Gene expression of the IGF pathway family distinguishes subsets of gastrointestinal stromal tumors wild type for KIT and PDGFRA

Gastrointestinal stromal tumors (GISTs) arise from the interstitial cells of Cajal (ICCs) and are the most common mesenchymal neoplasm of the gastrointestinal tract. While the majority of GISTs harbor activating mutations in either the v-kit Hardy-Zuckerman feline sarcoma viral oncogene homolog (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinases, approximately 10–15% of adult GISTs and 85% of pediatric GISTs lack such mutations. These “wild-type” GISTs have been reported to express high levels of the insulin-like growth factor 1 receptor (IGF1R), and IGF1R-targeted therapy of wild-type GISTs is being evaluated in clinical trials. However, it is not clear that all wild-type GISTs express IGF1R, because studies to date have predominantly focused on a particular subtype of gastric wild-type GIST that is deficient in the mitochondrial succinate dehydrogenase (SDH) complex. This study of a series of 136 GISTs, including 72 wild-type specimens, was therefore undertaken to further characterize wild-type GIST subtypes based on the relative expression of transcripts encoding IGF1R. Additional transcripts relevant to GIST biology were also evaluated, including members of the IGF-signaling pathway (IGF1, IGF2, and insulin receptor [INSR]), neural markers (CDH2[CDH: Cadherin], neurofilament, light polypeptide, LHX2 [LHX: LIM homeobox], and KIRREL3 [KIRREL: kin of IRRE like]), KIT, PDGFRA, CD34, and HIF1A. Succinate dehydrogenase complex, subunit B protein expression was also assessed as a measure of SDH complex integrity. In addition to the previously described SDH-deficient, IGF1Rhigh wild-type GISTs, other SDH-intact wild-type subpopulations were defined by high relative expression of IGF1R, neural markers, IGF1 and INSR, or low IGF1R coupled with high IGF2. These results underscore the complexity and heterogeneity of wild-type GISTs that will need to be factored into molecularly-targeted therapeutic strategies

Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.

Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD. We identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles, "mitochondria-on-a-string" (MOAS). Our data suggest that MOAS formation may occur at the final stages of fission process and was not associated with altered translocation of activated dynamin related protein 1 (Drp1) to mitochondria but with reduced GTPase activity. Since MOAS formation was also observed in the brain tissue of wild-type mice in response to hypoxia or during chronological aging, fission arrest may represent fundamental compensatory adaptation to bioenergetic stress providing protection against mitophagy that may preserve residual mitochondrial function. The discovery of novel mitochondrial phenotype that occurs in the brain tissue in response to energetic stress accurately detected only using 3D EM reconstruction argues for a major role of mitochondrial dynamics in regulating neuronal survival

Dynamic changes in cellular infiltrates with repeated cutaneous vaccination: a histologic and immunophenotypic analysis

<p>Abstract</p> <p>Background</p> <p>Melanoma vaccines have not been optimized. Adjuvants are added to activate dendritic cells (DCs) and to induce a favourable immunologic milieu, however, little is known about their cellular and molecular effects in human skin. We hypothesized that a vaccine in incomplete Freund's adjuvant (IFA) would increase dermal Th1 and Tc1-lymphocytes and mature DCs, but that repeated vaccination may increase regulatory cells.</p> <p>Methods</p> <p>During and after 6 weekly immunizations with a multipeptide vaccine, immunization sites were biopsied at weeks 0, 1, 3, 7, or 12. In 36 participants, we enumerated DCs and lymphocyte subsets by immunohistochemistry and characterized their location within skin compartments.</p> <p>Results</p> <p>Mature DCs aggregated with lymphocytes around superficial vessels, however, immature DCs were randomly distributed. Over time, there was no change in mature DCs. Increases in T and B-cells were noted. Th2 cells outnumbered Th1 lymphocytes after 1 vaccine 6.6:1. Eosinophils and FoxP3⁺cells accumulated, especially after 3 vaccinations, the former cell population most abundantly in deeper layers.</p> <p>Conclusions</p> <p>A multipeptide/IFA vaccine may induce a Th2-dominant microenvironment, which is reversed with repeat vaccination. However, repeat vaccination may increase FoxP3⁺T-cells and eosinophils. These data suggest multiple opportunities to optimize vaccine regimens and potential endpoints for monitoring the effects of new adjuvants.</p> <p>Trail Registration</p> <p>ClinicalTrials.gov Identifier: NCT00705640</p

The Lantern Vol. 10, No. 1, December 1941

• Misty • The Evils of Initiations • Ursinus, Fifty Years Ago • My Conversion • Our Gang • From Rabble to Royalty • So You Want to be an Editor! • Tempo • A Musician\u27s Allegory • Flotsam • The Years • Common Things • Sea Moods • Aunt Agatha\u27s Pillow • Peace at Autumn Twilighthttps://digitalcommons.ursinus.edu/lantern/1025/thumbnail.jp

Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models

Hearing loss is a major risk factor for tinnitus, hyperacusis, and central auditory processing disorder. Although recent studies indicate that hearing loss causes neuroinflammation in the auditory pathway, the mechanisms underlying hearing loss-related pathologies are still poorly understood. We examined neuroinflammation in the auditory cortex following noise-induced hearing loss (NIHL) and its role in tinnitus in rodent models. Our results indicate that NIHL is associated with elevated expression of proinflammatory cytokines and microglial activation-two defining features of neuroinflammatory responses-in the primary auditory cortex (AI). Genetic knockout of tumor necrosis factor alpha (TNF-alpha) or pharmacologically blocking TNF-alpha expression prevented neuroinflammation and ameliorated the behavioral phenotype associated with tinnitus in mice with NIHL. Conversely, infusion of TNF-alpha into AI resulted in behavioral signs of tinnitus in both wild-type and TNF-alpha knockout mice with normal hearing. Pharmacological depletion of microglia also prevented tinnitus in mice with NIHL. At the synaptic level, the frequency of miniature excitatory synaptic currents (mEPSCs) increased and that of miniature inhibitory synaptic currents (mIPSCs) decreased in AI pyramidal neurons in animals with NIHL. This excitatory-to-inhibitory synaptic imbalance was completely prevented by pharmacological blockade of TNF-alpha expression. These results implicate neuroinflammation as a therapeutic target for treating tinnitus and other hearing loss-related disorders.National Institute of Health [DC009259, DC014335]; Department of Defense [W81XWH-15-1-0028, W81XWH-15-1-0356, W81XWH-15-1-0357]; Food and Health Bureau of Hong Kong Special Administrative Region Government [04150076]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Dietary cadmium and risk of invasive postmenopausal breast cancer in the VITAL cohort.

This study does not support the hypothesis that dietary cadmium intake is a risk factor for breast cancer. However, non-differential measurement error in the estimate of cadmium intake is likely the most important factor that could have obscured an association

Gas Source Molecular Beam Epitaxy of Compound Semiconductors

Contains an introduction and reports on seven research projects.Defense Advanced Research Projects Agency Subcontract 284-25041Joint Services Electronics Program Contract DAAL04-95-1-0038National Center for Integrated Photonic Technology Contract 542-381U.S. Army Research Office/ AASERT Contract DAAH04-93-G-0175National Science Foundation Grant DMR 92-02957Joint Services Electronics Program Grant DAAL04-95-1-0038National Science Foundation Grant DMR 90-22933National Science Foundation Grant DMR 92-02957National Center for Integrated Photonic Technology Contract 542-381MIT Lincoln LaboratoryNational Center for Integrated Photonic Technology Subcontract 542-383National Science Foundation DMR 94-0033