tbuckley/cabot-search huggingface dataset:
Abstract #1069: Tigatuzumab (CS-1008), a novel humanized DR5 agonist antibody, eradicates pancreas cancer stem cells and results in long term cures, in combination with gemcitabine, in direct pancreas cancer xenografts
Authors: N.V Rajeshkumar, Zeshaan Rasheed, Elena García-García, Antonio Jimeno, Kosaku Fujiwara, William Matsui, Manuel Hidalgo
Journal: Cancer Research (2009)

Background and Aim: Pancreatic adenocarcinoma remains one of the most deadly and chemo resistant cancers. Emerging data suggest that pancreatic cancer contains a small subset of distinct cancer stem cells that are responsible for tumor initiation, growth and are thought to be the major culprit behind cancer metastasis and recurrence after clinical remission. Treatment with standard chemotherapeutics may result in tumor shrinkage, but majority of the tumors recur, likely because the cancer stem cells survives and fuels tumor regeneration. Agents specifically targeting pancreatic cancer stem cells will likely be needed for tumor eradication and improve the poor prognosis of pancreatic cancer patients. To this end, we evaluated the antitumor potential of a novel humanized death receptor-5 (DR5) agonist antibody, Tigatuzumab (CS-1008), in combination with gemcitabine in pancreatic tumor xenografts. Experimental procedure: Flow cytometry was used to examine the expression of DR5 by pancreas cancer stem cells (ALDH+CD24+CD44+). Ten patient-derived tumor xenografts growing in nude mice were treated with 1) Tigatuzumab 3 mg/kg., i.v once weekly for 4 weeks 2) Gemcitabine 100 mg/kg i.p twice weekly for 4 weeks and 3) Gemcitabine + Tigatuzumab in the above mentioned dose and frequency. Tumor size was measured twice per week and relative tumor growth index and tumor doubling time was calculated versus control mice. Immunohistochemical staining was performed to determine the ALDH and CD24 expression in control and treated tumor samples. Results: Pancreas cancer stem cells are relatively enriched for DR5 expression (94% of ALDH+ cells and 89% of CD24+CD44+ cells) compared to non-stem cell bulk populations (30%). Gemcitabine treatment alone reduced tumor size and resulted in the enrichment of tumor cells that express ALDH+ and/or CD24+CD44+. But tumors reliably recurred after treatment discontinuation. However, treatment with gemcitabine + Tigatuzumab eliminated the pancreas cancer stem cells, significantly increased tumor doubling time and resulted in long term cures in 50% of cases. Conclusion: Pancreas cancer stem cells express DR5. Targeting DR5 with Tigatuzumab eliminates pancreatic cancer stem cell population and potentiates gemcitabine sensitivity. This study supports the rational to test this promising combination in a clinical setting of pancreatic cancer.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1069.
Abstract P358: Consumption of Better Quality Grain Products and Fat Sources is Associated With the Greatest Increments in Diet Quality for US Adults
Authors: Valerie Sullivan, Kristina Petersen, Victor Fulgoni, Fulya Eren, Martha E Cassens, Michael T Bunczek, Penny M Kris-etherton
Journal: Circulation (2020)

Introduction: The Healthy Eating Index (HEI)-2015 quantifies alignment with the 2015-2020 Dietary Guidelines for Americans by scoring and totaling 13 components. Higher scores have been associated with lower all-cause and cardiovascular disease (CVD) mortality. The contributions of individual components toward total diet quality and associations with health in American adults have not been determined. Hypothesis: It was hypothesized that the individual HEI-2015 components would differentially contribute to total diet quality and correlate with CVD risk factors in U.S. adults. Methods: Non-pregnant, non-lactating adult participants (age 19+ years) in the National Health and Nutrition Examination Survey (NHANES) 2001-2016 with at least one reliable 24-hour dietary recall were included in the analysis (n=39,799). Total and component HEI-2015 scores were calculated per person using a single recall. Linear regression models accounting for the complex sampling design were used to assess associations between total and component HEI-2015 scores and CVD risk factors after adjustment for potential confounders. Significance of beta coefficients was defined by p&lt;0.01. Results: Total HEI-2015 score was positively associated with high-density lipoprotein cholesterol (HDL-C; ß±SE, 0.10±0.01 mg/dL) and inversely associated with BMI (-0.05±0 kg/m 2 ), waist circumference (WC; -0.13±0.01 cm), systolic blood pressure (SBP; -0.04±0.01 mmHg), low-density lipoprotein cholesterol (LDL-C; -0.09±0.03 mg/dL), triglycerides (-0.20±0.08 mg/dL), fasting glucose (-0.05±0.02 mg/dL), and insulin (-0.03±0.01 μU/mL). All component scores increased with total score. The Whole Grains and Fatty Acid Ratio components made the greatest contributions (both +0.12 points or 12%) to each one-unit increase in HEI-2015, followed by moderation components Refined Grains and Saturated Fat (both +0.11 or 11%). Increases in the Fatty Acid Ratio score were explained by decreasing saturated fat (-1.67 g/unit, 95% CI: -1.73 to -1.61) and increasing polyunsaturated fat (PUFA; 1.17 g/unit, 95% CI: 1.12, 1.22); increases in monounsaturated fats were relatively small (0.18 g/unit, 95% CI: 0.11 to 0.25). The predominant PUFA was linoleic acid, which increased 1.06 g/unit (95% CI: 1.02 to 1.11). Scores for grain-related components were favorably associated with BMI, WC, SBP and HDL-C; fat quality components were inversely associated with BMI, WC, HDL-C, LDL-C, and triglycerides. Conclusion: Diet quality is favorably associated with several CVD risk factors. Approximately 50% of each 1-point increase in HEI-2015 is related to the quality of grain-based products and fat sources. Choosing whole grains instead of refined grains, and PUFA in place of saturated fats, is associated with improvements in diet quality and cardiovascular health.
RTID-11. GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Meredith Buxton, Brian Alexander, Donald Berry, Webster Cavenee, Howard Colman, John de Groot, Benjamin Ellingson, Gary Gordon, Mustafa Khasraw, Andrew Lassman, Wenbin Lee, Michael Lim, Ingo Mellinghoff, James Perry, Erik Sulman, Kirk Tanner, Michael Weller, Patrick Wen, W K Alfred Yung, Timothy Cloughesy, G B M Agile Investigators
Journal: Neuro-Oncology (2020)

Abstract Developing new therapies for patients with glioblastoma (GBM) requires focused interaction between industry, academia, nonprofits, patient advocacy, and health authorities, and novel approaches to clinical trials. GBM Adaptive Global Innovative Learning Environment (GBM AGILE) Trial was designed by over 130 global key opinion leaders in consultation with health authorities to provide an optimal mechanism for phase 2/3 development in GBM. The Sponsor of GBM AGILE is the Global Coalition for Adaptive Research, whose mission is to accelerate the development of treatments rare and deadly diseases by serving as sponsor of innovative trials. GBM AGILE is an international platform trial designed to evaluate multiple therapies in newly diagnosed and recurrent GBM. Its goals are to identify effective therapies for GBM and match effective therapies with patient subtypes, with data generated to support regulatory filing for new drug applications. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. The primary endpoint is overall survival. The trial is being conducted under a master Investigational New Drug Application/Clinical Trial Agreement and Master Protocol, allowing multiple drugs from different companies to be evaluated simultaneously and/or over time. The plan is to add experimental therapies as new information is identified and remove therapies as they complete their individual evaluation against a common control. GBM AGILE received IND approval from the FDA in April 2019, screening its first patient in June 2019. As of June 2020 over 200 patients have been screened. Expansion to Canada, Europe, China, and Australia is also underway. There is currently one investigational arm under evaluation in the trial, with two additional arms to be added in Q4 2020/ Q1 2021. Clinical trial information: NCT03970447.
RADT-23. IMPACT OF REIRRADIATION UTILIZING STEREOTACTIC RADIOSURGERY ON RECURRENT GLIOBLASTOMA
Authors: O’Dell Patrick, H Nickols, R LaRocca, K Sinicrope, D Sun, A Spalding
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients who have recurrent glioblastoma have limited treatment options. We conducted a retrospective review of patients with recurrent glioblastoma treated with standard initial radiation and temozolomide with tumor treating fields to investigate whether reirradiation using radiosurgery would be associated with improved outcomes. METHODS We reviewed the records of 54 consecutively treated patients with recurrent glioblastoma with ECOG 0 or 1 at recurrence and conducted Kaplan-Meier analysis with Log-rank testing to determine significance between groups. RESULTS We identified 24 patients who were treated without radiation therapy (control) while 30 patients underwent re-irradiation using radiosurgery (ReSRS) with a median total dose of 25Gy in five fractions. All patients had completed standard initial therapy, and there was no difference in the time to recurrence between the two groups (10 months for control, 15 months for ReSRS, [P = 0.17, HR for progression 0.65 (95% CI 0.38-1.13)]. A larger proportion of patients in the control arm (54%) had subtotal or gross total resection of the recurrence compared with the ReSRS group (44%, P &amp;lt; 0.05). The majority of patients had recurrence confirmed with biopsy (18/22 in control group, 25/31 in the ReSRS group). MGMT methylation status did not differ between control vs ReSRS (29% vs. 27%). ReSRS was associated with improved median survival from the time of first recurrence of 11.6 months versus 3.8 months in the control arm [P&amp;lt; 0.0001, HR for death 0.33 (95% CI 0.18-0.6)]. CONCLUSIONS In a group of patients with high performance status diagnosed with recurrent glioblastoma, reirradiation with stereotactic radiosurgery was associated with nearly one year median survival after recurrence. Additional analyses are warranted to determine the impact of concurrent systemic therapies with irradiation and underlying tumor or patient factors to predict outcomes.
The cost-effectiveness of banning highly hazardous pesticides to prevent suicides due to pesticide self-ingestion across 14 countries: an economic modelling study
Authors: Y Y Lee, D Chisholm, M Eddleston, D Gunnell, A Fleischmann, F Konradsen, M Y Bertram, C Mihalopoulos, R Brown, D F Santomauro, J Schess, M van Ommeren
Journal: The Lancet Global Health (2020)

BackgroundReducing suicides is a key Sustainable Development Goal target for improving global health. Highly hazardous pesticides are among the leading causes of death by suicide in low-income and middle-income countries. National bans of acutely toxic highly hazardous pesticides have led to substantial reductions in pesticide-attributable suicides across several countries. This study evaluated the cost-effectiveness of implementing national bans of highly hazardous pesticides to reduce the burden of pesticide suicides.MethodsA Markov model was developed to examine the costs and health effects of implementing a national ban of highly hazardous pesticides to prevent suicides due to pesticide self-poisoning, compared with a null comparator. We used WHO cost-effectiveness and strategic planning (WHO-CHOICE) methods to estimate pesticide-attributable suicide rates for 100 years from 2017. Country-specific costs were obtained from the WHO-CHOICE database and denominated in 2017 international dollars (I$), discounted at a 3% annual rate, and health effects were measured in healthy life-years gained (HLYGs). We used a demographic projection model beginning with the country population in the baseline year (2017), split by 1-year age group and sex. Country-specific data on overall suicide rates were obtained for 2017 by age and sex from the Global Burden of Disease Study 2017 Data Resources. The analysis involved 14 countries spanning low-income to high-income settings, and cost-effectiveness ratios were analysed at the country-specific level and aggregated according to country income group and the proportion of suicides due to pesticides.FindingsBanning highly hazardous pesticides across the 14 countries studied could result in about 28 000 (95% uncertainty interval [UI] 24 000–32 000) fewer suicide deaths each year at an annual cost of I$0·007 per capita (95% UI 0·006–0·008). In the population-standardised results for the base case analysis, national bans produced cost-effectiveness ratios of $94 per HLYG (95% UI 73–123) across low-income and lower-middle-income countries and $237 per HLYG (95% UI 191–303) across upper-middle-income and high-income countries. Bans were more cost-effective in countries where a high proportion of suicides are attributable to pesticide self-poisoning, reaching a cost-effectiveness ratio of $75 per HLYG (95% UI 58–99) in two countries with proportions of more than 30%.InterpretationNational bans of highly hazardous pesticides are a potentially cost-effective and affordable intervention for reducing suicide deaths in countries with a high burden of suicides attributable to pesticides. However, our study findings are limited by imperfect data and assumptions that could be improved upon by future studies.FundingWHO.
NCOG-71. GENOME ASSOCIATIONS WITH NEUROCOGNITIVE OUTCOMES, CEREBRAL MICROBLEEDS (CMBS), AND BRAIN VOLUME AND WHITE MATTER (WM) CHANGES IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Cassie Kline, Schuyler Stoller, Lennox Byer, Caleb Edwards, Rachna Prasad, Joseph Torkildson, Karen Gauvain, David Samuel, Janine Lupo, Melanie Morrison, Elizabeth Tong, Solomiia Savchuk, Christian Rodrigo Ugaz Valencia, Andreas Rauschecker, Jeffrey Rudie, Thomas Hoffmann, Dena Dubal, Heather Fullerton, Sabine Mueller
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To identify genetic predictors of neurocognition, CMBs, brain volume, and WM changes in pediatric brain tumor survivors. METHODS Patients were selected from an existing cohort (RadART) if they had: 1) at least one neurocognitive evaluation using computer-based CogState; 2) available DNA; 3) standard imaging. Candidate gene or genome-wide genotyping was performed on all patients. CMBs were identified using a semi-automated algorithm developed in MATLAB. Volume of T2/FLAIR WM signal abnormality was measured using a semi-automated method based on a convolutional neural network. Brain volume and cortical thickness were measured using FreeSurfer volumetric analysis. Logistic and linear regression were done to compare phenotypes with candidate genotypes. Genome-wide efficient mixed-model analysis was done to compare neurocognition and CMBs. Gene set analysis was done using https://fuma.ctglab.nl/. RESULTS APOE4 was a candidate variant associated with non-lobar, larger volume CMBs (p&amp;lt; 0.05). At the GWAS-level (n=225), specific genes trended with visual memory, psychomotor function, and CMB count (p&amp;lt; 5x10-8). Using gene set analyses, there were gene set trends seen with CMB count and psychomotor function. Small sample size and low mutant allele frequency limited reliability of these findings. Preliminary volumetric analysis show reduced volume within the right parietal, medial occipital and inferior temporal lobes with increased cortical thickness in the left occipital and medial parietal lobe in patients carrying the ApoE4 allele. WM signal assessments are ongoing. CONCLUSION Genetic markers may be associated with neurocognition, CMBs, brain volume and WM changes in pediatric brain tumor survivors; however, larger cohorts are needed to confirm specific gene relevance.
PCL and PCL/bioactive glass biomaterials as carriers for biologically active polyphenolic compounds: Comprehensive physicochemical and biological evaluation
Authors: Michal Dziadek, Kinga Dziadek, Kamila Checinska, Barbara Zagrajczuk, Monika Golda-Cepa, Monika Brzychczy-Wloch, Elzbieta Menaszek, Aneta Kopec, Katarzyna Cholewa-Kowalska
Journal: Bioactive Materials (2020)

In this work, polymeric and bioactive glass (BG)-modified composite films were successfully loaded with polyphenols (PPh) extracted from sage. It was hypothesized that PPh, alone and in combination with BGs particles, would affect physicochemical and biological properties of the films. Furthermore, sol-gel-derived BG particles would serve as an agent for control the release of the polyphenolic compounds, and other important properties related to the presence of PPh. The results showed that polyphenolic compounds significantly modified numerous material properties and also acted as biologically active substances. On the one hand, PPh can be considered as plasticizers for PCL, on the other hand, they can act as coupling agent in composite materials, improving their mechanical performance. The presence of PPh in materials improved their hydrophilicity and apatite-forming ability, and also provided antioxidant activity. What is important is that the aforementioned properties and kinetics of PPh release can be modulated by the use of various concentrations of PPh, and by the modification of PCL matrix with sol-gel-derived BG particles, capable of binding PPh. The films containing the lowest concentration of PPh exhibited cytocompatibility, significantly increased alkaline phosphatase activity and the expression of bone extracellular matrix proteins (osteocalcin and osteopontin) in human normal osteoblasts, while they reduced intracellular reactive oxygen species production in macrophages. Furthermore, materials loaded with PPh showed antibiofilm properties against Gram positive and Gram negative bacteria. The results suggest that obtained materials represent potential multifunctional biomaterials for bone tissue engineering with a wide range of tunable properties.
Surgery, angioplasty, or medical therapy for symptomatic multivessel coronary artery disease: Is there an indisputable “winning strategy” from evidence-based clinical trials?**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: William E Boden
Journal: Journal of the American College of Cardiology (2004)
The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis
Authors: Vicente Arroyo, Paolo Angeli, Richard Moreau, Rajiv Jalan, Joan Clària, Jonel Trebicka, Javier Fernández, Thierry Gustot, Paolo Caraceni, Mauro Bernardi
Journal: Journal of Hepatology (2020)

Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and left ventricular dysfunction, hepatic encephalopathy to hyperammonaemia, and variceal haemorrhage to portal hypertension. Recent large-scale European observational studies have shown that systemic inflammation is a hallmark of AD. Here we present a working hypothesis, the systemic inflammation hypothesis, suggesting that systemic inflammation through an impairment of the functions of one or more of the major organ systems may be a common theme and act synergistically with the traditional mechanisms involved in the development of AD. Systemic inflammation may impair organ system function through mechanisms which are not mutually exclusive. The first mechanism is a nitric oxide-mediated accentuation of the preexisting splanchnic vasodilation, resulting in the overactivation of the endogenous vasoconstrictor systems which elicit intense vasoconstriction and hypoperfusion in certain vascular beds, in particular the renal circulation. Second, systemic inflammation may cause immune-mediated tissue damage, a process called immunopathology. Finally, systemic inflammation may induce important metabolic changes. Indeed, systemic inflammatory responses are energetically expensive processes, requiring reallocation of nutrients (glucose, amino acids and lipids) to fuel immune activation. Systemic inflammation also inhibits nutrient consumption in peripheral (non-immune) organs, an effect that may provide one mechanism of reallocation and prioritisation of metabolic fuels for inflammatory responses. However, the decrease in nutrient consumption in peripheral organs may result in decreased mitochondrial production of ATP (energy) and subsequently impaired organ function.
Dual role of Snail transcription factor in epithelial to mesenchymal transition and neuroendocrine differentiation in human prostate cancer cells
Authors: Valerie Odero-Marah, Chunmeng Shi, Haiyen Zhau, Leland Chung
Journal: Cancer Research (2007)

1027  Snail transcription factor induces EMT via decreased cell adhesion-associated molecules like E-cadherin, and increased mesenchymal markers like vimentin. We transfected Snail transcription factor cDNA into LNCaP or ARCaP cells to establish an EMT model, and to investigate the molecular mechanisms by which EMT promotes tumor progression in prostate cancer cells. Overexpression of Snail resulted in an EMT characterized by redistribution of E-cadherin from predominantly cell membrane to intracellular in LNCaP cells, and decreased E-cadherin expression in ARCaP cells, while vimentin expression was increased in both cell lines. Biologically, the ARCaP- and LNCaP- Snail transfected cells were more migratory while the LNCaP-Snail transfectant was less proliferative in vitro. Interestingly, Snail transfection into LNCaP cells resulted in cells acquiring a neuroendocrine (NE) morphology with long neurite-like processes. Furthermore these cells displayed increase in the neuroendocrine markers, neuron specific enolase (NSE) and chromogranin A (CgA) as well as translocation of androgen receptor to the nucleus. Conditioned medium from the LNCaP-Snail transfectants increased proliferation of LNCaP and PC-3 parental cells. Overall our data provide evidence that Snail transcription factor may promote tumor aggressiveness through multiple processes; induction of EMT may be required to promote migration and subsequent metastasis, while a novel role for Snail in NE differentiation may promote tumor proliferation of surrounding cancer cells. Therefore, therapeutic targeting of Snail may prove beneficial in not only abrogating EMT but also NE differentiation.
Abstract 16567: Serum Soluble Klotho As A Novel Biomarker For Coronary Artery Calcification Of Culprit Lesions In Patients With Stable Angina Pectoris
Authors: Seiji Koga, Satoshi Ikeda, Rhohei Akashi, Yuki Yamagata, Tsuyoshi Yonekura, Hiroaki Kawano, Koji Maemura
Journal: Circulation (2019)

Introduction: Klotho, which was originally identified as an aging suppressor, is a key regulator of bone and mineral metabolism. Transmembrane and soluble forms of Klotho protein have been identifi...