tbuckley/cabot-search huggingface dataset:
LGG-14. THE GENETIC LANDSCAPE OF DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS
Authors: Payal Jain, Lea F Surrey, Bo Zhang, Joshua Straka, Xiaonan Zhao, Phillip B Storm, Adam C Resnick, Brian N Harding, Marilyn M Li, Anna M Buccoliero, Mariarita Santi, Angela J Waanders
Journal: Neuro-Oncology (2019)

Classic dysembryoplastic neuroepithelial tumor (DNT) is a low-grade pediatric neoplasm defined histologically by specific glioneuronal elements with mucin-matrix floating neurons. However, many tumors preclude confident morphologic classification and are better designated as mixed neuronal-glial tumors (MNGTs). To determine if a molecular signature is associated with classic DNT morphology, we retrospectively examined the histological, genetic and molecular profile of a DNT/MNGT cohort. In this multi-institutional study, 34 patients with DNT (11) and MNGT (23) were included. Methodology included combinations of fusion detection by anchored multiplex PCR or RNA sequencing, sequence alterations in 238 cancer gene panel or whole genome by next generation sequencing (NGS), and copy number variants (CNVs) by genome wide array or NGS. A novel fusion was characterized by generating NIH3T3 stable cells for pathway analysis and transformation assays. Based on genetic profiles, tumors were classified as follows: ‘BRAF-altered’ included 23% (8/34) with BRAF V600E or BRAF-fusions; ‘FGFR-altered’ included 20.5% (7/34), where we further characterized the rare FGFR2-CTNNA3 fusion; ‘Other alteration’ encompassed 26% (9/34) with NTRK2 fusion, KDM5C and PDGFRA mutations or CNVs; ‘no alteration’ included 29% (10/34) with no known pathogenic mutations (variants of unknown significance excluded). Three patients had potential cancer predisposition syndromes (ATMx2, NF1). In cell models, FGFR2-CTNNA3 was an oncogenic driver activating MAPK/PI3K pathways. Overall, we found genetic alterations affecting MAPK/PI3K pathways in 44% (15/34) of tumors, including 20.5% with gene fusions. Given the spectrum of abnormalities and small cohort size, a definitive genetic profile distinguishing classic DNT from MNGT was not identified. However, all the BRAF-altered cases exhibited MNGT histology, whereas the other 3 sub-groups spanned both histologies. The BRAF-altered group also showed recurrence free survival (maximum follow-up of 60 months). This study highlights the genetic diversity prevalent across DNT/MNGT and the difficulty of assigning a molecular classifier to this tumor group.
GENE-15. HISTONE H3.3 MUTATIONS DRIVE TUMORIGENESIS THROUGH CHROMOSOMAL INSTABILITY
Authors: Florina-Nicoleta Grigore, Charles Day, Hana Yang, Edward Hinchcliffe, James Robinson
Journal: Neuro-Oncology (2019)

BACKGROUND: Heterozygous mutations in Histone H3.3 (K27M, G34R/V) occur in 70–80% of pediatric high-grade gliomas and 78% of diffuse intrinsic pontine gliomas (DIPG). These mutations are also found in low-grade gliomas that progress to higher grade tumors. Epigenetic dysregulation resulting from altered methylation at or near the mutated sites is believed to drive malignant transformation H3 differs from H3.1 by only 5 amino acids, which includes a unique phosphorylation site, Serine 31. S31 is phosphorylated by Chk1 kinase at pericentromeric heterochromatin in mitosis and on the arms of missegregated chromosomes. Masking S31 phosphorylation by antibody injection or using a non-phosphorylatable S31A substitution prevents cell cycle arrest in response to chromosome missegregation. OBJECTIVE: To determine if H3.3 K27M or G34R/V mutations alter the regulation of S31 phosphorylation to promote chromosome missegregation, aneuploidy, and tumorigenesis. METHODS: Live cell imaging and an established mouse model of glioma. RESULTS: DIPG cells with the K27M mutations show decreased mitotic Ser31 phosphorylation and increased chromosome missegregation. In both model cell lines and normal astrocytes, K27M and G34R mutations abolish S31 phosphorylation. Expression of S31A, K27M, or G34R mutants results in increased chromosome missegregation and aneuploidy, whereas cells expressing phosphomimetic double mutants (K27M/S31E or G34R/S31E) divide normally. Using the RCAS/TVA mouse model, H3.3WT, K27M, and S31A constructs were introduced into the brains of newborn mice along with mouse BRAFV600E. 0/13 tumors developed in the BRAFV600E + H3.3WT cohort; however, 80% (16/20) of H3.3K27M + BRAFV600E and 70% (7/10) H3.3S31A + BRAFV600E cohorts developed high-grade gliomas within 100 days. CONCLUSION: A single heterozygous H3.3 mutation is sufficient to generate aneuploid cells, allows them to reenter the cell cycle and to promote tumorigenesis. Restoring cell cycle checkpoint activity by modulating S31 phosphorylation may be a rational treatment for DIPG or to prevent the progression of low-grade gliomas with H3.3 mutations.
Ramesh Chandra Joshi
Authors: Alan Cunnington, Anil Joshi, Raj Joshi
Journal: BMJ (2019)

Ramesh Chandra Joshi had a long and distinguished career as a consultant physician in respiratory medicine, during which he developed a modern respiratory medicine service, including a first class clinical measurement unit at Walsall Manor Hospital. He was born in Kanpur, India. Both of his parents, Sohan Lal Joshi and Dayawati Joshi, and his grandparents were doctors. He lived an interesting early life before and after the partition of India. His family became the first car owners in the area; they had a black Morris, the only make and colour available. He had a menagerie of pets, including stray dogs, mynah birds, and a monkey (which did not stay in the household for long). During the summer months, as he grew older, he used to visit the hill station of Nainital, enjoying walking by himself in the foothills of the Himalayas.

Ramesh's first intention was to join the Indian Air Force, but when he presented the recruitment document to his father for approval it was immediately ripped up. However, their loss was definitely a gain for medicine and for all the people he treated during his long …
Screening Preteens in the Emergency Department for Suicide Risk
Authors: Rita Rubin
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
ATRT-04. UNBIASED METABOLIC PROFILING OF ATYPICAL TERATOID/RHABDOID TUMORS PREDICTS SENSITIVITY TO GLUTAMINE METABOLIC INHIBITORS
Authors: Sabrina Wang, Brad Poore, Jesse Alt, Antoinette Price, Sariah Allen, Brent Orr, Rana Rais, Barbara Slusher, Charles Eberhart, Eric Raabe, Jeffrey Rubens
Journal: Neuro-Oncology (2019)

Atypical teratoid rhabdoid tumors (AT/RT) are deadly tumors of infancy in need of new, targeted therapies to reduce morbidity and improve survival. Molecular analyses have revealed considerable molecular heterogeneity dividing AT/RT into three distinct subgroups. MYC expression is identified in a particularly aggressive subgroup of AT/RT. MYC is challenging to target directly given large, flat, featureless protein-protein binding sites. To identify anomalies that can be targeted in high MYC-expressing AT/RT, we performed unbiased metabolic profiling of each of our 8 AT/RT cell lines using high pressure liquid chromatography mass spectrometry (HPLC-MS). Partial Least Squares-Discriminant Analysis (PLS-DA) identified a distinct metabolic profile in high MYC-expressing cell lines. Further pathway analysis highlighted unique patterns of glutamine utilization in these cell lines. In fact, high-MYC expressing cell lines were more dependent on glutamine for growth and survival (MTS assay, glutamine-free media vs normal media). Due to this dependence on glutamine metabolism, we hypothesized that high-MYC expressing AT/RT would be especially sensitive to glutamine metabolic inhibitors. We showed that the glutamine analogue, 6-diazo-5-oxo-L-norleucine (DON) slowed high-MYC expressing AT/RT cell growth (MTS assay, p<0.001), induced high rates of apoptosis (C-PARP by western blot), and improved survival in orthotopic mouse models (p<0.01 by log-rank test). In contrast, low-MYC expressing models were relatively resistant to DON. Metabolic flux experiments showed that DON inhibited glutamine-dependent synthesis of glutathione, depleting cells of intracellular glutathione. This DON-induced depletion of glutathione sensitized cells to carboplatin, leading to increased AT/RT cell death (cell viability assay, p<0.001 by ANOVA) and extended survival in mice bearing AT/RT orthotopic xenografts (p< 0.001 by log rank test). We aim to translate these findings into a new clinical trial to improve survival in this deadly disease.
To strive is human, to abuse malign: discrimination and non-accidental violence of professional athletes without employee-style statutory protection
Authors: Victoria Louise Roberts, Victor Eduardo Sojo
Journal: British Journal of Sports Medicine (2019)

A recent judgement from a landmark employment case against British Cycling and UK Sport found that Jess Varnish, a former professional British cyclist, was neither an employee nor a worker of either organisation within the meaning of the Employment Rights Act 1996 or the Equality Act 2010. The relationship between the cyclist and British Cycling was judged to be more akin to a relationship between a student and a University (eg, service provider), and that funding provided to the cyclist by UK Sport was analogous to a grant.1

Jess Varnish brought her claims of unfair dismissal (ie, termination of her Athlete Performance Award, which is a means-tested financial contribution towards an athlete’s living expenses), direct sex discrimination, victimisation and unlawful detriment for having made protected disclosures (ie, whistle-blowing) to the Employment Tribunal.1 She sought protections offered to employees or workers but not offered to professional athletes.

The case highlights a problem: athletes are not considered to be employees nor workers and therefore are not entitled to employee nor worker protection, but no other equivalent form of protection for athletes exists.

Why …
Abstract 12961: No Effect of Hepatic Impairment on the Pharmacokinetics of Serelaxin, a Recombinant Human Relaxin-2 in Development for the Treatment of Acute Heart Failure
Authors: Zhanna Kobalava, Atef Halabi, Andreas Zähringer, Yinuo Pang, Marion Dahlke
Journal: Circulation (2013)

Introduction: The RELAX-AHF (Relaxin in Acute Heart Failure [AHF]) Phase lll study (NCT00520806) examined the effects of serelaxin (recombinant human relaxin-2) in patients with AHF, and demonstrat...
Parity, breastfeeding and breast cancer risk by hormone receptor status in women with late age at first birth - A case-control study
Authors: Sarah Lord, Leslie Bernstein, Karen Johnson, Kathi Malone, Linda Weiss, Jill McDonald, Giske Ursin
Journal: Cancer Research (2007)

2610  Early age at first term pregnancy and increasing parity (number of term pregnancies) are consistently associated with a reduced risk of estrogen and progesterone receptor (ERPR) positive breast cancer, whereas breastfeeding reduces the risk of both receptor positive and receptor negative cancers. The protection afforded by an early first term pregnancy is more clearly observed after completion of women’s reproductive years. We investigated whether age at first term pregnancy and breastfeeding modify the effect of parity on risk of ERPR-positive and ERPR-negative breast cancer in postmenopausal women to gain greater understanding of these associations.  We used data collected from 995 incident invasive breast cancer case patients (728 ERPR-positive, 267 ERPR-negative) and 1498 control subjects aged 55 years or older who participated in the Women’s Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case-control study of breast cancer in White and African American women. We stratified parous women by age at first birth (  The protective effect of ever having a term pregnancy on ERPR-positive tumors was observed among women who gave birth before age 25 years (OR =0.59, 95% CI=0.42-0.82), but not among women with first birth at age 25 years or later (OR=1.05, 95% CI=0.73-1.51). Further, among women who first gave birth after age 25 years, ever having a term pregnancy was associated with an increased risk of ERPR negative cancers (OR=2.07, 95% CI=1.03-4.16). Additional pregnancies after the first further increased this risk (p trend=0.03).  Breastfeeding was protective for both receptor subtypes regardless of when women first gave birth. Further, the protective effect of parity on ERPR-positive cancers was only observed among women who breastfed (p-trend 0.001), but not among those who never breastfed (p-trend 0.29). Among those with a first birth at age 25 years or later who never breastfed, parity was associated with an increased risk of breast cancer, both for ERPR positive (p-trend 0.04) and ERPR negative breast cancer (p trend 0.02). No such statistically significant increased risk was observed among women who had ever breastfed.  These findings suggest that the effect of parity on a woman’s long-term risk of ERPR-positive and ERPR-negative breast cancer is modified by age at first birth and by breastfeeding. In women with delayed childbirth who do not benefit substantially from the protective effects of an early pregnancy, breastfeeding may offer broad benefits.
TEMPORARY BILIARY METAL STENT PLACEMENT IN THE CYSTIC DUCT AS AN AID TO CHOLANGIOSCOPY-GUIDED LASER LITHOTRIPSY OF MIRIZZI SYNDROME (MS)
Authors: R Sanchez-Ocaña, A Yaiza Carbajo, FJ Garcia-Alonso, M De Benito, S Bazaga, J Tejedor, C De la Serna Higuera, M Perez-Miranda
Journal: Endoscopy (2019)

Cholangioscopy-guided lithotripsy is a minimally invasive alternative to surgical treatment of Mirizzi Syndrome (MS).
Identification of myeloid cells in the human enthesis as the main source of local IL-23 production
Authors: Charlie Bridgewood, Abdulla Watad, Tobias Russell, Timothy M Palmer, Helena Marzo-Ortega, Almas Khan, Peter A Millner, Robert Dunsmuir, Abhay Rao, Peter Loughenbury, Miriam Wittmann, Richard J Cuthbert, Dennis G McGonagle
Journal: Annals of the Rheumatic Diseases (2019)

We investigated whether the normal human spinal enthesis contained resident myeloid cell populations, capable of producing pivotal proinflammatory cytokines including tumour necrosis factor (TNF) and interleukin (IL)-23 and determined whether these could be modified by PDE4 inhibition.Normal human enthesis soft tissue (ST) and adjacent perientheseal bone (PEB) (n=15) were evaluated using immunohistochemistry (IHC), digested for myeloid cell phenotyping, sorted and stimulated with different adjuvants (lipopolysaccharide and mannan). Stimulated enthesis fractions were analysed for inducible production of spondyloarthropathy disease-relevant mediators (IL-23 full protein, TNF, IL-1β and CCL20). Myeloid populations were also compared with matched blood populations for further mRNA analysis and the effect of PDE4 inhibition was assessed.A myeloid cell population (CD45+ HLADR+ CD14+ CD11c+) phenotype was isolated from both the ST and adjacent PEB and termed 'CD14+ myeloid cells' with tissue localisation confirmed by CD14+ IHC. The CD14- fraction contained a CD123+ HLADR+ CD11c- cell population (plasmacytoid dendritic cells). The CD14+ population was the dominant entheseal producer of IL-23, IL-1β, TNF and CCL20. IL-23 and TNF from the CD14+ population could be downregulated by a PDE4I and other agents (histamine and 8-Bromo-cAMP) which elevate cAMP. Entheseal CD14+ cells had a broadly similar gene expression profile to the corresponding CD14+ population from matched blood but showed significantly lower CCR2 gene expression.The human enthesis contains a CD14+ myeloid population that produces most of the inducible IL-23, IL-1β, TNF and CCL20. This population has similar gene expression profile to the matched blood CD14+ population.
Microbiological changes observed over 48 weeks of treatment with inhaled liposomal ciprofloxacin in individuals with non-cystic fibrosis bronchiectasis and chronic Pseudomonas aeruginosa lung infection
Authors: D.R. VanDevanter, I. Gonda, J. Dahms, D. Cipolla, A.M. Davis, J.D. Chalmers, J. Froehlich
Journal: Clinical Microbiology and Infection (2019)
GENE-18. PAN-OMIC ANALYSIS OF DIFFUSE INTRINSIC PONTINE GLIOMA FROM CHILDREN ENROLLED IN THE PNOC003 PRECISION MEDICINE TRIAL IDENTIFIES OPPORTUNITIES AND CHALLENGES IN CLINICAL IMPLEMENTATION OF A MULTI-OMICS SEQUENCING APPROACH
Authors: Payal Jain, Sabine Mueller, Winnie S Liang, Eshini Panditharatna, Bo Zhang, Yuankun Zhu, Madhuri Kambhampati, Cassie Kline, Lindsay Kilburn, Nalin Gupta, Xiaodong Yang, Kellie Nazemi, Suresh N Magge, John Crawford, Anu Banerjee, Roger J Packer, Alison Roos, Joanna Philips, David Solomon, Annette Molinaro, Sridevi Yadavili, John Kuhn, Sara A Byron, Michael Prados, Javad Nazarian, Michael Berens, Adam C Resnick
Journal: Neuro-Oncology (2019)

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is an infiltrative, inoperable midline tumor with devastating outcomes. We have recently completed a prospective clinical trial for children and young adults with newly diagnosed DIPG that included clinical whole exome sequencing (WES) and RNA sequencing (RNAseq) of tumors and development of a personalized treatment plan. In this study, we retrospectively expanded sequencing efforts to include whole genome sequencing (WGS) and methylation profiling of paired tumor/normal (T/N) samples as well as longitudinal tumor specimens. We sought to perform a pan-omics analysis to determine which sequencing platform combination could most benefit patient outcomes in future precision medicine DIPG trials. METHODS: Thirty-three DIPG patients underwent successful biopsy in PNOC003. Clinical WES/exome panel sequencing and RNAseq was generated for 30 primary tumors and 2 progression tumors. We performed research-based WGS and methylation profiling of all tumors to do a pan-omics analysis. Cross-platform analysis was performed to compare WGS and WES and define additional mutations. RESULTS: In addition to WES and RNAseq, we performed WGS on all 33 primary T/N pairs, 2 progression samples, and 3 autopsy samples. Methylation profiling was done on 30 primary, 1 recurrent and 6 autopsy tumor samples. WGS identified all the actionable coding alterations called by WES and further identified non-coding variants of potential clinical significance. A pan-omics analysis spanning WGS, WES, RNAseq and methylation data is being performed. Tumor evolution was demonstrated by longitudinal comparison of genetic alterations across primary, recurrent and autopsy tumor samples to highlight tumor-intrinsic versus treatment-driven alterations in DIPGs. DISCUSSION: The ongoing pan-omic analysis from PNOC003 has begun informing the next generation of molecularly-driven DIPG clinical trials by suggesting inclusion of WGS in clinical sequencing panels as well as offering additional insights into the diverse mutational landscape of DIPGs.
Diagnosis and immunotherapy of mould allergy
Authors: H.‐J. Malling, S. Dreborg, B. Weeke
Journal: Allergy (1987)

The IgE‐response was evaluated by skin prick test, bronchial provocation test and RAST in a 1‐year placebo‐controlled double‐blind immunotherapy study. Eleven adult asthmatics were treated with a Cladosporium allergen preparation and 11 comparable patients received histamine placebo. The bronchial sensitivity (PC 20 ) decrease &gt; 0.5 log step in 8/11 (73%) Cladosporium ‐treated versus 3/11 (27%) in the placebo group. Corresponding figures for skin prick test sensitivity was 10/11 (91%) and 1/11 (9%) respectively. Circulating IgE showed a temporary boost in the Cladosporium group and then values approaching the pretreatment value. Only minimal and insignificant changes were found in the placebo‐treated patients. Changes in IgE‐reactivity were not related to allergen dose, clinical efficacy or to the occurrence of side effects. Some interrelation between changes in skin prick test, bronchial provocation test and RAST was found indicating a differentiated effect of immunotherapy on various IgE compartments. In spite of the pathogenetic role of IgE in allergic diseases, changes in IgE‐reactivity do not seem directly involved in the mechanisms underlying the clinical efficacy of immunotherapy but might be of importance in a complex interaction with other immunological parameters.
IMMU-08. UNLOCKING CANCER IMMUNOTHERAPY AGAINST PEDIATRIC BRAIN TUMORS WITH TRANSCRIPTOME LOADED NANOPARTICLES
Authors: Elias Sayour, Sridharan Gururangan, Brian Stover, Adam Grippin, James McGuiness, Frances Weidert, Loic Deleyrolle, Bikash Sahay, Sheila Carrera-Justiz, Hector Mendez-Gomez, Duane Mitchell
Journal: Neuro-Oncology (2019)

BACKGROUND: Pediatric brain tumors are poorly immunogenic preventing current immunotherapies (i.e. checkpoint blockers) from having significant activity. Unlocking immunotherapy against these malignancies is predicated on reprogramming their immunogenicity. OBJECTIVE/METHODS: We developed a novel treatment platform, which leverages the use of clinically translatable lipid-nanoparticles (NPs) combined with tumor derived mRNA that simultaneously function as both vaccines and immunomodulating agents to reprogram the systemic/local microenvironments of pediatric brain cancers. RESULTS: Systemic tumor mRNA-NPs localize to lymphoid organs (i.e. liver, spleen lymph nodes) and to the intratumoral milieu, activating the immunologic microenvironment therein through release of type I interferon from plasmacytoid dendritic cells. This culminates in a CD4 and CD8 central memory T cell response against H3.1K27M murine gliomas. In immunologically resistant murine tumor models, RNA-NPs induce robust anti-tumor efficacy and mediate synergistic activity in settings where immune checkpoint inhibitors (i.e. anti-PD-L1 therapy) do not confer therapeutic benefit. We demonstrate safety of RNA-NPs in acute/chronic murine toxicity studies and in a client-owned canine (pet dog) diagnosed with a malignant glioma. In our first canine subject, RNA-NPs elicited activation of dendritic cells, release of type I interferon and activation of CD8+ T cells. CONCLUSION: RNA-NPs bypass MHC restriction and can be made readily available for all patients (and not only HLA specific haplotypes); they also provide a renewable antigen resource that can be used to continuously vaccinate patients for months/years after diagnosis. Through partnership with the Pacific Pediatric Neuro-Oncology Consortium (PNOC), we are in the final stages of FDA-IND submission before first-in-human trials.