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A recent International Diabetes Federation report suggests that more than 463 million people between 20 and 79 years have diabetes. Of the 20 million women affected by hyperglycemia during pregnancy, 84% have gestational diabetes. In addition, more than 1.1 million children or adolescents are affected by type 1 diabetes. Factors contributing to the increase in diabetes prevalence are complex and include contributions from genetic, environmental, and epigenetic factors. However, molecular regulatory mechanisms influencing the progression of an individual towards increased susceptibility to metabolic diseases such as diabetes are not fully understood. Recent studies suggest that the pathogenesis of diabetes involves epigenetic changes, resulting in a persistently dysregulated metabolic phenotype. This review summarizes the role of epigenetic mechanisms, mainly DNA methylation and histone modifications, in the development of the pancreas, their contribution to the development of diabetes, and the potential employment of epigenetic modulators in diabetes treatment.

Type 1 diabetes mellitus (DM1) is linked to a decrease in bone strength. Bone strength entails both bone mineral density and bone quality. Limited data are available regarding diabetes-induced microdamage, which can severely influence bone quality. This study has investigated bone microdamage as a measure of bone quality in an animal model of DM1. Microdamage in the neck of the femur was labelled in vivo using multiple fluorochromes at 4, 12 and 24 weeks after the onset of DM1. Microcracks were quantified and their morphology analyzed using microscopy techniques. The mean length of microcracks at 24 weeks, and crack numerical and surface densities were significantly higher (p in vivo at different time points of DM1. DM1is associated with microcracks from the early stage, however bone microstructure shows toughening mechanisms that arrest their growth but disease progression further deteriorates bone quality resulting in longer microcracks which may increase fracture risk.

The metabolic sensor Per-Arnt-Sim (Pas) domain-containing serine/threonine kinase (PASK) is expressed predominantly in the cytoplasm of different cell types, although a small percentage is also expressed in the nucleus. Herein, we show that the nuclear PASK associates with the mammalian H3K4 MLL2 methyltransferase complex and enhances H3K4 di- and tri-methylation. We also show that PASK is a histone kinase that phosphorylates H3 at T3, T6, S10 and T11. Taken together, these results suggest that PASK regulates two different H3 tail modifications involving H3K4 methylation and H3 phosphorylation. Using muscle satellite cell differentiation and functional analysis after loss or gain of Pask expression using the CRISPR/Cas9 system, we provide evidence that some of the regulatory functions of PASK during development and differentiation may occur through the regulation of these histone modifications.

T2DM is linked to an increase in the fracture rate as compared to the nondiabetic population even with normal or raised bone mineral density (BMD). Hence, bone quality plays an important role in the pathogenesis of skeletal fragility due to T2DM. This study analyzed the changes in the trabecular bone microstructure due to T2DM at various time points in ovariectomized and nonovariectomized rats. Animals were divided into four groups: (I) control (sham), (II) diabetic (sham), (III) ovariectomized, and (IV) ovariectomized with diabetes. The trabecular microarchitecture of the femoral head was characterized using a micro-CT. The differences between the groups were analyzed at 8, 10, and 14 weeks of the onset of T2DM using a two-way analysis of variance and by post hoc multiple comparisons. The diabetic group with and without ovariectomies demonstrated a significant increase in trabecular separation and a decrease in bone volume fraction, trabecular number, and thickness. BMD decreased in ovariectomized diabetic animals at 14 weeks of the onset of T2DM. No significant change was found in connectivity density and degree of anisotropy among groups. The structural model index suggested a change towards a weaker rod-like microstructure in diabetic animals. The data obtained suggested that T2DM affects the trabecular structure within a rat’s femoral heads negatively and changes are most significant at a longer duration of T2DM, increasing the risk to hip fractures.

Introduction: Obesity is a metabolic disease that accumulates an excessive level of fat. It also leads to comorbidities such as cardiovascular diseases, type 2 diabetes, high blood pressure, osteoarthritis and hormonal imbalances. Obesity has also been associated with an increased risk of developing cancers and may also enhance cancer-related mortality. The global prevalence rate of obesity and overweight, especially among children, is on the rise, and the United Arab Emirates (UAE) is no exception. Methods: A recent report suggests that the prevalence of overweight and obesity is 17% and 16%, respectively, in the UAE among children between 6 and 18 years of age. Thus, this is a serious health problem that needs urgent attention. Hence in this review we have analysed the risk factors which influence DNA Methylation in Childhood Obesity by using published literature. Results: Although genetic factors contribute to childhood obesity, epigenetic factors also play a significant role in its development. Discussion: This review article discusses the different risk factors and their contribution/s through epigenetic modification, DNA methylation and the associated changes in gene expression that eventually lead to childhood obesity. Understanding how these risk factors modulate gene expression could help to avoid or reduce the impact of exposures to such factors and thus may help to evolve a healthy future generation.

Background Diabetes mellitus (DM) is associated with osteoporosis and increase fracture risk1. Increase fractures in type 1 DM are linked to decrease bone mineral density (BMD) but BMD alone does not explain the increase fracture rate seen in diabetics. Alterations in bone quality which entails bone microarchitecture, material and composition of bone tissue also contributes to diabetic osteopathy2. Chronic state of hyperglycaemia, hypoinsulinemia, inflammation, low levels of insulin growth factor-1 (IGF-1), increased marrow adiposity, altered adipokine and endocrine factors, increased cell death and accumulation of advanced glycation products that compromise matrix properties impairs normal bone metabolism in type 1 DM1. While BMD is detected clinically using a dual-energy X-ray absorptiometry (DEXA) scan, methods to detect changes in bone quality are limited. Estimating bone markers in serum and urine are used in assessing bone quality. An imbalance in bone remodelling as measured by various bone markers is observed in type I DM. But due to discrepancy in results of various studies the exact mechanisms is still elusive. Objectives To investigate the underlying mechanism of altered bone quality in type 1diabetes: 1. By measuring the bone formations and resorption markers. 2. By measuring the advanced glycation end products. 3. By analysing the changes at cellular level in type I diabetes Methods Experimental diabetes mellitus was induced in 24 Wistar rats by injecting streptozotocin 60 mg/kg body weight intraperitoneally. Rats were sacrificed at 6th, 8th and 12th week of developing diabetes. Blood and bone specimens were collected. Serum levels of osteocalcin, bone alkaline phosphatase, C-terminal cross-linked telopeptide of type-I collagen (CTX) and pentosidine were measured using ELISA to investigate bone turnover in type I DM. The bone specimens were fixed, processed, sectioned and stained for bone histomorphometry3. Histological analysis was carried out using an ‘Olympus Research Inverted Microscope Model IX53’ complete with fluorescent attachment equipped with a DP73 camera (Olympus). Statistical analysis was carried out using sigmastat 4.0. Results Low levels of osteocalcin and bone alkaline phosphatase and increased levels of pentosidine and CTx levels in serum were found in 6th and 12th week duration of diabetes. Additionally increase number of mast cells p Conclusions Chronic hyperglycaemic state in type I DM impairs bone remodelling by decreasing bone formation and increasing bone resorption. Increase in advanced glycation end products and mast cells also contribute to diabetic osteopathy. References [1] Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL & On behalf of the IOF Bone and Diabetes Working Group. Mechanisms of diabetes mellitus-induced bone fragility. Nature Reviews Endocrinology2017;13:208–219. [2] Motyl K, McCabe LR. Streptozotocin, type I diabetes severity and bone. Biol Proced Online2009;11:296–315. [3] Mohsin S, O’Brien FJ, Lee TC. Osteonal crack barriers in ovine compact bone. Journal of Anatomy2006;208: 81–89. Acknowledgements We fully acknowledge grants received from United Arab Emirates University for this research. Ethical approval was obtained from animal research comittee at UAEU. Disclosure of Interest None declared

The use of attenuated bacteria as cancer therapeutic tools has garnered increasing scientific interest over the past 10 years. This is largely due to the development of bacterial strains that maintain good anti-tumor efficacy, but with reduced potential to cause toxicities to the host. Because of its ability to replicate in viable as well as necrotic tissue, cancer therapy using attenuated strains of facultative anaerobic bacteria, such as Salmonella, has several advantages over standard treatment modalities, including chemotherapy and radiotherapy. Despite some findings suggesting that it may operate through a direct cytotoxic effect against cancer cells, there is accumulating evidence demonstrating that bacterial therapy acts by modulating cells of the immune system to counter the growth of the tumor. Herein, we review the experimental evidence underlying the success of bacterial immunotherapy against cancer and highlight the cellular and molecular alterations in the peripheral immune system and within the tumor microenvironment that have been reported following different forms of bacterial therapy. Our improved understanding of these mechanisms should greatly aid in the translational application of bacterial therapy to cancer patients.

Although the existence of a close relationship between the early maternal developmental environment, fetal size at birth and the risk of developing disease in adulthood has been suggested, most studies, however, employed experimentally induced intrauterine growth restriction as a model to link this with later adult disease. Because embryonic size variation also occurs under normal growth and differentiation, elucidating the molecular mechanisms underlying these changes and their relevance to later adult disease risk becomes important. The birth weight of rat pups vary according to the uterine horn positions. Using birth weight as a marker, we compared two groups of rat pups – lower birth weight (LBW, 5th to 25th percentile) and average birth weight (ABW, 50th to 75th percentile) – using morphological, biochemical and molecular biology, and genetic techniques. Our results show that insulin metabolism, Pi3k/Akt and Pparγ signaling and the genes regulating growth and metabolism are significantly different in these groups. Methylation at the promoter of the InsII (Ins2) gene and DNA methyltransferase 1 in LBW pups are both increased. Additionally, the Dnmt1 repressor complex, which includes Hdac1, Rb (Rb1) and E2f1, was also upregulated in LBW pups. We conclude that the Dnmt1 repressor complex, which regulates the restriction point of the cell cycle, retards the rate at which cells traverse the G1 or G0 phase of the cell cycle in LBW pups, thereby slowing down growth. This regulatory mechanism mediated by Dnmt1 might contribute to the production of small-size pups and altered physiology and pathology in adult life., Summary: This study suggests an important link between the early embryonic environment and later adult physiology and pathology. At least one process by which this might be coordinated is through the regulatory mechanisms mediated by Dnmt1.

Epidemiological evidence suggests that obesity is linked to increased risk of developing several types of cancer. However, the mechanisms underlying this phenomenon remain unknown. Successful growth of cancer cells depends on developing mechanisms to evade host immunosurveillance, particularly within the tumor microenvironment. In the current study, we utilized a high-fat-diet (HFD)-induced obese mouse model to gain mechanistic insight into the effect of obesity on progression of implantable syngeneic tumors. When lean or obese mice were implanted with B16.F1 melanoma or MC38 colon carcinoma, tumor growth was more robust in obese group than lean controls, suggesting that obese conditions promote tumor growth. Multi-color flow cytometric analysis and gene expression profiling were carried out on distinct subpopulations of intratumoral myeloid cells. Tumors of lean mice had higher percentages of myeloid cells compared to obese counterparts with characteristics typical of activated inflammatory macrophages. In contrast, tumors of obese mice had disproportionately higher frequency of myeloid derived suppressor cells (MDSC) with a gene signature suggestive of immunosuppressive potential. These findings highlight the role of metaflammation in tumor growth promotion via the regulation of frequency and activation status of distinct subpopulations of intratumoral myeloid cells.

Obesity is a metabolic disorder characterized by a state of chronic inflammation. Based on epidemiological evidence, obesity has been linked to increased risk of developing several types of cancer. However, the mechanisms underlying this phenomenon remain unknown. Successful growth of cancer cells hinges on developing mechanisms to evade host immunosurveillance, particularly within the tumor microenvironment. In the current study, we utilized a high-fat-diet (HFD)-induced obesity mouse model to gain mechanistic insight into the effect of obesity on progression of implantable syngeneic tumors. When lean or obese mice were implanted with B16.F1 melanoma or MC38 colon carcinoma, tumor growth was more robust in obese group than lean controls, suggesting that obese conditions promote tumor growth. Multi-color flow cytometric analysis and gene expression profiling were carried out on distinct subpopulations of intratumoral myeloid cells. Tumors of lean mice had higher percentages of myeloid cells compared to obese counterparts with characteristics typical of activated inflammatory macrophages. In contrast, tumors of obese mice had disproportionately higher frequency of myeloid derived suppressor cells (MDSC) with a gene signature suggestive of immunosuppressive potential. These findings highlight the role of metaflammation in tumor growth promotion via the regulation of frequency and activation status of distinct subpopulations of intratumoral myeloid cells. Citation Format: Basel K. al-Ramadi, Suneesh Kaimala, Yassir A. Mohamed, Ashraf Al-Sbiei, Ghada Bashir, Maria J. Fernandez-Cabezudo. Tumor growth enhancement under obese conditions: Role of intratumoral myeloid cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A70.

In mammals, the casein locus consists of stretches of non-coding DNA, the functions of most of which are unknown. These regions are believed to harbour elements responsible for spatio-temporally regulated expression of genes in this locus and so far, only a few such elements have been identified. In this study, we report a novel regulatory element in the casein locus. Comparative analysis of genomic DNA sequences of casein loci from different mammals identified a 147bp long evolutionarily conserved region (ECR) upstream of Odam, a gene in this locus. The ECR was found in close proximity of Odam gene in all the mammals examined. In-silico analysis predicted the ECR as a potential regulatory element. Functional analysis in different cell lines identified it as a unidirectional repressor element. From our findings we speculate that the ECR may be involved in the repression of the Odam expression in the mammary gland during lactation.

The effectiveness of attenuated Salmonella in inhibiting tumor growth has been demonstrated in many therapeutic models, but the precise mechanisms remain incompletely understood. In this study, we show that the anti-tumor capacity of Salmonella depends on a functional MyD88-TLR pathway and is independent of adaptive immune responses. Since myeloid suppressor cells play a critical role in tumor growth, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics, and functional activation in spleen and tumor tissue of B16.F1 melanoma-bearing mice. Salmonella treatment led to increased accumulation of splenic and intratumoral CD11b(+)Gr-1(+) myeloid cells, exhibiting significantly increased expression of various activation markers such as MHC class II, costimulatory molecules, and Sca-1/Ly6A proteins. Gene expression analysis showed that Salmonella treatment induced expression of iNOS, arginase-1 (ARG1), and IFN-γ in the spleen, but down-regulated IL-4 and TGF-β. Within the tumor, expression of iNOS, IFN-γ, and S100A9 was markedly increased, but ARG1, IL-4, TGF-β, and VEGF were inhibited. Functionally, splenic CD11b(+) cells maintained their suppressive capacity following Salmonella treatment, but intratumoral myeloid cells had significantly reduced suppressive capacity. Our findings demonstrate that administration of attenuated Salmonella leads to phenotypic and functional maturation of intratumoral myeloid cells making them less suppressive and hence enhancing the host's anti-tumor immune response. Modalities that inhibit myeloid suppressor cells may be useful adjuncts in cancer immunotherapy.

Mammary gland stem cells (MaSC) have not been identified in spite of extensive research spanning over several decades. This has been primarily due to the complexity of mammary gland structure and its development, cell heterogeneity in the mammary gland and the insufficient knowledge about MaSC markers. At present, Lin (-) CD29 (i) CD49f (i) CD24 (+/mod) Sca- 1 (-) cells of the mammary gland have been reported to be enriched with MaSCs. We suggest that the inclusion of stem cell markers like Oct4, Sox2, Nanog and the mammary gland differentiation marker BRCA-1 may further narrow down the search for MaSCs. In addition, we have discussed some of the other unresolved puzzles on the mammary gland stem cells, such as their similarities and/or differences with mammary cancer stem cells, use of milk as source of mammary stem cells and the possibility of in vitro differentiation of embryonic stem (ES) cells into functional mammary gland structures in this review. Nevertheless, it is the lack of identity for a MaSC that is curtailing the advances in some of the above and other related areas.

Tumor development is associated with changes in hematopoiesis that lead to an increase in myelomonocytic cells in systemic sites as well as within the tumor tissue. The accumulation of myeloid cells within tumors not only promotes angiogenesis and tissue remodeling required for tumor growth but also maintains the tumor milieu as an immunosuppressive environment. We have previously shown that attenuated strains of the facultative anaerobic bacteria, Salmonella enterica serovar Typhimrium, can effectively retard tumor growth in a therapeutic melanoma model. Given that Salmonella organisms utilize host macrophages as their primary niche for survival, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics and functional activation within tumor tissue of B16.F1 melanoma-bearing animals. Treatment with Salmonella led a preferential expansion, within spleen and tumor tissues, of CD11b+Gr-1+, but not CD11b+Gr-1-, myeloid cells. Using 6-color FACS analysis, CD11b+Gr-1+ cells were shown to exhibit significant up-regulation in the expression of activation markers, including MHC class II, CD80, and Sca-1/Ly6A proteins. Moreover, the functional activities of total tumor infiltrating cells or CD11b-purified cells from tumor tissue were assessed by qRT-PCR. Salmonella treatment induced a dramatic increase in iNOS and IFN-g gene expression but inhibited ARG1 and IL-4 genes. Further, while expression of TGF-b and VEGF was reduced, the level of inflammation-related S100A9 gene was increased. Our findings demonstrate that systemic administration of attenuated Salmonella leads to phenotypic and functional changes in tumor myeloid suppressor cells, with a shift from a predominantly M2 phenotype to an activated, effector macrophage phenotype. Citation Format: Basel K. Al-Ramadi, Suneesh Kaimala, Yassir A. Mohamed, Jincy M. Issac, Eyad Elkord, Salem Chouaib, Maria J. Fernandez-Cabezudo. Targeting of tumor myeloid suppressor cells by Salmonella bacteria causes a shift to M1 phenotype and leads to inhibition of tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3632. doi:10.1158/1538-7445.AM2014-3632