A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis

Extracellular matrix interactions have essential roles in normal physiology and many pathological processes. Although the importance of extracellular matrix interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Here we report a novel-screening platform capable of measuring phenotypic responses to combinations of extracellular matrix molecules. Using a genetic mouse model of lung adenocarcinoma, we measure the extracellular matrix-dependent adhesion of tumour-derived cells. Hierarchical clustering of the adhesion profiles differentiates metastatic cell lines from primary tumour lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8 or laminin. We show that these molecules correlate with human disease and that their interactions are mediated in part by α3β1 integrin. Thus, our platform allowed us to interrogate interactions between metastatic cells and their microenvironments, and identified extracellular matrix and integrin interactions that could serve as therapeutic targets.National Institutes of Health (U.S.) (Grant K99-CA151968)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service AwardStand Up To Cancer (SU2C/AACR)David H. Koch Institute for Integrative Cancer Research at MIT (CTC Project)Harvard Stem Cell Institute (SG-0046-08-00)National Cancer Center (Postdoctoral Fellowship)National Cancer Institute (U.S.) (U54CA126515)National Cancer Institute (U.S.) (U54CA112967)Howard Hughes Medical InstituteMassachusetts Institute of Technology. Ludwig Center for Molecular Oncolog

Chinese beliefs in luck are linked to gambling problems via strengthened cognitive biases:A mediation test

10.1007/s10899-017-9690-6Journal of gambling studies3341325-133

Preference for novel faces in male infant monkeys predicts cerebrospinal fluid oxytocin concentrations later in life

The ability to recognize individuals is a critical skill acquired early in life for group living species. In primates, individual recognition occurs predominantly through face discrimination. Despite the essential adaptive value of this ability, robust individual differences in conspecific face recognition exist, yet its associated biology remains unknown. Although pharmacological administration of oxytocin has implicated this neuropeptide in face perception and social memory, no prior research has tested the relationship between individual differences in face recognition and endogenous oxytocin concentrations. Here we show in a male rhesus monkey cohort (N = 60) that infant performance in a task used to determine face recognition ability (specifically, the ability of animals to show a preference for a novel face) robustly predicts cerebrospinal fluid, but not blood, oxytocin concentrations up to five years after behavioural assessment. These results argue that central oxytocin biology may be related to individual face perceptual abilities necessary for group living, and that these differences are stable traits

Iliotibial band release as an adjunct to the surgical management of patellar stress fracture in the athlete: a case report and review of the literature

Stress fracture of the patella is rare. In this report, a case of patellar stress fracture occurring in an amateur athlete is presented, and an operative adjunct to the surgical management of this condition is proposed

Large-scale integration of cancer microarray data identifies a robust common cancer signature

<p>Abstract</p> <p>Background</p> <p>There is a continuing need to develop molecular diagnostic tools which complement histopathologic examination to increase the accuracy of cancer diagnosis. DNA microarrays provide a means for measuring gene expression signatures which can then be used as components of genomic-based diagnostic tests to determine the presence of cancer.</p> <p>Results</p> <p>In this study, we collect and integrate ~ 1500 microarray gene expression profiles from 26 published cancer data sets across 21 major human cancer types. We then apply a statistical method, referred to as the <it>T</it>op-<it>S</it>coring <it>P</it>air of <it>G</it>roups (TSPG) classifier, and a repeated random sampling strategy to the integrated training data sets and identify a common cancer signature consisting of 46 genes. These 46 genes are naturally divided into two distinct groups; those in one group are typically expressed less than those in the other group for cancer tissues. Given a new expression profile, the classifier discriminates cancer from normal tissues by ranking the expression values of the 46 genes in the cancer signature and comparing the average ranks of the two groups. This signature is then validated by applying this decision rule to independent test data.</p> <p>Conclusion</p> <p>By combining the TSPG method and repeated random sampling, a robust common cancer signature has been identified from large-scale microarray data integration. Upon further validation, this signature may be useful as a robust and objective diagnostic test for cancer.</p

Modeling CICR in rat ventricular myocytes: voltage clamp studies

<p>Abstract</p> <p>Background</p> <p>The past thirty-five years have seen an intense search for the molecular mechanisms underlying calcium-induced calcium-release (CICR) in cardiac myocytes, with voltage clamp (VC) studies being the leading tool employed. Several VC protocols including lowering of extracellular calcium to affect <it>Ca</it>²⁺loading of the sarcoplasmic reticulum (SR), and administration of blockers caffeine and thapsigargin have been utilized to probe the phenomena surrounding SR <it>Ca</it>²⁺release. Here, we develop a deterministic mathematical model of a rat ventricular myocyte under VC conditions, to better understand mechanisms underlying the response of an isolated cell to calcium perturbation. Motivation for the study was to pinpoint key control variables influencing CICR and examine the role of CICR in the context of a physiological control system regulating cytosolic <it>Ca</it>²⁺concentration ([<it>Ca</it>²⁺]<it>_myo</it>).</p> <p>Methods</p> <p>The cell model consists of an electrical-equivalent model for the cell membrane and a fluid-compartment model describing the flux of ionic species between the extracellular and several intracellular compartments (cell cytosol, SR and the dyadic coupling unit (DCU), in which resides the mechanistic basis of CICR). The DCU is described as a controller-actuator mechanism, internally stabilized by negative feedback control of the unit's two diametrically-opposed <it>Ca</it>²⁺channels (trigger-channel and release-channel). It releases <it>Ca</it>²⁺flux into the cyto-plasm and is in turn enclosed within a negative feedback loop involving the SERCA pump, regulating[<it>Ca</it>²⁺]<it>_myo</it>.</p> <p>Results</p> <p>Our model reproduces measured VC data published by several laboratories, and generates graded <it>Ca</it>²⁺release at high <it>Ca</it>²⁺gain in a homeostatically-controlled environment where [<it>Ca</it>²⁺]<it>_myo</it>is precisely regulated. We elucidate the importance of the DCU elements in this process, particularly the role of the ryanodine receptor in controlling SR <it>Ca</it>²⁺release, its activation by trigger <it>Ca</it>²⁺, and its refractory characteristics mediated by the luminal SR <it>Ca</it>²⁺sensor. Proper functioning of the DCU, sodium-calcium exchangers and SERCA pump are important in achieving negative feedback control and hence <it>Ca</it>²⁺homeostasis.</p> <p>Conclusions</p> <p>We examine the role of the above <it>Ca</it>²⁺regulating mechanisms in handling various types of induced disturbances in <it>Ca</it>²⁺levels by quantifying cellular <it>Ca</it>²⁺balance. Our model provides biophysically-based explanations of phenomena associated with CICR generating useful and testable hypotheses.</p

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond.

Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation of ubiquitinated proteins and autophagy, a regulated process of ‘self-eating’ where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by toll-like receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses. Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis

Acute oxytocin improves memory and gaze following in male but not female nursery-reared infant macaques

Rationale: Exogenous oxytocin administration is widely reported to improve social cognition in human and nonhuman primate adults. Risk factors of impaired social cognition, however, emerge in infancy. Early interventions—when plasticity is greatest—are critical to reverse negative outcomes. Objective: We tested the hypothesis that oxytocin may exert similar positive effects on infant social cognition, as in adults. To test this idea, we assessed the effectiveness of acute, aerosolized oxytocin on two foundational social cognitive skills: working memory (i.e., ability to briefly hold and process information) and social gaze (i.e., tracking the direction of others’ gaze) in 1-month-old nursery-reared macaque monkeys (Macaca mulatta). We did not predict sex differences, but we included sex as a factor in our analyses to test whether our effects would be generalizable across both males and females. Results: In a double-blind, placebo-controlled design, we found that females were more socially skilled at baseline compared to males, and that oxytocin improved working memory and gaze following, but only in males. Conclusions: These sex differences, while unexpected, may be due to interactions with gonadal steroids and may be relevant to sexually dimorphic disorders of social cognition, such as male-biased autism spectrum disorder, for which oxytocin has been proposed as a potential treatment. In sum, we report the first evidence that oxytocin may influence primate infant cognitive abilities. Moreover, these behavioral effects appear sexually dimorphic, highlighting the importance of considering sex differences. Oxytocin effects observed in one sex may not be generalizable to the other sex