tbuckley/cabot-search huggingface dataset:
THER-26. PHARMACOKINETIC AND UPDATED OUTCOME DATA FROM PNOC-002: A SAFETY STUDY OF VEMURAFENIB, AN ORAL INHIBITOR OF BRAFV600E, IN CHILDREN WITH RECURRENT/REFRACTORY BRAFV600E MUTANT BRAIN TUMORS
Authors: Theodore Nicolaides, Ashley Margol, Amar Gajjar, Stewart Goldman, Karen Gauvain, Lindsay Kilburn, Kellie Nazemi, Jane Minturn, Sarah Leary, Nicholas Whipple, Sridharan Gururangan, John Crawford, Janel Long-Boyle, Hechuan Wang, Vijay Ivaturi, Mariam Aboian, Annette Molinaro, Sabine Mueller, Michael Prados
Journal: Neuro-Oncology (2019)

BACKGROUND: Vemurafenib is an orally administered inhibitor of BRAF-V600E kinase approved for the treatment of BRAF-V600E mutated melanoma. We have previously presented favorable radiographic response and safety data for vemurafenib in children with BRAF-V600E mutated brain tumors and report here an update on outcomes of this cohort, as well as pharmacokinetic (PK) data of patients taking whole (n=18) or crushed (n=6) tablets. METHODS: Vemurafenib was given orally, either as crushed or whole tablets, beginning at the adult dose equivalent of 550 mg/m2, twice daily. Toxicity, PK, and response were assessed. Doses of 420 mg/m2 and 550 mg/m2 were assessed by a 3 + 3 design in a dose de-escalation study. PK plasma samples were analyzed using HPLC at Covance Inc and modeled by standard PK methods using Phoenix v8 (Certera, Princeton, New Jersey). RESULTS: PK analyses demonstrated a significant accumulation factor (approximately six-fold) over time with each vemurafenib dose. In the “crushed” tablet cohort, bioavailability was approximately 96% of that seen in patients receiving whole tablets. The steady-state area-under-the-curve (AUCss) median (range) was 754mg*h/L (464–920) in the whole tablet cohort and 621mg*h/L (184–1043) in the crushed tablet cohort. Updated best radiographic objective responses are: one complete response (CR), eleven partial responses (PR), and seven with stable disease (SD). Sustained responses were observed for over 50 months. Patients with SD had 30% lower AUCss compared PR+CR. However, a logistic regression model using AUCss as a predictor of PR+CR was not significant given the observed variability. CONCLUSIONS: Children with BRAF-V600E mutated brain tumors treated with vemurafenib have durable responses. PK modeling confirmed similar PK paramaters in children as compared to adults treated for melanoma. Using crushed tablets to administer a liquid suspension of drug resulted in similar drug exposure to whole tablets.
SUCCESFUL RETRIEVAL OF A PROXIMALLY MIGRATED PANCREATIC STENT BY DIGITAL PANCREATOSCOPY
Authors: V Araya Arce, J Vargas, F Rezvani, J Vargas
Journal: Endoscopy (2019)

With the increasing use of pancreatic duct stenting, its complications have also been recognized. Proximal stent migration has been described in 5.2% of patients and it represents a challenging situation. Although there is no consensus for the best strategy for retrieval, several endoscopic techniques have been described. These techniques have a success rate of 87%, but not infrequently distal pancreatectomy is needed. More recently, the use of digital pancreatoscopy for this matter has been described.
Abstract 15472: Daily Symptom and High Sodium Food Monitoring Intervention Reduces Sodium Intake and Symptom Burden in Patients With Symptomatic Heart Failure
Authors: Eun Kyeung Song, Seok-Min Kang, Choung Ryou, Debra K Moser, Terry A Lennie
Journal: Circulation (2017)

Introduction: Low sodium intake is recommended for patients with heart failure (HF) to reduce symptom burden, however continued non-adherence results in sodium intake and symptom burden remaining h...
Image Gallery: Optical coherence tomography for intravital human hair follicle analyses <i>ex vivo</i>
Authors: J. Lehmann, B. Kemper, A. Barroso Peña, J. Schnekenburger, R. Paus, M. Bertolini, J. Chéret
Journal: British Journal of Dermatology (2019)

DEAR EDITOR, Typically, human scalp hair follicles (HFs) need fixing to discern histological anatomy in sufficient detail. 1 Here we introduce label-free optical coherence tomography (OCT) (Ganymede Series Spectral Domain OCT System; Thorlabs, Newton
The Gut‐Liver Axis in Primary Sclerosing Cholangitis: Are Pathobionts the Missing Link?
Authors: Steven P. O’Hara, Nicholas F. LaRusso
Journal: Hepatology (2019)

O'Hara, Steven P. Ph.D.; LaRusso, Nicholas F. M.D.Editor(s): Corey, Kathleen E.2; Malhi, Harmeet3 Author Information
Abstract 18424: Elective Cardiac Arrest in Isolated Aortic Valve Surgery: Comparison of Blood-cardioplegia versus HTK-Bretschneider Solution in 7005 Consecutive Patients
Authors: Alexandro A Hoyer, Sven Lehmann, Andreas Oberbach, Denis A Merk, Stefan Feder, Konstantin vonAspern, Christian D Etz, Farhad Bakhtiary, Martin Misfeld, Friedrich W Mohr
Journal: Circulation (2015)

Introduction: Assessing the impact of HTK-Bretschneider solution versus blood-cardioplegia on short- and long-term outcome after isolated aortic valve replacement (AVR). Hypothesis: HTK-Bretschneider is not inferior to Blood-cardioplegia for isolated aortic valve replacement. Methods: Screening of our institutional database revealed 7290 consecutive patients who underwent AVR between 11/1994 and 06/2015. In the majority of patients (n=5998; 83%) antegrade infusion of htk-bretschneider solution (custodiol®) was used for elective cardiac arrest (Group A). Intermittent cold blood-cardioplegia was chosen in 1007 patients (14%; Group B). All preoperative risk-factors were considered for risk-factor analysis influencing outcome. Results: Early mortality was equal between the subgroups (p=0.22). Postoperative complications like pacemaker implantation (p=0.01) or low cardiac output were more likely to occur in group B (p=0.02). Overall long term survival was inferior for patients receiving elective cardiac arrest with cold blood cardioplegia (p&lt;0.001). Cox-regression identified age (HR: 1.063 ; p&lt;0.001), end stage renal disease (ESDR; HR:4.8; p&lt;0.001), history of PCI (HR: 1.3; p=0.03), active infective endocarditis (AIE; HR: 2.1; p&lt;0.001), neurological dysfunction (HR: 1.4; p=0.02), low ejection fraction (EF&lt;30%; HR: 2.5; p&lt;0.001), prior cardiac surgery (HR:1,5; p=0.02) and emergent surgical intervention (HR: 2.5; p&lt;0.001) being highly associated with long term survival and occurring more frequently in group B. Artificial low-risk and high-risk groups showed no differences in longevity depending on cardioplegic solutions (p=0.35). Conclusions: Blood-cardioplegia for elective cardiac arrest seems to be preferred when complex aortic valve surgery is expected. However, HTK-Bretschneider solution yields equivalent longevity to blood-cardioplegia, even after surgery demanding extended cross-clamp times.
Pegaspargase: A Review in Acute Lymphoblastic Leukaemia
Authors: Young-A. Heo, Yahiya Y. Syed, Susan J. Keam
Journal: Drugs (2019)

Pegaspargase (Oncaspar®), a pegylated form of native Escherichia coli-derived l-asparaginase (hereafter referred as E. colil-asparaginase), is indicated in the USA and EU for the treatment of acute lymphoblastic leukaemia (ALL) as a component of multi-agent chemotherapy in paediatric and adult patients. Relative to E. colil-asparaginase, pegaspargase has a prolonged circulation time, thereby offering less frequent administration. Moreover, pegylation of E. colil-asparaginase may diminish the immunogenicity of the enzyme. Based on extensive evidence, intramuscular (IM) or intravenous (IV) administration of pegaspargase as a component of a multi-agent chemotherapy is an effective first-line treatment for paediatric and adult patients with ALL, as well as for the treatment of paediatric and adult patients with ALL and hypersensitivity to E. colil-asparaginase. Pegaspargase had a manageable tolerability profile in paediatric and adult patients with newly diagnosed ALL, with the most commonly occurring adverse events being generally consistent to that seen with E. colil-asparaginase. Pegaspargase treatment in patients with relapsed ALL and hypersensitivity to E. colil-asparaginase had a similar tolerability profile to that observed in patients with newly diagnosed ALL. Given the potentially reduced immunogenicity and more convenient dosage regimen over E. colil-asparaginase, pegaspargase remains an important and effective treatment option for paediatric and adult patients with ALL, including those with hypersensitivity to E. colil-asparaginase.
More Than the Sum of the Respiratory Events: Personalized Medicine Approaches for Obstructive Sleep Apnea
Authors: Bradley A. Edwards, Susan Redline, Scott A. Sands, Robert L. Owens
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Section:ChooseTop of pageAbstract <<Phenotypes of OSAEndotypes Underlying OSAEvidence Linking the Endo...Future of OSA Endotyping ...OSA Genomic Risk FactorsPutting It All Together: ...ReferencesCITING ARTICLES
Abstract 13561: Extracorporeal Membrane Oxygenation Promotes Long Chain Fatty Acid Metabolism in the Immature Swine Heart in vivo
Authors: Masaki Kajimoto, Colleen M O'Kelly Priddy, Dolena R Ledee, Nancy Isern, Chun Xu, Aaron K Olson, Michael A Portman
Journal: Circulation (2012)

Background: Extracorporeal membrane oxygenation (ECMO) unloads the heart and is frequently used in infants with postoperative cardiopulmonary failure, but the associated survival rate is still low. Nutritional manipulation may preserve or improve cardiac recovery, but little is known regarding the impact of ECMO on myocardial metabolism. Fatty acid (FA) oxidation is implicated in various models as a regulator of cardiac remodeling. We assessed the hypothesis that ECMO modulates free FA metabolism in the immature heart. Methods and Results: Twenty two immature pigs (age 25-38 days) were divided into 4 groups by left ventricular (LV) loading status: Control (normal circulation) or ECMO (mechanically unloaded), and by delivery of [2-13C]lactate, [2,4,6,8-13C]octanoate (medium chain FA) and [U-13C]long chain FAs either directly into the coronary artery (high dose) or systemically (low dose; near physiological intracoronary concentration). LV tissue then underwent nuclear magnetic resonance (NMR) analysis for ...
TMOD-09. TUMOR ASSOCIATED MACROPHAGE DYNAMICS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: James Ross, Zhihong Chen, Frank Szulzewsky, Lenore Monterroza, Matthew Schniederjan, Oren Becher, Dolores Hambardzumyan
Journal: Neuro-Oncology (2019)

Pediatric high-grade gliomas (pHGG) drastically differ from their adult counterparts in terms of genetic and epigenetic alterations, suggesting they may also differ in the constituency of their tumor microenvironment.It is known tumor associated macrophages (TAMs) can constitute up to 30-40% of the total tumor cell mass in adult high-grade gliomas, yet little is known for pHGGs.This raises the question of whether pHGGs possess a distinct constituency of TAMs due to their unique genetic and epigenetic landscapes.To uncover the composition and behavior of TAMs in pHGG we utilize RCAS/tva, a somatic cell-type specific gene transfer system in which we administer RCAS-PDGFA or RCAS-PDGFB to Nestin-positive cells in the brain of immunocompetent Cdkn2a knockout mice.We observe PDGFB-driven tumors have a significantly lower median survival compared to PDGFA-driven tumors.PDGFB tumors also have increased infiltration of TAMs, made evident by immunohistochemical staining for IBA1.Flow cytometry indicates the increased number of TAMs is due to bone-marrow derived inflammatory monocytes, not the microglial population.Unsupervised clustering and principle component analysis indicates these tumors possess distinct expression profiles.Several chemokines and receptors are highly expressed in PDGFB tumors such as Ccl2, Ccl3, and Ccl7, suggesting chemokine mediated infiltration of TAMs may be occurring.To study PDGF signaling and TAM infiltration in human pHGGs, we stained over 40 tumors for IBA1, PDGF-receptors, and PDGF-ligands.There is a positive correlation between PDGFRβ, PDGFB, and CD31 staining with IBA1, suggesting a stromal role exists for the infiltration of TAMs.Current in vivo studies are being conducted to determine if TAM infiltration can be inhibited by genetically or pharmacologically targeting chemokine signaling pathways.In vivo and in vitro studies are also being performed to determine which cell types are the main sources of chemokines and inflammatory molecules are in the microenvironment.
MEDU-15. STRUCTURAL BRAIN NETWORK PROPERTIES AND COGNITIVE IMPAIRMENT IN ADOLESCENTS AFTER RADIATION THERAPY
Authors: Justin Yuan, Melanie Morrison, Angela Jakary, Sabine Mueller, Olga Tymofiyeva, Duan Xu, Janine Lupo
Journal: Neuro-Oncology (2019)

INTRODUCTION: Cranial radiation therapy (CRT) has significantly benefitted pediatric brain cancer treatment. The improved prognosis has led to an increasing population of cancer survivors, but CRT is also associated with negative side effects. These include neurocognitive impairments in attention and working memory. Similar declines have been observed in adults with prior pediatric CRT and the newly-diagnosed elderly receiving CRT. Magnetic resonance imaging (MRI) studies have found that CRT has structural effects in the brain, such as altering white matter (WM). Graph network analysis of WM connectivity is a promising method to study the effects of CRT on cognitive functions that engage multiple brain regions. The method models the brain as a network of connected edges and nodes, which are quantitatively described with graph theory. This study used graph analysis to examine associations between neurocognitive deficits and WM connectivity. METHODS: Ten adolescent and young adult subjects (17.7±5yrs.) with prior CRT (7 whole-brain, 3 whole-ventricular) for pediatric brain cancers were scanned on a 7-Tesla MRI. Subjects were also assessed with a computerized cognitive battery (CogState). High resolution T1 anatomical and multiband two-shell diffusion sequences were acquired. A diffusion-based WM connectivity network was constructed and assessed with global and local graph metrics. Local analysis examined node strength at executive function and working memory areas. RESULTS: The analysis found significant negative correlations between graph metrics and cognitive measures of spatial working memory and executive function. Globally, this included measures of segregation (clustering coefficient and transitivity) and integration (efficiency); locally, this included node strength at domain-related regions. CONCLUSION: These preliminary findings suggest that cognitive performance is inversely correlated with graph metrics characterizing WM structural connectivity. The tumors’ infratentorial locations suggest that the findings were treatment-related rather than tumor-related. Our work suggests that CRT-related cognitive effects may potentially be assessed using WM structural graph analysis.
Evening primrose extract induces apoptosis and inhibits the DNA synthesis in Ehrlich ascites tumor cells via at least two pathways differentially modulated by reactive oxygen species
Authors: Isao Matsui-Yuasa, Tsutomu Arimura, David Opare Kennedy, Akiko Kojima-Yuasa
Journal: Cancer Research (2005)

1745   Introduction: We previously demonstrated that evening primrose extract (EPE) induced apoptosis in Ehrlich ascites tumor cells (EATC), and this effect was specific on tumor cells. We also demonstrated that EPE exposure elicited a rapid increase in intracellular peroxide levels. These changes caused translocation of Bax to mitochondria and a subsequent release of mitochondrial cytochrome c. However, no activation of caspase-3 was observed in EPE-treated EATC. On the other hand, apoptosis-inducing factor (AIF) was translocated from mitohondria to nuclei, which was suppressed with the addition of catalase. Here, we elucidated the intracellular peroxide-dependent mechanism governing cell cycle dynamics during growth arrest by EPE. We also investigated the involvement of polyamines in EPE-induced in increase in apoptosis as well as in EPE-induced decrease in DNA synthesis. Methods: EATC were cultured in Eagle’s MEM containing 10% FCS. 2’,7’-Dichlorodihydrofluorescein diacetate was used as a probe for intracellular ROS formation. The intracellular polyamines were analyzed by HPLC equipped with fluorescence detector. Results: EPE elicited a dose-dependent accumulation of cells in the G1 phase and inhibited DNA synthesis. The cell cycle arrest and inhibition of proliferation in EATC by EPE were associated with decreased Rb phosphorylation. Furthermore, inhibitions of Rb phosphorylation and DNA synthesis by EPE were not suppressed with the addition of catalase. EPE also brought about a significant decrease in intracellular polyamine levels. Furthermore, the addition of polyamines reversed the EPE-induced in cell viavility and suppressed the EPE-induced in intracellular hydrogen peroxide. However the addition of polyamines did not reverse EPE-induced decrease in DNA synthesis and phosphorylation of Rb protein, and EPE-induced translocation of AIF. Conclusion:We demonstrated previously that an EPE-induced rapid increase in intracellular peroxides level triggers off induction of apoptosis in EATC. However the findings in the present study suggest that intracellular peroxides do not cause an EPE-induced G1 arrest. Hence, EPE-induced inhibition of the growth of EATC are via at least two pathways differentially modulated by ROS, notably intracellular peroxides. These are (a) the EPE-induced apoptosis pathway which is dependent on increase in hydrogen peroxide and decrease in polyamines and (b) the EPE-induced of cell proliferation which is hydrogen peroxide independent.
Prognostic significance of upfront radiation therapy in patients with multiple myeloma
Authors: Xavier Orcutt, Peter Barth, Adam J. Olszewski
Journal: American Journal of Hematology (2019)

from transplant status, suggesting that high-risk patients may benefit from posttransplant maintenance therapy.In conclusion, IC is more effective than HMA as frontline treatment of younger patients with MDS and elevated bone marrow blasts, independently from baseline karyotype and TP53 status.We acknowledge the limits of our analysis due to its retrospective nature and the unequal distribution of baseline characteristics between the two arms.Future strategies, combining targeted agents with either HMA or IC, should be investigated to determine whether this advantage will be maintained for IC.
Intestinal organoids to model cystic fibrosis
Authors: Peter van Mourik, Jeffrey M. Beekman, Cornelis K. van der Ent
Journal: European Respiratory Journal (2019)

<b>CF can be studied using patient-specific intestinal organoids. CFTR protein function in intestinal organoids correlates with clinical disease severity and drug testing in organoids could aid in finding drugs for people with rare CFTR mutations.</b>https://bit.ly/2GryRl0
Doctors still see own mental health problems as sign of weakness, research finds
Authors: Abi Rimmer
Journal: BMJ (2019)

Employers in the medical profession must take steps to reduce the stigma of mental illness among their workforce so that doctors feel able to get help, researchers from Swansea University have said.

The recommendation came as a survey of UK doctors, conducted by the BMA, found that most doctors (80%) were at a high or very high risk of burnout, with junior doctors most at risk.1

For their study, to be published in an upcoming edition of the International Review of …
Comparative Analysis of Medicines Safety Advisories Released by Australia, Canada, the United States, and the United Kingdom
Authors: Lucy T. Perry, Alice Bhasale, Alice Fabbri, Joel Lexchin, Lorri Puil, Maisah Joarder, Barbara Mintzes
Journal: JAMA Internal Medicine (2019)

This study examines how often medicines regulators in Australia, Canada, the United Kingdom, and the United States were concordant in their decisions to issue safety advisories on approved prescription medicines.
New Molecular Insights into Immune Cell Development
Authors: Ana Cumano, Claire Berthault, Cyrille Ramond, Maxime Petit, Rachel Golub, Antonio Bandeira, Pablo Pereira
Journal: Annual Review of Immunology (2019)

During development innate lymphoid cells and specialized lymphocyte subsets colonize peripheral tissues, where they contribute to organogenesis and later constitute the first line of protection while maintaining tissue homeostasis. A few of these subsets are produced only during embryonic development and remain in the tissues throughout life. They are generated through a unique developmental program initiated in lympho-myeloid-primed progenitors, which lose myeloid and B cell potential. They either differentiate into innate lymphoid cells or migrate to the thymus to give rise to embryonic T cell receptor–invariant T cells. At later developmental stages, adaptive T lymphocytes are derived from lympho-myeloid progenitors that colonize the thymus, while lymphoid progenitors become specialized in the production of B cells. This sequence of events highlights the requirement for stratification in the establishment of immune functions that determine efficient seeding of peripheral tissues by a limited number of cells.
Abstract 15466: Bioactive Contents and Cardiovascular Regenerative Potential of Extracellular Vesicles Derived From Induced Pluripotent Stem Cells
Authors: Marta Adamiak, Sylwia Bobis-Wozowicz, Elzbieta Karnas, Sylwia Kedracka-Krok, Michal Sarna, Guangming Cheng, Anweshan Samanta, Magdy Girgis, Zbigniew Madeja, Buddhadeb Dawn, Ewa Zuba-Surma
Journal: Circulation (2015)

Introduction: Extracellular vesicles (EVs) are tiny membrane-enclosed vesicles released by cells by membrane budding or exocytosis. The molecular profile of contents and regenerative potential of EVs derived from murine induced pluripotent stem cells (miPSCs) have not been investigated. Hypothesis: We hypothesized that miPSC-derived EVs carry bioactive substances, including mRNA and miRNA, which would influence the biology and fate of target cells. Methods: Murine iPSCs were generated using established protocols and EVs were isolated from culture supernatants by sequential centrifugation. Atomic force microscopy (AFM), flow cytometry, and real-time RT-PCR were used to characterize EV contents. Endothelial cells were exposed to miPSC-EVs in culture. Results: AFM and dynamic light scattering showed that miPSC-EVs are homogenous spherical vesicles smaller than 100 nm (Fig, A). High-sensitivity flow cytometry confirmed the presence of several iPSC- specific markers along with typical exosomal markers (CD9, CD63 and CD81) on miPSC-EVs. miPSC-EVs were enriched in mRNAs, miRNAs and proteins from donor iPSCs as shown by real-time RT-PCR and mass spectroscopy, respectively. Moreover, miPSC-EVs contained transcripts regulating pluripotency, self-renewal and differentiation, including Oct-4, Nanog, GATA-4 as well as miR290-295 cluster (Fig, B,C). Importantly, several miRNAs were found to be higher in EVs when compared with parental miPSCs (Fig, B,C). Endothelial cells treated with miPSC-EVs exhibited greater proliferative, metabolic and angiogenic activities, and were more resistant to apoptosis. Conclusions: Our data show, for the first time, that miPSC-derived EVs are natural nanocarriers capable of transferring bioactive contents to mature cells affecting target cell function as well as regenerative potential. We conclude that iPSC-EVs may represent safe therapeutic alternatives to whole cell-based therapy for cardiovascular repair.