tbuckley/cabot-search huggingface dataset:
Leaning Into Uncertainty and Discomfort With Hope
Authors: Evelyn Anthony, Katherine Files, Suzanne C. Danhauer
Journal: JAMA Oncology (2021)

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California and federal school nutrition policies and obesity among children of Pacific Islander, American Indian/Alaska Native, and Filipino origins: Interrupted time series analysis
Authors: Mika Matsuzaki, Brisa N. Sánchez, R. David Rebanal, Joel Gittelsohn, Emma V. Sanchez-Vaznaugh
Journal: PLoS Medicine (2021)

Obesity prevalence remains high among children of Pacific Islander (PI) origin, Filipino (FI), and American Indian/Alaska Native (AIAN) origins in the United States. While school nutrition policies may help prevent and reduce childhood obesity, their influences specifically among PI, FI, and AIAN children remain understudied. We evaluated the association of the California (CA) state school nutrition policies for competitive food and beverages and the federal policy for school meals (Healthy, Hunger-Free Kids Act of 2010 (HHFKA 2010)) with overweight/obesity among PI, FI, and AIAN students.
Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors
Authors: Daan P. Hurkmans, Sebastiaan D.T. Sassen, Karlijn de Joode, Lisanne Putter, Edwin A. Basak, Annemarie J.M. Wijkhuijs, Markus Joerger, Reno Debets, Birgit C.P. Koch, Cor H. Van der Leest, Marco W.J. Schreurs, Astrid A.M. van der Veldt, Joachim G.J.V. Aerts, Ron H.J. Mathijssen, Stijn L.W. Koolen
Journal: Journal for ImmunoTherapy of Cancer (2021)

Dosing schemes of pembrolizumab (anti-programmed cell death protein 1 monoclonal antibody) are solely based on pharmacokinetic (PK) modelling derived from phase I-III trials. The current study aimed to determine factors affecting PK and its relationship with clinical outcome in the real-world setting.Advanced-stage cancer patients, who were treated with pembrolizumab monotherapy (2 mg/kg Q3W or 200 mg flat Q3W), were prospectively included for serial sampling to obtain trough concentrations. A PK model was generated, covariate effects assessed and internally validated by a bootstrap procedure. PK parameters were related to overall survival (OS) and the occurrence of immune-related adverse events (irAEs).588 serum samples derived from 122 patients with (non-)small-cell lung cancer ([N]SCLC), malignant pleural mesothelioma (MPM), melanoma and urothelial cell cancer (UCC) were analyzed. Median follow-up was 2.2 years. A one-compartment PK model was generated: body surface area (BSA) and serum albumin had a significant effect on drug clearance (CL; covariate estimate 1.46 and -1.43, respectively), and serum lactate dehydrogenase (LDH) on the distribution volume(Vd; 0.34). A significant inverse CL-OS relationship was determined for NSCLC (HR:1.69; 95%CI1.07-2.68; p=0.024) and MPM (HR: 3.29; 95% CI 1.08 to 10.09; p=0.037), after correction for prognostic factors, which could not confirmed for melanoma (p=0.22) or UCC (p=0.34). No relationship could be determined between CL and grade >3 irAEs (p=0.70).High interpatient variability of pembrolizumab PK is determined by BSA and serum albumin (on CL) and LDH (on Vd). A strong inverse CL-OS relationship was demonstrated for NSCLC and MPM, which could not be observed for melanoma and UCC. The findings suggest that personalized dosing should be prospectively explored.
Phase I, First-in-Human Study of the Probody Therapeutic CX-2029 in Adults with Advanced Solid Tumor Malignancies
Authors: Melissa Johnson, Anthony El-Khoueiry, Navid Hafez, Nehal Lakhani, Hirva Mamdani, Jordi Rodon, Rachel E. Sanborn, Javier Garcia-Corbacho, Valentina Boni, Mark Stroh, Alison L. Hannah, Song Wang, Henry Castro, Alexander Spira
Journal: Clinical Cancer Research (2021)

Abstract Purpose: PROCLAIM-CX-2029 is a phase I first-in-human study of CX-2029, a Probody–drug conjugate targeting CD71 (transferrin receptor 1) in adults with advanced solid tumors. Although the transferrin receptor is highly expressed across multiple tumor types, it has not been considered a target for antibody–drug conjugates (ADCs) due to its broad expression on normal cells. CX-2029 is a masked form of a proprietary anti-CD71 antibody conjugated to monomethyl auristatin E, designed to be unmasked in the tumor microenvironment by tumor-associated proteases, therefore limiting off-tumor toxicity and creating a therapeutic window for this previously undruggable target. Patients and Methods: This was a dose-escalation, multicenter trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029. The primary endpoint was to determine the maximum tolerated dose (MTD) and cycle 1 dose-limiting toxicity (DLT). CX-2029 was administered i.v. every 3 weeks. Results: Forty-five patients were enrolled in eight dose levels. No DLTs were reported in the dose escalation through 4 mg/kg. At 5 mg/kg, there were two DLTs (febrile neutropenia and pancytopenia). Following expansion of the 4 mg/kg dose to six patients, two additional DLTs were observed (infusion-related reaction and neutropenia/anemia). Both the 4 and 5 mg/kg doses were declared above the maximum tolerated dose. The recommended phase II dose is 3 mg/kg. The most common dose-dependent hematologic toxicities were anemia and neutropenia. Confirmed partial responses were observed in three patients, all with squamous histologies. Conclusions: The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity. See related commentary by Oberoi and Garralda, p. 4459
Abstract 13834: Nicotinamide Nucleotide Transhydrogenase (NNT) Regulates Oxldl Induced Endothelial Activation
Authors: Shashanka Rao, Sibile Pardue, Xinggui Shen, David M Krzywanski
Journal: Circulation (2019)

Endothelial dysfunction is a critical step in the development of atherosclerosis and increasing evidence implicates mitochondrial reactive oxygen species (ROS) as an important contributor to endoth...
POS0398 ADIPONECTIN INDUCES SYNOVIAL ANGIOGENESIS IN RHEUMATOID ARTHRITIS THROUGH METABOLIC REMODELING
Authors: L. Wang, W. Tan, F. Wang, M. Zhang
Journal: Annals of the Rheumatic Diseases (2021)

Background: Our team have previously reported that Adiponectin correlates well with synovial inflammation and progressive bone erosion in rheumatoid arthritis (RA). Angiogenesis is another important part, which plays a critical role in the pathogenesis of RA. Objectives: We hypothesized that adiponectin induces synovial angiogenesis in RA. Methods: Single-cell RNA sequencing (scRNA-Seq) was used to screen cellular changes in local knee joint of collagen-induced arthritis (CIA) after intraarticularly injected of adiponectin. Chimera models of synovium-cartilage-NOD/SCID mice, matrigel plug assay and rat aortic ring assay were performed to demonstrate the pro-angiogenesis role of adiponectin. Cellular experiment, including proliferation, migration, apoptosis, tube formation and angiogenesis related gene expression profile, were detected with Human Umbilical Vein Endothelial Cells (HUVEC) and Mice Lung Microvessel Endothelial Cell (MLMEC) after adiponectin stimulation. Seahorse was performed to clear the influence of adiponectin to cell metabolism. Results: The synovium and pannus hyperplasia worse in CIA model after intraarticularly injected of adiponectin, along with more serious synovitis and bone erosion. ScRNA-Seq of synovial tissues separated from CIA reminded that endothelial cell barbarically grows via metabolic remodeling after stimulated with adiponectin. Synovial chimera, matrigel plug and rat aortic ring shows adiponectin accelerates angiogenesis significantly in different background conditions. In vitro, endothelial cell proliferation detecting by RCTA and CCK8, migration by wound healing and transwell, apoptosis by FACS, tube formation and angiogenesis related gene expression profile by PCR-ARRAY were promoted by adiponectin in both HUVEC and MLMEC. Seahorse showed HUVEC made more use of glycolysis after co-cultured with adiponectin, a method of cell energy supply that tumor cells possess called warburg effect, that drives endothelial cell hyperplasia in severe environment. Conclusion: As a classic metabolic regulator, adiponectin exacerbates CIA by promoting angiogenesis through metabolic remodeling. The findings not only provide a novel insight into the pathogenic role of adiponectin, but also reveals a potential therapeutical strategy to attenuate revascularization in RA. Disclosure of Interests: None declared
Type 17 immunity promotes the exhaustion of CD8<sup>+</sup> T cells in cancer
Authors: Byung-Seok Kim, Da-Sol Kuen, Choong-Hyun Koh, Hyung-Don Kim, Seon Hee Chang, Sehui Kim, Yoon Kyung Jeon, Young-Jun Park, Garam Choi, Jiyeon Kim, Keon Wook Kang, Hye Young Kim, Suk-Jo Kang, Shin Hwang, Eui-Cheol Shin, Chang-Yuil Kang, Chen Dong, Yeonseok Chung
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Multiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8 + tumor-infiltrating lymphocytes (TILs) remain unclear. Methods To determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8 + TILs in Il17a −/− mice, Il17a Cre R26 DTA mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4 + T cells or CD11b + Gr-1 hi myeloid cells in vivo , respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset. Results Depletion of CD4 + T cells promotes the exhaustion of CD8 + T cells with a concomitant increase in IL-17-producing CD8 + T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8 + T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103 + KLRG1 − IL-7Rα hi tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1 hi Tim3 + TOX + terminally exhausted CD8 + T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8 + T cells and also delays tumor growth in vivo . Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8 + T cell exhaustion signature gene sets in multiple cancers. Conclusion IL-17-producing cells promote terminal exhaustion of CD8 + T cells and tumor progression in vivo , which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8 + T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.
AB0130 QUESTIONING THE USEFULNESS OF CDAI AS A MEASURE OF DISEASE ACTIVITY IN A TREAT TO TARGET PROGRAMME
Authors: C. Lally, I. Ali, C. Silke, B. Whelan, M. O’sullivan
Journal: Annals of the Rheumatic Diseases (2021)

Background: Rheumatoid arthritis (RA) is a chronic autoimmune condition which if not treated can lead to joint destruction and long term disability. In RA, the concept of T2T is recommended as the appropriate method to manage early arthritis 1 . It has shown promising results to achieve clinical remission (CR) or low disease activity (LDA) 2 . Objectives: The objective of this study was to investigate the potential to achieve remission or LDA according to the Clinical Disease Activity Index (CDAI) for RA, during treatment with Disease-Modifying Anti-Rheumatic Drugs (DMARDs) and Biologics, and the factors that affect the remission/LDA outcome. Methods: We performed an observational prospective study on patients’ data available from our Early Arthritis Cohort. All patients with newly diagnosed RA who met the American College of Rheumatology (ACR) criteria were enrolled. Patients are managed by an Advanced Nurse Practitioner (ANP) with consultant supervision. To assess their response to treatment, we used the Clinical Disease Activity Index 3 . Analysis was performed using SPSS. Results: Out of a total of 459 patients, 353 completed the programme. 217 patients (61.5%) were female and (136) 38.5 % were male. Mean age was 53.98 (SD 14.66). 195 patients were on monotherapy, 40 on combination DMARDs and 115 were on Biologics/Janus Kinase Inhibitors (JAK-Inh). Remission-rates in the monotherapy and combination DMARDs groups were approximately 60%, whilst the remission rate in the Biologics/JAK-Inh group was 41.7%. Amongst female patients 15.9% had erosions on X-ray at the time of diagnosis whilst the equivalent figure for male patients was 29.6%. Conclusion: An association between male gender and the likelihood of erosions on X-Ray was observed. In addition an association between final medication and outcome was observed. An increased likelihood of non-remission was noted in patients that required escalation to Biologics/JAKs. A possible explanation for the lower levels of remission seen throughout the groups is the difficulty in achieving remission under the CDAI score as compared to DAS-28. References: [1]Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Annals of the Rheumatic Diseases. 2016;75(1):3. [2]Scott IC, Ibrahim F, Panayi G, Cope AP, Garrood T, Vincent A, Scott DL, Kirkham B; TITRATE Programme Investigators. The frequency of remission and low disease activity in patients with rheumatoid arthritis, and their ability to identify people with low disability and normal quality of life. Semin Arthritis Rheum. 2019 Aug;49(1):20-26. doi: 10.1016/j.semarthrit.2018.12.006. Epub 2018 Dec 28. PMID: 30685064. Disclosure of Interests: None declared
Enhancing the Collaborative Experience of a Collaborative Game to Achieve Lifestyle Change
Authors: Paul L. Hebert
Journal: JAMA Network Open (2021)

Mitesh S. Patel, MD, MBA; Dylan S. Small, PhD; Joseph D. Harrison, MBDS; Victoria Hilbert, MPH, RD; Michael P. Fortunato, BA; Ai Leen Oon, BA; Charles A. L. Rareshide, MS; Kevin G. Volpp, MD, PhD
OP0303-HPR IT IS NOT JUST ABOUT THE SEX: VIEWPOINTS OF DUTCH ADULT MEN WITH INFLAMMATORY ARTHRITIS REGARDING THE IMPACT OF THE DISEASE ON THEIR SEXUAL HEALTH
Authors: L. F. Perez-Garcia, E. Röder, H. Pastoor, H. Bolt, J. Van Exel, R. Dolhain
Journal: Annals of the Rheumatic Diseases (2021)

Background: Sexual health (SH) can be impaired in men with inflammatory arthritis (IA) (1). In addition to biological factors, such as inflammation, subjective factors such as personal beliefs can also impair SH. The Q methodology combines aspects of qualitative and quantitative approaches to systematically study subjectivity, and has been applied successfully in other medical fields. Objectives: To describe the viewpoints of adult men with IA on the impact of IA on their SH using the Q methodology. Methods: Men, 18 years and older, diagnosed with RA or JIA were invited by their rheumatologist. Participants ranked 34 opinion statements about potential impacts of IA on their SH on an agreement scale. A by-person factor analysis identified common patterns in the rankings. These patterns represent the different viewpoints among the men. Data from interviews, in which the men explained their ranking, was used to further interpret the viewpoints. A Q-methodology study usually consists of 30-40 participants. Results: 30 men with IA were included. Their mean age was 43.2 (range 22–77) years. The analysis revealed three viewpoints: 1.“I am satisfied with my sex life” Men with viewpoint 1 experience no significant impact of IA on their SH. However, most men indicated that when their disease was active, IA had a negative impact on their SH. 2.“Arthritis has a negative influence on my sex life” Men with viewpoint 2 experience a dramatic impact, due to pain, fatigue and gloom. Their relationship worsened and they feel guilty towards their partner. Discussing their problems is not difficult. 3.“I am keeping up appearances” Men with viewpoint 3 experience SH impairment mainly as a result of pain. IA impairs them physically, makes them feel less of a man, less attractive and reduces their self-confidence. Due to problems with accepting their disease and communicating their problems, these men tend to hide their problems. Conclusion: We identified 3 viewpoints on the impact of IA on male SH, 2 of them revealing a negative influence that goes beyond the physical act of sex. IA can also affect relationships, self-confidence and manhood. Future research will focus on identifying men with SH problems in the clinic and the best counseling approach. References: [1]Perez-Garcia LF, Te Winkel B, Carrizales JP, Bramer W, Vorstenbosch S, van Puijenbroek E, et al. Sexual function and reproduction can be impaired in men with rheumatic diseases: A systematic review. Semin Arthritis Rheum. 2020;50(3):557-73. Disclosure of Interests: Luis Fernando Perez-Garcia Consultant of: Galapagos, Esther Röder: None declared, Hester Pastoor: None declared, Hanneke Bolt: None declared, Job van Exel: None declared, Radboud Dolhain Speakers bureau: Abbvie, UCB, Genzyme, Consultant of: Galapagos, Grant/research support from: UCB.
POS0143 POST-STRESS ULTRASOUND ASSESSMENT OF THE ACHILLES TENDON IS USEFUL TO DIFFERENCIATE PSORIATIC ARTHRITIS FROM THE PHYSIOLOGICAL ADAPTATION TO EXERCISE
Authors: C. Guillén-Astete, V. García García, N. García-Montes, Á. Andreu-Suárez
Journal: Annals of the Rheumatic Diseases (2021)

Background: Achilles enthesitis is the most accessible psoriatic arthritis hallmark to assess through ultrasound scan. Recently it has been demonstrated that continuous mechanical stress such as experimented by runners can drive to the development of physiological morphological changes that resembles those observed in psoriatic arthritis. In a subject with the suspicious diagnostic of psoriatic arthritis who practice any sports associated to continuous impact over the heels, the challenge to determine in what extent the morphological changes are linked to the exercise or to the disease, is remarkable. Objectives: To determine morphological differences between patients with psoriatic arthritis, trained runners and sedentary volunteers through ultrasound scan of the Achilles tendon. Methods: An ultrasound scan of the Achilles tendon was performed to the following subjects: Patients with diagnosis of psoriatic arthritis with a DAPSA score of low activity in at least six months and with history of heel pain in the past, volunteers runners with not less of 3-year sport activity at least three times a week and sedentary volunteers. In the group of patients, ultrasound scan was performed over the feet with history of heel pain. In the case of volunteers, the ultrasound scan was performed in the dominant feet. The selection of volunteers was not randomly-based in order to match their age and sex to the patients as much as possible. Besides demographic features, a comparison between tendon thickness at the level of the calcaneus bone border and the height of the retrocalcaneus bursae in the longitudinal axis were performed through ANOVA test. Power Doppler signal was scaned in all subjects before and after a controlled mechanical stress of the Achilles tendon by climbing stairs (100 steps, two times). Results: Female/male distribution of the group of patients, runners and sedentary people were: 12/10, 18/18 and 20/18, respectively. Achilles tendon mean thickness ± standard deviation was 6.61 ± 1.05, 5.91 ± 1.44 and 4.61 ± 2.1mm, respectively ( P =0.01). Retrocalcaneus bursae height was 3.42 ± 0.21, 3.22 ± 0.27 and 2.21 ± 0.31 ( P =0.01). Basal PD signal was present into the enthesis of 2/22, 1/36 and 0/38, respectively (P not significant). After exercise, PD signal was present in 8/22, 5/36 and 0/38, respectively (P&lt;0.001). Conclusion: Power Doppler signal after exercise was identified as the most relevant ultrasound hallmark to distinguish a patient with psoriatic arthritis from a trained runner, even when psoriatic arthritis were considered as low activity. Post exercise ultrasound scan should be considered as a diagnosis tool in sportsmen with suspicious of psoriatic arthritis, until further studies confirm our findings. Disclosure of Interests: None declared
Frataxin and endothelial cell senescence in pulmonary hypertension
Authors: Allan Lawrie, Sheila E. Francis
Journal: Journal of Clinical Investigation (2021)

Pulmonary hypertension (PH), increased blood pressure within the lungs, is classified into five diagnostic groups based on etiology, with treatment assigned on this basis. Currently, only Group 1 pulmonary arterial hypertension (PAH) and Group 4 chronic thromboembolic PH (CTEPH) have pharmacological treatments available. The role of the endothelial cell in pulmonary hypertension has long been debated, and in this issue of the JCI, Culley et al. present evidence for the reduction in frataxin expression across multiple groups of PH. Reduced frataxin expression led to endothelial cell senescence and associated with the development of PH. Removal of the senescent cells using the senolytic drug Navitoclax in multiple models of PH effectively treated PH, suggesting a new class of treatments that may work beyond Group 1 and Group 4 PH in patients with evidence of pulmonary vascular endothelial senescence.
Interactions between ALS-linked FUS and nucleoporins are associated with defects in the nucleocytoplasmic transport pathway
Authors: Yen-Chen Lin, Meenakshi Sundaram Kumar, Nandini Ramesh, Eric N. Anderson, Aivi T. Nguyen, Boram Kim, Simon Cheung, Justin A. McDonough, William C. Skarnes, Rodrigo Lopez-Gonzalez, John E. Landers, Nicolas L. Fawzi, Ian R. A. Mackenzie, Edward B. Lee, Jeffrey A. Nickerson, David Grunwald, Udai B. Pandey, Daryl A. Bosco
Journal: Nature Neuroscience (2021)