RESUMEN
The cell is the smallest unit of life. It is a structure that maintains order through self-organization, characterized by a high level of dynamism, which in turn is characterized by work. For this work to take place, a continuous high flow of energy is necessary. However, a focused view of the physical relationship between energy and work is inadequate for describing complex biological/medical mechanisms or systems. In this review, we try to make a connection between the fundamental laws of physics and the mechanisms and functions of biology, which are characterized by self-organization. Many different physical work processes (work) in human cells are called cell work and can be grouped into five forms: synthetic, mechanical, electrical, concentration, and heat generation cell work. In addition to the flow of energy, these cell functions are based on fundamental processes of self-organization that we summarize with the term Entirety of molecular interaction (EoMI). This illustrates that cell work is caused by numerous molecular reactions, flow equilibrium, and mechanisms. Their number and interactions are so complex that they elude our perception in their entirety. To be able to describe cell functions in a biological/medical context, the parameters influencing cell work should be summarized in overarching influencing variables. These are "biological" energy, information, matter, and cell mechanics (EMIM). This makes it possible to describe and characterize the cell work involved in cell systems (e.g., respiratory chain, signal transmission, cell structure, or inheritance processes) and to demonstrate changes. If cell work and the different influencing parameters (EMIM influencing variables) are taken as the central property of the cell, specific gene mutations cannot be regarded as the sole cause for the initiation and progression of cancer. This reductionistic monocausal view does not do justice to the dynamic and highly complex system of a cell. Therefore, we postulate that each of the EMIM influencing variables described above is capable of changing the cell work and thus the order of a cell in such a way that it can develop into a cancer cell.
RESUMEN
Cells are open, highly ordered systems that are far away from equilibrium. For this reason, the first function of any cell is to prevent the permanent threat of disintegration that is described by thermodynamic laws and to preserve highly ordered cell characteristics such as structures, the cell cycle, or metabolism. In this context, three basic categories play a central role: energy, information, and matter. Each of these three categories is equally important to the cell and they are reciprocally dependent. We therefore suggest that energy loss (e.g., through impaired mitochondria) or disturbance of information (e.g., through mutations or aneuploidy) or changes in the composition or distribution of matter (e.g., through micro-environmental changes or toxic agents) can irreversibly disturb molecular mechanisms, leading to increased local entropy of cellular functions and structures. In terms of physics, changes to these normally highly ordered reaction probabilities lead to a state that is irreversibly biologically imbalanced, but that is thermodynamically more stable. This primary change-independent of the initiator-now provokes and drives a complex interplay between the availability of energy, the composition, and distribution of matter and increasing information disturbance that is dependent upon reactions that try to overcome or stabilize this intracellular, irreversible disorder described by entropy. Because a return to the original ordered state is not possible for thermodynamic reasons, the cells either die or else they persist in a metastable state. In the latter case, they enter into a self-driven adaptive and evolutionary process that generates a progression of disordered cells and that results in a broad spectrum of progeny with different characteristics. Possibly, 1 day, one of these cells will show an autonomous and aggressive behavior-it will be a cancer cell.
RESUMEN
In this study, we report p-coumaric acid as novel and effective response marker for indirectly measuring the levels of hypoxia in normal primary bronchial epithelial cells. We developed a simple and rapid technique based on hydrophilic interaction chromatography-electrospray ionization-mass spectrometry (HILIC-ESI-MS). During 168h of hypoxia without induction of reactive oxygen species (ROS), an almost linear increase of p-coumaric acid levels was observed. We interpret the increasing p-coumaric acid concentrations during hypoxia as a result of cell damage, triggered by reduced co-enzyme Q10 levels, because the oxidative cascade was not able to supply sufficient energy. The HILIC-ESI-MS assay within p-coumaric acid exhibited a linear dynamic range from 60 to 610 ng/µL with correlation coefficient of 0.9998. The precision of the assay was ≤15% RSD and method accuracies between 97 and 108%.
Asunto(s)
Biomarcadores/análisis , Hipoxia de la Célula/fisiología , Cromatografía Líquida de Alta Presión/métodos , Ácidos Cumáricos/análisis , Estrés Oxidativo/fisiología , Espectrometría de Masa por Ionización de Electrospray/métodos , Actinas/análisis , Actinas/metabolismo , Biomarcadores/metabolismo , Núcleo Celular/química , Núcleo Celular/metabolismo , Células Cultivadas , Ácidos Cumáricos/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Subunidad alfa del Factor 1 Inducible por Hipoxia/análisis , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Propionatos , Reproducibilidad de los Resultados , Mucosa Respiratoria/citología , Ubiquinona/análogos & derivadosRESUMEN
Primary leiomyosarcoma (LMS) of bone is an exceedingly rare entity on which to date no molecular data have been reported. In a series of 6 tumors (5 grade IIB, 1 grade IIA), we assessed the prevailing genetic stability by microsatellite analysis at 7 loci. The IIB tumors demonstrated a rate of genomic loss as high as 90%, accompanied by an intratumoral heterogeneity in 30% of conspicuous markers. High microsatellite instability in the severe type was not observed, although hMLH1 immunostaining was consistently negative. We assume that intraosseous LMS pertains to "deletor phenotype" tumors. We did observe a locus-specific MSI in our marker linked with hMSH2. Immunostaining and allelotyping indicated a knock-out of pRb in all cases, confirming its major role in sarcomas. Only the stage IIB tumors (4 of 5) pointed to p53 inactivation. In addition, the human telomerase subunit-linked markers exhibited high rates of chromosomal loss. The stage IIA tumor still confined to the bone displayed no genetic instability. Moreover, the proliferation index made a clear distinction between the IIA and IIB tumors (5% vs 30%). We propose to further investigate the usefulness of loss of heterozygosity as a progression marker in this entity.
Asunto(s)
Neoplasias Óseas/genética , Inestabilidad Genómica , Leiomiosarcoma/genética , Repeticiones de Microsatélite/genética , Adulto , Alelos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Proliferación Celular , ADN de Neoplasias/análisis , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Leiomiosarcoma/metabolismo , Leiomiosarcoma/secundario , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Proteína 2 Homóloga a MutS , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
PURPOSE: Telomerase activity appears to play a crucial role in the development of many tumors. More than 80% of all malignant human tumors show an increased telomerase activity. However, conflicting results have been reported about telomerase activity in sarcomas. The aim of the study was to obtain more information about telomerase activity in sarcomas based on a large number of cases. METHODS: Telomerase activity was measured in 69 different tumor samples (33 malignant bone tumors and 36 soft tissue sarcomas). Tumor samples were obtained intraoperatively and frozen immediately in liquid nitrogen. Telomerase activity was detected by the telomeric repeat amplification assay (TRAP-assay). RESULTS: Only 7% of the samples showed telomerase activity. No correlation between staging and telomerase activity could be observed. DISCUSSION: The fact that only five out of 69 examined tumor samples showed a telomerase activity provides experimental evidence that in sarcomas the reactivation of telomerase may play a subordinate role. Our results suggest that alternative mechanisms for cell immortalization, yet to be determined, seem to be involved in the development and/or maintenance of soft-tissue sarcomas and malignant bone tumors.