Regulation of N-myc expression in development and disease.
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Animals↗
Biomedical subjects
W Lutz
Publications and source records attributed to W Lutz.
The end of world population growth.
There has been enormous concern about the consequences of human population growth for the environment and for social and economic development. But this growth is likely to come to an end in the foreseeable future. Improving on earlier methods of probabilistic forecasting, here we show that there is around an 85 per cent chance that the world's population will stop growing before the end of the century. There is a 60 per cent probability that the world's population will not exceed 10 billion people before 2100, and around a 15 per cent probability that the world's population at the end of the century will be lower than it is today. For different regions, the date and size of the peak population will vary considerably.
Fertility↗
Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo.
Dendritic cells (DCs) play a central role in regulating immune activation and responses to self. DC maturation is central to the outcome of antigen presentation to T cells. Maturation of DCs is inhibited by physiological levels of 1alpha,25 dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] and a related analog, 1alpha,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-19-nor-vitamin D(3) (D(3) analog). Conditioning of bone marrow cultures with 10(-10) M D(3) analog resulted in accumulation of immature DCs with reduced IL-12 secretion and without induction of transforming growth factor beta1. These DCs retained an immature phenotype after withdrawal of D(3) analog and exhibited blunted responses to maturing stimuli (CD40 ligation, macrophage products, or lipopolysaccharide). Resistance to maturation depended on the presence of the 1alpha,25(OH)(2)D(3) receptor (VDR). In an in vivo model of DC-mediated antigen-specific sensitization, D(3) analog-conditioned DCs failed to sensitize and, instead, promoted prolonged survival of subsequent skin grafts expressing the same antigen. To investigate the physiologic significance of 1alpha,25(OH)(2)D(3)/VDR-mediated modulation of DC maturity we analyzed DC populations from mice lacking VDR. Compared with wild-type animals, VDR-deficient mice had hypertrophy of subcutaneous lymph nodes and an increase in mature DCs in lymph nodes but not spleen. We conclude that 1alpha,25(OH)(2)D(3)/VDR mediates physiologically relevant inhibition of DC maturity that is resistant to maturational stimuli and modulates antigen-specific immune responses in vivo.
Animals↗
The role of heat shock protein 70 in vitamin D receptor function.
We previously demonstrated that the 1alpha,25-dihydroxyvitamin D(3) receptor (VDR) interacts with the constitutive heat shock protein, hsc70 in vitro, and with DnaK (Biochem. Biophys. Res. Commun. 260, 446-452, 1999). The biological significance of VDR-heat shock protein interactions, however, is unknown. To examine the role of such interactions in eukaryotic cells, we heterologously expressed VDR and RXRalpha together with a vitamin D-responsive reporter system in Saccharomyces cerevisiae and examined the consequences of heat shock protein 70 gene (SSA) deletion in these cells. We show that heterologously expressed VDR associates with the yeast cytosolic hsp70 protein, Ssa1p. Deletion of the SSA2, SSA3, and SSA4 genes and reduction of Ssa1p activity, reduces the intracellular concentrations of the VDR and its heterodimeric partner, RXRalpha and reduces the activity of a vitamin D-dependent gene. Hsp70-like chaperone proteins play a role in controlling concentrations of the VDR within the cell.
Adenosine Triphosphatases↗
Phosphorylation of centrin during the cell cycle and its role in centriole separation preceding centrosome duplication.
Once during each cell cycle, mitotic spindle poles arise by separation of newly duplicated centrosomes. We report here the involvement of phosphorylation of the centrosomal protein centrin in this process. We show that centrin is phosphorylated at serine residue 170 during the G(2)/M phase of the cell cycle. Indirect immunofluorescence staining of HeLa cells using a phosphocentrin-specific antibody reveals intense labeling of mitotic spindle poles during prophase and metaphase of the cell division cycle, with diminished staining of anaphase and no staining of telophase and interphase centrosomes. Cultured cells undergo a dramatic increase in centrin phosphorylation following the experimental elevation of PKA activity, suggesting that this kinase can phosphorylate centrin in vivo. Surprisingly, elevated PKA activity also resulted intense phosphocentrin antibody labeling of interphase centrosomes and in the concurrent movement of individual centrioles apart from one another. Taken together, these results suggest that centrin phosphorylation signals the separation of centrosomes at prophase and implicates centrin phosphorylation in centriole separation that normally precedes centrosome duplication.
Amino Acid Sequence↗
Plant orthologs of p300/CBP: conservation of a core domain in metazoan p300/CBP acetyltransferase-related proteins.
p300 and CBP participate as transcriptional coregulators in the execution of a wide spectrum of cellular gene expression programs controlling cell differentiation, growth and homeostasis. Both proteins act together with sequence-specific transcription factors to modify chromatin structure of target genes via their intrinsic acetyltransferase activity directed towards core histones and some transcription factors. So far, p300-related proteins have been described in animals ranging from Drosophila and Caenorhabditis elegans to humans. In this report, we describe p300/CBP-like polypeptides in the plant Arabidopsis thaliana. Interestingly, homology between animal and plant p300/CBP is largely restricted to a C-terminal segment, about 600 amino acids in length, which encompasses acetyltransferase and E1A-binding domains. We have examined whether this conservation in sequence is paralleled by a conservation in function. The same amino acid residues critical for acetyltransferase activity in human p300 are also critical for the function of one of the plant orthologs. Remarkably, plant proteins bind to the adenovirus E1A protein in a manner recapitulating the binding specificity of mammalian p300/CBP. The striking conservation of an extended segment of p300/CBP suggests that it may constitute a functional entity fulfilling functions that may be essential for all metazoan organisms.
Acetyltransferases↗
Prediction of dose-response relations based on patient characteristics.
The recent discussion of evidence-based, adaptive treatment planning highlights the need for models for the prediction of courses of treatment response. We combine a dose-response model with growth curve modeling to determine dose-response relations for well-being, symptoms, and functioning. Hierarchical linear modeling was used to model each patient's expected course of improvement. The resulting predictions were cross-validated on two samples of psychotherapy outpatients. The results give further empirical support for the dose-response model and the phase model of psychotherapy as well as for the usefulness of patient treatment response profiling for individual treatment management.
Adult↗
An iterative EPID calibration procedure for dosimetric verification that considers the EPID scattering factor.
There has been an increasing interest in the application of electronic portal imaging devices (EPIDs) to dosimetric verification, particularly for intensity modulated radiotherapy. Although not water equivalent, the phantom scatter factor of an EPID, Spe, is generally assumed to be that of a full phantom, Sp, a slab phantom, Sps, or a mini phantom. This assumption may introduce errors in absolute dosimetry using EPIDs. A calibration procedure that iteratively updates Spe and the calibration curve (pixel value to dose rate) is presented. The EPID (Varian Portal Vision) is irradiated using a 20 x 20 cm2 field with different beam intensities. The initial guess of dose rates in the EPID is calculated from ionization chamber measurements in air, multiplied by Sp or Sps. The calibration curve is obtained by fitting EPID readings from pixels near the beam central axis and dose rates in EPID to a quadratic equation. The Spe is obtained from EPID measurements in 10 X 10 cm2 and 20 x 20 cm2 field and from the calibration curve, and is in turn used to adjust the dose rate measurements and hence the calibration curve. The above procedure is repeated until it converges. The final calibration curve is used to convert portal dose to dose in the slab phantom, using the calibrated Spe, or assuming Spe = Sp or Spe=Sps . The converted doses are then compared with the dose measured using an ionization chamber. We also apply this procedure to off-axis points and study its dependence on the energy spectrum. The hypothesis testing results (on the 95% significance level) indicate that systematic errors are introduced when assuming Spe = Sp or Spe=Sps and the dose calculated using Spe is more consistent with ionization chamber measurements. Differences between Spe and Sps are as large as 2% for large field sizes. The measured relative dose profile at dmax using the EPID agrees well with the measured profile at dmax of the isocentric plane using film in a polystyrene phantom with full buildup and full backup, for open and wedged fields, and for a broad range of field sizes of interest. The dependence of the EPID response on the energy spectrum is removed once the calibration is performed under the same conditions as the actual measurements.
Algorithms↗
Assessing treatment progress of individual patients using expected treatment response models.
The dosage model provides a normative estimate of the overall pattern of patient improvement in psychotherapy. The phase model further specifies patterns of change in the domains of subjective well-being, symptom remediation, and functioning. The expected treatment response (ETR) approach uses patient characteristics to predict an expected path of progress for each patient. With repeated measures of mental health status, the treatment progress of an individual patient can be assessed against the patient's ETR to support decisions that would enhance the quality of a clinical service while it is being delivered.
Adaptation, Psychological↗
[Genetic polymorphism of glutathione s-transferase as a factor predisposing to allergic dermatitis].
In the inductive phase of contact allergic dermatitis, simple chemical compounds (haptens) produce together with epidermic proteins adducts presented by Langerhans cells to T lymphocytes. Binding to protein carrier is a necessary condition of transforming a low-molecular allergen into immunogenic one and evoking immunological reaction. The production of allergen adducts with proteins is conditioned by the presence of electrophilic groups in their molecules, or their acquiring during biotransformation phase I. Active allergen metabolites undergo further alterations during biotransformation phase II which leads most frequently to the decline in their chemical activity and more rapid excretion from the body. The number of reactive metabolites (reactive allergens) available for producing adducts with proteins keeps the balance between activation and deactivation reactions. Glutathione S-transferases play a particular role in the allergens (or their metabolites) deactivation process in biotransformation phase II. These enzymes catalyse reactions responsible for the declined electrophilic potential of allergens (or their metabolites), and thus for the decrease in the number of allergen molecules able to produce protein covalent bindings (adducts). Glutathione S-transferases, occurring in the human cellular cytoplasm belong to five classes: alpha(GST A), mu(GST M), theta(GST P), pi(GST T) and Z(GST Z), as well as to one class present in microsomes. The study indicated the presence of isoenzymes GST T1 and GST M1 in the skin. Both isoforms participate in the process of low-molecular allergen biotransformation. Carriers of defective genes GST T1 and/or GST M1 are more vulnerable to allergenic effect of some allergens, e.g. thimerosal, which is associated with the absence of or decrease in the activity of isoenzymes GST T1 and GST M1.
Allergens↗
[Psychoneuroimmunology. A new approach to the function of immunological system].
The most recent evidence suggests that the immune system responses are not regulated only by the presence of antigens but they are also influenced by the brain and behavior. It has been known for some time that stressful conditions alter the functioning of the immune system. Despite methodological difficulties in the quantitation of stress, and its association with the onset of illness, the concept of the stress impact on susceptibility to several diseases is widely acknowledged. This paper reviews the effects of stress on the endocrine and central nervous systems and presents the interactions between these systems and the immune response after exposure to stress signals.
Antigens↗
Zinc increases the activity of vitamin D-dependent promoters in osteoblasts.
Zinc modulates the structure and binding of the DNA binding domain of the 1alpha,25-dihydroxyvitamin D(3) receptor to specific vitamin D response element DNA (Nature Biotechnology 16, 262-266, 1998). To determine whether zinc alters 1alpha,25-dihydroxyvitamin D(3)-regulated genes in cells, we permanently transfected rat osteoblasts with two vitamin D-dependent promoter-reporter systems and examined their responses to 1alpha,25-dihydroxyvitamin D(3) in the presence of increasing amounts of extracellular zinc. When extracellular zinc concentrations were increased in the presence of 1alpha,25-dihydroxyvitamin D(3), there was an increase in the activity of 1alpha,25-dihydroxyvitamin D(3)-dependent promoters with increasing concentrations of zinc. The effect was specific for zinc since metals such as copper failed to increase the activity of 1alpha,25-dihydroxyvitamin D(3)-dependent promoters. The concentration of the vitamin D receptor within the cell and the affinity of 1alpha,25-dihydroxyvitamin D(3) for its receptor remained unchanged with added zinc. Our results show that zinc increases the activity of 1alpha,25-dihydroxyvitamin D(3)-dependent promoters in osteoblasts.
Animals↗
Relative profile and dose verification of intensity-modulated radiation therapy.
PURPOSE: To develop a quality assurance (QA) procedure to assess the intensity profile and dosimetry for intensity-modulated (IM) treatment fields using electronic portal imaging devices (EPIDs). METHODS AND MATERIALS: A series of rapidly acquired (approximately 1/sec) portal images are summed and converted to dose. For relative intensity QA, the intended profile is subtracted point-by-point from the measured profile forming a series of error values. The standard deviation, sigma, of the errors, a measure of the goodness of the match, is minimized by applying a normalization and uniform scatter subtraction from the measured profile. For dose verification (dose to isocenter), an empirically determined phantom-correction factor is added to incorporate the effect of patient presence on EPID readings. Seventy prostate treatment fields were used in a phantom study to verify these approaches. Sensitivity was studied by creating artificial mismatches. RESULTS: The average sigma for relative profile verification is 3.3% (percentage of average intended intensity) whereas artificial mismatches resulted in sigma values from 5% to 27%. The average isocentric dose calculated from EPID readings is 1.001 relative to the planned dose with a standard deviation of 0.018. CONCLUSIONS: An EPID can be used for profile verification and absolute isocentric dose measurement for IM fields.
Algorithms↗
Multivariate analysis-based prediction rule for pulmonary embolism.
The diagnosis of pulmonary embolism (PE) is still an unresolved problem. The aim of this prospective observational study was to derive and validate a prediction rule (PEscore) by which PE can be diagnosed by easily obtainable and rapidly available investigations. Included were consecutive patients with a clinical suspicion of PE admitted to a community hospital. Risk factors and clinical and instrumental investigations were registered. PE was diagnosed by angiography, scintigraphy, or autopsy. In 168 patients, PE was either diagnosed (angiography, n = 28; autopsy, n = 18) or excluded (angiography, n = 12; scintigraphy, n = 99; autopsy, n = 11). Based on the results of clinical and instrumental findings, a PEscore was derived by a multiple regression analysis, calculated as: [0.29 x proven leg vein thrombosis (0 = no, 1 = yes)] + [0.25 x ECG right heart strain (0 = no, 1 = yes)] + [0.22 x neck vein distension (0 = no, 1 = yes)] + [0.20 x dyspnoea (0 = no, 1 = yes)] + [0.13 x suspicious chest X-ray (0 = no, 1 = yes)] - [0.17 (constant)]. The PEscore was tested further in 139 subsequent cases. In these patients, the PEscore was 0.65+/-0.17 (diagnosed PE, n = 47) and 0.18+/-0.17 (excluded PE, n = 92), respectively (p = 0.0001). Depending on a given PE-score, the level of probability of PE can be assessed. Calculation of the PEscore can be helpful in clinical decisions when PE is suspected.
Adult↗
MycN sensitizes neuroblastoma cells for drug-triggered apoptosis.
BACKGROUND: Amplification of the MYCN gene is found in a large proportion of neuroblastomas and is associated with a poor prognosis. PROCEDURE: To investigate the effect of ectopic MycN expression on the susceptibility of neuroblastoma cells to cytotoxic drugs, we used a human neuroblastoma cell line with tetracycline-controlled expression of MycN. RESULTS: Neither conditional expression of MycN alone nor low drug concentrations induced apoptosis. However, MycN and cytotoxic drugs cooperated to induce cell death. Apoptosis triggered by MycN and doxorubicin was mediated by cleavage of caspases and involved activation of the CD95 system. MycN overexpression and cytotoxic drugs also synergized to induce p53 and Bax protein expression and to trigger mitochondrial permeability transition and cytochrome c release. CONCLUSION: In that amplification of MYCN is considered an adverse prognostic factor, these findings suggest that dysfunctions in apoptosis pathways may be a mechanism by which MycN-induced apoptosis of neuroblastoma cells is inhibited.
Apoptosis↗
Metabolic genotype in relation to individual susceptibility to environmental carcinogens.
Earlier research indicates that within the human population there are considerable differences in the response to the carcinogenic activity of environmental carcinogens. Genetic polymorphism associated with several variants of the gene products participating in the biotransformation of various xenobiotics (including carcinogens) found in human populations constitutes a major cause of those differences. Enzymes coded by different variants of the same gene can differ in their catalytic activities. Up to the present time, most information on the effect of genetic polymorphism on the individual's ability to activate or deactivate environmental carcinogenic xenobiotics, and the associated risk of cancer, has been collected from studies of cytochromes P-450 belonging to gene families CYP1, CYP2 and CYP3, and of glutathione S-transferases and N-acetyltransferases. As carcinogen metabolism comprises a chain of chemical reactions involving numerous enzymes and enzyme-coding genes, research performed hitherto is able to offer only a very limited explanation of the associations between genetic polymorphism and the individual's susceptibility to cancer.
Carcinogens, Environmental↗
The predicted and observed course of psychotherapy for anxiety and mood disorders.
By applying hierarchical linear modeling (HLM) techniques, patient clinical characteristics at the beginning of treatment were used to predict individual patient responses (N = 160) to psychotherapy. Four diagnostic groups (mood, anxiety, other, and no diagnosis) were formed among the patients based on intake-administered Structured Diagnostic Interview for the Diagnosis of DSM-III-R axis I Disorders. Patients with mood and anxiety disorders had predicted courses of response to psychotherapy that were similar but different from patients with other disorders and no diagnosis. Predicted and observed courses of response to psychotherapy in a subsample (N = 75) who had provided enough data to model the actual course of treatment showed high levels of congruence, thus supporting the validity of predicting course of response. HLM predictive profiling offers a new approach for assessing treatment effectiveness of psychotherapy with patients having axis I diagnostic conditions by considering an individual patient's clinical characteristics.
Adolescent↗
[N-acetyltransferase genetic polymorphism and its role in the development of neoplastic disease].
N-acetyltransferases are the enzymes present in the cells of most mammal species. In human cells, the activity of two N-acetyltransferases, known as NAT1 and NAT2, is expressed. These enzymes are coded by two different genes: NAT1 and NAT2. Gene NAT1 is expressed in the cells of the majority of tissues and organs, whereas gene NAT2 only in the liver and intestine. Acetylation polymorphism and resultant division into the fast and free acetylators is caused by the occurrence of gene wild allele NAT2 and its mutated forms. A given person shows the fast acetylation phenotype if at least one allele NAT2 is wild. The presence of mutation in both alleles NAT2 is manifested by a free acetylation phenotype. It was indicated that gene NAT1 is also polymorphic, and together with its wild form, the mutated forms are also observed. Genetic polymorphism of NAT1 and NAT2 has serious pharmacological and toxicological consequences. Epidemiological studies show that the free acetylation phenotypes are more susceptible to bladder cancer than the fast ones if they smoke or work under exposure to bicyclic aromatic amines. It has also been evidenced that the fast acetylation phenotypes show enhanced risk of large intestine cancer in conditions of environmental and occupational exposure to heterocyclic amines. It has not as yet been found out whether the acetylation status may be linked with the increased risk of lung cancer.
Alleles↗