A Thermodynamic Approach to the Metaboloepigenetics of Cancer.

We present a novel thermodynamic approach to the epigenomics of cancer metabolism. Here, any change in a cancer cell's membrane electric potential is completely irreversible, and as such, cells must consume metabolites to reverse the potential whenever required to maintain cell activity, a process driven by ion fluxes. Moreover, the link between cell proliferation and the membrane's electric potential is for the first time analytically proven using a thermodynamic approach, highlighting how its control is related to inflow and outflow of ions; consequently, a close interaction between environment and cell activity emerges. Lastly, we illustrate the concept by evaluating the Fe2+-flux in the presence of carcinogenesis-promoting mutations of the TET1/2/3 gene family.

Thermomagnetic Resonance Effect of the Extremely Low Frequency Electromagnetic Field on Three-Dimensional Cancer Models.

In our recent studies, we have developed a thermodynamic biochemical model able to select the resonant frequency of an extremely low frequency electromagnetic field (ELF-EMF) specifically affecting different types of cancer, and we have demonstrated its effects in vitro. In this work, we investigate the cellular response to the ELF electromagnetic wave in three-dimensional (3D) culture models, which mimic the features of tumors in vivo. Cell membrane was modelled as a resistor-capacitor circuit and the specific thermal resonant frequency was calculated and tested on two-dimensional (2D) and three-dimensional (3D) cell cultures of human pancreatic cancer, glioblastoma and breast cancer. Cell proliferation and the transcription of respiratory chain and adenosine triphosphate synthase subunits, as well as uncoupling proteins, were assessed. For the first time, we demonstrate that an ELF-EMF hampers growth and potentiates both the coupled and uncoupled respiration of all analyzed models. Interestingly, the metabolic shift was evident even in the 3D aggregates, making this approach particularly valuable and promising for future application in vivo, in aggressive cancer tissues characterized by resistance to treatments.

Application of proteomics to the study of Helicobacter pylori and implications for the clinic.

INTRODUCTION: Helicobacter pylori (H. pylori) is a gram-negative bacterium that colonizes the gastric epithelium and mucous layer of more than half the world's population. H. pylori is a primary human pathogen, responsible for the development of chronic gastritis, peptic ulceration and gastric cancer. Proteomics is impacting several aspects of medical research: understanding the molecular basis of infection and disease manifestation, identification of therapeutic targets and discovery of clinically relevant biomarkers. Areas covered: The main aim of the present review is to provide a comprehensive overview of the contribution of proteomics to the study of H. pylori infection pathophysiology. In particular, we focused on the role of the bacterium and its most important virulence factor, CagA, in the progression of gastric cells transformation and cancer progression. We also discussed the proteomic approaches aimed at the investigation of the host response to bacterial infection. Expert commentary: In the field of proteomics of H. pylori, comprehensive analysis of clinically relevant proteins (functional proteomics) rather than entire proteomes will result in important medical outcomes. Finally, we provided an outlook on the potential development of proteomics in H. pylori research.

An engineering thermodynamic approach to select the electromagnetic wave effective on cell growth.

To date, the choice of the characteristics of the extremely low-frequency electromagnetic field beneficial in proliferative disorders is still empirical. In order to make the ELF interaction selective, we applied the thermodynamic and biochemical principles to the analysis of the thermo-chemical output generated by the cell in the environment. The theoretical approach applied an engineering bio-thermodynamic approach recently developed in order to obtain a physical-mathematical model that calculated the frequency of the field able to maximize the mean entropy changes as a function of cellular parameters. The combined biochemical approach envisioned the changes of entropy as a metabolic shift leading to a reduction of cell growth. The proliferation of six human cancer cell lines was evaluated as the output signal able to confirm the correctness of the mathematical model. By considering the cell as a reactive system able to respond to the unbalancing external stimuli, for the first time we could calculate and validate the frequencies of the field specifically effective on distinct cells.

Cardiac concentric hypertrophy promoted by activated Met receptor is mitigated in vivo by inhibition of Erk1,2 signalling with Pimasertib.

Cardiac hypertrophy is a major risk factor for heart failure. Hence, its attenuation represents an important clinical goal. Erk1,2 signalling is pivotal in the cardiac response to stress, suggesting that its inhibition may be a good strategy to revert heart hypertrophy. In this work, we unveiled the events associated with cardiac hypertrophy by means of a transgenic model expressing activated Met receptor. c-Met proto-oncogene encodes for the tyrosine kinase receptor of Hepatocyte growth factor and is a strong inducer of Ras-Raf-Mek-Erk1,2 pathway. We showed that three weeks after the induction of activated Met, the heart presents a remarkable concentric hypertrophy, with no signs of congestive failure and preserved contractility. Cardiac enlargement is accompanied by upregulation of growth-regulating transcription factors, natriuretic peptides, cytoskeletal proteins, and Extracellular Matrix remodelling factors (Timp1 and Pai1). At a later stage, cardiac hypertrophic remodelling results into heart failure with preserved systolic function. Prevention trial by suppressing activated Met showed that cardiac hypertrophy is reversible, and progression to heart failure is prevented. Notably, treatment with Pimasertib, Mek1 inhibitor, attenuates cardiac hypertrophy and remodelling. Our results suggest that modulation of Erk1.2 signalling may constitute a new therapeutic approach for treating cardiac hypertrophies.

Heterogeneous phenotype of human glioblastoma: in vitro study.

Glioblastomas (GBMs) are the most lethal primary brain tumours. Increasing evidence shows that brain tumours contain the population of stem cells, so-called cancer stem cells (CSCs). Stem cell marker CD133 was reported to identify CSC population in GBM. Further studies have indicated that CD133 negative cells exhibiting similar properties and are able to initiate the tumour, self-renew and undergo multilineage differentiation. GBM is a highly heterogeneous tumour and may contain different stem cell populations with different functional properties. We characterized five GBM cell lines, established from surgical samples, according to the marker expression, proliferation and differentiation potential. CD133 positive cell lines showed increased proliferation rate in neurosphere condition and marked differentiation potential towards neuronal lineages. Whereas two cell lines low-expressing CD133 marker showed mesenchymal properties in vitro, that is high proliferation rate in serum condition and differentiation in mesenchymal cell types. Further, we compared therapy resistance capacity of GBM cell lines treated with hydroxyurea. Our results suggest that CSC concept is more complex than it was believed before, and CD133 could not define entire stem cell population within GBM. At least two different subtypes of GBM CSCs exist, which may have different biological characteristics and imply different therapeutic strategies.

The exposure to extremely low frequency electromagnetic-fields inhibits the growth and potentiates the sensitivity to chemotherapy of bidimensional and tridimensional human osteosarcoma models.

We previously established a thermodynamical model to calculate the specific frequencies of extremely low frequency-electromagnetic field (ELF-EMF) able to arrest the growth of cancer cells. In the present study, for the first time, we investigated the efficacy of this technology on osteosarcoma, and we applied a precise frequency of the electromagnetic field on three human osteosarcoma cell lines, grown as adherent cells and spheroids. We evaluated the antitumour efficacy of irradiation in terms of response to chemotherapeutic treatments, which is usually poor in this type of cancer. Importantly, the results of this novel combinatorial approach revealed that the specific exposure can potentiate the efficacy of several chemotherapeutic drugs, both on bidimensional and tridimensional cancer models. The effectiveness of cisplatinum, methotrexate, ifosfamide and doxorubicin was greatly increased by the concomitant application of the specific ELF-EMF. Moreover, our experiments confirmed that ELF-EMF inhibited the proliferation and modulated the mitochondrial metabolism of all cancer models tested, whereas mesenchymal cells were not affected. The latter finding is extremely valuable, given the importance of preserving the cell reservoir necessary for tissue regeneration after chemotherapy. Altogether, this novel evidence opens new avenues to the clinical applications of ELF-EMF in oncology.