tbuckley/cabot-search huggingface dataset:
GENE-30. TRANSCRIPTION ELONGATION FACTORS REPRESENT IN VIVO CANCER DEPENDENCIES IN GLIOBLASTOMA
Authors: Tyler E Miller, Brian Liau, Lisa C Wallace, Andrew Morton, Qi Xie, Deobrat Dixit, Daniel Factor, Leo Kim, James Morrow, Qiulian Wu, Stephen Mack, Christopher Hubert, Patrick J Paddison, Craig Horbinski, Bradley Bernstein, Paul Tesar, Jeremy Rich
Journal: Neuro-Oncology (2017)

Glioblastoma is a universally lethal cancer with a median survival of approximately 15 months. Despite substantial efforts to define druggable targets, there are no therapeutic options that meaningfully extend glioblastoma patient lifespan. While previous work has largely focused on in vitro cellular models, here we demonstrate a more physiologically relevant approach to target discovery in glioblastoma. We adapted pooled RNA interference (RNAi) screening technology for use in orthotopic patient-derived xenograft (PDX) models, creating a high-throughput negative selection screening platform in a functional in vivo tumour microenvironment. Using this approach, we performed parallel in vivo and in vitro screens and discovered that the chromatin and transcriptional regulators necessary for cell survival in vivo are non-overlapping with those required in vitro. We identified transcription pause-release and elongation factors as one set of in vivo-specific cancer dependencies and determined that these factors are necessary for enhancer-mediated transcriptional adaptations that enable cells to survive the tumour microenvironment. Our lead hit, JMJD6, mediates the upregulation of in vivo stress and stimulus response pathways through enhancer-mediated transcriptional pause-release, promoting cell survival specifically in vivo. Targeting JMJD6 or other identified elongation factors extends survival in orthotopic xenograft mouse models, supporting targeting the transcription elongation machinery as a therapeutic strategy for glioblastoma. More broadly, this study demonstrates the power of in vivo phenotypic screening to identify new classes of 'cancer dependencies' not identified by previous in vitro approaches, which could supply untapped opportunities for therapeutic intervention.
Characterization of Gene Alterations following Editing of the β-Globin Gene Locus in Hematopoietic Stem/Progenitor Cells
Authors: Joseph Long, Megan D. Hoban, Aaron R. Cooper, Michael L. Kaufman, Caroline Y. Kuo, Beatriz Campo-Fernandez, Dianne Lumaquin, Roger P. Hollis, Xiaoyan Wang, Donald B. Kohn, Zulema Romero
Journal: Molecular Therapy (2017)

The use of engineered nucleases combined with a homologous DNA donor template can result in targeted gene correction of the sickle cell disease mutation in hematopoietic stem and progenitor cells. However, because of the high homology between the adjacent human β- and δ-globin genes, off-target cleavage is observed at δ-globin when using some endonucleases targeted to the sickle mutation in β-globin. Introduction of multiple double-stranded breaks by endonucleases has the potential to induce intergenic alterations. Using a novel droplet digital PCR assay and high-throughput sequencing, we characterized the frequency of rearrangements between the β- and δ-globin paralogs when delivering these nucleases. Pooled CD34+ cells and colony-forming units from sickle bone marrow were treated with nuclease only or including a donor template and then analyzed for potential gene rearrangements. It was observed that, in pooled CD34+ cells and colony-forming units, the intergenic β-δ-globin deletion was the most frequent rearrangement, followed by inversion of the intergenic fragment, with the inter-chromosomal translocation as the least frequent. No rearrangements were observed when endonuclease activity was restricted to on-target β-globin cleavage. These findings demonstrate the need to develop site-specific endonucleases with high specificity to avoid unwanted gene alterations. The use of engineered nucleases combined with a homologous DNA donor template can result in targeted gene correction of the sickle cell disease mutation in hematopoietic stem and progenitor cells. However, because of the high homology between the adjacent human β- and δ-globin genes, off-target cleavage is observed at δ-globin when using some endonucleases targeted to the sickle mutation in β-globin. Introduction of multiple double-stranded breaks by endonucleases has the potential to induce intergenic alterations. Using a novel droplet digital PCR assay and high-throughput sequencing, we characterized the frequency of rearrangements between the β- and δ-globin paralogs when delivering these nucleases. Pooled CD34+ cells and colony-forming units from sickle bone marrow were treated with nuclease only or including a donor template and then analyzed for potential gene rearrangements. It was observed that, in pooled CD34+ cells and colony-forming units, the intergenic β-δ-globin deletion was the most frequent rearrangement, followed by inversion of the intergenic fragment, with the inter-chromosomal translocation as the least frequent. No rearrangements were observed when endonuclease activity was restricted to on-target β-globin cleavage. These findings demonstrate the need to develop site-specific endonucleases with high specificity to avoid unwanted gene alterations.
Low-dose CT detects more progression of bone formation in comparison to conventional radiography in patients with ankylosing spondylitis: results from the SIAS cohort
Authors: Anoek de Koning, Freek de Bruin, Rosaline van den Berg, Sofia Ramiro, Xenofon Baraliakos, Juergen Braun, Floris A van Gaalen, Monique Reijnierse, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2017)

Objectives To compare the CT Syndesmophyte Score (CTSS) for low-dose CT (ldCT) with the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) for conventional radiographs (CR) in patients with ankylosing spondylitis (AS). Methods Patients with AS in the Sensitive Imaging in Ankylosing Spondylitis cohort had lateral cervical and lumbar spine CR and whole spine ldCT at baseline and 2 years. CR and ldCT images were scored by two readers, paired by patient, blinded to time order, per imaging modality. For the total score analysis, we used average scores of readers per corner on CR or quadrant on ldCT. For the syndesmophyte analysis we used individual reader and consensus scores, regarding new or growing syndesmophyte at the same corner/quadrant. Results 50 patients were included in the syndesmophyte analysis and 37 in the total score analysis. Mean (SD) status scores for mSASSS (range 0–72) and CTSS (range 0–552) at baseline were 17.9 (13.8) and 161.6 (126.6), and mean progression was 2.4 (3.8) and 17.9 (22.1). Three times as many patients showed new or growing syndesmophytes at ≥3 quadrants on ldCT compared with ≥3 corners on CR for individual readers; for consensus this increased to five times. In 50 patients, 36 new or growing syndesmophytes are seen on CR compared with 151 on ldCT, most being found in the thoracic spine. Conclusions ldCT, covering the whole spine, detects more progression in the form of new and growing syndesmophytes in patients with AS compared with CR, which is limited to the cervical and lumbar spine. Most progression occurred in the thoracic spine.
ATIM-26. A PHASE 1 STUDY OF Ad-RTS-hIL-12 + VELEDIMEX IN ADULT RECURRENT GLIOBLASTOMA
Authors: E Antonio Chiocca, John Yu, Rimas V Lukas, Jill Buck, Nate Demars, John Barrett, Yijun Yang, Laurence Cooper, Francois Lebel
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is an aggressive brain tumor affecting ~74,000 people worldwide annually. Recurrent GBM patients have a median overall survival (mOS) of 6–7 months. OS in patients who have failed temozolomide, bevacizumab or equivalent salvage chemotherapy, is ~3–5 months. New therapies are urgently needed. Ad-RTS-hIL-12 is a novel gene therapy expressing IL-12 under the control of an oral activator ligand, veledimex, via the RheoSwitch Therapeutic System® gene switch. Intratumoral administration of Ad-RTS-hIL-12 results in targeted tumor cytotoxicity and induction of systemic T cell memory. Ad-RTS-hIL-12 + veledimex is a treatment strategy to extend the IL-12 therapeutic window. In a multicenter, Phase I dose escalation trial and expansion cohort of subjects with recurrent or progressive Grade III or IV glioma undergoing resection, Ad-RTS-hIL-12 + veledimex was well tolerated; toxicities were predictable and reversible upon discontinuing veledimex with a correlation between veledimex dose, BBB penetration and drug related AEs to assigned dose level. The most common adverse reactions were related to cytokine exposure in the form of fever, decrease in peripheral lymphocytes and platelets, and elevation of liver transaminases. Emerging biomarker data appear to show that serum CD8+/FOXP3 ratio might represents a putative predictor of response. Subjects treated with 20mg of veledimex had a mOS of 12.5 months and when given ≤10mg of dexamethasone during the first 15 days of treatment, overall survival was improved, possibly suggesting a negative effect of steroids on immunostimulation. The tolerability and encouraging survival observed to date warrant additional clinical studies of this controlled immunogene therapy.
Abstract 21244: The Association Between Transthoracic Echocardiography, Transesophageal Echocardiography, and No Ultrasound Use on the Duration of Pulse Checks During Cardiopulmonary Resuscitation
Authors: James Fair, Aaron Adler, Michael Mallin, Patrick Ockerse, Joseph Tonna, Scott T Youngquist
Journal: Circulation (2017)

Background: Minimizing compression pauses during cardiopulmonary resuscitation (CPR) reduces total ischemic time and contributes to better outcomes. Guidelines suggest considering ultrasound when available to guide resuscitation management in cardiac arrest and identify cardiac motion. Due to availability and ease of use, transthoracic echocardiography (TTE) is most often employed in cardiac arrest, but requires space on the patient’s chest and clear images can be difficult to obtain. Hypothesis: We hypothesized that transesophageal echocardiography (TEE), due to its superior image quality and lack of interference with compressions, may allow for shorter pulse check times. Methods: We analyzed a cohort of sequential cardiac arrests treated in the emergency department of a major tertiary care hospital utilizing video recordings of resuscitation attempts. The duration of each pulse check was recorded by blinded reviewers as well as whether TTE, TEE, or no ultrasound was concomitantly employed. A mixed effects linear regression model was used to estimate the average pause time of pulse checks, accounting for the repeated measures design while controlling for victim body mass index. Results: A total of 23 cardiac arrest victims were included in the analysis providing 208 pulse checks for analysis. Mean age of victims was 56 years and 42% were female. The mean pulse check duration for palpation alone, TTE, and TEE was 15 sec (95% CI 10-20), 23 sec (95% CI 16-30), and 12 sec (95% CI 7-18), respectively (P 0.00, 0.013, 0.00). TEE was associated with significantly shorter pulse check times when compared to TTE and palpation alone, although the latter difference was not statistically significant (FIGURE). Conclusion: In this observational study, pulse check duration was significantly shorter when using TEE during CPR when compared to TTE but not to palpation alone. This factor should be taken into consideration when deciding ultrasound modalities during resuscitation.
Impact of Nivolumab versus Docetaxel on Health-Related Quality of Life and Symptoms in Patients with Advanced Squamous Non–Small Cell Lung Cancer: Results from the CheckMate 017 Study
Authors: Martin Reck, Fiona Taylor, John R. Penrod, Michael DeRosa, Laura Morrissey, Homa Dastani, Lucinda Orsini, Richard J. Gralla
Journal: Journal of Thoracic Oncology (2017)
Placental Drug Transport‐on‐a‐Chip: A Microengineered In Vitro Model of Transporter‐Mediated Drug Efflux in the Human Placental Barrier
Authors: Cassidy Blundell, Yoon‐Suk Yi, Lin Ma, Emily R. Tess, Megan J. Farrell, Andrei Georgescu, Lauren M. Aleksunes, Dongeun Huh
Journal: Advanced Healthcare Materials (2017)

Abstract The current lack of knowledge about the effect of maternally administered drugs on the developing fetus is a major public health concern worldwide. The first critical step toward predicting the safety of medications in pregnancy is to screen drug compounds for their ability to cross the placenta. However, this type of preclinical study has been hampered by the limited capacity of existing in vitro and ex vivo models to mimic physiological drug transport across the maternal–fetal interface in the human placenta. Here the proof‐of‐principle for utilizing a microengineered model of the human placental barrier to simulate and investigate drug transfer from the maternal to the fetal circulation is demonstrated. Using the gestational diabetes drug glyburide as a model compound, it is shown that the microphysiological system is capable of reconstituting efflux transporter‐mediated active transport function of the human placental barrier to limit fetal exposure to maternally administered drugs. The data provide evidence that the placenta‐on‐a‐chip may serve as a new screening platform to enable more accurate prediction of drug transport in the human placenta.
Los primeros resultados del nuevo sistema de vigilancia del VIH en Francia
Authors: F Lot, C Semaille, F Cazein, F Barin, R Pinget, J Pillonel, J C Desenclos
Journal: Eurosurveillance (2004)

Como complemento a la vigilancia del sida, los datos sobre las infecciones por el VIH son necesarios para seguir mejor la dinamica de la epidemia. Este articulo presenta los primeros resultados del sistema de declaracion obligatoria y anonima del VIH, en relacion a la vigilancia virologica de las infecciones recientes por el VIH y de los tipos, grupos y sub-tipos de VIH en circulacion.
Las notificaciones obligatorias son iniciadas por los microbiologos que crean un codigo anonimo para cada paciente. Los medicos clinicos completan ese formulario de notificacion con las informaciones clinicas y epidemiologicas. Las declaraciones son entonces enviadas a las autoridades sanitarias locales y transmitidas al Institut de veille sanitaire (InVS).
Los laboratorios mandan, de forma voluntaria, las muestras de sangre seca al laboratorio nacional de referencia del VIH. Este realiza una prueba de inmunidad para detectar las infecciones recientes (l6 meses) y un serotipado para determinar el grupo y sub-tipo. Los resultados virologicos son enviados al InVS donde son ligados a las informaciones de la notificacion obligatoria. 
El 43% de los nuevos casos de VIH diagnosticados en 2003 eran mujeres. Globalmente, el 53% de los casos notificados eran heterosexuales, de los cuales el 47% eran originarios de Africa sub-sahariana. El 36% de los casos masculinos declarados eran homosexuales. El 64% de los nuevos diagnosticos de VIH tenian disponible una muestra de sangre seca. En el 38,4% de los casos se identifico una infeccion reciente, con un 22,2% en UDVP y 58,1% en homosexuales. Esa tasa era de 26% en los de origen sub-Sahariano. Las infecciones por el VIH-1 eran el 98% de la totalidad de las notificaciones, con un 47,8% de sub-tipos no-B. 
Los primeros resultados de nuestro sistema de notificacion del VIH muestran que la transmision heterosexual predomina en Francia, especialmente en personas originarias de Africa sub-sahariana. Mas de la mitad de las infecciones recientes se encontraron en hombres homosexuales, indicando quizas un aumento de la incidencia del VIH en esa poblacion.
Nuova variante della malattia di Creutzfeldt-Jakob
Authors: D Dormont
Journal: Eurosurveillance (2000)

Attraverso oltre 10 anni di studi di patologia sperimentale, sono emerse le caratteristiche biologiche particolari dell'agente dell'ESB, responsabile della nuova variante della malattia di Creutzfeldt-Jakob (nvMCJ). Contrariamente al quadro classico della MCJ, l’agente responsabile della nvMCJ ha un'ampia distribuzione periferica nel corpo degli esseri umani. Questo rende necessario riesaminare la sicurezza dei trapianti, dei farmaci di origine umana o bovina e delle trasfusioni sanguigne.
P1.07-035 Lymphocytes and Neutrophils Count After Two Cycles and TTF1 Expression as Early Outcome Predictors During Immunotherapy
Authors: I. Baraibar, M. Roman Moreno, E. Castañón, M.Á. García Del Barrio, C. Rolfo, J.M. López-Picazo, J.L. Perez-Gracia, A. Gúrpide, I. Gil-Bazo
Journal: Journal of Thoracic Oncology (2017)
P1.09-001 Multiplexed Biomarker Strategies Based on Targeted Proteomics for Detection of Malignant Pleural Mesothelioma in Blood
Authors: F. Cerciello, M. Choi, K. Lome, J. Amann, E. Felley-Bosco, R. Stahel, B. Robinson, J. Creaney, H. Pass, O. Vitek, D. Carbone
Journal: Journal of Thoracic Oncology (2017)
TMOD-47. GENERATION AND EVALUATION OF ORGANOID CULTURES FROM PATIENT-DERIVED GLIOBLASTOMA CELLS
Authors: Alejandra Velazquez Ojeda, Blake Brewster, Christine Brown, Michael Barish
Journal: Neuro-Oncology (2017)

Three dimensional cultures in vitrothat form self-assembling structures termed organoids that are reminiscent of their source tissue have emerged as a valuable technique in fundamental/translational medical science. We are interested in using this preparation to study cellular process of brain tumor development and progression. Here we describe using characterized patient-derived glioblastoma (GBM) cells (PBT017) to initiate organoid cultures in Matrigel. Grown in appropriate media with gentle circular mixing, brain tumor organoids survive without signs of necrosis for over two months. We explored temporal and spatial expression of markers of neural lineage and tumor progression, as well as probes of tumor microenvironment and physiological state. Over time (30-60 days in culture), PBT017 organoids became highly heterogeneous. Hypoxia is thought to be an important physiological factor contributing to the cellular organization of brain tumor masses. Expression of carbonic anhydrase IX (CA-IX), a marker of hypoxia, defined circumscribed regions in PBT017 organoids grown under both normoxic and hypoxic conditions. Tumor cells expressing the proliferation marker Ki67 were found at markedly higher concentrations in areas devoid of CA-IX immunoreactivity, with gradients of decreasing Ki67 expression extending into hypoxic regions. Similarly, fibrous nestin-expressing PBT017 GBM cells (nestin expression is a common characteristic of GBM tumors) were excluded from regions of high CA-IX expression. We are continuing examination of other determinants of tumor structure and how they may relate to phenotypic heterogeneity. Together, these data suggest that these three-dimensional organoids are capable of recapitulating behaviors of glioblastoma cells in patients, and that they may provide a physiologically-relevant experimental system for study of intrinsic tumor biology as well as potentially a platform for preclinical in vitro evaluation of nascent therapies for patients with GBM.
IMMU-24. PD-1/PD-L PATHWAY IS ASSOCIATED WITH TWO CELL PATTERN FORMATION IN INTRACRANIAL GERMINOMA
Authors: Yoshiki Arakawa, Bin Liu, Ryuta Yokogawa, Shinya Tokunaga, Etsuko Hattori, Nobuyuki Fukui, Yukinori Terada, Yasuzumi Matsui, Masahiro Tannji, Yohei Mineharu, Susumu Miyamoto
Journal: Neuro-Oncology (2017)

Intracranial germinoma has two cell pattern with large undifferentiated tumor cell and tumor infiltrating lymphocytes (TILs) but the meaning of this phenotype has not been known. Recently, PD-1/PD-L pathway has been recognized to work as anti-tumor immune system. In this study, we evaluated a relationship between TILs and PD-1/PD-L pathway in intracranial germinoma. In formalin-fixed, paraffin-embedded tumor specimens from 25 patients with intracranial germinomas, we immunohistochemically analyzed the expressions of PD-L1/2 in tumor cells and TILs with PD-1, CD3+, CD8+, CD4+, Foxp3+. Statistical analysis was performed these expressions and clinical data. PD-1 expression in TILs was detected in 76% (19/25). PD-L1 and PD-L2 expression in tumor cells were detected in 96% (24/25) and 84% (21/25), respectively. High expression of PD-1 was inclined to increase CD3+ TILS. Expression of PD-1 was correlated with Foxp3+ TILs density, CD8+ TILs density, but not with CD4+ TILs density. Furthermore, expression of PD-1 is strongly correlated with Foxp3+/CD4+ ratio in TILs. The increase of PD-1+ TILs induces immune dysfunction of CD8+ TILs. The induction of Foxp3+ TILs from CD4+TILs causes immune tolerance. These observations indicate that the breakdown of anti-tumor immune system may be associated with two cell pattern formation as well as oncogenesis in intracranial germinoma.
CSIG-31. PRE-CLINICAL STUDY AND CLINICAL DEVELOPMENT OF AXL-TARGETING THERAPY FOR RECURRENT GLIOBLASTOMA
Authors: Hirokazu Sadahiro, Kyung-Don Kang, Burt Nabors, Lyse Norian, Dolores Hambardzumyan, Biplab Dasgupta, Mitsutoshi Nakada, Ichiro Nakano
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is a lethal disease without effective therapies. Previously we reported that the TAM receptor tyrosine kinase family member AXL is upregulated in mesenchymal GBM and its knockdown induces apoptosis of mesenchymal but not proneural glioma sphere cultures (GSCs). In this study, we report that BGB324, a novel small molecule inhibitor for AXL, prolongs the survival of immunocompromised mice bearing mesenchymal GSC-derived GBM-like intracranial tumors by inhibition of AXL activation in tumor cells. Mechanistically, we identified that protein S (PROS1), known as a ligand for other TAM receptors, is secreted by tumor-associated macrophages, thereby physically associates and activates AXL in mesenchymal GSCs. The PROS1-driven phosphorylation of AXL resulted in the NF-kB activation in mesenchymal GSCs and this activation was eliminated by BGB324 treatment. In addition, BGB324 downregulated the immune checkpoint protein PD-L1 both in vitro and in vivo. Combination of BGB324 with Nivolumab - the neutralizing antibody for PD-1 (a receptor for PD-L1) was effective to prolong the survival of immunocompetent mice bearing syngeneic GBM models. Clinically, both AXL and PROS1 expression indicated poorer prognosis of GBM patients. These data suggest that the PROS1/AXL pathway regulates intrinsic mesenchymal signaling as well as extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors. To translate the pre-clinical data to human GBM patients, we designed a surgical PK/PD clinical trial with BGB324 for recurrent GBM and this trial is currently under review by the Brain Malignancy Steering Committee in the National Cancer Institute.
Perioperative Morbidity of Lymph Node Dissection for Renal Cell Carcinoma: A Propensity Score–based Analysis
Authors: Boris Gershman, Daniel M. Moreira, R. Houston Thompson, Stephen A. Boorjian, Christine M. Lohse, Brian A. Costello, John C. Cheville, Bradley C. Leibovich
Journal: European Urology (2017)
Uncertain overseas recruitment is threatening care, NHS leaders warn
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Continuing uncertainty over the recruitment of staff from other countries in the wake of Brexit is threatening the provision of safe, high quality care in the NHS, hospital leaders have warned.

In a new report NHS Providers, which represents NHS trusts, says that domestic “quick fixes” are not an option for solving severe workforce shortages in the NHS.1 The report warns that any significant reduction in the number of overseas staff in the next few years would have a “serious and damaging impact” on services.

NHS Providers criticises the Department of Health for England and its national arm’s length bodies for a …
OA 10.01 Detection of EGFR mutations from plasma ctDNA in the osimertinib Phase III trial (AURA3): comparison of three plasma assays
Authors: M. Ahn, J. Han, C. Tsai, A. Delmonte, T. Hsia, J. Laskin, S. Kim, Y. He, T. Hida, M. Maemondo, T. Kato, S. Jenkins, A. Markovets, K. Thress, T. Mok
Journal: Journal of Thoracic Oncology (2017)