tbuckley/cabot-search huggingface dataset:
A Novel Small-Molecule Inhibitor of MRCK Prevents Radiation-Driven Invasion in Glioblastoma
Authors: Joanna L. Birch, Karen Strathdee, Lesley Gilmour, Antoine Vallatos, Laura McDonald, Ariadni Kouzeli, Richa Vasan, Abdulrahman Hussain Qaisi, Daniel R. Croft, Diane Crighton, Kathryn Gill, Christopher H. Gray, Jennifer Konczal, Mokdad Mezna, Duncan McArthur, Alexander W. Schüttelkopf, Patricia McConnell, Mairi Sime, William M. Holmes, Justin Bower, Heather J. McKinnon, Martin Drysdale, Michael F. Olson, Anthony J. Chalmers
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurologic, cognitive, and psychologic symptoms. Symptoms are caused and exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain and disrupt normal function. Recent research has indicated that although radiotherapy (RT) remains the most effective component of multimodality therapy for patients with GBM, it can provoke a more infiltrative phenotype in GBM cells that survive treatment. Here, we demonstrate an essential role of the actin-myosin regulatory kinase myotonic dystrophy kinase-related CDC42-binding kinase (MRCK) in mediating the proinvasive effects of radiation. MRCK-mediated invasion occurred via downstream signaling to effector molecules MYPT1 and MLC2. MRCK was activated by clinically relevant doses per fraction of radiation, and this activation was concomitant with an increase in GBM cell motility and invasion. Furthermore, ablation of MRCK activity either by RNAi or by inhibition with the novel small-molecule inhibitor BDP-9066 prevented radiation-driven increases in motility both in vitro and in a clinically relevant orthotopic xenograft model of GBM. Crucially, treatment with BDP-9066 in combination with RT significantly increased survival in this model and markedly reduced infiltration of the contralateral cerebral hemisphere. Significance: An effective new strategy for the treatment of glioblastoma uses a novel, anti-invasive chemotherapeutic to prevent infiltration of the normal brain by glioblastoma cells.Cancer Res; 78(22); 6509–22. ©2018 AACR.
Early delayed radiation-induced brain injury in mice: preliminary findings using magnetic resonance imaging
Authors: Mr Abdulrahman Qaisi, Dr Antoine Vallatos, Dr Katrina Stevenson, Lindsay Gallagher, Dr Rodrigo Gutierrez-quintana, Dr Apostolos Zarros, Dr Lesley Gilmour, Prof Anthony J Chalmers, Dr William Holmes
Journal: Neuro-Oncology (2018)

Radiotherapy has improved survival outcomes for central nervous system (CNS) malignancies. However, the negative impact of radiotherapy on the healthy tissue surrounding these malignancies, is increasingly becoming a concern. We aimed to investigate whether the employment of magnetic resonance imaging (MRI) techniques could be used to detect crucial aspects of the time-dependent effects resulting from the exposure of the CNS to ionizing radiation (IR). We hereby report preliminary MRI findings of a study examining the early delayed IR-induced CNS injury in adult CD-1 nude mice that had their right brain hemisphere exposed to a 20 Gy single IR dose by a Small Animal Radiation Research Platform (SARRP). T2 mapping and multiple b value diffusion weighted imaging (DWI) with a range of observation times of the whole brain were acquired with a 7T small animal preclinical MRI scanner at 6 time-points: before irradiation and then at 1, 10, 17, 60 and 80 days post irradiation. The acquired T2 mapping data indicated no significant change in actual T2 values and revealed no significant deviation from normal mono-exponential decay. Similarly, DWI data with short observation times (20–80 ms) showed no significant deviation from Gaussian behaviour, suggesting the existence of no CNS microstructural changes due to IR. However, multiple b value DWI with a 200 ms observation time showed deviations from Gaussian behaviour, suggesting that the assessment of diffusion kurtosis imaging (DKI) could be informative for identifying early delayed radiation-induced brain injury in mice. Our promising MRI findings are examined in parallel with neuropathological observations in the brain tissue of these mice (obtained at 80 days post irradiation), resulting from the assessment of haematoxylin-eosin, cresyl violet, glial fibrillary acidic protein (GFAP) and Luxol fast blue staining in CNS structures of relevance (such as the hippocampus, fimbria, external capsule, thalamus and selected cortical regions).
FIRST UK EXPERIENCE WITH NAVIGATED TRANSCRANIAL MAGNETIC STIMULATION IN PRE-SURGICAL MAPPING
Authors: Josephine Jung, José Pedro Lavrador, Sabina Patel, Jordan Lam, Anastasios Giamouriadis, Ranj Bhangoo, Francesco Vergani
Journal: Neuro-Oncology (2018)

Surgery for lesions in eloquent brain areas is challenging due to the underlying risk of causing permanent neurological deficits. To date, Direct Cortical Stimulation (DCS) and intra-operative neuro-monitoring (IOM) represent the gold standard in minimising such risk. Recently, Transcranial Magnetic Stimulation (TMS) has emerged as a mapping tool that assists in optimising surgical planning. The aim of this study is to validate our TMS findings against DCS. Retrospective single-centre analysis of 35 adult patients with TMS, DCS and IOM for space occupying lesion (SOL) at King’s College Hospital from February 2017 to February 2018. Patients with arteriovenous malformation were excluded from analysis. We collected data on patient demographics, tumour entity/location, extent of resection (EoR), change of surgical strategy, neurological outcome, and correlated TMS with DCS/IOM. 24/35 patients (68.6%) had pre-operative motor mapping and 11/35 (31.4%) were mapped for language. Histopathology demonstrated a glioma in 85.7% of patients (high grade n=24; low grade n=6) and metastasis (n=2), cavernoma (n=1) and other cases (n=2). TMS resulted in a change of surgical strategy in 34.3% (craniotomy size n=7; surgical pathway n=3; EoR n=1; surgical indication n=1). Sensitivity of TMS for language was 70.6% with a positive predictive value of 60.0% (n=9). TMS motor mapping correlated with DCS/IOM in all cases with snapshot hotspot conformity of 100% (n=5). A total of 12 patients had a new transient neurological deficit which resolved/significantly improved except for one case (expressive dysphasia). TMS is a non-invasive, safe and effective adjunct in surgery planning in eloquent brain areas. It is reliable in predicting M1/motor mapping and shows promising results for language mapping. Larger randomised controlled trials are needed to validate these findings.
Abstract 11753: Disjunction of the Mitral Annulus Is Associated With Paradoxical Systolic Expansion and Flattening in Degenerative Mitral Valve Disease: A Real-time 3-dimensional Transesophageal Echocardiographic Study
Authors: Alex P Lee, Chun-na Jin, Malcolm J Underwood, Randolph Wong, Zhe Tang, Karen Yi-ting Fan, Jing-ping Sun, Wan Song
Journal: Circulation (2015)

Introduction: Disjunction of the mitral annulus, defined as a separation between the atrial wall-mitral valve junction and the left ventricular attachment, is commonly seen on echocardiography in patients with degenerative mitral valve prolapse (MVP). Few data exists on the three-dimensional (3D) geometry of annular disjunction and its relationship with the annular dynamic function. Hypothesis: We assessed the hypothesis that annular disjunction is associated with abnormal annulus structure and function. Methods: A total of 138 subjects including 108 MVP patients (58±11years) and 30 subjects with normal MV (57±15years) were studied using real-time 3D transesophageal echocardiography. The annular circumference was examined in multiple radial planes at 10° intervals for any disjunction. The location, separation distance, and circumferential extent of disjunction were assessed. The annular area, width, and height were measured at end-diastole and end-systole. Results: Annular disjunction was evident in 61 (56%) MVP patients and 3 (10%) normal subjects (P&lt;0.0001). Among MVP patients, disjunction is usually located adjacent to the prolapsed segments, circumferentially spanning over 79°±42° (20° to 190°) of the annulus, with the maximal separation measuring 8.7±3.8mm. Annular disjunction is associated with more prolapsed segment (2.0±1.6 vs 1.3±0.6, P=0.0021), more severe mitral regurgitation (effective regurgitant orifice area=0.64±0.49 vs 0.45±0.23cm 2 , P&lt;0.0001), paradoxical systolic increase in annular area and decrease in height-to-commissural width ratio (AHCWR) (Figure), despite normal ventricular ejection fraction (62±5% vs 62±7%, P=0.97). Conclusions: Mitral annular disjunction is associated with decoupling of annular and ventricular function leading to paradoxical annular expansion and flattening of the annular saddle-shape during systole in patients with MVP and may require specific surgical correction.
Abstract 15120: Attenuated Renal Injury After the Post-Resuscitation Administration of Doxycycline in Surviving Newborn Piglets With Severe Hypoxia-Reoxygenation
Authors: Tze-Fun Lee, Min Lu, Daina Domahidi, Georg Schmolzer, Po-Yin Cheung
Journal: Circulation (2017)

Background: Asphyxiated neonates often have multi-organ failure with myocardial dysfunction and renal insufficiency. Previously we demonstrated that doxycycline (DOX) improved cardio-renal function...
Kent experience with 1st line Temozolamide in elderly patients with High Grade Glioma
Authors: Dr Jessica Gough, Dr Kannon Nathan, Elaine Kennaird, Dr Jennifer Glendenning
Journal: Neuro-Oncology (2018)

Following publication of two RCT’s demonstrating benefit particularly in those with MGMT methylated (MGMTm) tumours, Temozolomide (T) as an alternative to radiotherapy in elderly patients with Glioblastoma Multiforme (GBM)was adopted as a treatment option in Kent. METHODS: Patients over the age of 60 with new diagnosis of GBM treated with first line T at the Kent Oncology Centre were retrospectively identified from patient records. Baseline demographics, diagnosis details, comorbidity and survival outcomes recorded. RESULTS: Between December 2012 and August 2017 17 patients, median age 72 (range 61–80) commenced T. GBM was histologically confirmed in 59% (10/17), all with MGMT methylation >10% (MGMTm). Diagnosis was radiological in the remainder and MGMT status therefore unknown (MGMTu). 47% had multifocal disease, 52% had significant medical comorbidity and 52% had performance status ≥2. For the whole cohort 13/17 patients have died, MS 9 months (range 1.8–25.5). 5 patients survived over 1 year, 4 of whom had confirmed MGMTm. Median 6.5 cycles (range 1–150 were delivered in those with MGMTm compared to median 3 cycles (range 1–4) in those with radiological diagnosis. 3 patients with MGMTm continue on treatment, median OS 9 months (range 1.9–25.5) in the remainder compared to 1 with radiological diagnosis, median OS 6.7 months (range 1.9 to 11.4 months). CONCLUSIONS Despite significant comorbidity and fitness burdens, the survival outcomes following T in those with MGMTm GBM in our Kent cohort compare favourably to those reported in the NORDIC and NOA-08 trials. Our data supports more limited benefit in those with comorbidity that precludes histological diagnosis and in this situation careful discussion with patients is warranted.
Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk‐stratification and management
Authors: Ayalew Tefferi, Tiziano Barbui
Journal: American Journal of Hematology (2018)

Disease Overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR, or myeloproliferative leukemia mutations. In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. Survival: Median survivals are 14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET. Risk of thrombosis is higher in JAK2-mutated ET. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. Thrombosis Risk: In PV, 2 risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors); in ET, 4 risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). Risk-Adapted Therapy: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once- or twice-daily aspirin (81 mg), in the absence of contraindications. Very low-risk ET might not require therapy while aspirin therapy is advised for low-risk disease. Cytoreductive therapy is recommended for high-risk ET and PV but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs.
Abstract 12202: New York Heart Association Class and the Mortality Benefit From Primary Prevention Implantable Cardioverter Defibrillator Use: A Pooled Analysis of 4 Randomized Control Trials
Authors: Daniel J Friedman, Sana M Al-Khatib, Emily P Zeitler, JooYoon Han, Gust H Bardy, J. T Bigger, Alfred E Buxton, Arthur J Moss, Kerry L Lee, Richard Steinman, Paul Dorian, Alfred Hallstrom, Riccardo Cappato, Alan H Kadish, Peter J Kudenchuk, Daniel B Mark, Lurdes Y Inoue, Gillian D Sanders
Journal: Circulation (2016)

Introduction: Primary prevention implantable cardioverter defibrillators (ICDs) reduce all-cause mortality by reducing sudden cardiac death. There are conflicting data regarding whether patients with more advanced heart failure (HF) derive ICD benefit owing to the competing risk of death from pump failure. Methods: We performed a patient level data meta-analysis of 4 primary prevention ICD trials (MADIT-I, MADIT-II, DEFINITE, SCD-HeFT) to determine the effect of ICD use on all-cause mortality by NYHA class. We included ICD and control patients with EF ≤35%, NYHA II or III HF, and myocardial infarction ≥40 days prior to randomization. Bayesian-Weibull survival regression models were employed to assess the impact of the ICD on mortality among the study population and by NYHA class. Results: Of the 2,763 patients who met study criteria, 68% (n=1,867) were NYHA II and 52% (n=1,435) were randomized to an ICD. In a multivariable model including all study patients, the ICD reduced mortality [HR 0.65, 95% posterior credibility interval (PCI) 0.40-0.99]. The interaction between NYHA class and ICD use on mortality was significant (posterior probability of no interaction = 0.036). The unadjusted effect of the ICD on mortality by NYHA class is depicted in Figures A&amp;B. In stratified multivariable models including an interaction term for the NYHA class and ICD therapy, the ICD reduced mortality among NYHA II (HR 0.55, 95% PCI 0.35-0.85) and there was a trend toward reduced mortality in NYHA III patients (HR 0.76, 95% PCI 0.48-1.24). Between trial differences in mortality rates were observed across the NYHA III control patients ( Figure C) suggesting heterogeneous risk profiles. Conclusions: Primary prevention ICDs reduce mortality in NYHA II patients and trend towards reducing mortality in NYHA III patients. An improved understanding of the heterogeneous natural history of NYHA III patients may help improve patient selection for primary prevention ICDs in this important subgroup.
Contraceptive drugs mitigate experimental stroke-induced brain injury
Authors: Mohamad El Amki, Nadine Binder, Riccardo Steffen, Hannah Schneider, Andreas R Luft, Michael Weller, Bruno Imthurn, Gabriele S Merki-Feld, Susanne Wegener
Journal: Cardiovascular Research (2018)

Effective stroke treatments beyond reperfusion remain scant. The natural steroid hormone progesterone has shown protective effects in experimental models of brain injury and cardiovascular disease. However, unfavourable bioavailability limits its clinical use. Desogestrel and drospirenone are new generation progestins with progesterone-like properties, developed as oral contraceptives with excellent bioavailability and safety profile. We investigated the neuroprotective properties of these progestins in vivo using transient middle cerebral artery occlusion (MCAO) and in vitro using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in primary neuronal cells.MCAO was induced in female, female ovariectomized (modelling postmenopausal females) and male mice. Treatment with the progestins resulted in less severe strokes after MCAO and less neuronal death in OGD/R. Desogestrel and drospirenone induced higher expression levels of GABAAR α4 and delta subunits within the brain, suggesting changes in GABAAR configuration favouring tonic inhibition as potential mechanism of action. Treatment with the GABAAR blocker picrotoxin abolished the protection afforded by the progestins in vivo and in vitro.For the first time, here, we delineate a potential role of desogestrel and drospirenone, both clinically approved and safe drugs in mitigating the consequences of stroke. Contraception with desogestrel and drospirenone in progestin-only preparations may be particularly beneficial for women at risk of stroke.
US drug wholesaler to pay $625m over allegations it tampered with cancer drugs for profit
Authors: Owen Dyer
Journal: BMJ (2018)

AmerisourceBergen Corporation, one of the largest drug wholesalers in the United States, will pay $625m (£480m; €543m) to resolve government allegations that it tampered with cancer patients’ drugs in a scheme to increase profits.

As part of the agreement, AmerisourceBergen admits that its subsidiary Medical Initiatives, at an Alabama facility from 2001 to 2014, pooled the contents of thousands of vials of cancer drugs in untested plastic containers, then filled syringes from those containers which were then sent to doctors.

Drug manufacturers routinely put slightly more than the labelled quantity in the vials they produce. By filling the syringes with exact doses from the pooled contents, AmerisourceBergen was able to …
Abstract 16251: Back to Basics: Diagnosing a Hidden Cause of High-Output Cardiac Failure
Authors: Natalia C Berry, Piotr Sobieszczyk, Joshua Beckman
Journal: Circulation (2014)

An 85-year-old female with a history of AF and recent onset CHF presented with progressive dyspnea and langour. Her history was notable for five episodes of recurrent hematochezia over the previous 6 months. Extensive evaluation was unrevealing necessitating cessation of her anticoagulation. Initial current inpatient physical examination was notable for elevated JVP and a II/VI holosystolic murmur. TTE revealed normal LVEF, RV enlargement with moderately decreased function, pulmonary hypertension, severe tricuspid TR and a dilated IVC. Abdominal ultrasound showed a calcified structure with arterial flow adjacent to the right kidney and possible renal artery aneurysm. Vascular Medicine was consulted. On our physical exam, we noted a loud right sided flank bruit that persisted throughout the cardiac cycle, and abdominal CT revealed a large right renal AV fistula with 4.5 cm renal artery aneurysm. Right heart catheterization to characterize the hemodynamic effect of the fistula revealed elevated filling pres...
Fatal Encephalitis Associated with Borna Disease Virus 1
Authors: Klaus Korn, Roland Coras, Tobias Bobinger, Sibylle M Herzog, Hannes Lücking, Robert Stöhr, Hagen B Huttner, Arndt Hartmann, Armin Ensser
Journal: New England Journal of Medicine (2018)

Fatal Borna Disease Virus 1 Infection This report describes a fatal case of severe encephalitis due to Borna disease virus 1.
Abstract 16619: Calmodulin-Mediated Modulation of Scn10a Channel Gating
Authors: Liang Hong, Meihong Zhang, Brandon Chalazan, William Gomes, Arvind Sridhar, Dawood Darbar
Journal: Circulation (2017)

Background: The voltage-gated Na channels play a key role in the generation and propagation of the cardiac action potential (AP). Emerging data show that Nav1.8, encoded by SCN10A, is a modulator o...
Long-term strategies for thyroid health monitoring after nuclear accidents: recommendations from an Expert Group convened by IARC
Authors: Kayo Togawa, Hyeong Sik Ahn, Anssi Auvinen, Andrew J Bauer, Juan P Brito, Louise Davies, Ausrele Kesminiene, Dominique Laurier, Evgenia Ostroumova, Furio Pacini, Christoph Reiners, Sergey Shinkarev, Geraldine Thomas, Mykola Tronko, Salvatore Vaccarella, Joachim Schüz
Journal: The Lancet Oncology (2018)
Lipid conjugation of TLR7 agonist Resiquimod ensures co-delivery with the liposomal Cationic Adjuvant Formulation 01 (CAF01) but does not enhance immunopotentiation compared to non-conjugated Resiquimod+CAF01
Authors: Alexander Wilkinson, Eric Lattmann, Carla B. Roces, Gabriel K. Pedersen, Dennis Christensen, Yvonne Perrie
Journal: Journal of Controlled Release (2018)
Abstract 20923: Knockout Mice With Gene Ablation of the Acid-Extruding Membrane Protein Nbcn1 Develop Neuroprotection
Authors: Hae Jeong Park, Jayre A jones, Yu-Yo Sun, Chia-Yi Kuan, Inyeong Choi
Journal: Circulation (2016)

Acidification is observed in stroke ranging between pH 6.1 and 6.5 in focal and global ischemia. This acidification induces deleterious effects including release of protease and calcium, activation of acid-sensing ion channels, mitochondrial destruction, and more. The pathological aspects of acidification have been well documented; nonetheless our understanding of how pH contributes to neuronal death in cerebral ischemia is still incomplete. Here, we examined the vulnerability of NBCn1 knockout mice to neuronal death induced by brain insults. Compared to wild-type littermates, NBCn1 knockout mice develop low plasma and CSF pH. To determined neuroprotective effect, mice were administered with NMDA (75 mg/kg body weight; intraperitoneal injection; 8 males for each group of knockouts and wild types). Knockout mice showed substantially reduced expression and activity of active caspase-3, and low TUNEL staining. Thus, knockout mice exhibit reduced neuronal death. In cultures of hippocampal neurons from postnat...
Abstract 17461: Annuloplasty Rings Designed to Treat Functional/Ischemic Mitral Regurgitation Do Not Alter Left-Ventricular Dimensions in the Acutely Ischemic Ovine Heart
Authors: Wolfgang Bothe, John-Peder Escobar Kvitting, Tomasz A Timek, Julia C Swanson, Neil B Ingels, D. C Miller
Journal: Circulation (2017)

Introduction: Annuloplasty rings to treat functional/ischemic mitral regurgitation (FMR/IMR) include a greater downsizing of the septal-lateral (S-L) than the commissure-commissure (C-C) mitral ann...
Risk of Systemic Adverse Events Associated with Intravitreal Anti–VEGF Therapy for Diabetic Macular Edema in Routine Clinical Practice
Authors: Maya H. Maloney, Stephanie R. Schilz, Jeph Herrin, Lindsey R. Sangaralingham, Nilay D. Shah, Andrew J. Barkmeier
Journal: Ophthalmology (2018)