tbuckley/cabot-search huggingface dataset:
BSTM-04. NEURONAL-ACTIVITY SECRETED BDNF INCREASES DIPG PROLIFERATION.
Authors: Kathryn Taylor, Razina Aziz-Bose, Ariane Blank, Anna Geraghty, Michelle Monje
Journal: Neuro-Oncology (2019)

Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that critically require novel therapeutic options. We have previously demonstrated that pHGG hijacks mechanisms of brain development and plasticity to their advantage. One key process, neuronal activity, robustly drives proliferation of pHGG via the secretion of the synaptic protein neuroligin-3 (NLGN3) and the neurotrophin brain-derived neurotrophic factor (BDNF) into the tumor microenvironment. Diffuse intrinsic pontine gliomas (DIPG) exhibit copy-number gain of neurotrophin receptor genes in a substantial fraction of cases (71/239, 29% cases with NTRK1, NTRK2 or NTRK3 gain/amplification), and primary DIPG tumor RNA-Seq confirms expression of the canonical BDNF receptor TrkB. Here, we investigated the role of microenvironmental BDNF on DIPG, independent of the NTRK fusion events commonly identified in infant HGG. We found spatio-temporal patterns of BDNF expression in normal brain during the postnatal developmental period that highlight this growth factor as particularly relevant to childhood gliomas. Conditioned media (CM) collected from optogenetically stimulated acute cortical slices robustly increases patient-derived DIPG cell proliferation, an effect that is abrogated with CM collected from mice deficient of activity-regulated BDNF expression. The BDNF ligand increases patient-derived DIPG cell proliferation and activates the canonical downstream MAPK signaling pathway. CRISPR deletion of the TrkB receptor, NTRK2, in DIPG cells abrogates the proliferative response to BDNF ligand exposure and subsequent p42/44 MAPK pathway activation. We are currently testing the in vivo growth potential of TrkB-deficient DIPG xenografts and the therapeutic potential of pharmacological TrkB antagonists. Disrupting DIPG responses to microenvironmental cues may highlight tumor dependencies and elucidate effective combinatorial therapeutic strategies. Funding: Abbie's Army Foundation
Improvements in air quality: whose lungs benefit?
Authors: Ulrike Gehring, Gerard H. Koppelman
Journal: European Respiratory Journal (2019)

Exposure to ambient air pollution is a major contributor to the global burden of disease, and is associated with increased risk of mortality and morbidity, in particular from pulmonary and cardiovascular diseases [1, 2]. The health effects of air pollution have been intensively studied during the past decades. Acute effects have been demonstrated by short-term studies linking day-to-day variation in air pollution to day-to-day variation in health; chronic effects have been shown in long-term cohort studies following subjects with different levels of exposure over time [3]. The benefits of improved air quality extend across the life span into the elderly population <http://ow.ly/Pi9q30o6M8o>
Abstract 11607: Association of Systolic Blood Pressure With Subclinical Atherosclerosis and Cardiovascular Disease Events in the Absence of Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis
Authors: Seamus P Whelton, John W McEvoy, Leslee Shaw, Bruce Psaty, Joao Lima, Matthew Budoff, Khurram Nasir, Moyses Szklo, Roger Blumenthal, Michael Blaha
Journal: Circulation (2018)

Introduction: The association of systolic blood pressure (SBP) with subclinical atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) is uncertain among healthy individuals without oth...
Pathophysiology of pachyonychia congenita‐associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment
Authors: A.G. Zieman, P.A. Coulombe
Journal: British Journal of Dermatology (2019)

Pachyonychia congenita (PC), a rare genodermatosis, primarily affects ectoderm‐derived epithelial appendages and typically includes oral leukokeratosis, nail dystrophy and very painful palmoplantar keratoderma (PPK). PC dramatically impacts quality of life although it does not affect lifespan. PC can arise from mutations in any of the wound‐repair‐associated keratin genes KRT6A, KRT6B, KRT6C, KRT16 or KRT17. There is no cure for this condition, and current treatment options for PC symptoms are limited and palliative in nature. This review focuses on recent progress made towards understanding the pathophysiology of PPK lesions, the most prevalent and debilitating of all PC symptoms. We reviewed the relevant literature with a particular focus on the Krt16 null mouse, which spontaneously develops footpad lesions that mimic several aspects of PC‐associated PPK. There are three main stages of progression of PPK‐like lesions in Krt16 null mice. Ahead of lesion onset, keratinocytes in the palmoplantar (footpad) skin exhibit specific defects in terminal differentiation, including loss of Krt9 expression. At the time of PPK onset, there is elevated oxidative stress and hypoactive Keap1–Nrf2 signalling. During active PPK, there is a profound defect in the ability of the epidermis to maintain or return to normal homeostasis. The progress made suggests new avenues to explore for the treatment of PC‐based PPK and deepens our understanding of the mechanisms controlling skin tissue homeostasis. What's already known about this topic? Pachyonychia congenita (PC) is a rare genodermatosis caused by mutations in KRT6A, KRT6B, KRT6C, KRT16 and KRT17, which are normally expressed in skin appendages and induced following injury. Individuals with PC present with multiple clinical symptoms that usually include thickened and dystrophic nails, palmoplantar keratoderma (PPK), glandular cysts and oral leukokeratosis. The study of PC pathophysiology is made challenging because of its low incidence and high complexity. There is no cure or effective treatment for PC. What does this study add? This text reviews recent progress made when studying the pathophysiology of PPK associated with PC. This recent progress points to new possibilities for devising effective therapeutics that may complement current palliative strategies.
Post Hoc Bayesian Analyses
Authors: Scott K. Aberegg
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Sarcopenia: Ammonia metabolism and hepatic encephalopathy
Authors: Ankur Jindal, Rakesh Kumar Jagdish
Journal: Clinical and Molecular Hepatology (2019)

Sarcopenia (loss of muscle mass and/or strength) frequently complicates liver cirrhosis and adversely affects the quality of life; cirrhosis related liver decompensation and significantly decreases wait-list and post-liver transplantation survival. The main therapeutic strategies to improve or reverse sarcopenia include dietary interventions (supplemental calorie and protein intake), increased physical activity (supervised resistance and endurance exercises), hormonal therapy (testosterone), and ammonia lowering agents (L-ornithine L-aspartate, branch chain amino acids) as well as mechanistic approaches that target underlying molecular and metabolic abnormalities. Besides other factors, hyperammonemia has recently gained attention and increase sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Sarcopenia contributes to frailty and increases the risk of minimal and overt hepatic encephalopathy.
Prospective Comparative Evaluation of Flow Cytometric Scores Regarding the Sensitivity and Specificity As Well As Prognosis in 616 Patients with Proven or Suspected MDS
Authors: Uta Oelschlaegel, Lorenz Oelschlaeger, Brigitte Mohr, Katja Sockel, Martin Bornhäuser, Uwe Platzbecker
Journal: Blood (2018)
Changes in the prevalence of asthma and respiratory symptoms in western Sweden between 2008 and 2016
Authors: Eivind Borna, Bright I. Nwaru, Anders Bjerg, Roxana Mincheva, Madeleine Rådinger, Bo Lundbäck, Linda Ekerljung
Journal: Allergy (2019)

Abstract Background Asthma is a common chronic inflammatory disease of the airways, with a noticeable increase in prevalence during the second half of the 20th century. Recent studies assessing the prevalence trends among adults have been inconsistent. We investigated the changes in the prevalence of asthma, respiratory symptoms, and risk factors between 2008 and 2016 in western Sweden. Methods The West Sweden Asthma Study (WSAS) is a population‐based study which started in 2008 (WSAS I) and then repeated in 2016 (WSAS II) in western Sweden. Randomly selected individuals aged 16‐75 years (N = 18 087 in 2008 and N = 24 534 in 2016) completed a questionnaire regarding obstructive lung diseases, respiratory symptoms, potential risk factors, and also questions from the GA 2 LEN survey. Results The prevalence of reported ever asthma, physician‐diagnosed asthma, use of asthma medication, and current asthma increased significantly from 9.6% to 11%, 8.3% to 10%, 8.6% to 9.8%, and 8.1% to 9.1%, respectively, between 2008 and 2016. There were also increases in the prevalence of respiratory symptoms during the same period. The greatest increase occurred in young adults aged 16‐25 years. Female gender, allergic rhinitis, obesity, and family history of asthma remained the strongest risk factors for asthma in 2016 as it was in 2008. Conclusion There were moderate increases in asthma and respiratory symptoms in adults in western Sweden between 2008 and 2016, the greatest increase occurring in younger adults. The potential risk factors for asthma remained the same during the study period.
LGG-01. BRAF V600E MUTANT OLIGODENDROGLIOMA-LIKE TUMORS WITH CHROMOSOMAL INSTABILITY IN ADOLESCENT AND YOUNG ADULT
Authors: Kohei Fukuoka, Mamatjan Yashin, Scott Ryall, Martin Komosa, Julie Benett, Michal Zapotocky, Julia Keith, Sten Myrehaug, Lili-Naz Hazrati, Kenneth Aldape, Norm Laperriere, Eric Bouffet, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2019)

We performed genome-wide methylation analysis on 136 pediatric low grade gliomas, identifying a unique cluster consisting of BRAF V600E mutant tumors with chromosomal instability, including gain of Chromosome 7 and loss of Chromosome 10. The tumors were all located in the temporal lobe. Patients presented between 10 and 36 years of age, most with a history of seizures. All patients are alive with no recurrence, three with longer-term follow-up (3.2 to 13.2 years). Microscopically, all showed oligodendroglioma-like features, including round nuclei with perinuclear halos, a chicken-wire pattern of branching capillaries and microcalcification. None showed astrocytic features or characteristics suggestive of high-grade tumors including necrosis or mitotic figures. Copy number analysis showed whole chromosomal copy number abnormalities in more than 10 chromosomes in each case, however none showed 1p/19q co-deletion. IDH1 was wild-type in all cases and one showed a TERT promoter mutation. Although the series is small, these cases demonstrate a new category of IDH wild-type low grade gliomas which may be confused with “molecular GBM”. Further, they highlight the heterogeneity of IDH wild-type gliomas and the relatively indolent behavior of “pediatric-type” gliomas.
On the Association Between Fluoroquinolones and Neuropathy
Authors: Nathan P. Staff, P. James B. Dyck
Journal: JAMA Neurology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Prognostic value of circulating tumour cells in limited-stage small-cell lung cancer: analysis of the concurrent once-daily versus twice-daily radiotherapy (CONVERT) randomised controlled trial
Authors: R.Y. Tay, F. Fernández-Gutiérrez, V. Foy, K. Burns, J. Pierce, K. Morris, L. Priest, J. Tugwood, L. Ashcroft, C.R. Lindsay, C. Faivre-Finn, C. Dive, F. Blackhall
Journal: Annals of Oncology (2019)

BackgroundThe clinical significance of circulating tumour cells (CTCs) in limited-stage small-cell lung cancer (LS-SCLC) is not well defined. We report a planned exploratory analysis of the prevalence and prognostic value of CTCs in LS-SCLC patients enrolled within the phase III randomised CONVERT (concurrent once-daily versus twice-daily chemoradiotherapy) trial.Patients and methodsBaseline blood samples were enumerated for CTCs using CellSearch in 75 patients with LS-SCLC who were enrolled in the CONVERT trial and randomised between twice- and once-daily concurrent chemoradiation. Standard statistical methods were used for correlations of CTCs with clinical factors. Log-rank test and Cox regression analyses were applied to establish the associations of 2, 15 and 50 CTC thresholds with progression-free survival (PFS) and overall survival (OS). An optimal CTC count threshold for LS-SCLC was established.ResultsCTCs were detected in 60% (45/75) of patients (range 0–3750). CTC count thresholds of 2, 15 and 50 CTCs all significantly correlate with PFS and OS. An optimal CTC count threshold in LS-SCLC was established at 15 CTCs, defining 'favourable' and 'unfavourable' prognostic risk groups. The median OS in <15 versus ≥15 CTCs was 26.7 versus 5.9 m (P = 0.001). The presence of ≥15 CTCs at baseline independently predicted ≤1 year survival in 70% and ≤2 years survival in 100% of patients.ConclusionWe report the prognostic value of baseline CTC count in an exclusive LS-SCLC population at thresholds of 2, 15 and 50 CTCs. Specific to LS-SCLC, ≥15 CTCs was associated with worse PFS and OS independent of all other factors and predicted ≤2 years survival. These results may improve disease stratification in future clinical trial designs and aid clinical decision making.Trial registrationClinicalTrials.gov identifier: NCT00433563.
Long-Term Drug Therapy and Drug Discontinuations and Holidays for Osteoporosis Fracture Prevention
Authors: Howard A. Fink, Roderick MacDonald, Mary L. Forte, Christina E. Rosebush, Kristine E. Ensrud, John T. Schousboe, Victoria A. Nelson, Kristen Ullman, Mary Butler, Carin M. Olson, Brent C. Taylor, Michelle Brasure, Timothy J. Wilt
Journal: Annals of Internal Medicine (2019)

Background: Optimal long-term osteoporosis drug treatment (ODT) is uncertain. Purpose: To summarize the effects of long-term ODT and ODT discontinuation and holidays. Data Sources: Electronic bibliographic databases (January 1995 to October 2018) and systematic review bibliographies. Study Selection: 48 studies that enrolled men or postmenopausal women aged 50 years or older who were being investigated or treated for fracture prevention, compared long-term ODT (>3 years) versus control or ODT continuation versus discontinuation, reported incident fractures (for trials) or harms (for trials and observational studies), and had low or medium risk of bias (ROB). Data Extraction: Two reviewers independently rated ROB and strength of evidence (SOE). One extracted data; another verified accuracy. Data Synthesis: Thirty-five trials (9 unique studies) and 13 observational studies (11 unique studies) had low or medium ROB. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate SOE), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate SOE). Long-term bisphosphonates increased risk for 2 rare harms: atypical femoral fractures (low SOE) and osteonecrosis of the jaw (mostly low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapy reduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms. After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE). Limitation: No trials studied men, clinical fracture data were sparse, methods for estimating harms were heterogeneous, and no trials compared sequential treatments or different durations of drug holidays. Conclusion: Long-term alendronate and zoledronic acid therapies reduce fracture risk in women with osteoporosis. Long-term bisphosphonate treatment may increase risk for rare adverse events, and continuing treatment beyond 3 to 5 years may reduce risk for vertebral fractures. Long-term hormone therapy reduces hip fracture risks but has serious harms. Primary Funding Source: National Institutes of Health and Agency for Healthcare Research and Quality. (PROSPERO: CRD42018087006)
Treatment of moderate‐to‐severe atopic dermatitis with dupilumab in real clinical practice: a multicentre, retrospective case series
Authors: J.C. Armario‐Hita, J. Pereyra‐Rodriguez, J.F. Silvestre, R. Ruiz‐Villaverde, A. Valero, R. Izu‐Belloso, I. Jáuregui‐Presa, L. Curto‐Barredo, I. Figueras‐Nart, P. Herranz‐Pinto, L. Herraez‐Herrera, F.J. Ortiz‐de‐Frutos, L. Martinez‐Pilar, J. Sastre, E. Serra‐Baldrich
Journal: British Journal of Dermatology (2019)
DIPG-03. TARGETING PI3K USING THE BLOOD BRAIN BARRIER PENETRABLE INHIBITOR, GDC-0084, FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Ryan Duchatel, Evangeline Jackson, Adjanie Patabendige, Jason Cain, Maria Tsoli, Michelle Monje, Frank Alvaro, David Ziegler, Matthew Dun
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND: Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating, incurable childhood brain cancer. 80% of patients harbour a genetic lesion to Histone-H3 with a substitution of lysine 27 for a methionine (K27M) (H3F3A/H3.3 and HIST1H3B/H3.1) which results in the loss of methylation, interfering with chromatin function, activating oncogenic transcription. Unfortunately, H3 mutations are not directly targetable. RTK-RAS-PI3Kpathway alterations occur in more than half of these patients (69%), and may represent a more promising therapeutic target. However, PI3K inhibitors have been notoriously ineffective due to their inability to cross the blood-brain-barrier (BBB). Targeting downstream components of the PI3K-AKT-mTOR signalling axis is a promising paradigm for PI3K mutant patients. This project aims to overcome the limitations of targeting downstream effectors of the PI3K pathway by utilising a novel PIK3CA specific, BBB permeable inhibitor, GDC-0084, currently in clinical trials for Glioblastoma (GBM) and DIPG. METHODS: Utilising DIPG patient derived (PDX) cells harboringH3K27M mutations (n=6), and +/- PI3Kmutations, we examined the in-vitroefficacy of GDC-0084 on cell proliferation compared to Rapamycin. Phosphoproteomic profiling is currently underway investigating the role GDC-0084 has on inhibition of downstream oncogenic signalling pathways. Assessment of efficacy in a PDX in-vivo model is currently in progress. RESULTS: GDC-0084 significantly reduced the growth of all DIPG cell lines regardless of whether they harboredPI3K mutations (p=&amp;lt;0.001), and were significantly more cytotoxic than the mTORC1 inhibitor Rapamycin (p=&amp;lt;0.01). DIPG cell lines were also more sensitive to PI3K inhibition by GDC-0084 compared to GBM cell lines (n=4, p=&amp;lt;0.001) highlighting the therapeutic potential of GDC-0084 for the treatment of DIPG. Combining GDC-0084 and Vandetanib in DIPG revealed synergistic effects. CONCLUSIONS: While there are currently no therapeutics effective against the transcriptional programs elicited by H3 mutations, these studies re-ignite the potential for PI3K inhibition as a therapeutic target for DIPG.