A mathematical analysis of a model for tumour angiogenesis

In order to accomplish the transition from avascular to vascular growth, solid tumours secrete a diffusible substance known as tumour angiogenesis factor (TAF) into the surrounding tissue. Neighbouring endothelial cells respond to this chemotactic stimulus in a well-ordered sequence of events comprising, at minimum, of a degradation of their basement membrane, migration and proliferation. A mathematical model is presented which takes into account two of the most important events associated with the endothelial cells as they form capillary sprouts and make their way towards the tumour i.e. cell migration and proliferation. The numerical simulations of the model compare very well with the actual experimental observations. We subsequently investigate the model analytically by making some relevant biological simplifications. The mathematical analysis helps to clarify the particular contributions to the model of the two independent processes of endothelial cell migration and proliferation.     

Chemical and immunochemical characterisation of substance P-like immunoreactivity and physalaemin-like immunoreactivity in a carcinoid tumour

Extracts of a carcinoid tumour, resected from the mid-portion of the ileum of a patient with no symptoms of endocrine disorder, were associated with a high concentration of substance P-like immunoreactivity. Using reverse-phase high performance liquid chromatography and antisera specifically directed against the C-terminal and N-terminal regions of substance P and against the N-terminal region of physalaemin, the following components were isolated and identified: substance P and its oxidised form, [pGlu⁵]substance P-(5–11) peptide and its oxidised form, and the oxidised form of physalaemin. The identity of tumour substance P with the undecapeptide was confirmed by amino acid analysis and high performance ion-exchange chromatography. In vitro incubation of tumour tissue from a lymph node metastasis from the same patient with [³H]leucine resulted in incorporation of radioactivity into newly synthesised substance P.     

A weakly nonlinear analysis of a model of avascular solid tumour growth

 In this paper we study a mathematical model that describes the growth of an avascular solid tumour. Our analysis concentrates on the stability of steady, radially-symmetric model solutions with respect to perturbations taken from the class of spherical harmonics. Using weakly nonlinear analysis, previous results are extended to show how the amplitudes of the asymmetric modes interact. Attention focuses on a special case for which the model equations simplify. Analysis of the simplified model equations leads to the identification of a two-parameter family of asymmetric steady solutions, the dimensions of whose stable and unstable manifolds depend on the system parameters. The asymmetric steady solutions limit the basin of attraction of the radially-symmetric steady state when it is linearly stable. On the basis of these numerical and analytical results we postulate the existence of fully nonlinear steady solutions which are stable with respect to time-dependent perturbations. Received: 25 October 1998 / Revised version: 20 June 1998     

Oscillations in growth of multicellular tumour spheroids: a revisited quantitative analysis

Objectives: Multicellular tumour spheroids (MTS) provide an important tool for study of the microscopic properties of solid tumours and their responses to therapy. Thus, observation of large‐scale volume oscillations in MTS, reported several years ago by two independent groups ( 1 , 2 ), in our opinion represent a remarkable discovery, particularly if this could promote careful investigation of the possible occurrence of volume oscillations of tumours ‘in vivo’. Materials and methods: Because of high background noise, quantitative analysis of properties of observed oscillations has not been possible in previous studies. Such an analysis can be now performed, thanks to a recently proposed approach, based on formalism of phenomenological universalities (PUN). Results: Results have provided unambiguous confirmation of the existence of MTS volume oscillations, and quantitative evaluation of their properties, for two tumour cell lines. Proof is based not only on quality of fitting of the experimental datasets, but also on determination of well‐defined values of frequency and amplitude of the oscillations for each line investigated, which would not be consistent with random fluctuation. Conclusions: Biological mechanisms, which can be directly responsible for observed oscillations, are proposed, which relates also to recent work on related topics. Further investigations, both at experimental and at modelling levels, are also suggested. Finally, from a methodological point of view, results obtained represent further confirmation of applicability and usefulness of the PUN approach.     

Chemical analysis of Azospirillum lipopolysaccharides

Lipopolysaccharides (LPS) were extracted by hot phenol-water from five strains each of Azospirillum lipoferum and Azospirillum brasilense. Rhamnose, glucose, glucosamine and 3-deoxy-d-mannooctulosonic acid were comon sugar constituents of all LPS preparations. 2-O-Mefucose, 3-O-Me-fucose, 3-O-Me-rhamnose and 2-O-Megalactose were found in LPSs of some A. brasilense strains. Fatty acid spectra from all LPSs studied were almost identical with predominance of 3-hydroxymyristic and 3-hydroxypalmitic acids. 3-Hydroxypalmitic acid was the only amide-linked fatty acid. Lipopolysaccharides isolated from A. brasilense showed higher heterogeneity in sugar composition than those from A. lipoferum.Abbreviations glc gas liquid chromatography - ms mass spectrometry - LPS lipopolysaccharide - dOclA 3-deoxy-d-mannooctulosonic acid - 3-OH-16:0 3-hydroxypalmitic acid - nir^- nitrite reductase negative - nir⁺ nitrite reductase positive     

Chemical synthesis, expression and product assessment of a gene coding for biologically active human tumour necrosis factor alpha

A gene encoding human tumour necrosis factor alpha (TNF-alpha) has been chemically synthesized, cloned and expressed to yield a biologically active protein in Escherichia coli. The 480-bp gene was assembled by enzymic ligation of 32 oligonucleotides, cloned directly into M13mp18 for sequence verification and expressed in the broad host range high-level expression vector pMMB66EHST. Expressed recombinant TNF-alpha was shown to have the correct molecular weight, processed N-terminal sequence, antibody cross-reactivity and tumour cell killing activity. The expression product of the synthetic gene has been purified to homogeneity by a two-step ion-exchange procedure and the purified material shown to be active.     

Clinical applications of image cytometry to human tumour analysis

Image cytometry (ICM) is widely applied to the automated screening, the detection, the diagnosis, the classification, the prognosis and the therapeutic follow-up of different types of cancers (breast, bladder, cervix,...). This review describes the analysis methods and the applications of nuclear image analysis, the determination of DNA content and the analysis of morphometry and of nuclear texture. DNA content analysis can contribute to a prognostic information in addition to other prognostic factors for breast, renal and prostate cancers. For ovarian cancer, aneuploidy seems to be related to prognosis. Bladder tumours with DNA aneuploidy were frequently of high malignancy while ploidy was significantly correlated to relapse risk. For digestive cancers, patients presenting DNA diploid tumours show a better survival than patients with aneuploid ones. Morphometry seems to be a more important criterion than other conventional prognostic factors of invasive breast and digestive carcinomas. A differential diagnosis between normal and neoplastic thyroids is more precise when based on a quantitative evaluation of texture associated to morphometry. Textural parameters permit the discrimination of two populations of patients having a different prognosis and could thus be an aid for prognosis in prostatic cancers. Morphonuclear parameters contribute to separate low and high grade bladder carcinomas. Although ICM was frequently reported, results from the reported examples were not always obvious. In conclusion, the measurements obtained with ICM could be helpful for a decision in several cancers but could not be a substitute for the classical approach of the pathologist.     

Quantitative analysis of Ehrlich tumour cell nucleoli during interphase

Nuclear and nucleolar growth throughout interphase has been analysed by stereological methods. The nuclear volume and the volumes of the different nucleolar components have been determined in Ehrlich tumour cells selected at various stages of the cell cycle. These quantitative electron microscopic investigations demonstrate that the nuclear and nucleolar volumes are twice as large in G2 as in G1 cells. In addition, all the nucleolar constituents participate in this latter process.     

The biology and analysis of single disseminated tumour cells

Despite an increasing molecular-genetic understanding of the development of malignant epithelial neoplasias, the frontline therapy for patients with carcinomas is still surgery. Systemic adjuvant treatments such as chemotherapy or immunotherapy have had limited success perhaps because they are based on analysis of the primary tumour or on cell lines derived from metastasis. However, the characteristics of systemically disseminated tumour cells can be very different from that of the primary tumour or end-stage metastasis. Consequently, there is a need to study the evolution and nature of systemic cancer directly in order to identify new target structures for therapy present on the potential precursors of metastasis--the disseminated tumour cells.     

Structural analysis of MHC alleles in an RSV tumour regression chicken using a BAC library

The chicken major histocompatibility complex (MHC-B locus) has a strong association with resistance and susceptibility to numerous diseases. We have found a B haplotype designated WLA that associated with the regression of tumours caused by Rous sarcoma virus J strain (RSV-J). Haplotype WLA was identical to the regressive B6 haplotype when partial genotyping was performed (Poultry Science, 89, 2010, 651). We then constructed a bacterial artificial chromosome (BAC) library from a WLA homozygote chicken to evaluate the structure of this regression haplotype and compared it to those of the B6 haplotype. Comparison between WLA and B6 above 59 kb within the 167 kb, including 14 genes from BG1 to BF2, revealed 75 SNPs and 14 indels. However, several genes were identical between WLA and B6, including the BF1 and BF2 genes, which encode a class I molecule previously suggested to be related to the regression phenotype. The BLB2 gene encoding the MHC class II beta chain showed the greatest diversity, with 19 non-synonymous SNPs. A comparison of WLA and B6 haplotpyes that are associated with tumour regression and RIRa and B24 haplotypes associated with tumour progression suggests that DMA1, DMA2, BRD2, TAPBP and BLB2 genes are not involved in the intensity of RSV J tumour regression.     

Chemical analysis of cryoglobulins observed in a case of essential IgG-IgA cryoglobulinaemia

In a case of essential mixed (IgG-IgA) cryoglobulinaemia the carbohydrate and aminoacid composition of cryoglobulins was chemically analyzed. A normal aminoacid and sialic acid composition was observed, whereas the glucide percentage was augmented with respect to the normal range for the two classes of Ig.