tbuckley/cabot-search huggingface dataset:
3D Mathematical Modeling of Glioblastoma Suggests That Transdifferentiated Vascular Endothelial Cells Mediate Resistance to Current Standard-of-Care Therapy
Authors: Huaming Yan, Mónica Romero-López, Lesly I. Benitez, Kaijun Di, Hermann B. Frieboes, Christopher C.W. Hughes, Daniela A. Bota, John S. Lowengrub
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, cross-talk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Furthermore, GSC also transdifferentiate into bona fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional antiangiogenic therapies. Here we use three-dimensional mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSCs drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with antiangiogenic therapies reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSCs and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GECs maintain GSCs. Our study suggests that a combinatorial regimen targeting the vasculature, GSCs, and GECs, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication. Cancer Res; 77(15); 4171–84. ©2017 AACR.
Cellular and Molecular Mechanisms of Autoimmune Hepatitis
Authors: G.J. Webb, G.M. Hirschfield, E.L. Krawitt, M.E. Gershwin
Journal: Annual Review of Pathology Mechanisms of Disease (2017)

Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.
The necessity of using baseline data to determine balance recovery post-concussion during the asymptomatic phase
Authors: Laura Fedy, Michael Cinelli
Journal: British Journal of Sports Medicine (2017)

Objective To determine whether sensory manipulation balance testing was able to detect balance control impairments in previously concussed asymptomatic (PCA) athletes. We hypothesised that PCA athletes would have balance control deficits in the A/P direction with sensory manipulations. Participants 27 female athletes (19.78±1.3 years); 13 were previously concussed (PC) within the past 12 months and 14 had no history of concussions (NC). Design Manipulation of visual, somatosensory, and vestibular contribution to balance control within the following trials: 3 eyes open (EO); 3 eyes closed (EC); 1 dual-task arithmetic (DUAL); compliant surface with eyes open (EOc) and eyes closed (ECc); 1 horizontal eye movement task (VOR); and 1 horizontal head turns with EC (HHT). Participants tested prior to the start of season; four of them sustained a concussion during the season and were retested following the resolution of symptoms (i.e., RTP-2). Procedures Participants stood for 45s on a Bertec force plate (collected at 100Hz) in a Romberg stance. Trials were presented in order of increasing difficulty: EO1, EC1, dual task, EOc, ECc, VOR, EO2, EC2, HHT, EO3, and EC3. Data analysis Root mean square (RMS) of centre of pressure displacement and velocity (dCOP and vCOP) were calculated in the A/P and M/L directions. Statistical analysis Independent (PC vs. NC) and paired (baseline vs. RTP-2) t-tests were performed for each condition in both directions for dCOP and vCOP. Main results HHT condition revealed that A/P vCOP RMS (mm/s) was significantly greater in PC (Mean Diff=2.63, p=0.02) and within at RTP-2 (Mean Diff=5.24, p=0.02). Conclusions Balance impairments exist up to 12 months post-concussion in PCA athletes when their vestibular systems were perturbed (HHT) and higher-order analyses (vCOP) were calculated. Competing interests None.
Mutation analysis in cystic fibrosis (II)
Authors: P. Gasparini, P. F. Pignatti, G. Novelli, B. Dallapiccola, V. Nunes, T. Casals, X. Estivill, E. Fernandez, A. Balassopoulou, D. Loukopoulos, J. Javinha, L. Simova, R. Komel
Journal: New England Journal of Medicine (1990)
Predictors of clinical recovery from concussion: a systematic review
Authors: Grant L Iverson, Andrew J Gardner, Douglas P Terry, Jennie L Ponsford, Allen K Sills, Donna K Broshek, Gary S Solomon
Journal: British Journal of Sports Medicine (2017)

Objective A systematic review of factors that might be associated with, or influence, clinical recovery from sport-related concussion. Clinical recovery was defined functionally as a return to normal activities, including school and sports, following injury. Design Systematic review. Data sources PubMed, PsycINFO, MEDLINE, CINAHL, Cochrane Library, EMBASE, SPORTDiscus, Scopus and Web of Science. Eligibility criteria for selecting studies Studies published by June of 2016 that addressed clinical recovery from concussion. Results A total of 7617 articles were identified using the search strategy, and 101 articles were included. There are major methodological differences across the studies. Many different clinical outcomes were measured, such as symptoms, cognition, balance, return to school and return to sports, although symptom outcomes were the most frequently measured. The most consistent predictor of slower recovery from concussion is the severity of a person’s acute and subacute symptoms. The development of subacute problems with headaches or depression is likely a risk factor for persistent symptoms lasting greater than a month. Those with a preinjury history of mental health problems appear to be at greater risk for having persistent symptoms. Those with attention deficit hyperactivity disorder (ADHD) or learning disabilities do not appear to be at substantially greater risk. There is some evidence that the teenage years, particularly high school, might be the most vulnerable time period for having persistent symptoms—with greater risk for girls than boys. Conclusion The literature on clinical recovery from sport-related concussion has grown dramatically, is mostly mixed, but some factors have emerged as being related to outcome.
Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor
Authors: Vera Münch, Luca Trentin, Julia Herzig, Salih Demir, Felix Seyfried, Johann M. Kraus, Hans A. Kestler, Rolf Köhler, Thomas F. E. Barth, Geertruy te Kronnie, Klaus-Michael Debatin, Lüder H. Meyer
Journal: Blood (2017)
An open label phase I study of ABR-217620, a fusion protein of the 5T4 antibody moiety and an engineered superantigen, in patients with non-small cell lung, renal cell or pancreatic cancer
Authors: R. B. Cohen, C. J. Langer, R. K. Alpaugh, S. Dueland, S. Aamdal, R. E. Hawkins, R. W. Griffiths, G. Hedlund, G. Forsberg, S. Kilany
Journal: Journal of Clinical Oncology (2006)

3083 Background: ABR-217620 (naptumomab estafenatox) is a recombinant fusion protein that consists of the 5T4Fab moiety genetically fused to the engineered superantigen variant SEA/E-120. This fusion protein is a new generation tumor-targeted superantigen based on the previously described ABR-214936 (anatumomab mafenatox). ABR-217620 was designed to reduce antigenicity and toxicity. The 5T4 antigen is expressed on more than 95 % of tumors from patients with non-small cell lung (NSCLC), renal cell (RCC) and pancreatic cancer (PC). In clinical PET studies 124 I-labeled ABR-217620 has been shown to localize to 5T4 positive tumors. Methods: The compound was administered as a 5 min bolus infusion for 5 consecutive days. Patients with disease control at day 28 were offered a second cycle of therapy. Dose escalation has been performed using a Bayesian model starting at 0.5 μg/kg/day. The primary endpoint is determination of MTD. Secondary endpoints include characterization of side effects, immunological response, efficacy and pharmacokinetics. Results: 31 patients to date have been treated (19 NSCLC, 8 RCC, 4 PC). 3 patients have had dose limiting toxicities (fever, hypotension and nausea, grade 3) at doses between 23 and 28 μg/kg/day. The side effects were resolved quickly. Based on the experience from ABR-214936, these side effects were expected, but the MTD is ∼ 200 times higher. ABR-217620 leads to a dose dependent systemic increase of cytokines including IL-2 and IFN-γ after infusion. It also leads to an expansion of the superantigen reactive T cell population. 16/29 evaluable patients investigated had SD while 13 patients had PD. In contrast to ABR-214936, the first cycle of ABR-217620 treatment can be given without factoring in the titer of preformed anti-superantigen antibodies. Conclusions: ABR-217620 treatment had predicted and manageable side effects with fever, hypotension and nausea being dose limiting toxicities. Treatment with ABR-217620 resulted in a restricted systemic activation of the immune system. A large fraction of the patients have had stable disease. [Table: see text]
MEDU-34. INTELLECTUAL OUTCOME IN CHILDREN WITH SENSORINEURAL HEARING LOSS FOLLOWING TREATMENT FOR EMBRYONAL BRAIN TUMORS.
Authors: Christine Dahl, Iska Moxon-Emre, Vijay Ramaswamy, Ute Bartels, Uri Tabori, Annie Huang, Normand Laperriere, Donald Mabbott, Eric Bouffet
Journal: Neuro-Oncology (2017)

BACKGROUND: Neurological side effects associated with childhood brain tumors and their treatments contribute to long term neurocognitive morbidity. The aims of this study were to identify the incidence of sensorineural hearing loss (SNHL) in a large sample of children treated for malignant embryonal brain tumors, and to evaluate the effect of SNHL on intellectual functioning following the completion of treatment. METHODS: We conducted a single center review of 119 prospectively followed patients treated for malignant embryonal brain tumors at the Hospital for Sick Children, between 1996–2015, to evaluate the impact of significant SNHL (Chang > 2b) on intellectual function. Hearing and intellectual function were assessed post-treatment, at comparable time points (median ages: hearing assessment 13.5y (+4.5); intellectual function 12.8y (+ 4.1)). The median interval since treatment was 5.9 y + 3.7. RESULTS: Significant SNHL was identified in half the patients (48.7%, n = 58/119), of which 53% required a hearing aid (31/58). We identified a subset of patients (n = 61) who had assessments of intellectual function. In these patients, intellectual function was significantly affected by severe SNHL, even after controlling for the effect of craniospinal radiation (severe SNHL 22.4 Gy + 13.3, no/mild hearing loss 20.4 Gy +12.8) and boost dose. Severe hearing loss resulted in lower overall IQ (severe SNHL: 72.4 + 16.6; no/mild hearing loss: 92.0 + 20.5) p<0.001 and in significantly lower verbal comprehension (severe SNHL: 78.7 + 15.9; no/mild hearing loss: 94.7 + 13.8) p<0.001, and working memory (severe SNHL: 78.2+ 17.6; no/mild hearing loss: 94.8 + 16.4) p<0.001. CONCLUSION: Hearing loss is a much more significant complication in children with embryonal tumors than previously estimated. We show the profound impact of hearing loss on intellectual deficit in children. Our results have major implications on future trial design of children being treated with intensive protocols.
Advances in wearable impact sensors for monitoring and reducing brain injury risks due to cumulative head impact trauma in athletic and military environments
Authors: John Ralston, Jason Thibado, Jonathan Woodard
Journal: British Journal of Sports Medicine (2017)

Objective Assess utility of wearable impact sensors to monitor and reduce cumulative brain injury risks in athletic and military environments. Design Analysis of results generated in multiple laboratory and on-field cohort studies. Setting Youth, college, and professional football, rugby, soccer, lacrosse, boxing; military training exercises. Participants Participants across multiple activities were monitored for head impacts using wearable sensors. Intervention Participants suffering a concussion underwent neurocognitive testing and entered a supervised return-to-play protocol. Outcome measures The influence of sensor design and data processing on the accuracy and reproducibility of head impact data have been assessed. Differences in head impact incidence and severity have been compared between training regimes that did/did not implement behavioural modifications based on sensor data. Head impact data have been combined with finite element modelling and high resolution MRI/DSI imaging to study spatial distribution of tissue damage and changes in neural connectivity. Main results Reduced size and weight skin-affixed sensors worn on the mastoid provide a stable and universally applicable solution for head impact monitoring. Behavioural modifications using these devices have reduced high risk head impacts by 30%−70%. Significant localised tissue damage and changes in neural connectivity are predicted and observed even in the absence of clinically diagnosed concussion symptoms. Conclusions Wearable impact sensors are enabling significant reductions in head injury risks and incidence in athletic and military environments. These devices show promise as neuro-trauma dosimeters that can assist in monitoring cumulative brain damage due to repetitive sub-concussive head impacts, and developing more comprehensive and personalised remove-from-play thresholds. Competing interests X2 Biosystems designs and manufactures wearable impact sensors
Abstract 283: The Coupling of Tumor Endothelial Marker-8 and Capillary Morphogenesis Gene-2 Receptors to Contractile-Related Signaling Pathway in Cardiac Myocytes
Authors: Damir Nizamutdinov, Honey B Golden, Hao Feng, Fnu Gerilechaogetu, Donald M Foster, Carl W Tong, Shannon S Glaser, David E Dostal
Journal: Circulation Research (2012)

Recent molecular and pharmacological studies performed on non-cardiac tissues suggest that tumor endothelial marker-8 (TEM-8), also known as anthrax toxin receptor 1 (ANTXR1) and capillary morphogenesis gene-2 (CMG-2), known as anthrax toxin receptor 2 (ANTXR2) regulate survival, proliferation, cell shape, as well as polarity, adhesion, migration and differentiation. However, downstream signaling mechanisms and function of these molecules have not been studied. Recent studies indicate that activation of protein kinase B (Akt) and c-Jun N-terminal kinases (JNK) have been associated with hypertrophic growth, as well as regulation of contractility in cardiac myocytes (CM). In this study we’ve investigated the role of ANTXR1 and ANTXR2 receptors in intracellular pathways of contractility regulation in neonatal rat ventricular myocytes (NRVM). Primary culture of NRVM was used to determine the effects of ANTXR1/ANTXR2 activation on Akt and JNK phosphorylation by Western blot analysis. Flow cytometry and immunostaining of alive CM were used to determine expression levels and distribution of anthrax receptors throughout the cells. Furin-activated form of anthrax protective antigen (PA 63 ) was used in order to selectively stimulate ANTXR1/ANTXR2 receptors and get understanding of downstream signaling mechanisms coupled to them. The treatments with angiotensin II, type1 receptor (AT 1 ) inhibitors were used in order to separate responses of distinct regulatory pathways of contractility. All treatments were done at variable time courses started in seconds and finished in half of hour to determine a sequence of phosphorylation reactions going from cellular membrane to deep inside of cell. As a result, abundant expression of both receptors was observed in cardiac myocytes. Activation of one phospho-site of focal adhesion kinase (FAK 861 ) was started in 15 sec with subsequent phosphorylation of JNK and Akt 473 in 5 and 10 minutes. Involvement of new molecules was observed in cascade chain reaction of contractility regulation. In conclusion, ANTXR1/ANTXR2 were demonstrated to couple to mechano-sensor molecules: FAK, Akt and JNK, as well as interact with the AT 1 receptors to mediate downstream signaling events responsible for regulation of contractility.
Oncogenic H-ras facilitates apoptosis induced by histone deacetylase inhibitors in human urinary bladder cancer cells
Authors: Shambhunath Choudhary, Hwa-Chain Wang
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

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We sought to understand the connection between the selectivity of histone deacetylase inhibitors (HDACIs), a new class of anticancer agents shown to induce apoptosis in transformed cancer cells, and the pro-apoptotic ability of oncogenic H-Ras to facilitate that apoptosis. More than 35% of human urinary bladder cancers involve oncogenic H-Ras activation. In addition to tumorigenic ability, oncogenic H-Ras possesses a novel pro-apoptotic potential to facilitate the induction of apoptosis by HDACIs, which are highly toxic to transformed cells. To understand this connection, we introduced oncogenic H-Ras into urinary bladder J82 cancer cells to mimic an acquisition of H-ras gene activation in tumor development. Expression of oncogenic H-Ras promoted J82 cells to acquire tumorigenic ability. Meanwhile, oncogenic H-Ras increased susceptibility and reduced resistance of J82 cells to HDACIs, including FR901228 and Trichostatin A (TSA), for inducing apoptosis. The extrinsic and intrinsic caspase pathways, the B-Raf and extracellular signal regulatory kinase (ERK) pathway, the stress-activated protein kinase (SAPK) pathway, the cell cycle dependent kinase inhibitors p21Cip1 and p27Kip1, and core histone contents are regulated differently by FR901228 in oncogenic H-Ras-expressed J82 cells than their counterparts in parental J82 cells, contributing to the increased susceptibility to the induction of selective apoptosis. Our results lead us to a suggestion that HDACIs activate the pro-apoptotic potential of oncogenic H-Ras, indicating a potential therapeutic value of this new class of anticancer agents in the control of human urinary bladder cancer that has acquired oncogenic H-Ras.
Acute rest does not predict symptom recovery in collegiate student athletes
Authors: Thomas A Buckley, Barry A Munkasy, Brandy P Clouse, Kelsey M Evans
Journal: British Journal of Sports Medicine (2017)

Objective To assess the effect of acute cognitive and physical activity level and sleep on concussion recovery. Design Prospective. Setting: College sports medicine. Participants: Forty-one college student athletes (51.2% Female; Age: 19.6 + 1.2 years) diagnosed with sports-related concussions. Interventions The independent variables were the participant’s self-reported physical and cognitive activity levels (1–5 based on Majerske) and the number of hours slept the first two days post-concussion. Outcome measures The dependent variables were the number of days until the participant 1) self-report asymptomatic and 2) had full return-to-participation which required achieving baseline values on balance, cognitive, neuropsychological testing and completing a progressive return to activity protocol. The independent variables (activity levels and sleep) were used as predictors of recovery with a linear regression. Main results The participants were asymptomatic 4.7 + 2.8 (95% CI: 3.8–5.5) days and returned-to-participation 13.0 + 4.2 (95% CI: 11.8–14.3) days post-concussion. Participants reported a mean 7.8 + 1.9 hours of sleep per night and low physical (1.4 + 0.7) and cognitive (2.7 + 1.4) activity levels. There were no significant correlations and the overall model did not predict days until asymptomatic (F=1.224, P=0.315) or return-to-participation time (F=0.036, P=0.991). None of the independent variables were significant predictors. Conclusions The activity levels and reported sleep in the first two days post-concussion did not predict recovery time. This finding is consistent with emerging literature suggesting acutely restricting activity may not improve concussion recovery time. Future studies should utilise sleep logs and objectively measure activity levels. Competing interests None.
Reducing the costs of chronic kidney disease while delivering quality health care: a call to action
Authors: Raymond Vanholder, Lieven Annemans, Edwina Brown, Ron Gansevoort, Judith J. Gout-Zwart, Norbert Lameire, Rachael L. Morton, Rainer Oberbauer, Maarten J. Postma, Marcello Tonelli, Wim Van Biesen, Carmine Zoccali
Journal: Nature Reviews Nephrology (2017)