Cancer: A matter of life cycle?

In the last decade, the concept of "cancer stem cells" has emerged, recognised by the fact that only a small fraction of tumour cells appears to retain the stem cell properties of self-renewal and unlimited proliferation. At the same time, it is well known that cancer is an age-related disease developing at the limit of proliferating cell senescence. The apparent need to link senescence and the capacity for self-renewal has lead some authors to suggest that cancers develop from amongst senescing stem cells. However, an alternative solution has recently been proffered by Sundaram M, Guernsey DL, Rajaraman MM, Rajaraman R [Neosis: a novel type of cell division in cancer. Cancer Biol Ther 2004;3:207-18], who suggest that stemness may be a transient, cyclic property afforded by de-polyploidisation of senescing cells which have undergone polyploidisation. In this mini-review, we attempt to reconcile both of these views by the idea that cycling polyploidy intermitting senescence and rejuvenation may be features of a life cycle analogous to the life cycles of certain unicellular organisms. Furthermore, we suggest that mitotic catastrophe may represent a mechanism through which the cell can switch from the usual mitotic cell-cycle to this evolutionarily conserved life cycle. Intriguingly, some most recent data suggest that cell senescence may be reversible and that stem cells are tolerant to polyploidy caused by genotoxic stress.     

Cadherins and the cortex: A matter of time?

Cell adhesion systems commonly operate in close partnership with the cytoskeleton. Adhesion receptors bind to the cortex and regulate its dynamics, organization and mechanics; conversely, the cytoskeleton influences aspects of adhesion, including strength, stability and ductility. In this review we consider recent advances in elucidating such cooperation, focusing on interactions between classical cadherins and actomyosin. The evidence presents an apparent paradox. Molecular mechanisms of mechanosensation by the cadherin-actin apparatus imply that adhesion strengthens under tension. However, this does not always translate to the broader setting of confluent tissues, where increases in fluctuations of tension can promote intercalation due to the shrinkage of adherens junctions. Emerging evidence suggests that understanding of timescales may be important in resolving this issue, but that further work is needed to understand the role of adhesive strengthening across scales.     

Does distance matter? Variations in alternative 3′ splicing regulation

Alternative splicing constitutes a major mechanism creating protein diversity in humans. This diversity can result from the alternative skipping of entire exons or by alternative selection of the 5′ or 3′ splice sites that define the exon boundaries. In this study, we analyze the sequence and evolutionary characteristics of alternative 3′ splice sites conserved between human and mouse genomes for distances ranging from 3 to 100 nucleotides. We show that alternative splicing events can be distinguished from constitutive splicing by a combination of properties which vary depending on the distance between the splice sites. Among the unique features of alternative 3′ splice sites, we observed an unexpectedly high occurrence of events in which a polypyrimidine tract was found to overlap the upstream splice site. By applying a machine-learning approach, we show that we can successfully discriminate true alternative 3′ splice sites from constitutive 3′ splice sites. Finally, we propose that the unique features of the intron flanking alternative splice sites are indicative of a regulatory mechanism that is involved in splice site selection. We postulate that the process of splice site selection is influenced by the distance between the competitive splice sites.     

A HAT for sleep?: Epigenetic regulation of sleep by Tip60 in Drosophila

Sleep disturbances are common in neurodegenerative diseases such as Alzheimer disease (AD). Unfortunately, how AD is mechanistically linked with interference of the body’s natural sleep rhythms remains unclear. Our recent findings provide insight into this question by demonstrating that sleep disruption associated with AD is driven by epigenetic changes mediated by the histone acetyltransferase (HAT) Tip60. In this study, we show that Tip60 functionally interacts with the AD associated amyloid precursor protein (APP) to regulate axonal growth of Drosophila small ventrolateral neuronal (sLNv) pacemaker cells, and their production of neuropeptide pigment dispersing factor (PDF) that stabilizes appropriate sleep-wake patterns in the fly. Loss of Tip60 HAT activity under APP neurodegenerative conditions causes decreased PDF production, retraction of the sLNv synaptic arbor required for PDF release and disruption of sleep-wake cycles in these flies. Remarkably, excess Tip60 in conjunction with APP fully rescues these sleep-wake disturbances by inducing overelaboration of the sLNv synaptic terminals and increasing PDF levels, supporting a neuroprotective role for Tip60 in these processes. Our studies highlight the importance of epigenetic based mechanisms underlying sleep disturbances in neurodegenerative diseases like AD.     

Intraspecific competition in tadpoles of Rana arvalis: does it matter in nature? A field experiment

Tadpole growth and development are easily affected by intraspecific competition in tank experiments, provided treatment density is sufficiently high. Is this a phenomenon also observed in nature? A pond was divided into four tadpole-proof sections. Each year for 8 years, all spawn laid by moorfrogs (Rana arvalis) in this pond was relocated to create relative spawn and tadpole densities of 1 : 4 : 1 : 4. No direct effect of the density manipulation on survival, tadpole size, and development and metamorph timing and size could be demonstrated. However, I also measured actual tadpole density during the time of development. Apart from the experimental density manipulation, this measure included effects of between-year variation in amount of spawn, natural tadpole mortality, and pond drying (which concentrated the tadpoles by decreasing the area of the pond sections). Actual density had limited but significant effects on tadpole size and development. I suggest that density regulation, acting on the tadpole stage, may be present in the population but was of less short-term importance than abiotic factors and, possibly, adult density regulation. Consequences of the findings for conservation are discussed.     

The occurrence of chloroplast peripheral reticulum in grasses: a matter of phylogeny or a matter of function?

The chloroplast peripheral reticulum (PR) is a structure of unknown function. Some authors postulated that it is a characteristic feature of C₄ plants, although it was reported from C₃ species as well. It is unknown whether the occurrence of PR follows a phylogenetic (it is found in clades containing C₄ species, regardless of the photosynthetic type) or functional (photosynthetic pathway dependent) pattern. Here, we present a phylogenetically controlled analysis of the occurrence, form and functional aspects of PR in grasses. The occurrence of the PR follows a functional and not a phylogenetic pattern. Its most elaborated form (PR type I) is a unique feature of C₄ species. Although PR was found in some of the studied C₃ grasses, it was always less developed than PR in the chloroplasts of Kranz mesophyll cells of C₄ species. The size of PR in C₄ plants was found to increase when the plants were grown under low light intensity. Additional observations, such as a negative correlation between PR size and chloroplast surface and PR occurrence in vicinity of mitochondria or plasmodesmata, suggest that PR may play some role in C₄ metabolism.     

Telomerase in T lymphocytes: use it and lose it?

The enzyme telomerase counteracts telomere loss in proliferating cells and extends their capacity for replication. The importance of telomerase is highlighted by the award of the 2006 Albert Lasker Prize for Basic Medical Research for its discovery. Malignant cells subvert telomerase induction to their advantage, and up-regulation of this enzyme confers these populations with unlimited proliferative potential with obvious detrimental consequences. However this enzyme is also essential for the lifelong maintenance of normal cell populations that have a high rate of turnover. Thymic involution in early adulthood dictates that memory T cell populations have to be maintained by continuous proliferation. This highlights the inherent paradox that telomerase down-regulation in T cells may protect against malignancy yet also lead to replicative exhaustion of repeatedly activated memory T cells. In this article, we review the data on telomerase regulation in T lymphocytes and the implications this has for the maintenance of T cell memory.     

Condensed tannins in the diets of primates: a matter of methods?

To understand the ways in which condensed tannins (CT) affect primate diet selection and nutritional status, correct measurements are essential. In the majority of studies of the CT contents of primate foods, a tannin source such as "quebracho" is used to standardize CT assays, but the CT in quebracho tannin may not be similar to those in the plants of interest. We investigated how the choice of standard to calibrate CT assays affects the estimation of CT in the diets of mountain gorillas (Gorilla beringei). We purified the CT from gorilla foods and compared the actual amounts of CT in the foods with estimates produced by using the quebracho tannin. When quebracho was used, the estimates of CT contents of gorilla foods were, on average, 3.6 times the actual content of CT so that the amounts in frequently eaten gorilla foods were substantially overestimated. The overestimation for a given plant could not be predicted reliably and the ranking of plants by tannin content differed according to the standard used. Our results demonstrate that accurate measurements of CT necessitate the use of tannins purified from the plant species of interest. A reevaluation of primatology studies using interspecific comparisons of tannin content will provide new insights into primate food selection and nutritional ecology.     

Diffusion of genetic testing in oncology: what criteria for regulation?

Does gene testing indicate a switch from an histopathological to a molecular approach of human diseases ? Disease management in oncology is already improved by gene testing, at least for some specific cancers. It is however necessary to distinguish the analysis of genes specific to the tumour which gives clues about the fate of the tumours, from those unique to the patients, which gives clues about the future of the person. For the latter so-called germline mutations, wide scale gene-default screening would put pressure on resource allocation from the health care systems of developed countries. Currently the cost of detecting of 700 genes in the whole French population would exceed the whole health budget of the country for the next 10 years. Even if we can anticipate a dramatic decrease in the unit cost of these genetic tests in the future, their diffusion should not be controlled exclusively by technological and market forces. In this paper, we propose to discuss four main parameters for regulating these genetic tests, using as an archetypal example their application to cancer prevention and treatment: (1) which specific cancer disease is targeted by the test (prevalence, incidence, likelihood of cure with current therapeutics, number of years of life potentially saved...); (2) what are the characteristics of the genes tested and which level of evidence is required about the predictive value of the test; (3) what are the size and characteristics of the population who will be offered the test, and (4) which process and public control are necessary before market approval of the test and reimbursement of related expenditures by health care insurance schemes.     

RIP2: A novel player in the regulation of keratinocyte proliferation and cutaneous wound repair?

We could recently demonstrate an important role of receptor interacting protein 4 (RIP4) in the regulation of keratinocyte differentiation. Now, we analyzed a potential role of the RIP4 homolog RIP2 in keratinocytes. Specifically, we demonstrate here that rip2 expression is induced by scratch-wounding and after the induction of differentiation in these cells. Furthermore, serum growth factors and cytokines can induce rip2, with TNF-α-dependent induction being dependent on p38 MAPK. In addition, we demonstrate that scratch-induced upregulation of rip2 expression is completely blocked by the steroid dexamethasone. Since we also show that RIP2 is an important player in the regulation of keratinocyte proliferation, these data suggest that inhibition of rip2 upregulation after wounding might contribute to the reduced and delayed wound re-epithelialization phenotype seen in glucocorticoid-treated patients.     

Targeting phosphoinositide-3-kinase pathway in biliary tract cancers: A remedial route?

Biliary tract cancers (BTC) are aggressive tumours with a low survival rate. At the advent of the genomic era, various genetic mutations in cell signalling pathways have been incriminated in carcinogenesis. Genomic analysis studies have connected main components of the phosphoinositide-3-kinase (PI3K) signalling pathway to BTC. PI3K pathway playing a central role in cell signalling and being deregulated in various tumours has been studied as a target for chemotherapy. Novel compounds have also been identified in preclinical trials that specifically target the PI3K pathway in BTCs, but these studies have not accelerated to clinical use. These novel compounds can be examined in upcoming studies to validate them as potential therapeutic agents, as further research is required to combat the growing need for adjuvant chemotherapy to successfully battle this tumour type. Furthermore, these molecules could also be used along with gemcitabine, cisplatin and 5-fluorouracil to improve sensitivity of the tumour tissue to chemotherapy. This review focuses on the basics of PI3K signalling, genetic alterations of this pathway in BTCs and current advancement in targeting this pathway in BTCs. It emphasizes the need for gene-based drug screening in BTC. It may reveal various novel targets and drugs for amelioration of survival in patients with BTC and serve as a stepping stone for further research.     

Distance-to-target weighting in LCA—A matter of perspective

The International Journal of Life Cycle Assessment - Weighting can enable valuable support for decision-makers when interpreting life cycle assessment (LCA) results. Distance-to-target (DtT)...     

Osmotic regulation of starch synthesis in potato tubers?

Using potato (Solanum tuberosum L.) tuber discs incubated in a range of mannitol concentrations it has been demonstrated that both sucrose uptake and the conversion of sucrose to starch are sensitive to the osmotic environment of the storage cells. Starch synthesis was optimised at 300 mM but declined sharply at both lower and higher osmotic concentrations. The decline in starch synthesis on either side of optimum was not proportional to the change in mannitol concentration, indicating different inhibitory mechanisms under low and high osmotica. The fraction of the total sucrose converted to starch i.e. the partitioning between sucrose and starch, was also influenced by osmotic environment. The amount of soluble material taken up by the storage cells, but not converted to starch, was maintained under mannitol concentrations (300–400 mM) which inhibited starch synthesis, indicating that sucrose uptake continued during declining starch synthesis. At mannitol concentrations above 400 mM, sucrose uptake was greatly enhanced but no significant change in starch synthesis occurred.     

Are prostaglandins involved in the regulation of coronary blood flow? A review of the evidence

Prostaglandins (PG's) fulfil most of the criteria required for the metabolic "coupler" linking increases in myocardial activity with increases in coronary blood flow. They are synthesized by the heart and coronary vessels, profoundly modify coronary blood flow in low concentrations and are released under conditions of hypoxia and myocardial ischaemia. Studies with inhibitors of PG-synthetase however provide no firm evidence that PG's are involved in the physiological regulation of myocardial blood flow. These studies are reviewed.     

Lead-phase and red-stripe color morphs of red-backed salamanders Plethodon cinereus differ in hematological stress indices: A consequence of differential predation pressure?

Throughout the animal kingdom there are species that have two or more phenotypic forms or 'morphs', and many of these are amphibians. In North America, the red-backed salamander Plethodon cinereus can have either a red dorsal stripe or no dorsal stripe (lead-phase form), and evidence to date indicates the lead-phase form incurs a greater number of attacks from predators. In a recent collection of 51 P. Cinereus, blood smears of both color morphs (35 red-stripe, 16 lead-phase) were examined to obtain numbers of circulating leukocytes (via light microscopy), which can be used to indirectly estimate levels of stress hormones in vertebrates via a 'hematological stress index', which is the ratio between the number of two leukocyte types (neutrophils and lymphoeytes). Our results showed that lead-phase salamanders tended to have greater numbers of circulating neutrophils and lower numbers of circulating iymphocytes than red-stripe morphs, leading to higher average neutrophil-lymphocyte ratios in lead-phase individuals. Since the salamanders were held (refrigerated) for 7 days before sampling, we cannot be certain if this effect is a stress reaction to the captivity or the normal level for this morph. However comparison with two sets of related salamanders that were captured and sampled immediately indicates the red-stripe salamanders were either not stressed from the captivity at all, or their white blood cell distributions had returned to normal after 7 days of captivity. Taken together, our results indicate that lead-phase forms of P. Cinereus have higher stress levels than the red-stripe forms, which may be a consequence of their higher exposure to, and/or attacks from, predators. They may also indicate that the lead-phase form is less-suited to captivity than the red-stripe form of this species.