tbuckley/cabot-search huggingface dataset:
Abstract A47: Inhibition of histone methyltransferase with novel epipolythiodioxopiperazines (ETP) alkaloids in pediatric high-grade glioma
Authors: Stephen Dombrowski, Thamara Abou-Antoun, Anthony Mansour, Rewa Arar, Mohammad Movassaghi, Erin Murphy, Shuvojit Banerjee, Xiao-Nan Li, Peter Houghton, Darell Bigner, Angel Montero Carcaboso, Jeremy Rich, Violette Recinos
Journal: Cancer Research (2018)

Abstract Pediatric high-grade glioma (HGG), which ranks among the most lethal of cancers among children, contain two recurrent mutations within the histone H3 gene H3F3A (K27M and G34R/V). It is not known whether these mutations directly alter specific epigenetic regulatory mechanisms that may be involved in tumor proliferation and growth, or contribute to their therapeutic resistance and rapid recurrence. Preliminary findings from our lab have identified that Chaetocin (CH), a pan histone methyltransferase (HMT) inhibitor, and two newly synthesized epipolythiodioxopiperazines (ETP) alkaloids that are structurally and functionally distinct HMT inhibitors can effectively kill pediatric HGG (N=7), including three that contain the H3 K27M mutation. In addition, CH and ETPs can also inhibit tumor sphere formation and cell migration at low concentrations (&amp;lt;0.5uM) through in vitro studies. In H3 K27M tumors, these HMTi were shown to reverse hypomethylation of K27me3 transiently (&amp;lt;48 hours). We also found these HMTis to decrease tumor stem cell expression (Sox2, Oct4), and increase tumor-suppressor activity (PTEN, p53) for three pediatric HGG up to 72 hours. These results suggest ETP effectiveness that acts through direct HMT inhibition may also influence other tumorigenic pathways, which may in part contribute to their aggressive nature. Results from this investigation have advanced our understanding of epigenetic regulation of solid brain tumors, and identified drugs that may specifically target pediatric H3 K27M tumor subtypes and could ultimately improve overall survival in pediatric patients with high-grade glioma. Citation Format: Stephen Dombrowski, Thamara Abou-Antoun, Anthony Mansour, Rewa Arar, Mohammad Movassaghi, Erin Murphy, Shuvojit Banerjee, Xiao-Nan Li, Peter Houghton, Darell Bigner, Angel Montero Carcaboso, Jeremy Rich, Violette Recinos. Inhibition of histone methyltransferase with novel epipolythiodioxopiperazines (ETP) alkaloids in pediatric high-grade glioma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A47.
Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease
Authors: Muhammad O. Chohan, Serena Marchiò, Leslie A. Morrison, Richard L. Sidman, Webster K. Cavenee, Elisabetta Dejana, Howard Yonas, Renata Pasqualini, Wadih Arap
Journal: JAMA Neurology (2018)

Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality.We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions.We propose methods to exploit specific molecular pathways to design patient-tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need.
Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem
Authors: Hyon-Xhi Tan, Sinthujan Jegaskanda, Jennifer A. Juno, Robyn Esterbauer, Julius Wong, Hannah G. Kelly, Yi Liu, Danielle Tilmanis, Aeron C. Hurt, Jonathan W. Yewdell, Stephen J. Kent, Adam K. Wheatley
Journal: Journal of Clinical Investigation (2018)

Both natural influenza infection and current seasonal influenza vaccines primarily induce neutralizing antibody responses against highly diverse epitopes within the “head” of the viral hemagglutinin (HA) protein. There is increasing interest in redirecting immunity toward the more conserved HA stem or stalk as a means of broadening protective antibody responses. Here we examined HA stem–specific B cell and T follicular helper (Tfh) cell responses in the context of influenza infection and immunization in mouse and monkey models. We found that during infection, the stem domain was immunologically subdominant to the head in terms of serum antibody production and antigen-specific B and Tfh cell responses. Similarly, we found that HA stem immunogens were poorly immunogenic compared with the full-length HA with abolished sialic acid binding activity, with limiting Tfh cell elicitation a potential constraint to the induction or boosting of anti-stem immunity by vaccination. Finally, we confirm that currently licensed seasonal influenza vaccines can boost preexisting memory responses against the HA stem in humans. An increased understanding of the immune dynamics surrounding the HA stem is essential to inform the design of next-generation influenza vaccines for broad and durable protection.
Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities
Authors: Michela Serresi, Bjorn Siteur, Danielle Hulsman, Carlos Company, Matthias J. Schmitt, Cor Lieftink, Ben Morris, Matteo Cesaroni, Natalie Proost, Roderick L. Beijersbergen, Maarten van Lohuizen, Gaetano Gargiulo
Journal: The Journal of Experimental Medicine (2018)

Kras-driven non–small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs.
Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia
Authors: Piers Blombery, Mary Ann Anderson, Jia-nan Gong, Rachel Thijssen, Richard W. Birkinshaw, Ella R. Thompson, Charis E. Teh, Tamia Nguyen, Zhen Xu, Christoffer Flensburg, Thomas E. Lew, Ian J. Majewski, Daniel H.D. Gray, David A. Westerman, Constantine S. Tam, John F. Seymour, Peter E. Czabotar, David C.S. Huang, Andrew W. Roberts
Journal: Cancer Discovery (2018)

Abstract The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. Significance: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is sufficient to confer resistance. See related commentary by Thangavadivel and Byrd, p. 320. This article is highlighted in the In This Issue feature, p. 305
Wireless, battery-free, flexible, miniaturized dosimeters monitor exposure to solar radiation and to light for phototherapy
Authors: Seung Yun Heo, Jeonghyun Kim, Philipp Gutruf, Anthony Banks, Pinghung Wei, Rafal Pielak, Guive Balooch, Yunzhou Shi, Hitoshi Araki, Derrick Rollo, Carey Gaede, Manish Patel, Jean Won Kwak, Amnahir E. Peña-Alcántara, Kyu-Tae Lee, Yeojeong Yun, June K. Robinson, Shuai Xu, John A. Rogers
Journal: Science Translational Medicine (2018)

Wireless, battery-free, flexible dosimeters measure personalized exposure to electromagnetic radiation outdoors and in clinical environments.
Safety and Feasibility of a Nonpledgeted Suture Technique for Heart Valve Replacement
Authors: Patrick G. Chan, Ernest G. Chan, Laura Seese, Ibrahim Sultan, Arman Kilic, Thomas G. Gleason, Danny Chu
Journal: JAMA Surgery (2018)

This medical record review assesses the safety and feasibility of using nonpledgeted sutures for patients undergoing heart valve replacement.
Effect of residential air cleaning interventions on risk of cancer associated with indoor semi-volatile organic compounds: a comprehensive simulation study
Authors: Shanshan Shi, Bin Zhao, Junfeng (Jim) Zhang
Journal: The Lancet Planetary Health (2018)

Human exposure to multiphase semi-volatile organic compounds (SVOCs) via multiple routes has been associated with health risks. Residential air cleaning interventions remove SVOCs adsorbed on airborne particles, which subsequently affects indoor concentrations of SVOCs in other phases. We aimed to investigate the effect of residential air cleaning interventions on the overall cancer risk associated with multiphase SVOCs.We simulated concentrations of eight multiphase SVOCs (including seven polycyclic aromatic hydrocarbons [PAHs] and di(2-ethylhexyl) phthalate [DEHP]) using a kinetic partition mass balance model for three exposure scenarios: naturally ventilated residences without intervention (scenario 1), naturally ventilated residences with portable air purifiers (scenario 2), and mechanically ventilated residences with air filtration units (scenario 3). We converted indoor concentrations of the individual PAHs into indoor concentrations of equivalent benzo[a]pyrene (BaPeq) using the BaP cancer potency equivalent factor for each PAH. We estimated indoor exposure to SVOCs via inhalation, dermal absorption, and ingestion. For each scenario, we calculated the incremental lifetime cancer risk (ILCR) associated with indoor exposure to each SVOC via the three routes and the total ILCR (all three routes combined).Mean total ILCRs associated with exposure to BaPeq were 4·42 × 10-6 (SD 2·84) for scenario 1, 2·36 × 10-6 (1·53) for scenario 2, and 4·88 × 10-6 (4·86) for scenario 3. Mean total ILCRs associated with exposure to DEHP were 3·61 × 10-6 (3·60) for scenario 1, 7·51 × 10-7 (5·34) for scenario 2, and 1·48 × 10-5 (2·02) for scenario 3. Ingestion of settled dust was the most important contributor to the total ILCR for both BaPeq and DEHP in all the studied scenarios.The large-scale use of mechanical ventilation systems in urban residences in China needs to be evaluated owing to their potential exacerbation of the cancer risks associated with common indoor SVOCs.National Key Project of the Ministry of Science and Technology and Natural Science Foundation of China.
Endogenous Notch Signaling in Adult Kidneys Maintains Segment-Specific Epithelial Cell Types of the Distal Tubules and Collecting Ducts to Ensure Water Homeostasis
Authors: Malini Mukherjee, Jennifer deRiso, Karla Otterpohl, Ishara Ratnayake, Divya Kota, Phil Ahrenkiel, Indra Chandrasekar, Kameswaran Surendran
Journal: Journal of the American Society of Nephrology (2018)

Background Notch signaling is required during kidney development for nephron formation and principal cell fate selection within the collecting ducts. Whether Notch signaling is required in the adult kidney to maintain epithelial diversity, or whether its loss can trigger principal cell transdifferentiation (which could explain acquired diabetes insipidus in patients receiving lithium) is unclear. Methods To investigate whether loss of Notch signaling can trigger principal cells to lose their identity, we genetically inactivated Notch1 and Notch2 , inactivated the Notch signaling target Hes1 , or induced expression of a Notch signaling inhibitor in all of the nephron segments and collecting ducts in mice after kidney development. We examined renal function and cell type composition of control littermates and mice with conditional Notch signaling inactivation in adult renal epithelia. In addition, we traced the fate of genetically labeled adult kidney collecting duct principal cells after Hes1 inactivation or lithium treatment. Results Notch signaling was required for maintenance of Aqp2-expressing cells in distal nephron and collecting duct segments in adult kidneys. Fate tracing revealed mature principal cells in the inner stripe of the outer medulla converted to intercalated cells after genetic inactivation of Hes1 and, to a lesser extent, lithium treatment. Hes1 ensured repression of Foxi1 to prevent the intercalated cell program from turning on in mature Aqp2 + cell types. Conclusions Notch signaling via Hes1 regulates maintenance of mature renal epithelial cell states. Loss of Notch signaling or use of lithium can trigger transdifferentiation of mature principal cells to intercalated cells in adult kidneys.
Naomi Shirley Richman
Authors: Philip Graham, Rachel Richman
Journal: BMJ (2018)

Naomi Shirley Richman was born and brought up in Leeds. Her parents were second generation Jewish immigrants from eastern Europe. She won a place at the local grammar school, Roundhay High School and later read medicine at St Hilda’s College, Oxford, with clinical training at the Middlesex Hospital Medical School. She trained in psychiatry at the Maudsley Hospital between 1961 and 1964. Subsequently, she spent some years in the USA, some of the time as a research fellow on a course in the epidemiology of mental handicap run by Zena Stein at Columbia University Medical School, New York.

In the 1970s and 1980s she carried out many …
A Neural Circuit Mechanism for Encoding Aversive Stimuli in the Mesolimbic Dopamine System
Authors: Johannes W. de Jong, Seyedeh Atiyeh Afjei, Iskra Pollak Dorocic, James R. Peck, Christine Liu, Christina K. Kim, Lin Tian, Karl Deisseroth, Stephan Lammel
Journal: Neuron (2018)
Correction: Tadalafil Augments Tumor-specific Immunity in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Joseph A. Califano, Zubair Khan, Kimberly A. Noonan, Lakshmi Rudraraju, Zhe Zhang, Hao Wang, Steven Goodman, Christine G. Gourin, Patrick K. Ha, Carole Fakhry, John Saunders, Marshall Levine, Mei Tang, Geoffrey Neuner, Jeremy D. Richmon, Ray Blanco, Nishant Agrawal, Wayne M. Koch, Shanthi Marur, Donald T. Weed, Paolo Serafini, Ivan Borrello
Journal: Clinical Cancer Research (2018)

In the original version of [this article][1] ([1][2]), the authors did not disclose that the investigational agent used, tadalafil, was supplied by Lilly, Inc. This information is now included in the Acknowledgements. The error has been corrected in the latest online HTML and PDF versions of the
Maternal history of miscarriages and measures of fertility in relation to childhood asthma
Authors: Peter G Gibson
Journal: Thorax (2018)

The miracle of life is that conception and birth is turning out to be vitally important for airway diseases. Parental factors and events during pregnancy influence neonatal outcomes and infant bronchiolitis,1 2 and increase the risk of childhood asthma and adult COPD.3 4 Crucially, data are now emerging from randomised controlled trials that interventions during pregnancy can modify the incidence of childhood asthma.5–7 Because asthma is so common, and is manageable, this raises the possibility that asthma in pregnancy is an important and potentially modifiable risk factor for the associated adverse maternal and fetal outcomes, and for childhood asthma outcomes. This knowledge is now driving intense interest in the developmental origins of adult lung disease, and the role of interventions to prevent adult lung disease.8 

What’s been missing from this conversation is sex, or more specifically conception. Is there something going on here that is also relevant to the development of childhood asthma? In this issue of Thorax , the article by Maria Magnus and colleagues says the answer is yes, and then goes on to tease out some of the relevant factors (Magnus M et al ).9 It’s a little known fact that women with asthma have more trouble conceiving than non-asthmatic women. Time to pregnancy is increased in asthma, and this is particularly obvious after the age of 35.10 11 This leads to …
Disease-modifying effects of metabolic perturbations in ALS/FTLD
Authors: Ali Jawaid, Romesa Khan, Magdalini Polymenidou, Paul E. Schulz
Journal: Molecular Neurodegeneration (2018)

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative disorders with considerable clinical, pathological and genetic overlap. Both disorders are characterized by the accumulation of pathological protein aggregates that contain a number of proteins, most notably TAR DNA binding protein 43 kDa (TDP-43). Surprisingly, recent clinical studies suggest that dyslipidemia, high body mass index, and type 2 diabetes mellitus are associated with better clinical outcomes in ALS. Moreover, ALS and FTLD patients have a significantly lower incidence of cardiovascular disease, supporting the idea that an unfavorable metabolic profile may be beneficial in ALS and FTLD. The two most widely studied ALS/FTLD models, super-oxide dismutase 1 (SOD1) and TAR DNA binding protein of 43 kDA (TDP-43), reveal metabolic dysfunction and a positive effect of metabolic strategies on disease onset and/or progression. In addition, molecular studies reveal a role for ALS/FTLD-associated proteins in the regulation of cellular and whole-body metabolism. Here, we systematically evaluate these observations and discuss how changes in cellular glucose/lipid metabolism may result in abnormal protein aggregations in ALS and FTLD, which may have important implications for new treatment strategies for ALS/FTLD and possibly other neurodegenerative conditions.
Results of a Phase 2, Open-Label Study of Idarubicin (I), Cytarabine (A) and Nivolumab (Nivo) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS)
Authors: Rita Assi, Hagop M. Kantarjian, Naval G. Daver, Guillermo Garcia-Manero, Christopher B. Benton, Philip A. Thompson, Gautam Borthakur, Tapan M. Kadia, Yesid Alvarado, Elias J. Jabbour, Marina Y. Konopleva, Koichi Takahashi, Steven M. Kornblau, Courtney D. DiNardo, Zeev E. Estrov, Wilmer Flores, Sreyashi Basu, James P Allison, Padmanee Sharma, Sherry A. Pierce, Allison Pike, Jorge E. Cortes, Farhad Ravandi
Journal: Blood (2018)
Performance of two faecal immunochemical tests for the detection of advanced neoplasia at different positivity thresholds: a cross-sectional study of the Dutch national colorectal cancer screening programme
Authors: Clasine M de Klerk, Els Wieten, Iris Lansdorp-Vogelaar, Patrick M Bossuyt, Manon CW Spaander, Evelien Dekker
Journal: The Lancet. Gastroenterology & hepatology (2018)
Development and validation of the palliative care preferences scale (PCPS).
Authors: Laura M Perry, Adina S Kazan, James Louis Rogers, Michael Hoerger
Journal: Journal of Clinical Oncology (2018)

151 Background: Research has not thoroughly examined patient-level factors such as perceptions that could contribute to underutilization of palliative care, which may be due in part to a lack of existing measures for this purpose. Therefore, this investigation aimed to develop and validate a 9-item measure called the Palliative Care Preferences Scale (PCPS-9), which was comprised of three subscales: emotional, cognitive, and behavioral. Methods: Data were collected in three separate online studies of individuals with cancer (study 1: N = 633; study 2: N = 462) or one of the following non-cancer serious illnesses: COPD, heart failure, or kidney failure (study 3: N = 248). Analyses assessed various psychometric properties of the scale in cancer and non-cancer patients, including internal consistency reliability, confirmatory factor analyses (CFAs), multigroup CFAs, and convergent validity associations with related constructs. Results: Across all three studies, results supported the internal consistency reliability for the total scale (αs from 0.76 to 0.83) and subscales: emotional (αs from 0.83 to 0.84), cognitive (αs from 0.60 to 0.77), behavioral (αs from 0.87 to 0.91). CFAs supported the three-factor model of the PCPS-9 (CFI ≥ 0.97, NNFI ≥ 0.96, RMSEA ≤ 0.07, SRMR ≤ 0.04), and a multigroup CFA supported the generalizability of its factor structure across cancer and non-cancer serious illness subgroups (ΔCFIs ≤ 0.006, ΔRMSEA ≤ 0.003). Finally, convergent validity analyses in studies 2 and 3 found that the PCPS-9 was significantly associated with related constructs, including a separate measure of palliative care preferences ( ps &lt; 0.001) and a measure of palliative care knowledge ( ps &lt; 0.001). Conclusions: Findings support the overall reliability and validity of the PCPS-9 in cancer and non-cancer serious illness samples and have implications for increasing palliative care utilization via clinical care and future research efforts.