References of "Schneider, Jochen 50003032"
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See detailTurn up the heat: circulating serotonin tunes our internal heating system.
Schneider, Jochen UL; Nadeau, Joseph H.

in Cell metabolism (2015), 21(2), 156-8

Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al ... [more ▼]

Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al. (2014) find that peripheral serotonin controls thermogenesis in adipose tissue by modulating beta-adrenergic stimulation of UCP-1, thereby affecting glucose homeostasis and weight gain. [less ▲]

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See detailNecrotizing Sarcoid Granulomatosis (NSG): A Diagnostic Pitfall to Watch Out For!
Schiekofer, Stephan; Zirngibl, Christina; Schneider, Jochen UL

in Journal of Clinical and Diagnostic Research (2015), 9(7), 02

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See detailComparison of a healthy miRNome with melanoma patient miRNomes: are microRNAs suitable serum biomarkers for cancer?
Margue, Christiane UL; Reinsbach, Susanne UL; Philippidou, Demetra UL et al

in Oncotarget (2015), 6(14), 12110-27

MiRNAs are increasingly recognized as biomarkers for the diagnosis of cancers where they are profiled from tumor tissue (intracellular miRNAs) or serum/plasma samples (extracellular miRNAs). To improve ... [more ▼]

MiRNAs are increasingly recognized as biomarkers for the diagnosis of cancers where they are profiled from tumor tissue (intracellular miRNAs) or serum/plasma samples (extracellular miRNAs). To improve detection of reliable biomarkers from blood samples, we first compiled a healthy reference miRNome and established a well-controlled analysis pipeline allowing for standardized quantification of circulating miRNAs. Using whole miRNome and custom qPCR arrays, miRNA expression profiles were analyzed in 126 serum, whole blood and tissue samples of healthy volunteers and melanoma patients and in primary melanocyte and keratinocyte cell lines. We found characteristic signatures with excellent prognostic scores only in late stage but not in early stage melanoma patients. Upon comparison of melanoma tissue miRNomes with matching serum samples, several miRNAs were identified to be exclusively tissue-derived (miR-30b-5p, miR-374a-5p and others) while others had higher expression levels in serum (miR-3201 and miR-122-5p). Here we have compiled a healthy and widely applicable miRNome from serum samples and we provide strong evidence that levels of cell-free miRNAs only change significantly at later stages of melanoma progression, which has serious implications for miRNA biomarker studies in cancer. [less ▲]

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See detailPlatelet activation and aggregation promote lung inflammation and influenza virus pathogenesis.
Le, Vuong Ba; Schneider, Jochen UL; Boergeling, Yvonne et al

in American journal of respiratory and critical care medicine (2015), 191(7), 804-19

RATIONALE: The hallmark of severe influenza virus infection is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and ... [more ▼]

RATIONALE: The hallmark of severe influenza virus infection is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and inflammatory responses is unknown. OBJECTIVES: To determine the role of platelets during influenza A virus infections and propose new therapeutics against influenza. METHODS: We used targeted gene deletion approaches and pharmacologic interventions to investigate the role of platelets during influenza virus infection in mice. MEASUREMENTS AND MAIN RESULTS: Lungs of infected mice were massively infiltrated by aggregates of activated platelets. Platelet activation promoted influenza A virus pathogenesis. Activating protease-activated receptor 4, a platelet receptor for thrombin that is crucial for platelet activation, exacerbated influenza-induced acute lung injury and death. In contrast, deficiency in the major platelet receptor glycoprotein IIIa protected mice from death caused by influenza viruses, and treating the mice with a specific glycoprotein IIb/IIIa antagonist, eptifibatide, had the same effect. Interestingly, mice treated with other antiplatelet compounds (antagonists of protease-activated receptor 4, MRS 2179, and clopidogrel) were also protected from severe lung injury and lethal infections induced by several influenza strains. CONCLUSIONS: The intricate relationship between hemostasis and inflammation has major consequences in influenza virus pathogenesis, and antiplatelet drugs might be explored to develop new antiinflammatory treatment against influenza virus infections. [less ▲]

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See detailMolecular and Clinical Evidence for an ARMC5 Tumor Syndrome: Concurrent Inactivating Germline and Somatic Mutations are Associated with both Primary Macronodular Adrenal Hyperplasia and Meningioma
Eibelt, Ulf; Trovato, Alissa; Kloth, Michael et al

in Journal of Clinical Endocrinology and Metabolism (2014)

Context:Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome (CS), which may present in the context of different familial multitumor syndromes. Heterozygous inactivating ... [more ▼]

Context:Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome (CS), which may present in the context of different familial multitumor syndromes. Heterozygous inactivating germline mutations of armadillo repeat containing 5 (ARMC5) have very recently been described as cause for sporadic PMAH. Whether this genetic condition also causes familial PMAH in association with other neoplasias is unclear. Objective: The aim of the present study was to delineate the molecular cause in a large family with PMAH and other neoplasias. Patients and Methods: Whole genome sequencing and comprehensive clinical and biochemical phenotyping was performed in members of a PMAH affected family. Nodules derived from adrenal surgery and pancreatic and meningeal tumor tissue were analysed for accompanying somatic mutations in the identified target genes. Results: PMAH presenting either as overt or subclinical CS was accompanied by a heterozygous germline mutation in ARMC5 (p.A110fs*9) located on chromosome 16. Analysis of tumor tissue showed different somatic ARMC5 mutations in adrenal nodules supporting a “second hit” hypothesis with inactivation of a tumor suppressor gene. A damaging somatic ARMC5 mutation was also found in a concomitant meningioma (p.R502fs) but not in a pancreatic tumor suggesting biallelic inactivation of ARMC5 as causal also for the intracranial meningioma. Conclusions: Our analysis further confirms inherited inactivating ARMC5 mutations as a cause of familial PMAH and suggests an additional role for the development of concomitant intracranial meningiomas. [less ▲]

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See detailDynamic change of host gastrointestinal microbiome and immune status in relation to mucosal barrier effects during chemotherapy and immune ablative intervention in humans
Kaysen, Anne UL; Heintz, Anna UL; Lebrun, Laura UL et al

Poster (2014, April)

The human gastrointestinal tract is colonized by communities of endogenous microbes, commonly referred to as the microbiome. Here, the microbiota are in close contact with the host intestinal mucosa and ... [more ▼]

The human gastrointestinal tract is colonized by communities of endogenous microbes, commonly referred to as the microbiome. Here, the microbiota are in close contact with the host intestinal mucosa and its innate and adaptive immune systems. The fact that certain stimuli induce an inflammatory response whereas others induce tolerance suggests, that the host immune system interacts with the microbiota and vice versa in different ways. However, the exact details of theses interactions remain largely unknown. It is known that cancer treatment can result in severe adverse effects like mucositis and in combination with allogeneic stem cell transplantation (Tx), in graft-versus host disease (GvHD). However, there is at present only sparse information available on the effects of chemotherapy on the intestinal microbiota and resulting changes in microbiome-immune system interactions. Almost no data exists on the effect of allogeneic stem cell Tx on the composition of the gastrointestinal microbiota. In this project, we are studying the complex interactions between the host and the intestinal microbiota after chemotherapy with or without allogeneic Tx and the occurrence of severe adverse side effects such as mucositis and GvHD. Using a systems biology approach including metagenomics and RNAseq, fecal samples and blood plasma samples from patients undergoing these treatments for malignancies will be analysed to identify the composition of the gastrointestinal microbiome and bacterial small RNAs. The main research hypothesis is that there are quantitative and qualitative changes in the gastrointestinal microbiome following chemotherapy and allogeneic Tx which are linked to the immune status of the patients and possible treatment side-effects, in particular mucositis and GvHD. We aim to provide knowledge on how the host's intestinal mucosa and immune system influence the gastrointestinal microbiome and on the role and involvement of the gastrointestinal microbiota in development in mucositis and GvHD. Importantly, this could help in the formulation of measures to prevent mucositis and GvHD development. [less ▲]

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See detailCombinatorial regulation of lipoprotein lipase by microRNAs during mouse adipogenesis
Liivrand, Maria UL; Heinäniemi, Merja UL; John, Elisabeth UL et al

in RNA Biology (2014), 11(1), 76-91

MicroRNAs (miRNAs) regulate gene expression directly through base pairing to their targets or indirectly through participating in multi-scale regulatory networks. Often miRNAs take part in feed-forward ... [more ▼]

MicroRNAs (miRNAs) regulate gene expression directly through base pairing to their targets or indirectly through participating in multi-scale regulatory networks. Often miRNAs take part in feed-forward motifs where a miRNA and a transcription factor act on shared targets to achieve accurate regulation of processes such as cell differentiation. Here we show that the expression levels of miR-27a and miR-29a inversely correlate with the mRNA levels of lipoprotein lipase (Lpl), their predicted combinatorial target, and its key transcriptional regulator peroxisome proliferator activated receptor gamma (Pparg) during 3T3-L1 adipocyte differentiation. More importantly, we show that Lpl, a key lipogenic enzyme, can be negatively regulated by the two miRNA families in a combinatorial fashion on the mRNA and functional level in maturing adipocytes. This regulation is mediated through the Lpl 3′UTR as confirmed by reporter gene assays. In addition, a small mathematical model captures the dynamics of this feed-forward motif and predicts the changes in Lpl mRNA levels upon network perturbations. The obtained results might offer an explanation to the dysregulation of LPL in diabetic conditions and could be extended to quantitative modeling of regulation of other metabolic genes under similar regulatory network motifs. [less ▲]

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See detailInverse association of the endogenous thrombin potential (ETP) with cardiovascular death: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.
Schneider, Jochen UL; Isermann, Berend; Kleber, Marcus E. et al

in International journal of cardiology (2014), 176(1), 139-44

BACKGROUND: Coagulation and prothrombotic potential have genuinely been associated with increased cardiovascular risk. However, not all studies in this regard are conclusive. Some clinical trials have ... [more ▼]

BACKGROUND: Coagulation and prothrombotic potential have genuinely been associated with increased cardiovascular risk. However, not all studies in this regard are conclusive. Some clinical trials have shown an increased frequency of cardiovascular complications in patients receiving direct thrombin inhibitors. Previous data from human subjects after acute cardiovascular events showed an inverse association between the thrombin generation marker F1+2 and cardiovascular endpoints indicating that not the lowest, but a slightly elevated propensity for thrombin generation is associated with a lower risk of cardiovascular events. This observation has been supported by findings in animal models of atherosclerosis. Hence, we evaluated the association between the endogenous thrombin potential (ETP) and cardiovascular death (CVD) and markers of vascular dysfunction in a large prospective study with long-term follow up. METHOD: After excluding patients receiving anticoagulants we tested ETP in 2196 participants (median follow-up 10 years) for its ability to predict vascular death (CVD). In addition, the association between ETP and sVCAM-1, sICAM-1, LpPLA2, hsCRP and SAA was determined. RESULTS: We observed an inverse association between ETP and CVD with the lowest hazard ratio in the 4th ETP quartile. The nadirs of sICAM-1 or sVCAM-1 were observed in the 3rd, for LpPLA2 in the 4th ETP quartile. Conversely, hsCRP and SAA were highest in the 4th quartile. CONCLUSIONS: These results demonstrate that not the lowest ETP possible, but slightly higher levels are associated with a reduced risk of CVD and lower markers of endothelial dysfunction, suggesting a more complex role of thrombin in cardiovascular disease. [less ▲]

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See detailAcute depletion of endothelial beta3-integrin transiently inhibits tumor growth and angiogenesis in mice.
Steri, Veronica; Ellison, Tim S.; Gontarczyk, Aleksander Maksym et al

in Circulation Research (2014), 114(1), 79-91

RATIONALE: The dramatic upregulation of alphavbeta3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for ... [more ▼]

RATIONALE: The dramatic upregulation of alphavbeta3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against alphavbeta3-integrin that are currently in clinical trials. In 2002, we reported that beta3-integrin-knockout mice exhibit enhanced tumor growth and angiogenesis. However, as beta3-integrin is expressed by a wide variety of cells, endothelial cell-specific contributions to tumor angiogenesis are muddied by the use of a global knockout of beta3-integrin function. OBJECTIVE: Our aim was to examine the endothelial-specific contribution beta3-integrin makes to tumor growth and angiogenesis. METHODS AND RESULTS: We have crossed beta3-integrin-floxed (beta3-floxed) mice to 2 endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo, and in vitro. We show that acute depletion of endothelial beta3-integrin inhibits tumor growth and angiogenesis preventatively, but not in already established tumors. However, the effects are transient, and long-term depletion of the molecule is ineffective. Furthermore, long-term depletion of the molecule correlates with many molecular changes, such as reduced levels of focal adhesion kinase expression and a misbalance in focal adhesion kinase phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial beta3-integrin expression. CONCLUSIONS: Our findings imply that timing and length of inhibition are critical factors that need to be considered when targeting the endothelial expression of beta3-integrin to inhibit tumor growth and angiogenesis. [less ▲]

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See detailAssociation between a gene variant near ataxia telangiectasia mutated and coronary artery disease in men.
Schiekofer, Stephan; Bobak, Izabela; Kleber, Marcus E. et al

in Diabetes and Vascular Disease Research (2014), 11(1), 60-3

OBJECTIVE: Type 2 diabetes is accompanied by increased mortality from coronary artery disease (CAD), but the mechanisms linking these conditions remain elusive. Hence, treatment of hyperglycaemia alone is ... [more ▼]

OBJECTIVE: Type 2 diabetes is accompanied by increased mortality from coronary artery disease (CAD), but the mechanisms linking these conditions remain elusive. Hence, treatment of hyperglycaemia alone is not sufficient to avoid CAD in diabetes. Alternative views suggest that metabolic and vascular diseases share unifying cellular defects that could serve as targets for novel therapeutic strategies. Recently, a variant [single-nucleotide polymorphism (SNP); rs11212617] near the gene for ataxia telangiectasia mutated (ATM) has been associated with glycaemic response to metformin. MATERIALS AND METHODS: We determined rs11212617 in 240 male patients who underwent elective coronary angiography. RESULTS: While the variant was not associated with glucose concentrations, the A allele was significantly associated with the presence of CAD (chi-square, p = 0.003), as well as with logarithmically transformed quantitative CAD indices [severe score (SS): 0.5 (0.4-0.6) vs 0.3 (0.2-0.5); extent score (ES): 2.63 (2.4-2.9) vs 1.94 (1.4-2.4), both p < 0.05, respectively]. Multivariate analysis revealed an independent association between the A allele with ES (beta = 0.17, p < 0.01). CONCLUSION: Our data suggest that ATM-dependent signalling might play a role in the development of atherosclerotic vascular disease, but larger studies are necessary to substantiate such a hypothesis. [less ▲]

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See detailPrevalence and determinants of osteoporosis in patients with type 1 and type 2 diabetes mellitus.
Leidig-Bruckner, Gudrun; Grobholz, Sonja; Bruckner, Thomas et al

in BMC endocrine disorders (2014), 14

BACKGROUND: Increased risk of osteoporosis and its clinical significance in patients with diabetes is controversial. We analyze osteoporosis prevalence and determinants of bone mineral density (BMD) in ... [more ▼]

BACKGROUND: Increased risk of osteoporosis and its clinical significance in patients with diabetes is controversial. We analyze osteoporosis prevalence and determinants of bone mineral density (BMD) in patients with type 1 and 2 diabetes. METHODS: Three hundred and ninety-eight consecutive diabetic patients from a single outpatient clinic received a standardized questionnaire on osteoporosis risk factors, and were evaluated for diabetes-related complications, HbA1c levels, and lumbar spine (LS) and femoral neck (FN) BMD. Of these, 139 (71 men, 68 women) type 1 and 243 (115 men, 128 women) type 2 diabetes patients were included in the study. BMD (T-scores and values adjusted for age, BMI and duration of disease) was compared between patient groups and between patients with type 2 diabetes and population-based controls (255 men, 249 women). RESULTS: For both genders, adjusted BMD was not different between the type 1 and type 2 diabetes groups but was higher in the type 2 group compared with controls (p < 0.0001). Osteoporosis prevalence (BMD T-score < -2.5 SD) at FN and LS was equivalent in the type 1 and type 2 diabetes groups, but lower in type 2 patients compared with controls (FN: 13.0% vs 21.2%, LS: 6.1% vs 14.9% men; FN: 21.9% vs 32.1%, LS: 9.4% vs 26.9% women). Osteoporosis prevalence was higher at FN-BMD than at LS-BMD. BMD was positively correlated with BMI and negatively correlated with age, but not correlated with diabetes-specific parameters (therapy, HbBA1c, micro- and macrovascular complications) in all subgroups. Fragility fracture prevalence was low (5.2%) and not different between diabetes groups. Fracture patients had lower BMDs compared with those without fractures; however, BMD T-score was above -2.5 SD in most patients. CONCLUSIONS: Diabetes-specific parameters did not predict BMD. Fracture occurrence was similar in both diabetes groups and related to lower BMD, but seems unrelated to the threshold T-score, <-2.5 SD. These results suggest that osteoporosis, and related fractures, is a clinically significant and commonly underestimated problem in diabetes patients. [less ▲]

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See detailRecent development and biomedical applications of probabilistic Boolean networks
Trairatphisan, Panuwat UL; Mizera, Andrzej UL; Pang, Jun UL et al

in Cell Communication and Signaling (2013), 11(46),

Probabilistic Boolean network (PBN) modelling is a semi-quantitative approach widely used for the study of the topology and dynamic aspects of biological systems. The combined use of rule-based ... [more ▼]

Probabilistic Boolean network (PBN) modelling is a semi-quantitative approach widely used for the study of the topology and dynamic aspects of biological systems. The combined use of rule-based representation and probability makes PBN appealing for large-scale modelling of biological networks where degrees of uncertainty need to be considered. A considerable expansion of our knowledge in the field of theoretical research on PBN can be observed over the past few years, with a focus on network inference, network intervention and control. With respect to areas of applications, PBN is mainly used for the study of gene regulatory networks though with an increasing emergence in signal transduction, metabolic, and also physiological networks. At the same time, a number of computational tools, facilitating the modelling and analysis of PBNs, are continuously developed. A concise yet comprehensive review of the state-of-the-art on PBN modelling is offered in this article, including a comparative discussion on PBN versus similar models with respect to concepts and biomedical applications. Due to their many advantages, we consider PBN to stand as a suitable modelling framework for the description and analysis of complex biological systems, ranging from molecular to physiological levels. [less ▲]

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See detailH-infinity Static Output Feedback Control for a Fractional-Order Glucose-Insulin System
Ndoye, Ibrahima UL; Voos, Holger UL; Darouach, Mohamed et al

in 6th Workshop on Fractional Differentiation and Its Applications. Part of 2013 IFAC Joint Conference SSSC, TDS and FDA (2013), Grenoble, February 4-6, 2013 (2013)

This paper presents the H-infinity static output feedback control of nonlinear fractional-order glucose-insulin systems. In this paper, it is an attempt to incorporate fractional-order into the ... [more ▼]

This paper presents the H-infinity static output feedback control of nonlinear fractional-order glucose-insulin systems. In this paper, it is an attempt to incorporate fractional-order into the mathematical minimal model of glucose-insulin system dynamics and it is still an interesting challenge to show, how the order of a fractional di erential system a ects the dynamics of system in the presence of meal disturbance. A static output feedback control is considered for the problem. Su fficient conditions are derived in terms of linear matrix inequalities (LMIs) formulation by using the fractional Lyapunov direct method where the fractional-order \alpha belongs to 0<\alpha<1. Finally, numerical simulations are carried out to illustrate our proposed results and show that the nonlinear fractional-order glucose-insulin systems are as stable as their integer-order counterpart in the presence of exogenous glucose infusion or meal disturbance. [less ▲]

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See detailFrom meta-omics to causality: experimental models for human microbiome research
Fritz, Joëlle UL; Desai, Mahesh UL; Shah, Pranjul UL et al

in Microbiome (2013), 1(14),

Large-scale ‘meta-omic’ projects are greatly advancing our knowledge of the human microbiome and its specific role in governing health and disease states. A myriad of ongoing studies aim at identifying ... [more ▼]

Large-scale ‘meta-omic’ projects are greatly advancing our knowledge of the human microbiome and its specific role in governing health and disease states. A myriad of ongoing studies aim at identifying links between microbial community disequilibria (dysbiosis) and human diseases. However, due to the inherent complexity and heterogeneity of the human microbiome, cross-sectional, case–control and longitudinal studies may not have enough statistical power to allow causation to be deduced from patterns of association between variables in high-resolution omic datasets. Therefore, to move beyond reliance on the empirical method, experiments are critical. For these, robust experimental models are required that allow the systematic manipulation of variables to test the multitude of hypotheses, which arise from high-throughput molecular studies. Particularly promising in this respect are microfluidics-based in vitro co-culture systems, which allow high-throughput first-pass experiments aimed at proving cause-and-effect relationships prior to testing of hypotheses in animal models. This review focuses on widely used in vivo, in vitro, ex vivo and in silico approaches to study host-microbial community interactions. Such systems, either used in isolation or in a combinatory experimental approach, will allow systematic investigations of the impact of microbes on the health and disease of the human host. All the currently available models present pros and cons, which are described and discussed. Moreover, suggestions are made on how to develop future experimental models that not only allow the study of host-microbiota interactions but are also amenable to high-throughput experimentation. [less ▲]

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See detailA randomized phase II trial investigating the effect of platelet function inhibition on circulating tumor cells in patients with metastatic breast cancer.
Roop, Ryan P.; Naughton, Michael J.; Van Poznak, Catherine et al

in Clinical breast cancer (2013), 13(6), 409-15

BACKGROUND: Blockade of platelet activation and aggregation can inhibit metastasis in preclinical models and is associated with cancer prevention. To test whether disruption of platelet function with ... [more ▼]

BACKGROUND: Blockade of platelet activation and aggregation can inhibit metastasis in preclinical models and is associated with cancer prevention. To test whether disruption of platelet function with clopidogrel and aspirin would decrease the number of circulating tumor cells (CTCs) in patients with metastatic breast cancer, a randomized phase II study was performed. METHODS: Patients with metastatic breast cancer who were not currently receiving cytotoxic chemotherapy were eligible. Patients were randomized to receive either clopidogrel and aspirin or to a control group receiving no treatment. Phlebotomy was performed at baseline, at 2 and 4 weeks, and monthly thereafter to obtain specimens to assess CTC, platelet aggregation, and thrombin activity. The primary end point was the proportion of patients with detectable CTCs at 1 month. RESULTS: Forty-eight patients were enrolled and 42 were evaluable at 1 month. Baseline CTC numbers were >/= 5 in 13% and >/= 1 in 65% of patients. Despite adequate platelet function inhibition in the treatment group, the proportion of patients with detectable CTCs was similar between the clopidogrel/aspirin and control groups at baseline (P = .21) and 4 weeks (P = .75), showing no treatment effect. Measured endogenous thrombin potential did not correlate with CTC number. No bleeding-related serious adverse events (SAEs) occurred. CONCLUSION: The baseline CTC numbers were lower than expected, decreasing the ability to detect an impact of platelet inhibition on CTCs. Clopidogrel and aspirin were well tolerated. Future studies evaluating the potential therapeutic role of antiplatelet therapy in breast cancer remain of interest, and they may be informed by these results. [less ▲]

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See detailAn Unknown Input Fractional-Order Observer Design for Fractional-Order Glucose-Insulin System
Ndoye, Ibrahima UL; Voos, Holger UL; Darouach, Mohamed et al

in IEEE EMBS Conference on Biomedical Engineering and Sciences, Malaysia, 17th - 19th December, 2012 (2012)

In this paper, we introduce fractional-order derivatives into a generalized minimal model of glucose-insulin. A fractional-order state observer is designed for estimating the structure of a blood glucose ... [more ▼]

In this paper, we introduce fractional-order derivatives into a generalized minimal model of glucose-insulin. A fractional-order state observer is designed for estimating the structure of a blood glucose-insulin with glucose rate disturbance to show the complete dynamics of the glucose-insulin system where the fractional-order \alpha belonging to 0<\alpha<1. A nonlinear fractional-order unknown input observer strategy is used where the glucose rate disturbance is considered as an unknown input to the perspective dynamical system. The developed method provides the observer estimation algorithm for a glucose-insulin system with unknown time-varying glucose rate disturbance. The stability analysis of the fractional-order error system is completed and showed that the fractional-order observer design is as stable as their integer-order counterpart and guarantees the best convergence of the estimation error. Finally, numerical simulations are given to illustrate the effectiveness of the proposed method. [less ▲]

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See detailShort-term akt activation in cardiac muscle cells improves contractile function in failing hearts
Shiojima, I.; Schiekofer, S.; Schneider, Jochen UL et al

in American Journal of Pathology (2012), 181(6), 1969-76

Akt is a serine/threonine protein kinase that is activated by a variety of growth factors or cytokines in a phosphatidylinositol 3-kinase-dependent manner. By using a conditional transgenic system in ... [more ▼]

Akt is a serine/threonine protein kinase that is activated by a variety of growth factors or cytokines in a phosphatidylinositol 3-kinase-dependent manner. By using a conditional transgenic system in which Akt signaling can be turned on or off in the adult heart, we previously showed that short-term Akt activation induces a physiological form of cardiac hypertrophy with enhanced coronary angiogenesis and maintained contractility. Here we tested the hypothesis that induction of physiological hypertrophy by short-term Akt activation might improve contractile function in failing hearts. When Akt signaling transiently was activated in murine hearts with impaired contractility, induced by pressure overload or doxorubicin treatment, contractile dysfunction was attenuated in both cases. Importantly, improvement of contractility was observed before the development of cardiac hypertrophy, indicating that Akt activation improves contractile function independently of its growth-promoting effects. To gain mechanistic insights into Akt-mediated positive inotropic effects, transcriptional profiles in the heart were determined in a pressure overload-induced heart failure model. Biological network analysis of differentially expressed transcripts revealed significant alterations in the expression of genes associated with cell death, and these alterations were reversed by short-term Akt activation. Thus, short-term Akt activation improves contractile function in failing hearts. This beneficial effect of Akt on contractility is hypertrophy-independent and may be mediated in part by inhibition of cell death associated with heart failure. [less ▲]

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See detailAdiponectin Fails in Improving Angiogenic Repair in Streptozocin-Treated or Lepr db/db Mice after Hind Limb Ischemia
Belisle, Kurt UL; Andrassy, Martin; Schneider, Jochen UL et al

in International Scholarly Research Notices (2012), 2012

Type 1 and 2 diabetes carry risk factors for the development of microvascular diseases with associated impairment of angiogenic repair. Here, we investigated whether adiponectin, an adipocyte-specific ... [more ▼]

Type 1 and 2 diabetes carry risk factors for the development of microvascular diseases with associated impairment of angiogenic repair. Here, we investigated whether adiponectin, an adipocyte-specific adipocytokine with antiatherosclerotic and antidiabetic properties, regulates angiogenic repair in response to tissue ischemia in Leprdb/db and streptozocin-treated diabetic mouse models. Methods. Adenoviral vectors containing the gene for β-galactosidase, full-length mouse adiponectin, and dominant-negative AMPKα2 were used in streptozocin-treated male Leprdb/db mice, after which hind limb blood flow was measured using a laser doppler blood flow analyzer. Results. The angiogenic repair of ischemic hind limbs was impaired in both streptozocin-treated and Leprdb/db mice compared to wild-type mice as evaluated by laser doppler flow and capillary density analyses. Adenovirus-mediated administration of adiponectin accelerated angiogenic repair after hind limb ischemia in WT mice, but not in Leprdb/db mice or mice treated with streptozocin. In vitro experiments using HUVECs highlighted the antiapoptotic and proangiogenic properties of adiponectin but could not demonstrate accelerated differentiation of endothelial cells into tube- like structures at elevated glucose levels. Conclusions. External administration of adiponectin at elevated glucose levels may not be useful in the treatment of diabetes mellitus-related vascular deficiency diseases. [less ▲]

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