tbuckley/cabot-search huggingface dataset:
Abstract 457: Protein Arginine Methyltransferase-1 is Required for Epicardial Epithelial-to-Mesenchymal Transition
Authors: Olan Jackson-Weaver, Jian Wu, Yongchao Gou, Shihong Shi, Henry Sucov, Jian Xu
Journal: Circulation Research (2016)

Rationale: Epicardial epithelial-to-mesenchymal trasition (EMT) is a vital process in embryonic heart development. During EMT, epicardial cells acquire migratory and invasive properties, and differentiate into new cell types, including cardiac fibroblasts and coronary smooth muscle cells. EMT is characterized by an increase in mesenchymal proteins such as Slug and Fibronectin, and a decrease in cell-junction proteins such as E-Cadherin, and is dependent on TGF-β signaling. We have recently demonstrated that protein arginine methyltransferase-1 (PRMT1) is necessary for TGF-β family signaling and EMT in non-epicardial cell types. Objective: To determine the role of PRMT1 in epicardial EMT. Methods and Results: We investigated the role of PRMT1 in epicardial EMT in mouse epicardial cells. PRMT1 siRNA prevented the increase in Slug and Fibronectin and the decrease in E-Cadherin in TGF-β treatment-induced EMT of mouse epicardial cell line MEC1. PRMT1 siRNA also reduced the migration and invasion of MEC1 cells. These results demonstrate that PRMT1 is required for epicardial EMT. In WT1-Cre ERT ;ROSA-YFP fl/fl mouse embryos, PRMT1 siRNA reduced epicardial EMT in a thorax culture model. Among the key transcription factors that regulate the EMT program, Slug, but not Snail, is specifically regulated by PRMT1. We further identified that PRMT1 siRNA also increased the expression of p53, a key regulator of the Slug degradation pathway. PRMT1 siRNA increases p53 expression by decreasing p53 degradation, and shifted p53 localization to the cytoplasm. In vitro methylation assays further demonstrated that PRMT1 methylates p53. Knockdown of p53 increased Slug levels and enhanced EMT, establishing p53 as a regulator of epicardial EMT through controlling Slug expression. Conclusions: The PRMT1-p53-Slug pathway is necessary for epicardial EMT in cultured MEC1 cells as well as in the epicardium ex vivo .
Quantitative <i>In Vivo</i> Analyses Reveal a Complex Pharmacogenomic Landscape in Lung Adenocarcinoma
Authors: Chuan Li, Wen-Yang Lin, Hira Rizvi, Hongchen Cai, Christopher D. McFarland, Zoe N. Rogers, Maryam Yousefi, Ian P. Winters, Charles M. Rudin, Dmitri A. Petrov, Monte M. Winslow
Journal: Cancer Research (2021)

Abstract The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most critical gaps in enabling the effective use of cancer therapies. Here, we couple a multiplexed and quantitative experimental platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. The complex map of genotype-specific treatment responses uncovered that over 20% of possible interactions show significant resistance or sensitivity. Known and novel interactions were identified, and one of these interactions, the resistance of KEAP1-mutant lung tumors to platinum therapy, was validated using a large patient response data set. These results highlight the broad impact of tumor suppressor genotype on treatment responses and define a strategy to identify the determinants of precision therapies. Significance: An experimental and analytical framework to generate in vivo pharmacogenomic maps that relate tumor genotypes to therapeutic responses reveals a surprisingly complex map of genotype-specific resistance and sensitivity.
Nasal Cauterization with Silver Nitrate for Recurrent Epistaxis
Authors: David A. Gudis, Zachary M. Soler
Journal: New England Journal of Medicine (2021)

Most epistaxis is isolated or self-limited, but it is recurrent in approximately 16% of the general population, many of whom seek medical advice. This video demonstrates the evaluation of a patient with recurrent epistaxis and the technique used to perform nasal cauterization with silver nitrate in the office.
Effect of the covid-19 pandemic in 2020 on life expectancy across populations in the USA and other high income countries: simulations of provisional mortality data
Authors: Steven H Woolf, Ryan K Masters, Laudan Y Aron
Journal: BMJ (2021)

To estimate changes in life expectancy in 2010-18 and during the covid-19 pandemic in 2020 across population groups in the United States and to compare outcomes with peer nations.Simulations of provisional mortality data.US and 16 other high income countries in 2010-18 and 2020, by sex, including an analysis of US outcomes by race and ethnicity.Data for the US and for 16 other high income countries from the National Center for Health Statistics and the Human Mortality Database, respectively.Life expectancy at birth, and at ages 25 and 65, by sex, and, in the US only, by race and ethnicity. Analysis excluded 2019 because life table data were not available for many peer countries. Life expectancy in 2020 was estimated by simulating life tables from estimated age specific mortality rates in 2020 and allowing for 10% random error. Estimates for 2020 are reported as medians with fifth and 95th centiles.Between 2010 and 2018, the gap in life expectancy between the US and the peer country average increased from 1.88 years (78.66 v 80.54 years, respectively) to 3.05 years (78.74 v 81.78 years). Between 2018 and 2020, life expectancy in the US decreased by 1.87 years (to 76.87 years), 8.5 times the average decrease in peer countries (0.22 years), widening the gap to 4.69 years. Life expectancy in the US decreased disproportionately among racial and ethnic minority groups between 2018 and 2020, declining by 3.88, 3.25, and 1.36 years in Hispanic, non-Hispanic Black, and non-Hispanic White populations, respectively. In Hispanic and non-Hispanic Black populations, reductions in life expectancy were 18 and 15 times the average in peer countries, respectively. Progress since 2010 in reducing the gap in life expectancy in the US between Black and White people was erased in 2018-20; life expectancy in Black men reached its lowest level since 1998 (67.73 years), and the longstanding Hispanic life expectancy advantage almost disappeared.The US had a much larger decrease in life expectancy between 2018 and 2020 than other high income nations, with pronounced losses among the Hispanic and non-Hispanic Black populations. A longstanding and widening US health disadvantage, high death rates in 2020, and continued inequitable effects on racial and ethnic minority groups are likely the products of longstanding policy choices and systemic racism.
<scp>BNT162b2 COVID</scp>‐19 vaccine is significantly less effective in patients with hematologic malignancies
Authors: Katrin Herzog Tzarfati, Odit Gutwein, Arie Apel, Naomi Rahimi‐Levene, Maya Sadovnik, Lotem Harel, Patricia Benveniste‐Levkovitz, Adina Bar Chaim, Maya Koren‐Michowitz
Journal: American Journal of Hematology (2021)

Patients with hematologic malignancies have an increased risk of severe COVID-19 infection. Vaccination against COVID-19 is especially important in these patients, but whether they develop an immune response following vaccination is unknown. We studied serologic responses to the BNT162b2 vaccine in this population. A lower proportion of patients were seropositive following vaccination (75%) than in a comparison group (99%; p < 0.001), and median (interquartile range [IQR]) antibody titers in patients were lower (90 [12.4-185.5] and 173 [133-232] AU/ml, respectively; p < 0.001). Older age, higher lactate dehydrogenase, and number of treatment lines correlated with lower seropositivity likelihood and antibody titers, while absolute lymphocyte count, globulin level, and time from last treatment to vaccination correlated with higher seropositivity likelihood and antibody titers. Chronic lymphocytic leukemia patients had the lowest seropositivity rate followed by indolent lymphoma. Patients recently treated with chemo-immunotherapy, anti-CD20 antibodies, BCL2, BTK or JAK2 inhibitors had significantly less seropositive responses and lower median (IQR) antibody titers (29%, 1.9 [1.9-12] AU/ml; 0%, 1.9 [1.9-1.9] AU/ml; 25%, 1.9 [1.9-25] AU/ml; 40%, 1.9 [1.9-92.8] AU/ml; and 42%, 10.9 [5.7-66.4] AU/ml, respectively; p < 0.001). Serological response to BNT162b2 vaccine in patients with hematologic malignancies is considerably impaired, and they could remain at risk for severe COVID-19 infection and death.
Coronary Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction—Common, Unrecognized, and Prevalent in Patients With or Without Epicardial CAD
Authors: Viviany R. Taqueti
Journal: JAMA Cardiology (2021)

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進行性固形腫瘍患者(pts)における毎3週の1日目および8日目のivスケジュールにおいて投与された新規ドラスタチン10誘導体TZT-1027の第1相および薬物動態研究
Authors: Verweij J, Madretsma S, Van Der Gaast A, Van Doorn L, Lems A, Boot I, Jenner A, Wanders J, Satomi M, De Jonge M
Journal: Clinical Cancer Research (2003)
Maintenance Rituximab after First Line Treatment in Veterans with Follicular Lymphoma Is Associated with Prolonged Overall Survival
Authors: Ahmad S. Halwani, Kelli Rasmussen, Vikas Patil, Zach Burningham, Clarke Low, Carolina M Reyes, Anthony Masaquel, Kevin Henderson, Elisha Delong-Sieg, Brian C Sauer
Journal: Blood (2017)
Systematic review of empirical studies comparing the effectiveness of non-pharmaceutical interventions against COVID-19
Authors: Alba Mendez-Brito, Charbel El Bcheraoui, Francisco Pozo-Martin
Journal: Journal of Infection (2021)

ObjectivesTo evaluate which non-pharmaceutical interventions (NPIs) have been more and less effective in controlling the COVID-19 pandemic.MethodsWe performed a systematic review of published and unpublished empirical studies, either observational or interventional, analysing the comparative effectiveness of NPIs against the COVID-19 pandemic. We searched Embase/Medline and medRxiv to identify the relevant literature.ResultsWe identified 34 studies. During the first wave of the COVID-19 pandemic, school closing was the most effective NPI, followed by workplace closing, business and venue closing and public event bans. Public information campaigns and mask wearing requirements were also effective in controlling the pandemic while being less disruptive for the population than other NPIs. There was no evidence on the effectiveness of public transport closure, testing and contact tracing strategies and quarantining or isolation of individuals. Early implementation was associated with a higher effectiveness in reducing COVID-19 cases and deaths, while general stringency of the NPIs was not.ConclusionsIn this systematic review, we found that school closing, followed by workplace closing, business and venue closing and public event bans were the most effective NPIs in controlling the spread of COVID-19. An early response and a combination of specific social distancing measures are effective at reducing COVID-19 cases and deaths. Continuous monitoring of NPIs effectiveness is needed in order to adapt decision making.
ATR Inhibitors and Paclitaxel in Melanoma
Authors: Alan Ashworth
Journal: Clinical Cancer Research (2021)

Abstract A phase I study defined a tolerable combination of the ATR inhibitor ceralasertib with paclitaxel and responses were seen in patients with melanoma who had progressed on an immune checkpoint inhibitor. This combination warrants further exploration to determine the extent and molecular determinants of clinical activity. See related article by Kim et al., p. 4700
Importance of Coronary Artery Spasm in Ventricular Fibrillation Out-of-Hospital Cardiac Arrest Patients with No Structural Heart Disease
Authors: Hatano Mai, Ito Noritoshi, Tonomura Daisuke, Kurozumi Yuma, Natsukawa Tomoki, Sawano Hirotaka, Kaibe Shouji, Okada Kenichiro, Doi Yasuji, Hayashi Toru
Journal: Circulation (2010)
Abstract 86: Compromised Sarcolemmal Membrane Repair Contributes to the Progression of Heart Failure
Authors: Sayak Bhattacharya, Zhaobin Xu, Liubov Gushchina, Prasanthi Appikatla, Eric X Beck, Jenna Alloush, Ahmet Kilic, Peter J Mohler, Paul M Janssen, Noah Weisleder
Journal: Circulation Research (2016)

A conserved sarcolemmal membrane repair response exist to counteract membrane damage and restore membrane barrier function in order to maintain normal cellular homeostasis. This response can involve various mechanisms including activation of signaling pathways that trigger vesicular trafficking to the site of injury followed by vesicular fusion with the damaged portion of the membrane to patch the membrane disruption. Previous studies indicate that compromised repair capacity can exacerbate cardiac injury while increasing membrane repair capacity can reduce cardiac pathology. In our studies, membrane repair assays on cardiac and non-cardiac cell lines demonstrated that this process is dependent on activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling axis through the downstream target Akt1. One mechanism found to increase membrane repair following PI3K/Akt1 activation is elevated exocytotic and endocytotic activity. Further studies indicate that the PI3K/Akt1 pathway is relevant to membrane repair in native hearts. Thick slices of myocardium from explanted human and mouse hearts were probed using multi-photon microscopy to determine the membrane repair capacity. These studies indicate decreased repair capacity in failing human myocardium as well as in mouse hearts following transaortic constriction (TAC). This membrane repair response requires PI3K/Akt1 signaling as genetically modified mice null for Akt1 show compromised sarcolemmal membrane repair. Additionally, PI3K or Akt1 inhibition prevents membrane resealing in non-failing human or mouse myocardium. The compromised membrane repair observed in failing human myocardium can be ameliorated by PI3K or Akt1 agonists. Treatment of TAC mice with multiple therapeutic compounds known to increase membrane repair capacity can minimize the development of structural and functional hallmarks of heart failure. Our results indicate that failing cardiomyocytes exhibit compromised membrane repair and that increased PI3K/Akt1 signaling can increase repair capacity thereby demonstrating potential as a heart failure treatment.
Assessing the Association Between Social Gatherings and COVID-19 Risk Using Birthdays
Authors: Christopher M. Whaley, Jonathan Cantor, Megan Pera, Anupam B. Jena
Journal: JAMA Internal Medicine (2021)

<h3>Importance</h3> Many policies designed to stop the spread of COVID-19 address formal gatherings, such as workplaces and dining locations. Informal social gatherings are a potentially important mode of SARS-CoV-2 transmission, but studying their role in transmission is challenged by data and methodological limitations; birthdays offer an opportunity to empirically quantify the potential role of small social gatherings in COVID-19 spread. <h3>Objective</h3> To assess the association between social gatherings and SARS-CoV-2 transmission by studying whether COVID-19 rates increase after birthdays in a household. <h3>Design, Setting, and Participants</h3> This cross-sectional study used nationwide data from January 1 to November 8, 2020, from 2.9 million US households with private insurance to compare COVID-19 infections between households with and without a birthday in the preceding 2 weeks, stratified according to county-level COVID-19 prevalence in that week and adjusting for household size and both week- and county-specific differences. The study also compared how birthday-associated infection rates differed by type of birthday (eg, child vs adult birthday, or a milestone birthday such as a 50th birthday), county-level precipitation on the Saturday of each week (which could move gatherings indoors), political leanings in the county, and state shelter-in-place policies. <h3>Main Outcomes and Measures</h3> Household-level COVID-19 infection. <h3>Results</h3> Among the 2.9 million households in the study, in the top decile of counties in COVID-19 prevalence, households with a birthday in the 2 weeks prior had 8.6 more diagnoses per 10 000 individuals (95% CI, 6.6-10.7 per 10 000 individuals) compared with households without a birthday in the 2 weeks prior, a relative increase of 31% above the county-level prevalence of 27.8 cases per 10 000 individuals, vs 0.9 more diagnoses per 10 000 individuals (95% CI, 0.6-1.3 per 10 000 individuals) in the fifth decile (<i>P</i> &lt; .001 for interaction). Households in the tenth decile of COVID-19 prevalence had an increase in COVID-19 diagnoses of 15.8 per 10 000 persons (95% CI, 11.7-19.9 per 10 000 persons) after a child birthday, compared with an increase of 5.8 per 10 000 persons (95% CI, 3.7-7.9 per 10 000 persons) among households with an adult birthday (<i>P</i> &lt; .001 in a test of interactions). No differences were found by milestone birthdays, county political leaning, precipitation, or shelter-in-place policies. <h3>Conclusions and Relevance</h3> This cross-sectional study suggests that birthdays, which likely correspond with social gatherings and celebrations, were associated with increased rates of diagnosed COVID-19 infection within households in counties with high COVID-19 prevalence.
Effect of Oral Ranitidine on Urinary Excretion of<i>N</i>-Nitrosodimethylamine (NDMA)
Authors: Jeffry Florian, Murali K. Matta, Ryan DePalma, Victoria Gershuny, Vikram Patel, Cheng-Hui Hsiao, Robbert Zusterzeel, Rodney Rouse, Kristin Prentice, Colleen Gosa Nalepinski, Insook Kim, Sojeong Yi, Liang Zhao, Miyoung Yoon, Susan Selaya, David Keire, Joyce Korvick, David G. Strauss
Journal: JAMA (2021)

<h3>Importance</h3> In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen<i>N</i>-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption. <h3>Objective</h3> To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo. <h3>Design, Setting, and Participants</h3> Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020. <h3>Interventions</h3> Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA. <h3>Main Outcome and Measure</h3> Twenty-four–hour urinary excretion of NDMA. <h3>Results</h3> Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, −6.9 to 0] ng;<i>P</i> = .54) or a cured-meats diet (median of the paired differences, −1.1 [IQR, −9.1 to 11.5] ng;<i>P</i> = .71). No drug-related serious adverse events were reported. <h3>Conclusions and Relevance</h3> In this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT04397445
Cytomegalovirus mediates expansion of IL-15–responsive innate-memory cells with SIV killing function
Authors: Gema Méndez-Lagares, Ning Chin, W.L. William Chang, Jaewon Lee, Míriam Rosás-Umbert, Hung T. Kieu, David Merriam, Wenze Lu, Sungjin Kim, Lourdes Adamson, Christian Brander, Paul A. Luciw, Peter A. Barry, Dennis J. Hartigan-O’Connor
Journal: Journal of Clinical Investigation (2021)

Interindividual immune variability is driven predominantly by environmental factors, including exposure to chronic infectious agents such as cytomegalovirus (CMV). We investigated the effects of rhesus CMV (RhCMV) on composition and function of the immune system in young macaques. Within months of infection, RhCMV was associated with impressive changes in antigen presenting cells, T cells, and NK cells-and marked expansion of innate-memory CD8+ T cells. These cells express high levels of NKG2A/C and the IL-2 and IL-15 receptor beta chain, CD122. IL-15 was sufficient to drive differentiation of the cells in vitro and in vivo. Expanded NKG2A/C+CD122+CD8+ T cells in RhCMV-infected macaques, but not their NKG2-negative counterparts, were endowed with cytotoxicity against class I-deficient K562 targets and prompt IFN-γ production in response to stimulation with IL-12 and IL-18. Because RhCMV clone 68-1 forms the viral backbone of RhCMV-vectored SIV vaccines, we also investigated immune changes following administration of RhCMV 68-1-vectored SIV vaccines. These vaccines led to impressive expansion of NKG2A/C+CD8+ T cells with capacity to inhibit SIV replication ex vivo. Thus, CMV infection and CMV-vectored vaccination drive expansion of functional innate-like CD8 cells via host IL-15 production, suggesting that innate-memory expansion could be achieved by other vaccine platforms expressing IL-15.