The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

PLoS BIOLOGY Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor Jean-Philippe Coppe 1 , Christopher K. Patil 1[ , Francis Rodier 1,2[ , Yu Sun 3 , Denise P. Mun oz 1,2 , Joshua Goldstein 1¤ , Peter S. Nelson 3 , Pierre-Yves Desprez 1,4 , Judith Campisi 1,2* 1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America, 2 Buck Institute for Age Research, Novato, California, United States of America, 3 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 4 California Pacific Medical Center Research Institute, San Francisco, California, United States of America Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA- damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment. Citation: Coppe JP, Patil CK, Rodier F, Sun Y, Mun oz DP, et al. (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6(12): e301. doi:10.1371/journal.pbio.0060301 Introduction Cancer is a multistep disease in which cells acquire increasingly malignant phenotypes. These phenotypes are acquired in part by somatic mutations, which derange normal controls over cell proliferation (growth), survival, invasion, and other processes important for malignant tumorigenesis [1]. In addition, there is increasing evidence that the tissue microenvironment is an important determinant of whether and how malignancies develop [2,3]. Normal tissue environ- ments tend to suppress malignant phenotypes, whereas abnormal tissue environments such at those caused by inﬂammation can promote cancer progression. Cancer development is restrained by a variety of tumor suppressor genes. Some of these genes permanently arrest the growth of cells at risk for neoplastic transformation, a process termed cellular senescence [4–6]. Two tumor suppressor pathways, controlled by the p53 and p16INK4a/pRB proteins, regulate senescence responses. Both pathways integrate multiple aspects of cellular physiology and direct cell fate towards survival, death, proliferation, or growth arrest, depending on the context [7,8]. Several lines of evidence indicate that cellular senescence is a potent tumor-suppressive mechanism [4,9,10]. Many poten- tially oncogenic stimuli (e.g., dysfunctional telomeres, DNA PLoS Biology | www.plosbiology.org damage, and certain oncogenes) induce senescence [6,11]. Moreover, mutations that dampen the p53 or p16INK4a/pRB pathways confer resistance to senescence and greatly increase cancer risk [12,13]. Most cancers harbor mutations in one or both of these pathways [14,15]. Lastly, in mice and humans, a senescence response to strong mitogenic signals, such as those delivered by certain oncogenes, prevents premalignant lesions from progressing to malignant cancers [16–19]. Academic Editor: Julian Downward, Cancer Research UK, United Kingdom Received June 27, 2008; Accepted October 22, 2008; Published December 2, 2008 Copyright: O 2008 Coppe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abbreviations: CM, conditioned medium; DDR, DNA damage response; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial–mesenchymal transition; GSE, genetic suppressor element; IL, interleukin; MIT, mitoxantrone; PRE, presenescent; PrEC, normal human prostate epithelial cell; REP, replicative exhaustion; SASP, senescence-associated secretory phenotype; SEN, senescent; shRNA, short hairpin RNA; XRA, X-irradiation * To whom correspondence should be addressed. E-mail: jcampisi@lbl.gov [ These authors contributed equally to this work. ¤ Current address: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America December 2008 | Volume 6 | Issue 12 | e301

Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment and their potential multiple suppressive mechanisms. Strategies for therapeutic targeting of regulatory T cells and the effect of regulatory T cells on current immunotherapeutic and vaccine regimens are discussed.

Regulatory T cells, tumour immunity and immunotherapy

https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1006&context=covid19

SARS-CoV-2

Erroneous communication between the innate and adaptive immune systems through cytokines results in exaggerated or attenuated immune response. It is not known whether the pathologic immune response in inflammatory bowel disease has its origin in a dysbalance of pro- and anti-inflammatory cytokine release or whether it is secondary in subsequence of a defective intestinal barrier or the destructive power of aggressive microbiota in the gut lumen.

Cytokines in inflammatory bowel disease

Gene expression analysis in human peripheral eosinophils by various cytokine stimuli

To evaluate the clinical factors associated with the outcome of tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, thereby clarifying who would most likely benefit from that surgery.

Can the effectiveness of tonsillectomy for PFAPA syndrome be predicted based on clinical factors

PROBLEM TO BE SOLVED: To provide a digital copying machine by which an original larger than a maximum placing size of an original platen board is copied at a low cost in a processing time of a practical level. SOLUTION: Image data of devided originals outputted from an original scanning input means 1 are converted into reduced image data in response to a copy size by an image reduction means 2, the reduced image data are stored in a data storage means 3, and a pattern matching means 4 compares common image data in the reduced divided image data to discriminate the coincidence of the image data. An address setting means 5 generates a joint position address corresponding to each joint position in each storage area based on the discrimination result. A data output control means 6 joints sequentially the reduced image data of adjacent images stored in each storage area and reads them. An image output means 7 generates a copied image of the original onto a prescribed recording medium according to the reduced image data.

Image forming method and device

Interleukin-33 and Thymic Stromal Lymphopoietin Are Preferentially Elevated In The Sera Of Infants With Eosinophilic Gastroenteritis

Erika Jensen-Jarolim, MD, Michael Kundi, Eva Untersmayr, Isabella Pali-Schoell, Berthold Reichardt, and Galateja Jordakieva; Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria, Medical University of Vienna, Vienna, Austria, Medical University of Vienna, Department of Pathophysiology and Allergy Research, Vienna, Austria, The Interuniversity Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University of Vienna and University of Vienna, Austria, Vienna, Austria, Sickness Fund Burgenland, Eisenstadt, Austria. RATIONALE: Anti-ulcer drugs, such as proton pump inhibitors (PPI), are widely prescribed and used in developed countries worldwide. Recently concerns about the promotion of allergic sensitizations following gastric pH modulation have been raised in mechanistic and observational studies. We aimed to assess the frequency of anti-allergic drug prescription following gastric acid inhibitors use in a population-wide study in Austria. METHODS: In this cross-sectional study, age and gender controlled data from health insurance claim records between 2009 and 2013, covering 8.2 million subjects (approx. 97% of the Austrian population), were analyzed regarding prescriptions of i) gastric acid inhibitors (PPI, H2-receptor antagonists, sucralfate, prostaglandin E2) and anti-allergic medication (antihistamines, desensitization therapy). Other commonly prescribed drugs (lipid-modifying and antihypertensive substances) served as controls by Cox regression in a regional subgroup. RESULTS: Prescription of anti-allergic drugs following gastric acidinhibitors showed a rate ratio of 1.96 (95%CI:1.95-1.97) in overall Austrian data and 3.07 (95%-CI:2.89-3.27) in the regional data set, which wasmore prominent in women (P<0.001). Age and gender adjusted hazard ratio was found to be 2.05 (95%CI:1.91-2.19), and was elevated independent of prescribed gastric acid-inhibiting substances. Further, rate ratios increased from 1.47 (95%CI:1.45-1.49) in subjects <20 years of age, to 5.20 (95%-CI:5.15-5.25) in >60 year olds. CONCLUSIONS: The increased use of anti-allergy medication subsequent to gastric acid suppression suggests an association with the occurrence of allergic symptoms. Prescription of anti-ulcer drugs should be restricted to cases with clear indication and adequate diagnosis to minimize the risk for allergic comorbidities.

Kenji Matsumoto

Papers

Gene expression analysis in human peripheral eosinophils by various cytokine stimuli

Can the effectiveness of tonsillectomy for PFAPA syndrome be predicted based on clinical factors

Image forming method and device

Interleukin-33 and Thymic Stromal Lymphopoietin Are Preferentially Elevated In The Sera Of Infants With Eosinophilic Gastroenteritis

Allergy, depression and quality of life among pregnant women in the Japan Environment and Children’s Study (JECS)