Somatostatin analogs: angiogenesis inhibitors with novel mechanisms of action.
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Amino Acid Sequence↗
Biomedical subjects
E Keenan
Publications and source records attributed to E Keenan.
Severity of alcohol dependence and its relationship to neurological soft signs, neuropsychological impairment and family history.
We examined the relationship between severity of alcohol dependence, subtle neurological impairment, neuropsychological deficits and genetic vulnerability among 36 day hospital attenders who satisfied the DSM-III-R criteria for alcohol dependence. Severity of alcohol dependence was unrelated to the presence of a family history, but was correlated with neurological soft signs and neuropsychological impairment. Neurological soft signs were correlated with neuropsychological impairment on both Trail A and Trail B. Patients with an affected first-degree relative exhibited more neurological soft signs. These data indicate that severity of alcohol dependence is related not only to neuropsychological impairment, but also to subtle neurological deficits which may not be apparent on conventional neurological examination. Patients with a positive family history of alcohol dependence may be particularly susceptible to the neurological sequelae of alcohol dependence, or may have neurological deficits which antedate their alcohol dependence.
Adult↗
Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors.
PURPOSE AND METHODS: Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer. RESULTS: The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine. CONCLUSION: This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.
Adult↗
Transcriptional up-regulation of the human androgen receptor by androgen in bone cells.
Androgen regulation of androgen receptor (AR) expression has been observed in a variety of tissues, generally as inhibition, and is thought to attenuate cellular responses to androgen. AR is expressed in osteoblasts, the bone-forming cell, suggesting direct actions of androgens on bone. Here we characterized the effect of androgen exposure on AR gene expression in human osteoblastic SaOS-2 and U-2 OS cells. Treatment of osteoblastic cells with the nonaromatizable androgen 5alpha-dihydrotestosterone increased AR steady state messenger RNA levels in a time- and dose-dependent fashion. Reporter assays with 2.3 kilobases of the proximal 5'-flanking region of the human AR promoter linked to the chloramphenicol acetyltransferase gene in transfected cultures showed that up-regulation of AR promoter activity by androgen was time and dose dependent. Treatment with other steroid hormones, including progesterone, 17beta-estradiol, and dexamethasone, was without effect. The antiandrogen hydroxyflutamide completely antagonized androgen up-regulation. Thus, in contrast to many other androgen target tissues, androgen exposure increases steady state AR messenger RNA levels in osteoblasts. This regulation occurs at least partially at the level of transcription, is mediated by the 5'-promoter region of the AR gene, and is dependent on functional AR. These results suggest that physiological concentrations of androgens have significant effects on AR expression in skeletal tissue.
Bone Neoplasms↗
Induction paclitaxel and carboplatin followed by concurrent chemoradiotherapy in patients with unresectable, locally advanced non-small cell lung carcinoma: report of Fox Chase Cancer Center study 94-001.
The paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/carboplatin combination has demonstrated promising activity in patients with incurable non-small cell lung cancer (NSCLC). Our exploratory study is designed to evaluate the efficacy of this combination as induction therapy in patients with locally advanced NSCLC, to determine the maximally tolerated doses of paclitaxel and carboplatin administered every 3 weeks during radical thoracic radiation after induction treatment, and to determine the efficacy of granulocyte colony-stimulating factor (G-CSF) priming before induction treatment, followed by conventional G-CSF, compared with conventional G-CSF alone. Eligibility stipulated Karnofsky performance status > or =70%, < or =5% weight loss, and stages IIIB or bulky IIIA NSCLC. Induction treatment consisted of two cycles of paclitaxel 175 to 225 mg/m2 infused over 3 hours combined with carboplatin (target area under the concentration-time curve of 7.5) given on days 1 and 22. On days 2 through 15 and 23 through 36, all patients received G-CSF 5 microg/kg; half were randomized to receive priming G-CSF daily for 5 days before day 1 of treatment. On day 43, thoracic radiation (60 Gy in 30 2-Gy fractions daily, 5 days a week for 6 weeks) was initiated. At dose level 1, patients received carboplatin dosed to a target area under the concentration-time curve of 3.75 and paclitaxel 67.5 mg/m2 over 3 hours on days 43 and 64. In the absence of dose-limiting toxicity, phase I escalation in three-patient cohorts proceeded to a maximum carboplatin area under the concentration-time curve of 5.0 and a paclitaxel dose of 175 mg/m2, delivered over 3 hours. To date, 35 patients (83% stage IIIB) have received induction treatment, 29 of whom are evaluable for response. Myelosuppression and neurotoxicity have been mild during induction treatment, prompting a paclitaxel dose increase to 225 mg/m2 on days 1 and 22 after the first seven patients were accrued. The phase III portion of the study evaluating G-CSF priming remains coded. Sixteen patients have received concurrent thoracic radiation and chemotherapy and are evaluable for response and toxicity. In sequential cohorts, the paclitaxel dose on days 43 and 64 has been escalated to 175 mg/m2 with only one episode each of grade 4 granulocytopenia and grade 3 anemia. In the first 13 patients evaluated, the severity of esophagitis corresponded to the length of the esophagus in the radiation treatment field: grade 1 in all six patients with esophageal exposure < or =16 cm and grade > or =2 in six of seven patients with > or =16 cm of the esophagus irradiated. Three episodes of grade > or =2 steroid-responsive pulmonary toxicity have occurred 2 to 6 months after the conclusion of concurrent thoracic radiation and chemotherapy. The major response rate is 38% to induction treatment and 59% to combined-modality treatment. Of the first 21 patients accrued, 62% survived 1 year. Induction paclitaxel/carboplatin therapy is active and well tolerated by patients with locally advanced NSCLC. The maximum tolerated doses of paclitaxel and carboplatin during concurrent thoracic radiation and the role of G-CSF priming are not yet established. Severity of esophagitis corresponds to the extent of esophagus irradiated during concurrent thoracic radiotherapy and chemotherapy.
Adult↗
Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group.
PURPOSE: To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma. PATIENTS AND METHODS: Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity. RESULTS: Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months. CONCLUSION: Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.
Adult↗
The Microphthalmia gene product interacts with the retinoblastoma protein in vitro and is a target for deregulation of melanocyte-specific transcription.
Little is known of the molecular mechanisms underlying the differentiation of the melanocyte from the melanoblast or the progression from the melanocyte to a malignant melanoma. Since the adenovirus E1A products have proved a useful tool for understanding control of differentiation in other systems, we explored the possibility of using E1A as a probe for factors controlling melanocyte-specific gene expression and differentiation. The results obtained show that the adenovirus E1A 13S, but not the 12S, product can transform the highly pigmented and TPA-dependent melanocyte cell line melan-a. Transformation is characterised by a morphological change, loss of TPA-dependence, the ability to grow in soft agar and strikingly, loss of pigmentation which correlates with loss of expression of the melanocyte-specific TRP-1 and tyrosinase genes. Cotransfection assays demonstrated that repression of TRP-1 by E1A correlated with E1A binding to p105Rb and p300, with the target in the TRP-1 promoter being the M-box, and 11 bp basic-Helix-loop-Helix (bHLH) factor-binding motif conserved between melanocyte-specific promoters. Consistent with the M-box acting as a target for E1a-mediated transcription repression, we also show that the basic-helix-loop-helix-leucine zipper (bHLH-LZ) protein (Mi) encoded by the microphthalmia gene (mi), which is required for pigment cell differentiation, is a positive acting transcription factor which can interact with the retinoblastoma product in vitro and activate the TRP-1 promoter. Moreover, expression of the mi gene was reduced around 50-fold in the non-pigmented E1a-transformed melan-a cells compared to the nontransformed melan-a cell line, with ectopic expression of Mi able to prevent repression of the tyrosinase and TRP-1 promoters in the presence of E1A. Mi therefore appears to play a crucial role in melanocyte-specific gene expression. The parallels between repression of myogenesis and muscle cell bHLH factors, and Mi and melanocyte differentiation are discussed.
Adenovirus E1A Proteins↗
Gender differences in needle sharing behaviour patterns.
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Adult↗
Six year follow up of forty five pregnant opiate addicts.
Forty five pregnant addicts had attended the National Drug Treatment Centre between 1984-1986. At that time they received intensive counselling, low dose Methadone maintenance and both ante natal and post natal care. Our aim was to follow these women six years later focusing on their drug use and outcome of their children. The women were followed up by chart review, individual interviews and liaison with the social and probation services. Results indicate that a high proportion of the women abused chaotically (50%). There is a worrying high incidence of HIV positive patients (53.4%) and a mortality figure of 15.5% (7). However only 13 women (28.6%) have had further children and 22 women (49%) are currently using some form of contraception. Only 23 women (51.1%) have had further contact with probation services. Five children (11.3%) are under formal care order and 4 children have become HIV positive in their own right. In conclusion, while these women have benefitted in certain areas e.g. family planning, contact with probation services, in other areas they have remained chaotic e.g. continued drug abuse or HIV risk taking behaviour. Thus the authors believe that future programmes should concentrate more directly on detoxification and rehabilitation after pregnancy. We also believe that because of the chaotic nature of these women some review of an "at risk" register for the children should be carried out.
Acquired Immunodeficiency Syndrome↗
Fragile X syndrome--a review.
Since the discovery of the Fragile X syndrome some 20 years ago, there have been numerous articles concerning clinical features, cognitive profile and transmission. It is a syndrome of importance to all those working in the mental health field and those involved in community health, such as General Practitioners, since it is second only to Down syndrome as a genetic cause of mental handicap.
Abnormalities, Multiple↗
A C-terminal alpha-helix plus basic region motif is the major structural determinant of p53 tetramerization.
The p53 gene product has been implicated in both human and animal tumorigenesis. p53 forms heterologous complexes with the transforming proteins encoded by several different DNA tumor viruses. p53 also assembles into stable homo-oligomers. We demonstrate that the major structural determinant for the tetramerization of p53 is an alpha-helical plus basic region motif near the C-terminus of the protein. A monomeric p53 mutant adopts a conformation distinct from both 'wild-type' and 'mutant' form as defined by PAb1620 and PAb240 monoclonal antibody recognition. Nevertheless, monomeric and dimeric mutant p53 proteins retain the ability to suppress SV40 origin-directed DNA replication in vivo. Thus, p53-p53 interaction and expression of the PAb1620 epitope is not a prerequisite for such activity. We present data suggesting that suppression of replication by p53 may occur by a mechanism that is independent of detectable p53-T antigen association.
Amino Acid Sequence↗
A human tumour-derived mutant p53 protein induces a p34cdc2 reversible growth arrest in fission yeast.
We have expressed wild-type and human tumour-derived mutant p53 cDNA genes in the fission yeast Schizosaccharomyces pombe. In the case of one mutant this resulted in a growth arrest of recipient yeast cells. In contrast, wild-type p53 and three other mutant proteins tested did not block outgrowth of colonies. Human and yeast cdc2 acted as functionally equivalent extragenic suppressors of the mutant-induced growth arrest allowing the establishment of viable p53 expressor strains. In cotransformation assays the mutant allele was found to be dominant over wt p53. Our results provide the first evidence of a functional relationship between p53 and p34cdc2 in an in-vivo system and suggest that the wide variety of mutant proteins present in human tumours may fall into functionally distinct subclasses.
Blotting, Northern↗
Smoking and its promotion in Greece. A 20th century Trojan horse.
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Adult↗
Meters of dangerous driving.
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Automobile Driving↗
The importance of treatment sequence in advanced and metastatic carcinoma of the breast.
From 1965 to the present, 287 patients with advanced and metastatic carcinoma of the breast have been treated according to a uniform philosophy of sequential therapy. Surgical castration was the initial procedure for premenopausal women and for postmenopausal women with clinical or laboratory evidence of endocrine responsive tumors. Tumor progression following castration was treated with major endocrine ablation, either adrenalectomy or hypophysectomy. Patients who relapsed following major ablation were treated with antiestrogen therapy as it became available. Nonresponders to major ablation and patients relapsing after antiestrogen therapy were treated with combination chemotherapy including cytoxan, methotrexate, 5-fluorouracil, and vincristine followed by adriamycin alone or in combination. Progression following chemotherapy was treated with additive hormonal therapy. Radiation therapy was used throughout for the control of localized disease, usually following complete hormonal ablation, except in cases of brain and spinal metastatic disease. The median survival for the entire group was 40.5 months from the onset of metastatic disease. Patients who responded to both oophorectomy and major ablation had a median survival of 61 months, which compares favorably to survival of 14 to 22 months reported in major combination chemotherapy trials. Survival following this method of sequential therapy is superior to other plans of management.
Adrenalectomy↗
The effect of human serum on 3H-thymidine incorporation in human prostate tumors in tissue culture.
Human prostatic tumors, 4 adenomas and 4 adenocarcinomas, were established in tissue culture. We used the incorporation of 3H-thymidine into deoxyribonucleic acid as a measure of cell activity to compare the effects of supplementing the culture media with human or fetal calf serum. 3H-thymidine incorporation was greater with human serum, with up to 120 per cent increase observed. The addition of dihydrotestosterone (10(-8)M.) did not enhance or inhibit 3H-thymidine incorporation.
Animals↗
Effects of cholecalciferol on the translocation of calcium by non-everted chick ileum in vitro.
An apparatus is described that allows perfusion of a non-everted segment of intestine in vitro and the study of the accumulation of substances within the mucosal cells. The translocation of Ca(2+) by rachitic-chick ileum and the effect of pretreatment with cholecalciferol was investigated, with the following conclusions. (1) Entry of Ca(2+) across the microvilli into mucosal cells is by diffusion; it does not require metabolic energy or the presence of any other inorganic ions. (2) Pretreatment of the chick with cholecalciferol causes increased permeability of the microvillus to Ca(2+) in both directions (lumen to cell, cell to lumen). The increased transport brought about by cholecalciferol in vivo can be partially mimicked by sodium dodecyl sulphate added in vitro. (3) The sign and the magnitude of the electrical potential difference prevailing across the ileum does not influence Ca(2+) transport. (4) Exit of Ca(2+) from the mucosal cell is temperature-sensitive, requires metabolic energy and Na(+). (5) Pretreatment with cholecalciferol caused increased movement of Ca(2+) out of the cell across the basement membranes. This effect of cholecalciferol given in vivo could be markedly increased by the presence of dicyclohexylcarbodi-imide in the perfusion fluid. These observations suggested that cholecalciferol increased Ca(2+) entry (and exit) at the mucosal surface and also caused Ca(2+) to be more available to the pump at the serosal surface.
Anaerobiosis↗
The doctor and literature. 3.
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History, 18th Century↗