tbuckley/cabot-search huggingface dataset:
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Authors: Iris Navarro‐Millán, Mary K. Crow
Journal: Arthritis & Rheumatology (2020)

To the Editor: We appreciate Drs. Cavalli and Dagna's comments regarding our article addressing the potential utility of anakinra for avoiding the need for mechanical ventilation in patients with COVID-19, acute hypoxic respiratory failure, and evidence of cytokine storm syndrome. We thank them for pointing out the similarities between our patients and the patients in their recently reported study of COVID-19 patients who received high-dose intravenous anakinra. Indeed, 25 of 29 patients treated with anakinra in their similar study had severe acute respiratory distress syndrome, which Drs. Cavalli and Dagna defined as a partial pressure of arterial oxygen:fraction of inspired oxygen ratio of ≤100 mm Hg in the setting of bilateral pulmonary infiltrates and a positive end-expiratory pressure of ≥5 cm H2O (1). Drs. Cavalli and Dagna discuss the observations of elevated serum liver enzyme levels in some patients receiving anakinra in both studies and suggest that those elevations might not be attributable to anakinra. In their study, 3 of 29 patients who received anakinra developed elevated liver enzyme levels, while 5 of 16 similar patients who did not receive anakinra also had increased enzyme levels. We also noted that the observed elevations of liver enzyme levels could be a consequence of cytokine storm syndrome. We chose to taper anakinra and observed that the liver enzyme levels responded to decreasing the anakinra dose. We agree that additional data will be needed to understand whether anakinra can promote altered liver function in the special clinical circumstances of severe acute respiratory distress syndrome coronavirus 2 infection. Results from both studies point to the significant need for well-controlled investigations to evaluate the efficacy and safety of anakinra in patients with severe COVID-19 with the goal of gaining control of cytokine storm syndrome and avoiding the need for mechanical ventilation. In addition, our results suggest that the timing of initiation of anakinra should be carefully considered, as the outcomes in our patients who received treatment within 36 hours of the onset of severe respiratory failure were more favorable than those in patients with more prolonged respiratory failure prior to initiation of therapy. Dr. Navarro-Millán's work was supported by the NIH (grant K23-AR-068449 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases).
Pathogenicity and transmissibility of an H9N2 avian influenza virus that naturally harbors the mammalian-adaptive molecular factors in the hemagglutinin and PB2 proteins
Authors: Kaituo Liu, Xiaoquan Wang, Daxiu Jiang, Naiqing Xu, Ruyi Gao, Wenwen Han, Min Gu, Jiao Hu, Xiaowen Liu, Shunlin Hu, Xiufan Liu
Journal: Journal of Infection (2020)
Endoplasmic reticulum stress and autophagy dysregulation in alcoholic and non-alcoholic liver diseases
Authors: Yun Seok Kim, Sang Geon Kim
Journal: Clinical and Molecular Hepatology (2020)

Alcoholic and non-alcoholic liver diseases begin from an imbalance in lipid metabolism in hepatocytes as the earliest response. Both liver diseases share common disease features and stages (i.e., steatosis, hepatitis, cirrhosis, and hepatocellular carcinoma). However, the two diseases have differential pathogenesis and clinical symptoms. Studies have elucidated the molecular basis underlying similarities and differences in the pathogenesis of the diseases; the factors contributing to the progression of liver diseases include depletion of sulfhydryl pools, enhanced levels of reactive oxygen and nitrogen intermediates, increased sensitivity of hepatocytes to toxic cytokines, mitochondrial dysfunction, and insulin resistance. Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins and calcium depletion, contributes to the pathogenesis, often causing catastrophic cell death. Several studies have demonstrated a mechanism by which ER stress triggers liver disease progression. Autophagy is an evolutionarily conserved process that regulates organelle turnover and cellular energy balance through decomposing damaged organelles including mitochondria, misfolded proteins, and lipid droplets. Autophagy dysregulation also exacerbates liver diseases. Thus, autophagy-related molecules can be potential therapeutic targets for liver diseases. Since ER stress and autophagy are closely linked to each other, an understanding of the molecules, gene clusters, and networks engaged in these processes would be of help to find new remedies for alcoholic and non-alcoholic liver diseases. In this review, we summarize the recent findings and perspectives in the context of the molecular pathogenesis of the liver diseases.
Corrigendum to “Delivery of oncolytic adenovirus into the nucleus of tumorigenic cells by tumor microparticles for virotherapy” [Biomaterials 89 (2016) 56–66]
Authors: Li Ran, Xiaohua Tan, Yanchun Li, Huafeng Zhang, Ruihua Ma, Tiantian Ji, Wenqian Dong, Tong Tong, Yuying Liu, Degao Chen, Xiaonan Yin, Xiaoyu Liang, Ke Tang, Jingwei Ma, Yi Zhang, Xuetao Cao, Zhuowei Hu, Xiaofeng Qin, Bo Huang
Journal: Biomaterials (2020)
The High Cost of Diabetes Drugs: Disparate Impact on the Most Vulnerable Patients
Authors: Simeon I. Taylor
Journal: Diabetes Care (2020)

> The arc of the moral universe is long, but it bends toward justice.
> 
> —Martin Luther King, Jr.

Diabetes exacts a high cost in human suffering, including increased burdens of cardiovascular disease, blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated the value of intensive pharmacotherapy to delay or prevent chronic complications of diabetes (1–6). Over the past decade, clinical trials demonstrated that several sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists decrease the risks of major adverse cardiovascular events, hospitalization for heart failure, and progression of diabetic kidney disease (7–12). In this issue of Diabetes Care , Zhou et al. (13) estimate the economic cost of glucose-lowering drugs at $57.6 billion per year in the U.S. in 2015–2017 (∼15–20% of the estimated annual cost for all prescription drugs in the U.S.). At a human level, the financial burden has a devastating impact on people without health insurance and people whose insurance imposes high deductibles—the people least able to afford the high cost of diabetes drugs. Thus, the high cost of diabetes drugs has important implications for both public policy and social justice.

Zhou et al. (13) obtained data from the Medical Expenditure Panel Survey, a nationally representative survey for the civilian noninstitutionalized population in the U.S. National spending on glucose-lowering drugs was estimated by extrapolating to the entire U.S. population. The authors estimated that total national spending on glucose-lowering medications increased by 240% (from $16.9 to $57.6 billion per year expressed in 2017 dollars) in 2015–2017 compared with 2005–2007. Over the same time period, the authors estimated a 38% increase in the number of people using glucose-lowering drugs (from 15.3 to 21.1 million) and a 147% increase in the average annual cost per user (from $1,106 to $2,727). Further analysis …
Macrophages and the maintenance of homeostasis
Authors: David M. Mosser, Kajal Hamidzadeh, Ricardo Goncalves
Journal: Cellular and Molecular Immunology (2020)

Abstract There have been many chapters written about macrophage polarization. These chapters generally focus on the role of macrophages in orchestrating immune responses by highlighting the T-cell-derived cytokines that shape these polarizing responses. This bias toward immunity is understandable, given the importance of macrophages to host defense. However, macrophages are ubiquitous and are involved in many different cellular processes, and describing them as immune cells is undoubtedly an oversimplification. It disregards their important roles in development, tissue remodeling, wound healing, angiogenesis, and metabolism, to name just a few processes. In this chapter, we propose that macrophages function as transducers in the body. According to Wikipedia, “A transducer is a device that converts energy from one form to another.” The word transducer is a term used to describe both the “sensor,” which can interpret a wide range of energy forms, and the “actuator,” which can switch voltages or currents to affect the environment. Macrophages are able to sense a seemingly endless variety of inputs from their environment and transduce these inputs into a variety of different response outcomes. Thus, rather than functioning as immune cells, they should be considered more broadly as cellular transducers that interpret microenvironmental changes and actuate vital tissue responses. In this chapter, we will describe some of the sensory stimuli that macrophages perceive and the responses they make to these stimuli to achieve their prime directive, which is the maintenance of homeostasis.
Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia
Authors: Pinar Ataca Atilla, Mary K McKenna, Haruko Tashiro, Madhuwanti Srinivasan, Feiyan Mo, Norihiro Watanabe, Brian Wesley Simons, Alexandra McLean Stevens, Michele S Redell, Helen E Heslop, Maksim Mamonkin, Malcolm K Brenner, Erden Atilla
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background C-type lectin-like molecule 1 (CLL-1) is highly expressed in acute myeloid leukemia (AML) but is absent in primitive hematopoietic progenitors, making it an attractive target for a chimeric antigen receptor (CAR) T-cell therapy. Here, we optimized our CLL-1 CAR for anti-leukemic activity in mouse xenograft models of aggressive AML. Methods First, we optimized the CLL-1 CAR using different spacer, transmembrane and costimulatory sequences. We used a second retroviral vector to coexpress transgenic IL15. We measured the effects of each construct on T cell phenotype and sequential (recursive) co culture assays with tumor cell targets to determine the durability of the anti tumor activity by flow cytometry. We administered CAR T cells to mice engrafted with patient derived xenografts (PDX) and AML cell line and determined anti tumor activity by bioluminescence imaging and weekly bleeding, measured serum cytokines by multiplex analysis. After euthanasia, we examined formalin-fixed/paraffin embedded sections. Unpaired two-tailed Student’s t-tests were used and values of p&lt;0.05 were considered significant. Survival was calculated using Mantel-Cox log-rank test. Results In vitro, CLL-1 CAR T cells with interleukin-15 (IL15) were less terminally differentiated (p&lt;0.0001) and had superior expansion compared with CD28z-CD8 CAR T cells without IL15 (p&lt;0.001). In both AML PDX and AML cell line animal models, CLL-1 CAR T coexpressing transgenic IL15 initially expanded better than CD28z-CD8 CAR T without IL15 (p&lt;0.0001), but produced severe acute toxicity associated with high level production of human tumor necrosis factor α (TNFα), IL15 and IL2. Histopathology showed marked inflammatory changes with tissue damage in lung and liver. This acute toxicity could be managed by two strategies, individually or in combination. The excessive TNF alpha secretion could be blocked with anti-TNF alpha antibody, while excessive T cell expansion could be arrested by activation of an inducible caspase nine safety switch by administration of dimerizing drug. Both strategies successfully prolonged tumor-free survival. Conclusion Combinatorial treatment with a TNFα blocking antibody and subsequent activation of the caspase-9 control switch increased the expansion, survival and antileukemic potency of CLL-1 CAR T-cells expressing transgenic IL15 while avoiding the toxicities associated with excessive cytokine production and long-term accumulation of activated T-cells.
Land-Use Changes and Heart Disease Risk: Evidence That Rapid Development Plays a Role
Authors: Charles W. Schmidt
Journal: Environmental Health Perspectives (2020)

Hyderabad, a city in the South Indian state of Telangana, is known for its iconic bazaars and 16th century architecture 1 as well as a booming tech industry that is fueling massive growth. 2 Undeveloped landscapes and farmland in the area are being rapidly lost to development, and the city's traffic congestion ranks among the worst in India. 3Now a recent study in Environmental Health Perspectives reports that heart disease risk among Hyderabad's local population is increasing as the pace of landuse changes accelerates. 4athryn Tonne, an environmental epidemiologist at the Barcelona Institute for Global Health, is the study's senior author.She says higher levels of air pollution and reduced physical activity resulting from land-use changes in and around Hyderabad may contribute to the findings, which she describes as "remarkably consistent."Several years ago, Tonne and her colleagues launched a project called Cardiovascular Health Effects of Air Pollution in Telangana, India (CHAI), to measure combustion air pollutants in households and quantify the corresponding relationships between exposure and cardiovascular disease end points.For this
Risk for Serious Infection With Low-Dose Glucocorticoids in Patients With Rheumatoid Arthritis
Authors: Michael D. George, Joshua F. Baker, Kevin Winthrop, Jesse Y. Hsu, Qufei Wu, Lang Chen, Fenglong Xie, Huifeng Yun, Jeffrey R. Curtis
Journal: Annals of Internal Medicine (2020)

Background: Low-dose glucocorticoids are frequently used for the management of rheumatoid arthritis (RA) and other chronic conditions, but the safety of long-term use remains uncertain. Objective: To quantify the risk for hospitalized infection with long-term use of low-dose glucocorticoids in patients with RA receiving stable disease-modifying antirheumatic drug (DMARD) therapy. Design: Retrospective cohort study. Setting: Medicare claims data and Optum's deidentified Clinformatics Data Mart database from 2006 to 2015. Patients: Adults with RA receiving a stable DMARD regimen for more than 6 months. Measurements: Associations between glucocorticoid dose (none, ≤5 mg/d, >5 to 10 mg/d, and >10 mg/d) and hospitalized infection were evaluated using inverse probability–weighted analyses, with 1-year cumulative incidence predicted from weighted models. Results: 247 297 observations were identified among 172 041 patients in Medicare and 58 279 observations among 44 118 patients in Optum. After 6 months of stable DMARD use, 47.1% of Medicare patients and 39.5% of Optum patients were receiving glucocorticoids. The 1-year cumulative incidence of hospitalized infection in Medicare patients not receiving glucocorticoids was 8.6% versus 11.0% (95% CI, 10.6% to 11.5%) for glucocorticoid dose of 5 mg or less per day, 14.4% (CI, 13.8% to 15.1%) for greater than 5 to 10 mg/d, and 17.7% (CI, 16.5% to 19.1%) for greater than 10 mg/d (all P < 0.001 vs. no glucocorticoids). The 1-year cumulative incidence of hospitalized infection in Optum patients not receiving glucocorticoids was 4.0% versus 5.2% (CI, 4.7% to 5.8%) for glucocorticoid dose of 5 mg or less per day, 8.1% (CI, 7.0% to 9.3%) for greater than 5 to 10 mg/d, and 10.6% (CI, 8.5% to 13.2%) for greater than 10 mg/d (all P < 0.001 vs. no glucocorticoids). Limitation: Potential for residual confounding and misclassification of glucocorticoid dose. Conclusion: In patients with RA receiving stable DMARD therapy, glucocorticoids were associated with a dose-dependent increase in the risk for serious infection, with small but significant risks even at doses of 5 mg or less per day. Clinicians should balance the benefits of low-dose glucocorticoids with this potential risk. Primary Funding Source: National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Synergetic Chemo‐Phototherapy: A pH‐Sensitive Self‐Assembled and Carrier‐Free Nanoparticle Based on Charge Reversal for Enhanced Synergetic Chemo‐Phototherapy (Adv. Healthcare Mater. 17/2020)
Authors: Chen Liu, Qiuhong Liu, Luping Chen, Mao Li, Jieli Yin, Xuan Zhu, Dengyue Chen
Journal: Advanced Healthcare Materials (2020)

In article 2000899 by Xuan Zhu, Dengyue Chen, and co-workers, pH-sensitive carrier-free nanoparticles, based on the negative-to-positive charge reversal property, are synthesized for notable synergetic chemo-photo therapy. This targeted nanoparticle, based on pH and laser responsive release, has the capability of multistage imaging for tracing drug distribution in vivo.
Response to: ‘Correspondence on ‘Systemic evaluation of the relationship between psoriasis, psoriatic arthritis and osteoporosis: observational and Mendelian randomisation study’ by Lee
Authors: Jiangwei Xia, Lin Xu, Ke-Qi Liu, Zhi-Min Ying, Shu-Yang Xie, Hou-Feng Zheng
Journal: Annals of the Rheumatic Diseases (2020)

We would like to thank the interests and comments from Cui et al 1 on our study2 entitled ‘Systemic evaluation of the relationship between psoriasis, psoriatic arthritis and osteoporosis: observational and Mendelian randomization study’. Here, we responded the comments point by point.

First, the potential confounders we included were age, sex, height, weight, smoking status, drinking status, regular physical activity and mediation treatment. The selected confounders were known potentially to have effect on the outcome (bone mineral density, BMD),3 and were typically recorded in UK Biobank dataset. The mediation analysis suggested that 63% of the effect of psoriatic arthritis (PsA) on BMD were mediated by treatment with methotrexate or ciclosporin; thus, there were many other unmeasured confounders to be discovered. In addition, we excluded participants …
Comparative evaluation of involved free light chain and monoclonal spike as markers for progression from monoclonal gammopathy of undetermined significance to multiple myeloma
Authors: Charlotte Gran, Johan Liwing, Arnika Kathleen Wagner, Andre Verhoek, Ana Gezin, Evren Alici, Hareth Nahi
Journal: American Journal of Hematology (2020)

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder, with a 1% yearly risk of progression to multiple myeloma (MM). Evolution of M‐spike and serum free light chain (sFLC) during follow‐up could identify patients at high risk of progression. In this region‐wide study, including 4756 individuals, 987 patients with MGUS were identified, and baseline factors as well as evolving involved FLC (iFLC) were evaluated as potential markers for risk of progression from MGUS to MM. Furthermore, evolving iFLC and M‐spike were assessed quarterly for a median of 5 years. At baseline, patients that progressed had significantly higher iFLC compared to non‐progressors. The risk factors of M‐spike &gt;1.5 g/dL, age &gt;65 years and iFLC &gt;100 mg/L were all independently associated with increased risk of MGUS to MM progression. For patients that had any two or three risk factors, the 5‐year cumulative probability of progression was significantly higher (31%) compared to no risk factors (2%). Evolving iFLC &gt;100 mg/L during follow‐up was consistently associated with increased risk of progression. Based on our observations, we propose to include iFLC as a monitoring tool for all MGUS patients. Furthermore, we recommend a quarterly monitoring in all high‐risk patients. Finally, we suggest that the risk of MGUS progression should be stratified with age, M‐spike, and iFLC at baseline.
Wall Shear Stress and Plaque Vulnerability
Authors: Takayoshi Toba, Hiromasa Otake, Gilwoo Choi, Hyun Jin Kim, Hiroyuki Onishi, Yoichiro Sugizaki, Ryo Takeshige, Akira Nagasawa, Yuichiro Nagano, Yoshiro Tsukiyama, Kenichi Yanaka, Hiroyuki Yamamoto, Hiroyuki Kawamori, Shumpei Mori, Masahito Kawata, Charles A. Taylor, Ken-ichi Hirata
Journal: JACC. Cardiovascular imaging (2020)
IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis
Authors: Heather J. Faust, Hong Zhang, Jin Han, Matthew T. Wolf, Ok Hee Jeon, Kaitlyn Sadtler, Alexis N. Peña, Liam Chung, David R. Maestas, Ada J. Tam, Drew M. Pardoll, Judith Campisi, Franck Housseau, Daohong Zhou, Clifton O. Bingham, Jennifer H. Elisseeff
Journal: Journal of Clinical Investigation (2020)

Senescent cells (SnCs) are implicated in the pathogenesis of age-related diseases including osteoarthritis (OA), in part via expression of a senescence-associated secretory phenotype (SASP) that includes immunologically relevant factors and cytokines. In a model of posttraumatic OA (PTOA), anterior cruciate ligament transection (ACLT) induced a type 17 immune response in the articular compartment and draining inguinal lymph nodes (LNs) that paralleled expression of the senescence marker p16INK4a (Cdkn2a) and p21 (Cdkn1a). Innate lymphoid cells, γδ+ T cells, and CD4+ T cells contributed to IL-17 expression. Intra-articular injection of IL-17–neutralizing antibody reduced joint degeneration and decreased expression of the senescence marker Cdkn1a. Local and systemic senolysis was required to attenuate tissue damage in aged animals and was associated with decreased IL-17 and increased IL-4 expression in the articular joint and draining LNs. In vitro, we found that Th17 cells induced senescence in fibroblasts and that SnCs skewed naive T cells toward Th17 or Th1, depending on the presence of TGF-β. The SASP profile of the inflammation-induced SnCs included altered Wnt signaling, tissue remodeling, and cell-cycle pathways not previously implicated in senescence. These findings provide molecular targets and mechanisms for senescence induction and therapeutic strategies to support tissue healing in an aged environment.
Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis
Authors: Mark R. Deneau, Cara Mack, Douglas Mogul, Emily R. Perito, Pamela L. Valentino, Achiya Z. Amir, Matthew DiGuglielmo, Laura G. Draijer, Wael El‐Matary, Katryn N. Furuya, Nitika Gupta, Jessica T. Hochberg, Simon Horslen, M. Kyle Jensen, Maureen M. Jonas, Nanda Kerkar, Bart G.P. Koot, Trevor J. Laborda, Christine K. Lee, Kathleen M. Loomes, Mercedes Martinez, Alexander Miethke, Tamir Miloh, Saeed Mohammad, Nadia Ovchinsky, Girish Rao, Amanda Ricciuto, Pushpa Sathya, Kathleen B. Schwarz, Uzma Shah, Ruchi Singh, Bernadette Vitola, Andréanne Zizzo, Stephen L. Guthery
Journal: Hepatology (2020)

Background and Aims Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. Approach and Results We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty‐four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention‐to‐treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma‐glutamyltransferase normalized in 53%, 49%, and 52% ( P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% ( P = NS), and the 5‐year probability of liver transplant listing was 21%, 10%, and 12% ( P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. Conclusions We presented the largest‐ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end‐stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo‐controlled treatment trials are needed to identify effective treatments for pediatric PSC.