tbuckley/cabot-search huggingface dataset:
Tumors establish resistance to immunotherapy by regulating T<sub>reg</sub>recruitment via CCR4
Authors: Lisa A Marshall, Sachie Marubayashi, Aparna Jorapur, Scott Jacobson, Mikhail Zibinsky, Omar Robles, Dennis Xiaozhou Hu, Jeffrey J Jackson, Deepa Pookot, Jerick Sanchez, Martin Brovarney, Angela Wadsworth, David Chian, David Wustrow, Paul D Kassner, Gene Cutler, Brian Wong, Dirk G Brockstedt, Oezcan Talay
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Checkpoint inhibitors (CPIs) such as anti-PD(L)-1 and anti-CTLA-4 antibodies have resulted in unprecedented rates of antitumor responses and extension of survival of patients with a variety of cancers. But some patients fail to respond or initially respond but later relapse as they develop resistance to immune therapy. One of the tumor-extrinsic mechanisms for resistance to immune therapy is the accumulation of regulatory T cells (T reg ) in tumors. In preclinical and clinical studies, it has been suggested that tumor trafficking of T reg is mediated by CC chemokine receptor 4 (CCR4). Over 90% of human T reg express CCR4 and migrate toward CCL17 and CCL22, two major CCR4 ligands that are either high at baseline or upregulated in tumors on CPI treatment. Hence, CCR4 antagonism has the potential to be an effective antitumor treatment by reducing the accumulation of T reg into the tumor microenvironment (TME). Methods We developed in vitro and in vivo models to assess T reg migration and antitumor efficacy using a potent and selective CCR4 antagonist, CCR4-351. We used two separate tumor models, Pan02 and CT26 mouse tumors, that have high and low CCR4 ligand expression, respectively. Tumor growth inhibition as well as the frequency of tumor-infiltrating T reg and effector T cells was assessed following the treatment with CCR4 antagonist alone or in combination with CPI. Results Using a selective and highly potent, novel small molecule inhibitor of CCR4, we demonstrate that migration of CCR4 + T reg into the tumor drives tumor progression and resistance to CPI treatment. In tumor models with high baseline levels of CCR4 ligands, blockade of CCR4 reduced the number of T reg and enhanced antitumor immune activity. Notably, in tumor models with low baseline level of CCR4 ligands, treatment with immune CPIs resulted in significant increases of CCR4 ligands and T reg numbers. Inhibition of CCR4 reduced T reg frequency and potentiated the antitumor effects of CPIs. Conclusion Taken together, we demonstrate that CCR4-dependent T reg recruitment into the tumor is an important tumor-extrinsic mechanism for immune resistance. Blockade of CCR4 led to reduced frequency of T reg and resulted in increased antitumor activity, supporting the clinical development of CCR4 inhibitors in combination with CPI for the treatment of cancer. Statement of significance CPI upregulates CCL17 and CCL22 expression in tumors and increases T reg migration into the TME. Pharmacological antagonism of the CCR4 receptor effectively inhibits T reg recruitment and results in enhanced antitumor efficacy either as single agent in CCR4 ligand high tumors or in combination with CPIs in CCR4 ligand low tumors.
Abstract 12947: In Vivo Efficacy of a Novel, Inhaled Pdgfra/b Inhibitor, Gb002, in The Rat Monocrotaline and Pneumonectomy Model of Pulmonary Arterial Hypertension
Authors: Ravi Sitapara, Debbie Slee, Luisa Salter-Cid, Larry Zisman
Journal: Circulation (2019)

Introduction: The PDGF pathway has been demonstrated to be involved in vascular remodeling in pulmonary arterial hypertension (PAH). GB002 is a novel, potent, clinical stage inhibitor of PDGFRα/β d...
Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations
Authors: Jian Carrot-Zhang, Giovanny Soca-Chafre, Nick Patterson, Aaron R. Thorner, Anwesha Nag, Jacqueline Watson, Giulio Genovese, July Rodriguez, Maya K. Gelbard, Luis Corrales-Rodriguez, Yoichiro Mitsuishi, Gavin Ha, Joshua D. Campbell, Geoffrey R. Oxnard, Oscar Arrieta, Andres F. Cardona, Alexander Gusev, Matthew Meyerson
Journal: Cancer Discovery (2020)

Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden, and specific driver mutations in
Development and validation of a prognostic index (BODEXS90) for mortality in stable chronic obstructive pulmonary disease
Authors: R. Golpe, C. Esteban, J.M. Figueira-Gon..alves, C.A. Amado-Diago, N. Blanco-Cid, A. Aramburu, I. Garc.ía-Talavera, M. Cristeto, M. Acosta-Sorensen
Journal: Pulmonology (2020)

Several multidimensional indices have been proposed to predict mortality in chronic obstructive pulmonary disease (COPD). The BODEX index is simple and easy to use for this purpose in all clinical settings. Only a few prognostic indices have integrated oxygenation variables, with measurement methods that are not practical for real life clinical practice in all settings.To develop and externally validate a new prognostic index (BODEXS90) that combines the variables included in BODEX index with rest peripheral oxygen saturation measured with finger oximetry (SpO2) to predict all-cause mortality in stable COPD.Observational, non-intervention, multicenter historic cohort study. The BODEXS90 index was developed in a derivation cohort and externally validated in a validation cohort. Calibration of the index was carried out using Hosmer-Lemeshow test. The discrimination capacity of BODEXS90 and BODEX were compared by means of receiver-operating characteristics curves. Modelling of the index was carried out by crude and adjusted Cox regression analysis.The derivation and validation cohorts included 787 and 1179 subjects, respectively. SpO2 predicted all cause-mortality independently of BODEX index. Discrimination capacity of BODEXS90 to predict the outcome was significantly higher than that of BODEX, particularly for more severely affected patients, both in the derivation and in the validation cohorts.The new index is potentially useful for designing clinical decision-making algorithms in stable COPD.
Removal of Race From Estimates of Kidney Function
Authors: Keith C. Norris, Nwamaka D. Eneanya, L. Ebony Boulware
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
THU0111 PHYSICIAN’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS: WHAT DO WE REALLY MEAN?
Authors: L. Saraiva, L. Brites, A. R. Cunha, H. Assunção, A. R. Prata, M. Luis, F. Costa, P. Freitas, M. Sousa, J. A. P. Da Silva, C. Duarte
Journal: Annals of the Rheumatic Diseases (2020)

Background: Physician’s global assessment of disease activity (PhGA) is included in some scores of disease activity and, demonstrably, plays a major role upon treatment decisions in rheumatoid arthritis (RA) [1, 2, 3]. Therefore, understanding the reasons underlying the physician´s assessment is crucial. Objectives: To understand the reasons underlying the physician´s assessment. Methods: Cross-sectional study, including consecutive RA patients followed in a Tertiary Rheumatology Department. Socio-demographic (age and gender) and clinical data were collected through a standardized protocol, including 28 tender (TJ28) and swollen (SJC28) joints count, C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), Disease activity Score (DAS28-4v-CRP and DAS28-4v-ESR), PhGA and Patient Global Assessment of disease Activity (PGA) through a Visual Analogic Scale (VAS) 0-100mm, Health Assessment Questionnaire (HAQ), European Quality of Life-5 Dimensions (EQ-5D) and Hospital Anxiety and Depression Scale (HADS). Correlation between PhGA and other continuous variables was evaluated through Pearson´s Correlation Coefficient and variables with p&lt;0.05 in univariate analysis were included in multivariable linear regression (stepwise model). Results: 392 RA patients (80.6% female, 65.3±12.6 years) were included. PhGA was weakly correlated with CRP (r=0.23), TJC28 (r=0.35), PGA (r=0.26), HAQ (r=0.31) and EQ5D (r=-0.21). Moderate correlations were observed with SJC28 (r=0.45) and DAS-4V-CRP (r=0.48). In multivariable analysis, SJC28 (β=4.14, 95%CI:3.16-5.12), CRP (β=0.22; 95%CI: 0.02-0.03), HAQ (β=4.46, 95%CI:1.50-7.42) and PGA (β=0.08; 95%CI:0.00-0.16) remained as independent correlates of PhGA (R2=0.27, p&lt;0,05). Conclusion: In this study, PhGA was associated with SJC28, CRP, HAQ and PGA, suggesting that physicians adopt a comprehensive reading of the disease into account. However, a large proportion of the variance of PhGA remains unexplained. Given its driving role in treatment decisions, the need to standardize and better understand PhGA seems to deserve a closer attention. References: [1]Ward MM, et al. Art Car Res. 2017;69(8):1260-5. [2]Desthieux C, et al. Art Car Res (Hoboken). 2016;68(12):1767-73. [3]Kaneko Y, et al. Mod Rheumatol. 2018;28(6):960-7. Disclosure of Interests: LILIANA SARAIVA: None declared, Luisa Brites: None declared, Ana Rita Cunha: None declared, Helena Assunção: None declared, Ana Rita Prata: None declared, Mariana Luis: None declared, Flavio Costa: None declared, Pedro Freitas: None declared, Marlene Sousa: None declared, José Antonio P. da Silva Grant/research support from: Pfizer, Abbvie, Consultant of: Pfizer, AbbVie, Roche, Lilly, Novartis, Catia Duarte: None declared
AB0635 HOW ARE NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAID) PRESCRIBED IN AXIAL SPONDYLOARTHRITIS?
Authors: K. Ben Abdelghani, Y. Gzam, A. Fazaa, S. Miladi, K. Ouenniche, S. Kassab, L. Souabni, S. Chekili, A. Laatar
Journal: Annals of the Rheumatic Diseases (2020)

Background: For decades, NSAID have been used as the first-line drugs to treat axial spondyloarthritis (ax-SpA). However, the NSAID prescription strategy is not clearly detailed and it varies from one clinician to another. Objectives: The aim of this study was to assess the NSAID prescription modalities adopted in ax-SpA and the differences between these modalities. Methods: This is a descriptive study including 200 cases of ax-SpA fulfilling the ASAS 2009 criteria and diagnosed between January 2000 and October 2019. The demographic and clinical features of the ax-SpA were collected and the modalities of prescription of NSAID were retrospectively assessed. Results: Our population consists of 138 men and 62 women with a mean age of 43,3 ± 11,2 years. The HLA B-27 antigen was present in 50,8% of cases. The ax-SpA was a pure axial form in 67% of patients, associated with peripheral arthritis, enthesitis and dactylitis in 19%, 21,5% and 1,5% respectively. One hundred eighty patients (90%) had been treated with NSAIDs. The NSAIDs used were: the Diclofenac (57.5%), Indomethacin (37.5%), Piroxicam (36%), clecoxib (34%), Naproxen (29.5%) and ketoprofen (13%). Seventy-three patients (36.5%) had used at least 3 NSAIDs. Among the 180 patients treated with NSAID, 88 patients (48,8%) were treated with conventional synthetic DMARDs (csDMARDs) in association with NSAID: Salazopyrine (43,3%) and Methotrexate (13,3%). Seventy-one patients (39,4%) had necessitated the use of anti-TNF alpha. NSAIDs were used continuously in 115 patients (63.8%) and the maximum dose of NSAIDs was used in 78 patients (43.3%). By comparing patients who used maximum doses of NSAIDs and those who used NSAID continuously with other patients, we noticed that the use of biological treatments was more frequent in those groups (p = 0,01 and p=0,004 respectively). In addition, while comparing the group of patients co-treated with csDMARDs with other patients treated with NSAID on monotherapy, we noted that this group of patients had more arthritis (p&lt;0,0001), enthesitis (p=0,02), psoriasis (p=0,04) and necessitated more biological treatments (p=0,01). Conclusion: Our results suggest that maximal doses and/or continuous prescription of NSAID were mainly used if there was no response to that treatment. The csDMARDs were more prescribed if there were peripheral manifestations or psoriatic arthritis and those forms were also more candidates to biological treatments. References: [1]Wang R, et al. Arthritis Rheumatol Hoboken NJ. 2019; Disclosure of Interests: None declared
A Journey Through Myeloma Evolution: From the Normal Plasma Cell to Disease Complexity
Authors: Matteo C. Da Vià, Bachisio Ziccheddu, Akihiro Maeda, Filippo Bagnoli, Giulia Perrone, Niccolò Bolli
Journal: HemaSphere (2020)

Abstract The knowledge of cancer origin and the subsequent tracking of disease evolution represent unmet needs that will soon be within clinical reach. This will provide the opportunity to improve patient's stratification and to personalize treatments based on cancer biology along its life history. In this review, we focus on the molecular pathogenesis of multiple myeloma (MM), a hematologic malignancy with a well‐known multi‐stage disease course, where such approach can sooner translate into a clinical benefit. We describe novel insights into modes and timing of disease initiation. We dissect the biology of the preclinical and pre‐malignant phases, elucidating how knowledge of the genomics of the disease and the composition of the microenvironment allow stratification of patients based on risk of disease progression. Then, we explore cell‐intrinsic and cell‐extrinsic drivers of MM evolution to symptomatic disease. Finally, we discuss how this may relate to the development of refractory disease after treatment. By integrating an evolutionary view of myeloma biology with the recent acquisitions on its clonal heterogeneity, we envision a way to drive the clinical management of the disease based on its detailed biological features more than surrogates of disease burden.
15156 Autoimmune cutaneous disorders associated with PD-1 and PD-L1 inhibitors: Pharmacovigilance analysis of the FDA Adverse Event Reporting System from the Research on Adverse Drug Events and Reports program
Authors: Rohail Memon, Ryan C. Kelm, Maia K. Erickson, Jennifer N. Choi, Anne E. Laumann, Dennis P. West, Beatrice Nardone
Journal: Journal of the American Academy of Dermatology (2020)
SP0054 Polymyalgia rheumatica remission criteria
Authors: B Leeb
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Introduction</h3> Polymyalgia rheumatica (PMR) is not a benign disease. Additional morbidity may arise from prolonged administration of high doses of corticosteroids. No stringent response criteria have been established yet, however, they obviously seem to be of great importance for the quality of patient care and to compare alternative treatment modalities against the golden standard of steroid treatment as steroid sparing medications would be most desirable in PMR. <h3>Patients and methods</h3> Patients from several European countries were enrolled into a study to validate existing diagnostic criteria for PMR as well as into the remission criteria study. Serological findings (ESR, CRP, haemoglobin, serum iron and alpha2-globuline) and clinical features (VAS pain, VAS physicians assessment, morning stiffness, elevation of upper limbs, myalgia, tenderness on pressure of upper/lower limbs, response time after initiation of steroids, head aches, swelling or tenderness of the temporal artery and masseter muscle claudication) were chosen for the characterisation of disease activity. After the initial examination patients were seen at week 1, 4, 8, 16, 24 and 32, study endpoint was at week 48. Starting dose and reduction of corticosteroids as well as co-medication was at the discretion of the local investigator.&nbsp;Patients found to have a disease other than PMR will be excluded from final analysis in the response criteria study. <h3>Results</h3> As expected most of the patients responded well and quickly to steroid treatment. The results concerning the single response parameters will be given on date. Consisting of those criteria performing best a response score should be proposed. The efficacy of treatment may thus easily be reflected by a single figure.
Recent advances in treatment of haemodialysis
Authors: James O. Burton, Richard W. Corbett, Philip A. Kalra, Prashanth Vas, Vivian Yiu, Constantina Chrysochou, Dimitrios Kirmizis
Journal: Journal of the Royal Society of Medicine (2020)

Haemodialysis remains the most widely used treatment for patients with end-stage renal disease. Despite the progress that has occurred in the treatment of end-stage renal disease over the last six decades, there has been a failure to translate this into the desired clinical benefits, with morbidity and mortality rates among patients on haemodialysis remaining unacceptably high. Recently, however, there have been expectations that the significant advances that took place over the last few years may result in improved outcomes. New medications for the treatment of anaemia and secondary hyperparathyroidism, as well as novel trends in the areas of iron therapy, diabetes management and physical exercise are among the most important advances which, taken together, are changing the standards of care for patients on haemodialysis. The latest advances, of relevance not only to specialists in Renal Medicine but also to general practitioners caring for these patients, are reviewed in this collaborative paper.
Abstract PO-20: Molecular characterization of a mouse model of peripheral T-cell lymphoma with Tfh and Th2 features
Authors: Elizabeth Kuczynski, Giulia Morlino, Alison Peter, Dinis Calado, Charles Sinclair, Larissa Carnevalli
Journal: Blood Cancer Discovery (2020)

Abstract Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of malignancies with an aggressive clinical course. Molecular and immunophenotypic analysis have linked PTCL subgroups to derivation from differentiated T cells, including T follicular helper (Tfh), Th1, and Th2 cells. Effective therapies for these PTCLs are undefined and tumor models are limited. We developed a novel mouse model of PTCL and applied it to evaluate responses to therapy. An in vivo transplantable cell line was isolated by passaging a splenic lymphoma arising from a mouse with B cell-specific Blimp1-deletion (Cγ1-Cre Blimp1fl/fl) into C57bl/6J mice. Lymphomas were profiled by flow cytometry, immunohistochemistry, RNA, and exome sequencing. Mice intravenously inoculated with lymphoma cells developed disseminated disease affecting primarily lymphoid tissues and the liver. Model latency to welfare endpoint was 3-4 weeks. Transplantable cells expressed multiple T-cell lineage markers, were CD8 negative and CD4 positive, but gradually downregulated CD4 with passaging. Lymphoma cells (“mPTCL”) also expressed a single TCRvβ chain, suggesting origin from a T helper cell clone. Immunophenotypically, mPTCL stably expressed Tfh markers ICOS, PD-1, CD40L, and low BCL6, and thus was potentially classifiable as a surrogate PTCL of Tfh phenotype. However, the transcriptome of purified mPTCL or spleens indicated a resemblance to Th2 cells and corresponding PTCL-GATA3 subtype (a PTCL-not otherwise specified). In accord with Tfh and Th2 helper function, B cells in the tumor microenvironment had an activated phenotype but were nonexpansive. Investigation into oncogenic pathways in mPTCL revealed a predicted deleterious mutation in Ctnnb1 (β-catenin) and enrichment for Myc-activated, cell cycle regulation, and DNA damage response genes. In vivo, mPTCL progression was significantly and potently delayed by monotherapy inhibition of ataxia telangiectasia and Rad3-related (ATR), a kinase central to resolving replication stress. Taken together, we established a novel model of PTCL with overlapping Tfh and Th2 features. Our findings in this model suggest the use of a DNA damage response inhibitor as a potential treatment strategy for aggressive PTCL-GATA3 lymphomas. Citation Format: Elizabeth Kuczynski, Giulia Morlino, Alison Peter, Dinis Calado, Charles Sinclair, Larissa Carnevalli. Molecular characterization of a mouse model of peripheral T-cell lymphoma with Tfh and Th2 features [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-20.
EmPHasis-10 as a measure of health-related quality of life in pulmonary arterial hypertension: data from PHAR
Authors: Marissa Borgese, David Badesch, Todd Bull, Murali Chakinala, Teresa DeMarco, Jeremy Feldman, H. James Ford, Dan Grinnan, James R. Klinger, Lena Bolivar, Oksana A. Shlobin, Robert P. Frantz, Jeffery S. Sager, Stephen C. Mathai, Steven Kawut, Peter J. Leary, Michael P. Gray, Rita A. Popat, Roham T. Zamanian
Journal: European Respiratory Journal (2020)

While the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States. Using the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score. We analysed data from 565 PAH (75% female) adults aged mean±sd 55.6±16.0 years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of -6.0 points (range -5.0--7.6 points). The e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions.