tbuckley/cabot-search huggingface dataset:
Associations of Cord Blood Vitamin D and Preeclampsia With Offspring Blood Pressure in Childhood and Adolescence
Authors: Mingyu Zhang, Erin D. Michos, Guoying Wang, Xiaobin Wang, Noel T. Mueller
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Maternal preeclampsia may be one of the early risk factors for childhood and adolescence elevated blood pressure (BP). It is unknown whether the intergenerational association between maternal preeclampsia and offspring BP differs by cord blood vitamin D levels. <h3>Objective</h3> To assess the associations between maternal preeclampsia and offspring systolic BP (SBP) across childhood and adolescence and to test whether these associations vary by cord blood 25-hydroxyvitamin D [25(OH)D] concentrations (a biomarker of in utero vitamin D status). <h3>Design, Setting, and Participants</h3> This prospective cohort study analyzed 6669 SBP observations from 754 mother-child pairs from the Boston Birth Cohort, who were enrolled from December 1998 to June 2009. Data were analyzed from October 2019 to March 2020. <h3>Exposures</h3> Physician-diagnosed maternal preeclampsia. Plasma 25(OH)D concentrations measured in cord blood samples collected at delivery. <h3>Main Outcomes and Measures</h3> Repeated SBP measures between 3 and 18 years of age. The SBP percentile was calculated based on the 2017 American Academy of Pediatrics hypertension guidelines. Mean difference in SBP percentile in children born to mothers with vs without preeclampsia was compared across different cord blood 25(OH)D levels. <h3>Results</h3> There were 6669 SBP observations from the 754 children; 50.0% were female and 18.6% were born preterm. Of the 754 mothers, 62.2% were Black and 10.5% had preeclampsia. Median cord blood 25(OH)D was 12.2 (interquartile range, 7.9-17.2) ng/mL. Maternal preeclampsia was associated with 5.34 (95% CI, 1.37-9.30) percentile higher SBP after adjusting for confounders. This association varied by quartiles of cord blood 25(OH)D concentrations: the differences in SBP percentile comparing children born to mothers with vs without preeclampsia were 10.56 (95% CI, 2.54-18.56) for quartile 1 (lowest), 7.36 (95% CI, –0.17 to 14.88) for quartile 2, 4.94 (95% CI, –3.07 to 12.96) for quartile 3, and –1.87 (95% CI, –9.71 to 5.96) for quartile 4 (highest). When cord blood 25(OH)D was analyzed continuously, children born to mothers with preeclampsia had 3.47 (95% CI, 0.77-6.18) percentile lower SBP per 5 ng/mL 25(OH)D increment. These associations did not differ by child sex or developmental stages. <h3>Conclusions and Relevance</h3> In this study of a US high-risk birth cohort, maternal preeclampsia was associated with higher offspring SBP from early childhood to adolescence. These associations were attenuated by higher cord blood 25(OH)D levels in a dose-response fashion. Additional studies, including clinical trials, are warranted.
Differences in biomarkers and molecular pathways according to age for patients with HFrEF
Authors: João Pedro Ferreira, Wouter Ouwerkerk, Bernadet T Santema, Dirk J van Veldhuisen, Chim C Lang, Leong L Ng, Stefan D Anker, Kenneth Dickstein, Marco Metra, John G F Cleland, Samani J Nilesh, Gerasimos Filippatos, Joseph-Pierre Aboumsallem, Rudolf A de Boer, Sylwia Figarska, Iziah E Sama, Adriaan A Voors, Faiez Zannad
Journal: Cardiovascular Research (2020)

Abstract Aims Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with ageing in HFrEF potentially leading to targeted therapies in this vulnerable population. Methods and results From a panel of 363 cardiovascular biomarkers available in 1611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged &amp;gt;75 vs. &amp;lt;65 years. Second, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly vs. younger patients. After adjustment, multiple test correction [false discovery rate (FDR) 1%], and cross-validation, 27/363 biomarkers were associated with older age, 22 positively and 5 negatively. The biomarkers that were positively associated with older age were associated with tumour cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumourigenesis. Among the 27 biomarkers, WFDC2 (WAP four-disulphide core domain protein 2)—that broadly functions as a protease inhibitor—was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed. Conclusions In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumour cell regulation were activated, while pathways associated with tumour proliferation functions were down-regulated. These findings may help in a better understanding of the ageing processes in HFrEF and identify potential therapeutic targets.
Pleural Manometry Does Not Reduce Procedural Discomfort During Large Volume Therapeutic Thoracentesis: A Multicenter Randomized Trial
Authors: R J Lentz, A D Lerner, J K Pannu, C Merrick, L J Roller, C Walston, S Valenti, T Goddard, H Chen, J T Huggins, O B Rickman, L B Yarmus, I Psallidas, N M Rahman, F Maldonado
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Integrated analysis of the aging brain transcriptome and proteome in tauopathy
Authors: Carl Grant Mangleburg, Timothy Wu, Hari K. Yalamanchili, Caiwei Guo, Yi-Chen Hsieh, Duc M. Duong, Eric B. Dammer, Philip L. De Jager, Nicholas T. Seyfried, Zhandong Liu, Joshua M. Shulman
Journal: Molecular Neurodegeneration (2020)

Tau neurofibrillary tangle pathology characterizes Alzheimer's disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes.Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutant form causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy.TauWT induced 1514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a ~ 70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes.Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.
Abstract PR16: Specific activation of the G protein-coupled estrogen receptor inhibits melanoma and other cancers and potentiates immune and targeted therapies
Authors: Chris Natale, Jinyang Li, Jun Zhang, Cristina Aquirre, Ankit Dahal, Tzvete Dentchev, John Seykora, Ben Stanger, Todd Ridky
Journal: Cancer Research (2020)

Abstract Modern immune and targeted therapies appear more effective against advanced melanoma in women than in men. Melanoma incidence is also lower in women. Similar sex differences are observed in other tumors that are not classically considered sex hormone responsive. Here, we show that much of the protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on tumor cells. Selective GPER activation in primary male and female melanocytes, and in melanoma cells, induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemic delivery of a small-molecule, selective GPER agonist was well tolerated, and cooperated with PD-1 directed immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against rechallenge with naive tumor cells. Specific GPER activation in the BRaf-driven murine melanoma model (YUMM1.7) also delayed resistance to targeted BRaf inhibition in vivo. Similar antitumor responses were observed in genetically defined KRas-driven syngeneic pancreatic ductal carcinoma (PDAC) models. The GPER agonist used has favorable pharmacokinetics and oral bioavailability in mice and higher vertebrates and appears to have a large therapeutic window. Together, these data suggest that GPER may be a useful, pharmacologically accessible target for melanoma and other common cancers. This abstract is also being presented as Poster B15. Citation Format: Chris Natale, Jinyang Li, Jun Zhang, Cristina Aquirre, Ankit Dahal, Tzvete Dentchev, John Seykora, Ben Stanger, Todd Ridky. Specific activation of the G protein-coupled estrogen receptor inhibits melanoma and other cancers and potentiates immune and targeted therapies [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR16.
Clinical utility of Epstein‐Barr virus DNA and other liquid biopsy markers in nasopharyngeal carcinoma
Authors: Rong Tan, Sean Kean Ann Phua, Yoke Lim Soong, Lynette Lin Ean Oon, Kian Sing Chan, Sasidharan Swarnalatha Lucky, Jamie Mong, Min Han Tan, Chwee Ming Lim
Journal: Cancer Communications (2020)

Abstract Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor ubiquitously associated with the Epstein‐Barr virus (EBV), which is highly prevalent in South China, Southeast Asia, and North Africa. Despite being a highly radio‐sensitive and treatable cancer, a majority of NPC patients are diagnosed in their advanced stage, and locoregional and distant relapses following definitive treatment contribute largely to cancer‐specific mortality among these patients. Given that EBV‐driven NPC is the predominant variant seen in endemic regions, various EBV detection methods have been developed and are utilized in screening, prognostication, and post‐treatment surveillance of NPC patients. While the Immunoglobulin A (IgA) serology assay is the most extensively studied EBV detection method, the detection of plasma EBV DNA released during replication or cellular apoptosis has shown superior outcomes in endemic population screening, prognostication, and detection of distant relapse. Furthermore, there is emerging evidence on the use of circulating tumor cells, microRNAs, DNA hypermethylation, and combination assays in various clinical scenarios. Herein, this paper provides a comprehensive overview of the relevant studies using various EBV detection techniques in the management of NPC. Specifically, the recent advances, clinical evidence, and challenges associated with the clinical application of EBV liquid biopsies in population screening, prognostication, and surveillance of NPC are presented.
Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy
Authors: Anastasia Prokopi, Christoph H Tripp, Bart Tummers, Florian Hornsteiner, Sarah Spoeck, Jeremy Chase Crawford, Derek R Clements, Mirjana Efremova, Katharina Hutter, Lydia Bellmann, Giuseppe Cappellano, Bruno L Cadilha, Sebastian Kobold, Louis Boon, Daniela Ortner, Zlatko Trajanoski, Suzie Chen, Tanja D de Gruijl, Juliana Idoyaga, Douglas R Green, Patrizia Stoitzner
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Immunotherapy with checkpoint inhibitors has shown impressive results in patients with melanoma, but still many do not benefit from this line of treatment. A lack of tumor-infiltrating T cells is a common reason for therapy failure but also a loss of intratumoral dendritic cells (DCs) has been described. Methods We used the transgenic tg(Grm1)EPv melanoma mouse strain that develops spontaneous, slow-growing tumors to perform immunological analysis during tumor progression. With flow cytometry, the frequencies of DCs and T cells at different tumor stages and the expression of the inhibitory molecules programmed cell death protein-1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells were analyzed. This was complemented with RNA-sequencing (RNA-seq) and real-time quantitative PCR (RT-qPCR) analysis to investigate the immune status of the tumors. To boost DC numbers and function, we administered Fms-related tyrosine 3 ligand (Flt3L) plus an adjuvant mix of polyI:C and anti-CD40. To enhance T cell function, we tested several checkpoint blockade antibodies. Immunological alterations were characterized in tumor and tumor-draining lymph nodes (LNs) by flow cytometry, CyTOF, microarray and RT-qPCR to understand how immune cells can control tumor growth. The specific role of migratory skin DCs was investigated by coculture of sorted DC subsets with melanoma-specific CD8+ T cells. Results Our study revealed that tumor progression is characterized by upregulation of checkpoint molecules and a gradual loss of the dermal conventional DC (cDC) 2 subset. Monotherapy with checkpoint blockade could not restore antitumor immunity, whereas boosting DC numbers and activation increased tumor immunogenicity. This was reflected by higher numbers of activated cDC1 and cDC2 as well as CD4+ and CD8+ T cells in treated tumors. At the same time, the DC boost approach reinforced migratory dermal DC subsets to prime gp100-specific CD8+ T cells in tumor-draining LNs that expressed PD-1/TIM-3 and produced interferon γ (IFNγ)/tumor necrosis factor α (TNFα). As a consequence, the combination of the DC boost with antibodies against PD-1 and TIM-3 released the brake from T cells, leading to improved function within the tumors and delayed tumor growth. Conclusions Our results set forth the importance of skin DC in cancer immunotherapy, and demonstrates that restoring DC function is key to enhancing tumor immunogenicity and subsequently responsiveness to checkpoint blockade therapy.
Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory hypersensitivity
Authors: Yuta Kohro, Tsuyoshi Matsuda, Kohei Yoshihara, Keita Kohno, Keisuke Koga, Ryuichi Katsuragi, Takaaki Oka, Ryoichi Tashima, Sho Muneta, Takuya Yamane, Shota Okada, Kazuya Momokino, Aogu Furusho, Kenji Hamase, Takumi Oti, Hirotaka Sakamoto, Kenichiro Hayashida, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Hidetoshi Tozaki-Saitoh, Katsuhiko Mikoshiba, Verdon Taylor, Kazuhide Inoue, Makoto Tsuda
Journal: Nature Neuroscience (2020)
Elderly Black Non-Hispanic Patients With Head and Neck Squamous Cell Cancer Have the Worst Survival Outcomes
Authors: Jessica D. McDermott, Megan Eguchi, Rustain Morgan, Arya Amini, Julie A. Goddard, Evelinn A. Borrayo, Sana D. Karam
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: In this population study, we compared head and neck cancer (HNC) prognosis and risk factors in 2 underserved minority groups (Hispanic and Black non-Hispanic patients) with those in other racial/ethnicity groups. Methods: In this SEER-Medicare database study in patients with HNC diagnosed in 2006 through 2015, we evaluated cancer-specific survival (CSS) between different racial/ethnic cohorts as the main outcome. Patient demographics, tumor factors, socioeconomic status, and treatments were analyzed in relation to the primary outcomes between racial/ethnic groups. Results: Black non-Hispanic patients had significantly worse CSS than all other racial/ethnic groups, including Hispanic patients, in unadjusted univariate analysis (Black non-Hispanic patients: hazard ratio, 1.48; 95% CI, 1.33–1.65; Hispanic patients: hazard ratio, 1.12; 95% CI, 0.99–1.28). To investigate the association of several variables with CSS, data were stratified for multivariate analysis using forward Cox regression. This identified socioeconomic status, cancer stage, and receipt of treatment as predictive factors for the survival differences. Black non-Hispanic patients were most likely to present at a later stage (odds ratio, 1.62; 95% CI, 1.38–1.90) and to receive less treatment (odds ratio, 0.67; 95% CI, 0.55–0.81). Unmarried status, high poverty areas, increased emergency department visits, and receipt of healthcare at non-NCI/nonteaching hospitals also significantly impacted stage and treatment. Conclusions: Black non-Hispanic patients have a worse HNC prognosis than patients in all other racial/ethnic groups, including Hispanic patients. Modifiable risk factors include access to nonemergent care and prevention measures, such as tobacco cessation; presence of social support; communication barriers; and access to tertiary centers for appropriate treatment of their cancers.
Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity
Authors: Yin Xiao, Musga Qureischi, Lena Dietz, Martin Vaeth, Subrahmanya D. Vallabhapurapu, Stefan Klein-Hessling, Matthias Klein, Chunguang Liang, Anika König, Edgar Serfling, Anja Mottok, Tobias Bopp, Andreas Rosenwald, Mathias Buttmann, Ingolf Berberich, Andreas Beilhack, Friederike Berberich-Siebelt
Journal: The Journal of Experimental Medicine (2020)

Posttranslational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is largely unexplored. The NFAT transcription factors play an essential role in antigen receptor-mediated gene regulation. SUMOylation of NFATc1 represses IL-2 in vitro, but its role in T cell–mediated immune responses in vivo is unclear. To this end, we generated a novel transgenic mouse in which SUMO modification of NFATc1 is prevented. Avoidance of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. Elevated IL-2 production in T cells promoted T reg expansion and suppressed autoreactive or alloreactive immune responses. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Then, Blimp-1 repressed IL-2 itself, as well as the induced, proliferation-associated survival factor Bcl2A1. Collectively, these data demonstrate that prevention of NFATc1 SUMOylation fine-tunes T cell responses toward lasting tolerance. Thus, targeting NFATc1 SUMOylation presents a novel and promising strategy to treat T cell–mediated inflammatory diseases.
Tacrolimus 0.1% versus ciclopiroxolamine 1% for maintenance therapy in patients with severe facial seborrheic dermatitis: A multicenter, double-blind, randomized controlled study
Authors: Pascal Joly, Ines Tejedor, Florence Tetart, Hélène Collas Cailleux, Alice Barrel, Paul Arnaud De Preville, Nathalie Mion-Mouton, Germaine Gabison, Sophie Baricault, Catherine Girardin Tordeur, Martin Xavier Dore, Bernard Rossi, Catherine Bourseau-Quetier, Mélanie Chamaillard, Sandra Ly, Olivier Chosidow, Marie-Aleth Richard-Lallemand, Jean-Claude Rzeznik, Jean-Michel Amici, Guillaume Lair, Sylvie Bechu, Jacques Benichou, Caroline Thill, Marie Beylot-Barry
Journal: Journal of the American Academy of Dermatology (2020)
Mineralocorticoid receptor antagonists in patients with chronic kidney disease
Authors: Cosimo Cosimato, Thomas Agoritsas, Thomas A. Mavrakanas
Journal: Pharmacology & Therapeutics (2020)

Mineralocorticoid receptor antagonists (MRA) can reduce cardiovascular morbidity and mortality in patients with heart failure and ischemic heart disease. In addition, these agents have been used in patients with diabetic nephropathy to control proteinuria and slow down chronic kidney disease (CKD) progression. Current guidelines recommend against the use of MRAs in patients with advanced CKD. However, there is growing interest on their use in this population that has unmet needs (high cardiovascular morbidity and mortality) and unique challenges (risk of acute kidney injury or hyperkalemia). This narrative review discusses the emerging role of MRAs for the management of cardiovascular disease and/or the prevention of CKD progression, highlighting results from randomized controlled trials and presenting real-world data from available registries. Results from recent trials in patients on maintenance dialysis are also discussed.
The state of the art in kidney and kidney tumor segmentation in contrast-enhanced CT imaging: Results of the KiTS19 challenge
Authors: Nicholas Heller, Fabian Isensee, Klaus H. Maier-Hein, Xiaoshuai Hou, Chunmei Xie, Fengyi Li, Yang Nan, Guangrui Mu, Zhiyong Lin, Miofei Han, Guang Yao, Yaozong Gao, Yao Zhang, Yixin Wang, Feng Hou, Jiawei Yang, Guangwei Xiong, Jiang Tian, Cheng Zhong, Jun Ma, Jack Rickman, Joshua Dean, Bethany Stai, Resha Tejpaul, Makinna Oestreich, Paul Blake, Heather Kaluzniak, Shaneabbas Raza, Joel Rosenberg, Keenan Moore, Edward Walczak, Zachary Rengel, Zach Edgerton, Ranveer Vasdev, Matthew Peterson, Sean McSweeney, Sarah Peterson, Arveen Kalapara, Niranjan Sathianathen, Nikolaos Papanikolopoulos, Christopher Weight
Journal: Medical Image Analysis (2020)
Photoimmunotherapy with cetuximab-conjugated gold nanorods reduces drug resistance in triple negative breast cancer spheroids with enhanced infiltration of tumor-associated macrophages
Authors: Fakhrossadat Emami, Shiva Pathak, Tiep Tien Nguyen, Prakash Shrestha, Srijan Maharjan, Jong Oh Kim, Jee-Heon Jeong, Simmyung Yook
Journal: Journal of Controlled Release (2020)
Estimating unbiased sports injury rates: a compendium of injury rates calculated by athlete exposure and athlete at risk methods
Authors: Joseph El-Khoury, Steven D. Stovitz, Ian Shrier
Journal: British Journal of Sports Medicine (2020)

A basic principle in epidemiology is that an injury rate should only include time when a person is ‘at risk’ for the outcome. However, when calculating injury rates in sports medicine, many investigators use a method known as ‘athlete- exposures’ (AE) which was originally proposed by the National Collegiate Athletic Association (NCAA) surveillance programme.1 The AE method overestimates game injury rates when compared with using individual player time as the AE method attributes a full exposure to those who do not play a full game.2 Another method of capturing player exposure to injury is called the athletes-at-risk (AAR) method.2 The AAR method follows proper epidemiological principles, provides results very similar to the individual player time method in most contexts, and is easier to calculate. While the AE method will most often underestimate injury rates, the amount of underestimation depends on the sport and context. Our previous publication2 discusses these concepts …