tbuckley/cabot-search huggingface dataset:
Homozygous MESP1 knock-in reporter hESCs facilitated cardiovascular cell differentiation and myocardial infarction repair
Authors: Lin Wang, Fengzhi Zhang, Fuyu Duan, Rujin Huang, Xi Chen, Jia Ming, Jie Na
Journal: Theranostics (2020)

Different populations of cardiovascular progenitor cells have been shown to possess varying differentiation potentials. They have also been used to facilitate heart repair. However, sensitive reporter cell lines that mark the human cardiovascular progenitors are in short supply. Methods: MESP1 marks the earliest population of cardiovascular progenitor cells during embryo development. Here, we generated a homozygous MESP1 knock-in reporter hESC line where mTomato gene joined to the MESP1 coding region via a 2A peptide, in which both MESP1 alleles were preserved. We performed transcriptome and functional analysis of human MESP1+ cardiovascular progenitor cells and tested their therapeutic potential using a rat model of myocardial infarction. Results: MESP1-mTomato knock-in reporter faithfully recapitulated the endogenous level of MESP1. Transcriptome analysis revealed that MESP1+ cells highly expressed early cardiovascular genes and heart development genes. The activation of MESP1 relied on the strength of canonical Wnt signaling, peak MESP1-mTomato fluorescence correlated with the window of canonical Wnt inhibition during in vitro differentiation. We further showed that MESP1 bound to the promoter of the WNT5A gene and the up-regulation of WNT5A expression suppressed canonical Wnt/β-CATENIN signaling. Moreover, induced MESP1 expression could substitute the canonical Wnt inhibition step and promote robust cardiomyocyte formation. We used a configurable, chemically defined, tri-lineage differentiation system to obtain cardiomyocytes, endothelial cells, and smooth muscle cells from MESP1+ cells at high efficiency. Finally, we showed that the engraftment of MESP1+ cells repaired rat myocardial infarction model. Conclusions: MESP1-mTomato reporter cells offered a useful platform to study cardiovascular differentiation from human pluripotent stem cells and explore their therapeutic potential in regenerative medicine.
New observatory will set out actions to tackle racism “within months,” say campaigners
Authors: Zosia Kmietowicz
Journal: BMJ (2020)

The architects behind the new NHS Race and Health Observatory have vowed that it will deliver actionable recommendations within months to tackle the structural racism that exists throughout healthcare.

Victor Adebowale and Mala Rao called for an observatory to tackle the ethnic health inequalities in the UK in a special issue of The BMJ that they co-edited in February (bmj.com/racism-in-medicine) and NHS England confirmed at the end of the May that the centre would go ahead.1

Speaking at a meeting to discuss the aims of the observatory on 12 June, Adebowlae told more than 20 assembled stakeholders that he wanted the new centre “to fire on all cylinders,” making recommendations for changes …
Abstract IA10: Targeting glutamine metabolism as a means of enhancing immunotherapy for cancer
Authors: Jonathan Powell, Robert Leone, Min-Hee Oh, Rana Rais, Pavel Majer, Barbara Slusher
Journal: Clinical Cancer Research (2020)

Abstract Tumors possess specialized metabolic programming that facilitates their rapid growth. We have developed a novel glutamine antagonist that not only demonstrates single-agent efficacy in a variety of mouse tumor models but also synergizes with anti-PD-1, adoptive cellular therapy (ACT), and A2aR antagonism to overcome resistance to immunotherapy and promote durable cures. Our data demonstrate that targeting tumor glutamine metabolism alters the tumor microenvironment by making it less acidic, less hypoxic, and more nutrient replete. These alterations lead to enhanced endogenous antitumor responses (in the absence of additional immunotherapy). Further analysis of tumor-infiltrating lymphocyte (TIL) reveals markedly increased infiltration of CD8+ T cells with increased proliferative index (Ki67) and the generation of robust memory phenotypes in the treated mice. Further, RNA sequencing data revealed that CD8+ TIL from vehicle-treated mice showed significantly enhanced expression of apoptotic transcriptional programs compared with TIL from treated mice. Additionally, targeting glutamine metabolism leads to decreased MDSC with an increase in inflammatory TAMs. Furthermore, we observe a downregulation of IDO and a marked decrease in kynurenine in the tumors of treated mice. These changes in macrophage subsets also correlated with decreased metastasis. Overall our findings suggest a novel “metabolic” approach to enhancing immunotherapy for cancer. Citation Format: Jonathan Powell, Robert Leone, Min-Hee Oh, Rana Rais, Pavel Majer, Barbara Slusher. Targeting glutamine metabolism as a means of enhancing immunotherapy for cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA10.
The potential impact of COVID-19 in refugee camps in Bangladesh and beyond: A modeling study
Authors: Shaun Truelove, Orit Abrahim, Chiara Altare, Stephen A. Lauer, Krya H. Grantz, Andrew S. Azman, Paul Spiegel
Journal: PLoS Medicine (2020)

Background COVID-19 could have even more dire consequences in refugees camps than in general populations. Bangladesh has confirmed COVID-19 cases and hosts almost 1 million Rohingya refugees from Myanmar, with 600,000 concentrated in the Kutupalong-Balukhali Expansion Site (mean age, 21 years; standard deviation [SD], 18 years; 52% female). Projections of the potential COVID-19 burden, epidemic speed, and healthcare needs in such settings are critical for preparedness planning. Methods and findings To explore the potential impact of the introduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the Kutupalong-Balukhali Expansion Site, we used a stochastic Susceptible Exposed Infectious Recovered (SEIR) transmission model with parameters derived from emerging literature and age as the primary determinant of infection severity. We considered three scenarios with different assumptions about the transmission potential of SARS-CoV-2. From the simulated infections, we estimated hospitalizations, deaths, and healthcare needs expected, age-adjusted for the Kutupalong-Balukhali Expansion Site age distribution. Our findings suggest that a large-scale outbreak is likely after a single introduction of the virus into the camp, with 61%–92% of simulations leading to at least 1,000 people infected across scenarios. On average, in the first 30 days of the outbreak, we expect 18 (95% prediction interval [PI], 2–65), 54 (95% PI, 3–223), and 370 (95% PI, 4–1,850) people infected in the low, moderate, and high transmission scenarios, respectively. These reach 421,500 (95% PI, 376,300–463,500), 546,800 (95% PI, 499,300–567,000), and 589,800 (95% PI, 578,800–595,600) people infected in 12 months, respectively. Hospitalization needs exceeded the existing hospitalization capacity of 340 beds after 55–136 days, between the low and high transmission scenarios. We estimate 2,040 (95% PI, 1,660–2,500), 2,650 (95% PI, 2,030–3,380), and 2,880 (95% PI, 2,090–3,830) deaths in the low, moderate, and high transmission scenarios, respectively. Due to limited data at the time of analyses, we assumed that age was the primary determinant of infection severity and hospitalization. We expect that comorbidities, limited hospitalization, and intensive care capacity may increase this risk; thus, we may be underestimating the potential burden. Conclusions Our findings suggest that a COVID-19 epidemic in a refugee settlement may have profound consequences, requiring large increases in healthcare capacity and infrastructure that may exceed what is currently feasible in these settings. Detailed and realistic planning for the worst case in Kutupalong-Balukhali and all refugee camps worldwide must begin now. Plans should consider novel and radical strategies to reduce infectious contacts and fill health worker gaps while recognizing that refugees may not have access to national health systems.
NLRP3 inflammasome <i>via</i> IL-1β regulates PCSK9 secretion
Authors: Zufeng Ding, Xianwei Wang, Shijie Liu, Sichang Zhou, Rajshekhar A Kore, Shengyu Mu, Xiaoyan Deng, Yubo Fan, Jawahar L Mehta
Journal: Theranostics (2020)

Background: Both PCSK9 and NLRP3 inflammasome play important roles in atherogenesis.This study was designed to test the hypothesis that NLRP3 inflammasome via IL-1β induces PCSK9 secretion.The inter-twined relationship between NLRP3 inflammasome, IL-1β and PCSK9 may be relevant in atherogenesis.Methods: We studied NLRP3 inflammasome-mediated PCSK9 secretion in mouse peritoneal macrophages and in a variety of tissues, such as liver, kidney and small intestine.Macrophages were derived from wild-type (WT) and a variety of gene deletion mice to define the mechanistic basis of NLRP3 inflammasome -mediated PCSK9 secretion.Additional studies were performed in high-fat diet fed mice.Results: We observed that NLRP3 and its downstream signals ASC, Caspase-1, IL-18, and IL-1β all participate in PCSK9 secretion.IL-1β seems to be more important than IL-18 in the induction of PCSK9 secretion.Further, there appears to be significant involvement of MAPKs in this process.Lastly, we observed that mice fed high fat diet have high expression of NLRP3 and a greater secretion of PCSK9 than mice fed a standard diet, and this increased secretion of PCSK9 in high fat diet-fed mice was attenuated in IL-1β -/-mice.Conclusions: This study based on extensive in vitro and in vivo data provides evidence that NLRP3 inflammasome via IL-1β plays an important role in determining PCSK9 secretion, particularly in the presence of high-fat diet.
Idiopathic pulmonary fibrosis: do scientists focus on publishing rather than on clinical relevance?
Authors: C. Arnold Spek, JanWillem Duitman
Journal: European Respiratory Journal (2020)

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disorder characterised by excessive accumulation of extracellular matrix in the interstitial and alveolar spaces, resulting in scar formation and destruction of the normal pulmonary epithelium with consequent respiratory failure and eventual death [1]. Around 3 million people are affected by IPF, and the prognosis of these patients is devastating, with a median survival after diagnosis of approximately 3 years [2–4]. Despite the US Food and Drug Administartion approval of pirfenidone [5] and nintedanib [6] for the treatment of IPF in 2014, pharmacological treatment options for IPF remain limited. Although both drugs reduce the decline of lung function in IPF patients, they have serious side-effects, show no benefit on quality of life and do not stop nor reverse the disease [7–11]. Additional therapies to improve the prognosis and quality of life of IPF patients are thus urgently awaited [12]. Advocating the use of therapeutic treatment strategies in preclinical IPF research remains challenging <https://bit.ly/39Ob77c>
Onion Epithelial Membrane Scaffolds Transfer Corneal Epithelial Layers in Reconstruction Surgery
Authors: Guoliang Wang, Pei Chen, Yanzi Wang, Yixin Wang, Peter S. Reinach, Yuhua Xue, Zuguo Liu, Cheng Li
Journal: Advanced Healthcare Materials (2020)

Plants and their extracts have been used especially in China for more than ten centuries for preventing and treating disease. However, there are only few reports describing their use in animal cell culture and tissue transplantation. In this study, onion epithelial membranes (OEM) is used as scaffolds to support cultures of a variety of cells such as fibroblasts and epithelial cells notably; they maintain the phenotypic characteristics of corneal epithelial cells. This improvement includes preservation of the proliferative potential and stemness of rabbit corneal epithelial cells (RCECs). Such an outcome suggests that this cost-effective technology warrants further evaluation to determine if OEM is a viable candidate for use as scaffolds in corneal epithelial transplantation surgery. To test this possibility, rabbit corneal epithelial cells expanded on OEM are transplanted to treat corneal epithelial defects in limbal stem cell deficient rabbits. This procedure is successful because it shortens the time required for wound healing to restore losses in corneal epithelial integrity, and forms a more compact and stratified epithelium framework than the untreated group. Ultimately, should they be proven to be effective in other relevant animal model systems, their usefulness for treating wounds in a clinical setting warrants consideration.
SFED recommendations for IBD endoscopy during COVID-19 pandemic: Italian and French experience
Authors: Federica Furfaro, Lucine Vuitton, Gionata Fiorino, Stephane Koch, Mariangela Allocca, Daniela Gilardi, Alessandra Zilli, Ferdinando D’Amico, Simona Radice, Jean-Baptiste Chevaux, Marion Schaefer, Stanislas Chaussade, Silvio Danese, Laurent Peyrin-Biroulet
Journal: Nature Reviews Gastroenterology & Hepatology (2020)
Abstract A21: Increasing use of adjuvant radiation for parathyroid carcinoma is associated with improved survival outcomes: A population-based study
Authors: Richard B. Cannon, Patrick S. Carpenter, Luke O. Buchmann, Jason P. Hunt, Shane Lloyd, Ying Hitchcock, Marcus M. Monroe
Journal: Clinical Cancer Research (2020)

Abstract Objectives: Parathyroid carcinoma is rare and treatment for these cancers varies between institutions. The primary purposes of this study were to use the Surveillance, Epidemiology, and End Results (SEER) database to evaluate current practice patterns in the use of adjuvant radiation for parathyroid cancers and to investigate the efficacy in a population-based setting. Methods: There were 508 patients treated surgically for parathyroid cancer from 1973 to 2013 identified in the SEER database. Patients with metastatic disease and other prior malignancies were excluded. Three hundred and twenty-one patients (63%) had local disease, while 187 had regional lymph node involvement (37%). Of these patients, 78 (15%) were treated with adjuvant radiation. 5-year disease-specific survival (DSS) and overall survival (OS) were the primary outcomes. Results: Treatment with adjuvant radiation therapy was significantly associated with improved 5-year DSS (94% versus 89%; p=0.045) and OS (81% versus 74%; p=0.036). Improved DSS and OS were significant after controlling for other known covariates on multivariate analysis (HR 0.59, 95% CI 0.44-0.87, p&amp;lt;0.001; HR 0.65, 95% CI 0.47-0.92, p&amp;lt;0.001). The percent utilization of adjuvant radiation for patients with parathyroid carcinoma has significantly increased through the study time period from 7% (1973 to 1986) to 11% (1987 to 2000) to 18% (2001 to 2013) (p=0.011). Conclusion: Adjuvant radiation appears to provide a survival benefit for patients with parathyroid carcinoma. Utilization of adjuvant radiation is increasing over time for these patients. Citation Format: Richard B. Cannon, Patrick S. Carpenter, Luke O. Buchmann, Jason P. Hunt, Shane Lloyd, Ying Hitchcock, Marcus M. Monroe. Increasing use of adjuvant radiation for parathyroid carcinoma is associated with improved survival outcomes: A population-based study [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A21.
Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells
Authors: Huizhen Sun, Husheng Wang, Xue Wang, Yoichi Aoki, Xinjing Wang, Yufei Yang, Xi Cheng, Ziliang Wang, Xipeng Wang
Journal: Theranostics (2020)

Rationale: Cisplatin derivatives are first-line chemotherapeutic agents for epithelial ovarian cancer. However, chemoresistance remains a major hurdle for successful therapy and the underlying molecular mechanisms are poorly understood at present. Methods: RNA sequencing of organoids (PDO) established from cisplatin-sensitive and -resistant ovarian cancer tissue samples was performed. Glucose metabolism, cell senescence, and chemosensitivity properties were subsequently examined. Immunoprecipitation, mass spectrometry, Fӧrster resonance energy transfer-fluorescence lifetime imaging (FRET-FLIM), luciferase reporter assay, ChIP and animal experiments were conducted to gain insights into the specific functions and mechanisms of action of the serine/threonine kinase, Aurora-A, in ovarian cancer. Results: Aurora-A levels were significantly enhanced in cisplatin-resistant PDO. Furthermore, Aurora-A promoted chemoresistance through suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Mechanistically, Aurora-A bound directly to the transcription factor sex determining region Y-box 8 (SOX8) and phosphorylated the Ser327 site, in turn, regulating genes related to cell senescence and glycolysis, including hTERT, P16, LDHA and HK2, through enhancement of forkhead-box k1 (FOXK1) expression. Conclusions: Aurora-A regulates cell senescence and glucose metabolism to induce cisplatin resistance by participating in the SOX8/FOXK1 signaling axis in ovarian cancer. Our collective findings highlight a novel mechanism of cisplatin resistance and present potential therapeutic targets to overcome chemoresistance in ovarian cancer.
AB1046 JOINT MANIFESTATIONS IN A COHORT OF PATIENTS WITH SARCOIDOSIS IN A THIRD LEVEL HOSPITAL.
Authors: I. Madroñal García, C. Aguilera Cros, L. Mendez Diaz
Journal: Annals of the Rheumatic Diseases (2020)

Background: Sarcoidosis (S) is a systemic granulomatous disease of unknown etiology, which most frequently affects the ganglion, lung and skin, although it can affect other organs, including the musculoskeletal system. Objectives: - Describe the clinical, analytical and radiological characteristics of patients diagnosed with S presenting joint manifestations. - To assess the association between patients who have joint manifestations and the use of corticosteroids (C) and immunosuppressants (IS), with respect to those without joint involvement. Methods: Retrospective descriptive study of patients with diagnosis of S with joint manifestations, treated in our Hospital from 2017 to 2019. Data were obtained by reviewing medical records. Chi square tests and Fisher’s exact test have been performed to establish the differences described in the objectives. Results: From a database of 102 patients with S, 18 presented joint manifestations (50% women), with a mean age of 57 ± 6 years. Of these patients, 4 (22.2%) have presented positive ANA. Regarding the clinic, 3 patients presented the association of polyarthritis and bilateral ankle swelling, 8 patients presented with polyarthritis, 3 monoatritis and 4 patients presented bilateral ankle swelling. 61.1% had fever at the onset of the disease. 14 patients (77.8%) had high ACE values at the onset of the disease, without presenting significant differences with respect to all patients diagnosed with S who do not have joint involvement. All patients received treatment with C and 10 patients (55.5%) needed an IS treatment, finding no differences with respect to patients who do not have joint involvement (p=0.92). On the course of the disease, the majority of patients with joint involvement have a chronic course (72.2%). Nor were significant differences found when compared with patients who have no joint involvement (p = 0.73). Conclusion: Patients with joint involvement in our study have been 17.6% (18), an approximate result to that described in the literature (over 10%), although our result may be increased by the fact that the patients who are followed in Rheumatology present or have presented joint involvement. No significant differences were found between patients with S who presented joint involvement and those who did not, with respect to the initial ACE values, treatment and disease course. Prospective, multicenter and larger sample studies are necessary to better understand these associations. Disclosure of Interests: None declared
Simultaneous Consideration of HbA1c and Insulin Resistance Improves Risk Assessment in White Individuals at Increased Risk for Future Type 2 Diabetes
Authors: James B. Meigs, Bianca Porneala, Aaron Leong, Dov Shiffman, James J. Devlin, Michael J. McPhaul
Journal: Diabetes Care (2020)

Type 2 diabetes (T2D) prevalence increases unabated even as interventions focused on individuals at high risk can prevent T2D (1). Best approaches to identify individuals at high risk continue to be refined. Current risk assessment focuses on elevated glycemia, commonly estimated by fasting glucose (FG) and HbA1c levels, despite imperfect sensitivity and specificity (2). We previously showed that risk for T2D increases progressively as HbA1c increases, independently and in addition to increasing FG (3,4). As risk assessment for T2D depends on more than glycemia alone, simultaneous consideration of another physiological axis may improve biomarker-based diagnostic precision. Here, we test the hypothesis that simultaneous consideration of HbA1c and insulin resistance (IR), assessed with fasting insulin as HOMA of IR (HOMA-IR), can substantially improve risk assessment for T2D.

We have previously detailed our statistical approach, IR and T2D diagnostic criteria, and particulars of the Framingham Heart Study (FHS) (3). Using the same FHS data and excluding those with T2D at baseline, we categorized individuals according to HbA1c <5.7% or 5.7–6.49% and into HOMA-IR tertiles and followed them for a mean (SD) of 16.4 (4.5) years for incident T2D.

Age- and sex-adjusted T2D incidence rates and counts of subjects are shown in Fig. 1 A for all …
Inhibition of mite‐induced dermatitis, pruritus, and nerve sprouting in mice by the endothelin receptor antagonist bosentan
Authors: Makiko Kido‐Nakahara, Bing Wang, Fumitaka Ohno, Gaku Tsuji, Dugarmaa Ulzii, Masaki Takemura, Masutaka Furue, Takeshi Nakahara
Journal: Allergy (2020)

Abstract Background Endothelin‐1 (EDN1) can evoke histamine‐independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL‐25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model. Methods We analyzed the mite‐induced AD‐like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3 weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation. Results Topical application of bosentan significantly attenuated the development of mite‐induced AD‐like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation‐regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13 , Il17 , and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose‐ and time‐dependent manner, bosentan treatment attenuated this. Conclusions EDN1 plays a significant role in mite‐induced inflammation and itch. Topical bosentan is a potential protective candidate for AD.