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T Vaughan

Publications and source records attributed to T Vaughan.

At least 19 recordsLinked to original sources
PubMed2006

Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo.

The unique properties of the tumour microenvironment can be exploited by using recombinant anaerobic clostridial spores as highly selective gene delivery vectors. Although several recombinant Clostridium species have been generated during the past decade, their efficacy has been limited. Our goal was to substantially improve the prospects of clostridia as a gene delivery vector. Therefore, we have assessed a series of nitroreductase (NTR) enzymes for their capacity to convert the innocuous CB1954 prodrug to its toxic derivative. Among the enzymes tested, one showed superior prodrug turnover characteristics. In addition, we established an efficient gene transfer procedure, based on conjugation, which allows for the first time genetic engineering of Clostridium strains with superior tumour colonisation properties with high success rates. This conjugation procedure was subsequently used to create a recombinant C. sporogenes overexpressing the isolated NTR enzyme. Finally, analogous to a clinical setting situation, we have tested the effect of multiple consecutive treatment cycles, with antibiotic bacterial clearance between cycles. Importantly, this regimen demonstrated that intravenously administered spores of NTR-recombinant C. sporogenes produced significant antitumour efficacy when combined with prodrug administration.

Animals↗
PubMed2005

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells through activation of TRAIL-R1 and TRAIL-R2 death signalling receptors. Here, we describe the characterisation and activity of HGS-ETR1, the first fully human, agonistic TRAIL-R1 mAb that is being developed as an antitumour therapeutic agent. HGS-ETR1 showed specific binding to TRAIL-R1 receptor. HGS-ETR1 reduced the viability of multiple types of tumour cells in vitro, and induced activation of caspase 8, Bid, caspase 9, caspase 3, and cleavage of PARP, indicating activation of TRAIL-R1 alone was sufficient to induce both extrinsic and intrinsic apoptotic pathways. Treatment of cell lines in vitro with HGS-ETR1 enhanced the cytotoxicity of chemotherapeutic agents (camptothecin, cisplatin, carboplatin, or 5-fluorouracil) even in tumour cell lines that were not sensitive to HGS-ETR1 alone. In vivo administration of HGS-ETR1 resulted in rapid tumour regression or repression of tumour growth in pre-established colon, non-small-cell lung, and renal tumours in xenograft models. Combination of HGS-ETR1 with chemotherapeutic agents (topotecan, 5-fluorouracil, and irinotecan) in three independent colon cancer xenograft models resulted in an enhanced antitumour efficacy compared to either agent alone. Pharmacokinetic studies in the mouse following intravenous injection showed that HGS-ETR1 serum concentrations were biphasic with a terminal half-life of 6.9-8.7 days and a steady-state volume of distribution of approximately 60 ml kg(-1). Clearance was 3.6-5.7 ml(-1) day(-1) kg(-1). These data suggest that HGS-ETR1 is a specific and potent antitumour agent with favourable pharmacokinetic characteristics and the potential to provide therapeutic benefit for a broad range of human malignancies.

Animals↗
PubMed2001

Removal of selected metal ions from aqueous solution using modified corncobs.

The objective of this study was to convert corncobs to metal ion adsorbents for wastewater treatment. Ground corncobs were modified with either 0.6 M citric acid (CA) or 1.0 M phosphoric acid (PA) to help improve their natural adsorption capacity. The effect of a combination of wash and modification treatment was tested for corncob adsorption efficiency with five different metal ions (cadmium, copper, lead, nickel, zinc) individually or in a mixed solution containing each metal at a 20 mM concentration. Results were compared to those of commercial resins Amberlite IRC-718, Amberlite 200, Duolite GT-73 and carboxymethylcellulose (CMC). Modified corncobs showed the same adsorption efficiency as Duolite GT-73 for cadmium, copper, nickel and zinc ions and had greater adsorption than CMC for nickel and zinc ions. For mixed metals, the modified corncobs exhibited the same adsorption efficiency as Duolite GT-73 for cadmium and copper ions and the same or higher adsorption than Amberlite IRC-718 for lead ions. Adsorption capacities of modified samples were compared to those of Amberlite IRC-718, Amberlite 200 and Duolite GT-73. Commercial resins generally had higher adsorption capacities than modified corncobs. However, the adsorption capacity of modified corncobs for copper and lead ions was equivalent to Duolite GT-73, but was lower than for Amberlite IRC-718 or Amberlite 200. Depending on the specific metal ion and the presence or absence of other metal ions, chemically modified corncobs were at least equivalent in adsorption properties to all of the commercial cation exchange resins examined in this study.

Adsorption↗
PubMed2000

Mapping of a syndrome of X-linked thrombocytopenia with Thalassemia to band Xp11-12: further evidence of genetic heterogeneity of X-linked thrombocytopenia.

X-linked thrombocytopenia with thalassemia (XLTT; Online Mendelian Inheritance in Man [OMIM] accession number 314050) is a rare disorder characterized by thrombocytopenia, platelet dysfunction, splenomegaly, reticulocytosis, and unbalanced hemoglobin chain synthesis. In a 4-generation family, the gene responsible for XLTT was mapped to the X chromosome, short arm, bands 11-12 (band Xp11-12). The maximum lod score possible in this family, 2.39, was obtained for markers DXS8054 and DXS1003, at a recombination fraction of 0. Recombination events observed for XLTT and markers DXS8080 and DXS8023 or DXS991 define a critical region that is less than or equal to 7.65 KcM and contains the gene responsible for the Wiskott-Aldrich syndrome (WAS; OMIM accession number 301000) and its allelic variant X-linked thrombocytopenia (XLT; OMIM accession number 313900). Manifestations of WAS include thrombocytopenia, eczema, and immunodeficiency. In WAS/XLT the platelets are usually small, and bleeding is proportional to the degree of thrombocytopenia. In contrast, in XLTT the platelet morphology is normal, and the bleeding time is disproportionately prolonged. In this study no alteration in the WAS gene was detected by Northern blot or Western blot analysis, flow cytometry, or complimentary DNA dideoxynucleotide fingerprinting or sequencing. As has been reported for WAS and some cases of XLT, almost total inactivation of the XLTT gene-bearing X chromosome was observed in granulocytes and peripheral blood mononuclear cells from 1 asymptomatic obligate carrier. The XLTT carrier previously found to have an elevated alpha:beta hemoglobin chain ratio had a skewed, but not clonal, X-inactivation pattern favoring activity of the abnormal allele. Clinical differences and results of the mutation analyses make it very unlikely that XLTT is another allelic variant of WAS/XLT and strongly suggest that X-linked thrombocytopenia mapping to band Xp11-12 is a genetically heterogeneous disorder.

Blotting, Northern↗
PubMed2000

Limb salvage of lower-extremity wounds using free gracilis muscle reconstruction.

An extensive series reviewing the benefits and drawbacks of use of the gracilis muscle in lower-extremity trauma has not previously been collected. In this series of 50 patients, the use of microvascular free transfer of the gracilis muscle for lower-extremity salvage in acute traumatic wounds and posttraumatic chronic wounds is reviewed. In addition, the wound size, injury patterns, problems, and results unique to the use of the gracilis as a donor muscle for lower-extremity reconstruction are identified. In a 7-year period from 1991 to 1998, 50 patients underwent lower-extremity reconstruction using microvascular free gracilis transfer at the University of Maryland Shock Trauma Center, Johns Hopkins Hospital, and Johns Hopkins Bayview Medical Center. There were 22 patients who underwent reconstruction for coverage of acute lower-extremity traumatic soft-tissue defects associated with open fractures. The majority of patients were victims of high-energy injuries with 91 percent involving motor vehicle or motorcycle accidents, gunshot wounds, or pedestrians struck by vehicles. Ninety-one percent of the injuries were Gustilo type IIIb tibial fractures and 9 percent were Gustilo type IIIc. The mean soft-tissue defect size was 92.2 cm2. Successful limb salvage was achieved in 95 percent of patients. Twenty-eight patients with previous Gustilo type IIIb tibia-fibula fractures presented with posttraumatic chronic wounds characterized by osteomyelitis or deep soft-tissue infection. Successful free-tissue transfer was accomplished in 26 of 28 patients (93 percent). All but one of the patients in this group who underwent successful limb salvage (26 of 27, or 96 percent) are now free of infection. Use of the gracilis muscle as a free-tissue transfer has been shown to be a reliable and predictable tool in lower-extremity reconstruction, with a flap success and limb salvage rate comparable to those in other large studies.

Accidents, Traffic↗
PubMed1999

Association of A vitamin D receptor polymorphism with sporadic breast cancer development.

Breast cancer is the leading cause of cancer death among Australian women and its incidence is annually increasing. Genetic factors are involved in the complex etiology of breast cancer. The seco-steroid hormone, 1.25 dihydroxy vitamin D3 can influence breast cancer cell growth in vitro. A number of studies have reported correlations between vitamin D receptor (VDR) gene polymorphisms and several diseases including prostate cancer and osteoporosis. In breast cancer, low vitamin D levels in serum are correlated with disease progression and bone metastases, a situation also noted in prostate cancer and suggesting the involvement of the VDR. In our study, 2 restriction fragment length polymorphisms (RFLP) in the 3' region (detected by Apa1 and Taq1) and an initiation codon variant in the 5' end of the VDR gene (detected by Fok1) were tested for association with breast cancer risk in 135 females with sporadic breast cancer and 110 cancer-free female controls. Allele frequencies of the 3' Apa1 polymorphism showed a significant association (p = 0.016; OR = 1.56, 95% CI = 1.09-2.24) while the Taq1 RFLP showed a similar trend (p = 0.053; OR = 1.45, 95% CI = 1.00-2.00). Allele frequencies of the Fok1 polymorphism were not significantly different (p = 0.97; OR = 0.99, 95% CI = 0.69-1.43) in the study population. Our results suggest that specific alleles of the VDR gene located near the 3' region may identify an increased risk for breast cancer and justify further investigation of the role of VDR in breast cancer.

Adult↗
PubMed1998

Evaluation of a public-private certified nurse-midwife maternity program for indigent women.

OBJECTIVES: This study assessed the impact of a public-private certified nurse-midwife program on prenatal and delivery outcomes among medically indigent women. METHODS: A population-based quasi-experimental design was used to compare 1 intervention county with 2 nonintervention counties. RESULTS: The program significantly reduced the number of women who received no prenatal care and the risk of acquiring less than adequate prenatal care. Reductions in the proportion of infants born premature or with low birth-weights were of borderline significance. The use of induction and/or stimulation of labor was statistically elevated. CONCLUSIONS: These results suggest that the intervention program was instrumental in reducing some, but not all, negative prenatal and delivery outcomes.

Adult↗
PubMed1996

Cancer incidence among alachlor manufacturing workers.

A historical cohort study was conducted to evaluate cancer incidence among chemical workers with occupational and environmental exposure to alachlor, the active ingredient in a family of pre-emergent acetanilide herbicides. The study followed 943 workers with at least 1 year of cumulative employment at the Monsanto plant in Muscatine, Iowa, from startup of the alachlor manufacturing process in March 1968 through December 1990. Approximately 96% of all workers were successfully traced to determine their last known residence and cancer status. Eighteen workers were diagnosed with cancer during the follow-up period, based on pathology information from the statewide cancer registry maintained by the State Health Registry of Iowa. The standardized incidence ratio for all cancers was 1.5 (95% CI 0.9-2.4) for all workers exposed to alachlor, which was due primarily to elevated rates for colorectal cancer and chronic myeloid leukemia. Workers with 5 or more years in estimated high alachlor exposure jobs had elevated rates of colorectal cancer (3 cases, SIR = 5.2, 95% CI 1.1-15.1). Interpretation of the study results is limited by the small size of the study population, minimal length of follow-up, and current information concerning alachlor metabolism in primates and humans. Nonetheless, the findings suggest the need for continued evaluation of this and other alachlor-exposed cohorts.

Acetamides↗
PubMed1995

Proton nuclear magnetic resonance spectroscopic imaging of human temporal lobe epilepsy at 4.1 T.

We performed proton magnetic resonance spectroscopic imaging (MRSI) at high magnetic field (4.1 T) to study N-acetylaspartate, creatine, and choline levels in the brains of normal control subjects and patients with intractable temporal lobe epilepsy. We compared the results of MRSI to those of other presurgical techniques to determine the sensitivity of this method in the lateralization of the epileptic focus. The normal hippocampal creatine-N-acetylaspartate ratio was 0.71 +/- 0.14 with no differences between left and right. Using the mean control hippocampal creatine-N-acetylaspartate ratio plus 2 standard deviations to identify statistically significant changes, we found lateralizing metabolic abnormalities corresponding to the operated temporal lobe in all patients. Four patients (40%) had contralateral abnormalities, and 2 of them had bilateral independent seizure onset confirmed by intracranial electroencephalographic studies. Statistically significant increases in the choline-N-acetylaspartate ratio in comparison to healthy volunteers were observed in 8 of the 10 patients. With the creatine-N-acetylaspartate ratio, MRSI demonstrated a 100% sensitivity compared to magnetic resonance imaging, which identified pathology in 70% of the patients. These findings suggest that proton MRSI yields a distinctive metabolic profile in patients with temporal lobe epilepsy and is sensitive in detecting bilateral metabolic abnormalities in some patients. These preliminary findings suggest that MRSI is more sensitive than magnetic resonance imaging in the lateralization of epileptic foci in temporal lobe epilepsy.

Adult↗
PubMed1994

Blunt traumatic rupture of the heart, pericardium, and supradiaphragmatic inferior vena cava: case report.

Before 1955 blunt traumatic ruptures of the heart and pericardium were reported almost exclusively in autopsy reports. Since then, because of improved prehospital care and early triage, it has been demonstrated that injuries resulting in rupture of the heart and pericardium are no longer always fatal. We present a case of a patient who arrived at the hospital with increasing abdominal girth and a tender abdomen who on exploration was found to have a tear of the pericardium and atrial appendage compounded by a supradiaphragmatic tear of the inferior vena cava.

Accidents, Traffic↗
PubMed1993

Nasal melanoma.

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Formaldehyde↗
PubMed1991

Homologies between members of the germin gene family in hexaploid wheat and similarities between these wheat germins and certain Physarum spherulins.

By screening approximately 10(6) plaques in a wheat DNA library with a "full-length" germin cDNA probe, two genomic clones were detected. When digested with EcoRI, one clone yielded a 2.8-kilobase pair fragment (gf-2.8) and the other yielded a 3.8-kilobase pair fragment (gf-3.8). By nucleotide sequencing, each of gf-2.8 and gf-3.8 was found to encode a complete sequence for germin and germin mRNA, and to contain appreciable amounts of 5'- and 3'-flanking sequences. The "cap" site in gf-2.8 was determined by primer extension and the corresponding site in gf-3.8 was deduced by analogy. The mRNA coding sequences in gf-2.8 and gf-3.8 are intronless and 87% homologous with one another. The 5'-flanking regions in gf-2.8 and gf-3.8 contain recognizable sites of what are probably cis-acting elements but there is otherwise little if any significant similarity between them. In addition to putative TATA and CAAT boxes in the 5'-flanking regions of gf-2.8 and gf-3.8, there are AT-rich inverted-repeats, GC boxes, long purine-rich sequences, two 19-base pair direct-repeat sequences in gf-2.8, and a remarkably long (200-base pair) inverted-repeat sequence (approximately 90% homology) in gf-3.8. An 8% difference between the mature-protein coding regions in gf-2.8 and gf-3.8 is reflected by a corresponding 7% difference between the corresponding 201-residue proteins. Most significantly, the same 8% difference between the mature-protein coding regions in gf-2.8 and gf-3.8 is allied with no change whatever in a central part (61-151) of the encoded polypeptide sequences. It seems likely that this central, strongly conserved core in the germins is of first importance in the biochemical involvements of the proteins. When an equivalence is assumed between like amino acids, the gf-2.8 and gf-3.8 germins show significant (approximately 44%) similarity to spherulins 1a and 1b of Physarum polycephalum, a similarity that increases to approximately 50% in the conserved core of germin. Near the middle (87-96) of the conserved core in the germins is a rare PH(I/T)HPRATEI decapeptide sequence which is shared by spherulins (1a and 1b) and germins (gf-2.8 and gf-3.8). These similarities are discussed in the context of evidence which can be interpreted to suggest that the biochemistry of germins and spherulins is involved with cellular, perhaps cell-wall responses to desiccation, hydration, and osmotic stress.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1985

Amine transport into chromaffin ghosts. Kinetic measurements of net uptake of biologically and pharmacologically relevant amines using an on-line amperometric technique.

The kinetic parameters for net transport of dopamine, epinephrine, norepinephrine, 5-hydroxytryptamine, S alpha-methyldopamine, R alpha-methyldopamine, and 1R,2S alpha-methylnorepinephrine into highly purified bovine chromaffin ghosts were determined using an on-line amperometric technique. Chromaffin ghosts devoid of endogenous amines were formed from lysis of chromaffin granules under hypotonic conditions, extensive washing of the scattered membranes, followed by resuspension in iso-osmotic media and overnight dialysis. When chromaffin ghosts formed so as to generate and maintain a large delta pH were suspended in 185 mM KCl, 10 mM Hepes at pH 7.0, 37 degrees C, the addition of MgATP resulted in rapid acidification of the intravesicular space, which was maintained at pH 6.0 (+/- 0.1) for over 30 min. Kinetic net amine transport was subsequently measured with a glassy carbon electrode. The initial rates of uptake were found to follow Michaelis-Menten kinetics. Computer based statistical analysis of the data using distribution-free procedures yielded Km (and V) values as follows: in microM (nmol X mg protein-1 X min-1) dopamine, 16.2 (14.0); R-norepinephrine, 32.5 (12.9); R-epinephrine, 35.1 (15.2); 5-hydroxytryptamine, 4.7 (5.1); S alpha-methyldopamine, 17.7 (11.2); R alpha-methyldopamine, 44.2 (9.9); 1R,2S alpha-methylnorepinephrine, 76.5 (12.5). The physiologic and pharmacologic implications of these kinetic parameters are discussed.

Adrenal Medulla↗
PubMed1985

Design of a limited-access facility and safety program for a genetic toxicology laboratory.

A limited-access facility has been designed as a result of the need for laboratories for testing hazardous materials found in the environment. The facility design features include room air flow and filtration, hood types, sink design and placement, design of countertops, type of flooring and wall sealant, and traffic flow within the laboratories. These laboratories required the diversity to handle weighing of stock hazardous materials, preparation and handling of aliquots, maintenance of dosed animals as well as sterile conditions required for tissue culture and continuous cell culture methods. A safety and health program was also developed which included specific dress (e.g., scrub suit, TYVEK jumpsuit, gloves, safety glasses and safety shoes), safety advisory group, safety response group, medical monitoring program and training of current and new staff members. The design and use of the facility are continuously reevaluated and changes are made as necessitated by either research needs or improved safety methods.

Accident Prevention↗