Taking a broader view of things: towards a transdisciplinary approach to cancer

Cancer is widely considered an abnormality that emerges from within the body and which must be destroyed and defeated. But we still do not know precisely how and why cancer starts, and while a ‘magic bullet’ cure has failed to materialise, those adopting a more pragmatic stance are increasingly arguing that if we cannot eradicate all cancer cells, we should look instead towards a ‘stalemate’ and find ways of managing cancer as a chronic disease. This article seeks to extend the reach of research in this field by taking a broader view and working towards a transdisciplinary approach in order to better understand cancer. First, we draw attention to obstacles that hinder progress in formulating new perspectives on cancer. Second, we ask why the genocentric approach to cancer remains dominant. One explanation is the legacy of Cartesian thinking. Third, we consider new ways of conceptualizing cancer so that it is not only a scientific object but also an object of life that has a framed existence within the body as part of a wider process of biological evolution. We draw on two key examples which highlight the importance of adopting a transdisciplinary approach: multi-drug resistance and cancer genomics

Physical and biological characteristics of multi drug resistance (MDR): an integral approach considering pH and drug resistance in cancer

The role of the Warburg effect in cancer remains to be elucidated with a resurgence in research efforts over the past decade. Why a cancer cell would prefer to use energy inefficient glycolysis, leading to an alteration of pH both inside and outside of the cell, remains to be uncovered. The development of MDR represents a major challenge in the treatment of cancer and it is explained, so far, by the over expression of drug transporters such as the well-known and archetypal P-glycoprotein (Pgp). However, controversies exist regarding the function of Pgp in multi-drug resistance. We suggest here that Pgp-mediated MDR relies fundamentally on pH alterations mediated by the Warburg effect. Furthermore, we propose that the use of proton pump and/or transporters inhibitors (PPIs/PTIs) in cancer are key to controlling both MDR, i.e. sensitize tumors to antineoplastic agents, and drug-related adverse effects

Computed tomography in veterinary medicine: currently published and tomorrow’s vision

The utilisation of Computed Tomography (CT) in veterinary practice has been increasing rapidly in line with reduced cost, improved availability and the increase in expertise and technology. This review briefly examines the recent technological advancements in imaging in the veterinary sector, and explores how CT and micro-CT (μCT) have furthered basic understanding and knowledge, and influenced clinical practice and medicine. The uses of CT technology in veterinary research, especially in relation to bone, vasculature and soft tissues, are explored and compared in relation to the different species. CT is essential not only for the diagnosis and treatment of many disorders, but it is now being used to understand areas ranging from drug delivery and surgical advancements through to anatomical and educational uses throughout the world

Physics of nail conditions: why do ingrown nails always happen in the big toes?

Although surgical treatment of nail conditions can be traced back centuries to the writings of Paul Aegineta (625–690 AC), little is known about the physical laws governing nail growth. Such a poor understanding together with the increasing number of nail salons in the high street should raise legitimate concerns regarding the different procedures applied to nails. An understanding of the physics of nail growth is therefore essential to engage with human medicine and to understand the aetiology of nail conditions. In this context, a theory of nail plate adhesion, including a physical description of nail growth can be used to determine the transverse and longitudinal curvatures of the nail plate that are so important in the physical diagnosis of some nail conditions. As a result physics sheds light on: (a) why/how nails/hooves adhere strongly, yet grow smoothly; (b) why hoof/claw/nail growth rates are similar across species; (c) potential nail damage incurred by poor trimming; (d) the connection between three previously unrelated nail conditions, i.e. spoon-shaped, pincer and ingrown nails and; last but not least, (e) why ingrown nails occur preferentially in the big toes

Theoretical evaluation of wall teichoic acids in the cavitation-mediated pores formation in Gram-positive bacteria subjected to an electric field

Background: Electroporation is a method of choice to transform living cells. The ability of electroporation to transfer small or large chemicals across the lipid bilayer membrane of eukaryotic cells or Gram-negative bacteria relies on the formation of transient pores across the membrane. To exist, these pores rely on an insulator (the bilayer membrane) and the presence of a potential difference on either side of the membrane mediated by an external electric field. In Gram-positive bacteria, however, the wall is not an insulator but pores can still form when an electric field is applied. Past works have shown that the electrostatic charge of teichoic acids, a major wall component; sensitizes the wall to pore formation when an external electric field is applied. These results suggest that teichoic acids mediate the formation of defects in the wall of Gram-positive bacteria.Methods: We model the electrostatic repulsion between teichoic acids embedded in the bacterial wall composed of peptidoglycan when an electric field is applied. The repulsion between teichoic acids gives rise to a stress pressure that is able to rupture the wall when a threshold value has been reached. The size of such small defects can diverge leading to the formation of pores.Results: It is demonstrated herein that for a bonding energy of about ~ 1 − 10 kBT between peptidoglycan monomers an intra-wall pressure of about ~ 5 − 120 kBT/nm3 generates spherical defects of radius ~ 0.1 − 1 nm diverging in size to create pores.Conclusion: The electrostatic cavitation of the bacterial wall theory has the potential to highlight the role of teichoic acids in the formation pores, providing a new step in the understanding of electroporation in Gram positive bacteria without requiring the use of an insulator

The role of proton dynamics in the development and maintenance of multidrug resistance in cancer

With a projected 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm in 2015, improving treatment is an essential focus of cancer research today. Multi-drug resistance (MDR) is the leading cause of chemotherapeutic failure in the treatment of cancer, the term denoting a characteristic of the disease-causing agent to avoid damage by drugs designed to bring about their destruction. MDR is also characterised by a reversal of the pH gradient across cell membranes leading to an acidification of the outer milieu and an alkalinisation of the cytosol that is maintained by the proton pump vacuolar-type ATPase (V-ATPase) and the proton transporters: Na+/H+ exchanger (NHE1), Monocarboxylate Transporters (MCTs), Carbonic anhydrases (CAs) (mainly CA-IX), adenosinetriphosphate synthase, Na+/HCO3− co-transporter and the Cl−/HCO3−exchanger. This review aims to give an introduction to MDR. It will begin with an explanation for what MDR actually is and go on to look at the proposed mechanisms by which a state of drug resistance is achieved. The role of proton-pumps in creating an acidic extracellular pH and alkaline cytosol, as well as key biomechanical processes within the cell membrane itself, will be used to explain how drug resistance can be sustained

Bio-inspired hierarchical designs for stiff, strong interfaces between materials of differing stiffness

Throughout biology, geometric hierarchy is a recurrent theme in structures where strength is achieved with efficient material usage. Acting over vast timescales, evolution has brought about beautiful solutions to problems of mechanics that are only now being understood and incorporated into engineering designs. One particular example of structural hierarchy is found in the junction between stiff keratinised material and the soft biological matter within the hooves of ungulates. Using this biological interface as a design motif, we investigate the role of hierarchy in the creation of a stiff, robust interface between two materials. We show that through hierarchical design, we can manipulate the scaling laws relating constituent material stiffness and overall interface stiffness under loading. Furthermore, we demonstrate that through use of a hierarchical geometry, we can reduce the maximum stress the materials experience for a given loading, and tailor the ratio of maximum stresses in the constituent materials. We demonstrate that when joining two materials of different stiffness hierarchical geometries are linked with beneficial mechanical properties and enhanced tailorability of mechanical response

Pinocytosis as the Biological Mechanism That Protects Pgp Function in Multidrug Resistant Cancer Cells and in Blood–Brain Barrier Endothelial Cells

Cancer is the second leading cause of death worldwide. Chemotherapy has shown reasonable success in treating cancer. However, multidrug resistance (MDR), a phenomenon by which cancerous cells become resistant to a broad range of functionally and structurally unrelated chemotherapeutic agents, is a major drawback in the effective use of chemotherapeutic agents in the clinic. Overexpression of P-glycoprotein (Pgp) is a major cause of MDR in cancer as it actively effluxes a wide range of structurally and chemically unrelated substrates, including chemotherapeutic agents. Interestingly, Pgp is also overexpressed in the endothelial cells of blood–brain barrier (BBB) restricting the entry of 98% small molecule drugs to the brain. The efficacy of Pgp is sensitive to any impairment of the membrane structure. A small increase of 2% in the membrane surface tension, which can be caused by a very low drug concentration, is enough to block the Pgp function. We demonstrate in this work by mathematical equations that the incorporation of drugs does increase the surface tension as expected, and the mechanism of endocytosis dissipates any increase in surface tension by augmenting the internalisation of membrane per unit of time, such that an increase in the surface tension of about 2% can be dissipated within only 4.5 s

On the meaning of averages in genome-wide association studies: What should come next?

Identifying the association between phenotypes and genotypes is the fundamental basis of genetic analyses. Although genomic technologies used to generate data have rapidly advanced within the last 20 years, the statistical models used in genome-wide associations studies (GWAS) to analyse the data are still predominantly based on the model developed by Fisher more than 100 years ago. The question is, does Fisher’s theory need to be replaced or improved, and if so, what should come next? The theory developed by Fisher was inspired by the field of probability. To make use of probability not only did Fisher have to assume valid a number of questionable hypotheses, but he also had to conceptually frame genotypephenotype associations in a specific way giving primordial importance to the notion of average. However, the ‘average’ in probability results from the notions of ‘imprecision’ or ‘ignorance’. After reviewing thehistorical emergence and societal impact of probability as a method, it is clear what is needed now is a new method acknowledging precision in measurements. That is, a method that does not rely on categorizing or binning data

The Anatomy, Histology and Physiology of the Healthy and Lame Equine Hoof

Satisfactory investigations of the equine foot appear to be limited by the histo-morphological complexity of internal hoof structures. Foot lameness is considered to be one of the most debilitating pathological disorders of the equine foot. In most species, foot lameness is traditionally linked to hoof deformity, and a set of molecular events have been defined in relation to the disease. So far, there is controversy regarding the incidence of foot lameness in horses, as it is unclear whether it is foot lameness that triggers hoof distortions or vice-versa. In order to develop a better understanding of foot lameness, we review both the healthy and lame foot anatomy, cell biology and vascularisation and using micro-computed tomography show new methods of visualising internal structures within the equine foot