tbuckley/cabot-search huggingface dataset:
The combination of IMO-2055, a synthetic agonist of toll-like receptor-9 (TLR9), and the multikinase inhibitor sorafenib tosylate demonstrate enhanced antitumor activity in a human non-small cell lung cancer xenograft model
Authors: Paul Gonzales, Bernardo Chavira, Kristen Swetel, Kathleen McCambridge
Journal: Cancer Research (2007)

4771  IMO-2055 is a synthetic agonist of TLR9 developed through extensive structure-activity studies at Idera Pharmaceuticals. Previous in vitro and in vivo studies have shown that IMO-2055 induces Th1-type innate and adaptive immune responses. IMO-2055 has also shown potent antitumor activity in a number of tumor models in preclinical studies alone and in combination with various chemotherapeutic agents. In the present study, we tested IMO-2055 alone and in combination with sorafenib in the H460 human NSCLC xenograft model. Peritumoral injection of IMO-2055 administered three times weekly resulted in 56.8% growth inhibition, and oral administration of sorafenib resulted in 61.9% growth inhibition, compared to PBS control group on day 14. The combination of IMO-2055 and sorafenib lead to increased antitumor effects with 67.9% tumor growth inhibition on day 14. A synergistic interaction trend for the drug combination occurred at day 24 with the IMO-2055/sorafenib combination mean tumor weight of 716 mg compared to the single agent mean tumor weights of IMO-2055, 1360 mg and sorafenib, 1326 mg (P
Education and wealth inequalities in healthy ageing: a population-based study of eight harmonised cohorts in the Ageing Trajectories of Health: Longitudinal Opportunities and Synergies (ATHLOS) consortium
Authors: Yu-Tzu Wu, Christina Daskalopoulou, Albert Sanchez Niubo, Fernando Rodriguez-Artalejo, Jose Luis Ayuso-Mateos, Martin Bobak, Francisco Felix Caballero, Javier de la Fuente, Alejandro de la Torre-Luque, Esther Garcia-Esquinas, Jose Maria Haro, Seppo Koskinen, Ilona Koupil, Matilde Leonardi, Andrzej Pajak, Demosthenes Panagiotakos, Denes Stefler, Beata Tobias-Adamczyk, Martin Prince, Matthew Prina
Journal: The Lancet Public Health (2020)
Rapid POC tests have low sensitivity for <i>C trachomatis</i> in nonpregnant women or men of reproductive age
Authors: Ameeta Singh
Journal: Annals of Internal Medicine (2020)

Grillo-Ardila CF, Torres M, Gaitan HG. Rapid point of care test for detecting urogenital Chlamydia trachomatis infection in nonpregnant women and men at reproductive age. Cochrane Database Syst Rev. 2020;1:CD011708. 31995238.
The TICONC (Ticagrelor-Oncology) Study
Authors: Joy R. Wright, Meera Chauhan, Chirag Shah, Alistair Ring, Anne L. Thomas, Alison H. Goodall, David Adlam
Journal: JACC CardioOncology (2020)

In cancer, platelets may facilitate metastatic spread by a number of mechanisms as well as contribute to thrombotic complications. Ticagrelor, a platelet antagonist- that blocks adenosine diphosphate activation of platelet P2Y12 receptors, is widely used in the treatment of cardiovascular disease, but its efficacy in cancer remains unknown.This study sought to evaluate the effect of aspirin and ticagrelor monotherapy, as well as dual antiplatelet therapy, on platelet activation in cancer.This study consisted of 2 phases: first, an in vitro study of human platelet-tumor cell interaction; and second, a randomized crossover clinical trial of 22 healthy donors and 16 patients with metastatic breast or colorectal cancer. Platelet activation and inhibition were measured by aggregometry and flow cytometry.In vitro, tumor cells induced cellular clusters that were predominantly platelet-platelet aggregates. Ticagrelor significantly inhibited formation of large tumor cell-induced platelet-platelet aggregates: 65.4 ± 4.8% to 50.9 ± 5.9% (p = 0.002) and 62.3 ± 3.1% to 48.3 ± 7.3% (p = 0.014) for MCF-7 and HT-29-induced aggregation, respectively. Supporting this finding, cancer patients on ticagrelor had significantly reduced levels of spontaneous platelet aggregation and activation compared with baseline; 14.8 ± 2.7% at baseline to 7.8 ± 2.3% with ticagrelor (p = 0.012).Our findings suggested that P2Y12 inhibition with ticagrelor might reduce spontaneous platelet aggregation and activation in patients with metastatic cancer and merits further investigation in patients at high risk of cancer-associated thrombosis. (Ticagrelor-Oncology [TICONC] Study; EudraCT: 2014-004049-29).
THU0383 GENDER DIFFERENCES IN NONRADIOGRAPHIC AXIAL SPONDYLOARTHRITIS: FROM CLINICAL CHARACTERISTICS TO EFFECTIVENESS OF TNF INHIBITORS
Authors: R. Neuenschwander, M. Hebeisen, R. Micheroli, K. Buerki, P. Exer, K. Niedermann Schneider, M. Nissen, A. Scherer, A. Ciurea
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Background:</h3> While a male predominance is found in radiographic axial spondyloarthritis (r-axSpA), an equal male to female distribution was repeatedly reported for the nonradiographic disease form (nr-axSpA). Some important differences in clinical manifestations and response to treatment with tumor necrosis factor inhibitors (TNFi) between the sexes have been delineated for r-axSpA. It remains unclear, whether comparable sex differences can be assumed for nr-axSpA. Indeed, existing data on gender differences in nr-axSpA is limited to subgroups and is particularly scarce regarding effectiveness of treatment. <h3>Objectives:</h3> To investigate sex differences with regard to demographics, clinical manifestations and response to TNFi in nr-axSpA after exclusion of patients with co-morbid fibromyalgia (FM). <h3>Methods:</h3> Response to a first TNFi was assessed in 85 women and 78 men with nr-axSpA and without concomitant FM in the Swiss Clinical Quality Management Cohort. The primary outcome was the proportion of patients achieving a 40% improvement in the Assessment of Spondyloarthritis international Society criteria (ASAS40) at 1 year. Additional response outcomes were evaluated as secondary outcomes. Patients having discontinued TNFi were considered nonresponders. Logistic regression analyses were adjusted for baseline differences (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Maastricht ankylosing spondylitis enthesitis score (MASES), diagnostic delay, body mass index (BMI)). <h3>Results:</h3> Baseline characteristics of women and men are shown in Table 1. Significant differences were restricted to diagnostic delay, BASDAI, MASES and BMI. An ASAS40 response was achieved by 17% of women and 38% of men (OR 0.34, 95% CI 0.12; 0.93, p=0.02). A lower response rate in women was confirmed in the adjusted analysis (OR 0.19, 95% CI 0.05; 0.62, p=0.009) as well as for the other outcomes assessed (Table 2). <h3>Conclusion:</h3> Despite only few sex differences in patient characteristics in nr-axSpA, response rates to TNFi are significantly lower in women than in men. <h3>Disclosure of Interests:</h3> Regula Neuenschwander: None declared, Monika Hebeisen: None declared, Raphael Micheroli: None declared, Kristina Buerki: None declared, Pascale Exer: None declared, Karin Niedermann Schneider: None declared, Michael Nissen Grant/research support from: Abbvie, Consultant of: Novartis, Lilly, Abbvie, Celgene and Pfizer, Speakers bureau: Novartis, Lilly, Abbvie, Celgene and Pfizer, Almut Scherer: None declared, Adrian Ciurea Consultant of: Consulting and/or speaking fees from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck Sharp &amp; Dohme, Novartis and Pfizer.
Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery
Authors: Binfan Chen, Ang Gao, Bin Tu, Yonghui Wang, Xiaolu Yu, Yingshu Wang, Yanfeng Xiu, Bing Wang, Yakun Wan, Yongzhuo Huang
Journal: Biomaterials (2020)
Cardiotoxicity Surveillance and Risk of Heart Failure During HER2 Targeted Therapy
Authors: Anthony F. Yu, Chaya S. Moskowitz, Katherine Lee Chuy, Ji Yang, Chau T. Dang, Jennifer E. Liu, Kevin C. Oeffinger, Richard M. Steingart
Journal: JACC CardioOncology (2020)

Guidelines recommend left ventricular ejection fraction (LVEF) assessments every 3 months for cardiotoxicity monitoring during human epidermal growth factor receptor 2 (HER2) targeted therapy. Evidence in support of this practice is lacking. This study examines the association between adherence to cardiotoxicity surveillance guidelines and heart failure (HF) in HER2-positive breast cancer patients. A case-control study was performed in 53 patients who developed cardiotoxicity during HER2 targeted therapy, and 159 controls matched by age, anthracycline exposure, and year of treatment. Cardiotoxicity was defined as HF (New York Heart Association functional class III or IV) or cardiac death. Adherence to cardiotoxicity surveillance guidelines was ascertained from the beginning of HER2 targeted therapy to the diagnosis date of HF for cases or the corresponding timepoint for matched controls. Conditional logistic regression was used for case-control comparisons. Eighty-one percent of cases and controls were previously treated with an anthracycline. Adherence to cardiotoxicity surveillance guidelines during the entire observation period or during the first 6 months of treatment was not associated with lower risk of HF. An LVEF <55% at any surveillance timepoint was identified in 49% of cases and 3% of controls, and an LVEF <55% during the final surveillance timepoint before developing HF was identified in 54% of cases and 4% of controls. In multivariable-adjusted analyses, LVEF <55% at any timepoint or during the final surveillance timepoint (odds ratio: 27.0; 95% confidence interval: 9.3 to 78.8 and odds ratio: 25.6; 95% confidence interval: 7.3 to 90.3, respectively) was associated with HF. Patients with LVEF <55% on routine surveillance during HER2 targeted therapy are at increased risk for HF. Additional studies to define their optimal management are warranted.
AB0730 ASSOCIATION OF SPONDYLOARTHRITIS AND FAMILIAL MEDITERRANEAN FEVER AND IMPACT ON DISEASE PHENOTYPE: A SYSTEMATIC REVIEW OF THE LITERATURE
Authors: N. Ziade, A. Nassar
Journal: Annals of the Rheumatic Diseases (2020)

Background: Spondyloarthritis (SpA) and Familial Meditaerranean fever (FMF) may co-exist in certain populations, and have some overlapping manifestations (oligo-arthritis, hip involvement). Their association may impact disease phenotype and may affect disease management. Objectives: To evaluate the association of SpA and FMF and its impact on disease phenotype and management. Methods: A systematic literature search was conducted with the keywords spondyloarthritis and familial mediterranean fever from Janurary 1990 to January 2020 in PubMed and using manual cross-reference methods. Results: The search retrieved 74 articles, out of which 37 articles were relevant to the study question; most of the articles were case reports, with some large cohort studies of FMF and SpA (Flowchart in Figure 1). In large FMF cohorts, the prevalence of SpA was higher compared to the general population (7.5-13%, OR around 10). M694V was a risk factor for SpA. These FMF-SpA patients were older at diagnosis, had lower fever attacks, and higher disease duration, inflammatory back pain, chronic arthritis, enthesopathy, persistent inflammation and higher resistance to Colchicine. In case series, they were responsive to anti-TNF therapy. In large SpA cohorts, MEFV mutation, particularly M694V, was found in 15-35% (even without associated FMF). In most cohorts, MEFV mutation carriers didn’t have any distinct disease phenotype, except for some reports of higher ESR, more hip involvement, higher BASFI and higher BASDAI. Genome-wide association studies and case reports suggest an implication for IL-1 and thus a role for Anakinra therapy in these patients. Conclusion: In FMF or SpA patients with resistance to conventional therapy, the evaluation of disease association should be performed as it may have significant impact on disease management. References: [1]Li et al, Plos Genetics 2019. Watad et al, Frontiers Immunol 2019. Atas et al, Rheumatol Int 2019. Cherqaoui et al, JBS 2017. Zhong et al. Plos One 2017. Ornek et al, Arch Rheumatol 2016. Cinar et al, Rheumatol Int 2008. Durmur et al, JBS 2007. Figure 1. Flowchart of the systematic literature search (Spondyloarthritis, Familial Mediterranean Fever; January 1990-2020). Disclosure of Interests: Nelly Ziade Speakers bureau: Abbvie, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Aref Nassar: None declared
In Vivo Validation of Essential Genes for Myeloma Cells By CRISPR/Cas9 Studies in a Scaffold-Based System Engineered to Establish a "Humanized" Bone Marrow-like Microenvironment
Authors: Ryosuke Shirasaki, Csikos Tamas, Geoffrey Matthews, Ricardo De Matos Simoes, Subhashis Sarkar, Olga Dashevsky, Hu Yiguo, Jeffrey Sorrell, Michal Sheffer, Eugen Dhimolea, Megan Bariteau, Brian Glassner, Aedin Culhane, Richard W. J. Groen, Constantine S. Mitsiades
Journal: Blood (2017)
Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study
Authors: Stefan Groeneweg, Ferdy S van Geest, Ayhan Abacı, Alberto Alcantud, Gautam P Ambegaonkar, Christine M Armour, Priyanka Bakhtiani, Diana Barca, Enrico S Bertini, Ingrid M van Beynum, Nicola Brunetti-Pierri, Marianna Bugiani, Marco Cappa, Gerarda Cappuccio, Barbara Castellotti, Claudia Castiglioni, Krishna Chatterjee, Irenaeus F M de Coo, Régis Coutant, Dana Craiu, Patricia Crock, Christian DeGoede, Korcan Demir, Alice Dica, Paul Dimitri, Anna Dolcetta-Capuzzo, Marjolein H G Dremmen, Rachana Dubey, Anina Enderli, Jan Fairchild, Jonathan Gallichan, Belinda George, Evelien F Gevers, Annette Hackenberg, Zita Halász, Bianka Heinrich, Tony Huynh, Anna Kłosowska, Marjo S van der Knaap, Marieke M van der Knoop, Daniel Konrad, David A Koolen, Heiko Krude, Amy Lawson-Yuen, Jan Lebl, Michaela Linder-Lucht, Cláudia F Lorea, Charles M Lourenço, Roelineke J Lunsing, Greta Lyons, Jana Malikova, Edna E Mancilla, Anne McGowan, Veronica Mericq, Felipe M Lora, Carla Moran, Katalin E Müller, Isabelle Oliver-Petit, Laura Paone, Praveen G Paul, Michel Polak, Francesco Porta, Fabiano O Poswar, Christina Reinauer, Klara Rozenkova, Tuba S Menevse, Peter Simm, Anna Simon, Yogen Singh, Marco Spada, Jet van der Spek, Milou A M Stals, Athanasia Stoupa, Gopinath M Subramanian, Davide Tonduti, Serap Turan, Corstiaan A den Uil, Joel Vanderniet, Adri van der Walt, Jean-Louis Wémeau, Jolante Wierzba, Marie-Claire Y de Wit, Nicole I Wolf, Michael Wurm, Federica Zibordi, Amnon Zung, Nitash Zwaveling-Soonawala, W Edward Visser
Journal: The Lancet Diabetes & Endocrinology (2020)
AB0968 DIAGNOSIS OF INFLAMMATORY BACK PAIN (IBP) IN A LOW-INCOME POPULATION USING ASAS IBP DEFINITION
Authors: J. Oliveira, R. Nunes, G. Da Silva, I. Nogueira, A. Azevedo, X. Baraliakos, A. Rocha
Journal: Annals of the Rheumatic Diseases (2020)

Background: Inflammatory back pain (IBP) is an important entry criterion for identifying patients with axial spondyloarthritis. Due to the very frequent prevalence of chronic non-inflammatory back pain (CBP), IBP is difficult to differentiate and recognize in many clinical practices. CBP is a frequent diagnosis in populations with low socioeconomic status. Objectives: To investigate whether IBP ASAS definition help discriminate from CBP in a low-income population. Methods: A total of 202 consecutive individuals were directly interviewed in Fortaleza/Brazil, for the prevalence of IBP (ASAS definition), monthly family income (US$), school education [&gt;/≤ 8 school-years(SY)], and smoking habit (present/absent). People from all social levels were included. Results: Mean age was 38.9±12.9 years, 100 (49.5%) were male and 36 (17.8%) were smokers; 135 (66.8%) declared less than 730US$ family earnings per month and 71 (35.1%) had less than 8 SY. Although 122 (60.3%) declared lumbar pain, in comparison, 29 (14.3%), 22 (10.9%) and 59 (29.2%) fulfilled ASAS, Berlin, and Calin’s IBP criteria, respectively. There were 39 (58.02%) vs. 83 (61.5%) with vs. without CBP and 9 (13.4%) vs. 20 (14.8%) fulfilling vs. not fulfilling the ASAS IBP definition among those with more or less than 730US$ earnings (P&gt;0.05), respectively. Conclusion: This is the first report on the prevalence of IBP in a very low-income population. Over one-third had less than 8SY, revealing very low literacy. Smoking prevalence was also low if compared to 28% smoking prevalence WHO estimates across Europe*. These IBP prevalence data are similar to those reported in wealthier populations, living in higher latitude. Data suggest that ASAS IBP definition may be used to discriminate patients with IBP from those with CBP, regardless of income and literacy. References: This is the first report on the prevalence of IBP in a very low-income population. Over one-third had less than 8SY, revealing very low literacy. Smoking prevalence (17.8%) was also low if compared to 28% smoking prevalence WHO estimates across Europe*. These IBP prevalence data are similar to those reported in wealthier populations, living in higher latitude. Data suggest that ASAS IBP definition may be used to discriminate patients with IBP from those with CBP, regardless of income and literacy. Disclosure of Interests: Jobson Oliveira: None declared, Rodolfo Nunes: None declared, Guilherme da Silva: None declared, Igor Nogueira: None declared, Artur Azevedo: None declared, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Airton Rocha Speakers bureau: Not related to the present work
Kawasaki disease in a COVID-19-struck region
Authors: Hannah Stower
Journal: Nature Medicine (2020)

Aging T cells regulate multiple features of aging in mice, and their dysfunction may lead to age-associated disease.Aging is known to result in an increased susceptibility to disease, but the mechanisms by which this occurs are largely unknown.There are known changes in metabolism that occur during the aging process that are thought to contribute to this.Desdín-Micó et al. mimic a process in mice that occurs during aging -the loss of mitochondrial function in T cells -through the use of genetic knockout models.This results in multiple age-related features, including the increase in circulating cytokines known as 'inflammaging' , which, they show, induces senescence in mice.This role of T cells in regulating organismal lifespan could be involved in age-associated diseases.
Stretch-induced sarcoplasmic reticulum calcium leak is causatively associated with atrial fibrillation in pressure-overloaded hearts
Authors: Yi Zhang, Ying Qi, Jing-Jing Li, Wen-Jin He, Xiao-Hang Gao, Yu Zhang, Xia Sun, Jie Tong, Jianbao Zhang, Xiu-Ling Deng, Xiao-Jun Du, Wenjun Xie
Journal: Cardiovascular Research (2020)

Despite numerous reports documenting an important role of hypertension in the development of atrial fibrillation (AF), the detailed mechanism underlying the pathological process remains incompletely understood. Here, we aim to test the hypothesis that diastolic sarcoplasmic reticulum (SR) Ca2+ leak in atrial myocytes, induced by mechanical stretch due to elevated pressure in the left atrium (LA), plays an essential role in the AF development in pressure-overloaded hearts.
Design and evaluation of oral delivery dosage forms of homoharringtonine
Authors: Dennis Brown, Shawnya Michaels
Journal: Cancer Research (2007)

4730  Homoharringtonine (HHT) is in clinical development for the treatment of a number of leukemia indications including CML resistant to tyrosine kinase inhibitor therapies, as well as AML and MDS. Initial Phase I and II clinical studies administered HHT intravenously (IV) by short and continuous infusion (CI) schedules. Improved antileukemic results were observed when drug was provided by CI over many days of treatment (e.g. 7 days). Currently, the drug is administered subcutaneously (SC, b.i.d.) to patients in schedules up to 14 days with similar efficacy and toxicity profiles as CI. For either route of administration, HHT, an ester, is rapidly converted in plasma to its acid form. This metabolite has been demonstrated to be less active in vitro. Therefore, sustained presentation of the parent molecule is important. A sustained release system may benefit HHT by maximizing the plasma levels of the active parent molecule. SC dosing has allowed for some sustained release, and recent clinical results demonstrate similar pharmacokinetics for SC and CI administration. While SC dosing allows for greater patient convenience than CI, developing an oral formulation of HHT may further be of value for ease of administration and patient compliance. Moreover, the potential for slow/controlled drug release systems may better mimic the PK profile observed in the CI and SC settings. To test oral formulations for efficacy, we are identifying formulation characteristics to optimize delivery by the oral route (PO) (e.g. compatibility, stability, release kinetic, etc.) in an effort to develop dosage forms for clinical evaluation.  Using the RIF-1 murine tumor growth delay model, we have evaluated the efficacy of HHT after PO delivery with a series of formulation excipients that may be utilized for further preformulation studies. These include aqueous-based solvents, suspension systems, protein, lipid, carbohydrate excipients, and various combinations of these materials. The efficacy of HHT in an aqueous delivery system is similar after either PO or intraperitoneal (IP) administration, suggesting high bioavailability. The use of a protein-based delivery system did not increase efficacy, however HHT in a lipid-based system had a beneficial effect on efficacy, and was not reduced by the use in combination with the protein excipients. Further stability studies, as well as pilot PK assessment is warranted for some of the test formulations. These results suggest that oral formulations for HHT could be developed to increase the ease of administration and patient compliance without sacrificing efficacy.