The role of oxidative metabolism in the up-regulation/activation of stress-inducible signaling pathways as well as induction of micronucleus formation in bystander cells was investigated. By immunoblotting and in situ immunofluorescence,... more
The role of oxidative metabolism in the up-regulation/activation of stress-inducible signaling pathways as well as induction of micronucleus formation in bystander cells was investigated. By immunoblotting and in situ immunofluorescence, active Cu-Zn superoxide dismutase (SOD) en- zyme and active catalase enzyme were shown to inhibit the up-regulation of p21Waf1 as well as the induction of micronucleus formation in bystander cells
Research Interests: Cancer, Signal Transduction, Humans, Reactive Oxygen Species, NF-kappa B, and 13 moreCatalase, Superoxide Dismutase, Transcription Factor, Mitogen Activated Protein Kinase, Enzyme, NADPH oxidase, Hydrogen Peroxide, Enzyme activity, Alpha Particles, Human Fibroblasts, Oxidation-Reduction, Immunoblotting, and Oxidative Metabolism
Intracranial vessels were examined in 55 patients with both conventional selective catheterization and intravenous digital subtraction angiography using a prototype digital subtraction unit. In 65% of the patients, the digital subtraction... more
Intracranial vessels were examined in 55 patients with both conventional selective catheterization and intravenous digital subtraction angiography using a prototype digital subtraction unit. In 65% of the patients, the digital subtraction angiogram was diagnostic, but the overall quality was inferior to conventional selective angiography. In 22%, the digital subtraction angiogram provided diagnostic information, but there was a significant chance of misinterpreting the results of the study. In 13% of cases, the subtraction angiogram was not diagnostic. As now developed, digital subtraction angiography can replace conventional cerebral angiography for preoperative evaluation of the juxtasellar carotid artery prior to transphenoidal surgery because the large intracerebral vessels are consistently well visualized with digital subtraction. The dural sinuses are better visualized with digital subtraction than with conventional angiography because with digital subtraction all the vessels of the brain are opacified, whereas with conventional angiography, there is a mixture of opacified and unopacified blood in the sinuses. Combined with computed tomography, digital subtraction angiography can replace conventional angiography for determining the preoperative extent and vascularity of tumors. It can be used for postoperative evaluation of aneurysms, arteriovenous malformations, extracranial to intracranial bypasses, and after the embolization of vascular lesions.
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A novel interference with measurements of serum free thyroxine (FT4) caused by rheumatoid factor (RhF) is described. We found misleading, sometimes gross, increases of FT4 results in 5 clinically euthyroid elderly female patients with... more
A novel interference with measurements of serum free thyroxine (FT4) caused by rheumatoid factor (RhF) is described. We found misleading, sometimes gross, increases of FT4 results in 5 clinically euthyroid elderly female patients with high RhF concentrations. All 5 patients had high FT4 on Abbott AxSYM or IMx analyzers. "NETRIA" immunoassays gave misleading results in 4 of the 5 patients; Amerlex-MAB in 2 of 4 patients; AutoDELFIA in 2 of the 5; and Corning ACS-180 and Bayer Diagnostics Immuno 1 in 1 of the 5. BM-ES700 system results for FT4 in these women remained within the reference range. Results for serum T4, thyroid-stimulating hormone, free triiodothyronine, thyroid-hormone-binding globulin, and FT4 measured by equilibrium dialysis were normal in all 5 patients. Drugs, albumin-binding variants, and anti-thyroid-hormone antibodies were excluded as interferences. Addition to normal serum of the RhF isolated from each of the 5 patients increased the apparent FT4 (Abbot...
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A hallmark of cancer cells is their pronounced genetic instability, which has been implicated in both tumor development and negative treatment outcomes. Recently, it has been reported that ionizing radiation may induce a persistent state... more
A hallmark of cancer cells is their pronounced genetic instability, which has been implicated in both tumor development and negative treatment outcomes. Recently, it has been reported that ionizing radiation may induce a persistent state of hypermutability in mammalian cells that lasts for many (>30) cell divisions. In this study, we examined whether other stress signals (both DNA-damaging non-DNA-damaging) can initiate a similar process. We show that persistent genetic instability was induced by nongenotoxic stress exposures such as heat treatment, serum starvation, or the tumor microenvironment, as well as genotoxic stresses such as ionizing radiation and exposure to hydrogen peroxide. Progeny of 10-20% of surviving cells exhibited persistent and pronounced genetic instability at both an artificially transfected gene and a genomic minisatellite locus 23 cell divisions after the initial exposure. Stress-induced persistent genetic instability may be a general response of tumor ce...
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To further understand the mechanism(s) by which DNA damage activates p53, we analysed the expression levels of p53 and HDM2 (the human homolog of murine MDM2) in various human diploid fibroblast and tumor cell strains during the period... more
To further understand the mechanism(s) by which DNA damage activates p53, we analysed the expression levels of p53 and HDM2 (the human homolog of murine MDM2) in various human diploid fibroblast and tumor cell strains during the period that precedes activation of known downstream effectors of p53. In X-irradiated human cells, HDM2 protein was rapidly phosphorylated in serine/threonine residues in a p53, p14ARF and p73-independent manner. In p53 wild-type cells, HDM2 phosphorylation precedes a detectable increase in the levels of p53 and is not observed in ataxia telangiectasia (AT) fibroblasts. The transfection of AT cells with a vector expressing ATM restored the ability to rapidly phosphorylate HDM2 following X-irradiation, confirming a role for ATM in its phosphorylation. We also show that ATM complexes with HDM2. The DNA lesions signaling the early rapid phosphorylation of HDM2 are a result of X-ray and not UV-type damage. The ATM-promoted early covalent modification of HDM2 in ...
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The cytotoxic effects of radiation delivered in daily fractions of 2.0 Gy were examined in plateau phase cultures of human tumor cells of varying in vitro radiosensitivity, derived from tumors of varying radiocurability. Among the eight... more
The cytotoxic effects of radiation delivered in daily fractions of 2.0 Gy were examined in plateau phase cultures of human tumor cells of varying in vitro radiosensitivity, derived from tumors of varying radiocurability. Among the eight cell lines examined, three types of responses to fractionated irradiation were observed. In the group composed of tumor cell lines that were radioresistant in culture (D0 > 2 Gy) and derived from known local radiation failures or from tumor histologies associated with radiation failure, a gradual linear reduction in surviving fraction versus total dose was observed. In a second group, composed of cell lines that were radiosensitive in culture (D0 approximately 1 Gy) but derived from known radiation failures, the surviving fraction initially declined and began to plateau after 6 Gy (three fractions of 2 Gy). In the third group, composed of radiosensitive cell lines derived from tumors associated with high radiocurability, a rapid decline in survivi...
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We report on a family where four of the eleven children presented with reduced visual acuities, a red-green deficit at the Farnsworth-Munsel FM 100-hue test, normal appearing fundi and unexpected electroretinographic findings. Light-... more
We report on a family where four of the eleven children presented with reduced visual acuities, a red-green deficit at the Farnsworth-Munsel FM 100-hue test, normal appearing fundi and unexpected electroretinographic findings. Light- (photopic) and dark- (scotopic) adapted electroretinograms (ERG) and oscillatory potentials (OPs) were obtained following an accepted standard protocol. The b-wave of their photopic ERG was significantly more attenuated than the a-wave due to the specific abolition of OP4, while the amplitudes of OP2 and OP3 were within the normal range, giving to the b-wave a truncated appearance reminiscent of that seen in congenital stationary night blindness (CSNB) with myopia. Interestingly in the latter condition, which is believed to result from an ON-retinal pathway anomaly, it is OP2 and OP3 which are specifically abolished while OP4 is of normal amplitude thus resulting in an OP response pattern which complements that seen with our patients. Also of interest i...
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We present here an analysis of the spectrum of mutations of the p53 gene seen in 127 bone and soft tissue sarcomas of various histological classifications. Gross rearrangements were analyzed by Southern blotting using a complementary DNA... more
We present here an analysis of the spectrum of mutations of the p53 gene seen in 127 bone and soft tissue sarcomas of various histological classifications. Gross rearrangements were analyzed by Southern blotting using a complementary DNA probe from the p53 gene, and subtle alterations in the entire coding sequence (exons 2 through 11) were identified by a combination of single-strand conformation polymorphism analysis and direct genomic sequencing. A total of 42 somatic alterations of the p53 gene were found, of which 21 were gross rearrangements and 21 were subtle alterations. These included 17 cases of a single base substitution, 3 small deletions, and one single base insertion. In contrast to reported findings for other types of cancer, we found that mutations of the p53 gene in sarcomas are quite heterogeneous both in their distribution throughout the gene and in the type of genetic alterations that result. All 13 missense mutations we found occurred at highly conserved residues...
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The objective of this investigation was to correlate Xenon-133 inhalation rCBF measurements with the pattern of cortical arterial filling on intravenous DSA in 18 patients with unilateral internal carotid artery occlusion. Of 9 patients... more
The objective of this investigation was to correlate Xenon-133 inhalation rCBF measurements with the pattern of cortical arterial filling on intravenous DSA in 18 patients with unilateral internal carotid artery occlusion. Of 9 patients showing symmetrical filling of hemispheric cortical arteries, none showed an inter-hemispheric difference in rCBF ( delta Fg) greater than 10ml/100gm/min. Of 9 patients showing delayed cortical opacification ipsilateral to the internal artery occlusion, 3 showed a delta Fg greater than 10ml/100gm/min, 3 showed a delta Fg in the 7-10ml/100gm/min range, and 3 had a delta Fg less than 7ml/100gm/min. All patients with asymmetric abnormalities in the rCBF profile had the delayed pattern of cortical filling on DSA. The presence of symmetrical hemispheric opacification of cortical arteries on DSA indicates adequate interhemispheric redistribution of rCBF and patent inter-hemispheric collateral channels, but not necessarily normal cerebral blood flow. The presence of delayed cortical arterial opacification on the side of internal carotid artery occlusion does not necessarily imply significant inter-hemispheric rCBF differences, nor does it rule out a normal rCBF. The presence of bilateral reduction of rCBF and symmetrical cortical artery filling on DSA may represent an "interhemispheric steal".
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ABSTRACT Infrared sensor technology is critical to many commercial and military defense applications. Traditionally, cooled infrared material systems such as indium antimonide, platinum silicide, mercury cadmium telluride, and arsenic... more
ABSTRACT Infrared sensor technology is critical to many commercial and military defense applications. Traditionally, cooled infrared material systems such as indium antimonide, platinum silicide, mercury cadmium telluride, and arsenic doped silicon (Si:As) have dominated infrared detection. Improvement in surveillance sensors and interceptor seekers requires large size, highly uniform, and multicolor IR focal plane arrays involving medium wave, long wave, and very long wave IR regions. Among the competing technologies are the quantum well infrared photodetectors based on lattice matched or strained III-V material systems. This paper discusses cooled IR technology with emphasis on QWIP and MCT. Details will be given concerning device physics, material growth, device fabrication, device performance, and cost effectiveness for LWIR, VLWIR, and multicolor focal plane array applications.
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Eighty-eight patients with brain ischemia underwent cerebral angiography and measurement of regional cerebral blood flow (rCBF) after 133Xe inhalation. A fast compartment flow rate and an initial slope index were computed for each... more
Eighty-eight patients with brain ischemia underwent cerebral angiography and measurement of regional cerebral blood flow (rCBF) after 133Xe inhalation. A fast compartment flow rate and an initial slope index were computed for each detector and for each hemisphere. The clinical presentation, angiographic findings, and rCBF results were then examined for significant correlations. Patients with hemispheric infarction most frequently showed bilateral diffusely decreased rCBF. In patients with transient ischemic attacks, no specific pattern emerged. Patients with unilateral internal carotid artery occlusion frequently hd bilateral diffusely decreased rCBF. Patients with severe internal carotid artery stenosis were more likely to show decreased rCBF than were patients with mild or moderate stenosis. The initial slope index seemed to be a more sensitive indicator of brain ischemia than the fast compartment flow rate. The possible pathophysiological significance and relationship to patient management of the various rCBF patterns are discussed.
Research Interests: Neurosurgery, Nuclear medicine, Cardiovascular disease, Humans, Beta decay, and 19 moreFemale, Male, Central Nervous System, Brain Ischemia, Clinical Sciences, Middle Aged, Cardiovascular system, Blood Flow, Regional Cerebral Blood Flow, Indexation, Flow Rate, Carotid Artery, Clinical Presentation, Neurosciences, Blood Vessel, Transient Ischemic Attack (TIA), Internal Carotid Artery, Cerebral Infarction, and Cerebral Angiography
The role of oxidative metabolism in the up-regulation/activation of stress-induciblesignaling pathways as well as induction of micronucleus formation in bystander cells was investigated. By immunoblotting and in situ immunofluorescence,... more
The role of oxidative metabolism in the up-regulation/activation of stress-induciblesignaling pathways as well as induction of micronucleus formation in bystander cells was investigated. By immunoblotting and in situ immunofluorescence, active Cu-Zn superoxide dismutase (SOD) enzyme and active catalase enzyme were shown to inhibit the up-regulation of p21(Waf1) as well as the induction of micronucleus formation in bystander cells from confluent cultures of normal human diploid fibroblasts irradiated with 0.3-3 cGy of alpha-particles. Enzyme activity assays indicated that exogenous SOD became significantly associated with the cells. Reactive oxygen species apparently derived from a flavin-containing oxidase enzyme [presumably an NAD(P)H-oxidase] appeared to be major contributors to the bystander-induced up-regulation of p53 and p21(Waf1) as well as micronucleus formation, as evidenced by the inhibition of these effects with diphenyliodonium. Rapid activation of nuclear factor kappaB,...
Research Interests: Cancer, Signal Transduction, Humans, Reactive Oxygen Species, NF-kappa B, and 12 moreCatalase, Superoxide Dismutase, Transcription Factor, Mitogen Activated Protein Kinase, Enzyme, NADPH oxidase, Hydrogen Peroxide, Enzyme activity, Alpha Particles, Human Fibroblasts, Oxidation-Reduction, and Immunoblotting
Pretreatment functional brain imaging was examined for never-hospitalized outpatients with unipolar depression compared with control subjects in a crossover treatment trial involving bupropion or venlafaxine monotherapy. Patients (n = 20)... more
Pretreatment functional brain imaging was examined for never-hospitalized outpatients with unipolar depression compared with control subjects in a crossover treatment trial involving bupropion or venlafaxine monotherapy. Patients (n = 20) with unipolar depression received baseline (medication-free) fluorine-18 deoxyglucose (FDG) positron emission tomography (PET) scan and then at least 6 weeks of bupropion or venlafaxine monotherapy in a single-blind crossover trial. Age-matched healthy control subjects (n = 20) also received baseline FDG PET scans. For each medication PET data from patients compared with control subjects was analyzed as a function of treatment response (defined as moderate to marked improvement on the Clinical Global Impression Scale). Treatment response rates were similar for buproprion (32%) and venlafaxine (33%). Compared with control subjects, responders but not nonresponders, to both drugs demonstrated frontal and left temporal hypometabolism. Selectively, com...
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We consider the matrix ZP=ZP+ZPt, where the entries of ZP are the values of the zeta function of the finite poset P. We give a combinatorial interpretation of the determinant of ZP and establish a recursive formula for this determinant in... more
We consider the matrix ZP=ZP+ZPt, where the entries of ZP are the values of the zeta function of the finite poset P. We give a combinatorial interpretation of the determinant of ZP and establish a recursive formula for this determinant in the case in which P is a boolean algebra.
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Controlling hypolimnetic hypoxia is a key goal of water quality management. Hypoxic conditions can trigger the release of reduced metals and nutrients from lake sediments, resulting in taste and odor problems as well as nuisance algal... more
Controlling hypolimnetic hypoxia is a key goal of water quality management. Hypoxic conditions can trigger the release of reduced metals and nutrients from lake sediments, resulting in taste and odor problems as well as nuisance algal blooms. In deep lakes and reservoirs, hypolimnetic oxygenation has emerged as a viable solution for combating hypoxia. In shallow lakes, however, it is difficult to add oxygen into the hypolimnion efficiently, and a poorly designed hypolimnetic oxygenation system could potentially result in higher turbidity, weakened thermal stratification, and warming of the sediments. As a result, little is known about the viability of hypolimnetic oxygenation in shallow bodies of water. Here, we present the results from recent successful tests of side stream supersaturation (SSS), a type of hypolimnetic oxygenation system, in a shallow reservoir and compare it to previous side stream deployments. We investigated the sensitivity of Falling Creek Reservoir, a shallow ...
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Cholinergic neurotransmission is thought to be modulated by serotonin as documented in animal and human studies. We examined the effects of the muscarinic antagonist scopolamine (0.4 mg IV) given alone or together with the serotonin mixed... more
Cholinergic neurotransmission is thought to be modulated by serotonin as documented in animal and human studies. We examined the effects of the muscarinic antagonist scopolamine (0.4 mg IV) given alone or together with the serotonin mixed agonist/antagonist m-chlorophenylpiperazine (m-CPP, 0.08 mg/kg IV), and the selective 5-HT3 receptor antagonist ondansetron (0.15 mg/kg IV). Ten normal elderly volunteers each received five separate pharmacologic challenges (placebo, ondansetron, scopolamine, scopolamine+ondansetron, and scopolamine+m-CPP). Cognitive, behavioral, and physiologic variables were analyzed using repeated measures analysis of variance. The acute effects of scopolamine in certain cognitive, behavioral, and physiological measures were significantly exaggerated by the addition of m-CPP. Scopolamine's cognitive effects were unaffected by ondansetron at the dose tested, nor did ondansetron given alone affect basal cognitive performance. This pilot study suggests that the serotonin mixed agonist/antagonist m-CPP may influence cholinergic neurotransmission. The changes associated with the combination of scopolamine and m-CPP do not appear to be secondary to simple pharmacokinetic alterations and suggest a complex interaction between the cholinergic and serotonergic systems centrally.
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The recA and lexA proteins of EScherichia coli are involved in a complex regulatory circuit that allows the expression of a diverse set of functions after DNA damage or inhibition of DNA replication. Exponentially growing cells contain a... more
The recA and lexA proteins of EScherichia coli are involved in a complex regulatory circuit that allows the expression of a diverse set of functions after DNA damage or inhibition of DNA replication. Exponentially growing cells contain a low level of recA protein, and genetic evidence suggests that lexA protein is involved in its regulation, perhaps as a simple repressor. Recent models for recA derepression after DNA damage have suggested that an early event in this process is the proteolytic cleavage of lexA protein, leading to high-level expression of recA. We present several lines of evidence that the specific protease activity of the recA protein, previously described with the lambda repressor as substrate, is capable of cleaving the wild-type lexA+ protein. First, lexA protein can be cleaved in vitro under the same conditions as prevously described for lambda repressor cleavage in a reaction requring both recA protease and ATP or an analogue, adenosine 5'-[lambda-thio]-triphosphate. Second, lexA protein can be observed in vivo as a physical entity after infection with lambda lexA+ transducing phage of host strains containing ittle or no active protease, but not in strains containing high levels of active protease. Finally, infection of host cells containing active protease with a lambda lexA+ transducing phage does not lead to repression of recA, but does so in cells lacking active protease. In all of these conditions the mutant lexA3 protein is largely resistant to inactivation or cleavage; this resistance can explain the dominant phenotype of lexA3 over lexA+. We discuss models for recA derepression and re-establishment of repression which propose that modulation of the protease activity of recA protein regulates both of these transitions.
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Two groups of consecutive patients from two different plastic surgical practice populations were evaluated to determine psychosocial differences between those who underwent nipple-areola reconstruction in addition to breast reconstruction... more
Two groups of consecutive patients from two different plastic surgical practice populations were evaluated to determine psychosocial differences between those who underwent nipple-areola reconstruction in addition to breast reconstruction (N = 33) versus those who did not undergo nipple-areola reconstruction in addition to breast reconstruction (N = 26). Psychological assessment consisted of a standardized symptom inventory (Brief Symptom Inventory) and a specially designed self-report questionnaire investigating reactions unique to surgeries for breast cancer and breast reconstruction. Both groups were equivalent sociodemographically, with the exception of age, where the nipple-added group was significantly younger (P = 0.035) than the nipple-not-added group. The nipple-added group reported significantly greater satisfaction with breast reconstruction with regard to overall satisfaction (P = 0.004), satisfaction with size (P = 0.02), satisfaction with softness (P = 0.0004), sexual sensitivity (P = 0.006), and satisfaction with nude appearance (P = 0.02). Of the nine scales of clinical symptomatology on the Brief Symptom Inventory, the nipple-added group showed more increased symptoms on seven of the nine. The nipple-added group was significantly higher on two of these scales, namely, paranoid ideation (P = 0.009) and anxiety (P = 0.03).
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Two groups of consecutive patients from two different plastic surgical practice populations were evaluated to determine psychosocial differences between those who underwent immediate (n = 25) versus delayed (n = 38) breast reconstruction.... more
Two groups of consecutive patients from two different plastic surgical practice populations were evaluated to determine psychosocial differences between those who underwent immediate (n = 25) versus delayed (n = 38) breast reconstruction. Psychological assessment consisted of a standardized symptom inventory (BSI) and a specially designed self-report questionnaire investigating reactions unique to mastectomy and reconstruction. Both groups were extremely equivalent with regard to sociodemographic data, with the typical subject being a well-educated and employed Caucasian wife. Verbal reports of physical complaints revealed no significant differences between the two groups except for difficulty with arm movement, which was statistically higher for the immediate group (p = 0.006.). This difference most likely was due to the axillary dissection being performed simultaneously at the time of reconstruction. The relationship between timing of reconstruction and self-reported distress over the mastectomy experience revealed that only 25 percent of the women who underwent immediate repair reported "high distress" in recalling their mastectomy surgery compared with 60 percent of the delayed reconstruction group (p = 0.02). In reference to the two scales measuring psychological symptoms, a general trend was present, with the delayed group scoring higher (although not statistically significantly) on 9 of our 12 scales. Ninety-six percent of the immediate group and 89 percent of the delayed group reported satisfaction with results.(ABSTRACT TRUNCATED AT 250 WORDS)
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Evidence accumulated over the past two decades has indicated that exposure of cell populations to ionizing radiation results in significant biological effects occurring in both the irradiated and nonirradiated cells in the population.... more
Evidence accumulated over the past two decades has indicated that exposure of cell populations to ionizing radiation results in significant biological effects occurring in both the irradiated and nonirradiated cells in the population. This phenomenon, termed the 'bystander response', has been shown to occur both in vitro and in vivo and has been postulated to impact both the estimation of risks of exposure to low doses/low fluences of ionizing radiation and radiotherapy. Several mechanisms involving secreted soluble factors, oxidative metabolism and gap-junction intercellular communication have been proposed to regulate the radiation-induced bystander effect. Our current knowledge of the biochemical and molecular events involved in the latter two processes is reviewed in this article.
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Recent studies have identified germline mutations of the p53 tumor-suppressor gene in families with the Li-Fraumeni syndrome, a rare inherited disorder characterized by a high risk of sarcomas of bone and soft tissue, breast cancer, and... more
Recent studies have identified germline mutations of the p53 tumor-suppressor gene in families with the Li-Fraumeni syndrome, a rare inherited disorder characterized by a high risk of sarcomas of bone and soft tissue, breast cancer, and other tumors. In this report, we address the possibility that some sporadic sarcomas may be associated with new germline mutations of the p53 gene, which would not be manifested as familial cancer unless the patient survived to reproduce. We studied DNA from peripheral leukocytes of 196 patients with sarcoma and from 200 controls. Of the 196 patients with sarcoma, 15 were selected because they had had multiple primary cancers or had a family history of cancer. The entire coding sequence and splice junctions of the p53 gene were analyzed for mutations. Eight germline mutations were found, three in patients with no known family history of cancer and five in patients with an unusual personal or family history of cancer. Four mutations caused amino acid substitutions, and four caused stop codons. These mutations were not present in any of the 200 controls. New germline mutations of the p53 gene are rare among patients with "sporadic" sarcoma but may be common in patients with sarcoma whose background includes either multiple primary cancers or a family history of cancer. Diverse mutations of this gene were associated with an increased likelihood of cancer; hence, the entire gene should be considered a target for heritable mutation. It appears that the group of patients with cancer who carry germline mutations of the p53 gene is more diverse than is suggested by the clinical definition of the Li-Fraumeni syndrome. The identification of carriers could be of substantial clinical importance.
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Mutations of the retinoblastoma gene, most of which cannot be detected by conventional Southern blotting, are known to cause both the nonhereditary and hereditary forms of retinoblastoma and have been implicated in the development of... more
Mutations of the retinoblastoma gene, most of which cannot be detected by conventional Southern blotting, are known to cause both the nonhereditary and hereditary forms of retinoblastoma and have been implicated in the development of other cancers. Nonhereditary retinoblastoma is caused by a somatic mutation. Hereditary retinoblastoma is caused by a germ-cell mutation, most often a new one, and thus there is usually no family history of the disease. Unlike patients with the nonhereditary disease, those with the hereditary form are at risk for additional retinoblastomas, and their progeny are at risk for the tumors. We used a sensitive technique of primer-directed enzymatic amplification, followed by DNA sequence analysis, to identify mutations as small as a single nucleotide change in tumors from seven patients with simplex retinoblastoma (with no family history of the disease). In four patients the mutation involved only the tumor cells, and in three it involved normal somatic cells as well as tumor cells but was not found in either parent; thus, these mutations appeared to be new, germ-cell mutations. In addition, we found point mutations in cells from a bladder carcinoma, a small-cell carcinoma of the lung, and another retinoblastoma. We conclude that the technique that we have described can distinguish hereditary from nonhereditary retinoblastoma and that it is useful in risk estimation and genetic counseling.
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LITTLE is known about the mechanisms of carcinogenesis. The fact that most carcinogens are mutagenic has led to speculation that the primary step in cancer induction may be mutational 1, 2; there is evidence from both in vivo 2 and in... more
LITTLE is known about the mechanisms of carcinogenesis. The fact that most carcinogens are mutagenic has led to speculation that the primary step in cancer induction may be mutational 1, 2; there is evidence from both in vivo 2 and in vitro 3 studies that a strong ...
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MAMMALIAN cell death, observed as deterioration of cellular structure or function, has not been characterised at the molecular level. We report here that human and rodent cells treated with several diverse agents which cause cell death as... more
MAMMALIAN cell death, observed as deterioration of cellular structure or function, has not been characterised at the molecular level. We report here that human and rodent cells treated with several diverse agents which cause cell death as measured by other criteria, ...
Research Interests: Cell Biology, Multidisciplinary, Nature, DNA, Cell line, and 7 moreLiver, Animals, Cell Death, Lung, Tritium, Molecular weight, and Cell Survival
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Research Interests: Earth Sciences, Limnology, Temporal Resolution, Biological Sciences, Environmental Sciences, and 10 moreOxygen Uptake, Biological Oceanography and Limnology, Steady state, Field Study, Bottom Boundary Layer, Dissolved Oxygen, Vertical Distribution, Oxygen Consumption, Energy Dissipation Rate, and Oxygen uptake rate
Congenital heart defects are generally assumed to have a multifactorial aetiology. We have tested this hypothesis by studying adults with heart defects and their families. We identified 1094 patients who survived surgery for major cardiac... more
Congenital heart defects are generally assumed to have a multifactorial aetiology. We have tested this hypothesis by studying adults with heart defects and their families. We identified 1094 patients who survived surgery for major cardiac defects before 1970. We chose individuals with disturbance of situs or segmental connection, with atrioventricular septal defect or with tetralogy of Fallot. After exclusion and non-participation, 727 individuals were traced. Each was visited by an investigator and completed a detailed questionnaire. If possible, all "normal" offspring were examined by a paediatric cardiologist. The 727 individuals had 393 live offspring. There were 71 miscarriages and five terminated pregnancies. Overall, we found recurrent heart defects in 16 liveborn offspring--a recurrence risk of 4.1%. This result differed significantly from sibling risk (2.1%; p=0.021). More congenital heart defects occurred in the offspring of affected women than in those of affected men (p=0.047); when all malformations (cardiac and non-cardiac) in the offspring were taken into account the excess was more significant (p=0.032). We found an excess of miscarriages in the offspring of affected women (p=0.001). In tetralogy of Fallot, heart defects occurred in seven (3.1%) of 223 offspring, 12 (2.2%) of 539 siblings, five (0.3%) of 1575 second-degree relatives, and eight (0.3%) of 2728 third-degree relatives. Our findings do not support a polygenic basis for all heart defects. Atrioventricular septal defect seems to be a single-gene defect and tetralogy of Fallot a polygenic disorder with a small number of interacting genes. Our data suggest that isolated transposition of the great arteries is a sporadic defect.
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Fluorescein angiography and xenon-133 (133Xe) clearance studies were performed during surgery on 15 patients who were undergoing superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis. Fourteen patients had... more
Fluorescein angiography and xenon-133 (133Xe) clearance studies were performed during surgery on 15 patients who were undergoing superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis. Fourteen patients had occlusive disease of the internal carotid artery (ICA), and one patient had severe stenosis of the MCA. Before anastomosis, fluorescein angiography showed slow filling of the MCA branches through collateral channels. Focal areas of impaired microcirculatory filling and washout were seen in the territory of severely sclerotic cortical arteries. The findings of preanastomotic 133Xe clearance studies were variable and a uniform pattern of regional cerebral blood flow (rCBF) changes was not defined. In 55% of the patients, rCBF was reduced to 25 ml/100 gm/min or less at one or more detector sites. Fluorescein angiography provided an immediate assessment of anastomotic patency and clearly displayed the distribution of blood entering the epicerebral circulation through the STA. In 67% of patients, multiple MCA cortical branches filled with fluorescein, whereas in 33% filling was restricted to the receptor artery territory. An immediate, substantial (greater than or equal to 15 ml/100 gm/min) increase in rCBF was demonstrated in 73% of patients after anastomosis. The rCBF changes were consistently better in patients with donor and receptor arteries greater than 1 mm in diameter. Redistribution of collateral input acted to increase rCBF in areas distant from the anastomotic site. Some improvement in fluorescein circulation and rCBF also was seen in cortex supplied by sclerotic MCA branches.
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Research Interests: Medical Informatics, Biotechnology, Radiotherapy, Cancer treatment, Molecular Mechanics, and 16 moreNew Technology, Humans, Survivors, United States, Carcinogens, Registries, Research Priorities, Neoplasms, Cancer Incidence, Cancer Survivor, National Cancer Institute, Genetic Susceptibility, Antineoplastic Agents, Syndrome, Case Control Studies, and Cohort Studies
In cancer, gene silencing via hypermethylation is as common as genetic mutations in p53. Understanding the relationship between mutant p53 and hypermethylation of other tumor suppressor genes is essential when elucidate mechanisms of... more
In cancer, gene silencing via hypermethylation is as common as genetic mutations in p53. Understanding the relationship between mutant p53 and hypermethylation of other tumor suppressor genes is essential when elucidate mechanisms of tumor development. In this study, two isogenic human B lymphoblast cell lines with different p53 status include TK6 containing wild-type p53 and WTK1 with mutant p53 were used and contrasted. Lower levels of p16(ink4A) protein were detected in WTK1 cells than in TK6 cells, which were accompanied by increased DNA (cytosine-5)-methyltransferase 1 (DNMT1) gene expression as well as hypermethylation of the p16 ( ink4A ) promoter. siRNA experiments to transiently knock down wild-type p53 in TK6 cells resulted in increase of DNMT1 expression as well as decrease of p16(ink4A) protein. Conversely, siRNA knockdown of mutant p53 in WTK1 cells did not alter either DNMT1 or p16(ink4A) protein levels. Furthermore, loss of suppression function of mutant p53 to DNMT1 in WTK1 was caused by the attenuation of its binding ability to the DNMT1 promoter. In summary, we provide evidences to elucidate the relationship between mutant p53 and DNMT1. Our results indicate that mutant p53 loses its ability to suppress DNMT1 expression, and thus enhances methylation levels of the p16 ( ink4A ) promoter and subsequently down-regulates p16(ink4A )protein.
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... We have examined here the duration of the G2/M delay with the anti-BrdUrd antibody staining pro-cedure in three human squamous carcinoma cell lines with widely differing cellular radiosensitivities, along with two groups of... more
... We have examined here the duration of the G2/M delay with the anti-BrdUrd antibody staining pro-cedure in three human squamous carcinoma cell lines with widely differing cellular radiosensitivities, along with two groups of radiosensitive mutants and their parental wild-type ...
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The anti-inflammatory activity of the IL-1 receptor antagonist, IL-1ra, was evaluated in the acetic acid (HOAc)-induced model of colitis in rats. Animals treated with 10 mg/kg IL-1ra or vehicle were evaluated for general health, acute... more
The anti-inflammatory activity of the IL-1 receptor antagonist, IL-1ra, was evaluated in the acetic acid (HOAc)-induced model of colitis in rats. Animals treated with 10 mg/kg IL-1ra or vehicle were evaluated for general health, acute phase response, and colonic in flammation 24 hours after the initiation of inflammation. A significant decrease in the accumulation of neutrophils in the colonic mucosa as measured by myeloperoxidase activity was seen in animals with HOAc induced colitis that were treated intraperitoneally with IL-1ra when compared to animals with colitis that had been treated with vehicle. IL-1ra also reduced colonic necrosis measured grossly, although there was no effect on the histology IL-1ra had a modest effect on the HOAc-induced acute phase response, as indicated by changes in the serum iron, albumin and transferrin, but the results were not statistically significant. The number of circulating erythrocytes and neutrophils was significantly increased in animals with HOAc-induced colitis and treated with IL-1ra, suggesting that IL-1ra under these experimental conditions inhibited the migration of neutrophils to the injured colon and also the overall intestinal necrosis in the colon as assessed by gross pathology. IL-1ra may be useful as an intestinal anti-inflammatory agent.