Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene

BACKGROUND: Metastatic pancreatic cancer is uniformly fatal because no effective chemotherapy is available. Mutations in the p53 tumor suppressor gene are found in up to 70% of pancreatic adenocarcinomas. We examined the efficacy of a retroviral vector containing the wild-type p53 gene on metastatic pancreatic cancer in a nude mouse model. METHODS: Bxpc3 human pancreatic cancer cells were transduced with either a retroviral p53 vector or an LXSN empty vector. Cells were examined for incorporation of tritiated thymidine to determine the effect of p53 retroviral transduction on DNA synthesis, and a TACS2 assay for apoptosis was performed. The functional activity of p53 in transduced cells was assessed by Western blot analysis with an antibody to WAF1/p21. In vivo effects of intraperitoneal injections of the p53 vector were examined in a nude mouse model of peritoneal carcinomatosis. RESULTS: Cells treated with the p53 vector exhibited a 59% to 85.5% reduction in cell number compared with the control cells (P < .05). p53-treated cells demonstrated decreased incorporation of tritiated thymidine (12.7% +/- 0.7% vs 17.5% +/- 1.4%; P = .002), increased staining for apoptosis, and increased expression of the WAF1/p21 protein. Treatment of nude mice with the retroviral p53 vector resulted in a significant inhibition of growth of the primary pancreatic tumor, as well as the peritoneal tumor deposits, compared with the LXSN control vector. CONCLUSIONS: Intraperitoneal delivery of a retroviral p53 vector may provide a novel treatment approach for peritoneal carcinomatosis from pancreatic cancer.     

Adolescent perceptions as mediators of parenting: genetic and environmental contributions

Erwinia chrysanthemi causes soft rot on various plants. The maceration of plant tissues is mainly due to the action of endopectate lyases. The E. chrysanthemi strain 3937 produces eight endopectate lyases (PelA, PelB, PelC, PelD, PelE, PelI, PelL and PelZ) that are secreted by the Out pathway. The necrotic response elicited by the wild-type E. chrysanthemi strain on tobacco leaves is due to an extracellular protein secreted by the Out machinery. Purification of the active factor revealed that it corresponds to a pectate lyase presenting immunological cross-reaction with PelI. Analysis of pelI and out mutants indicated that the necrosis-inducing pectate lyase results from a post-translational modification of PelI occurring extracellularly both in culture media and in planta. This modification consists of the cleavage of 97 N-terminal amino acids by the extracellular proteases of E. chrysanthemi. The enzymatic properties of the maturated form, PelI-3, are not, or only weakly, modified. However, this maturation gives rise to a small size and basic form that is active as a defence elicitor in plants.     

A histomorphometric long-term longitudinal study of trabecular bone loss in glucocorticoid-treated patients: prednisone versus deflazacort

We synthesized three artificial human hemoglobin mutants in which Lys-66(E10)beta was replaced by Ser, Arg or Thr by site-directed mutagenic protein engineering. These engineered hemoglobins were designated as eHb K66betaS, eHb K66betaR and eHb K66betaT, respectively. By synthesizing these mutants we attempted to control the oxygen affinity of hemoglobin with cooperativity preserved and to clarify the functional role of Lys-66(E10)beta, as well. Such attempts may be useful for creating an oxygen carrier suitable as a blood substitute. The oxygen affinities of eHbs K66betaS, K66betaR and K66betaT were 1.3-, 1.5- and 2.3-fold, respectively, lower than that of reconstituted Hb A. Their allosteric properties such as the Bohr effect and the effect of inositol hexaphosphate were well preserved. Since the oxygen affinity of eHb K66betaT is comparable with that of red cells, it may be a potential candidate for a blood substitute. X-Ray crystallographic data for Hb Chico [Lys-66beta-->Thr], which is identical with eHb K66betaT, together with our computer simulation indicate that an interaction between the introduced Thr and the distal His via a water molecule lowers the oxygen affinity for the T state eHb K66betaT.     

Ethylene responses are negatively regulated by a receptor gene family in Arabidopsis thaliana

Disseminated neuroblastoma frequently show a very poor prognosis. N-myc gene amplification, 1p deletion and lack of CD44 gene expression, are all genetic factors associated with the disease's dissemination. Human neuroblastoma xenografts in nude mice has permitted to characterize, in disseminated neuroblasts, oncogenes overexpression, inactivation of tumor suppressor genes as well as detoxifying genes activation which contributes to increase cellular resistance to chemotherapy. These genetic abnormalities permit to propose a nosology of this very aggressive pediatric solid tumor. Hopefully, this genetic classification could be of great value for new therapeutic approaches.     

Socioeconomic status, standard of living, and neurotic disorder

BACKGROUND: Evidence on the association between socioeconomic status and the prevalence of neurotic disorder is contradictory. We studied the association between three elements of socioeconomic status and the prevalence of neurotic psychiatric disorder in a representative sample of adults aged 16-64 living in private households in the UK. METHODS: A cross-sectional survey of 10,108 adults aged 16-65 resident in private households in the UK was selected by a multi-stage, clustered, random-sampling design. Neurotic disorders were defined using a standardised interview, the revised clinical interview schedule (CIS-R). Data for 9570 people were available for this study. FINDINGS: We used housing tenure and access to cars as measures of standard of living; both were associated with the prevalence of neurotic disorder even after adjustment for other socioeconomic and demographic variables, including Registrar General's Social Class and educational attainment. Those people with no access to a car had an odds ratio for neurotic disorder of 1.4 (95% CI 1.1-1.7), compared with those who had access to two or more cars. People who rented their homes were also at increased risk (1.3 [1.1-1.5]). We estimated that about 10% of the neurotic disorder in the UK could be attributed to the increased prevalence of those without cars who rented their homes. There was a complex interaction between Registrar General's Social Class and sex, and there was no independent association with educational attainment. INTERPRETATION: There is an independent association between low standard of living and the prevalence of neurotic psychiatric disorder. The UK has experienced one of the largest increases in income inequality within western market economies over the past 20 years, and this inequality may have had adverse consequences for the mental health of the population.     

Sensorineural hearing loss in the mdx mouse: a model of Duchenne muscular dystrophy

Sensorineural hearing loss has been identified in several types of muscular dystrophy, but few studies have investigated any relationship between Duchenne muscular dystrophy and hearing. An animal model of Duchenne muscular dystrophy, the mdx mouse, exhibits the same genetic defect as humans. We performed brainstem auditory evoked responses on mdx and control mice in order to assess sensorineural hearing loss. The amplitude and latency of wave I for each animal were measured at increasing sound pressure levels. A significant increase in threshold and a decrease in wave I amplitude were found in the mdx mice. These results indicate that significant sensorineural hearing loss is associated with muscular dystrophy in the mdx mouse. Possible cellular mechanisms contributing to the hearing deficit are presented.     

Effect of isovolaemic haemodilution on visual outcome in branch retinal vein occlusion

The relationship between the activation of platelets (PLT) in urine and renal histological findings in children with IgA nephropathy (IgAN), thin basement membrane disease (TBMD), and minimal-change nephrotic syndrome (MCNS) was examined. The ratio of activated PLT to total PLT (activated and nonactivated PLT) was examined by double immunofluorescence using rhodamine-conjugated P selectin antibody (activated PLT) and fluorescein isothiocyanate conjugated PLT membrane glycoprotein antibody (GPIIb/IIIa, total PLT); the effect of urine on activation on PLT was also investigated. The number of activated PLT and the ratio of activated PLT to total PLT in urinary sediments were significantly higher in children with IgAN with diffuse mesangial proliferation than in those with TBMD or MCNS. PLT were activated by addition of urine in 13 out of 27 children with IgAN, and the activity was higher in the urine of those with active glomerular or interstitial lesions, while the urine of children with TBMD or MCNS had no effect. The presence of activated PLT and the effect of urine on PLT activation may be associated with the active glomerular or interstitial lesions in IgAN.