tbuckley/cabot-search huggingface dataset:
The Coronavirus Pandemic 1 Year On—What Went Wrong?
Authors: Lawrence O. Gostin
Journal: JAMA (2021)

January 30, 2021, marked the first anniversary of the declaration by the World Health Organization (WHO) of COVID-19 as a public health emergency of international concern (PHEIC). Thus far, the world has been no match for SARS-CoV-2, with more than 100 million cases and 2.5 million deaths. The US has been among the world’s poorest performers in addressing the pandemic, with more than 500 000 deaths.

Vaccines offer the best chance of returning to normal, but circulating variants pose a major obstacle, particularly the emergence of variants that are more transmissible and are developing partial resistance to vaccines against SARS-CoV-2. With rampant global circulation, SARS-CoV-2 will have ample opportunity to mutate further.

What went wrong and how can society learn from its greatest failures?
Seasonal changes of mite allergen (Der 1) levels in houses with different architectural styles and ventilation systems
Authors: Hideharu Shirai, Hiromichi Yamaguchi, Kohara Yudai, Makoto Yoshida, Junko Ishihara, Jumpei Uchiyama, Masahiho Sakaguchi
Journal: Journal of Allergy and Clinical Immunology (2021)
Prognostic Implications of a Novel Algorithm to Grade Secondary Tricuspid Regurgitation
Authors: Federico Fortuni, Marlieke F. Dietz, Edgard A. Prihadi, Pieter van der Bijl, Gaetano M. De Ferrari, Juhani Knuuti, Jeroen J. Bax, Victoria Delgado, Nina Ajmone Marsan
Journal: JACC. Cardiovascular imaging (2021)
Pediatric Severe Asthmatics in a Southern US State Face Multiple Challenges and Barriers to Care
Authors: Robbie Pesek, Brandi Whitaker, Erhan Ararat, Amika Sood, Matthew Pertzborn, Amber Davidson, Kim Cobb, Kristin Hines, Callie Margiotta, Jessica Turner, Akilah Jefferson, Tamara Perry
Journal: Journal of Allergy and Clinical Immunology (2021)
Early life environmental exposures have a minor impact on the gut ecosystem following a natural birth
Authors: Nishat Tasnim, Candice Quin, Sandeep Gill, Chuanbin Dai, Miranda Hart, Deanna L. Gibson
Journal: Gut Microbes (2021)

A growing body of evidence suggests that the environment is an important source of colonizing bacteria for the gastrointestinal tract of C-section delivered infants, who undergo multiple birth-related interventions; however, the extent to which environmental microbes impact vaginally delivered infants remains unclear. Here we investigated the impact of rural and urban environmental exposures on microbial establishment and immunity in vaginally delivered mice. We simulated rural and urban home environments by adding soil types to cages from breeding to weaning. Our aims were to determine the impact of rural and urban soil exposures on the gut microbiome in young mice and to understand whether these changes persisted into adulthood. Host immune cytokines and microbial short-chain fatty acids were quantified to understand the impact on immunity. We found that early-life soil exposure had a minor effect on the richness of the neonatal gut microbiota contributing 5% and 9% variation in the bacterial community structure between mice during early-life and adulthood, respectively. Exposure to urban soil increased Clostridiaceae and propionic acid which persisted into adulthood. While soil exposure had a limited effect on the gut taxa, systemic cytokine and chemokine profiles were altered in adulthood. The findings presented here show that unlike in C-section deliveries previously reported, environmental exposures following a natural birth have a limited impact on the gut microbial taxa but potentially play an important role in immune-mediated disease susceptibility later in life.
Eosinophils attenuate hepatic ischemia-reperfusion injury in mice through ST2-dependent IL-13 production
Authors: Yaochun Wang, Yang Yang, Meng Wang, Shuhong Wang, Jong-Min Jeong, Long Xu, Yankai Wen, Christoph Emontzpohl, Constance Lynn Atkins, Kevin Duong, Nicolas F. Moreno, Xiaoyi Yuan, David R. Hall, Wasim Dar, Dechun Feng, Bin Gao, Yong Xu, Zoltan Czigany, Sean P. Colgan, J. Steve Bynon, Shizuo Akira, Jared M. Brown, Holger K. Eltzschig, Elizabeth A. Jacobsen, Cynthia Ju
Journal: Science Translational Medicine (2021)

Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow-derived eosinophils normalized liver injury of eosinophil-deficient mice and reduced hepatic ischemia and reperfusion injury in wild-type mice. Mechanistic studies combining genetic and adoptive transfer approaches identified a critical role of suppression of tumorigenicity (ST2)-dependent production of interleukin-13 by eosinophils in the hepatoprotection against ischemia-reperfusion-induced injury. Together, these data provide insight into a mechanism of eosinophil-mediated liver protection that could serve as a therapeutic target to improve outcomes of patients undergoing liver transplantation.
Microglia and Central Nervous System–Associated Macrophages—From Origin to Disease Modulation
Authors: Marco Prinz, Takahiro Masuda, Michael A. Wheeler, Francisco J. Quintana
Journal: Annual Review of Immunology (2021)

The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.
Molecular Characterization of Post-Transplant Plasmablastic Lymphomas Implicates RAS, TP53, and NOTCH Mutations and MYC Deregulation in Disease Pathogenesis
Authors: Rebecca J Leeman-Neill, Patricia M. Raciti, Susan J Hsiao, Murty Vundavalli, Bachir Alobeid, Mahesh M Mansukhani, Govind Bhagat
Journal: Blood (2017)
Comprehensive landscape and future perspectives of circular RNAs in colorectal cancer
Authors: Fei Long, Zhi Lin, Liang Li, Min Ma, Zhixing Lu, Liang Jing, Xiaorong Li, Changwei Lin
Journal: Molecular Cancer (2021)

Colorectal cancer (CRC) is a common hereditary tumor that is often fatal. Its pathogenesis involves multiple genes, including circular RNAs (circRNAs). Notably, circRNAs constitute a new class of noncoding RNAs (ncRNAs) with a covalently closed loop structure and have been characterized as stable, conserved molecules that are abundantly expressed in tissue/development-specific patterns in eukaryotes. Based on accumulating evidence, circRNAs are aberrantly expressed in CRC tissues, cells, exosomes, and blood from patients with CRC. Moreover, numerous circRNAs have been identified as either oncogenes or tumor suppressors that mediate tumorigenesis, metastasis and chemoradiation resistance in CRC. Although the regulatory mechanisms of circRNA biogenesis and functions remain fairly elusive, interesting results have been obtained in studies investigating CRC. In particular, the expression of circRNAs in CRC is comprehensively modulated by multiple factors, such as splicing factors, transcription factors, specific enzymes and cis-acting elements. More importantly, circRNAs exert pivotal effects on CRC through various mechanisms, including acting as miRNA sponges or decoys, interacting with RNA binding proteins, and even translating functional peptides. Finally, circRNAs may serve as promising diagnostic and prognostic biomarkers and potential therapeutic targets in the clinical practice of CRC. In this review, we discuss the dysregulation, functions and clinical significance of circRNAs in CRC and further discuss the molecular mechanisms by which circRNAs exert their functions and how their expression is regulated. Based on this review, we hope to reveal the functions of circRNAs in the initiation and progression of cancer and highlight the future perspectives on strategies targeting circRNAs in cancer research.
Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants With Late-Onset Infection
Authors: Noa Fleiss, Sarah A. Coggins, Angela N. Lewis, Angela Zeigler, Krista E. Cooksey, L. Anne Walker, Ameena N. Husain, Brenda S. de Jong, Aaron Wallman-Stokes, Mhd Wael Alrifai, Douwe H. Visser, Misty Good, Brynne Sullivan, Richard A. Polin, Camilia R. Martin, James L. Wynn
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Infection in neonates remains a substantial problem. Advances for this population are hindered by the absence of a consensus definition for sepsis. In adults, the Sequential Organ Failure Assessment (SOFA) operationalizes mortality risk with infection and defines sepsis. The generalizability of the neonatal SOFA (nSOFA) for neonatal late-onset infection-related mortality remains unknown. <h3>Objective</h3> To determine the generalizability of the nSOFA for neonatal late-onset infection-related mortality across multiple sites. <h3>Design, Setting, and Participants</h3> A multicenter retrospective cohort study was conducted at 7 academic neonatal intensive care units between January 1, 2010, and December 31, 2019. Participants included 653 preterm (&lt;33 weeks) very low-birth-weight infants. <h3>Exposures</h3> Late-onset (&gt;72 hours of life) infection including bacteremia, fungemia, or surgical peritonitis. <h3>Main Outcomes and Measures</h3> The primary outcome was late-onset infection episode mortality. The nSOFA scores from survivors and nonsurvivors with confirmed late-onset infection were compared at 9 time points (T) preceding and following event onset. <h3>Results</h3> In the 653 infants who met inclusion criteria, median gestational age was 25.5 weeks (interquartile range, 24-27 weeks) and median birth weight was 780 g (interquartile range, 638-960 g). A total of 366 infants (56%) were male. Late-onset infection episode mortality occurred in 97 infants (15%). Area under the receiver operating characteristic curves for mortality in the total cohort ranged across study centers from 0.71 to 0.95 (T0 hours), 0.77 to 0.96 (T6 hours), and 0.78 to 0.96 (T12 hours), with utility noted at all centers and in aggregate. Using the maximum nSOFA score at T0 or T6, the area under the receiver operating characteristic curve for mortality was 0.88 (95% CI, 0.84-0.91). Analyses stratified by sex or Gram-stain identification of pathogen class or restricted to infants born at less than 25 weeks’ completed gestation did not reduce the association of the nSOFA score with infection-related mortality. <h3>Conclusions and Relevance</h3> The nSOFA score was associated with late-onset infection mortality in preterm infants at the time of evaluation both in aggregate and in each center. These findings suggest that the nSOFA may serve as the foundation for a consensus definition of sepsis in this population.
Abstract IA007: The mutational landscape of normal human endometrial epithelium
Authors: Luiza Moore
Journal: Clinical Cancer Research (2021)

Abstract Human endometrium is a highly dynamic tissue that undergoes numerous cycles of breakdown, rapid repair and remodelling in response to the oscillating levels of oestrogen and progesterone. The marked regenerative capacity of the tissue’s epithelial compartment is maintained by the intra-glandular adult stem cells (ASCs) that are retained during menstruation. Although the endometrial epithelial ASCs were first described over a decade ago, they remain poorly characterised in comparison to their counterparts in other tissues, such as the small and arge intestine. In particular, the size of the stem cell pool within individual glands, clonal dynamics and genomic landscape are largely unknown. In this study, we laser-capture microdissected 257 morphologically normal endometrial glands from pre- and post-menopausal women (aged 19 to 81). In selected donors, we also obtained samples of normal endocervical and Fallopian tubular epithelium. Isolated cellular material was subjected to our modified library preparation protocol and subsequent whole genome sequencing (WGS). Analysis of the WGS data identified that the majority of the glands were clonal cell populations sharing a recent common ancestor. Somatic mutations accumulated at a rate of 29 substitutions per year. Total mutation burden in the normal endometrial epithelium is higher than in other normal cells and manyfold lower than in endometrial cancers. Overall, despite the heterogeneity in age, reproductive history and BMI, we found relatively homogenous mutational processes to be operative in this tissue with only occasional outliers. Remarkably, we not only identify recurrent acquisitions of certain cancer-associated mutations, particularly those that are advantageous to cell growth, proliferation and migration, but also show that such events occur early in life, potentially even before adolescence. Using a generalised linear mixed effect model, we found that age has a positive association with the accumulation of driver mutations, while parity has a negative association. Over time, the mutant ASCs serve as a reservoir for the acquisition of further driver mutations to the extent that in some cases, the entire sampled endometrium becomes ‘neoplastic’ on the genomic level while still retaining the apparently normal phenotype. Our data identify a distinct mutational landscape in normal endometrium that is in keeping with the presence of early positive selection in this highly regenerative tissue. Citation Format: Luiza Moore. The mutational landscape of normal human endometrial epithelium [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA007.
SARS-CoV-2 Viral Variants—Tackling a Moving Target
Authors: John R. Mascola, Barney S. Graham, Anthony S. Fauci
Journal: JAMA (2021)

Wenjuan Zhang, PhD; Brian D. Davis, BSc; Stephanie S. Chen, BSc; Jorge M. Sincuir Martinez, BS; Jasmine T. Plummer, PhD; Eric Vail, MD
Trends in predominant causes of death in individuals with and without diabetes in England from 2001 to 2018: an epidemiological analysis of linked primary care records
Authors: Jonathan Pearson-Stuttard, James Bennett, Yiling J Cheng, Eszter P Vamos, Amanda J Cross, Majid Ezzati, Edward W Gregg
Journal: The Lancet Diabetes & Endocrinology (2021)

BackgroundThe prevalence of diabetes has increased in the UK and other high-income countries alongside a substantial decline in cardiovascular mortality. Yet data are scarce on how these trends have changed the causes of death in people with diabetes who have traditionally died primarily of vascular causes. We estimated how all-cause mortality and cause-specific mortality in people with diabetes have changed over time, how the composition of the mortality burden has changed, and how this composition compared with that of the non-diabetes population.MethodsIn this epidemiological analysis of primary care records, we identified 313 907 individuals with diabetes in the Clinical Practice Research Datalink, a well described primary care database, between 2001 to 2018, and linked these data to UK Office for National Statistics mortality data. We assembled serial cross sections with longitudinal follow-up to generate a mixed prevalence and incidence study population of patients with diabetes. We used discretised Poisson regression models to estimate annual death rates for deaths from all causes and 12 specific causes for men and women with diabetes. We also identified age-matched and sex matched (1:1) individuals without diabetes from the same dataset and estimated mortality rates in this group.FindingsBetween Jan 1, 2001, and Oct 31, 2018, total mortality declined by 32% in men and 31% in women with diagnosed diabetes. Death rates declined from 40·7 deaths per 1000 person-years to 27·8 deaths per 1000 person-years in men and from 42·7 deaths per 1000 person-years to 29·5 deaths per 1000 person-years in women with diagnosed diabetes. We found similar declines in individuals without diabetes, hence the gap in mortality between those with and without diabetes was maintained over the study period. Cause-specific death rates declined in ten of the 12 cause groups, with exceptions in dementia and liver disease, which increased in both populations. The large decline in vascular disease death rates led to a transition from vascular causes to cancers as the leading contributor to death rates in individuals with diagnosed diabetes and to the gap in death rates between those with and without diabetes.InterpretationThe decline in vascular death rates has been accompanied by a diversification of causes in individuals with diagnosed diabetes and a transition from vascular diseases to cancers as the leading contributor to diabetes-related death. Clinical and preventative approaches must reflect this trend to reduce the excess mortality risk in individuals with diabetes.FundingWellcome Trust.
Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism
Authors: Vincent Ten Cate, Jürgen H. Prochaska, Andreas Schulz, Thomas Koeck, Alejandro Pallares Robles, Michael Lenz, Lisa Eggebrecht, Steffen Rapp, Marina Panova-Noeva, H. Ardeschir Ghofrani, F. Joachim Meyer, Christine Espinola-Klein, Karl J. Lackner, Matthias Michal, Alexander K. Schuster, Konstantin Strauch, Alexander M. Zink, Volker Laux, Stefan Heitmeier, Stavros V. Konstantinides, Thomas Münzel, Miguel A. Andrade-Navarro, Kirsten Leineweber, Philipp S. Wild
Journal: Blood (2021)
Covid-19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant
Authors: Elisabeth Mahase
Journal: BMJ (2021)

The SARS-CoV-2 vaccine produced by the US biotechnology company Novavax is 95.6% effective against the original variant of SARS-CoV-2 but also provides protection against the newer variants B.1.1.7 (85.6%) and B.1.351 (60%), preliminary data from clinical trials show.

Interim results have been released from a phase III trial carried out in the UK with more than 15 000 participants aged between 18 and 84, including 27% over the age of 65. The trial tested two doses of the vaccine administered three weeks apart and reported 62 symptomatic cases of covid-19, of which 56 were in the placebo group (saline) and six in the vaccine group. Of the 62 cases, only one was severe (in the placebo group), and 32 were with the UK variant.

A phase II trial of the Novavax vaccine is also ongoing in South Africa with 4400 volunteers, in which …
Asthma care during the COVID-19 pandemic: Differences in attitudes and expectations between physicians and patients
Authors: Nonie Arora, Desmond Lowe, Nadeen Sarsour, Hannah Jaffee, Sanaz Eftekhari, Laurie Carpenter, Priya Bansal, Alan Baptist
Journal: Journal of Allergy and Clinical Immunology (2021)

Specific behaviors and beliefs that asthma patients and physicians have during the COVID-19 pandemic are unknown. The goal of this study was to understand differences in attitudes and expectations related to COVID-19 between physicians and patients. An anonymous survey was distributed through email and social media channels to adult patients with asthma for a 3-week period between April-May 2020. A separate survey was sent to physicians. The surveys asked about demographic information, including asthma-specific demographics, specific challenges due to COVID-19, and attitudes/behaviors during COVID-19. A total of 1171 patients and 225 physicians completed the surveys. Overall, patients with asthma and physicians had large differences regarding COVID-19 expectations. Patients were more likely to believe that individuals with asthma are at a higher risk to get COVID-19 (37.5% vs. 12.0%, p<0.001), would require hospitalization from COVID-19 (90.7% vs. 62.2%, p<0.001), and should not go to work (62.7% vs 11.9%, p <0.001). Patients also faced increased financial difficulties obtaining their medications due to COVID-19 more often than physicians anticipated (28.0% vs 16.4%, p< 0.001). Among patients, those with severe asthma (n=102, 8.7% of patients) were significantly more impacted (e.g., became unemployed [OR 2.15] and had difficulty getting asthma meds [OR 2.37]) compared to those with mild or moderate asthma. Patients with asthma and their physicians have markedly different attitudes and opinions regarding care during COVID-19. There are also differences in attitudes and experiences between patients with severe asthma and those with mild/moderate asthma. Such differences have important implications for patient care.
Vitamin C activates pyruvate dehydrogenase (PDH) targeting the mitochondrial tricarboxylic acid (TCA) cycle in hypoxic <i>KRAS</i> mutant colon cancer
Authors: Aiora Cenigaonandia-Campillo, Roberto Serna-Blasco, Laura Gómez-Ocabo, Sonia Solanes-Casado, Natalia Baños-Herraiz, Laura Del Puerto-Nevado, Jose Antonio Cañas, María Jesús Aceñero, Jesús García-Foncillas, Óscar Aguilera
Journal: Theranostics (2021)

Background:In hypoxic tumors, positive feedback between oncogenic KRAS and HIF-1α involves impressive metabolic changes correlating with drug resistance and poor prognosis in colorectal cancer.Up to date, designed KRAS-targeting molecules do not show clear benefits in patient overall survival (POS) so pharmacological modulation of aberrant tricarboxylic acid (TCA) cycle in hypoxic cancer has been proposed as a metabolic vulnerability of KRAS-driven tumors.Methods: Annexin V-FITC and cell viability assays were carried out in order to verify vitamin C citotoxicity in KRAS mutant SW480 and DLD1 as well as in Immortalized Human Colonic Epithelial Cells (HCEC).HIF1a expression and activity were determined by western blot and functional analysis assays.HIF1a direct targets GLUT1 and PDK1 expression was checked using western blot and qRT-PCR.Inmunohistochemical assays were perfomed in tumors derived from murine xenografts in order to validate previous observations in vivo.Vitamin C dependent PDH expression and activity modulation were detected by western blot and colorimetric activity assays.Acetyl-Coa levels and citrate synthase activity were assessed using colorimetric/fluorometric activity assays.Mitochondrial membrane potential (Δψ) and cell ATP levels were assayed using fluorometric and luminescent test.Results: PDK-1 in KRAS mutant CRC cells and murine xenografts was downregulated using pharmacological doses of vitamin C through the proline hydroxylation (Pro402) of the Hypoxia inducible factor-1(HIF-1)α, correlating with decreased expression of the glucose transporter 1 (GLUT-1) in both models.Vitamin C induced remarkable ATP depletion, rapid mitochondrial Δψ dissipation and diminished pyruvate dehydrogenase E1-α phosphorylation at Serine 293, then boosting PDH and citrate synthase activity. Conclusion:We report a striking and previously non reported role of vitamin C in the regulation of the pyruvate dehydrogenase (PDH) activity, then modulating the TCA cycle and mitochondrial metabolism in KRAS mutant colon cancer.Potential impact of vitamin C in the clinical management of anti-EGFR chemoresistant colorectal neoplasias should be further considered.