Promoting the Self-Regulation of Stress in Health Care Providers: An Internet-Based Intervention.

The aim of our internet-based intervention study was to find out whether healthcare professionals can autonomously down-regulate the stress they experience at their workplace, using an established self-regulation tool called Mental Contrasting with Implementation Intentions (MCII). Applying MCII to reduce stress implied for our participants to repeatedly engage in a mental exercise that (1) required specifying a wish related to reducing stress, (2) identifying and imagining its most desired positive outcome, (3) detecting and imagining the obstacle that holds them back, and (4) coming up with an if-then plan on how to overcome it. We recruited on-line nurses employed at various health institutions all over Germany, and randomly assigned participants to one of three groups. In the MCII group (n = 33), participants were taught how to use this exercise via email and the participants were asked to engage in the exercise on a daily basis for a period of 3 weeks. As compared to two control groups, one being a no-treatment control group (n = 35) and the other a modified MCII group (n = 32), our experimental MCII group showed a reduced stress level and an enhanced work engagement. We discuss the strengths and weaknesses of the present study as well as ways to intensify MCII effects on stress reduction.

Clear cell hepatocellular carcinoma: origin, metabolic traits and fate of glycogenotic clear and ground glass cells.

Clear cell hepatocellular carcinoma (CCHCC) has hitherto been considered an uncommon, highly differentiated variant of hepatocellular carcinoma (HCC) with a relatively favorable prognosis. CCHCC is composed of mixtures of clear and/or acidophilic ground glass hepatocytes with excessive glycogen and/or fat and shares histology, clinical features and etiology with common HCCs. Studies in animal models of chemical, hormonal and viral hepatocarcinogenesis and observations in patients with chronic liver diseases prone to develop HCC have shown that the majority of HCCs are preceded by, or associated with, focal or diffuse excessive storage of glycogen (glycogenosis) which later may be replaced by fat (lipidosis/steatosis). In ground glass cells, the glycogenosis is accompanied by proliferation of the smooth endoplasmic reticulum, which is closely related to glycogen particles and frequently harbors the hepatitis B surface antigen (HBsAg). From the findings in animal models a sequence of changes has been established, commencing with preneoplastic glycogenotic liver lesions, often containing ground glass cells, and progressing to glycogen-poor neoplasms via various intermediate stages, including glycogenotic/lipidotic clear cell foci, clear cell hepatocellular adenomas (CCHCA) rich in glycogen and/or fat, and CCHCC. A similar process seems to take place in humans, with clear cells frequently persisting in CCHCC and steatohepatitic HCC, which presumably represent intermediate stages in the development rather than particular variants of HCC. During the progression of the preneoplastic lesions, the clear and ground glass cells transform into cells characteristic of common HCC. The sequential cellular changes are associated with metabolic aberrations, which start with an activation of the insulin signaling cascade resulting in pre-neoplastic hepatic glycogenosis. The molecular and metabolic changes underlying the glycogenosis/lipidosis are apparently responsible for the dramatic metabolic shift from gluconeogenesis to the pentose phosphate pathway and Warburg-type glycolysis, which provide precursors and energy for an ever increasing cell proliferation during progression.

Pleasure Now, Pain Later: Positive Fantasies About the Future Predict Symptoms of Depression.

Though common sense suggests that positive thinking shelters people from depression, the four studies reported here showed that this intuition needs to be qualified: Positive thinking in the form of fantasies about the future did indeed relate to decreased symptoms of depression when measured concurrently; however, positive fantasies predicted more depressive symptoms when measured longitudinally. The pattern of results was observed for different indicators of fantasies and depression, in adults and in schoolchildren, and for periods of up to 7 months (Studies 1-4). In college students, low academic success partially mediated the predictive relation between positive fantasies and symptoms of depression (Study 4). Results add to existing research on the problematic effects of positive fantasies on performance by suggesting that indulging in positive fantasies predicts problems in mental health.

The ZnR/GPR39 interacts with the CaSR to enhance signaling in prostate and salivary epithelia.

Zinc signaling is mediated by the zinc sensing receptor, ZnR, recently suggested to be the same receptor as G-protein coupled receptor 39, GPR39. However, it is unknown if GPR39 is mediating Zn(2+) -dependent signaling in prostate and salivary tissue where changes in zinc concentrations are frequent and of physiological significance. Here, we show that GPR39 is mediating Zn(2+) -dependent Ca(2+) responses and is regulating activity of MAP and PI3 pathways in prostate cancer cells, PC3, and ductal salivary gland cells, HSY. We next ask whether ZnR/GPR39 interacts with other GPCR family members. We find that endogenous ZnR/GPR39 activity is regulated by the expression and activity of another cation sensing GPCR, the Ca(2+) -sensing receptor (CaSR). Although CaSR is not activated by Zn(2+), co-expression of CaSR and ZnR/GPR39 synergistically enhances Ca(2+) responses in PC3 and HSY cells. Silencing of the CaSR using siRNA or a dominant negative construct reduces the Zn(2+) -dependent signaling. Importantly, overexpression of GPR39 in HEK293 cells is sufficient to trigger Zn(2+) -dependent responses. Nevertheless, application of the CaSR agonist spermine, at concentration below its threshold, enhanced Zn(2+) -dependent Ca(2+) response. Our results suggest that the CaSR interacts with ZnR/GPR39 and thereby regulates its activity. Finally, we show that in PC3 cells ZnR/GPR39 is required for mediating the Zn(2+) -dependent activation of MAPK and PI3K, pathways leading to enhanced cell growth. Importantly, Zn(2+) -dependent activation of ZnR/GPR39 also enhances the expression of the Ca(2+) -binding protein S100A4 that is linked to invasion of prostate cancer cells.

Impact of S100A8/A9 expression on prostate cancer progression in vitro and in vivo.

The proinflammatory S100A8/A9 proteins, which are expressed in myeloid cells under physiological conditions, are strongly expressed in human prostate cancer epithelial cells. Their role in the tumor cells and in tumor progression is largely unclear. We established a prostate cancer epithelial cell line (PC-3 TO-A8/A9) expressing S100A8 and S100A9 simultaneously under doxycycline control, to study the role of S100A8/A9 on tumor growth and infiltration of immune cells in subcutaneous xenografts in male NMRI nu/nu mice. Colonization of distant organs was studied after intracardial injection of the tumor cells in male NOD/SCID mice. PC-3 TO-A8/A9 cells grown in vitro and subcutaneous xenografts in mice not treated with doxycycline expressed high levels of S100A8/A9 mRNA and protein, whereas doxycycline treatment suppressed S100A8/A9 expression. S100A8/A9 expression did not significantly alter growth rate and invasion of the subcutaneous tumors into surrounding tissues. However, S100A8/A9 expression caused increased infiltration of immune cells, especially neutrophils. In intracardially injected mice sporadic tumor settlement was observed in muscle and lymph nodes. Colonies of tumor cells and micro-metastases were observed in the lung of 64.3% (9 out of 14) of mice not treated with doxycycline and in 33.3% (5 out of 15) of mice treated with doxycycline. Our data demonstrate for the first time that S100A8/A9 expression in epithelial cancer cells causes enhanced infiltration of immune cells, especially neutrophils, and stimulates settlement of the cancer cells in the lung.

Eph receptor B4 is a regulator of estrogen receptor alpha in breast cancer cells.

BACKGROUND: Estrogen receptor alpha (ER-α) plays an important role in breast cancer initiation and progression and represents a major target in cancer therapy. The expression and activity of ER-α is regulated by multiple mechanisms at the transcriptional and post-translational level. Interaction of tyrosine kinase receptor-activated signaling pathways with ER-α function has been reported. We previously performed a kinome-wide small interfering RNA high-throughput screen to identify novel protein kinases involved in the regulation of ER-α transcriptional activity in human breast cancer cells. Our screening analysis identified the Eph receptor tyrosine kinases (Eph) as potential positive regulators of ER-α. RESULTS: In this study, we demonstrate Eph receptor B4 (EphB4), a member of Eph kinase family, a positive regulator of ER-α in human breast cancer cell lines (MCF-7, T-47D and BT-474). Down-regulation of EphB4 by RNA interference technology impairs estrogen-dependent ER-α transcriptional activity in breast cancer cells. Decreased activity of ER-α after EphB4 knockdown is the consequence of diminished ER-α messenger RNA and protein expression. Furthermore, phosphorylation of Akt, a downstream mediator of EphB4, is reduced following EphB4 silencing. CONCLUSIONS: Our data suggests EphB4 as an upstream regulator of ER-α in human breast cancer cells by modulating ER-α transcription. The results also suggest Akt as a relevant downstream signaling molecule in this novel EphB4-ER-α pathway.

Insulin-like growth factor binding protein-4 and -5 modulate ligand-dependent estrogen receptor-α activation in breast cancer cells in an IGF-independent manner.

Insulin-like growth factor binding proteins (IGFBPs) are modulators of numerous cellular processes including cell proliferation. Although IGFBPs classically act by sequestration of extracellular insulin-like growth factors (IGFs), thereby contributing to the fine-tuning of growth factor signals, IGF-independent actions of IGFBPs have also been described. In the breast, growth factor signaling in association with estradiol (E2)-stimulated estrogen receptor function is organized in a complex cross-talk. The importance of phosphatidylinositol 3-kinase/protein kinase B (Akt/PKB) pathway components for the E2-induced activation of estrogen receptor-alpha (ERα) is well accepted. Here we show that in the absence of IGFs, IGFBP-4 or IGFBP-5, either overexpressed in MCF-7 breast cancer cells or added exogenously, decreased the capability of E2 to induce ERα transcriptional activity. In addition, overexpression or addition of recombinant IGFBP-4 or IGFBP-5 resulted in reduction of E2-induced phosphorylation of Akt/PKB, GSK-3α/ß and ERα in MCF-7 cells. The activation of the Akt/PKB-pathway describes a non-genomic effect of E2, which did not involve activation/phosphorylation of the IGF-I receptor (IGF-IR). Furthermore, knockdown of the IGF-IR did not affect the inhibition of E2-induced ERα phosphorylation by IGFBP-4 and 5. Moreover, IGFBP-4 and IGFBP-5 strongly decreased E2-triggered growth of MCF-7 cells. Our data suggest that IGFBPs interfere with the E2-induced activation of the Akt/PKB-pathway and prevent full hormone-dependent activation of ERα and breast cancer cell growth in an IGF- and IGF-IR-independent manner.

Interaction of JAK with steroid receptor function.

The function of steroid receptors is not only regulated by steroid hormones, but also by multiple cellular signaling cascades activated by membrane-bound receptors which are stimulated by growth factors or cytokines. Cross-talk between JAK and steroid receptors plays a central role in the regulation of a multitude of physiological processes and aberrant signaling is involved in the development of numerous diseases including cancer. In this review we provide a brief summary of the knowledge of interactions between JAK and the function of steroid receptors in normal cells and tissues and in diseases.

Prostaglandin E2 stimulates S100A8 expression by activating protein kinase A and CCAAT/enhancer-binding-protein-beta in prostate cancer cells.

S100A8 and S100A9 are strongly expressed in epithelial cells of human prostate cancer. However, the regulation of their expression is unclear. Here we show that S100A8 and to a lesser extent S100A9 mRNA expression is induced by prostaglandin E2 in a dose and time-dependent manner in PC-3 prostate cancer cells as well as in BPH-1 benign prostatic epithelial cells. Prostanoid receptor EP2 antagonist AH6809 and EP4 antagonist AH23848, as well as protein kinase A inhibitor H89, inhibited prostaglandin E2 mediated increase in S100A8 mRNA expression as well as promoter activity. Sequence analysis detected a potential binding site of the transcription factor CCAAT/enhancer-binding-protein-beta within the proximal S100A8 promoter. CCAAT/enhancer-binding-protein-beta overexpression increased S100A8 mRNA and protein expression as well as its promoter activity. The latter was prevented by mutation of the potential CCAAT/enhancer-binding-protein-beta binding site within the S100A8 promoter. Chromatin immunoprecipitation revealed increased binding of CCAAT/enhancer-binding-protein-beta to the S100A8 promoter in prostaglandin E2 treated cells. Knockdown of CCAAT/enhancer-binding-protein-beta by siRNA blocked prostaglandin E2 mediated induction of S100A8 promoter activity and mRNA expression. Our results indicate that in prostate cancer cells, S100A8 expression is stimulated by prostaglandin E2 via EP2 and EP4 receptors through activation of the protein kinase A signaling pathway and subsequent stimulation of CCAAT/enhancer-binding-protein-beta binding to the S100A8 promoter.

Hypoxia and HIF-1 increase S100A8 and S100A9 expression in prostate cancer.

S100A8 and S100A9, two heterodimer-forming members of the cytosolic S100 Ca(2+) signaling protein family, are overexpressed in various cancer types, including prostate cancer. They act as proinflammatory danger signals when secreted to the extracellular space and are thought to play an important role during tumorigenesis, affecting inflammatory processes, proliferation, invasion and metastasis of tumor cells. Despite this fact, little is known about tumor environmental factors influencing S100A8/A9 expression. The aim of this study was to test the effect of hypoxia and its master transcriptional regulator hypoxia-inducible factor 1 (HIF-1) on S100A8/A9 expression. Hypoxia treatment resulted in induction of S100A8/A9 protein and mRNA expression in prostate epithelial BPH-1 cells, the latter was also confirmed in the prostate cancer cell lines PC-3 and DU-145. Furthermore, overexpression of HIF-1α caused increase in S100A8/A9 protein and mRNA expression as well as secretion. Functional hypoxia response elements mediating promoter activation on HIF-1α overexpression were identified within the S100A8 and S100A9 promoters using promoter luciferase reporter constructs. Binding of HIF-1α to S100A8 and S100A9 promoters was confirmed by chromatin immunoprecipitation. Immunohistochemical analysis of a prostate cancer tissue array showed clear correlation of S100A8 and S100A9 with HIF-1α expression. Multivariate proportional hazard analysis revealed association of high S100A9 level with time to prostate cancer recurrence. In conclusion, we identified hypoxia and HIF-1 as novel regulators of S100A8/A9 expression in prostate cancer. S100A9 might be useful as prognostic marker for prostate cancer recurrence after radical prostatectomy.

Janus kinase 2--a novel negative regulator of estrogen receptor α function.

Estrogen receptor α (ERα) functions as a transcription factor to regulate a wide range of cellular activities in response to 17ß-estradiol (E2). The regulation of ERα transcriptional activity is highly complex and not yet fully understood. In this respect, recent studies have highlighted the importance of certain cellular protein kinases. To identify novel protein kinases regulating ERα activity, we performed a high-throughput siRNA screening in combination with a luciferase reporter assay in an ERα positive breast cancer cell line. Among the vast majority of potential positive regulators, we found Janus kinase 2 (JAK2), a member of the Janus kinase family of non-receptor tyrosine kinases, to have a negative regulatory effect on E2 induced luciferase activity. In addition, silencing of JAK2 resulted in increased expression of endogenous ERα target genes, pS2 and GREB1. In an attempt to understand the mechanism underlying JAK2 mediated regulation of ERα transcriptional activity, we found that JAK2 negatively regulates ERα protein level. Gene expression analysis revealed no significant influence of JAK2 on ERα mRNA level. Subsequently, a role of JAK2 in regulating ERα protein degradation was analyzed. Inhibition of the lysosome did not alter JAK2 mediated downregulation of ERα. In contrast, using proteasome inhibitors MG132 and lactacystin, we demonstrated that JAK2 governs ERα protein stability via the ubiquitin-proteasome pathway. In contrast to JAK2, the two other members of the JAK family expressed in the breast (JAK1 and TYK2) had no influence on ERα function. In addition, we found that prolonged E2 treatment upregulates JAK2 mRNA and protein levels. These results suggest a novel negative regulation of ERα activity and protein by JAK2 in breast cancer cells and indicate a potential new cross-talk.

Targeting AMP-activated protein kinase in adipocytes to modulate obesity-related adipokine production associated with insulin resistance and breast cancer cell proliferation.

BACKGROUND: Adipokines, e.g. TNFα, IL-6 and leptin increase insulin resistance, and consequent hyperinsulinaemia influences breast cancer progression. Beside its mitogenic effects, insulin may influence adipokine production from adipocyte stromal cells and paracrine enhancement of breast cancer cell growth. In contrast, adiponectin, another adipokine is protective against breast cancer cell proliferation and insulin resistance.AMP-activated protein kinase (AMPK) activity has been found decreased in visceral adipose tissue of insulin-resistant patients. Lipopolysaccharides (LPS) link systemic inflammation to high fat diet-induced insulin resistance. Modulation of LPS-induced adipokine production by metformin and AMPK activation might represent an alternative way to treat both, insulin resistance and breast cancer. METHODS: Human preadipocytes obtained from surgical biopsies were expanded and differentiated in vitro into adipocytes, and incubated with siRNA targeting AMPKalpha1 (72 h), LPS (24 h, 100 µg/ml) and/or metformin (24 h, 1 mM) followed by mRNA extraction and analyses. Additionally, the supernatant of preadipocytes or derived-adipocytes in culture for 24 h was used as conditioned media to evaluate MCF-7 breast cancer cell proliferation. RESULTS: Conditioned media from preadipocyte-derived adipocytes, but not from undifferentiated preadipocytes, increased MCF-7 cell proliferation (p < 0.01). Induction of IL-6 mRNA by LPS was reduced by metformin (p < 0.01), while the LPS-induced mRNA expression of the naturally occurring anti-inflammatory cytokine interleukin 1 receptor antagonist was increased (p < 0.01). Silencing of AMPKalpha1 enhanced LPS-induced IL-6 and IL-8 mRNA expression (p < 0.05). CONCLUSIONS: Adipocyte-secreted factors enhance breast cancer cell proliferation, while AMPK and metformin improve the LPS-induced adipokine imbalance. Possibly, AMPK activation may provide a new way not only to improve the obesity-related adipokine profile and insulin resistance, but also to prevent obesity-related breast cancer development and progression.

Sad mood promotes self-initiated mental contrasting of future and reality.

Self-regulation by mentally contrasting a positive future with negative reality leads people to differentiate in their goal commitments: They commit to goals when expectations of success are high and let go when expectations of success are low. On the contrary, when indulging in the positive future or dwelling on negative reality, people fail to consider expectations of success and do not form selective goal commitments (Oettingen, Pak, & Schnetter, 2001). Whereas prior research has examined the effects of experimentally induced mental contrasting, we address sad mood as a contextual influence promoting self-initiated mental contrasting. Across various mood inductions, sad moods--which are associated with problem solving strategies--facilitated self-initiated mental contrasting more than neutral moods (Studies 1, 5) or happy moods (Studies 2, 3, 4, 6). Importantly, mood did not affect the relation between mental contrasting and selective formation of goal commitment (Studies 5, 6). The results suggest that sad moods aid in self-regulation by making people self-initiate goal commitments that are sensitive to their expectations of success.

Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis.

The molecular mechanisms underlying the development of hepatocellular carcinoma (HCC) are not yet fully understood. Preneoplastic foci of altered hepatocytes regularly precede HCC in various species. The predominant earliest type of foci of altered hepatocytes, the glycogen storage focus (GSF), shows an excess of glycogen (glycogenosis) in the cytoplasm. During progression from GSF to HCC, the stored glycogen is gradually reduced, resulting in complete loss in basophilic HCC. We have previously shown that in N-nitrosomorpholine-induced hepatocarcinogenesis, insulin receptor substrate (IRS-1) is strongly expressed in GSF and reduced during progression to HCC, thus correlating with the glycogen content. In the present study, we observed increased levels of insulin receptor, IGF-I receptor (IGF-IR), IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 in GSF, following the same pattern of expression as IRS-1. We conclude that the abundance of IRS-1, IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 coincides with a concerted upregulation of both IR and IGF-IR induced by the hepatocarcinogen. Our data suggest that in early hepatocellular preneoplasia, the upregulation of IR elicits glycogenosis through IRS-1 and/or IRS-2, whereas the increased level of the IGF-IR may lead to the increased cell proliferation previously reported in GSF. Therefore, the concerted upregulation of both IR and IGF-IR may represent initial events in hepatocarcinogenesis.

Estrogens promote invasion of prostate cancer cells in a paracrine manner through up-regulation of matrix metalloproteinase 2 in prostatic stromal cells.

Accumulating evidence suggests an enhancing effect of estrogens on prostate cancer (PCa) progression. Matrix metalloproteinase 2 (MMP2), which plays an important role in prostate cancer invasion, is mainly expressed in prostatic stromal cells (PrSC). Here we show that estradiol (E(2)) treatment up-regulates MMP2 production in PrSC, which promotes PCa cell invasion in a paracrine manner. Conditioned medium (CM) was collected from E(2)-treated prostatic stromal cell line WPMY-1 and primary PrSC. The CM of E(2)-treated WPMY-1 and PrSC promoted invasion of PCa cells, as measured by Matrigel transwell assays. Treatment with E(2) and 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, an estrogen receptor-alpha (ERα) specific agonist, significantly up-regulated MMP2 expression in WPMY-1 and PrSC cells at both mRNA and protein levels. The CM treated with an anti-MMP2 antibody lost the stimulatory effect on invasion of PCa cells. The ER inhibitor ICI 182,780, as well as a TGFß1 neutralizing antibody and ERα-specific small interfering RNA effectively suppressed E(2)-induced MMP2 expression in WPMY-1 cells. Mechanistic studies showed that E(2) up-regulated MMP2 in an indirect manner: E(2) induced TGFß1 expression via ERα; TGFß1 stimulated MMP2 expression in PrSC; the invasion of PCa cells were stimulated by elevated MMP2 expression induced by E(2) in a paracrine manner. Our data show that E(2) induces MMP2 expression in WPMY-1 and PrSC cells, which was mediated by TGFß1. The effect of E(2) on invasion of PCa cells is mediated by up-regulation of MMP2 in a paracrine mechanism.

ß-Catenin Is a Positive Regulator of Estrogen Receptor-α Function in Breast Cancer Cells.

Estrogen receptor-alpha (ERα) is a key factor in the development of breast cancer in humans. The expression and activity of ERα is regulated by a multitude of intracellular and extracellular signals. Here we show a cross-talk between ß-catenin and ERα in human breast cancer cells. Knockdown of ß-catenin by RNAi resulted in significant reduction of ERα mRNA and/or protein levels in MCF-7, T-47D, and BT-474 breast cancer cells and in significant reduction of estradiol-induced expression of the ERα target genes pS2 and GREB1. In addition ß-catenin silencing resulted in significant decrease of growth of MCF-7 cells both in the absence and presence of estradiol. ß-catenin and ERα could not be co-immunoprecipitated by ERα antibodies from lysates of E2-treated or untreated cells suggesting lack of direct physical interaction. It is concluded that ß-catenin is a positive regulator of ERα mRNA and protein expression.

Meeting report: 3rd international workshop on insulin & cancer heidelberg, Germany, october 30-31, 2010.

The 3rd International Workshop on Insulin & Cancer was held on October 30-31, 2010 at the German Cancer Research Centre in Heidelberg/Germany. The topics followed-up the discussions of the previous workshops: possible differences in mitogenicity between natural insulin and genetically engineered insulin derivatives (insulin analogues), as shown by laboratory studies and epidemiologic studies alike; molecular studies on the links between metabolic and mitogenic effects of insulin, and of hyperinsulinaemia in particular; epidemiologic evidence of interferences between insulin and other hormones, particularly sex hormones, and obesity-associated cancer; the involvement of inflammatory cytokines produced by fat tissue in obesity-associated cancer; aspects of drug-design (binding drugs to albumin) and, last but not least, detection and investigation of circulating cancer cells.

Epigenetically deregulated microRNA-375 is involved in a positive feedback loop with estrogen receptor alpha in breast cancer cells.

Estrogen receptor α (ERα) upregulation causes abnormal cell proliferation in about two thirds of breast cancers, yet understanding of the underlying mechanisms remains incomplete. Here, we show that high expression of the microRNA miR-375 in ERα-positive breast cell lines is a key driver of their proliferation. miR-375 overexpression was caused by loss of epigenetic marks including H3K9me2 and local DNA hypomethylation, dissociation of the transcriptional repressor CTCF from the miR-375 promoter, and interactions of ERα with regulatory regions of miR-375. Inhibiting miR-375 in ERα-positive MCF-7 cells resulted in reduced ERα activation and cell proliferation. A combination of expression profiling from tumor samples and miRNA target prediction identified RASD1 as a potential miR-375 target. Mechanistic investigations revealed that miR-375 regulates RASD1 by targeting the 3' untranslated region in RASD1 mRNA. Additionally, we found that RASD1 negatively regulates ERα expression. Our findings define a forward feedback pathway in control of ERα expression, highlighting new strategies to treat ERα-positive invasive breast tumors.

Treatment with insulin glargine (Lantus) increases the proliferative potency of the serum of patients with type-1 diabetes: a pilot study on MCF-7 breast cancer cells.

CONTEXT AND OBJECTIVE: Insulin glargine (Lantus) stimulates growth of MCF-7 cells stronger than human insulin. We investigated if serum from diabetic patients treated with glargine versus human insulin may display a similar effect. METHODS: Pairs of serum samples from 31 C-peptide negative type-1 diabetic patients were investigated. In cross-over fashion, 23 patients were treated with glargine plus rapid-acting insulin analogues, and similar doses of human NPH and rapid-acting insulin. For comparison, eight patients were treated with insulin detemir (Levemir) and human NPH. MCF-7 cells were incubated with 10% serum and proliferation was assessed after 72 hours. RESULTS: Serum containing insulin glargine was 1.11(95% CI 1.05-1.18) fold more mitogenic than human insulin-containing serum (p < 0.005); mitogenicity of serum containing detemir was 0.99(95% CI 0.98-1.02) fold that of human insulin-containing serum. CONCLUSION: The serum of diabetic patients was slightly stronger mitogenic when using glargine as compared to human insulin or detemir for treatment.

Self-regulation of commitment to reduce cigarette consumption: mental contrasting of future with reality.

The model of fantasy realisation (Oettingen, 2000) specifies mental contrasting of a positive future with negative reality as a strategy that creates strong goal commitments. We propose that fantasies about a positive and negative future produce strong goal commitments when contrasted with the respective reality. The present study supports this hypothesis in the area of reducing cigarette consumption. Mental contrasting of a positive future with negative reality as well as mental contrasting of a negative future with positive reality led to taking immediate action when participants had high expectations of success. Results indicate that both fantasies about a positive future and a negative future can be used to commit to goals that benefit health and prevent disease.