tbuckley/cabot-search huggingface dataset:
Oleic acid-induced NOX4 is dependent on ANGPTL4 expression to promote human colorectal cancer metastasis
Authors: Chih-Jie Shen, Kwang-Yu Chang, Bo-Wen Lin, Wei-Ting Lin, Che-Min Su, Jhih-Peng Tsai, Yu-Han Liao, Liang-Yi Hung, Wen-Chang Chang, Ben-Kuen Chen
Journal: Theranostics (2020)

Background: Colorectal cancer (CRC) progression and related mortality are highly associated with metabolic disorders. However, the molecular mechanism involved in the regulation of hyperlipidemia-associated CRC metastasis remains unclear. This study aimed to investigate the effects of angiopoietin-like 4 (ANGPTL4) on NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) production, which might provide new targets for improving outcomes in patients with hyperlipidemia-associated CRC metastasis. Methods: The clinical relevance of relationship between NOX4 expression and ANGPTL4 was examined in CRC patients by the Oncomine and TCGA data set. Expressions of NOX4, epithelial-mesenchymal transition (EMT) markers, and gene regulation of NOX4 in free fatty acids (FFAs)-treated CRC cells were determined. The FFAs-triggered metastatic ability of CRC cells under treatments of antioxidants or knockdown of NOX4, ANGPTL4, and MMPs was evaluated in vitro and in vivo. In addition, effects of antioxidants and depletion of metastasis-associated molecules on the correlation between ROS production and FFAs-promoted CRC metastasis were also clarified. Results: In this study, we found that the induction of NOX4, followed by the increased ROS was essential for oleic acid (OA)-promoted CRC cell metastasis. The depletion of ANGPTL4 significantly inhibited c-Jun-mediated transactivation of NOX4 expression, accompanied with reduced levels of ROS, MMP-1, and MMP-9, resulting in the disruption of OA-promoted CRC cell metastasis. Moreover, knockdown of ANGPTL4, NOX4, MMP-1, and MMP-9 or the treatment of antioxidants dramatically inhibited circulating OA-enhanced tumor cell extravasation and metastatic seeding of tumor cells in lungs, indicating that the ANGPTL4/NOX4 axis was critical for dyslipidemia-associated tumor metastasis. Conclusion: The coincident expression of NOX4 and ANGPTL4 in CRC tumor specimens provides the insight into the potential therapeutic targets for the treatment of dyslipidemia-associated CRC metastasis.
AB0132 ALTERATIONS IN PERIPHERAL T-CELLS AND B-CELLS SUBSETS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND SJÖGREN’S SYNDROME UNDERGOING THERAPEUTIC PLASMA EXCHANGE OR IMMUNOADSORPTION
Authors: Y. Jiang, Q. Wei, Q. Lv, X. Zhang, W. Zhu, J. Gu
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) are systemic autoimmune diseases characterized by a broad spectrum of clinical manifestations and disease course. Alternative therapies such as therapeutic plasma exchange (TPE), immunoadsorption are recommended to the patients who lack a good response to standard therapy [1]. Objectives: Our observational study was to explored whether abnormalities in T-cells, B-cells and their subtypes were present in the patients who had TPE or immunoadsorption in patients with SLE and SS compared with healthy controls (HC). Methods: Demographic, clinical variables and autoantibodies were recorded. Flow cytometry was used to establish the frequencies of lineage subsets. Monoclonal antibodies against 21 surface markers such as CD3, CD4, CD8, were used to distinguish and evaluate T-cells’ and B-cells’ subpopulation. SLE acvity was measured using systemic lupus erythematosus disease activity index (SLEDAI). Comparisons between subgroups were undertaken using paired T-test, Mann-Whitney U test and ANOVA. Figure 1. Altered expression of CD4+ T-cell subsets in the patients with SLE and SS after treated with plasma exchange or immunoadsorption Results: 6 SS patients and 1 SLE patient underwent immune adsorption, while the other 5 SLE patients had plasma exchange all for three times. There was no significant difference among SLE, SS and HC in the proportion of T-cells and B-cells. The proportion of CD3-CD19+CD27+IgD+ B-cells were reduced in SLE, while CD3+CD4+CD25+CD127- T-cells were elevated in SS. The proportion of CD3+CD4+CD45RA+CCR7+T-cells were increased ( p = 0.045), while CD3+CD4+CD25+CD127- T-cells were declined ( p = 0.027) and CD3+CD4+CXCR5+PD-1+ T-cells went down after the therapies ( p ≤ 0.030). The proportion of CD3-CD19+IgD-IgM-CD27+CD38+ B-cells was also reduced after TPE or immunoadsorption ( p = 0.032) with ANA titers and IgG decreasing dramatically. SLEDAI scores were reduced after the therapy in SLE patients. Conclusion: The T-cell and B-cell’s profiles were proved to have alteration after TPE or immunoadsorption which shed light on the complicated mechanisms of these relatively novel therapy in SLE and SS. References: [1]Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. ANN RHEUM DIS 2012;71:1771-1782. Acknowledgments: None. Disclosure of Interests: None declared
Auxiliary trafficking subunit GJA1-20k protects connexin-43 from degradation and limits ventricular arrhythmias
Authors: Shaohua Xiao, Daisuke Shimura, Rachel Baum, Diana M. Hernandez, Sosse Agvanian, Yoshiko Nagaoka, Makoto Katsumata, Paul D. Lampe, Andre G. Kleber, TingTing Hong, Robin M. Shaw
Journal: Journal of Clinical Investigation (2020)

Connexin-43 (Cx43) gap junctions provide intercellular coupling, which ensures rapid action potential propagation and synchronized heart contraction. Alterations in Cx43 localization and reductions in gap junction coupling occur in failing hearts, contributing to ventricular arrhythmias and sudden cardiac death. Recent reports have found that an internally translated Cx43 isoform, GJA1-20k, is an auxiliary subunit for the trafficking of Cx43 in heterologous expression systems. Here, we have created a mouse model by using CRISPR technology to mutate a single internal translation initiation site in Cx43 (M213L mutation), which generates full-length Cx43, but not GJA1-20k. We found that GJA1M213L/M213L mice had severely abnormal electrocardiograms despite preserved contractile function, reduced total Cx43, and reduced gap junctions, and they died suddenly at 2 to 4 weeks of age. Heterozygous GJA1M213L/WT mice survived to adulthood with increased ventricular ectopy. Biochemical experiments indicated that cytoplasmic Cx43 had a half-life that was 50% shorter than membrane-associated Cx43. Without GJA1-20k, poorly trafficked Cx43 was degraded. The data support that GJA1-20k, an endogenous entity translated independently of Cx43, is critical for Cx43 gap junction trafficking, maintenance of Cx43 protein, and normal electrical function of the mammalian heart.
Infective Endocarditis After Transcatheter Aortic Valve Replacement
Authors: Stefan Stortecky, Dik Heg, David Tueller, Thomas Pilgrim, Olivier Muller, Stephane Noble, Raban Jeger, Stefan Toggweiler, Enrico Ferrari, Maurizio Taramasso, Francesco Maisano, Rebeca Hoeller, Peter Wenaweser, Fabian Nietlispach, Andreas Widmer, Christoph Huber, Marco Roffi, Thierry Carrel, Stephan Windecker, Anna Conen
Journal: Journal of the American College of Cardiology (2020)
Author Correction: Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention
Authors: Chun Loong Ho, Hui Qing Tan, Koon Jiew Chua, Aram Kang, Kiat Hon Lim, Khoon Lin Ling, Wen Shan Yew, Yung Seng Lee, Jean Paul Thiery, Matthew Wook Chang
Journal: Nature Biomedical Engineering (2020)
Efficacy and safety of weekly rifapentine and isoniazid for tuberculosis prevention in Chinese silicosis patients: a randomized controlled trial
Authors: Qiao-ling Ruan, Xi-tian Huang, Qing-luan Yang, Xue-feng Liu, Jing Wu, Ke-chuan Pan, Yao-jie Shen, Li-min Cai, Qiao Ling, Tian Jiang, Jin-jing Hong, Xiao-dan Wang, Chun-lian Ma, Guan-qing Peng, Xiu-zhen Wang, Jin-chao Mao, Tian-zhou Wu, Miao-yao Lin, Ling-yun Shao, Wen-hong Zhang
Journal: Clinical Microbiology and Infection (2020)
AB0082 INHIBITION OF TGFβ SIGNALING USING SB-505124 BLOCKS TH17 DIFFERENTIATION AND RESTORES THE TH17/TREG BALANCE IN VIVO, BUT DOES NOT SUPPRESS EXPERIMENTAL ARTHRITIS
Authors: J. Aarts, A. Van Caam, M. Helsen, B. Walgreen, E. Vitters, F. Van de Loo, P. Van Lent, P. Van der Kraan, M. Koenders
Journal: Annals of the Rheumatic Diseases (2020)

Background: TGFβ is an important growth factor that promotes the differentiation of T helper 17 (Th17) as well as regulatory T-cells (Treg). Due to its dual role, the potential of TGFβ as therapeutic target is unclear. Objectives: In this study we aimed to investigate the effect of inhibition of TGFβ signaling with the ALK5 inhibitor SB-505124 on human Th17 differentiation in vitro , on cytokine production by human rheumatoid arthritis (RA) synovial explants, and study the effects of local SB-505124 treatment in vivo during innate immune and Th17-driven experimental arthritis models. Methods: Magnetic sorted naïve human T cells were differentiated into Th17 cells with CD3/CD28 activation beads, IL-2, TGFβ, IL-1β, IL-23, αIFNƳ and αIL-4 for 6 days. Human RA synovial biopsies were cultured for 24h w/o 5µM SB-505124, and supernatant was analyzed by Luminex. T cell-independent SCW arthritis and Th17-driven IL-1/mBSA arthritis were induced in C57Bl6, and mice were treated with SB-505124 by daily intra-articular injections from day 0-4. Results: SB-505124 potently reduced human Th17 differentiation in vitro by decreasing IL-17 and RORƳt gene expression and IL-17 protein production. SB-505124 significantly suppressed IL-6 and TNFα protein production by human RA synovial explants. In addition, SB-505124 did not affect acute joint inflammation during SCW-arthritis (T-cell independent model). Interestingly, SB-505124 reduced Th17 levels in draining lymph nodes (dLN) during IL-1/mBSA arthritis while increased levels of Tregs were observed. Surprisingly, despite this skewed Th17/Treg balance, this did not result in suppression of joint inflammation and destruction in this Th17-driven arthritis model, whereas anti-IL-17 antibody treatment showed significant therapeutic effects. Conclusion: We revealed suppressive effects of SB-505124 on human Th17 differentiation and the Th17/Treg balance in arthritic mice. However, SB-505124 did not suppress joint inflammation and destruction. This indicates that despite the importance of TGFβ in Th17 differentiation, targeting TGFβ signaling is not enough to suppress experimental arthritis. Disclosure of Interests: None declared
Impact of TREM2R47H variant on tau pathology–induced gliosis and neurodegeneration
Authors: Maud Gratuze, Cheryl E.G. Leyns, Andrew D. Sauerbeck, Marie-Kim St-Pierre, Monica Xiong, Nayeon Kim, Javier Remolina Serrano, Marie-Ève Tremblay, Terrance T. Kummer, Marco Colonna, Jason D. Ulrich, David M. Holtzman
Journal: Journal of Clinical Investigation (2020)

Alzheimer's disease (AD) is characterized by plaques containing amyloid-β (Aβ) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and Aβ, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2- to 4-fold. It is likely that these TREM2 variants increase AD risk by decreasing the response of microglia to Aβ and its local toxicity. However, neocortical Aβ pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the AD-associated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed PS19 mice expressing human TREM2CV (common variant) or human TREM2R47H. PS19-TREM2R47H mice had significantly attenuated brain atrophy and synapse loss versus PS19-TREM2CV mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in PS19-TREM2R47H versus PS19-TREM2CV mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2R47H in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy.
Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort
Authors: Marie Pouletty, Charlotte Borocco, Naim Ouldali, Marion Caseris, Romain Basmaci, Noémie Lachaume, Philippe Bensaid, Samia Pichard, Hanane Kouider, Guillaume Morelle, Irina Craiu, Corinne Pondarre, Anna Deho, Arielle Maroni, Mehdi Oualha, Zahir Amoura, Julien Haroche, Juliette Chommeloux, Fanny Bajolle, Constance Beyler, Stéphane Bonacorsi, Guislaine Carcelain, Isabelle Koné-Paut, Brigitte Bader-Meunier, Albert Faye, Ulrich Meinzer, Caroline Galeotti, Isabelle Melki
Journal: Annals of the Rheumatic Diseases (2020)

Current data suggest that COVID-19 is less frequent in children, with a milder course. However, over the past weeks, an increase in the number of children presenting to hospitals in the greater Paris region with a phenotype resembling Kawasaki disease (KD) has led to an alert by the French national health authorities. Multicentre compilation of patients with KD in Paris region since April 2020, associated with the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ('Kawa-COVID-19'). A historical cohort of 'classical' KD served as a comparator. Sixteen patients were included (sex ratio=1, median age 10 years IQR (4·7 to 12.5)). SARS-CoV-2 was detected in 12 cases (69%), while a further three cases had documented recent contact with a quantitative PCR-positive individual (19%). Cardiac involvement included myocarditis in 44% (n=7). Factors prognostic for the development of severe disease (ie, requiring intensive care, n=7) were age over 5 years and ferritinaemia >1400 µg/L. Only five patients (31%) were successfully treated with a single intravenous immunoglobulin (IVIg) infusion, while 10 patients (62%) required a second line of treatment. The Kawa-COVID-19 cohort differed from a comparator group of 'classical' KD by older age at onset 10 vs 2 years (p<0.0001), lower platelet count (188 vs 383 G/L (p<0.0001)), a higher rate of myocarditis 7/16 vs 3/220 (p=0.0001) and resistance to first IVIg treatment 10/16 vs 45/220 (p=0.004). Kawa-COVID-19 likely represents a new systemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children. Further prospective international studies are necessary to confirm these findings and better understand the pathophysiology of Kawa-COVID-19. Trial registration number NCT02377245.
Larry Kramer: author and founding father of AIDS activism
Authors: Bob Roehr
Journal: BMJ (2020)

Credit: Stephen Dunn/Hartford Courant/PA

The disease didn’t have a name yet, only a few studies had appeared in peer reviewed journals, but already the gay men of New York City knew that something evil was stalking them, sickening them, bringing the kind of grotesque assaults on the human body that modern medicine had seemingly banished from Western society. In January 1982, about 80 met in Larry Kramer’s apartment to form the first organised response to what would become known as the AIDS epidemic.

The fact that Kramer had a place large enough to accommodate the group was a testament to his established success. He was an accomplished script writer with several movies to his credit, most notably the screenplay he adapted from the DH Lawrence novel Women in Love and for which he received an Academy Award nomination in 1969. Glenda Jackson took home the Oscar for best actress for her performance in the film.

The Gay Men’s Health Crisis (GMHC) eventually emerged from that meeting, with Kramer as one of the incorporators. It was created even before the words HIV and AIDS had been whispered and continues to this day as one of the largest HIV service providers in New York City.

The 1970s were a golden age of promiscuity for gay men, particularly for baby boomers coming of age after the Stonewall rebellion began to break the hold of the closet. Discos and bath houses proliferated, and Fire Island became a summer bacchanal. Kramer was the great naysayer—sort of. His 1978 novel, Faggots , lambasted the shallowness of that lifestyle while wallowing in the lurid details of the behaviour he condemned. Many in the gay community came to see him as a self-righteous scold, a pariah, even while devouring the salacious bits that made his novel a bestseller.

“1112 and Counting,” was …
AB1180 THE EVOLUTION OF AN FLS IN SEARCH OF EXCELLENCE: THE EXPERIENCE OF GRAN CANARIA.
Authors: A. Naranjo, A. Molina, C. Sepúlveda, C. Torres, F. Santana, F. Rubiño, R. López, S. Ojeda
Journal: Annals of the Rheumatic Diseases (2020)

Background: The implementation of an FLS in the Spanish public health system is not an easy task since there are no official plans for the incorporation of personnel dedicated to the unit Objectives: To expose the consolidation and improvement of an FLS after its implementation as well as the problems that have arisen over time. Methods: The health program for secondary fracture prevention was implemented in 2012. Initially worked with the same staff assigned to the Rheumatology service, since 2016 we have a part-time support nurse. Patients are identified from the emergency registry and, more recently, from patients admitted for hip fracture and treated in a monographic osteoporosis clinic. The baseline visit consists of consultation with the nurse, DXA and bone metabolism analytics. Falling patients are referred to a fall prevention school. Most patients are referred to their primary care physician to start a treatment. Results: Of the 2,416 patients attended the baseline visit, 30% were forearm fractures, 27% hip, 20% humerus, 10% spine and 11% other fractures. In comparison to 2012, in 2019 the monthly average of patients has doubled, increased the number of hip and spine fractures, and increased the percentage of captured patients (Table). In spite of consolidating the unit, getting a support nurse for the admitted patients and establishing a solid alliance with primary care, it is pending the involvement of Primary Care Nurses and start first prescription at the hospital. Table. Comparison of the first year with the last year of implementation of our FLS. 2012 2019 Mean monthly number of fractures, N 22 42 Type of fracture: forearm/hip/spine, % 37/20/6 28/40/11 Captured patients of elegible, % 57 77 Delay in weeks until first visit to FLS, median 14 12 Patient origin: emergency list/inpatient/outpatient, % 100/0/0 59/31/9 DXA performed, % 100 61 Referral to fall prevention school, % 0 26 Criteria to start a treatment, % 67 90* Referral to the osteoporosis clinic, % 37 7 *We apply the 2019 recommendations of the Spanish Society of Rheumatology Conclusion: We present the achievements made by our FLS along 8 years and the difficulties within the Spanish public health system. Disclosure of Interests: Antonio Naranjo Grant/research support from: amgen, Consultant of: UCB, Speakers bureau: AMGEN, Amparo Molina Speakers bureau: AMGEN, STADA, Cristina Sepúlveda: None declared, Candelaria Torres: None declared, Fabiola Santana: None declared, Francisco Rubiño: None declared, Rubén López: None declared, Soledad Ojeda Speakers bureau: AMGEN, LILLY, GEBRO
Ranking microbiome variance in inflammatory bowel disease: a large longitudinal intercontinental study
Authors: Adam G Clooney, Julia Eckenberger, Emilio Laserna-Mendieta, Kathryn A Sexton, Matthew T Bernstein, Kathy Vagianos, Michael Sargent, Feargal J Ryan, Carthage Moran, Donal Sheehan, Roy D Sleator, Laura E Targownik, Charles N Bernstein, Fergus Shanahan, Marcus J Claesson
Journal: Gut (2020)

Objective The microbiome contributes to the pathogenesis of inflammatory bowel disease (IBD) but the relative contribution of different lifestyle and environmental factors to the compositional variability of the gut microbiota is unclear. Design Here, we rank the size effect of disease activity, medications, diet and geographic location of the faecal microbiota composition (16S rRNA gene sequencing) in patients with Crohn’s disease (CD; n=303), ulcerative colitis (UC; n = 228) and controls (n=161), followed longitudinally (at three time points with 16 weeks intervals). Results Reduced microbiota diversity but increased variability was confirmed in CD and UC compared with controls. Significant compositional differences between diseases, particularly CD, and controls were evident. Longitudinal analyses revealed reduced temporal microbiota stability in IBD, particularly in patients with changes in disease activity. Machine learning separated disease from controls, and active from inactive disease, when consecutive time points were modelled. Geographic location accounted for most of the microbiota variance, second to the presence or absence of CD, followed by history of surgical resection, alcohol consumption and UC diagnosis, medications and diet with most (90.3%) of the compositional variance stochastic or unexplained. Conclusion The popular concept of precision medicine and rational design of any therapeutic manipulation of the microbiota will have to contend not only with the heterogeneity of the host response, but also with widely differing lifestyles and with much variance still unaccounted for.
808 nm light triggered lanthanide nanoprobes with enhanced down-shifting emission beyond 1500 nm for imaging-guided resection surgery of tumor and vascular visualization
Authors: Youbin L i, Mingyang Jiang, Zhenluan Xue, Songjun Zeng
Journal: Theranostics (2020)

Lanthanide based nanoprobe with high efficient down-shifting second near-infrared (NIR-II, 1000-1700 nm) emission has emerged as a promising agent for tumor-associated vascular visualization. However, most of the developed lanthanide-based NIR-II-emissive probes are activated by 980 nm laser, leading to the concern of biological overheating effect. Herein, the high quality 808 nm laser activated NaYF4:Gd/Yb/Er/Nd/Ce@NaYF4:Nd core-shell nanoprobes with significantly improved NIR-II emission beyond 1500 nm and eliminated overheating effect were developed for imaging-guided resection surgery of tumor and vascular visualization. Methods: The core-shell nanoprobe with boosted NIR-II emission and eliminated heating effect was achieved with combination of Nd-sensitizing and Ce-doping strategies. The NIR-II optical imaging and toxicity assessment were demonstrated by in vivo and in vitro experiments. Results: The designed core-shell nanoprobe presented superior NIR-II emission beyond 1500 nm than the core only nanoparticle and NIR-II emission intensity was improved up to 11.0 times by further suppressing the upconversion (UC) pathway through doping Ce3+. More importantly, non-invasive tumor vascular imaging and NIR-II optical imaging-guided surgical resection of tumor were successfully achieved. Conclusion: It is expected that the Nd-sensitized lanthanide-based nanoprobe with significant improvement in NIR-II emission and eliminated overheating effect is a highly promising probe for NIR-II imaging, making it more competitive in non-invasive vascular imaging and imaging-guided tumor resection surgery.