tbuckley/cabot-search huggingface dataset:
The Role of Peroxisome Proliferator–Activated Receptor Gamma (PPARγ) in Mono(2-ethylhexyl) Phthalate (MEHP)-Mediated Cytotrophoblast Differentiation
Authors: Hussein Shoaito, Julia Petit, Audrey Chissey, Nicolas Auzeil, Jean Guibourdenche, Sophie Gil, Olivier Laprévote, Thierry Fournier, Séverine A. Degrelle
Journal: Environmental Health Perspectives (2019)

Background: Phthalates are environmental contaminants commonly used as plasticizers in polyvinyl chloride (PVC) products. Recently, exposure to phthalates has been associated with preterm birth, low birth weight, and pregnancy loss. There is limited information about the possible mechanisms linking maternal phthalate exposure and placental development, but one such mechanism may be mediated by peroxisome proliferator–activated receptor γ (PPARγ). PPARγ belongs to the nuclear receptor superfamily that regulates, in a ligand-dependent manner, the transcription of target genes. Studies of PPARγ-deficient mice have demonstrated its essential role in lipid metabolism and placental development. In the human placenta, PPARγ is expressed in the villous cytotrophoblast (VCT) and is activated during its differentiation into syncytiotrophoblast. Objectives: The goal of this study was to investigate the action of mono(2-ethylhexyl) phthalate (MEHP) on PPARγ activity during in vitro differentiation of VCTs. Methods: We combined immunofluorescence, PPARγ activity/hCG assays, western blotting, and lipidomics analyses to characterize the impacts of physiologically relevant concentrations of MEHP (0.1, 1, and 10μM) on cultured VCTs isolated from human term placentas. Results: Doses of 0.1μM and 1μM MEHP showed significantly lower PPARγ activity and less VCT differentiation in comparison with controls, whereas, surprisingly, a 10μM dose had the opposite effect. MEHP exposure inhibited hCG production and significantly altered lipid composition. In addition, MEHP had significant effects on the mitogen-activated protein kinase (MAPK) pathway. Conclusions: This study suggests that MEHP has a U-shaped dose–response effect on trophoblast differentiation that is mediated by the PPARγ pathway and acts as an endocrine disruptor in the human placenta. https://doi.org/10.1289/EHP3730
NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 5.2018
Authors: David S. Ettinger, Dara L. Aisner, Douglas E. Wood, Wallace Akerley, Jessica Bauman, Joe Y. Chang, Lucian R. Chirieac, Thomas A. D'Amico, Thomas J. Dilling, Michael Dobelbower, Ramaswamy Govindan, Matthew A. Gubens, Mark Hennon, Leora Horn, Rudy P. Lackner, Michael Lanuti, Ticiana A. Leal, Rogerio Lilenbaum, Jules Lin, Billy W. Loo, Renato Martins, Gregory A. Otterson, Sandip P. Patel, Karen Reckamp, Gregory J. Riely, Steven E. Schild, Theresa A. Shapiro, James Stevenson, Scott J. Swanson, Kurt Tauer, Stephen C. Yang, Kristina Gregory, Miranda Hughes
Journal: Journal of the National Comprehensive Cancer Network (2018)

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.
SP0068 Links between Angiogenesis, Inflammation and Pain in OA
Authors: D.A. Walsh
Journal: Annals of the Rheumatic Diseases (2016)

Pain is the most troublesome symptom for people with arthritis, and yet the relationships between pathological change within the joint and symptoms are often weak. Key progress on understanding which specific pathological processes contribute to the generation of pain signals from the arthritic joint have pointed to new blood vessel growth (angiogenesis). Angiogenesis is a component of normal tissue growth and even pathological angiogenesis need not of itself cause pain, for example in diabetic retinopathy. However, angiogenesis is also characteristic of chronic inflammation, and the various growth factors and cytokines that stimulate blood vessel growth can also induce sensitisation of peripheral sensory nerves. Furthermore, vascular growth factors can also stimulate neuronal growth and, reciprocally, nerve growth factors might be angiogenic. This close interplay between vascular and neuronal growth is reflected in the normal sequence by which angiogenesis is followed by the extension of sensory nerve terminals, often into diseased tissues that would not normally receive innervation nor be a source of pain. Examples of tissues that might be sources of pain from arthritic, but not normal joints include the non-calcified articular cartilage and inner two thirds of knee menisci. Angiogenesis might also facilitate inflammation, permitting increased cellular recruitment, concomitant release of other neuronal sensitising factors and exacerbation of structural change. Furthermore, blood vessel growth is a prerequisite for endochondral ossification, contributing directly to structural change and altered biomechanics within the joint. Angiogenesis might be a marker for other pathological processes associated with pain. For example, vascular breaching of the osteochondral junction in OA is associated with subchondral marrow replacement by fibrovascular tissues that is characteristic of some bone marrow lesions observed by MRI scanning. Angiogenesis inhibitors have potential to prevent or relieve arthritis pain, but their application to human arthritis has been limited by potential toxicity that might result from inhibition of physiological angiogenesis (e.g. during the menstrual cycle or pregnancy) or tissue repair. Reduction of pain by angiogenesis inhibitors might result from indirect effects on inflammation that could be achieved by other strategies. However, more recent research into the plurality of effects of vascular endothelial growth factor and its isoforms suggests that inhibition of angiogenic factors might also directly influence pain transmission in the central nervous system, independent of effects on blood vessel growth. Continuing research into angiogenesis in arthritis is revealing previously unexpected insights into the relationship between joint structure and patient symptoms, particularly pain. <h3>Disclosure of Interest</h3> None declared
Performance Characteristics of Fecal Immunochemical Tests for Colorectal Cancer and Advanced Adenomatous Polyps
Authors: Thomas F. Imperiale, Rachel N. Gruber, Timothy E. Stump, Thomas W. Emmett, Patrick O. Monahan
Journal: Annals of Internal Medicine (2019)

Studies report inconsistent performance of fecal immunochemical tests (FITs) for colorectal cancer (CRC) and advanced adenomas.To summarize performance characteristics of FITs for CRC and advanced adenomas in average-risk persons undergoing screening colonoscopy (reference standard) and to identify factors affecting these characteristics.Ovid MEDLINE, PubMed, Embase, and the Cochrane Library from inception through October 2018; reference lists of studies and reviews.Two reviewers independently screened records to identify published English-language prospective or retrospective observational studies that evaluated FIT sensitivity and specificity for colonoscopic findings in asymptomatic, average-risk adults.Two authors independently extracted data and evaluated study quality.Thirty-one studies (120 255 participants; 18 FITs) were included; all were judged to have low to moderate risk of bias. Performance characteristics depended on the threshold for a positive result. A threshold of 10 µg/g resulted in sensitivity of 0.91 (95% CI, 0.84 to 0.95) and a negative likelihood ratio of 0.10 (CI, 0.06 to 0.19) for CRC, whereas a threshold of greater than 20 µg/g resulted in specificity of 0.95 (CI, 0.94 to 0.96) and a positive likelihood ratio of 15.49 (CI, 9.82 to 22.39). For advanced adenomas, sensitivity was 0.40 (CI, 0.33 to 0.47) and the negative likelihood ratio was 0.67 (CI, 0.57 to 0.78) at 10 µg/g, and specificity was 0.95 (CI, 0.94 to 0.96) and the positive likelihood ratio was 5.86 (CI, 3.77 to 8.97) at greater than 20 µg/g. Studies had low to high heterogeneity, depending on the threshold. Although several FITs had adequate performance, sensitivity and specificity for CRC for 1 qualitative FIT were 0.90 and 0.91, respectively, at its single threshold of 10 µg/g; positive and negative likelihood ratios were 10.13 and 0.11, respectively. Comparison of 3 FITs at 3 thresholds was inconclusive: CIs overlapped, and the comparisons were across rather than within studies.Only English-language studies were included. Incomplete reporting limited quality assessment of some evidence. Performance characteristics are for 1-time rather than serial testing.Single-application FITs have moderate to high sensitivity and specificity for CRC, depending on the positivity threshold. Sensitivity of 1-time testing for advanced adenomas is low, regardless of the threshold.Department of Medicine, Indiana University School of Medicine.
Thrombin-Generating Capacity of Microvesicles (MVs) in Patients with Immune Thrombocytopenia (ITP) before and during Treatment with Thrombopoietin-Receptor Agonists (TPO-RA)
Authors: Lamya Garabet, Waleed Ghanima, Marit Hellum, Per Morten Sandset, James B. Bussel, Carola E. Henriksson
Journal: Blood (2018)
Abstract 5455: Integrative analysis of the Cancer Cell Line Encyclopedia reveals genetic and transcriptional predictors of compound sensitivity
Authors: Jordi Barretina, Nicolas Stransky, Giordano Caponigro, Sungjoon Kim, Adam Margolin, Kavitha Venkhatesan, Gregory Kryukov, Michael Berger, John Monahan, Paula Morais, Jodi Meltzer, Scott Mahan, Dmitriy Sonkin, Pichai Raman, Michael Jones, Vic Meyer, Christopher Wilson, Joseph Thibault, Lauren Murray, Adam Callahan, John Che, Aaron Shipway, Nanxin Li, Ingo Engels, Andrew Su, Reid Pinchback, Jared Nedzel, Ted Liefeld, Lili Niu, Charles Hatton, Emanuele Palescandolo, Supriya Gupta, Robert Onofrio, Carrie Sougnez, Laura MacConaill, Wendy Winckler, Michael Reich, Jill Mesirov, Kristin Ardlie, Gad Getz, Michael Morrissey, Markus Warmuth, Matthew Meyerson, Peter Finan, Todd Golub, Barbara Weber, Jennifer Harris, William Sellers, Robert Schlegel, Levi Garraway
Journal: Cancer Research (2011)

Abstract Comprehensive genomic characterization of cancer is proceeding at a rapidly accelerating pace, mainly due to the expanded use of massively parallel sequencing. Despite the promise of cancer genomics, many cancer drugs still fail in the clinic due to nonresponsive patients and this translates into a significant unmet medical need. Accurate predictions of which patients are more likely to respond to drugs in development could speed clinical trials and personalize treatments. Here we propose the use of a compendium of experimentally tractable cancer model systems, ∼1000 human genomically-annotated cancer cell lines (at the level of gene expression, DNA copy number alterations and mutations), coupled with pharmacological profiling, to systematically link genetic and transcriptional features to drug response. This resource, the Cancer Cell Line Encyclopedia (CCLE), is available online at www.broadinstitute.org/ccle. Through computational predictive modeling we have both rediscovered molecular features that predict response to several drugs and also uncovered a number of novel potential biomarkers of sensitivity and resistance to targeted agents and chemotherapy drugs. For instance, we have found that response to topoisomerase 1 inhibitors seem to be driven by expression of a single gene. We have also observed that tissue lineage is a key predictor for sensitivity to certain compounds, providing rationale for clinical trials of these drugs in particular cancer types. Our cell line-based platform provides a valuable tool for the development of personalized cancer medicine, revealing critical tumor dependencies and helping to stratify patients for clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5455. doi:10.1158/1538-7445.AM2011-5455
Plasma HER2 (<i>ERBB2</i>) Copy Number Predicts Response to HER2-targeted Therapy in Metastatic Colorectal Cancer
Authors: Giulia Siravegna, Andrea Sartore-Bianchi, Rebecca J. Nagy, Kanwal Raghav, Justin I. Odegaard, Richard B. Lanman, Livio Trusolino, Silvia Marsoni, Salvatore Siena, Alberto Bardelli
Journal: Clinical Cancer Research (2019)

ERBB2 (HER2) amplification is an emerging biomarker in colon cancer, conferring sensitivity to combination anti-HER2 therapy. Measurement of HER2 copy number is typically performed using surgical specimens, but cell-free circulating tumor DNA (ctDNA) analysis may be a noninvasive alternative. We determined the sensitivity of plasma copy number (pCN) for detecting ERBB2 amplifications and whether pCN correlated with tissue-detected copy number. We also assessed response to HER2-targeted therapy based on pCN and suggest a pCN threshold predictive of response.Forty-eight pretreatment and progression plasma samples from 29 HER2-positive patients in the HERACLES A clinical trial were tested using the Guardant360 cfDNA assay. We correlated ERRB2 pCN with progression-free survival (PFS) and best objective response (BOR) and applied an adjustment method based on tumor DNA shedding using the maximum mutant allele fraction as a surrogate for tumor content to accurately determine the pCN threshold predictive of response.Forty-seven of 48 samples had detectable ctDNA, and 46 of 47 samples were ERBB2-amplified on the basis of cfDNA [2.55-122 copies; 97.9% sensitivity (95% confidence interval, 87.2%-99.8%)]. An adjusted ERBB2 pCN of ≥25.82 copies correlated with BOR and PFS (P = 0.0347).cfDNA is a viable alternative to tissue-based genotyping in the metastatic setting. The cfDNA platform utilized correctly identified 28 of 29 (96.6%) of pretreatment samples as ERBB2-amplified and predicted benefit from HER2-targeted therapy. In this study, an observed pCN of 2.4 and an adjusted pCN of 25.82 copies of ERBB2 are proposed to select patients who will benefit from HER2-targeted therapy.
Interim Estimates of 2021–22 Seasonal Influenza Vaccine Effectiveness — United States, February 2022
Authors: Jessie R. Chung, Sara S. Kim, Rebecca J. Kondor, Catherine Smith, Alicia P. Budd, Sara Y. Tartof, Ana Florea, H. Keipp Talbot, Carlos G. Grijalva, Karen J. Wernli, C. Hallie Phillips, Arnold S. Monto, Emily T. Martin, Edward A. Belongia, Huong Q. McLean, Manjusha Gaglani, Michael Reis, Krissy Moehling Geffel, Mary Patricia Nowalk, Juliana DaSilva, Lisa M. Keong, Thomas J. Stark, John R. Barnes, David E. Wentworth, Lynnette Brammer, Erin Burns, Alicia M. Fry, Manish M. Patel, Brendan Flannery
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

In the United States, annual vaccination against seasonal influenza is recommended for all persons aged ≥6 months. Each season since 2004-05, CDC has estimated the effectiveness of seasonal influenza vaccine to prevent influenza-associated, medically attended acute respiratory illness (ARI). This report uses data from 2,319 children and adults enrolled in the U.S. Influenza Vaccine Effectiveness (Flu VE) Network during December 2, 2013-January 23, 2014, to estimate an interim adjusted effectiveness of seasonal influenza vaccine for preventing laboratory-confirmed influenza virus infection associated with medically attended ARI. During this period, overall vaccine effectiveness (VE) (adjusted for study site, age, sex, race/ethnicity, self-rated health, and days from illness onset to enrollment) against influenza A and B virus infection associated with medically attended ARI was 61%. The influenza A (H1N1)pdm09 (pH1N1) virus that emerged to cause a pandemic in 2009 accounted for 98% of influenza viruses detected. VE was estimated to be 62% against pH1N1 virus infections and was similar across age groups. As of February 8, 2014, influenza activity remained elevated in the United States, the proportion of persons seeing their health-care provider for influenza-like illness was lower than in early January but remained above the national baseline, and activity still might be increasing in some parts of the country. CDC and the Advisory Committee on Immunization Practices routinely recommend that annual influenza vaccination efforts continue as long as influenza viruses are circulating. Persons aged ≥6 months who have not yet been vaccinated this season should be vaccinated. Antiviral medications are an important second line of defense to treat influenza illness and should be used as recommended among suspected or confirmed influenza patients, regardless of patient vaccination status. Early antiviral treatment is recommended for persons with suspected influenza with severe or progressive illness (e.g., hospitalized persons) and those at high risk for complications from influenza, no matter how severe the illness.
Novel Functional Renal PET Imaging With 18F-FDS in Human Subjects
Authors: Rudolf A. Werner, Alvaro A. Ordonez, Julian Sanchez-Bautista, Charles Marcus, Constantin Lapa, Steven P. Rowe, Martin G. Pomper, Jeffrey P. Leal, Martin A. Lodge, Mehrbod S. Javadi, Sanjay K. Jain, Takahiro Higuchi
Journal: Clinical Nuclear Medicine (2019)

The novel PET probe 2-deoxy-2-F-fluoro-D-sorbitol (F-FDS) has demonstrated favorable renal kinetics in animals. We aimed to elucidate its imaging properties in 2 human volunteers. F-FDS was produced by a simple 1-step reduction from F-FDG. On dynamic renal PET, the cortex was delineated and activity gradually transited in the parenchyma, followed by radiotracer excretion. No adverse effects were reported. Given the higher spatiotemporal resolution of PET relative to conventional scintigraphy, F-FDS PET offers a more thorough evaluation of human renal kinetics. Due to its simple production from F-FDG, F-FDS is virtually available at any PET facility with radiochemistry infrastructure.
Abstract 4672: Anti-angiogenic effects of zoledronic acid on osteotropic breast cancer cells
Authors: Cynthia Contreras, Shaghayegh Morshedian, Walid Hamud, Bishal Dhakal, Bijay Khanal, Jason A. Bush
Journal: Cancer Research (2012)

Abstract Emerging data suggest the bisphosphonate, zoledronic acid (ZOL), exerts both indirect and direct anti-tumor effects by decreasing tumor cell proliferation, increasing apoptosis, and inhibiting angiogenesis. Recent data indicate that anti-angiogenic factors exert cellular effects via suppression of mitochondrial oxidative phosphorylation/respiration and elevation of intracellular ROS levels. This project intended to define proteins involved in response to ZOL-treatment of an osteotropic breast cancer cell line, MDA-231BO. Results demonstrate that MDA-231BO cells are more sensitive to ZOL cytotoxicity and salutary effects are both media- and calcium-dependent. To investigate pro-apoptotic mechanisms of ZOL, total RNA, whole cell protein lysates, or mitochondrial-enriched fractions were isolated from MDA-231BO cells and using a combination of RT-PCR, 1D/2D-PAGE separation and MALDI-MS/MS, we identified several angiogenesis inhibitors that were upregulated and pro-angiogenic factors that were downregulated after ZOL treatment. Functional studies demonstrate the improved efficacy of ZOL on MDA-231BO compared to MDA-MB-231 controls. Taken together, these results further support a model that ZOL tips the ‘angiogenic switch’ in favor of anti-angiogenic factors in cancer cells with a propensity for bone metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4672. doi:1538-7445.AM2012-4672
Abstract 5778: Fragment-based drug discovery of selective inhibitors of fibroblast growth factor receptor (FGFr)
Authors: Gordon Saxty, M S. Squires, C W. Murray, V Berdini, G A. Ward, D Miller, S J. Rich, A Cleasby, S M. Saalau-Bethell, J Coyle, A Madin, M G. Carr, M A. O'Brien, C Griffiths Jones, E Vickerstaff, R K. Nijjar, B Graham, A Pike, E J. Lewis, T Perera, P Angibaud, H Newell
Journal: Cancer Research (2010)

Abstract Recent data in a number of tumour types has implicated Fibroblast Growth Factor (FGF) and Fibroblast Growth Factor receptor (FGFr) signalling as being key to the molecular pathology of cancer. This poster will describe fragment based drug discovery using biophysical screening to identify initial fragments. Subsequently, in the fragments-to-leads stage a detailed structural understanding of the binding interactions between the fragment and its target protein utilised X-ray crystallography and NMR. Starting with different fragments allows several lead series to be identified, often by synthesizing only small numbers of compounds. A fragment screening campaign was conducted against the FGFr-1 to detect very low molecular weight compounds that bound to the hinge region of the kinase. The screening produced several fragment molecules (Molecular Weight &amp;lt;250 Da) which were in the micromolar range and confirmed binding mode in X-ray crystallography. One X-ray hit series that was 120 uM verse FGFr-3 will be described. Several iterations of structure-guided medicinal chemistry led to the identification of a lead compound with 3 nM affinity for FGFr-3, good cell activity and 30-fold selectivity verse VEGFr-2 with good oral activity. The lead was optimised to afford a compound that showed good PK/PD and efficacy. This poster represents first disclosure of the structure of the lead series and illustrates how a fragment-based drug discovery approach can be efficiently used to discover compounds advanced nanomolar compounds with oral bioavailability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5778.
Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies
Authors: Andres Forero-Torres, Radhakrishnan Ramchandren, Abdulraheem Yacoub, Michael S. Wertheim, William J. Edenfield, Paolo Caimi, Martin Gutierrez, Luke Akard, Carolina Escobar, Justin Call, Daniel Persky, Swaminathan Iyer, Douglas J. DeMarini, Li Zhou, Xuejun Chen, Fitzroy Dawkins, Tycel J. Phillips
Journal: Blood (2019)