Mechanisms and in vivo functions of contact inhibition of locomotion

Contact inhibition of locomotion (CIL) is a process whereby a cell ceases motility or changes its trajectory upon collision with another cell. CIL was initially characterized more than half a century ago and became a widely studied model system to understand how cells migrate and dynamically interact. Although CIL fell from interest for several decades, the scientific community has recently rediscovered this process. We are now beginning to understand the precise steps of this complex behaviour and to elucidate its regulatory components, including receptors, polarity proteins and cytoskeletal elements. Furthermore, this process is no longer just in vitro phenomenology; we now know from several different in vivo models that CIL is essential for embryogenesis and in governing behaviours such as cell dispersion, boundary formation and collective cell migration. In addition, changes in CIL responses have been associated with other physiological processes, such as cancer cell dissemination during metastasis

Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples

Spinal Pathologies in Fossil Hominins

Back disorders are often conjectured to be a trade-off to the evolution of upright bipedalism. Yet, this association has not been substantiated so far. This chapter presents an overview of the known spinal pathologies in the hominin fossil record. Apart from a benign primary bone tumour in MH1 (Australopithecus sediba) and developmental defects in the Middle Pleistocene Pelvis 1 individual from Sima de los Huesos, the Kebara 2 Neanderthal and two individuals from El Sidrón, they include pathologies related to the biomechanical failure of the growing spine and degenerative osteoarthritis. While the latter is particularly common in Neanderthals, biomechanical failure of the growing spine seems to have affected all hominin species. This includes spondylolisthesis in the Pelvis 1 individual from Sima de los Huesos, traumatic juvenile disc herniation in KNM-WT 15000 (Homo erectus), anterior disc herniation (limbus vertebra) in StW 431 (A. africanus), and Scheuermann’s disease in A.L. 288-1 (A. afarensis) and three isolated thoracic vertebrae from Hadar, Sts 14 (A. africanus), SKX 3342 (Paranthropus robustus), the Pelvis 1 individual from Sima de los Huesos and perhaps Kebara 2 and Shanidar 3. Juvenile disc herniation, traumatic anterior disc herniation and Scheuermann’s disease all involve displacement of disc material and have a higher incidence following strains and trauma to the spine during the increased vulnerability phase of the pubertal growth spurt. The remarkably high prevalence of this kind of disorders in our ancestors might suggest that our spine has become less vulnerable during the course of human evolution

Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney

With the prevalence of end-stage renal disease rising 8% per annum globally, there is an urgent need for renal regenerative strategies. The kidney is a mesodermal organ that differentiates from the intermediate mesoderm (IM) through the formation of a ureteric bud (UB) and the interaction between this bud and the adjacent IM-derived metanephric mesenchyme (MM). The nephrons arise from a nephron progenitor population derived from the MM (ref. ). The IM itself is derived from the posterior primitive streak. Although the developmental origin of the kidney is well understood, nephron formation in the human kidney is completed before birth. Hence, there is no postnatal stem cell able to replace lost nephrons. In this study, we have successfully directed the differentiation of human embryonic stem cells (hESCs) through posterior primitive streak and IM under fully chemically defined monolayer culture conditions using growth factors used during normal embryogenesis. This differentiation protocol results in the synchronous induction of UB and MM that forms a self-organizing structure, including nephron formation, in vitro. Such hESC-derived components show broad renal potential ex vivo, illustrating the potential for pluripotent-stem-cell-based renal regeneration