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

PURPOSE:To surely judge a knock by measuring the bias voltage to be added to the knock sensor output with a bias voltage measuring means, and outputting the reference signal containing the bias set voltage value. CONSTITUTION:A microcomputer 5 is operated by an engine key action. The judgment value of a measurement signal generating means 15 is set to the minimum and compared with the bias voltage B by a comparator 7 via a reference signal generating means 12 and a D/A converter 6 while being increased. The judgment value when the output of the comparator 7 is converted into a high level is stored. The judgment value is set to the maximum, the judgment value when the output of the comparator 7 is converted into a low level while being decreased is obtained, and the average value between this value and the stored judgment value is set to the bias set value. During the knock gate period, knock judgment signals Kn... containing the bias set value are outputted to judge the presence of a knock, during the noise gate period, noise reference signals Nn... containing the bias set value are outputted to calculate the knock judgment level with the background noise level.

Knock control device

A 58-year-old woman was urgently admitted to the hospital because of a swelling and severe pain of the right calf. There was a previous history of undergoing a mitral valve replacement 11 years before, and thereafter she was controlled with an oral anticoagulant agent (Warfarin). She was also taking antidepressive agents for recent 2 years. Phlebography revealed a thrombotic occlusion localized in the right calf. After anticoagulant and thrombolytic therapies, the recanalization of the occlusive region was obtained. However, the patient was reluctant to walking, and developed the foot drop and steppage gait on the 19th after admission. The deep venous thrombosis complicated by peroneal nerve palsy like our experience is very rare. It is suggested that the compartment syndrome might be related to the cause, which developed the peroneal nerve palsy. In addition, this case emphasizes the inportance that we should improve the swelling of the calf by walking as soon as possible, and avoid the long-term leg abduction position on bed, in order to prevent this complication.

A case report of deep venous thrombosis complicated by peroneal nerve palsy

The reaction of 2-alkynylazetidines and alcohols with a gold catalyst is described. A variety of substituted δ-amino-α,β-unsaturated ketones were synthesized via gold-promoted nucleophilic attack of alcohols followed by ring-opening of azetidine ring.

Gold-Catalyzed Nucleophilic Ring-Opening Reaction of 2-Alkynylazetidines with Alcohols.

長年にわたる基礎的，臨床的な病態解明研究の積み重ねと，昨今の医薬品開発技術の進歩により，疾患の病態メカニズムに基づいた治療薬の開発が可能になりつつある．病態形成に関与する特定の分子を標的として開発された治療薬を分子標的薬と呼び，主に細胞外分子（細胞膜上の受容体やサイトカイン等の液性因子等）を標的としたモノクローナル抗体等の高分子化合物と，主に細胞内分子（細胞内のシグナル伝達分子等）を標的としたJAK阻害剤やPDE4阻害剤等の低分子化合物が存在する．分子標的薬は病態に関与する特定の分子を標的にするため，従来の治療では治癒できなかった症例においても，症状の劇的な改善につながることも多い．一方で，アレルギー疾患は均一な疾患ではなく，ヘテロな集団で構成されているため，特定の分子標的薬が奏効する患者と，効果を示さない患者も存在する．故に病態メカニズムに基づき疾患を分類し，それぞれのサブグループに最適な治療を選択する，層別化医療を行っていく必要がある． 

免疫アレルギー疾患における分子標的薬の基礎知識

Adult men are, on average, ~13 cm taller than adult women. Although previous studies have suggested a significant contribution of sex chromosomal genes to sexual dimorphism in height, all attempts to identify a male-specific growth gene have failed. In the present study, we analyzed transcripts from cartilage tissues, and found that the expression of SHOX, a growth-promoting gene in the pseudoautosomal region on the X and Y chromosomes, was lower in females than in males. DNA methylation analyses showed that SHOX has some characteristics of genes subjected to X chromosome inactivation (XCI). These findings indicate that sex difference in human height is mainly ascribed to incomplete spreading of XCI on a pseudoautosomal gene. More importantly, RT-PCR of fibroblast clones revealed XCI-independent random clonal monoallelic expression of SHOX. We presume that during eutherian evolution, SHOX translocated from an autosome to the proto-sex chromosome without losing the epigenetic memory of random clonal monoallelic expression and subsequently underwent partial XCI. This study provides a novel model of epigenetic gene regulation leading to phenotypic diversity in humans.

https://biorxiv.org/content/10.1101/2021.08.23.457290v1.full.pdf

Kenji Matsumoto

Papers

Knock control device

A case report of deep venous thrombosis complicated by peroneal nerve palsy

Gold-Catalyzed Nucleophilic Ring-Opening Reaction of 2-Alkynylazetidines with Alcohols.

免疫アレルギー疾患における分子標的薬の基礎知識

Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height