-gamma induction and for formation of one of the DNA-protein complexes. By antibody reactivity, we show that a 91-kDa protein, first identified as a component of ISGF3, the IFN-alpha-induced transcription complex, is present in at least two of the DNA-protein complexes. IFN-alpha can induce the formation of the faster-migrating 91-kDa protein-GAS complex but not the slower-migrating complex. Furthermore, IFN-alpha does not result in appreciable transcriptional activation of Fc gamma RI or constructs containing the GRR. Thus, these data demonstrate that the IFN-gamma-activated 91-kDa protein is required for IFN-gamma induction of Fc gamma RI and suggest that an additional complex may be required for optimal expression and specificity.
187 citations
TL;DR: A cell culture system that supports the differentiation of male germ cells through meiosis is described, which takes advantage of the properties of a cell line, 15P-1, established from testicular cells of transgenic mice that express the large T protein of polyoma virus in the seminiferous epithelium.
174 citations
TL;DR: Sequence analysis and proteolytic dissection reveal that NSF contains two tandem "ATP domains," each containing the consensus sequence for the binding of nucleotide.
TL;DR: It is concluded that coat proteins are required for budding from Golgi membranes when budding diminishes as a result of immunodepletion of coat protein pools, and tubules are not formed at the expense of vesicles.
Abstract: Do the coats on vesicles budded from the Golgi apparatus actually cause the budding, or do they simply coat buds (Fig. 1)? One view (the membrane-mediated budding hypothesis) is that budding is an intrinsic property of Golgi membranes not requiring extrinsic coat proteins. Assembly of coats from dispersed subunits is super-imposed upon the intrinsic budding process and is proposed to convert the tips of tubules into vesicles. The alternative view (the coat-mediated budding hypothesis) is that coat formation provides the essential driving force for budding. The membrane-mediated budding hypothesis was inspired by the microtubule-dependent extension of apparently uncoated, 90-nm-diameter membrane tubules from the Golgi apparatus and other organelles in vivo after treatment with brefeldin A, a drug that inhibits the assembly of coat proteins onto Golgi membranes. This hypothesis predicts that tubules will be extended when coat proteins are unavailable to convert tubule-derived membrane into vesicles. Here we use a cell-free system in which coated vesicles are formed from Golgi cisternae to show that, on the contrary, when budding diminishes as a result of immunodepletion of coat protein pools, tubules are not formed at the expense of vesicles. We conclude that coat proteins are required for budding from Golgi membranes.
TL;DR: C-kit expression is absent in bone-marrow-derived Wsh/Wsh mast cells, the fetal and the adult lung, and the digestive tract at embryonic day 13 1/2, tissues that normally express c-kit, and ectopic c-Kit expression in the somitic dermatome affects early melanogenesis in a dominant fashion.
Abstract: The receptor tyrosine kinase c-kit and its cognate ligand KL are encoded at the white spotting (W) and steel (Sl) loci of the mouse, respectively. Mutations at both the W and the Sl locus cause deficiencies in gametogenesis, melanogenesis and hematopoiesis (erythrocytes and mast cells). The W-sash mutation differs from most W mutations in that it affects primarily mast cells and melanogenesis but not other cellular targets of W and Sl mutations. Thus, Wsh/Wsh mice are fertile and not anemic, but they lack mast cells in their skin and intestine and are devoid of coat pigment. Heterozygotes are black with a broad white sash/belt in the lumbar region. In order to determine the basis for the phenotypes of W-sash mice, we investigated c-kit RNA and protein expression patterns in adult Wsh/Wsh mice and during embryonic development. We show that c-kit expression is absent in bone-marrow-derived Wsh/Wsh mast cells, the fetal and the adult lung, and the digestive tract at embryonic day 13 1/2 (E13 1/2), tissues that normally express c-kit. Unexpectedly, in E10 1/2 and 11 1/2d Wsh/Wsh embryos, we found c-kit expression in the dermatome of the somites, the mesenchyme around the otic vesicle and the floorplate of the neural tube, structures known to express the c-kit ligand in wild-type embryos. The ectopic c-kit expression in Wsh homozygous embryos does not affect c-kit ligand expression. The presumed Wsh/Wsh melanoblasts appeared to be normal and, at E10 1/2, similar numbers were found in normal and homozygous mutant embryos. At E13 1/2 +/+ embryos had a graded distribution of melanoblasts from cranial to caudal with a minimum in the lumbar region. Whereas E13 1/2 homozygous Wsh/Wsh embryos essentially lacked c-kit-positive cells in the skin, E13 1/2 heterozygous Wsh/+ embryos had reduced numbers of melanoblasts compared to +/+ with few or none in the lumbar region (future sash). It is proposed that ectopic c-kit expression in the somitic dermatome affects early melanogenesis in a dominant fashion. Molecular analysis of Wsh chromosomal DNA revealed a deletion or rearrangement in the vicinity of the c-kit gene. These results provide an explanation for the Wsh phenotype and have implications for the control of c-kit expression.
TL;DR: This review describes the various genetic, biochemical, and structural experiments that have been carried out primarily for the DNA‐binding domains of the glucocorticoid and estrogen receptors and postulates how receptors discriminate closely related response elements through sequence‐specific contacts and distinguish symmetry of target sites through protein‐protein interactions.
Abstract: The nuclear hormone receptor DNA-binding domain consists of two zinc finger-like modules whose amino acids are highly conserved among the members of the receptor superfamily. In this review, we describe the various genetic, biochemical, and structural experiments that have been carried out primarily for the DNA-binding domains of the glucocorticoid and estrogen receptors. We describe how the structural and functional information have permitted us to predict properties of the DNA-binding domains of other nuclear receptors. We postulate how receptors discriminate closely related response elements through sequence-specific contacts and distinguish symmetry of target sites through protein-protein interactions. This mechanism explains in part how the receptors regulate diverse sets of genes from a limited repertoire of core response elements. Lastly, we describe the stereochemical basis of nuclear receptor dysfunction in certain clinical disorders. © 1993 Wiley-Liss, Inc.
TL;DR: The proto-oncogene c-kit is allelic with the white spotting locus (W) on mouse chromosome 5 and it encodes a transmembrane protein tyrosine kinase which belongs to the platelet-derived growth factor and macrophage-colony stimulating factor (CSF-1) receptor subfamily.
TL;DR: Observations support, but do not prove, the hypothesis that vitiligo is an autoimmune disease and that anti-pigment cell antibodies have a role in inducing the disease.
TL;DR: The data suggest that, regardless of the fat content of the diet, quercetin and RU are capable of modifying or inhibiting events in the development of chemically induced colonic neoplasia.
Abstract: Dietary quercetin (QU) and rutin (RU), phenolic flavonoids found in many fruits and vegetables, when fed to mice on a low-fat diet successfully modified the response to azoxymethanol (AOM) by initially inhibiting hyperproliferation and the formation of foci of dysplasia (FADs) and ultimately reducing tumor incidence (Carcinogenesis 12, 1193-1196, 1991). In this study, we tested the efficacy of QU and RU when a high-fat diet was presented. An AIN 76A diet made with 20% corn oil (CO) was supplemented with QU (0.5%, 2.0%, or 5.0%) and RU (2.0% or 4.0%). These five diets, as well as a 5.0% and a 20.0% CO diet, were fed to a group of CF1 female mice for nine weeks. Both QU and RU showed nonsignificant dose-related trends toward normalization of the AOM-induced upward extension of S phase cells. Examination of 500 microns of serially sectioned distal colon revealed that 29% of mice fed the 20% CO control diet were free of FADs. Among the mice fed QU, regardless of dose, > 80% were free of FADs. When the three groups fed QU were pooled and compared with the control 20% CO-fed mice, the degree of protection was significant (p < 0.01). Mice fed RU expressed a level of protection that bordered on the significant (p < 0.08). These data suggest that, regardless of the fat content of the diet, QU and RU are capable of modifying or inhibiting events in the development of chemically induced colonic neoplasia.
TL;DR: In clinical trial planning, in vitro colony-forming assays can be used to elucidate schedule dependency of myelotoxicity, to plan cytokine support, and to estimate dose-escalation effects.
Abstract: Myelosuppression is the dose-limiting side effect for most anti-cancer and many anti-human immunodeficiency virus agents, which can be quantitated with optimized colony-forming assays (granulocyte-macrophage, late erythroid, and megakaryocytic [for murine only] colony-forming units and early erythroid burst-forming units (BFUs)). When applied to new drug development, the assays are used for therapeutic index-based screening (e.g., less myelosuppressive analogues, structure-toxicity studies, new drug leads), interpreting efficacy data from xenotransplant models, and selecting the most accurate animal model for human hematopoietic toxicity. However, other types of assays may be required to identify the mechanism underlying myelosuppression. In clinical trial planning, in vitro colony-forming assays can be used to elucidate schedule dependency of myelotoxicity (which in turn provides clues about mechanism of action), to plan cytokine support, and to estimate dose-escalation effects. The inhibition of colony formation can be measured relative to a compound with known clinical myelotoxicity and schedule dependency to provide some idea of the toxicity expected at particular doses, and the degree of heterogeneity between individuals, during clinical trials. The predictive accuracy of the in vitro data has been proven by validation studies with alkylating agents.
TL;DR: Comparison of the sequences of capping enzymes and polynucleotide ligases from diverse sources suggests that KX(D/N)G may be a signature element for covalent catalysis in nucleotidyl transfer.
TL;DR: The ts16 mutation of vaccinia virus WR has been mapped by marker rescue to the I7L open reading frame located within the genomic HindIII I DNA fragment, which shows amino acid sequence similarity to the type II DNA topoisomerase of Saccharomyces cerevisiae.
Abstract: The ts16 mutation of vaccinia virus WR (R. C. Condit, A. Motyczka, and G. Spizz, Virology 128:429-443, 1983) has been mapped by marker rescue to the I7L open reading frame located within the genomic HindIII I DNA fragment. The I7 gene encodes a 423-amino-acid polypeptide. Thermolabile growth was attributed to an amino acid substitution, Pro-344-->Leu, in the predicted I7 protein. A normal temporal pattern of viral protein synthesis was elicited in cells infected with ts16 at the nonpermissive temperature (40 degrees C). Electron microscopy revealed a defect in virion assembly at 40 degrees C. Morphogenesis was arrested at a stage subsequent to formation of spherical immature particles. Western immunoblot analysis with antiserum directed against the I7 polypeptide demonstrated an immunoreactive 47-kDa polypeptide accumulating during the late phase of synchronous vaccinia virus infection. Immunoblotting of extracts of wild-type virions showed that the I7 protein is encapsidated within the virus core. The I7 polypeptide displays amino acid sequence similarity to the type II DNA topoisomerase of Saccharomyces cerevisiae. Images
TL;DR: It is indicated that cellular adaptation to oxidative stress renders cells resistant to DNA damage as well as to cytotoxicity associated with cisplatin treatment.
Abstract: Studies designed to better understand the involvement of cellular resistance to oxidative stress in mechanisms of cellular resistance to cisplatin were undertaken using H2O2-resistant variants of the HA 1 Chinese hamster fibroblast cell line. H2O2-resistant cell lines were resistant to clonogenic inactivation mediated by cisplatin with dose modifying factors at 10% survival of 1.5–3.0, relative to HA 1 cells. The most cisplatin resistant of these cell lines (OC5) also demonstrated fewer DNA–DNA crosslinks induced by cisplatin, relative to HA 1. Since H2O2-resistant cells contained increased catalase activity as well as total glutathione (GSH) content, the involvement of these cellular antioxidants in the resistance to cisplatin toxicity was evaluated. Treatment of HA 1 and H2O2-resistant cell lines (OC5, OC14) with 9 mM aminotriazole reduced catalase activity by 60–65% but had no effect on the cytotoxicity of cisplatin. In contrast, treatment with 5 mM buthionine sulfoximine reduced total GSH by 90% and sensitized the cells to cisplatin cytotoxicity. Furthermore, extracellular reaction of GSH with cisplatin prior to treating HA 1 cells reduced the toxicity of the compound, indicating that this reaction is capable of participating in the detoxification of cisplatin. These results indicate that cellular adaptation to oxidative stress renders cells resistant to DNA damage as well as to cytotoxicity associated with cisplatin treatment. Furthermore, increases in total GSH content (but not catalase activity) appear to partially account for cisplatin resistance demonstrated by H2O2-resistant cells. © 1993 Wiley-Liss, Inc.
TL;DR: The distribution of the disialoganglioside GD2 in the human nervous system was studied by immunostaining using monoclonal antibodies 3F8 and 3A7, suggesting that GD2 may have a distinct functional role(s) in the brain, and is not merely a metabolic intermediate.
Abstract: The distribution of the disialoganglioside GD2 in the human nervous system was studied by immunostaining using monoclonal antibodies 3F8 and 3A7. Positive staining was detected throughout the central nervous system, predominantly in neuronal cell bodies and neuropil of the gray matter. The specific localization of reactivity in such structures as cerebellum and hippocampus differs from that of related gangliosides, suggesting that GD2 may have a distinct functional role(s) in the brain, and is not merely a metabolic intermediate. GD2 expression was also analyzed in a series of 39 neuroblastomas. Staining of both primitive neuroblastic and differentiating ganglioneuromatous elements was seen, although some tumor cell heterogeneity was noted. The results have implications for immunotherapy of neuro-blastomas using anti-GD2 antibodies.
Journal Article•
TL;DR: The bcr/abl gene and its fusion protein are promising targets for development of novel specific therapies, but before this can be accomplished it will be necessary to understand more completely the molecular and biochemical abnormalities and to correlate them with the biological manifestations of the disease.
Abstract: Despite recent advances in our understanding of the molecular and biological abnormalities in chronic myelogenous leukemia (CML) this new knowledge has not yet led to significant improvements in treatment. We have reviewed what is known and still unknown about the molecular and biological abnormalities in CML that may be relevant to developing improved, more selective treatment. CML originates in a multipotential stem cell due to its acquiring a highly consistent specific chromosomal translocation between chromosomes 9 and 22; this results in a fused bcr/abl gene and an abnormal 210 kDa fusion protein which has increased intrinsic protein tyrosine kinase activity compared to the normal c-abl protein. It is still unknown how p210bcr-abl alters the signal transduction pathways, but the main biological abnormality is discordant or asynchronous maturation, with the cytoplasm generally maturing more rapidly than the nucleus. The major expansion of the CML population takes place in the intermediate and later maturation compartments rather than in the stem cell or early progenitor cell compartments. The expansion occurs slowly, probably taking several years to reach a trillion or more cells, at which time clinical symptoms begin to develop. The maturing leukemic progenitors do not have an increased proliferative rate, but they undergo one or more additional divisions and also live longer than comparable normal progenitors. The earliest CML blast cell population we have been able to study has reduced ultimate proliferative capacity compared to a comparable primitive normal blast cell population. Although no quantitative stem cell assay is available, indirect evidence suggests that the CML stem cells' biological behavior may be relatively unaffected or deviate only slightly from normal. The bcr/abl gene and its fusion protein are promising targets for development of novel specific therapies, but before this can be accomplished it will be necessary to understand more completely the molecular and biochemical abnormalities and to correlate them with the biological manifestations of the disease.
TL;DR: An ordered telomere-to-telomere contig map of P. falciparum chromosome 2 is constructed by isolating overlapping yeast artificial chromosome clones and reveals that polymorphisms of chromosome 2 are restricted to regions at either end, representing 20% of the chromosome.
Abstract: CLASSICAL genetic studies on the human malaria parasite Plasmodium falciparum have been hampered by a complex life cycle which alternates between vertebrate and invertebrate hosts. Consequently, only a few genetic crosses have been performed so far1–4. In addition, molecular genetics has provided only limited access to the genes of this pathogen, a consequence of an unusually high A + T content5,6. To overcome these limitations we have constructed an ordered telomere-to-telomere contig map of P. falciparum chromosome 2 by isolating overlapping yeast artificial chromosome clones. This approach was used to examine the strain-dependent polymorphisms commonly observed for P. falciparum chromosomes7,8. Our analysis reveals that polymorphisms of chromosome 2 are restricted to regions at either end, representing 20% of the chromosome. Transcription mapping of the entire chromosome suggests a compartmentalization of chromosome 2 into a transcribed central domain and silent polymorphic ends.
TL;DR: It is shown that purified elongation complexes contain an intrinsic nuclease activity that shortens nascent RNA from the 3'-end of vaccinia virus RNA polymerase containing 3'-OMeGMP-arrested transcripts.
TL;DR: Analysis of the cleavage of DNA duplexes containing 2'OMe sugars suggests that the inability of the vaccinia topoisomerase to cleave either an RNA duplex or an RNA:DNA hybrid can be accounted for by the interfering effects of a 2' sugar substituent at two or more sites within the pentamer.
TL;DR: In a 29 year old white male with osteonecrosis of both hips and a shoulder, and in his family, basal and stimulated fibrinolytic activity was measured to determine whether low fibrinogen activator inhibitor activity might be heritable and etiologically associated with oste onecrosis.
Abstract: In a 29 year old white male with osteonecrosis of both hips and a shoulder, and in his family, we measured basal and stimulated (10 min cuff venous occlusion at 100 mgHg) fibrinolytic activity to determine whether low fibrinolytic activity might be heritable and etiologically associated with osteonecrosis. The proband's basal tPA-Fx was low, 0.08 IU/ml (normal 0.11-1.94), tPA-Ag was normal (11.6 ng/ml), plasminogen activator inhibitor activity (PAI-Fx) was very high, 119 U/ml (normal 3.5-27), as was his plasminogen activator inhibitor antigen (PAI-Ag), 202 ng/ml (normal 3.2-37.1). The proband's basal PAI-Fx (119) and PAI-Ag (202) were respectively 6 and 13 standard deviations greater than the mean PAI-Fx (17 +/- 15 U/ml) and the mean PAI-Ag (25 +/- 13 ng/ml) in 172 concomitantly studied hyperlipidemic men. Alpha-2 antiplasmin, fibrinogen, plasminogen and Lp(a) were normal. Despite lowering TG to 301 mg/dl, basal tPA-Fx remained low, 0.05; PAI-Fx and PAI-Ag remained very high (109 and 191). Following venous occlusion, stimulated tPA-Fx remained very low, 0.1 (normal 2.3-11.3), but tPA-Ag rose normally to 17 (normal 8.4-31.4); stimulated PAI-Fx and PAI-Ag were very high, 134 and 223, (normal PAI-Fx 3.6-24, PAI-Ag 12-96). Stimulated D-dimer was < the 10th percentile, 0.084 micrograms/ml. With such high PAI-Fx available to bind tPA, occlusion-stimulated tPA-Fx could not rise, and fibrinolysis could not be initiated. Neither diseases nor drugs could explain the high PAI-Fx and PAI-Ag, low tPA-Fx; or osteonecrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: It is suggested that NTP hydrolysis by RNA-bound NPH-II drives processive translocation of the protein in a 3' to 5' direction along the RNA strand, whereas energy utilization by DNA-bound enzyme leads to dissociation without extensive protein movement.
TL;DR: The nomographic guide for planning 103Pd implants calls for total seed strength to increase significantly faster as a function of target volume average dimension than is the case for 125I, and a nomograph has been constructed on the basis of this power function relationship.
Abstract: 103Pd is being substituted for 125I in permanent implants for which it is desired to deliver a higher initial dose rate while maintaining readily achieved radiation protection. We have constructed a nomograph to assist in determining both the total seed strength required and the appropriate needle spacing for 103Pd implants. We have calculated the "matched peripheral dose" (MPD), that is, the dose for which the isodose contour volume is equal to the target volume, for 64 125I and 13 103Pd actual implants as if 103Pd had been used for all of them, employing a computer lookup table based on single-seed dose distribution measurements in solid water. The calculated data were used to obtain a least-squares fit to a linear relationship between the logarithm of the total seed strength for a given MPD and the logarithm of the average dimension, da (cm). We found that, for a nominal MPD of 11,500 cGy, total seed strength (in mCi) is given by 3.2 da2.56. A 103Pd nomograph has been constructed on the basis of this power function relationship. Our nomographic guide for planning 103Pd implants calls for total seed strength to increase significantly faster as a function of target volume average dimension than is the case for 125I. This nomograph will facilitate the application of 103Pd seeds in permanent implants.
TL;DR: New clinico‐pathologic subsets with shared abnormalities of chromosome 9 are identified and reported here, which should facilitate new approaches to the analysis of the etiology and clinical behavior of NHL.
Abstract: In this study we analyzed nonrandom aberrations affecting chromosome 9 in a series of 426 consecutively ascertained, karyotypically abnormal non-Hodgkin's lymphoma (NHL) tumors derived from 407 patients. Cytogenetic abnormalities were correlated with clinical, histologic, and immunologic features. Structural abnormalities of chromosome 9 were identified in 60 specimens derived from 59 patients. The recurring abnormalities among these were associated with 4 clinico-pathologic subsets. The first comprised 7 cases of t(9;14)(p13;q32), 6 of which had small lymphocytic lymphoma, plasmacytoid subtype, and an indolent clinical course. The second group included 12 cases with breaks at 9q11–13 and diffuse lymphomas with a large-cell component and a typical response to combination chemotherapy. The third group was comprised of 7 cases with 9q deletions, with a common deleted region encompassing 9q31–32. These cases were characterized by diffuse B-cell histology, young age, and poor clinical outcome. The fourth subset included 5 intermediate- to high-grade T-cell tumors with breaks at 9q34. This analysis of chromosome 9 aberrations in NHL comprises the first such effort based on a large series of tumors. We identify and report here new clinico-pathologic subsets with shared abnormalities of chromosome 9, which should facilitate new approaches to the analysis of the etiology and clinical behavior of NHL. © 1993 Wiley-Liss, Inc.