tbuckley/cabot-search huggingface dataset:
Correction of recessive dystrophic epidermolysis bullosa by homology-directed repair-mediated genome editing
Authors: Jose Bonafont, Angeles Mencía, Esteban Chacón-Solano, Wai Srifa, Sriram Vaidyanathan, Rosa Romano, Marta Garcia, Rosario Hervás-Salcedo, Laura Ugalde, Blanca Duarte, Matthew H. Porteus, Marcela Del Rio, Fernando Larcher, Rodolfo Murillas
Journal: Molecular Therapy (2021)

Genome-editing technologies that enable the introduction of precise changes in DNA sequences have the potential to lead to a new class of treatments for genetic diseases. Epidermolysis bullosa (EB) is a group of rare genetic disorders characterized by extreme skin fragility. The recessive dystrophic subtype of EB (RDEB), which has one of the most severe phenotypes, is caused by mutations in COL7A1. In this study, we report a gene-editing approach for ex vivo homology-directed repair (HDR)-based gene correction that uses the CRISPR-Cas9 system delivered as a ribonucleoprotein (RNP) complex in combination with donor DNA templates delivered by adeno-associated viral vectors (AAVs). We demonstrate sufficient mutation correction frequencies to achieve therapeutic benefit in primary RDEB keratinocytes containing different COL7A1 mutations as well as efficient HDR-mediated COL7A1 modification in healthy cord blood-derived CD34+ cells and mesenchymal stem cells (MSCs). These results are a proof of concept for HDR-mediated gene correction in different cell types with therapeutic potential for RDEB. Genome-editing technologies that enable the introduction of precise changes in DNA sequences have the potential to lead to a new class of treatments for genetic diseases. Epidermolysis bullosa (EB) is a group of rare genetic disorders characterized by extreme skin fragility. The recessive dystrophic subtype of EB (RDEB), which has one of the most severe phenotypes, is caused by mutations in COL7A1. In this study, we report a gene-editing approach for ex vivo homology-directed repair (HDR)-based gene correction that uses the CRISPR-Cas9 system delivered as a ribonucleoprotein (RNP) complex in combination with donor DNA templates delivered by adeno-associated viral vectors (AAVs). We demonstrate sufficient mutation correction frequencies to achieve therapeutic benefit in primary RDEB keratinocytes containing different COL7A1 mutations as well as efficient HDR-mediated COL7A1 modification in healthy cord blood-derived CD34+ cells and mesenchymal stem cells (MSCs). These results are a proof of concept for HDR-mediated gene correction in different cell types with therapeutic potential for RDEB.
Susceptibility-Associated Genetic Variation in <i>NEDD9</i> Contributes to Prostate Cancer Initiation and Progression
Authors: Dong Han, Jude N. Owiredu, Bridget M. Healy, Muqing Li, Maryam Labaf, Jocelyn S. Steinfeld, Susan Patalano, Shuai Gao, Mingyu Liu, Jill A. Macoska, Kourosh Zarringhalam, Kellee R. Siegfried, Xin Yuan, Timothy R. Rebbeck, Changmeng Cai
Journal: Cancer Research (2021)

Although American men of European ancestry represent the largest population of patients with prostate cancer, men of African ancestry are disproportionately affected by prostate cancer, with higher prevalence and worse outcomes. These racial disparities in prostate cancer are due to multiple factors, but variations in genomic susceptibility such as SNP may play an important role in determining cancer aggressiveness and treatment outcome. Using public databases, we have identified a prostate cancer susceptibility SNP at an intronic enhancer of the neural precursor expressed, developmentally downregulated 9 (
Validation of the 2019 ACR/EULAR criteria for IgG4-related disease in a Japanese kidney disease cohort: a multicentre retrospective study by the IgG4-related kidney disease working group of the Japanese Society of Nephrology
Authors: Takako Saeki, Tasuku Nagasawa, Yoshifumi Ubara, Yoshinori Taniguchi, Motoko Yanagita, Shinichi Nishi, Michio Nagata, Yutaka Yamaguchi, Takao Saito, Hitoshi Nakashima, Mitsuhiro Kawano
Journal: Annals of the Rheumatic Diseases (2021)

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect various organs. The kidney is one of the organs most frequently affected and IgG4-related tubulointerstitial nephritis (TIN) is the most dominant feature.1 However, several radiologically characteristic lesions within the kidney have also been shown to be diagnostic for IgG4-RD affecting the kidney, in the setting of definitively diagnosed IgG4-related lesions in extrarenal organs.2 Therefore the term ‘IgG4-related kidney disease (IgG4-RKD)’ has been proposed as a comprehensive term for the renal lesions associated with IgG4-RD.2 3

In 2011, the IgG4-RKD working group of the Japanese Society of Nephrology proposed diagnostic criteria for IgG4-RKD.4 Recently, we validated those criteria in a Japanese kidney cohort and developed a revised version.5 On the other hand, the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for IgG4-RD (the ACR/EULAR criteria) were proposed in 2019.6 According to the latter criteria, exclusion criteria should be applied first to any potential IgG4-RD case. Then, inclusion criteria consisting of eight weighted domains are applied to any case that does not satisfy any of the exclusion criteria, and if …
Re: Nicolas Mottet, Roderick C.N. van den Bergh, Erik Briers, et al. EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer—2020 Update. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2021;79:243–62
Authors: Michael Froehner, Rainer Koch, Markus Graefen
Journal: European Urology (2021)
Using deep learning for dermatologist-level detection of suspicious pigmented skin lesions from wide-field images
Authors: Luis R. Soenksen, Timothy Kassis, Susan T. Conover, Berta Marti-Fuster, Judith S. Birkenfeld, Jason Tucker-Schwartz, Asif Naseem, Robert R. Stavert, Caroline C. Kim, Maryanne M. Senna, José Avilés-Izquierdo, James J. Collins, Regina Barzilay, Martha L. Gray
Journal: Science Translational Medicine (2021)

A reported 96,480 people were diagnosed with melanoma in the United States in 2019, leading to 7230 reported deaths. Early-stage identification of suspicious pigmented lesions (SPLs) in primary care settings can lead to improved melanoma prognosis and a possible 20-fold reduction in treatment cost. Despite this clinical and economic value, efficient tools for SPL detection are mostly absent. To bridge this gap, we developed an SPL analysis system for wide-field images using deep convolutional neural networks (DCNNs) and applied it to a 38,283 dermatological dataset collected from 133 patients and publicly available images. These images were obtained from a variety of consumer-grade cameras (15,244 nondermoscopy) and classified by three board-certified dermatologists. Our system achieved more than 90.3% sensitivity (95% confidence interval, 90 to 90.6) and 89.9% specificity (89.6 to 90.2%) in distinguishing SPLs from nonsuspicious lesions, skin, and complex backgrounds, avoiding the need for cumbersome individual lesion imaging. We also present a new method to extract intrapatient lesion saliency (ugly duckling criteria) on the basis of DCNN features from detected lesions. This saliency ranking was validated against three board-certified dermatologists using a set of 135 individual wide-field images from 68 dermatological patients not included in the DCNN training set, exhibiting 82.96% (67.88 to 88.26%) agreement with at least one of the top three lesions in the dermatological consensus ranking. This method could allow for rapid and accurate assessments of pigmented lesion suspiciousness within a primary care visit and could enable improved patient triaging, utilization of resources, and earlier treatment of melanoma.
COVID-19 Outbreak Among Attendees of an Exercise Facility — Chicago, Illinois, August–September 2020
Authors: Frances R. Lendacki, Richard A. Teran, Stephanie Gretsch, Marielle J. Fricchione, Janna L. Kerins
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

the Chicago Department of Public Health (CDPH) was notified of a potential outbreak of coronavirus disease 2019 (COVID-19) at an exercise facility.COVID-19 cases were identified among 55 (68%) of 81 attendees of in-person classes held during August 24-September 1, 2020, including 49 (60%) cases confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) testing and six (7%) probable cases among attendees who had compatible symptoms but negative or no RT-PCR test results.Overall, 43 (78%) attendees with COVID-19 participated in multiple classes while potentially infectious.*Twenty-two (40%) attendees with COVID-19 attended on or after the day of symptom onset.Among 58 exercise class attendees who provided information on in-class behaviors, 44 (76%) reported infrequent mask use, including 32 of 38 (84%) attendees with COVID-19 and 12 of 20 (60%) without COVID-19.The increased respiratory exertion that occurs in the enclosed spaces of indoor exercise facilities facilitates transmission of SARS-CoV-2, the virus that causes COVID-19, in these settings (1,2).To reduce SARS-CoV-2 transmission in exercise facilities, employees and patrons should wear a mask, even during high-intensity activities when ≥6 ft apart.In addition, facilities should provide engineering and administrative controls including 1) improving ventilation; 2) enforcing consistent and correct mask use and physical distancing (maintaining ≥6 ft of distance between all persons and limiting physical contact, class size, and crowded spaces); 3) reminding infected employees and patrons to stay home and away from others for ≥10 days after symptom onset or, if asymptomatic, after a positive test result, as well as to observe quarantine guidance after close contact with a person with COVID-19 and while awaiting test results; and 4) increasing opportunities for hand hygiene.Conducting exercise activities entirely outdoors or virtually could further reduce SARS-CoV-2 transmission risk.* The infectious period was presumed to begin 2 days before symptom onset or positive SARS-CoV-2 test result, whichever was known to be first, and presumed to end ≥10 days after symptom onset or positive test result as long as other symptoms (except loss of taste or smell) were improving and the patient had been fever-free for 24 hours without fever-reducing medication.https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/end-home-isolation.html
Ian Guy Lloyd
Authors: Ian Christopher Lloyd, Brian Pike
Journal: BMJ (2021)

Ian Guy Lloyd was born in Fatfield, County Durham, a village near Sunderland. His father, Alfred Guy Lloyd, was a GP in the area—one of a long line of family doctors. His mother, Honora Patricia, was the daughter of a prominent local businessman who had been a mayor of Durham.

Ian was bright and good at sport. At Douai School in Berkshire, he was a key member of the schools very successful first rugby XV. He went on to represent his county in both rugby and tennis.

He took up a place to read medicine in Newcastle in 1954—in those days part of Durham University. He enjoyed medical school, played rugby for the Newcastle Medicals first XV, alongside his cousin, Ricky Oliver (a dental student). After qualifying he worked in junior posts at the Royal Victoria Infirmary, Newcastle, and Sunderland General Hospital. He met and fell in love with Kathleen Grange, a student nurse in Newcastle. After marrying her in …
Greenness may improve lung health in low–moderate but not high air pollution areas: Seven Northeastern Cities’ study
Authors: Yang Zhou, Dinh S Bui, Jennifer L Perret, Adrian J Lowe, Caroline J Lodge, Iana Markevych, Joachim Heinrich, Michael S Bloom, Luke D Knibbs, Bin Jalaludin, Bo-Yi Yang, Hong-Yao Yu, Xiao-Wen Zeng, Yunjiang Yu, Shyamali C Dharmage, Guang-Hui Dong
Journal: Thorax (2021)

Introduction There is growing interest in the impact of greenness exposure on airway diseases, but the impact of greenness on lung function in children is limited. We aimed to investigate the associations between greenness surrounding schools and lung function in children and whether these associations are modified by air pollution exposure. Methods Between 2012 and 2013, a cross-sectional survey and spirometry were performed among 6740 school children. Lung function patterns were determined as obstructive forced expiratory volume 1 s/forced vital capacity (FEV 1 /FVC &lt;0.8) or restrictive (FEV 1 /FVC ≥0.8 but FVC &lt;80% of predicted). School greenness was defined by Normalized difference vegetation index (NDVI) and soil-adjusted vegetation index. Nitrogen dioxide, sulphur dioxide and particular matter concentrations were assessed using a spatiotemporal model and national monitoring data. Two-level generalised linear models were used to investigate associations and interactions. Results Overall, an IQR in NDVI within 500 m was associated with higher FEV 1 (+57 mL 95% CI 44 to 70) and FVC (+58 mL 95% CI 43 to 73). NDVI was similarly associated with 25% reduced odds of spirometric restriction (OR: 0.75, 95% CI 0.65 to 0.86). However, among children exposed to the highest compared with the lowest quartile of particulate matter, increasing NDVI was paradoxically associated with lower −40 mL FVC (95% CI −47 to –33, p interaction &lt;0.05). Discussion Our findings suggest that, in this study population, greening urban areas may promote lung health in low–moderate pollution areas but not in high air pollution areas. If the findings are replicated in other moderate-to-high pollution settings, this highlights a need to have a flexible green policy.
Phosphorylation of SMAD3 in immune cells predicts survival of patients with early stage non-small cell lung cancer
Authors: Sebastian Marwitz, Carmen Ballesteros-Merino, Shawn M Jensen, Martin Reck, Christian Kugler, Sven Perner, Daniel Drömann, Torsten Goldmann, Bernard A Fox
Journal: Journal for ImmunoTherapy of Cancer (2021)

The interplay of immune and cancer cells takes place in the tumor microenvironment where multiple signals are exchanged. The transforming growth factor beta (TGFB) pathway is known to be dysregulated in lung cancer and can impede an effective immune response. However, the exact mechanisms are yet to be determined. Especially which cells respond and where does this signaling take place with respect to the local microenvironment. Human non-small cell lung cancer samples were retrospectively analyzed by multiplexed immunohistochemistry for SMAD3 phosphorylation and programmed death ligand 1 expression in different immune cells with respect to their localization within the tumor tissue. Spatial relationships were studied to examine possible cell-cell interactions and analyzed in conjunction with clinical data. TGFB pathway activation in CD3, CD8, Foxp3 and CD68 cells, as indicated by SMAD3 phosphorylation, negatively impacts overall and partially disease-free survival of patients with lung cancerindependent of histological subtype. A high frequency of Foxp3 regulatory T cells positive for SMAD3 phosphorylation in close vicinity of CD8 T cells within the tumor discriminate a rapidly progressing group of patients with lung cancer. TGFB pathway activation of local immune cells within the tumor microenvironment impacts survival of early stage lung cancer. This might benefit patients not eligible for targeted therapies or immune checkpoint therapy as a therapeutic option to re-activate the local immune response.
Abstract PS16-28: Runx3 regulates emt during development lapatinib resistance
Authors: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Yoonjung Park, Yu Jin Kim, Seock-Ah Im
Journal: Cancer Research (2021)

Abstract RUNX3 regulates EMT during development lapatinib resistanceBackground: Lapatinib is a small molecular inhibitor of HER2 and EGFR tyrosine kinase, which is used for HER2 positive metastatic breast cancer patients. However, significant proportion of patients relapse due to acquired resistance. The epithelial to mesenchymal transition (EMT), which induces cell migration, invasion and cancer stem cell progression, was one of the mechanism that confers to drug resistance. We determined the correlation of lapatinib resistance and EMT, and identified a regulatory factor of EMT which associated with the development process of acquired lapatinib resistance.Methods: Acquired lapatinib resistant SK-BR-3 (SK-BR-3 LR) cells were established by continuously exposing to lapatinib for 7 months. The sensitivity of lapatinib was confirmed by MTT assay. Cell cycle progression was verified using flow cytometry analysis. Expression of signal transduction molecules were determined using quantitative PCR, western blotting and transcriptome data analysis. Cell migration and invasion ability were verified using wound healing assay and Boyden chamber assay. siRNA knock-down system were used for further analysis. Results: Lapatinib resistant (SK-BR-3 LR) cells showed aggressive morphology compared with parental cells. The growth rate and cell cycle progression were increased in SK-BR-3 LR cells. Expression of Snail, Vimentin, SOX2, Nanog, TGF-b1 and Smad proteins increased in SK-BR-3 LR cells. In SK-BR-3 LR cells, cell migration and invasion were significantly increased. Correlated with a promoter methylation of RUNX3, expression of RUNX3 was down-regulated in SK-BR-3 LR cells. In Runx3 knock-down cells TGF-b1, SOX2, smad molecules were up-regulated. Conclusion: SK-BR-3 LR cells showed aggressive phenotype. Expression of EMT markers, cancer stem cell markers, TGF-β pathway associated molecules and Smad proteins were increased in SK-BR-3 LR cells. Also, the increase of cell migration and invasion was observed in LR cells. RUNX3 affected to cell migration and invasion through regulation of EMT associated molecules. Therefore, RUNX3 might be a specified molecule, which partially contributes resistance to lapatinib through regulates EMT. Citation Format: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Yoonjung Park, Yu Jin Kim, Seock-Ah Im. Runx3 regulates emt during development lapatinib resistance [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-28.
Paracardial fat and vitamin A: a mechanism for regulating exercise performance
Authors: Leroy C. Joseph, John P. Morrow
Journal: Journal of Clinical Investigation (2021)

Different fat depots have different physiologic functions. In a provocative study published in this issue of the JCI, Petrosino et al. investigate the role of paracardial fat in whole-body metabolism and exercise physiology. Petrosino et al. show that paracardial fat samples from older mice or mice fed a Western diet had decreased levels of alcohol dehydrogenase 1 (ADH1). Paracardial fat samples from humans with obesity also had decreased levels of ADH1 mRNA, supporting the translational relevance. Additional experiments with Adh1-KO mice and surgical fat transplantation experiments provide additional mechanistic insight. Paracardial fat may regulate exercise performance by altering circulating metabolites and/or endocrine effects. ADH1 appears to regulate the mitochondrial content of paracardial fat, a mechanism mediated by retinaldehyde. When ADH1 is active, the paracardial fat has characteristics of brown fat, which is beneficial for exercise performance. Further research is warranted to determine the translational potential of these findings, such as whether removing paracardial fat at the time of open-heart surgery might improve recovery time by increasing exercise capacity.
Improving Value in Bronchiolitis Care
Authors: Alan R. Schroeder, Julia A. Marlow, Chris P. Bonafide
Journal: JAMA Network Open (2021)

Promoting high value care.Safely doing less.Deimplementing overused interventions.These aspirational concepts are increasingly being invoked in health care as we strive for better outcomes delivered within a system free of ineffective, unnecessary, and wasteful practices.The most immediate, obvious targets of these calls to action are high-frequency, non-evidence based interventions for high-prevalence conditions.As such, bronchiolitis, a leading cause of hospitalization and urgent care and emergency department visits in young children, has been a prime target.Bronchiolitis is common, costly, and frequently triggers a downstream cascade of testing and treatment.Four of the five 2013 Pediatric Hospital Medicine Choosing Wisely recommendations involve bronchiolitis care, 1 highlighting the pervasive sentiment that all too often we fail hospitalized children with bronchiolitis by delivering ineffective, wasteful, and potentially harmful care.Two recent studies provide valuable information on progress to date.The study by House et al 2 reviewed temporal trends in nonrecommended therapies, and the study by Stollar et al 3 provided further insights into one of the more vexing issues-overreliance on pulse oximetry.
FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non–small Cell Lung Cancer, A Collaborative Project Orbis Review
Authors: Paz J. Vellanki, Flora Mulkey, Adnan A. Jaigirdar, Lisa Rodriguez, Yibo Wang, Yuan Xu, Hong Zhao, Jiang Liu, Grant Howe, Jian Wang, Qiuyi Choo, Sarah J. Golding, Victoria Mansell, Kwadwo Korsah, Dianne Spillman, R. Angelo de Claro, Richard Pazdur, Julia A. Beaver, Harpreet Singh
Journal: Clinical Cancer Research (2021)

On May 26, 2020, the FDA approved nivolumab with ipilimumab and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. The approval was based on results from Study CA2099LA (CheckMate 9LA), an open-label trial in which 719 patients with NSCLC were randomized to receive nivolumab with ipilimumab and two cycles of chemotherapy (n = 361) or four cycles of platinum-doublet chemotherapy (n = 358). Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.1 months [95% confidence interval (CI), 13.2-16.2] compared with 10.7 months (95% CI, 9.5-12.5) for patients who received chemotherapy (HR, 0.69; 96.71% CI, 0.55-0.87; P = 0.0006). Progression-free survival and overall response rate per blinded independent central review were also statistically significant. This was the first NSCLC application reviewed under FDA's Project Orbis, in collaboration with Singapore's Health Sciences Authority, Australia's Therapeutic Goods Administration, and Health Canada. The benefit-risk analysis supports FDA's approval of nivolumab with ipilimumab and chemotherapy.
Monocyte chemoattractant-1 (MCP-1), secreted by bone marrow endothelial cells, induces chemoattraction of multiple myeloma cells.
Authors: Karin Vanderkerken, I. Vande Broeck, Decio Eizerik, Els Van Valckenborgh, Kewal Asosingh, Benjamin Van Camp, Ivan Van Riet
Journal: Blood (2000)