tbuckley/cabot-search huggingface dataset:
Phase I Study of P-cadherin–targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors
Authors: Vivek Subbiah, William Erwin, Osama Mawlawi, Asa McCoy, David Wages, Catherine Wheeler, Carlos Gonzalez-Lepera, Holly Liu, Homer Macapinlac, Funda Meric-Bernstam, David S. Hong, Shubham Pant, Dao Le, Elmer Santos, Jose Gonzalez, Jason Roszik, Takeaki Suzuki, Ruth Ann Subach, Timothy Madden, Mary Johansen, Fumiko Nomura, Hirokazu Satoh, Tadashi Matsuura, Masamichi Kajita, Eri Nakamura, Yuichi Funase, Satoshi Matsushima, Gregory Ravizzini
Journal: Clinical Cancer Research (2020)

Abstract Purpose: 90Y-FF-21101 is an Yttrium-90–conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. Patients and Methods: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5–25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. Results: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. Conclusions: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.
“Autoinflammatory psoriasis”—genetics and biology of pustular psoriasis
Authors: Ranjitha Uppala, Lam C. Tsoi, Paul W. Harms, Bo Wang, Allison C. Billi, Emanual Maverakis, J. Michelle Kahlenberg, Nicole L. Ward, Johann E. Gudjonsson
Journal: Cellular and Molecular Immunology (2020)
Abstract 6562: Design, synthesis and anticancer properties of trans-cinnamaldehyde and curcumin based scaffolds compounds
Authors: Abdel-Sattar M. Omar, Ahmed M. Al-Abd
Journal: Cancer Research (2020)

Abstract Cinnamaldehyde and curcumin scaffolds are known for their anticancer potential via reactive oxygen species (ROS) generation and cellular damage. Herein, we synthesized a set of heterocyclic compounds build on the naturally-occurring trans-cinnamaldehyde and curcumin scaffolds and assessed their antiproliferative/cytotoxic properties against hepatocellular carcinoma (HepG2), breast adenocarcinoma (MCF-7) and colorectal cancer cells (HCT-116). The general structure of the synthesized compounds comprised 2-(4-fluorophenyl)-4-imidazolone nucleus attached to a 2-phenylpropylidene moiety. The imidazolone's N1 diversity point was attached to a variety of groups that are different in steric as well as electronic properties. Compounds FC01, FC09, FC11, FC12, FC14, FC30 and FC37 (groups attached to N1 diversity point are phenyl, methyl, 4-methylpiperazinyl, n-propyl, 4-hydroxyphenyl, 2-furylmethyl, and 4-methoxyphenyl, respectively) showed considerable cytotoxicity with IC50 ranging from 0.1 to 11.9 µM against MCF-7, HepG2, and HCT-116 cells. Within one hour of exposure to the IC50's of compounds FC09, FC12 and FC31, total ROS was significantly increased to 143.3±1.2%, 158.2±8.6% and 138±9.3% of control. After 2 hours of exposure, compounds FC09, FC12, FC14, FC30 and FC31 significantly raised the total ROS by 148.3±2.1%, 144.2±5.9%, 112±3.1%, 134.8±10.3% and 140.7±5.7%, respectively. Interestingly, all compounds under investigation significantly raised the intracellular ROS within 1.5 h of exposure. After 24 h of exposure, only compounds FC01, FC07, FC30, and FC31 kept the intracellular level of ROS significantly higher than control cells (111.1±3.6, 113.8±4.3%, 110.4±2.2%, and 117.7±7.5%, respectively). On the other hand, the ROS level within cells treated with the IC50 of compounds FC09 and FC12 for 24 h was significantly lower than control cells (85.7±1.3 and 68.4±4.7, respectively). Apoptosis/necrosis differential assessment using annexin-V/FITC with PI as a counterstain coupled with flow cytometric analysis, showed that compounds FC01, FC09, and FC12 induced significant apoptosis as well as necrosis by 2-5 folds compared to control cells. Compound FC14 failed to induce any significant apoptosis or necrosis. In conclusion, trans-cinnamaldehyde and curcumin scaffold-based compounds under investigation, particularly FC01, FC09 and FC12 might represent promising candidates in anticancer molecules for further optimization. Citation Format: Abdel-Sattar M. Omar, Ahmed M. Al-Abd. Design, synthesis and anticancer properties of trans-cinnamaldehyde and curcumin based scaffolds compounds [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6562.
3P’s of Wermer/MEN1 Syndrome on 68Ga-DOTANOC PET/CT Scan
Authors: Sarthak Tripathy, Sneha Prakash, Sreedharan Thankarajan Arun Raj, Arunav Kumar, Shamim Ahmed Shamim
Journal: Clinical Nuclear Medicine (2020)

Wermer/MEN1 syndrome is composed of the triad of pancreatic, pituitary, and parathyroid (3P's) tumors. We describe the Ga-DOTANOC PET/CT findings of a 43-year-old man, which revealed the classic 3P's of MEN1 syndrome with somatostatin receptor expression. The patient further underwent surgery for parathyroid lesions, which were suggestive of adenomas.
Efficacy and Safety Over 2 Years of Exenatide Plus Dapagliflozin in the DURATION-8 Study: A Multicenter, Double-Blind, Phase 3, Randomized Controlled Trial
Authors: Serge A. Jabbour, Juan P. Frías, Azazuddin Ahmed, Elise Hardy, Jasmine Choi, C. David Sjöström, Cristian Guja
Journal: Diabetes Care (2020)

In patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin produced greater reductions in glycemic parameters (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], and 2-h postprandial glucose [2-h PPG]), weight, and systolic blood pressure (SBP) than exenatide QW or dapagliflozin alone after 28 weeks of treatment in DURATION-8. Following a 24-week extension period, improvements were sustained at 52 weeks. In this study, we investigated efficacy and safety at 104 weeks after randomization.DURATION-8 was a 104-week, multicenter, double-blind, randomized, active-controlled, phase 3 trial. In total, 695 adults (aged ≥18 years) with type 2 diabetes and inadequate glycemic control (HbA1c 8.0-12.0% [64-108 mmol/mol]) despite stable metformin monotherapy (≥1,500 mg/day) were randomly assigned (1:1:1) to receive exenatide 2 mg QW plus once-daily dapagliflozin 10 mg, exenatide QW plus placebo, or dapagliflozin plus placebo. All 104-week evaluations were exploratory.At week 104, 431 (62.0%) patients completed treatment. The adjusted least squares mean change (SE) from baseline to week 104 in HbA1c was greater with exenatide QW plus dapagliflozin (-1.70% [0.11]) versus exenatide QW plus placebo (-1.29% [0.12]; P = 0.007) and dapagliflozin plus placebo (-1.06% [0.12]; P < 0.001). Clinically relevant changes in FPG, 2-h PPG, weight, and SBP were also observed with exenatide QW plus dapagliflozin. There were no unexpected safety findings, and exenatide QW plus dapagliflozin was well tolerated, with no episodes of major hypoglycemia.In this exploratory analysis, among those individuals who completed the trial without rescue therapy, there was clinically relevant efficacy over 2 years with exenatide QW plus dapagliflozin, with no unexpected safety findings.
SAT0662 SERUM INFLAMMATORY ANGIOGENIC AND TISSUE REMODELING BIOMARKERS IN PERIPHERAL SPONDYLOARTHRITIS BEFORE AND AFTER IL-17A BLOCKADE
Authors: Merlijn Kaaij, Leonieke van Mens, Jan Piet van Hamburg, Dominique Baeten, Marleen van de Sande, Sander W. Tas
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Spondyloarthritis (SpA) is characterized by extensive angiogenesis, tissue remodeling and inflammation of both the enthesis and the synovial tissue. Several studies have shown a relation between angiogenic/tissue remodeling serum markers and disease progression. Secukinumab, an anti-IL-17A inhibitor, is an effective treatment in SpA, but it's effects on serum markers of angiogenesis, tissue remodeling and inflammation are largely unknown. <h3>Objectives:</h3> The purpose of this study was to analyze several candidate biomarkers of these processes in patients with SpA treated with anti-IL-17A. <h3>Methods:</h3> Serum samples from 20 active peripheral SpA patients that were included in a 12 week open-label trial with secukinumab were analyzed for several markers with luminex technology. Study design and primary results were previously published (1). <h3>Results:</h3> Serum levels of IL-6, MMP-3, osteopontin (all P &lt; 0.001), Vascular Endothelial Growth Factor A (VEGF-A), tumour necrosis factor (TNF)-alpha, IL-31, IL-33, S100A8, S100A9 (all P &lt; 0.05) decreased significantly upon treatment with anti-IL-17A. These serum level changes correspond with the clinical responses and the published effects on inflamed target tissues of this cohort. Meanwhile, serum levels of DKK-1, ROBO4, sclerostin and CD40L remained unchanged. <h3>Conclusion:</h3> These results indicate that anti-IL-17A not only diminishes inflammation, but also impacts on other processes such as angiogenesis and tissue remodeling. Whether these observations are predictive of disease progression or outcome remains to be determined. <h3>References</h3> [1] van Mens, L. J. J. et al. IL-17 blockade with secukinumab in peripheral spondyloarthritis impacts synovial immunopathology without compromising systemic immune responses. Arthritis Rheumatol. (2018). doi:10.1002/art.40581 <h3>Disclosure of Interests:</h3> Merlijn Kaaij: None declared, Leonieke van Mens: None declared, Jan Piet van Hamburg: None declared, Dominique Baeten Employee of: UCB Pharma, Marleen van de Sande Grant/research support from: Research support from Janssen, Novartis, Eli Lily, Consultant for: Received consultation fees from Abbvie and Novartis, Sander W. Tas: None declared
Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor
Authors: Peng Zhao, Jeremy L. Praissman, Oliver C. Grant, Yongfei Cai, Tianshu Xiao, Katelyn E. Rosenbalm, Kazuhiro Aoki, Benjamin P. Kellman, Robert Bridger, Dan H. Barouch, Melinda A. Brindley, Nathan E. Lewis, Michael Tiemeyer, Bing Chen, Robert J. Woods, Lance Wells
Journal: Cell Host & Microbe (2020)
THU0557 QUALITY ASSESSMENT OF CLINICAL PRACTICE GUIDELINES IN AXIAL AND PERIPHERAL SPONDYLOARTHRITIS: A SYSTEMATIC APPRAISAL
Authors: W. Bautista-Molano, E. Jauregui, L. Saldarriaga, M. X. Rojas, J. R. Pieschacón
Journal: Annals of the Rheumatic Diseases (2020)

Background: Clinical practice guidelines (CPG) in spondyloarthritis (SpA) serves as a tool for rheumatologists, health-care providers and patients in the selection of appropriate treatment framework in common clinical scenarios guiding decision-making processes. However, the quality of these guidelines has not yet been evaluated systematically in the field. Objectives: The aim of the study was to evaluate the quality of the CPG available for the treatment of axial and peripheral SpA. Methods: A systematic and scientific literature search between 2014 and 2019 was performed in order to identify and select CPG focused on the treatment of axial and peripheral SpA. The authors systematically searched the main guideline databases and guideline developer websites completing the search in PUBMED/MEDLINE and EMBASE. Four independent reviewers with methodological and clinical expertise in the field of SpA, assessed the eligible guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. Their degree of agreement was evaluated with the intra-class correlation coefficient (ICC). The statistical analyses as done using the R psych package. Results: Twelve CPG were selected for evaluation. The scores for each of the AGREE II domains were: scope and purpose 86% (range: 67–99%); stakeholder involvement 71% (range: 22–93%); rigour of development 61% (range: 29–82%); clarity and presentation 79% (range: 68–86%); applicability 48% (range: 21–71%); and editorial independence 72% (range: 19–92%). Most of the appraised guidelines could be recommended (n=12) or recommended with limitations (n=12) for use in clinical practice. The overall agreement among reviewers was moderate (ICC: 0.40; 95% CI 0.16 to 0.82). The CPG with the best quality assessment using the AGREE II instrument was the NICE guideline developed by the National Institute for Health and Care Excellence. A slightly higher quality assessment of CPG developed by research agencies or guideline developers was observed, in comparison to those developed by scientific societies. Figure 1. .ssessment cientific societies.eld of ocieties and XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX Conclusion: Quality assessment of guidelines for the treatment of axial and peripheral SpA is good with an average of 69%. However, a cut-off point has not been clearly established. Measures should be taken to assure that CPGs are based on the best available evidence and rigorously developed and reported. Additional efforts are needed to provide high-quality guidelines that serve as a useful and reliable instrument for clinical decision-making process in the field of SpA. Disclosure of Interests: None declared
Author Correction: Seroprevalence of immunoglobulin M and G antibodies against SARS-CoV-2 in China
Authors: Xin Xu, Jian Sun, Sheng Nie, Huiyuan Li, Yaozhong Kong, Min Liang, Jinlin Hou, Xianzhong Huang, Dongfeng Li, Tean Ma, Jiaqing Peng, Shikui Gao, Yong Shao, Hong Zhu, Johnson Yiu-Nam Lau, Guangyu Wang, Chunbao Xie, Li Jiang, Ailong Huang, Zhenglin Yang, Kang Zhang, Fan Fan Hou
Journal: Nature Medicine (2020)
DNA adduct formation and induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide or glycidamide
Authors: Linda S. Von Tungeln, Mona I. Churchwell, Daniel R. Doerge, Lynda J. McGarrity, Suzanne M. Morris, Robert H. Heflich, Gonçalo Gamboa Da Costa, M. Matilde Marques, Frederick A. Beland
Journal: Cancer Research (2005)

2110  Acrylamide, a water-soluble α,β-unsaturated amide, is a high-volume industrial chemical, a component of cigarette smoke, and more recently, has been detected as a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread. Acrylamide is a carcinogen in experimental animals; however, the mechanism of tumor induction is controversial, with both genotoxic and nongenotoxic pathways being proposed. Since neonatal mice are very sensitive to the effects of genotoxic carcinogens, we have compared the extent of DNA adduct formation and the induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide and its electrophilic metabolite glycidamide to obtain information concerning the mechanism of acrylamide carcinogenicity. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8, and 15 with 0.14 and 0.70 mmol/kg acrylamide or glycidamide. On PND 16, the B6C3F1/Tk+/+ mice were killed and hepatic DNA adduct levels and the extent of peripheral blood micronuclei were measured. Three weeks after the last treatment, the B6C3F1/Tk+/− mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. Hepatic levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua), the major adduct formed from glycidamide, were determined by HPLC coupled with electrospray ionization tandem mass spectrometry and found to be 3.5 ± 0.1 adducts/106 nucleotides for 0.14 mmol/kg acrylamide, 7.2 ± 0.5 adducts/106 nucleotides for 0.70 mmol/kg acrylamide, 4.5 ± 0.2 adducts/106 nucleotides for 0.14 mmol/kg glycidamide, and 25.7 ± 1.0 adducts/106 nucleotides for 0.70 mmol/kg glycidamide, as compared to 0.01 ± 0.01 adducts/106 nucleotides in control mice. N3-(2-Carbamoyl-2-hydroxyethyl)adenine was also detected, at approximately 1% of the level of N7-GA-Gua. The induction of micronuclei was assessed in reticulocytes and normochromatic erythrocytes; only 0.70 mmol/kg glycidamide caused a significant induction (0.33 ± 0.02% and 0.27 ± 0.02%, respectively, versus 0.18 ± 0.01 and 0.16 ± 0.01% in the control mice). Both 0.14 and 0.70 mmol/kg glycidamide induced a significant increase in the Tk mutant frequency (59 ± 5 and 51 ± 7 mutants/106 lymphocytes, respectively, versus 25 ± 5 mutants/106 lymphocytes in the control mice); only 0.70 mmol/kg glycidamide caused a significant increase in the Hprt mutant frequency (6.8 ± 2.1 mutants/106 lymphocytes versus 0.8 ± 0.3 mutants/106 lymphocytes in the controls). The higher adduct levels obtained upon glycidamide treatment, and the observations of micronuclei and mutant induction by glycidamide only, suggest that the genotoxicity of acrylamide is mediated through its metabolism to glycidamide. (Supported by an Interagency Agreement between the FDA/NCTR and NIEHS/NTP.)
Let us spend time pitchside for our athletes’ benefit: a call to broaden collaboration by Sport and Exercise Medicine Switzerland (SEMS)
Authors: Philippe Matthias Tscholl
Journal: British Journal of Sports Medicine (2020)

Bringing athletes to their peak and keeping them performing at that level requires many factors, such as talent, persistence, eagerness, as well as excellent collaboration and communication among the coaching, technical and medical staff. The various professionals (coaches, advisors, health professionals) who serve the athlete may have different visions of how to pursue the common goal of success—especially with respect to player health. Whether the issue is an injury, illness, or a plan to prevent injuries/illness, the medical team might be challenged by the often short-term performance goals of the technical staff and coaches (and also the athlete). These goals (long-term health, a long career vs immediate performance) can be at odds.

We clinicians have a duty to protect the athlete’s health but situations may arise immediately prior or throughout the season that require reasonable compromise in the treatment of the athlete as some …
Abstract 21531: Inducible Kinase-Independent Effects of Phosphoinositide-3-Kinase Gamma on Cardiac Contractility
Authors: Benjamin W Van Tassell, Stefano Toldo, Ignacio M Seropian, Eleonora Mezzaroma, Federico Damilano, Emilio Hirsch, Antonio Abbate
Journal: Circulation (2010)

Background: Phosphoinositide-3-kinase gamma (PI3Kγ) is a key inflammatory mediator and a fine regulator of cardiac contractility. Interleukin-1β (IL-1β) is a prototypal inflammatory cytokine with d...
SP0131 Conservative treatment for improving working activity in subacute and chronic low back pain-a meta analysys
Authors: PR Oesch, JP Kool, S Bachmann, O Knüsel, R de Bie, P van den Brandt
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Introduction</h3> The primary goal in the rehabilitation of patients with chronic aspecific low back pain is return to work. Return to work was not reported in Tulder's review (1997), who found strong evidence for the effectiveness of manipulation, back schools and exercise therapy for chronic low back pain especially for short-term effects. Van der Weide's review (1997) investigated vocational outcome after treatment of patients with CLBP based on RCT until December 1996. No evidence was found for the effectiveness of behavioural treatment, exercise, manipulation or back school. Since then, several studies regarding RCT reporting vocational outcome were performed. It remains questionable whether return to work can be improved. Therefore a new review is performed. <h3>Method</h3> Literature search: MEDLINE, Cochrane Clinical Trial Register, EMBASE, PSYCLIT, cross reference tracing. The search combined the key word 'low back pain' with one of the following terms: absenteeism, (re)employment, sick leave, return to work, sickness absence, occupational disability and employment status. Criteria for inclusion of studies were: randomised clinical trial, subacute or chronic aspecific low back pain (&gt; 4 weeks), subjects at working age, outcome return to work or sick days, conservative intervention. Based on prior reviews passive treatment modalities were excluded. To assess methodological quality internal validity was rated on a 10 point scale (1 = concealment of treatment allocation, 2 = blinded assessment, 3 = blinding of patients, 4 = blinding of therapist, 5 = intention to treat analysis, 6 = timing of outcome assessment comparable, 7 = withdrawal/drop out rate, 8 = cointervention avoided or equal, 9 = compliance, 10 = outcome measurements relevant). Four levels of evidence were defined. Level 1, Strong evidence: multiple relevant high quality RCTs. Level 2, Moderate evidence: One relevant, high quality RCT and one or more relevant, low quality RCTs. Level 3, Limited evidence: one relevant, high quality RCT or multiple relevant, low quality RCTs. Level 4, No evidence: only one relevant, low quality RCT, no relevant RCTs or contradictory outcomes. <h3>Results</h3> More then 900 publications were identified. 120 were further examined. So far 14 RCTs fulfilled the inclusion criteria. Results on methodological quality and treatment effectiveness will be presented at the EULAR Conference in Prague.
Circadian misalignment on submarines and other non-24-h environments – from research to application
Authors: Jin-Hu Guo, Xiao-Hong Ma, Huan Ma, Yin Zhang, Zhi-Qiang Tian, Xin Wang, Yong-Cong Shao
Journal: Military Medical Research (2020)

Abstract Circadian clocks have important physiological and behavioral functions in humans and other organisms, which enable organisms to anticipate and respond to periodic environmental changes. Disturbances in circadian rhythms impair sleep, metabolism, and behavior. People with jet lag, night workers and shift workers are vulnerable to circadian misalignment. In addition, non-24-h cycles influence circadian rhythms and cause misalignment and disorders in different species, since these periods are beyond the entrainment ranges. In certain special conditions, e.g., on submarines and commercial ships, non-24-h watch schedules are often employed, which have also been demonstrated to be deleterious to circadian rhythms. Personnel working under such conditions suffer from circadian misalignment with their on-watch hours, leading to increased health risks and decreased cognitive performance. In this review, we summarize the research progress and knowledge concerning circadian rhythms on submarines and other environments in which non-24-h watch schedules are employed.
In older adults, some antidepressants were associated with increased fracture risk
Authors: William J. Hall
Journal: Annals of Internal Medicine (2020)

Source Citation Tamblyn R, Bates DW, Buckeridge DL, et al. Multinational investigation of fracture risk with antidepressant use by class, drug, and indication. J Am Geriatr Soc. 2020;68:1494-503. 32181493