tbuckley/cabot-search huggingface dataset:
Association of Microvascular Dysfunction With Late-Life Depression
Authors: Marnix J. M. van Agtmaal, Alfons J. H. M. Houben, Frans Pouwer, Coen D. A. Stehouwer, Miranda T. Schram
Journal: JAMA Psychiatry (2017)

The etiologic factors of late-life depression are still poorly understood. Recent evidence suggests that microvascular dysfunction is associated with depression, which may have implications for prevention and treatment. However, this association has not been systematically reviewed.To examine the associations of peripheral and cerebral microvascular dysfunction with late-life depression.A systematic literature search was conducted in MEDLINE and EMBASE for and longitudinal studies published since inception to October 16, 2016, that assessed the associations between microvascular dysfunction and depression.Three independent researchers performed the study selection based on consensus. Inclusion criteria were a study population 40 years of age or older, a validated method of detecting depression, and validated measures of microvascular function.This systematic review and meta-analysis has been registered at PROSPERO (CRD42016049158) and is reported in accordance with the PRISMA and MOOSE guidelines. Data extraction was performed by an independent researcher.The following 5 estimates of microvascular dysfunction were considered in participants with or without depression: plasma markers of endothelial function, albuminuria, measurements of skin and muscle microcirculation, retinal arteriolar and venular diameter, and markers for cerebral small vessel disease. Data are reported as pooled odds ratios (ORs) by use of the generic inverse variance method with the use of random-effects models.A total of 712 studies were identified; 48 were included in the meta-analysis, of which 8 described longitudinal data. Data from 43 600 participants, 9203 individuals with depression, and 72 441 person-years (mean follow-up, 3.7 years) were available. Higher levels of plasma endothelial biomarkers (soluble intercellular adhesion molecule-1: OR, 1.58; 95% CI, 1.28-1.96), white matter hyperintensities (OR, 1.29; 95% CI, 1.19-1.39), cerebral microbleeds (OR, 1.18; 95% CI, 1.03-1.34), and cerebral (micro)infarctions (OR, 1.30; 95% CI, 1.21-1.39) were associated with depression. Among the studies available, no significant associations of albuminuria and retinal vessel diameters with depression were reported. Longitudinal data showed a significant association of white matter hyperintensities with incident depression (OR, 1.19; 95% CI, 1.09-1.30).This meta-analysis shows that both the peripheral and cerebral forms of microvascular dysfunction are associated with higher odds of (incident) late-life depression. This finding may have clinical implications because microvascular dysfunction might provide a potential target for the prevention and treatment of depression.
DIPG-30. DIFFERENTIAL HYPOXIC RESPONSE IN HUMAN DIPG CELL LINES
Authors: Christopher Waker, Maryam Shahin, Aria Kamian, Zoe Lober, Robert Lober
Journal: Neuro-Oncology (2017)

BACKGROUND: Diffuse Intrinsic Pontine Glioma (DIPG) are rare and aggressive childhood tumors, with an abysmal prognosis and limited experimental models available for study. A recent report showed that DIPG are hypoperfused compared to surrounding brain tissue, suggesting that the tumor cells are exposed to a hypoxic microenvironment. This stimulus may induce widespread transcriptional changes through activation of Hypoxia-inducible Factors (HIF), which have been associated with invasion, metastasis, angiogenesis, and resistance to radiation therapy and chemotherapy. Therefore, in vitro models using DIPG cells cultured in conditions of normal oxygen tension may not be representative of in vivo tumors because of artificial differences in HIF activation. METHODS: To test cellular responses to hypoxia, human DIPG cell lines with H3.1 K27M and H3.3 K27M mutations were treated with the hypoxia-mimetic compound, cobalt (II) chloride, for 24 hours. Simulated hypoxic responses were assayed using Western blot analysis, proliferation assays, and extracellular flux analysis. RESULTS: The H3.3 K27M cell line increased expression of HIF1a with cobalt (II) chloride treatment and correlated with an increase in glycolytic rates and increased expression of proteins involved in glucose transport and glycolysis. The H3.1 K27M cell line increased expression of HIF2a and not HIF1a after cobalt (II) chloride treatment, correlating with an increase in some glycolysis-associated proteins but no change in glycolytic rate. CONCLUSION: These data suggest that the effects of a hypoxic microenvironment should be considered in experimental models using cultured DIPG cell lines to understand differences in cell behavior, patient prognosis, and predicted treatment responses. Activation of specific HIF isoforms may underlie differences in hypoxic responses among cell lines.
PWE-253 Adalimumab improves health-related quality of life for 52 weeks in patients with ulcerative colitis: Abstract PWE-253 Table 1
Authors: W J Sandborn, G Van Assche, R B Thakkar, A Lazar, M Kron, M Yang, S P Patel, J Chao, P M Mulani
Journal: Gut (2012)

<h3>Introduction</h3> We investigated effects of adalimumab (ADA) maintenance therapy on health-related quality of life (HRQOL) through 52 weeks (wks) in patients (pts) with ulcerative colitis (UC). <h3>Methods</h3> 494 pts with moderate to severe UC (Mayo score, 6–12 points; endoscopic subscore, 2–3 points; anti–tumour necrosis factor [anti-TNF]–naïve and anti-TNF–experienced [40.3%]) who had failed conventional therapy were enrolled in a 52-wk, randomised, double-blind, placebo (PBO)-controlled maintenance trial. ADA-treated pts received induction therapy (160/80 mg @ Wks 0/2) and 40-mg every-other-week (eow) maintenance therapy. Pts with inadequate response could switch to open-label eow therapy after Wk 12 and subsequently to weekly therapy. HRQOL was measured by Inflammatory Bowel Disease Questionnaire (IBDQ). Intent-to-treat population was analysed. IBDQ response rates were compared between treatment groups using Cochran-Mantel-Haenszel test stratified for prior anti-TNF use whereas χ<sup>2</sup> test was used in anti-TNF-naïve pts. Non-responder imputation was used for response variables. For change of IBDQ scores, ANCOVA model with treatment and prior anti-TNF status as factors and baseline value as covariate was used. Missing values were imputed through last observation carried forward (LOCF). <h3>Results</h3> Significantly more ADA-treated pts were IBDQ responders (increase in IBDQ score ≥16 points from baseline) throughout Wks 8, 32, and 52 compared with PBO. Mean changes from baseline IBDQ scores were consistently greater for ADA- vs PBO-treated pts (Abstract PWE-253 table 1). In anti-TNF–naïve pts, improvements from baseline for IBDQ were 34±38 and 22±37 at Wk 8 (p=0.002), 33±43 and 24±43 at Wk 32 (p=0.03), and 33±44 and 23±42 at Wk 52 (p=0.02) for ADA and PBO, respectively. IBDQ responder rates were 68% and 52% at Wk 8 (p=0.004), 42% and 27% at Wk 32 (p=0.006), 32% and 21% at Wk 52 (p=0.040) for ADA and PBO, respectively, among anti-TNF–naïve pts. <h3>Conclusion</h3> For pts with moderate to severe UC who failed conventional therapy, ADA was more effective than PBO for inducing and maintaining improvements in HRQOL, as measured by IBDQ through 52 wks. <h3>Competing interests</h3> W Sandborn Grant/Research Support from: Abbott, Consultant for: Abbott, G Van Assche Grant/Research Support from: Abbott, R Thakkar Shareholder with: Abbott, Employee of: Abbott, A Lazar Shareholder with: Abbott, Employee of: Abbott, M Kron Shareholder with: Abbott, Employee of: Abbott, M Yang Shareholder with: Abbott, Employee of: Abbott, S Patel Shareholder with: Abbott, Employee of: Abbott, J Chao Shareholder with: Abbott, Employee of: Abbott, P Mulani Shareholder with: Abbott, Employee of: Abbott.
Pre-season concussion testing in high school students with academic difficulties or attention deficit hyperactivity disorder
Authors: Mark Herceg, Magdalena Wojtowicz, Grant Iverson
Journal: British Journal of Sports Medicine (2017)

Objective Learning disabilities and/or ADHD are considered to be important risk factors or modifiers for concussion assessment and management. The purpose of this study was to examine cognition and symptom reporting in high school students with academic difficulties or ADHD and compare to those without at baseline. Design Retrospective analysis of three measures routinely given as part of a high school yearly concussion baseline protocol. Setting The library of a high school in Westchester County, NY. Participants A sample of 143 high school students who participate in collision/contact sports [Age M (SD)=15.4 (1.2); Boys=78, 54.5%] completed baseline testing. Main results Non-parametric tests were used because of violations of normality. High school students with academic difficulties or ADHD (n=21) were compared to controls (n=122) on King- Devick, SAC, ImPACT Cognitive Composite scores, and Total Symptom ratings. Students with LD or ADHD performed significantly more poorly on King-Devick (p=0.003; d=0.79), Visual Motor Speed Composite of ImPACT (p=0.007; d=0.79), and reported more symptoms at baseline on the Post-Concussion Scale (p=0.005; d=0.59). No significant differences found between groups on SAC (p=0.11; d=0.36) or ImPACT Verbal Memory (p=0.54; d=0.16), Visual Memory (p=0.20; d=0.26), or Reaction Time (p=0.14; d=0.55) Composites. Conclusions To our knowledge this is the first study to examine performance on three different baseline measures. High school students with academic difficulties or ADHD performed more poorly on King-Devick, the Visual Motor Speed Composite of ImPACT, and reported more symptoms at baseline. Findings suggest these students need to be monitored for specific post injury changes. This study was approved by the Committee for Human Rights Research, Burke Rehabilitation Hospital, White Plains, NY, USA. Protocol # BRC-455. Competing interests None.
Non-linear correlation between cumulative sub-concussive head impact trauma and severity of localised brain white matter changes in college athletes
Authors: Ralston John, Thibado Jason, Jonathan Woodard, Matthew Cieslak, Asturias Alex, Grafton Scott
Journal: British Journal of Sports Medicine (2017)

Objective Test for a dose dependent relationship between cumulative sub-concussive head trauma loading and localised changes of brain white matter in college athletes. Design Prospective cohort study Setting NCAA Division I Women’s Soccer Participants 10 players were monitored for head impacts throughout a soccer season using wearable sensors. Linear and rotational accelerations recorded during impacts were processed to calculate the cumulative impact power. Diffusion spectrum imaging (DSI) data were acquired at season start and at 3 additional intervals. 11 age and gender matched control data sets were acquired. Intervention One athlete suffered a concussion, was removed from play for neurocognitive testing, and entered a supervised return-to-play protocol. Outcome measures Cumulative impact power was used as a measure of the head trauma load accumulated prior to each MRI. Multi-dimensional anisotropy (MDA) values assessed localised severity of white matter changes. Session specific differences between each player’s MDA values and those of the control population were used to relate cumulative impact power and the severity of white matter changes. Main results Highly significant clusters of abnormal voxels were observed in athletes with no diagnosed concussion symptoms. Injury severity correlated with cumulative head impact power and demonstrated a pronounced threshold behaviour. MDA diffusion changes were located mainly within the frontal and occipital cortex at the gray-white boundary, and to a lesser degree in deep subcortical areas where there is a higher proportion of crossing fibres. Conclusions This cohort demonstrates dose dependent changes in white matter integrity as a function of cumulative sub-concussive head trauma. Competing interests SG is supported, in part, by a research grant from X2 Biosystems and a General Electric-National Football League Head Health Challenge award.
Retrospective analysis of the first year of an elite sports multidisciplinary complex concussion service in the uk
Authors: Sylvester Richard, Medici Akbar de, Adejewon Ademola
Journal: British Journal of Sports Medicine (2017)

Objective To define the characteristics, investigation, diagnosis and management of elite athletes attending a complex concussion service. Design Retrospective analysis of case notes. Setting Secondary care single centre. Participants All patients (n=38, aged 16-35, 79% male) seen between April 2015 and April 2016. Outcomes Patient characteristics (sport, position played in rugby, previous concussion history), referral reason, investigations, diagnosis, interventions. Main results Most referrals came from Rugby (74% Rugby, 16% soccer, 8% other). Back row (57%) and centre (25%) were the commonest rugby positions seen. The average number of previous concussions of this cohort was 2.5 (95% CI±0.85). Referral reasons included chronic symptoms following concussion (53%), delayed GRTP (21% of which 28% were due to reduced performance on computerised neuropsychological testing), multiple concussions (18%) and severe injury (8%). 95% of patients had brain MRI imaging (with SWI sequences) and 4 patients (10%) had abnormalities (cortical cavernoma, brainstem cavernoma, diffuse axonal injury, obstructive hydrocephalus). 30% of patients required additional vestibular and/or neuropsychological assessment in addition to screening. Post-traumatic migraine was the commonest single diagnosis (36%) followed by isolated vestibular dysfunction (16%). 30% had multiple diagnoses (usually migraine, vestibular dysfunction and mood disorder). 8% did not have concussion. Intervention with medical management for migraine was initiated in 40%, vestibular rehabilitation in 20% and psychological intervention in 15%. Conclusions A proportion of elite athletes with sports related concussion in the UK have complex needs. These require expert MDT assessment and management. The limited provision of such services needs to be addressed. Competing interests None.
Trump’s worst appointment
Authors: Douglas Kamerow
Journal: BMJ (2017)

New head of family planning is—you guessed it—against birth control



How about a little contest? What is President Donald J Trump’s worst appointment—so far? (I have to add that caveat because he has named so few senior staff, but that’s another rant.) Is it his housing secretary, Ben Carson, who is a retired brain surgeon with no demonstrable policy experience in that area? Or his education secretary, Betsy DeVos, who showed no understanding of publicly supported education in her confirmation hearings? How about the new head of the Environmental Protection Agency, Scott Pruitt, who previously specialized in suing the agency he now heads? Until recently, I thought the prize was going to the energy secretary, Rick Perry, who spent an entire presidential campaign calling for the abolition of …
Tumor Microvessel Density as a Potential Predictive Marker for Bevacizumab Benefit: GOG-0218 Biomarker Analyses
Authors: Carlos Bais, Barbara Mueller, Mark F Brady, Robert S Mannel, Robert A Burger, Wei Wei, Koen M Marien, Mark M Kockx, Amreen Husain, Michael J Birrer
Journal: JNCI Journal of the National Cancer Institute (2017)

Combining bevacizumab with frontline chemotherapy statistically significantly improved progression-free survival (PFS) but not overall survival (OS) in the phase III GOG-0218 trial. Evaluation of candidate biomarkers was an exploratory objective. Patients with stage III (incompletely resected) or IV ovarian cancer were randomly assigned to receive six chemotherapy cycles with placebo or bevacizumab followed by single-agent placebo or bevacizumab. Five candidate tumor biomarkers were assessed by immunohistochemistry. The biomarker-evaluable population was categorized into high or low biomarker-expressing subgroups using median and quartile cutoffs. Associations between biomarker expression and efficacy were analyzed. All statistical tests were two-sided. The biomarker-evaluable population (n = 980) comprising 78.5% of the intent-to-treat population had representative baseline characteristics and efficacy outcomes. Neither prognostic nor predictive associations were seen for vascular endothelial growth factor (VEGF) receptor–2, neuropilin-1, or MET. Higher microvessel density (MVD; measured by CD31) showed predictive value for PFS (hazard ratio [HR] for bevacizumab vs placebo = 0.40, 95% confidence interval [CI] = 0.29 to 0.54, vs 0.80, 95% CI = 0.59 to 1.07, for high vs low MVD, respectively, Pinteraction = .003) and OS (HR = 0.67, 95% CI = 0.51 to 0.88, vs 1.10, 95% CI = 0.84 to 1.44, Pinteraction = .02). Tumor VEGF-A was not predictive for PFS but showed potential predictive value for OS using a third-quartile cutoff for high VEGF-A expression. These retrospective tumor biomarker analyses suggest a positive association between density of vascular endothelial cells (the predominant cell type expressing VEGF receptors) and tumor VEGF-A levels and magnitude of bevacizumab effect in ovarian cancer. The potential predictive value of MVD (CD31) and tumor VEGF-A is consistent with a mechanism of action driven by VEGF-A signaling blockade.
Omega-3 fatty acids improve proteomic and lipidomic markers of endoplasmic reticulum (ER) stress and mitochondrial dysfunction in a randomized controlled trial in subjects with Nonalcoholic Steatohepatitis
Authors: Livia Rodrigues, Claudia P. Oliveira, Jose Tadeu Stefano, Monize A. Nogueira, Ismael D. Silva, Edson G. Lo Turco, Venancio Avancini F. Alves, Flair J. Carrilho, Puneet Puri, Dan Waitzberg
Journal: Hepatology (2015)
Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology
Authors: Elisa Goina, Paolo Peruzzo, Bruno Bembi, Andrea Dardis, Emanuele Buratti
Journal: Molecular Therapy (2017)

Glycogen storage disease type II (GSDII) is a lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme, leading to the accumulation of glycogen within the lysosomes. The disease has been classified in infantile and late-onset forms. Most late-onset patients share a splicing mutation c.-32-13T > G in intron 1 of the GAA gene that prevents efficient recognition of exon 2 by the spliceosome. In this study, we have mapped the splicing silencers of GAA exon 2 and developed antisense morpholino oligonucleotides (AMOs) to inhibit those regions and rescue normal splicing in the presence of the c.-32-13T > G mutation. Using a minigene approach and patient fibroblasts, we successfully increased inclusion of exon 2 in the mRNA and GAA enzyme production by targeting a specific silencer with a combination of AMOs. Most importantly, the use of these AMOs in patient myotubes results in a decreased accumulation of glycogen. To our knowledge, this is the only therapeutic approach resulting in a decrease of glycogen accumulation in patient tissues beside enzyme replacement therapy (ERT) and TFEB overexpression. As a result, it may represent a highly novel and promising therapeutic line for GSDII.
LGG-14. THE ROLE OF BRAF MUTATIONS IN CLINICAL OUTCOMES IN PEDIATRIC LOW GRADE SPINAL CORD TUMORS
Authors: Sydney Grob, Kurtis Davies, Dara Aisner, Andrew Morin, Shadi Zahedi, Nicholas Foreman, Jean Mulcahy Levy
Journal: Neuro-Oncology (2017)

Over activation of MAPK signaling by oncogenic BRAF occurs in multiple malignancies making it a potential target in oncology. There is also a great body of research evidence to show that BRAF mutations occur in pediatric intracranial tumors. Most low grade gliomas (LGG) of the cerebellum have activation of MAPK/ERK pathway because of KIAA1549-BRAF fusion gene resulting in constitutively active growth signals. Low grade gliomas elsewhere in the brain have lower percentage of gliomas contain a KIAA1549-BRAF fusion. BRAFV600E mutation is seen in a much wider range of both systemic and central nervous tumors including the brain, desmoplastic infantile gangliogliomas, diffuse astrocytomas, gangliogliomas, pleomorphic xanthroastrocytomas, and epitheloid glioblastomas. Alterations in the BRAF gene has been implicated as clinically important in potential outcomes and clinical therapeutic options. We evaluated local clinical and available spinal tumors to determine BRAF mutational status and evaluate if detectable BRAF mutations correlate with clinical outcomes. We evaluated patients with a low grade spinal cord tumor diagnosis made between 1995 and 2016 with a confirmed Grade I or Grade II diagnosis. Twenty-three patients who met all inclusion criteria were evaluated for clinical data including treatment, progression free survival and overall survival. Available tumor samples were evaluated with a cancer gene focused mutation panel to assess for BRAF alterations in addition to other commonly associated LGG alterations in CDKN2A, FGFR, and PIK3CA. Technical difficulties included identification of tumor samples with quality DNA for analysis, particularly associated with early tumor samples which have the greatest clinical follow up. Long-term clinical correlation with mutational changes is particularly important in LGG spinal tumors due to late progression and complications.
HGG-11. THE Β-CATENIN/CBP-ANTAGONIST ICG-001 INHIBITS PEDIATRIC GLIOMA GROWTH IN A WNT-INDEPENDENT MANNER
Authors: Maria Wiese, Neele Walther, Christopher Diederichs, Fabian Schill, Sebastian Monecke, Gabriela Salinas, Dominik Sturm, Ralf Dressel, Stefan M. Pfister, Christof M. Kramm
Journal: Neuro-Oncology (2017)

Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with a poor prognosis due to a lack of efficient therapeutic strategies. The β-catenin/Wnt-signaling pathway was shown to hold promising potential as a treatment target in adult high-grade gliomas by abrogating tumor cell invasion and the acquisition of stem cell-like characteristics. Since pedHGG differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of β-catenin/Wnt-signaling pathway-inhibition by the β-catenin/CBP antagonist ICG-001 in pedHGG cell lines. In contrast to adult HGG, pedHGG cells displayed minimal detectable canonical Wnt-signaling activity. Nevertheless, low doses of ICG-001 inhibited cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, suggesting that ICG-001 affects pedHGG tumor cell characteristics independent of β-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/β-catenin-independent effect of ICG-001 on target gene transcription, revealing strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. Among these, high mRNA expression of cell cycle regulator JDP2 was found to confer a better prognosis for pedHGG patients. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients functioning to regulate cell phenotype and gene expression programs in absence of Wnt/β-catenin signaling-activity.