tbuckley/cabot-search huggingface dataset:
BIOL-06. NOVEL ONCOGENIC ROLE FOR NFIA IN GLIOMA
Authors: Edlira Hoxha, Kloetgen Andreas, Hae-Ri Song
Journal: Neuro-Oncology (2017)

The Nuclear Factor I-A (NFIA) transcription factor is a glioma tumor promoter. However, the mechanism by which NFIA regulates glioma cell survival and drug resistance is still unknown. Here we report that the NFIA pro-survival effect is mediated via an NFIA-NFκB p65 feedforward loop. We examined effects of gain- and loss-of-function manipulations of NFIA and NFκB p65 on cell growth, colony formation, apoptosis and sensitivity to chemotherapy in patient-derived glioma stem cell (GSC). Ectopic NFIA inhibited apoptosis by activation of NFkB p65 and its downstream anti-apoptotic factors. Induction of NFκB by NFIA was required for apoptosis evasion, and inhibition of NFκB effectively reversed the NFIA anti-apoptotic effect. Furthermore, overexpression of NFIA promoted colony formation of non-transformed glial cells. Conversely, NFIA knockdown decreased expression of NFκB and its downstream anti-apoptotic genes and increased baseline apoptosis. Using a genome-wide approach, we demonstrated that NFIA directly regulated NFκB transcription. Interestingly, we also found that NFκB activated the NFIA transcription and that knockdown of NFIA was sufficient to attenuate the NFκB pro-survival effect, suggesting a reciprocal regulation between NFIA and NFκB in governing GBM cell growth and survival. Supporting this, NFIA and NFκB expression levels were highly correlated in human GBMs and GSC. Collectively, these data define a novel NFIA-NFκB feedforward regulation that promotes GBM malignant behavior.
In Vivo Genome-Wide Crispr Library Screen in a Xenograft Mouse Model of Tumor Growth and Metastasis of Multiple Myeloma
Authors: Yujia Shen, Salomon Manier, Jihye Park, Yuji Mishima, Marzia Capelletti, Aldo M. Roccaro, Daisy Huynh, Antonio Sacco, Sabrin Tahri, Glenn Cowley, John G Doench, David Root, Irene M. Ghobrial
Journal: Blood (2016)
HGG-16. A COMPARISON OF PRIMARY AND RECURRENT PEDIATRIC HIGH-GRADE GLIOMAS VIA RNA SEQUENCING AND DRUG SCREENING
Authors: Patrick Flannery, John DeSisto, Rakeb Lemma, Andrew Donson, Nicholas Foreman, Rajeev Vibhakar, Kenneth Jones, Adam Green
Journal: Neuro-Oncology (2017)

BACKGROUND: High-grade gliomas (HGG) comprise 6–10% of all brain tumors in children but account for the majority of deaths, with a median survival rate of 15 months. Recurrent HGG is incurable, and median survival is five months from recurrence. METHODS: To study the changes that take place between primary diagnosis and recurrence, we performed RNA sequencing on matched initial and recurrent tumor samples from eight pediatric patients diagnosed with HGG. We then used six patient-derived pediatric HGG cell lines, three from biopsy and three from autopsy, as an in vitro model of primary and recurrent tumors. We screened these lines for survival with a panel of all FDA-approved chemotherapy drugs. RESULTS: The median age of subjects was 9.5 years at initial diagnosis. 7 of 8 subjects received radiation, and 3 of 8 tumor pairs had BRAF V600E mutations. Gene set enrichment analysis of the samples revealed that as compared with the initial tumors, recurrences are strongly enriched for gene expression characteristic of neural progenitor cells on three separate analyses, suggesting regression of the recurrent tumors to a less differentiated, more anaplastic state (Normalized Enrichment Scores 7.25–8.71, False Discovery Rate <0.001 for all). On drug screening, the autopsy-derived lines were significantly more sensitive to several agents, including trametinib, vinblastine, and etoposide. DISCUSSION: Pediatric HGG appears to take on a more stem-like state at recurrence compared to primary diagnosis. Cell lines from recurrent tumors show increased sensitivity to several agents already in use for pediatric brain tumors, raising the potential for improved treatments. Future work includes analysis of mutations that develop between primary diagnosis and recurrence, as well as development of cell line and animal models of matched primary and recurrent pairs to further investigate changes in tumor biology and potential therapies.
Etiology and clinical presentation of birth defects: population based study
Authors: Marcia L Feldkamp, John C Carey, Janice L B Byrne, Sergey Krikov, Lorenzo D Botto
Journal: BMJ (2017)

<b>Objective</b>&nbsp;To assess causation and clinical presentation of major birth defects. <b>Design</b>&nbsp;Population based case cohort. <b>Setting</b>&nbsp;Cases of birth defects in children born 2005-09 to resident women, ascertained through Utah’s population based surveillance system. All records underwent clinical re-review. <b>Participants</b>&nbsp;5504 cases among 270 878 births (prevalence 2.03%), excluding mild isolated conditions (such as muscular ventricular septal defects, distal hypospadias). <b>Main outcome measures</b>&nbsp;The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects). <b>Results</b>&nbsp;Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.8% (n=266). In this cohort, 92.1% (5067/5504) were live born infants (isolated and non-isolated birth defects): 75.3% (4147/5504) were classified as having an isolated birth defect (unknown or known etiology). <b>Conclusions</b>&nbsp;These findings underscore the gaps in our knowledge regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing impact of these exposures on fetal development highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and better ways to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the critical period of organogenesis.
The world rugby pitch side concussion assessment (psca) phase 2 study: a prospective cohort study investigating the diagnosis of concussion in elite adult rugby union
Authors: Philippe DECQ, Nathalie Gault, Gordon Fuller, Simon PT Kemp
Journal: British Journal of Sports Medicine (2017)

Objective Rugby Union, in common with other elite sports, has developed systems to identify, evaluate and treat players sustaining sports related concussions. This study examines the clinical progress of players following head impact events and investigates which components of the clinical assessment influence a final diagnosis of concussion. Design Prospective cohort study using logistic regression modelling to determine the predictive value of components of clinical assessments in influencing a final diagnosis of concussion. Setting Phase 2 of the World Rugby PSCA study between September 2013 and May 2014 Participants Consecutive players sustaining head impact events with the potential for concussion during ten national and international elite adult Rugby Union competitions Intervention Participants underwent 3 standardised clinical assessments: Initial pitch-side screening; early 3 hours post-match SCAT 3 assessment; and late diagnostic assessment after 2 nights with symptom evaluation and a neuro-cognitive assessment tool. Outcome measures Diagnosis of concussion determined at the last clinical assessment. Main results During the 8 months study period 229 players participated in the PSCA process. 130 (56.7%) players were diagnosed with concussion. The 3 hours post-match number of reported symptoms and Standardised Assessment of Concussion (SAC), and the presence of symptoms at 2 nights post injury were independently associated with a final diagnosis of concussion (p&lt;0.05). Other clinical assessments provided no additional prognostic information. Conclusions The number of symptoms reported and SAC post-match were factors independently associated with a final diagnosis of concussion. Balance tests and severity of post-match symptoms did not appear to provide any additional information in the diagnosis of concussion. Competing interests None.
Impact of tumour infiltrating lymphocytes-therapy for metastatic melanoma versus ipilimumab on patient outcomes and health care costs: An early stage health economic analysis.
Authors: Lotte Steuten, Valesca Retel, Janne Mewes, Wim van Harten
Journal: Journal of Clinical Oncology (2015)

e17774 Background: Metastatic melanoma has a poor prognosis with 10 year survival being < 5%. Standard therapy in the Netherlands is the effective but costly Ipilimumab. An emerging 1st line immunotherapy is Tumor Infiltrating Lymphocytes (TIL)-treatment, with response rates > 50% and expected survival rates of 25%-42% versus 45% (1yr) and 23.5% (2yr) for Ipilimumab. TIL is highly personalized, however complex and requests substantial upfront investments from the hospital in expensive lab-equipment, staff expertise and training. Therefore, an exploratory projection of its impact on patient outcomes and health care costs was made using health economic modelling. Methods: A Markov decision model including three health states (stable disease, progressive disease and death) was developed to estimate the expected costs and outcomes (quality adjusted life years; QALYs) for TIL versus Ipilimumab in metastatic melanoma patients from a societal perspective over a life long time horizon. Data sources include a pilot study and published literature. Technical failures and treatment non-compliance were incorporated in the analysis to reflect real world effectiveness. Results: TIL is expected to improve QALYs (+0.39) compared to Ipilimumab at higher incremental cost (+€12.416) with an ICER of €31.000/QALY. It has the highest probability of being cost-effective at WTP values of €30k/QALY (50% certainty) and higher, up to 90% certainty at a WTP of €80k/QALY. The model outcomes are most sensitive to changes in survival estimates. Conclusions: Based on an exploratory analysis,TIL is expected to improve QALYs compared to Ipilimumab at lower incremental cost and has the highest probability of being cost-effective. To reduce decision uncertainty, a future clinical trial to investigate survival should be prioritized.
Survey of directors of public health suggests that STPs may be falling short of ambition
Authors: Patrick J Saunders, J D Middleton, Susan Lloyd
Journal: BMJ (2017)

The Faculty of Public Health supports sustainability and transformation plans (STPs) and their reflection of a renewed commitment to “integration, collaboration, and planning” and “improving prevention” critical to delivering the Five Year Forward Plan.1 The faculty anticipated that the 2013 reintegration of the NHS public health function with local authorities was an opportunity for powerful public health input. It surveyed directors of public health …
Depth perception differences in athletes reporting a concussion history
Authors: Jason P Mihalik, Erin B Wasserman
Journal: British Journal of Sports Medicine (2017)

<h3>Objective</h3> Vision testing is becoming more commonplace in concussion assessment. The purpose of our study was to determine vision domain deficits in athletes reporting a concussion history. <h3>Design</h3> Cross-sectional. <h3>Setting</h3> Clinical research centre. <h3>Subjects</h3> High school and college student-athletes (n=224; 183 males) completed a multi-modal vision and sensory performance assessment. <h3>Intervention</h3> Participants completed a valid and reliable visual performance evaluation (Nike SPARQ Sensory Station). Participants were categorised by self-reported concussion history: no history (n=158) vs. 1 or more concussions (n=66). <h3>Outcome measures</h3> The Nike SPARQ Sensory Station measures visual acuity, contrast sensitivity, depth perception, near-far quickness, target capture, perception span, eye-hand coordination, go/no-go, and reaction time. We employed Wilcoxon two-sample nonparametric analyses comparing concussion history groups for each outcome. <h3>Results</h3> Student-athletes with a concussion history (median=1553 ms) responded more slowly to primary gaze depth perception tasks than student-athletes with no concussion history (median=1363 ms; <i>P</i>=0.02). Left gaze depth perception also yielded significant differences between those with concussion history (median=1383 ms) and those without concussion history (median=1162 ms; <i>P</i>=0.03), but not right gaze depth perception (<i>P</i>=0.07). No other significant differences were observed (<i>P</i>&gt;0.05). <h3>Conclusions</h3> Depth perception is worse in student-athletes with concussion history, suggesting the eyes’ ability to work in tandem may be compromised following concussion. It is also possible that observed visual performance differences may have previously existed and subsequently placed those athletes at a higher risk for concussion. Future prospective studies should explore the predictive value of visual performance screening in reducing concussion risk. <h3>Competing interests</h3> Wasserman – None. Dr. Mihalik has an equity interest in Senaptec LLC, a licensee of the intellectual property employed in this study.
No Association Between Quick Sequential Organ Failure Assessment and Outcomes of Patients With Cirrhosis and Infections
Authors: Kavish R. Patidar, Jawaid Shaw, Chathur Acharya, Leroy R. Thacker, Melanie B. White, Dinesh Ganapathy, Andrew Fagan, Edith A. Gavis, Jasmohan S. Bajaj
Journal: Clinical Gastroenterology and Hepatology (2017)
Malaria Surveillance — United States, 2014
Authors: Kimberly E. Mace, Paul M. Arguin
Journal: MMWR Surveillance Summaries (2017)

Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers.
Role of T-cell immunity to embryonal stem (ES) cell antigen SOX2 in the progression of myeloma
Authors: M. V. Dhodapkar, V. Bolejack, J. Shaughnessy, P. Matthews, R. Pickering, P. Qu, A. Hoering, J. Crowley, B. Barlogie
Journal: Journal of Clinical Oncology (2009)

8522 Background: Clinical outcome in patients (pts) with asymptomatic plasma-proliferative disorders, monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic myeloma (AMM), is highly variable. There is a need to identify specific tumor or host related features that predict the risk of disease progression. In prior studies, we have shown that patients with MGUS commonly mount a T cell immune response against SOX2, an antigen critical for pluripotency of ES cells. Methods: Patients with MGUS/AMM were enrolled in a prospective observational clinical protocol (SWOG S0120). All patients underwent detailed staging evaluation at registration and were observed without therapy. The presence of T cell immunity to SOX2 in freshly isolated blood / marrow mononuclear cells was analyzed using an overlapping peptide library at study entry. Results: Anti-SOX2 T cell responses were detected in 39/109 (36%) pts tested. Progression to symptomatic MM was observed in only 2 of 39 patients with anti-SOX2 immunity compared to 17 of 59 pts lacking these responses, resulting in 2-yr progression-free survival 96 v 63% (p=0.003). Responses to viral antigens and polyclonal mitogens as controls were preserved in patients lacking SOX2 immunity indicating that the absence of immunity to SOX2 was not due to global immune-suppression. Immunity to SOX2 correlated with features of lower risk including serum-M component &lt; 1.5 g/dL (p=0.008), marrow plasmacytosis &lt; 10% (p&lt;0.001) and normal serum free light chain ratio (p=0.01). Conclusions: These data demonstrate in the context of a prospective trial that T cell immunity to stem cell genes strongly correlates with a reduced risk of progression to clinical myeloma. These data point to SOX2 as a potential target for the prevention of disease progression in MGUS/AMM. No significant financial relationships to disclose.
Reversal of Methicillin Resistance in Staphylococcus aureus by Thioridazine: a universal phenomenon?
Authors: Marianne Østergaard Poulsen, Janne Kudsk Klitgaard, Eva Maria Sternkopf Lillebæk, Marianne Nielsine Skov, Birgitte H. Kallipolitis, Hans Jørn Kolmos
Journal: Clinical Microbiology and Infection (2010)
Serum neurofilament light concentration increases following a season of american football
Authors: Colin Wallace, Zetterberg Henrik, Henriksen Kim, Donkelaar Paul van
Journal: British Journal of Sports Medicine (2017)

Objective To examine neurofilament light (NF-L), a microtubule-associated protein widely regarded to be central nervous system (CNS) specific, concentrations in serum prior to and following a season of contact (American football) and non-contact (cross-country running) in elite, collegiate-aged athletes. Design Prospective cohort. Setting Laboratory. Participants 13 male American football athletes (19±1.2 years) and 11 cross-country runners (20±1.9 years). Intervention Pre- and post-season blood samples were obtained from all participants and spun at 2000 g for 10 minutes to extract serum. NF-L was detected through the isolation of individual immunocomplexes on pragmatic beads using standard ELISA reagents. The beads were then trapped in single-molecule, femtolitre-sized wells, allowing for a digital readout of each individual bead. The digital nature of this technique allows an average of 1000x sensitivity increase over conventional assays. Outcome measures Analysis of pre- and post-season serum samples provide NF-L concentrations. Results Serum samples from American football players showed a significant increase (p=0.04) from pre-season NF-L serum concentrations (95% CI: 6.51 – 9.19 pg/mL) to post-season (95% CI: 7.08 – 11.70 pg/mL). Serum NF-L concentrations in cross-country runners showed no change (p=0.57) from pre-season (95% CI: 5.05 – 6.94 pg/mL) to post-season (95% CI: 5.05 – 6.88 pg/mL). Conclusions Experiencing repetitive subconcussive head-trauma throughout a season of American football elevates serum NF-L concentrations. This finding indicates multiple head-impacts may lead to CNS axonal damage. Competing interests None.
DIPG-20. THE DEVELOPMENT OF THERANOSTIC [18F]F2B-CONJUGATES FOR PHARMACOKINETIC MONITORING OF DIRECT DRUG DELIVERY
Authors: Umberto Tosi, Hari Krishna Kommidi, Christopher Marnell, Sarah Guo, Melanie Schweitzer, Julia Voronina, Uday Bhanu Maachani, Richard Ting, Mark Souweidane
Journal: Neuro-Oncology (2017)

Diffuse intrinsic pontine gliomas (DIPG) carry a particularly poor prognosis, with median survival shorter than one year. Recent efforts aimed at traversing the blood-brain barrier have explored the capability of convection-enhanced delivery (CED) as a possible alternative to systemic delivery. Accurate pharmacokinetic information (distribution and clearance) is problematic since most agents have no intrinsic imaging capacity. This information however is critical in designing optimal infusion parameters and monitoring response. The mainstay of current practice is to rely on imaging surrogates to estimate molecular kinetics. These imaging tracers, however, have no homologous bioactive profile with the therapeutic molecule. Our objective of the current work was to perform direct labeling using a positron-emitting [18F]F2B- moiety that could be imaged by PET/CT. In the initial phase of this project, we first coupled the kinase-inhibitor dasatinib, a therapeutic chosen for its ability to tolerate the alteration of its molecular-structure. In vitro cell viability assays were performed to confirm that our modifications did not affect drug bioactivity. Labelled therapeutics were then delivered via CED to the frontal lobe in mice. We observed that the clearance properties vary greatly depending on the functional group added to the dasatinib backbone, with both distribution and clearance following injection being group-specific. We subsequently repeated these modifications with panobinostat. We observed that panobinostat distributes very differently from dasatinib, despite their similar molecular weight, both spatially (i.e. brain regions involved) and temporally (different clearance following infusion). This data suggests that surrogate tracers may not adequately estimate pharmacokinetics of locally delivered therapeutic compounds. If chemically possible, PET-imaging affords a more representative assessment of drug kinetics which would be more beneficial in defining dosing and scheduling. Our findings demonstrate the feasibility of designing theranostic compounds that are suitable for accurate pharmacokinetic monitoring with CED.
David Oliver: Should practical quality improvement have parity of esteem with evidence based medicine?
Authors: David Oliver
Journal: BMJ (2017)

As I qualified in 1989, my career has coincided with the growing evidence based medicine movement. It’s been a major advance in evaluating clinical interventions, defining best practice, and moving beyond a reliance on expert opinion or tradition. It’s given us methodologically consistent systematic reviews such as Cochrane, and evidence based guidelines such as those from NICE.123

Medics learn that good systematic reviews and meta-analyses top the evidence pyramid, then randomised controlled trials (RCTs).45 In conventional evidence based medicine, even good local observational and implementation data are ranked as less weighty evidence. …