Activated PPARγ Targets Surface and Intracellular Signals That Inhibit the Proliferation of Lung Carcinoma Cells

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Their discovery in the 1990s provided insights into the cellular mechanisms involved in the control of energy homeostasis, the regulation of cell differentiation, proliferation, and apoptosis, and the modulation of important biological and pathological processes related to inflammation and cancer biology, among others. Since then, PPARs have become an exciting target for the development of therapies directed at many disorders including cancer. PPARs are expressed in many tumors including lung cancer, and their function has been linked to the process of carcinogenesis. Consequently, intense research is being conducted in this area with the hope of discovering new PPAR-related therapeutic targets for the treatment of lung cancer. This review summarizes the research being conducted in this area, and focuses on the mechanisms by which a member of this family (PPARγ) is believed to affect lung tumor cell biology

Rosiglitazone, an Agonist of PPARγ, Inhibits Non-Small Cell Carcinoma Cell Proliferation In Part through Activation of Tumor Sclerosis Complex-2

PPARγ ligands inhibit the proliferation of non-small cell lung carcinoma (NSCLC) cells in vitro. The mechanisms responsible for this effect remain incompletely elucidated, but PPARγ ligands appear to inhibit the mammalian target of rapamycin (mTOR) pathway. We set out to test the hypothesis that PPARγ ligands activate tuberous sclerosis complex-2 (TSC2), a tumor suppressor gene that inhibits mTOR signaling. We found that the PPARγ ligand rosiglitazone stimulated the phosphorylation of TSC2 at serine-1254, but not threonine-1462. However, an antagonist of PPARγ and PPARγ siRNA did not inhibit these effects. Rosiglitazone also increased the phosphorylation of p38 MAPK, but inhibitors of p38 MAPK and its downstream signal MK2 had no effect on rosiglitazone-induced activation of TSC2. Activation of TSC2 resulted in downregulation of phosphorylated p70S6K, a downstream target of mTOR. A TSC2 siRNA induced p70S6K phosphorylation at baseline and inhibited p70S6K downregulation by rosiglitazone. When compared to a control siRNA in a thymidine incorporation assay, the TSC2 siRNA reduced the growth inhibitory effect of rosiglitazone by fifty percent. These observations suggest that rosiglitazone inhibits NSCLC growth partially through phosphorylation of TSC2 via PPARγ-independent pathways

Priming quantifier scope:Reexamining the evidence against scope inversion

In a study of quantifier-scope priming, Chemla and Bott (2015) found evidence suggesting that, while representations of quantifiers’ relative scope can be primed, a scope inversion operation cannot. We identify a confound in their materials. In Experiment 1, we replicate their finding with this confound intact. In Experiment 2, we remove the confound and find that all priming disappears. This confound demonstrates how structural priming paradigms can be sensitive to many dimensions of similarity, pointing to a need for task-specific controls. We conclude that the prior study does not provide evidence concerning the priming of either relative scope representations or operations. While priming of scope representations has been independently found in other paradigms, the jury is still out on Chemla and Bott’s more novel finding – the absence of priming of a scope inversion operation

Fibroblasts-Warriors at the Intersection of Wound Healing and Disrepair

Wound healing is triggered by inflammation elicited after tissue injury. Mesenchymal cells, specifically fibroblasts, accumulate in the injured tissues, where they engage in tissue repair through the expression and assembly of extracellular matrices that provide a scaffold for cell adhesion, the re-epithelialization of tissues, the production of soluble bioactive mediators that promote cellular recruitment and differentiation, and the regulation of immune responses. If appropriately deployed, these processes promote adaptive repair, resulting in the preservation of the tissue structure and function. Conversely, the dysregulation of these processes leads to maladaptive repair or disrepair, which causes tissue destruction and a loss of organ function. Thus, fibroblasts not only serve as structural cells that maintain tissue integrity, but are key effector cells in the process of wound healing. The review will discuss the general concepts about the origins and heterogeneity of this cell population and highlight the specific fibroblast functions disrupted in human disease. Finally, the review will explore the role of fibroblasts in tissue disrepair, with special attention to the lung, the role of aging, and how alterations in the fibroblast phenotype underpin disorders characterized by pulmonary fibrosis

Peroxisome Proliferator-Activated Receptors in Lung Cancer

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Their discovery in the 1990s provided insights into the cellular mechanisms involved in the control of energy homeostasis; the regulation of cell differentiation, proliferation, and apoptosis; and the modulation of important biological and pathological processes related to inflammation, among others. Since then, PPARs have become an exciting therapeutic target for several diseases. PPARs are expressed by many tumors including lung carcinoma cells, and their function has been linked to the process of carcinogenesis in lung. Consequently, intense research is being conducted in this area with the hope of discovering new PPAR-related therapeutic targets for the treatment of lung cancer. This review summarizes the research being conducted in this area and focuses on the mechanisms by which PPARs are believed to affect lung tumor cell biology

A systematic review of overlapping microRNA patterns in systemic sclerosis and idiopathic pulmonary fibrosis

Lung fibrosis can be observed in systemic sclerosis and in idiopathic pulmonary fibrosis, two disorders where lung involvement carries a poor prognosis. Although much has been learned about the pathogenesis of these conditions, interventions capable of reversing or, at the very least, halting disease progression are not available. Recent studies point to the potential role of micro messenger RNAs (microRNAs) in cancer and tissue fibrogenesis. MicroRNAs are short non-coding RNA sequences (20–23 nucleotides) that are endogenous, evolutionarily conserved and encoded in the genome. By acting on several genes, microRNAs control protein expression. Considering the above, we engaged in a systematic review of the literature in search of overlapping observations implicating microRNAs in the pathogenesis of both idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). Our objective was to uncover top microRNA candidates for further investigation based on their mechanisms of action and their potential for serving as targets for intervention against lung fibrosis. Our review points to microRNAs of the -29 family, -21-5p and -92a-3p, -26a-5p and let-7d-5p as having distinct and counter-balancing actions related to lung fibrosis. Based on this, we speculate that readjusting the disrupted balance between these microRNAs in lung fibrosis related to SSc and IPF may have therapeutic potential

The logic in language: How all quantifiers are alike, but each quantifier is different

Quantifier words like EACH, EVERY, ALL and THREE are among the most abstract words in language. Unlike nouns, verbs and adjectives, the meanings of quantifiers are not related to a referent out in the world. Rather, quantifiers specify what relationships hold between the sets of entities, events and properties denoted by other words. When two quantifiers are in the same clause, they create a systematic ambiguity. ‘‘Every kid climbed a tree” could mean that there was only one tree, climbed by all, or many different trees, one per climbing kid. In the present study, participants chose a picture to indicate their preferred reading of different ambiguous sentences – those containing EVERY, as well as the other three quantifiers. In Experiment 1, we found large systematic differences in preference, depending on the quantifier word. In Experiment 2, we then manipulated the choice of a particular reading of one sentence, and tested how this affected participants’ reading preference on a subsequent target sentence. We found a priming effect for all quantifiers, but only when the prime and target sentences contained the same quantifier. For example, ALL-A sentences prime other ALL-A sentences, while EACH-A primes EACH-A, but sentences with EACH do not prime sentences with ALL or vice versa. In Experiment 3, we ask whether the lack of priming across quantifiers could be due to the two sentences sharing one fewer word. We find that changing the verb between the prime and target sentence does not reduce the priming effect. In Experiment 4, we discover one case where there is priming across quantifiers – when one number (e.g. THREE) is in the prime, and a different one (e.g. FOUR) is in the target. We discuss how these findings relate to linguistic theories of quantifier meaning and what they tell us about the division of labor between conceptual content and combinatorial semantics, as well as the mental representations of quantification and of the abstract logical structure of language.LinguisticsPsychologyOther Research Uni

Activation of Tissue Remodeling Precedes Obliterative Bronchiolitis in Lung Transplant Recipients

Obliterative bronchiolitis (OB) and Bronchiolitis Obliterans Syndrome (BOS) are frequent complications in the lung transplant recipient, and are the leading cause of mortality after transplantation. The mechanisms responsible for OB remain elusive, but inflammatory and tissue remodeling responses are implicated. We hypothesized that alterations in markers of tissue remodeling in BALF of lung transplant recipients could predict development of OB. To test this, we identified 13 lung transplant recipients who developed both BOS and histologic OB (OB group) at median post-operative day (POD) 485 (range 73–2070). Bronchoalveolar lavage fluid (BALF) was obtained at median POD 387 (range 45–2205), which preceded the onset of OB and BOS by a median of 140 days (range 60–365). As a control, BALF was also obtained from a group of 21 stable recipients without OB (non-OB group) at median POD 335 (range 270–395). BALF was examined for gelatinolytic activity, fibronectin gene transcription, and transforming growth factor-β1 (TGF-β1) expression. Gelatin zymography of BALF from the OB group showed increased matrix metalloproteinase-9 (MMP-9) activity over that of the non-OB group (p < 0.005). Similarly, BALF from the OB group induced greater fibronectin expression in fibroblasts compared to the non-OB group (p < 0.03). The induction of fibronectin also correlated with the amount of TGF-β1 protein in BALF (r = 0.71) from the OB group. We conclude that activation of tissue remodeling precedes the onset of OB, and analysis of gelatinolytic and/or fibronectin-inducing activity in BALF can serve as an early, pre-clinical marker for OB

Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury.

Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally; fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression assessed. Bone marrow-derived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(-) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(-) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(-) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast trans-differentiation that renders the "aging lung" susceptible to fibrosis

2011-2012 Dean\u27s Showcase No. 1

https://spiral.lynn.edu/conservatory_deansshowcase/1021/thumbnail.jp