Biomedical subjects
Publications and source records attributed to G T Matioli.
In rare occasions, cancer cells have chromatids with segments stacked in inverted order vis-a-vis their normal counterparts. The paper discusses a mechanism for these anomalies as well as for their statistical incidences. The proposed mechanism and its telenomic implications have been adapted from ideas discussed in a preceding note.
This paper reviews matters related to the inversion of a chromatid segment. While the main conclusions are congruent with those of a preceding note, preservation of the physical and functional integrity of the chromosome is dependent upon the way the inverted segment changes the 'intrinsic' coordination order along the chromatid stack.
Explore the source record for details and available documents.
The mechanism of SCE discussed in previous papers (3, 4) is adapted to account for the absence of kinks on chromatids experiencing an exchange limited to their KSs. The paper ends with a brief digression on kinks. Equivalent to solitons, such dynamic malformations can function as carriers of information along the chromatid stack.
The paper discusses a mechanism for the coordination of a differentiation path through activation of slave genes by transcriptional complexes (excitons) organised by master genes. Entrainment occurs when master-slave genes form partnerships of closely apposed entities. Sister chromatid exchanges provide the action necessary for successful entrainment. Although concerned mainly with normal hematopoietic (stem) cells, the model applies also to certain leukemic cells, regarding in particular retrodifferentiation back to the stem state followed by attenuation of malignancy.
The theory of solitons is applied to the normalisation of a malformed loop from a kinked chromatid. When interpreted in the context of dividing cells, the proposed mechanism adds novel functions to those traditionally attributed to the mitotic spindle.
The so-called 'Apollonian gasket' offers interesting suggestions on how chromatids might be packaged among microtubular bundles of the mitotic spindle. While transiting through the spindle's viscous environment, the helical motions of coiled chromatids engender important interactions via synergistic or antagonistic torques that are instrumental for both shape and function of normal genomes as well as for certain anomalies (aneuploidy, nuclear deformations, etc) often associated to the malignant state.
We discuss a mechanism leading to antipodal polarisation of sister chromatids. The information to migrate to opposite poles originates from the interaction between spindle microtubules and the kinetochores when two sister chromatids disentangle from each other at the centromeric braid.
After a brief digression on certain types of noise of generic interest, it is concluded that 1/f noise offers interesting interpretations for unusual modes of SC differentiation such as the precipitous maturation of a subset of the macrophage lineage. Functionally equivalent to weak, spurious sources these specialized cells support the proliferation and maturation of erythroid cells extending thus the stimulatory influence of true, strong sources although in a rather indirect fashion.
Considerations are given to special features of the nuclear envelope that might occasion segmental exchange between sister chromatids. The underlying dynamics may lead to illegal apposition of originally distant sequences and/or to modulations in the topologic orientation of genes on chromatid segments involved in such exchanges.
The model for SCE, proposed by (1), is adapted to the exchange of one or more segments located midway along the chromatid axis. In spite of conflicts in the handedness of these midsegments, the model accounts for the undistorted stacking of both sister chromatids.
After developing a map for certain states typical of hemopoietic stem cells (SCs), we identify a number of parameters (e.g. fractal dimensions, oscillatory behavior in a multistable landscape, etc.) that scale down to subcellular structures such as interphase genome, chromatids, chromatin entanglements and DNA segmental motions. A curious aspect is the continuous reappearance of recursive processes even at very small biologic scales. These iterations are relevant not only for the normal behavior of (hemopoietic) cells but also for amplifying hidden genomic singularities above some critical threshold. When that happens, there are sudden quali-quantitative and often clonal changes in the cell behavior. As illustrated by specific leukemic cases, many paradoxes of malignant growth seem best explained by the peculiar sensitivity to initial condition of (hemopoietic) cells. Interpreted as chaotic oscillators, these cells display a spectrum of disorders that, in spite of appearing as random, are in fact triggered by amplification of subtle preconditions with statistico-deterministic outcomes, that are predictable within certain time limits.
We discuss a mechanical model for the mirror-symmetric inversion of the scaffold's helicity of replicated chromatids vis-a-vis that of their templates. The paper ends with comments on the orientability of certain genes and on the effects of such topologies upon (a)symmetric gene expression, in general. Our model and its generalizations apply only to the special subclass of 'coiled' chromatids whose statistical distribution in the genome of normal and of malignant cells is not known precisely.
We reconsider the proposal that a stem cell (SC) is the initiator of clonal (human) leukemias. Using chronic myeloid leukemia (CML) as an example, we discuss some conceptual and experimental inconsistencies of the above conjecture. As an alternative, it is proposed that CML is initiated by an immature myeloblast. The main idea is that CML results from certain growth-related accidents encountered along the myeloid differentiation path. Retrodifferentiation of (semi) autonomous myeloblasts back to the SC state seems the principle cause for the distribution of clonal markers across all hemopoietic lineages, including those that are not involved in the leukemic process.
We discuss a model for the organization of differentiation paths within the vector spaces of the cell genome. It is conjectured that the nuclear vesicle apparatus participates in the coordination of genes along nuclear trajectories directing cell commitment to terminal maturation. In this scenario, nuclear (onco)genes are interpreted as regulators of transcriptional exchanges among spatially correlated genes. The paper digresses on events leading to anachronistic acquisition of immortal growth by normally dependent cells as well as on the time and path dependent incidence of cancer, in vivo. Albeit the mathematico-physical foundations have been largely ignored, the basic ideas were derived from order-disorder transitions in chaotic systems whose dynamics are not pervasively random. The paper ends with a brief note on tumor heterogeneity, seen as a logistic phenomenon complementing the interpretation offered by (1).
After some comments on the topology of chromatids, restructuring of the interphase nucleus is conjectured to depend upon the nuclear vesicle apparatus. These vesicles change the intrinsic shape of chromatids to fit the different topology of the interphase nuclear spheroid. Reciprocal translocations between selected chromatids result whenever the nucleus of malignant cells organizes de novo certain exceptional or emergency differentiation paths. However, the almost unavoidable chimeric genes resulting from these translocations may be less ominous than hitherto suspected. This seems to be the case for chronic myelogenous leukemia, where the bcr-abl chimeric gene lessens the aggressiveness of the primary clone when functioning in the context of myelomonocitic differentiation. Finally, our model estimates the statistical incidences of the bcr-abl chimera. These estimates are found to agree with clinical data better than evaluations from the random mutation theory.
We make quantitative estimates for the relative stimulatory efficiency at various points on the membrane of a hemopoietic source. This cell produces a stimulus, P, which supports renewal of parasitic stem cells (SCs) in physical contact with the source's surface. We find that the tips of long pseudopods extending from the source's main body should have the highest stimulatory efficiency.
We elaborate on the pathogenesis of (human) hemopoietic leukemias according to a model whereby malignant growth follows the anachronistic expression of gene P in a rare cell at a certain stage of differentiation (1,2). P is a stimulus needed for renewal of hemopoietic cells. When illegally autocatalytic for P any mitotically competent cell (not necessarily pluripotent, at least originally) acquires the marginal (seldom complete) autonomous growth of malignant cells. Rather than confrontational, these views complement advantageously the mutation model and account for certain peculiarities of (human) leukemic cells, such as the propensity to differentiate terminally when isolated from their in vivo microenvironments. In addition, we discuss the rare occurrence of certain human leukemias (e.g., erythroleukemias and polycythemia veras) comparatively to the surprisingly more frequent chronic and acute myelogenous leukemias. This occurs in spite of the similarity between erythroid and myeloid populations in terms of size (mass of cells) and number of targets at mutational risk. Thus the classic mutation model predicts that random hits, after radiation exposure for example, should induce erythroid and myeloid leukemias with similar frequencies in contrast to clinical findings (3) and the predictions from our model.