tbuckley/cabot-search huggingface dataset:
Gasdermin D activity in inflammation and host defense
Authors: Judy Lieberman, Hao Wu, Jonathan C. Kagan
Journal: Science Immunology (2019)

The mechanisms underlying the release of interleukin-1 (IL-1) family cytokines from phagocytes have been the subject of intense investigations for more than 30 years. The absence of an amino-terminal secretion signal from members of this family suggests a previously unknown mechanism of protein secretion that transfers cytosolic IL-1 directly across the plasma membrane into the extracellular space. The pore-forming protein gasdermin D (GSDMD) has emerged as the conduit for IL-1 secretion from the cytosol, serving to induce the release of IL-1 from living (hyperactive) or dead (pyroptotic) cells. In this Review, we discuss the mechanism by which GSDMD pore formation is regulated by the activity of inflammatory caspases, which are commonly associated with inflammasomes. We discuss how GSDMD promotes IL-1 release from hyperactive or pyroptotic cells, with a specific focus on defining how these distinct cell fates associated with GSDMD activity can be regulated. Last, the physiological consequences of GSDMD activity and therapeutic potential of targeting this pore-forming protein are discussed, which highlight the abundance of questions that remain to be answered by the community.
Inpatient Outcomes and Rates of Venous Thromboembolism and Gastrointestinal Hemorrhage in Patients with Gastric Cancer: Results from Nationwide Inpatient Sample Database 2009-2014
Authors: Harry E Fuentes-Bayne, Urshila Durani, Robert D. McBane, Rajiv K. Pruthi, Aneel A. Ashrani, Ariela L. Marshall
Journal: Blood (2018)
Response to: ‘Novel NLRP12 variant presenting with familial cold autoimmunity syndrome phenotype’ by Gupta <i>et al</i>
Authors: Charlotte Eijkelboom, Nienke M Ter Haar, Joost Frenkel, Marco Gattorno
Journal: Annals of the Rheumatic Diseases (2019)

Response to: 'Novel NLRP12 variant presenting with familial cold autoimmunity syndrome phenotype' by Gupta et alWe read with great interest the letter by Aggarwal. 1 Her case is one of early-onset autoinflammatory disease.Her case is not directly similar to any of the 187 cases we described in our paper on undefined autoinflammatory diseases. 2iven the finding of novel potentially pathogenic NLRP12variants in homozygosity, we think the authors have most likely identified a hitherto unknown cause of this child's symptoms.
NO-054. ELUCIDATING GLIOBLASTOMA REGIONAL EDEMA AND HYPOXIA CHANGES INDUCED BY ANTI-ANGIOGENIC TREATMENT THROUGH MATHEMATICAL MODELING COMBINED WITH CLINICAL IMAGING
Authors: Andrea Hawkins-Daarud, Pamela Jackson, Kristin Swanson
Journal: Neuro-Oncology (2013)

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a median survival of 14 months despite rigorous treatment protocols. As increased vascularity is a defining characteristic for these tumors and is necessary for invasive growth, there is a push for using anti-angiogenic th
P14.64 Primary Central Nervous System Lymphoma (PCNSL) with HD- MTX based chemotherapy: tolerability and results
Authors: A Silvani, E Anghileri, G Simonetti, M Eoli, G Finocchiaro, B Pollo, M Farinotti, L Fariselli, P Gaviani
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Primary Central nervous system (CNS) lymphomas (PCNSL) are extranodal, malignant non- Hodgkin lymphomas of the diff use large B-cell type, confined to CNS. It accounts for up to 1% of all lymphomas and about 3% of all CNS tumours. The incidence continues to rise in immuno- competent elderly patients.Although the prognosis of PCNSL remains poor, it has improved in the past two decades as a result of better treatment strategies. However, treatment recommendations still result mainly from retrospective series or single-arm phase 2 studies and a few three completed randomised trials. We described a series of patients with newly diagnosis of PCNSL treated with modified-schedula published by Omuro MATERIAL AND METHODS Patients was treated with HD-MTX, procarbazine, vincristine, received four 28-day cycles of chemotherapy, on schedule: HD-MTX (3·5 g/m²) days 1 and 15; Procarbazine (100 mg/m²) on days 1–7. Vincristine (1·4 mg/m²) on days 1 and 15. Toxicity was assessed with Common Terminology Criteria for Adverse Events version 4. The International PCNSL Collaborative Group Response Criteria were used for response assessment. Endpoints include overall survival (OS) and adverse events (AE). RESULTS 21 immunocompetent patients (12 females and 9 males) were retrospectively studied, among 2014 to 2019. Median age at diagnosis 61 years (range 41–76). Median KPS at diagnosis was 70 (range 40–100). Clinical and radiological data and treatment related toxicity were described CONCLUSION Present combination regimen is effective; however, AE incidence is high, and often induces schedule modification
OS2.4 Using FineSA MRI for early detection of Spinal Metastases
Authors: A Niina, A Davies, N Farooq, K Rowley, K Elias, I Collins
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Early detection of spinal metastases is important to facilitate early management and delay vertebral fracture or metastatic cord compression. The gold standard investigation to detect spinal metastasis is MRI, but it cannot quantify the metastasis and prognosis is poor due to its late presentation. Fine Structural Analysis (FineSA) is a custom software added to MRI using a non-radiating proprietary data acquisition technique. It analyses data at a resolution 10 times higher than MRI to quantify the trabecular microstructure which has the potential to enable early detection and management of vertebral fracture or metastatic cord compression. MATERIAL AND METHODS 18 patients with known, symptomatic spinal metastases from Swansea Bay University Health Board and 11 age and sex-matched control subjects were recruited to have a FineSA MRI Spine. FineSA analysed and produced a structural spectrum of a defined area from the metastatic lesion. Statistical comparisons were made with the control data by extracting several metrics from the spectra, which were represented as an index score relative to a normal range. RESULTS Preliminary results using One Way ANOVA show a highly significant difference in trabecular microstructure between patients with spinal metastases and the age and sex-matched control patients, where p= 3.99e-11. CONCLUSION Preliminary results show that there is a highly significant difference between metastatic and control bone structure. Follow-up of the patients after one year will look at if fracture has occurred and whether there is a difference in the FineSA index score between the two groups. FineSA has the potential to be used to identify which metastatic lesions are most likely to be symptomatic and fracture, so that targeted radiotherapy can be done before symptoms are either present or intrusive.
P14.32 Spatial discrepancies between FET PET and conventional MRI in patients with newly diagnosed glioblastoma
Authors: P Lohmann, P Stavrinou, K Lipke, E K Bauer, G Ceccon, J Werner, G R Fink, N J Shah, K Langen, N Galldiks
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND In patients with glioblastoma, the tissue showing contrast enhancement (CE) in MRI is usually the target for resection or radiotherapy. However, the solid tumor mass typically extends beyond the area of CE. Amino acid PET can detect tumor parts that show no CE. We systematically investigated tumor volumes delineated by amino acid PET and MRI in newly diagnosed, untreated glioblastoma patients. MATERIAL AND METHODS Preoperatively, 50 patients with subsequently neuropathologically confirmed glioblastoma underwent O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET, fluid-attenuated inversion recovery (FLAIR), and CE MRI. Areas of CE were manually delineated. FET PET tumor volumes were segmented using a tumor-to-brain ratio ≥ 1.6. The percentage of overlapping volumes (OV), as well as Dice and Jaccard spatial similarity coefficients (DSC; JSC), were calculated. FLAIR images were evaluated visually. RESULTS In 86% of patients (n = 43), the FET PET tumor volume was significantly larger than the volume of CE (21.5 ± 14.3 mL vs. 9.4 ± 11.3 mL; P &lt; 0.001). Forty patients (80%) showed both an increased uptake of FET and CE. In these 40 patients, the spatial similarity between FET and CE was low (mean DSC, 0.39 ± 0.21; mean JSC, 0.26 ± 0.16). Ten patients (20%) showed no CE, and one of these patients showed no FET uptake. In 10% of patients (n = 5), increased FET uptake was present outside of areas of FLAIR hyperintensity. CONCLUSION Our results show that the metabolically active tumor volume delineated by FET PET is significantly larger than tumor volume delineated by CE. The data strongly suggest that the information derived from FET PET should be integrated into the management of newly diagnosed glioblastoma patients. FUNDING This work was supported by the Wilhelm-Sander Stiftung, Germany
Not Taking New Patients
Authors: J. Rush Pierce
Journal: Annals of Internal Medicine (2019)

On Being a Doctor3 September 2019Not Taking New PatientsJ. Rush Pierce Jr., MD, MPHJ. Rush Pierce Jr., MD, MPHUniversity of New Mexico School of Medicine, Albuquerque, New Mexico (J.R.P.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-3283 Audio Reading - “Not Taking New Patients” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Not Taking New Patients” by J. Rush Pierce Jr., MD, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Gladys taught kindergarten with my wife. Our 10-year-olds played on the same soccer team. Walking off the field together after their season's final game, Gladys remarked to me, “I called your office to make an appointment, and they told me you weren't taking new patients.” It was unquestionably true. However, Gladys' statement implied an unspoken question with an answer that would be difficult for both of us to understand. I answered her unstated question with another question.“How soon do you need to be seen?”“It's not urgent, just whenever,” she answered quickly.I took her number and told her ... Author, Article, and Disclosure InformationAffiliations: University of New Mexico School of Medicine, Albuquerque, New Mexico (J.R.P.)Corresponding Author: J. Rush Pierce Jr., MD, MPH, 6807 West Jewell Drive, Lakewood, CO 80227; e-mail, rush.[email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “Not Taking New Patients” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Not Taking New Patients” by J. Rush Pierce Jr., MD, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 3 September 2019Volume 171, Issue 5Page: 378-379KeywordsAnxietyBreast cancerEmotionsGamesHypertensionNursesResidencySurgeonsSurgeryWalking ePublished: 3 September 2019 Issue Published: 3 September 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Can the RNA World Still Function without Cytidine?
Authors: Andrew S Tupper, Ralph E Pudritz, Paul G Higgs
Journal: Molecular Biology and Evolution (2019)

Most scenarios for the origin of life assume that RNA played a key role in both catalysis and information storage. The A, U, G, and C nucleobases in modern RNA all participate in secondary structure formation and replication. However, the rapid deamination of C to U and the absence of C in meteorite samples suggest that prebiotic RNA may have been deficient in cytosine. Here, we assess the ability of RNA sequences formed from a three-letter AUG alphabet to perform both structural and genetic roles in comparison to sequences formed from the AUGC alphabet. Despite forming less thermodynamically stable helices, the AUG alphabet can find a broad range of structures and thus appears sufficient for catalysis in the RNA World. However, in the AUG case, longer sequences are required to form structures with an equivalent complexity. Replication in the AUG alphabet requires GU pairing. Sequence fidelity in the AUG alphabet is low whenever G's are present in the sequence. We find that AUG sequences evolve to AU sequences if GU pairing is rare, and to RU sequences if GU pairing is common (R denotes A or G). It is not possible to conserve a G at a specific site in either case. These problems do not rule out the possibility of an RNA World based on AUG, but they show that it wouldbe significantly more difficult than with a four-base alphabet.
P11.22 Radiotherapy effects in GBM Rat model CNS1
Authors: O Furman, D Daniels, D Guez, D Last, S Sharabi, A Talianski, Y Mardor, L Zach
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND CNS1 is a syngeneic glioma model in Lewis Rats. It is an aggressive infiltrating tumor cell line that mimics important aspects of human GBM such as rapid growth, dispersal along blood vessels and white matter, pseudopallisading cells with features of hemorrhage and necrosis. CNS1 tumors are infiltrated with macrophages and T-cells, and were studied in the context of immunotherapy and gene therapy, extracellular matrix and invasion, but CNS1 response to radiation has not yet been described. If we wish to combine novel immune-based therapies with existing GBM protocols that include radiation and chemotherapy, we will need models that respond to these protocols. As a first step in this direction, we sought to describe CNS1 response to radiation in vitro and in vivo. MATERIAL AND METHODS In vitro, survival of irradiated CNS1 cells was assessed with clonogenic assay. Radiation varied in dose from 0 to 10 Gy and was delivered via Kimtron Polaris X-ray generator. In vivo, male Lewis rats were intra-cranially inoculated with 0.5*106 CNS1 tumor cells and monitored for survival. Treated rats (N=6) were subjected to a single 20Gy whole-head radiation treatment under full anesthesia, delivered five days post-inoculation. Control rats (N=5) were anesthetized but not irradiated. Tumor size was monitored using contrast enhanced T1-weighted MRI in both treated and control rats at several time points (4, 6, 11, 18 and 32 days post tumor inoculation). RESULTS CNS1 cells are sensitive to radiation in vitro, as cell survival decreased after exposure to increasing amounts of radiation. In vivo, while initial tumor size did not significantly differ between groups, rats treated with radiation survived significantly longer than control rats (23.8 ± 5.0 days vs. 11 ± 4.1 days, p&lt;0.005). Growth arrest following irradiation in vivo was not detected 1d after treatment but was observed 6d post-irradiation. Growth arrest was recorded in half of the treated rats, showing no increase in tumor size (N=2) or reduction in tumor volume (N=1) relative to 1d post-irradiation. Tumor growth rates were lower in all irradiated rats relative to control rats. Survival time was negatively correlated with initial tumor size in the control group but not in the treatment group. CONCLUSION CNS1 rat model of GBM is a valid model of radiotherapy effects on GBM tumors. Further studies combining radiation and chemotherapy are the next step. Support for this work was provided by Israel Cancer Association.
Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma
Authors: Laura Rosiñol, Albert Oriol, Rafael Rios, Anna Sureda, María Jesús Blanchard, Miguel Teodoro Hernández, Rafael Martínez-Martínez, Jose M. Moraleda, Isidro Jarque, Juan Bargay, Mercedes Gironella, Felipe de Arriba, Luis Palomera, Yolanda González-Montes, Josep M. Martí, Isabel Krsnik, Jose M. Arguiñano, Maria Esther González, Ana Pilar González, Luis Felipe Casado, Lucia López-Anglada, Bruno Paiva, Maria-Victoria Mateos, Jesus F. San Miguel, Juan-José Lahuerta, Joan Bladé
Journal: Blood (2019)
P05.04 Phase 2 open-label study of maintenance treatment with ibrutinib following first line methotrexate-based immuno-chemotherapy in elderly patients with primary CNS lymphoma (PCNSL)
Authors: O Bairey, A Amiel, S Yust-Katz, R Gurion, T Siegal
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment proved to prolong PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas. MATERIAL AND METHODS Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate-based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and maintenance ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months. RESULTS Of the 14 patients screened for the study 2 were excluded due to relapse while on screening. 12 patients have been enrolled with a median age of 74 (61–80) years. The median interval between diagnosis of PCNSL and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months and she is still alive after 24 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed. CONCLUSION Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-Methotrexate based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.
Meta-Analysis of Low–Glycemic Index Diets in the Management of Diabetes
Authors: Jennie C. Brand-Miller, Peter Petocz, Stephen Colagiuri
Journal: Diabetes Care (2003)

In the editorial by Franz (1) on the value of low–glycemic index diets, the results of our meta-analysis, which were published in the same issue of Diabetes Care (2), have been misinterpreted and therefore misrepresented. Specifically, the author contrasts the overall decrease in HbA1c of ∼1–2% seen with various nutrition interventions with a reduction of 0.43% from low–glycemic index diets. The 0.43% reduction, however, is not the overall effect of a low–glycemic index diet, but the incremental effect of a low–glycemic index diet over and above that seen with an equally intensive nutrition intervention. Thus if …
Emergence of diversity in carbapenemase-producing Escherichia coli ST131, England, January 2014 to June 2016
Authors: Nicholas Ellaby, Michel Doumith, Katie L Hopkins, Neil Woodford, Matthew J Ellington
Journal: Eurosurveillance (2019)

BackgroundEscherichia coli ST131, a global, high-risk clone, comprises fluoroquinolone resistance (FQ-R) mutations and CTX-M extended-spectrum beta-lactamases associated with the fimH30-encoding clades, C1 and C2. Further carbapenem resistance development in ST131 is a public health concern.AimThis observational study aimed to probe the diversity of carbapenemase-producing E. coli (CP E. coli) ST131 across England.MethodsST131 isolates were identified using whole-genome sequencing (WGS) data generated for all non-duplicate CP E. coli from human samples submitted to the national reference laboratory from January 2014 to June 2016. Antimicrobial resistance (AMR) gene content and single nucleotide polymorphism (SNP) data were compared against a published ST131 phylogeny and analysed alongside patient metadata.ResultsThirty-nine genetically diverse ST131 CP E. coli, from eight of nine regions, represented 10% of CP E. coli isolates sequenced. Ten and eight isolates were from the FQ-susceptible (FQ-S) clades A and B, while eight and 15 isolates belonged to the FQ-R clades C1 or C2, respectively. Seven distinct carbapenemases were identified: KPC-2 (21 isolates, 6 regions) frequently occurred among clade C2 isolates (n = 10). OXA-48-producers (10 isolates, 3 regions) were often from clade A (n = 5). NDM-1 (n = 4), NDM-5 (n = 1), VIM-1 (n = 1), VIM-4 (n = 1) and OXA-181 (n = 1) were also identified. Clade C2 isolates encoded more AMR genes than those from clades A (p = 0.02), B (p = 9.6 x 10-3) or C1 (p = 0.03).ConclusionWhen compared with its global predominance among ESBL-E. coli, ST131 represented a fraction of the CP E. coli received, belonging to diverse clades and encoding diverse carbapenemases. The greater accumulation of resistance genes in clade C2 isolates highlights the need for ongoing monitoring of this high-risk lineage.
Should terminally ill patients have the right to take drugs that pass phase I testing? No
Authors: Dean Gesme
Journal: BMJ (2007)

The United States is considering allowing experimental drugs to be given to people at the end of life. <b>Emil J Freireich </b>believes patients should be able to judge the risks for themselves, and <b>Dean Gesme</b> counters that use o such drugs outside trials will damage both individuals and science