tbuckley/cabot-search huggingface dataset:
Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial
Authors: Jean-Michel Molina, Kathleen Squires, Paul E Sax, Pedro Cahn, Johan Lombaard, Edwin DeJesus, Ming-Tain Lai, Anthony Rodgers, Lisa Lupinacci, Sushma Kumar, Peter Sklar, George J Hanna, Carey Hwang, Elizabeth Anne Martin, Debbie P. Hagins, Olayemi O. Osiyemi, David James Prelutsky, Moti N. Ramgopal, Anthony John Scarsella, Robin Dretler, Edwin DeJesus, Christopher J. Bettacchi, James Sims, Patrick G. Clay, Nicholaos C. Bellos, Melanie A. Thompson, Jose Montero, Cheryl K. McDonald, Catherine Creticos, David Shamblaw, Miguel Mogyoros, Antonio E. Terrelonge, Martin Valdes, Karen T. Tashima, William J. Robbins, Franco Antonio Felizarta, Richard A. Elion, Jihad Slim, Sandra S. Win, Sujata N. Lalla-Reddy, Peter Jerome Ruane, Anthony Mills, Jerry L. Cade, Craig A. Dietz, David Scott Rubin, Cynthia Mayer, Juan Carlos Rondon, Paul P. Cook, Eric Daar, Princy N. Kumar, Susan Swindells, Jose Guillermo Castro, Ivan Melendez-Rivera, Javier O. Morales-Ramirez, Lizette Santiago, Jorge L. Santana-Bagur, Marcelo Martins, Pedro Enrique Cahn, Gustavo D. Lopardo, Norma Porteiro, Mark Theo Bloch, David Alfred Baker, Norman Roth, Richard James Moore, Robert James Finlayson, James McMahon, Armin Rieger, Alexander Zoufaly, Sylvia Hartl, Robert Zangerle, Fiona Smaill, Sharon L. Walmsley, Brian Conway, Anita Rachlis, Graham H.R. Smith, Carlos Perez, Alejandro Afani, Maria Isabel Campos, Carolina Eugenia Chahin, Marcelo Wolff Reyes, Jan Gerstoft, Nina Weis, Alex Lund Laursen, Jean-Michel Molina, Yazdan Yazdanpanah, Laurent Cotte, Francois Raffi, Philippe Morlat, Pierre-Marie Girard, Christine Katlama, Juergen K. Rockstroh, Keikawus Arasteh, Stefan Esser, Albrecht Stoehr, Hans-Juergen Stellbrink, Matthias Stoll, Dirk Schuermann, Gerd Faetkenheuer, Johannes Bogner, Thomas Lutz, Axel Baumgarten, Hans Jaeger, Andrea Gori, Gabriel Coltan, Felicia Constandis, Simona Manuela Erscoiu, Liviu-Jany Prisacariu, Sorin Rugina, Adrian Streinu-Cercel, Vadim Valentinovich Pokrovsky, Natalia V. Zakharova, Andrey Anatolyevich Shuldyakov, Elena Pavlovna Ryamova, Valeriy Viktorovich Kulagin, Olga Aleksandrovna Tsybakova, Elena Orlova-Morozova, Firaya Nagimova, Evgeniy Voronin, Tatyana Evgenyevna Shimonova, Oleg Anatolyevich Kozyrev, Catherine Orrell, Johannes Jurgens Lombaard, Marleen de Jager, Joaquin Portilla Segorb, Josep Mallolas, Maria Jesus Perez Elias, Josep M. Gatell, Jose Ramon Arribas Lopez, Eugenia Negredo Puigmal, Daniel Podzamczer Palter, Federico Pulido Ortega, Jesus Troya Garcia, Ignacio De los Santos Gil, Juan Berenguer Berenguer, Ian G. Williams, Margaret A. Johnson, Gabriel Schembri, Amanda Clarke, Mark Gompels, Julie Meriel Fox, Steven John Taylor, David Harold Dockrell, Stephen Kegg
Journal: The Lancet HIV (2019)
Non-Invasive Prenatal Diagnosis (NIPD) of Sickle-Cell Disease By Massively Parallel Sequencing of Cell-Free Fetal DNA in Maternal Serum
Authors: Yvonne Daniel, Julia Van Campen, Lee Silcock, Michael Yau, Joo Wook Ahn, Caroline Ogilvie, Kathy Mann, Eugene Oteng-Ntim
Journal: Blood (2019)
Use of Modeling to Inform Tuberculosis Elimination Strategies
Authors: Masahiro Narita, Jeanne Sullivan Meissner, Joseph Burzynski
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

airways with higher BMI, and the amount of airway fat correlates with wall thickness and the number of inflammatory cells (13).Airway adipose tissue accumulation by itself may therefore partly explain some of the changes seen in asthma, including airway narrowing and remodeling.Future studies should examine whether excess visceral and/or pericardial fat in children denotes a phenotype of obesity that tends to accumulate adipose tissue in certain organs, including the airways.We must also learn whether certain adiposity distribution profiles have a more immediate proinflammatory effect on the lungs.The BMI will certainly continue to play an important role in epidemiological studies of obesity (and consequently of obese asthma).But in the era of big data, detailed phenotyping, multiomics, gene editing, and machine-learning, we owe it to our patients to shift our focus to a more nuanced approach-one that better characterizes "obesity" and studies the specific profiles and characteristics of adipose tissue that lead to obese asthma.
NIMG-10. BRAIN TUMOR MRI STRUCTURED REPORTING ALLOWS CALCULATION OF INTERRATER AGREEMENT OF PATIENTS REVIEWED AT TUMOR BOARD
Authors: Maxwell Cooper, Michael Hoch, Syed Abidi, Ranliang Hu, Hyunsuk Shim, Brent Weinberg
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Longitudinal imaging evaluation of brain tumor patients with MRI is a challenging endeavor, as there is considerable overlap between imaging findings of tumor progression and treatment related changes. There is felt to be a high degree of variation between individual interpreters, particularly in complex cases. Structured reporting systems, such as the recently described brain tumor reporting and data system (BT-RADS), attempt to maximize consistency between reading radiologists, although how successful they are at achieving this is unknown. METHODS Patients with a diagnosis of a primary brain tumor with imaging presented at adult brain tumor board between October 2017 and March 2019 were reviewed. The most recent follow-up MRI was scored on an 8-point scale as described by BT-RADS, ranging from 0 to 4 with increasing suspicion for worsening disease, as described in the original radiologist report. Secondary review of MRI was performed by one of three neuroradiologists routinely participating in brain tumor conference. Interrater agreement between primary and secondary review were calculated using rates of exact agreement and linear weighted kappa. RESULTS Of studies reviewed, 270 out of 275 had imaging and reports suitable for repeat structured scoring. Grade 4 astrocytoma (glioblastoma) was the most common diagnosis, followed by grade 2 oligodendroglioma and grade 2 astrocytoma. The overall agreement rate between initial and secondary review was 83.0% with kappa of 0.89 +/- .05. There was perfect agreement on studies with improvement (1a or 1b) with lower levels of agreement (63.6–82.4%) for studies with worsening imaging findings (3a-4). CONCLUSIONS Using a structured reporting system to categorize MRIs in brain tumor patients allows for precise characterization of variation between report conclusions on primary and secondary review. Overall agreement is good, but variation rates increase with worsening findings which may be harder to correctly interpret.
TMIC-17. ASTROCYTE SENESCENCE CONTRIBUTES TO SEX DIFFERENCES IN THE AGE-RELATED INCREASE IN GLIOBLASTOMA INCIDENCE
Authors: Lauren Broestl, Jasmin Sponagel, Gina Rhee, Lucia Grandison, Najla Kfoury, Nathan Rockwell, Cameron Hill, Joshua Rubin
Journal: Neuro-Oncology (2019)

Abstract Incidence rates for glioblastoma increase exponentially with age in a sex-specific manner, with a steeper increase observed in men. This suggests that age may be a more significant factor in promoting male tumors than female tumors. Drivers in the age-related cancer increase include both the accumulation of DNA damage and microenvironment changes, specifically an increase in the number of senescent cells. Cellular senescence comprises two distinct components – a cell cycle arrest program that prevents proliferation of mutated cells and acts as a potent anti-cancer mechanism, and a paracrine signaling component that can have both pro- and anti-tumorigenic properties. The contribution of senescence to brain tumor incidence and outcome is currently unknown; additionally, no research has been done on whether there are sex differences in mechanisms of senescence induction or in the secretory phenotype of senescent cells. Using both wildtype astrocytes and a glioblastoma model, we show that female cells have a lower threshold for senescence induction in response to oxidative stress, telomere shortening, and DNA damage, and that sex differences in senescence induction in response to DNA damage are in part mediated by differences in the regulation of p21. In addition, we show that male and female senescent astrocytes differ in their secretory phenotypes. Male senescent astrocytes secrete more tumor promoting factors, and conditioned media from male but not female senescent astrocytes promotes tumor cell proliferation. These findings provide a potential explanation for sex differences in glioblastoma incidence rates. Achieving a better understanding of mechanisms of senescence and how they differ in male and female cells could advance development of senescence directed therapies and potentially improve cancer treatment for a range of tumor types.
Novel Thermostable Inhibitor of Contact Activation Tica Effectively Blocks Contact Activation in Low Tissue Factor Thrombin Generation
Authors: Tom Van De Berg, Dennis P.L. Suylen, M.G.L. Christella D. Thomassen, Rene van Oerle, Henri M.H. Spronk, Rafael Apitz, H. Coenraad Hemker, Tilman M. Hackeng
Journal: Blood (2019)
NCOG-05. IMPACT OF ADDITIONAL RITUXIMAB TO STANDARD THERAPY ON COGNITIVE PERFORMANCES IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA PATIENTS
Authors: Matthijs van der Meulen, Linda Dirven, Esther Habets, Katerina Bakunina, Martin Taphoorn, Martin van den Bent, Samar Issa, Jeanette K Doorduijn, Jacoline E C Bromberg
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The goal of treatment of primary central nervous system lymphoma patients is to improve survival, without compromising neurocognitive functioning. The aim of this study was to analyze the effect of Rituximab and low-dose whole brain radiotherapy (WBRT) on cognition. METHODS 199 patients from a phase III trial (HOVON 105/ ALLG NHL 24), randomized to standard chemotherapy (and 30Gy WBRT for patients &lt; 61 years-old only) with or without Rituximab, were asked to participate in a short neuropsychological evaluation (NPE) before and during treatment, and up to 2 years of follow-up or until progression. A difference in z-score, corrected for sex, age and education, of ≥ 1 point was considered as clinically relevant. The primary outcome was a difference over time between the arms in multiple cognitive domains, assessed by linear mixed models (LMM). Changes in cognitive performances between baseline and 24 months after treatment were assessed for both arms in cross-sectional analyses. Effect of WBRT was analyzed in irradiated patients only. RESULTS 105/199 patients completed at least one NPE; baseline characteristics were similar to the total trial population. Compliance was &gt;60% at all evaluation points. No clinically relevant differences over time between the arms were seen in all domains in LMM analysis. Comparing changes from baseline to 24 months of follow-up, mean cognitive scores remained stable in both arms for attention, executive functioning (TMT B), and information processing speed. A clinically relevant improvement was seen in both arms for executive functioning (TMT A), memory and motor speed. In the irradiated patients (n=33) all scores remained stable after WBRT, up to 24 months of follow-up in all domains. CONCLUSION Cognitive performance remained stable or improved after treatment. Addition of Rituximab to standard treatment did not impact cognitive performance over time. After low-dose WBRT, cognition remained stable up to 2 years.
Detection of Circulating and Disseminated Neuroblastoma Cells Using the ImageStream Flow Cytometer for Use as Predictive and Pharmacodynamic Biomarkers
Authors: Swathi Merugu, Lindi Chen, Elizabeth Gavens, Hany Gabra, Mark Brougham, Guy Makin, Antony Ng, Dermot Murphy, Alem S. Gabriel, Michael L. Robinson, Jennifer H. Wright, Susan A. Burchill, Angharad Humphreys, Nick Bown, David Jamieson, Deborah A. Tweddle
Journal: Clinical Cancer Research (2019)

Circulating tumor cells (CTCs) serve as noninvasive tumor biomarkers in many types of cancer. Our aim was to detect CTCs from patients with neuroblastoma for use as predictive and pharmacodynamic biomarkers.We collected matched blood and bone marrow samples from 40 patients with neuroblastoma to detect GD2+/CD45- neuroblastoma CTCs from blood and disseminated tumor cells (DTCs) from bone marrow using the Imagestream Imaging flow cytometer (ISx). In six cases, circulating free DNA (cfDNA) extracted from plasma isolated from the CTC sample was analyzed by high-density single-nucleotide polymorphism (SNP) arrays.CTCs were detected in 26 of 42 blood samples (1-264/mL) and DTCs in 25 of 35 bone marrow samples (57-291,544/mL). Higher numbers of CTCs in patients with newly diagnosed, high-risk neuroblastoma correlated with failure to obtain a complete bone marrow (BM) metastatic response after induction chemotherapy (P < 0.01). Ex vivo Nutlin-3 (MDM2 inhibitor) treatment of blood and BM increased p53 and p21 expression in CTCs and DTCs compared with DMSO controls. In five of six cases, cfDNA analyzed by SNP arrays revealed copy number abnormalities associated with neuroblastoma.This is the first study to show that CTCs and DTCs are detectable in neuroblastoma using the ISx, with concurrently extracted cfDNA used for copy number profiling, and may be useful as pharmacodynamic biomarkers in early-phase clinical trials. Further investigation is required to determine whether CTC numbers are predictive biomarkers of BM response to first-line induction chemotherapy.
Safety and Efficacy of Midostaurin in Combination with High-Dose Daunorubicin in 7+3 Induction for Acute Myeloid Leukemia with FLT3 Mutation
Authors: Yehuda E. Deutsch, Robert Wilkinson, Amanda Brahim, Stephanie Boisclair, Jose Sandoval-Sus, Annie Kuehnel, Terrence J Bradley, Chetasi Talati, Ellen Madarang, Jillian Lykon, Justin M. Watts, David A Sallman, Kendra L. Sweet, Jeffrey E. Lancet, Hugo F. Fernandez
Journal: Blood (2019)
Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis
Authors: Nupur K. Das, Andrew J. Schwartz, Gabrielle Barthel, Naohiro Inohara, Qing Liu, Amanda Sankar, David R. Hill, Xiaoya Ma, Olivia Lamberg, Matthew K. Schnizlein, Juan L. Arqués, Jason R. Spence, Gabriel Nunez, Andrew D. Patterson, Duxin Sun, Vincent B. Young, Yatrik M. Shah
Journal: Cell Metabolism (2019)
Systemic Sclerosis Dermal Fibroblasts Induce Cutaneous Fibrosis Through Lysyl Oxidase–like 4: New Evidence From Three‐Dimensional Skin‐like Tissues
Authors: Mengqi Huang, Guoshuai Cai, Lauren M. Baugh, Zhiyi Liu, Avi Smith, Matthew Watson, Dillon Popovich, Tianyue Zhang, Lukasz S. Stawski, Maria Trojanowska, Irene Georgakoudi, Lauren D. Black, Patricia A. Pioli, Michael L. Whitfield, Jonathan Garlick
Journal: Arthritis & Rheumatology (2019)

Systemic sclerosis (SSc) is a clinically heterogeneous disease characterized by increased collagen accumulation and skin stiffness. Our previous work has demonstrated that transforming growth factor β (TGFβ) induces extracellular matrix (ECM) modifications through lysyl oxidase-like 4 (LOXL-4), a collagen crosslinking enzyme, in bioengineered human skin equivalents (HSEs) and self-assembled stromal tissues (SAS). We undertook this study to investigate cutaneous fibrosis and the role of LOXL-4 in SSc pathogenesis using HSEs and SAS.SSc-derived dermal fibroblasts (SScDFs; n = 8) and normal dermal fibroblasts (NDFs; n = 6) were incorporated into HSEs and SAS. These 3-dimensional skin-like microenvironments were used to study the effects of dysregulated LOXL-4 on ECM remodeling, fibroblast activation, and response to TGFβ stimulation.SScDF-containing SAS showed increased stromal thickness, collagen deposition, and interleukin-6 secretion compared to NDF-containing SAS (P < 0.05). In HSE, SScDFs altered collagen as seen by a more mature and aligned fibrillar structure (P < 0.05). With SScDFs, enhanced stromal rigidity with increased collagen crosslinking (P < 0.05), up-regulation of LOXL4 expression (P < 0.01), and innate immune signaling genes were observed in both tissue models. Conversely, knockdown of LOXL4 suppressed rigidity, contraction, and α-smooth muscle actin expression in SScDFs in HSE, and TGFβ-induced ECM aggregation and collagen crosslinking in SAS.A limitation to the development of effective therapeutics in SSc is the lack of in vitro human model systems that replicate human skin. Our findings demonstrate that SAS and HSE can serve as complementary in vitro skin-like models for investigation of the mechanisms and mediators that drive fibrosis in SSc and implicate a pivotal role for LOXL-4 in SSc pathogenesis.
MNGI-12. PLEIOTROPIC MLLT10 VARIATION CONFERS RISK OF MENINGIOMA, BREAST, AND OVARIAN CANCERS
Authors: Kyle Walsh, Chenan Zhang, Lisa Calvocoressi, Helen Hansen, Andrew Berchuck, Joellen Schildkraut, Melissa Bondy, Joseph Wiemels, Elizabeth Claus
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Women ages 35–44 have three-fold higher risk of meningioma compared to men. Epidemiologic studies have implicated exogenous hormone use, but endogenous hormonal factors are inconsistently associated. Elevated body mass index (BMI) is consistently associated with meningioma risk in both men and women, and personal history of breast cancer has also been associated with meningioma risk. Recent genome-wide association studies (GWAS) have identified a meningioma risk locus on chromosome 10p12 near previous GWAS hits for breast and ovarian cancers. METHODS To elucidate the pleiotropic role of 10p12 variation in predisposition to diverse tumors - possibly via a common mediating factor - we performed imputation‐based fine‐mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28108 cases, 22209 controls), and ovarian cancer (25509 cases, 40941 controls). Analyses were stratified by sex (meningioma), estrogen receptor status (breast), and histotype (ovarian), then combined using ASSET meta-analysis. Lead variants were queried for association with &gt;700 additional traits to identify potential effect-mediators. RESULTS Two-sided ASSET meta-analysis identified a lead variant near the MLLT10 promoter (P=1.4x10-13) associated with significantly increased risk of meningioma in women (OR=1.42, 95% CI: 1.20–1.69) and non-significantly increased risk in men (OR=1.19, 95% CI: 0.91–1.57). The meningioma risk allele was also associated with ovarian cancer risk (OR=1.09, 95% CI: 1.06–1.12) and ER+ breast cancer risk (OR=1.05, 95% CI: 1.02–1.08), but protected against ER- breast cancer (OR=0.91, 95% CI: 0.86–0.96). The risk allele was associated with higher body fat percentage, waist circumference and BMI at genome-wide levels (P&lt; 5.0x10-8), but mediation analysis adjusting for BMI did not attenuate its association with meningioma risk. CONCLUSION We identify a MLLT10 eQTL that confers risk of female meningioma, ER+ breast cancer, ovarian cancer, and obesity, but which protects against ER- breast cancer. Our results implicate a possible estrogenic mechanism underlying meningioma tumorigenesis.
Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free Pediatric-Inspired ALL Regimen with Imatinib
Authors: Ruiqi Chen, Xing Liu, Solaf Kanfar, Dawn Maze, Steven M Chan, Vikas Gupta, Karen W.L. Yee, Mark D. Minden, Aaron D Schimmer, Andre C. Schuh, Caroline J McNamara, Tracy Murphy, Anna Xu, Umberto Falcone, Jack Seki, Hassan Sibai
Journal: Blood (2019)
ATIM-17. A PHASE I TRIAL OF HYPOFRACTIONATED STEREOTACTIC IRRADIATION (HFSRT) COMBINED WITH NIVOLUMAB (NIVO), IPILIMUMAB (IPI) AND BEVACIZUMAB (BEV) IN PATIENTS (PTS) WITH RECURRENT HIGH GRADE GLIOMAS
Authors: Solmaz Sahebjam, Peter Forsyth, Nam Tran, Arnold Etame, John Arrington, Michael Jaglal, Sepideh Mokhtari, Robert MacAulay, Melissa Wicklund, Brittany Evernden, Tyra Gatewood, Timothy Robinson, Raju Raval, Michael Yu
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND There is strong pre-clinical evidence that combining CTLA4 and PD-1/PDL-1 blockade with antiangiogenic agents and HFSRT independently enhance anti-tumor immune responses and tumor regression. METHODS This phase I study includes a safety cohort of 6 pts followed by dose expansion cohort of 26 pts. Pts with Bev naïve recurrent WHO grade III or IV gliomas (maximum diameter of enhancing brain lesion ≤ 4 cm) are eligible. An interval of at least 6 months after the end of prior RT is required unless there is a new recurrence outside of the previous RT treatment field. Eligible pts are treated with HFSRT to the recurrent tumor (30 Gy in 5 fractions) and 4 cycles of Nivo (3 mg/kg), Ipi (1 mg/kg) and Bev (15 mg/kg) every 3 weeks followed by Nivo 240 mg and Bev 10 mg/kg every 2 weeks for 4 months. After 4 months, Nivo is administered every 4 weeks at 480 mg flat dose and Bev is continued at every 2 week schedule. The primary study objectives are to determine safety and tolerability of above treatment. Secondary endpoints include response rate, 6 and 9-months survival rates, and exploring tissue and imaging biomarkers. RESULTS As of June 2019, safety cohort has been completed and accrual to dose expansion cohort is ongoing. Combination of HFSRT, Nivo, Ipi and Bev as above is well tolerated. The most common toxicities were grade 1 anorexia, grade 1 diarrhea, grade 1 elevation of alanine aminotransferase, grade 1 elevation of lipase and grade 1 infusion related reaction. One patient had grade 3 confusion which was reversible with use of corticosteroids. No dose limiting toxicity has been observed. CONCLUSIONS Combination of HFSRT with Nivo, Ipi and Bev was considered safe to be studied in expansion cohort. Updated safety and efficacy data will be presented.
Integrated Multi-Level Omics to Characterize Bortezomib Resistance in Multiple Myeloma
Authors: David C. Koomen, Mark B. Meads, Dario M. Magaletti, Joy D. Guingab, Paula S. Oliveira, Bin Fang, Victoria Izumi, Rafael Renatino-Canevarolo, Praneeth Reddy Sudalagunta, Maria Silva, Raghunandanreddy Alugubelli, Gabe De Avilla, Alex Tungeskiv, Eric A. Welsh, Laurel E. Meke, Wei Zhang, Steven A. Eschrich, Timothy J. Garrett, Ariosto Siqueira Silva, John M. Koomen, Kenneth H. Shain
Journal: Blood (2019)