tbuckley/cabot-search huggingface dataset:
AB0219 PREDICTIVE FACTORS FOR THE PROGRESSION OF EARLY INFLAMMATORY ARTHRITIS TO RHEUMATOID ARTHRITIS
Authors: F. Rahal, R. Chetouane, S. Bencheikh, S. Haid, N. Khaldoun, N. Brahumi, A. Ladjouze-Rezig, F. Hanni
Journal: Annals of the Rheumatic Diseases (2020)

Objectives: To identify factors predicting the progression of early inflammatory arthritis (EIA) to rheumatoid arthritis (RA) Methods: This was a prospective longitudinal study of inflammatory rheumatism that could not be classified according to defined rheumatism criteria. Demographic, biological, immunological and radiographic data were collected at the time of inclusion in the study. Disease activity as determined by the Disease Activity Score 28-CPR (DAS28-CPR: 4 variables), functional handicap as calculated by Heath Assessment Score (HAQ), and bone and joint damage as evaluated by Sharp-Van der Heijde (SVDH) score. ultrasound joint imaging were evaluated at the beginning of the study and then 1 year later. Logistic regression was performed to identify predictive factors for progression to RA. Results: One hundred seventy two patients were included (24 men, 148 women), with an mean age 43.13±14.07 years and an mean time to diagnosis 10.24±6.84 months The mean ESR was 46.81±31.16 mm/1st hour, and the mean CRP level was 22.84±39.8 mg/l. Rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPAs) were present in 48.8% and 53% of patients, respectively. The erosion, joint space narrowing, and total SVDH scores were 3.38±3.48, 5.08±3.32, and 5.95±4.94, respectively. One hundred sixty one patients were followed up for 12 months. Multivariate regression analysis showed that a DAS28-CRP level &gt;5.2 (OR=28.6; CI95% 8.7-94.5), an RF level &gt;60 IU/L (OR=11.2; CI95% 4.3-87.5), and an ACPA level &gt;60 IU/L (OR=5.4; CI95% 1.9-15.3) were predictive for progression to RA. Conclusion: Our study suggests that clinical evaluation of EIA by DAS28-CRP from the time of diagnosis, as well as evaluating the presence of RA auto-antibodies, can predict progression to RA. Disclosure of Interests: None declared
Doctors call for meeting to clarify why president resigned from Royal College of Physicians of Edinburgh
Authors: Bryan Christie
Journal: BMJ (2020)

A group of doctors has called for the Royal College of Physicians of Edinburgh to hold an extraordinary general meeting to explain the president’s surprise resignation.

College fellows were informed in an email from the college’s chief executive, Keith McKellar, on 29 May that Andrew Elder had resigned with immediate effect “due to personal reasons,” less than three months after he took office on 2 March 2020.

Colleagues who contacted Elder were told that he had been forced out of office because of an alleged conflict of interest. This relates to his previous role as medical director of MRCP(UK), the body that organises examinations for the three UK royal colleges of physicians in Edinburgh, …
Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
Authors: Bryan Ngo, Eugenie Kim, Victoria Osorio-Vasquez, Sophia Doll, Sophia Bustraan, Roger J. Liang, Alba Luengo, Shawn M. Davidson, Ahmed Ali, Gino B. Ferraro, Grant M. Fischer, Roozbeh Eskandari, Diane S. Kang, Jing Ni, Ariana Plasger, Vinagolu K. Rajasekhar, Edward R. Kastenhuber, Sarah Bacha, Roshan K. Sriram, Benjamin D. Stein, Samuel F. Bakhoum, Matija Snuderl, Paolo Cotzia, John H. Healey, Nello Mainolfi, Vipin Suri, Adam Friedman, Mark Manfredi, David M. Sabatini, Drew R. Jones, Min Yu, Jean J. Zhao, Rakesh K. Jain, Kayvan R. Keshari, Michael A. Davies, Matthew G. Vander Heiden, Eva Hernando, Matthias Mann, Lewis C. Cantley, Michael E. Pacold
Journal: Cancer Discovery (2020)

A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.This article is highlighted in the In This Issue feature, p. 1241.
Abstract A33: Impact of tumor-derived exosomes on CD28 expression in T cells
Authors: Ashley J. Schulte, Lauren J. Mills, Kelly M. Makielski, Taylor A. DePauw, Jaime F. Modiano
Journal: Clinical Cancer Research (2020)

Abstract Osteosarcoma is a rare disease with a disproportionate impact, as it is seen mostly in children and adolescents. Despite aggressive treatment, more than 50% of patients succumb to their disease within 10 years of diagnosis, making safe and effective treatments a huge unmet need. Immunotherapy, including immune checkpoint blockade, is drastically changing cancer treatment by increasing the antitumor immune response. Mechanisms of resistance to immune checkpoint blockade are incompletely understood; therefore, there is currently no available method to specifically identify patients who will respond favorably to immunotherapy. Exosomes are extracellular vesicles that can carry proteins, lipids, mRNA, microRNA, and DNA and play a role in extracellular communication. Exosomes can be found in circulation, making them an attractive tool for diagnostic testing. One potential mechanism of immunotherapy resistance could be destabilization of the CD28 coreceptor in T cells by microRNAs secreted in tumor-derived exosomes. Utilizing next-generation RNA-sequencing, we previously identified 2 microRNAs in dogs and 2 microRNAs in humans that were inversely correlated with CD28 expression in 44 human and 39 canine osteosarcoma tissues. Current work entails isolating exosomes from canine and human osteosarcoma tumor cell lines. Using a species mismatched approach, we can identify canine microRNAs in human T cells that were treated with canine exosomes, and vice versa, to verify delivery of microRNAs to T cells via tumor-derived exosomes. We are also using the CRISPR-Cas system to genetically engineer a human osteosarcoma cell line (HOS) that expresses the exosome marker CD63 linked to GFP so we can track exosome uptake by T cells by flow cytometry and determine the effect on CD28 expression levels. Identifying mechanisms of resistance will lead to improved patient selection and identification of therapeutic targets to combat this resistance. Citation Format: Ashley J. Schulte, Lauren J. Mills, Kelly M. Makielski, Taylor A. DePauw, Jaime F. Modiano. Impact of tumor-derived exosomes on CD28 expression in T cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A33.
A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer
Authors: Susanne Hipp, Vladimir Voynov, Barbara Drobits-Handl, Craig Giragossian, Francesca Trapani, Andrew E. Nixon, Justin M. Scheer, Paul J. Adam
Journal: Clinical Cancer Research (2020)

Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues.The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3+ T-cells.Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3.This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.
Gerald Wilson Black
Authors: Dennis L Coppel
Journal: BMJ (2020)

Gerald Wilson Black (“Gerry”) completed his medical degree at Queen’s University Belfast. After a research fellowship in the department of anesthesiology, University of Pennsylvania, USA, he was appointed as consultant paediatric anaesthetist to the Royal Belfast Hospital for Sick Children (RBHSC) in 1960, in which capacity he served until his retirement in 1990. Much of his work involved the perioperative care of newborn infants and, recognising the need for more intensive medical and nursing care for critically ill children, he pioneered the development of paediatric intensive care in Northern Ireland. The paediatric intensive care unit in RBHSC, of which he was in administrative charge, was one of the first in the UK. He was recognised internationally as a leading authority in volatile anaesthetics and considered to be one of the outstanding anaesthetists of his generation.

For many years Gerry was involved in the investigation of the sympatho-adrenal, metabolic, and circulatory effects of the various inhalation anaesthetics. A close relation was found …
Opportunistic screening for atrial fibrillation by clinical pharmacists in UK general practice during the influenza vaccination season: A cross-sectional feasibility study
Authors: Vilius Savickas, Adrian J. Stewart, Melanie Rees-Roberts, Vanessa Short, Sukvinder K. Bhamra, Sarah A. Corlett, Alistair Mathie, Emma L. Veale
Journal: PLoS Medicine (2020)

Background Growing prevalence of atrial fibrillation (AF) in the ageing population and its associated life-changing health and resource implications have led to a need to improve its early detection. Primary care is an ideal place to screen for AF; however, this is limited by shortages in general practitioner (GP) resources. Recent increases in the number of clinical pharmacists within primary care makes them ideally placed to conduct AF screening. This study aimed to determine the feasibility of GP practice–based clinical pharmacists to screen the over-65s for AF, using digital technology and pulse palpation during the influenza vaccination season. Methods and findings Screening was conducted over two influenza vaccination seasons, 2017–2018 and 2018–2019, in four GP practices in Kent, United Kingdom. Pharmacists were trained by a cardiologist to pulse palpate, record, and interpret a single-lead ECG (SLECG). Eligible persons aged ≥65 years (y) attending an influenza vaccination clinic were offered a free heart rhythm check. Six hundred four participants were screened (median age 73 y, 42.7% male). Total prevalence of AF was 4.3%. All participants with AF qualified for anticoagulation and were more likely to be male (57.7%); be older; have an increased body mass index (BMI); and have a CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes, previous Stroke, Vascular disease, Age 65–74 years, Sex category) score ≥ 3. The sensitivity and specificity of clinical pharmacists diagnosing AF using pulse palpation was 76.9% (95% confidence interval [CI] 56.4–91.0) and 92.2% (95% CI 89.7–94.3), respectively. This rose to 88.5% (95% CI 69.9–97.6) and 97.2% (95% CI 95.5–98.4) with an SLECG. At follow-up, four participants (0.7%) were diagnosed with new AF and three (0.5%) were initiated on anticoagulation. Screening with SLECG also helped identify new non-AF cardiovascular diagnoses, such as left ventricular hypertrophy, in 28 participants (4.6%). The screening strategy was cost-effective in 71.8% and 64.3% of the estimates for SLECG or pulse palpation, respectively. Feedback from participants (422/604) was generally positive. Key limitations of the study were that the intervention did not reach individuals who did not attend the practice for an influenza vaccination and there was a limited representation of UK ethnic minority groups in the study cohort. Conclusions This study demonstrates that AF screening performed by GP practice–based pharmacists was feasible, economically viable, and positively endorsed by participants. Furthermore, diagnosis of AF by the clinical pharmacist using an SLECG was more sensitive and more specific than the use of pulse palpation alone. Future research should explore the key barriers preventing the adoption of national screening programmes.
Hyper-CVAD Plus Ofatumumab As Frontline Therapy in CD20+ Acute Lymphoblastic Leukemia: Updated Results of a Phase II Trial
Authors: Abhishek Maiti, Hagop M. Kantarjian, Farhad Ravandi, Maria Khouri, Deborah A Thomas, Guillermo Garcia-Manero, Rebecca Garris, Jorge E. Cortes, Nicholas J Short, Nitin Jain, Prithviraj Bose, Srdan Verstovsek, Marina Konopleva, Koji Sasaki, Ghayas C. Issa, Marie Ghosn, Heather M Schroeder, Tapan Kadia, Naval Daver, Susan M. O'Brien, Elias J. Jabbour
Journal: Blood (2017)
Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling
Authors: Jason E. Fish, Carlos Perfecto Flores Suarez, Emilie Boudreau, Alexander M. Herman, Manuel Cantu Gutierrez, Dakota Gustafson, Peter V. DiStefano, Meng Cui, Zhiqi Chen, Karen Berman De Ruiz, Taylor S. Schexnayder, Christopher S. Ward, Ivan Radovanovic, Joshua D. Wythe
Journal: Circulation Research (2020)

We previously identified somatic activating mutations in the KRAS (Kirsten rat sarcoma viral oncogene homologue) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations; a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to arteriovenous malformations, remains unknown. To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for arteriovenous malformations. Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce brain arteriovenous malformations. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity but instead seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibition of the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling. We demonstrate that active KRAS expression in the endothelium is sufficient for brain arteriovenous malformations, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for arteriovenous malformation patients. Graphical Abstract: A graphical abstract is available for this article.
Doctors who persist in denying misconduct should not be at risk of harsher sanctions, says High Court
Authors: Clare Dyer
Journal: BMJ (2020)

A High Court Judge has declared that doctors who face misconduct charges at medical practitioners tribunals should not be at risk of harsher sanctions because they persist in denying wrongdoing.1

Mr Justice Mostyn rejected an appeal by the General Medical Council against a tribunal decision in November 2019 that a GP, Hafeez-ur Rehman Awan, should be suspended from the UK medical register for nine months rather than struck off.

Awan had logged on to a chatroom hosted by the web company Lycos in January 2016, when he was working as a GP in Leeds and Wakefield. He started exchanging messages with “Sophiasheff,” who told him she was 13 years old. He told her he was a doctor …
The lung tissue microbiota features of 20 deceased patients with COVID-19
Authors: Jun Fan, Xiang Li, Yong Gao, Junjie Zhou, Sihua Wang, Bo Huang, Junhua Wu, Qin Cao, Yajun Chen, Zhenkao Wang, Danju Luo, Ting Zhou, Ruiting Li, You Shang, Xiu Nie
Journal: Journal of Infection (2020)
Intravital Dynamic and Correlative Imaging of Mouse Livers Reveals Diffusion‐Dominated Canalicular and Flow‐Augmented Ductular Bile Flux
Authors: Nachiket Vartak, Georgia Guenther, Florian Joly, Amruta Damle‐Vartak, Gudrun Wibbelt, Jörns Fickel, Simone Jörs, Brigitte Begher‐Tibbe, Adrian Friebel, Kasimir Wansing, Ahmed Ghallab, Marie Rosselin, Noemie Boissier, Irene Vignon‐Clementel, Christian Hedberg, Fabian Geisler, Heribert Hofer, Peter Jansen, Stefan Hoehme, Dirk Drasdo, Jan G. Hengstler
Journal: Hepatology (2020)

Background and Aims Small‐molecule flux in tissue microdomains is essential for organ function, but knowledge of this process is scant due to the lack of suitable methods. We developed two independent techniques that allow the quantification of advection (flow) and diffusion in individual bile canaliculi and in interlobular bile ducts of intact livers in living mice, namely fluorescence loss after photoactivation and intravital arbitrary region image correlation spectroscopy. Approach and Results The results challenge the prevailing “mechano‐osmotic” theory of canalicular bile flow. After active transport across hepatocyte membranes, bile acids are transported in the canaliculi primarily by diffusion. Only in the interlobular ducts is diffusion augmented by regulatable advection. Photoactivation of fluorescein bis‐(5‐carboxymethoxy‐2‐nitrobenzyl)‐ether in entire lobules demonstrated the establishment of diffusive gradients in the bile canalicular network and the sink function of interlobular ducts. In contrast to the bile canalicular network, vectorial transport was detected and quantified in the mesh of interlobular bile ducts. Conclusions The liver consists of a diffusion‐dominated canalicular domain, where hepatocytes secrete small molecules and generate a concentration gradient and a flow‐augmented ductular domain, where regulated water influx creates unidirectional advection that augments the diffusive flux.
Primary aortogastric fistula: an extraordinary rare endoscopic finding in the setting of upper gastrointestinal bleeding
Authors: Alberto Martino, Raffaele Bennato, Gaspare Oliva, Armando Pontarelli, Desiree Picascia, Luigia Romano, Giovanni Lombardi
Journal: Endoscopy (2020)

A 78-year-old lady with a history of arterial hypertension and left upper lobectomy 4 months previously for stage IIB lung adenocarcinoma was admitted to our bleeding unit with severe anemia (hemoglobin level on admission 6.7 g/dL) and recent onset of melena. No hemodynamic instability was observed and, after a blood transfusion had been given, urgent esophagogastroduodenoscopy was performed with the patient under monitored anesthesia care. The retroflexion maneuver revealed an extrinsic pulsating bulging mass, partially covered by adherent large blood clots, originating from the fundus and extending to the posterior wall of the proximal body of the stomach. No active bleeding was noted ([Fig. 1]; [Video 1]).
Malnutrition in children with ichthyosis: Recommendations for monitoring from a multidisciplinary clinic experience
Authors: Silvia Rodríguez-Manchón, Consuelo Pedrón-Giner, Elvira Cañedo-Villarroya, Rosa Ana Muñoz-Codoceo, Ángela Hernández-Martín
Journal: Journal of the American Academy of Dermatology (2020)
Comment on: “To consider varicella-like exanthem associated with COVID-19, virus varicella zoster and virus herpes simplex must be ruled out. Characterization of herpetic lesions in hospitalized COVID-19 patients”
Authors: Diego Fernandez-Nieto, Daniel Ortega-Quijano, Ana Suarez-Valle, Patricia Burgos-Blasco, Juan Jimenez-Cauhe, Montserrat Fernandez-Guarino
Journal: Journal of the American Academy of Dermatology (2020)
Finding the true prevalence of obstructive lung disease: two steps forward and one step back
Authors: Richard E.K. Russell, Kay Wang
Journal: European Respiratory Journal (2020)

<b>Getting a true measure of disease prevalence is difficult but fundamental to medicine. The process itself is valuable, but the results have to be reviewed in the context of the healthcare system and country they were collected in.</b>https://bit.ly/2ThxaxF
Overexpression of Histone Demethylase KDM6B in the Hematopoietic Compartment Promotes the Effect of Innate Immune Activation and Results in Myelodysplastic Syndrome (MDS)-like Phenotype in Mice
Authors: Yue Wei, Guillermo Garcia-Manero, Hong Zheng, Yu Jia, Naran Bao, Shan Jiang, Joseph David Khoury, Caleb Class, Simona Colla, Carlos E. Bueso-Ramos
Journal: Blood (2017)
Using Neonatal Intensive Care Units More Wisely for At-Risk Newborns and Their Families
Authors: DeWayne M. Pursley, John A. F. Zupancic
Journal: JAMA Network Open (2020)

David Braun, MD; Eric Braun, BA; Vicki Chiu, MS; Anthony E. Burgos, MD, MPH; Mandhir Gupta, MD; Marianna Volodarskiy, MSN, RN, NE-BC; Darios Getahun, MD, MPH, PhD