tbuckley/cabot-search huggingface dataset:
Impact of intranasal fentanyl in nurse initiated protocols for sickle cell vaso‐occlusive pain episodes in a pediatric emergency department
Authors: Bolanle Akinsola, Robert Hagbom, April Zmitrovich, Patricia L. Kavanagh, Ashley Ashkouti, Harold K Simon, Alesia Fleming, Shabnam Jain, Carlton Dampier, Claudia R. Morris
Journal: American Journal of Hematology (2018)
A phase 1b/2 study of ibrutinib combination therapy in selected advanced genitourinary and gastrointestinal tumors.
Authors: Jordan Berlin, Edwin M. Posadas, Teresa Mercade Macarulla, Alex Cacovean, Karl Eckert, Brian Munneke, George W. Cole, Danelle Frances James, Robert J. Motzer
Journal: Journal of Clinical Oncology (2016)

TPS2600 Background: For patients with advanced genitourinary (GU) and gastrointestinal (GI) tumors, effective treatment options are limited. Ibrutinib (ibr) is a first-in-class, covalent inhibitor of Bruton’s tyrosine kinase (BTK), as well as a covalent inhibitor of other relevant kinases in solid tumor development pathways. In solid tumor models, ibr exhibited direct antitumor effects and enhanced the effects of other anticancer agents (Masso-Valles, Cancer Res 2015; Sagiv-Barfi, PNAS 2015; Chen, AACR-NCI-EORTC 2015, Gunderson Cancer Disc 2015). Preclinical models suggest that inhibition of BTK and interleukin-2–inducible kinase (ITK) may have efficacy by targeting the tumor microenvironment, which is composed of MAST cells, B cells, and other tumor-infiltrating leukocytes. Based on these preclinical results, we propose that ibr in combination with existing therapies may offer increased efficacy without overlapping toxicity in select solid tumors (Chanan-Khan, ASCO 2015). This study will evaluate ibr in combination with available effective therapies in patients with previously treated GU and GI tumors. Methods: This open-label, phase 1b/2 multicenter study (NCT02599324; PCYC-1128) will evaluate ibr in combination with existing therapies in up to 189 patients who have either metastatic renal cell carcinoma (RCC), advanced urothelial carcinoma (UC), advanced gastric adenocarcinoma (GA), or metastatic colorectal adenocarcinoma (CRC). All patients will receive oral ibr; patients will also receive oral everolimus for RCC; IV paclitaxel for UC; IV docetaxel for GA or IV cetuximab for CRC. The primary objective of phase 1b is to determine the safety of the combinations and establish the recommended phase 2 dose of ibr. The objectives of phase 2 are to determine overall response rate, progression-free and overall survival, and disease control rate, and to assess biomarkers. Eligible patients will have adequate hematologic, hepatic, and renal function, no prior treatment with study drugs or related agents, and no known CNS metastasis. Enrollment in the study has been initiated in the United States and European Union. Results: N/A Conclusions: N/A Clinical trial information: NCT02599324.
Paediatric mastocytosis: long-term follow-up of 53 patients with whole sequencing of<i>KIT</i>. A prospective study
Authors: C. Meni, S. Georgin-Lavialle, L. Le Saché de Peufeilhoux, J.P. Jais, S. Hadj-Rabia, J. Bruneau, S. Fraitag, K. Hanssens, P. Dubreuil, O. Hermine, C. Bodemer
Journal: British Journal of Dermatology (2018)

Mastocytosis is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells. The adult and paediatric forms differ in their clinical and genetic features and outcomes.To describe the clinical evolution of a well-characterized cohort of paediatric mastocytosis (PM), and to analyse the relationship between KIT mutation and the clinical course.This was a prospective cohort study performed at the National Clinical Reference Center for Mastocytosis. Diagnosis was confirmed by identification of KIT mutation on lesional skin biopsy. Mastocytosis subtype, mast cell mediator-related symptoms (MC MRS) and clinical course were recorded. Fifty-three patients with PM and > 4 years of disease course were enrolled. The mean ± SD age at the final evaluation was 13·2 ± 4·8 years. The main outcome was the type of KIT mutation as a predictor of evolution and clinical characteristics.Patients presented with maculopapular cutaneous mastocytosis (n = 44), diffuse cutaneous mastocytosis (n = 6) or mastocytoma (n = 3). The mean duration of disease was 12·1 years. Substantial or partial cutaneous regression (18 of 53 and 16 of 53), stabilization or aggravation (16 of 53) and complete cutaneous regression (three of 53) were noted. MC MRS mainly regressed (21 of 53). For 22 patients, evolution of MC MRS and evolution of cutaneous lesions were different. No significant association between evolution and KIT mutation or between evolution and type of cutaneous mastocytosis was found. A late onset of the disease (after 2 years) is associated with worse evolution.PM is not systematically self-regressive. MC MRS manifestations and cutaneous lesions can persist or increase overtime. KIT mutation is not a predictor of evolution.
Comorbid science?
Authors: David Danks, Stephen Fancsali, Clark Glymour, Richard Scheines
Journal: Behavioral and Brain Sciences (2010)

Abstract We agree with Cramer et al.'s goal of the discovery of causal relationships, but we argue that the authors' characterization of latent variable models (as deployed for such purposes) overlooks a wealth of extant possibilities. We provide a preliminary analysis of their data, using existing algorithms for causal inference and for the specification of latent variable models.
Nurse-Led Communication in the Intensive Care Unit
Authors: Daniela Lamas
Journal: New England Journal of Medicine (2018)

We examine him each day — the elderly patient, intubated, sedated, with a bewildered wife at his bedside. We should sit down with his wife before we ask her to make hard decisions about her husband's care, but the unit is so busy that we find ourselves scurrying by, pausing only to offer rushed updates that do not allow for the exchange of meaningful information. This is a familiar scenario. Approximately one in five people in the United States dies in the intensive care . . .
Is methotrexate an effective and safe treatment for maintaining hair regrowth in people with alopecia totalis? A Critically Appraised Topic
Authors: R. Browne, L. Stewart, H.C. Williams
Journal: British Journal of Dermatology (2018)

Is methotrexate (MTX) an effective and safe treatment for maintaining hair regrowth in people with alopecia totalis?Alopecia areata (AA) is a common disorder causing nonscarring hair loss with an estimated lifetime prevalence of approximately 2%. Treatment of extensive AA is challenging. The aim of this Critically Appraised Topic was to assess the current evidence regarding use of MTX for inducing and maintaining hair growth in patients with alopecia totalis.We critically appraised the literature identified from searching PubMed, Ovid MEDLINE, Ovid Embase and Cochrane Central (October 2017), using the search terms ("alopecia areata" OR "alopecia totalis" OR "alopecia universalis") AND (methotrexate).Two prospective studies and 11 retrospective case series were included, comprising 226 patients with alopecia varying from 30% hair loss to alopecia universalis at baseline. MTX was usually given with systemic corticosteroids for induction of hair regrowth rather than regrowth maintenance. Regrowth, defined as anything from 50% to complete regrowth, was reported in 20-90% of patients. Relapse occurred in 20-80%, with variable regrowth on retreatment. Most series were small, with limited methodological detail and follow-up data. Adverse effects ranged from 7% to 60%.We found insufficient evidence to conclude whether MTX is useful for maintaining regrowth in extensive AA. We found some evidence to suggest that hair regrowth may be induced by MTX when used in combination with systemic corticosteroids, but it was difficult to attribute responses to any one treatment or spontaneous regrowth. Included case series were at a high risk of bias. Randomized controlled trials are needed to evaluate whether MTX alone, or in combination with corticosteroids, vs. placebo is useful for inducing and/or maintaining remission of hair regrowth. In the meantime, MTX may occasionally be considered in people with severe disease that significantly impacts on their quality of life.
Immunogenicity and reactogenicity of high- vs. standard-dose trivalent inactivated influenza vaccine in healthcare workers: a pilot randomized controlled trial
Authors: C. Volling, B.L. Coleman, K. Katz, A.E. Simor, M. Muller, J. Powis, J. McElhaney, A. McGeer
Journal: Clinical Microbiology and Infection (2018)
A study of the focal adhesion kinase inhibitor GSK2256098 in patients with recurrent glioblastoma with evaluation of tumor penetration of [11C]GSK2256098
Authors: Nicholas F Brown, Matthew Williams, Hendrik-Tobias Arkenau, Ronald A Fleming, Jerry Tolson, Li Yan, Jianping Zhang, Rajendra Singh, Kurt R Auger, Laurie Lenox, David Cox, Yvonne Lewis, Christophe Plisson, Graham Searle, Azeem Saleem, Sarah Blagden, Paul Mulholland
Journal: Neuro-Oncology (2018)

GSK2256098 is a novel oral focal adhesion kinase (FAK) inhibitor. Preclinical studies demonstrate growth inhibition in glioblastoma cell lines. However, rodent studies indicate limited blood–brain barrier (BBB) penetration. In this expansion cohort within a phase I study, the safety, tolerability, pharmacokinetics (PK), and clinical activity of GSK2256098 were evaluated in patients with recurrent glioblastoma. Biodistribution and kinetics of [11C]GSK2256098 were assessed in a substudy using positron-emission tomography (PET). Patients were treated with GSK2256098 until disease progression or withdrawal due to adverse events (AEs). Serial PK samples were collected on day 1. On a single day between days 9 and 20, patients received a microdose of intravenous [11C]GSK2256098 and were scanned with PET over 90 minutes with parallel PK sample collection. Response was assessed by MRI every 6 weeks. Thirteen patients were treated in 3 dose cohorts (1000 mg, 750 mg, 500 mg; all dosed twice daily). The maximum tolerated dose was 1000 mg twice daily. Dose-limiting toxicities were related to cerebral edema. Treatment-related AEs (>25%) were diarrhea, fatigue, and nausea. Eight patients participated in the PET substudy, with [11C]GSK2256098 VT (volume of distribution) estimates of 0.9 in tumor tissue, 0.5 in surrounding T2 enhancing areas, and 0.4 in normal brain. Best response of stable disease was observed in 3 patients, including 1 patient on treatment for 11.3 months. GSK2256098 was tolerable in patients with relapsed glioblastoma. GSK2256098 crossed the BBB at low levels into normal brain, but at markedly higher levels into tumor, consistent with tumor-associated BBB disruption. Additional clinical trials of GSK2256098 are ongoing.
Lung-Resident Mesenchymal Stromal Cells Reveal Transcriptional Dynamics of Lung Development in Preterm Infants
Authors: Ruggero Spadafora, Junjie Lu, Radhika S. Khetani, Cheng Zhang, Aimee Iberg, Hu Li, Yang Shi, Paul H. Lerou
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Bronchopulmonary dysplasia (BPD) is the most common long-term pulmonary complication associated with extreme preterm birth (1).BPD is a complex lung injury syndrome caused by a combination of prenatal and postnatal insults associated with prematurity that result in altered lung development (2).A major challenge to development of adequate prevention and treatment strategies is limited understanding of BPD endotypes, which are subtypes with distinct pathobiological mechanisms (1).Moreover, characterization of the molecular landscape of late-stage human lung development and how it is affected by premature birth remains incomplete, in part owing to limited availability of human tissue samples.To address these limitations, we explored the potential of tracheal aspirate-derived mesenchymal stromal cells (MSCs) to reflect the molecular landscape of the preterm lung.Earlier reports have demonstrated that these cells are lung-resident stromal cells and can be expanded in culture (3).We applied weighted gene coexpression network analysis (WGCNA) to explore the highly dimensional gene expression space of premature tracheal aspirate-derived MSC lines (4).The gene regulatory network analysis revealed gene modules that correlated with the corrected gestational age (CGA) at MSC collection and the severity of BPD, suggesting that tracheal aspirate-derived MSC transcriptomes retain transcriptional dynamics of the preterm lung.Some of the results of this study were previously reported in the form of an abstract (5).
Dual HDAC and PI3K Inhibition Abrogates NFκB- and FOXM1-Mediated DNA Damage Response to Radiosensitize Pediatric High-Grade Gliomas
Authors: Sharmistha Pal, David Kozono, Xiaodong Yang, Wojciech Fendler, Whitney Fitts, Jing Ni, John A. Alberta, Jean Zhao, Kevin X. Liu, Jie Bian, Nathalene Truffaux, William A. Weiss, Adam C. Resnick, Pratiti Bandopadhayay, Keith L. Ligon, Steven G. DuBois, Sabine Mueller, Dipanjan Chowdhury, Daphne A. Haas-Kogan
Journal: Cancer Research (2018)

Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFκB/FOXM1 protected from CUDC-907-induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFκB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG.Significance: These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. Cancer Res; 78(14); 4007-21. ©2018 AACR.
GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever
Authors: Apurva Kanneganti, R.K. Subbarao Malireddi, Pedro H.V. Saavedra, Lieselotte Vande Walle, Hanne Van Gorp, Hiroto Kambara, Heather Tillman, Peter Vogel, Hongbo R. Luo, Ramnik J. Xavier, Hongbo Chi, Mohamed Lamkanfi
Journal: The Journal of Experimental Medicine (2018)

Pyroptosis is an inflammasome-induced lytic cell death mode, the physiological role of which in chronic inflammatory diseases is unknown. Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting an estimated 150,000 patients. The disease is caused by missense mutations in Mefv that activate the Pyrin inflammasome, but the pathophysiologic mechanisms driving autoinflammation in FMF are incompletely understood. Here, we show that Clostridium difficile infection of FMF knock-in macrophages that express a chimeric FMF-associated MefvV726A Pyrin elicited pyroptosis and gasdermin D (GSDMD)-mediated interleukin (IL)-1β secretion. Importantly, in vivo GSDMD deletion abolished spontaneous autoinflammatory disease. GSDMD-deficient FMF knock-in mice were fully protected from the runted growth, anemia, systemic inflammatory cytokine production, neutrophilia, and tissue damage that characterize this autoinflammatory disease model. Overall, this work identifies pyroptosis as a critical mechanism of IL-1β-dependent autoinflammation in FMF and highlights GSDMD inhibition as a potential antiinflammatory strategy in inflammasome-driven diseases.
Biological Stimulus‐Driven Assembly/Disassembly of Functional Nanoparticles for Targeted Delivery, Controlled Activation, and Bioelimination
Authors: Xi Hu, Fangyuan Li, Shuying Wang, Fan Xia, Daishun Ling
Journal: Advanced Healthcare Materials (2018)

Nanoassembly technology has emerged as a powerful tool for targeted drug delivery and provides a basis for fabricating medical theranostic nanosystems. However, it is extremely difficult to concentrate nanoparticles at tumor sites, and the poor target-to-background ratio undoubtedly obstructs the accurate diagnosis and effective therapy of cancerous tissues. Importantly, the addition of biological stimulus-responsive groups to nanoassembly systems can enable a biological stimulus-driven assembly-disassembly mutual switch or structural composition/conformation change, thereby amplifying the imaging signal and/or enhancing the therapeutic effect. This progress report provides an overview of well-designed biological stimulus-responsive nanosystems that can realize precise assembly-disassembly switches by disrupting or rebuilding the intricate balance between the entropy and enthalpy of the nanosystems in response to stimuli (pH, redox, enzymes, etc.) in tumor tissues. The discussion encompasses different biological stimulus-responsive groups, fabrication approaches, and outstanding selective "turn-on" performance for efficient tumor imaging, therapy, and bioelimination. This progress report is expected to inspire more extensive research for the development of smart "turn-on" nanomaterials with increased signal-to-noise (S/N) ratios for diagnosis and drug delivery, which may pave the way for precise nanomedicine with site-specific theranostic features and biocompatibility.
Cardiomyocyte GTP Cyclohydrolase 1 and Tetrahydrobiopterin Accelerate Myocardial Relaxation by Increasing NOS1 Activity and Phospholamban Phosphorylation
Authors: R Carnicer, A B Hale, S Suffredini, X Liu, J K Bendall, Lim Gbs., M Crabtree, N J Alp, K M Channon, B Casadei
Journal: Circulation Research (2012)
RNP-Granule Assembly via Ataxin-2 Disordered Domains Is Required for Long-Term Memory and Neurodegeneration
Authors: Baskar Bakthavachalu, Joern Huelsmeier, Indulekha P. Sudhakaran, Jens Hillebrand, Amanjot Singh, Arnas Petrauskas, Devasena Thiagarajan, M. Sankaranarayanan, Laura Mizoue, Eric N. Anderson, Udai Bhan Pandey, Eric Ross, K. VijayRaghavan, Roy Parker, Mani Ramaswami
Journal: Neuron (2018)
The fecal metabolome as a functional readout of the gut microbiome
Authors: Jonas Zierer, Matthew A. Jackson, Gabi Kastenmüller, Massimo Mangino, Tao Long, Amalio Telenti, Robert P. Mohney, Kerrin S. Small, Jordana T. Bell, Claire J. Steves, Ana M. Valdes, Tim D. Spector, Cristina Menni
Journal: Nature Genetics (2018)
Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice
Authors: Kozo Ikuta, Akihisa Fukuda, Satoshi Ogawa, Kenji Masuo, Norihiro Goto, Yukiko Hiramatsu, Motoyuki Tsuda, Yoshito Kimura, Yoshihide Matsumoto, Yuto Kimura, Takahisa Maruno, Keitaro Kanda, Kiyoto Nishi, Kyoichi Takaori, Shinji Uemoto, Shigeo Takaishi, Tsutomu Chiba, Eiichiro Nishi, Hiroshi Seno
Journal: Gut (2018)

Objective Nardilysin (NRDC), a zinc peptidase, exhibits multiple localisation-dependent functions including as an enhancer of ectodomain shedding in the extracellular space and a transcriptional coregulator in the nucleus. In this study, we investigated its functional role in exocrine pancreatic development, homeostasis and the formation of pancreatic ductal adenocarcinoma (PDA). Design We analysed Ptf1a-Cre; Nrdc flox/flox mice to investigate the impact of Nrdc deletion. Pancreatic acinar cells were isolated from Nrdc flox/flox mice and infected with adenovirus expressing Cre recombinase to examine the impact of Nrdc inactivation. Global gene expression in Nrdc-cKO pancreas was analysed compared with wild-type pancreas by microarray analysis. We also analysed Ptf1a-Cre; Kras G12D ; Nrdc flox/flox mice to investigate the impact of Nrdc deletion in the context of oncogenic Kras. A total of 51 human samples of pancreatic intraepithelial lesions (PanIN) and PDA were examined by immunohistochemistry for NRDC. Results We found that pancreatic deletion of Nrdc leads to spontaneous chronic pancreatitis concomitant with acinar-to-ductal conversion, increased apoptosis and atrophic pancreas in mice. Acinar-to-ductal conversion was observed mainly through a non-cell autonomous mechanism, and the expression of several chemokines was significantly increased in Nrdc -null pancreatic acinar cells. Furthermore, pancreatic deletion of Nrdc dramatically accelerated Kras G12D -driven PanIN and subsequent PDA formation in mice. These data demonstrate a previously unappreciated anti-inflammatory and tumour suppressive functions of Nrdc in the pancreas in mice. Finally, absence of NRDC expression was observed in a subset of human PanIN and PDA. Conclusion Nrdc inhibits pancreatitis and suppresses PDA initiation in mice.
UK is taken to court for failing to tackle air pollution
Authors: Jacqui Wise
Journal: BMJ (2018)

The European Commission is taking the UK, Germany, and France to the European Court of Justice for failing to meet EU limits on nitrogen dioxide. Italy, Romania, and Hungary have also been referred to the court for breaching limits on particulate matter.

The commission issued a final warning to the six countries in January and said that it had decided to proceed with legal action because they “did not present credible, effective and timely measures to reduce pollution within the agreed limits and as soon as possible.” Three other countries—the Czech Republic, Slovakia, and Spain—are being closely monitored but have put measures in place, or …
Implantable cardioverter‐defibrillators in heart failure patients with reduced ejection fraction and diabetes
Authors: Abhinav Sharma, Sana M. Al‐Khatib, Justin A. Ezekowitz, Lauren B. Cooper, Christopher B. Fordyce, G. Michael Felker, Gust H. Bardy, Jeanne E. Poole, J. Thomas Bigger, Alfred E. Buxton, Arthur J. Moss, Daniel J. Friedman, Kerry L. Lee, Richard Steinman, Paul Dorian, Riccardo Cappato, Alan H. Kadish, Peter J. Kudenchuk, Daniel B. Mark, Eric D. Peterson, Lurdes Y.T. Inoue, Gillian D. Sanders
Journal: European Journal of Heart Failure (2018)