tbuckley/cabot-search huggingface dataset:
Characterization of Alzheimer Disease Biomarker Discrepancies Using Cerebrospinal Fluid Phosphorylated Tau and AV1451 Positron Emission Tomography
Authors: Pierre-François Meyer, Alexa Pichet Binette, Julie Gonneaud, John C. S. Breitner, Sylvia Villeneuve
Journal: JAMA Neurology (2020)

Fluid and imaging biomarkers of Alzheimer disease (AD) are often used interchangeably, but some biomarkers may reveal earlier stages of disease.To characterize individuals with tau abnormality indicated by cerebrospinal fluid (CSF) assay or positron emission tomography (PET).Between 2010 and 2019, 322 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent CSF and PET assessments of tau pathology. Data-driven, clinically relevant thresholds for CSF phosphorylated tau (P-tau) (≥26.64 pg/mL) and flortaucipir-PET meta-regions of interest (ROI) (standard uptake value ratio ≥1.37) indicated participants' tau status as CSF-/PET-, CSF+/PET-, CSF-/PET+, and CSF+/PET+. Of 1659 ADNI participants with a CSF or flortaucipir assessment, 588 had both measures (1071 were excluded). Among these, 266 were further excluded because they did not have flortaucipir and CSF testing within less than 25 months, leaving 322 for analysis. Of these, 213 were cognitively unimpaired (CU); 98 had mild cognitive impairment (MCI); and 11 had AD dementia.We compared tau-positive vs tau-negative groups as indicated by either modality or demographic and clinical variables, amyloid β-PET burden, and flortaucipir-PET binding across Braak stage-related ROIs. We also compared 5-year rates of CSF P-tau accumulation and cognitive decline prior to flortaucipir-PET scanning.Among the 322 study participants, 180 were women (56%), and the mean (SD) age was 73.08 (7.37) years. Two hundred ten participants were CSF-/PET- (65%); 63 were CSF+/PET- (19.5%); 15 were CSF-/PET+ (4.6%); and 34 were CSF+/PET+ (10.5%). Most CSF-/PET+ participants had measures near CSF or PET tau thresholds. The CSF+/PET- participants showed faster 5-year accrual of P-tau and increased flortaucipir-PET binding in early Braak ROIs but similar memory decline compared with CSF-/PET- participants. Tau-positive individuals by either measure showed increased amyloid β-PET burden. All CSF+/PET+ individuals were amyloid-positive, and 26 had MCI or AD dementia (76%). Compared with the CSF-/PET- group, CSF+/PET+ individuals had experienced faster 5-year accrual of CSF P-tau and decline in memory and executive function, resulting in reduced cognitive abilities at the time of flortaucipir-PET assessment.Suprathreshold CSF P-tau without flortaucipir-PET abnormality may indicate a stage of AD development characterized by early tau abnormality without measurable loss in cognitive performance. Persons with both tau CSF and PET abnormality appear to have reduced cognitive capacities resulting from faster antecedent cognitive decline. Elevation of CSF P-tau appears to precede flortaucipir-PET positivity in the progression of AD pathogenesis and related cognitive decline.
Evolution of Transcriptional Repressors Impacts <i>Caenorhabditis</i> Vulval Development
Authors: Helen M Chamberlin, Ish M Jain, Marcos Corchado-Sonera, Leanne H Kelley, Devika Sharanya, Abdulrahman Jama, Romy Pabla, Adriana T Dawes, Bhagwati P Gupta
Journal: Molecular Biology and Evolution (2020)

Comparative genomic sequence analysis has found that the genes for many chromatin-associated proteins are poorly conserved, but the biological consequences of these sequence changes are not understood. Here, we show that four genes identified for an Inappropriate Vulval cell Proliferation (ivp) phenotype in the nematode Caenorhabditis briggsae exhibit distinct functions and genetic interactions when compared with their orthologs in C. elegans. Specifically, we show that the four C. briggsae ivp genes encode the noncanonical histone HTZ-1/H2A.z and three nematode-specific proteins predicted to function in the nucleus. The mutants exhibit ectopic vulval precursor cell proliferation (the multivulva [Muv] phenotype) due to inappropriate expression of the lin-3/EGF gene, and RNAseq analysis suggests a broad role for these ivp genes in transcriptional repression. Importantly, although the C. briggsae phenotypes have parallels with those seen in the C. elegans synMuv system, except for the highly conserved HTZ-1/H2A.z, comparable mutations in C. elegans ivp orthologs do not exhibit synMuv gene interactions or phenotypes. These results demonstrate the evolutionary changes that can underlie conserved biological outputs and argue that proteins critical to repress inappropriate expression from the genome participate in a rapidly evolving functional landscape.
iPSC modeling of young-onset Parkinson’s disease reveals a molecular signature of disease and novel therapeutic candidates
Authors: A. H. Laperle, S. Sances, N. Yucer, V. J. Dardov, V. J. Garcia, R. Ho, A. N. Fulton, M. R. Jones, K. M. Roxas, P. Avalos, D. West, M. G. Banuelos, Z. Shu, R. Murali, N. T. Maidment, J. E. Van Eyk, M. Tagliati, C. N. Svendsen
Journal: Nature Medicine (2020)
Human DNA-PK activates a STING-independent DNA sensing pathway
Authors: Katelyn Burleigh, Joanna H. Maltbaek, Stephanie Cambier, Richard Green, Michael Gale, Richard C. James, Daniel B. Stetson
Journal: Science Immunology (2020)

Detection of intracellular DNA by the cGAS-STING pathway activates a type I interferon-mediated innate immune response that protects from virus infection. Whether there are additional DNA sensing pathways, and how such pathways might function, remains controversial. We show here that humans-but not laboratory mice-have a second, potent, STING-independent DNA sensing pathway (SIDSP). We identify human DNA-dependent protein kinase (DNA-PK) as the sensor of this pathway and demonstrate that DNA-PK activity drives a robust and broad antiviral response. We show that the E1A oncoprotein of human adenovirus 5 and the ICP0 protein of herpes simplex virus 1 block this response. We found heat shock protein HSPA8/HSC70 as a target for inducible phosphorylation in the DNA-PK antiviral pathway. Last, we demonstrate that DNA damage and detection of foreign DNA trigger distinct modalities of DNA-PK activity. These findings reveal the existence, sensor, a specific downstream target, and viral antagonists of a SIDSP in human cells.
Clinicopathologic Characteristics of BRG1-Deficient NSCLC
Authors: Ibiayi Dagogo-Jack, Alexa B. Schrock, Marina Kem, Nicholas Jessop, Jessica Lee, Siraj M. Ali, Jeffrey S. Ross, Jochen K. Lennerz, Alice T. Shaw, Mari Mino-Kenudson
Journal: Journal of Thoracic Oncology (2020)
A reply to Demirci et al .
Authors: Hai Zhou, Ming Hou
Journal: American Journal of Hematology (2020)

To the Editor: We would like to thank Demirci et al. for their interest and attention to our study of low dose decitabine in refractory ITP patients.1 They proposed three important and interesting questions, and cited three recently updated guidelines or consensus reports.2-4 We carefully read through the latest three guidelines. First, we are clear that spontaneous remission may occur in children and in patients in the first year after initial diagnosis. In our decitabine study, the median ITP duration was 25 months (IQR 14-58) in responders and 22 months (IQR 14-61) in non-responders, respectively. The spontaneous remission in our study should be scarcely possible. Second, the detection of Helicobacter pylori infection for every ITP patient is included at the diagnosis with the urea breath test or the stool antigen test. The detection was recommended in 2011 ASH guideline for ITP and 2019 updated international primary ITP consensus report, but not addressed in the 2019 ASH guideline for ITP (listed in Table 2 in 2019 ASH guideline for ITP). The detection was recommended by the panel for adult patients in the appropriate geographic setting (eg, Japan and Italy). Third, we agree with the viewpoint that combined therapy can be used in refractory ITP patients. However, we need to worry about that the combination of alternatives (which have been failed as monotherapy) would be less likely to be effective.
Gene content evolution in the arthropods
Authors: Gregg W. C. Thomas, Elias Dohmen, Daniel S. T. Hughes, Shwetha C. Murali, Monica Poelchau, Karl Glastad, Clare A. Anstead, Nadia A. Ayoub, Phillip Batterham, Michelle Bellair, Greta J. Binford, Hsu Chao, Yolanda H. Chen, Christopher Childers, Huyen Dinh, Harsha Vardhan Doddapaneni, Jian J. Duan, Shannon Dugan, Lauren A. Esposito, Markus Friedrich, Jessica Garb, Robin B. Gasser, Michael A. D. Goodisman, Dawn E. Gundersen-Rindal, Yi Han, Alfred M. Handler, Masatsugu Hatakeyama, Lars Hering, Wayne B. Hunter, Panagiotis Ioannidis, Joy C. Jayaseelan, Divya Kalra, Abderrahman Khila, Pasi K. Korhonen, Carol Eunmi Lee, Sandra L. Lee, Yiyuan Li, Amelia R. I. Lindsey, Georg Mayer, Alistair P. McGregor, Duane D. McKenna, Bernhard Misof, Mala Munidasa, Monica Munoz-Torres, Donna M. Muzny, Oliver Niehuis, Nkechinyere Osuji-Lacy, Subba R. Palli, Kristen A. Panfilio, Matthias Pechmann, Trent Perry, Ralph S. Peters, Helen C. Poynton, Nikola-Michael Prpic, Jiaxin Qu, Dorith Rotenberg, Coby Schal, Sean D. Schoville, Erin D. Scully, Evette Skinner, Daniel B. Sloan, Richard Stouthamer, Michael R. Strand, Nikolaus U. Szucsich, Asela Wijeratne, Neil D. Young, Eduardo E. Zattara, Joshua B. Benoit, Evgeny M. Zdobnov, Michael E. Pfrender, Kevin J. Hackett, John H. Werren, Kim C. Worley, Richard A. Gibbs, Ariel D. Chipman, Robert M. Waterhouse, Erich Bornberg-Bauer, Matthew W. Hahn, Stephen Richards
Journal: Genome biology (2020)

Abstract Background Arthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods. Results Using 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality, and chemoperception. Conclusions These analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity.
Association of Longitudinal Values of Glycated Hemoglobin With Cardiovascular Events in Patients With Type 2 Diabetes and Multivessel Coronary Artery Disease
Authors: Paulo Cury Rezende, Mark Andrew Hlatky, Whady Hueb, Rosa Maria Rahmi Garcia, Luciano da Silva Selistre, Eduardo Gomes Lima, Cibele Larrosa Garzillo, Thiago Luis Scudeler, Gustavo Andre Boeing Boros, Fernando Faglioni Ribas, Carlos Vicente Serrano, Jose Antonio Franchini Ramires, Roberto Kalil Filho
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Glycated hemoglobin (HbA<sub>1c</sub>) values are used to guide glycemic control, but in patients with type 2 diabetes and multivessel coronary artery disease (CAD), the association of the longitudinal values of HbA<sub>1c</sub>with cardiovascular outcomes is unclear. <h3>Objective</h3> To assess whether longitudinal variation of HbA<sub>1c</sub>is associated with cardiovascular events in long-term follow-up among patients with diabetes and multivessel CAD. <h3>Design, Setting, and Participants</h3> This cohort study included 888 patients with type 2 diabetes and multivessel CAD in the Medicine, Angioplasty, or Surgery Study (MASS) Registry of the Heart Institute of the University of São Paulo from January 2003 to December 2007. Data were analyzed from January 15, 2018, to October 15, 2019. <h3>Exposure</h3> Longitudinal HbA<sub>1c</sub>values. <h3>Main Outcomes and Measures</h3> The combined outcome of all-cause mortality, myocardial infarction, and ischemic stroke. <h3>Results</h3> Of 888 patients with type 2 diabetes and multivessel CAD, 725 (81.6%; median [range] age, 62.4 [55.7-68.0] years; 467 [64.4%] men) had complete clinical and HbA<sub>1c</sub>information during a median (interquartile range) follow-up period of 10.0 (8.0-12.3) years, with a mean (SD) of 9.5 (3.8) HbA<sub>1c</sub>values for each patient. The composite end point of death, myocardial infarction, or ischemic stroke occurred in 262 patients (36.1%). A 1-point increase in the longitudinal value of HbA<sub>1c</sub>was significantly associated with a 14% higher risk of the combined end point of all-cause mortality, myocardial infarction, and ischemic stroke (hazard ratio, 1.14; 95% CI, 1.04-1.24;<i>P</i> = .002) in the unadjusted analysis. After adjusting for baseline factors (ie, age, sex, 2-vessel or 3-vessel CAD, initial CAD treatments, ejection fraction, and creatinine and low-density lipoprotein cholesterol levels), a 1-point increase in the longitudinal value of HbA<sub>1c</sub>was associated with a 22% higher risk of the combined end point (hazard ratio, 1.22; 95% CI, 1.12-1.35;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Longitudinal increase of HbA<sub>1c</sub>was independently associated with higher rates of cardiovascular events in patients with type 2 diabetes and multivessel CAD.
The Cost of Pharmaceutical Company Detailing Visits and Medication Samples
Authors: B. Joseph Guglielmo
Journal: JAMA Internal Medicine (2020)

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Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy
Authors: A. Moretti, L. Fonteyne, F. Giesert, P. Hoppmann, A. B. Meier, T. Bozoglu, A. Baehr, C. M. Schneider, D. Sinnecker, K. Klett, T. Fröhlich, F. Abdel Rahman, T. Haufe, S. Sun, V. Jurisch, B. Kessler, R. Hinkel, R. Dirschinger, E. Martens, C. Jilek, A. Graf, S. Krebs, G. Santamaria, M. Kurome, V. Zakhartchenko, B. Campbell, K. Voelse, A. Wolf, T. Ziegler, S. Reichert, S. Lee, F. Flenkenthaler, T. Dorn, I. Jeremias, H. Blum, A. Dendorfer, A. Schnieke, S. Krause, M. C. Walter, N. Klymiuk, K. L. Laugwitz, E. Wolf, W. Wurst, C. Kupatt
Journal: Nature Medicine (2020)
18F-FDG PET/CT Evaluation of Crizotinib and Lorlatinib Therapy in Metastatic ROS-1–Positive Non–Small Cell Lung Cancer
Authors: Sébastien Dejust, Abdenasser Moubtakir, Alain Prevost, Khadija El Farsaoui, David Morland
Journal: Clinical Nuclear Medicine (2019)

Abstract ROS-1–positive non–small cell lung cancers (NSCLCs) are rare (approximately 1% of all NSCLCs) and require a first-line treatment by crizotinib. Crizotinib resistance is frequent within the first 12 months of treatment. Lorlatinib is a novel tyrosine kinase inhibitor of ROS-1 recently indicated for metastatic or locally advanced crizotinib-resistant NSCLC. We report the use of lorlatinib as second-line with a complete tumoral response after only 3 months of treatment. This case shows the major role of 18 F-FDG PET/CT in treatment evaluation and monitoring targeted therapy in metastatic NSCLC.
Evaluation of the Biofire FilmArray meningitis/encephalitis assay for the detection of Cryptococcus neoformans/gattii
Authors: T.T. Van, T.H. Kim, S.M. Butler-Wu
Journal: Clinical Microbiology and Infection (2020)

ObjectivesCryptococcal meningitis (CM) remains an important cause of morbidity and mortality among immunocompromised patients. Laboratory diagnostics for CM includes antigen detection, staining and culture. Data on the performance of the Biofire® FilmArray® meningitis/encephalitis (ME) panel for detecting Cryptococcus neoformans/gattii is limited, with several reports describing false negativity for this target.MethodsA retrospective analysis of 1384 physician-ordered ME panel tests ordered between January 2017 to October 2018 was performed. ME panel results were compared to cerebrospinal fluid (CSF) cryptococcal antigen (CrAg) and CSF culture testing and clinical significance of cryptococcal detection was determined.ResultsThere were 34 patients positive for cryptococcal detection by either ME panel, CSF CrAg or CSF culture in 2.7% of CSF specimens tested (38/1384). Of the 34 patients positive for cryptococcal detection, 85.3% were human immunodeficiency virus positive (29/34). The ME panel detected 32/38 (84.2%) cryptococcal-positive specimens, culture detected 28/38 (73.7%) and CSF CrAg was positive in 37/38 specimens (97.4%). The ME panel had a sensitivity and specificity of 96.4% (95% CI 81.7–99.9%) and 99.6% (95% CI 99.2–99.9%) compared with culture, and 83.8% (95% CI 68.0–93.8%) and 99.9% (95% CI 99.6–100.0%) compared to CSF CrAg testing, respectively. CrAg titres were lower among ME panel-negative, culture-negative specimens compared with ME panel-positive, culture-negative specimens (reciprocal median end-point titres of 128 ± 60 vs. 1920 ± 1730, p 0.04). All five CrAg-positive, ME panel- and culture-negative specimens were obtained from previously treated CM patients.DiscussionThe ME panel had high correlation with CSF culture and a somewhat lower correlation with CSF CrAg testing. The potential utility of using negative ME panel test results to predict culture sterility among patients undergoing treatment for CM warrants further study.
Remission of acute myeloid leukemia with t(8;21) following CD19 CAR T-cells
Authors: Ivetta Danylesko, Elad Jacoby, Ronit Yerushalmi, Noga Shem-Tov, Michal J. Besser, Helly Vernitsky, Victoria Marcu-Malina, Avichai Shimoni, Abraham Avigdor, Arnon Nagler
Journal: Leukemia (2020)
Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial
Authors: Matthew K Hoffman, Shivaprasad S Goudar, Bhalachandra S Kodkany, Mrityunjay Metgud, Manjunath Somannavar, Jean Okitawutshu, Adrien Lokangaka, Antoinette Tshefu, Carl L Bose, Abigail Mwapule, Musaku Mwenechanya, Elwyn Chomba, Waldemar A Carlo, Javier Chicuy, Lester Figueroa, Ana Garces, Nancy F Krebs, Saleem Jessani, Farnaz Zehra, Sarah Saleem, Robert L Goldenberg, Kunal Kurhe, Prabir Das, Archana Patel, Patricia L Hibberd, Emmah Achieng, Paul Nyongesa, Fabian Esamai, Edward A Liechty, Norman Goco, Jennifer Hemingway-Foday, Janet Moore, Tracy L Nolen, Elizabeth M McClure, Marion Koso-Thomas, Menachem Miodovnik, R Silver, Richard J Derman, Emmah Achieng, Melissa Bauserman, Carl Bose, Sherri Bucher, Waldemar Carlo, Umesh S Charantimath, Javier Chicuy, Elwyn Chomba, Prabir Das, Richard Derman, Fabian Esamai, Lester Figueroa, MS Ganachari, Ana Garces, Noman Goco, Robert Goldenberg, Shivaprasad Goudar, Jennifer Hemingway-Foday, Patricia Hibberd, Matthew Hoffman, Narayan V Honnungar, Saleem Jessani, Avinash Kavi, Bhalachandra Kodkany, Marion Koso-Thomas, Nancy Krebs, Yogesh Kumar Shashikanth, Kunal Kurhe, Edward Liechty, Adrien Lokangaka, Emily MacGuire, Ashalata A Mallapur, Elizabeth McClure, Mrityunjay Metgud, Menachem Miodovnik, Janet Moore, Abigail Mwapule, Musaku Mwenechanya, Farnaz Naqvi, Seemab Naqvi, Robert Nathan, Tracy Nolen, Paul Nyongesa, Jean Okitawutshu, Suchita Parepalli, Archana Patel, Umesh Y Ramadurg, Sarah Saleem, Robert Silver, Manjunath Somannavar, Zahid Soomro, Antoinette Tshefu, Sunil S Vernekar, Dennis Wallace, Farnaz Zehra
Journal: The Lancet (2020)
Genome-Wide Natural Selection Signatures Are Linked to Genetic Risk of Modern Phenotypes in the Japanese Population
Authors: Yoshiaki Yasumizu, Saori Sakaue, Takahiro Konuma, Ken Suzuki, Koichi Matsuda, Yoshinori Murakami, Michiaki Kubo, Pier Francesco Palamara, Yoichiro Kamatani, Yukinori Okada
Journal: Molecular Biology and Evolution (2020)

Elucidation of natural selection signatures and relationships with phenotype spectra is important to understand adaptive evolution of modern humans. Here, we conducted a genome-wide scan of selection signatures of the Japanese population by estimating locus-specific time to the most recent common ancestor using the ascertained sequentially Markovian coalescent (ASMC), from the biobank-based large-scale genome-wide association study data of 170,882 subjects. We identified 29 genetic loci with selection signatures satisfying the genome-wide significance. The signatures were most evident at the alcohol dehydrogenase (ADH) gene cluster locus at 4q23 (PASMC = 2.2 × 10-36), followed by relatively strong selection at the FAM96A (15q22), MYOF (10q23), 13q21, GRIA2 (4q32), and ASAP2 (2p25) loci (PASMC < 1.0 × 10-10). The additional analysis interrogating extended haplotypes (integrated haplotype score) showed robust concordance of the detected signatures, contributing to fine-mapping of the genes, and provided allelic directional insights into selection pressure (e.g., positive selection for ADH1B-Arg48His and HLA-DPB1*04:01). The phenome-wide selection enrichment analysis with the trait-associated variants identified a variety of the modern human phenotypes involved in the adaptation of Japanese. We observed population-specific evidence of enrichment with the alcohol-related phenotypes, anthropometric and biochemical clinical measurements, and immune-related diseases, differently from the findings in Europeans using the UK Biobank resource. Our study demonstrated population-specific features of the selection signatures in Japanese, highlighting a value of the natural selection study using the nation-wide biobank-scale genome and phenotype data.
Erratum for the Research Article: “Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers” by M. B. Nilsson, H. Sun, L. Diao, P. Tong, D. Liu, L. Li, Y. Fan, A. Poteete, S.-O. Lim, K. Howells, V. Haddad, D. Gomez, H. Tran, G. A. Pena, L. V. Sequist, J. C. Yang, J. Wang, E. S. Kim, R. Herbst, J. J. Lee, W. K. Hong, I. Wistuba, M.-C. Hung, A. K. Sood, J. V. Heymach
Journal: Science Translational Medicine (2019)
Structural determinants of gender inequality: why they matter for adolescent girls’ sexual and reproductive health
Authors: Asha S George, Avni Amin, Claudia Marques de Abreu Lopes, T K Sundari Ravindran
Journal: BMJ (2020)

More comprehensive understanding of gender inequality is required, particularly the broader structural drivers that underpin the political economy of gender power relations, say <b>Asha George and colleagues</b>
A18 Culture of Immortalized Human Alveolar Epithelial Cells in 2D and 3D to Model Lung Adenocarcinoma Progression in Vitro
Authors: E. Tran, T. Shi, X. Liu, H. Wang, C. Marconett, B. Zhou, Z. Borok, I.A. Offringa
Journal: Journal of Thoracic Oncology (2020)