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PubMedDate not supplied

Stochastic theory of oncogenesis.

It is generally agreed that most malignancies, particularly those that arise "spontaneously", are caused by randomly occurring mutations at specific sites of the genome. Hence oncogenesis of these spontaneous tumors can be described by stochastic mathematical models. In this paper we offer a mathematical approach to oncogenesis. A stochastic model was developed to calculate the number of mutations required for malignant transformation. This model demonstrates that the two hit model, as originally proposed by Knudson for retinoblastoma in children, is not tenable for tumors in adults. Our results show that malignant transformation is more likely to be due to a specific set of four mutations. This stochastic model is compatible with most current views on oncogenesis and most phenomena in oncology.

Cell Transformation, Neoplastic↗
PubMed2003

A new transformation-regeneration procedure in the model legume Lotus japonicus: root explants as a source of large numbers of cells susceptible to Agrobacterium-mediated transformation.

We describe herein a simple and efficient transformation procedure for the production of transgenic Lotus japonicus plants. In this new procedure, dedifferentiated root explants, used as starting material, are the source of a large number of cells that are competent for the regeneration procedure, with a high susceptibility to Agrobacterium infection. The application of this protocol resulted in a tenfold increase in the number of transformants produced by a single plant in comparison to the widely used hypocotyl transformation procedure. Furthermore, our procedure allowed the use of intact plants stored for a long time at 4 degrees C, thus providing a potential continuous supply of explants for transformation experiments. The overall time of incubation under tissue culture conditions required to obtain a plant transferable into soil is 4 months. The transgenic nature of the transformants was demonstrated by the detection of beta-glucuronidase (GUS) activity in the primary transformants and by molecular analysis. Stable transformation was indicated by Mendelian segregation of the hygromycin selectable marker and of the gusA activity after selfing of the transgenic plants.

Agrobacterium tumefaciens↗
PubMed2002

Phenotypic variations and dynamic topography of transformed cells in an experimental model of diethylstilbestrol-induced renal tumour in male Syrian hamster.

This work explores the phenotypic changes affecting transformed cells in an experimental model of diethylstilbestrol (DES)-induced renal tumours in male Syrian hamster. This estrogen-induced neoplasm presents an important cytological pleomorphism and its origin remains largely controversial. In order to characterize phenotypic variations during tumour progression, the occurrence of seven lineage markers was analysed by a morphometric approach in kidney sections of DES-exposed hamsters (6-11 months). S100 protein, neuron-specific enolase (NSE) and vimentin are expressed by a large percentage of malignant cells during tumour development. Glial fibrillary acidic protein (GFAP), protein gene product 9.5 (PGP 9.5) and desmin are mostly evidenced in advanced neoplasm whereas Leu 7 always presents a focal expression. As evidenced by double-label immunofluorescence, the coexpression of three important neuroectodermal lineage markers (S100, NSE and PGP 9.5) in earliest tumour buds points to a peripheral nerve sheath origin for this neoplasm thus confirming previously published data. For each marker, the fluctuations of expression levels during tumour progression as well as the spatial heterogeneity of distribution suggest variable phenotypic differentiation of transformed cell populations. This observation is largely corroborated by double-label immunofluorescence showing coexpression modification of several markers during tumour progression. This points to a complex dynamic and spatial self-organization of different phenotypes within neoplasms. Altogether, these results support the concept that DES-induced kidney tumours are not made of unstructured cell populations but represent adaptive complex dynamic biosystems.

Animals↗
PubMedDate not supplied

Analysis of laser Doppler flux motion in man: comparison of autoregressive modelling and fast Fourier transformation.

In order to investigate laser Doppler (LD) flux motion in healthy subjects and patients with peripheral arterial occlusive disease (PAOD), spectrum analysis of LD signals is needed. Autoregressive analysis (AR) is presented as an alternative method of power spectrum estimation. This procedure is compared to the commonly used fast Fourier transform algorithm (FFT) by describing the analytical power of both spectra in the analysis of flux motion waves. LD signals were recorded from the forefoot of 8 healthy volunteers and 11 patients with different degrees of PAOD. The flux, concentration of moving blood cells and velocity signal was digitized and stored for off-line analysis. Special software was designed to calculate AR and FFT spectra of the LD signals and to compare the suitability of both methods for the spectral analysis of LD recordings. Additionally, three-dimensional spectrum diagrams were calculated to demonstrate time-dependent flux changes during standardized provocation maneuvers. AR facilitates the determination of frequency and amplitude of flux motion waves as compared to the FFT. Low frequency-large amplitude waves (LF waves) were detected in both groups. High frequency-small amplitude waves (HF waves), which predominantly appear in severe ischemia, were observed in 7 of the 11 patients and in 2 of the 8 controls. The spectra revealed pulsatile waves in all healthy controls, but only in 1 of the 11 patients. AR modelling allows a reliable description of important flux motion components and has considerable advantages in spectral estimation of LD signals as compared to the FFT.

Algorithms↗
PubMed2003

In situ monitoring of wet granulation using online X-ray powder diffraction.

PURPOSE: Polymorphic transformations during the wet granulation of a metastable polymorph of flufenamic acid were monitored in situ using online X-ray powder diffraction. The resulting data were used in testing a proposed process induced transformation rate model, which allows the extent and occurrence of polymorphic transformations during wet granulation to be controlled by adjusting the granulation time. METHODS: A small-scale, top mixing granulator was designed for compatibility with novel X-ray powder diffraction equipment (available from X-Ray Optical Systems of East Greenbush, NY). RESULTS: The unique polycapillary optic and X-ray source allowed the transformation of the metastable to the stable polymorph to be followed during the granulation. Following a diffraction peak each for the metastable and stable forms demonstrated that polymorphic transformations during the wetting phase of granulation follow the trends predicted by the model. CONCLUSIONS: The advanced online monitoring may allow real-time control of the process by the adjustment of process parameters, such as granulation time, and clearly qualifies as a PAT (process analytical technology).

Flufenamic Acid↗
PubMed2002

Transformational leadership and the mental health team.

Bass's (1990) multifactor model contrasts transformational and transactional styles of leadership with an essentially ineffective style: laissez-faire leadership. This study examines the relationship between these leadership styles and measures of organizational culture and staff burnout in mental health services teams. There were 236 leaders and 620 subordinates from 54 mental health teams who provided their perceptions of leadership style, organizational culture, and burnout in their program. Results show transformational leadership to be positively associated with a cohesive organizational culture and negatively associated with burnout. Moreover, leaders and subordinates differ in their ratings of transformational leadership-leaders viewed themselves more positively. These findings are helpful for understanding the central role of leaders in the organizational structure of teams.

Burnout, Professional↗
PubMedDate not supplied

[Characteristics of the toxic effect of lead ingested with food in model experiments].

A transformed form of lead was obtained in model experiments. It was established that administration of lead in the ionic form (repeated action, 21 times) in a dose of 0.2 mg/kg bw produces a toxic effect. Administration of the transformed form of lead did not bring about any statistically significant alterations on the part of the toxic and specific indicators.

Animals↗
PubMed2006

Transformations that preserve detailed balance in Markov models.

Aggregated Markov processes related by similarity transformation are equivalent in that they cannot be distinguished by steady-state experiments. We derive an explicit formula for the set of all detailed-balance preserving similarity transformations between such continuous time Markov chains with N states. The matrices that define the allowed similarity transformations are found to be a simple non-linear function applied to almost any element of the special orthogonal group in N dimensions. Since a model is identifiable only if there is no similarity transformations to an equivalent model, we expect this result to prove useful in the theory of identification of aggregated Markov chains, an enterprise of growing importance as more and more single molecules yield to observation.

Biometry↗
PubMed1989

Interaction of the glucocorticoid receptor with the Mr 90,000 heat shock protein: an evolving model of ligand-mediated receptor transformation and translocation.

Reports from several laboratories support a model for glucocorticoid receptor (GR) transformation in cytosol in which a heteromeric 9S complex of GR and the Mr 90,000 heat shock protein undergo a temperature-dependent and hormone-promoted dissociation to yield the free DNA-binding form of the receptor. In this paper, we review evidence that the 9S heteromeric complex is derived from the normal inactive state of the receptor in the intact cell and that both Mr 90,000 heat shock protein and the untransformed GR localize by immunofluorescence with specific monoclonal antibodies to microtubules in a variety of cell types in culture. We propose that an association with cytoskeleton may be required for translocating the GR from its cytoplasmic site of synthesis to its nuclear site of action and that the 9S complex is derived from this cytoskeleton-associated form. Similar molybdate-stabilized 9S complexes can be obtained for all of the steroid receptors, several of which clearly are localized to the nucleus prior to exposure to hormone. These receptors may have moved to the terminus of the translocation pathway where they remain in a cytoskeleton-bound "docking" position. We speculate that, in the intact cell, ligand-dependent dissociation of Mr 90,000 heat shock protein permits the steroid receptors to progress by some ordered mechanism to their high affinity sites of action within the nucleus.

Animals↗
PubMed2004

In vivo positron-emission tomography imaging of progression and transformation in a mouse model of mammary neoplasia.

Imaging mouse models of human cancer promises more effective analysis of tumor progression and reduction of the number of animals needed for statistical power in preclinical therapeutic intervention trials. This study utilizes positron emission tomography imaging of 2-[18F]-fluoro-deoxy-D-glucose to monitor longitudinal development of mammary intraepithelial neoplasia outgrowths in immunocompetent FVB/NJ mice. The mammary intraepithelial neoplasia outgrowth tissues mimic the progression of breast cancer from premalignant ductal carcinoma in situ to invasive carcinoma. Progression of disease is clearly evident in the positron emission tomography images, and tracer uptake correlates with histological evaluation. Furthermore, quantitative markers of disease extracted from the images can be used to track proliferation and progression in vivo over multiple time points.

Animals↗
PubMed2000

The absence of Msh2 alters abelson virus pre-B-cell transformation by influencing p53 mutation.

Defects in DNA mismatch repair predispose cells to the development of several types of malignant disease. The absence of Msh2 or Mlh1, two key molecules that mediate mismatch repair in eukaryotic cells, increases the frequency of mutation and also alters the response of some cells to apoptosis and cell cycle arrest. To understand the way these changes contribute to cancer predisposition, we examined the effects of defective mismatch repair on the multistep process of pre-B-cell transformation by Abelson murine leukemia virus. In this model, primary transformants undergo a prolonged apoptotic crisis followed by the emergence of fully transformed cell lines. The latter event is correlated to a loss of function of the p53 tumor suppressor protein and down-modulation of the p53 regulatory protein p19Arf. Analyses of primary transformants from Msh2 null mice and their wild-type littermates revealed that both types of cells undergo crisis. However, primary transformants from Msh2 null animals recover with accelerated kinetics, a phenomenon that is strongly correlated to the appearance of cells that have lost p53 function. Analysis of the kinetics with which p53 function is lost revealed that this change provides the dominant stimulus for emergence from crisis. Therefore, the absence of mismatch repair alters the molecular mechanisms involved in transformation by affecting a gene that controls apoptosis and cell cycle progression, rather than by affecting these processes directly.

Abelson murine leukemia virus↗
PubMed1989

Induced differentiation of erythroleukemia cells by hexamethylene bisacetamide: a model for cytodifferentiation of transformed cells.

There is considerable evidence that malignant transformation need not eliminate the potential for a cell to express its developmental capabilities. This review explores the process whereby polar compounds, hexamethylene bisacetamide (HMBA) in particular, induce murine erythroid leukemoid cells (MELC) to express the differentiated erythroid phenotype, including hemoglobin production and cessation of cell division. This is a multi-step process which, although the mechanisms of action of HMBA are not yet fully understood, is amenable to experimental definition and analysis. Early effects, including changes in protein kinase C activity, in ion transport, and in expression of certain nuclear proto-oncogenes, have been examined in relation to the onset of terminal cell differentiation. This experimental experience has formed the context for initiating preliminary clinical studies designed to examine the pharmacology of HMBA and to explore its potential for modifying the natural history of cancer.

Acetamides↗
PubMed2006

Proteolytic enzymes in skeletal development: histochemical methods adapted to the study of matrix lysis during the transformation of a "cartilage model" into bone.

The replacement of a "cartilage model" by definitive bone is characterized by a series of localized excavations of the cartilage which are eventually followed by bone deposition. Each excavation requires lysis of cartilage components (defined here as the breakdown of a peptide bond) and their eventual resorption (defined here as microscopical visible cartilage loss). More precisely we have proposed that the lysis is affected by proteases capable of breaking down the main proteoglycan "aggrecan" and the main fibril element, "type II collagen". Four approaches combining biochemical, immunologic and microscopic techniques have been adapted to test this hypothesis. Each is applied to the rat tibial head's "cartilage model" where proteases have been shown to be major contributors to secondary ossification center formation. The approaches have been found both effective and distinct as cartilage resorbing enzymes have not only been identified but also detected in situ before and after activation. Achieved overall is an understanding of when, where and how specified proteases contribute to tissue component lyses. While the focus resides on the in situ proteolysis of cartilage, three of the approaches could be translated without change to other tissues, whereas one may require tissue specific adjustments before use.

Aggrecans↗