Circulating fibrinogen is a prognostic and predictive biomarker in malignant pleural mesothelioma.

Background:To investigate the clinical utility of pretreatment plasma fibrinogen levels in malignant pleural mesothelioma (MPM) patients.Methods:A retrospective multicenter study was performed in histologically proven MPM patients. All fibrinogen levels were measured at the time of diagnosis and clinical data were retrospectively collected after approval of the corresponding ethics committees.Results:In total, 176 MPM patients (mean age: 63.5 years+/-10.4 years, 38 females and 138 males) were analysed. Most patients (n=154, 87.5%) had elevated (>/=390 mg dl-1) plasma fibrinogen levels. When patients were grouped by median fibrinogen, patients with low level (</=627 mg dl-1) had significantly longer overall survival (OS) (19.1 months, confidence interval (CI) 14.5-23.7 months) when compared with those with high level (OS 8.5; CI 6.2-10.7 months). In multivariate survival analyses, fibrinogen was found to be an independent prognostic factor (hazard ratio 1.81, CI 1.23-2.65). Most interestingly, fibrinogen (cutoff 75th percentile per 750 mg dl-1) proved to be a predictive biomarker indicating treatment benefit achieved by surgery within multimodality therapy (interaction term: P=0.034). Accordingly, only patients below the 75th percentile benefit from surgery within multimodality therapy (31.3 vs 5.3 months OS).Conclusions:Fibrinogen is a novel independent prognostic biomarker in MPM. Most importantly, fibrinogen predicted treatment benefit achieved by surgery within multimodality therapy.British Journal of Cancer advance online publication, 16 January 2014; doi:10.1038/bjc.2013.815 www.bjcancer.com

Tres medici, duo athei? The Physician as Atheist and the Medicalization of the Soul

Until recently, examinations of the ‘mind-body problem’ in historical context paid only cursory attention to its specifically medical dimension, if at all. At best, some ‘folk physiology’ was entertained, usually to laugh at it (the pineal gland, animal spirits). Conversely, historians of neuroscience or of artificial intelligence (Jeannerod 1985, Dupuy 2000) often present figures like La Mettrie as heroic early cases of ‘naturalization’, giving an experimental basis to materialism: their symmetrically inverse mistake is to take professions of medical authority too literally (although there are genuine cases where all of the above does coalesce – where ‘actors’ categories mysteriously transcend historiographic projections –, such as Hieronymus Gaub’s reflections on the ‘regimen of the mind’ in the mid-eighteenth century, or, more theoretically, Guillaume Lamy’s Epicurean-inflected Anatomical Discourses on the Soul, eighty years earlier). Contrary to the denial of the relevance of medicine in early modern philosophy, as regards issues such as the body-soul (then body-mind) relation among others, it seems patently difficult to separate medical theory, medically nourished philosophical speculation, and metaphysics. This is the case, whether in Descartes, Gaub, the ‘animist’ Georg-Ernest Stahl, or materialists such as Guillaume Lamy and La Mettrie: medicine, or rather ‘a certain idea of medicine’, is everywhere. Here I focus on the motif of a radical medicine – a medical precursor of the Radical Enlightenment (Israel 2001, 2006, 2007), symbolized negatively by the slogan, tres medici, duo athei, or ‘where there are three doctors, there are two atheists’, i.e. medicine as a basis for atheism. This theme runs through various works of medical or medico-theological propaganda: Thomas Browne’s 1643 De religio medici begins with Browne regretting rumors of doctors being atheists as the “general scandal of my Profession”; Germain de Bezançon’s 1677 Les médecins à la censure works hard at rebutting the saying, “Bon Physicien, mauvais chrétien.” But these are examples of the fear of a radical medicine – a medicine that denies the existence of an immortal soul, or even defends materialism and atheism. Are there positive statements of this doctrine? Indeed, attacks on it are much more common than statements identifying with it, like medical versions of natural theology in general. In fact, just as there were theologically motivated medical works, there were also medically motivated works of radical or heretical theology, like William Coward’s Second Thoughts on the Human Soul (Coward 1702, building on Overton 1644), which engaged in polemics concerning the nature of the soul – mortal or immortal? (Thomson 2008). Parallel to the mortalist trend, but flowing into a common genre of radical, medico-materialist texts (sometimes anonymous, such as L’Âme Matérielle, from the 1720s) are at least two other strands of radical medicine: a post-Cartesian focus on medicina mentis and the nature of the mind (Henricus Regius, Hieronymus Gaub, Antoine Le Camus), and an Epicurean medicine, in which mind and body are organismically united, with an additional hedonistic component, notably in Lamy, Mandeville and La Mettrie (Wright 1991, Wolfe and van Esveld 2014). The focus on a medicine of the mind (Corneanu, ms. 2013) is obviously connected to a ‘medicalization of the soul’: there was a body-soul problem in and for medicine, a sort of medicalized ‘pneumatology’. Radical medicine is located somewhere in between the early forms of ‘naturalization’ or ‘medicalization’ of the soul and the pose of scientific neutrality that is characteristic of early nineteenth-century medicine (as in Cabanis, Bichat or Bernard): it is a short-lived episode. I seek to reconstruct this intellectual figure, in which mortalist, post-Cartesian and Epicurean strands intersect and sometimes come together. I suggest that medically influenced materialism in the Radical Enlightenment (e.g. in the later French cases, La Mettrie, Ménuret and Diderot), is different from later, more experimentally focused and more quantitatively oriented forms of medical materialism, precisely because of its radical dimension. This radical medicine often insists on vitality, as opposed to “anatomie cadavérique”: it is vital and hedonistic, a medicine concerned with maintaining bodily pleasure.Until recently, examinations of the 'mind-body problem' in historical context paid only cursory attention to its specifically medical dimension, if at all. At best, some 'folk physiology' was entertained, usually to laugh at it (the pineal gland, animal spirits). Conversely, historians of neuroscience or of artificial intelligence (Jeannerod M, The brain machine. The development of neurophysiological thought, trans. D. Urion, Harvard University Press, Cambridge, 1985; Dupuy J-P, The mechanization of the mind: on the origins of cognitive science, trans. M.B. DeBevoise, Princeton University Press, Princeton, 2000) often present figures like La Mettrie as heroic early cases of 'naturalization', giving an experimental basis to materialism: their symmetrically inverse mistake is to take professions of medical authority too literally (although there are genuine cases where all of the above does coalesce where 'actors' categories mysteriously transcend historiographic projections -, such as Hieronymus Gaub's reflections on the 'regimen of the mind' in the mid-eighteenth century, or, more theoretically, Guillaume Lamy's Epicurean-inflected Anatomical Discourses on the Soul, eighty years earlier). Contrary to the denial of the relevance of medicine in early modern philosophy, as regards issues such as the body-soul (then body-mind) relation among others, it seems patently difficult to separate medical theory, medically nourished philosophical speculation, and metaphysics. This is the case, whether in Descartes, Gaub, the 'animist' Georg-Ernest Stahl, or materialists such as Guillaume Lamy and La Mettrie: medicine, or rather 'a certain idea of medicine', is everywhere.Here I focus on the motif of a radical medicine - a medical precursor of the Radical Enlightenment (Israel J, Radical enlightenment. Philosophy and the making of modernity, 1650-1750, Oxford University Press, Oxford, 2001; Israel J, Enlightenment contested. Oxford University Press, Oxford, 2006, Israel J, Enlightenment, radical enlightenment and the "medical revolution" of the late seventeenth and eighteenth centuries. In: Grell OP, Cunningham A (ed) Medicine and religion in enlightenment Europe. Ashgate, Aldershot, pp 5-28, 2007), symbolized negatively by the slogan, tres medici, duo athei, or 'where there are three doctors, there are two atheists', i.e. medicine as a basis for atheism. This theme runs through various works of medical or medico-theological propaganda: Thomas Browne's 1643 De religio medici begins with Browne regretting rumors of doctors being atheists as the "general scandal of my Profession"; Germain de Bezancon's 1677 Les medecins a la censure works hard at rebutting the saying, "Bon Physicien, mauvais chretien." But these are examples of the fear of a radical medicine - a medicine that denies the existence of an immortal soul, or even defends materialism and atheism. Are there positive statements of this doctrine? Indeed, attacks on it are much more common than statements identifying with it, like medical versions of natural theology in general.In fact, just as there were theologically motivated medical works, there were also medically motivated works of radical or heretical theology, like William Coward's Second Thoughts on the Human Soul (Coward W, Second thoughts on the human soul. R. Basset, London, 1702, building on Overton 1644), which engaged in polemics concerning the nature of the soul - mortal or immortal? (Thomson A, Bodies of thought: science, religion, and the soul in the early enlightenment. Oxford University Press, Oxford, 2008). Parallel to the mortalist trend, but flowing into a common genre of radical, medico-materialist texts (sometimes anonymous, such as L'Ame Materielle, from the 1720s) are at least two other strands of radical medicine: a post-Cartesian focus on medicina mentis and the nature of the mind (Henricus Regius, Hieronymus Gaub, Antoine Le Camus), and an Epicurean medicine, in which mind and body are organismically united, with an additional hedonistic component, notably in Lamy, Mandeville and La Mettrie (Wright JP, Locke, Willis, and the seventeenth-century epicurean soul. In: Osler MJ (ed) Atoms, Pneuma, and Tranquillity: Epicurean and stoic themes in European thought. Cambridge University Press, Cambridge, pp 239-258, 1991; Wolfe CT, van Esveld M, The material soul: strategies for naturalising the soul in an early modern epicurean context. In: Kambaskovic D (ed) Conjunctions: body, soul and mind from Plato to the enlightenment. Springer, Dordrecht, pp 371-421, 2014). The focus on a medicine of the mind (Corneanu, (ms. 2013), The care of the whole man: medicine and theology in the late renaissance, 2013) is obviously connected to a 'medicalization of the soul': there was a body-soul problem in and for medicine, a sort of medicalized 'pneumatology'. Radical medicine is located somewhere in between the early forms of 'naturalization' or 'medicalization' of the soul and the pose of scientific neutrality that is characteristic of early nineteenth-century medicine (as in Cabanis, Bichat or Bernard): it is a short-lived episode. I seek to reconstruct this intellectual figure, in which mortalist, post-Cartesian and Epicurean strands intersect and sometimes come together. I suggest that medically influenced materialism in the Radical Enlightenment (e.g. in the later French cases, La Mettrie, Menuret and Diderot), is different from later, more experimentally focused and more quantitatively oriented forms of medical materialism, precisely because of its radical dimension. This radical medicine often insists on vitality, as opposed to "anatomie cadaverique": it is vital and hedonistic, a medicine concerned with maintaining bodily pleasure

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Transcriptome analyses of immune tissues from three Japanese frogs (genus Rana ) reveals their utility in characterizing major histocompatibility complex class II

Abstract Background In Japan and East Asia, endemic frogs appear to be tolerant or not susceptible to chytridiomycosis, a deadly amphibian disease caused by the chytrid fungus Batrachochytridium dendrobatidis (Bd). Japanese frogs may have evolved mechanisms of immune resistance to pathogens such as Bd. This study characterizes immune genes expressed in various tissues of healthy Japanese Rana frogs. Results We generated transcriptome data sets of skin, spleen and blood from three adult Japanese Ranidae frogs (Japanese brown frog Rana japonica, the montane brown frog Rana ornativentris, and Tago’s brown frog Rana tagoi tagoi) as well as whole body of R. japonica and R. ornativentris tadpoles. From this, we identified tissue- and stage-specific differentially expressed genes; in particular, the spleen was most enriched for immune-related genes. A specific immune gene, major histocompatibility complex class IIB (MHC-IIB), was further characterized due to its role in pathogen recognition. We identified a total of 33 MHC-IIB variants from the three focal species (n = 7 individuals each), which displayed evolutionary signatures related to increased MHC variation, including balancing selection. Our supertyping analyses of MHC-IIB variants from Japanese frogs and previously studied frog species identified potential physiochemical properties of MHC-II that may be important for recognizing and binding chytrid-related antigens. Conclusions This is one of the first studies to generate transcriptomic resources for Japanese frogs, and contributes to further understanding the immunogenetic factors associated with resistance to infectious diseases in amphibians such as chytridiomycosis. Notably, MHC-IIB supertyping analyses identified unique functional properties of specific MHC-IIB alleles that may partially contribute to Bd resistance, and such properties provide a springboard for future experimental validation