tbuckley/cabot-search huggingface dataset:
The <i>BRCA1</i> Pseudogene Negatively Regulates Antitumor Responses through Inhibition of Innate Immune Defense Mechanisms
Authors: Yoo Jane Han, Jing Zhang, Jung-Hyun Lee, Jennifer M. Mason, Olga Karginova, Toshio F. Yoshimatsu, Qinyu Hao, Ian Hurley, Laia Paré Brunet, Aleix Prat, Kannanganattu V. Prasanth, Michaela U. Gack, Olufunmilayo I. Olopade
Journal: Cancer Research (2021)

Innate immune defense mechanisms play a pivotal role in antitumor responses. Recent evidence suggests that antiviral innate immunity is regulated not only by exogenous non-self-RNA but also by host-derived pseudogene RNAs. A growing body of evidence also indicates a biological role for pseudogenes as gene expression regulators or immune modulators. Here, we report an important role for BRCA1P1, the pseudogene of the BRCA1 tumor-suppressor gene, in regulating innate immune defense mechanisms in breast cancer cells. BRCA1P1 expresses a long-noncoding RNA (lncRNA) in breast cancer cells through divergent transcription. Expression of lncRNA-BRCA1P1 is increased in breast tumors compared with normal breast tissues. Depletion of BRCA1P1 induces an antiviral defense-like program, including the expression of antiviral genes in breast cancer cells. Furthermore, BRCA1P1-deficient cancer cells mimic virus-infected cells by stimulating cytokines and inducing cell apoptosis. Accordingly, depletion of BRCA1P1 increases host innate immune responses and restricts virus replication. In converse, overexpression of BRCA1P1 reduces cytokine expression in breast cancer cells. Mechanistically, lncRNA-BRCA1P1 is localized in the nucleus, binds to the NF-κB subunit RelA, and negatively regulates antiviral gene expression. Finally, in a xenograft mouse model of breast cancer, depletion of BRCA1P1 stimulates cytokine expression and local immunity, and suppresses tumor growth. Our results suggest an important role for BRCA1P1 in innate immune defense mechanisms and antitumor responses. This mechanism of antiviral immunity regulated by a host-derived pseudogene RNA may guide the development of novel therapies targeting immune responses in breast cancer. SIGNIFICANCE: This study identifies a novel mechanism of innate immunity driven by a host pseudogene RNA that inhibits innate immune defense mechanisms and antitumor responses through regulation of antiviral gene expression.
Approval of artificial intelligence and machine learning-based medical devices in the USA and Europe (2015–20): a comparative analysis
Authors: Urs J Muehlematter, Paola Daniore, Kerstin N Vokinger
Journal: The Lancet Digital Health (2021)

There has been a surge of interest in artificial intelligence and machine learning (AI/ML)-based medical devices. However, it is poorly understood how and which AI/ML-based medical devices have been approved in the USA and Europe. We searched governmental and non-governmental databases to identify 222 devices approved in the USA and 240 devices in Europe. The number of approved AI/ML-based devices has increased substantially since 2015, with many being approved for use in radiology. However, few were qualified as high-risk devices. Of the 124 AI/ML-based devices commonly approved in the USA and Europe, 80 were first approved in Europe. One possible reason for approval in Europe before the USA might be the potentially relatively less rigorous evaluation of medical devices in Europe. The substantial number of approved devices highlight the need to ensure rigorous regulation of these devices. Currently, there is no specific regulatory pathway for AI/ML-based medical devices in the USA or Europe. We recommend more transparency on how devices are regulated and approved to enable and improve public trust, efficacy, safety, and quality of AI/ML-based medical devices. A comprehensive, publicly accessible database with device details for Conformité Européene (CE)-marked medical devices in Europe and US Food and Drug Administration approved devices is needed.
Predisposition to cancer in children and adolescents
Authors: Christian P Kratz, Marjolijn C Jongmans, Hélène Cavé, Katharina Wimmer, Sam Behjati, Lea Guerrini-Rousseau, Till Milde, Kristian W Pajtler, Lisa Golmard, Marion Gauthier-Villars, Rosalyn Jewell, Catriona Duncan, Eamonn R Maher, Laurence Brugieres, Kathy Pritchard-Jones, Franck Bourdeaut
Journal: The Lancet Child & Adolescent Health (2021)
ACEi reduces hypertension-induced hyperinflammation in COVID-19
Authors: Gregory B. Lim
Journal: Nature Reviews Cardiology (2021)

Antihypertensive therapy, particularly with the use of an angiotensin-converting enzyme inhibitor, improves outcomes in patients with hypertension and SARS-CoV-2 infection, who are susceptible to hyperinflammation and severe outcomes with COVID-19.
Author Correction: Fit older adults with advanced myelodysplastic syndromes: who is most likely to benefit from transplant?
Authors: Gregory A. Abel, Haesook T. Kim, Andrew Hantel, David P. Steensma, Richard Stone, Anand Habib, Vincent T. Ho, Martha Wadleigh, Areej El-Jawahri, Edwin P. Alyea, Daniel J. DeAngelo, John Koreth, Joseph H. Antin, Robert J. Soiffer, Corey Cutler
Journal: Leukemia (2021)
Abstract 15440: Risk Factors for Bleeding in Children With Acquired and Congenital Heart Disease Treated With Warfarin
Authors: Paul Esteso, Beth Hawkins, Courtney Ventresco, Amy Hellinger, Austin Liou, Lynn A Sleeper, Jesse Esch, Elizabeth Blume, Christina J VanderPluym
Journal: Circulation (2019)

Introduction: Despite the widespread use of warfarin for prevention and treatment of thrombosis, little is known about its risk in children with heart disease. This study sought to describe the uti...
A retrospective multicenter study: Clinicopathological factors affecting recurrence-free survival in operable gastric cancer patients.
Authors: Emre Yekeduz, İzzet Dogan, Hakan Akbulut, Senem Karabulut, Gungor Utkan, Yuksel Urun
Journal: Journal of Clinical Oncology (2021)

185 Background:Gastric cancer is one of the most common cancers in Asian countries, particularly. However, according to the American Cancer Society, 27,600 new gastric cancer cases and 11,010 deaths due to gastric cancer will be observed in the US in 2020. The rates of 5-year overall survival (OS) are 69.5% and 32% in the localized and regional diseases. Despite surgery and adjuvant treatment, gastric cancer’s recurrence rate is still not reasonable. In this multicenter study, we aimed to identify the clinicopathological factors that affect gastric cancer recurrence. Methods: Clinical and pathological data of the patients performed surgery between the 2009-2018 in the two university hospitals in Turkey was collected retrospectively. Recurrence-free survival (RFS) was estimated using Kaplan-Meier and categorical variables were compared using a log-rank test. After identifying clinicopathological factors affecting RFS, a multivariate analysis was performed using Cox regression analysis. All statistical analyses were performed using IBM SPSS Statistics software, version 27 (IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27 Armonk, NY: IBM Corp.). Results: Three hundred fifty-four patients were included in this study. Two out of three of all patients were male and the median age at diagnosis was 56 years old (Interquartile Range (IQR):48-64). The median follow-up was 25 months (IQR:15-50). The median RFS was 53.2 months (95% Confidence Interval (CI) could not calculated). 5-year survival rate was 64% and the median overall survival (OS) was 136 months (95% CI: 98-173). According to results of multivariate analysis, there was an increased risk for recurrence in patients with preoperative hypoalbuminemia (albumin &lt; 3.5 gr/dl) [Hazard Ratio (HR): 5.3 (95% CI: 1.2-23.4]; p=0.005), and performed R1 resection [HR:5.7 (95% CI:1.2-25.3), p=0.02]. Additionally, patients administered chemoradiotherapy (CRT) had a lower risk for recurrence compared to those administered chemotherapy (CT) alone [HR:0.15 (95% CI:0.04-0.57), p=0.005]. Conclusions: Hypoalbuminemia in the preoperative setting and R1 resection were independent factors that affected gastric cancer recurrence. However, postoperative CRT decreased the recurrence rate of gastric cancer compared to CT alone. Low albumin level is an indicator of a systemic inflammatory response and according to previous studies, hypoalbuminemia was a poor prognostic factor in gastric cancer patients. Although CT alone is considered efficient for patients undergone D2 lymph node dissection, our study showed that CRT decreased the recurrence rates compared to CT alone. This result might be related to the higher number of patients undergone D1 dissection in our study.
THU0174 Reactive amyloidosis in patients with rheumatod arthritis
Authors: P Wiland, R Wojtala, J Szechiñski
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> It has been known that reactive (secondary, AA) amyloidosis (RAA) is a major complication of rheumatoid arthritis and amyloidosis is still a main cause of death in rheumatoid arthritis (RA) patients. Diagnosis of amyloidosis is based on Congo red staining of amyloid deposits in tissue biopsies. The safe and simple examination is abdominal fat aspiration biopsy (AFAB). <h3>Objectives</h3> The aim of the study was to investigate the positive rate of amyloid deposits in AFAB samples and to clarify whether the presence of amyloid deposits is correlated with the clinical features of patients. <h3>Methods</h3> AFAB was performed in patients with established diagnosis of RA referred to our department during the period from 1996 to 2001. <h3>Results</h3> Among 103 patients (15 males, 88 females) marked amyloidosis deposits were found in 34 (33%) cases. The incidence of amyloidosis was more frequent in male than female patients (53% male vs 29% female). Raised levels of creatinine (&gt;1,3 mg%) were found in 27% patients with amyloidosis and 3% without amyloidosis; proteinuria respectively in 35% with positive AFAB and 13% with negative AFAB results. There was no difference in both groups according to age, presence of rheumatoid factor, values of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), bacteriuria, presence of erosions in hand and weight. It was found, that patients with proven amyloidosis in AFAB had longer duration of RA (15 years) than patients without amyloidosis (4,5 years). The patients without amyloidosis were more intensively treated with disease-modifying antirheumatic drugs (DMARDs) than patients with amyloidosis what was especially distinct in patients with duration of RA at least ten years; simultaneously time of corticosteroid treatment was longer in patients with amyloidosis. <h3>Conclusion</h3> The observed frequency of amyloidosis was very high when compared with results from other countries. In our opinion the reason probably lies in fact that RA patients were treated only with corticosteroids instead of intensive use of DMARDs. In addition AFAB gives a possibility to find the early phase of amyloidosis before occurrence of overt clinical symptoms like proteinuria or renal insufficiency.
Can We Protect Pregnant Women and Young Infants From COVID-19 Through Maternal Immunization?
Authors: Flor M. Munoz
Journal: JAMA Pediatrics (2021)

Dustin D. Flannery, DO, MSCE; Sigrid Gouma, PhD; Miren B. Dhudasia, MBBS, MPH; Sagori Mukhopadhyay, MD, MMSc; Madeline R. Pfeifer, BS; Emily C. Woodford, BA; Jourdan E. Triebwasser, MD, MA; Jeffrey S. Gerber, MD, PhD; Jeffrey S. Morris, PhD; Madison E. Weirick, BS; Christopher M. McAllister, BS; Marcus J. Bolton, BS; Claudia P. Arevalo, BS; Elizabeth M. Anderson, PhD; Eileen C. Goodwin, BA; Scott E. Hensley, PhD; Karen M. Puopolo, MD, PhD
Abstract 19772: MANF, a Structurally Unique ER Stress-Inducible Protein, Restores ER-Protein Folding in ER Stressed Cardiac Myocytes and in the Ischemic Heart
Authors: Adrian Arrieta, Erik A Blackwood, Winston T Stauffer, Amber N Pentoney, Donna J Thuerauf, Shirin Doroudgar, Christopher C Glembotski
Journal: Circulation (2016)

Introduction: The sarco/endoplasmic reticulum (SR/ER) of cardiomyocytes is a critical site of protein synthesis and folding where most secreted and membrane proteins, such as receptors, growth fact...
In search of novel synthetic lethality anti-cancer drug targets in intrahepatic cholangiocarcinoma: <i>MTAP</i> genomic loss.
Authors: Jeffrey S. Ross, Alexa Betzig Schrock, Russell Madison, Natalie Danziger, Dean Pavlick, Ethan Sokol, Amanda Hemmerich, Richard Huang, Shakti H. Ramkissoon, Mason A. Israel, Ole Gjoerup, Jeffrey Michael Venstrom, Kimberly McGregor
Journal: Journal of Clinical Oncology (2021)

337 Background: The association of BRCA tumor suppressor gene (TSG) inactivation and PARP inhibitor efficacy through a mechanism of synthetic lethality (SL) is now well-established. Recently, the PRMT5 arginine methyltransferase dependence in cells with MTAP (S-methyl-5'-thioadenosine phosphorylase) genomic alterations (GA) has been proposed as a new SL based anti-tumor strategy and under consideration for development for intrahepatic cholangiocarcinoma (IC). Methods: 2,170 cases of clinically advanced IC were submitted for comprehensive genomic profiling (CGP) to detect genomic alterations (GA), tumor mutational burden (TMB) and microsatellite instability (MSI) using a hybrid capture based assay (F1CDx). PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC and scored using the tumor proportion score (TPS) method. Results: 328 (15%) ICs featured MTAP inactivation (MTAP-IC). 48% of MTAP-IC cases were female and 52% were male with a median age of 66 years (range 26-93 years). MTAP-IC featured 6.3 GA per sample. The median TMB was 2.5 mut/Mb with only 2% of cases with TMB ≥10 mut/Mb. No (0%) MTAP-IC cases were MSI-high. Of 112 MTAP-IC IHC stained for PD-L1, 4% were PD-L1 high (&gt; 50%), 14% were PD-L1 low (1-49%) and 82% were PD-L1 negative. 99% of MTAP inactivation was by copy number (CN) loss and 1% was due to non-CN mutation. In MTAP-IC, 99% featured CDKN2A loss and 95% featured CDKN2B loss (9p21 co-deletion). TP53 was mutated in 31% and KRAS in 24% (3% G12C). Other currently non-targetable GA included ARID1A (19%), BAP1 (16%) and SMAD4 (13%). Among potentially targetable GA, the MTAP-IC featured 12% FGFR2 GA (8% rearrangements), 10% BRAF (8% V600E), 7% IDH1, 7% PIK3CA, 4% BRCA2, 4% ERBB2 (2% amplification) and 3% MET. Conclusions: Comprehensive genomic profiling elucidated that MTAP GA are frequent in IC and features relatively high GA/tumor, including 9p21 co-deletion, but relatively low TMB and PD-L1 expression. Isolated MTAP deletion without CDKN2A/B co-deletion was extremely rare. In addition to the potential targeting of PRMT5 in MTAP-IC tumors, co-altered genes known to be targets in IC such as FGFR2, IDH1 and BRAF are still prevalent in MTAP-IC, indicating potential for combining targeted therapies in some MTAP-IC patients.
Severity grading system for acute allergic reactions: A multidisciplinary Delphi study
Authors: Timothy E. Dribin, David Schnadower, Jonathan M. Spergel, Ronna L. Campbell, Marcus Shaker, Mark I. Neuman, Kenneth A. Michelson, Peter S. Capucilli, Carlos A. Camargo, David C. Brousseau, Susan A. Rudders, Amal H. Assa’ad, Kimberly A. Risma, Mariana Castells, Lynda C. Schneider, Julie Wang, Juhee Lee, Rakesh D. Mistry, David Vyles, Michael Pistiner, John K. Witry, Yin Zhang, Hugh A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2021)
Food Allergies and Intolerances: A Clinical Approach to the Diagnosis and Management of Adverse Reactions to Food
Authors: Frances Onyimba, Sheila E. Crowe, Sarah Johnson, John Leung
Journal: Clinical Gastroenterology and Hepatology (2021)

Food allergy is an aberrant immunological response to food antigen, which can result in potentially life-threatening reactions. It is often challenging to differentiate food allergy from other adverse reactions to food because their presentations can be indistinguishable. The purpose of this article is to give an overview of the classification, evaluation, and management of adverse food reactions, key differentiating features of food allergy, roles and limitations of various food allergy testing, and promising areas of emerging research. Case studies are used to highlight some of the clinical pearls in diagnosing and managing food-related diseases.
Cell‐Laden Gradient Hydrogel Scaffolds for Neovascularization of Engineered Tissues
Authors: Yusheng J. He, Martin F. Santana, Austeja Staneviciute, Marja B. Pimentel, Feipeng Yang, Jacob Goes, Keigo Kawaji, Marcella K. Vaicik, Rayan Abdulhadi, Narutoshi Hibino, Georgia Papavasiliou
Journal: Advanced Healthcare Materials (2021)

Abstract Gradients in mechanical properties, physical architecture and biochemical composition exist in a variety of complex tissues, yet 3D in vitro models that enable investigation of these cues on cellular processes, especially those contributing to vascularization of engineered tissues are limited. Here, a photopolymerization approach to create cell‐laden hydrogel biomaterials with decoupled and combined gradients in modulus, immobilized cell adhesive peptide (RGD) concentration, and proteolytic degradation enabling spatial encapsulation of vascular spheroids is reported to elucidate their impact on vascular sprouting in 3D culture. Vascular spheroids encapsulated in these gradient scaffolds exhibit spatial variations in total sprout length. Scaffolds presenting an immobilized RGD gradient promote biased vascular sprouting toward increasing RGD concentration. Importantly, biased sprouting is found to be dependent on immobilized RGD gradient characteristics, including magnitude and slope, with increases in these factors contributing to significant enhancements in biased sprouting responses. Conversely, reduction in biased sprouting responses is observed in combined gradient scaffolds possessing opposing gradients in RGD and modulus. The presented work is the first to demonstrate the use of a cell‐laden biomaterial platform to systematically investigate the role of multiple scaffold gradients as well as gradient slope, magnitude and orientation on vascular sprouting responses in 3D culture.
Role of gut microbiota in regulating gastrointestinal dysfunction and motor symptoms in a mouse model of Parkinson’s disease
Authors: Yogesh Bhattarai, Jie Si, Meng Pu, Owen A. Ross, Pamela J. McLean, Lisa Till, William Moor, Madhusudan Grover, Karunya K. Kandimalla, Kara G. Margolis, Gianrico Farrugia, Purna C. Kashyap
Journal: Gut Microbes (2021)

Parkinson's disease (PD) is a common neurodegenerative disorder characterized primarily by motor and non-motor gastrointestinal (GI) deficits. GI symptoms' including compromised intestinal barrier function often accompanies altered gut microbiota composition and motor deficits in PD. Therefore, in this study, we set to investigate the role of gut microbiota and epithelial barrier dysfunction on motor symptom generation using a rotenone-induced mouse model of PD. We found that while six weeks of 10 mg/kg of chronic rotenone administration by oral gavage resulted in loss of tyrosine hydroxylase (TH) neurons in both germ-free (GF) and conventionally raised (CR) mice, the decrease in motor strength and coordination was observed only in CR mice. Chronic rotenone treatment did not disrupt intestinal permeability in GF mice but resulted in a significant change in gut microbiota composition and an increase in intestinal permeability in CR mice. These results highlight the potential role of gut microbiota in regulating barrier dysfunction and motor deficits in PD.
Evaluation of the effect of store-and-forward teledermatology on in-person health care system utilization in a safety-net public health and hospital system
Authors: Lawrence W. Wu, Sung K. Cho, Bahir Chamseddin, John Ashworth, Linda S. Hynan, Benjamin F. Chong, Arturo R. Dominguez
Journal: Journal of the American Academy of Dermatology (2021)
Donald John Macleod
Authors: Ian Alexander Macleod
Journal: BMJ (2021)

Donald John Macleod (“John”) was born in Thurso, the second of four sons to parents who were both native Gaelic speakers from the island of Lewis. The family moved to the Maryhill area in Glasgow, where as a child John witnessed severe poverty. He could recall seeing children standing barefoot in the snow begging for crusts of bread.

Bilingual at school, a native Gaelic speaker, and a lively boy, John excelled. He did work experience in the accident and emergency department at Glasgow Royal Infirmary while still at school. On his first visit to “Gate” at Glasgow Royal Infirmary, he was given a scalpel and told to incise an abscess.

He studied medicine at Glasgow University, where he was awarded many merit certificates and formed many friendships.

On the night of the Clydebank blitz, John walked for miles in the darkened city with a red glow in the sky, checking on the welfare of family and friends The day after the blitz, he sat his professional exams, and he remembered students from the Clydebank area arriving late …
Psychological impact of genetic and clinical screening for pulmonary fibrosis on asymptomatic first-degree relatives of affected individuals
Authors: Nikkola Carmichael, Jose M Martinez Manzano, Luisa D Quesada-Arias, Sergio de Frías Poli, Maura Alvarez Baumgartner, Maria A Planchart Ferretto, Lisa DiGianni, Shannon Gampala-Sagar, Dominick A Leone, Swati Gulati, Souheil Y El-Chemaly, Hilary J Goldberg, Rachel Putman, Hiroto Hatabu, Ivan O Rosas, Gary M Hunninghake, Benjamin A Raby
Journal: Thorax (2021)

Screening for pulmonary fibrosis may help to identify early stages of the disease. We assessed the psychological impact of screening undiagnosed first-degree relatives of patients with pulmonary fibrosis by administering two validated measures after participants received their results: the Decisional Regret Scale and the Feelings About genomiC Testing Results Questionnaire. More than 90% of relatives reported either no or mild decisional regret. Increased measures of decisional regret and negative feelings were present in those found to have a low diffusion capacity of carbon monoxide or interstitial lung abnormalities. Results of telomere length and genetic testing did not significantly impact regret.
SAT0184 Screening for osteoporosis by calcaneus ultrasonography in ankylosing spondylitis
Authors: TT Jansen, MH Aarts, GA Bruyn, S Zanen
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Ankylosing spondylitis (AS) is a chronic rheumatic disorder resulting in axial deformation due to (osteo)sclerosis and postinflammatory vertebral decalcification. Therefore measuring axial bone density is complicated in AS. Limited data are available on the potential role of quantitative ultrasound (QUS) for screening of osteo-porosis in a high-risk patient group with AS. We evaluated test characteristics of Sahara calcaneus QUS by comparison with data from dual-energy X-ray absorptiometry (DEXA) in AS. <h3>Objectives</h3> <h3>Methods</h3> From July 1999 up to July 2000, 39 consecutive AS patients were recruited, after informed consent, at the Outpatient Department Rheumatology of Leeuwarden/Zwolle. All patients had Sahara calcaneus QUS (hologic) and DEXA (hologic/lunar) with an interval of less than 3 mos. <h3>Results</h3> 12 female, 27 male AS patients, mean age 49 yr (SD:12 yr), mean SI score 3.3–3.3 (0–4) were assessed: AS duration &gt; 10 yrs: n = 29, &lt;9 yrs: n = 10. HLA B27 positivity in 88%. Mean (SD) bone density was 532 (114) in calcaneus using Sahara QUS, 838 (112) in femoral column using DEXA, and 615 (178) in Ward's using DEXA. Pearson correlation of estimated calcaneal density using QUS – lumbar AP T score is 0.41 (p &lt; 0.05), and QUS – Ward's T score 0.36 (p &lt; 0.05). <h3>Conclusion</h3> In our study population pretest probability for axial/femoral osteopenia increases 18–19%; pretest probability for axial osteoporosis increases 30% using T &lt;-1.0 in calcaneus QUS. Prior to applying QUS for screening of osteoporosis in high-risk populations as AS a further improvement of QUS is warranted.