tbuckley/cabot-search huggingface dataset:
TMOD-12. YAP/TAZ FUNCTION IN PEDIATRIC GLIOBLASTOMAS
Authors: Renee Read, Se-Yeong Oh, Matthew Schniederjan, Anna Kenney, Oren Becher, Jeffrey Olson
Journal: Neuro-Oncology (2017)

Malignant high-grade gliomas (HGGs), neoplasms of glial cells and their precursors, such as glioblastomas (GBMs) and diffuse intrinsic pontine gliomas (DIPGs), are the most deadly primary brain tumors in children, and are incurable with current therapies. The most frequent genetic lesions in pediatric HGGs (pHGGs) include amplification/mutation/overexpression of receptor tyrosine kinases (RTKs), such as PDGFRA, and neomorphic K27M mutations in histone H3 proteins that dominantly block H3-K27 methylation and prevent normal epigenetic gene silencing. Current data indicates that RTK signaling and H3-K27M mutations cooperate to drive tumor pathology and confer therapeutic resistance. To understand how these mutations drive tumorigenesis, my research program uses a multidisciplinary approach that includes functional screening in Drosophila glioma models and drug testing in patient-derived HGG tumor stem cell cultures. Our studies yielded strong preliminary evidence that the YAP transcriptional activator is overexpressed and activated in RTK-mutant pHGG cells, and that YAP transcriptional activity is required for proliferation and survival of pHGG cells, particularly in pHGGs harboring H3-K27M mutations. YAP family transcription factors can normally stimulate expansion of stem/progenitor cell populations in response to physiological RTK signaling. Established YAP transcriptional target genes, which are normally controlled by methylation and epigenetic silencing, include genes that can drive HGG tumor cell self-renewal, proliferation, and therapeutic resistance when overexpressed. Therefore, we hypothesize that, as a consequence of oncogenic RTK alterations, YAP becomes constitutively activated to drive a gene expression program that promotes uncontrolled expansion of neural stem/progenitor cells to create malignant tumors, and that this is exacerbated by H3-K27M epigenetic dysregulation. In testing this hypothesis, we generated compelling preliminary data showing that inhibition of YAP specifically provokes growth arrest and cell death of RTK-overexpressing H3-K27M-mutant pHGG cells. Our research indicates that YAP inhibition may be a promising therapeutic strategy for pHGGs.
IMMU-10. ENGINEERED PD-L1 RECEPTORS AUGMENT ANTI-TUMOR ACTIVITY OF HER2 CAR T CELLS IN HIGH GRADE GLIOMA
Authors: Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Heba Samaha, Joseph Formella, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde
Journal: Neuro-Oncology (2017)

HER2-specific chimeric antigen receptor (CAR) T cells induced objective yet transient responses in children with high grade glioma (HGG; NCT01109095; JAMA Oncology in press). At this stage, it becomes mandatory to seek conceptual “tumor specific” innovations in preclinical models if complete tumor elimination is to be achieved. For HGG, a strategy to combat the immunosuppressive tumor microenvironment is necessary. We endowed HER2 CAR T cells with resistance to programmed cell death-1 (PD-1) using chimeric checkpoint reversal receptors (CPRs). CPRs consisted of the native PD-1 extracellular domain followed by a transmembrane domain fused to an intracellular signaling domain. The signaling domain contained co-stimulatory T cell molecules such as CD28 and 4-1BB. Engagement of the CPRs with PD-L1 molecules within the tumor bed would thus elicit co-stimulatory survival signals rather than the native inhibitory signal. We designed a panel of candidate CPRs and co-expressed these with our clinical-grade HER2-CAR (FRP5.CD28ζ) on HGG patients’ T cells using a bicistronic transgene. HER2 CAR T cells expressing CPRs exhibited higher activation potential and sustained in vitro anti-tumor activity against autologous HGG over unmodified HER2-CAR T cells. CAR T cells with CPRs containing the 4-1BB domain preferentially developed a central memory phenotype optimal for sustained anti-tumor activity in patients. Three-dimensional reconstitution and quantification of super-resolution confocal images of the CAR T-cell/tumor-cell interface revealed a more stable immunological synapse and demonstrated higher levels of activated signaling kinases in T-cell co-stimulatory pathways. Interestingly, activated CAR T cells expressing CPRs exhibited increased aerobic glycolysis while unmodified HER2-CAR T cells exhibited higher lipid oxidation denoting metabolic stress. HER2 CAR T cells with 4-1BB CPRs also significantly improved survival in a murine xenograft model. We conclude that CPRs, the synthetic PD-1 fusion molecules, improve the differentiation, metabolism, and molecular signaling of HER2 CAR T cells, thereby increasing their anti-glioma activity.
Abstract 201: BMP-pSmad1/5/8 Pathway Activation in a Novel Mouse Model of Calcific Aortic Valve Disease
Authors: Maria V Gomez, Jonathan D Cheek, Elaine E Wirrig, Katherine E Yutzey
Journal: Circulation Research (2013)

Calcific Aortic Valve Disease (CAVD) affects &gt;2% of the population over the age of 65, for whom the current standard of care is valve replacement surgery. To date, there are no pharmacologic-based therapies that prevent the progression or inhibit the development of CAVD, thus highlighting the necessity for new therapeutic approaches. Despite its clinical significance, the pathogenic mechanisms that drive the development of CAVD, and that could serve as potential therapeutic targets, remain unknown. We have recently identified Klotho-deficient mice, an established model of premature aging, as a novel model of CAVD that exhibit aortic valve calcification on the fibrosa side of the hinge region, closely mimicking human CAVD pathology. Unlike previous models, calcification occurs independent of inflammation and valve thickening in these mice, supporting a distinct mechanism of age-related calcification common in elderly patients. In bone, BMP-mediated osteogenic gene induction is essential for the process of calcification. Notably, pSmad1/5/8 activation, indicative of active BMP signaling, is observed prior to the onset of calcification and later is localized with calcific nodule formation in klotho-deficient mice with CAVD. Our hypothesis is that activation of BMP-pSmad1/5/8 signaling pathway promotes osteogenic gene induction and aortic valve mineralization in CAVD. Osteogenic factors, Runx2 and Osteopontin, are significantly increased in the aortic valves of klotho-deficient mice, suggesting an osteogenic-like mechanism of disease. Likewise, pSmad1/5/8 activation precedes osteogenic gene induction in these mice. Moreover, increased BMP2/4 ligand expression is detected prior to the onset of disease, as well as during calcific nodule formation, thus supporting an active role for the BMP-pSmad1/5/8 signaling cascade during aortic valve calcification. Our ongoing work includes BMP pathway inhibition studies to determine if this is an effective therapeutic strategy for the treatment of CAVD in the klotho-deficient mice. Altogether our data support a role for the BMP-pSmad1/5/8 signaling cascade as a critical mechanism in the initial onset and progression of aortic valve calcification in a novel mouse model of CAVD.
Abstract 88: Microrna-21* Controls Sepsis-induced Cardiac Dysfunction
Authors: Hui Wang, Yihua Bei, Jing Shi, Wei Sun, Hui Liu, Xinli Li, Junjie Xiao, Xiangqing Kong
Journal: Circulation Research (2015)

Background: Sepsis-induced cardiac dysfunction is charactered by cardiac contractility dysfunction, myocardial inflammation and cardiac metabolism abnormal. Dysfunction of microRNAs (miRNAs, miRs) contributes to a variety of human diseases. However, their roles in sepsis-induced cardiac dysfunction are unclear. Methods and Results: Cardiac dysfunction was induced by E.coli lipopolysaccharide (LPS) administration in mice and 8 dysregulated miRNAs were identified by miRNA arrays. Among them, miR-21* was found to be increased most obviously as determined by quantitative reverse transcription polymerase chain reactions. Inhibition of miR-21* in vivo by antagomir attenuated the reduction of factional shortening (FS) and ejection fraction (EF) induced by LPS administration while forced over-expression of miR-21* in vivo by agomir accelerated LPS-induced cardiac dysfunction. Besides that, S100A8 and S100A9, two genes related to cardiac contractility were also found to be regulated in vivo by injection of miR-21* agomirs and antagomirs. Interestingly, cardiac inflammation indictors such as TNF-α and IL-6 and cardiac metabolism regulators including PPAR family, CD36, FATP, GLUT1, GLUT4, PDK4 were not changed by miR-21* in vivo. These data indicate that miR-21* controls sepsis-induced cardiac dysfunction by direct affecting cardiac contractility instead of cardiac inflammation and metabolism. SORBS2 was identified as a target gene of miR-21* and it was decreased by miR-21* agomir and increased by miR-21* antagomir in vivo. In consist with this, circulating levels of miR-21* were also increased in patients with sepsis compared with healthy controls. Conclusion: miR-21* controls sepsis-induced cardiac dysfunction by regulating SORBS2. Inhibition of miR-21* represents a novel therapeutic strategy for sepsis-induced cardiac dysfunction.
Transcriptomic Perspectives on Neocortical Structure, Development, Evolution, and Disease
Authors: Ed S. Lein, T. Grant Belgard, Michael Hawrylycz, Zoltán Molnár
Journal: Annual Review of Neuroscience (2017)

The cerebral cortex is the source of our most complex cognitive capabilities and a vulnerable target of many neurological and neuropsychiatric disorders. Transcriptomics offers a new approach to understanding the cortex at the level of its underlying genetic code, and rapid technological advances have propelled this field to the high-throughput study of the complete set of transcribed genes at increasingly fine resolution to the level of individual cells. These tools have revealed features of the genetic architecture of adult cortical areas, layers, and cell types, as well as spatiotemporal patterning during development. This has allowed a fresh look at comparative anatomy as well, illustrating surprisingly large differences between mammals while at the same time revealing conservation of some features from avians to mammals. Finally, transcriptomics is fueling progress in understanding the causes of neurodevelopmental diseases such as autism, linking genetic association studies to specific molecular pathways and affected brain regions.
COMORBILIDAD ASOCIADA A HALLAZGOS EN CÁPSULA ENDOSCÓPICA
Authors: A Martínez Sánchez, A Zatarain Vallés, F Sánchez Ceballos, P Mateos Sánchez, M Arranz Álvarez, M Asteinza Daganzo, JM Esteban López-Jamar, E Rey Díaz-Rubio
Journal: Endoscopy (2015)

Introducción: La cápsula endoscópica (CE) es una exploración no invasiva establecida para el diagnóstico de las enfermedades del intestino delgado (ID).
Comparison of inertial sensors and bess in balance testing of professional football players with respect to concussion
Authors: Christopher Bockisch, Karin Mani, Konrad Weber, Alexander Tarnutzer, Dominik Straumann, Feddermann Nina
Journal: British Journal of Sports Medicine (2017)

Objective Balance problems are a frequent symptom after head trauma including concussion, and the Balance Error Scoring System (BESS) is routinely used as a subjective screening test. Low-cost inertial sensors are an attractive objective alternative to elaborative force plates in objective testing balance in athletes. Design Case series. Setting Training area of professional players. Participants 310 professional male and female football players from highest league in Switzerland (19/20 (95%) teams). Intervention Subjects were scored on their ability to maintain posture while standing in the six BESS conditions. Errors were counted by a test administrator, while an IPOD worn in a waist belt recorded linear acceleration and rotational velocity. Outcome measures A variety of measures of stability (e.g., area of 2D surface plot, normalised path length (NPL)) were computed. In order to determine which measure was most sensitive to changes in balance, receiver operating characteristic (ROC) curves were created comparing firm to foam surfaces, and then the area under the ROC was calculated. Main results BESS and inertial measures correlated well overall (&gt;0.7). Inertial measurements perform well in easier conditions (ROC area &gt;0.95 for double stance), whereas BESS is insensitive to subtle changes in balance (ROC area=0.5). BESS, however, performs better on difficult conditions (ROC area &gt;0.9 for single stance). Conclusions Accelerometer assisted balance tests are a useful laboratory test in assessing balance problems. Normative values for athletes should be established. Competing interests None.
Hydroxychloroquine toxicity and aromatase inhibitors
Authors: R. Hambly, A. Lally
Journal: British Journal of Dermatology (2017)

Hydroxychloroquine (HCQ) is a widely used treatment for many dermatologic conditions and is generally well tolerated. Retinal toxicity is a recognised side effect and is dependent on daily dose and duration of use.1 Guidelines from the Royal College of Ophthalmologists (2009) recommend a maximum daily dose of 6.5mg/kg lean body weight.2 Recent guidelines (2016) from the American Academy of Ophthalmology (AAO) recommend a maximum daily dose of 5mg/kg real body weight.1 Baseline fundus examination is recommended to rule out pre-existing maculopathy, followed by annual screening from 5 years, in patients without major risk factors e.g. high daily dose, renal disease, pre-existing retinal or macular disease.1 A 2014 retrospective case-control study of 2361 patients on HCQ for the previous 5 years identified concomitant tamoxifen therapy as an additional major risk factor for developing retinal toxicity (odds ratio 4.59).3

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French comment on article Endoscopic ultrasound-guided biliary access versus precut papillotomy in patients with failed biliary cannulation: a retrospective study1 Accès biliaire guidé par échoendoscopie versus précoupe chez les patients avec échec de canulation biliaire: étude rétrospective
Journal: Endoscopy (2017)

L’échec de canulation biliaire sélective échoue dans 10 % des CPRE environ. La précoupe (PC) est la technique de recours la plus utilisée, mais l’apparition dans l’arsenal thérapeutique des techniques guidées par échoendoscopie (EEBD), à savoir rendez-vous, drainage antérograde, anastomose hépaticogastrique ou cholédocoduodénale, qui ont un haut niveau de succès technique pourrait modifier l’algorithme de prise en charge. Cette étude a comparé 2 cohortes de 2 centres hospitaliers différents: la cohorte A (CA, 1053pts) où PC et EEBD étaient disponibles et la cohorte B (CB = 1062pts) où seule la PC était réalisable. Les échecs de canulation étaient observés dans 10 % des cas dans les 2 cohortes. Les 2 cohortes n’étaient pas comparables, les patients de CB étant plus jeune, plus masculin et l’indication était plus souvent biliaires. Le taux d’échec de CPRE après utilisation d’une thérapeutique avancée était plus faible dans CA (1 % vs 3,6 %). EEBD était réalisée dans 4,7 % dans CA. Une PC était réalisée dans 4,8 % de cas dans CA et 8,6 % dans CB. Une PC était indiquée plus souvent pour calculs biliaires et EEBD pour sténose tumorale. EEBD était utilisée en 1ere intention dans CA dans 49 % des cas et efficace dans 93 % et après échec de PC dans 12 cas (succès 100 %). En groupant les 2 cohortes, le taux de succès de EEBD était supérieur à PC, notamment pour les sténoses tumorales. Ce point est important, car il est certains que l’étiologie et la raison de l’échec de canulation doivent être intégrées à l’algorithme pour le choix de la technique de seconde intention. Ceci explique peut être la différence d’indications entre les 2 cohortes, certaines sténoses tumorales complexes étant référées pour un drainage percutané d’émblée dans la CB alors qu’ils étaient traités par voie endoscopique dans la CA.
Antitumor efficacy of poxvirus-based active immunotherapy alone and in combination with subtherapeutic dosing with immune checkpoint inhibitors.
Authors: Susan P Foy, Ryan B Rountree, Joseph Cote, Evan Gordon, Erica Trent, Alexis J. Franzusoff, James Bradley Breitmeyer, Stefanie J Mandl
Journal: Journal of Clinical Oncology (2014)

3058 Background: PROSTVAC PSA-targeted immunotherapy for metastatic castration-resistant prostate cancer is being tested in the PROSPECT phase 3 trial. Another poxvirus-based immunotherapy product, MVA-BN-HER2, was tested in early phase clinical trials for breast cancer. We hypothesized that active immunotherapy in combination with immune checkpoint inhibitors (ICI) CTLA-4, PD-1, PDL-1, or LAG-3 would yield significant synergistic benefit for anti-tumor efficacy in non-clinical models compared to any approach alone. Due to toxicities that are associated with some high dose ICI regimens that provide clinical benefit, we tested poxvirus-based immunotherapy combined with lower dose ICI regimens for anti-tumor efficacy. Methods: In therapeutic CT26-HER2 solid and metastatic tumor models, mice were administered MVA-BN-HER2 immunotherapy alone or in combination with single and double CTLA-4, PD-1, PD-L1, or LAG-3 ICI regimens. Dose regimens (10, 3, and 1 mg/kg) of ICIs alone and in combination with targeted active immunotherapy were also evaluated. Results: Synergistic benefit for anti-tumor efficacy in therapeutic mouse models was observed with various regimens combining poxvirus-based active immunotherapy with single and double ICI dosing. Complete tumor regression resulted from combining MVA-BN-HER2 immunotherapy with anti-PD-1 plus anti-LAG-3. In addition, ICI dose reduction retained significant improvement in survival in combination with MVA-BN-HER2 poxvirus active immunotherapy, even at 1 mg/kg dose. When given without MVA-BN-HER2, ICIs were ineffective at improving survival in lower dose regimens. Conclusions: Overall survival following poxvirus-based active immunotherapy shows synergy with single and dual combinations of ICIs in solid and metastatic tumor models. Lowering ICI doses to sub-therapeutic benefit levels still yields survival benefit when combined with poxvirus-based immunotherapy. Therefore, combination therapy of reduced-dose ICIs with poxvirus-based active immunotherapy is predicted to support improved clinical benefit, safety and tolerability over ICI therapy alone.
RUNX3 Attenuates β-Catenin/T Cell Factors in Intestinal Tumorigenesis
Authors: Kosei Ito, Anthony Chee-Beng Lim, Manuel Salto-Tellez, Lena Motoda, Motomi Osato, Linda Shyue Huey Chuang, Cecilia Wei Lin Lee, Dominic Chih-Cheng Voon, Jason Kin Wai Koo, Huajing Wang, Hiroshi Fukamachi, Yoshiaki Ito
Journal: Cancer Cell (2009)
Immunological long-term follow-up of neuroblastoma stage IV patients after anti-GD2 CH14.18 antibody treatment.
Authors: Simone Kayser, Vanya Icheva, Stefan Stevanovic, Nikolai Siebert, Judith Feucht, Holger N. Lode, Rupert Handgretinger, Tobias Feuchtinger
Journal: Journal of Clinical Oncology (2015)

3029 Background: Neuroblastoma stage IV is associated with low cure rates. Treatment with the GD2 antibody ch14.18 could improve the long-term overall survival. Apart from GD2 other tumor antigens (TA) are expressed in neuroblastoma and studies implicated that T-cell responses to TA are associated with a better outcome. For the present study we analyzed the immune response in long term neuroblastoma survivors treated with anti GD2 ch14.18. Methods: Blood and serum of 17 neuroblastoma long-term survivors after GD2 therapy with > 5 years follow up (patients group) and 17 age and gender matched healthy donors (control group) were analyzed. Serum was analyzed for antibodies binding to neuroblastoma cell lines and antibodies to a nominal antigen GD2. T cells were stimulated with overlapping peptides of the tumor antigens (TA) NY-ESO-1, WT-1, Survivin, MAGE-A1 and two mimotope peptides to GD2 for 10 days and analyzed for IFN-γ secretion in flow cytometry. Results: T-cell responses to at least one TA could be found in 82% of healthy and in 93% of patients with no significant difference in the number of TA responders between the two groups to any of these TA (Fisher´s exact test). In contrast, T-cell responses to at least one of the GD2 mimotopes were found in 53% of neuroblastoma survivors but in 0% of healthy donors. Moreover, even priming with GD2 mimotope loaded dendritic cells did not induce a T-cell response in healthy donor cells. No differences between patient and control group could be detected in binding of antibodies to neuroblastoma cell lines and no GD2-specific antibodies were detected in patients and controls. Conclusions: Survivors of neuroblastoma treated with anti-GD2 ch14.18 demonstrated robust T-cell responses to neuroblastoma associated TA that was comparable to healthy donors. This could enable patients to attack minimal residual disease efficiently. Moreover more than half of the patients had T-cell responses to GD2 which could be an effect of the GD2 antibody therapy. Our results show that involvement of the cellular immune system might have an impact on the better outcome of this treatment in stage IV neuroblastoma patients.
The impact of disability in survivors of critical illness
Authors: Carol L. Hodgson, Andrew A. Udy, Michael Bailey, Jonathan Barrett, Rinaldo Bellomo, Tracey Bucknall, Belinda J. Gabbe, Alisa M. Higgins, Theodore J. Iwashyna, Julian Hunt-Smith, Lynne J. Murray, Paul S. Myles, Jennie Ponsford, David Pilcher, Craig Walker, Meredith Young, D. J. Cooper
Journal: Intensive Care Medicine (2017)
Facial Rash, Fever, and Anemia in a Newborn
Authors: Chihiro Shiiya, Mitsuhito Ota
Journal: JAMA (2017)

A 19-day-old Japanese male infant presented with a 12-day history of low-grade fevers and erythematous plaques with central atrophy and raised margins on the forehead and periorbital areas. Laboratory testing showed mild anemia and an elevated C-reactive protein level. What would you do next?