tbuckley/cabot-search huggingface dataset:
DIPG-10. TP53 PATHWAY ALTERATION IS DRIVING RADIORESISTANCE IN DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Authors: Coralie Werbrouck, Clàudia Silva-Evangelista, Maria Jesus Lobón, Emilie Barret, Gwnenaël Le Teuff, Jane Merlevede, Romain Brusini, Thomas Kergrohen, Stéphanie Bolle, Kevin Beccaria, Nathalie Boddaert, Stéphanie Puget, Jacques Grill, Marie-Anne Debily, David Castel
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumours. Though accepted as the main therapeutic, radiotherapy is only transiently efficient and not even in every patient. We previously identified an heterogeneous response to radiotherapy at diagnosis depending on the type of histone H3 mutated (Castel et al., 2015). We aimed at defining possible molecular determinants of this response to radiotherapy. We assessed in vitro response to ionizing radiations in a collection of DIPG cellular models derived from treatment-naïve biopsies reflecting the variability encountered in patients and correlated it to their principal molecular alterations. The in vitro 50% lethal dose of these DIPG cellular models ranged from 0.5 to 7 Gy and were correlated to time to progression after radiotherapy in the corresponding patients. We uncovered TP53 mutation as the main driver of increased radioresistance. We validated this finding in 4 isogenic pairs of DIPG cells with TP53WT and TP53 knock-down, confirming the pivotal role of TP53 inactivation in inducing DIPG radioresistance irrespective of the type of canonical or variant histone H3 mutated. Clinical and radiological response to radiotherapy and overall survival of an extended cohort of 73 DIPG was analysed according to their genotype and we demonstrated that mutated TP53 patients had a poor response to radiotherapy. Using a kinome-wide synthetic lethality RNAi screen, we further identified target genes that can sensitize TP53MUT DIPG to ionizing radiations. CHK1 inhibition increases response to radiation specifically in TP53MUT cells and could be considered as a new therapeutic approach in this setting. In all, TP53 alterations drive radioresistance in DIPG cells and TP53 mutational status is a biomarker to predict poor response to radiotherapy in patients. These findings will allow defining more tailored radiotherapy in DIPG and suggesting alternative treatment strategies to mitigate radioresistance with for example CHK1 inhibitors.
Health status, health-related quality of life, and socioeconomic outcome in childhood brain tumor survivors: a German cohort study
Authors: Cathy Scholtes, Katja Baust, Leonie Weinhold, Ursula Creutzig, Astrid Gnekow, Andreas Hinz, Peter Kaatsch, Kiana Kreitz, Thorsten Langer, Stefan Rutkowski, Susanne Singer, Claudia Spix, Carmen Teske, Matthias Schmid, Dagmar Dilloo, Gabriele Calaminus
Journal: Neuro-Oncology (2019)

With rising numbers of childhood cancer survivors, somatic and socioeconomic outcome as well as health-related quality of life (QoL) gain increasing relevance. Based on the first nationwide German Survey on Life Situation, State of Health, and Quality of Life of Childhood Cancer Survivors, the VIVE survey, we report the outcome of survivors of childhood brain tumors localized in the posterior fossa.Two hundred seventy participants with a median follow-up period of 21.9 years completed a questionnaire on socioeconomic and somatic late effects as well as a standardized QoL questionnaire (European Organisation for Research and Treatment of Cancer QLQ-C30). Comparisons were performed between World Health Organization (WHO) grades I-II, WHO grades III-IV brain tumor survivors (BTS), and the general population adjusting for potential confounders.The socioeconomic and QoL results of WHO grades I-II BTS were largely comparable to the general population, while grades III-IV BTS were at higher risk for significantly worse outcomes. Of WHO grades III-IV BTS, 36.8% were still living with their parents or in assisted living facilities compared with 16.1% of grades I-II BTS and 7.8% of the age-adjusted general population. Of grades III-IV BTS, 60.8% achieved at least an intermediate school degree in comparison to 80.5% of grades I-II BTS and 75.6% of the general population. Grades III-IV BTS developed up to 2 times more somatic late effects than survivors of grades I-II tumors.Derived from a large and homogeneous cohort, these results stress the importance of an appropriate follow-up period focusing not only on physical aspects but encompassing the entire living situation to allow patient-tailored support.
Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension
Authors: Rita Papp, Chandran Nagaraj, Diana Zabini, Bence M. Nagy, Miklós Lengyel, Davor Skofic Maurer, Neha Sharma, Bakytbek Egemnazarov, Gabor Kovacs, Grazyna Kwapiszewska, Leigh M. Marsh, Andelko Hrzenjak, Gerald Höfler, Miroslava Didiasova, Malgorzata Wygrecka, Laura K. Sievers, Peter Szucs, Péter Enyedi, Bahil Ghanim, Walter Klepetko, Horst Olschewski, Andrea Olschewski
Journal: European Respiratory Journal (2019)

Our systematic analysis of anion channels and transporters in idiopathic pulmonary arterial hypertension (IPAH) showed marked upregulation of the Cl − channel TMEM16A gene. We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing pulmonary arterial hypertension (PAH). We investigated healthy donor lungs (n=40) and recipient lungs with IPAH (n=38) for the expression of anion channel and transporter genes in small pulmonary arteries and pulmonary artery smooth muscle cells (PASMCs). In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl − current in PASMCs (n=9–10). These cells were depolarised and could be repolarised by TMEM16A inhibitors or knock-down experiments (n=6–10). Inhibition/knock-down of TMEM16A reduced the proliferation of IPAH-PASMCs (n=6). Conversely, overexpression of TMEM16A in healthy donor PASMCs produced an IPAH-like phenotype. Chronic application of benzbromarone in two independent animal models significantly decreased right ventricular pressure and reversed remodelling of established pulmonary hypertension. Our findings suggest that increased TMEM16A expression and activity comprise an important pathologic mechanism underlying the vasoconstriction and remodelling of pulmonary arteries in PAH. Inhibition of TMEM16A represents a novel therapeutic approach to reverse remodelling in PAH.
The importance of differentiating behavioural and psychological treatment effects from placebo in respiratory interventions
Authors: Ben Ainsworth, Doug Hardman, Mike Thomas
Journal: European Respiratory Journal (2019)

We read with interest the piece by Pattinson and Wanigasekera [1], discussing the clinical implications of the recent trial reported by Currow et al . [2], which demonstrated parity between sertraline and placebo for improving breathlessness intensity. In particular, Pattinson and Wanigasekera [1] noted that differential response expectations can potentially confound outcomes between otherwise balanced intervention versus placebo-controlled groups. Such expectations have clinical implications: the management of response expectations should be examined and potentially harnessed to improve treatment outcomes for patients with chronic breathlessness, as suggested by Similowski and Serresse [3]. Well-designed nonpharmacological interventions can harness treatment responses seen in the placebo arm <http://ow.ly/EgoM30o7k1v>
Hes1 attenuates type I IFN responses via VEGF-C and WDFY1
Authors: Fei Ning, Xiaoyu Li, Li Yu, Bin Zhang, Yuna Zhao, Yu Liu, Baohong Zhao, Yingli Shang, Xiaoyu Hu
Journal: The Journal of Experimental Medicine (2019)

Induction of type I interferons (IFNs) is critical for eliciting competent immune responses, especially antiviral immunity. However, uncontrolled IFN production contributes to pathogenesis of autoimmune and inflammatory diseases. We found that transcription factor Hes1 suppressed production of type I IFNs and expression of IFN-stimulated genes. Functionally, Hes1-deficient mice displayed a heightened IFN signature in vivo, mounted enhanced resistance against encephalomyocarditis virus infection, and showed signs of exacerbated experimental lupus nephritis. Mechanistically, Hes1 did not suppress IFNs via direct transcriptional repression of IFN-encoding genes. Instead, Hes1 attenuated activation of TLR upstream signaling by inhibition of an adaptor molecule, WDFY1. Genome-wide assessment of Hes1 occupancy revealed that suppression of WDFY1 was secondary to direct binding and thus enhancement of expression of VEGF-C by Hes1, making Vegfc a rare example of an Hes1 positively regulated gene. In summary, these results identified Hes1 as a homeostatic negative regulator of type I IFNs for the maintenance of immune balance in the context of antiviral immunity and autoimmune diseases.
The Physics of Cancer
Authors: Forest M. White, Robert A. Gatenby, Claudia Fischbach
Journal: Cancer Research (2019)

Abstract While often described as a “disease of the genes,” cancer is, in fact, a complex dynamic system in which evolving cells both affect and are affected by the physical properties of their environment. About 10 years ago, after a number of multidisciplinary workshops and meetings, the NCI leadership embarked on a bold program to systematically integrate physical sciences into cancer biology and treatment through formation of the Physical Sciences-Oncology Network (PS-ON). Here, we highlight key areas in which the two disciplines have been successfully integrated and lessons learned from the first decade of the PS-ON experiment.
Critically Ill Healthcare Workers With The Middle East Respiratory Syndrome (mers)
Authors: Y M Arabi, A Alomari, Y Mandourah, F Al-Hameed, A Sindi, B Al-Raddadi, S Shalhoub, A AlMotairi, K Alkhatib, A Abdulmomen, I Qushmaq, A Mady, O Solaiman, A Alaithan, R Alradadi, A Rajab, G Almekhlafi, A Alharthy, M Alahmadi, M Sadat, S Abdukahil, A Toledo, H Almutairi, E Alqasim, A S Aldawood, L Merson, R Fowler, F Hayden, H Balkhy
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Abstract 15447: Trends in Use of Pulmonary Artery Catheterization in Heart Failure in the United States, 2006 - 2012
Authors: Rohan Khera, Ambarish Pandey, Nilay Kumar, Saket Girotra, Gregg C Fonarow
Journal: Circulation (2015)

Introduction: Use of pulmonary artery(PA) catheterization in heart failure(HF) patients without cardiogenic shock has not been shown to improve clinical outcomes (ESCAPE trial, 2005) and is not routinely recommended in the absence of shock or respiratory failure. However, contemporary trends in PA catheter use among HF patients are not known. Methods: The National Inpatient Sample (2006-2012) was used to identify adults(&gt;18 years) hospitalized with a primary diagnosis of HF using ICD-9 codes 402.x1, 404.x1, 404.x3 and 428.x. PA catheter use was identified using procedure codes 89.6x. Patients undergoing major surgery or receiving mechanical circulatory support were excluded. Propensity-matched analyses were performed to compare risk-adjusted in-hospital mortality in patients with and without PA catheter use. Results: During 2006-2012, PA catheters were used in 39,247 HF hospitalizations, at a rate of 6 per 1000 HF admissions. Patients with PA catheter placement were younger and more commonly had cardiogenic shock (11%) or respiratory failure (11%). PA catheter use increased significantly over time from 5.3/1000 HF(2006) to 7.9/1000 HF(2012)(P&lt;0.001,Figure). In subgroup analyses, in patients with cardiogenic shock, the proportional use of PA catheter was higher and increased only modestly (118 to 121/1000 HF cases,Ptrend 0.04). In contrast, patients without shock or respiratory failure had lower proportional use of PA catheter with a substantial increase during the study period (4.2 to 6.5 per 1000 HF cases, Ptrend&lt; 0.001). In propensity-matched analyses of patients without shock or respiratory failure, mortality in HF was higher with the use of PA catheter compared to no PA catheter use (Risk-adjusted odd ratio 1.42, 95%CI 1.30, 1.56) Conclusions: PA catheter use has increased significantly over time among patients hospitalized with HF after ESCAPE, even in patients without cardiogenic shock/respiratory failure and is associated with worse outcomes.
Response by Raghavan et al to Letter Regarding Article, “Protein Kinase Cθ via Activating Transcription Factor 2–Mediated CD36 Expression and Foam Cell Formation of Ly6C <sup>hi</sup> Cells Contributes to Atherosclerosis”
Authors: Somasundaram Raghavan, Nikhlesh K. Singh, Sivaiah Gali, Arul M. Mani, Gadiparthi N. Rao
Journal: Circulation (2019)
THER-24. TARGETED RADIOIMMUNOTHERAPY FOR EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES
Authors: Kayleen Bailey, Neeta Pandit-Taskar, John Humm, Pat Zanzonico, Stephen Gilheeney, Nai-Kong Cheung, Kim Kramer
Journal: Neuro-Oncology (2019)

IMPORTANCE: Embryonal Tumor/Multilayered Rosettes (ETMR) is an aggressive, lethal, CNS tumor in young childr. B7-H3 is an inhibitory ligand for natural killer cells and T cell overexpressed in a number of embryonal tumors. 131-Omburtomab (8H9) is a radiolabeled monoclonal antibody under investigation for intraventricular administration for primary and metastatic CNS disease. We explored the use of intraventricular 131I-8H9 targeting B7-H3 in patients with ETMR. DESIGN: Patients were enrolled in an IRB approved trial. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR Patients received 2 mCi 131I-Omburtamab as a tracer followed by 1 or 2 therapeutic 131I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after 131I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.5 years and 2 years after diagnosis, respectively; patient 3 died of progressive disease 7 month after therapy, 2 years after diagnosis. CONCLUSIONS: 131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.
Abstract 11297: S-Glutathionylation, One of the Oxidative Protein Modifications, Stimulates Adipogenesis and Obesity by Stabilizing C/EBP Beta Through Inhibition of SUMO E3 Ligase PIAS1 Interaction
Authors: Yosuke Watanabe, Kazuhiro Watanabe, Daisuke Fujioka, Kazuto Nakamura, Kenichi Kawabata, Hiroki Kishi, Yuki Fujihara, Reiko Matsui, Markus M Bachschmid, Richard A Cohen, Kugiyama Kiyotaka
Journal: Circulation (2018)

Introduction: Reactive oxygen species (ROS) are increased during adipogenesis and obesity. On the other hand, ROS stimulate adipogenesis. ROS not only damage cells but stimulate cell signaling trou...
INFLUENCE OF BOWEL PREPARATION (BP) QUALITY ON THE DETECTION OF SERRATED POLYPS (SP): A PROSPECTIVE STUDY IN A REGIONAL FOBT-BASED COLORECTAL CANCER SCREENING PROGRAM
Authors: C Satorres, M García-Campos, N García-Morales, N Alonso, M Ponce, L Argüello, V Pons, M Bustamante-Balen
Journal: Endoscopy (2019)

to describe the proportion of serrated lesions detected in second examinations performed after a poor-prepared initial screening colonoscopy.
Bile Acids as Metabolic Regulators and Nutrient Sensors
Authors: John Y. L. Chiang, Jessica M. Ferrell
Journal: Annual Review of Nutrition (2019)

Bile acids facilitate nutrient absorption and are endogenous ligands for nuclear receptors that regulate lipid and energy metabolism. The brain-gut-liver axis plays an essential role in maintaining overall glucose, bile acid, and immune homeostasis. Fasting and feeding transitions alter nutrient content in the gut, which influences bile acid composition and pool size. In turn, bile acid signaling controls lipid and glucose use and protection against inflammation. Altered bile acid metabolism resulting from gene mutations, high-fat diets, alcohol, or circadian disruption can contribute to cholestatic and inflammatory diseases, diabetes, and obesity. Bile acids and their derivatives are valuable therapeutic agents for treating these inflammatory metabolic diseases.
DIPG-14. MULTISITE STEREOTACTIC NEEDLE ASPIRATION BIOPSY IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA — A PROMISED SAFE PROCEDURE
Authors: Yang Zhao, Yipeng Han, Wei Meng, Zixuan Wang, Baocheng Wang, Chenran Zhang, Jie Ma
Journal: Neuro-Oncology (2019)

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a highly malignant tumor raised from pons, causing various symptoms in affected cranial nerves. DIPG accounts for about 10% in tumors of central nervous system tumors in children. DIPG has a poor prognosis, with less than 10 percent of the children surviving for more than two years. OBJECTIVE: This study is a retrospective study in assessment of the safety of multisite stereotactic needle aspiration biopsy in children with DIPG. Furthermore, biological characteristics of DIPGs will be studied in advanced molecular pathology. METHOD: Clinical data of children with DIPG from December 2006 to July 2018 in Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine was collected and analyzed. Conditions of the patients in post stereotactic biopsy and follow-up period were compared with those with open biopsy. DNA methylation array (Illumina 850K) and H3K27M mutation measurement were conducted. RESULT: 66 patients with DIPG were enrolled with 35 males and 31 females. KPS score range of 50 to 80 points, the median was 60 points. 55 cases were positive in H3K27M test, 9 cases were negative in H3K27M test. The Kaplan-Meier analysis showed that there was no significant difference in survival by gender, biopsy methods and with/without chemotherapy. KPSs shifts were only found in 3 patients whose scores were lower than 40 before biopsy (either open or stereotactic biopsy). Different biopsy sites in multisite stereotactic biopsy showed different pathology characteristics in DIPG. CONCLUSION: DIPG is a deadly malignancy with poor prognosis. While, stereotactic biopsy is a promised safe procedure for patients and could provide valuable biological information for further research and target therapies.
EPEN-14. EXPLORATION OF INTRA- AND INTER-TUMOR CELLULAR HETEROGENEITY IN SUPRATENTORIAL EPENDYMOMA
Authors: Andrew Donson, Austin Gillen, Kent Riemondy, Jay Hesselberth, Vladimir Amani, Andrea Griesinger, Bridgit Sanford, Ken Jones, Todd Hankinson, Michael Handler, Sujatha Venkataraman, Rajeev Vibhakar, Nicholas Foreman
Journal: Neuro-Oncology (2019)

Cellular heterogeneity is a critical determinant of ependymoma biology. Analysis of bulk tumor samples therefore presents a significant barrier to fully understanding ependymoma biology. Single cell RNAseq analysis (scRNAseq) addresses this problem, and has recently provided us with unparalleled insights into the biology of posterior fossa ependymoma (EPNPF). In the present study we have applied this approach to explore the intra- and inter-tumor cellular heterogeneity of supratentorial ependymoma (EPNST). Using the 10x Chromium Drop-seq platform we analyzed approximately 1500 cells from 3 EPNST C11orf95-RELA fusion patient samples. These cells were compared to approximately 2000 cells from 10 EPNPF patient samples. Unsupervised tSNE clustering showed that the EPNST cells clustered separately from EPNPF. Examination of EPNST marker gene expression identified RELA and L1CAM as significantly overexpressed in all EPNST versus EPNPF. Analysis of single cell regulatory pathways demonstrated upregulation of the RELA regulatory network in EPNST. Despite clustering differences, key EPNPF genes were also expressed by EPNST, most notably IGF2 and midkine (MDK). In EPNPF, IGF2 and MDK are expressed by a subpopulation of tumor cells with an undifferentiated phenotype that are associated with a worse clinical outcome. IGF2 and MDK may therefore underlie the malignant phenotype of both EPNPF and EPNST. Whereas all EPNPF patient samples clustered predominantly together, EPNST patient samples did not, suggesting greater inter-tumor heterogeneity in EPNST than EPNPF. These findings increase our biological understanding of EPNST with RELA-fusions, and reveal molecular features that potentially underlie oncogenesis in both EPNST and EPNPF.
Association of Antibiotic Resistance With Antibiotic Use for Epidermal Growth Factor Receptor Inhibitor–Related Papulopustular Eruption
Authors: Kelsey Hirotsu, Timothy M. Dang, Shufeng Li, Joel W. Neal, Silvina Pugliese, Aruna Subramanian, Bernice Y. Kwong
Journal: JAMA Dermatology (2019)

This medical record review investigates whether use of topical clindamycin and/or oral tetracyclines during management of epidermal growth factor receptor (EGFR) inhibitor–related papulopustular eruption is associated with antibiotic-resistant bacterial infection.
Synchronous Paraganglioma Masquerading as 68Ga-PSMA PET/CT–Avid Metastasis in Carcinoma Prostate—How Specific Is 68Ga-PSMA PET/CT?
Authors: Shantanu Tyagi, Shrawan Kumar Singh, Tushar Aditya Narain, Harmandeep Singh, Rajender Kumar, Shelvin Kumar Vadi
Journal: Clinical Nuclear Medicine (2019)

We present a case of biopsy-proven prostatic adenocarcinoma with a tracer-avid left paravertebral location at D4 to D5 vertebrae, suggestive of metastasis. However, in view of uncommon location of single-site metastasis at paravertebral region with no tracer-avid regional lymphadenopathy, image-guided biopsy was done, which was suggestive of paraganglioma. Ga-PSMA is known to have variable tracer avidity in multiple nonprostatic benign as well as malignant lesions, and our case adds to the list of nonspecific uptake by this once considered "specific" to prostate PET radiotracer.
Chronic urticaria and osteoporosis
Authors: G. Shalom, K. Kridin, M. Babaev, E. Magen, S. Tiosano, J. Dreiher, A. Horev, R. Khury, D. Comaneshter, N. Agmon‐Levin, A.D. Cohen
Journal: British Journal of Dermatology (2019)

Osteoporosis is a condition in which the bones are thinner and more liable to fracture. It is commoner in women and in people over 50. It cannot be cured so the focus is on prevention, which means identifying and addressing risk factors such as obesity, low vitamin D, chronic inflammation and prolonged steroid medication. Chronic urticaria (hives, CU) is an inflammatory condition, so one might expect it to be linked with osteoporosis, but that has never been investigated. If people with CU are indeed more likely to develop osteoporosis, they could be advised about preventative measures. To study this, doctors from Israel identified 11,944 patients diagnosed with CU in a large medical database covering 4.5 million people. A potential difficulty was that people with CU are more likely to be female, obese and to have been treated with systemic steroids, all of which also increase the risk of osteoporosis. Therefore for each CU patient they studied 5 age‐ and sex‐matched control patients (people of the same age and sex but without CU) and their analyses took into account other known risk factors for osteoporosis. During a 16 year period 8.7% of the patients with CU were diagnosed with osteoporosis compared with 6.8% of the controls. They concluded that CU is a small but significant additional risk factor for osteoporosis. An accompanying editorial cautions against basing conclusions on routine health records which may not have all the information required. Nonetheless, doctors treating chronic urticaria might bear in mind the risk of osteoporosis in their patients, and counsel accordingly.