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Obesity, Diabetes and Cancer: A Mechanistic Perspective
Cifarelli V1*, Hursting SD2,3
1 Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA.
2 Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
*Corresponding Author
Vincenza Cifarelli,
Department of Medicine, Center for Human Nutrition,
Washington University School of Medicine, St. Louis, MO 63110, USA.
Tel: (314) 362 8206
Fax: (314) 362 8230
E-mail: email@example.com
Received: July 24, 2015; Accepted: September 25, 2015; Published: September 28, 2015
Citation: Cifarelli V, Hursting SD (2015) Obesity, Diabetes and Cancer: A Mechanistic Perspective. Int J Diabetol Vasc Dis Res, S4:001, 1-7. doi: dx.doi.org/10.19070/2328-353X-SI04001.
Copyright: Cifarelli V© 2015. 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.
Nearly 35% of adults and 20% of children in the United States are obese, defined as having a body mass index (BMI) ≥ 30 kg/m2. Obesity is an established risk factor for many cancers, and obesity-associated metabolic perturbations often manifest in Type 2 diabetes mellitus and/or the metabolic syndrome. As part of the growth-promoting, proinflammatory microenvironment of the obese and/or diabetic state, crosstalk between macrophages, adipocytes, and epithelial cells occurs via metabolically-regulated hormones, cytokines, and other mediators to enhance cancer risk and/or progression. This review synthesizes the evidence on key biological mechanisms underlying the associations between obesity, diabetes and cancer, with particular emphasis on enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent mechanistic targets for disrupting the obesity-diabetes-cancer link, and several diabetes drugs, such as metformin and rosiglitazone, are being intensely studied for repurposing as cancer chemopreventive agents.
3.Dysregulated Growth Signals
3.1 Insulin and IGF-I
3.2 Signaling Pathways Downstream of the Insulin Receptor and IGF-1R
3.3 Leptin, Adiponectin and their Ratio
4.Chronic Inflammation
4.1 Cytokines and Crosstalk Between Adipocytes, Macrophages and Epithelial Cells
4.2 Inflammation and Cancer
5.Vascular Integrity-Related Factors
5.1 Plasminogen Activator Inhibitor-1 (PAI-1)
5.2 Vascular Endothelial Growth Factor (VEGF)
5.3 Tumor angiogenesis
6.Cancer and Diabetes: Role of Antioxidant
7.Cancer and Antidiabetic Drugs
7.1 Metformin
7.2 Rosiglitazone
Obesity; Diabetes; Cancer; Metformin.
The prevalence of obesity, defined as having a body mass index (BMI) ≥30 kg/m2, has increased dramatically in recent decades in the United States, and more than 35% of adults and 20% of children are now obese [1]. Among obese individuals, approximately 65% of males and 56% of females meet the criteria for the metabolic syndrome, a state of metabolic dysregulation characterized by insulin resistance, hyperglycemia, dyslipidemias (particularly hypertriglyceridemia), and hypertension [2]. In obesity and/or metabolic syndrome, alterations also occur in circulating levels of insulin, bioavailable insulin-like growth factor (IGF)-1, adipokines (eg, leptin and adiponectin), inflammatory factors (eg, cytokines), and vascular integrity-related factors (eg, plasminogen activator inhibitor [PAI]-1 and vascular endothelial growth factor [VEGF]) [3, 4]. Through these mediators, and likely several others, obesity and metabolic syndrome are linked to various chronic diseases [3,5] including cardiovascular disease, Type II diabetes (T2D), and the focus of this review, cancer.
Evidence-based guidelines for cancer prevention urge avoiding behaviors that can lead to obesity, including overconsumption of energy-dense foods and beverages and a sedentary lifestyle [6]. Overall, 20-25% of all cancer deaths in the US have been attributed to overweight and obesity [7]. In their position statement on obesity and cancer, the American Society of Clinical Oncology states that obesity has emerged as the leading preventable cause of cancer that can also increase risk of cancer recurrence and lower survival. They predict that the US will see 500,000 new obesity- related cancer cases per year by 2030 unless corrective action is taken [8]. In terms of specific cancers, obesity is associated with increased mortality from cancer of the prostate and stomach in men; breast (postmenopausal), endometrium, cervix, uterus and ovaries in women; and kidney (renal cell), colon, esophagus (adenocarcinoma), stomach, pancreas, gallbladder, and liver in both genders [9].
T2D is a progressive metabolic disorder associated with overweight, obesity and several pathological abnormalities including glucose intolerance, insulin resistance, and dyslipidemia. In the United States, 1.9 million of people are newly diagnosed with diabetes mellitus and 90%-95% of all diagnosed are affected by T2D [10]. Emerging evidence indicates that T2D associates with an increased risk of cancer at specific sites. The risk of developing pancreatic, hepatocellular, or endometrial cancer is almost twice in diabetic patients compared to that of the nondiabetic population [10-15]. Other types of cancer that associate with diabetes are breast [16], bladder [17, 18], kidney [19], and colorectal cancer [20]. No association has been identified between diabetes and prostate cancer [21, 22]. It is still not understood why diabetes associates with increased risk of developing some but not all types of cancers, and further investigation is needed regarding this issue.
Herein, we discuss possible mechanisms underlying the links between obesity, T2D and cancer, with emphasis on obesity-associated enhancements in growth factor signaling, inflammation, and angiogenic processes and on the crosstalk between macrophages, adipocytes, endothelial cells and epithelial cells in many cancers.
Dysregulated Growth Signals
Insulin is a peptide hormone produced by pancreatic beta cells and released in response to elevated blood glucose. Hyperglycemia, a hallmark of metabolic syndrome, is associated with insulin resistance, aberrant glucose metabolism, chronic inflammation, and the production of other metabolic hormones such as IGF-I, leptin and adiponectin [23]. Sharing ~50% sequence homology with insulin, IGF-I is a peptide growth factor produced primarily by the liver following stimulation by growth hormone. IGF-I regulates growth and development of many tissues, particularly prenatally [24]. IGF-I in circulation is typically bound to IGF binding proteins (IGFBPs) that regulate the amount of free IGF-I bioavailable to bind to the IGF-I receptor (IGF-IR) and elicit growth or survival signaling [24]. In metabolic syndrome, the amount of bioavailable IGF-I increases, possibly via hyperglycemia-induced suppression of IGFBP synthesis and/or hyperinsulinemia-induced promotion of hepatic growth hormone receptor expression and IGF-I synthesis [23]. Elevated circulating IGF-I is an established risk factor for many cancer types [25].
In many tumors, binding of IGF-I and IGF-II to the IGF-IR inhibits apoptosis and promotes cell proliferation. IGF-I can also bind and form heterodimers with insulin receptors subtypes A and B (IR-A and IR-B), generating hybrids. IR-A has high affinity for insulin and IGF-II but binds IGF-I with low affinity. IR-A binds insulin with 1.5-fold higher affinity than IR-B, possesses a higher dissociation and internalization rate, and mimics many of the cell signaling and cell survival activities of IGF-IR (described below). In contrast, IR-B is thought to mediate most of the classic metabolic responses induced by insulin, and also binds IGF-I and IGF-II with low and intermediate affinity, respectively [26]. Both IGFs- and insulin-mediated induction of cell proliferation and migration is more effective in cells containing IGF-IR/IR-A hybrids than in cells containing IGF-IR/IR-B hybrids [27]. Interestingly, an increase in the IR-A to IR-B ratio has been reported in Type 2 diabetes [28, 29]. Activation of the IR-A by insulin-like IGF-II bypasses the IGF-IR and its inhibition may explain the reason of the failure of monotherapy trials with IGF-IR targeted antibody or with IGF-IR specific tyrosine kinase inhibitors [30].
Downstream targets of IR-A and IGF-IR comprise a signaling network regulating cellular growth and survival predominately through induction of the phosphatidylinositol-3 kinase (PI3K)/ Akt pathway [24]. This signaling cascade, elegantly reviewed by Cantley and colleagues [31], is one of the most commonly altered pathways in human epithelial tumors. Engagement of the PI3K/Akt pathway allows both intracellular and environmental cues, such as energy availability and growth factor supply, to affect cell growth, proliferation, survival and metabolism. Activation of the insulin receptor or IGF-IR stimulates PI3K to produce the lipid second messenger, phosphatidyl-inositol-3,4,5-trisphosphate. This messenger recruits and anchors Akt to the cell membrane for further phosphorylation and activation. Akt is a cAMP-dependent, cGMP-dependent protein kinase C that when constitutively active is sufficient for cellular transformation by stimulating cell cycle progression and cell survival and by inhibiting apoptosis. Frequently associated with the aberrant Akt signaling commonly seen in human cancers is an increase in mTOR (mammalian target of rapamycin) signaling [32]. mTOR is a serine/threonine protein kinase that is activated by Akt and inhibited by an opposing signal from AMP-activated kinase (AMPK). At the interface of the Akt and AMPK pathways, mTOR dictates translational control of new proteins in response to both growth factor signals and nutrient availability through phosphorylation of its downstream mediators [33, 34]. Ultimately, activation of mTOR results in cell growth, cell proliferation, and resistance to apoptosis. Additionally, elevated cellular amino acids (particularly branched chain amino acids), glucose, and ATP concentrations, which occur during high-energy conditions, signal for mTOR activation [34].
Leptin is a peptide hormone produced by adipocytes, is positively correlated with adipose stores and nutritional status, and functions as an energy sensor to signal the brain to reduce appetite. In the obese state, adipose tissue overproduces leptin, and the brain no longer responds to the signal. Insulin, glucocorticoids, tumor necrosis factor-alpha (TNF-α), and estrogens all stimulate leptin release [35, 36]. Leptin has direct effects on peripheral tissues, indirect effects on hypothalamic pathways and modulates immune function, cytokine production, angiogenesis, carcinogenesis and other biological processes [36]. The leptin receptor has similar homology to class I cytokines that signal through the janus kinase and signal transducer activator of transcription (JAK/STAT) pathway that is often dysregulated in cancer [36].
Adiponectin is a hormone mainly secreted from visceral adipose tissue. Levels of adiponectin, in contrast with leptin, negatively correlate with adiposity. Adiponectin functions to counter the metabolic program associated with obesity and hyperleptinemia by modulating glucose metabolism, increasing fatty acid oxidation and insulin sensitivity, and decreasing production of inflammatory cytokines [37]. The possible mechanisms through which adiponectin exerts anticancer effects may include increasing insulin sensitivity, and decreasing insulin/IGF-1 and mTOR signaling via activation of AMPK. Adiponectin also reduces (and leptin increases) proinflammatory cytokine expression via modulation of JAK/STAT pathway and the the nuclear factor kappa-lightchain- enhancer of activated B-cells (NF-kB) [38-40]. Although in vitro, animal and epidemiologic evidence linking leptin [41-44] or adiponectin [39-45] individually to cancer risk is mixed, data suggest that the adiponectin:leptin ratio is a useful atherogenic and metabolic syndrome index, particularly in Type 2 diabetics, and is also associated with cancer risk [45]. However, further characterization of these links is needed.
Chronic Inflammation
Obesity and metabolic syndrome are associated with a low-grade, chronic state of inflammation characterized by increased circulating free fatty acids and chemoattraction of immune cells (such as macrophages that also produce inflammatory mediators) into the local milieu [46-48]. These effects are further amplified by the release of inflammatory cytokines such as interleukin (IL)-1β, IL- 6, TNF α and monocyte chemoattractant protein (MCP)-1. Adipocytes can enlarge past the point of effective oxygen diffusion, which results in hypoxia and eventually necrosis. Free fatty acids escape the engorged/necrotic adipocytes and deposit in other tissues, which in turn promotes insulin resistance and diabetes (through downregulation of insulin receptors and glucose transporters), hypertension, and fatty liver disease and also activates signaling molecules involved in epithelial carcinogenesis, such as NF-kB [49, 50].
NF-кB is a transcription factor that is activated in response to bacterial and viral stimuli, growth factors, and inflammatory molecules (eg, TNF-α, IL-6, and IL-1β), and is responsible for inducing gene expression associated with cell proliferation, apoptosis, inflammation, metastasis, and angiogenesis. Activation of NF-кB is a common characteristic of many tumors and is associated with insulin resistance and elevated circulating levels of leptin, insulin, and/or IGF-1 [49, 50].
The link between chronic inflammation and cancer development was first noticed more than 100 years ago by Rudolph Virchow when he observed an abundance of leukocytes in neoplastic tissue [51]. Now, several tissue-specific inflammatory lesions are established neoplastic precursors for invasive cancer, including gastritis for gastric cancer, inflammatory bowel disease for colon cancer, and pancreatitis for pancreatic cancer [52, 53].
Tumor microenvironments are composed of multiple cell types including epithelial cells, fibroblasts, mast cells, and cells of the innate and adaptive immune system [53, 54]. As discussed previously, macrophages, which are activated in the obese state, infiltrate tumors and amplify the inflammatory tumor microenvironment through production of cytokines, prostaglandins, and angiogenic factors [53]. Another important cancer-related inflammatory mediator is cyclooxygenase (COX)-2, an enzyme that is upregulated in most tumors and catalyzes the synthesis of the potent inflammatory lipid metabolite, prostaglandin E2. COX-2 overexpression is an indicator of poor prognosis in multiple cancer types [55].
Vascular Integrity-Related Factors
PAI-1 is a serine protease inhibitor produced by endothelial cells, stromal cells and adipocytes in visceral white adipose tissue [62]. Increased circulating PAI-1 levels, frequently found in obese subjects, are associated with increased risk of atherogenesis and cardiovascular disease, diabetes and several cancers [4, 56]. PAI-1, through its inhibition of urokinase-type and tissue-type plasminogen activators, regulates fibrinolysis and integrity of the extracellular matrix. PAI-1 is also involved in angiogenesis and thus may contribute to obesity-driven tumor cell growth, invasion and metastasis [4].
VEGF, a heparin-binding glycoprotein produced by adipocytes and tumor cells, has angiogenic, mitogenic and vascular permeability- enhancing activities specific for endothelial cells [57]. Circulating levels of VEGF are increased in obese, relative to lean, humans and animals, and increased tumoral expression of VEGF is associated with poor prognosis in several obesity-related cancers [58]. The need for nutrients and oxygen triggers tumor cells to produce VEGF, which leads to the formation of new blood vessels to nourish the rapidly growing tumor and facilitate the metastatic spread of tumors cells [57]. Adipocytes communicate with endothelial cells by producing a variety of proangiogenic and vascular permeability-enhancing factors. These include VEGF, IGF-1, PAI-1, leptin, hepatocyte growth factor, and fibroblast growth factor-2 [59]. In the obese, nontumor setting, these factors stimulate neovascularization in support of the expanding fat mass. These adipose-derived factors may also contribute to obesity- associated enhancement of tumor angiogenesis. However, the relative contributions of tumor-derived, versus adipocyte-derived, proangiogenic factors in tumor development, progression and metastasis remain unclear.
Adipocytes communicate with endothelial cells by producing a variety of proangiogenic and vascular permeability-enhancing factors, including vascular endothelial growth factor (VEGF), IGF-1, plasminogen activator inhibitor (PAI)-1, leptin, hepatocyte growth factor, and fibroblast growth factor-2 [59]. In the obese state, these factors stimulate neovascularization in support of the expanding fat mass. Insulin resistance also drives abornomalities in endothelial and vascular smooth muscle function via alterations in many of the same proangiogenic and vasular altering factors [59]. These factors may also contribute to obesity-associated enhancement of tumor angiogenesis. For example, VEGF is a heparin-binding glycoprotein produced by adipocytes and tumor cells that has angiogenic, mitogenic and vascular permeabilityenhancing activities specific for endothelial cells [57]. Circulating levels of VEGF are increased in obese, relative to lean, humans and animals, and increased tumoral expression of VEGF is associated with poor prognosis in several obesity-related cancers [58]. The need for nutrients and oxygen triggers tumor cells to produce VEGF, which leads to the formation of new blood vessels to nourish the rapidly growing tumor and may facilitate the metastatic spread of tumors cells [57]. Bevacizumab-based therapy (ie, anti- VEGF therapy), in combination with conventional chemotherapy, is considered a first-line treatment option for patients with advanced colorectal cancer; however, decreased efficacy in obese patients is reported and speculated to be associated with increased levels of VEGF (and/or other proangiogenic factors) produced by visceral white adipose tissue [60, 61]. The relative contributions of tumor-derived, versus adipocyte-derived, proangiogenic factors in tumor development, progression and metastasis remain unclear. PAI-1 is a serine protease inhibitor produced by endothelial cells, stromal cells and adipocytes in visceral white adipose tissue [56]. Increased circulating PAI-1 levels, frequently found in obese subjects, are associated with increased risk of atherogenesis and cardiovascular disease, diabetes and several cancers [56, 4]. PAI-1, through its inhibition of urokinase-type and tissue-type plasminogen activators, regulates fibrinolysis and integrity of the extracellular matrix. PAI-1 is also involved in angiogenesis and thus may contribute to obesity-driven tumor cell growth, invasion and metastasis [4].
Cancer and Diabetes: Role of Antioxidant
T2D shares multiple risk factors with several cancers, such as obesity, hyperinsulinemia and hyperglycemia. The cancer-obesity association has been known for many years [62, 63], and could be explained by the fact that central obesity often leads to chronic levels of inflammation and oxidative stress [64], which are risk factors for the development of many cancers. Excess body weight and adiposity associates with reduced insulin sensitivity, which is compensated by increased insulin secretion, to avoid an increase in blood glucose level [65]. Obesity-related hyperinsulinemia regulates the secretion of adipokines by adipocytes that together with macrophages infiltrating the adipose tissue, secrete a number of pro-inflammatory cytokines as tumor necrosis factor (TNF)-α and interleukin-(IL)-6. The induced systemic inflammatory response worsens insulin resistance [66], contributing to increase the risk of pancreatic cancer through insulin/IGF-1 signaling cascades.
Obesity-induced reactive oxygen species (ROS) production represents an additional risk factor for the development of pancreatic cancer in T2D patients. Hyperglycemia increases oxidative stress and up-regulate the oxidative machinery. Specifically, hyperglycemia activates the polyol pathway through increased expression and activity of aldose reductase. It has been hypothesized that the hyperglycemia-induced activation of polyol metabolism may explain the decreased pancreatic secretion observed in insulindependent diabetes mellitus patients [67, 68]. In vitro, glucoseinduced activation of sorbitol accumulation and nuclear factor- κB (NFκB) activation can be prevented by normalizing levels of mitochondrial ROS [69]. Additional studies have also reported lower levels of other cellular antioxidants, namely copper/zinc superoxide dismutase, catalase, and glutathione peroxidase (GPx), in human pancreatic cancer specimens compared with normal pancreatic specimens [67, 70]. Although these mechanisms still need to be more clarified, these findings suggest that cellular antioxidants play a crucial role in regulating pancreatic tumor growth.
Cancer and Antidiabetic Drugs
Metformin (1,1-dimethylbiguanide hydrocloride) is a member of the biguanide class of oral agents developed for the treatment of hyperglycaemia and T2D. Discovered more than 50 years ago, metformin still represents the most commonly prescribed drug for T2D patients as initial or combined therapy [71]. Epidemiologic studies suggest that metformin use is associated with reduced risk among diabetics of being either diagnosed with, or dying from several cancers, particularly pancreatic cancer (PC) [72]. However, the causal relationship and potential mechanisms underlying the association between metformin and reduced PC have not been established.
With regard to diabetes, metformin decreases hyperglycemia by inhibiting hepatic gluconeogenesis and increasing glucose uptake in the peripheral tissues, as skeletal muscles and adipose tissue, ultimately improving insulin sensitivity [73]. These effects are achieved by activation of AMPK a sensor of the cellular metabolic state [74, 75]. Metformin-induced AMPK negatively regulates mTOR pathway, which is involved in protein synthesis and cell proliferation. With respect of cancer, metformin might directly achieve inhibition of tumor cell growth through induction of AMPK. Indirectly, metformin affects tumor growth in T2D patients by decreasing insulin, a promoting-growth hormone, with mitogenic effects. It has been proposed that hyperinsulinemia together with insulin resistance might promote carcinogenesis [76] since several in vivo studies have shown that antitumour effect of metformin is more effective in mice on high-energy diet associated with hyperinsulinemia than those on control diet [77]. Metformin has been shown to inhibit cell proliferation, colony formation and partial cell cycle arrest [78-80] in several cancer cell lines. In addition to the above mechanisms, metformin may also exert its anti-tumor effect through regulation of microRNA (miRNAs), noncoding RNA molecules that post-transcriptionally regulate gene expression [81]. MiRs regulate cellular processes involved in cancer initiation, recurrence, and metastasis [82]. Our recent study conducted in a murine pancreatic cancer transplant model in obese/prediabetic mice found that metformin induced tumoral expression of miRNA-34a [83], a miR typically lost during cancer progression, including pancreatic tumors [84, 85]. MiR-34a has been shown to contribute to reduce survivability in those diagnosed with pancreatic cancer [86]. MicroRNA-34a suppresses key events of the epithelial-to-mesenchymal transition (EMT) by acting as a negative regulator of the signaling pathway activated by transforming growth factor-β (TGF-β), a master regulator of EMT [87]. Expression of EMT mediators, such as Snail is profoundly linked to TGF-β signaling and miR-34a expression. Specifically, as TGF-β increases, expression of miR-34a is diminished and Snail is enhance [88], while re-expression of miR-34a reduces expression of Snail and other EMT mediators such as Notch and Slug [89]. Metformin modulates EMT-related targets, such as Notch, in a miR-34a-dependent manner [90]. Dysregulation of Notch signaling, a targeted perturbation in many cancer types has been shown to enhance hypoxia-induced tumor cell migration and invasion and influence expression of Snail and Slug [91].
Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The thiazolidinediones are agonists for peroxisome-proliferator–activated receptor γ (PPAR-γ). PPAR-γ receptors are ligand-activated nuclear transcription factors that modulate gene expression, lowering blood glucose primarily by increasing insulin sensitivity in peripheral tissues [92]. However, despite clear benefits in glycemic control, this class of drugs has recently fallen into disuse due to concerns over side effects and adverse events as extensively discussed by Soccio and colleagues in a recent review [93]. Results of available epidemiological studies on the incidence of cancer in rosiglitazonetreated patients are not univocal [94]. Evidence of both pro-carcinogenic and anti-tumorigenic effects of PPARγ agonists have been mainly reported in vitro and in vivo models that do not take into full account the metabolic characteristics of patients with diabetes. A population-based report published by Govindarajan and colleagues [95] showed that TZDs associates with reduced risk of lung cancer in diabetic patients in agreement with previous in vitro studies [96]. Ramos-Nino and colleagues showed an association between the use of TZDs and cancer in a community-based population of adults with diabetes participating in the Vermont Diabetes Information System (VDIS) [97]. The association was observed primarily among rosiglitazone users and not among subjects using pioglitazone. Furthermore, the association was found in women, but not in men. A case-control study published in 2013 showed that long-term exposure to rosiglitazone, or pioglitazone, increases the risk of bladder cancer in T2D patients [98].
Multiple hormones, growth factors, cytokines and other mediators associated with the obese state and the metabolic syndrome enable crosstalk between macrophages, adipocytes, endothelial cells and epithelial cells and contribute to cancer-related processes (including growth signaling, inflammation and vascular alterations) (Figure 1). Components of these interrelated pathways represent promising mechanism-based targets for the resolution of diabetes- induced cancer. Moreover, compounds that are beneficial for diabetes and cancer such as metformin represent a promising intervention that should be tested in future translational studies evaluating new strategies for breaking the diabetes-cancer link.
Figure 1. Obesity, metabolic syndrome and cancer: overview of mechanisms. An arrow preceding text denotes a directional effect (eg, activity or concentration). Abbreviations: IGF-1, insulin-like growth factor-1; PAI 1, plasminogen activator inhibitor 1; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor
Dr. S. Hursting is funded, in part, by grants from the National Cancer Institute (R01CA129409), the Breast Cancer Research Foundation (UTA09-001068), and the National Institute of Environmental Health Sciences (P30ES007784). The authors have nothing to disclose.
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- Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, et al. (2010) Diabetes and cancer: a consensus report. Diabetes Care 33: 1674- 1685.
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- Bruce WR, Wolever TM, Giacca A (2000) Mechanisms linking diet and colorectal cancer: the possible role of insulin resistance. Nutr Cancer 37(1): 19-26.
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- Busik JV, Hootman SR, Greenidge CA, Henry DN (1997) Glucose-specific regulation of aldose reductase in capan-1 human pancreatic duct cells in vitro. J Clin Invest 100(7): 1685-1692.
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- Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, et al. (2009) Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32(1): 193-203.
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- Algire C, Zakikhani M, Blouin MJ, Shuai JH, Pollak M (2008) Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer 15(3): 833-839.
- Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M (2006) Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66: 10269-10273.
- Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T,et al. (2009) Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 8: 909-915.
- Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, at al. (2009) Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 8(13): 2031-2040.
- Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2): 281-297.
- Gregory PA, Bracken CP, Bert AG, Goodall GJ (2008) MicroRNAs as regulators of epithelial-mesenchymal transition. Cell cycle 7(20): 3112-3118.
- Cifarelli V, Lashinger LM, Devlin KL, Dunlap SM, Huang J (2015) Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms. Diabetes 64(5):1632-1642.
- Kashat M, Azzouz L, Sarkar SH, Kong D, Li Y, et al. (2012) Inactivation of AR and Notch-1 signaling by miR-34a attenuates prostate cancer aggressiveness. Am J Transl Res 4(4): 432-442.
- Ji Q, Hao X, Zhang M, Tang W, Yang M, et al. (2009) MicroRNA miR- 34 inhibits human pancreatic cancer tumor-initiating cells. PloS One 4(8): e6816.
- Jamieson NB, Morran DC, Morton JP, Ali A, Dickson EJ, et al. (2012) MicroRNA molecular profiles associated with diagnosis, clinicopathologic criteria, and overall survival in patients with resectable pancreatic ductal adenocarcinoma. Clin Cancer Res 18(2): 534-545.
- Zhang J, Tian XJ, Zhang H, Teng Y, Li R, et al. (2014) TGF-beta-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci Signal 7(345): ra91.
- Niessen K, Fu Y, Chang L, Hoodless PA, McFadden D, et al. (2008) Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol 182(2): 315-325.
- Wang Z, Li Y, Banerjee S, Sarkar FH (2009) Emerging role of Notch in stem cells and cancer. Cancer Lett 279(1): 8-12.
- Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, et al. (2007) Jagged1- mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med 204(12): 2935-2948.
- Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 105(17): 6392-6397.
- Vamecq J, Latruffe N (1999) Medical significance of peroxisome proliferator- activated receptors. Lancet 354(9173): 141-148.
- Soccio RE, Chen ER, Lazar MA (2014) Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab 20(4): 573-591.
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Shuttles are becoming the new 'in' mode of travel these days and this is due to multiple reasons. Foremost is the fact that the shuttle vans are highly comfortable cars that give you an easy and comfy journey time. Since these are big cars, they have ample space where you can sit relaxing rather than being erect like in a taxi pr cab. Then another bling to these vans is the fact that they can accommodate a large number of people, making it easier for you to travel together with your family or group of your friends. You do not have to hire multiple cars to travel now, rather just charter one shuttle and all of you can now travel together, enjoying your travelling time. The best attraction that just makes the shuttle service your favorite is the fact that these highly comfy and relaxing cars are available at unbelievably economical rates. As much as the quality of service and comfort you get, the price is next to none for what you pay for other modes of transportation, making these shuttle vans a big hit amongst tourists to the city of Denver.
Airport Denver Limo is renowned for its classy and affordable service; hence, we bring forth for you the best Denver Airport Shuttle service that certainly stands out in its level of service as well the charges that you pay for it. We provide you best DIA shuttle service that you can either avail by taking up the shuttles that visit DIA after regular intervals, or you may charter a shuttle as per your own schedule. We would send you a spic and span van at the airport and you can use at as per your requirements. These vans are best for DIA transportation as they would not only accommodate you, but would carry your luggage easily as well. Also, the fun of travelling with family and friends has its own charm that you can fulfill by travelling in these vans.
We not only provide you top class van service for airport, we provide you Denver shuttle service as well, and that gives you the ease of travelling in Denver in these vans as per your ease. You can visit Denver and the skiing resorts by hiring a shuttle. These vans are best for mountain transportation as these are big vehicles with a good grip on the road. Also we have trained drivers behind the steering who are trained for this kind of driving, so you never have to fear getting stuck in the snow or getting the vehicle out of control on a slippery road. We would take you to the amazing ski resort on the top of Rocky Mountains with great care, letting you enjoy the travel time in the comfy van while you feast your eyes on the serene scenery that is a special treat for tourists to Denver.

subset: commoncrawl


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10 Months Pool & Gym €420.00
10 Months Pool OR Gym €330.00
10 Months (Couple) Pool & Gym €780.00
10 Months (Couple) Pool OR Gym €620.00
6 Months Pool & Gym €320.00
6 Months Pool OR Gym €240.00
6 Months (Couple) Pool & Gym €510.00
6 Months (Couple) Pool or Gym €420.00
3 Months Pool & Gym €200.00
(June, July, August €270.00 - subject to availability)
3 Months Pool OR Gym €150.00
(June, July, August €220.00 - subject to availability)
1 Months Pool & Gym €85.00
(June, July, August €100.00 - subject to availability)
1 Months Pool OR Gym €65.00
(June, July, August €85.00 - subject to availability)
Please note: Swim hats must be worn at all times in the Aqua Club and are for-sale at €2 each. Swim arm-bands for children are advisable and are for-sale in the Aqua Club shop.
Combi Pool & Gym (2hrs) €18.00
Book of 10 Swim Vouchers €88.00 (available during Public Swim Times: Sun - Sat 11.00am - 4.00pm EXCEPT for Mon & Thurs 12.00 - 4 pm)
Please call our Aqua Club today (053) 9173513 for further information on membership and classes, or view our Spring / Autumn Fitness Brochure here.
Memberships can carry over into the following year while the hotel is closed in December. Fitness classes are separate to pool and gymnasium memberships. Personal training available on request with our qualified trainer, €40.00 per session. Private / Group training available.
As a non-resident, to purchase a ticket to guarantee your swim please call to the Aqua Club Reception where they go on sale each morning from 9.00am. This will avoid disappointment, especially on wet days. Please note towels and swim aids for children are not provided. Swimming hats are compulsory and available on sale for €2.00.
Join our classes at Kelly's Resort Hotel with our health and fitness consultants.
AQUA AEROBICS with Eileen Rowe who has a vast knowledge in the field of fitness and holds an NCEF qualification, along with over 20 years' experience & has travelled to Australia, USA & England throughout her career. Aqua Aerobic in the Top Pool every Monday & Thursday at 11.00am
FITNESS CLASS with ex-professional footballer Brian McGovern, Tuesday & Thursday at 11.30am
PILATES with Nikki McGovern who holds a qualification in mat pilates, every Monday & Wednesday at 9.00am
Classes times and days can change during the year, please call the Aqua Club directly on (053) 9173513 for the up-to-date timetable.


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We were lucky and not so lucky!on April 1, 2014
This week was the week of almost disaster. This was the week where we were put in our place and made to understand the might of an ocean.
We've all seen those dramatic, lump in the throat images on the big screen. Those of huge ocean liners that are rolled onto their sides and engulfed by waves the size of mountains. It always seemed surreal to me, vaguely possible but inevitably it remained in the category of tsunami fiction. This week we had reality visit us like we have not imaged it would. Rowing in our second hour of the morning session in tough conditions; we had a giant wave hit us and capsize our entire boat. I was thrown entirely out while Vasti hung on for dear life. We were lucky; and not so lucky.
Vasti spotted the swell after I had already called for her to row 'left'. Usually a term to warn each other of a breaking wave. The boat needed to turn for it not to hit us side on. This case the wave was racing towards us from the left. Vasti only had time to join me on one strong left oar stroke before the wave came crashing onto us and over. The wave made contact with the aft(back) left side of the boat forts, exactly where I am seated still trying to make another oar stroke while Vasti says she could see the wave break over me and then she just remember grabbing on for dear life. Her decision at the moment probably wiser than mine. She held onto the safety harnesses either side of her, leaving her oars to flay wildly about.
For me I remember the violent impact, then seeing white, the boat falling down over me and then the realization that my feet were stuck in the foot holds. I thought of Vasti and if she would be able to get out. And then…. Then it was over. I spluttered water out my mouth, wiped my hair away and came to the rope clasped firmly in my right hand. I don't know how it got there. I was alongside the boat, a few meters away, and saw Vasti still in her original rowing position. Her face draped in fear. For me it still felt like a dream.
For Vasti, she remembers looking to her right as the boat was hit downwards. Then she was underwater and holding on no matter what. It's what I had begged her to do if this ever happened. The boat had rolled right over her. She too realized her feet were stuck in the footholds and, still while turned upside down, under water, Vasti clearly remembers telling herself to focus on the undoing of her feet. She began to untie her feet but at the same time she could feel the self righting design of the boat kicking in. Relief engulfed her as she realized the boat was turning her back to the surface. And that's when she saw me in the water, outside of the boat. Vasti screamed to swim as fast as I could, unknown to her that I had the rope in hand. We were lucky.
What though has been a very demoralizing aspect to this accident is that our Imtech Communications Satelite phone has been damaged beyond repair. We spent a day and a half successfully drying out the interior electronics of the exterior dome that holds the satellite receiver, to get it to work again.
This was the way we did all our radio interviews, sent the photos for our articles and more importantly how we weekly made contact with loved ones. I know Vasti especially is going to miss the Sunday afternoon chat to her mom and dad, her very emotional and understandably rejuvenating chats.
As to the guys at Imtech Communications, I can imagine they have already begun mobilizing friends in ships all over the Atlantic Ocean. Maybe we will see some magic delivery of sorts in the next few weeks.
We are safe, rattled but grateful for our good fortune. Africa to USA is not an easy thing, or else everybody would be doing it. Wouldn't they?
Riaan and Vasti are attempting to be the first in history to row from mainland Africa to New York, USA.
Follow us on our Facebook page: Take Me 2 New York and @TM2NY on Twitter. For live updates on position and progress visit http://my.yb.tl/TM2NY.


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Although no written works by Kāpālikas are known to us, this antinomian Śaiva movement of skull bearers, who took up the attributes of Śiva's frightening form, Bhairava, was once very much present from Kashmir and Nepal to the Tamil-speaking south. The earliest mention of Kāpālikas is found perhaps in Hāla's Saṭṭasaī, datable to the 3rd to 5th centuries CE (Lorenzen, 1991, 13), but most of our sources on them come from the 7th to the 12th centuries …
Kāpālikas(4,574 words)
Cite this pageJudit Törzsök, "Kāpālikas", in: Brill's Encyclopedia of Hinduism, Edited by: Knut A. Jacobsen, Helene Basu, Angelika Malinar, Vasudha Narayanan. Consulted online on 18 February 2019 <http://dx.doi.org/10.1163/2212-5019_beh_COM_9000000048>
First published online: 2012
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Geometric LoveMarch 22, 2013 12:30 pm
Help. I need all of this. Now. As you can tell, all I can think of lately is black and white (with neon accents). I am mainly in love with Alexander Wang's new SS13 collection. Everything is geometric, structured, cut-out, and most importantly black and white. The Acne buckle boots below are also currently the apple of my eye. I ran into a friend who works at Acne the other day and he was with a girl that had them in black. I WILL hunt these down. It pains me not to have them. If I could have any outfit, it would be the below.
1. Alexander Wang cut out t-shirt
2. Juliet & Company necklace
3. Acne Jacket
4. ASOS cuffs
5. Alexander Wang Glow in the dark shoulder bag
6. Acne Lila ankle boots
7. Alexander Wang Croc effect leather shorts
Categorised in: Collages, Monochrome, Trending


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Gemstone Adjustable Bracelet 7 Chakras (Each)
This lovely, adjustable bracelet with semi-precious stone round beads will fit most wrists. A different semi-precious tumbled stone represents one of the seven major Chakras and the stones are clustered in groups of 3 with a silver spacer bead between each set. Wear this bracelet to promote healing and enhance a greater overall sense of well-being.
- Semi-precious stones
- Length: 7 inches
- Adjustable
Code: 98280
Shipping Weight: 0.03 pounds
3 available for immediate delivery
Quantity in Basket: None
Red items are required
Price: $7.37


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"Christmas time, mistletoe and wine, building Trumpton one block at a time. With flats by the river and parking galore, we just have to hope that it's better than before".
Yes folks that's what Councillor Pamela Fleming is absolutely insisting gets sung before all meetings at Richmond Council this Christmas. We're not sure if she can actually hold a tune but we do know that she can hold a (party) line.
Christmas is upon us just as it was at this time last year. It's a time when we look forward to wincing at our bank balances and praying that our guests will leave (just bloody leave!) but we also look back on the year that's ending. It's been year of strange events, plucky Leicester City winning the Premier League, plucky Brits voting for Brexit, and plucky billionaire bully-boy businessman Donald Trump winning The Pres Factor across the pond. Here in Twickenham we've had our fair share of surprises too. Surprise that LBRuT, aka 'El Brute', stuck with their unpopular scheme and chosen architect for Twickenham Riverside despite strong local opposition. Surprise that the high street at the end of the year looks very similar to the way it looked at the beginning, and surprise too that a new third runway at Heathrow got the nod from the government. Actually none of those three was remotely surprising but they warranted a token mention.
What of the riverside scheme? Here at twickerati HQ we've been disappointed that the Council have persisted with a plan that doesn't do justice to the potential of the site, is overloaded in terms of scale and features a design that pays a traditionalist homage to a non-existent past. After all these years of dithering and deliberation Twickenham looks set to end up with something that's 'sort of OK' rather than something great. It's a shame. But on the bright side we do have a wonderful new station to enjoy as we go about our business. You've not seen it? What?? Well it was definitely going to be built after the Rugby World Cup. Definitely! The rugby world cup ended over a year ago but nothing's been started yet. On the plus side, it's not actually behind schedule because the phrase 'after the rugby world cup' applies to all dates from November 2015 to the very end of time. Hurrah!
At least the development opposite the station on the former post office sorting office site is nearly complete. It's even got our new 'community building' / 'cultural hub' in it where things will happen that the community can do or look at or maybe wear or something. In truth, we've no idea. If it can support a thriving theatre-cum-performance space then that will be good but the only concrete idea we've had is that it might have been better to have a community building as part of the riverside development but what do we know?
On the high street, long standing Chinese restaurant Jun Ming closed, Arthur's is up for sale and we said farewell to the mysterious Cakes World and Marc Jason's Shoeworld. The Press Room and Caffe a Roma arrived but so did Costa. The Heath Road restaurant that never lasts and which was most recently called Flavours of Sicily didn't last. Former Blockbuster video store turned Morrison's supermarket closed its doors again and is now turning into a Screwfix and a Co-op mini-supermarket has appeared in what was the Old Anchor pub. This, my friends, is the way of the world these days.
So what else happened? We had summer festivals and Christmas lights. New primary schools opened, more places are on the way in a giant new block at St Richard Reynolds College as is a whole new secondary school on the Richmond College site in Egerton Road. A man made national news when he brought Twickenham traffic to a standstill on a rugby day by throwing bricks and tiles off a roof and thieves blew up a cash point on Heath Road and made off with the contents. Richmond Council continued its merger with Wandsworth with the aim of making savings in back office costs through sharing resources. And if you wanted an ice rink to get you in the festive mood then you were to be disappointed. El Brute rejected proposals for a temporary winter rink in Radnor Gardens. Apparently school kids need the space…. even when they're on holiday.
Here at twickerati we even managed to disappoint ourselves by living up to our recently lowered expectations. We updated the site only occasionally and focused on the same few stories over and over again. The simple fix of finding more time, of writing with more wit and style and of securing regular contributors proved to be not quite so simple after all. But we battle on and, after all, why wouldn't we with plenty of Twick-o-centric developments likely in 2017. Work on the riverside, maybe that new station, some new flats that look just like all the others, shops closing, shops opening, a permanent home for the Eel Pie Music museum.
This is what living in God's own leafy outer London suburb is all about. This plus the parks, the river, the pubs, cafes and restaurants and above all else the people, i.e. you lovely lot.
As we conclude we say to you, put away thoughts of that charming John Lewis advert and think instead of the new seasonal YouTube video from El Brute Supremo, the Blue Baron aka Lord True. Buster the Boxer's got nothing on him. This Council video is all about listening to Sir True's view of the world whilst looking at the back of his head in a giant mirror. Nothing says Christmas quite like that!
And that, little friends, is that. Have a great Christmas, have a wonderful New Year and thanks for reading this blog over the last 12 months.


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I was a bit more ambitious in February.
I started with the pink blocks but then couldn't resist the urge to make the orange-y one to fill in the empty spot on the design wall! I'm planning for 20 blocks overall, mostly in the yellow-orange-pink range. I think I'm actually going to need a bit more yellow before I'm done! I haven't gone to the length of deciding how many blocks to make in each color or how many to make each month. For the time being I'm just playing it by ear. There's no rush, no deadline, for this project. It just provides a pleasant change from projects that may be more pressing or challenging (like the wedding quilt coming up!).
Next month I suspect you will see some truly orange blocks. Or maybe there will be more pink - you never know. ;- )


text: Home › About Us › Work Exchange Work Exchange First Name (required) Last Name (required) Your Email (required) Phone Number (required) Have you taken a class here before? YesNo Do you have experience doing work/exchange or working at a movement studio? YesNo Are you available 4-5 hours/week? YesLessMore Which days are you available? MondayTuesdayWednesdayThursdayFridaySaturdaySunday What is your primary reason for interest in work/exchange? Are you a student or employed full-time?


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Arrest in Langbar fraud case in which Lord Levy's "cash for Coronets " sidekick Barry Townsley was involved with other N London football supporters
Spanish police arrested six people tied to a $600 million fraud committed at Langbar International Ltd., (AKA Crown Corp) is a murky Bermuda-based "investment company" . It has been the subject of leisurely scrutiny by the Serious Fraud Office since 2005.
In a nutshell Crown/Langbar is a Bermuda-registered company, founded by a Polish-Canadian, backed by Israeli money, which traded in Argentina, banked its money in Brazil (Banco de Brasil) , had its accounts audited in Spain (Barcelona based Gironella Velasco ) ... and, which thanks to British financial advisers (see below - all keen supporters of North London football clubs) , listed its shares on the London stock market.
The Spanish police have just arrested 6 people ( between 56 and 76 years old at residences in Madrid, Barcelona and Alicante) in what they claim is a US$600 Mn. fraud .
The company operated as a "cash shell" quoted on London Alternative Investment Market (AIM) , shareholders included at one time Merrill Lynch and Gartmore . The fraud originally came to notice when it was announced £ 370 Mn. had evaporated from its accounts.
"The present board of Langbar International is determined to discover exactly what has transpired concerning company funds and to pursue their recovery," the company said on its Web site. "Our aim is to restore value for shareholders to the maximum that can be achieved."
The fraud appears to date back to 2003, when the suspects allegedly attracted investors through false claims about the company's assets, police said. This involved all sorts of floated lies that there was the "very exciting" $294m demerger of Crown Pharmaceutical, which was going to buy a Russian drugs company, and Crown Development, an eastern European property company.Once the shares rose, the suspects sold their holdings, according to the Spanish police.
El Pais reported that the six men arrested were charged and released and that one of the suspects was a former Israeli Mossad agent - believed to be 2 metre tall, 30 lb gorilla Abraham "Avi" Arad, and said to be a mathematical genius - who is understood to be the same person as one of the men arrested on January 21 as the fascinating and much sought after, Abraham Hochman.
The SFO declined to comment on any plans to extradite the arrested men.
Officials at the U.K.'s Financial Services Authority declined to comment, as did those at the City of London Police and the London Stock Exchange.
In April Langbar's founder, Mariusz Rybak, agreed to pay about 30 million pounds in April to settle a lawsuit brought by the company's directors and the judge made him sell his house in Monaco. They alleged that Rybak falsified the company's assets as part of a fraud against investors. Mrs Izabela Rybak (''Mrs Rybak''), and a company incorporated in Monaco, SCI Atol a company allegedly owned and controlled by Mrs Rybak and her daughter also seems to feature sonwehere in this tangled tale.
In 2007 Nabarro Wells, the finance house that floated Langbar, was fined £250,000 by the London Stock Exchange for failings related to the affair. NW has since April 2008 been part of Ambrian Capital plc , an AIM listed specialist investment banking group focused on the mining, oil & gas, alternative energy and new technology sectors.
Mariusz Rybak, is / was described as a Canadian technology executive, and Jean-Pierre Regli, a Swiss-Italian banker were the co-founders . It may surprise many to discover that they were on good terms with Barry Townsley and Simon Fox of stockbroker Insinger Townsley. Barry was of course also a great supporter of frank Donson's abortive bid to be Mayor of London.
Barry of course was/is a good friend of the Karaoke King (AKA Lord Levy and pal of the Qratet's envoy in the Middle East Tony Blair) who promised him and Earldom and half of Surrey, and a string of live in chorus girls as well as eternal life , in exchange for a loan to the New Labour Party. Read more here about the men who run David Miliband's favourite footie team. and post Monday, September 18, 2006 Panorama exposes the corruption at the heart of European football ...again. Also see Times 4/12/2005 A Crown farce: how Langbar mislaid £365m. Accountant David Buchler was involved at one time trying to sort out the mess.
See also Wikipedia entry on Langbar


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FIA tries to unfreeze engines
The Formula 1 manufacturers and the FIA agreed a few months ago to freeze Formula 1 engines until 2013. At Monaco there was an FIA poposal to move the goalposts and reduce the freeze until 2011.
The idea was rejected by the manufacturers because they have made their plans and budgets for the next few years and moving the end of the freeze would mean a need for immediate investment to get new engines built in time for the start of the 2011 season.
The key point of interest is why such a change was suddenly proposed. There are two schools of thought on this: the first is that the recent rise in the price of oil has caused the federation to explore quicker ways in which the FIA can switch F1 to a more pro-active role in the development of energy-saving technologies; the second is that Max Mosley was hoping for a quick deal to present to the General Assembly to show that despite the scandal he is still able to operate effectively in F1 circles.


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Animal Advocates
When you become an Animal Advocate at Audubon Community Nature Center, you are directly supporting animal care. Not only are you assisting to purchase food and other needed supplies for the in-house live animals, but you are also helping Audubon accomplish their mission. The live animals at Audubon help in educational programs both on and offsite that foster the connection between people to nature.
Animal Advocate packages make great souvenirs or gifts for any occasion.
Advocate Packages
Advocate packages are available for a donation of $20 and include:
- Personalized Animal Advocate certificate
- Supported animal biography card
- Species fact sheet
- 4x6 Photo of your supported animal
- A copy of the current ACNC newsletter
Animal Ambassadors in the advocate program include:
Bald Eagle (Liberty)
American Toad
Box Turtle (Lincoln)
Box Turtle (Milton)
California King Snake
False Map Turtle
Leopard Frog
Garter Snake
Snapping Turtle
Painted Turtle
Red Eared Slider
Musk Turtle
Spotted Turtle
Wood Turtle
Gray Treefrog
Spring Peeper
Audubon Community Nature Center
1600 Riverside Road
Jamestown, NY 14701
(716) 569-2345
Monday - Saturday
10:00 a.m. - 4:30 p.m.
1:00 p.m. - 4:30 p.m.


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Paperless self-assessment proposed
HM Revenue & Customs (HMRC) has announced plans to make the online self-assessment (SA) service "a more complete end-to-end digital experience".
In 2011/12, 7.65 million SA returns were submitted online but 75 per cent of communications with those customers were made by print-and-post.
Under the plans, the SA online service will be upgraded to allow users to receive electronic communications from HMRC. If a user opted-in, they would receive a message - by email or SMS - telling them that certain notices, reminders or statements were available to view in their online account.
The consultation on these proposals will run until 27 December 2013 and HMRC said it planned to start trialling the new system early in the 2014/15 tax year.
The Exchequer Secretary to the Treasury, David Gauke, said:
"HMRC's Digital Strategy will make processes like SA faster and simpler. It will deliver the tax system for the 21st century that taxpayers expect."
"The vast majority of HMRC's SA customers already file electronically, but only 25 per cent of their dealings with HMRC are online. Paperless SA will allow customers to do it all online."
We can handle your self-assessment for you, from completing and filing your return to dealing with HMRC. Contact us to discuss.


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An anti-tumor compound isolated from the Yew Tree (Taxus sp.)
Cephalomannine was first discovered in the tree, Cephalotaxus mannii (Powell, 1979). Since then, it has been discovered in yew trees, Taxus sp., and is commonly eluted with taxol during extract purification (Cardellina, 1991).
Biological Activity:Cephalomannine is one of three major taxanes produced by yew trees as a chemical defense. A typically yew tree will have a 10:5:1 ratio of paclitaxel, cephalomannine, and baccatin III, respectively (Elmer, 1994).
Taxanes disrupt mitosis by preventing microtubule destabilization and spindle fiber formation in animal cells (Molè-Bajer, 1983). As a consequence of this mechanism, yew trees are slow growing organisms. Without mitosis, cells, especially cells with a high replication rate such as tumor cells, cannot divide. Taxanes are currently being investigated as possible treatment for certain cancers, and paclitaxel is currently approved by the FDA for treatment of AIDS-related Kaposi sarcoma, breast cancer, non-small cell lung cancer, and ovarian cancer (National Cancer Institute, 2012).
References:Cardellina J. (1991) HPLC Separation of Taxol and Cephalomannine. Journal of Liquid Chromatography. 14, 659-665.
Elmer W, Mattina M and MacEachern G. (1994) Sensitivity of plant pathogenic fungi to taxane extracts from ornamental yews. Phytopathology. 84(10), 1179-1185.
Molè-Bajer J and Bajer A. (1983) Action of Taxol on Mitosis: Modification of Microtubule Arrangements and Function of the Mitotic Spindle in Haemanthus Endosperm. Journal of Cell Biology. 96, 527-540.
National Cancer Institute. (2012) Cancer Drug Information: Paclitaxel. www.cancer.gov
Powell R, Miller R, Smith Jr C. (1979) Cephalomannine; a New Antitumour Alkaloid from Cephalotaxus mannii. Journal of the Chemical Society. 102-104.


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Esperance receives two nominations for WA Young Achiever Awards
Two Esperance locals have been recognised for their work in the community with a nomination for a WA Young Achiever Award.
The award promotes young people up to 29 years of age for achievements in 2017.
World renowned drone videographer, Jaimen Hudson and cattle farmer Asher Goddard will find out if they have made the semi finals in March.
Jaimen Hudson was nominated for The Diamond Club Online Achievement Award, awarded to 'digitally savvy innovators'.
Mr Hudson uses drones to capture video and pictures, which has helped bring the world's attention to the picturesque landscapes of Esperance and promote tourism.
After a motorcycle accident left him a Quadriplegic in 2008, he found a new passion in drones.
"After my accident I knew I didn't want it to define me, I didn't want to sit at home feeling sorry for myself," he said.
"Droning has changed my life, I can't see my life without it."
Mr Hudson is working on a biographical documentary about his life and social media success with Sea Dog TV International.
National Geographic has expressed genuine interest in producing and broadcasting the film, he said.
Mr Hudson said social media would help the tourism season last longer as people see what Esperance has to offer.
Cattle farmer and educator, Asher Goddard was nominated for the WAFarmers and Rural Bank Agriculture Award.
Ms Goddard was recognised, in part, for her volunteer work, educating VET students at the Cattle Handler's Club.
"It's great to see kids that have never even handled cattle leading an animal around the ring with confidence [after three days]," she said.
She believed education was needed to correct the perception of farming as cruel and prevent farming techniques from being lost.
Ms Goddard was initially daunted by the prospect of moving to the country and entering a male dominated industry as a young female, but is now determined to stay in agriculture.
She works as a Cattle Supervisor at Ranch East, Esperance and aims to have her own herd one day.
The winners will be announced on May 26, 2018.


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Application Essay on Leadership
The main reason why I am interested in your leadership program is because your program seems very exciting and interesting. Your university community also appears to be an interesting community of which I desire to be part of. However, I am mainly attracted to your university community because, based on its mission statement, your institution stresses the importance of leadership through the involvement of community service, something that I am also very passionate about.
I have desired to be in a leadership position since I was young. I am not just interested in the authority and power that comes with leadership, but I am also very interested in being able to positively lead those under my authority so they can achieve their very best in whatever role is assigned to them. I deeply believe that your leadership training program has all the elements that will enable me to become a good and influential leader in my future endeavors. I also want to join your leadership program because I think that your institution has the right training that will not simply prepare me to be a good leader but also to be a great leader who stands out in many aspects. I want to be able to develop skills that will make me an interactive leader who will not simply issue instructions but will also listen to my followers in order to make the best informed decisions with regards to leadership….


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LR Baggs Stage Pro Electronics
Unlike typical undersaddle acoustic guitar pickups that are dependent on string compression for their sound, the Stage Pro was engineered to mirror the soundboard's actual movement as you play. At the heart of the pickup, a flexible film sensor only 2 thousands of an inch thick picks up the guitar's most delicate nuances. Tracking the motion of the top rather than a direct string attack suppresses "quack" caused by compression and unlocks the Stage Pro's unrivaled dynamic range.