p53 is phosphorylated in vitro and in vivo by the delta and epsilon isoforms of casein kinase 1 and enhances the level of casein kinase 1 delta in response to topoisomerase-directed drugs

The p53 tumour suppressor protein plays a key role in the integration of stress signals. Multi-site phosphorylation of p53 may play an integral part in the transmission of these signals and is catalysed by many different protein kinases including an unidentified p53-N-terminus-targeted protein kinase (p53NK) which phosphorylates a group of sites at the N-terminus of the protein. In this paper, we present evidence that the delta and epsilon isoforms of casein kinase 1 (CK1delta and CK1epsilon) show identical features to p53NK and can phosphorylate p53 both in vitro and in vivo. Recombinant, purified glutathione S-transferase (GST)-CK1delta and GST-CK1epsilon fusion proteins each phosphorylate p53 in vitro at serines 4, 6 and 9, the sites recognised by p53NK. Furthermore, p53NK (i) co-purifies with CK1delta/epsilon, (ii) shares identical kinetic properties to CK1delta/epsilon, and (iii) is inhibited by a CK1delta/epsilon-specific inhibitor (IC261). In addition, CK1delta is also present in purified preparations of p53NK as judged by immunoanalysis using a CK1delta-specific monoclonal antibody. Treatment of murine SV3T3 cells with IC261 specifically blocked phosphorylation in vivo of the CK1delta/epsilon phosphorylation sites in p53, indicating that p53 interacts physiologically with CK1delta and/or CK1epsilon. Similarly, over-expression of a green fluorescent protein (GFP)-CK1delta fusion protein led to hyper-phosphorylation of p53 at its N-terminus. Treatment of MethAp53ts cells with the topoisomerase-directed drugs etoposide or camptothecin led to increases in both CK1delta-mRNA and -protein levels in a manner dependent on the integrity of p53. These data suggest that p53 is phosphorylated by CK1delta and CK1epsilon and additionally that there may be a regulatory feedback loop involving p53 and CK1delta.     

Comparison of serum PSMA, PSA levels with results of Cytogen-356 ProstaScint scanning in prostatic cancer patients

The development and evaluation of new drugs often rely on surrogacy. An intermediate outcome becomes a surrogate outcome if it fulfils certain criteria, it should be easier to measure compared with the clinical outcome, a statistical relationship should exist between the clinical outcome and the surrogate outcome, a relation should exist allowing prediction of the degree of clinical effect based on the measured effect on the surrogate outcome. Development and authorization of drugs today often rely on so-called surrogate outcomes. Is this use sound? The validity of such outcomes has been reviewed in different therapeutic areas: hypertension, venous thromboembolism, AIDS, osteoporosis, hepatitis C. Based on this review, a pragmatic strategy is proposed which allows for the validation and proper use of surrogate outcomes.     

Asthma prevalence, morbidity and management practices in South Australia, 1992-1995

BACKGROUND: The Spring South Australian Health Omnibus Survey (SSAHOS) has been used to monitor trends in asthma prevalence, asthma morbidity and asthma management practices between 1992 and 1995. AIMS: To determine if self-reported asthma prevalence and availability of asthma action plans were increasing. To identify deficiencies in asthma management and opportunities for intervention. METHODS: Representative population survey by trained interviewers using a multistage, systematic, clustered area sample of 4200 households in South Australia where people aged 15 years or more are living. RESULTS: Over 3000 interviews were conducted each year. Between 1992 and 1995 the self-reported prevalence of asthma in those aged 15 years or more increased significantly from 15.7% to 20.3% (p < 0.0005), and the prevalence of current asthma increased from 9.3% to 11.4% (p < 0.05). The self-reported availability of individual asthma action plans increased from 21.9% in 1992 to 42.2% in 1995 (p < 0.0005). In 1992, 21% had a nebuliser at home, and 10.5% had a peak flow meter. In 1993, 61.4% were using preventive medications, and 35% thought bronchodilators were 'preventer' medications. In 1994 and 1995, between 12.5% and 15.6% had nocturnal awakening weekly or more often, and 31.4% had morning asthma symptoms weekly or more often. Between 20.1% and 20.8% had lost days from usual activities during the last year. Those on incomes below $20,000 had more symptoms, had more admissions to hospital, and required more medication than those on higher incomes. CONCLUSIONS: Self-reported asthma prevalence has increased. There remains a gap between current asthma management and that recommended by the National Asthma Campaign.     

Intrauterine tracheal obstruction, a new treatment for congenital diaphragmatic hernia, decreases amniotic fluid sodium and chloride concentrations in the fetal lamb

The chemoattractant N-formyl-methionyl-leucyl-phenylalanine (fMLP) interacts with neutrophils, generating signals that induce activation of the superoxide anion/hydrogen peroxide-producing NADPH-oxidase. Low temperature binding of fMLP to its neutrophil surface receptors is associated with a desensitization of the cells with respect to activation of the oxidase. Other stimuli can still activate the oxidase (in fact even induce a primed response), indicating that the observed phenomenon is stimulus specific and could not be accounted for by an effect on the oxidase itself. Furthermore, no desensitization is obtained in the presence of cytochalasin B, suggesting that the cytoskeleton is involved in the process leading to desensitization. Okadaic acid is a toxin produced by dinoflagellates and exerts its effects by an inhibition of cellular phosphatases. To investigate the role of phosphorylation/dephosphorylation events in the desensitization process we used okadaic acid as a scientific tool. We show that neutrophils treated with okadaic acid are primed with respect to the fMLP-induced production of superoxide anion, and that no desensitization is obtained in toxin-treated cells. Because the recovery of ligand-receptor complexes in a Triton X-100-insoluble fraction is very low in the cells treated with okadaic acid, we suggest that protein dephosphorylation is required to obtain binding to the cytoskeleton of occupied fMLP receptors; binding of the occupied receptors to the cell cytoskeleton being the mechanism behind desensitization.     

Cost-effectiveness in diagnosing infantile hypertrophic pyloric stenosis

PURPOSE: The purpose of this study was to determine which imaging study, upper gastrointestinal series (UGI) or abdominal ultrasonography (US), is more cost-effective in diagnosing infantile hypertrophic pyloric stenosis (IHPS) using a decision analysis model. METHODS: Probabilities were calculated from a review of the records of all infants less than 6 months of age referred for UGI or US to rule out IHPS over a 3-year period from January 1992 to December 1995. Cost-effectiveness was determined from hospital charges for each imaging study and its possible outcomes. RESULTS: The positive predictive value of UGI was 1.0 and US was 0.98 in the 246 infants evaluated for possible IHPS. In patients who had an initially normal study finding (UGI or US), 25% of patients undergoing US first required a second study for persistent symptoms, whereas only 6% of patients who had a negative initial UGI finding required a second study. CONCLUSIONS: Cost analysis found UGI to be more cost-effective than US because fewer secondary studies were required. UGI provides information regarding other pathological conditions as compared with US.     

Building open programmable multimedia networks

Recent advances in distributed systems and transportable software and increasing demand for better quality of service (QoS) control in multiservice networks are driving a reexamination of network software architectures. We established the Comet (Control, Management, and Telemedia) Group at Columbia University's Center for Telecommunications Research to provide comprehensive understanding of network software architecture for the 1990s and beyond. This research focuses on developing new network architectures that support service creation, QoS control, and the joint allocation of computing and communications resources. This provides an opportunity to reconcile the perspectives of the computing and communication communities. Future multiservice (multimedia) networks will carry traffic such as video, audio, and computer data with diverse QoS requirements. Such networks will thus require that we develop ways to manage many physical and logical entities, services, and users     

Protein expression of the cell-cycle inhibitor p27Kip1 in malignant melanoma: inverse correlation with disease-free survival

In the present study we analyzed, by immunohistochemistry, a panel of human melanomas for protein expression of the cyclin-dependent kinase (cdk) inhibitor p27Kip1 and evaluated whether deregulated expression correlates with clinical outcome for this type of cancer. We found that p27Kip1 was strongly expressed by normal melanocytes and benign nevi, whereas in malignant melanoma, a heterogeneous expression pattern was observed. In the case of nodular melanomas, the level of p27Kip1 was found to correlate significantly with the thickness of the tumor, with less protein expressed in thicker lesions. We also found that patients having tumors with fewer than 5% p27Kip1-staining cells had a significantly higher risk of early relapse of their disease compared with those expressing moderate or high levels. In contrast, the level of p27Kip1 did not correlate with tumor thickness or disease-free survival in patients with superficial spreading melanomas, suggesting that p27Kip1 may play different roles in these two major pathological subgroups of malignant melanoma. Furthermore, p27Kip1 did not appear to have an influence on overall survival for either subgroup. When we examined the combined effect of p21WAF1/CIP1 (another cdk inhibitor) and p27Kip1 on clinical outcome, we found that analysis of these two cdk inhibitors together may have greater prognostic potential than either alone. In conclusion, our results suggest that virtually complete loss of p27Kip1 protein expression has potential importance as a prognostic indicator of early relapse in patients with nodular melanoma The results, furthermore, underscore the value of analyzing multiple cell cycle regulatory proteins to obtain the most reliable indication of prognosis.     

The use of mountain air therapy for the correction of acid formation in patients with hypo- and hyperacidic syndromes

In a consecutive series of 326 patients with primary lung cancer, sarcoid reactions were observed in the regional lymph node or resected lung in 7 patients (2.2%). The average age of the 7 patients, 4 males and 3 females, was 54 years, range 45-70. All the patients underwent lobectomy. The sites in which sarcoid reactions were found were the regional lymph node (N) in 3 patients, the lung parenchyma (L) in 2, N and L in 1, and the tumor stroma in 1. The histologic types were adenocarcinoma in 4 patients, squamous cell carcinoma in 2, and small cell carcinoma in 1. Two patients died of recurrence and myocardial infarction, and five patients are alive, range 5-64 months. The patients with lung cancer complicating sarcoid reactions were significantly younger than the control group (p<0.01), and not significant in prognosis. We conclude that the complication of sarcoid reactions do not influence the prognosis, but that the sarcoid reactions may be a local reaction or resistance to cancer cells.