tbuckley/cabot-search huggingface dataset:
Abstract 18632: Relationship Between History of Tobacco Smoking and the Clinical Manifestation of Non-obstructive Coronary Artery Disease
Authors: Andrej Teren, Frank Beutner, Ralph Burkhardt, Markus Scholz, Gerhard Schuler, Joachim Thiery
Journal: Circulation (2017)

Introduction: The influence of environmental risk factors on the clinical manifestation of non-obstructive coronary artery disease (nobCAD) has not been studied in detail. Hypothesis: We explored t...
Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis
Authors: Li-Hao Huang, Bernd H. Zinselmeyer, Chih-Hao Chang, Brian T. Saunders, Andrew Elvington, Osamu Baba, Thomas J. Broekelmann, Lina Qi, Joseph S. Rueve, Melody A. Swartz, Brian S. Kim, Robert P. Mecham, Helge Wiig, Michael J. Thomas, Mary G. Sorci-Thomas, Gwendalyn J. Randolph
Journal: Cell Metabolism (2018)
MEDU-27. ENHANCING SELUMETINIB-MEDIATED KILLING OF SHH MEDULLOBLASTOMA
Authors: Brent Guppy, Lisa Liang, Stephen Cheng, Christopher Porter, Tamra Werbowetski-Ogilvie
Journal: Neuro-Oncology (2019)

Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer with at least 5 distinct molecular subgroups. Of these subgroups, Sonic Hedgehog (SHH) MB exhibits extensive cellular heterogeneity, increased SHH signaling, and has an intermediate prognosis. Consequently, improved chemotherapeutic strategies designed to better treat SHH MB are needed. A major contributing factor to cellular heterogeneity, and thus drug resistance and disease progression, are rare putative brain tumor-propagating cells (TPC). We recently identified the neurotrophin receptor (CD271) within the SHH MB subgroup as a biomarker delineating TPC populations and associated with elevated MEK/ERK signaling. Moreover, we showed that selumetinib, a MEK inhibitor, reduced CD271 levels, decreased TPC growth, and extended survival in mouse models. While promising, these mice ultimately succumb to disease progression; thus, an enhanced selumetinib-based chemotherapeutic strategy is merited. Here, we employed RNA-sequencing to identify 543 genes differentially expressed in selumetinib resistant xenografts. Further, gene set enrichment analysis revealed significant changes in certain signaling pathways including JAK/STAT, predicted to underlie selumetinib resistance. Thus, we employed selumetinib in combination with the JAK/STAT inhibitors AZD1480 or pacritinib, to assess tumorsphere size and calculate drug synergy within human SHH MB cells. Following single agent IC50 studies, drug combinations were evaluated in our high-content tumorsphere assay. Preliminary results showed a synergistic reduction in tumorsphere size when combining selumetinib with JAK/STAT inhibition. We next evaluated cell migration and found that JAK/STAT inhibition alone was sufficient to produce a significant dose dependent reduction in migration. Interestingly, combinatorial drug treatment resulted in a synergistic reduction in cell migration, further supporting the use of selumetinib and JAK/STAT inhibitors as a potentially promising therapeutic combination. Our studies will reveal mechanisms of SHH MB drug resistance and identify novel drug combinations that may ultimately enhance MB patients’ survival and quality of life.
Recent insights in magnetic hyperthermia: From the “hot-spot” effect for local delivery to combined magneto-photo-thermia using magneto-plasmonic hybrids
Authors: Esther Cazares-Cortes, Sonia Cabana, Charlotte Boitard, Emilie Nehlig, Nébéwia Griffete, Jérôme Fresnais, Claire Wilhelm, Ali Abou-Hassan, Christine Ménager
Journal: Advanced Drug Delivery Reviews (2018)
Epidermal γδ T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult
Authors: Rebecca Gentek, Clément Ghigo, Guillaume Hoeffel, Audrey Jorquera, Rasha Msallam, Stephan Wienert, Frederick Klauschen, Florent Ginhoux, Marc Bajénoff
Journal: The Journal of Experimental Medicine (2018)

The murine epidermis harbors two immune cell lineages, Langerhans cells (LCs) and γδ T cells known as dendritic epidermal T cells (DETCs). LCs develop from both early yolk sac (YS) progenitors and fetal liver monocytes before locally self-renewing in the adult. For DETCs, the mechanisms of homeostatic maintenance and their hematopoietic origin are largely unknown. Here, we exploited multicolor fate mapping systems to reveal that DETCs slowly turn over at steady state. Like for LCs, homeostatic maintenance of DETCs is achieved by clonal expansion of tissue-resident cells assembled in proliferative units. The same mechanism, albeit accelerated, facilitates DETC replenishment upon injury. Hematopoietic lineage tracing uncovered that DETCs are established independently of definitive hematopoietic stem cells and instead originate from YS hematopoiesis, again reminiscent of LCs. DETCs thus resemble LCs concerning their maintenance, replenishment mechanisms, and hematopoietic development, suggesting that the epidermal microenvironment exerts a lineage-independent influence on the initial seeding and homeostatic maintenance of its resident immune cells.
SURG-02. A NOVEL RISK MODEL TO DEFINE THE RELATIVE BENEFIT OF MAXIMAL EXTENT OF RESECTION WITHIN PROGNOSTIC GROUPS IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Annette Molinaro, Shawn Hervey-Jumper, Seunggu J. Han, Ramin Morshed, Marisa Lafontaine, Nicole Ebrahimi, Jacob Young, Joanna J Phillips, Anny Shai, Gayathri Warrier, Terri Rice, Yi Lin, Jason Crane, Sarah Nelson, Margaret Wrensch, John Wiencke, Arie Perry, Nancy Ann Oberheim Bush, Jennie Taylor, Nicholas Butowski, Michael Prados, Jennifer Clarke, Susan Chang, Edward Chang, Manish Aghi, Philip Theodosopoulos, Michael McDermott, Mitchel Berger
Journal: Neuro-Oncology (2018)

Although the overall prognostic significance of maximal surgical resection of contrast-enhancing tumor in glioblastoma patients is well established, prior studies have not evaluated the combined importance of resection, molecular markers, patient characteristics, and chemoradiation. Incorporation of these factors may redefine the relative benefit of cytoreductive surgery and establish differing thresholds for extent of resection in varying clinical presentations. In the first study of its kind, we examine the interactive effects of volumetric extent of resection with molecular and clinical factors to develop a new roadmap for cytoreductive surgery. Based on a 20-year retrospective cohort of 850 glioblastoma patients who had initial surgery at UCSF, we employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS), both in the entire cohort as well as a subset diagnosed since 2005 (Stupp-era) with IDH1 mutation status available (n=470). For the entire cohort and the Stupp-era subset, the RPAs elucidate the combinatorial consequence of treatment, age, IDH1 status (in the subset), and resection of both enhancing and non-enhancing tumor. In the Stupp-era, temozolomide-treated patients that are IDH-wildtype and >65 clearly benefit from a reduction of the enhancing tumor (median OS: 10.1 vs 15.8 months). IDH-wildtype, temozolomide-treated patients under 65 benefit from reduction of both enhancing and non-enhancing tumor with a median survival similar to that of IDH-mutant, temozolomide-treated patients (combined median OS: 33.7 months). The patients faring worst are those that did not receive temozolomide that are >65 and/or have ≥0.3 cm3 residual enhancing tumor (median OS: 4 months). These risk models outperform all published prognostic models. This is the first study to combine resection of contrast-enhancing and non-enhancing tumor in conjunction with molecular and clinical information in a large single-institution study, and paves the way for rethinking surgical strategies for individual patients with newly diagnosed glioblastoma.
Role of KATP channel activation on measures of mitochondrial function in cancer cells
Authors: Ian M. Hons, Gurmit Singh
Journal: Cancer Research (2005)

822  The ATP gated, inward rectifying, potassium channel (KATP) has been extensively studied in neuronal cells, cardiac myocytes, and pancreatic beta cells. In cardiac myocytes a mitochondrial localized isoform (mtKATP) is thought to be involved in ischemic preconditioning. This channel also has an important role in oncogenesis and tumor promotion of non-excitable cells by modulating plasma membrane potential, inhibiting apoptotic volume decrease, and altering reactive oxygen species (ROS) production and inner membrane potential of the mitochondria. Non-toxic concentrations of ROS have been shown to promote cell survival. We demonstrate a novel function of the mtKATP channel in cancer physiology. RT-PCR and western-blotting were used to examine expression of specific KATP channel subunits. To determine the expression of the complete mtKATP channel, two measures of mitochondrial function were examined. Changes in the mitochondrial inner membrane potential were measured through flow cytometry by comparing changes in the uptake of the potential sensitive dye tetramethyrhodamine methyl ester (TMRM). ROS production was examined by analysis of the conversion of Dichlorofluorescin diacetate (DCFH-DA) to the fluorescent dichloroflurescin also by flow cytometry. We have shown mRNA and protein expression of the pore forming Kir6.2 subunit in human prostate carcinoma (2008 and C13) and human colorectal carcinoma (HT29) cell lines. The observation that the mtKATP channel blocker 5-Hydroxydecanoate (5-HD) could inhibit proliferation of 2008 and C13 cells is consistent with a physiological role for these channels. To determine the consequences of mtKATP blockade we examined the production of ROS in the presence of 5-HD and the mtKATP channel opener Diazoxide (Dia). We found a slight (2.4 fold) increase in ROS production during 5-HD treatment and a 4.6 fold increase in ROS with Dia treatment in the mouse ovarian carcinoma (MLL) cell line. Initial TMRM results suggest 5-HD is able to slightly dissipate the inner mitochondrial membrane potential in 2008 cells. These results demonstrate that non-excitable tumor derived cell lines express a pore forming subunit of the KATP channel. The ability of 5-HD and Dia to act on mitochondrial function suggest that this subunit is expressed as part of a functional mtKATP channel. The impact of potassium permeation through the mtKATP channel into the mitochondrial matrix is postulated to promote oncogensis and tumor promotion through the manipulation of ROS production and maintenance of ATP levels in response to hypoxia. The mtKATP channel could be a novel target for anti-cancer therapy. (This work was supported by the Canadian Institute for Health Research)
DDIS-11. A CK1a ACTIVATOR PENETRATES THE BRAIN, AND SHOWS EFFICACY AGAINST DRUG-RESISTANT METASTATIC MEDULLOBLASTOMA
Authors: Jezabel Rodriguez Blanco, Bin Li, Jun Long, Darren Orthon, Nagi Ayad, Heather MaCrea, Martine Roussel, William Weiss, Anthony Capobianco, David Robbins
Journal: Neuro-Oncology (2018)

Although most children with medulloblastoma (MB) are cured of their disease, SONIC HEDGEHOG (SHH) subgroup MB driven by TRP53 mutations is essentially lethal. Casein Kinase 1a (CK1a phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a second-generation CK1a activator against, TRP53mutant, MYCNamplified MB. Our novel CK1a activator inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH MB. SSTC3 accumulated at high levels in the brain, inhibited growth of SHH MB tumors, and blocked metastases in a genetically-engineered vismodegib-resistant mouse model of SHH MB. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derivedTRP53 mutant, MYCN amplified, SHH subgroup MB xenografts, increasing overall survival. Thus, a CK1a agonist penetrates into the brain, and shows efficacy against metastatic TRP53mutant MB, which are resistant to existing therapies including the SMO inhibitors currently being evaluated clinically.
EXTH-55. CONCOMITANT INHIBITION OF RAC1 AND Bcl-2/Bcl-xL INTERFERES WITH THE Mcl-1/Usp9X AXIS AND YIELDS SYNERGISTIC ANTI-GLIOMA ACTIVITY
Authors: Michal Hlavac, Annika Dwucet, Mike-Andrew Westhoff, Richard Eric Kast, Jens Engelke, Markus Siegelin, Christian Rainer Wirtz, Marc-Eric Halatsch, Georg Karpel-Massler
Journal: Neuro-Oncology (2018)

The purpose of this study was to examine whether inhibition of RAC1 would enhance the pro-apoptotic reprogramming of glioblastoma’s cellular circuitry following selective Bcl-2/Bcl-xL inhibition by BH-3 mimetics. Preclinical drug testing and molecular profiling was performed in different glioblastoma model systems including established, primary and glioma stem-like cells. Our data show that combined inhibition of RAC1 and Bcl-2/Bcl-xL resulted in synergistic anti-proliferative and pro-apoptotic effects in a panel of different glioblastoma cells. RAC1 inhibition lead to decreased expression of the deubiquitinase Usp9X and depletion of endogenous Mcl-1 through a post-translational mechanism. The combination treatment diminished the expression of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL. In addition, the migratory activity of glioblastoma cells was significantly inhibited by the combination treatment. Lastly, tumor formation on the chorion allantoic membrane of chicken embryos was significantly impaired by simultaneous inhibition of RAC1 and Bcl-2/Bcl-xL. In conclusion, our data suggest that inhibition of RAC1 strongly enhances the pro-apoptotic shift in glioblastoma cells induced by BH-3-mimetics via counteracting mechanisms of resistance such as upregulation of Mcl-1. From a mechanistic point of view, RAC1 inhibition affects protein stability of Mcl-1 which is likely to be subsequent to decreased expression of Usp9X. Overall, the promising biological anti-cancer activity of this multi-targeting strategy warrants further in vivo testing.
ATIM-30. HOW TO MONITOR IMMUNOGENIC CELL DEATH IN PATIENTS WITH GLIOBLASTOMA
Authors: Stefaan Van Gool, Oliver Feyen, Jennifer Makalowski, Andrea Neinhuis, Volker Schirrmacher, Wilfried Stuecker
Journal: Neuro-Oncology (2018)

Immunotherapy approaches become prominent in the treatment of patients with GBM. One pathway is the induction of immunogenic cell death of tumor cells (ICD). Instant monitoring of the effects of ICD might help the physician to continuously adapt these therapies. For this, blood liquid biopsy like biological biopsy might help. The presence and evolution of tumor-derived TKTL1 and Apo10 in circulating monocytes, both components of the PanTum tests using the EDIM platform, were studied in a series of 57 patients with glioma treated with 2 cycles of multimodal immunotherapy consisting of modulated electrohyperthermia (mEHT), injections of Newcastle Disease Virus (NDV), autologous mature dendritic cell vaccinations loaded with autologous tumor antigens, and immunomodulatory strategies depending on the functioning immune system. Median age was 44 years (ranging 1–73). Patients had high grade glioma (n=48), grade II glioma (n=3), DIPG (n=4), ependymoma (n=1) and metastasized paraganglioma (n=1). A significant increase of TKTL1 and Apo10 was measured after 5 days of mEHT/NDV-based ICD treatment. Three weeks later, the markers were dropped but rose again significantly upon ICD treatment. Increase was observed for all disease entities. Values were relatively lower in lower grade tumors. The effect of ICD can be monitored through TKTL1 and Apo10 measurements. Whether the dynamics of these markers upon treatment predict efficacy of multimodal immunotherapy is focus of current research.
The TROY receptor is overexpressed in human glioblastoma multiforme and fosters glioma cell migration and tumor cell survival
Authors: Nhan Tran, Kelsey Drake, Matthew Ennis, Brock Armstrong, Caitlin Auther, Wendy McDonough, Michael Berens
Journal: Cancer Research (2007)

1360  Glial tumors progress to malignant grades by heightened proliferation and relentless dispersion into normal brain. Understanding genetic and biochemical processes that foster these behaviors is likely to reveal specific and effective targets for therapeutic intervention. We have identified TROY / TNFRSF19 as a novel transmembrane receptor that is overexpressed in glioblastoma multiforme. TROY is a member of the tumor necrosis factor receptor (TNFR) superfamily. Unlike the classical TNFR members, TROY lacks a death domain but possesses a single TRAF binding domain. The interaction of TROY and TRAF proteins has been shown to promote cell survival via members of the Rho GTPases and NFκB pathway. Our data show that levels of TROY mRNA expression correlate with glial tumor grade; among malignant gliomas, TROY expression correlates inversely with overall patient survival. Additionally, migrating glioma cells in vitro and invading glioma cells in vivo express high levels of TROY mRNA and harbor an abundance of TROY protein product. Depletion of TROY expression by siRNA oligonucleotides reduces glioma cell migration and invasion. These findings suggest that TROY participated directly or indirectly in biochemical pathways that influence glioma cell motility and invasion. Understanding the function of TROY in glioma biology may lead to the development of effective therapies against invasive gliomas. (Supported by Ruth L. Kirschstein National Research Service Award F32 CA112986-01 and NIH NS42263).
DRES-02. CILIARY PROTEIN ARL13B PROMOTES CHEMORESISTANCE BY MODULATE GLIOBLASTOMA PURINE BIOSYNTHESIS
Authors: Jack Shireman, Fatemeh Atashi, Cheol Park, Louisa Warnke, Jason Miska, Atique Ahmed
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) carries with it an almost 100% recurrence rate due to development of resistance to all conventional therapies. Our lab has demonstrated ARL13B, an ADP-ribosylation factor-like protein critical for cilia formation, plays an important role in promoting resistance to temozolomide (TMZ)-based chemotherapy. Knockdown of ARL13B in patient derived xenograft cells significantly increased survival of mice in an orthotropic GBM model when compared to controls (p<0.0001).The Cancer Genome Atlas (TCGA) dataset demonstrates time to recurrence in patients with downregulated ARL13B is substantially increased as compared to ARL13B upregulated patients (log-rank p-value=0.0012).To better understand the role of ARL13B in therapeutic adaptation we performed mass spectrometry analysis of an ARL13B pulldown during TMZ therapy and identified inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme in de-novo guanine nucleotide biosynthesis, as a significant binding partner of ARL13B during TMZ chemotherapy (p<0.0001). Immunoprecipitation analysis across multiple GBM cell lines validated this interaction and its increase during TMZ therapy. Probing this interaction further we examined the de novo and salvage purine biosynthesis pathways using radiolabeled carbon tracing experiments. In ARL13B knockdown cells, purine salvage pathway usage is upregulated 7-fold (p<0.0001) while de-novo pathway usage was decreased about 50% (p=0.004) in a TMZ specific manner. Moreover, ARL13B knockdown GBM cells treated with TMZ show a robust increase in DNA double-strand breaks compared to control cells exposed to TMZ, demonstrated by γH2X staining. Based on these observations, we hypothesize that ARL13B is a novel regulator of IMPDH2 allowing GBM cells to block salvage pathway biosynthesis to avoid TMZ induced DNA damage. However, when ARL13B is lost, GBM cells are forced into salvage pathway synthesis thus becoming sensitized to TMZ therapy due to increased incorporation of alkylated purines, a known function of TMZ.
“Candy cane” syndrome: a report of a mini-invasive endoscopic treatment using OverStitch, a novel endoluminal suturing system
Authors: Antonino Granata, Noemi Cicchese, Michele Amata, Lavinia De Monte, Alessandro Bertani, Dario Ligresti, Mario Traina
Journal: Endoscopy (2018)

A 25-year-old woman with a history of Barrett’s esophagus with dysplasia underwent Ivor Lewis esophagectomy at the age of 18 years.
Prevalence of Distress Associated With Difficulty Controlling Sexual Urges, Feelings, and Behaviors in the United States
Authors: Janna A. Dickenson, Neil Gleason, Eli Coleman, Michael H. Miner
Journal: JAMA Network Open (2018)

The veracity, nomenclature, and conceptualizations of sex addiction, out-of-control sexual behavior, hypersexual behavior, and impulsive or compulsive sexual behavior are widely debated. Despite such variation in conceptualization, all models concur on the prominent feature: failing to control one's sexual feelings and behaviors in a way that causes substantial distress and/or impairment in functioning. However, the prevalence of the issue in the United States is unknown.To assess the prevalence of distress and impairment associated with difficulty controlling sexual feelings, urges, and behaviors among a nationally representative sample in the United States.This survey study used National Survey of Sexual Health and Behavior data to assess the prevalence of distress and impairment associated with difficulty controlling sexual feelings, urges, and behaviors and determined how prevalence varied across sociodemographic variables. Participants between the ages of 18 and 50 years were randomly sampled from all 50 US states in November 2016.Distress and impairment associated with difficulty controlling sexual feelings, urges, and behavior were measured using the Compulsive Sexual Behavior Inventory-13. A score of 35 or higher on a scale of 0 to 65 indicated clinically relevant levels of distress and/or impairment.Of 2325 adults (1174 [50.5%] female; mean [SD] age, 34.0 [9.3] years), 201 [8.6%] met the clinical screen cut point of a score of 35 or higher on the Compulsive Sexual Behavior Inventory. Gender differences were smaller than previously theorized, with 10.3% of men and 7.0% of women endorsing clinically relevant levels of distress and/or impairment associated with difficulty controlling sexual feelings, urges, and behavior.The high prevalence of this prominent feature associated with compulsive sexual behavior disorder has important implications for health care professionals and society. Health care professionals should be alert to the high number of people who are distressed about their sexual behavior, carefully assess the nature of the problem within its sociocultural context, and find appropriate treatments for both men and women.