Targeting microRNA to improve diagnostic and therapeutic approaches for malignant mesothelioma

Malignant mesothelioma is an aggressive and often fatal cancer associated with asbestos exposure. The disease originates in the mesothelial lining of the serosal cavities, most commonly affecting the pleura. Survival rates are low as diagnosis often occurs at an advanced stage and current treatments are limited. Identifying new diagnostic and therapeutic targets for mesothelioma remains a priority, particularly for the new wave of victims exposed to asbestos through do-it-yourself renovations and in countries where asbestos is still mined and used. Recent advances have demonstrated a biological role for the small but powerful gene regulators microRNA (miRNA) in mesothelioma. A number of potential therapeutic targets have been identified. MiRNA have also become popular as potential biomarkers for mesothelioma due to their stable expression in bodily fluid and tissues. In this review, we highlight the current challenges associated with the diagnosis and treatment of mesothelioma and discuss how targeting miRNA may improve diagnostic, prognostic and therapeutic approaches

Opposing actions of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) in regulating microtubule stabilization during cardiac hypertrophy

Excessive proliferation and stabilization of the microtubule (MT) array in cardiac myocytes can accompany pathological cardiac hypertrophy, but the molecular control of these changes remains poorly characterized. In this study, we examined MT stabilization in two independent murine models of heart failure and revealed increases in the levels of post-translationally modified stable MTs, which were closely associated with STAT3 activation. To explore the molecular signaling events contributing to control of the cardiac MT network, we stimulated cardiac myocytes with an a-adrenergic agonist phenylephrine (PE), and observed increased tubulin content without changes in detyrosinated (glutubulin) stable MT’s. In contrast, the hypertrophic interleukin-6 (IL6) family cytokines increased both the glu-tubulin content and glu-MT density. When we examined a role for ERK in regulating cardiac MTs, we showed that the MEK/ERK-inhibitor U0126 increased glu-MT density in either control cardiac myocytes or following exposure to hypertrophic agents. Conversely, expression of an activated MEK1 mutant reduced glu-tubulin levels. Thus, ERK signaling antagonizes stabilization of the cardiac MT array. In contrast, inhibiting either JAK2 with AG490, or STAT3 signaling with Stattic or siRNA knockdown, blocked cytokine-stimulated increases in glu-MT density. Furthermore, the expression of a constitutively active STAT3 mutant triggered increased glu-MT density in the absence of hypertrophic stimulation. Thus, STAT3 activation contributes substantially to cytokine-stimulated glu-MT changes. Taken together, our results highlight the opposing actions of STAT3 and ERK pathways in the regulation of MT changes associated with cardiac myocyte hypertrophy

Food Sharing across Borders

Evolutionary models consider hunting and food sharing to be milestones that paved the way from primate to human societies. Because fossil evidence is scarce, hominoid primates serve as referential models to assess our common ancestors’ capacity in terms of communal use of resources, food sharing, and other forms of cooperation. Whereas chimpanzees form male-male bonds exhibiting resource-defense polygyny with intolerance and aggression toward nonresidents, bonobos form male-female and female-female bonds resulting in relaxed relations with neighboring groups. Here we report the first known case of meat sharing between members of two bonobo communities, revealing a new dimension of social tolerance in this species. This observation testifies to the behavioral plasticity that exists in the two Pan species and contributes to scenarios concerning the traits of the last common ancestor of Pan and Homo. It also contributes to the discussion of physiological triggers of in-group/out-group behavior and allows reconsideration of the emergence of social norms in prehuman societies

The evolution of the upright posture and gait—a review and a new synthesis

During the last century, approximately 30 hypotheses have been constructed to explain the evolution of the human upright posture and locomotion. The most important and recent ones are discussed here. Meanwhile, it has been established that all main hypotheses published until the last decade of the past century are outdated, at least with respect to some of their main ideas: Firstly, they were focused on only one cause for the evolution of bipedality, whereas the evolutionary process was much more complex. Secondly, they were all placed into a savannah scenario. During the 1990s, the fossil record allowed the reconstruction of emerging bipedalism more precisely in a forested habitat (e.g., as reported by Clarke and Tobias (Science 269:521–524, 1995) and WoldeGabriel et al. (Nature 412:175–178, 2001)). Moreover, the fossil remains revealed increasing evidence that this part of human evolution took place in a more humid environment than previously assumed. The Amphibian Generalist Theory, presented first in the year 2000, suggests that bipedalism began in a wooded habitat. The forests were not far from a shore, where our early ancestor, along with its arboreal habits, walked and waded in shallow water finding rich food with little investment. In contrast to all other theories, wading behaviour not only triggers an upright posture, but also forces the individual to maintain this position and to walk bipedally. So far, this is the only scenario suitable to overcome the considerable anatomical and functional threshold from quadrupedalism to bipedalism. This is consistent with paleoanthropological findings and with functional anatomy as well as with energetic calculations, and not least, with evolutionary psychology. The new synthesis presented here is able to harmonise many of the hitherto competing theories

Strategies for the Use of Fallback Foods in Apes

Researchers have suggested that fallback foods (FBFs) shape primate food processing adaptations, whereas preferred foods drive harvesting adaptations, and that the dietary importance of FBFs is central in determining the expression of a variety of traits. We examine these hypotheses in extant apes. First, we compare the nature and dietary importance of FBFs used by each taxon. FBF importance appears greatest in gorillas, followed by chimpanzees and siamangs, and least in orangutans and gibbons (bonobos are difficult to place). Next, we compare 20 traits among taxa to assess whether the relative expression of traits expected for consumption of FBFs matches their observed dietary importance. Trait manifestation generally conforms to predictions based on dietary importance of FBFs. However, some departures from predictions exist, particularly for orang-utans, which express relatively more food harvesting and processing traits predicted for consuming large amounts of FBFs than expected based on observed dietary importance. This is probably due to the chemical, mechanical, and phenological properties of the apes’ main FBFs, in particular high importance of figs for chimpanzees and hylobatids, compared to use of bark and leaves—plus figs in at least some Sumatran populations—by orang-utans. This may have permitted more specialized harvesting adaptations in chimpanzees and hylobatids, and required enhanced processing adaptations in orang-utans. Possible intercontinental differences in the availability and quality of preferred and FBFs may also be important. Our analysis supports previous hypotheses suggesting a critical influence of the dietary importance and quality of FBFs on ape ecology and, consequently, evolution

P018 SOCS1 and 3 expression is determined by fibroblast phenotype in IPF

STAT3 signaling is implicated in IPF pathogenesis but the mechanisms regulating STAT3 expression and function are unknown. SOCS1 and SOCS3 inhibit STAT3 signaling and reduced SOCS1 levels have been reported in IPF lung fibroblasts and is also associated with increased collagen production. Using IPF and control lung fibroblasts and tissue, the mechanisms underlying SOCS1 downregulation in IPF were investigated. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed and a trend towards reduced SOCS3 demonstrated. However there was no difference in their ability to phosphorylate STAT1 or STAT3 or increase SOCS3 expression following IL-6 stimulation or to phosphorylate STAT1 and increase SOCS1 mRNA after IFNγ treatment. Methylation of SOCS1 in control and IPF fibroblasts was low and unaffected by 5’-aza-2’-deoxycytidine’ treatment. SOCS1 is a target of microRNA (miR)-155 and although the miR155 level was increased in IPF tissue, expression was reduced in IPF fibroblasts. Therefore, SOCS1 is not regulated by mRNA stability, SOCS1 gene methylation or miR155 in these cells. Interestingly, reanalysis of cells based on collagen (COLIA1) and alpha smooth muscle actin (ACTA2) mRNA levels showed that cells classified as fibrotic (high COLIA1 and ACTA2), actually had increased SOCS1 and SOCS3 mRNA levels, opposite to the original findings when grouped based on clinical diagnosis. In conclusion, these findings question the role of SOCS1 in driving lung fibrosis in IPF, and demonstrate that phenotypic characterization, in addition to clinical diagnosis will provide a more complete picture of the differential behaviour between IPF and normal lung fibroblasts