tbuckley/cabot-search huggingface dataset:
A novel immune-modulatory role of neutrophils in viral infections
Authors: F.S. Tang, P.M. Hansbro, J.K. Burgess, K.J. Baines, B.G. Oliver
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: Rhinovirus (RV) is the major precipitant of asthma exacerbations. Whilst neutrophilic lung inflammation occurs during such infections, its role remains unclear. Neutrophilic inflammation is associated with increased asthma severity and steroid refractory disease. Neutrophils are vital for controlling infections but also have immune-modulatory functions utilising PD1/PD-L1 interactions. Previously, we found that neutrophils respond to viral mimetics but are not directly activated by replication competent RV. Here we investigated if neutrophils are activated or have other functions when co-cultured with virus-infected monocytes. Methods: Primary human neutrophils and autologous monocytes were co-cultured +/- RV16 or LPS, with either direct contact or separated by transwells to assess the importance of cell contact (n=5-13). RV16 infected or LPS stimulated monocytes were also exposed to killed neutrophils, neutrophil membrane components or soluble neutrophil intracellular components (n=4-6). Monocytes were pre-incubated with an anti-PD1 antibody to investigate the importance of PD1/PD-L1 interactions (n=3). IL-6 and CXCL8 mRNA and proteins were measured by qPCR and ELISA at 24h (n=4-7). Results: The constitutive release of monocyte derived IL-6 and CXCL8 was inhibited in the presence of live neutrophils (p
Best Practices for the Diagnosis and Evaluation of Infants With Robin Sequence
Authors: Corstiaan C. Breugem, Kelly N. Evans, Christian F. Poets, Sunjay Suri, Arnaud Picard, Charles Filip, Emma C. Paes, Felicity V. Mehendale, Howard M. Saal, Hanneke Basart, Jyotsna Murthy, Koen F. M. Joosten, Lucienne Speleman, Marcus V. M. Collares, Marie-José H. van den Boogaard, Marvick Muradin, Maud Els-Marie Andersson, Mikihiko Kogo, Peter G. Farlie, Peter Don Griot, Peter A. Mossey, Rona Slator, Veronique Abadie, Paul Hong
Journal: JAMA Pediatrics (2016)

Robin sequence (RS) is a congenital condition characterized by micrognathia, glossoptosis, and upper airway obstruction. Currently, no consensus exists regarding the diagnosis and evaluation of children with RS. An international, multidisciplinary consensus group was formed to begin to overcome this limitation.To report a consensus-derived set of best practices for the diagnosis and evaluation of infants with RS as a starting point for defining standards and management.Based on a literature review and expert opinion, a clinical consensus report was generated.Because RS can occur as an isolated condition or as part of a syndrome or multiple-anomaly disorder, the diagnostic process for each newborn may differ. Micrognathia is hypothesized as the initiating event, but the diagnosis of micrognathia is subjective. Glossoptosis and upper airway compromise complete the primary characteristics of RS. It can be difficult to judge the severity of tongue base airway obstruction, and the possibility of multilevel obstruction exists. The initial assessment of the clinical features and severity of respiratory distress is important and has practical implications. Signs of upper airway obstruction can be intermittent and are more likely to be present when the infant is asleep. Therefore, sleep studies are recommended. Feeding problems are common and may be exacerbated by the presence of a cleft palate. The clinical features and their severity can vary widely and ultimately dictate the required investigations and treatments.Agreed-on recommendations for the initial evaluation of RS and clinical descriptors are provided in this consensus report. Researchers and clinicians will ideally use uniform definitions and comparable assessments. Prospective studies and the standard application of validated assessments are needed to build an evidence base guiding standards of care for infants and children with RS.
Official American Thoracic Society Clinical Practice Guidelines: Diagnostic Evaluation of Infants with Recurrent or Persistent Wheezing
Authors: Clement L. Ren, Charles R. Esther, Jason S. Debley, Marianna Sockrider, Ozge Yilmaz, Nikhil Amin, Alia Bazzy-Asaad, Stephanie D. Davis, Manuel Durand, Jeffrey M. Ewig, Hasan Yuksel, Enrico Lombardi, Terry L. Noah, Peggy Radford, Sarath Ranganathan, Alejandro Teper, Miles Weinberger, Jan Brozek, Kevin C. Wilson
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Section:ChooseTop of pageAbstract <<ContentsOverviewIntroductionUse of These GuidelinesMethodsResultsLimitations and Future Di...ReferencesCITING ARTICLES
Abstract 4531: Dynamic long-range chromatin interaction controls expression of Il-21 in CD4+ T cells
Authors: Yeeun Choi
Journal: Cancer Research (2016)

Abstract IL-21, a member of four-α-helical bundle type I cytokines, causes many pleiotropic effects, including terminal differentiation of B cells, immunoglobulin production, and the development of follicular helper T cells. IL-21 also promotes differentiation of Th17 cells and is implicated in the development of autoimmune disease. IL-21 can be strongly induced in CD4+ T cells by IL-6; however, very little is known about the mechanisms underlying the transcriptional regulation of the Il-21 gene at the chromatin level. Here, we identified insulator elements in the Il-21 locus with enhancer-blocking activity, which constitutively bind CTCF and cohesin. In naïve CD4+ T cells, these upstream and downstream CTCF-binding sites interact with each other to make a DNA loop; however, the Il-21 promoter does not interact with any cis-elements in the Il-21 locus. In contrast, stimulation of CD4+ T cells with IL-6 in the presence of αCD3 and αCD28 leads to recruitment of STAT3 and NFAT transcription factors to the promoter, as well as to novel distal enhancer region. This induces dynamic changes in chromatin configuration, bringing the promoter and the regulatory elements in close spatial proximity, facilitating IL-21 expression. The long-range interaction between the promoter and distal enhancer region was dependent on JAK/STAT3 signaling pathway but was disrupted in regulatory T cells, where IL-21 expression was repressed. In addition, we demonstrated that CTCF was required for optimal IL-21 expression and formation of chromatin looping in the Il-21 locus. Thus, our work uncovers a novel topological chromatin framework underlying proper transcriptional regulation of Il-21 gene. Citation Format: Yeeun Choi. Dynamic long-range chromatin interaction controls expression of Il-21 in CD4+ T cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4531.
Evaluating cell-free DNA genetic alterations in men with metastatic castrate resistant prostate cancer.
Authors: Ratish Gambhira, Elisa M. Ledet, Aryeneesh Dotiwala, Diptasri Mandal, Oliver Sartor
Journal: Journal of Clinical Oncology (2015)

244 Background: Personalizing CRPC therapy is desirable but difficult as biomarkers that have predictive value other than AR-V7 are scarce. Novel biomarkers that can be repetitively assessed via non-invasive methods may provide important insights into disease biology and therapeutic selection. Cell free DNA (cfDNA) is found in the blood of advanced cancer patients and potentially reflects tumor-related genetic alterations. Herein, we evaluated plasma cfDNA genetic alterations in men with CRPC. Methods: We isolated cfDNA from the plasma of 11 men with metastatic CRPC. Following library prep, paired-end sequencing was performed using Illumina Hi-Seq 2000. A bioinformatics pipeline was used for data pre-possessing including alignment, duplicate removal, normalization and variant calling. Visualization and statistical analyses were performed with SNP &amp; Variation Suite v8.x. Additional analyses will follow on translocations. Results: Preliminary analysis of cfDNA showed stopgain mutations in CDC27, FAM104B and non-synonymous mutations in HNRNPCP5, PDE4DIP, JTB and OR2B11. Additionally, insertions were annotated in CYP1B1, CD81, and HSP90AA1 along with CD24 deletion. These genetic alterations are not yet validated using PCR or direct tumor based nucleic acid assays. Missense mutations in HNRNPCP5, PDE4DIP and OR2B11 and a deletion in CD24 have been previously reported in the genetics literature when directly sequencing tumor DNA. Conclusions: When compared to published databases, these preliminary analyses suggest but do not prove that prostate cancer specific genetic changes are detectable in plasma cfDNA. Further characterization of these alterations, in larger matched germline/tumor/plasma samples may provide insights into tumor evolution in CRPC patients. We hypothesize that these genetic changes may contain important predictive and/or prognostic information.
Prognostic factors in muscle-infiltrating bladder cancer (MIBC) treated with an organ-sparing treatment with concurrent gemcitabine (GEM) and radiotherapy (XRT): Results of a patient-based cumulative analysis of seven phase I-II trials.
Authors: Orazio Caffo, Catherine Thompson, Maria De Santis, Borut Kragelj, Daniel A. Hamstra, David Azria, Giovanni Pappagallo, Giovanni Fellin, Ananya Choudhury
Journal: Journal of Clinical Oncology (2015)

e15529 Background: GEM is a highly effective radiosensitiser and has been combined with XRT in MIBC after transurethral resection to achieve bladder preservation. Several phase I-II trials were conducted to identify a GEM dose able to both maximize its synergy with XRT and produce acceptable toxicity. All these studies confirmed that concurrent GEM and XRT is a treatment able to achieve good disease control and a high rate of organ preservation. We performed a patient-based cumulative analysis of the published trials with concurrent GEM/XRT in MIBC and we report the assessment of prognostic factors. Methods: Each institution provided primary data for patients (pts) enrolled in all published studies on GEM/XRT. Cox’s hazards regression model was performed to identify clinical variables associated with overall survival (OS), disease specific survival (DSS), and bladder intact survival (BIS). The assessed variables were: age, sex, suitability for surgery, clinical stage, presence of in situ disease, multifocality, hydronephrosis, GEM dose, cisplatin addition, complete remission (CR) achievement. Results: A total of 190 pts were treated in seven phase I-II GEM/XRT trials. At the end of the treatment 178 pts received a re-evaluation cystoscopy, with a CR rate of 93.3%. After a median follow-up of 43 mos, 101 are alive, while 89 pts dead (63% in absence of active disease). Thirty-six pts experienced a bladder recurrence with 14 pts undergoing cystectomy after the treatment end. The variables with a prognostic value are showed in the table. Conclusions: From the analysis of prognostic factors, it appears that CR achievement is the main variable which influences the survival outcomes of the MIBC pts treated with GEM/XRT. OS DSS BIS Univariate Multivariate Univariate Multivariate Univariate Multivariate HR P value HR P value HR P value HR P value HR P value HR P value Age 1.039 0.027 1.037 0.037 Stage 0.343 0.001 0.416 0.038 0.534 0.017 Hydronephrosis 2.834 0.010 2.759 0.015 0.294 0.010 0.313 <0.0001 CR achievement 1.039 0.027 1.037 0.037 5.374 0.001 3.622 0.022 6.862 <0.0001 4.808 <0.0001
E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor–mediated antifungal innate immunity
Authors: Le-Le Zhu, Tian-Ming Luo, Xia Xu, Ya-Hui Guo, Xue-Qiang Zhao, Ting-Ting Wang, Bing Tang, Yuan-Ying Jiang, Jin-Fu Xu, Xin Lin, Xin-Ming Jia
Journal: The Journal of Experimental Medicine (2016)

Activation of various C-type lectin receptors (CLRs) initiates potent proinflammatory responses against various microbial infections. However, how activated CLRs are negatively regulated remains unknown. In this study, we report that activation of CLRs Dectin-2 and Dectin-3 by fungi infections triggers them for ubiquitination and degradation in a Syk-dependent manner. Furthermore, we found that E3 ubiquitin ligase Casitas B-lineage lymphoma protein b (Cbl-b) mediates the ubiquitination of these activated CLRs through associating with each other via adapter protein FcR-γ and tyrosine kinase Syk, and then the ubiquitinated CLRs are sorted into lysosomes for degradation by an endosomal sorting complex required for transport (ESCRT) system. Therefore, the deficiency of either Cbl-b or ESCRT subunits significantly decreases the degradation of activated CLRs, thereby resulting in the higher expression of proinflammatory cytokines and inflammation. Consistently, Cbl-b-deficient mice are more resistant to fungi infections compared with wild-type controls. Together, our study indicates that Cbl-b negatively regulates CLR-mediated antifungal innate immunity, which provides molecular insight for designing antifungal therapeutic agents.
Abstract 1721: Desmoplasia stem and progenitor cells within the tumor microenvironment
Authors: Tamsin Lannagan, Susan Woods, Laura Vrbanac, Miao Yang, Jia Ng, Tongtong Wang, Yagnesh Tailor, Samuel Asfaha, Timothy Wang, Daniel L. Worthley
Journal: Cancer Research (2016)

Abstract All developing and adult organs are supported by connective tissues. We recently demonstrated that Gremlin 1 expressing cells in the bone (osteochondroreticular stem cells) and the bowel (intestinal reticular stem cells) are connective tissue stem cells, during development and healing. The contribution of these stem cells to the desmoplasia surrounding gastrointestinal and skeletal cancers, however, is unknown. In this study we first established that typical markers of bone marrow skeletal stem cells, also identify colony forming unit-fibroblasts (CFU-Fs) in the tumour microenvironment (identified by CD45-Ter-119-CD31-CD1040a+CD105+). Next we tested the local origins of alpha-smooth muscle actin (Acta2) expressing cancer-associated fibroblasts in orthotopic (colonoscopically delivered MC38 and carcinogenesis AOM/DSS) mouse models of colorectal cancer. Using transgenic mouse models to lineage trace and report the connective tissues in the bone and bowel, including Grem1-creERT;R26-LSL-ZsGreen; Acta2-RFP and our Acta2-CreERT line, we found that normal Grem1-expressing and Acta2-expressing cells each contribute to some, but not all, of the reactive cancer-associated fibroblasts surrounding our mouse models of cancer. Whilst, neoplastic cells appear to make a significant contribution to cancer-associated fibroblasts in some other cancers, using an epithelial specific Cre (K19-cre) there was no contribution of epithelium to Acta2-expressing cells in our AOM-DSS colorectal cancer models. We investigated Grem1 and Acta2 derived cells from the tumor microenvironment and found that these cells were clonagenic. Finally, we compared their capacity to support the in vitro growth of colorectal normal and neoplastic organoids compared to other colonic mesenchymal cell types. We are currently examining the role of these cells on expanding intestinal stem cells in normal and neoplastic gastrointestinal glands and examining the secreted factors from these cells that are relevant to tumor initiation and spread. Citation Format: Tamsin Lannagan, Susan Woods, Laura Vrbanac, Miao Yang, Jia Ng, Tongtong Wang, Yagnesh Tailor, Samuel Asfaha, Timothy Wang, Daniel L. Worthley. Desmoplasia stem and progenitor cells within the tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1721.
Multiple Copies of MLL Is The Most Commonly Detected Cytogenetic Abnormality In Newly Diagnosed Multiple Myeloma and May Modify Disease Risk
Authors: Chrystal Landry, Dory Londono, Sean M. Devlin, Alex Lesokhin, Nikoletta Lendvai, Hani Hassoun, David J Chung, Guenther Koehne, Suresh C. Jhanwar, Sergio A Giralt, Heather Landau
Journal: Blood (2013)
Abstract 643: Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1
Authors: Seiya Sato, Nao Oumi, Hiroaki Itamochi, Tetsuro Oishi, Tasuku Harada, Toru Sugiyama
Journal: Cancer Research (2016)

Abstract Malignant peritoneal mesothelioma (MPM) is a rare aggressive neoplasm of the peritoneum, and its molecular biological characteristics and mechanisms of development are poorly understood. We, therefore, established a new cell line of human MPM, TU-MM-1, to elucidate its biological properties and to develop novel therapeutic strategies. The cells showed polygonal morphology, grew in monolayers without contact inhibition and were arranged like a jigsaw puzzle. The chromosome numbers ranged from 41 to 44. A low rate of proliferation was observed and the doubling time was 67.9 h. Genomic DNA sequencing revealed that TU-MM-1 cells harbored missense mutations in APC, LATS2, BRCA1/2, and TP53, and mutation of a splice donor site in BAP1 and loss of CDKN2A gene. We observed the absence of BAP1 and p16INK4a proteins, underexpression of LATS2 protein, and overexpression of p53 protein in TU-MM-1 cells in western blot analysis. Heterotransplantation to nude mice produced tumors that had the characteristics of the original tumor. This cell line may be useful for studying biological properties and contribute to novel treatment strategies. Citation Format: Seiya Sato, Nao Oumi, Hiroaki Itamochi, Tetsuro Oishi, Tasuku Harada, Toru Sugiyama. Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 643.
Website aims to help people understand health research
Authors: Matthew Limb
Journal: BMJ (2016)

Academics have created a website to help people understand published health research and distinguish between “good” and “bad” studies.

The Understanding Health Research site (understandinghealthresearch.org) was launched on 8 August and has been tested with patients and medical professionals.[1] It was created by Glasgow University’s social and public health sciences unit in collaboration with an advisory panel of academics and is being promoted by the charity Sense About Science.

Shona Hilton, deputy director of the unit, which is funded by the Medical Research Council and the Scottish Government Chief Scientist Office, said that the website would help people “ask the right questions to understand and evaluate research studies.”

Scientists say that …
Abstract 4977: Immunogenic chemotherapy synergize PD-1 blockade by enhancing dendritic cells infiltration in triple-negative breast cancer (TNBC)
Authors: Xiangliang Yuan, Yi Xiao, Wenling Kuo, Dihua Yu
Journal: Cancer Research (2016)

Abstract Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) has achieved noteworthy benefit in multiple cancers. However, their efficacy remains unsatisfactory in triple-negative breast cancer (TNBC). Breast cancer is not highly mutagenic and immune checkpoints blockade therapies for TNBC is not as effective as for melanoma or lung cancer with high mutation rates. Combination of different modalities offers an opportunity to enhance their effect. We studied the synergistic effect of cancer chemotherapy and immunotherapy in TNBC mouse model. Here we report that the combination of Doxisome (liposomal encapsulated formulation of Doxorubicin) and anti-PD-1 antibody suppresses tumor growth, reduces lung metastasis and improves survival of mice bearing 4T1-triple negative breast cancer. Moreover, the combination of Doxisome and anti-PD-1 was able to overcome low dose Doxisome resistance in mouse models of TNBC. The success of anticancer chemotherapy is linked to a durable immune response of targeting tumor. We present evidence that the synergistic therapeutic activity of Doxisome with anti-PD1 blockade results in enhanced T cell anti-tumor immune responses. Moreover, the synergetic effect is due to increased dendritic cells (DCs) infiltration in tumor microenvironment, which internalize tumor antigens and subsequently activate tumor-reactive T cells. In TNBC mouse model, by combining anti-PD1 checkpoint blockade while shifting the immune response towards CD4+ Th1 with Doxisome, immune tolerance to TNBC tumor can be overcome. Enhancing antigen presenting cells (APCs, e.g. DCs) infiltration by immunogenic chemotherapy and T cell activation by anti-PD1 blockade increase therapy response in TNBC. These results provide rationale for several newly planned clinical trials combining immunogenic chemotherapy with PD-1 or PD-L1 blockade in breast cancer and exploration of such a combination in others solid tumors. Citation Format: Xiangliang Yuan, Yi Xiao, Wenling Kuo, Dihua Yu. Immunogenic chemotherapy synergize PD-1 blockade by enhancing dendritic cells infiltration in triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4977.