tbuckley/cabot-search huggingface dataset:
FRI0009 Infliximab in the treatment of rheumatoid arthritis (ra): referral patterns, response to treatment, and adverse events in a real world setting
Authors: Y Yazici, D Erkan, I Kulman, L Leff, J Markenson, MJ Harrison
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Infliximab is a chimeric, monoclonal antibody against tumour necrosis factor (TNF) alpha, recently developed to complement methotrexate therapy in RA patients with a less than optimal response to treatment. To date it has only been studied in clinical trials. <h3>Objectives</h3> To describe referral patterns, patient response to treatment, and adverse events in a cohort of RA patients treated with infliximab in a real world setting. <h3>Methods</h3> Patients who had received their first dose of infliximab between 1/00 and 6/00 were included to ensure the possibility of at least 6 months of drug exposure. We evaluated patients at baseline, and followed them prospectively every 2 months for a total of 6 months. Patients completed several questionnaires regarding RA history, treatment, and disease activity (HAQ, pain, fatigue, tender and swollen joint counts) at each infusion. All subjects were contacted between infusions for reporting of side effects. <h3>Results</h3> 36 patients were treated with infliximab between January 1 – June 30, 2000 (female n = 33, mean age = 63 ± 12.9 y, disease duration = 15.3 ± 10.2 y). They had previously failed an average of 3 DMARDs. 24 patients were on oral steroids at baseline. 16 patients received infliximab without concurrent MTX. 12 of 36 patients discontinued treatment before 6 months. Discontinuation reasons were inadequate response (n = 5), repeated episodes of dyspnea (n = 3), asthma (n = 1), chest tightness (n = 1), phlebitis (n = 1), and patient noncompliance (n = 1). Table 1 shows individual measures of disease activity in 24 patients who completed 6 months of infliximab. We detected a significant improvement in HAQ scores, and trends toward improvement in pain scores and tender joint counts. HAQ scores improved in 19/24, stiffness in 14/24, pain in 13/24, fatigue in 13/24, tender joint counts in 13/24 and swollen joints in 15/24 of patients. Since initiating infliximab therapy, of the 36 patients receiving 198 infusions, 18 patients reported a total of 33 adverse events (headaches n = 8, nausea n = 2, abdominal pain n = 2, chest pain n = 1, chills n = 2, dyspnea n = 3, myalgias n = 3, pruritis n = 4, fatigue n = 3, and rash n = 5). <h3>Conclusion</h3> Infliximab is often used in more difficult RA patients (older, long-standing RA, multiple DMARD failures). This referral pattern may explain the increased incidence of adverse events and suboptimal clinical response noted in our cohort. However, our results suggest a trend towards rapid, clinically important improvement in measures of disease activity. Ongoing follow-up of this growing group of patients will provide necessary information regarding the appropriate role of infliximab in the treatment of RA.
Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline
Authors: Waqaar Shah, Toby Hillman, E Diane Playford, Lyth Hishmeh
Journal: BMJ (2021)

<h3>Abstract</h3> This study quantifies the relationship between school closure timing and COVID-19 deaths and cases in the general population in all U.S. states. COVID-19 has higher symptomatic infection rates among the elderly, suggesting school closures could be unrelated to transmission. However, predicting daily cumulative COVID-19 deaths by state, earlier school closure is related to fewer deaths per capita and slower growth in deaths per capita. Results are similar for COVID-19 cases per capita.
Mechanisms underlying low-clinical responses to PD-1/PD-L1 blocking antibodies in immunotherapy of cancer: a key role of exosomal PD-L1
Authors: Zi Yin, Min Yu, Tingting Ma, Chuanzhao Zhang, Shanzhou Huang, Mohammad Reza Karimzadeh, Amir Abaas Momtazi-Borojeni, Sheng Chen
Journal: Journal for ImmunoTherapy of Cancer (2021)

Exosomes, as the main group of extracellular vesicles, are biologically active lipid-bilayer vesicles that are naturally released from different types of normal or tumor cells. These vesicles play an important role in intercellular communication and influence the extracellular environment and the immune system. Emerging evidence demonstrates that cancer-derived exosomes are enriched in immunosuppressive proteins, such as the programmed death-ligand 1 (PD-L1). PD-L1 and its receptor programmed cell death protein 1 (PD-1) are the key immune checkpoint molecules that promote tumor progression via negative regulation of immune responses. PDL-1 is highly expressed on the surface of tumor cells and binds to PD-1 on the surface of activated T cells, leading to suppression of T cells, which consequently enables cancer cells to escape antitumor immunity. Currently, there are several Food and Drug Administration-approved monoclonal antibodies blocking PD-1/PD-L1 interaction, which are clinically used for cancer treatment. However, despite impressive treatment outcomes, some patients show poor response to PD-1/PD-L1 blockade. Of note, tumor-derived exosomes containing PD-L1 can recapitulate the effect of cell-surface PD-L1. There is evidence that reveals a significant association between levels of circulating exosomal PD-L1 and rate of response to anti-PD-1/PD-L1 antibody therapy. The present article reviews the role of exosomal PDL-1 in the therapeutic resistance to anti-PD-1/PD-L1 treatment. Importantly, it is suggested that the removal of exosomal PDL-1 could serve as a therapeutic adjuvant for enhancing the efficacy of anti-PD-1/PD-L1 therapy in patients with cancer.
Clinicopathological characteristics and impact on efficacy of three versus six months of adjuvant chemotherapy in early-onset colon cancer: ACHIEVE and ACHIEVE-2 trials.
Authors: Eiji Oki, Masahito Kotaka, Dai Manaka, Manabu Shiozawa, Yasuhiro Sakamoto, Yoshinori Munemoto, Tetsuya Eto, Kohei Shitara, Takeshi Kato, Akio Shiomi, Junichi Hasegawa, Akitaka Makiyama, Takeharu Yamanaka, Tsunekazu Mizushima, Kentaro Yamazaki, Eiji Sunami, Atsushi Ohtsu, Yoshihiko Maehara, Masaki Mori, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2021)

60 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s but several data such as the SEER CRC registry show that the incidence of early onset colon cancer (eoCC, age 20-49) and RC keep increasing. There is limited results suggesting eoCC may have different behaviors compared to traditional CC (tCC, age ≥ 50). Methods: Individual patient data of 1,805 high-risk stage II/III colon cancer (CC) patients (pts) as the modified ITT population in ACHIEVE and ACHIEVE-2 trials were investigated. Clinicopathological features and treatment-related data were assessed by age group. Disease-free survival (DFS) was assessed by Kaplan-Meier curves and Cox multivariable models adjusted by trials, regimen, T and N. Results: Of the 1,805 pts, eoCC were 155 pts (8.6%). Using 5% difference between age groups as clinically meaningful cutoff, eoCC had similar gender (female, 52 vs 48%), PS (PS = 1, 1 vs 4%), risk group (high-risk, 43 vs 42%) and T stage (T4, 30 vs 30%) as tCC, while eoCC were less likely right-sided colon primary (32 vs 39%), had N1 disease (48 vs 54%), and treated by FOLFOX (16 vs 23%). Overall, eoCC significantly had a worse DFS than tCC (3y-DFS, 75 vs 82%; Adjusted Hazard Ratio = 1.40: 95% Confidence Interval, 1.00-1.95: p= 0.0478); in addition, similar DFS were observed among tCC pts (age 50-69 vs &gt;70). eoCC experienced less neutropenia, thrombocytopenia and stomatitis, but had more diarrhea, nausea and/or vomiting. There were 38 and 297 pts with an initial relapse in eoCC and tCC, respectively. Of those, peritoneal metastases were more frequently seen in eoCC (n = 13, 34%) than in tCC (n = 63, 21%) (p = 0.097), whereas liver and lung metastases were similar between the two groups. Impact on DFS of 3 versus 6 months of adjuvant chemotherapy in eoCC (3y-DFS, 75% vs 76%) is similar to that in tCC (83% vs 81%). Conclusions: eoCC had unique characteristics; the difference in DFS between eoCC and tCC were potentially due to a different metastatic spread. eoCC had a different adverse event profile compared to tCC. No impact on DFS of treatment duration in eoCC was suggested. Clinical trial information: UMIN000013036.
It takes a village: lessons from collaborative science
Authors: E. Dale Abel
Journal: Journal of Clinical Investigation (2021)

Like many physician-scientists, I started my research career in earnest during my fellowship training, which for me was an endocrinology fellowship in the 1990s.These were relatively early days in the era of using mouse genetics to elucidate in vivo biology and to model disease.The expectation was to obtain a K08 clinical investigator award and then leverage that work into an R01 grant.The traditional approach at that time was to focus on a scientific question that could be used to define your reputation in the field.In my case, my research centered on glucose transport (1, 2) and insulin signaling in the heart (3), largely based on insights gained from my prior work generating cardiomyocyte-restricted deletions of these metabolic regulators.I made the case that these murine models could inform the pathophysiology of diabetic cardiomyopathy, which at the time was beginning to be recognized as a distinct cardiovascular complication of diabetes.When I moved to the University of Utah in 2000 as an assistant professor, I presented a vision of developing a research program based on elucidating the contribution of changes in insulin signaling and glucose metabolism to diabetes-related heart failure and obtained individual grant funding from the NIH, the American Diabetes Association, and the American Heart Association to continue these studies as the sole principal investigator.
Abstract 14297: A Mouse Model of Recurrent Myocardial Infarction Reports Diminished Emergency Hematopoiesis and Cardiac Inflammation
Authors: Sebastian Cremer, Maximillian Schloss, Claudio Vinegoni, Shuang Zhang, David Rohde, Feruglio Paolo Fumene, Schmidt Stephen, Wojtkiewicz Greg, Ralph Weissleder, Filip K Swirski, Matthias Nahrendorf
Journal: Circulation (2019)

Recurrent myocardial infarction is common in patients with coronary artery disease and associated with high mortality. Here we describe a surgical mouse model in which two subsequent infarcts affec...
The ability of the neonatal immune response to handle SARS-CoV-2 infection – Authors' reply
Authors: Chris Gale, Maria A Quigley, Anna Placzek, Marian Knight, Shamez Ladhani, Elizabeth S Draper, Don Sharkey, Cora Doherty, Helen Mactier, Jennifer J Kurinczuk
Journal: The Lancet Child & Adolescent Health (2021)
Ambient air pollution exposure and chronic bronchitis in the Lifelines cohort
Authors: Dany Doiron, Jean Bourbeau, Kees de Hoogh, Anna L Hansell
Journal: Thorax (2021)

Background Few large studies have assessed the relationship of long-term ambient air pollution exposure with the prevalence and incidence of symptoms of chronic bronchitis and cough. Methods We leveraged Lifelines cohort data on 132 595 (baseline) and 65 009 (second assessment) participants linked to ambient air pollution estimates. Logistic regression models adjusted for sex, age, educational attainment, body mass index, smoking status, pack-years smoking and environmental tobacco smoke at home were used to assess associations of air pollution with prevalence and incidence of chronic bronchitis (winter cough and sputum almost daily for ≥3 months/year), chronic cough (winter cough almost daily for ≥3 months/year) and prevalence of cough and sputum symptoms, irrespective of duration. Results Associations were seen for all pollutants for prevalent cough or sputum symptoms. However, for prevalent and incident chronic bronchitis, statistically significant associations were seen for nitrogen dioxide (NO 2 ) and black carbon (BC) but not for fine particulate matter (PM 2.5 ). For prevalent chronic bronchitis, associations with NO 2 showed OR: 1.05 (95% CI: 1.02 to 1.08) and with BC OR: 1.06 (95% CI: 1.03 to 1.09) expressed per IQR; corresponding results for incident chronic bronchitis were NO 2 OR: 1.07 (95% CI: 1.02 to 1.13) and BC OR: 1.07 (95% CI: 1.02 to 1.13). In subgroup analyses, slightly stronger associations were observed among women, never smokers and younger individuals. Conclusion This is the largest analysis to date to examine cross-sectional and longitudinal associations between ambient air pollution and chronic bronchitis. NO 2 and BC air pollution was associated with increased odds of prevalent and incident chronic bronchitis.
Biomarker Discovery in Patients with Immunotherapy-Treated Melanoma with Imaging Mass Cytometry
Authors: Sandra Martinez-Morilla, Franz Villarroel-Espindola, Pok Fai Wong, Maria I. Toki, Thazin Nwe Aung, Vasiliki Pelekanou, Brian Bourke-Martin, Kurt A. Schalper, Harriet M. Kluger, David L. Rimm
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Imaging mass cytometry (IMC) is among the first tools with the capacity for multiplex analysis of more than 40 targets, which provides a novel approach to biomarker discovery. Here, we used IMC to characterize the tumor microenvironment of patients with metastatic melanoma who received immunotherapy in efforts to find indicative factors of treatment response. In spite of the new power of IMC, the image analysis aspects are still limited by the challenges of cell segmentation. Experimental Design: Here, rather than segment, we performed image analysis using a newly designed version of the AQUA software to measure marker intensity in molecularly defined compartments: tumor cells, stroma, T cells, B cells, and macrophages. IMC data were compared with quantitative immunofluorescence (QIF) and digital spatial profiling. Results: Validation of IMC results for immune markers was confirmed by regression with additional multiplexing methods and outcome assessment. Multivariable analyses by each compartment revealed significant associations of 12 markers for progression-free survival and seven markers for overall survival (OS). The most compelling indicative biomarker, beta2-microglobulin (B2M), was confirmed by correlation with OS by QIF in the discovery cohort and validated in an independent published cohort profiled by mRNA expression. Conclusions: Using digital image analysis based on pixel colocalization to assess IMC data allowed us to quantitively measure 25 markers simultaneously on formalin-fixed, paraffin-embedded tissue microarray samples. In addition to showing high concordance with other multiplexing technologies, we identified a series of potentially indicative biomarkers for immunotherapy in metastatic melanoma, including B2M.
A Magnetically Guided Self‐Rolled Microrobot for Targeted Drug Delivery, Real‐Time X‐Ray Imaging, and Microrobot Retrieval
Authors: Kim Tien Nguyen, Gwangjun Go, Zhen Jin, Bobby Aditya Darmawan, Ami Yoo, Seokjae Kim, Minghui Nan, Sang Bong Lee, Byungjeon Kang, Chang‐Sei Kim, Hao Li, Doyeon Bang, Jong‐Oh Park, Eunpyo Choi
Journal: Advanced Healthcare Materials (2021)

Targeted drug delivery using a microrobot is a promising technique capable of overcoming the limitations of conventional chemotherapy that relies on body circulation. However, most studies of microrobots used for drug delivery have only demonstrated simple mobility rather than precise targeting methods and prove the possibility of biodegradation of implanted microrobots after drug delivery. In this study, magnetically guided self-rolled microrobot that enables autonomous navigation-based targeted drug delivery, real-time X-ray imaging, and microrobot retrieval is proposed. The microrobot, composed of a self-rolled body that is printed using focused light and a surface with magnetic nanoparticles attached, demonstrates the loading of doxorubicin and an X-ray contrast agent for cancer therapy and X-ray imaging. The microrobot is precisely mobilized to the lesion site through automated targeting using magnetic field control of an electromagnetic actuation system under real-time X-ray imaging. The photothermal effect using near-infrared light reveals rapid drug release of the microrobot located at the lesion site. After drug delivery, the microrobot is recovered without potential toxicity by implantation or degradation using a magnetic-field-switchable coiled catheter. This microrobotic approach using automated control method of the therapeutic agents-loaded microrobot has potential use in precise localized drug delivery systems.
Proteomic and metabolomic advances uncover biomarkers of mitochondrial disease pathophysiology and severity
Authors: Marjan Gucek, Michael N. Sack
Journal: Journal of Clinical Investigation (2021)

Advancing proteomic and metabolomic technologies that integrate curated omic databases have crossed a threshold to enable their clinical utility. In this issue of the JCI, Sharma et al. exploit emerging technologies to evaluate whether biomarkers identified in the mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome could refine disease characterization, uncover pathways to monitor therapeutic efficacy, and/or delineate disease-modifying targets. The authors analyzed blood and urine samples from patients with this genetic mitochondrial disease and elucidated proteins and metabolites related to NADH-reductive stress. These circulating biomarkers have intriguing clinical potential that implicate disease pathophysiology and may prove important biomarkers for the future management of MELAS.
Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma
Authors: Michael D. Jain, Hua Zhao, Xuefeng Wang, Reginald Atkins, Meghan Menges, Kayla Reid, Kristen Spitler, Rawan Faramand, Christina Bachmeier, Erin A. Dean, Biwei Cao, Julio C. Chavez, Bijal Shah, Aleksandr Lazaryan, Taiga Nishihori, Mohammed Hussaini, Ricardo J. Gonzalez, John E. Mullinax, Paulo C. Rodriguez, Jose R. Conejo-Garcia, Claudio Anasetti, Marco L. Davila, Frederick L. Locke
Journal: Blood (2021)
AB0571 IS RITUXIMAB AN ADEQUATE GLUCOCORTICOID SPARING AGENT IN IDIOPATHIC INFLAMMATORY MYOPATHIES?
Authors: B. H. Egeli, S. Ergun, Y. K. Gursoy, A. Cetin, S. Ugurlu
Journal: Annals of the Rheumatic Diseases (2020)

Background: Idiopathic inflammatory myopathies (IIM) are essentially treated aiming improvement of muscle function and extra muscular disease manifestations. The backbone of the treatment is corticosteroids enhancing the survival and patient quality of life. The lack of consensus on target-specific immunosuppressive treatment highlights the need for further studies evaluating alternative treatment methods. Rituximab is potentially a glucocorticoid-sparing agent which was reviewed in multiple studies with small sample sizes due to the rarity of the disease. Objectives: Higher statistical power can enhance the trustworthiness of alternative treatment methods yielding the main objective of this study. Methods: This retrospective study was conducted at a tertiary rheumatology center. Patients were diagnosed with an idiopathic inflammatory myopathy (dermatomyositis [DM], polymyositis [PM]) and were treated with rituximab in order to be included in this study. Clinical signs and symptoms of the presentation were noted during the first patient encounter as well as the follow-up. Parameters of disease activity including acute phase reactants, muscle enzyme levels, and disease-specific autoantibodies were analyzed. Results: The study includes 28 patients (20 DM, 8 PM). The age of diagnosis was 43.44 ± 15.77 years, follow-up duration was 60.7 ± 70.7 months. The presenting signs and symptoms of the patients are shown in Figure 1. The parameters of disease activity before and after treatment are summarized in Table 1. The mean corticosteroid dose decreased from 31.429 ±23.934 mg to 10.278 ±12.001 (p=0.001). Other treatment methods were methotrexate (n=18), Intravenous Immunoglobulin (IVIG) (n=7), and cyclophosphamide (n=2). There were not any deaths during the follow-up. Two patients were lost to follow-up. Table 1. The Parameters of Disease Activity Before and After Treatment Before Treatment After Treatment P Value CPK, mean ± std (U/L ) 1426 ± 2049.92 263.44 ± 265.63 0.004 LDH, mean ± std (U/L ) 557.5 ± 365 379.78 ± 192.1 0.03 AST, mean ± std (U/L ) 62.52 ± 59 30.16 ± 27.59 0.01 ALT, mean ± std (U/L ) 56.48 ± 49.21 27.64 ± 24.52 0.008 ESR, mean ± std (mm/hour ) 26.38 ± 28.98 20.39 ± 18.76 0.36 CRP, mean ± std (mg/L ) 19.23 ± 46.15 12.53 ± 26.67 0.5 RF, mean ± std (U/mL ) 0 (0) N/A N/A ANA, n (% ) 3 (10.71) N/A N/A Figure 1. The Presenting Signs and Symptoms of the Patients Conclusion: Rituximab is shown to be effective in treating myositis along with corticosteroids as well as a corticosteroid-sparing agent in retrospective studies and open-label clinical trials; however, lack of statistical power should be underlined. Long term decrease in steroid use and decrease in disease activity markers hints the effective use of rituximab as a glucocorticoid sparing agent as well as its safety with minimal side effects. Disclosure of Interests: None declared
FRI0035 Risk factors for clinically important upper gi events: the vigour study
Authors: C Bombardier, L Laine, AS Reicin, DR Shapiro, RS Sperling
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The VIGOUR (VIOXX GI Outcomes Research) study was a prospective, randomised, double-blind comparison of rofecoxib (a COX-2 inhibitor) vs. naproxen (a dual COX-1/COX-2 inhibitor) in &gt; 8000 patients with rheumatoid arthritis (RA). The study showed that rofecoxib was associated with significantly fewer clinically important upper gastrointestinal (GI) events (perforation, obstruction, bleeding, symptomatic gastric and duodenal ulcers) than naproxen. <h3>Objectives</h3> To assess whether the risk reduction in clinically important upper GI events seen with rofecoxib was similar in “high risk” and “low risk” sub-populations; and, to predict the risk of these events based on baseline characteristics. <h3>Methods</h3> In the VIGOUR trial, 8076 RA patients expected to require NSAIDs for &gt; 1 yr were randomly assigned rofecoxib 50 mg qd or naproxen 500 mg bid for minimum of 6-month follow-up. Patients were classified as “low risk” or “high risk” for clinically important upper GI events based on recognised risk factors – age, steroid use, previous history of clinical GI events, and H. pylori sero-status. Relative risk analyses were conducted in both low- and high-risk subgroups. A multifactorial model to predict clinically important upper GI events was developed. Multiple steps in the analysis included: 1. Covariates were examined in a univariate Cox model; 2. Factors that trended (p &lt; 0.20) plus treatment were put into Cox model and backwards stepwise regression chose significant (p = 0.05) predictors; and, 3. Interactions between each covariate with treatment were tested one at a time in Cox models. <h3>Results</h3> The % risk reduction (rofecoxib relative to naproxen) of clinically important upper GI events was 88% in the low-risk subgroup, 51% in the high- risk subgroup and 54% in the overall population. <h3>Conclusion</h3> (1) The relative risk reduction of GI events in the rofecoxib group was maintained in both the high and low risk subgroups. (2) Multivariate analyses found the risk factors significantly associated with GI events to include age, prior history or clinical GI events (complicated and uncomplicated), disease severity, duration of disease, prior history of GI symptoms, prior use of low dose H2 blockers, steroids, and NSAIDs.
Successful Recruitment of Black Men to Prostate Cancer Clinical Trials—A Lesson in Achievement
Authors: Andrew W. Hahn, Mehmet A. Bilen, Neeraj Agarwal
Journal: JAMA Network Open (2021)

Ulka N. Vaishampayan, MD; Lance K. Heilbrun, PhD; Paul Monk III, MD; Sheela Tejwani, MD; Guru Sonpavde, MD; Clara Hwang, MD; Daryn Smith, MS; Pallavi Jasti, MD; Kimberlee Dobson, BS; Brenda Dickow, RN; Elisabeth I. Heath, MD; Louie Semaan, BS; Michael L. Cher, MD; Joseph A. Fontana, MD; Sreenivasa Chinni, PhD