tbuckley/cabot-search huggingface dataset:
OP0143 Genetic determinants of the th1 bias in rheumatoid arthritis
Authors: A Skapenko, J Wendler, R Mueller, PE Lipsky, JR Kalden, H Schulze-Koops
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, which is likely to be driven by activated pro-inflammatory Th1 cells. In contrast, Th2 cells and their cytokines, in particular IL-4 are rarely found in RA. It could recently be demonstrated that memory T cells from patients with early RA manifest a profound functional deficit in that they cannot differentiate into Th2 cells even at very early stages of the disease. The inability of memory T cells to mount immunomodulatory Th2 effectors might contribute to the Th1 bias in RA and, thus, might by critically involved in the initiation of chronic autoimmune inflammation. The mechanisms, however, involved in this abnormality have not been delineated in detail. We have recently established a system to analyse T cell differentiation <i>in vitro</i> and have identified molecular mechanisms regulating Th2 effector generation in healthy individuals. In the current proposal, molecular mechanisms will be identified that are involved in the development of Th1 mediated immunity in patients with very early rheumatoid arthritis (symptoms at time of blood collection of ≤2 weeks) using gene chip microarray technology. Selected candidate genes associated with the Th2 cell differentiation defect will be tested for their functional significance in biological assays. The definition of mechanisms contributing to the Th1 differentiation bias in very early RA will provide important insights into the pathogenesis of the disease, in particular into the initial steps of the evolving immune response, and might lead to the development of novel therapeutic strategies.
Dietary Inflammatory Potential and Risk of Cardiovascular Disease Among Men and Women in the U.S.
Authors: Jun Li, Dong Hoon Lee, Jie Hu, Fred K. Tabung, Yanping Li, Shilpa N. Bhupathiraju, Eric B. Rimm, Kathryn M. Rexrode, JoAnn E. Manson, Walter C. Willett, Edward L. Giovannucci, Frank B. Hu
Journal: Journal of the American College of Cardiology (2020)
AB0008 THE IMPACT OF STAT4 RS7574865, IL6 RS1800795, IL6R RS2228145 AND RS4845618 ON RHEUMATOID ARTHRITIS SUSCEPTIBILITY IN BELARUSIAN POPULATION
Authors: E. Siniauskaya, T. Kuzhir, V. Yagur, R. Goncharova
Journal: Annals of the Rheumatic Diseases (2020)

Background: Rheumatoid arthritis (RA) is a chronic systemic disorder of the connective tissue of still unknown aetiology and complex autoimmune pathogenesis that primarily affects small joints. HLA alleles provide for 11-37% of the RA heritability, suggesting the substantial role of the non-HLA loci in genetic predisposition to RA. Among non-HLA loci, IL6, IL6R and STAT4 genes attract attention, however, the data concerning their influence on RA risk are somewhat contradictory. Objectives: The aim of the study was to analyze the involvement of four SNPs ( STAT4 rs7574865, IL6 rs1800795, IL6R rs2228145 and rs4845618) in RA susceptibility. Methods: 187 patients diagnosed with RA (mean age 58.2 ± 11.9), and 380 healthy blood donors (mean age 37.18 ± 10.69 years) were included into the study. DNA extraction from peripheral blood samples was performed using the phenol-chloroform method. SNPs were genotyped using the real-time PCR with fluorescent probes. The allele and genotype frequencies were compared using the χ2 test. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using the VassarStats online tool. Results: Utilizing recessive genetic model we found an association between TT genotype of STAT4 rs7574865 (OR = 2.362; 95%CI [1.0378 – 5.376], p = 0.038) and RA. For IL6 rs1800795, it was found that CC genotype had significantly higher frequency among patients with rheumatoid arthritis as compared to that in controls (OR = 1.52; 95%CI [1.02 – 2.27], p = 0.0456). No associations of IL6R rs2228145 and rs4845618 SNPs with risk of RA were found in the total group of patients vs. controls. It was also shown that IL6 rs1800795 CC genotype frequency was significantly higher among the patients with RF-negative status (p = 0.0019). Conclusion: Thus, we provide evidence for association of the STAT4 rs7574865 and IL6 rs1800795 variants with risk of RA in the Belarusian population, some features of interplay being revealed between gene polymorphisms analyzed and RA antibody status. Abovementioned SNPs may contribute to RA genetic susceptibility in the Belarusian population. Disclosure of Interests: None declared
Xeno-MCL: Genomic, Transcriptomic and Pathologic Landscape Associated with Disease Progression, Clonal Evolution and Tissue Tropism in Patient-Derived Xenografts of Mantle Cell Lymphoma
Authors: Vivian Changying Jiang, Shaojun Zhang, Shuangtao Zhao, Yang Liu, Joseph McIntosh, Linghua Wang, Michael Wang
Journal: Blood (2020)
Different Pattern of Bone Scintigraphy in Mandibular Osteosarcoma Arising From Fibrous Dysplasia in a Patient With McCune-Albright Syndrome
Authors: Tse-Hao Lee, Lee-Shing Chu, Chih-Yung Chang, Wen-Sheng Huang
Journal: Clinical Nuclear Medicine (2020)

Abstract McCune-Albright syndrome is a rare condition consisting of triad of fibrous dysplasia, hyperfunctioning endocrinopathy, and café au lait macules of skin. A 31-year-old man was diagnosed with fibrous dysplasia 18 years before presenting with pathologic fracture. No workup for polyostotic fibrous dysplasia was performed at that time. He now presented with left facial swelling and skeletal features of acromegaly. MRI revealed a 15-cm enhancing tumor diagnosed histopathologically as high-grade osteosarcoma. 99m Tc–methylene diphosphonate bone scintigraphy revealed decreased uptake at the tumor site contrary to the usual finding of avid uptake by the neoplastic bone forming tumor.
Nanoparticle-Directed Targeting of Clustered PSGL-1 Mitigates Neutrophil-Derived Thrombosis in Antiphospholipid Antibody Syndrome
Authors: David R Sweet, Asha Thomas, Stephanie D Lapping, Kenneth A Kalikasingh, Thomas L. Ortel, Mukesh K Jain, Andrei Maiseyeu, Lalitha V. Nayak
Journal: Blood (2020)
Myeloproliferative/Myelodysplastic Neoplasms Presenting All Diagnostic Criteria of Chronic Myelomonocytic Leukemia but with Absolute Peripheral Blood Monocytosis 0.5-1× 109/L Should be Classified As CMML
Authors: Sandra Castaño-Díez, Monica Lopez-Guerra, Daniel Esteban, Francesca Guijarro, Alex Bataller Torralba, Paola Charry, Carlos Castillo, Carlos Jiménez-Vicente, Colomer Dolors, María Rozman, Jordi Esteve, Marina Diaz-Beyá
Journal: Blood (2020)
Upfront Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients with Idiopathic Aplastic Anemia: A Study on Behalf of the Saawp of EBMT
Authors: Audrey Françoise Petit, Dirk-Jan Eikema, Alexey Maschan, Dalila Adjaoud, Aleksander Kulagin, Alessandro Rambaldi, Franca Fagioli, Laimonas Griškevičius, John A Snowden, Jan-Erik Johansson, Jean-Hugues Dalle, Jenny Byrne, Antonio Risitano, Regis Peffault De Latour
Journal: Blood (2020)
Enlisting a Traditional Chinese Medicine to tune the gelation kinetics of a bioactive tissue adhesive for fast hemostasis or minimally invasive therapy
Authors: Haoqi Tan, Dawei Jin, Junjie Sun, Jialin Song, Yao Lu, Meng Yin, Xin Chen, Xue Qu, Changsheng Liu
Journal: Bioactive Materials (2020)

Gelation kinetics is important in tailoring chemically crosslinked hydrogel-based injectable adhesives for different applications. However, the regulation of gelation rate is usually limited to varying the gel precursor and/or crosslinker concentration, which cannot reach a fine level and inevitably alters the physical properties of hydrogels. Amidation reactions are widely used to synthesize hydrogel adhesives. In this work, we propose a traditional Chinese medicine (Borax)-input strategy to tune the gelation rate of amidation reaction triggered systems. Borax provides an initial basic buffer environment to promote the deprotonation process of amino groups and accelerate this reaction. By using a tissue adhesive model PEG-lysozyme (PEG-LZM), the gelation time can be modulated from seconds to minutes with varying Borax concentrations, while the physical properties remain constant. Moreover, the antibacterial ability can be improved due to the bioactivity of Borax. The hydrogel precursors can be regulated to solidify instantly to close the bleeding wound at emergency. Meanwhile, they can also be customized to match the flowing time in the catheter, thereby facilitating minimally invasive tissue sealing. Because this method is easily operated, we envision Borax adjusted amidation-type hydrogel has a promising prospect in clinical application.
Results of a Phase 2, Randomized, Double-Blind Study of Sorafenib Versus Placebo in Combination with Intensive Chemotherapy in Previously Untreated Patients with FLT3-ITD Acute Myeloid Leukemia (ALLG AMLM16)
Authors: Andrew H Wei, Glen A Kennedy, Kirk L Morris, Andrew Grigg, Simon He, Anthony Schwarer, Stephen B Ting, Anoop Kumar Enjeti, Sam Yuen, James D'Rozario, Maya Latimer, Paula Marlton, Ian Bilmon, John Taper, Gavin Cull, Campbell Tiley, Emma Verner, Uwe H Hahn, Devendra K Hiwase, Harry Iland, Nichloas Murphy, Sundra Ravanathan, Uyen Nguyen, Doen Ming Ong, Sun Loo, Ing-Soo Tiong, Meaghan Wall, Natasha S Anstee, Mark Levis, Michael Murray, Tristan Rawling, Joanna Leadbetter, Ashish Bajel, Andrew W Roberts
Journal: Blood (2020)
Venetoclax Alone or in Combination with Chemotherapy: Responses in Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia with Heterogeneous Genomic Profiles
Authors: Seth E. Karol, Henrique Bittencourt, Daniel A. Morgenstern, Margaret E. Macy, Seong Lin Khaw, Todd M. Cooper, Arnaud Petit, Giridharan Ramsingh, Bo Tong, Kristina Unnebrink, Deeksha Vishwamitra, Fengjiao Dunbar, Betty A. Prine, Tammy L. Palenski, Andrew E. Place
Journal: Blood (2020)
Abstract 502: Inhibition of Histone Deacetylase 6 Protects Human Induced Pluripotent Stem Cells-derived Cardiomyocytes Through Inhibition of Autophagy
Authors: Narasimman Gurusamy, SHEEJA RAJASINGH, Vinoth Sigamani, Shivaani Kirankumar, Jayavardini Vasanthan, Rajasingh Johnson
Journal: Circulation Research (2020)

Introduction: Autophagy is known to play an important role in mediating cardiac hypertrophy. However, the mechanism is poorly understood. Since the protein histone deacetylase 6 (HDAC6) contributes to cardiac dysfunction in response to angiotensin II (AngII) signaling, we have examined the role of HDAC6 inhibitor tubastatin A (TBA) in AngII-induced remodeling in human induced pluripotent stem cells-derived cardiomyocytes (iCMCs). Hypothesis: We hypothesize that the inhibition of HDAC6 protects iCMCs from AngII-induced cardiac hypertrophy through inhibition of autophagy. Methods and Results: We have generated and characterized induced pluripotent stem cells from human adult skin fibroblasts and subsequently differentiated them into iCMCs. Treatment with 10 μM angiotensin II for 24 hrs increased the HDAC6 activity and lead to hypertrophy in iCMCs. The AngII-induced hypertrophy, and the excessive contractility in iCMCs were reversed by the inhibition of HDAC6 with TBA (1 μM for 24 hours). The number of LC3-positive iCMCs, and the mRNA and the protein expression of autophagic genes Beclin-1, LC3, and p62 were increased by the presence of AngII, and the anti-autophagic gene Bcl2 was decreased by AngII. The inhibition of HDAC6 with TBA reversed the AngII-mediated changes in the autophagic genes expressions in iCMCs. Autophagic vacuoles were identified with monodansylcadaverine (MDC, green) and lysosomes with LysoTracker (red) (Fig. 1A) . The number of autophagolysosomes were increased by AngII, and this was decreased with TBA in iCMCs (Fig. 1B) . Conclusions: Our report indicates for the first time that the AngII-induced cardiac hypertrophy-mediated autophagy is effectively inhibited by the suppression of HDAC6 in human iCMCs.
HP0016 Familial risk to osteoporosis in the irish population
Authors: M Daly, K Quane, F Wynne, F Drummond, MG Molloy
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Osteoporosis is a disease characterised by a low bone mineral density (BMD) and microarchitectural deterioration of bone tissue leading to fractures, especially of the hip and spine. It is a major public health problem of western societies that affects the elderly population. Both environmental and genetic factors have been evoked as determinants of peak bone mass, but the major determinant of BMD is heritability. Families were recruited as part of an ongoing study to identify susceptibility genes to low BMD. Osteoporotic and osteopenic women were identified retrospectively from records at the Bone Densitometry Unit of Cork University Hospital. Individuals with a disease or on medications known to influence calcium metabolism were excluded. Participants were requested to nominate both female and male relatives for bone densitometry measurement. Relatives over 40 years of age, with a history of fracture or dowager's hump were preferentially selected for inclusion in the study. Of the 220 families who participated in the study to date, relative pairs with low BMD were found in 152 families. There was a total of 525 low BMD pairs among the 152 families, of whom 310 were sib-pairs. Our study will help to increase public awareness in Ireland of the familial risk of osteoporosis.
Endogenous Labeling for Light Microscopy during HIV-1 Immune Responses
Authors: Minette Salmon, Irene Carlon-Andres, Sergi Padilla-Parra
Journal: Trends in Immunology (2020)

New approaches in single molecule spectroscopy and microscopy are able to resolve the spatial and temporal resolution of T cell receptor signaling in the context of immune responses to HIV-1 infection. These approaches need to be complemented with novel techniques that endogenously tag the protein or proteins of interest, yet avoid overexpression, to image protein dynamics under physiological conditions.
ITGB2-mediated metabolic switch in CAFs promotes OSCC proliferation by oxidation of NADH in mitochondrial oxidative phosphorylation system
Authors: Xiaoxin Zhang, Yingchun Dong, Mengxiang Zhao, Liang Ding, Xihu Yang, Yue Jing, Yuxian Song, Sheng Chen, Qingang Hu, Yanhong Ni
Journal: Theranostics (2020)

Objectives: Integrins, the coordinator of extracellular and intracellular signaling, are often found to be aberrant in tumors and can reshape the tumor microenvironment. Although previous studies showed that integrin beta 2 (ITGB2) is important for host defense, its expression profile and role in tumors, especially in cancer associated fibroblasts (CAFs) are still unknown. Methods: Immunofluorescence stain and fluorescence activated cell sorting were used to analyze the ITGB2 expression profile in oral squamous cell carcinoma (OSCC). RT-PCR and western blot were used to compare ITGB2 expression in normal fibroblasts (NFs) and cancer associated fibroblasts (CAFs). Clinical data and function-based experiments were used to investigate the promoting tumor growth ability of ITGB2 expressing CAFs. Enhanced glycolysis activity was identified by using bioinformatics analyses and GC/MS assays. MCT1 knockdown OSCC cell lines were constructed to explore the pro-proliferative mechanisms of ITGB2 expressing CAFs in multiple in vitro and in vivo assays. Results: We found that CAFs exhibited significantly higher ITGB2 expression than the matched NFs. In addition, higher ITGB2 expression in CAFs was correlated with higher TNM stages and more Ki67+ tumor cells, indicating its ability to promote OSCC proliferation. Further, co-culture assay demonstrated that ITGB2-mediated lactate release in CAFs promoted OSCC cell proliferation. Mechanically, ITGB2 regulated PI3K/AKT/mTOR pathways to enhance glycolysis activity in CAFs. Accordingly, lactate derived from ITGB2-expressing CAFs was absorbed and metabolized in OSCC to generate NADH, which was then oxidized in the mitochondrial oxidative phosphorylation system (OXPHOS) to produce ATP. Notably, inhibiting the OXPHOS system with metformin delayed the proliferative capacity of OSCC cells cultured in the ITGB2-expressing CAFs medium. Conclusions: Our study uncovered the ITGB2high pro-tumoral CAFs that activated the PI3K/AKT/mTOR axis to promote tumor proliferation in OSCC by NADH oxidation in the mitochondrial oxidative phosphorylation system.
Abstract MP133: Development of β-arrestin-biased Positive Allosteric Modulators for the β <sub>1</sub> Adrenergic Receptor
Authors: Jialu Wang, Ilhan Gokhan, Xinyu Xiong, Alem W Kahsai, Haoran Jiang, Conrad T Pfeiffer, William Tian, Biswaranjan Pani, Seungkirl Ahn, Robert J Lefkowitz, Howard A Rockman
Journal: Circulation Research (2020)

The β 1 adrenergic receptor (β 1 AR) is a central regulator of cardiac function and an important therapeutic target for cardiac diseases. Two emerging areas of receptor biology are biased agonism: ligand directed selective engagement of a receptor toward either a G protein or β-arrestin transducer; and allosteric modulation: ligands that bind to topographically distinct sites on the receptor to modulate its activity. Advances in these areas have the potential to yield new drugs that precisely enhance cardioprotective effects while limiting untoward detrimental actions. Compound 6 (Cmpd6) is a newly discovered positive allosteric modulator (PAM) for the β 2 AR. Interestingly, we now show that Cmpd6 has the unique property to enhance the binding affinity of the β-arrestin-biased agonist carvedilol to both the β 2 AR and the β 1 AR, while having minimal effect on the affinity of a panel of agonists and antagonists of the β 1 AR. We further tested the effect of Cmpd6 on β 1 AR signaling induced by a broad range of ligands. Cmpd6 selectively enhanced carvedilol-stimulated ERK activation in a β-arrestin-dependent signaling fashion, while having no effect on carvedilol-induced G protein-dependent cAMP production. To test the in vivo effect of Cmpd6 on cardiac injury, mice were pretreated with carvedilol with or without Cmpd6, then underwent ischemia/reperfusion through the left anterior descending artery ligation. Cell apoptosis was assessed by TUNEL. Carvedilol decreased the level of I/R-induced apoptosis compared to the vehicle-treated animals, and Cmpd6 significantly positively enhanced the anti-apoptotic effects of carvedilol. In conclusion, we identified Cmpd6 as a potential β-arrestin-biased PAM for the β 1 AR that enhances the cardioprotective effect of carvedilol. Ongoing studies will test Cmpd6 on heart failure post myocardial infarction.
Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions
Authors: David Bauché, Smita Mauze, Christina Kochel, Jeff Grein, Anandi Sawant, Yulia Zybina, Wendy Blumenschein, Peng Yang, Lakshmanan Annamalai, Jennifer H Yearley, Juha Punnonen, Edward P Bowman, Alissa Chackerian, Drake Laface
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Programmed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events. Methods We have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody. Results Sustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit. Conclusion These data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade.
Younger HLA-Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation (allo-HCT) for Myelodysplastic Syndromes (MDS) Is Associated with Superior Disease-Free Survival Compared to Older HLA-Identical Sibling Donors: CIBMTR Analysis
Authors: Guru Subramanian Guru Murthy, Soyoung Kim, Zhen-Huan Hu, Noel Estrada-Merly, Ryotaro Nakamura, Betul Oran, Bart L. Scott, Ronald Sobecks, Wael Saber
Journal: Blood (2020)
Assessment of Minimal Residual Disease in a Phase 1b Study of Once-Weekly Carfilzomib Combined with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma
Authors: Ola Landgren, Melissa Alsina, Noa Biran, David H. Vesole, Paul K. Wallace, Belle Fang, Gregory Arnold, Amy Kimball, David S. Siegel
Journal: Blood (2020)
WHAT IS THE ORIGIN OF THE PRESACRAL LOCAL RECURRENCE IN RECTAL CANCER? - AN ANATOMIC STUDY OF THE LATERAL LYMPH NODES IN HUMAN FETUSES
Authors: M. Kusters, C. Wallner, M.C. DeRuiter, M.M. Lange, C.J.H. van de Velde, H.J.T. Rutten
Journal: Annals of Oncology (2010)
MicroRNA‐17‐5p Reduces Inflammation and Bone Erosions in Mice With Collagen‐Induced Arthritis and Directly Targets the JAK/STAT Pathway in Rheumatoid Arthritis Fibroblast‐like Synoviocytes
Authors: Aurélie Najm, François‐Marie Masson, Pauline Preuss, Steven Georges, Benjamin Ory, Thibaut Quillard, Shatakshi Sood, Carl S. Goodyear, Douglas J. Veale, Ursula Fearon, Benoit Le Goff, Frédéric Blanchard
Journal: Arthritis & Rheumatology (2020)

We undertook this study to examine microRNA (miRNA) expression across rheumatoid arthritis (RA) phenotypes, along with the effects and mechanisms of action of miRNA-17-5p (miR-17).A miRNA array was performed in synovial tissue biopsied from patients with naive erosive RA (n = 3) and patients with nonerosive RA (n = 3). MicroRNA-17 lipoplex was delivered intraarticularly in the murine collagen-induced arthritis model. Clinical, histologic, and structural effects were studied over the course of arthritis. In-depth studies of the mechanisms of action of miR-17 were performed in primary RA fibroblast-like synoviocytes (FLS) isolated from synovial tissue.Fifty-five miRNAs including miR-17 were reduced in erosive RA. The miR-17 transfection into arthritic paws reduced the clinical inflammation score between day 2 and day 7 (2.8 versus 1.9; P = 0.03). Synovial B cell, T cell, macrophage, and polynuclear neutrophil infiltration was significantly reduced. Structural damage was also decreased, as shown by a reduction in the number of osteoclasts detected using tartrate-resistant acid phosphatase staining (osteoclast surface/bone surface 32% versus 18%; P = 0.005) and erosion score by computed tomography analysis (2.9 versus 1.7; P = 0.023). Proinflammatory cytokines from the interleukin-6 (IL-6) family and IL-1β expression were also significantly reduced, but tumor necrosis factor was not. MicroRNA-17 directly targeted the 3'-untranslated regions of STAT3 and JAK1. STAT3 and JAK1 messenger RNA (mRNA) and protein expression were reduced in RA FLS following miR-17 transfection. STAT3 and JAK1 mRNA and activation of STAT3, as assessed by immunohistochemistry, were also reduced in injected paws (% stained area 93% versus 62%; P = 0.035).We demonstrate an antiinflammatory and antierosive role of miR-17 in vivo. This effect involves the suppression of the IL-6 family autocrine-amplifying loop through the direct targeting of JAK1 and STAT3.