tbuckley/cabot-search huggingface dataset:
The burden of chronic spontaneous urticaria is substantial: Real‐world evidence from <scp>ASSURE</scp>‐<scp>CSU</scp>
Authors: M. Maurer, M. Abuzakouk, F. Bérard, W. Canonica, H. Oude Elberink, A. Giménez‐Arnau, C. Grattan, K. Hollis, A. Knulst, J.‐P. Lacour, C. Lynde, A. Marsland, D. McBride, A. Nakonechna, J. Ortiz de Frutos, C. Proctor, G. Sussman, C. Sweeney, H. Tian, K. Weller, D. Wolin, M.‐M. Balp
Journal: Allergy (2017)

Abstract Background Chronic spontaneous urticaria ( CSU ) can be debilitating, difficult to treat, and frustrating for patients and physicians. Real‐world evidence for the burden of CSU is limited. The objective of this study was to document disease duration, treatment history, and disease activity, as well as impact on health‐related quality of life ( HRQ oL) and work among patients with inadequately controlled CSU , and to describe its humanistic, societal, and economic burden. Methods This international observational study assessed a cohort of 673 adult patients with CSU whose symptoms persisted for ≥12 months despite treatment. Demographics, disease characteristics, and healthcare resource use in the previous 12 months were collected from medical records. Patient‐reported data on urticaria and angioedema symptoms, HRQ oL, and work productivity and activity impairment were collected from a survey and a diary. Results Almost 50% of patients had moderate‐to‐severe disease activity as reported by Urticaria Activity Score. Mean ( SD ) Dermatology Life Quality Index and Chronic Urticaria Quality of Life Questionnaire scores were 9.1 (6.62) and 33.6 (20.99), respectively. Chronic spontaneous urticaria markedly interfered with sleep and daily activities. Angioedema in the previous 12 months was reported by 66% of enrolled patients and significantly affected HRQ oL. More than 20% of patients reported ≥1 hour per week of missed work; productivity impairment was 27%. These effects increased with increasing disease activity. Significant healthcare resources and costs were incurred to treat CSU . Conclusions Chronic spontaneous urticaria has considerable humanistic and economic impacts. Patients with greater disease activity and with angioedema experience greater HRQ oL impairments.
Letter by Saritas Regarding Article, “Total Anomalous Pulmonary Venous Connection: The Current Management Strategies in a Pediatric Cohort of 768 Patients”
Authors: Bulent Saritas
Journal: Circulation (2017)

al 1 that reported the authors' experiences with patients with total anomalous pulmonary venous connection (TAPVC) corrected surgically.TAPVC is a rare congenital heart defect consisting of an anomalous connection of the pulmonary veins into the systemic veins.It is crucial whether there is an obstruction at the site of connection that determines the clinical presentation of TAPVC in the neonatal period.An infant with obstructed TAPVC usually presents with marked respiratory distress, cyanosis, and metabolic acidosis.Immediate relief of the obstruction is required, and, even with surgical intervention, the reported mortality is 5% to 7%. 2 It is controversial whether the vertical vein should be ligated at the time of TAPVC repair. 3However, the vertical vein left open can serve as a reservoir for the right and left ventricles in patients with pulmonary hypertension that developed as a consequence of obstruction.It is recommended that the vertical vein should be kept open in patients with serious pulmonary hypertension. 4ccording to Shi et al's article, 192 (25%) of the 768 patients had obstructed TAPVC, of whom a higher proportion of patients (17%) developed acidosis or multisystem organ dysfunction before surgery.And, there is not enough information in the text about opening or ligating the vertical vein.If they had left the vertical vein open, especially in patients with pulmonary hypertension, would the mortality rate have decreased to a lower rate than they had?DISCLOSURES
Reply to “Tolerogenic insulin peptide therapy precipitates type 1 diabetes”
Authors: Carolin Daniel, Benno Weigmann, Harald von Boehmer
Journal: The Journal of Experimental Medicine (2017)

In this issue of JEM, Bergman et al. (https://doi.org/10.1084/jem.20160471) challenge the data published in our previous JEM paper on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Here, we provide a response to these data and suggest that appropriate subimmunogenic conditions are required to induce Foxp3+ regulatory T cell conversion.
Long Non-Coding RNAs Annotation and Their Involvement in Multiple Myeloma
Authors: Arantxa Carrasco, Teresa Ezponda, Cem Meydan, Marta Kulis, Raquel Ordoñez, Leire Garate, Victor Segura, Diego Alignani, Bruno Paiva, Jesus San Miguel, José I. Martin Subero, Ari Melnick, Felipe Prosper, Xabier Agirre
Journal: Blood (2016)
Erratum: Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence.
Authors: Suzanne Sniekers, Sven Stringer, Kyoko Watanabe, Philip R Jansen, Jonathan R I Coleman, Eva Krapohl, Erdogan Taskesen, Anke R Hammerschlag, Aysu Okbay, Delilah Zabaneh, Najaf Amin, Gerome Breen, David Cesarini, Christopher F Chabris, William G Iacono, M Arfan Ikram, Magnus Johannesson, Philipp Koellinger, James J Lee, Patrik K E Magnusson, Matt McGue, Mike B Miller, William E R Ollier, Antony Payton, Neil Pendleton, Robert Plomin, Cornelius A Rietveld, Henning Tiemeier, Cornelia M van Duijn, Danielle Posthuma
Journal: Nature Genetics (2017)
DDIS-12. CYTO-MITO™ - A NOVEL CLASS OF DUAL-ACTING Hsp90 INHIBITORS FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Allan Rubenstein, Srinivasa Reddy, Shyama Sidique, David Carney, Ann Mladek, Jeffrey Stebbins, Li Yang, Pooi San Lee, Daniel Brimberry, Robert Ardecky, Peter Teriete, Jann Sarkaria, Nicholas Cosford, Sridhar Prasad
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is a highly invasive and aggressive primary brain tumor and is considered one of the deadliest forms of cancer. Despite aggressive therapies, half of GBM patients die within 15 months after diagnosis and only 2% survive more than 5 years. Therefore, effective treatments for GBM represent an urgent unmet medical need. Genetic profiling of glioma has shown multiple oncogenes critical for cell-signaling are not only mutated and/or amplified but can also circumvent the otherwise clinically promising targeted therapeutics. Therefore, a therapy that can simultaneously suppress multiple cell-signaling oncogenes using a single agent may be a more effective therapeutic strategy for GBM. Cytosolic Hsp90 facilitates GBM tumor cell growth and survival by assisting in the proper folding and active conformation maintenance of many oncoproteins. The mitochondrial Hsp90 homolog, TNF Receptor Associated Protein-1 (TRAP1) is also elevated in GBM tumors and participates in pleiotropic signaling circuitries of organelle integrity and cellular homeostasis. Thus, dual-acting Hsp90/TRAP1 inhibitors benefit from the advantage of simultaneously disrupting a multitude of cancer-promoting pathways and have successfully demonstrated anti-tumor effectiveness against a number of glioma cell lines and in vivo preclinical models. Taken together, these data support concomitant inhibition of cytosolic Hsp90 and the mitochondrial TRAP1 using a single agent represents a novel “double-pronged” approach for effective GBM treatment. Plex has discovered dual-acting (Hsp90/TRAP1) inhibitors demonstrating low sub-micromolar efficacy in multiple clinically relevant Mayo Clinic GBM patient-derived cell lines. Consistent with sub-micromolar efficacy, our compounds caused ≥50% suppression in EGFR and Akt1 levels in these cell lines. In addition, the compounds induced mitochondrial dysfunction, both in cells and in isolated mitochondria. Preliminary studies also show, a compound in our Hsp90/TRAP1 inhibitor series achieved effective concentrations in normal rat brains, indicating effective blood brain barrier crossing. This work was supported by National Institutes of Health grant (1R43GM090383)
Palliative care from diagnosis for all ages including children and young people
Authors: Sarah Mitchell, Jeremy Dale
Journal: BMJ (2017)

Murray and colleagues describe late palliative care as a missed opportunity to do better for patients, families, and healthcare services.1 Their work focused on adults, but a growing number of children and young people could benefit from better palliative care.2 Just as for adults, palliative care for children and young people is often delayed, with referrals to specialist …
Calcium release channel RyR2 regulates insulin release and glucose homeostasis
Authors: Gaetano Santulli, Gennaro Pagano, Celestino Sardu, Wenjun Xie, Steven Reiken, Salvatore Luca D’Ascia, Michele Cannone, Nicola Marziliano, Bruno Trimarco, Theresa A. Guise, Alain Lacampagne, Andrew R. Marks
Journal: Journal of Clinical Investigation (2015)
Relationship between king devick TEST, SCAR3 and 3D mot in cognitive assessment
Authors: Kimberly R Oslund, Hilary M Cullen, Kristina Kowalski, Brian Christie
Journal: British Journal of Sports Medicine (2017)

Objective To examine the relationship between aspects of the Sport Concussion Assessment Tool 3 (SCAT3), the King-Devick Test (KDT) and Three-Dimensional Multiple Object Tracking (3D MOT) at baseline. Design Prospective design. Setting University resarch laboratory. Participants A convenience sample of 304 healthy, non-concussed, athletic participants (101 females, 203 males) ranging in age from 11.69 20.41 years (mean age=16.05 + 4.36) were included in the analysis. Outcome measures Participants completed the SCAT3, KDT and 3D MOT in a single visit. A regression analysis was performed to see if any aspects of the SCAT3 (immediate memory (IM), coordination (COOR), and delayed recall (DR)), and/or the KDT, predicted 3D MOT scores. Main results A multiple linear regression was calculated to see if KDT, IM, DR and COOR predicted the speed of the 3D MOT. The assumptions of multivariate regression were tested and corrections were applied as needed. Using the stepwise method, it was found that KD, DR and COOR explain a significant amount of the variance in the speed of the 3D MOT (F(3, 256))=11.82, p&lt;0.000 with an R2 of 0.12. Participants predicted 3D MOT score is equal to 1.05 –0.01 KD + 0.07 DR + 0.23 COOR, where KDT is measured in seconds, DR is measured in units between 0–5, and COOR is measured as 1=successful, 0?= not successful. The analysis shows that KD (Beta=–0.01, p?&lt; 0.000), DR (Beta=0.07, p&lt;0.02), and COOR (Beta=0.23, p&lt;0.03), were significant predictors of 3D MOT scores. Conclusions Results suggest that King Devick Test, Delayed Recall, and Coordination tests share predictive validity of the 3D MOT in an athletic population between the ages of 6-29 at baseline. Future studies should examine these relationships post-injury and through concussion recovery. This could provide valuable information to better inform clinicians responsible for making Return to Play determinations. Competing interests None.
Abstract 16584: Association of Lower Height and Higher LDL-c in a Statewide Schoolchild Cholesterol Screening Program
Authors: Lee A Pyles, Christa Lilly, Eloise Elliott, William A Neal
Journal: Circulation (2015)

Introduction: The Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) Project has screened West Virginia 5th graders since 1998 to facilitate primordial prevention of coronary heart disease (CHD) in WV. LDL-c levels above 175 mg/dl in children suggest Familial Hyperlipidemia (FH) in the child’s family and a level above 160 mg/dl with history of CHD in relatives can also establish a diagnosis. Hypothesis: Based on previous adult literature, the association of lower height with higher LDL level observed in adults begins in childhood and is prominent in children with LDL in FH range. Methods: Fifth graders are screened yearly in WV schools with parental consent for Body Mass Index and lipid panel. Lipids were analyzed with respect to either short stature &lt; 2 SD for height or comparing 1st (shortest) and 4th quartiles of the population. Statistical analysis for age- and gender-adjusted height percentiles was performed in SAS. Results: 59,386 children had lipid and height data. Mean LDL-c for 1st vs. 4th quartile of height was 94.08 mg/dl (95% Confidence Interval-CI 93.66-94.51) vs. 90.03 mg/dl (CI 89.65-90.42). First quartile of height students had average 4.05 mg/dl higher LDL-c (95% CI 3.48 -4.62 mg/dl). 4398 children had an LDL level above 130 g/dl, 632 above 160 mg/dl and 247 above 175 mg/dl. The Chi square analysis of short stature (height 130 g/dl was also significant (p=0.013) with increased odds of LDL-c above 130 g/dl compared to non-short stature (OR= 1.37, CL 1.07-1.75). Table 1 shows odds ratio for varying levels of elevated LDL-c for the first (shortest) vs. 4th (tallest) quartile of students. Conclusions: Shorter stature is associated with higher LDL-c level in WV 5th graders generally and in those children with increased risk for genetic dyslipidemia. The trend to increasing odds ratio in strata of higher LDL-c supports a recent report of association of single nucleotide polymorphisms selecting for lower genetic height and higher LDL-c.
The antioxidants (-)-epigallocatechin-3-gallate and curcumin inversely regulate human involucrin promoter activity via opposing effects on CCAAT /enhancer binding protein function.
Authors: Sivaprakasam Balasubramanian, James F. Crish, Richard L. Eckert
Journal: Cancer Research (2004)

3134  Antioxidants are important candidate agents for the prevention of disease. However, the possibility that different antioxidants may produce opposing effects in tissues has not been adequately explored. We have previously reported that (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol antioxidant, stimulates expression of the keratinocyte differentiation marker, involucrin (hINV), via a RAS, MEKK1, MEK3, p38δ signaling cascade (Balasubramanian et al., J Biol Chem. 277, 828-36, 2002). In the present study, we demonstrate a role for CCAAT/enhancer-binding protein (C/EBP) transcription factors in the EGCG-dependent regulation of hINV gene expression. EGCG (20 μg/ml) promotes a 4-fold increase in hINV promoter activity. Moreover, EGCG treatment increases C/EBPα and C/EBPβ level, and C/EBP factor binding to hINV promoter C/EBP DNA binding site. Mutation of a functionally important C/EBP site within the hINV promoter proximal regulatory region (PRR) eliminates the regulation as does the presence of GADD153, a dominant-negative C/EBP factor. These results suggest that EGCG activates a RAS, MEKK1, MEK3, p38δ signaling pathway that targets C/EBP transcription factors to enhance hINV gene expression. A second antioxidant, curcumin, inhibits the EGCG- and C/EBPα-dependent promoter activation. This is associated with inhibition of the EGCG-dependent increase in C/EBP factor level and C/EBP factor binding to the hINV promoter. Treatment with curcumin also inhibits the EGCG-dependent increase in endogenous hINV levels. An important finding of this study is that curcumin inhibits this EGCG-dependent regulation, indicating an antagonistic action of EGCG and curcumin in normal human keratinocytes. These results indicate that possible opposing actions of antioxidants must be considered when designing therapy.
Post-treatment PET scan is highly predictive of outcome (PFS and OS) in MCL pts treated with R-Hyper-CVAD in the frontline setting regardless of MIPI score.
Authors: Anthony R. Mato, Ewelina Protomastro, Tania Zielonka, Tatyana Feldman, Harry Agress, Mary Timberg, Gabriella Gadaleta, Pritish Bhattacharyya, Alexandria Campaiola, Jakub Svoboda, Susan Stives, Coleen Bejot, Kar Fai Chow, Larysa Jessica Gromko, Andrew Pecora, Andre Goy
Journal: Journal of Clinical Oncology (2014)

8557 Background: MIPI score (age, LDH, WBC, ECOG PS) defines 3 distinct risk groups in MCL pts. Though MIPI has been validated in series with dose intensive (DI) strategies and rituximab, a number of other prognostic factors have been reported that affect MCL survival. There remains a need to further stratify pts in each MIPI risk category despite optimal treatment approaches. We previously identified (Mato et al, Cancer 2012) FDG PET-CT as an important prognostic marker for survival in MCL pts following R-HyperCVAD completion. We examined here the additive prognostic utility of post-treatment PET-CT imaging to baseline MIPI scores. Methods: Primary endpoints were PFS and OS. PET-CT images were dichotomized using IHP response criteria (Juweid et al, JCO 2007). Reviewers were blinded to outcomes. MIPI scores were calculated as described by Hoster et al (Blood, 2008). Utilizing KM methods, we compared outcomes stratified by post-treatment PET-CT status and MIPI risk groups. Utilizing Cox regression, we tested the association between PET-CT + MIPI and survival. Results: 140 MCL pts (med age 60, 95% stage IV) treated with 1st line R-HyperCVAD were identified in our MCL outcome database. Of these, 58 pts had a post-treatment PET-CT available for review. MIPI scores were 44% low, 34% intermediate and 22% high risk. Post treatment PET-CTs were 18% (+) and 82% (-). Med PFS and OS estimates were 56 and 108 mo respectively (med follow up 35.2 mo). Both MIPI (HR 1.9 CI: 1.1-3.2 p=.012) and PET-CT (HR 7.1 CI:2.9-17.1 p=.001) independently correlated with PFS and OS MIPI (HR 3.3 CI: 1.5-7.3 p=.04) and PET-CT (HR 9.2 CI: 2.5-33.0 p=.001). The following defines a model, which includes baseline MIPI and PET-CT status: Low MIPI (HR=1), Int MIPI (HR=2.1), High MIPI (HR=3.5), PET-CT (-) (HR=1), PET-CT (+) (HR=7.1). Conclusions: Post treatment FDG-PET status and MIPI are validated independent predictors of survival in MCL pts treated with R-HyperCVAD. Outcomes are extremely poor in PET (+) patients regardless of MIPI risk group: Low risk / PET (+) had similar PFS as high risk / PET (-). Our results may identify MCL patient candidates for novel maintenance / consolidation approaches after 1st line therapy.
MEDU-39. YAP1 IS NECESSARY FOR TUMORIGENESIS AND CANCER STEM CELL MAINTENANCE IN SHH-INDUCED MEDULLOBLASTOMAS
Authors: Sivaraman Natarajan, Joshy George, Fernando Camargo, Kyuson Yun
Journal: Neuro-Oncology (2017)

Treatments with minimal adverse effects are particularly important for pediatric brain tumor patients to preserve normal brain development and function. We propose that SHH medulloblastomas may be safely treated with a YAP1 inhibitor. YAP1, a transcriptional effector of the Hippo signaling pathway, is amplified or over-expressed specifically in the SHH subgroup of medulloblastomas. To directly test whether this observation reflects significant functional interaction between the SHH pathway and YAP1, we genetically deleted Yap1 in a mouse model of SHH-induced medulloblastoma, SMO-M2;GFAP-Cre. All SMO-M2;GFAP-Cre mice succumb to medulloblastomas by weaning age. However, when Yap1 is genetically deleted, ~50% of Yap1f/f; SMO-M2;GFAP-Cre mice are rescued from medulloblastoma formation. Analyses of young pups indicate that Yap1 is dispensable for tumor initiation but necessary for tumor maintenance. Considering its known function in stem cell homeostasis, we hypothesized that Yap1 may be necessary to maintain cancer stem cells (CSCs). To test this, we isolated and manipulated Yap1 levels in tumorspheres from two different SHH medulloblastoma models: Ptch+/-;p53 and SMO-M2;GFAP-Cre. 100% of SMO-M2;GFAP-Cre tumors generated tumorsphere cultures that can be passaged for > 10 passages. In contrast, all Yap1-null cultures from Yap1f/f; SMO-M2;GFAP-Cre mice quickly exhausted their self-renewal ability by passage 3. Furthermore, either siRNA or a small molecule inhibitor (verteporfin) treatment in established Ptch+/-;p53 or SMO-M2;GFAP-Cre tumorspheres significantly reduced the number of secondary spheres, indicating that Yap1 function is necessary to maintain SHH medulloblastoma CSCs. To determine whether YAP1 inhibition has potential therapeutic value, we treated SMO-M2;GFAP-Cre pups with verteporfin in vivo and observed significant increase in overall survival. Importantly, neither verteporfin treatment nor genetic deletion of Yap1 showed gross adverse effects in brain development or neural stem cell function, indicating a clear therapeutic window. In summary, this study provides compelling evidences that YAP1 inhibitors may provide significant therapeutic benefit to SHH medulloblastoma patients.
Pharmacokinetics (PK) and Pharmacodynamics (PD), Safety and Tolerability of a Single-Dose Oral Solution of Dabigatran Etexilate Given after Standard Anticoagulant Therapy in Children from Birth to Less Than One Year Old, with Venous Thromboembolism
Authors: Jacqueline ML Halton, Anne-Caroline Picard, Ruth Harper, Fenglei Huang, Martina Brueckmann, Savion Gropper, Hugo Maas, Igor Tartakovsky, Ildar Nurmeev, Lesley G Mitchell, Leonardo R. Brandão, Manuela Albisetti
Journal: Blood (2016)
Impact of Molecular Response of Nilotinib (NIL) for BCR/ABL1 Transcripts ≥ 10% with Imatinib (IM) 3 and/or 6 Months By Sokal Risk in Chronic Phase Chronic Myelogenous Leukemia (CML-CP)
Authors: Zhijian Cao, Zhaomin Zhan, Jun Ma
Journal: Blood (2016)
Keyboard: A Novel Bayesian Toxicity Probability Interval Design for Phase I Clinical Trials
Authors: Fangrong Yan, Sumithra J. Mandrekar, Ying Yuan
Journal: Clinical Cancer Research (2017)

Abstract The primary objective of phase I oncology trials is to find the MTD. The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides better accuracy to identify the MTD but tends to overdose patients. We propose the keyboard design, an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval. The keyboard design can be implemented in a simple way, similar to the traditional 3+3 design, but provides more flexibility for choosing the target toxicity rate and cohort size. Our simulation studies demonstrate that compared with the 3+3 design, the keyboard design has favorable operating characteristics in terms of identifying the MTD. Compared with the mTPI design, the keyboard design is safer, with a substantially lower risk of treating patients at overly toxic doses, and has the better precision to identify the MTD, thereby providing a useful upgrade to the mTPI design. Software freely available at http://www.trialdesign.org facilitates the application of the keyboard design. Clin Cancer Res; 23(15); 3994–4003. ©2017 AACR. See related commentary by Paoletti et al., p. 3977
On the brink: The demise of the item in visual search moves closer
Authors: Johan Hulleman, Christian N. L. Olivers
Journal: Behavioral and Brain Sciences (2017)

Abstract We proposed to abandon the item as conceptual unit in visual search and adopt a fixation-based framework instead. We treat various themes raised by our commentators, including the nature of the Functional Visual Field and existing similar ideas, alongside the importance of items, covert attention, and top-down/contextual influences. We reflect on the current state of, and future directions for, visual search.