tbuckley/cabot-search huggingface dataset:
LGG-17. DECREASED FUNCTION OF ISOPRENYLCYSTEINE CARBOXYLMETHYLTRANSFERASE RESULTS IN INCREASED SENSITIVITY TO CHEMORADIATION IN OLIGODENDROGLIOMA
Authors: David Altshuler, Vivekanand Yadav, Maria Ventosa Rosales, Maria Castro, Pedro Lowenstein
Journal: Neuro-Oncology (2019)

Oligodendroglioma is an indolent, chemosensitive glioma characterized by 1p/19q co-deletion. This loss of genetic information may be responsible for its unique treatment sensitivity. Our preliminary data suggests a role for the 1p gene, isoprenylcysteine carboxylmethyltransferase (ICMT). ICMT is the only enzyme to methylate prenylcysteine subtrates and has broad influence on lamin A function in the nucleus. We hypothesized that ICMT may be responsible for the unique treatment sensitivity of oligodendroglioma. An in vivo brain tumor model was established in ICMT knock-down transgenic mice whereby subventricular zone cells of neonates were transfected with oncogenic plasmids and a transposase to generate a tumor, recapitulating de novo glial oncogenesis. A Kaplan-Meier analysis was performed for mice treated with CCNU chemotherapy grouped according to ICMT expression levels from low to high by genotype (hypomorphic, heteromorphic, or wildtype). In vitro RNA interference studies were performed in glioma cell lines expressing a short-hairpin against ICMT. Procarbazine, carmustine, vincristine (PCV) and radiosensitivity assays were performed. The impact of ICMT inhibition on lamin A function was characterized by immunofluorescence. There was a significant difference in the median overall survival of CCNU treated transgenic mice by ICMT genotype. Hypomorphic mice had the longest median survival (91±29 days,n=9) compared to heteromorphs (78±19,n=14) and wildtype (72±44,n=16). In vitro, cells with ICMT inhibited demonstrated increased sensitivity to PCV and radiation. Lamin A immunofluorescence revealed disrupted nuclear membranes in ICMT-inhibited cells, suggesting potential increased sensitivity to DNA damaging agents. The 1p/19q co-deletion that is a characteristic of oligodendroglioma may be related to its unique treatment sensitivity. Preliminary in vivo and in vitro data implicate ICMT as a gene on chromosome 1p that may play an important role. Further characterization of the involved molecular mechanisms may lead to novel therapeutic strategies that exploit associated vulnerabilities in oligodendroglioma and other glial neoplasms. MEDULLOBLASTOMA
Microbiota as a cornerstone in the development of primary sclerosing cholangitis: paving the path for translational diagnostic and therapeutic approaches
Authors: Catherine Mooser, Stephanie Christine Ganal-Vonarburg
Journal: Gut (2019)

In the last decades, the proportion of host–microbiota interaction studies in biomedical research continuously increased, mainly driven by the quest for a better understanding of microbiota-associated human diseases. Among the numerous medical conditions the courses of which have been shown to be influenced by the microbiota, GI disorders and especially IBDs have been studied extensively, either in experimental murine models or in clinical studies (reviewed in ref 1). Among the plethora of immune pathways impacted and dysregulated by the microbiota and thus leading to pathologies, inflammasome signalling has been shown to severely affect the progression of GI disorders2 and to be associated with microbiota composition.3 Primary sclerosing cholangitis (PSC) represents a rare disease characterised by chronic inflammation and concomitant fibrosis of the biliary tree with a poor outcome. A microbiota-dependent pathogenesis of PSC, similar to that of IBD, has been suggested.4 However, the number of clinical and experimental studies addressing host–microbiota interactions in PSC remains limited. Rederivation of PSC models into germ-free conditions caused either attenuation or aggravation of the phenotype,5 emphasising the microbiota-dependent character of this pathology and …
Abstract 17762: Osteopontin is Associated with Vascular Smooth Muscle Cell Autophagy in Bicuspid Aortic Valve Aneurysm
Authors: Malcolm West, Maria Nataatmadja, Hong Lien Do, Jennifer West, Margaret Passmore, Sulistiana Prabowo, Andrew Dettrick, Fraser Russell
Journal: Circulation (2012)

Ascending thoracic aortic aneurysm (TAA) develops in about 35% of subjects with bicuspid aortic valve (BAV). It is a congenital disorder of unknown cause with a population prevalence of 1%-2%. In previous studies we have shown up-regulation of vascular smooth muscle cell (VSMC) apoptosis and cystic medial necrosis in the tunica media of BAV aneurysm tissue similar to Marfan syndrome (MFS) aortic aneurysm. In BAV but not MFS aneurysm we have identified in electron microscopy studies autophagy as an additional cause of VSMC loss. Osteopontin (OPN) exerts pro-inflammatory effects on VSMCs and has recently been shown to stimulate autophagy and down-regulate Notch1. In this study we examined apoptosis, autophagy and expression of OPN in human aortic aneurysm tissue. Thoracic aortic aneurysm tissue was obtained from subjects with BAV (6M; 5F; 31-75yr) and Marfan syndrome (MFS; 5M; 3F; 26-76yr) at the time of surgery. Normal thoracic aorta (TAC; 1M; 4F; 22-56yr) was obtained from organ donors. The number of VSMC...
Addition of an Intimate Partner Violence Intervention to a Nurse Home Visitation Program
Authors: Dara Grennan, Thomas B. Cole
Journal: JAMA (2019)

Susan M. Jack, RN, PhD; Michael Boyle, PhD; Christine McKee, MA; Marilyn Ford-Gilboe, RN, PhD; C. Nadine Wathen, PhD; Philip Scribano, DO, MSCE; Danielle Davidov, PhD; Diane McNaughton, RN, PhD; Ruth O’Brien, RN, PhD; Carolyn Johnston, RN, MA; Mariarosa Gasbarro, MA; Masako Tanaka, PhD; Melissa Kimber, PhD; Jeffrey Coben, MD; David L. Olds, PhD; Harriet L. MacMillan, CM, MD
DIPG-30. ISOFORM SPECIFIC OVEREXPRESSION OF WILMS’ TUMOR PROTEIN IN DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Sulgi Lee, Madhuri Kambhampati, Sridevi Yadavilli, Heather Gordish-Dressman, Krutika Gaonkar, Pichai Raman, Conrad Cruz, Roger Packer, M Isabel Almira-Suarez, Oren Becher, Adam Resnick, Sabine Mueller, Eugene Hwang, Javad Nazarian
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brain cancer constituting 10–15% of all central nervous system (CNS) tumors in children. Its anatomical location and infiltrative nature make it one of the most challenging tumors to treat. As such, targeted therapies are gaining more interest in CNS tumors. To identify a suitable therapeutic target, we evaluated publicly available gene expression data of pediatric glioblastoma specimens (n=34, GSE50161), DIPG specimens (n=35, GSE50021) and gene expression data of DIPG specimens from our previous dataset (n=5). Further analysis using 37 pediatric midline glioma specimens collected at autopsy in accordance with Children’s National Health System Institutional Review Board approval, indicated overexpression of one candidate protein, Wilms’ tumor protein (WT1), by immunohistochemistry. Interestingly, our immunohistochemistry and immunofluorescence analysis showed that WT1 in DIPG specimens is localized in the cytoplasm. Real-Time Quantitative Reverse Transcription PCR analysis using fresh frozen tumor specimens also showed that H3.3K27M-DIPG subtypes (n=3) to express higher levels of WT1 protein compared to those with H3.1K27M (n=2) (5.3 fold). More importantly, RNA-seq analysis of DIPG tumors (n=23) revealed specific transcriptome expression of WT1 transcript variant F. Nuclear export signal prediction analysis of the WT1 protein sequence translated by this transcript showed a higher nuclear export signal prediction score compared to other isoforms of WT1. Our findings suggest that WT1, particularly WT1 variant F, is a robust tumor specific antigen in DIPG, which may reveal its biological role in tumorigenesis and may have implications for clinical translation as an immunotherapeutic target.
Reducing tuberculosis transmission: a consensus document from the World Health Organization Regional Office for Europe
Authors: Giovanni Battista Migliori, Edward Nardell, Askar Yedilbayev, Lia D'Ambrosio, Rosella Centis, Marina Tadolini, Martin van den Boom, Soudeh Ehsani, Giovanni Sotgiu, Masoud Dara
Journal: European Respiratory Journal (2019)

Evidence-based guidance is needed on 1) how tuberculosis (TB) infectiousness evolves in response to effective treatment and 2) how the TB infection risk can be minimised to help countries to implement community-based, outpatient-based care. This document aims to 1) review the available evidence on how quickly TB infectiousness responds to effective treatment (and which factors can lower or boost infectiousness), 2) review policy options on the infectiousness of TB patients relevant to the World Health Organization European Region, 3) define limitations of the available evidence and 4) provide recommendations for further research. The consensus document aims to target all professionals dealing with TB ( e.g . TB specialists, pulmonologists, infectious disease specialists, primary healthcare professionals, and other clinical and public health professionals), as well as health staff working in settings where TB infection is prevalent.
Cancer drug resistance needs urgent attention, says research chief
Authors: Rebecca Coombes
Journal: BMJ (2019)

The biggest challenge facing cancer medicine today is that of drug resistance, a research leader has warned. Paul Workman, chief executive and president of the Institute of Cancer Research, told an audience in London that drug resistance in oncology was a little known problem but one that should be the “focus of all our activity.”

He told a Westminster Health Forum event on drug access, “We have had the success stories of Herceptin, leukaemia drugs, and treatment for prostate cancer. But we are seeing cancer evolution and drug resistance. We are seeing patients given the all clear who then come back for more treatment and find that they are drug resistant.”

One solution, said Workman, was to use combination treatments that attack cancer in …
HGG-09. A ROBUST CELL-FREE DNA (CFDNA) ASSAY TO DETECT MUTATIONS IN PLASMA SAMPLES OF PEDIATRIC HIGH GRADE GLIOMA PATIENTS DESPITE GENOMIC DNA (GDNA) CONTAMINATION
Authors: Agda Karina Eterovic, Nader Ezzeddine, Ping Song, Lin-ya Tang, Mohammad Mohammad, Shulin Li, Najat C Daw, Heather Meador, Jonathan Gill, Soumen Khatua, Michelle Hildebrandt, Wafik Zaky
Journal: Neuro-Oncology (2019)

Midline K27M gliomas are the most challenging type of gliomas in pediatric patients with very poor outcome (median survival, 9–12 months). Because their anatomic location, brainstem and thalamic gliomas are inoperable and hence no tissue is available to perform molecular analysis. Analysis of circulating biomarkers (liquid biopsies, including cfDNA) is a novel and promising, non-invasive alternative method for monitoring disease status that can tremendously facilitate biomarker screening for these pediatric patients. We have developed a robust cfDNA assay to detect genomic aberrations in plasma samples, despite genomic DNA contamination, which is a common issue in archival plasma samples. Our approach consisted of a modified droplet digital PCR (ddPCR) protocol that pre-selected the cfDNA molecules through the ligation of specific primers followed by PCR amplification. After pre-selection, cfDNA samples from 27 pediatric patients diagnosed with gliomas (17 diffuse intrinsic pontine glioma, 3 midline glioma, 7 high grade glioma) were screened using specific probes on a ddPCR platform to identify specific mutations in the H3F3A, PIK3CA and BRAF genes. Using this approach, we were able to identify low allele frequency mutations for H3F3A_K27M in 15 patients (62%; 11 with DIPG), PIK3CA_H1047R in 10 patients (37%), and BRAF_V600E with mutation allele frequencies ranging from 2% through 0.03% in 7 patients (26%). This very high sensitivity was achieved not only due to the nature of the ddPCR assay (1:20.000), but also due to the pre-selection of cfDNA molecules in our customized protocol. Since surgical resection is rarely an option for these patients, our non-invasive assay shows the feasibility of identifying these aberrations with a single blood sample. Additionally, because these mutations are associated with distinct prognosis and therapeutic implications, this cfDNA test can significantly impact clinical outcomes once implemented in a clinical lab to complement imaging for diagnosis and disease monitoring.
Abstract 16776: Circulating Androgens and the Risk of Atrial Fibrillation in Older Men: The Cardiovascular Health Study
Authors: Michael A Rosenberg, Molly M Shores, Alvin M Matsumoto, Leslie A Lange, Richard A Kronmal, Susan R Heckbert, Kenneth J Mukamal
Journal: Circulation (2017)

Introduction: Decline in serum androgens is common among older men and has been associated with cardiovascular disease, but the role of androgen levels in risk of AF has not been well defined. Meth...
A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia
Authors: Rosa Nguyen, Huiyun Wu, Stanley Pounds, Hiroto Inaba, Raul C. Ribeiro, David Cullins, Barbara Rooney, Teresa Bell, Norman J. Lacayo, Kenneth Heym, Barbara Degar, Deborah Schiff, William E. Janssen, Brandon Triplett, Ching-Hon Pui, Wing Leung, Jeffrey E. Rubnitz
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Abstract</h3> Consolidation therapies for children with intermediate- or high-risk acute myeloid leukemia (AML) are urgently needed to achieve higher cure rates while limiting therapy-related toxicities. We determined if adoptive transfer of natural killer (NK) cells from haploidentical killer immunoglobulin–like receptor (KIR)–human leukocyte antigen (HLA)-mismatched donors may prolong event-free survival in children with intermediate-risk AML who were in first complete remission after chemotherapy. Patients received cyclophosphamide (Day − 7), fludarabine (Days − 6 through − 2), and subcutaneous interleukin-2 (Days − 1, 1, 3, 5, 7, and 9). Purified, unmanipulated NK cells were infused on Day 0, and NK cell chimerism and phenotyping from peripheral blood were performed on Days 7, 14, 21, and 28. As primary endpoint, the event-free survival was compared to a cohort of 55 patients who completed chemotherapy and were in first complete remission but did not receive NK cells. Donor NK cell kinetics were determined as secondary endpoints. Twenty-one patients (median age at diagnosis, 6.0 years [range, 0.1–15.3 years]) received a median of 12.5 × 10<sup>6</sup> NK cells/kg (range, 3.6–62.2 × 10<sup>6</sup> cells/kg) without major side effects. All but 3 demonstrated transient engraftment with donor NK cells (median peak donor chimerism, 4% [range, 0–43%]). KIR–HLA-mismatched NK cells expanded in 17 patients (81%) and contracted in 4 (19%). However, adoptive transfer of NK cells did not decrease the cumulative incidence of relapse (0.393 [95% confidence interval: 0.182–0.599] vs. 0.35 [0.209–0.495]; <i>P =</i>&nbsp;.556) and did not improve event-free (60.7&nbsp;± 10.9% vs. 69.1&nbsp;± 6.8%; <i>P</i>&nbsp;= .553) or overall survival (84.2&nbsp;± 8.5% vs. 79.1&nbsp;± 6.6%; <i>P</i>&nbsp;= .663) over chemotherapy alone. The lack of benefit may result from insufficient numbers and limited persistence of alloreactive donor NK cells but does not preclude its potential usefulness during other phases of therapy, or in combination with other immunotherapeutic agents. <h3>Trial registration</h3> www.clinicaltrials.gov, NCT00703820. Registered 24 June 2008.
Association of Exposure to Infections in Childhood With Risk of Eating Disorders in Adolescent Girls
Authors: Lauren Breithaupt, Ole Köhler-Forsberg, Janne Tidselbak Larsen, Michael E. Benros, Laura Marie Thornton, Cynthia M. Bulik, Liselotte Petersen
Journal: JAMA Psychiatry (2019)

Infections are recognized as playing a critical role in the risk of psychiatric disorders and suicidal behavior; however, few studies have evaluated the risk of eating disorders.To evaluate the association of hospitalization for infections and treatment with anti-infective agents with the risk of an eating disorder diagnosis.A nationwide, population-based, prospective cohort study of 525 643 girls born from January 1, 1989, to December 31, 2006, and followed up until December 31, 2012, was conducted using individual-level data drawn from Danish longitudinal registers. Data were analyzed from January 15 to June 15, 2018, using survival analysis models and adjusted for age, calendar period, parental educational level, and parental history of psychiatric illness.Hospital admission for infections and prescribed anti-infective agents for infections.The main outcome of interest was diagnosis of an eating disorder (anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified) in a hospital, outpatient clinic, or emergency department setting. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and accompanying 95% CIs.The study population consisted of 525 643 adolescent girls: 2131 received a diagnosis of anorexia nervosa (median [range] age, 15.2 [8.6-21.3] years), 711 received a diagnosis of bulimia nervosa (median [range] age, 17.9 [13.4-22.7] years), and 1398 received a diagnosis of an eating disorder not otherwise specified (median [range] age, 15.6 [8.6-21.6] years). A total of 525 643 adolescent girls were followed up for 4 601 720.4 person-years until a mean age of 16.2 years (range, 10.5-22.7 years). Severe infections that required hospitalization were associated with an increased risk of a subsequent diagnosis of anorexia nervosa by 22% (HR, 1.22; 95% CI, 1.10-1.35), bulimia nervosa by 35% (HR, 1.35; 95% CI, 1.13-1.60), and eating disorder not otherwise specified by 39% (HR, 1.39; 95% CI, 1.23-1.57) compared with adolescent girls without hospitalizations for infections. Infections treated with anti-infective agents were associated with an increased risk of a subsequent diagnosis of anorexia nervosa by 23% (HR, 1.23; 95% CI, 1.10-1.37), bulimia nervosa by 63% (HR, 1.63; 95% CI, 1.32-2.02), and eating disorder not otherwise specified by 45% (HR, 1.45; 95% CI, 1.25-1.67) compared with adolescent girls without infections treated with anti-infective agents.The findings suggest that hospital-treated infections and less severe infections treated with anti-infective agents are associated with increased risk of subsequent anorexia nervosa, bulimia nervosa, and eating disorders not otherwise specified and that future studies should investigate whether these associations are causal and identify the exact mechanisms between infections and subsequent inflammatory processes with eating disorders.
MEDU-02. ABL1 AND 2 PLAY A KEY ROLE IN MEDULLOBLASTOMA GROUP 3 AND 4 TUMOR PROLIFERATION AND LEPTOMENINGEAL DISSEMINATION
Authors: Eric Thompson, Wafa Hassen, Jill Jones, Jacob Hoj, Ann Marie Pendergast
Journal: Neuro-Oncology (2019)

INTRODUCTION: The molecular underpinnings and treatment of leptomeningeal medulloblastoma metastases are not well characterized. The Abelson (ABL) family kinases play an important role in lung cancer cell migration, invasion, cell adhesion, and chemotherapy resistance. c-Abl is a key upstream regulator in the expression of c-myc in fibroblasts. The objective of this work was to elucidate the role of ABL kinases in medulloblastoma leptomeningeal dissemination. METHODS: ABL1 and ABL2 mRNA expression from a 272 pediatric tumor patient cohort and from a 767 medulloblastoma-only patient cohort was analyzed. ABL 1 and 2 protein expression from 7 medulloblastoma cell lines was determine using Western blots. shRNA was used to create stable double knockdowns of ABL1/2. The selective ABL1/2 inhibitors, nilotinib and GNF5, were used to determine their effect on medulloblastoma proliferation. RESULTS: In a cohort of 14 pediatric tumors, ABL1 and ABL2 expression was significantly higher in Group 3 and Group 4 medulloblastoma compared to other tumor types (P<0.05). In medulloblastoma patients, ABL1 and ABL2 levels were significantly higher in M+ than M0 patients (P=2.5x10-10 and 7.2x10-7, respectively) and overall survival was significantly reduced in patients with high ABL1 and 2 expression (P=6.9x10-3 and 7.8x10-5, respectively). ABL1 and 2 protein expression was robust in all cell lines. Knockdown of ABL1/2 significantly decreased c-myc expression (P<0.05). Pharmacologic inhibition of ABL1 and ABL2 resulted in significantly decreased cellular proliferation at 48 hours in multiple medulloblastoma cell lines. CONCLUSIONS: ABL1 and ABL2 are preferentially expressed in Group 3 and 4 medulloblastoma, in patients with metastases at diagnosis, and are associated with poor survival. Genetic inactivation of ABL1 and 2 resulted in decreased c-myc expression and pharmacologic inhibition resulted in decreased proliferation. This preliminary work suggests a role for ABL1/2 in the promotion of medulloblastoma leptomeningeal metastases and warrants further in vitro and in vivo exploration.
A blood-based prognostic biomarker in IBD
Authors: Daniele Biasci, James C Lee, Nurulamin M Noor, Diana R Pombal, Monica Hou, Nina Lewis, Tariq Ahmad, Ailsa Hart, Miles Parkes, Eoin F McKinney, Paul A Lyons, Kenneth G C Smith
Journal: Gut (2019)

We have previously described a prognostic transcriptional signature in CD8 T cells that separates patients with IBD into two phenotypically distinct subgroups, termed IBD1 and IBD2. Here we sought to develop a blood-based test that could identify these subgroups without cell separation, and thus be suitable for clinical use in Crohn's disease (CD) and ulcerative colitis (UC).
LRP6 Ectodomain Prevents SDF-1/CXCR4-Induced Breast Cancer Metastasis to Lung
Authors: Jiankang Zhang, Jinxiao Chen, Da Wo, Hongwei Yan, Peng Liu, En Ma, Limei Li, Liang Zheng, Daxin Chen, Zuoren Yu, Chunli Liang, Jun Peng, Dan-ni Ren, Weidong Zhu
Journal: Clinical Cancer Research (2019)

Lung metastasis is an important cause of breast cancer-related deaths, in which SDF-1/CXCR4 signaling pathway plays a critical role. Single transmembrane protein LRP6 is viewed as an oncogene via activating the Wnt/β-catenin signaling pathway. Our work aims to investigate the relationship between SDF-1/CXCR4 and LRP6 in breast cancer lung metastasis.We examined the expressions and functions of SDF-1/CXCR4 and LRP6 as well as their relationship in breast cancer in vitro and in vivo.LRP6 ectodomain (LRP6N) directly bound to CXCR4 and competitively prevented SDF-1 binding to CXCR4. LRP6N prevented SDF-1/CXCR4-induced metastasis to lung and prolonged survival in mice bearing breast tumors, whereas LRP6 knockdown activated SDF-1/CXCR4 signal transduction and promoted lung metastasis and tumor death. Furthermore, patients with breast cancer with high CXCR4 expression had poor prognosis, which was exacerbated by low LRP6 expression but improved by high LRP6 expression. Interestingly, a secreted LRP6N was found in the serum of mice and humans, which was downregulated by the onset of cancer metastasis in both mice bearing breast cancer as well as in patients with breast cancer.LRP6N might be a promising diagnostic marker for the early detection of breast cancer metastasis as well as an inhibitor of SDF-1/CXCR4-induced breast cancer metastasis. LRP6N also provides an interesting link between Wnt signaling and SDF-1/CXCR4 signaling, the two key pathways involved in cancer development.
Abstract 14410: Risk of Cardiovascular Events Among Persons Living With HIV in the Current Era
Authors: Robert S Rosenson, Lisandro D Colantonio, Demetria Hubbard, Keri L Monda, Stephanie R Reading, Ligong Chen, Paul J Dluzniewski, Greer A Burkholder, Paul Muntner
Journal: Circulation (2018)

Background: Studies from the early 2000s have shown that people living with human immunodeficiency virus (HIV) have a higher risk of atherosclerotic cardiovascular disease (CVD) compared to those w...
Serum Soluble Interleukin-2 Receptor as a Possible Biomarker for the Early Detection and Follow-up of Nivolumab-Induced Pneumonitis
Authors: Kazufumi Yoshida, Yuko Morishima, Toshihiro Shiozawa, Kensuke Nakazawa, Masashi Matsuyama, Takumi Kiwamoto, Yosuke Matsuno, Ikuo Sekine, Nobuyuki Hizawa
Journal: Journal of Thoracic Oncology (2019)