tbuckley/cabot-search huggingface dataset:
Increase in circulating cells coexpressing M1 and M2 macrophage surface markers in patients with systemic sclerosis
Authors: Stefano Soldano, Amelia Chiara Trombetta, Paola Contini, Veronica Tomatis, Barbara Ruaro, Renata Brizzolara, Paola Montagna, Alberto Sulli, Sabrina Paolino, Carmen Pizzorni, Vanessa Smith, Maurizio Cutolo
Journal: Annals of the Rheumatic Diseases (2018)

Alterations in macrophage polarisation are recognised among the possible immune system abnormalities contributing to systemic sclerosis (SSc) pathogenesis.1 

Macrophages have been classified as classically (M1) or alternatively (M2) activated, although growing evidence indicates that they may exhibit characteristics shared by more than one of the described phenotypes.2–5 

An M2 pre-eminent phenotype has been postulated for SSc monocytes/macrophages.2 The aim of the study was to widen a phenotype characterisation (M1, M2 and mixed M1/M2) of circulating monocytes/macrophages in patients with SSc and healthy subjects (HSs) through flow cytometry analysis. Fifty-eight consecutive patients with SSc (38 limited and 20 diffuse SSc) and 27 age-matched and gender-matched HSs were enrolled after signing informed consent. SSc diagnosis was based on the 2013 American College of Rheumatology/European League Against Rheumatism criteria (online supplementary file 1).6 For flow cytometry analysis, peripheral blood was collected and anti-CD14 and anti-CD45 antibodies were used to identify the monocyte/macrophage lineage; macrophage scavenger receptors (CD204, CD163) and mannose receptor 1 (CD206) were used as M2 phenotype markers; and co-stimulatory molecules (CD80, CD86) and Toll-like receptors (TLR4, TLR2) were used as M1 phenotype markers. CD66b was used to distinguish granulocytes (Miltenyi Biotech, Germany). Flow  c ytometry analysis was performed using the Navios flow cytometer and Kaluza analysis software (Beckman Coulter). A total of  5 × 10 6 cells  were evaluated and more than 30 events were detected in the smallest subset investigated, according to the consensus guidelines for minimal residual disease. Results were expressed in percentages over total circulating leu c ocytes, unless otherwise specified. The non-parametric al Mann-Whitney U test was used for statistical analysis and any p value lower than 0.05 was considered statistically significant.  Two initial gating strategies were used to study circulating M2-like monocytes/macrophages, the first gated CD14+cells and the second gated CD204 …
Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer
Authors: Maki Tanioka, Cheng Fan, Joel S. Parker, Katherine A. Hoadley, Zhiyuan Hu, Yan Li, Terry M. Hyslop, Brandelyn N. Pitcher, Matthew G. Soloway, Patricia A. Spears, Lynn N. Henry, Sara Tolaney, Chau T. Dang, Ian E. Krop, Lyndsay N. Harris, Donald A. Berry, Elaine R. Mardis, Eric P. Winer, Clifford A. Hudis, Lisa A. Carey, Charles M. Perou
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy. Experimental Design: We analyzed 137 pretreatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II to III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for covarying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from four independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNA), and gene signatures. Results: The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC = 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multiplatform models included amplifications of chromosome 6p, TP53 mutation, HER2-enriched subtype, and immune signatures. Variables predicting resistance included Luminal/ER+ features. Conclusions: Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer. Clin Cancer Res; 24(21); 5292–304. ©2018 AACR.
Interactions between Macrophages and Cyst-Lining Epithelial Cells Promote Kidney Cyst Growth in Pkd1-Deficient Mice
Authors: Yang Yang, Meihan Chen, Jie Zhou, Jiayi Lv, Shuwei Song, LiLi Fu, Jiejian Chen, Ming Yang, Changlin Mei
Journal: Journal of the American Society of Nephrology (2018)

Autosomal-dominant polycystic kidney disease (ADPKD) is the leading inherited renal disease worldwide. The proproliferative function of macrophages is associated with late-stage cyst enlargement in mice with PKD; however, the way in which macrophages act on cyst-lining epithelial cells (CLECs) has not been well elucidated.We generated a rapid-onset PKD mouse model by inactivating Pkd1 on postnatal day 10 (P10) and compared cell proliferation and differential gene expression in kidney tissues of the PKD mice and wild-type (WT) littermates.The cystic phenotype was dominant from P18. A distinct peak in cell proliferation in polycystic kidneys during P22-P30 was closely related to late-stage cyst growth. Comparisons of gene expression profiles in kidney tissues at P22 and P30 in PKD and WT mice revealed that arginine metabolism was significantly activated; 204 differentially expressed genes (DEGs), including Arg1, an arginine metabolism-associated gene, were identified in late-stage polycystic kidneys. The Arg1-encoded protein, arginase-1 (ARG1), was predominantly expressed in macrophages in a time-dependent manner. Multiple-stage macrophage depletion verified that macrophages expressing high ARG1 levels accounted for late-stage cyst enlargement, and inhibiting ARG1 activity significantly retarded cyst growth and effectively lowered the proliferative indices in polycystic kidneys. In vitro experiments revealed that macrophages stimulated CLEC proliferation, and that L-lactic acid, primarily generated by CLECs, significantly upregulated ARG1 expression and increased polyamine synthesis in macrophages.Interactions between macrophages and CLECs promote cyst growth. ARG1 is a key molecule involved in this process and is a potential therapeutic target to help delay ADPKD progression.
Abstract IA07: ER stress responses as new immune checkpoints in cancer
Authors: Juan R. Cubillos-Ruiz
Journal: Clinical Cancer Research (2018)

Abstract Harnessing the intrinsic ability of our immune system to eliminate malignant cells represents the most promising anticancer strategy since the development of chemotherapy. However, cancer cells employ diverse strategies that enable them to thrive under adverse conditions while simultaneously inhibiting antitumor immune responses. Diverse microenvironmental conditions within tumor masses, such as hypoxia and nutrient deprivation, disturb the protein-folding capacity of the endoplasmic reticulum (ER) and provoke a cellular state of “ER stress.” Sustained activation of ER stress sensors endows malignant cells with greater tumorigenic, metastatic, and drug-resistant capacity. Interestingly, recent studies demonstrate that tumor-infiltrating immune cells also experience ER stress, and that this process causes severe immune cell dysfunction and immunosuppression in cancer hosts. Aggressive ovarian cancers, for instance, cripple protective immunity by inducing excessive activation of the IRE1-XBP1 arm of the ER stress in tumor-associated dendritic cells. These recent findings uncover a new immunoregulatory role for ER stress in the tumor microenvironment and suggest that targeting aberrant ER stress responses may represent a new strategy to control tumor-induced immunosuppression and enhance the effectiveness of emerging immunotherapies. Citation Format: Juan R. Cubillos-Ruiz. ER stress responses as new immune checkpoints in cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA07.
<i>Notes from the Field:</i> Widespread Transmission of Circulating Vaccine-Derived Poliovirus Identified by Environmental Surveillance and Immunization Response — Horn of Africa, 2017–2018
Authors: Victor A. Eboh, Jeevan K. Makam, Rohit A. Chitale, Chukwuma Mbaeyi, Jaume Jorba, Derek Ehrhardt, Elias Durry, Tracie Gardner, Kamil Mohamed, Christopher Kamugisha, Peter Borus, Eltayeb Ahmed Elsayed
Journal: MMWR Morbidity and Mortality Weekly Report (2018)
Abstract B12: Therapeutic potential of NTRK3 in desmoplastic small round cell tumor
Authors: Lee Spraggon, Julija Hmeljak, Heather Magnan, Romel Somwar, Marina Asher, Alifiani B. Hartono, Sean Bong Lee, Marc Ladanyi
Journal: Clinical Cancer Research (2018)

Abstract Desmoplastic small round cell tumor (DSRCT) is a soft-tissue sarcoma that predominantly affects adolescent and young adult males and has a dismal prognosis, despite aggressive treatment. It is characterized by the t(11;22)(p13:q12) translocation that generates the EWSR1-WT1 chimeric transcription factor, a powerful oncogene and the main molecular driver of DSRCT. EWSR1-WT1 rewires global gene expression networks and activates aberrant expression of targets that contribute to an oncogenic expression program. It has been previously described that EWSR1-WT1 can activate neural gene expression (1), supporting the hypothesis that targeting neural differentiation markers might offer a novel therapeutic approach to treat DSRCT. Among those markers, our analysis of DSRCT tumors demonstrated prominent expression of neurotrophic tyrosine kinase receptor 3 (NTRK3; TrkC), a druggable receptor tyrosine kinase, specifically expressed in DSRCT compared to other translocation-driven sarcomas. We show that EWSR1-WT1 directly activates its expression, and that abrogation of NTRK3 reduces growth of DSRCT cells. Conversely, we show that pharmacologic targeting of NTRK3 is effective both in in vitro and in vivo models of DSRCT, suggesting that NTRK3 is a viable therapeutic target, especially in light of the recent clinical development of highly specific and effective NTRK inhibitors. Reference 1. Kang et al., Cancer Res 2014;15;74(16):4526-35. Citation Format: Lee Spraggon, Julija Hmeljak, Heather Magnan, Romel Somwar, Marina Asher, Alifiani B. Hartono, Sean Bong Lee, Marc Ladanyi. Therapeutic potential of NTRK3 in desmoplastic small round cell tumor [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B12.
Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells
Authors: Soren K. Thomsen, Anne Raimondo, Benoit Hastoy, Shahana Sengupta, Xiao-Qing Dai, Austin Bautista, Jenny Censin, Anthony J. Payne, Mahesh M. Umapathysivam, Aliya F. Spigelman, Amy Barrett, Christopher J. Groves, Nicola L. Beer, Jocelyn E. Manning Fox, Mark I. McCarthy, Anne Clark, Anubha Mahajan, Patrik Rorsman, Patrick E. MacDonald, Anna L. Gloyn
Journal: Nature Genetics (2018)
3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes
Authors: Marco Campisi, Yoojin Shin, Tatsuya Osaki, Cynthia Hajal, Valeria Chiono, Roger D. Kamm
Journal: Biomaterials (2018)

The blood-brain barrier (BBB) regulates molecular trafficking, protects against pathogens, and prevents efficient drug delivery to the brain. Models to date failed to reproduce the human anatomical complexity of brain barriers, contributing to misleading results in clinical trials. To overcome these limitations, a novel 3-dimensional BBB microvascular network model was developed via vasculogenesis to accurately replicate the in vivo neurovascular organization. This microfluidic system includes human induced pluripotent stem cell-derived endothelial cells, brain pericytes, and astrocytes as self-assembled vascular networks in fibrin gel. Gene expression of membrane transporters, tight junction and extracellular matrix proteins, was consistent with computational analysis of geometrical structures and quantitative immunocytochemistry, indicating BBB maturation and microenvironment remodelling. Confocal microscopy validated microvessel-pericyte/astrocyte dynamic contact-interactions. The BBB model exhibited perfusable and selective microvasculature, with permeability lower than conventional in vitro models, and similar to in vivo measurements in rat brain. This robust and physiologically relevant BBB microvascular model offers an innovative and valuable platform for drug discovery to predict neuro-therapeutic transport efficacy in pre-clinical applications as well as recapitulate patient-specific and pathological neurovascular functions in neurodegenerative disease.
Clonal hematopoiesis in patients with multiple myeloma undergoing autologous stem cell transplantation
Authors: Sneha Chitre, Friedrich Stölzel, Kirsty Cuthill, Mathew Streetly, Charlotte Graham, Claudia Dill, Azim Mohamedali, Alexander Smith, Johannes Schetelig, Heidi Altmann, Martin Bornhäuser, Ghulam J. Mufti
Journal: Leukemia (2018)
Dietary Fat, but Not Protein or Carbohydrate, Regulates Energy Intake and Causes Adiposity in Mice
Authors: Sumei Hu, Lu Wang, Dengbao Yang, Li Li, Jacques Togo, Yingga Wu, Quansheng Liu, Baoguo Li, Min Li, Guanlin Wang, Xueying Zhang, Chaoqun Niu, Jianbo Li, Yanchao Xu, Elspeth Couper, Andrew Whittington-Davies, Mohsen Mazidi, Lijuan Luo, Shengnan Wang, Alex Douglas, John R. Speakman
Journal: Cell Metabolism (2018)
Effect of a Lay Health Worker Intervention on Goals-of-Care Documentation and on Health Care Use, Costs, and Satisfaction Among Patients With Cancer
Authors: Manali I. Patel, Vandana Sundaram, Manisha Desai, Vyjeyanthi S. Periyakoil, James S. Kahn, Jay Bhattacharya, Steven M. Asch, Arnold Milstein, M. Kate Bundorf
Journal: JAMA Oncology (2018)

<h3>Importance</h3> Although lay health workers (LHWs) improve cancer screening and treatment adherence, evidence on whether they can enhance other aspects of care is limited. <h3>Objective</h3> To determine whether an LHW program can increase documentation of patients’ care preferences after cancer diagnosis. <h3>Design, Setting, and Participants</h3> Randomized clinical trial conducted from August 13, 2013, through February 2, 2015, among 213 patients with stage 3 or 4 or recurrent cancer at the Veterans Affairs Palo Alto Health Care System. Data analysis was by intention to treat and performed from January 15 to August 18, 2017. <h3>Interventions</h3> Six-month program with an LHW trained to assist patients with establishing end-of-life care preferences vs usual care. <h3>Main Outcomes and Measures</h3> The primary outcome was documentation of goals of care. Secondary outcomes were patient satisfaction on the Consumer Assessment of Health Care Providers and Systems “satisfaction with provider” item (on a scale of 0 [worst] to 10 [best possible]), health care use, and costs. <h3>Results</h3> Among the 213 participants randomized and included in the intention-to-treat analysis, the mean (SD) age was 69.3 (9.1) years, 211 (99.1%) were male, and 165 (77.5%) were of non-Hispanic white race/ethnicity. Within 6 months of enrollment, patients randomized to the intervention had greater documentation of goals of care than the control group (97 [92.4%] vs 19 [17.5%.];<i>P</i> &lt; .001) and larger increases in satisfaction with care on the Consumer Assessment of Health Care Providers and Systems “satisfaction with provider” item (difference-in-difference, 1.53; 95% CI, 0.67-2.41;<i>P</i> &lt; .001). The number of patients who died within 15 months of enrollment did not differ between groups (intervention, 60 of 105 [57.1%] vs control, 60 of 108 [55.6%];<i>P</i> = .68). In the 30 days before death, patients in the intervention group had greater hospice use (46 [76.7%] vs 29 [48.3%];<i>P</i> = .002), fewer emergency department visits (mean [SD], 0.05 [0.22] vs 0.60 [0.76];<i>P</i> &lt; .001), fewer hospitalizations (mean [SD], 0.05 [0.22] vs 0.50 [0.62];<i>P</i> &lt; .001), and lower costs (median [interquartile range], $1048 [$331-$8522] vs $23 482 [$9708-$55 648];<i>P</i> &lt; .001) than patients in the control group. <h3>Conclusions and Relevance</h3> Incorporating an LHW into cancer care increases goals-of-care documentation and patient satisfaction and reduces health care use and costs at the end of life. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02966509
Association of Self-regulation With Obesity in Boys vs Girls in a US National Sample
Authors: Sarah E. Anderson, Robert C. Whitaker
Journal: JAMA Pediatrics (2018)

<h3>Importance</h3> Poor self-regulation in childhood is associated with increased risk of obesity. However, studies have assumed that greater self-regulation is associated with a lower obesity risk and have rarely examined differences in the association by sex. <h3>Objectives</h3> To examine how different levels of toddler self-regulation are associated with the prevalence of obesity at kindergarten age and whether the pattern of association is different between boys and girls. <h3>Design, Setting, and Participants</h3> This was a prospective cohort study using data from the Early Childhood Longitudinal Study, Birth Cohort, a nationally representative sample of 10 700 US children born in 2001 and followed up through kindergarten entry (2006-2007). The analytic sample included 6400 children with observed toddler self-regulation. Data collection occurred in children's homes and consisted of a parent interview and direct assessment of the child. Data analysis took place between May 2016 and March 2018. <h3>Exposures</h3> During a standardized, in-home, developmental assessment at 24 months of age, observers scored 4 dimensions of children's self-regulation: adaptability, attention, persistence, and frustration tolerance. Self-regulation scores ranging from a low of 4 to a high of 20 were grouped into quartiles. <h3>Main Outcomes and Measures</h3> With use of measured heights and weights at 5.5 years, obesity was defined as a body mass index for age in the 95th percentile or greater. <h3>Results</h3> The analytic sample consisted of 6400 children (3250 boys [50.6%, weighted]), with a median age of 24.1 months (interquartile range, 23.4-24.7 months) and 64.5 months (interquartile range, 61.7-67.6 months) at the self-regulation and body mass index assessments, respectively. Self-regulation scores were lower for boys than for girls (mean, 13.7 [95% CI, 13.4-13.9] vs 14.9 [95% CI, 14.7-15.1]), and the lowest self-regulation quartile comprised more boys than girls (weighted percentages, 66.5% vs 33.5%). The prevalence of obesity at 5.5 years was 19.2% among boys and 16.5% among girls. The pattern of association between toddler self-regulation and obesity at 5.5 years was different for boys and girls (<i>P</i> = .008 for interaction). Among boys, the adjusted prevalence of obesity was 19.7%, 18.3%, 20.3%, and 15.9% from lowest to highest quartile of self-regulation. In contrast, among girls, there was a U-shaped association (adjusted prevalence of obesity from lowest to highest self-regulation quartile, 17.0%, 10.3%, 10.7%, and 15.0%). <h3>Conclusions and Relevance</h3> In a large national cohort of US children, there were differences between boys and girls in the pattern of the association between self-regulation at 24 months and obesity at 5.5 years of age. Obesity prevention efforts aimed at improving self-regulation may have different results for girls and boys.
Cytotoxic CD8+ T cells recognize and kill Plasmodium vivax–infected reticulocytes
Authors: Caroline Junqueira, Camila R. R. Barbosa, Pedro A. C. Costa, Andréa Teixeira-Carvalho, Guilherme Castro, Sumit Sen Santara, Rafael P. Barbosa, Farokh Dotiwala, Dhelio B. Pereira, Lis R. Antonelli, Judy Lieberman, Ricardo T. Gazzinelli
Journal: Nature Medicine (2018)
Cachectic Cancer Patients: Immune to Checkpoint Inhibitor Therapy?
Authors: Christopher C. Coss, Steven K. Clinton, Mitch A. Phelps
Journal: Clinical Cancer Research (2018)

Immune checkpoint inhibition is dramatically improving patient outcomes in diverse cancers, many of which responded poorly to traditional cytotoxic agents. Drivers of heterogeneous response to immune checkpoint therapy are poorly characterized. Cachectic cancer patients exhibit elevated pembrolizumab clearance and poor response, highlighting the immense therapeutic challenge posed by cancer cachexia.See related article by Turner et al., p. 5841.
Quantitative Magnetic Resonance Imaging Analysis of Neovasculature Volume in Carotid Atherosclerotic Plaque
Authors: WilliamKerwin, AndrewHooker, MarySpilker, PaoloVicini, MarinaFerguson, ThomasHatsukami, ChunYuan
Journal: Circulation (2003)

Background— Neovasculature within atherosclerotic plaques is believed to be associated with infiltration of inflammatory cells and plaque destabilization. The aim of the present investigation was to determine whether the amount of neovasculature present in advanced carotid plaques can be noninvasively measured by dynamic, contrast-enhanced MRI. Methods and Results— A total of 20 consecutive patients scheduled for carotid endarterectomy were recruited to participate in an MRI study. Images were obtained at 15-second intervals, and a gadolinium contrast agent was injected coincident with the second of 10 images in the sequence. The resulting image intensity within the plaque was tracked over time, and a kinetic model was used to estimate the fractional blood volume. For validation, matched sections from subsequent endarterectomy were stained with ULEX and CD-31 antibody to highlight microvessels. Finally, all microvessels within the matched sections were identified, and their total area was computed as a fr...