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Biomedical subjects

J A Williams

Publications and source records attributed to J A Williams.

At least 55 records · Page 3Linked to original sources
PubMed2000

Luminescence imaging microscopy and lifetime mapping using kinetically stable lanthanide(III) complexes.

The sensitised luminescence from stable lanthanide complexes (1 and 2) bearing a phenanthridine antenna has been used to generate time-resolved images of silica particles. The millisecond order luminescent lifetime of these complexes is utilised to demonstrate time-gated imaging of the sample from a fluorescent background and to facilitate lifetime mapping over the area of the sample.

Europium↗
PubMed2000

Hypercalcemia during the osteogenic phase after rat marrow ablation coincides with increased bone resorption assessed by the NTx marker.

Marrow ablation is a model of bone turnover in which the excavated tibial intramedullary cavity is rapidly and reproducibly filled by osteoblasts with new woven bone (days 6-8), which is then rapidly resorbed by osteoclasts (days 10-15). We showed previously (Magnuson et al., 1997) that marrow ablation induces a dramatic hypercalcemia and hypercalciuria in rats that unexpectedly peaked at the time of maximal osteogenesis and continued throughout the subsequent resorption phase. Based upon the amount of calcium mobilized and a peak of urinary hydroxyproline, we suggested that the hypercalcemia and hypercalciuria were due to increased systemic osteoclastic bone resorption induced by marrow ablation. We now apply a new enzyme-linked immunosorbent assay for rodent alpha(2)(I) N-telopeptide (NTx), a marker of bone resorption, to the marrow ablation model to demonstrate that excretion of NTx parallels that of calcium release in the operated control group. Specifically, maximal NTx/creatinine excretion coincides with the onset of hypercalcemia on days 7-8. A peak of NTx was also observed in methylprednisolone- and deflazacort-treated ablated animals. Analyses for urinary free deoxypyridinoline crosslink failed to detect a significant ablation-induced change in excretion. Interleukin 6 activity was increased in all operated control and glucocorticoid-treated groups after marrow ablation, whereas serum parathyroid hormone remained at presurgical levels in operated controls throughout the 15-day study period. The NTx results confirm that bilateral tibial marrow ablation induces a burst of extratibial bone resorption and hypercalcemia 7-8 days later. We have estimated that the osteogenic phase of the ablation model deposits 40 mg of calcium as hydroxyapatite crystals within the intramedullary cavity on days 6-8; this represents 33%-50% of the total blood calcium content of a young rat. We hypothesize that the size and rapidity of this demand for ionized calcium is met through an extratibial bone resorption pathway of osteoclast formation and activation that anticipates and fulfills this need, and that is initiated at the time of marrow ablation.

Animals↗
PubMed2000

The influence of dietary and environmental factors on prostate cancer risk.

Prostate cancer is the most common malignancy found in males and one of the most common causes of cancer death. The epidemiology implicates environmental and nutritional factors in the initiation and progression of the disease. Identification of these factors would allow chemoprevention strategies to be tested. Potent mutagenic and carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons are produced in cooked meat, and following metabolic activation some of them are strongly associated with prostate carcinogenesis in rodents. Primary cell cultures of human prostate epithelial cells were obtained from patients undergoing transurethral resection of the prostate. Metabolic activation of the cooked food carcinogens 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine (PhIP) and benzo[a]pyrene (B[a]P) was examined and resultant DNA damage (single strand breaks) measured using the Comet assay. Increased concentrations of carcinogen were associated with increased DNA damage and comet tail length compared to controls. Prostate Cancer and Prostatic Diseases (2000) 3, 256-258

Journal Article↗
PubMed2000

Regulation of the initiation of pancreatic digestive enzyme protein synthesis by cholecystokinin in rat pancreas in vivo.

BACKGROUND & AIMS: Cholecystokinin (CCK) is known to stimulate the synthesis of digestive enzymes in the pancreas at the translational level. We investigated in vivo the biochemical regulation of initiation factors important for the stimulation of translation of digestive enzyme protein in rat pancreas by CCK. METHODS: Intraperitoneal injection of CCK or intragastric administration of a trypsin inhibitor to elicit endogenous CCK release was followed by removal and preparation of pancreas for protein evaluation. Isoelectric focusing was used to evaluate the phosphorylation of the initiation factor eIF4E, and Western blotting and immunoprecipitation followed by Western blotting were used to study the phosphorylation state and amount of other interacting factors. RESULTS: CCK treatment induced a time- and dose-dependent phosphorylation of pancreatic eIF4E and its binding protein (PHAS-I). Because the release of eIF4E from its binding protein as a result of phosphorylation is followed by formation of a messenger RNA cap-binding complex that includes the initiation factor eIF4G, we evaluated the association of eIF4G with released eIF4E and showed that it was increased by CCK. These events occurred over a range of CCK doses from 0.2 to 5 microg/kg. We also evaluated the effect of endogenous CCK by administering a synthetic trypsin inhibitor, camostat (100 mg/kg). Camostat treatment markedly increased the phosphorylation of both PHAS-I and eIF4E and the formation of eIF4E-eIF4G complex. Thus, both exogenous and endogenous CCK activate translational initiation factors in vivo. CONCLUSIONS: Activation of translational machinery necessary for initiation of protein synthesis likely contributes to the normal postprandial synthesis of pancreatic digestive enzymes.

Animals↗
PubMed2000

Stress kinases and heat shock proteins in the pancreas: possible roles in normal function and disease.

Mitogen-activated protein kinases (MAPKs) and heat shock proteins (Hsps) are ubiquitous proteins that function in both normal and stress-related pathophysiological states of the cell. Recent advances in the study of such Hsps and their interaction with signaling kinase cascades, including the cloning of new members, has helped to define their physiological roles in various tissues. In the pancreas, three major MAPKs, ERKs, JNKs, and p38, have been demonstrated. While intracellular signals involved in the ERK cascade have been most extensively investigated, only a few upstream regulators and downstream effector proteins of the JNKs and p38 MAPK are known in the pancreas. Similarly, a number of Hsps have been identified in pancreas, including Hsp27, Hsp60, and Hsp70. Although the activation of various MAPKs and the induction of Hsp expression have clearly been demonstrated following experimental exposure of rodent pancreas to stress conditions, it remains to be determined whether Hsps have a protective or detrimental effect during acute pancreatitis or at the onset of pancreatic carcinoma. This review will summarize current knowledge of the regulation and function of stress-activated kinases and stress proteins in the pancreas.

Animals↗
PubMed2000

Regulation of macrophage interleukin-6 (IL-6) and IL-10 expression by prostaglandin E2: the role of p38 mitogen-activated protein kinase.

Prostaglandin E2 (PGE2) regulates production of a wide array of cytokines. We have found that PGE2 can upregulate the levels of both interleukin-10 (IL-10) and IL-6 produced by activated murine macrophages, but the molecular pathways leading to their augmentation differ. Synthesis of IL-10 in response to PGE2 is dependent on p38 MAP kinase activity, whereas synthesis of IL-6 is not. Evidence to support this derives from two experimental approaches. First, we established that PGE2 is effective in elevating IL-10 levels only when it is added to cells in which p38 kinase has been activated. In contrast, PGE2 can augment IL-6 levels regardless of whether or not p38 kinase is active. Second, we showed that inhibitors that are selective for p38 kinase prevent the IL-10 response to PGE2 but not the IL-6 response. We found that p38 kinase inhibitors are able to inhibit IL-6 production in activated macrophages, but this occurs primarily as a result of their concurrent inhibition of cyclooxygenase-2 and endogenous PGE2 synthesis. These results indicate that macrophage IL-10 and IL-6 expression is differentially regulated by PGE2 and p38 MAP kinase in murine inflammatory macrophages.

Animals↗
PubMed2000

Biodistribution and dosimetry of an aqueous solution containing sodium 3-(125I)iodo-4-hydroxybenzenesulfonate (Iotrex) for brachytherapy of resected malignant brain tumors.

UNLABELLED: Iotrex is an aqueous radiotherapy solution containing sodium 3-(125I)iodo-4-hydroxybenzenesulfonate (125I-HBS), which is used as the radiation source for the brachytherapy of resected of brain tumor cavity margins with the GliaSite catheter. During routine clinical use of this brachytherapy applicator and radiation source, approximately 0.1% of the afterloaded Iotrex will diffuse through the GliaSite balloon. Our purpose was to assess the radiation doses to normal organs under routine clinical use of the GliaSite. METHODS: Five groups of rats received intracerebral injections of an 131I-HBS solution (131I used as a surrogate for 125I in the synthesis of 125I-HBS) with one group sacrificed at 15 minutes, 30 minutes, 1 hour, 2 hours and 4 hours post-administration. Urine was collected and activity retention in numerous organs was measured. The biodistribution data were used to estimate radiation doses to normal organs of the Reference Adult Male and Female phantoms. RESULTS: Radioactivity was rapidly and completely cleared from the brain (98% cleared by 2 hours) and total body (urinary clearance; 93%@2 hours). No organ retained > 0.7% of the radioactivity at 4 hours. For 100% loss of the radiotherapy solution from the balloon catheter (device failure), all organs would receive less than 100 mGy (10 rad), except the bladder wall (2800 mGy, 280 rad), uterus (130 mGy, 13 rad) and distal colon (270 mGy, 27 rad). Under normal conditions, all organ doses are 1000-fold lower (< 3 mGy or 0.3 rad). CONCLUSIONS: Under routine clinical conditions, the radiation doses to normal organs are inconsequential. Should the maximum clinical load of Iotrex (16.7 GBq of 125I) be released intracerebrally, the radiation doses to all organs would be below the thresholds for deterministic effects.

Animals↗
PubMed2000

DNA damage in human breast milk cells and its induction by 'early' and 'late' milk extracts.

Environmental and dietary factors are thought to be significant in breast cancer aetiology. The alkaline single-cell gel electrophoresis ('Comet') assay was used to examine breast milk cells for DNA damage and to measure the activity of extracts of the milk in causing such damage. UK-resident women were recruited as donors (n = 16) and provided 'early' ( approximately 4 weeks post-partum) and/or 'late' ( approximately 4 months post-partum) milk samples. Cells (79-94% viable, trypan blue exclusion) were either examined immediately for DNA damage or were cultured for 1 week prior to treatment with a breast milk extract. DNA damage in the form of single-strand breaks was quantified as comet tail length (CTL). Cell preparations examined immediately exhibited interindividual variation in median CTL (range 2.0-40.0 microm) with or without the DNA repair inhibitors hydroxyurea (HU) and cytosine arabinoside (ara-C). DNA damage decreased following culture, suggesting either DNA repair or death of DNA-damaged cells. Some donors' breast milk extracts induced DNA damage in their cultured cells and increases in median CTL were significantly greater with HU/ara-C (range 4.0-72.5 microm) than without (range 2.5-27.5 microm). Genotoxicity occurred without cytotoxicity (81-97% viability after treatment). Comparisons between cells and extracts from 'early' and 'late' milk samples did not support the idea of a progressive clearance of genotoxins from mammary lipid during lactation. Donors whose untreated cells contained the most DNA damage tended to yield genotoxic breast milk extracts. Cells isolated from milk activated the rodent mammary carcinogens o-toluidine and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The relevance of genotoxic exposures to breast cancer initiation requires further investigation.

Adult↗
PubMed2000

Metabolic activation of carcinogens and expression of various cytochromes P450 in human prostate tissue.

Epidemiological evidence suggests a link between meat consumption and prostate cancer. In this study, benign prostatic hyperplasia tissues, obtained by transurethral resection or radical retropubic prostatectomy from UK-resident individuals (n = 18), were examined for CYP1 expression and for their ability, in short-term organ culture, to metabolically activate carcinogens found in cooked meat. Semi-quantitative RT-PCR analysis of CYP1 expression detected CYP1A2 mRNA transcripts in the prostates of four individuals, as well as mRNA transcripts from CYP1A1 and CYP1B1. The compounds tested for metabolic activation were 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP; 500 microM, n = 9) and its metabolite N:-hydroxy PhIP (20 microM, n = 8), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ; 500 microM, n = 6) and benzo[a]pyrene (B[a]P; 50 microM, n = 5). After incubation (PFMR medium, 22 h, 37 degrees C), DNA was isolated from tissue fragments and DNA adducts were detected and quantified by (32)P-postlabelling analysis. DNA adduct formation was detected in all samples incubated with PhIP (mean, adducts per 10(8) nucleotides), N:-hydroxy-PhIP (2736/10(8)) or B[a]P (1/10(8)). IQ-DNA adducts were detected in 5/6 tissues (mean, 1/10(8)). The CYP1 inhibitor alpha-naphthoflavone (10 microM) reduced B[a]P-DNA adduct formation in tissues from two individuals by 96 and 64%, respectively. This pilot study shows that human prostate tissue can metabolically activate 'cooked meat' carcinogens, a process that could contribute to prostate cancer development.

Adult↗
PubMed2000

Pathways of heterocyclic amine activation in the breast: DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) formed by peroxidases and in human mammary epithelial cells and fibroblasts.

Most human mammary carcinomas originate in the epithelial cells of the breast ducts. A potential role of heterocyclic amines (HAs) in the aetiology of this disease has led us to investigate peroxidase-catalysed and stromal (non-epithelial) activation of the HA 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), which may subsequently lead to DNA damage in the adjacent human mammary epithelial cells (HMECs). HAs are formed when proteinaceous foods are cooked at high temperature and some, but not all, can cause mammary tumours in rats. Myeloperoxidase (MPO) and lactoperoxidase (LPO) are peroxidase enzymes present in breast secretions. (32)P-post-labelling analysis showed that IQ-DNA adducts were formed after co-incubation of IQ (500 microM) with calf thymus DNA, hydrogen peroxide and either bovine LPO or horseradish peroxidase (HRP). The major HRP-mediated IQ-DNA adduct co-migrated on TLC and HPLC with the major adduct formed in HMECs, suggesting a common reactive intermediate (nitrenium ion). IQ-DNA adducts were also formed in extracellular DNA when phorbol myristate acetate-stimulated neutrophils (which activate IQ via MPO) were co-incubated with IQ (500 microM) and extracellular plasmid (4 +/- 1 adducts/10(8) nucleotides) or calf thymus DNA (6 +/- 2). Mean adduct formation was five to seven times greater in neutrophil DNA (31 +/- 20). Primary cultures of human mammary fibroblasts or epithelial cells isolated from reduction mammoplasty tissues (n = 4 individuals) were incubated with IQ (500 microM) and formed 2.5 and 14.8 adducts/10(8) nucleotides (mean values), respectively. Our results indicate the possible contribution of stromal cells and breast peroxidases to the metabolic activation of carcinogens in the mammary gland.

Adult↗
PubMed2000

Hip fracture outcomes: quality of life and functional status in older adults living in the community.

BACKGROUND: People who return to living in the community after a hip fracture are considered to have the best outcome. However, their quality of life (QOL) and its relationship with function over the longer term have not been fully assessed. AIMS: This case control study of community dwelling subjects six to 12 months post hip fracture aims to investigate their QOL and functional independence. METHOD: The Short Form-36 (SF-36) was utilised to measure QOL. The Modified Barthel Index (MBI), the Frenchay Activities of Daily Living Index (FAI), the Timed 'Up & Go' (TUG), and the Berg Balance Scale (Berg) were used to measure functionality. RESULTS: Ninety-two subjects and 92 controls were recruited. Despite being age and gender matched, the hip fracture subjects scored significantly (p<0.05) worse than the controls in all measures of function. The fracture group was slower on the TUG (19 vs 10.5 seconds), had more difficulties with balance (46 vs 54 out of 56), and was less active and more dependent than the control group (FAI 24 vs 31 out of 42). The SF-36 has eight domains: physical function, role physical, bodily pain, mental health, role emotional, social function, general health and vitality. The control group had a higher (p<0.05) perception of their QOL in all domains. CONCLUSION: The effects of impaired balance and mobility along with reduced functional and social independence are reflected in the diminished QOL perceived by the fracture group. This indicates that many do not return to their pre-fracture lifestyle.

Activities of Daily Living↗
PubMed2000

The formed visual hallucinations associated with vision loss.

BACKGROUND: Patients with acquired visual impairment, but without mental illness, may experience repetitive episodes of vividly detailed, clearly focused, formed visual hallucinations. Yet these may not be shared voluntarily with clinicians. We wanted to learn: (1) the prevalence of formed visual hallucinations and (2) the nature of any changes in the hallucinations after more than two years. METHODS: Part I--Eighty-eight visually impaired adult patients at the Massachusetts Eye and Ear Infirmary were surveyed during 1995. Age, gender, ocular diagnoses, visual acuities, and hallucination descriptions were recorded. Part II--Those subjects reporting hallucinations in 1995 were selected to participate in a second survey--more than two years later-to ascertain changes. RESULTS: Part I--Nine of 88 subjects (10.2% prevalence) reported formed visual hallucinations, frequently human faces or figures. Five additional subjects (5.6%) reported a history of formed hallucinations-beginning after their vision loss--that had either disappeared or changed to unformed hallucinations (lights and colors) before this survey. Part II--Seven of the eligible nine subjects were surveyed more than two years later. Hallucinations persisted for six. Five reported reduced frequency of hallucinations, despite failing acuity among four of these five. CONCLUSIONS: Formed visual hallucinations are not uncommon among patents with significant acquired losses in visual acuity and/or visual field (homonymous hemianopsia). Although formed hallucinations may persist for years, there appears to be a tendency toward reduced frequency of episodes over time. Silent isolated visual hallucinations, in the absence of psychopathology, imply an organic etiology. Eliciting these phenomena through an appropriate clinical history provides a valuable opportunity for referral, or patient education and reassurance.

Adult↗
PubMed1999

In vivo activity of leflunomide: pharmacokinetic analyses and mechanism of immunosuppression.

BACKGROUND: Leflunomide is an experimental drug with demonstrated ability to prevent and reverse acute allograft and xenograft rejection. The two biochemical activities reported for the active metabolite of leflunomide, A77 1726, are inhibition of tyrosine phosphorylation and inhibition of dihydroorotate dehydrogenase, an enzyme necessary for de novo pyrimidine synthesis. These activities can be distinctly separated in vitro by the use of uridine, which reverses the anti-proliferative effects of A77 1726 caused by inhibition of de novo pyrimidine synthesis. We report the effect of uridine on the in vivo immunosuppressive activities of leflunomide. METHODS: We first quantified the serum levels of A77 1726, the active metabolite of leflunomide, after a single treatment of leflunomide (5, 15, and 35 mg/kg). Additionally, we quantified the levels of serum uridine and of nucleotide triphosphates in the liver, spleen, and lymph nodes of Lewis rats after the administration of a single dose of uridine (500 mg/kg; i.p.). Lewis rats heterotopically transplanted with brown Norway or Golden Syrian hamster hearts were treated for 50 or 75 days with leflunomide (5, 15, and 35 mg/kg/day; gavage) alone or in combination with uridine (500 mg/ kg/day; i.p.). Hematocrits were determined and the levels of alloreactive or xenoreactive immunoglobulin (Ig)M and IgG were determined by flow cytometric analysis. The allograft and xenografts, small bowel, liver, kidney, and spleen were subjected to pathological examination. RESULTS: A linear relationship was observed between the serum A77 1726 concentrations in Lewis rats and the dose of leflunomide administered. Peak A77 1726 concentrations were 20.9, 71.8 and 129.3 mg/l (77.5, 266.1 and 478.8 microM) for the 5, 15, and 35 mg/kg doses of leflunomide, respectively. The concentration of uridine in the serum of normal Lewis rats is 6.5 microM; after i.p. administration of 500 mg/kg uridine, the serum uridine concentrations peaked at 384.1 microM in 15-30 min. The rapid elimination of uridine was not reflected in the lymphoid compartments, and the pharmacokinetics of pyrimidine nucleotides in the spleen resembled that of A77 1726. This dose of uridine, when administered daily (500 mg/kg/day, i.p.), weakly antagonized the immunosuppressive activities of leflunomide (5, 15, and 35 mg/kg/day) in the allotransplantation model. In contrast, in the xenotransplantation model, the same concentration of uridine completely antagonized the immunosuppressive activities of low-dose leflunomide (15 mg/kg/day) and partially antagonized the immunosuppressive activities of high-dose leflunomide (35 mg/kg/day). Toxicities associated with high-dose leflunomide (35 mg/kg/day) were anemia, diarrhea, and pathological changes in the small bowel and liver. These toxicities were significantly reduced by uridine co-administration. CONCLUSION: These studies reveal that the blood levels of A77 1726 in Lewis rats satisfy in vitro requirements for both inhibition of de novo pyrimidine synthesis and protein tyrosine kinase activity. Our data also illustrate that the in vivo mechanism of immunosuppression by leflunomide is complex and is affected by at least the following four factors: type and vigor of the immune response, availability of uridine for salvage by proliferating lymphocytes, species being investigated, and concentration of serum A77 1726.

Aniline Compounds↗
PubMed1999

Genotoxicity of human milk extracts and detection of DNA damage in exfoliated cells recovered from breast milk.

Genotoxic agents of environmental or dietary origin may play a role in breast cancer initiation. The ability of extracts of human milk to cause mutations in S. typhimurium TA1538 and YG1019 and to induce micronuclei and DNA strand breaks in MCL-5 cells was investigated. Twenty samples from different donors were analysed and of these, 6 were adjudged to produce positive mutagenic response in one or both bacterial strains. The same samples also induced significant micronucleus formation in MCL-5 cells. In the comet assay, 13/20 samples caused DNA strand breaks in MCL-5 cells. Viable exfoliated breast cells were recovered from fresh milk samples and the ability of milk extracts to cause DNA damage in these cells was demonstrated. The results show that human milk can contain components capable of causing genotoxic damage in test systems and in human breast cells, events that may be significant in the initiation of breast cancer

Breast↗
PubMed1999

Implantable polymers for tirapazamine treatments of experimental intracranial malignant glioma.

Malignant gliomas remain refractory to intensive radiotherapy and cellular hypoxia enhances clinical radioresistance. Under hypoxic conditions, the benzotriazine di-N-oxide (3-amino-1,2,4-benzotriazine 1,4-dioxide) (tirapazamine) is reduced to yield a free-radical intermediate that results in DNA damage and cellular death. For extracranial xenografts, tirapazamine treatments have shown promise. We therefore incorporated tirapazamine into the synthetic, biodegradable polymer, measured the release, and tested the efficacy both alone and in combination with external beam radiotherapy in the treatment of experimental intracranial human malignant glioma xenografts. The [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) (PCPP:SA ratio 20:80)] polymer was synthesized. The PCPP:SA polymer and solid tirapazamine were combined to yield proportions of 20% or 30% (wt/wt). Polymer discs (3 x 2 mm) (10 mg) were incubated (PBS, 37 degrees C), and the proportion of the drug released vs. time was recorded. Male nu/nu nude mice were anesthetized and received intracranial injections of 2 x 10(5) U251 human malignant glioma cells. For single intraperitoneal (i.p.) drug and/or external radiation treatments, groups of mice had i.p. 0.3 mmol/kg tirapazamine, 5 Gy cranial irradiation, or combined treatments on day 8 after inoculation. For fractionated drug and radiation treatments, mice had i.p. 0.15 mmol/kg tirapazamine, 5 Gy radiation, or combined treatments on days 8 and 9 after inoculation. For intracranial (i.c.) polymer treatments, mice had craniectomies and intracranial placement of polymer discs at the site of cellular inoculation. The maximally tolerated percentage loading of tirapazamine in the polymer.disc was determined. On day 7 after inoculation, groups of mice had i.c. empty or 3% tirapazamine alone or combined with radiation (5 Gy x 2 doses) or combined with i.p. drug (0.15 mmol/kg x 2 doses on days 8 and 9). Survival was recorded. Polymers showed controlled, protracted in vitro release for over 100 days. The 5 Gy x 1 treatment resulted in improved survival; 28.5 +/- 3.7 days (P = 0.01 vs. controls), while the single i.p. 0.3 mmol/kg tirapazamine treatment, 17.5 +/- 1.9 days (P = NS) and combined treatments; 21.5 +/- 5.0 days (P = NS) were not different. The fractionated treatments: 5 Gy x 2, i.p. 0.15 mmol/kg tirapazamine x 2 and the combined treatments resulted in improved survival: 44.5 +/- 3.9 (P < 0.001), 24.5 +/- 2.3 (P = 0.05) and 50.0 +/- 6.0 (P < 0.001), respectively. Survival after intracranial empty polymer was 16.5 +/- 3.0 days and increased to 31.0 +/- 3.0 (P = 0.003) days when combined with the 5 Gy x 2 treatment. The survival after the polymer bearing 3% tirapazamine alone vs. combined with radiation was not different. The combined 3% tirapazamine polymer, i.p. tirapazamine, and radiation treatments resulted in both early deaths and the highest long-term survivorship. The basis for potential toxicity is discussed. We conclude that implantable biodegradable polymers provide controlled intracranial release for treatment of experimental glioma. For treatment of malignant gliomas, the combination of continuous polymer-mediated delivery and fractionated systemic delivery of tirapazamine with external beam radiotherapy warrants further exploration.

Absorbable Implants↗
PubMed1999

Fluorescence in situ hybridization analysis of HER-2/neu, c-myc, and p53 in endometrial cancer.

Our objective was to evaluate the association between HER-2/neu, c-myc, p53, and clinicopathologic variables in endometrial cancer using fluorescence in situ hybridization (FISH) cytogenetic analysis. FISH analysis for HER-2/neu, c-myc, and p53 was performed on 47 endometrial cancer specimens. Amplification of HER-2/neu was seen in 4/47 (8.5%) cases and amplification of c-myc was seen in 7 of 47 (15%) cases; neither was associated with adverse clinicopathologic variables or survival. Deletion of p53 was seen in 31/47 (66%) cases and was associated with poor histologic grade (P = 0.008). There was no impact of genetic alterations on overall survival or disease-free interval. Grade 3 tumor was associated with poor overall survival (P = 0.032). This study found that p53 deletion is a common genetic alteration in endometrial cancer and is associated with poor-grade tumors.

Adult↗