tbuckley/cabot-search huggingface dataset:
“This is new and dynamic, and we are going to have to learn together”
Authors: Richard Vize
Journal: BMJ (2017)

The Metropolitan Police chief in charge of counterterrorism tells Richard Vize that the Prevent strategy is about safeguarding, not surveillance

The shift in the terrorist threat from networks to lone attacks has put mental health and the protection of vulnerable people at the centre of the UK’s counterterrorism strategy.

Metropolitan Police assistant commissioner Mark Rowley, the national lead on counterterrorism policing, tells The BMJ that the involvement of the NHS in Prevent—the part of the counterterrorism plan aimed at stopping people becoming terrorists—is “massively important, more important than it’s ever been.”

He says, “We have wrestled with terrorism in the UK for at least 50 years, but for most of that time—whether it was the IRA or Al Qaeda—there were secret networks planning attacks, and the sort of people they recruited had to be highly trustworthy and reliable.”

Now, terrorist groups try to incite people through propaganda on the internet and social media to carry out attacks: “Part of that has led them to—sometimes accidentally, sometimes very deliberately—trying to exploit vulnerable people.”

Rowley claims that, of the people involved in the 13 attacks that the security services say they have foiled since 2013, “a disproportionate number of them do have mental health issues.” He would not specify a number.

Rowley emphasises that any suggestion that mental …
a Combination of Ex Vivo and Computational Models Predicts Clinical Response in MM Treatment Combinations of Proteasome Inhibitors, Imids, Nuclear Export Inhibitors and Alkylating Agents
Authors: Ariosto Silva, Maria Silva, Timothy Jacobson, Mark B Meads, Allison Distler, Aunshka Collins, Chris Cubitt, Lia E Perez, Rachid Baz, Dmitri Rebatchouk, Robert Gatenby, Kenneth H. Shain
Journal: Blood (2016)
Aerobic and resistance exercise can boost brain power in over 50s, review finds
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

A combination of aerobic and resistance exercises can significantly boost the brain power of people over 50 regardless of cognitive status, a review in the British Journal of Sports Medicine has found.1

Physical exercise for older adults is seen as a promising means of maintaining brain health and cognitive abilities. But the evidence for its benefits is inconclusive, largely because of overly restrictive inclusion criteria in the reviews published to date, said researchers from the University of Canberra and the Australian National University in Canberra, Australia.

To …
P18.04 IDH-1 mutation determines health-related quality of life and cognitive deficit after surgery in high grade glioma.
Authors: S. Lee, Y. Jang
Journal: Neuro-Oncology (2017)

BACKGROUND: Deterioration of health-related quality of life (HRQOL) and cognitive function is a major concern in patients who underwent glioma surgery. While HRQOL is influenced by both tumor and non-tumor factors, the influence of molecular genetic features on HRQOL is not fully understood. Here we investigated the relations among HRQOL, cognitive function, and genotypes during high grade glioma surgery. METHODS: Consecutive patients who underwent glioma surgery were evaluated with HRQOL scores (EORTC QLQ-C30 and BN20 brain cancer modules) and cognitive function tests (digit span tests, verbal fluency, and the Trail Making Tests parts A and B) at both preoperative and postoperative time points. Tumor were evaluated for genotypes including IDH1/IDH2 mutation, 1p/19q deletion, MGMT promoter methylation, epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) loss, and c-Met expression. Patients with high grade glioma were included into the final analysis. Results: Total 61 patients were diagnosed with high grade glioma. The preoperative HRQOL and cognitive functions were not different between the gene mutant and non-mutant tumors. However, postoperative HRQOL (BN20, physical functioning, and communication deficits) and cognitive functions (Trail Making Tests, and verbal fluency) were better in the IDH-1 mutant tumors compared to the IDH-1 wild-type tumors. The associations between IDH-1 mutation, better HRQOL and cognitive functions were independent from other tumor and non-tumor factors such as age, performance score, tumor size, tumor locations, extent of resection, and other mutations. Other genetic features were not related to the HRQOL and cognitive function. CONCLUSION: The postoperative deterioration in HRQOL and cognitive functions is minimal in IDH-1 mutant high grade glioma. This might be related with a preoperative cortical remodeling in the secondary glioma, or other innate metabolic microenvironment in IDH-1 mutant tumors.
P16.08 Resection of primary motor cortex tumors: feasibility and surgical outcomes
Authors: S. T. Magill, J. Li
Journal: Neuro-Oncology (2017)

BACKGROUND: Brain tumors involving the primary motor cortex are often deemed unresectable due to the potential neurological consequences that result from injury to this region. Nevertheless, we have challenged this dogma for many years, and used asleep, as well as awake, intraoperative stimulation mapping to maximize extent of resection. It remains unclear whether these tumors can be resected with acceptable morbidity, whether performing the surgery awake or asleep impacts extent of resection, and how stimulation mapping influences outcomes. METHODS: A retrospective chart review from 1998-2016 was performed on the senior author’s cohort to identify patients who underwent surgical resection of tumors that were located within the primary motor cortex. Clinical notes, operative reports and radiographic images were reviewed to identify intraoperative stimulation mapping findings and functional outcomes following tumor resection. Extent of resection was quantified volumetrically. Characteristics of patients were analyzed to identify factors associated with post-operative motor deficits. Results: Forty-nine patients underwent 53 surgical resections of tumors located primarily within the motor cortex. Stimulation mapping was performed in all cases. Positive cortical sites for motor response were identified in 91% of cases, and sub-cortical sites in 74%. Awake craniotomy was performed in 65% of cases, while 35% were done under general anesthesia. The mean extent of resection was 91%. There was no difference in extent of resection in cases done awake compared to general anesthesia. New or worsened post-operative motor deficits occurred in 32 (60%) patients, and 20 (37%) patients had a permanent deficit. Of the permanent deficits, 14 were mild, 4 were moderate, and 2 were severe (3.7% of cases). Decreased intraoperative motor response and diffusion restriction on post-operative magnetic resonance imaging (MRI) findings were associated with permanent deficit. Awake motor mapping surgery was associated with increased diffusion signal on post-operative MRI. Conclusions: Resection of tumors from the primary motor cortex is associated with an increased risk of motor deficit, but most of these deficits are transient or mild and have little functional impact. Excellent extent of resection can be achieved with intraoperative stimulation mapping, suggesting that these tumors are indeed amenable to surgical resection and should not be labeled unresectable. Injury to small perforating or en passage blood vessels was the most common cause of infarction that caused moderate or severe deficits. Awake motor mapping was not superior to mapping done under general anesthesia with regards to long-term functional outcome.
Choroidal Imaging with Swept-Source Optical Coherence Tomography in Patients with Birdshot Chorioretinopathy
Authors: Anna I. Dastiridou, Elodie Bousquet, Laura Kuehlewein, Tudor Tepelus, Dominique Monnet, Sawsen Salah, Antoine Brezin, Srinivas R. Sadda
Journal: Ophthalmology (2017)
Prefibrotic Primary Myelofibrosis As an Entity Distinct from Other Philadelphia-Chromosome Negative Myeloproliferative Neoplasms - Data from the Austrian Reclassification Project
Authors: Georg Jeryczynski, Bettina Gisslinger, Martin Schalling, Maria Theresa Krauth, Leonhard Muellauer, Ana-Iris Schiefer, Christoph Kornauth, Ingrid Simonitsch-Klupp, Jürgen Thiele, Heinz Gisslinger
Journal: Blood (2016)
Pooled Analysis of the Prognostic and Predictive Effects of <i>TP53</i> Comutation Status Combined With <i>KRAS</i> or <i>EGFR</i> Mutation in Early-Stage Resected Non–Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy
Authors: Frances A. Shepherd, Benjamin Lacas, Gwénaël Le Teuff, Pierre Hainaut, Pasi A. Jänne, Jean-Pierre Pignon, Thierry Le Chevalier, Lesley Seymour, Jean-Yves Douillard, Stephen Graziano, Elizabeth Brambilla, Robert Pirker, Martin Filipits, Robert Kratzke, Jean-Charles Soria, Ming-Sound Tsao
Journal: Journal of Clinical Oncology (2017)

Purpose Our previous work evaluated individual prognostic and predictive roles of TP53, KRAS, and EGFR in non–small-cell lung cancer (NSCLC). In this analysis, we explore the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations in randomized trials of adjuvant chemotherapy versus observation. Patients and Methods Mutation analyses (wild-type [WT] and mutant) for TP53, KRAS, and EGFR were determined in blinded fashion in multiple laboratories. Primary and secondary end points of pooled analysis were overall survival and disease-free survival. We evaluated the role of TP53/KRAS comutation in all patients and in the adenocarcinoma subgroup as well as the TP53/EGFR comutation in adenocarcinoma only through a multivariable Cox proportional hazards model stratified by trial. Results Of 3,533 patients with NSCLC, 1,181 (557 deaths) and 404 (170 deaths) were used for TP53/KRAS and TP53/EGFR analyses. For TP53/KRAS mutation status, no prognostic effect was observed ( P = .61), whereas a borderline predictive effect ( P = .04) was observed with a deleterious effect of chemotherapy with TP53/KRAS comutations versus WT/WT (hazard ratio, 2.49 [95% CI, 1.10 to 5.64]; P = .03). TP53/EGFR comutation in adenocarcinoma was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. Conclusion We could identify no prognostic effect of the KRAS or EGFR driver and TP53 tumor suppressor comutation. Our observation of a potential negative predictive effect of TP53/KRAS comutation requires validation.
The wider role of regulatory scientists
Authors: Peter Doshi, Fiona Godlee
Journal: BMJ (2017)

Why they must help us improve the evidence base

In 1990, a research scientist at the US Food and Drug Administration wrote in a letter to the New England Journal of Medicine ( NEJM ), “I review many clinical-trial protocols. The results of some of these trials subsequently appear in the medical literature. On occasion, the published description of the study may differ from the prospective protocol in important aspects of study design or statistical analysis—eg, study size, clinical end-points, and statistical tests used. The potential for misuse … is tremendous.”1

These comments were eerily prophetic: subsequent years brought the scandals of rofecoxib,23 celecoxib,4 paroxetine,56 and oseltamivir.7 The comments also suggest that each of these scandals could have largely been averted if journals had taken better account of what regulators—particularly the FDA—had to say about the relevant trials. We agree. Long before NEJM issued an expression of concern about data on harms missing from its report of the VIGOR trial of rofecoxib, those same data were available on the FDA’s website.2 JAMA reported CLASS as a six month trial …
Erratum: Impact of genetic abnormalities on survival after allogeneic hematopoietic stem cell transplantation in multiple myeloma
Authors: G Schilling, T Hansen, A Shimoni, T Zabelina, J-A Pérez-Simón, N C Gutierrez, W Bethge, P Liebisch, R Schwerdtfeger, M Bornhäuser, S Otterstetter, E M M Penas, J Dierlamm, F Ayuk, D Atanackovic, U Bacher, C Bokemeyer, A Zander, J San Miguel, A Nagler, N Kröger
Journal: Leukemia (2008)
P01.08 miRNAs in serum exosomes, as reliable non-invasive biomarkers to facilitate the clinical management of patients with gliomas
Authors: A. Santangelo, G. Pinna, M. Meglio, F. Sala, G. Lippi, A. Scarpa, A. Tamanini, P. Imbrucè, G. Cabrini, M. Dechecchi
Journal: Neuro-Oncology (2017)

Malignant gliomas and mainly glioblastoma multiforme (GBM) are the most lethal primary brain tumors. Considering that the new (2016) classification of central nervous system tumors of World Health Organization proposes an integrated diagnostic approach combining histologic and molecular features, the identification of relevant diagnostic, prognostic and predictive biomarkers is a compelling need. Blood-derived biomarkers, including proteins, nucleic acids and tumor-derived extracellular vesicles, would hence appear particularly useful as minimally invasive indices to refine classification and improving prediction of therapy response and outcome. Extracellular vesicles such as exosomes, released from tumor, are a rich source of selectively packaged molecules, including miRNAs, and can be found in serum of patients with GBM. Therefore they may provide a means of detecting evolving genetic changes relative to tumour progression using serum samples drawn over time. This study was aimed to develop a non-invasive, clinically viable biomarker assay, based on circulating miRNA analysis to support diagnosis and enabling monitoring of tumor growth and responsiveness to treatment in patients with gliomas. We enrolled 71 patients with different histopathological diagnosis of gliomas (44 GBM grade IV, 13 Oligodendrogliomas-Astrocytomas grade III and 14 grade I-II), both before and after maximal surgical resection and 27 healthy controls. Exosomes were purified from serum by “ExoQuick-TC” exosome precipitation solution and expression of miR-21, 222 and 124 was analyzed with TaqMan probes and normalized to snRNAU6. MiRNA expression was significantly higher both in grade III and in GBM IV gliomas than in healthy controls, whereas in grade I-II gliomas very similar to that observed in healthy controls, thus suggesting that they could be useful candidates able to support neuroradiological image analysis in predicting the grading of glioma before surgery. Moreover we found a very significant decrease of miR-21, 222 and 124 in exosomes purified from serum collected after tumor resection in patients with high grade gliomas, indicating that they may derive from dissemination of microparticles from brain tumor to the blood stream. Very interestingly, levels of circulating miRNAs during follow-up seem to be in agreement with neuroradiological features. Overall these results indicate that the analysis of circulating miRNAs in the blood of patients affected by glioma promises to become a minimally invasive and innovative tool a) to help the differential diagnosis of tumor masses at their onset in the brain; b) to predict glioma grading before surgery and c) to early detecting glioma recurrence during post-surgical follow up of these patients. Supported by Verona Brain Research Foundation (VBRF).
OS01.6 Glioblastoma in the era of bevacizumab: an epidemiological study in the Canton of Zurich, Switzerland
Authors: D. Gramatzki, P. Roth, E. J. Rushing, J. Weller, N. Andratschke, S. Hofer, L. Regli, J. Oberle, S. Rohrmann, M. Weller
Journal: Neuro-Oncology (2017)

Background: The vascular endothelial growth factor antibody, bevacizumab (Avastin®), received approval for the treatment of recurrent glioblastoma in Switzerland in 2009. Here we explored the hypothesis that the approval of bevacizumab improved outcome in glioblastoma on a population level. Methods: The prognostic significance of epidemiological and clinical data, as well as molecular markers for glioblastoma patients diagnosed from 2010–2014 in the Canton of Zurich was analyzed using the log rank test and the Cox proportional hazards model. Data were compared to the years 2005–2009. Results: 310 glioblastoma patients were identified in the years 2010–2014. Median overall survival (OS) in this cohort was 13.1 months for all patients (independent of the isocitrate dehydrogenase (IDH) mutation status) and 13.5 months for patients with IDH wildtype (wt) tumors, compared with 11.3 months for all patients (p=0.554) and 11.3 months for IDH wt patients (p=0.675) before (2005–2009). In the present study, in the subgroup of IDH wt patients (n=247), 111 patients received bevacizumab at any time, half of them at time of first recurrence. Multivariate analysis demonstrated young age, high Karnofsky performance score, greater extent of resection, methylated O6-methylguanine DNA methyltransferase (MGMT) promoter, or first-line chemoradiotherapy, but not bevacizumab exposure, to be independently associated with survival. Conclusions: Despite a strong increase in bevacizumab use in the Canton of Zurich, Switzerland, on a population level, OS has moderately, but not significantly improved from 2005–2009 to 2010–2014. Our data do not support the notion that the minor increase in survival was directly linked to the availability of bevacizumab.
Abstract 313: STIM1 Silencing Reverses Pressure-overload Induced Cardiac Hypertrophy In Mice
Authors: Ludovic O Bénard, Daniel S Matasic, Mathilde Keck, Anne-Marie Lompré, Roger J Hajjar, Jean-Sébastien Hulot
Journal: Circulation Research (2013)

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We demonstrated that STIM1 silencing prevented the development of left ventricular hypertrophy (LVH) in rats after abdominal aortic banding. Our aim was to study the role of STIM1 during the transition from LVH to heart failure (HF). For experimental timeline, see figure. Transverse Aortic Constriction (TAC) was performed in C57Bl/6 mice. In vivo gene silencing was performed using recombinant Associated AdenoVirus 9 (AAV9). Mice were injected with saline or with AAV9 expressing shRNA control or against STIM1 (shSTIM1) (dose: 1e+11 viral genome), which decreased STIM1 cardiac expression by 70% compared to control. While cardiac parameters were similar between the TAC groups at weeks 3 and 6, shSTIM1 animals displayed a progressive and total reversion of LVH with LV walls thickness returning to values observed in sham mice at week 8. This reversion was associated with the development of significant LV dilation and severe contractile dysfunction, as assessed by echography. Hemodynamic analysis confirmed the altered contractile function and dilation of shSTIM1 animals. Immunohistochemistry showed a trend to more fibrosis. Despite hypertrophic stimuli, there was a significant reduction in cardiac myocytes cross-section area in shSTIM1-treated animals as compared to other TAC mice. This study showed that STIM1 is essential to maintain compensatory LVH and that its silencing accelerates the transition to HF.
P08.58 Impact of selected pentabromobenzylisothiourea (ZKK-3) combined with hyperbaric oxygen therapy on therapeutic response and oxygenation status of T98G glioblastoma cell line
Authors: K. Stępień, R. P. Ostrowski
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma (GBM), the primary brain tumour derived from astroglial cells, is the most frequently diagnosed intracranial malignancy in adults. Poor prognosis for GBM patients results from high invasiveness of neoplastic cells related with faulty angiogenesis and persistent hypoxia states. In such conditions glioma cells develop radio- and chemotherapy-resistant phenotype. It is postulated that application of hyperbaric oxygen (HBO) may improve therapeutic response via refinement of tumour tissue oxygenation. The more effective therapeutic strategies are also required. One of the novel compounds that exhibit anti-tumour properties are pentabromobenzylisothioureas. The aim of this study was to examine whether HBO may enhance anti-tumour efficacy of selected pentabromobenzylisothiourea when both agents were administered as combined ZKK-3/HBO therapy. Materials and Methods: Human glioblastoma T98G cell line was cultured in medium supplemented with novel isothiourea derivative - ZKK-3. The proliferation and viability of glioma cells cultured in hypoxia or hyperbaric oxygen conditions were examined. Cell proliferation was tested 24 hours after ZKK-3 addition using Nikon Inverted Microscope and Multisizer 3 Beckman Coulter. The viability assay was taken 24 and 48 hours post ZKK-3 supplementation by CellTiter 96®AQueous One Solution Cell Proliferation Assay (Promega). Hypoxia state of T98G cells was determined via the evaluation of HIF-1α protein expression using HIF-1A ELISA Kit (Thermo Scientific). Tests were performed on cells treated with ZKK-3 and cultured in various oxygen conditions: 1/ normoxia (24 hours), 2/ hypoxia (24 hours), 3/ HBO (2 ATA, 1 hour followed by 23 hours of normoxia), 4/ double hypoxia, 5/ hypoxia/HBO. Results: Proliferation of T98G cells treated with ZKK-3 was significantly decreased after hyperbaric oxygenation in comparison to hypoxia conditions. Administration of HBO resulted also in statistically significant diminution of glioma cells’ viability. Expression of HIF-1α in T98G cells strongly depended on oxygen conditions: in hypoxia and double hypoxia the level of protein was significantly elevated compared with normoxia, while after hyperbaric oxygenation no changes or even decrease of HIF-1α level was observed. Comparison of double hypoxia and hypoxia/HBO groups showed that HBO addition after ZKK-3 supplementation caused significant reduction of HIF-1α expression. Conclusions: Treatment of malignant glioma cells with selected isothiourea derivative is significantly more efficient when combined with hyperbaric oxygen administration. Beneficial effect of HBO on decreasing HIF-1α expression allows to consider hyperbaric oxygenation as the way to overcome tumour hypoxia. ACKNOWLEDGEMENT: The research was supported by the KNOW-MMRC project and Foundation for the Development of Diagnostic and Therapy.
Erratum: Cilostazol or pentoxifylline for claudication? (Circulation (1998) 98 Suppl I: (1-112))
Authors: David L Dawson, H. G. Beebe, M. H. Davidson, D. A. Chinoy, J. A. Herd, W. R. Hiatt, J. D. Heckman, B. Bortey, W. P. Forbes
Journal: Circulation (1999)