tbuckley/cabot-search huggingface dataset:
Risks to Bangladeshi children and young people during covid-19 outbreak
Authors: Md Sazedur Rahman, Zohra S Lassi, Sheikh Mohammad Shariful Islam
Journal: BMJ (2020)

<h3>Objective</h3> To examine the cross-sectional association between illicit sales of tobacco to minors, Washington DC tobacco outlet advertising practices, retail store type, the demographic make-up of the area surrounding each outlet, and the proximity of each outlet to high schools, recreational parks and public housing. <h3>Participants</h3> Seven hundred and fifty tobacco outlets in the DC area, n=347 of which were randomly selected for inspection by the Synar Inspection Program in 2009–2010. <h3>Main outcome measures</h3> The presence of tobacco advertisements on the interior and exterior of each outlet, and illicit tobacco sales to Synar Inspection Program youth volunteers. <h3>Results</h3> The presence of tobacco advertisements on the exterior of gas stations was much greater than on other retail store types (OR=6.68; 95% CI 4.05 to 11.01), as was the absence of any advertisements at bars or restaurants that sold tobacco (OR=0.33; 95% CI 0.22 to 0.52). Exterior tobacco advertisements were also more likely in predominantly African–American areas of the city (OR=3.11; 95% CI 2.28 to 4.25), and particularly likely on storefronts located closer to parks (OR=1.87; 95% CI 1.06 to 3.28). Illicit sales to minors were more common at gas stations (OR=3.01; 95% CI 1.5 to 6.3), outlets that displayed exterior tobacco advertisements closer to parks (OR=3.36; 95% CI 1.38 to 8.21), and outlets located closer to high schools in majority African–American block groups (OR=1.29; 95% CI 1.07 to 1.58). <h3>Conclusions</h3> Findings demonstrate that while illicit tobacco sales to minors are occurring at acceptably low rates by Synar standards, illicit sales vary considerably by retail store type, advertising approach and proximity to high schools, parks and African–American residential areas. Future work may help inform regulatory efforts to reduce youth access at the neighbourhood, city, state and national levels.
Home noninvasive positive-pressure ventilation reduces mortality and intubations in COPD with hypercapnia
Authors: Matthew B. Stanbrook
Journal: Annals of Internal Medicine (2020)

Wilson ME, Dobler CC, Morrow AS, et al. Association of home noninvasive positive pressure ventilation with clinical outcomes in chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2020;323:455-65. 32016309.
Targeted Heating of Mitochondria Greatly Augments Nanoparticle‐Mediated Cancer Chemotherapy
Authors: Jiangsheng Xu, James G. Shamul, Hai Wang, John Lin, Pranay Agarwal, Mingrui Sun, Xiongbin Lu, Katherine H. R. Tkaczuk, Xiaoming He
Journal: Advanced Healthcare Materials (2020)

Abstract Cancer is the second leading cause of mortality globally. Various nanoparticles have been developed to improve the efficacy and safety of chemotherapy, photothermal therapy, and their combination for treating cancer. However, most of the existing nanoparticles are low in both subcellular precision and drug loading content (&lt;≈5%), and the effect of targeted heating of subcellular organelles on the enhancement of chemotherapy has not been well explored. Here, a hybrid Py@Si‐TH nanoparticle is reported to first target cancer cells overexpressed with the variant CD44 via its natural ligand HA on the outermost surface of the nanoparticle before cellular uptake, and then target mitochondria after they are taken up inside cells. In addition, the nanoparticle is ultraefficient for encapsulating doxorubicin hydrochloride (DOX) to form Py@Si‐TH‐DOX nanoparticle. The encapsulation efficiency is ≈100% at the commonly used low feeding ratio of 1:20 (DOX:empty nanoparticle), and &gt;80% at an ultrahigh feeding ratio of 1:1. In combination with near infrared (NIR, 808 nm) laser irradiation, the tumor weight in the Py@Si‐TH‐DOX treatment group is 8.5 times less than that in the Py@Si‐H‐DOX (i.e., DOX‐laden nanoparticles without mitochondrial targeting) group, suggesting targeted heating of mitochondria is a valuable strategy for enhancing chemotherapy to combat cancer.
Lineage Reversion Drives WNT Independence in Intestinal Cancer
Authors: Teng Han, Sukanya Goswami, Yang Hu, Fanying Tang, Maria Paz Zafra, Charles Murphy, Zhen Cao, John T. Poirier, Ekta Khurana, Olivier Elemento, Jaclyn F. Hechtman, Karuna Ganesh, Rona Yaeger, Lukas E. Dow
Journal: Cancer Discovery (2020)

The WNT pathway is a fundamental regulator of intestinal homeostasis, and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer. To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that although WNT suppression blocks tumor growth in most organoid and in vivo colorectal cancer models, the accumulation of colorectal cancer-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of TP53 and SMAD4, transient TGFβ exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work identifies genetic and microenvironmental factors that drive WNT inhibitor resistance, defines a new mechanism for WNT-independent colorectal cancer growth, and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs. SIGNIFICANCE: Colorectal and intestinal cancers are driven by mutations in the WNT pathway, and drugs aimed at suppressing WNT signaling are in active clinical development. Our study identifies a mechanism of acquired resistance to WNT inhibition and highlights a potential strategy to target those drug-resistant cells.This article is highlighted in the In This Issue feature, p. 1426.
Early safety indicators of COVID-19 convalescent plasma in 5000 patients
Authors: Michael J. Joyner, R. Scott Wright, DeLisa Fairweather, Jonathon W. Senefeld, Katelyn A. Bruno, Stephen A. Klassen, Rickey E. Carter, Allan M. Klompas, Chad C. Wiggins, John R.A. Shepherd, Robert F. Rea, Emily R. Whelan, Andrew J. Clayburn, Matthew R. Spiegel, Patrick W. Johnson, Elizabeth R. Lesser, Sarah E. Baker, Kathryn F. Larson, Juan G. Ripoll, Kylie J. Andersen, David O. Hodge, Katie L. Kunze, Matthew R. Buras, Matthew N.P. Vogt, Vitaly Herasevich, Joshua J. Dennis, Riley J. Regimbal, Philippe R. Bauer, Janis E. Blair, Camille M. Van Buskirk, Jeffrey L. Winters, James R. Stubbs, Nigel S. Paneth, Nicole C. Verdun, Peter Marks, Arturo Casadevall
Journal: Journal of Clinical Investigation (2020)

BACKGROUND. Convalescent plasma is the only antibody-based therapy currently available for patients with coronavirus disease 2019 (COVID-19). It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19.
Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial
Authors: Panagiotis A Konstantinopoulos, Su-Chun Cheng, Andrea E Wahner Hendrickson, Richard T Penson, Susan T Schumer, L Austin Doyle, Elizabeth K Lee, Elise C Kohn, Linda R Duska, Marta A Crispens, Alexander B Olawaiye, Ira S Winer, Lisa M Barroilhet, Siqing Fu, Michael T McHale, Russell J Schilder, Anniina Färkkilä, Dipanjan Chowdhury, Jennifer Curtis, Roxanne S Quinn, Brittany Bowes, Alan D D'Andrea, Geoffrey I Shapiro, Ursula A Matulonis
Journal: The Lancet Oncology (2020)
Dynamic cytokine profiles combined with enzyme-linked immunospot assay are useful for immunologically confirming the dapsone hypersensitivity syndrome
Authors: Jiabao You, Lele Sun, Qing Zhao, Huimin Zhang, Pengcheng Huai, Gongqi Yu, Zhenzhen Wang, Zihao Mi, Zheng Pang, Hong Liu, Furen Zhang
Journal: Journal of the American Academy of Dermatology (2020)
Heme induces rapid endothelial barrier dysfunction via the MKK3/p38MAPK axis
Authors: Joel James, Anup Srivastava, Mathews Valuparampil Varghese, Cody A. Eccles, Marina Zemskova, Olga Rafikova, Ruslan Rafikov
Journal: Blood (2020)

Abstract Several studies demonstrate that hemolysis and free heme in circulation cause endothelial barrier dysfunction and are associated with severe pathological conditions such as acute respiratory distress syndrome, acute chest syndrome, and sepsis. However, the precise molecular mechanisms involved in the pathology of heme-induced barrier disruption remain to be elucidated. In this study, we investigated the role of free heme in the endothelial barrier integrity and mechanisms of heme-mediated intracellular signaling of human lung microvascular endothelial cells (HLMVECs). Heme, in a dose-dependent manner, induced a rapid drop in the endothelial barrier integrity of HLMVECs. An investigation into barrier proteins revealed that heme primarily affected the tight junction proteins zona occludens-1, claudin-1, and claudin-5, which were significantly reduced after heme exposure. The p38MAPK/HSP27 pathway, involved in the regulation of endothelial cytoskeleton remodeling, was also significantly altered after heme treatment, both in HLMVECs and mice. By using a knockout (KO) mouse for MKK3, a key regulator of the p38MAPK pathway, we showed that this KO effectively decreased heme-induced endothelial barrier dysfunction. Taken together, our results indicate that targeting the p38MAPK pathway may represent a crucial treatment strategy in alleviating hemolytic diseases.
Abstract B32: Impact of cancer-associated fibroblasts on head and neck cancer stem cells
Authors: Molly E. Heft Neal, John Henry J. Owen, Matthew E. Spector, Thomas E. Carey, Mark E.P. Prince, Steven B. Chinn
Journal: Clinical Cancer Research (2020)

Abstract Background: The tumor microenvironment (TME) is made up of epithelial cancer cells and mesenchymal stromal cells including tumor-infiltrating lymphocytes, cancer-associated fibroblasts (CAFs) and endothelial cells. Within the cancer cell population are cancer stem cells (CSC), a subpopulation of cells defined as having the capacity for self-renewal, tumorigenesis, and the ability to recapitulate a heterogeneous tumor. The interaction of the TME with cancer cells remains of interest. The focus of this study is to investigate the effect of patient-derived CAFs on head and neck CSC and tumor activity. Methods: Patient-derived head and neck cancer cell lines and patient-derived fibroblasts lines have previously been established by our group. Tumor cells were grown alone or in combination with patient-matched fibroblasts in a coculture chamber system, allowing for mixture of media but not cells. Scratch tests were performed and closure rates were compared between the two conditions (tumor cells alone and coculture). Tumor cells were then grown alone or in direct contact with matched fibroblasts for one week. Cancer cells were selected for based on epithelial cell adhesion molecule (EpCAM) status and in vitro tumor growth and stem cells percentages (defined as proportion of CD44-high and ALDH-positive cells) were calculated. Results: Patient-derived cancer cells cocultured with matched fibroblasts showed a significant increase in closure rates compared with tumor cells alone at three defined time points (p=0.03-0.002). Coculture conditions resulted in greater in vitro tumor growth after one week (6.4-fold vs. 3.7-fold increase) and an increased proportion of CD44-high tumor cells (9% vs. 5%). The effect of coculture on ALDH-positive percentages was variable. Conclusion: CAFs have previously been shown to potentiate tumorigenesis and metastases. We validated these findings with matched patient derived tumor cells and CAFs. We were then able to demonstrate that CAFs increase the proportion of head and neck CSC, suggesting the mechanism for CAF-associated increased tumor activity may be mediated through CSC. Further studies investigating the relationship between CAFs and CSC are warranted. Citation Format: Molly E. Heft Neal, John Henry J. Owen, Matthew E. Spector, Thomas E. Carey, Mark E.P. Prince, Steven B. Chinn. Impact of cancer-associated fibroblasts on head and neck cancer stem cells [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 B32.
Abstract PR07: WEE1 inhibition triggers premature mitotic entry in HPV16-E6-expressing cells independent of p53 inactivation
Authors: Ahmed Diab, Jherek Swanger, Hakan Gem, Denise Galloway, Eduardo Mendez, Julia Sidorova, Bruce Clurman
Journal: Clinical Cancer Research (2020)

Abstract Inhibition of the protein kinase WEE1 induces cancer cell death by forcing cells arrested in S-phase directly into mitosis. However, in the absence of S-phase perturbations, WEE1 inhibition is typically insufficient to trigger premature mitosis. Here, we show that WEE1 inhibition alone drives premature mitotic entry in HPV+ head and neck cancer cells. We also observed unscheduled mitotic entry in E6- and E6E7-expressing HPV-negative UMSCC74a cells upon WEE1 inhibition, but not in empty vector controls. Unlike E6 expression, p53 depletion alone was not sufficient to cooperate with WEE1 inhibition to effect forced mitotic entry. In vitro kinase assays showed elevated CDK1 activity in E6 and E6E7 cells compared to empty vector controls, particularly after WEE1 inhibition. We find that addiction of E6E7 cells to cell cycle inhibitor p21 causes the AZD1775-mediated CDK hyperactivation, therefore intensifying genotoxic replication stress. WEE1 inhibition therefore exacerbates E6E7-associated replication stress leading to slowing of replication forks, excess single-stranded DNA, and elevated RPA loading. RPA depletion further sensitized E6E7 cells to WEE1 inhibition-induced ssDNA accumulation, DNA damage, and cell death, implying a role for RPA in limiting WEE1i-induced replication stress in E6E7-expressing cells. Hallmarks of replication stress and DNA damage persisted in E6E7-expressing cells after recovery from WEE1 inhibition. These observations collectively explain the unique hypersensitivity of HPV+ head and neck tumors to WEE1i. Citation Format: Ahmed Diab, Jherek Swanger, Hakan Gem, Denise Galloway, Eduardo Mendez, Julia Sidorova, Bruce Clurman. WEE1 inhibition triggers premature mitotic entry in HPV16-E6-expressing cells independent of p53 inactivation [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 PR07.
FRI0276 EARLY TREATMENT WITH ANTI-TNF IS ASSOCIATED WITH HIGHER RESPONSE RATES IN PATIENTS WITH ACTIVE AXSPA
Authors: S. Gulle, İ. Sari, E. Durak Ediboglu, H. Candan, F. Onen, S. Akar
Journal: Annals of the Rheumatic Diseases (2020)

Background: Treatment options for axial spondyloarthritis (axSpA) is currently limited, and up to 40% of the patients require biologic therapies to control symptoms. Early commencement of biologics suggested to have higher response rates but data regarding this subject is limited. Objectives: The primary aim was to investigate tumor necrosis factor inhibitor (TNFi) response and retention rates in axSpA patients who were treated in the early disease period (symptom duration (≤5 years). Our secondary aim was to identify factors predicting response to TNFi. Methods: Adult axial SpA patients who started TNFi treatments within the five years of their symptoms were identified and defined as “Group 1”. Patients whose TNFi treatments started five years after their initial symptoms served as a control group (Group 2: 5-10 years and Group3: ≥10 years). Response and survival rates at 6, 12, and 24 months were calculated. Predictors of response on TNFi survival at 24 months were also analyzed. Results: There was a total of 364 axiSpA (Group 1: 95, Group 2: 82 and Group 3: 187) patients in the study (69.8% male, 46.8±12.6 years). Group 1 patients tended to be younger, with a lower baseline CRP titers and lower HLA–B27 rate compared to the other groups. Drug survival rates were similar between the groups. This finding also remained similar when AS and nraxSpA patients analyzed separately. However, regardless of symptom duration, the drug retention rates were significantly higher in the AS group than in nraxSpA (Table 2). ASAS40 responses were higher in Group 1 than in Group 3 both at 12 and 24 months. Predictors of response based on ASAS40 at 24 months were treatment within the five years of the symptoms (OR:2.2) and age at baseline (OR:0.97) in univariate analysis. However, baseline ASDAS (OR:1.4) was the only factor in multiple regression. Conclusion: In this study we showed the following: 1) TNFi started in the early disease course resulted in a better ASAS40 response at both 12 and 24 months, 2) TNFi timing (started in the early or late disease period) seems not affecting drug retention rates, and 3) baseline disease activity is the most important predictor in achieving ASAS40 response at 24 months. Disclosure of Interests: None declared
Mesoporous Silica Particles: Entrapping Digestive Enzymes with Engineered Mesoporous Silica Particles Reduces Metabolic Risk Factors in Humans (Adv. Healthcare Mater. 11/2020)
Authors: Erik R. Waara, Muhammad N. Iqbal, Ghislaine Robert‐Nicoud, Boubacar Benziane, Helen Vallhov, Agata M. Wasik, Maria Lindgren, Emilia Hagman, Mia Rinde, Natalia Kupferschmidt, Roger Berlin, Eric V. Johnston, Pernilla Danielsson, Tore Bengtsson
Journal: Advanced Healthcare Materials (2020)

In article number 202000057, Tore Bengtsson and co-workers report that oral intake of mesoporous silica particles (MSP) reduce glycated hemoglobin and low-density lipoprotein in healthy individuals with obesity. Preclinical investigations show sequestration of pancreatic a-amylase and lipase by MSP, suggesting that MSP lowers digestive enzymes availability in the small intestine, resulting in decreased digestion of macronutrients and reduced caloric uptake.
Ventilation–perfusion SPECT <i>versus</i> CTPA in young adult females with suspected pulmonary embolism
Authors: Sofie Lindskov Hansen, Robin de Nijs, Jann Mortensen, Ronan M.G. Berg
Journal: European Respiratory Journal (2020)

We read with interest the "2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism" developed by the European Society for Cardiology (ESC) in collaboration with the European Respiratory Society [1]. An important question addressed in the 2019 ESC Guidelines, which is also discussed in the recently updated guideline on ventilation–perfusion (VQ) scintigraphy from the European Association of Nuclear Medicine (EANM) [2], is whether computed tomography pulmonary angiography (CTPA) or VQ scintigraphy should be the diagnostic method of choice in suspected pulmonary embolism. This quandary is notably pertinent in young female adults who are at an increased risk of pulmonary embolism due to oral contraceptive use or pregnancy, and we would like to add to the discussion in relation to this patient group by raising specific points relating to the diagnostic performance and radiation exposure of VQ scintigraphy versus CTPA. Ventilation–perfusion SPECT should be preferred over CTPA in young adult females with suspected pulmonary embolism <https://bit.ly/2XYWdJ7>
Routine vaccination during covid-19 pandemic response
Authors: Sonia Saxena, Helen Skirrow, Helen Bedford
Journal: BMJ (2020)

Routine vaccination of pregnant women and children must remain a priority during the covid-19 pandemic response.The UK and other countries could experience outbreaks of measles and other vaccine preventable diseases if uptake of routine vaccinations falls, undoing decades of progress.Vaccination has been one of the most effective interventions in driving down infant mortality to historically low levels worldwide.Complete, timely vaccination protects and confers benefits across the whole of childhood.However, this protection is greatly reduced if vaccine schedules are delayed or incomplete. 1In the UK, almost 95% of infants have completed their primary vaccinations by their first birthday, 2 but uptake of later childhood vaccines and seasonal flu and whooping cough vaccines recommended in pregnancy, varies from year to year. 3 4 Uptake is lower in inner cities, in deprived postcodes, and among some minority ethnic groups. 3 Disease epidemics can disrupt healthcare and cause resurgence of vaccine preventable infections. 5In 2019, the UK lost its measles "elimination status" because of outbreaks resulting from historical low vaccine uptake. 6hildren risk becoming unseen victims of the covid-19 pandemic.
Age-dependent effects in the transmission and control of COVID-19 epidemics
Authors: Nicholas G. Davies, Petra Klepac, Yang Liu, Kiesha Prem, Mark Jit, Carl A. B. Pearson, Billy J. Quilty, Adam J. Kucharski, Hamish Gibbs, Samuel Clifford, Amy Gimma, Kevin van Zandvoort, James D. Munday, Charlie Diamond, W. John Edmunds, Rein M. G. J. Houben, Joel Hellewell, Timothy W. Russell, Sam Abbott, Sebastian Funk, Nikos I. Bosse, Yueqian Fiona Sun, Stefan Flasche, Alicia Rosello, Christopher I. Jarvis, Rosalind M. Eggo
Journal: Nature Medicine (2020)
Cardiac Tumors
Authors: Sara Tyebally, Daniel Chen, Sanjeev Bhattacharyya, Abdallah Mughrabi, Zeeshan Hussain, Charlotte Manisty, Mark Westwood, Arjun K. Ghosh, Avirup Guha
Journal: JACC CardioOncology (2020)

Cardiac masses are rare, but remain an important component of cardio-oncology practice. These include benign tumors, malignant tumors (primary and secondary) and tumor-like conditions (e.g., thrombus, Lambl's excrescences, and pericardial cyst). The advent of multimodality imaging has enabled identification of the etiology of cardiac masses in many cases, especially in conjunction with information from clinical settings. This paper provides a comprehensive review of the epidemiology, clinical presentation, imaging, diagnosis, management, and outcomes of cardiac masses.
Abstract IA14: Targeting the DNA damage response in head and neck cancers
Authors: Timothy A. Yap
Journal: Clinical Cancer Research (2020)

Abstract The discovery that BRCA1/2 mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase (PARP) has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumor agents targeting the DNA damage response (DDR) has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK, and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, including head and neck cancer. These approaches have involved evaluation of molecular predictive biomarker of response beyond BRCA1/2 mutations, and the development of rational, tolerable combinations with novel molecularly targeted agents to create a BRCAness phenotype, other DDR inhibitors, and immune-checkpoint inhibitors. Citation Format: Timothy A. Yap. Targeting the DNA damage response in head and neck cancers [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 IA14.