Cancer epigenetics

People with haemophilia in Iran live with the disabling legacy of international economic sanctions against the country, which were lifted in 2016 (see also S. Shahabi et al. Nature 520, 157; 2015).

Iran has the highest number of people with haemophilia in the Middle East. Timely administration of the blood-clotting protein factor VIII, which is deficient in haemophilia, can prevent physical disability.

According to the annual global survey by the World Federation of Hemophilia and reports from the director of Iran’s Haemophilia Society, the mean per capita use of factor VIII in Iran was 0.5 international units (IU) after sanctions were imposed in 2006, down from 1.6 before. The drop was a result of a shortage of the protein and inflated prices during the sanctions era. It left about 1,000 people who have haemophilia with physical impairment as a result of bleeding into their joints, and some individuals died from uncontrolled bleeding (see go.nature.com/2jfj9ow).

The lifting of sanctions has made a big difference: the per capita use of factor VIII in Iran has now risen to 2.7 IU. We hope that the slow improvement in the country’s public-health services and pharmaceutical research can continue uninterrupted by political interference.

Some of the key epigenetic regulatory mechanisms appeared early during evolution, and the acquisition of novel epigenetic regulators apparently facilitated certain evolutionary transitions. In this short review we focus
mainly on the major epigenetic mechanisms that control chromatin structure and accessibility in mammalian cells. The enzymes methylating CpG dinucleotides and those involved in the active demethylation of 5-metylcytosine (5mC) are outlined together with the members of the methyl binding protein (MBP) family that bind to and “interpret” the 5mC mark. The enzymes involved in reversible, covalent modifi cations of core histone proteins that affect chromatin structure are also described briefly. Proteins that build up Polycomb group (PcG) and Trithorax group (TrxG) protein complexes may also modify histones. By establishing heritable chromatin states, PcG and TrxG complexes contribute – similarly to cytosine methylation – to the transmission of cell type-specific gene expression
patterns from cell generation to cell generation. Novel players
involved in epigenetic regulation, including variant histones, pioneer transcription factors, long noncoding RNA molecules and the regulators of long-distance chromatin interactions are introduced as well, followed by the characterization of various chromatin types.

THERE ARE SEVERAL TYPES OF AETHERS I.E. THE ABORIGINAL CIRCULAR, THEN SQUARE THEN RECTANGULAR THEN THE HEXAGONAL AETHERS THAT WE SEE ALL AROUND US AND THE BOUNDARY LAYER THE PENTAGONAL AETHERS, WHICH PATRICK FLANAGAN POINTED OUT TO ME AS BEING WHERE DIFFERENTIATION STARTS.  THIS IS WHERE THE MAGIC HAPPENS.  ALL THINGS THAT HAVE A SKIN ARE INVOLVED WITH THE BOUNDARY LAYER AETHER. 

BLESSINGS,
MIKE

Environmentally-induced epigenetic changes of gene regulation could result from chronic, lifelong exposure, to low doses of environmental toxicants, such as chemicals including, tobacco smoking and endocrine disrupting compounds, or to other environmental factors such as nutritional changes, and lifestyle-related conditions. These environmentally-acquired epigenetic marks may influence the control of gene regulation through DNA methylation, histone modification, or through a large set of non-coding RNAs (ncRNAs). These epigenetic effects might be passed on to the developing embryo and child as inheritable non-genetic marks, which recapitulate previous lifelong history of exposure to environmental influences that start from the stage of primordial germ cell, passing through the maturing germ cell, and ending by the zygote stage. This involves the paternally transmitted information on the sperm that contribute to modulating embryogenesis functions and later childhood development, in concert with, the maternally transmitted information encountered by the exposure to a large milieu of environmental factors either periconceptionally or during lactation period.

An important feature of cancer development and progression is the change in DNA methylation patterns, characterized by the hypermethylation of specific genes concurrently with an overall decrease in the level of 5-methylcytosine. Hypomethylation of the genome can affect both single-copy genes, repeat DNA sequences and transposable elements, and is highly variable among and within cancer types. Here, we review our current understanding of genome hypomethylation in cancer, with a particular focus on hypomethylation of the different classes and families of repeat sequences. The emerging data provide insights into the importance of methylation of different repeat families in the maintenance of chromosome structural integrity and the fidelity of normal transcriptional regulation. We also consider the events underlying cancer-associated hypomethylation and the potential for the clinical use of characteristic DNA methylation changes in diagnosis, prognosis or classification of tumors.

Long non-coding RNAs (lncRNAs) refer to a group of RNAs that are usually more than 200 nucleotides and are not involved in protein generation. Instead, lncRNAs are involved in different regulatory processes, such as regulation of gene expression. Different lncRNAs exist throughout the genome. LncRNAs are also known for their roles in different human diseases such as cancer. HOTAIR is an lncRNA that plays a role as an oncogenic molecule in different cancer cells, such as breast, gastric, colorectal, and cervical cancer cells. Therefore, HOTAIR expression level is a potential biomarker for diagnostic and therapeutic purposes in several cancers. This RNA takes part in epigenetic regulation of genes and plays an important role in different cellular pathways by interacting with Polycomb Repressive Complex 2 (PRC2). In this review, we describe the molecular function and regulation of HOTAIR and its role in different types of cancers.

Dear Sir/Madam

We are currently hosting the Oncologist & Diagnostics Conference  which is going to be organized during August 28-30, 2017 Brussels, Belgium. With great pride and honour, we would like to invite you to participate in Oncologist & Diagnostics Conference in Brussels, Belgium

Kindly let me know about you interest toward participation as a Keynote, Speaker, Poster presentation, E-Poster and Video Presentation, delegate.
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Kindly contact us for any sort of further assistance.
We sincerely hope that you will honour us by accepting our invitation

Regards
Celina Crystal
Manager of oncology and conferences
P 702 508 5200 Ext 8033
#cancerdiagnostics@cancersummit.org

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ConferenceSeries Ltd invites all the participants across the globe to attend the Oncologist & Diagnostics Conference slated on August 28-30, 2017 at Brussels, Belgium.

Cancer Diagnostics 2017 directs towards addressing main issues as well as future strategies of Cancer. This is going to be the largest and most promising international conference where the program includes Clinical Oncologists, Registered Nurses, Nurse practitioners and the entire medical team involved in patient care, researchers, professional, early career individuals and patient advocates who wish to learn principles of tumor immunology and immunotherapy well as decision makers will come to discuss and debate on various aspects of the challenges, risks and investment opportunities throughout the complete information of Cancers. Cancer Diagnostics 2017 will also provide the three days of discussions on methods and strategies related to management and quality improvement of Diagnostics device developing and Cancer Research and as well as to explore the new ideas and concepts on global scale and the topics include lung cancer, breast cancer, bone cancer, leukemia, blood cancer, cervical cancer, colon-rectum cancer, pediatric cancer, surgical cancer, Prostate cancer, thyroid cancer.

According to 2012 statistics approximately 14.1 million cases are reported and 8.2 million deaths are reported. Lung, Liver, Stomach and bowel cancers cause the most common deaths among the worldwide that accounts nearly half of all the cancer deaths. About 70% increase in the cases are to be expected over the next 2 decades. In males 5 most common sites of cancer are diagnosed in 2012 were lung, prostate, colorectal and liver cancers. In females 5 most common sites diagnosed were breast, colorectal, cervix, lung and stomach cancer. Nearly 60% of the world’s total new cases occur in the Africa, Asia and Central and South America regions. All over the world Denmark ranks 1st in the cancer deaths USA is accompanied next to it.

ConferenceSeries Ltd  which is comprised of 3000+ Global Events with over 600+ Conferences, 1200+ Symposiums and 1200+Workshops on diverse Medical, Pharmaceutical, Clinical, Engineering, Science, Technology, Business and Management field is organizing conferences all over the globe. It hosts numerous Cancer Conferences, Cancer meeting, global cancer conference, European Oncology Conferences, Surgical oncology like skin cancer conference, breast cancer conference, liver cancer conference, lung cancer meetings, and Oncology Conferences where knowledge transfer takes place through debates, round table discussions, poster presentations, workshops, symposia and exhibitions and which helps get possibilities for treating the diseases with new era, technology and research.



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Polyploid giant cancer cells (PGCCs) found in different solid cancers are reproductive cyst-like structures surrounded by an actin envelop. They give rise by hyper-polyploidisation to numerous progeny (microcells, neotic cells) that start a primitive multi-lined lineage and generate subsequent PGCCs by asymmetric division and cyclic differentiation. This cancer cell life cycle has multiple similarities with the life cycle of lower eukaryotes (protists) substantiating the atavistic theory of cancer. The primitive cancer life cycle contains several cell types including primary cancer stem cells, somatic cells, as well as reproductive cells, that differentiate new atavistic cyst like structures (aCLSs, PGCCs). Accordingly, cancer stem cells are not transformed normal stem cells (hSCs). Similarities between CSCs and normal hSCs arise from the evolutionary common origin of primitive eukaryotic and more highly evolved stemness. The cell of origin of cancer, as postulated here is a deregulated human cell that has lost, not only relevant control mechanisms and mitotic capacity, but also its normal human p53 network becoming useless for the atavistic life cycle. We believe that this protoprecursor of cancer reactivates an ancient primitive TP53 network originating from the common eukaryotic ancestor. This atavistic p53 predecessor can repair genotoxic DNA damages of reproductive cancer cells including CSCs but not DNA damages of somatic cancer cells exposed to stress (genotoxic stress).

Histone deacetylases (HDACs) are enzymes that act on histone proteins to remove the acetyl group and thereby regulate the
chromatin state. HDACs act not only on histone protein but also nonhistone proteins that are key players in cellular processes such
as the cell cycle, signal transduction, apoptosis, and more. “Classical” HDACs have been shown to be promising targets for anticancer
drug design and development. However, the selectivity of HDAC inhibitors for HDAC isoforms remains the motivation of current
research in this field. Here, we explored Class I HDACs and HDAC6 by sequence alignment and structural superimposition, catalytic
channel extraction, and identification of critical residues involved in HDAC catalysis. Based on the general pharmacophore features
of known HDAC inhibitors, we developed a library of compounds by scaffold hopping on a fragment hit identified via structurebased
virtual screening of the molecular fragment library retrieved from the Otava database. Molecular docking assay revealed five of
these compounds to have increased potency and selectivity for HDACs 1 and 2. Furthermore, their predicted absorption, distribution,
metabolism, elimination, and toxicity (ADMET) properties were consistent with those of drug-like compounds. With further modelingbased and experimental investigations, we believe that these findings may offer additional potential HDAC inhibitors with improved
selectivity.

Invitation
Conference Series LLC welcomes you to attend the 2nd Cancer Diagnostics Conference & Expo during May 08-10, 2017 Barcelona, Spain.
We cordially invite all the participants who are interested in sharing their knowledge and research in the arena of 2nd Cancer Diagnostics Conference & Expo.
Cancer Diagnostics 2017 anticipates more than 200 participants around the globe with thought provoking Keynote lectures, Oral and Poster presentations. The attending delegates include Editorial Board Members of related Conference Series LLC Journals.
This is an excellent opportunity for the delegates from Universities and Institutes to interact with the world class Scientists.
The intending participants can confirm their participation by registering for the conference along with your colleagues. Avail the delegate early bird offer.
The main theme of the conference is “An insight into Advancing New methods of Cancer Diagnostics”

Regards,


Cancer Diagnostics 2017
Operating Committee
Cancer
Diagnostics 2017

Latent Epstein-Bar virus genomes undergo epigenetic
modifications which are dependent on the respective tissue type and cellular phenotype. These define distinct viral epigenotypes corresponding with latent viral gene expression profiles. Viral Latent Membrane Proteins 1 and 2A can induce cellular DNA methyltransferases, thereby
influencing the methylation status of the viral and cellular genomes. Therefore, not only the viral genomes carry epigenetic modifi cations, but also the cellular genomes
adopt major epigenetic alterations upon EBV infection. The distinct cellular epigenotypes of EBV-infected cells differ from the epigenotypes of their normal counterparts. In Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC) significant changes in the host cell methylome with a strong tendency towards CpG island hypermethylation are observed. Hypermethylated genes unique for EBVaGC suggest the existence of an EBV-specific “epigenetic signature”. Contrary to the primary malignancies carrying latent EBV genomes, lymphoblastoid cells (LCs) established by EBV infection of
peripheral B cells in vitro are characterized by a massive genome-wide demethylation and a signifi cant decrease and redistribution of heterochromatic histone marks. Establishing complete epigenomes of the diverse
EBV-associated malignancies shall clarify their similarities and differences and further clarify the contribution of EBV to the pathogenesis,
especially for the epithelial malignancies, NPC and EBVaGC.

Background: Cancer refers to a group of some of the worldwide most diagnosed and deadliest pathophysiological conditions that conquered researchers' attention for decades and yet begs for more questions for a full comprehension of its complex cellular and molecular pathology. Main body: The disease conditions are commonly characterized by unrestricted cell proliferation and dysfunctional replicative senescence pathways. In fact, the cell cycle operates under the rigorous control of complex signaling pathways involving cyclins and cyclin-dependent kinases assumed to be specific to each phase of the cycle. At each of these checkpoints, the cell is checked essentially for its DNA integrity. Genetic defects observed in these molecules (i.e., cyclins, cyclin-dependent kinases) are common features of cancer cells. Nevertheless, each cancer is different concerning its molecular and cellular etiology. These could range from the genetic defects mechanisms and/or the environmental conditions favoring epigenetically harbored homeostasis driving tumorigenesis alongside with the intratumoral heterogeneity with respect to the model that the tumor follows. Conclusions: This review is not meant to be an exhaustive interpretation of carcinogenesis but to summarize some basic features of the molecular etiology of cancer and the intratumoral heterogeneity models that eventually bolster anticancer drug resistance for a more efficient design of drug targeting the pitfalls of the models.

Prostate cancer is a major health burden within the ever-increasingly aging US population. The molecular mechanisms involved in prostate cancer are diverse and heterogeneous. In this context, epigenetic changes, both global and gene specific, are now an emerging alternate mechanism in disease initiation and progression. The three major risk factors in prostate cancer: age, geographic ancestry, and environment are all influenced by epigenetics and additional significant insight is required to gain an understanding of the underlying mechanisms. The androgen receptor and its downstream effector pathways, central to prostate cancer initiation and progression, are subject to a multitude of epigenetic alterations. In this review we focus on the global perspective of epigenetics and the use of recent next-generation sequencing platforms to interrogate epigenetic changes in the prostate cancer genome.

Background
Serrated adenocarcinoma (SAC) is a recently recognized colorectal cancer (CRC) subtype accounting for 7.5–8.7 % of CRCs. It has been shown that SAC has a worse prognosis and different histological and molecular features compared to conventional carcinoma (CC) but, to date, there is no study analysing its methylome profile.

Results
The methylation status of 450,000 CpG sites using the Infinium Human Methylation 450 BeadChip array was investigated in 103 colorectal specimens, including 39 SACs and 34 matched CCs, from Spanish and Finnish patients. Microarray data showed a higher representation of morphogenesis-, neurogenesis-, cytoskeleton- and vesicle transport-related functions and also significant differential methylation of 15 genes, including the iodothyronine deiodinase DIO3 and the forkhead family transcription factor FOXD2 genes which were validated at the CpG, mRNA and protein level using pyrosequencing, methylation-specific PCR, quantitative polymerase chain reaction (qPCR) and immunohistochemistry. A quantification study of the methylation status of CpG sequences in FOXD2 demonstrated a novel region controlling gene expression. Moreover, differences in these markers were also evident when comparing SAC with CRC showing molecular and histological features of high-level microsatellite instability.

Conclusions
This methylome study demonstrates distinct epigenetic regulation patterns in SAC which are consistent to previous expression profile studies and that DIO3 and FOXD2 might be molecular targets for a specific histology-oriented treatment of CRC.

Tumor dormancy is considered to be the last frontier in the battle to cure cancer. Although experimental evidence and clinical studies led to some consensus regarding the phenotypical characteristics of tumor dormancy, the underlying biological controls remain elusive. As a result, in the absence of dormancy-targeted therapeutic strategies, cancer drug resistance and recurrence are a certainty in a matter of time. In this review, we discuss a novel opportunity to target prostate tumor dormancy based on the expression of tumor suppressor maspin, an epithelial-specific endogenous inhibitor of histone deacetylase 1 (HDAC1).

Histone deacetylases (HDACs) are enzymes that act on histone proteins to remove the acetyl group and thereby regulate the chromatin state. HDACs act not only on histone protein but also nonhistone proteins that are key players in cellular processes such as the cell cycle, signal transduction, apoptosis, and more. “Classical” HDACs have been shown to be promising targets for anticancer drug design and development. However, the selectivity of HDAC inhibitors for HDAC isoforms remains the motivation of current research in this field. Here, we explored Class I HDACs and HDAC6 by sequence alignment and structural superimposition, catalytic channel extraction, and identification of critical residues involved in HDAC catalysis. Based on the general pharmacophore features of known HDAC inhibitors, we developed a library of compounds by scaffold hopping on a fragment hit identified via structurebased virtual screening of the molecular fragment library retrieved from the Otava database. Molec...

Direct reprogramming procedures reset the epigenetic memory of cells and convert differentiated somatic cells into pluripotent stem cells. In addition to epigenetic memory of cell identity, which is established during development, somatic cells can accumulate abnormal epigenetic changes that can contribute to pathological conditions. Aberrant promoter hypermethylation and epigenetic silencing of tumor suppressor genes (TSGs) are now recognized as an important mechanism in tumor initiation and progression. Here, we have studied the fate of the silenced TSGs p16(CDKN2A) during direct reprogramming. We find that following reprogramming, p16 expression is restored and is stably maintained even when cells are induced to differentiate. Large-scale methylation profiling of donor cells identified aberrant methylation at hundreds of additional sites. Methylation at many, but not all these sites was reversed following reprogramming. Our results suggest that reprogramming approaches may be applied to repair the epigenetic lesions associated with cancer. STEM CELLS 2010;28:1349–1354

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaque formation, tau pathology, neurodegeneration and inflammatory processes. Monocytes are involved in inflammation in AD and are recruited to the diseased brain. Recently it has been shown that aberrant epigenetic processes including acetylation are associated with the development of AD. The aim of the present study was to examine acetylation of histone H4 at lysine 12 (H4K12) in monocytes in two transgenic AD mouse models (the triple transgenic 3xTg and a model overexpressing amyloid-precursor protein APP with the Swedish-Dutch-Iowa mutations), and to compare with monocytes isolated from human patients with mild cognitive impairment (MCI) and AD. Methods: Mouse and human monocytes were selectively isolated with a positive (PluriSelect) respectively with a negative selection method (Miltenyi). Histones were extracted and acetylation of H4K12 was analyzed by a quantification fluorometric kit. Moreover, monocyte cytokine release was measured and cell death analyzed by FACS using incorporation of 7-AAD. Results: Our data show a significant increase of monocytic H4K12 acetylation in both transgenic AD mouse models early during development of the plaque deposition in the brain. In line with these data we found significantly elevated acetylation of H4K12 in human patients with MCI but not in patients with AD. Further we observed that the monocytes of AD mice and of AD patients were significantly more vulnerable to cell damage (as seen by 7-AAD incorporation in FACS analysis) and displayed an enhanced release of pro-inflammatory cytokines (MIP2 and TNFα). Conclusion: Our findings indicate that epigenetic changes in peripheral monocytes are an early event in AD-pathology. Thus H4K12 acetylation may be considered as a novel biomarker for early changes in AD development.

Resistance to chemotherapy, biological and targeted therapies is an important clinical problem. Resistance can arise and/or be selected for multiple mechanisms of action. Unfortunately, acquired resistance to antitumor agents or regimens is nearly inevitable in all patients with metastatic disease. Until recently, it was believed that this resistance was unalterable and irreversible, rendering retreatment with the same or similar drugs futile in most cases. However, the introduction of epigenetic therapies, including HDAC inhibitors and DNA methyltransferase inhibitors (DNMTIs), has provided oncologists with new strategies to potentially overcome this resistance. For example, if chemoresistance is the product of multiple non-genetic alterations, which develop and accumulate over time in response to treatment, then the ability to epigenetically modify the tumor to reconfigure it back to its baseline non-resistant state, holds tremendous promise for the treatment of advanced, metastatic cancer. This minireview aims (1) to explore the potential mechanisms by which a group of small molecule agents including HDACs (entinostat and vorinostat), DNA hypomethylating agents such as the DNMTIs (decitabine (DEC), 5-azacytidine (5-AZA)) and redox modulators (RRx-001) may reprogram the tumors from a refractory to non-refractory state, (2) highlight some recent findings in this area, and (3) discuss the therapeutic potential of resensitization approaches with formerly failed chemotherapies.

Aflatoxin B1 (AFB1) is currently the most commonly studied mycotoxin due to its great toxicity, its distribution in a wide variety of foods such as grains and cereals and its involvement in the development of + (HCC). HCC is one of the main types of liver cancer, and has become a serious public health problem, due to its high incidence mainly in Southeast Asia and Africa. Studies show that AFB1 acts in synergy with other risk factors such as hepatitis B and C virus (HBV and HCV) leading to the development of HCC through genetic and epigenetic modifications. The genetic modifications begin in the liver through the biomorphic AFB1, the AFB1-exo-8.9-Epoxy active, which interacts with DNA to form adducts of AFB1-DNA. These adducts induce mutation in codon 249, mediated by a transversion of G to T in the p53 tumor suppressor gene, causing HCC. Thus, this review provides an overview of the evidence for AFB1-induced epigenetic alterations and the potential mechanisms involved in the development of HCC, focusing on a critical analysis of the importance of severe legislation in the detection of aflatoxins.