mTCTScan: a comprehensive platform for annotation and prioritization of mutations affecting drug sensitivity in cancers

Cancer therapies have experienced rapid progress in recent years, with a number of novel small-molecule kinase inhibitors and monoclonal antibodies now being widely used to treat various types of human cancers. During cancer treatments, mutations can have important effects on drug sensitivity. However, the relationship between tumor genomic profiles and the effectiveness of cancer drugs remains elusive. We introduce Mutation To Cancer Therapy Scan (mTCTScan) web server (http://jjwanglab.org/mTCTScan) that can systematically analyze mutations affecting cancer drug sensitivity based on individual genomic profiles. The platform was developed by leveraging the latest knowledge on mutation-cancer drug sensitivity associations and the results from large-scale chemical screening using human cancer cell lines. Using an evidence-based scoring scheme based on current integrative evidences, mTCTScan is able to prioritize mutations according to their associations with cancer drugs and preclinical compounds. It can also show related drugs/compounds with sensitivity classification by considering the context of the entire genomic profile. In addition, mTCTScan incorporates comprehensive filtering functions and cancer-related annotations to better interpret mutation effects and their association with cancer drugs. This platform will greatly benefit both researchers and clinicians for interrogating mechanisms of mutation-dependent drug response, which will have a significant impact on cancer precision medicine.published_or_final_versio

A new modality of treatment for non-united fracture of the humerus in a patient with osteopetrosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Osteopetrosis introduces technical limitations to the traditional treatment of fracture management that may be minimised with specific pre-operative planning. Extreme care and caution are required when drilling, reaming, or inserting implants in patients with osteopetrosis. Caution must be exercised throughout the postoperative course when these patients are at greatest risk for device failure or further injury.</p> <p>Case presentation</p> <p>We present our experience of treating such a fracture where a patient presented with a non-united fracture of the humerus. The bone was already osteoporotic. We successfully used a new technique which has not been described in the literature before. This included the use of a high-speed drill to prepare the bone for screw fixation. Bone healing was augmented with bone morphogenic protein.</p> <p>Conclusion</p> <p>This technique can give invaluable experience to surgeons who are involved in treating these types of fracture.</p

Stromal SPOCK1 supports invasive pancreatic cancer growth

This research was supported by a KWF Dutch Cancer Society Research Project Grant to MFB and HWL (UVA 2012-5607 and UVA 2013- 5932), and continuous AMC Foundation support

Time and Origin of Cichlid Colonization of the Lower Congo Rapids

Most freshwater diversity is arguably located in networks of rivers and streams, but, in contrast to lacustrine systems riverine radiations, are largely understudied. The extensive rapids of the lower Congo River is one of the few river stretches inhabited by a locally endemic cichlid species flock as well as several species pairs, for which we provide evidence that they have radiated in situ. We use more that 2,000 AFLP markers as well as multilocus sequence datasets to reconstruct their origin, phylogenetic history, as well as the timing of colonization and speciation of two Lower Congo cichlid genera, Steatocranus and Nanochromis. Based on a representative taxon sampling and well resolved phylogenetic hypotheses we demonstrate that a high level of riverine diversity originated in the lower Congo within about 5 mya, which is concordant with age estimates for the hydrological origin of the modern lower Congo River. A spatial genetic structure is present in all widely distributed lineages corresponding to a trisection of the lower Congo River into major biogeographic areas, each with locally endemic species assemblages. With the present study, we provide a phylogenetic framework for a complex system that may serve as a link between African riverine cichlid diversity and the megadiverse cichlid radiations of the East African lakes. Beyond this we give for the first time a biologically estimated age for the origin of the lower Congo River rapids, one of the most extreme freshwater habitats on earth

A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer

Brain metastases represent an important cause of morbidity in patients with lung cancer and are associated with a mean survival of less than 6 months. Thus, new regimens improving the outcome of these patients are urgently needed. On the basis of promising data raised in a phase I/II trial, we initiated an open, randomised, prospective, multicentric phase III trial, comparing whole brain radiation therapy (WBRT; 20 × 2 Gy) alone with WBRT+topotecan (RCT; 0.4 mg m−2 day−1 × 20). A total of 320 patients with CNS-metastases due to SCLC or NSCLC were projected. The primary end point was overall survival, whereas second end points were local response and progression-free survival. However, until the cutoff date of study completion (i.e., a study duration of 34 months), only a total of 96 (RCT:47, WBRT:49) patients had been recruited, and so an analysis was performed at that time point. Although the numbers of grade 3/4 non-haematological toxicities (besides alopecia 115 (RCT/WBRT: 55 out of 60) were evenly distributed, the 25 haematological events occurred mainly in the combined treatment arm (24 out of 1). Local response, evaluated 2 weeks after treatment, was assessable in 44 (RCT/WBRT: 23 out of 21) patients, showing CR in eight (3 out of 5), PR in 17 (11 out of 6), SD in 14 (8 out of 6) and PD in five (1 out of 4) patients (all differences n.s.). Neither OAS (RCT/WBRT: median (days)): 87 out of 95, range 3–752/4–433; HR 1.32; 95% CI (0.83; 2.10)) nor PFS (median (days)): 71 out of 66, range, 3–399/4–228; HR 1.28, 95% CI (0.73; 2.43) differed significantly. On the basis of these results and the slow recruitment, a continuation of the study did not seem reasonable. The available data show no significant advantage for concurrent radiochemotherapy for patients with lung cancer; however, the recruited number of patients is too low to exhibit a small advantage of combined treatment

Simultaneous intra/extravascular administration of antiproliferative agents as a new strategy to inhibit restenosis: The peak of reactive cell proliferation as a hallmark for the duration of the treatment

BACKGROUND: Strictly intravascular approaches for the treatment of postangioplasty restenosis are effective in the intima and the inner parts of the media but may be insufficient to control redundant pathways in the more outer parts of the media and the adventitia. An inverse situation may occur subsequently to a strictly extravascular approach, like the recently suggested pericardial approach in pigs. We hypothesized that simultaneous intra/extravascular administration of anti-restenotic agents inhibits restenosis by blocking all stimulatory pathways in the entire arterial wall. METHODS: Fresh hearts of 25 domestic pigs were obtained from a local slaughterhouse. Left anterior descending coronary arteries (LAD) were harvested, cut into cylindric 5 mm segments, and cultured as ex vivo porcine organ cultures (POCs). After 9 bar ballooning simultaneous intra/extravascular administration of high dose diltiazem (50 μg/mL) was carried out for a period of 1, 2, 3, 4, 5, 6, and 7 days. At day 7 and 28 proliferative activity (BrdU), neointimal thickening, and staining against smooth muscle α-actin and vWF was analysed. RESULTS: 7 days after ballooning administration of diltiazem for 4, 5, 6, and 7 days inhibited reactive cell proliferation by more than 50% (n.s.) as compared to control, 28 days after ballooning administration for 6 and 7 days inhibited neointimal thickening by more than 75% (p < 0.05). Simultaneous intra/extravascular administration of high dose diltiazem did not affect the expression of vWF in endothelial cells or smooth muscle α-actin in smooth muscle cells. CONCLUSIONS: Simultaneous intra/extravascular administration of high dose diltiazem (50 μg/mL) has to be maintained for at least 6 days to achieve a significant inhibition of neointimal thickening. The data demonstrate the importance of the maximal reactive cell proliferation (= day 7 in the POC-model) for the calculation of the duration of the treatment period

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

Comparison of single versus fractionated dose of stereotactic radiotherapy for salvaging local failures of nasopharyngeal carcinoma: a matched-cohort analysis

BACKGROUND: Local failure is an important cause of morbidity and mortality in nasopharyngeal carcinoma (NPC). Although surgery or brachytherapy may be feasible in selected cases, most patients with local failure require external beam re-irradiation. Stereotactic radiation using single or multiple fractions have been employed in re-irradiation of NPC, but the optimal fractionation scheme and dose are not clear. METHODS: Records of 125 NPC patients who received salvage stereotactic radiation were reviewed. A matched-pair design was used to select patients with similar prognostic factors who received stereotactic re-irradiation using single fraction (SRS) or multiple fractions (SRM). Eighty-six patients were selected with equal number in SRS and SRM groups. All patients were individually matched for failure type (persistent or recurrent), rT stage (rT1-2 or rT3-4), and tumor volume (5-10 cc, or >10 cc). Median dose was 12.5 Gy in single fraction by SRS, and 34 Gy in 2-6 fractions by SRM. RESULTS: Local control rate was better in SRM group although overall survival rates were similar. One- and 3-year local failure-free rates were 70% and 51% in SRS group compared with 91% and 83% in SRM group (p = 0.003). One- and 3-year overall survival rates were 98% and 66% in SRS group compared with 78% and 61% in SRM group (p = 0.31). The differences in local control were mainly observed in recurrent or rT2-4 disease. Incidence of severe late complications was 33% in SRS group vs. 21% in SRM group, including brain necrosis (16% vs. 12%) and hemorrhage (5% vs. 2%). CONCLUSION: Our study showed that SRM was superior to SRS in salvaging local failures of NPC, especially in the treatment of recurrent and rT2-4 disease. In patient with local failure of NPC suitable for stereotactic re-irradiation, use of fractionated treatment is preferred.link_to_subscribed_fulltex