tbuckley/cabot-search huggingface dataset:
The risk of myocardial infarction, stroke, and revascularization among patients with psoriasis treated with apremilast compared with biologics and disease-modifying antirheumatic drugs: A cohort study in the US MarketScan database
Authors: Rebecca Persson, Katrina Wilcox Hagberg, Yiran Qian, Catherine Vasilakis-Scaramozza, Susan Jick
Journal: Journal of the American Academy of Dermatology (2020)
PET scan quantitative analysis in identifying vascular invasion and type of pathology in pancreatic cancer
Authors: Samah Mohamed, Samah Mohamed, Zsolt Lengyel, Ibnouf Sulieman, Ahmed Elaffandi, Ahmed Elaffandi, Mahmoud Saleh, Walid Elmoghazy, Walid Elmoghazy, Hatem Khalaf
Journal: International Journal of Surgery (2020)
Abstract P4-06-12: Understanding how precancerous lesions progress to breast cancer using mouse models
Authors: Wen Bu, Weiyu Jiang, Yi Li
Journal: Cancer Research (2020)

Abstract There are distinct cell subpopulations in normal epithelial tissue, including stem cells, progenitor cells, and more differentiated cells, all of which have been extensively studied for their susceptibility to tumorigenesis and intertumoral heterogeneity. However, normal cells usually have to progress through a precancerous lesion state before becoming a full-blown tumor. Precancerous early lesions are heterogeneous too. It remains unclear whether distinct subsets of precancerous cells contribute to the eventual cancer and intertumoral heterogeneity. By using mouse models of breast cancer that are tailored to address this question, we demonstrated that both precancerous stem cells (PcSCs) and more differentiated cells in the precancerous lesion can be induced to form cancer readily upon introduction of constitutively active versions of either HRAS or BRAF. However, the resulting tumors were dramatically different in protein profiles and histopathology: PcSCs gave rise to adenocarcinoma while more differentiated precancerous cells yielded metaplastic carcinoma with severe squamous differentiation and more robust activation of MEK/ERK signaling. In contrast, constitutively activated PIK3CA caused both PcSCs and more differentiated precancerous cells to progress into adenocarcinoma. Therefore, both cell types in precancerous lesions and the genetic mutations that these cells suffer contribute to the characteristics of the resulting cancer. This work identifies previously unknown players in cancer heterogeneity and suggests that cancer prevention should target precancerous cells broadly and not be limited to PcSC. Citation Format: Wen Bu, Weiyu Jiang, Yi Li. Understanding how precancerous lesions progress to breast cancer using mouse models [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-12.
Abstract P1-18-06: Targetable ERBB2 mutations independently predict an aggressive phenotype in primary, ERBB2 non-amplified, hormone receptor positive lobular breast cancer
Authors: Sasagu Kurozumi, Andrew R Green, Ian O Ellis, Emad A Rakha, Takaaki Fujii, Ken Shirabe, David Heery, Wilbert Zwart, Steffi Oesterreich, Simon J Johnston
Journal: Cancer Research (2020)

Abstract Invasive lobular carcinoma accounts for 10-15% of breast cancer cases and typically expresses hormone receptors. Despite this, lobular tumours respond less well to endocrine therapy, and long-term patient outcomes are inferior to those with other breast cancer subtypes. In primary lobular tumours, HER2 is rarely overexpressed due to relative infrequency of ERBB2 amplification. However, somatic mutation of ERBB2 may provide an alternative and tractable mechanism for upregulation of HER2 activity, which can be effectively targeted using a second generation HER2/EGFR tyrosine kinase inhibitor such as neratinib. In this study we performed comparative in silico analysis of ER/PR(+), HER2(-) cases of invasive lobular (N=352) and ductal carcinoma (N=1,820) from the three largest primary breast cancer clinical datasets with somatic mutations called from next generation sequencing (TCGA, METABRIC and MSK, N=2,172). Using existing functional data from in vitro, cell line and xenograft experiments, ERBB2 mutations were stratified into known ‘oncogenic‘ or ‘uncharacterized‘ and integrated with lymph node status, tumour size and grade. The primary endpoint was overall survival as these data were available across datasets. We find that lobular tumours comprise 11% of all cases but contain 40% of the somatic mutations in ERBB2 in the dataset. The overall rate of mutated ERBB2 in lobular cases is 6% (N=21) versus 1.8% (N=32) in ductal cases (p&amp;lt;0.0001). Using a Cox regression model, we show that oncogenic ERBB2 mutation status independently predicts overall poor survival only in lobular cases (HR 3.6, 95% CI 1.57 - 8.26; p=0.0026). For patients with lobular disease, overall survival was significantly lower if tumours harboured oncogenic ERBB2 mutation (median 64 versus 170 months, p&amp;lt;0.0002). We conclude that ERBB2 mutations are enriched in ERBB2 non-amplified, ER/PR(+) lobular tumours and predict poor outcome despite use of adjuvant endocrine therapy according to standard protocols. Targeted sequencing of ERBB2 should be available for patients with lobular breast cancer and represents an actionable strategy to improve patient outcomes. Citation Format: Sasagu Kurozumi, Andrew R Green, Ian O Ellis, Emad A Rakha, Takaaki Fujii, Ken Shirabe, David Heery, Wilbert Zwart, Steffi Oesterreich, Simon J Johnston. Targetable ERBB2 mutations independently predict an aggressive phenotype in primary, ERBB2 non-amplified, hormone receptor positive lobular breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-06.
The impact of unplanned school closure on children’s social contact: rapid evidence review
Authors: Samantha K Brooks, Louise E Smith, Rebecca K Webster, Dale Weston, Lisa Woodland, Ian Hall, G James Rubin
Journal: Eurosurveillance (2020)

Background Emergency school closures are often used as public health interventions during infectious disease outbreaks to minimise the spread of infection. However, if children continue mixing with others outside the home during closures, the effect of these measures may be limited. Aim This review aimed to summarise existing literature on children’s activities and contacts made outside the home during unplanned school closures. Methods In February 2020, we searched four databases, MEDLINE, PsycInfo, Embase and Web of Science, from inception to 5 February 2020 for papers published in English or Italian in peer-reviewed journals reporting on primary research exploring children’s social activities during unplanned school closures. Main findings were extracted. Results A total of 3,343 citations were screened and 19 included in the review. Activities and social contacts appeared to decrease during closures, but contact remained common. All studies reported children leaving the home or being cared for by non-household members. There was some evidence that older child age (two studies) and parental disagreement (two studies) with closure were predictive of children leaving the home, and mixed evidence regarding the relationship between infection status and such. Parental agreement with closure was generally high, but some disagreed because of perceived low risk of infection and issues regarding childcare and financial impact. Conclusion Evidence suggests that many children continue to leave home and mix with others during school closures despite public health recommendations to avoid social contact. This review of behaviour during unplanned school closures could be used to improve infectious disease modelling.
Tuberculosis Preventive Treatment Scale-Up Among Antiretroviral Therapy Patients — 16 Countries Supported by the U.S. President’s Emergency Plan for AIDS Relief, 2017–2019
Authors: Michael Melgar, Catherine Nichols, J. Sean Cavanaugh, Hannah L. Kirking, Diya Surie, Anand Date, Sevim Ahmedov, Susan Maloney, Rena Fukunaga, Ho Thi Van Anh, Peter R. Kerndt, Deus Lukoye, Daniel Magesa, Talent Maphosa, Magdalene M. Mayer, Katlego Motlhaoleng, Bethrand Odume, Munyaradzi Pasipamire, Sarah Porter, Ahmed Saadani Hassani, James Simpungwe, Edwin Sithole, Herman Weyenga, Gabriel Ekali, Clorata Gwanzura, Isaya Jelly, Muthoni Karanja, Patrick Lungu, Gugulethu Madonsela, Dorothy Maloboka, Ivan Manhiça, Do Thi Nhan, Stavia Turyahabwe, Emperor Ubochioma, Kgomotso Vilakazi Nhlapo, Thomas Webhale
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Tuberculosis preventive treatment (TPT) decreases morbidity and mortality among persons living with human immunodeficiency virus infection but remains underutilized. The U.S. President's Emergency Plan for AIDS Relief has committed to providing TPT to all eligible persons receiving antiretroviral therapy by 2021.
Abstract P3-02-12: CAV1, MCT1, and MCT4 expression in ductal carcinoma in situ of the breast and its association with clinicopathologic features
Authors: Ji Shin Lee, Nah Ihm Kim, Min Ho Park
Journal: Cancer Research (2020)

Abstract Background: Multicompartment tumor metabolism and metabolic coupling are markers of aggressive tumor behavior, clinically manifested as disease recurrence and progression. Loss of caveolin-1(CAV1) in stromal cells and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, in both stromal and cancer cells have been identified as playing an important role in the metabolic coupling necessary for release and uptake of metabolites. However, this phenomenon has only scarcely been described in ductal carcinoma in situ (DCIS) of the breast. The purpose of this study was to investigate the role of CAV1, MCT1, and MCT4 in DCIS carcinogenesis and its association with clinicopathologic factors. Materials and methods: CAV1, MCT1, and MCT4 expression was examined in 9 pairs of DCIS tissues and matched normal adjacent tissues at mRNA and protein levels by qRT-PCR, RNAscope in situ hybridization (ISH) and immunohistochemistry. Immunohistochemical staining of CAV1, MCT1, and MCT4 was done in 79 DCIS samples with known hormone receptor (HR) and human epidermal growth factor 2 (HER2) expression using tissue microarray. Results: CAV1 mRNA expression by qRT-PCR analysis was significantly decreased in DCIS tissues compared to their corresponding normal tissues. On the other hand, MCT1 and MCT4 mRNA expression in DCIS tissues were increased compared with corresponding normal tissues and the difference was statistically significant in MCT1. Compared with their corresponding normal tissues, DCIS tissues showed decreased stromal CAV1 mRNA and protein expression and increased epithelial MCT1 and MCT4 mRNA and protein expression by ISH and immunohistochemistry. Low stromal CAV1, high epithelial MCT1, and high epithelial MCT4 expressions were observed in 29 (36.7%), 51 (64.6%) and 15 (18.9%) cases with DCIS, respectively. Low stromal CAV1 expression was significantly associated with high nuclear grade (P &amp;lt; 0.05). High epithelial MCT4 expression was associated with larger tumor size and HER2 positivity (P &amp;lt; 0.05 and P &amp;lt; 0.05, respectively). Although not statistically significant, low stromal CAV1 and high epithelial MCT4 expression tended to be associated with recurrence of DCIS. No associations were observed between stromal CAV1 expression and epithelial MCT 1 or MCT4 expression. Conclusions: These results suggested that changes in CAV1, MCT1, and MCT4 are associated with carcinogenesis of DCIS, and further studies are needed for their clinical usefulness. Keywords: Ductal carcinoma in situ; CAV1; MCT1; MCT4; Metabolism Citation Format: Ji Shin Lee, Nah Ihm Kim, Min Ho Park. CAV1, MCT1, and MCT4 expression in ductal carcinoma in situ of the breast and its association with clinicopathologic features [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-12.
Covid-19: doctors’ visas are automatically extended for one year
Authors: Abi Rimmer
Journal: BMJ (2020)

Hypoglycaemia remains a serious and much feared complication of insulin therapy. In this study, patients attending an accident and emergency department in hypoglycaemic coma were randomized to treatment with either intravenous dextrose (25g) or intramuscular glucagon (1mg), administered into the right thigh. Restoration of normal conscious level was slower after glucagon than dextrose (9.0 vs 3.0 min, P less than 0.01), although the average duration of hypoglycaemic coma was 120 min. Two patients in the glucagon-treated group, who failed to show satisfactory recovery after 15 min, required additional treatment with intravenous dextrose. On questioning following recovery, all except two patients reported loss of awareness of the onset of hypoglycaemia Intramuscular glucagon is valuable in the treatment of severe hypoglycaemia outwith hospital and, although the slightly slower and less predictable recovery may appear to make it a less attractive option than intravenous dextrose in the accident and emergency department, this must be balanced against the advantages of ease of administration and a lower incidence of serious adverse effects.
Abstract P1-01-08: Optical metabolic imaging of the effects of acute and intermittent hypoxia in murine breast cancer cells
Authors: Lisa Rebello, Narasimhan Rajaram
Journal: Cancer Research (2020)

Abstract About 90% of the patients diagnosed with breast cancer succumb due to metastases and not from primary tumor. There are currently few methods that can distinguish indolent and aggressive breast tumors. Recent studies have shown differences in the metabolic profiles of primary, circulating, and metastatic breast cancer cells. One of the key regulators of metastases in breast cancer is the transcription factor Twist. The goal of our study was to determine the relationship between Twist expression and cellular metabolism, and the effect of this relationship on metastatic potential. Multiphoton microscopy can provide non-invasive, label-free and reproducible measurements of cellular metabolism. An optical redox ratio of endogenous fluorescence from nicotinamide adenine dicnucleotide (NADH) and flavin adenine dinucleotide (FAD) (calculated as FAD/NADH+FAD) can reflect the balance between mitochondrial oxidative phosphorylation and glucose catabolism in the cell. Because hypoxia is known to promote metastasis, we studied the effect of both intermittent and acute hypoxia on cellular metabolism in 4T1 murine breast cancer cells. We generated a 4T1-Twist− cell line using CRISPR-Cas9 technology. Western blots of Twist protein expression confirmed that Twist expression was significantly lower in the selected cell population compared with the parental 4T1 line. Both cell lines were exposed to 0.5% oxygen for 3 hours and one hour of reoxygenation (acute hypoxia), and 3 cycles of one-hour hypoxia followed by one-hour reoxygenation (intermittent hypoxia). Multiphoton imaging of endogenous fluorescence as well as metabolic flux analysis (Seahorse Biosciences) was performed for both hypoxic exposures in both cell lines. Our results indicate a significant increase in the optical redox ratio in 4T1 cells when exposed to acute hypoxia, indicating a possible increase in oxidative metabolism. There were no signfiicant differences in the 4T1-Twist− line. On the other hand, we observed a decrease in the optical redox ratio in response to intermittent hypoxia in the 4T1 cells and the opposite effect in the 4T1-Twist− line. In addition to these cell lines, we will also present data from sibling cell lines of the 4T1 with varying Twist levels and hence metastatic potential. These data indicate indicate potentially measurable metabolic differences between indolent and aggressive breast cancer cells when subject to a hypoxia-reoxygenation regimen. Citation Format: Lisa Rebello, Narasimhan Rajaram. Optical metabolic imaging of the effects of acute and intermittent hypoxia in murine breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-01-08.
CircFOXK2 Promotes Growth and Metastasis of Pancreatic Ductal Adenocarcinoma by Complexing with RNA-Binding Proteins and Sponging MiR-942
Authors: Chi Hin Wong, Ut Kei Lou, Youjia Li, Stephen L. Chan, Joanna HM Tong, Ka-Fai To, Yangchao Chen
Journal: Cancer Research (2020)

Abstract The detailed biological functions of circular RNA (circRNA) are largely unexplored. Using circRNA sequencing, we identified 169 differentially expressed circRNA in pancreatic ductal adenocarcinoma (PDAC) cells compared with nontumor human pancreatic ductal epithelial cells. Among them, circFOXK2 was validated with significant upregulation in PDAC cells and 63% of primary tumors (53 of 84). circFOXK2 promoted cell growth, migration, and invasion and was involved in cell-cycle progression and apoptosis. circFOXK2 contained multiple miRNA binding sites, functioning as a sponge for miR-942, which in turn promoted expression of ANK1, GDNF, and PAX6. A novel and highly specific circRNA-pulldown followed by mass spectrometry analysis identified 94 circFOXK2-interacting proteins, which were involved in cell adhesion, mRNA splicing, and structural molecule activity. Of these, circFOKX2 interactions with YBX1 and hnRNPK enhanced expression of oncogenes NUF2 and PDXK. Knockdown of circFOXK2 reduced binding of YBX1 and hnRNPK to NUF2 and PDXK, in turn decreasing their expression. Collectively, our findings demonstrate that circFOXK2 in complex with YBX1 and hnRNPK promotes expression of oncogenic proteins that contribute to PDAC progression. Significance: This study reveals a prominent role for the circRNA circFOXK2 in PDAC progression, suggesting that circFOXK2 might be a novel diagnostic marker for PDAC.
Abstract I15: Deciphering the origins of PDAC development
Authors: Brittany Flowers, Hang Xu, Kathryn Hanson, Christina Curtis, Hannes Vogel, Laura D. Wood, Laura D. Attardi
Journal: Cancer Research (2019)

Abstract The TP53 gene, encoding the p53 transcription factor, is mutated in the majority of human pancreatic cancers, underscoring its critical role as a barrier to PDAC development. Despite this essential function, however, the cellular and molecular pathways through which p53 acts in pancreatic cancer suppression have remained elusive. To gain a better understanding of the programs through which p53 suppresses PDAC development, which will provide key insight into how the disease develops, we have taken combined mouse genetic and genomic approaches. First, we have sought to understand whether p53 acts in acinar and/or ductal cells to restrain PDAC development. For these studies we have used adult mice to more accurately mimic the development of PDAC in humans. Second, we have sought to systematically deconstruct the role of p53 loss-of-function and gain-of-function mutations in driving cancer from these different cells of origin. In addition, we have characterized the trajectory of cancer development in these models through histologic analysis of lesions at different time points and through lineage tracing. This comprehensive analysis of large adult mouse cohorts has helped to define the role for p53 in restraining spontaneous PDAC development, an essential first step for understanding p53 programs involved in tumor suppression. To gain insight into the programs that become dysregulated during pancreatic cancer development, we have performed transcriptomic analysis on tumors arising from different compartments and driven by different genetic lesions. These studies have revealed the molecular profiles of tumors arising from acinar versus ductal cells as well those driven by different types of p53 mutations. Through comparison to human pancreatic cancer data, our studies will reveal the paths to PDAC development in humans and the underlying origins of different subtypes of this disease. Citation Format: Brittany Flowers, Hang Xu, Kathryn Hanson, Christina Curtis, Hannes Vogel, Laura D. Wood, Laura D. Attardi. Deciphering the origins of PDAC development [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I15.
Covid-19: UK deaths are higher than previously reported, new data suggest
Authors: Gareth Iacobucci
Journal: BMJ (2020)

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Effect of GenX on P-Glycoprotein, Breast Cancer Resistance Protein, and Multidrug Resistance–Associated Protein 2 at the Blood–Brain Barrier
Authors: Ronald E. Cannon, Alicia C. Richards, Andrew W. Trexler, Christopher T. Juberg, Birandra Sinha, Gabriel A. Knudsen, Linda S. Birnbaum
Journal: Environmental Health Perspectives (2020)

BACKGROUND: Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acid (GenX) is a replacement for perfluorooctanoic acid in the production of fluoropolymers used in a variety of consumer products.GenX alters fetal development and antibody production and elicits toxic responses in the livers and kidneys of rodents.The GenX effect on the blood-brain barrier (BBB) is unknown.The BBB protects the brain from xenobiotic neurotoxicants and harmful endogenous metabolites.OBJECTIVES: We aimed to investigate the effects of GenX on the transport activity and expression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) at the BBB.METHODS: Transporter activities were measured in isolated rat brain capillaries by a confocal microscopy-based method.ATPase (enzymatic hydrolysis of adenosine triphosphate to inorganic phosphate) levels were measured in vitro.Western blotting determined P-gp and BCRP protein levels.Cell survival after GenX exposure was determined for two human cell lines.RESULTS: Nanomolar levels of GenX inhibited P-gp and BCRP but not MRP2 transport activities in male and female rat brain capillaries.P-gp transport activity returned to control levels after GenX removal.GenX did not reduce P-gp-or BCRP-associated ATPase activity in an in vitro transport assay system.Reductions of P-gp but not BCRP transport activity were blocked by a peroxisome proliferator-activated receptor c (PPARc) antagonist.GenX reduced P-gp and BCRP transport activity in human cells.CONCLUSION: In rats, GenX at 0:1-100 nM rapidly (in 1-2 h) inhibited P-gp and BCRP transport activities at the BBB through different mechanisms.PPARc was required for the GenX effects on P-gp but not BCRP transport activity.
Sestrins induce natural killer function in senescent-like CD8+ T cells
Authors: Branca I. Pereira, Roel P. H. De Maeyer, Luciana P. Covre, Djamel Nehar-Belaid, Alessio Lanna, Sophie Ward, Radu Marches, Emma S. Chambers, Daniel C. O. Gomes, Natalie E. Riddell, Mala K. Maini, Vitor H. Teixeira, Samuel M. Janes, Derek W. Gilroy, Anis Larbi, Neil A. Mabbott, Duygu Ucar, George A. Kuchel, Sian M. Henson, Jessica Strid, Jun H. Lee, Jacques Banchereau, Arne N. Akbar
Journal: Nature Immunology (2020)