tbuckley/cabot-search huggingface dataset:
AB0001 INTERFERON SIGNATURE IN CHILDREN WITH CHRONIC NON-BACTERIAL OSTEOMYELITIS AND IT’S DYNAMIC AFTER BISPHOSPHONATES TREATMENT
Authors: M. Kostik, R. Raupov, R. Mulkidzhan, A. Kosmin, E. Suspitsin
Journal: Annals of the Rheumatic Diseases (2021)

Background: Chronic non-bacterial osteomyelitis (CNO) is an immune-mediated chronic inflammatory bone disease which predominantly affects children and adolescents. The pathogenesis of CNO related to imbalance between pro-inflammatory and anti-inflammatory cytokines. Interferon-I mediated pathway is associated with pathogenesis of different pediatric rheumatic diseases, such as juvenile systemic lupus erythematosus (jSLE), juvenile dermatomyositis (JDM), systemic onset of juvenile idiopathic arthritis (soJIA), and, most of all, with macrophage activation syndrome. The data on interferon-I- regulated pathway in CNO is absent. NSAIDs, non-biologic and biologic anti-inflammatory drugs and bisphosphonates (BF) are treatment options for patients with CNO. The main adverse event of BF is a flu-like syndrome probably caused by the excessive cytokine release stimulated by BF. Objectives: The aim of our study was to evaluate activity of Interferon-I mediated pathway in CNO patients and it’s dynamics after BF treatment. Methods: This prospective study included children with CNO requiring BF treatment (n=9), patients with soJIA (n=8), JDM (n=11) and jSLE (n=40) and healthy controls (HC, n=21). The activity of Interferon-I mediated pathway was assessed using interferon I score (IFN1 score). The score represented the median expression of 5 IFN1-regulated genes (IFI44L, IFI44, IFIT3, LY6E, MX1) measured by quantitative real-time PCR. Patients with CNO were treated with standard 3-day regimen (1 mg/kg/day). We measured interferon score before pamidronate (Day 0, n=9) and after (Day 3, n=7). Results: Median interferon score was 1.09 (0.96; 1.67) in CNO patients, 1.95 (1.3; 5.75) in soJIA, 7.6 (1.78; 29.0) in JDM and 16.9 (2.55; 40.3) in jSLE and 0.95 (0.82; 1.17) in HC (p=0.00001). Where were no difference in the IFN1 score between CNO and HC (p=0.222). In 6/7 CNO patients interferon score increased after pamidronate (p=0.015). The median interferon score after pamidronate increased and became 3.06 (0.87; 4,9, p=0.043); this may possibly explain the development of BF-related flu-like symptoms (cytokine release syndrome). Conclusion: While interferon I-regulated pathway is not directly associated with CNO pathogenesis, BF likely activates interferon-I-regulated pathway and thus could be a possible cause of flu-like syndrome. This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001). Disclosure of Interests: None declared
Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice
Authors: Chenxi Qiu, Onder Albayram, Asami Kondo, Bin Wang, Nami Kim, Ken Arai, Cheng-Yu Tsai, Mahmoud A. Bassal, Megan K. Herbert, Kazuo Washida, Peter Angeli, Shingo Kozono, Joseph E. Stucky, Sean Baxley, Yu-Min Lin, Yan Sun, Alexander Rotenberg, Barbara J. Caldarone, Eileen H. Bigio, Xiaochun Chen, Daniel G. Tenen, Mark Zeidel, Eng H. Lo, Xiao Zhen Zhou, Kun Ping Lu
Journal: Science Translational Medicine (2021)

Reducing brain blood flow induces toxic but druggable cis P-tau that drives progressive neurodegeneration and memory loss in mice.
Intracranial Efficacy of Selpercatinib in <i>RET</i> Fusion-Positive Non–Small Cell Lung Cancers on the LIBRETTO-001 Trial
Authors: Vivek Subbiah, Justin F. Gainor, Geoffrey R. Oxnard, Daniel S.W. Tan, Dwight H. Owen, Byoung Chul Cho, Herbert H. Loong, Caroline E. McCoach, Jared Weiss, Yu Jung Kim, Lyudmila Bazhenova, Keunchil Park, Haruko Daga, Benjamin Besse, Oliver Gautschi, Christian Rolfo, Edward Y. Zhu, Jennifer F. Kherani, Xin Huang, Suhyun Kang, Alexander Drilon
Journal: Clinical Cancer Research (2021)

Abstract Purpose: We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for RET fusion-positive non–small cell lung cancers (NSCLC). Patients and Methods: In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RET-altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with RET fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed. Results: Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0–10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60–95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, n = 38), median duration of intracranial response was not reached (95% CI, 9.3–NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9–NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population. Conclusions: Selpercatinib has robust and durable intracranial efficacy in patients with RET fusion-positive NSCLC.
Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy
Authors: Raphael Itzykson, Elise Fournier, Céline Berthon, Christoph Röllig, Thorsten Braun, Alice Marceau-Renaut, Cécile Pautas, Olivier Nibourel, Emilie Lemasle, Jean-Baptiste Micol, Lionel Adès, Delphine Lebon, Jean-Valère Malfuson, Lauris Gastaud, Laure Goursaud, Emmanuel Raffoux, Kevin-James Wattebled, Philippe Rousselot, Xavier Thomas, Sylvain Chantepie, Thomas Cluzeau, Hubert Serve, Nicolas Boissel, Christine Terré, Karine Celli-Lebras, Claude Preudhomme, Christian Thiede, Hervé Dombret, Claude Gardin, Nicolas Duployez
Journal: Blood (2021)
The Importance of SPECT/CT in Preoperative Localization of Sentinel Lymph Nodes in 2 Patients With Acral Melanoma in the Foot
Authors: Shu Zhang, Shikun Zhu, Surong Hua, Xiongfei Zou, Yaping Luo
Journal: Clinical Nuclear Medicine (2021)

Abstract A 68-year-old woman with melanoma in the left heel underwent sentinel node lymphoscintigraphy and radioguided biopsy. The sentinel node lymphoscintigraphy with SPECT/CT detected 3 foci of increased activity in the popliteal fossa and inguinal region. When coregistered to CT, the sentinel node was localized in the inguinal region, and the popliteal foci were considered tracer retention in lymphatic vessel. In another patient with melanoma in the foot, sentinel node lymphoscintigraphy detected 3 foci of increased activity in the popliteal fossa and inguinal region, which were all identified to be nodal uptake in SPECT/CT. The sentinel node was finally localized in popliteal fossa in this patient.
AB0836 DIAGNOSIS VALUE OF INTERLEUKIN 17 IN SPONDYLOARTHRITIS
Authors: L. Kharrat, M. Slouma, A. Tezeghdenti, W. Dkhili, R. Dhahri, E. Ghazouani, I. Gharsallah, L. Metoui, B. Louzir
Journal: Annals of the Rheumatic Diseases (2021)

Background: Interleukin 17 (IL-17) is pro-inflammatory cytokine that plays a crucial role in spondyloarthritis via the Th17/IL-17 axis. (1) Objectives: We aimed to study the diagnosis value of IL-17 serum in spondyloarthritis. Methods: We conducted a case-control study, including 104 subjects divided into 2 groups: -G1: 52 patients meeting the Assessment of SpondyloArthritis International Society (ASAS) criteria for spondyloarthritis (SA) -G2: 52 healthy controls matched for age and sex. The IL-17 level was measured using Enzyme-linked immunosorbent assay (ELISA). We performed a ROC analysis and computed the air under the curve (AUC) at IL-17 to assess the ability of IL-17 to diagnose SA. Statistical analysis was performed using “IBM SPSS Statistics” software version 25. Results: Eighty per cent of the patients were men (n=41). The mean age was 44.96 ± 13.09 years. The mean age at the onset of the disease was 35.07 ± 12.66 years. The disease duration was 9.25 ± 8.09 years. Axial radiographic spondyloarthritis and peripheral involvement were found in 53.8% (n=28) and 44.2% (n=23) of cases, respectively. Psoriasis was noted in 46% of cases (n=24). The mean ASDAS-CRP was 3.21 ± 1.64. IL-17 level was significantly higher in patients compared to healthy controls (92.76 ± 71.85 pg/mL and 2.67 ± 9.01 pg/mL, respectively, p&lt;0.0001). As shown in Figure 1, the AUC value to distinguish between spondyloarthritis and healthy control was 0.987 (p&lt;0.0001). IL-17 cut-off was 13.79 pg/mL (Sensibility= 94.2%, specificity=98.1%). Figure 1. AUC at IL-17 between SA patients and healthy controls 0.987 (p&lt;0.0001) Conclusion: According to previous studies, our study showed that serum IL-17 level is significantly higher in SA patients compared to healthy controls (2). Interestingly, IL-17 was able to distinguish between SA patients and healthy controls with a cut-off of 13.79 pg/mL. This finding suggests that IL-17 may be useful for the diagnosis of SA. References: [1]Ruiz de Morales JMG, Puig L, Daudén E, Cañete JD, Pablos JL, Martín AO, et al. Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies. Autoimmun Rev. janv 2020;19(1):102429. [2]Chen W-S, Chang Y-S, Lin K-C, Lai C-C, Wang S-H, Hsiao K-H, et al. Association of serum interleukin-17 and interleukin-23 levels with disease activity in Chinese patients with ankylosing spondylitis. J Chin Med Assoc. juill 2012;75(7):303-8. Disclosure of Interests: None declared
POS0403 RISK FACTORS FOR PROGRESSION OF RHEUMATOID ARTHRITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE: REASSURING IMPACT OF METHOTREXATE
Authors: C. Lucas, A. Tremblay, S. Jouneau, A. Perdriger
Journal: Annals of the Rheumatic Diseases (2021)

Background: Factors associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) progression and prognosis are not well identified, especially the impact of methotrexate. Objectives: Identify risk factors of ILD progression in RA-ILD patients in a longitudinal study. Methods: RA patients with ILD confirmed in 2 high resolution computed tomography (HRCT) chest scans spaced at least 6 months apart (T0: date of the first HRCT chest scan describing ILD; Tx: date of the last HRCT chest scan available) were consecutively included in this retrospective multi-centric study from 2010 to 2020. HRCT chest scans were analyzed for each patient at T0 and Tx by 2 independent radiologists to determinate ILD pattern (definite UIP, probable UIP, indeterminate UIP, non-UIP) and progression during the follow-up including variation of the fibrosis score (aggravated or non-aggravated). Characteristics of patients (demographic-clinical-biological findings, respiratory function tests, and treatments exposure) at ILD diagnosis and during the follow-up (T0-Tx) were analyzed as potential determinants of ILD progression through multivariable logistic regression analysis. Overall survival was analyzed using Kaplan-Meier method. Results: 74 RA-ILD patients were included. During a mean duration between T0-Tx of 2.8 years ± 2.4, 26 patients (35%) had ILD progression. Thirty-three patients (45%) were treated by methotrexate at ILD diagnosis (T0) and 29 of them (39%) continued methotrexate during T0-Tx. Logistic regression in multivariate analysis revealed that a treatment by methotrexate at ILD diagnosis was protective against ILD progression (OR=0.14 [0.04-0.52]; p=0.0031). Non-UIP pattern at ILD diagnosis was also protective against ILD progression (OR=0.09 [0.02-0.36]; p=0.0005). The follow-up for survival analysis was 5.1 years ± 2.9. Thirty-three patients (31%) died, and the 3-year survival rate was 80%. Survival was better for non-aggravated ILD patients (HR=3.5 [1.46-8.4]; p=0.004) and for patients treated by methotrexate during T0-Tx (HR= 0.36 [0.15-0.84]; p=0.018) and worse for definite UIP patterns (HR=2.570 [1.078-6.128]; p=0.0332). Conclusion: In RA-ILD patients, non-UIP pattern and methotrexate treatment are associated with better ILD evolution and prognosis. Disclosure of Interests: None declared
Challenges in the diagnosis of early rheumatoid arthritis in times of COVID-19
Authors: Bernardo D'Onofrio, Ludovico De Stefano, Bianca Lucia Palermo, Blerina Xoxi, Antonio Manzo, Carlomaurizio Montecucco, Serena Bugatti
Journal: Annals of the Rheumatic Diseases (2021)

Challenges in the provision of care and patients’ reluctance to access healthcare services and adhere to drug prescriptions in course of COVID-19 pandemic undermine the fundamental principles of early diagnosis and treat to target, which have revolutionised the natural history of many chronic inflammatory diseases starting from rheumatoid arthritis (RA).1 Although most rheumatologists have the impression that the intervals between symptom onset and first consultation have increased,2 no data currently indicate whether and to what extent the picture of early RA has changed during COVID-19.

Here, we analysed data from the Pavia Early Arthritis Clinic (EAC) inception cohort. Referral criteria have been described previously, and include the presence of signs and symptoms of suspected inflammatory arthritis for <12 months of duration.3 By 31 December 2020, the EAC collects information on 2.508 patients. The service has undergone complete closure during the first wave of COVID-19 pandemic from 9 March to 18 May 2020. In this period, emergency visits were guaranteed through the general rheumatology outpatient clinic. For this study, baseline characteristics of patients referred in the semester following the lockdown (July to December 2020) were compared with: (1) patients referred in the semester immediately preceding the lockdown (July to December 2019); (2) patients referred in a semester of routine use of the 2010 RA criteria (July to December 2015); (3) patients referred in the semester following the dissemination of the 2010 RA criteria (July to December 2011); and (4) patients referred in the semester preceding the publication of the 2010 …
Dysregulation of PI3K and Hippo signaling pathways synergistically induces chronic pancreatitis via CTGF upregulation
Authors: Takeshi Tamura, Takahiro Kodama, Katsuhiko Sato, Kazuhiro Murai, Teppei Yoshioka, Minoru Shigekawa, Ryoko Yamada, Hayato Hikita, Ryotaro Sakamori, Hirofumi Akita, Hidetoshi Eguchi, Randy L. Johnson, Hideki Yokoi, Masashi Mukoyama, Tomohide Tatsumi, Tetsuo Takehara
Journal: Journal of Clinical Investigation (2021)

The role of PI3K and Hippo signaling in chronic pancreatitis (CP) pathogenesis is unclear. Therefore, we assessed the involvement of these pathways in CP by examining the PI3K and Hippo signaling components PTEN and SAV1, respectively. We observed significant decreases in pancreatic PTEN and SAV1 levels in 2 murine CP models: repeated cerulein injection and pancreatic ductal ligation. Additionally, pancreas-specific deletion of Pten and Sav1 (DKO) induced CP in mice. Pancreatic connective tissue growth factor (CTGF) was markedly upregulated in both CP models and DKO mice, and pancreatic CCAAT/enhancer-binding protein-α (CEBPA) expression was downregulated in the CP models. Interestingly, in pancreatic acinar cells (PACs), CEBPA knockdown reduced PTEN and SAV1 and increased CTGF levels in vitro. Furthermore, CEBPA knockdown in PACs induced acinar-to-ductal metaplasia and activation of cocultured macrophages and pancreatic stellate cells. These results were mitigated by CTGF inhibition. CP in DKO mice was also ameliorated by Ctgf gene deletion, and cerulein-induced CP was alleviated by antibody-mediated CTGF neutralization. Finally, we observed significantly decreased PTEN, SAV1, and CEBPA and increased CTGF levels in human CP tissues compared with nonpancreatitis tissues. Taken together, our results indicate that dysregulation of PI3K and Hippo signaling induces CP via CTGF upregulation.
In situ delivery of iPSC-derived dendritic cells with local radiotherapy generates systemic antitumor immunity and potentiates PD-L1 blockade in preclinical poorly immunogenic tumor models
Authors: Takaaki Oba, Kenichi Makino, Ryutaro Kajihara, Toshihiro Yokoi, Ryoko Araki, Masumi Abe, Hans Minderman, Alfred E Chang, Kunle Odunsi, Fumito Ito
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Dendritic cells (DCs) are a promising therapeutic target in cancer immunotherapy given their ability to prime antigen-specific T cells, and initiate antitumor immune response. A major obstacle for DC-based immunotherapy is the difficulty to obtain a sufficient number of functional DCs. Theoretically, this limitation can be overcome by using induced pluripotent stem cells (iPSCs); however, therapeutic strategies to engage iPSC-derived DCs (iPSC-DCs) into cancer immunotherapy remain to be elucidated. Accumulating evidence showing that induction of tumor-residing DCs enhances immunomodulatory effect of radiotherapy (RT) prompted us to investigate antitumor efficacy of combining intratumoral administration of iPSC-DCs with local RT. Methods Mouse iPSCs were differentiated to iPSC-DCs on OP9 stromal cells expressing the notch ligand delta-like 1 in the presence of granulocyte macrophage colony-stimulating factor. Phenotype and the capacities of iPSC-DCs to traffic tumor-draining lymph nodes (TdLNs) and prime antigen-specific T cells were evaluated by flow cytometry and imaging flow cytometry. Antitumor efficacy of intratumoral injection of iPSC-DCs and RT was tested in syngeneic orthotopic mouse tumor models resistant to anti-PD-1 ligand 1 (PD-L1) therapy. Results Mouse iPSC-DCs phenotypically resembled conventional type 2 DCs, and had a capacity to promote activation, proliferation and effector differentiation of antigen-specific CD8 + T cells in the presence of the cognate antigen in vitro. Combination of in situ administration of iPSC-DCs and RT facilitated the priming of tumor-specific CD8 + T cells, and synergistically delayed the growth of not only the treated tumor but also the distant non-irradiated tumors. Mechanistically, RT enhanced trafficking of intratumorally injected iPSC-DCs to the TdLN, upregulated CD40 expression, and increased the frequency of DC/CD8 + T cell aggregates. Phenotypic analysis of tumor-infiltrating CD8 + T cells and myeloid cells revealed an increase of stem-like Slamf6 + TIM3 − CD8 + T cells and PD-L1 expression in tumor-associated macrophages and DCs. Consequently, combined therapy rendered poorly immunogenic tumors responsive to anti-PD-L1 therapy along with the development of tumor-specific immunological memory. Conclusions Our findings illustrate the translational potential of iPSC-DCs, and identify the therapeutic efficacy of a combinatorial platform to engage them for overcoming resistance to anti-PD-L1 therapy in poorly immunogenic tumors.
The role of senescence in the pathogenesis of atrial fibrillation: A target process for health improvement and drug development
Authors: Guangran Guo, Steven Watterson, Shu-Dong Zhang, Anthony Bjourson, Victoria McGilligan, Aaron Peace, Taranjit Singh Rai
Journal: Ageing Research Reviews (2021)

Cellular senescence is a state of growth arrest that occurs after cells encounter various stresses. Senescence contributes to tumour suppression, embryonic development, and wound healing. It impacts on the pathology of various diseases by secreting inflammatory chemokines, immune modulators and other bioactive factors. These secretory biosignatures ultimately cause inflammation, tissue fibrosis, immunosenescence and many ageing-related diseases such as atrial fibrillation (AF). Because the molecular mechanisms underpinning AF development remain unclear, current treatments are suboptimal and have serious side effects. In this review, we summarize recent results describing the role of senescence in AF. We propose that senescence factors induce AF and have a causative role. Hence, targeting senescence and its secretory phenotype may attenuate AF.
Reply to Santhanam Sundar and Paul Symonds’ Letter to the Editor re: Syed A. Hussain, Nuria Porta, Emma Hall, et al. Outcomes in Patients with Muscle-invasive Bladder Cancer Treated with Neoadjuvant Chemotherapy Followed by (Chemo)radiotherapy in the BC2001 Trial. Eur Urol 2021;79:307–15
Authors: Syed A. Hussain, Nuria Porta, Emma Hall, Muneeb Qureshi, Rebecca Lewis, Robert Huddart, Nicholas D. James
Journal: European Urology (2021)
A Longitudinal Study of Resting-State Connectivity and Response to Psychostimulant Treatment in ADHD
Authors: Luke J. Norman, Gustavo Sudre, Marine Bouyssi-Kobar, Wendy Sharp, Philip Shaw
Journal: American Journal of Psychiatry (2021)

Psychostimulants are first-line pharmacological treatments for attention deficit hyperactivity disorder (ADHD), although symptom reduction varies widely between patients and these individual differences in treatment response are poorly understood. The authors sought to examine whether the resting-state functional connectivity within and between cingulo-opercular, striato-thalamic, and default mode networks was associated with treatment response to psychostimulant medication, and whether this relationship changed with development.Patients with ADHD (N=110; 196 observations; mean age at first observation, 10.83 years, SD=2.2) and typically developing control subjects (N=142; 330 observations; mean age at first observation, 10.49 years, SD=2.81) underwent functional neuroimaging on up to five occasions during development (age range, 6-17 years). For patients, symptoms were assessed on and off psychostimulant medication (methylphenidate-based treatments: N=132 observations, 67%; amphetamine-based treatments: N=64 observations, 33%) using the Diagnostic Interview for Children and Adolescents for parents. Linear mixed-effects models examined whether resting-state connectivity was associated with treatment response and its interaction with age. Comparisons with typically developing control subjects were performed to contextualize any significant associations.Resting-state connectivity within the cingulo-opercular network was associated with a significant interaction between treatment response and age. Specifically, worse responses to treatment compared with better responses to treatment among patients and compared with typically developing control subjects were associated with an atypical increase in cingulo-opercular connectivity with increasing age from childhood to adolescence.This work delineates how resting-state connectivity may be associated over development with response to psychostimulants in ADHD. Functioning and development within the cingulo-opercular network may warrant further investigation as a contributor to differential response to psychostimulants.