tbuckley/cabot-search huggingface dataset:
GENE-22. MOLECULAR ALTERATIONS AND USE OF TARGETED THERAPY IN 160 PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Erin Wright, Demetri Boswell, Rebecca Sisson, Christine Fuller, Mariko DeWire, Peter de Blank, Trent Hummel, Maryam Fouladi, Ralph Salloum
Journal: Neuro-Oncology (2019)

BACKGROUND: Molecular profiling is commonly performed in pediatric CNS tumors, however the clinical utilization of genomic data in pediatric neuro-oncology is not fully characterized. We describe a single institution experience adopting a personalized therapeutic approach based on tumor genetic alterations. METHODS: We retrospectively analyzed genomic data, generated using fluorescent in situ hybridization, single gene, or panel sequencing, of pediatric CNS tumors in patients diagnosed between 2010 and 2018 at Cincinnati Children’s Hospital Medical Center. We aimed to identify common genetic aberrations, characterize targeted therapies used, and disease response. RESULTS: One hundred and sixty patients (median age: 7 years, range: 0–27 years) had tumor sequencing performed yielding 147 evaluable results. Low-grade lesions (LGL) (N=94, 63.9%), were mostly low-grade gliomas and glioneuronal tumors; high-grade lesions (HGL) (N=53, 36.0%) included high-grade gliomas (N=35), embryonal neoplasms (N=12), and choroid plexus carcinomas (N=3). Specific BRAF aberrations were more interrogated in LGL while larger panel sequencing was performed in HGL. Targetable aberrations were found in 99 patients (67.3%), most commonly BRAF alterations in LGL as expected, and aberrations in the RTK-PI3K pathway in HGL. Among 99 patients, 56.5% received therapy informed by sequencing data. Thirty three patients with LGL (35.1%) received targeted therapy after a median of 3 prior therapies and remained on treatment for a median of 7 months (range: 1–24 months). Twenty three patients with HGL (43.4%) received targeted therapy after a median of 2 therapies and remained on treatment for a median of 3 months (range: 1–23 months). Targeted therapy was most frequently stopped due to disease progression, only 5 patients developed toxicity that led to cessation of targeted agents. CONCLUSION: Targetable alterations are frequent in pediatric CNS tumors; when identified they guided therapy in a majority of patients commonly at progression and were used earlier and more often in HGL. GERM CELL TUMORS
Pharmacology of trifarotene
Authors: J. Aubert, D. Piwnica, B. Bertino, S. Blanchet‐Réthoré, I. Carlavan, S. Déret, B. Dreno, B. Gamboa, A. Jomard, A.P. Luzy, P. Mauvais, C. Mounier, J. Pascau, I. Pelisson, T. Portal, M. Rivier, P. Rossio, E. Thoreau, E. Vial, J.J. Voegel
Journal: British Journal of Dermatology (2018)
Abstract 15330: Work Productivity Losses in the Year Following Acute Coronary Syndrome or Stroke: Interim Results of a Multi-Country Survey in Europe
Authors: Kornelia Kotseva, Laetitia Gerlier, Eduard Sidelnikov, Lucie Kutikova, Mark Lamotte, Lieven Annemans, Pierre Amarenco
Journal: Circulation (2017)

Introduction: The burden of cardiovascular events (CVE) on patients’ work productivity is not well described. Our cross-sectional survey in 12 European countries aims to estimate the productivity l...
Randomized immunotherapy trial in dual‐allergic patients using “active allergen placebo” as control
Authors: Martin Wagenmann, Margitta Worm, Yasemin Akboga, Martin Karjalainen, Jens M. Hohlfeld
Journal: Allergy (2019)

Placebo control in allergen immunotherapy (AIT) trials presents ethical and blinding concerns. We tested a trial design with an "active allergen placebo," as proposed by ARIA-GA
Abstract 12423: The Tandem Zinc Finger mRNA Binding Protein, Tristetraprolin (TTP), is a Novel Regulator of Cardiac Branched Chain Amino Acid (BCAA) Catabolism
Authors: Hsiang-chun Chang, Sumeyye Yar, Hidemichi Kouzu, Chunlei Chen, Meng Shang, Hossein Ardehali
Journal: Circulation (2018)

Introduction: BCAA are essential nutrients that are obtained exclusively from diet, and their cellular levels are regulated by their catabolism. Heart failure is associated with increased levels of...
STEM-01. PREDICTABLE AND DISTINCT MECHANISMS DRIVE DE NOVO VS. ACQUIRED RESISTANCE TO SMO/SHH INHIBITORS IN SHH MEDULLOBLASTOMAS
Authors: Yaohui Chen, Joshy George, Nourhan Abdelfattah, Keiko Yamamoto, Brad Rybinski, Scott Adamson, Jeff Chuang, Kyuson Yun
Journal: Neuro-Oncology (2019)

Emergence of therapy resistance greatly reduces long-term utility of effective targeted therapies, including SMO/SHH pathway inhibitors. SHH signaling is elevated in ~25% of human medulloblastomas (MB), and FDA approved SMOi (to treat basal cell carcinoma (BCC)) are currently in clinical trials for MBs and acute myeloid leukemia. Accumulating clinical experience suggests that a significant number of BCC patients treated with SMOi develop acquired resistance over time and some show de novo resistance. A similar pattern is observed in MB patients, indicating the need to elucidate resistance mechanisms, particularly those driving de novo vs. acquired resistance, and develop new strategies to overcome both de novo and acquired resistance to SMOi. We report that we discovered a novel, epigenetic mechanism of therapy resistance to SMOi that underlies de novo resistance. Using two different mouse models of SHH MB, we tested our original hypothesis that the selective pressure on cancer stem cells (CSCs), but not bulk tumor cells, will determine the resistance mechanism at the molecular level. We show that acquired mutations in the SHH pathway genes (previously reported mechanism of resistance) occur only in tumors that contain CSCs that depend on the SHH pathway. In tumors where only the bulk tumor cells, but not CSCs, depend on SHH signaling, no acquired mutations in the SHH pathway genes are detected. Instead, in these tumors, epigenetic reprogramming through selective degradation of specific histone modifiers results in global changes in the epigenetic cell state and gene expression patterns. Importantly, we can predict the mechanism of resistance in individual tumors prior to treatment based on CSC phenotypes. Finally, we also report biomarkers that can be used to identify tumors with CSCs that are independent of SHH pathway, which can be exploited to design anticipatory combination therapies in the future. TRANSLATIONAL THERAPEUTICS
Abstract 15204: Inhibition of Shp2’s Phosphatase Activity Ameliorates Cardiac Hypertrophy in LEOPARD Syndrome Models
Authors: Christine Schramm, Michelle A Edwards, Kathryn Crombie, Maike Krenz
Journal: Circulation (2013)

Mutations in the protein tyrosine phosphatase Shp2 cause congenital heart disease, in particular Noonan Syndrome (NS) and LEOPARD Syndrome. Due to the substantial clinical overlap between the two s...
Stephanie Eisenbarth: Discovering the bigger picture
Authors: Stephanie Houston
Journal: The Journal of Experimental Medicine (2019)

Stephanie Eisenbarth is an Associate Professor in the Immunology Faculty at Yale University. Her work has shown that the guanine nucleotide exchange factor Dock8 plays a role in the migration of a specific dendritic cell subset, and that when Dock8 is missing, some dendritic cells can no longer prime CD4+ T cells. Stephanie’s laboratory now focuses on understanding how T cell–driven pathology is initiated. We chatted with Stephanie to find out about her journey in science.
Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients
Authors: Adam E. Snook, Trevor R. Baybutt, Bo Xiang, Tara S. Abraham, John C. Flickinger, Terry Hyslop, Tingting Zhan, Walter K. Kraft, Takami Sato, Scott A. Waldman
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8<sup>+</sup>, but not CD4<sup>+</sup>, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. <h3>Methods</h3> Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 10<sup>11</sup> viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. <h3>Results</h3> All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8<sup>+</sup> cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4<sup>+</sup> T cells are eliminated by self-tolerance, while CD8<sup>+</sup> T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. <h3>Conclusions</h3> Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8<sup>+</sup>, but not autoimmune CD4<sup>+</sup>, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. <h3>Trial registration</h3> This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737
Abstract OT1-01-02: An open-label, randomized, multi-center phase 2 study evaluating the activity of lasofoxifene relative to fulvestrant for the treatment of postmenopausal women with locally advanced or metastatic ER+/HER2 - breast cancer (MBC) with an ESR1 mutation
Authors: PV Plourde, LS Schwartzberg, GL Greene, DJ Portman, BS Komm, SN Jenkins, P-Y Liu, MD Portman, MP Goetz
Journal: Cancer Research (2019)

Abstract Endocrine based therapy is the standard treatment for estrogen receptor positive (ER+) MBC. Agents targeting the ER pathway including aromatase inhibitors (AIs), fulvestrant and tamoxifen along with CDK 4/6 inhibitors are considered standard for first and 2nd line treatment. However, endocrine resistance develops in nearly all patients and the optimal systemic therapy after progression on a CDK 4/6 inhibitor is unknown. Lasofoxifene is a third generation SERM previously investigated for the treatment of osteoporosis and vulvo-vaginal atrophy (VVA). In a large phase 3 trial evaluating the efficacy of lasofoxifene for the postmenopausal treatment of osteoporosis, lasofoxifene significantly reduced the incidence of ER+ breast cancer. Further unpublished preclinical data have demonstrated significant in vitro and in vivo efficacy in non-clinical breast cancer models including models with and without ESR1 mutants. Moreover, lasofoxifene significantly reduced metastases in ESR1 mutated models. These non-clinical and clinical data provide a strong rationale to pursue a phase 2 clinical trial in women with ER+, ESR1 mutated MBC. This open-label, multi-center study will compare the efficacy and tolerability of lasofoxifene (5 mg orally daily) to fulvestrant (IM 500 mg D1,15,29 and then q30 D) in a 1:1 randomization. Inclusion criteria include postmenopausal women with ER+ advanced breast cancer; progression on a non-steroidal AI in combination with a CDK 4/6 inhibitor; and a known ESR1 mutation. Approximately 90 patients with measurable or evaluable disease (i.e. bone only) will be recruited to have at least 40 patients per treatment arm. The primary endpoint will be progression free survival (PFS) with secondary endpoints of objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR) and time to response (TTR). It is assumed that lasofoxifene will double the median PFS compared to fulvestrant in this ESR1 mutation patient population for a hazard ratio 0.5 and a power of 89% to reach a 1-sided p of &amp;lt;0.05. The study will commence in 4Q2018 and will complete recruitment in 1 year. It is anticipated that 25-30 centers in the US will be participating. Citation Format: Plourde PV, Schwartzberg LS, Greene GL, Portman DJ, Komm BS, Jenkins SN, Liu P-Y, Portman MD, Goetz MP. An open-label, randomized, multi-center phase 2 study evaluating the activity of lasofoxifene relative to fulvestrant for the treatment of postmenopausal women with locally advanced or metastatic ER+/HER2 - breast cancer (MBC) with an ESR1 mutation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-02.
THER-21. TARGETING LIN28 WITH DFMO IN PATIENTS WITH ETMR SUGGESTS CLINICAL BENEFIT
Authors: Deanna Mitchell, Mary Durston, Abhinav Nagulapally, Julie Steinbrecher, Jacqueline Kraveka, William Ferguson, Don Eslin, Valerie Brown, Kathleen Neville, Genevieve Bergendahl, Giselle Saulnier Sholler
Journal: Neuro-Oncology (2019)

Embryonal tumor with multilayered rosettes (ETMR) is a rare and very aggressive brain tumor occurring in children less than 4 years of age. The survival is poor, with the best reported 1 year EFS and OS of 36% and 45%, respectively. EMTR demonstrates amplification of the miRNA cluster C19MC (95%) and high expression of LIN28A/LIN28B proteins. Since the LIN28 pathway is targeted and suppressed by DFMO (diflouromethylornithine), patients with ETMR were treated with DFMO and evaluated for safety and response. METHODS: One patient received DFMO through an EIND, followed by 7 additional patients enrolled on the Beat Childhood Cancer Consortium Expanded Access protocol for LIN28 driven tumors (NCT03581240). Patients received DFMO alone or in combination with another agent and/or radiation. Patients were seen monthly for safety and evaluated by MRI every 2–3 months. DNA exome and RNA sequencing was performed in 7 patients. Two patient cell lines and xenograft models were established. RESULTS: Three of 8 patients were treated at the completion of upfront intensive multimodal therapy and all remain in remission between 0.5–1.25 yrs to date. The remaining 5 patients enrolled following disease progression or relapse. Of these, one patient completed 2 years of DFMO and remains in remission 2 years off therapy, 3 remain on DFMO and with NED/SD between 0.25–1.1 years, and one patient experienced PD at 3 months. DFMO was well tolerated either alone or when combined with radiation, vorinostat, everolimus, etoposide or temozolomide. No SAEs related to DFMO have been reported. Adverse events included anemia, diarrhea, and reversible hearing loss. RNA sequencing showed activation of ODC/MYC/LIN28 pathway. CONCLUSION: Treatment with DFMO in children with ETMR was well tolerated and appears to confer clinical benefit with prolonged survival. Based on these results, a prospective clinical trial is ongoing through the Beat Childhood Cancer consortium.
DSP mutations and arrhythmogenic cardiomyopathy
Authors: T. Maruthappu, A. Posafalvi, S. Castelletti, P.J. Delaney, P. Syrris, E.A. O'Toole, K.J. Green, P.M. Elliott, P.D. Lambiase, A. Tinker, W.J. McKenna, D.P. Kelsell
Journal: British Journal of Dermatology (2019)

Arrhythmogenic Cardiomyopathy (AC) is a relatively rare inherited disorder of the heart muscle and can lead to sudden death in patients, often under 35 years of age. AC can be very difficult for doctors to diagnose because the initial symptoms are often subtle so they can go unnoticed. In a rare form of AC, affected patients also have striking curly hair and abnormally thickened skin on the palms and soles. This can make the diagnosis easier to make. This study, from London, UK, looked at families with a more common form of AC caused by mutations in desmoplakin, a protein which acts as a “glue” between cells in both the heart and skin. We show that the majority of family members with AC had curly hair, and a significant proportion of these patients also had the condition causing thickening of the skin. Skin biopsies from patients with AC revealed abnormalities in several proteins responsible for connecting cells to one another, these proteins are also critical in the heart for conducting impulses throughout the heart muscle and signalling contraction. Early diagnosis and family screening are the key goals in the management of AC. This study has identified two novel features in AC caused by desmoplakin mutation, the first is the presence of curly hair and the skin condition in the majority of affected family members. The second is the identification of abnormalities in several proteins in skin biopsies taken from patients with AC. Examination of the skin and hair could therefore provide a unique window of opportunity to facilitate the prompt diagnosis of AC.
EPEN-10. 5-FU ENHANCES RADIATION THERAPY IN IN VITRO AND IN VIVO TREATMENT OF 1q+ PFA EPENDYMOMA
Authors: Andrea Griesinger, Andrew Donson, Vladimir Amani, Andrew Domman, Angela Pierce, Benjamin Van Court, Sana Karam, Jenna Steiner, Natalie Serkova, Kathleen Dorris, Nicholas Foreman
Journal: Neuro-Oncology (2019)

BACKGROUND: Chemotherapy trials in relapsed pediatric ependymoma trials have failed to show reproducible benefit. High-risk 1q+PFA ependymoma show have a particularly bad outcome, with radiation and surgery showing no benefit at relapse. Using two 1q+PFA1 cell lines, we identified several ependymoma specific FDA-approved oncology drugs, including fluorouracil (5-FU). The goal of our study was to determine the effect of combining 5-FU and radiation in in-vitro and in-vivo 1q+PFA models. METHODS: MAF-811 and MAF-928 cell lines along with our newly established orthotopic xenografts MAF-811_XC and MAF-928_XC were used to measure treatment effects. Cesium radiation was used to treat cell lines and focal radiation was delivered to mice using 2Gy for 5 days. 30mg/kg 5-FU was dosed in mice once prior to radiation, once during, and weekly following radiation treatment for a total of 6 rounds of 5-FU. RESULTS: In-vitro studies, treating both 1q+PFA1 cell lines with escalating doses of 5-FU and radiation, we found synergistic effect on tritiated thymidine incorporation 7 days post radiation treatment. This effect was independent on sequence of drug and radiation dosage. In-vivo studies are ongoing with combining 10Gy focal radiation with 5-FU in both 1q+PFA xenografts. Preliminary studies have shown combination treatment appears to be well tolerated with 5-FU dosing. CONCLUSION: 5-FU treatment enhances the effect of radiation therapy in 1q+PFA models. Furthermore, these studies are the first to use both in-vitro and in-vivo models as rationale for developing clinical trials for this high-risk patient populations. An upfront clinical trial in 1q+PFA patients has been purposed.
EPEN-04. CXorf67 MIMICS ONCOGENIC HISTONE H3 K27M MUTATIONS AND FUNCTIONS AS INTRINSIC INHIBITOR OF PRC2 FUNCTION IN AGGRESSIVE POSTERIOR FOSSA EPENDYMOMA
Authors: Jens-Martin Hübner, Torsten Müller, Dimitris N Papageorgiou, Jeroen Krijgsveld, Robert B Russell, David W Ellison, Stefan M Pfister, Kristian W Pajtler, Marcel Kool
Journal: Neuro-Oncology (2019)

Posterior fossa A (PFA) ependymomas comprise one out of nine molecular groups of ependymoma. PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark. Recently, we reported overexpression of CXorf67 as hallmark of PFA ependymoma and that CXorf67 can interact with polycomb repressive complex 2 (PRC2) thereby inhibiting EZH2. However, a detailed description of the functional domains of CXorf67 and the exact mechanism of EZH2 inhibition is still lacking. We now have performed mass spectrometry (MS) analyses of different CXorf67 protein truncates to identify functional domains in the CXorf67 protein involved in the binding of PRC2 core components. Our results show that PRC2 components like EZH2 and SUZ12 specifically bind to the C-terminal part of the CXorf67 protein. Overexpression of this C-terminal part of CXorf67 was sufficient to induce a strong downregulation of H3K27me3 in HEK293 cell lines. Upon inspection of the amino acid sequence in the C-terminus we discovered that a small, highly conserved amino acid sequence is responsible for binding and inhibition of EZH2 resulting in the perturbation of PRC2 function. A synthetic 21 amino acids long peptide containing these conserved amino acids completely abolished PRC2 activity in a methyltransferase assay. Strikingly, in silico analyses showed that the CXorf67 peptide mimics the H3K27M peptide and both can bind to the SET domain of EZH2, suggesting that the mechanism of EZH2 inhibition by CXorf67 was highly similar to the mechanism observed in pediatric high-grade gliomas harboring H3K27M mutations. Taken together, our findings shed light on the functional domains of CXorf67 and reveal a crucial oncogenic mechanism that may be exploited for targeted therapy in PFA ependymoma.
Bioactive peptides and proteins as alternative antiplatelet drugs
Authors: Kannan R.R. Rengasamy, Haroon Khan, Imad Ahmad, Devina Lobine, Fawzi Mahomoodally, Shanoo Suroowan, Sherif T.S. Hassan, Suowen Xu, Seema Patel, Maria Daglia, Seyed Mohammad Nabavi, Shunmugiah Karutha Pandian
Journal: Medicinal Research Reviews (2019)

Abstract Antiplatelet drugs reduce the risks associated with atherothrombotic events and show various applications in diverse cardiovascular diseases including myocardial infarctions. Efficacy of the current antiplatelet medicines including aspirin, clopidogrel, prasugrel and ticagrelor, and the glycoprotein IIb/IIIa antagonists, are limited due to their increased risks of bleeding, and antiplatelet drug resistance. Hence, it is important to develop new effective antiplatelet drugs, with fewer side‐effects. The vast repertoire of natural peptides can be explored towards this goal. Proteins and peptides derived from snake venoms and plants represent exciting candidates for the development of novel and potent antiplatelet agents. Consequently, this review discusses multiple peptides that have displayed antiplatelet aggregation activity in preclinical drug development stages. This review also describes the antiplatelet mechanisms of the peptides, emphasizing the signaling pathways intervened by them. Also, the hurdles encountered during the development of peptides into antiplatelet drugs have been listed. Finally, hitherto unexplored peptides with the potential to prevent platelet aggregation are explored.
Unplanned but proven obsolescence for 19 G endoscopic ultrasound needles
Authors: Pierre H. Deprez
Journal: Endoscopy (2019)

Who would have bet on a long life for 19 G needles used for endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA)? These large-bore needles have never been popular among endosonographers, mainly due to their stiffness and known technical failures, especially when used transduodenally. Until recently, however, they were still considered essential in diseases for which a core specimen and histology was mandatory for diagnosis.