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Regulation of an S6/H4 Kinase in Crude Lymphosarcoma P1798 Preparations

Description: Purified S6/H4 kinase (Mr 60,000) requires autophosphorylation for activation. A rabbit anti-S6/H4 kinase peptide (SVIDPVPAPVGDSHVDGAAK) antibody recognized both the S6/H4 kinase holoenzyme and catalytic domain. Immunoreactivity with p60 kinase protein, and S6/H4 kinase activity were precisely correlated in fractions obtained from ion exchange chromatography of P1798 lymphosarcoma extracts. An enzyme which catalyzed the MgATP-dependent phosphorylation and activation of S6/H4 kinase coeluted with immunoreactivity from Mono 5, but not Mono Q chromatography. Since S6/H4 kinase is homologous with rac-activated PAK65, the observation that phosphorylation is also required for activation suggests a complex mechanism for in vivo activation of the S6/H4 kinase.
Date: December 1998
Creator: Taylor, Allison Antoinette
Partner: UNT Libraries

Highly Potent, Water Soluble Benzimidazole Antagonist for Activated (alpha)4(beta)1 Integrin

Description: The cell surface receptor {alpha}{sub 4}{beta}{sub 1} integrin, activated constitutively in lymphoma, can be targeted with the bisaryl urea peptidomimetic antagonist 1 (LLP2A). However, concerns on its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzimidazole moiety resulting in improved solubility while maintaining picomolar potency [5 (KLCA4); IC{sub 50} = 305 pM]. With exceptional solubility, this finding has potential for improving PK to help diagnose and treat lymphomas.
Date: August 29, 2007
Creator: Carpenter, R D; Andrei, M; Lau, E Y; Lightstone, F C; Liu, R; Lam, K S et al.
Partner: UNT Libraries Government Documents Department


Description: Splenomegaly is frequently found in non-Hodgkin's lymphoma (NHL) patients. This study evaluated the implications of splenic volume change in response to radioimmunotherapy (RIT). Twenty-nine NHL patients treated with radiolabeled-Lym-1 and 9 breast cancer patients (reference group) treated with radiolabeled-ChL6, BrE-3 or m170 were analyzed using CT splenic images obtained before and after RIT. Patient-specific radiation doses to spleen were determined using actual splenic volume determined by CT and body weight. In 13 of 29 NHL patients who had splenic volume {le} 310 ml, there was no or small change (-23 to 15 mL) in splenic volume, despite splenic doses as high as 14.4 Gy. Similarly, in a reference group of 9 breast cancer patients, there was no or small change (-5 to 13 mL), despite splenic doses as high as 11.4 Gy. In contrast, 13 of 29 NHL patients who had splenic volume 380-1400 mL, splenic volume decreased by 68 to 548 mL despite splenic doses as low as 1.40 Gy. Ten of 29 NHL patients with greater than a 15% decrease in splenic volume after RIT had nodal tumor regression (5 CR, 5 PR). In the remaining 19 NHL patients with less than a 15% decrease in splenic volume after RIT, there were 7 non-responders (5 CR and 7 PR). Splenic volume changes were found in NHL patients with splenomegaly. These splenic volume changes is likely due to therapeutic effect on malignant lymphocytes associated with splenomegaly. Nodal tumor response was more likely when splenomegaly decreased after RIT.
Date: April 6, 2005
Creator: Shen, S; DeNardo, G L; Yuan, A; Siantar, C H; O'Donnell, R T & DeNardo, S J
Partner: UNT Libraries Government Documents Department

Changes in the peripheral blood transcriptome associated with occupational benzene exposure identified by cross-comparison on two microarray platforms

Description: Benzene is an established cause of leukemia and a possible cause of lymphoma in humans but the molecular pathways underlying this remain largely undetermined. This study sought to determine if the use of two different microarray platforms could identify robust global gene expression and pathway changes associated with occupational benzene exposure in the peripheral blood mononuclear cell (PBMC) gene expression of a population of shoe-factory workers with well-characterized occupational exposures to benzene. Microarray data was analyzed by a robust t-test using a Quantile Transformation (QT) approach. Differential expression of 2692 genes using the Affymetrix platform and 1828 genes using the Illumina platform was found. While the overall concordance in genes identified as significantly associated with benzene exposure between the two platforms was 26% (475 genes), the most significant genes identified by either array were more likely to be ranked as significant by the other platform (Illumina = 64%, Affymetrix = 58%). Expression ratios were similar among the concordant genes (mean difference in expression ratio = 0.04, standard deviation = 0.17). Four genes (CXCL16, ZNF331, JUN and PF4), which we previously identified by microarray and confirmed by real-time PCR, were identified by both platforms in the current study and were among the top 100 genes. Gene Ontology analysis showed over representation of genes involved in apoptosis among the concordant genes while Ingenuity{reg_sign} Pathway Analysis (IPA) identified pathways related to lipid metabolism. Using a two-platform approach allows for robust changes in the PBMC transcriptome of benzene-exposed individuals to be identified.
Date: March 1, 2009
Creator: McHale, Cliona M.; Zhang, Luoping; Lan, Qing; Li, Guilan; Hubbard, Alan E.; Forrest, Matthew S. et al.
Partner: UNT Libraries Government Documents Department

Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice

Description: Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression induces formation of specific tumors in mice.
Date: April 15, 2002
Creator: Kurimasa, Akihiro; Burma, Sandeep; Henrie, Melinda; Ouyang, Honghai; Osaki, Mitsuhiko; Ito, Hisao et al.
Partner: UNT Libraries Government Documents Department

Discovery, SAR, and Radiolabeling of Halogenated Benzimidazole Carboxamide Antagonists as Useful Tools for (alpha)4(beta)1 Integrin Expressed on T- and B-cell Lymphomas

Description: The cell surface receptor {alpha}{sub 4}{beta}{sub 1} integrin is an attractive yet poorly understood target for selective diagnosis and treatment of T- and B-cell lymphomas. This report focuses on the rapid microwave preparation of medicinally pertinent benzimidazole heterocycles, structure-activity relationships (SAR) of novel halobenzimidazole carboxamide antagonists 3-6, and preliminary biological evaluation of radioiodinated agents 7, 8, and 18. The I-125 derivative 18 had good tumor uptake (12 {+-} 1% ID/g at 24 h; 4.5 {+-} 1% ID/g at 48 h) and tumor:kidney ratio ({approx}4:1 at 24 h; 2.5:1 at 48 h) in xenograft murine models of B-cell lymphoma. Molecular homology models of {alpha}{sub 4}{beta}{sub 1} integrin have predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. These high affinity ({approx} pM binding) halogenated ligands are attractive tools for medicinal and biological use; the fluoro and iodo derivatives are potential radiodiagnostic ({sup 18}F) or radiotherapeutic ({sup 131}I) agents, whereas the chloro and bromo analogues could provide structural insight into integrin-ligand interactions through photoaffinity cross-linking/mass spectroscopy experiments, as well as co-crystallization X-ray studies.
Date: February 8, 2010
Creator: Carpenter, R D; Natarajan, A; Lau, E Y; Andrei, M; Solano, D M; Lightstone, F C et al.
Partner: UNT Libraries Government Documents Department

Application of NMR Methods to Identify Detection Reagents for Use in the Development of Robust Nanosensors

Description: Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful technique for studying bi-molecular interactions at the atomic scale. Our NMR lab is involved in the identification of small molecules, or ligands that bind to target protein receptors, such as tetanus (TeNT) and botulinum (BoNT) neurotoxins, anthrax proteins and HLA-DR10 receptors on non-Hodgkin's lymphoma cancer cells. Once low affinity binders are identified, they can be linked together to produce multidentate synthetic high affinity ligands (SHALs) that have very high specificity for their target protein receptors. An important nanotechnology application for SHALs is their use in the development of robust chemical sensors or biochips for the detection of pathogen proteins in environmental samples or body fluids. Here, we describe a recently developed NMR competition assay based on transferred nuclear Overhauser effect spectroscopy (trNOESY) that enables the identification of sets of ligands that bind to the same site, or a different site, on the surface of TeNT fragment C (TetC) than a known ''marker'' ligand, doxorubicin. Using this assay, we can identify the optimal pairs of ligands to be linked together for creating detection reagents, as well as estimate the relative binding constants for ligands competing for the same site.
Date: April 29, 2004
Creator: Cosman, M; Krishnan, V V & Balhorn, R
Partner: UNT Libraries Government Documents Department


Description: Etoposide (ET) is a chemotherapeutic agent widely used in the treatment of leukemia, lymphomas and many solid tumors, such as testicular and ovarian cancers, that affect patients in their reproductive years. The purpose of the study was to use sperm FISH analyses to characterize the long-term effects of ET on male germ cells. We used a mouse model to characterize the induction of chromosomal aberrations (partial duplications and deletions) and whole chromosomal aneuploidies in sperm of mice treated with a clinical dose of ET. Semen samples were collected at 25 and 49 days after dosing to investigate the effects of ET on meiotic pachytene cells and spermatogonial stem-cells, respectively. ET treatment resulted in major increases in the frequencies of sperm carrying chromosomal aberrations in both meiotic pachytene (27- to 578-fold) and spermatogonial stem-cells (8- to 16-fold), but aneuploid sperm were induced only after treatment of meiotic cells (27-fold) with no persistent effects in stem cells. These results demonstrate that male meiotic germ cells are considerably more sensitive to ET than spermatogonial stem-cell and that increased frequencies of sperm with structural aberrations persist after spermatogonial stem-cell treatment. These findings predict that patients who undergo chemotherapy with ET may have transient elevations in the frequencies of aneuploid sperm, but more importantly, may have persistent elevations in the frequencies of sperm with chromosomal aberrations, placing them at higher risk for abnormal reproductive outcomes long after the end of their chemotherapy.
Date: July 15, 2005
Creator: Marchetti, F; Pearson, F S; Bishop, J B & Wyrobek, A J
Partner: UNT Libraries Government Documents Department

Effect of negative pions on the proliferative capacity of ascites tumor cells (lymphoma) grown in vivo

Description: We have attempted to determine the relative biological effectiveness (RBE) of negative pions in the Bragg-peak region as compared to the plateau region and to gamma rays. We irradiated LAF{sub 1} mice, bearing 5-day-old lymphoma ascites tumors, in the peak and plateau regions of a 90-MeV pion beam for 40 hours in temperature-controlled holders. The animals were then sacrificed; lymphoma cells were withdrawn and titrated into adult female LAF{sub 1} mice. The proliferative capacity of the irradiated tumor cells was evaluated after 8 weeks by observing the percentage of animals developing ascites tumors. Surviving fractions were then calculated from LD{sub 50}`s of control and irradiated animals. Radiation doses in the 50 plateau region were measured with LiF dosimeters calibrated against cobalt-60 gamma rays. We calculated peak doses from those at the plateau, using a measured average peak-to-plateau ionization ratio of 1.5. Doses in the plateau region ranged from 145 to 250 rads; doses in the peak region ranged from 220 to 380 rads. The survival curve for cells irradiated in the peak region gave a D{sub 0} of 65 {plus_minus} 15 rads. The plateau points were not reliable. A replicate experiment was performed using Co{sup 60} {gamma}-rays, yielding a survival-curve D{sub 0} of 350 {plus_minus} 50 rads. If the {gamma}-ray D{sub 0} is taken as a baseline, an RBE of 5.4 {plus_minus} 1.8 is obtained for negative pions in the peak region, based on the ratio of-peak-region D{sub 0} to Co{sup 60} D{sub 0}.
Date: March 30, 1967
Creator: Feola, J.M.; Richman, C.; Raju, M.R.; Curtis, S.B. & Lawrence, J.H.
Partner: UNT Libraries Government Documents Department

Final Technical Report

Description: The best summary of our results is probably provided by the list of publications based on work supported by this grant, which is given below. In general, the objectives were realized, and we have demonstrated, for the first time, that radiolabeled Abs can kill single tumor cells very effectively, and that they can also be effective in treating models of human tumors growing as xenografts in SCID mice. Our original work, as proposed in the application, was with Abs to B-lymphoma cells, namely anti-CD20 and anti-HLA-DR. After our successful efforts with these Abs, we decided to extend the results to other tumor types. Accordingly, carcinomas of the breast, ovary and other tissues were treated with radiolabeled Abs to EGFr and HER-2. These tumors cells were also effectively killed in vitro with radiolabeled Abs. This is significant because these Abs are widely used, and successful, in the clinic (unlabeled) and because the flattened shape of the cells, in vitro, is expected to make them considerably more difficult to kill than the spherical lymphoma cells. A major goal was to compare radionuclides emitting different types of radiation, namely low energy electrons (Auger and conversion electrons), {beta}-particles, and {alpha}-particles. All three types could effectively kill cells in vitro with considerable specificity. However, the low energy electrons, which we abbreviate LEEs, have significant advantages, mainly due to their lower level of non-specific toxicity. This was demonstrated both in vitro and in vivo. Thus, {beta}-particle emitters conjugated to anti-CD20 could protect mice against the growth of B-lymphoma tumor cells, but the therapeutic effect was limited by the maximum dose that could be administered, without killing the mouse. In contrast, the LEE emitters were more effective, largely because the toxicity was much less, allowing an approximately 10-fold higher {mu}Ci dose to be injected. Conjugates with {alpha}-particle ...
Date: June 10, 2005
Creator: Mattes, M. Jules
Partner: UNT Libraries Government Documents Department

Human radiation studies: Remembering the early years: Oral history of pathologist Clarence Lushbaugh, M.D., conducted October 5, 1994

Description: This report provides a transcript of an interview with Dr. Clarance Lushbaugh by representatives of the DOE Office of Human Radiation Experiments. Dr. Lushbaugh was chosen for this interview because of his research involving experimental use of irradiation with human beings at Los Alamos and at the Oak Ridge Institute of Nuclear Science (ORINS). After a brief biographical sketch Dr. Lushbaugh and his assistant Mrs. Ann Swipe defend their use of total body irradiation using the LETBI (Low Exposure Total Body Irradiation) and the LETBI (Medium Energy Total Body Irradiator). Dr. Lushbaugh also discusses his earlier experiments involving use of nitrogen mustards in chemotherapy application, his early interest in the LD50 for man, his early impressions of low-level spray radiation as introduced by Heubline, anedotal information for his duties a pathologist for Los Alamos, and his developing interest in establishing safer radiation limits for human exposure.
Date: April 1, 1995
Partner: UNT Libraries Government Documents Department

[News Clip: Cancer Patients]

Description: Video footage from the KXAS-TV/NBC station in Fort Worth, Texas, to accompany a news story by reporter about young adults living with cancer. The story focuses on members of the Young Texans Living with Cancer support group including Morton Hospital employee Robin McGill, Rob Howell, and Bob. The story aired at 6:00 P.M.
Date: December 17, 1985
Creator: KXAS-TV (Television station : Fort Worth, Tex.)
Partner: UNT Libraries Special Collections

Research in radiobiology: Final report of work in progress in immunobiology of experimental host-tumor relationships

Description: Our work on the immunobiology of tumors induced in normal mice by non-ionizing radiation and chemical carcinogens has previously demonstrated a correlation between MHC molecule expression and the immunogenicity of tumors in a transplanted syngeneic host. Such that immunogenic or regressive tumors were found to demonstrate higher constitutive or inducible levels of MHC expression, while most virulent, aggressive tumors exhibited a low level of MHC Class I expression. We attributed much of the control of MHC molecule expression by antigen-bearing tumors and normal cells to the immunological status of the host since the host must provide the appropriate stimulus to enhance MHC antigen expression by the invading tumor. Our results with UVR-induced tumors suggested that a significant role is played by the T-cell lymphokine, {gamma}-interferon ({gamma}IFN), in the modulation of MHC molecule expression in vivo. Virulent tumors, induced by boneseeking radionuclides, may be refractory to {gamma}IFN stimulation of MHC molecule expression. It is also possible that certain tumors might be fully responsive to the Class I modulatory influences by {gamma}IFN, but exhibit a reduced capacity to stimulate the synthesis of this lymphokine by host T cells. We present experiments designed to : Describe the virulence, latency period, and transplantation characteristics of {sup 238}PU, {sup 24l}Am, and {sup 228}Th tumors arising as osteogenic sarcomas and hepatic carcinomas, to determine the relationship between inducible expression of MHC Class I molecules by {gamma}IFN and in vivo immunogenicity of these radioisotype-induced tumors, and to elucidate any molecular mechanisms responsible for a lack of responsiveness to a {gamma}IFN failure by the host to induce host {gamma}IFN production.
Date: March 15, 1993
Partner: UNT Libraries Government Documents Department

Improved radioimmunotherapy of hematologic malignancies. Progress report, November 1, 1993--October 31, 1994

Description: This report summaries progress made during the time interval between November 1, 1993 and October 31, 1994 and briefly describes studies on the metabolism of antibodies targeting B cell antigens, retention of labeled antibodies by human B cell lymphocytes, and tissue distribution of Chloramine T and tyramine cellobiose labeled antibodies in mice harboring a human erythroleukemia tumor transplant.
Date: August 4, 1994
Creator: Press, O. W.
Partner: UNT Libraries Government Documents Department

Clinical manifestations of bovine leukosis

Description: The diagnosis of animals infected with BLV can be accurately identified with the available serologic tests. Diagnosis of animals in the incipient stage of leukosis is extremely difficult and can only be diagnosed by a positive tissue biopsy. Animals with frank tumor involvement can be suspected and diagnosed on a tentative clinical basis on the signs reported. Positive diagnosis must be made on the basis of a biopsy of the tumor or in some cases on a hemotological examination.
Date: January 1, 1979
Creator: Sorensen, D.K.
Partner: UNT Libraries Government Documents Department

Bovine lymphocytic leukemia: studies of etiology, pathogenesis, and mode of transmission. Progress report No. 19, June 1978-June 1979

Description: Bovine leukemia is believed to be caused by an oncogenic RNA virus designated bovine leukemia virus (BLV). The presence of BLV particles in lymphocyte cultures from leukemic cattle and cattle with a persistent lymphocytosis has been consistentily demonstrated. Concentrated, cell free, BLV preparations were used to inoculate 12 late stage bovine fetuses (in utero) and two newborn calves. Current studies involve extensive monitoring of these inoculated animals to detect precancerous changes and obtain a detailed description of the events preceding the development of lymphosarcoma. Ongoing monitoring studies will provide a complete record of all changes in the various leukemia associated parameters. We will then be able to detail when, in what sequence, and to what extent each parameter changes in the course of lymphosarcoma development. Fourteen animals were successfully inoculated during the study. Eleven remain alive, and comprise the current monitoring program. All eleven of these animals are definitely infected with BLV, and in nine the infection has substantially progressed with respect to the parameters being monitored. In addition to transmission and monitoring studies, various lymphocyte subpopulations were examined to determine which cell type(s) are involved in the pathogenesis of bovine lymphosarcoma. These studies have conclusively established that B-lymphocytes are the target cells for BLV infection and that they carry the morphologic nuclear abnormality associated with this disease.
Date: July 1, 1979
Creator: Sorensen, D.K.
Partner: UNT Libraries Government Documents Department

Long-term effects of intragastric instillations of silastic 386 foam elastomer

Description: Young male Sprague-Dawley rats (87 days old) were given a single dose (5 g/kg body weight (BW)) of Silastic 386 foam elastomer intragastrically (IG), and young female Swiss-Webster mice (83 days old) were given a single dose (5 g/kg BW) IG, or a dose (1 g/kg BW) IG on each of 5 consecutive days, of Silastic 386 foam elastomer. All animals were then maintained for the rest of their lives and autopsied at death. No significant effects resulting from the oral administration of this of this material were seen in any of the rats or mice.
Date: December 1, 1981
Creator: Smith, D.M.; Drake, G.A. & London, J.E.
Partner: UNT Libraries Government Documents Department

Prevalence and economics and bovine leukosis in the United States

Description: This paper reviews the prevalence of bovine leukosis in the US and discusses the economic significance of the disease. The term leukosis is used except when reporting the Meat Inspection Department data which used the term malignant lymphoma instead. (PCS)
Date: January 1, 1979
Creator: Sorensen, D.K. & Beal, V.C. Jr.
Partner: UNT Libraries Government Documents Department

Repair of DNA treated with. gamma. -irradiation and chemical carcinogens. Progress report, March 15, 1979-March 15, 1980

Description: The identification and purification of 3-methyladenine glycosylase from the cell nuclei of rat liver was completed. The characterization of 7-methylguanine N-glycosylase activity in E. coli is currently under investigation. Alkylated DNA in chromatin structures as a substrate for 3-methyladenine N-glycosylase is discussed. An enzyme from E. coli and mammalian tissue active on 2,6-diamino-4-hydroxy-5-N-methyldormamido-pyrimide is isolated and characterized. Studies are proceeding on the correlation of x-ray sensitivity with removal of alkylated bases from DNA in x-ray sensitive and x-ray resistant lines of lymphoma cells. The reaction of ..beta..-propiolactone with derivatives of adenine and with DNA is discussed.
Date: January 1, 1980
Creator: Goldthwait, D.A.
Partner: UNT Libraries Government Documents Department

Tissue enzyme changes in parabiotic rats with subcutaneous lymphoma

Description: A solid lymphoma was implanted into normal rats and into one partner of parabiotic pairs. Appreciable decreases in hepatic ornithine aminotransferase and arginase occurred about a week earlier (4 to 6 days after implantation) in single than in parabiotic hosts. By 18 to 21 days significant decreases in both enzymes were also apparent in the host partner. The hepatic thymidine kinase showed a 5-fold elevation in single hosts 4 days after implantation; by 14 days its levels were about 200 times above normal and had also risen in the parabiotic hosts (20-fold) and the host partners (4-fold). Implantation of fibrosarcoma caused qualitatively similar but generally less pronounced changes in the above 3 enzymes in livers of single hosts, parabiotic hosts, and host partners. The splenic thymidine kinase, 14 days after implantation, was increased from control levels of about 3 units/g to 50.6, 44.8, and 13.5 units/g in single hosts, parabiotic hosts, and host partners, respectively. At later stages, 17 to 20 days after implantation of the lymphoma, appreciable amounts of thymidine kinase appeared in the plasma: the units of activity per ml were 6.2 in single hosts, 0.79 in parabolic hosts, and 0.55 in host partners (control <0.05). The observations on the hepatic and splenic enzyme changes in parabiotic rats suggest that effects of neoplasms on distant host tissues are mediated by humoral factors. The less pronounced responses in parabiotic than in single hosts indicate that the tumor-free partner affords some protection against these systemic effects.
Date: January 1, 1977
Creator: Herzfeld, A; Greengard, O & Warren, S
Partner: UNT Libraries Government Documents Department