tbuckley/cabot-search huggingface dataset:
RADI-19. DIFFUSION KURTOSIS IMAGING CAN HELP DIFFERENTIATE LOW- AND HIGH-GRADE GLIOMAS IN PEDIATRIC PATIENTS WITH SPECIFIC LOCATION-RELATED PATTERNS: A PROSPECTIVE SINGLE CENTRE STUDY
Authors: Ioan Paul Voicu, Antonio Napolitano, Chiara Carducci, Lorenzo Lattavo, Andrea Carai, Maria Camilla Rossi Espagnet, Maria Vinci, Antonella Cacchione, Angela Mastronuzzi, Paolo Tomà, Giovanna Stefania Colafati
Journal: Neuro-Oncology (2018)

To investigate whether diffusion kurtosis imaging (DKI) differentiates pediatric low- and high-grade midline and hemispheric gliomas (mLGG, mHGG, hLGG and hHGG). MATERIALS AND After obtaining informed consent, fourteen children (median age 7.4 years, 8 males) with midline gliomas and eighteen children (median age 9.6 years, 9 males) with hemispheric gliomas were prospectively studied on a 3T magnet. Conventional and DKI sequences (30 directions, 3 b values: 0, 1000, 2000) acquired with simultaneous multislice technique (SMS) were obtained. Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK) and fractional anisotropy (FA) values were calculated. The enhancing and nonenhancing tumor volumes (VOIs) were segmented semiautomatically. Mean and highest 20 percentile (H20%) DKI values in tumor VOIs were calculated for each metric. Differences among DKI values in the enhancing and nonenhancing VOIs between LGG and HGG of each group were assessed with an independent sample t-test. After excluding three patients for artifacts, the scans of twelve children (8 mLGG and m4 HGG) with midline gliomas and seventeen children (12 mLGG and 5 mHGG) with hemispheric gliomas were analysed. In midline gliomas, significantly different H20% FA, mean MK, H20% MK, mean AK and H20% AK values were found in the nonenhancing tumor VOI (p<0.05, p<0.008, p<0.007, p<0.045 and p<0.001respectively). In hemispheric gliomas, significantly different mean RK, H20%RK, mean MK and H20% MK values were found in the enhancing tumor VOI (p<0.003, p<0.007, p<0.004 and p<0.001 respectively). DKI can help differentiate low and high-grade gliomas in pediatric patients with location-related patterns.
Defining endemic cholera at three levels of spatiotemporal resolution within Bangladesh
Authors: Daryl Domman, Fahima Chowdhury, Ashraful I. Khan, Matthew J. Dorman, Ankur Mutreja, Muhammad Ikhtear Uddin, Anik Paul, Yasmin A. Begum, Richelle C. Charles, Stephen B. Calderwood, Taufiqur R. Bhuiyan, Jason B. Harris, Regina C. LaRocque, Edward T. Ryan, Firdausi Qadri, Nicholas R. Thomson
Journal: Nature Genetics (2018)
12 Audit to assess the local blood transfusion practise in patients who present with acute upper gastrointestinal bleeds in muhimbili national hospital, dar es salaam, tanzania
Authors: J Tham
Journal: Gut (2017)

Background  Blood transfusion is a major component in the treatment of acute upper gastrointestinal bleeding. Its safety has been questioned in the treatment of less severe cases. A large randomised controlled trial showed significant reductions in re-bleeding and mortality rates in patients who were randomised to a restrictive policy (transfused when haemoglobin was less than 7 g/dL) compared to a liberal policy (transfused when haemoglobin was less than 9 g/dL).  Aim  The aim of this study is to identify whether Muhimbili National Hospital in Tanzania follows the evidence-based medicine that a restrictive policy in blood transfusion is advantageous in the treatment of acute upper gastrointestinal bleeding.  Method  I performed a prospective audit of patients presenting to Mulhimbili National Hospital (MNH) with AUGIB to assess the current transfusion practice in this patient group. During a 3 week period I identified patients admitted to MNH who presented with meleana and haematemesis. I collected data about haemoglobin levels and blood transfusion from patient’s notes.  Results  89.5% of patients who presented with haemoglobin  9 g/dL did receive a blood transfusion.  Conclusions  Muhimbili National Hospital in Dar Es Salaam in Tanzania do not follow the evidence-based medicine that restrictive policy in blood transfusion in acute upper gastrointestinal bleeding is beneficial compared to liberal blood transfusion.
The Value of Clinical Colorectal Cancer Registries in Colorectal Cancer Research
Authors: Caroline MacCallum, Anita Skandarajah, Peter Gibbs, Ian Hayes
Journal: JAMA Surgery (2018)

Clinical colorectal cancer registries (CCCRs) are potentially powerful tools in colorectal cancer research. They are resource intensive, but to our knowledge, no formal review of their value exists. While quality control, clinical audit, and benchmarking are important factors in assessing the value of maintaining CCCRs, they are difficult to quantify. This study focuses on registry research output as a measure of value; the study hypothesizes that CCCRs do not produce sufficient published research output of clinical significance to justify the resources required to maintain them.To assess the value of maintaining CCCRs by identifying and characterizing existing CCCRs and measuring their comparative research impact.We searched MEDLINE (PubMed) and Google Scholar for articles published from January 1990 to July 2016 that identified multi-institutional CCCRs with peer-reviewed published outcomes. Purely population-based registries were excluded. We then searched the same databases in the same time period for articles that were published by each included CCCR. The articles must have been based on outcomes relating to individual CCCR data. We categorized published outcomes into oncological, surgical, or other outcomes. We measured the research impact of each CCCR using the number of articles, citation index, impact factor, and Altmetric score.A total of 18 CCCRs were identified, with sample sizes between 104 and 1 400 000 cases. Data fields, published aims, and outcomes were similar between registries. The most frequently published outcomes related to anastomotic leak following colorectal surgery. The National Cancer Database formed the basis of the highest number of publications (66), the Northern Region Colorectal Cancer Audit Group had the highest median article citation number (28.5), the National Bowel Cancer Audit had the highest median impact factor (4.72), and the National Cancer Database had the highest median Altmetric score (4.5).There is a significant body of colorectal cancer outcomes research generated from the CCCRs. However, given the enormous resources required, the overall research output and impact of CCCRs is low in proportion to the size of the data sets. These registries hold key oncological and surgical outcomes data; focusing on data linkage between registries and developing automated data collection will enable international comparisons in colorectal cancer management and will increase the research impact of CCCRs, thereby increasing their value.
IMMU-02. PROTEOMIC ANALYSIS IDENTIFIED CECR1 MEDIATED RESPONSE IN MACROPHAGE AND TUMOR ASSOCIATED MACROPHAGE
Authors: Changbin Zhu, Yang Zhao, Johan Kros, Caroline Cheng, Jie Ma
Journal: Neuro-Oncology (2018)

Macrophage is of importance in both innate and tumor immunity. In malignant cancers, tumor associated macrophages with various phenotypes are widely distributed. M2-like tumor associated macrophages are capable of promoting tumor development. CECR1, as a defined M2-like TAM expressed protein, promotes M2 macrophage differentiation and promotes glioma development. However, the intracellular alteration by CECR1 in macrophage was remained to be unclear.THP-1 macrophage was knockdowned CECR1 by siRNA in vitro followed by co-stimulation of U87 cells. Cell lysate was analyzed by (nano)LC-MS. Significantly altered proteins were defined by P value< 0.05 followed by pathway analysis using STRING, Cytoscape. Key molecules were validated by real-time PCR and western blot at both transcription and translation level. In THP-1 macrophage, 67 proteins were enriched in cells with CECR1 knockdown which were mapped into three major pathways that most relevant to macrophage functions such as MHC I antigen presentation, Phagosome maturation and Endocytosis. U87 cells mediated macrophage response to CECR1 knockdown was related to the proliferation aspect mediated by attenuation of Proteasome formation. Further analysis showed U87 cells down regulated molecules involved in immune response, phagocytosis as well as endocytosis. There were two molecules S100A9, PLAU were down regulated by CECR1 knockdown in macrophages with/without U87 co-culture. LAT2 was the only protein upregulated by CECR1 knockdown in U87 co cultured macrophages which displayed a IL-10 low, IL-12 high M1-like phenotype. Thus, suppressing CECR1 expression in macrophages with/without U87 co-culture favored an anti-tumor phenotype by various approaches. CECR1 in macrophages would be a promising target of tumor immunotherapy.
ATRT-12. TARGETING SIRT2 IN SMARCB1 DEFICIENT ATRT
Authors: Irina Alimova, Sujatha Venkataraman, Angela M Pierce, Diane Birks, Rajeev Vibhakar, Nicholas K Foreman, Min Yang, Hinning Ling
Journal: Neuro-Oncology (2018)

Atypical Teratoid Rhabdoid Tumor (ATRT) is a highly aggressive and malignant pediatric brain tumor with poor outcomes. The central mechanism of ATRT tumorigenesis is SMARCB1 deficiency that leads to epigenetic dysregulation. To identify key epigenetic regulators that co-operate with SMARB1 deficiency and contribute to the tumorigenesis of ATRT, we performed an RNAi-based functional genomic screen. We targeted 406 genes associated with epigenetic regulation in ATRT cell lines. This screening revealed Sirtuin2 (SIRT2) as one of the top targets required for continued cell growth. SIRT2 is an NAD(+) (nicotinamide adenine dinucleotide)-dependent deacetylase and involved in the direct deacetylation of α-tubulin and histone H4. Inhibition of SIRT2 promotes c-Myc ubiquitination and degradation. C-Myc is an oncogene and highly expressed in ATRT, so SIRT2 is a promising target to treat c-Myc driven cancers. Genetic inactivation of SIRT2 with shRNA significantly suppressed ATRT cell growth, decreased c-Myc expression and activated p53. Recent studies suggest that targeting SIRT2 by small molecule inhibitors is a promising approach to tumor therapy. We found that chemical inhibition SIRT2 with AGK2,Tenovin6 and Thiomyristoyl (TM) significantly decreased cells growth, inhibited clonogenic potential, suppressed c-Myc level, and decreased S-phase length. In vivo, Tenovin6 and TM limited ATRT tumor growth both in flank and in intracranial mouse model due to increased apoptosis as measured by cleaved caspase 3 and decreased ki67 proliferative index. Moreover, TM treatment increased mice survival. In summary, we demonstrated that ATRT can be targeted by chemical or genetic SIRT2 inhibition.
MBCL-17. EPIDEMIOLOGY, TREATMENT AND OUTCOMES OF INFANT MEDULLOBLASTOMA: A SINGLE CENTRE STUDY IN SINGAPORE
Authors: Enrica Tan, Aubrey Pagaduan, Lee Ping Ng, Sharon Low
Journal: Neuro-Oncology (2018)

Historically, young children less than 3 years old with medulloblastoma have worse survival rates than older counterparts whose adjuvant therapy include craniospinal irradiation. Their poorer prognosis may be explained by frequent metastases and different biology. Desmoplastic histology has been associated with more favourable outcomes. MATERIALS AND Retrospective analysis of 11 children less than 3 years of age diagnosed with medulloblastoma between 1997 to 2015 was conducted. Data on patient demographics, tumour characteristics, treatment and survival was obtained from Singapore Children’s Cancer Registry and case records. Median age of diagnosis was 1.8 years (0.29 to 2.86). Male: female ratio was 2.7:1. Metastatic disease was found in 5 patients at diagnosis (45%). Gross total resection was achieved in 7 cases (64%). Histology subtyping showed 3 nodular/desmoplastic, 2 large cell/anaplastic, 2 classic and 2 not-otherwise specified, and two were unknown. Molecular subtyping via nanoString was performed on 7 available archival samples. One infant was too ill for any adjuvant therapy. Eight patients were treated with a baby brain chemotherapy strategy and 2 patients received intensive chemotherapy as per Headstart II protocol. There are 3 survivors, with a median follow-up of 18 years (2.8 - 19.8) and include the only two patients with localized nodular/desmoplastic medulloblastoma. They had been treated with a baby brain chemotherapy with no radiotherapy. Optimal treatment of infant medulloblastoma remains challenging. Nodular/desmoplastic histology and localized disease portend a better prognosis.
Abstract B35: NR2F1 limits early dissemination and phenotypic plasticity of early-progressed ErbB2+ tumor cells by maintaining luminal differentiation
Authors: Maria Soledad Sosa, Julie Cheung, Julio A. Aguirre-Ghiso
Journal: Cancer Research (2016)

Abstract Tumor cells derived from MMTV-Neu primary tumors (tumor-derived cells, TDC) are known to be able to complete all steps of the metastatic cascade. However, new evidence shows that cells derived from early stages of tumor progression (before detection of palpable tumors, ErbB2+ early-progressed tumor cells, EPTC) can disseminate and, as disseminated tumor cells (early DTCs), enter a non-proliferative state for prolonged periods at secondary organs. When EPTC are co-cultured with TDC, the tumor sphere formation capacity of the later is increased suggesting a synergistic contribution of early-progressed tumor cells to the growth of TDC. Thus, early DTCs are proposed to contribute to metastasis, but the mechanisms that would allow these cells, considered sessile and with few genetic alterations, to complete all steps of metastasis are unknown. Here we report that the orphan nuclear receptor NR2F1 is downregulated in human pre-malignant and malignant lesions and mouse ErbB2+ EPTC and TDC when compared with normal mammary tissue. In ErBb2+ EPTC further downregulation of NR2F1 activates a motile phenotype and this is coincident with the detection of circulating tumor cells (CTCs) and DTCs in lungs and bone marrow. Knock down of basal NR2F1 levels in ErBb2+ EPTC induced cell motility, loss of laminin-V deposition, β-catenin delocalization from the membrane and dramatic loss of E-cadherin junctions. Interestingly, TWIST, SMAD2, CK14 and ROR1 levels became upregulated upon NR2F1 depletion. This anti-EMT NR2F1-regulated program is ErbB2 oncogen-dependent. These results suggest that NR2F1 expression maintains epithelial identity and suppresses epithelial-mesenchymal transition (EMT), possibly by blocking WNT signaling. Knock down of NR2F1 in ErBb2+ EPTC also enhanced mammosphere formation efficiency and this was accompanied by upregulation of the pluripotency transcription factor NANOG and TWIST. These findings suggest that NR2F1 limits the spreading of ErBb2+ EPTC cells and it promotes a luminal differentiation-associated program by limiting the activation of a stem cell-like program. Our findings provide for the first time evidence that NR2F1 functions in mammary epithelial cells as a suppressor of pluripotency and dissemination during early stages of tumor progression. We propose that therapies that might restore expression of NR2F1 might limit early dissemination and the progression to metastasis of already disseminated tumor cells. Citation Format: Maria Soledad Sosa, Julie Cheung, Julio A. Aguirre-Ghiso. NR2F1 limits early dissemination and phenotypic plasticity of early-progressed ErbB2+ tumor cells by maintaining luminal differentiation. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B35.
Abstract 13940: Risk Stratification of Future Left Ventricular Dysfunction in Patients With Indications for Right Ventricular Pacing Owing to Bradycardia
Authors: Junichi Ooka, Hidekazu Tanaka, Yutaka Hatani, Keiko Hatazawa, Kumiko Dokuni, Hiroki Matsuzoe, Hiroyuki Shimoura, Hiroyuki Sano, Yoshiki Motoji, Yasuhide Mochizuki, Keiko Ryo, Kensuke Matsumoto, Ken-ichi Hirata
Journal: Circulation (2015)

Background: Although right ventricular (RV) pacing is the only effective treatment for patients with symptomatic atrioventricular block, it creates left ventricular (LV) mechanical dyssynchrony, which can induce LV dysfunction and heart failure. Current criterion for consideration of cardiac resynchronization therapy (CRT) is LV ejection fraction (LVEF) ≤35%, but indication for CRT in patients required for RV pacing with LVEF &gt;35% remains uncertain. Methods: We studied 35 consecutive patients with LVEF of 51±9% (all≥35%) who had undergone implantable cardioverter-defibrillator implantation (RV pacing &lt;5%). Echocardiography was performed at baseline and during RV pacing. LV dyssynchrony was determined by the anteroseptal-to-posterior wall delay from mid-LV short-axis view using two-dimensional speckle-tracking radial strain (≥130ms as significant). Patients were divided into two groups based on baseline LVEF: preserved LVEF≥50% (n=19) and mildly reduced LVEF of 35-50% (n=16). Results: LV dyssynchrony in patients with mildly reduced LVEF was significantly worsened during RV pacing compared to that in patients with preserved LVEF (from 86.0±103.9ms to 214.6±132.1ms vs. from 21.7±29.0ms to 65.6±90.9ms, p=0.01). Furthermore, the prevalence of significant LV dyssynchrony during RV pacing in patients with mildly reduced LVEF was significantly higher than that in patients with preserved LVEF (68% vs. 16%, p&lt;0.01). LVEF in patients with mildly reduced LVEF was also significantly worsened during RV pacing compared to that in patients with preserved LVEF (from 42.8±4.6% to 37.6±6.8% vs. from 58.3±5.7% to 57.9±6.9%, p&lt;0.01). Conclusions: The amount of RV pacing-induced LV dysfunction may be associated with baseline LV function. Thus, these adverse effects in patients with mildly reduced LVEF of 35-50% and indications for RV pacing owing to bradycardia can be prevented by CRT.
RONC-08. HIGHER PSEUDOPROGRESSION RATES AFTER PROTON VERSUS PHOTON RADIOTHERAPY IN PEDIATRIC PATIENTS WITH LOW-GRADE GLIOMA
Authors: Ethan Ludmir, Anita Mahajan, Arnold Paulino, Jeremy Jones, Leena Ketonen, Joann Ater, Jack Su, David Grosshans, Adekunle Adesina, Robert Dauser, Jeffrey Weinberg, Murali Chintagumpala
Journal: Neuro-Oncology (2018)

Pseudoprogression (PsP), a recognized post-radiotherapy (RT) phenomenon for high-grade glioma, is poorly characterized for low-grade glioma (LGG). Serial MRI scans of 83 pediatric LGG patients managed at two institutions between 1998 and 2017 were evaluated for PsP. 32 patients (39%) were treated with photon-based intensity-modulated RT (IMRT), and 51 (61%) were treated with proton beam therapy (PBT). The median age at time of RT was 10.0 years (range 1.0 - 17.2). The most common diagnoses were pilocytic astrocytoma (50/83, 60%) and grade 2 astrocytoma (22/83, 27%). No differences in age at RT, RT dose, treatment volume, or histology were identified between the IMRT and PBT groups. Post-RT radiographic tumor enlargement consistent with PsP was identified in 31/83 patients (37%), including 8/32 IMRT patients (25%) and 23/51 PBT patients (45%); PBT patients were more likely to have post-RT enlargement (HR 2.10, p=0.048). The enlargement peaked at a median of 4 months after RT (range 1-8 months), with a median increase of 22% (range 5-259%). Median time to stabilization was 12 months, with a median of 15 and 9.5 months for the IMRT and PBT cohorts, respectively (p=0.001). Confirmed local progression occurred in 10 patients: 7/32 IMRT patients (22%) and 3/51 PBT patients (6%). These data highlight substantial rates of PsP among patients treated with PBT, and further follow-up may elucidate whether these higher rates of PsP are associated with improved local disease control. PsP should be considered when assessing response to RT in LGG, particularly within the first year after RT.
ATRT-19. PRECLINICAL EFFICACY OF COMBINED INHIBITION OF MEK AND MELK IN ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Michaël Meel, Miriam Guillén Navarro, Mark de Gooijer, Piotr Waranecki, Naomi Petersen, Dannis van Vuurden, Gertjan Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2018)

Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant tumors of the central nervous system occurring predominantly in young children. Currently, the only curative therapeutic option consists of surgery combined with intensive chemo- and radiotherapy, often leading to severe long-term sequelae. Therefore, novel therapeutic strategies that reduce these sequelae while maintaining curative potential are urgently needed. Genetically, AT/RT is characterized by a biallelic inactivation of SMARCB1 or SMARCA4, causing aberrant chromatin remodeling and thereby expression of a variety of oncogenes. Recently, the importance of the mitogen-activated protein kinase (MAPK) pathway in the pathogenesis of AT/RT has been demonstrated, with preclinical efficacy of MEK inhibition in AT/RT cells. By in silico analysis of publicly available datasets we identified a strong overexpression of the Maternal Embryonic Leucine zipper Kinase (MELK) in AT/RT samples compared to normal brain and cerebellar tissue. Inhibition of MELK by the small molecule OTSSP167 strongly reduced proliferation and survival of primary AT/RT neurospheres. Combined treatment of primary AT/RT cells with OTSSP167 and the MEK inhibitor Trametinib showed strongly synergistic cytotoxicity at low nanomolar concentrations. Treatment of mice carrying newly developed primary, patient-derived VUMC-AT/RT-01-Fluc xenografts with the combination of OTSSP167 and Trametinib prolonged their survival and confirmed the reported synergy in vivo, even though both agents supposedly do not cross the blood brain barrier (BBB). Thus, besides demonstrating a novel potential therapeutic combination for AT/RT, these results indicate an, at least partially, functionally defective BBB in AT/RT, thereby suggesting the possibility to incorporate non-BBB penetrable drugs into therapeutic regimens for these tumors.
The relationship between maternal and infant vitamin D status and challenge-proven IgE-mediated food allergy at 1 year of age: a case-cohort study
Authors: John Desmond Molloy, K Allen, Fiona Collier, J Koplin, J Carlin, ML Tang, T Dwyer, Alister Ward, A-L Ponsonby, Peter Vuillermin
Journal: Allergy (2015)