tbuckley/cabot-search huggingface dataset:
Will fish be part of future healthy and sustainable diets?
Authors: Jessica R Bogard, Anna K Farmery, David C Little, Elizabeth A Fulton, Mat Cook
Journal: The Lancet Planetary Health (2019)

The adoption of healthy and sustainable diets and food systems is recognised as a means to address the global challenge of malnutrition and poor-quality diets, and unprecedented environmental damage from food production and consumption.1 Sustainable diets have also been recognised as a key strategy to achieve the Sustainable Development Goals. Reducing consumption of animal-source foods is frequently presented as key to improving the sustainability of food systems.2 Fish and seafood can have a lower environmental impact and in many cases are considered more efficient than terrestrial animal production (albeit with wide variation) depending on the type of production or capture method,3 yet remain largely absent, or insufficiently articulated in the sustainable diets literature, rendering their future role in healthy diets unclear.
Abstract 17320: Association of Loss-of-Function Mutation in SERPINE1 and Aging in Humans
Authors: Sadiya S Khan, Sanjiv J Shah, Ekaterina Klyachko, Abigail S Baldridge, Mesut Eren, Aaron T Place, Meadow Heiman, Sweta Gupta, Amy D Shapiro, Douglas E Vaughan
Journal: Circulation (2016)

Background: Plasminogen activator inhibitor-1 (PAI-1) is a key component of the senescence-related secretome and contributes to cellular senescence. Genetic deficiency and targeted inhibition of PA...
LGBTQ + and autism spectrum disorder: Experiences and challenges
Authors: Ashleigh Hillier, Nicholas Gallop, Eva Mendes, Dylan Tellez, Abigail Buckingham, Afreen Nizami, Derek OToole
Journal: International Journal of Transgender Health (2019)

Background: Research focused on gender identity, autism spectrum disorder (ASD), and the experiences of those who identify as LGBTQ+, remains minimal. Initial findings have indicated that those on the autism spectrum may be more likely to identify as homosexual and experience more fluid gender identity. Insufficient consideration has been given to intersectionality around a disability status and gender identity, and few have focused this conversation specifically on the experiences of those with ASD.Aim: The aim of this study was to improve current understanding of the first-hand experiences of those on the autism spectrum who identify as LGBTQ+, particularly regarding challenges stemming from these dual identities.Method: A focus group was conducted with four participants with ASD who presented with a range of gender identities (as they defined them) including male, transgender; agender/nonbinary; agender; and queer.Results: Qualitative analysis of the focus group transcription identified key themes: (1) Effect of Dual Identities: experiencing dual identities, autism spectrum, and LGBTQ+; (2) Multiple Minority Stressors: challenges experienced by the participants, the impact of discrimination/misunderstanding, and holding minority statuses; (3) Isolation: barriers caused by lack of understanding; (4) Lack of Service Provision.Discussion: These preliminary findings underline the need for better support, understanding, and practices regarding sexuality and gender identity among those on the autism spectrum. The current study is important for giving voice to adults on the autism spectrum who identify as LGBTQ+, and has implications for the disability community more broadly.
Abstract 87: Urinary LDH activities in patients with Kawasaki disease
Authors: Yoichi Kawamura, Takashi Kanai, Yuki Tsujita, Seiichiro Takeshita, Shigeaki Nonoyama
Journal: Circulation (2015)

Background: Kawasaki disease (KD) is a systemic vasculitis with unknown origin. KD patients often have leukocytes in urine as well as urinary tract infection (UTI). The aim of this study is to evaluate urinary LDH and its isozyme, which is useful in diagnosis with UTI, in patients with KD. Patients and methods: 158 patients with KD (including 4 with incomplete KD) and 52 patients with febrile sickness were enrolled as control group in this study. Urine samples were obtained at least one point. Results: Total level of urinary LDH in patients with KD was significantly higher than that in control group. Urinary LDH level in the acute phase was significantly higher than that with convalescent phase in patients with KD. Urinary LDH isozyme showed predominant elevations of LDH1 and LDH2. Some patients showed the elevation of urinary LDH level before the clinical criteria of KD were fulfilled. There was no correlation between urinary LDH concentration and pyuria. Conclusion: The levels of LDH isozyme (LDH4 and LDH5) in urine is known to increase in patients with acute upper urinary tract infection, while the level of its isozyme (LDH1 and LDH2) increased in acute phase of KD. The elevated levels of total urinary LDH and its isozyme (LDH1 and LDH2) may be useful for early diagnosis of KD and also for diagnosis of incomplete KD.
LGG-15. COMBINED SUPPRESSION OF THE MTOR AND MAPK PATHWAYS INHIBITS CELL PROLIFERATION AND DECREASES VASCULARITY IN PEDIATRIC LOW GRADE GLIOMA
Authors: Antje Arnold, Lauren Harris, Ming Yuan, Fausto Rodriguez, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2019)

Pediatric low-grade glioma (pLGG) is the most common brain tumor in children. We and others have identified constitutive activation of the mTOR and MEK-pathway in pLGG. This led us to investigate TAK228, a mTORC1/2-inhibitor, and the FDA approved MEK-inhibitor, trametinib, in mono- and combination therapy in pLGG. We examined antitumor activity in five patient-derived pLGG cell models treated with TAK228, trametinib, and combination: JHH_NF1_PA1NF1mut, BT66_SV40BRAF:KIAA1549, BT40BRAFV600E, Res186PTEN-/- and Res259CDKN2A-/-. In all cell lines, trametinib treatment led to suppression of phospho-ERK at low levels (1-5nM; Western Blot). TAK228 treatment led to inhibition of mTORC1/2 in low nanomolar range. Treatment with TAK228 or trametinib reduced cell proliferation in a dose and time dependent manner (MTS-assay). The combination treatment exerted a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells (Chou-Talay method). We tested trametinib and TAK228 against the mutant BT40BRAFV600E patient-derived xenograft cells in immunodeficient mice. Combination of TAK228 with trametinib showed greater antitumor activity than that of either mono-treatment in vivo. BT40 tumor growth was significantly decreased in combination compared to vehicle or either agent alone (p Our study provides evidence that pLGG-derived cell lines in vitro and in vivo are sensitive to mTORC1/2 kinase inhibition and MEK inhibition. Combination treatment with TAK228 and trametinib had a significant anti-tumor activity in vivo shown in survival rate, decreased tumor size, and reduced vascularity. These results provide a strong rationale for combination therapy with TAK228 and trametinib for clinical consideration in pLGG.
DIPG-01. THE IMPACT ON SURVIVAL BY THE H3K27M MUTATION IN PEDIATRIC HIGH GRADE GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Victor M Lu, Mohamad A Alvi, Kerrie McDonald, David J Daniels
Journal: Neuro-Oncology (2019)

OBJECTIVE: Pediatric high grade glioma (pHGG), including the diffuse intrinsic pontine glioma entity, present a prognostication challenge due to their lethality and rarity. A substitution mutation of lysine for methionine at position 27 in histone H3 (H3K27M) has been shown to be highly specific to these tumors. Data is accumulating regarding the poor outcomes of these tumors, however quantification of pooled outcomes remains lacking which can assist in prioritizing management. The aim of this study was to quantitatively pool the current literature regarding the H3K27M mutation as an independent prognostic factor in pHGG. METHODS: Searches of seven electronic databases from inception to March 2018 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted and pooled using meta-analysis of proportions. Meta-regression was used to identify potential sources of heterogeneity. RESULTS: Six observational studies satisfied the selection criteria for inclusion. They reported the survival outcomes of a pooled cohort of 474 pHGG patients, with 258 (54%) and 216 (46%) positive and negative for the H3K27M mutation respectively. Overall, the presence of the mutation was independently and significantly associated with worse prognosis (HR, 3.630; p<0.001). Overall survival was significantly shorter when the H3K27M mutation was present in pHGG by 2.300 years (p<0.001). Meta-regression did not identify any study covariates of heterogeneous concern. CONCLUSIONS: Based on the current literature, pHGG patients positive for the H3K27M mutation are more than 3 times susceptible to succumbing to this disease, by more than 2 years, compared to negative patients. More robust outcome data is required to improve our understanding of this pathological identity quantitatively to assist in prioritization of clinical management. Future larger, prospective, studies are required to overcome inherent biases in the current literature to validate the quantitative findings of this study.
DIPG-18. SONIC HEDGEHOG (SHH) SIGNALLING PROMOTES BLOOD BRAIN BARRIER (BBB) INTEGRITY IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Babu Sajesh, Ngoc On, Miller Donald, Colin Kazina, Demitre Serletis, Marc Del-Bigio, Sherry Krawitz, Esther Hulleman, Magimairajan Issai Vanan
Journal: Neuro-Oncology (2019)

DIPG is the most common brainstem tumor in children and is uniformly fatal. The BBB is intact in DIPG and plays an active role in restricting the delivery of systemically administered therapies into the tumor. Recent studies have shown that SHH signalling plays a major role in the maintenance of BBB integrity and this pathway is highly active in DIPG. We hypothesized that SHH signalling in DIPG plays a critical role in maintaining BBB integrity. Primary DIPG PDX (patient derived xenografts) secretes significantly higher quantities (~2-fold) of SHH compared to astrocytes and human brain microvascular endothelial cells (hBMVECs), (ELISA, P-value <0.0001). SHH and its pathway members were significantly higher in DIPG cells (>750-fold increase in mRNA) when compared to astrocytes or endothelial cells, (qRT-PCR, P-value <0.0001). Western blot analyses of PDX showed increased expression of SHH when compared to controls and was confirmed in a cohort of 5 postmortem tumor samples by immunohistochemistry. In vitro analyses showed that hBMVECs treated with DIPG tumor-conditioned media significantly increased trans-endothelial electrical impedance (TEER) and decreased permeability to both low (NaFl) and high molecular weight (IR dye PEG 800) compounds, suggesting increased barrier properties. These results were also corroborated using SHH pathway agonists, while the antagonists decreased TEER/permeability. We will present data of ongoing in vivo studies of BBB permeability in an orthotopic DIPG tumor model using PDX and SHH antagonists (Vismodegib, PF5274857 hydrochloride). Our results suggest that SHH pathway is integral to BBB integrity in DIPG tumors and pharmacological inhibition of the SHH pathway may disrupt the BBB and improve the delivery of therapeutic agents in the treatment of DIPG.
NEAR-FOCUS NBI CLASSIFICATION OF VILLOUS ATROPHY IN SUSPECTED COELIAC DISEASE: INTERNATIONAL DEVELOPMENT AND VALIDATION
Authors: S Gulati, A Emmanuel, P Pavlidis, M Patel, Z Vackova, V Sayer, T El Menabawey, S Plewa, P Dubois, J Martinek, H Neumann, A Haji, B Hayee
Journal: Endoscopy (2019)

To develop a reliable and validated endoscopic classification of villous atrophy in suspected coeliac disease using near focus Narrow Band Imaging (NF-NBI).
Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis
Authors: Kristen M. Gibson, Kimberly A. Morishita, Paul Dancey, Paul Moorehead, Britt Drögemöller, Xiaohua Han, Jinko Graham, Robert E. W. Hancock, Dirk Foell, Susanne Benseler, Rashid Luqmani, Rae S. M. Yeung, Susan Shenoi, Marek Bohm, Alan M. Rosenberg, Colin J. Ross, David A. Cabral, Kelly L. Brown
Journal: Arthritis & Rheumatology (2019)

Objective Individuals with deficiency of adenosine deaminase 2 ( DADA 2), a recently recognized autosomal recessive disease, present with various systemic vascular and inflammatory manifestations, often with young age at disease onset or with early onset of recurrent strokes. Their clinical features and histologic findings overlap with those of childhood‐onset polyarteritis nodosa ( PAN ), a primary “idiopathic” systemic vasculitis. Despite similar clinical presentation, individuals with DADA 2 may respond better to biologic therapy than to traditional immunosuppression. The aim of this study was to screen an international registry of children with systemic primary vasculitis for variants in ADA 2 . Methods The coding exons of ADA 2 were sequenced in 60 children and adolescents with a diagnosis of PAN , cutaneous PAN , or unclassifiable vasculitis ( UCV ), any chronic vasculitis with onset at age 5 years or younger, or history of stroke. The functional consequences of the identified variants were assessed by ADA 2 enzyme assay and immunoblotting. Results Nine children with DADA 2 (5 with PAN , 3 with UCV , and 1 with antineutrophil cytoplasmic antibody–associated vasculitis) were identified. Among them, 1 patient had no rare variants in the coding region of ADA 2 and 8 had biallelic, rare variants (minor allele frequency &lt;0.01) with a known association with DADA 2 (p.Gly47Arg and p.Gly47Ala) or a novel association (p.Arg9Trp, p.Leu351Gln, and p.Ala357Thr). The clinical phenotype varied widely. Conclusion These findings support previous observations indicating that DADA 2 has extensive genotypic and phenotypic variability. Thus, screening ADA 2 among children with vasculitic rash, UCV , PAN , or unexplained, early‐onset central nervous system disease with systemic inflammation may enable an earlier diagnosis of DADA 2.
Architectural Modification of Conformal PEG‐Bottlebrush Coatings Minimizes Anti‐PEG Antigenicity While Preserving Stealth Properties
Authors: Daniel Y. Joh, Zackary Zimmers, Manav Avlani, Jacob T. Heggestad, Hakan B. Aydin, Nancy Ganson, Shourya Kumar, Cassio M. Fontes, Rohan K. Achar, Michael S. Hershfield, Angus M. Hucknall, Ashutosh Chilkoti
Journal: Advanced Healthcare Materials (2019)

Poly(ethylene glycol) (PEG), a linear polymer known for its "stealth" properties, is commonly used to passivate the surface of biomedical implants and devices, and it is conjugated to biologic drugs to improve their pharmacokinetics. However, its antigenicity is a growing concern. Here, the antigenicity of PEG is investigated when assembled in a poly(oligoethylene glycol) methacrylate (POEGMA) "bottlebrush" configuration on a planar surface. Using ethylene glycol (EG) repeat lengths of the POEGMA sidechains as a tunable parameter for optimization, POEGMA brushes with sidechain lengths of two and three EG repeats are identified as the optimal polymer architecture to minimize binding of anti-PEG antibodies (APAs), while retaining resistance to nonspecific binding by bovine serum albumin and cultured cells. Binding of backbone- versus endgroup-selective APAs to POEGMA brushes is further investigated, and finally the antigenicity of POEGMA coatings is assessed against APA-positive clinical plasma samples. These results are applied toward fabricating immunoassays on POEGMA surfaces with minimal reactivity toward APAs while retaining a low limit-of-detection for the analyte. Taken together, these results offer useful design concepts to reduce the antigenicity of polymer brush-based surface coatings used in applications involving human or animal matrices.
HGG-18. ALTERNATIVE SPLICING OF NEUROFIBROMIN 1 IS ASSOCIATED WITH ELEVATED MAPK ACTIVITY AND POOR PROGNOSIS IN HIGH-GRADE GLIOMA
Authors: Robert Siddaway, Scott Milos, Arun Ramani, Man Yu, Scott Ryall, Christopher Li, Michael Brudno, Cynthia Hawkins
Journal: Neuro-Oncology (2019)

Pediatric high-grade gliomas (pHGG) are invasive tumors with poor prognosis. In particular, diffuse intrinsic pontine glioma (DIPG), arising in the brainstem, is incurable and the leading cause of brain-tumor death in children. Previous genomic studies have uncovered many driving mutations of pHGG, including frequent activating alterations of the RAS/MAPK/PI3K pathway. Here we performed RNA-Seq analysis on a large sample of pHGG (n=63) and normal brain (n=20), finding that, regardless of mutation status, RAS pathway activation was near universal. To try to understand the mechanism behind this, we focussed on alternative splicing, finding a network of alterations converging on the RAS pathway. One of the most significantly spliced genes was neurofibromin 1 (NF1), which switches from the NF1-I transcript in normal brain to NF1-II in pHGG. NF1-II splices the 21 aa exon23a into the GAP-related domain of NF1, rendering NF1 10 times less active in inhibiting RAS thus elevating MAPK signaling. Increased exon23a inclusion was associated with increased RAS activity. The same pattern was seen in adult glioma, where exon23a inclusion was associated with worse patient outcome independent of RAS pathway mutation. Exon23a splicing is regulated by the CELF and ELAV-like families of splice regulators, which are highly downregulated in pHGG leading to increased NF1-II levels. Together, our results identify a novel mechanism by which HGG can activate RAS signaling and promote tumorigenesis independently from mutations.
Appropriate treatment modality for solitary small hepatocellular carcinoma: Radiofrequency ablation vs. resection vs. transplantation?
Authors: Keun Soo Ahn, Koo Jeong Kang
Journal: Clinical and Molecular Hepatology (2019)

There has been controversy regarding the first-line treatment modality for the patients who have small solitary hepatocellular carcinoma (HCC); radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI), surgical hepatic resection (HR) and liver transplantation (LT). For selection of treatment modality of HCC, it should be considered of hepatic reservoir function as well as the tumor stage. If the liver function is good enough, HR may be the first choice regardless of the tumor size. However, recent studies comparing RFA with resection showed comparable outcome and similar survival rates. RFA, HR and LT provide good outcome for patients who have small HCCs. RFA would be desired in patients who have below 3.0 cm in size and low alpha-fetoprotein (<200 ng/mL). However, in small HCC with high tumor marker, HR should be considered. Better patient selection for the 'resection first' approach and early detection of recurrence can achieve better outcomes of the salvage LT strategy. Another benefit of resection first strategy is that it make possible to do enlist of LT for patients before recurrence at high risk of HCC recurrence after resection on the basis of pathologic aggressiveness, microvascular invasion and/or satellites nodule. They should be applied appropriately according to the tumor size, location, tumor markers and underlying liver parenchymal disease.
Маастрихтський консенсус-5: аналітичний огляд положень
Authors: Yu.M. Stepanov, I.Ya. Budzak
Journal: GASTROENTEROLOGY (2017)

У даній статті проаналізовано положення Ма­астрихтського консенсусу-5 з вивчення H. pylori-інфекції. Показано, як змінювались уяви щодо діагностики та лікування хелікобактерної інфекції в попередніх Маастрихтських консенсусах. Підкреслено, що сьогодні хелікобактерний гастрит вважається інфекційним захворюванням. Окремо розглянуто питання взаємозв’язку цієї інфекції з патологією гастродуоденальної зони, включаючи функціональну диспепсію, НПЗП-гастропатії та інші. Показані сучасні підходи до діагностики хелікобактеріозу з визначенням вибору найбільш оптимального методу діагностики в різних ситуаціях. Окремо розібрані підходи до антихелікобактерної терапії. Зроблено акцент на залежності сучасних схем терапії хелікобактеріозу від ступеня резистентності H. pylori до ключових антибіотиків. Підтверджена важливість ерадикації H. pylori щодо профілактики передракових змін шлунка. Показано зростаючий інтерес дослідників до нехелікобактерної флори в шлунку. Розглянута важлива роль пробіотиків в антихелікобактерній терапії.
Long‐Term Outcome of Ustekinumab Therapy for Behçet's Disease
Authors: Adrien Mirouse, Stéphane Barete, Anne‐Claire Desbois, Cloé Comarmond, Damien Sène, Fanny Domont, Bahram Bodaghi, Yasmina Ferfar, Patrice Cacoub, David Saadoun
Journal: Arthritis & Rheumatology (2019)

Oral ulcers, the hallmark lesion of Behçet's disease (BD), can be disabling and resistant to conventional treatment, and there is a need for safe and effective treatment. We undertook this study to investigate the long-term safety and efficacy of ustekinumab therapy for BD-related oral ulcers that are resistant to colchicine.This multicenter, prospective, open-label study included 30 patients who fulfilled the criteria of the International Study Group for BD and who were diagnosed as having active oral ulcers resistant to colchicine. Patients were treated subcutaneously with ustekinumab 90 mg at inclusion, at week 4, and then once every 12 weeks. Each patient was assessed longitudinally for the presence and number of oral ulcers, and median numbers of oral ulcers (with interquartile range [IQR]) were calculated. The primary efficacy end point was the proportion of patients at week 12 who experienced complete response, defined as having no oral ulcers.The median number of oral ulcers per patient during ustekinumab therapy was significantly lower at week 12 compared to baseline (0 [IQR 0-1] versus 2 [IQR 2-3]; P < 0.0001). Complete response was achieved in 60.0% and 88.9% of patients at weeks 12 and 24, respectively. The median Behçet's Syndrome Activity Score (in which higher scores indicate more active disease) was significantly lower at weeks 12 and 24 (17.5 [IQR 10-42.5] and 10 [IQR 8-11], respectively) versus baseline (70 [IQR 50-70]; P < 0.0001). After a median follow-up of 12 months (IQR 6-16 months), 26 patients (86.7%) were still receiving ustekinumab treatment. Reasons for ustekinumab discontinuation included BD flare (n = 3) and side effects (n = 1). Seven patients (23.3%) experienced adverse events, including headaches (n = 4) and asthenia (n = 2), with no serious side effects.Ustekinumab seems to be effective in treating BD-related oral ulcers that are resistant to treatment with colchicine.