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  • DKFZ Publication Database  (1,229)
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  • DKFZ Publication Database  (1,229)
Keywords
  • 1
    Keywords: MODEL ; POPULATION ; BREAST ; PROSTATE-CANCER ; PREDICTION ; BIOPSY ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; EXTERNAL VALIDATION ; PREVENTION TRIAL ; COMMON GENETIC-VARIANTS
    Abstract: PURPOSE: Detailed family history offers an inexpensive alternative to genetic profiling for individual risk assessment. The objective here was to update the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) to include detailed family history. MATERIALS AND METHODS: Data comprised 55168 prostate cancer cases and 638218 controls from the Swedish Family-Cancer Database who were 〉/= 55 years of age in 1999, had at least one male first-degree relative (FDR) 〉/= 40 years and one female FDR 〉/= 30 years. Likelihood ratios (LR) were computed as the ratio of risk of observing a specific family history pattern in a prostate cancer case compared to control and used to update the PCPTRC. RESULTS: Having at least one relative with prostate cancer increased the risk of prostate cancer. The LR was 1.63 for one FDR 〉/= 60 at diagnosis (10.1% of cancer cases, 6.2% of controls), 2.47 if the relative was 〈 60 years (1.5% versus 0.6%, respectively), 3.46 for 〉/= 2 relatives 〉/= 60 years (1.2% versus 0.3%), and 5.68 for 〉/= 2 relatives 〈 60 years (0.05% versus 0.009%). Among men with no diagnosed FDRs, the LR was 1.09 for one or more SDRs diagnosed with prostate cancer (12.7% versus 11.7%, respectively). Additional FDRs with breast cancer or FDRs or SDRs with prostate cancer compounded these risks. CONCLUSIONS: Detailed family history is an independent predictor of prostate cancer to the commonly-used risk factors and should be incorporated into decision-making regarding biopsy. Compared with costly other biomarkers, it is inexpensive and universally available.
    Type of Publication: Journal article published
    PubMed ID: 25242395
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  • 2
    Keywords: MODEL ; chemotherapy ; CHILDREN ; SUBTYPES ; GLIOBLASTOMA ; INTRATUMORAL HETEROGENEITY ; RISK MEDULLOBLASTOMA
    Abstract: Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.
    Type of Publication: Journal article published
    PubMed ID: 25689980
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  • 3
    Keywords: IN-VIVO ; MODEL ; VOLUME ; HEPATOCELLULAR-CARCINOMA ; TISSUE ; RADIOFREQUENCY ABLATION ; POWER ; embolization ; PORCINE KIDNEYS ; TRANSARTERIAL CHEMOEMBOLIZATION
    Abstract: PURPOSE: This study was designed to compare technical parameters during ablation as well as CT 3D rendering and histopathology of the ablation zone between sphere-enhanced microwave ablation (sMWA) and bland microwave ablation (bMWA). METHODS: In six sheep-livers, 18 microwave ablations were performed with identical system presets (power output: 80 W, ablation time: 120 s). In three sheep, transarterial embolisation (TAE) was performed immediately before microwave ablation using spheres (diameter: 40 +/- 10 mum) (sMWA). In the other three sheep, microwave ablation was performed without spheres embolisation (bMWA). Contrast-enhanced CT, sacrifice, and liver harvest followed immediately after microwave ablation. Study goals included technical parameters during ablation (resulting power output, ablation time), geometry of the ablation zone applying specific CT 3D rendering with a software prototype (short axis of the ablation zone, volume of the largest aligned ablation sphere within the ablation zone), and histopathology (hematoxylin-eosin, Masson Goldner and TUNEL). RESULTS: Resulting power output/ablation times were 78.7 +/- 1.0 W/120 +/- 0.0 s for bMWA and 78.4 +/- 1.0 W/120 +/- 0.0 s for sMWA (n.s., respectively). Short axis/volume were 23.7 +/- 3.7 mm/7.0 +/- 2.4 cm(3) for bMWA and 29.1 +/- 3.4 mm/11.5 +/- 3.9 cm(3) for sMWA (P 〈 0.01, respectively). Histopathology confirmed the signs of coagulation necrosis as well as early and irreversible cell death for bMWA and sMWA. For sMWA, spheres were detected within, at the rim, and outside of the ablation zone without conspicuous features. CONCLUSIONS: Specific CT 3D rendering identifies a larger ablation zone for sMWA compared with bMWA. The histopathological signs and the detectable amount of cell death are comparable for both groups. When comparing sMWA with bMWA, TAE has no effect on the technical parameters during ablation.
    Type of Publication: Journal article published
    PubMed ID: 25167958
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; MODEL ; DIFFERENTIATION ; PHOSPHORYLATION ; acetylation ; SKYLINE
    Abstract: The balance of effector and regulatory T cell function, dependent on multiple signals and epigenetic regulators, is critical to immune self-tolerance. Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis. Here, we report that Sirtuin 1 (SIRT1), a protein deacetylase previously reported to have an antiinflammatory function, in fact promotes autoimmunity by deacetylating RORgammat, the signature transcription factor of Th17 cells. SIRT1 increases RORgammat transcriptional activity, enhancing Th17 cell generation and function. Both T cell-specific Sirt1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis. Moreover, analysis of infiltrating cell populations during disease induction in mixed hematopoietic chimeras shows a marked bias against Sirt1-deficient Th17 cells. These findings reveal an unexpected proinflammatory role of SIRT1 and, importantly, support the possible therapeutic use of SIRT1 inhibitors against autoimmunity.
    Type of Publication: Journal article published
    PubMed ID: 25918343
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  • 5
    Keywords: MODEL ; SYSTEM ; HUMANS ; CLOCK ; LIGHT ; TEMPERATURE ; NEUROSPORA-CRASSA ; OSCILLATIONS ; INTRINSIC PERIOD ; PACEMAKER
    Abstract: The circadian clock coordinates daily physiological, metabolic and behavioural rhythms. These endogenous oscillations are synchronized with external cues ('zeitgebers'), such as daily light and temperature cycles. When the circadian clock is entrained by a zeitgeber, the phase difference psi between the phase of a clock-controlled rhythm and the phase of the zeitgeber is of fundamental importance for the fitness of the organism. The phase of entrainment psi depends on the mismatch between the intrinsic period tau and the zeitgeber period T and on the ratio of the zeitgeber strength to oscillator amplitude. Motivated by the intriguing complexity of empirical data and by our own experiments on temperature entrainment of mouse suprachiasmatic nucleus (SCN) slices, we present a theory on how clock and zeitgeber properties determine the phase of entrainment. The wide applicability of the theory is demonstrated using mathematical models of different complexity as well as by experimental data. Predictions of the theory are confirmed by published data on Neurospora crassa strains for different period mismatches tau - T and varying photoperiods. We apply a novel regression technique to analyse entrainment of SCN slices by temperature cycles. We find that mathematical models can explain not only the stable asymptotic phase of entrainment, but also transient phase dynamics. Our theory provides the potential to explore seasonal variations of circadian rhythms, jet lag and shift work in forthcoming studies.
    Type of Publication: Journal article published
    PubMed ID: 26136227
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  • 6
    Keywords: MODEL ; TIME ; RELAXATION ; MAGNETIC-FIELD ; INHOMOGENEITIES
    Abstract: The cylindrical Bessel differential equation and the spherical Bessel differential equation in the interval [Formula: see text] with Neumann boundary conditions are considered. The eigenfunctions are linear combinations of the Bessel function [Formula: see text] or linear combinations of the spherical Bessel functions [Formula: see text]. The orthogonality relations with analytical expressions for the normalization constant are given. Explicit expressions for the Lommel integrals in terms of Lommel functions are derived. The cross product zeros [Formula: see text] and [Formula: see text] are considered in the complex plane for real as well as complex values of the index [Formula: see text] and approximations for the exceptional zero [Formula: see text] are obtained. A numerical scheme based on the discretization of the two-dimensional and three-dimensional Laplace operator with Neumann boundary conditions is presented. Explicit representations of the radial part of the Laplace operator in form of a tridiagonal matrix allow the simple computation of the cross product zeros.
    Type of Publication: Journal article published
    PubMed ID: 26251774
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  • 7
    Keywords: EXPRESSION ; IN-VIVO ; MODEL ; SITES ; STEM-CELLS ; SAFETY ; INTEGRATION ; INFUSION ; LENTIVIRAL VECTOR ; ENHANCE
    Abstract: "Ex vivo" regional gene therapy using lentiviral (LV) vectors to over-express bone morphogenetic protein 2 (BMP-2) is an effective way to enhance bone healing in animal models. Here, we evaluated two different "ex vivo" approaches using either "same day" rat bone marrow cells (SDRBMCs) or cultured rat bone marrow cells (C-RBMCs), both transduced with a LV based two-step transcriptional activation system overexpressing GFP (LV-TSTA-EGFP), to assess the fate of the transduced cells and the safety of this approach. The transduced cells were implanted in femoral defects of syngeneic rats. Animals were sacrificed at 4, 14, 28 and 56 days after surgery (n=5 per group). Viral copies were detectable in the defect site of SD-RBMC group and gradually declined at 8w (5 log decrease compared to 4d). In the C-RBMC animals, there was a 2-4 log decline in the viral copy numbers at 2w and 4w, but at 8w there was a relative rise (about 100 fold) in the number of the viral vectors in the defect site of 4 (out of 5) animals compared to the previous time points. For both gene transfer approaches, the pattern of tissue distribution was non-specific and no histological abnormalities were noted in either group. In summary, we demonstrated that the LV-TSTA transduced cells remain in the defect site for at least 56 days, though the numbers decreased over time. There were no consistent findings of viral copies in internal organs which is encouraging with respect to the development of this strategy for use in humans.
    Type of Publication: Journal article published
    PubMed ID: 26264707
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  • 8
    Keywords: IN-VIVO ; MODEL ; TISSUE ; antibodies ; MOUSE ; IDENTIFICATION ; GENE-THERAPY ; TROPISM ; DISPLAY PEPTIDE LIBRARIES ; VIRUS TYPE-2
    Abstract: Adeno-associated viral (AAV) vectors yield high potential for clinical gene therapy but, like for other vectors systems, they frequently do not sufficiently transduce the target tissue and their unspecific tropism prevents their application for multifocal diseases such as disseminated cancer. Targeted AAV vectors have been obtained from random AAV display peptide libraries but so far, all vector variants selected from AAV libraries upon systemic administration in vivo retained some collateral tropism, frequently the heart. Here we explored, if this impediment can be overcome by microRNA-regulated transgene cassettes as the combination of library-derived capsid targeting and micro-RNA control has not been evaluated so far. We used a tumor-targeted AAV capsid variant (ESGLSQS) selected from random AAV-display peptide libraries in vivo with remaining off-target tropism toward the heart and regulated targeted transgene expression in vivo by complementary target elements for heart-specific microRNA (miRT-1d). Although this vector still maintained its strong transduction capacity for tumor target tissue after intravenous injection, transgene expression in the heart was almost completely abrogated. This strong and completely tumor-specific transgene expression was used for therapeutic gene transfer in an aggressive multifocal, transgenic, polyoma middle T-induced, murine breast cancer model. A therapeutic suicide gene, delivered systemically by this dual-targeted AAV vector to multifocal breast cancer, significantly inhibited tumor growth after one single vector administration while avoiding side effects compared with untargeted vectors.
    Type of Publication: Journal article published
    PubMed ID: 26446851
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  • 9
    Keywords: IN-VIVO ; MODEL ; TISSUE ; antibodies ; MOUSE ; IDENTIFICATION ; GENE-THERAPY ; TROPISM ; DISPLAY PEPTIDE LIBRARIES ; VIRUS TYPE-2
    Abstract: Adeno-associated viral (AAV) vectors yield high potential for clinical gene therapy but, like for other vectors systems, they frequently do not sufficiently transduce the target tissue and their unspecific tropism prevents their application for multifocal diseases such as disseminated cancer. Targeted AAV vectors have been obtained from random AAV display peptide libraries but so far, all vector variants selected from AAV libraries upon systemic administration in vivo retained some collateral tropism, frequently the heart. Here we explored, if this impediment can be overcome by microRNA-regulated transgene cassettes as the combination of library-derived capsid targeting and micro-RNA control has not been evaluated so far. We used a tumor-targeted AAV capsid variant (ESGLSQS) selected from random AAV-display peptide libraries in vivo with remaining off-target tropism toward the heart and regulated targeted transgene expression in vivo by complementary target elements for heart-specific microRNA (miRT-1d). Although this vector still maintained its strong transduction capacity for tumor target tissue after intravenous injection, transgene expression in the heart was almost completely abrogated. This strong and completely tumor-specific transgene expression was used for therapeutic gene transfer in an aggressive multifocal, transgenic, polyoma middle T-induced, murine breast cancer model. A therapeutic suicide gene, delivered systemically by this dual-targeted AAV vector to multifocal breast cancer, significantly inhibited tumor growth after one single vector administration while avoiding side effects compared with untargeted vectors.
    Type of Publication: Journal article published
    PubMed ID: 26034897
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  • 10
    Keywords: MODEL ; GENE ; MONTE-CARLO ; GENOME ORGANIZATION ; COEFFICIENT ; ANOMALOUS DIFFUSION ; GEOMETRY ; SUBDIFFUSION ; LIVING CELL-NUCLEI ; RANDOM-WALKS
    Abstract: eukaryotic cell nucleus harbours the DNA genome that is organized in a dynamic chromatin network and embedded in a viscous crowded fluid. This environment directly affects enzymatic reactions and target search processes that access the DNA sequence information. However, its physical properties as a reaction medium are poorly understood. Here, we exploit mobility measurements of differently sized inert green fluorescent tracer proteins to characterize the viscoelastic properties of the nuclear interior of a living human cell. We find that it resembles a viscous fluid on small and large scales but appears viscoelastic on intermediate scales that change with protein size. Our results are consistent with simulations of diffusion through polymers and suggest that chromatin forms a random obstacle network rather than a self-similar structure with fixed fractal dimensions. By calculating how long molecules remember their previous position in dependence on their size, we evaluate how the nuclear environment affects search processes of chromatin targets.
    Type of Publication: Journal article published
    PubMed ID: 25563347
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  • 11
    Keywords: MODEL ; GENOME ; DNA ; DYNAMICS ; METHYLATION ; GENE-REGULATION ; CHROMATIN FIBER ; HISTONE H3 ; MATRIX FORMALISM ; CHROMODOMAIN
    Abstract: Heterochromatin protein 1 (HP1) participates in establishing and maintaining heterochromatin via its histone-modification-dependent chromatin interactions. In recent papers HP1 binding to nucleosomal arrays was measured in vitro and interpreted in terms of nearest-neighbour cooperative binding. This mode of chromatin interaction could lead to the spreading of HP1 along the nucleosome chain. Here, we reanalysed previous data by representing the nucleosome chain as a 1D binding lattice and showed how the experimental HP1 binding isotherms can be explained by a simpler model without cooperative interactions between neighboring HP1 dimers. Based on these calculations and spatial models of dinucleosomes and nucleosome chains, we propose that binding stoichiometry depends on the nucleosome repeat length (NRL) rather than protein interactions between HP1 dimers. According to our calculations, more open nucleosome arrays with long DNA linkers are characterized by a larger number of binding sites in comparison to chains with a short NRL. Furthermore, we demonstrate by Monte Carlo simulations that the NRL dependent folding of the nucleosome chain can induce allosteric changes of HP1 binding sites. Thus, HP1 chromatin interactions can be modulated by the change of binding stoichiometry and the type of binding to condensed (methylated) and non-condensed (unmethylated) nucleosome arrays in the absence of direct interactions between HP1 dimers.
    Type of Publication: Journal article published
    PubMed ID: 25563825
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  • 12
    Keywords: radiotherapy ; MODEL ; DIAGNOSIS ; IMPACT ; WOMEN ; chemotherapy ; PREDICTORS ; ADJUVANT THERAPY ; QUALITY-OF-LIFE ; RESPONSE SHIFT
    Abstract: OBJECTIVE: Fatigue is among the most distressing symptoms across the breast cancer continuum. However, little is known about the factors contributing to long-term persisting fatigue. Therefore, we explored determinants of long-term physical, affective, and cognitive fatigue in a prospective cohort of breast cancer patients. METHODS: Breast cancer patients recruited in a population-based case-control study (MARIE study) provided comprehensive data on sociodemographics, lifestyle, and preexisting medical conditions. At follow-up (median 6.3 years post-diagnosis, MARIEplus), disease-free cancer survivors (N = 1928) reported current fatigue using a validated multidimensional questionnaire. Additionally, survivors retrospectively rated their fatigue levels before diagnosis, during the treatment phase, and 1 year post-surgery. Linear regression analyses were performed. RESULTS: As major determinants of long-term physical, affective, and cognitive fatigue, multiple regression analyses revealed preexisting psychological or depressive disorders, migraine, analgesic use, peripheral arterial obstructive disease (PAOD), and arthritis. A physically inactive lifestyle and obesity were associated with persisting physical fatigue. Aromatase inhibitors were also associated with long-term fatigue, especially cognitive fatigue. Chemotherapy and, to a lower extent, radiotherapy were major contributors to the development of fatigue during the treatment phase, yet were not associated with long-term fatigue. CONCLUSIONS: Although the development of fatigue in breast cancer patients seems largely impacted by cancer therapy, for the long-term persistence of fatigue, preexisting medical or psychological conditions related to depression or pain and lifestyle factors appear to be more relevant. Physicians, psycho-oncologists, and researchers may need to distinguish between acute fatigue during therapy and long-term persisting fatigue with regard to its pathophysiology and treatment. Copyright (c) 2014 John Wiley & Sons, Ltd.
    Type of Publication: Journal article published
    PubMed ID: 24839264
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  • 13
    Keywords: MODEL ; RISK ; ACTIVATION ; TARGET ; STEM-CELLS ; DIABETES-MELLITUS ; ARREST ; DUCTAL ADENOCARCINOMA ; METAANALYSIS ; TO-MESENCHYMAL TRANSITION
    Abstract: Metformin treatment is associated with a decreased risk and better prognosis of pancreatic cancer (PC) in patients with type 2 diabetes, but the mechanism of metformin's PC growth inhibition in the context of a prediabetic state is unknown. We used a Panc02 pancreatic tumor cell transplant model in diet-induced obese (DIO) C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC growth, glucose regulation, mTOR pathway signaling, and candidate microRNA (miR) expression. In DIO/prediabetic mice, metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR-related signaling. The rapamycin effects centered on decreased mTOR-regulated growth and survival signaling, including increased expression of let-7b and cell cycle-regulating miRs. Metformin (but not rapamycin) reduced glucose and insulin levels and expression of miR-34a and its direct targets Notch, Slug, and Snail. Metformin also reduced the number and size of Panc02 tumor spheres in vitro and inhibited the expression of Notch in spheroids. Our results suggest that metformin and rapamycin can both inhibit pancreatic tumor growth in obese, prediabetic mice through shared and distinct mechanisms. Metformin and direct mTOR inhibitors, alone or possibly in combination, represent promising intervention strategies for breaking the diabetes-PC link.
    Type of Publication: Journal article published
    PubMed ID: 25576058
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  • 14
    Keywords: ANGIOGENESIS ; tumor ; IN-VIVO ; MODEL ; CHORIOALLANTOIC MEMBRANE ASSAY
    Abstract: Fertilized chicken eggs are suggested as an alternative to mammalian models. The chorioallantoic membrane (CAM) of the chick embryo is widely used for examination of angiogenesis, xenotransplants and for virus production. Unfortunately, it is mostly not taken into account, that the chick embryo's ability to experience pain starts to develop at day 7 of breeding. In our view, this model is only in accordance with the 3 R principles, if an appropriate anesthesia of the chick embryo in potentially painful procedures is provided. Although many experimental approaches are performed on the none-innervated CAM, the euthanasia of the embryo strongly requires a more human technique than the usually used freezing at -20 degrees C, decapitation or in ovo fixation with paraformaldehyde without prior anesthesia. However, protocols regarding feasible and ethical methods for anesthesia and euthanasia of avian embryos are currently not available. Therefore, we established an easy and reliable method for the euthanasia and short-term anesthesia of the chick embryo.
    Type of Publication: Journal article published
    PubMed ID: 25592390
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  • 15
    Keywords: IN-VIVO ; MODEL ; GENE ; ACTIVATION ; IMMUNE-RESPONSES ; ACUTE LUNG INJURY ; SPINAL-CORD ; HYPERSENSITIVITY ; NERVE INJURY ; HUMAN NEUTROPHIL ELASTASE
    Abstract: Neuropathic pain is a major, intractable clinical problem and its pathophysiology is not well understood. Although recent gene expression profiling studies have enabled the identification of novel targets for pain therapy, classical study designs provide unclear results owing to the differential expression of hundreds of genes across sham and nerve-injured groups, which can be difficult to validate, particularly with respect to the specificity of pain modulation. To circumvent this, we used two outbred lines of rats, which are genetically similar except for being genetically segregated as a result of selective breeding for differences in neuropathic pain hypersensitivity. SerpinA3N, a serine protease inhibitor, was upregulated in the dorsal root ganglia (DRG) after nerve injury, which was further validated for its mouse homolog. Mice lacking SerpinA3N developed more neuropathic mechanical allodynia than wild-type (WT) mice, and exogenous delivery of SerpinA3N attenuated mechanical allodynia in WT mice. T lymphocytes infiltrate the DRG after nerve injury and release leukocyte elastase (LE), which was inhibited by SerpinA3N derived from DRG neurons. Genetic loss of LE or exogenous application of a LE inhibitor (Sivelastat) in WT mice attenuated neuropathic mechanical allodynia. Overall, we reveal a novel and clinically relevant role for a member of the serpin superfamily and a leukocyte elastase and crosstalk between neurons and T cells in the modulation of neuropathic pain.
    Type of Publication: Journal article published
    PubMed ID: 25915831
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  • 16
    Keywords: MODEL ; DRUG DISCOVERY ; docking ; PLATFORM ; ESTROGEN-RECEPTOR-BINDING ; TAVERNA ; GALAXY
    Abstract: Modern methods of drug discovery and development in recent years make a wide use of computational algorithms. These methods utilise Virtual Screening (VS), which is the computational counterpart of experimental screening. In this manner the in silico models and tools initial replace the wet lab methods saving time and resources. This paper presents the overall design and implementation of a web based scientific workflow system for virtual screening called, the Life Sciences Informatics (LiSIs) platform. The LiSIs platform consists of the following layers: the input layer covering the data file input; the pre-processing layer covering the descriptors calculation, and the docking preparation components; the processing layer covering the attribute filtering, compound similarity, substructure matching, docking prediction, predictive modelling and molecular clustering; post-processing layer covering the output reformatting and binary file merging components; output layer covering the storage component. The potential of LiSIs platform has been demonstrated through two case studies designed to illustrate the preparation of tools for the identification of promising chemical structures. The first case study involved the development of a Quantitative Structure Activity Relationship (QSAR) model on a literature dataset while the second case study implemented a docking-based virtual screening experiment. Our results show that VS workflows utilizing docking, predictive models and other in silico tools as implemented in the LiSIs platform can identify compounds in line with expert expectations. We anticipate that the deployment of LiSIs, as currently implemented and available for use, can enable drug discovery researchers to more easily use state of the art computational techniques in their search for promising chemical compounds. The LiSIs platform is freely accessible (i) under the GRANATUM platform at: http://www.granatum.org and (ii) directly at: http://lisis.cs.ucy.ac.cy.
    Type of Publication: Journal article published
    PubMed ID: 25747448
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  • 17
    Keywords: CANCER ; EXPRESSION ; MODEL ; NEOPLASIA ; PROGRESSION ; MUTATIONS ; APC GENE ; LYMPHOCYTE DEVELOPMENT ; TRANSCRIPTION FACTOR E2-2 ; COLORECTAL TUMORIGENESIS
    Abstract: Deregulation of Wnt/beta-catenin signaling following inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene is frequently found in colorectal cancer. We have previously shown that levels of ITF-2B, encoded by the beta-catenin target gene ITF2 that is located on the tumor suppressor gene locus 18q21, are increased in colonic adenomas with deregulated beta-catenin activity. However, during tumor progression ITF-2B levels are reduced, suggesting that ITF-2B interferes with tumor development. To investigate the role of ITF2 in intestinal tumorigenesis, we specifically inactivated Itf2 in the intestinal epithelium of Apc(Min/+) mice. We found that genetic disruption of Itf2 on the Apc(Min/+) background results in earlier death and a significant increase in tumor number and size in the small intestine. Based on these data Itf2 acts as a tumor suppressor gene of the intestinal tract that inhibits tumor initiation and growth.
    Type of Publication: Journal article published
    PubMed ID: 25869068
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  • 18
    Keywords: MODEL ; CELL-CYCLE ; REVEALS ; DNA-DAMAGE RESPONSE
    Abstract: KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.
    Type of Publication: Journal article published
    PubMed ID: 26140595
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  • 19
    Keywords: MODEL ; DIFFERENTIATION ; ANGIOGRAPHY ; phantom ; PULSE PILEUP ; RENAL MASSES ; X-RAY-DETECTORS ; COMPUTED TOMOGRAPHIC APPARATUS ; ITERATIVE-RECONSTRUCTION ; UNENHANCED IMAGES
    Abstract: PURPOSE: To study the performance of different dual energy computed tomography (DECT) techniques, which are available today, and future multi energy CT (MECT) employing novel photon counting detectors in an image-based material decomposition task. METHODS: The material decomposition performance of different energy-resolved CT acquisition techniques is assessed and compared in a simulation study of virtual non-contrast imaging and iodine quantification. The material-specific images are obtained via a statistically optimal image-based material decomposition. A projection-based maximum likelihood approach was used for comparison with the authors' image-based method. The different dedicated dual energy CT techniques are simulated employing realistic noise models and x-ray spectra. The authors compare dual source DECT with fast kV switching DECT and the dual layer sandwich detector DECT approach. Subsequent scanning and a subtraction method are studied as well. Further, the authors benchmark future MECT with novel photon counting detectors in a dedicated DECT application against the performance of today's DECT using a realistic model. Additionally, possible dual source concepts employing photon counting detectors are studied. RESULTS: The DECT comparison study shows that dual source DECT has the best performance, followed by the fast kV switching technique and the sandwich detector approach. Comparing DECT with future MECT, the authors found noticeable material image quality improvements for an ideal photon counting detector; however, a realistic detector model with multiple energy bins predicts a performance on the level of dual source DECT at 100 kV/Sn 140 kV. Employing photon counting detectors in dual source concepts can improve the performance again above the level of a single realistic photon counting detector and also above the level of dual source DECT. CONCLUSIONS: Substantial differences in the performance of today's DECT approaches were found for the application of virtual non-contrast and iodine imaging. Future MECT with realistic photon counting detectors currently can only perform comparably to dual source DECT at 100 kV/Sn 140 kV. Dual source concepts with photon counting detectors could be a solution to this problem, promising a better performance.
    Type of Publication: Journal article published
    PubMed ID: 26133632
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  • 20
    Keywords: EXPRESSION ; GROWTH ; MODEL ; ACTIVATION ; FAMILY ; METASTASIS ; MIGRATION ; RAGE ; HYALURONIC-ACID ; POOR SURVIVAL
    Abstract: Triple-negative breast cancer (TNBC) is a group of very aggressive breast tumours, characterised by lack of expression of oestrogen receptor (ER), progesterone receptor (PR) and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2). Nevertheless, TNBCs show different clinical characteristics and are very diverse regarding prognostic outcome. So far, only a few prognostic markers for TNBC have been reported that could be helpful for therapeutic stratification. Here we have analysed the expression of S100P and HYAL2 using immunohistochemistry (IHC) in a TNBC cohort of 98 patients with a follow-up for recurrence and death. TNBC patients with high expression of both proteins showed significantly shorter progression-free survival (PFS) (mean PFS=35.9months, P=0.001) compared to TNBC patients with high expression levels of only one of the proteins (mean PFS=69.4months) and to TNBC patients with low expression of both proteins (mean PFS=83.3months). Moreover, multivariate Cox-regression model showed the combined expression of S100P and HYAL2 as independent prognostic factor for PFS (P=0.001). The expression of S100P and HYAL2 indicated similar prognostic effect to the overall survival (OS) of TNBC patients. In addition, high expression levels of both S100P and HYAL2 showed significant association with different clinicopathological characteristics, such as more recurrence events (P=0.004), and higher occurrence of metastasis (P=0.002). Our study proposes S100P and HYAL2 as potential prognostic markers for TNBC.
    Type of Publication: Journal article published
    PubMed ID: 26112095
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  • 21
    Keywords: brain ; MODEL ; MRI ; NMR ; WHITE-MATTER ; WATER DIFFUSION ; Tensor
    Abstract: In medical imaging and porous media research, NMR diffusion measurements are extensively used to investigate the structure of diffusion restrictions such as cell membranes. Recently, several methods have been proposed to unambiguously determine the shape of arbitrary closed pores or cells filled with an NMR-visible medium by diffusion experiments. The first approach uses a combination of a long and a short diffusion-weighting gradient pulse, while the other techniques employ short gradient pulses only. While the eventual aim of these methods is to determine pore-size and shape distributions, the focus has been so far on identical pores. Thus, the aim of this work is to investigate the ability of these different methods to resolve pore-size and orientation distributions. Simulations were performed comparing the various pore imaging techniques employing different distributions of pore size and orientation and varying timing parameters. The long-narrow gradient profile is most advantageous to investigate pore distributions, because average pore images can be directly obtained. The short-gradient methods suppress larger pores or induce a considerable blurring. Moreover, pore-shape-specific artifacts occur; for example, the central part of a distribution of cylinders may be largely underestimated. Depending on the actual pore distribution, short-gradient methods may nonetheless yield good approximations of the average pore shape. Furthermore, the application of short-gradient methods can be advantageous to differentiate whether pore-size distributions or intensity distributions, e.g., due to surface relaxation, are predominant.
    Type of Publication: Journal article published
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  • 22
    Keywords: carcinoma ; MODEL ; RISK-FACTORS ; BIOLOGY ; VARIANTS ; METAANALYSIS ; susceptibility loci ; GENOME-WIDE ASSOCIATION
    Abstract: Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.
    Type of Publication: Journal article published
    PubMed ID: 26231222
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  • 23
    Keywords: MODEL ; TIME ; BEHAVIOR ; APPROXIMATION ; TRANSVERSE RELAXATION ; NMR SIGNAL ; INHOMOGENEITIES ; SIGNAL FORMATION ; LUNG-TISSUE ; PERTURBERS
    Abstract: In this work, the time evolution of the free induction decay caused by the local dipole field of a spherical magnetic perturber is analyzed. The complicated treatment of the diffusion process is replaced by the strong-collision-approximation that allows a determination of the free induction decay in dependence of the underlying microscopic tissue parameters such as diffusion coefficient, sphere radius and susceptibility difference. The interplay between susceptibility- and diffusion-mediated effects yields several dephasing regimes of which, so far, only the classical regimes of motional narrowing and static dephasing for dominant and negligible diffusion, respectively, were extensively examined. Due to the asymmetric form of the dipole field for spherical objects, the free induction decay exhibits a complex component in contradiction to the cylindrical case, where the symmetric local dipole field only causes a purely real induction decay. Knowledge of the shape of the corresponding frequency distribution is necessary for the evaluation of more sophisticated pulse sequences and a detailed understanding of the off-resonance distribution allows improved quantification of transverse relaxation.
    Type of Publication: Journal article published
    PubMed ID: 26133269
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  • 24
    Keywords: CANCER ; MODEL ; PERFUSION ; THERAPY ; liver ; TISSUE ; BLOOD-FLOW ; NUCLEAR-MAGNETIC-RESONANCE ; WEIGHTED MRI ; B-VALUES
    Abstract: PurposeThe pseudo-diffusion coefficient D-* in intravoxel incoherent motion (IVIM) imaging was found difficult to seize. Flow-compensated diffusion gradients were used to test the validity of the commonly assumed biexponential limit and to determine not only D-*, but also characteristic timescale and velocity v of the incoherent motion. Theory and MethodsBipolar and flow-compensated diffusion gradients were inserted into a flow-compensated single-shot EPI sequence. Images were obtained from a pipe-shaped flow phantom and from healthy volunteers. To calculate the IVIM signal outside the biexponential limit, a formalism based on normalized phase distributions was developed. ResultsThe flow-compensated diffusion gradients caused less signal attenuation than the bipolar ones. A signal dependence on the duration of the flow-compensated gradients was found at low b-values in the volunteer datasets. The characteristic IVIM parameters were estimated to be v=4.600.34 mm/s and =144 +/- 10 ms for liver and v=3.91 +/- 0.54 mm/s and =224 +/- 47 ms for pancreas. ConclusionOur results strongly indicate that the biexponential limit does not adequately model the diffusion signal in liver and pancreas. By using both bipolar and flow-compensated diffusion gradients of different duration, the characteristic timescale and velocity of the incoherent motion can be determined.
    Type of Publication: Journal article published
    PubMed ID: 25116325
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  • 25
    Keywords: CANCER ; EXPRESSION ; radiotherapy ; MODEL ; DISEASE ; NON-HODGKINS-LYMPHOMA ; PROFILES ; SIGNATURE ; MicroRNAs ; NERVOUS-SYSTEM LYMPHOMA
    Abstract: Despite improved therapeutic regimens, primary CNS lymphoma (PCNSL) remains a therapeutic challenge. A prognostic classification of PCNSL patients may represent an important step towards optimised patient-adapted therapy. However, only higher age and low Karnofsky Performance Status (KPS) have repeatedly been reported to be associated with shorter overall survival (OS). Here we characterised microRNA (miRNA) fingerprints in the blood of PCNSL patients with short-term survival (STS) versus long-term survival (LTS) to assess their potential as novel prognostic biomarkers. Blood was collected from patients enrolled in the G-PCNSL-SG1 trial, a phase III study for patients with newly diagnosed PCNSL. miRNAs were extracted from the blood and analysed by next generation sequencing. The STS group comprised 20 patients with a median OS of 3 months and was compared to 20 LTS patients with a median OS of 55 months. The cohorts were balanced for age and KPS. Twelve annotated miRNAs were significantly deregulated between the two groups. Among them, miR-151a-5p and miR-151b exhibited the most prominent differences. Importantly, the combination of several miRNA allowed for a good separation between short- and long-term survivors with maximal Area Under Curve (AUC) above 0.75. Besides the known miRNAs we identified putative novel miRNA candidates with potential regulatory influence of PCNSL. Finally, the differential regulation of the most promising candidate miRNAs was confirmed by real-time polymerase chain reaction (PCR) in a validation cohort consisting of 20 STS and LTS patients. In conclusion, peripheral blood miRNA expression patterns hold promise as a prognostic tool in PCNSL patients.
    Type of Publication: Journal article published
    PubMed ID: 25534293
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  • 26
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    Physical Review / E 91 (3-1), Art. Nr.: 032707- 
    Keywords: IN-VIVO ; MODEL ; HEART ; TIME ; TISSUES ; MAGNETIC-RESONANCE ; myocardium ; CAPILLARY
    Abstract: We analyze the free induction decay of nuclear spins under the influence of restricted diffusion in a magnetic dipole field around cylindrical objects. In contrast to previous publications no restrictions or simplifications concerning the diffusion process are made. By directly solving the Bloch-Torrey equation, analytical expressions for the magnetization are given in terms of an eigenfunction expansion. The field strength-dependent complex nature of the eigenvalue spectrum significantly influences the shape of the free induction decay. As the dipole field is the lowest order of the multipole expansion, the obtained results are important for understanding fundamental mechanisms of spin dephasing in many other applied fields of nuclear magnetic resonance such as biophysics or material science. The analytical methods are applied to interpret the spin dephasing in the free induction decay in cardiac muscle and skeletal muscle. A simple expression for the relevant transverse relaxation time is found in terms of the underlying microscopic parameters of the muscle tissue. The analytical results are in agreement with experimental data. These findings are important for the correct interpretation of magnetic resonance images for clinical diagnosis at all magnetic field strengths and therapy of cardiovascular diseases.
    Type of Publication: Journal article published
    PubMed ID: 25871144
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  • 27
    Keywords: MODEL ; SYSTEM ; SURGERY ; validation ; innovation ; PNEUMOPERITONEUM ; CHALLENGES ; SKILLS ; IMAGING INTERACTION TOOLKIT ; TECHNOLOGIES
    Abstract: BACKGROUND: Apart from animal testing and clinical trials, surgical research and laparoscopic training mainly rely on phantoms. The aim of this project was to design a phantom with realistic anatomy and haptic characteristics, modular design and easy reproducibility. The phantom was named open-source Heidelberg laparoscopic phantom (OpenHELP) and serves as an open-source platform. METHODS: The phantom was based on an anonymized CT scan of a male patient. The anatomical structures were segmented to obtain digital three-dimensional models of the torso and the organs. The digital models were materialized via rapid prototyping. One flexible, using an elastic abdominal wall, and one rigid method, using a plastic shell, to simulate pneumoperitoneum were developed. Artificial organ production was carried out sequentially starting from raw gypsum models to silicone molds to final silicone casts. The reproduction accuracy was exemplarily evaluated for ten silicone rectum models by comparing the digital 3D surface of the original rectum with CT scan by calculating the root mean square error of surface variations. Haptic realism was also evaluated to find the most realistic silicone compositions on a visual analog scale (VAS, 0-10). RESULTS: The rigid and durable plastic torso and soft silicone organs of the abdominal cavity were successfully produced. A simulation of pneumoperitoneum could be created successfully by both methods. The reproduction accuracy of ten silicone rectum models showed an average root mean square error of 2.26 (0-11.48) mm. Haptic realism revealed an average value on a VAS of 7.25 (5.2-9.6) for the most realistic rectum. CONCLUSION: The OpenHELP phantom proved to be feasible and accurate. The phantom was consecutively applied frequently in the field of computer-assisted surgery at our institutions and is accessible as an open-source project at www.open-cas.org for the academic community.
    Type of Publication: Journal article published
    PubMed ID: 25673345
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  • 28
    Keywords: radiotherapy ; IN-VIVO ; MODEL ; TUMORS ; RADIATION-THERAPY ; RELATIVE BIOLOGICAL EFFECTIVENESS ; cell migration ; BEAMS ; CANCER INVASION ; GROWTH DELAY
    Abstract: In a recent published study, we investigated the response of an experimental prostate carcinoma (R3327-AT1) after irradiation with 1, 2 or 6 fractions of carbon ions or photons, respectively. The original intention of this study was to measure the dose-dependent local control probability as well as the related relative biological effectiveness of carbon ions. However, we now report an increased metastatic rate when the number of fractions was increased from 2 to 6. In a total of 246 animals, the actuarial metastatic rates for 1, 2 and 6 fractions were 5.1 +/- 3.5%, 5.7 +/- 4.0% and 15.3 +/- 7.1% for photons and 9.8 +/- 7.5%, 4.0 +/- 3.9% and 20.3 +/- 6.5% for carbon ions, respectively. The increase was significant only for carbon ions (6 vs. 2 fractions, P = 0.03). Although the original experiment was not designed to investigate metastatic rates, this observation may be of general interest to researchers studying radiation-modulated metastatic activity.
    Type of Publication: Journal article published
    PubMed ID: 24844648
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  • 29
    Keywords: EXPRESSION ; MODEL ; cytokines ; MOUSE ; PRESSURE ; inflammation ; RESPIRATORY-DISTRESS-SYNDROME ; ACUTE LUNG INJURY ; LEUKOCYTE RECRUITMENT ; LOWER TIDAL VOLUMES
    Abstract: The pathogenesis of ventilator-induced lung injury has predominantly been attributed to overdistension or mechanical opening and collapse of alveoli, whereas mechanical strain on the airways is rarely taken into consideration. Here, we hypothesized that mechanical ventilation may cause significant airway distension, which may contribute to the pathological features of ventilator-induced lung injury. C57BL/6J mice were anesthetized and mechanically ventilated at tidal volumes of 6, 10, or 15 ml/kg body wt. Mice were imaged by flat-panel volume computer tomography, and central airways were segmented and rendered in 3D for quantitative assessment of airway distension. Alveolar distension was imaged by intravital microscopy. Functional dead space was analyzed in vivo, and proinflammatory cytokine release was analyzed in isolated, ventilated tracheae. CT scans revealed a reversible, up to 2.5-fold increase in upper airway volume during mechanical ventilation compared with spontaneous breathing. Airway distension was most pronounced in main bronchi, which showed the largest volumes at tidal volumes of 10 ml/kg body wt. Conversely, airway distension in segmental bronchi and functional dead space increased almost linearly, and alveolar distension increased even disproportionately with higher tidal volumes. In isolated tracheae, mechanical ventilation stimulated the release of the early-response cytokines TNF-alpha and IL-1beta. Mechanical ventilation causes a rapid, pronounced, and reversible distension of upper airways in mice that is associated with an increase in functional dead space. Upper airway distension is most pronounced at moderate tidal volumes, whereas higher tidal volumes redistribute preferentially to the alveolar compartment. Airway distension triggers proinflammatory responses and may thus contribute relevantly to ventilator-induced pathologies.
    Type of Publication: Journal article published
    PubMed ID: 24816486
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  • 30
    Keywords: MODEL ; navigation ; BEAM COMPUTED-TOMOGRAPHY ; augmented reality ; Nephrectomy
    Abstract: BACKGROUND: Laparoscopic liver surgery is particularly challenging owing to restricted access, risk of bleeding, and lack of haptic feedback. Navigation systems have the potential to improve information on the exact position of intrahepatic tumors, and thus facilitate oncological resection. This study aims to evaluate the feasibility of a commercially available augmented reality (AR) guidance system employing intraoperative robotic C-arm cone-beam computed tomography (CBCT) for laparoscopic liver surgery. METHODS: A human liver-like phantom with 16 target fiducials was used to evaluate the Syngo iPilot((R)) AR system. Subsequently, the system was used for the laparoscopic resection of a hepatocellular carcinoma in segment 7 of a 50-year-old male patient. RESULTS: In the phantom experiment, the AR system showed a mean target registration error of 0.96 +/- 0.52 mm, with a maximum error of 2.49 mm. The patient successfully underwent the operation and showed no postoperative complications. CONCLUSION: The use of intraoperative CBCT and AR for laparoscopic liver resection is feasible and could be considered an option for future liver surgery in complex cases.
    Type of Publication: Journal article published
    PubMed ID: 24178862
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  • 31
    Keywords: EXPRESSION ; IN-VIVO ; MODEL ; THERAPY ; DIFFERENTIATION ; PROGRESSION ; ES CELLS ; SELF-RENEWAL ; pluripotency ; TUMOR-INITIATING CELLS
    Abstract: Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis. Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-kappaB activity, self-renewal and differentiation potential, and stem cell signaling via spheroid- and colony-forming assays, FACS and western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL, though the agents acted synergistically when applied in combination. This was associated with the inhibition of TRAIL-induced NF-kappaB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition; and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target the cancer-specific activity of TRAIL in CSCs.
    Type of Publication: Journal article published
    PubMed ID: 24626333
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  • 32
    Keywords: CANCER ; IN-VITRO ; MODEL ; COPY NUMBER ; REPAIR ; DUAL ROLE ; MUTATIONS ; TRANSFORMATION ; LI-FRAUMENI-SYNDROME ; STATE
    Abstract: p53 loss of heterozygosity (p53LOH) is frequently observed in Li-Fraumeni syndrome (LFS) patients who carry a mutant (Mut) p53 germ-line mutation. Here, we focused on elucidating the link between p53LOH and tumor development in stem cells (SCs). Although adult mesenchymal stem cells (MSCs) robustly underwent p53LOH, p53LOH in induced embryonic pluripotent stem cells (iPSCs) was significantly attenuated. Only SCs that underwent p53LOH induced malignant tumors in mice. These results may explain why LFS patients develop normally, yet acquire tumors in adulthood. Surprisingly, an analysis of single-cell sub-clones of iPSCs, MSCs and ex vivo bone marrow (BM) progenitors revealed that p53LOH is a bi-directional process, which may result in either the loss of wild-type (WT) or Mut p53 allele. Interestingly, most BM progenitors underwent Mutp53LOH. Our results suggest that the bi-directional p53LOH process may function as a cell-fate checkpoint. The loss of Mutp53 may be regarded as a DNA repair event leading to genome stability. Indeed, gene expression analysis of the p53LOH process revealed upregulation of a specific chromatin remodeler and a burst of DNA repair genes. However, in the case of loss of WTp53, cells are endowed with uncontrolled growth that promotes cancer.
    Type of Publication: Journal article published
    PubMed ID: 24832469
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  • 33
    Keywords: APOPTOSIS ; IN-VITRO ; MODEL ; DISEASE ; METABOLISM ; PHARMACOKINETICS ; RECONSTRUCTION ; regeneration ; PRIMARY HEPATOCYTES ; GENE-EXPRESSION ALTERATIONS
    Type of Publication: Journal article published
    PubMed ID: 25331938
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  • 34
    Keywords: MODEL ; GENE-EXPRESSION ; GENOME ; REVEALS ; METHYLATION ; ARCHITECTURE ; TRANSCRIPTION FACTOR-BINDING ; ISLANDS ; CHROMATIN ACCESSIBILITY ; PLURIPOTENT CELLS
    Abstract: During differentiation of embryonic stem cells, chromatin reorganizes to establish cell type-specific expression programs. Here, we have dissected the linkages between DNA methylation (5mC), hydroxymethylation (5hmC), nucleosome repositioning, and binding of the transcription factor CTCF during this process. By integrating MNase-seq and ChIP-seq experiments in mouse embryonic stem cells (ESC) and their differentiated counterparts with biophysical modeling, we found that the interplay between these factors depends on their genomic context. The mostly unmethylated CpG islands have reduced nucleosome occupancy and are enriched in cell type-independent binding sites for CTCF. The few remaining methylated CpG dinucleotides are preferentially associated with nucleosomes. In contrast, outside of CpG islands most CpGs are methylated, and the average methylation density oscillates so that it is highest in the linker region between nucleosomes. Outside CpG islands, binding of TET1, an enzyme that converts 5mC to 5hmC, is associated with labile, MNase-sensitive nucleosomes. Such nucleosomes are poised for eviction in ESCs and become stably bound in differentiated cells where the TET1 and 5hmC levels go down. This process regulates a class of CTCF binding sites outside CpG islands that are occupied by CTCF in ESCs but lose the protein during differentiation. We rationalize this cell type-dependent targeting of CTCF with a quantitative biophysical model of competitive binding with the histone octamer, depending on the TET1, 5hmC, and 5mC state.
    Type of Publication: Journal article published
    PubMed ID: 24812327
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  • 35
    Keywords: MODEL ; FOLLOW-UP ; RANDOMIZED CONTROLLED-TRIAL ; BORDERLINE PERSONALITY-DISORDER ; outpatients ; DIALECTICAL BEHAVIOR-THERAPY ; EATING-DISORDERS ; BULIMIA-NERVOSA ; FEMALE-PATIENTS ; DYSREGULATION
    Abstract: Introduction Monitoring and reduction of aversive tension is a core issue in dialectical behaviour therapy of patients. It has been shown that aversive tension is increased in adult borderline personality disorder and is linked to low emotion labelling ability. However, until now there is no documented evidence that patients with anorexia nervosa suffer from aversive tension as well. Furthermore the usability of a smartphone application for ambulatory monitoring purposes has not been sufficiently explored. Methods and analysis We compare the mean and maximum self-reported aversive tension in 20 female adolescents (12-19years) with anorexia nervosa in outpatient treatment with 20 healthy controls. They are required to answer hourly, over a 2-day period, that is, about 30 times, four short questions on their smartphone, which ensures prompt documentation without any recall bias. At the close out, the participants give a structured usability feedback on the application and the procedure. Ethics and dissemination The achieved result of this trial has direct relevance for efficient therapy strategies and is a prerequisite for trials regarding dialectical behaviour therapy in anorexia nervosa. The results will be disseminated through peer-review publications. The ethics committee of the regional medical association in Mainz, Germany approved the study protocol under the reference number 837.177.13. Trial Registration number The trial is registered at the German clinical trials registration under the reference number DRKS00005228.
    Type of Publication: Journal article published
    PubMed ID: 24760350
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  • 36
    Keywords: MODEL ; RAT ; hippocampus ; NEURONS ; MAP ; GAMMA OSCILLATIONS ; PATH-INTEGRATION ; OLFACTORY-BULB OUTPUT ; POSITIVE INTERNEURONS ; PHASE PRECESSION
    Abstract: Grid cells in the medial entorhinal cortex (MEC) generate metric spatial representations. Recent attractor-network models suggest an essential role for GABAergic interneurons in the emergence of the grid-cell firing pattern through recurrent inhibition dependent on grid-cell phase. To test this hypothesis, we studied identified parvalbumin-expressing (PV(+)) interneurons that are the most likely candidate for providing this recurrent inhibition onto grid cells. Using optogenetics and tetrode recordings in mice, we found that PV(+) interneurons exhibited high firing rates, low spatial sparsity and no spatial periodicity. PV(+) interneurons inhibited all functionally defined cell types in the MEC and were in turn recruited preferentially by grid cells. To our surprise, we found that individual PV(+) interneurons received input from grid cells with various phases, which most likely accounts for the broadly tuned spatial firing activity of PV(+) interneurons. Our data argue against the notion that PV(+) interneurons provide phase-dependent recurrent inhibition and challenge recent attractor-network models of grid cells.
    Type of Publication: Journal article published
    PubMed ID: 24705183
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  • 37
    Keywords: MODEL ; RAT ; hippocampus ; WORKING-MEMORY ; A-DEFICIENT MICE ; ENTORHINAL CORTEX ; PLACE CELLS ; FIMBRIA-FORNIX LESIONS ; REFERENCE MEMORY ; THETA RHYTHM
    Abstract: The hippocampus and the parahippocampal region have been proposed to contribute to path integration. Mice lacking GluA1-containing AMPA receptors (GluA1(-/-) mice) were previously shown to exhibit impaired hippocampal place cell selectivity. Here we investigated whether path integration performance and the activity of grid cells of the medial entorhinal cortex (MEC) are affected in these mice. We first tested GluA1(-/-) mice on a standard food-carrying homing task and found that they were impaired in processing idiothetic cues. To corroborate these findings, we developed an L-maze task that is less complex and is performed entirely in darkness, thereby reducing numerous confounding variables when testing path integration. Also in this task, the performance of GluA1(-/-) mice was impaired. Next, we performed in vivo recordings in the MEC of GluA1(-/-) mice. MEC neurons exhibited altered grid cell spatial periodicity and reduced spatial selectivity, whereas head direction tuning and speed modulation were not affected. The firing associations between pairs of neurons in GluA1(-/-) mice were stable, both in time and space, indicating that attractor states were still present despite the lack of grid periodicity. Together, these results support the hypothesis that spatial representations in the hippocampal-entorhinal network contribute to path integration.
    Type of Publication: Journal article published
    PubMed ID: 24790195
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  • 38
    Keywords: MODEL ; HARTREE-FOCK ; FUNCTIONAL THEORY ; STATE ; FISSION ; FORCES ; PARAMETRIZATION ; MEAN-FIELD ; SKYRMES INTERACTION ; EXOTIC NUCLEI
    Abstract: Background: Nuclear density functional theory is the only microscopical theory that can be applied throughout the entire nuclear landscape. Its key ingredient is the energy density functional. Purpose: In this work, we propose a new parametrization UNEDF2 of the Skyrme energy density functional. Methods: The functional optimization is carried out using the POUNDerS optimization algorithm within the framework of the Skyrme Hartree-Fock-Bogoliubov theory. Compared to the previous parametrization UNEDF1, restrictions on the tensor term of the energy density have been lifted, yielding a very general form of the energy density functional up to second order in derivatives of the one-body density matrix. In order to impose constraints on all the parameters of the functional, selected data on single-particle splittings in spherical doubly-magic nuclei have been included into the experimental dataset. Results: The agreement with both bulk and spectroscopic nuclear properties achieved by the resulting UNEDF2 parametrization is comparable with UNEDF1. While there is a small improvement on single-particle spectra and binding energies of closed shell nuclei, the reproduction of fission barriers and fission isomer excitation energies has degraded. As compared to previous UNEDF parametrizations, the parameter confidence interval for UNEDF2 is narrower. In particular, our results overlap well with those obtained in previous systematic studies of the spin-orbit and tensor terms. Conclusions: UNEDF2 can be viewed as an all-around Skyrme EDF that performs reasonably well for both global nuclear properties and shell structure. However, after adding new data aiming to better constrain the nuclear functional, its quality has improved only marginally. These results suggest that the standard Skyrme energy density has reached its limits, and significant changes to the form of the functional are needed.
    Type of Publication: Journal article published
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  • 39
    Keywords: MODEL ; microarray ; IDENTIFICATION ; OBESITY ; smoking ; ALCOHOL ; nutrition ; WAIST CIRCUMFERENCE ; CUP ; Prospective cohort study ; cancer of unknown primary site (CUP)
    Abstract: Cancer of unknown primary site (CUP) may be called an "orphan" disease, as it is diagnosed when metastases are detected while the primary tumor typically remains undetected, and because little research has been done on its primary causes. So far, few epidemiological studies, if any, have addressed possible risk factors for CUP. We analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (N = 476,940). During prospective follow-up, a total of 651 cases of incident cases of CUP were detected (ICD-O-2 code C809). Proportional hazards models were conducted to examine the associations of lifetime history of smoking habits, alcohol consumption, levels of education and anthropometric indices of adiposity with risk of being diagnosed with CUP. Risk of being diagnosed with CUP was strongly related to smoking, with a relative risk of 3.66 [95% C.I., 2.24-5.97] for current, heavy smokers (26+ cigarettes/day) compared to never smokers (adjusted for alcohol consumption, body mass index, waist circumference and level of education) and a relative risk of 5.12 [3.09-8.47] for cases with CUP who died within 12 months. For alcohol consumption and level of education, weaker associations were observed but attenuated and no longer statistically significant after adjusting for smoking and indices of obesity. Finally, risk of CUP was increased by approximately 30 per cent for subjects in the highest versus lowest quartiles of waist circumference. Our analyses provide further documentation, in addition to autopsy studies, that a substantial proportion of cancers of unknown primary site may have their origin in smoking-related tumors, in particular.
    Type of Publication: Journal article published
    PubMed ID: 24692151
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  • 40
    Keywords: CANCER ; MODEL ; DISEASE ; MORTALITY ; POPULATION ; RISK ; HEALTH ; PROJECT ; nutrition ; HEART-DISEASE ; DIETARY-INTAKE MEASUREMENTS ; fruits and vegetables ; EUROPEAN COUNTRIES ; CANCER-MORTALITY ; cardiovascular disease ; CARDIOVASCULAR-DISEASE MORTALITY ; ALL-CAUSE ; HIROSHIMA/NAGASAKI LIFE-SPAN ; Respiratory disease
    Abstract: Consumption of fruits and vegetables is associated with a lower overall mortality. The aim of this study was to identify causes of death through which this association is established. More than 450,000 participants from the European Prospective Investigation into Cancer and Nutrition study were included, of which 25,682 were reported deceased after 13 years of follow-up. Information on lifestyle, diet and vital status was collected through questionnaires and population registries. Hazard ratios (HR) with 95 % confidence intervals (95 % CI) for death from specific causes were calculated from Cox regression models, adjusted for potential confounders. Participants reporting consumption of more than 569 g/day of fruits and vegetables had lower risks of death from diseases of the circulatory (HR for upper fourth 0.85, 95 % CI 0.77-0.93), respiratory (HR for upper fourth 0.73, 95 % CI 0.59-0.91) and digestive system (HR for upper fourth 0.60, 95 % CI 0.46-0.79) when compared with participants consuming less than 249 g/day. In contrast, a positive association with death from diseases of the nervous system was observed. Inverse associations were generally observed for vegetable, but not for fruit consumption. Associations were more pronounced for raw vegetable consumption, when compared with cooked vegetable consumption. Raw vegetable consumption was additionally inversely associated with death from neoplasms and mental and behavioral disorders. The lower risk of death associated with a higher consumption of fruits and vegetables may be derived from inverse associations with diseases of the circulatory, respiratory and digestive system, and may depend on the preparation of vegetables and lifestyle factors.
    Type of Publication: Journal article published
    PubMed ID: 25154553
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  • 41
    Keywords: MODEL ; DISEASE ; chemotherapy ; LONG-TERM SURVIVAL ; OLDER PATIENTS ; PERIOD ANALYSIS ; EMPIRICAL-EVALUATION ; cancer survival ; UP-TO-DATE ; DISPARITIES
    Abstract: Treatment for Hodgkin lymphoma (HL) is more aggressive in Germany than in the United States (US) and differences in treatment may lead to differences in population level survival. Patients diagnosed with HL in 11 German states in 1997-2006 were included in the analyses and were compared to similar analyses from patients in the Surveillance, Epidemiology, and End Results database in the US. Period analysis was used to calculate 5-year relative survival for the time period of 2002-2006 overall and by gender, age and histology. Overall 5-year relative survival for patients with HL in Germany was 84 center dot 3%, compared to 80 center dot 6% for the US. Survival was highest in patients aged 15-29years at 97 center dot 9% and decreased with age to 57 center dot 5% at age 60+ Survival for men and women, respectively, was 84 center dot 7% and 84 center dot 1% in Germany and 78 center dot 2% and 83 center dot 6% in the US. 5-year relative survival for patients diagnosed with HL in Germany was close to 100% for younger patients. Survival of HL patients in the US was lower than in Germany overall, but was comparable in older patients and in women. Population-based studies with longer follow-up are still needed to examine effects of late toxicity on long term survival.
    Type of Publication: Journal article published
    PubMed ID: 24433418
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    Keywords: PROTECTION ; MODEL ; prognosis ; colon ; TARGET ; chemotherapy ; microsatellite instability ; tumor marker ; inflammation ; tissue microarray ; cancer prognosis ; INFLAMMASOME ; CYTOPLASMIC DNA ; DSDNA ; interferon (IFN)
    Abstract: Functional studies on colorectal cancer cells indicated a protective role of the interferon-inducible dsDNA sensor Absent in Melanoma 2 (AIM2) in cancer progression. Given that a high mutation rate and lack of AIM2 expression was previously detected in a subset of colorectal cancers, we here investigated the association of AIM2 expression in tumor cells and patient prognosis (5-year follow-up). A tissue microarray analysis of 476 matched tissue pairs (colorectal tumor and adjacent normal colon epithelium) was performed by two independent observers. Samples from 62 patients were excluded because of missing follow-up information or due to neo-adjuvant therapy before tissue sampling. Out of the remaining 414 tissue pairs, 279 (67.4%) displayed reduced AIM2 expression in cancer cells when compared to epithelial cells of their normal counterpart. Thirty-eight patients (9.18%) had completely lost AIM2 expression in tumor cells. After adjustment for sex, age, cancer stage, tumor site, tumor grade and chemotherapy, complete lack of AIM2 expression was associated with an up to 3-fold increase in overall mortality (HR=2.40; 95% CI=1.44-3.99) and disease specific mortality (HR=3.14; 95% CI=1.75-5.65) in comparison to AIM2-positive tumor samples. Our results demonstrate that lack of AIM2 expression is closely associated with poor outcome in colorectal cancer. The data thus strongly substantiate a protective role of AIM2 against progression of colorectal tumors. Further studies are required to assess whether lack of AIM2 expression may be used as a biomarker for the identification of colorectal cancer patients with poor prognosis
    Type of Publication: Journal article published
    PubMed ID: 24729378
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    Keywords: GROWTH ; proliferation ; MODEL ; NETWORK ; DIFFERENTIATION ; MOUSE ; senescence ; PC3 CELLS
    Abstract: The miR-34 family was originally found to be a direct target of p53 and is a group of putative tumor suppressors. Surprisingly, mice lacking all mir-34 genes show no increase in cancer formation by 18 months of age, hence placing the physiological relevance of previous studies in doubt. Here, we report that mice with prostate epithelium-specific inactivation of mir-34 and p53 show expansion of the prostate stem cell compartment and develop early invasive adenocarcinomas and high-grade prostatic intraepithelial neoplasia, whereas no such lesions are observed after inactivation of either the mir-34 or p53 genes alone by 15 months of age. Consistently, combined deficiency of p53 and miR-34 leads to acceleration of MET-dependent growth, self-renewal, and motility of prostate stem/progenitor cells. Our study provides direct genetic evidence that mir-34 genes are bona fide tumor suppressors and identifies joint control of MET expression by p53 and miR-34 as a key component of prostate stem cell compartment regulation, aberrations in which may lead to cancer.
    Type of Publication: Journal article published
    PubMed ID: 24630988
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    Keywords: MODEL ; VENTILATION ; AIR ; FREQUENCY ; NEED ; BIOLOGICAL TISSUES ; DIELECTRIC-PROPERTIES ; ELECTRICAL-IMPEDANCE TOMOGRAPHY
    Abstract: Electrical impedance tomography (EIT) estimates an image of change in electrical properties within a body from stimulations and measurements at surface electrodes. There is significant interest in EIT as a tool to monitor and guide ventilation therapy in mechanically ventilated patients. In lung EIT, the EIT inverse problem is commonly linearized and only changes in electrical properties are reconstructed. Early algorithms reconstructed changes in resistivity, while most recent work using the finite element method reconstructs conductivity. Recently, we demonstrated that EIT images of ventilation can be misleading if the electrical contrasts within the thorax are not taken into account during the image reconstruction process. In this paper, we explore the effect of the choice of the reconstructed electrical properties (resistivity or conductivity) on the resulting EIT images. We show in simulation and experimental data that EIT images reconstructed with the same algorithm but with different parametrizations lead to large and clinically significant differences in the resulting images, which persist even after attempts to eliminate the impact of the parameter choice by recovering volume changes from the EIT images. Since there is no consensus among the most popular reconstruction algorithms and devices regarding the parametrization, this finding has implications for potential clinical use of EIT. We propose a program of research to develop reconstruction techniques that account for both the relationship between air volume and electrical properties of the lung and artefacts introduced by the linearization.
    Type of Publication: Journal article published
    PubMed ID: 24844670
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    Keywords: MODEL ; LOCI ; GENOME-WIDE ASSOCIATION ; COMMON VARIANTS ; CHRONIC HEART-FAILURE ; CARDIAC REPOLARIZATION ; SARCOPLASMIC-RETICULUM ; QRS DURATION ; PR INTERVAL ; TRPM7
    Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
    Type of Publication: Journal article published
    PubMed ID: 24952745
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    Keywords: CANCER ; CELLS ; SURVIVAL ; MODEL ; PATHWAY ; PROTEIN ; COMPLEX ; TARGET ; TRANSPORT ; FUSION ; MITOCHONDRIA ; DEGRADATION ; systems biology ; computational biology ; lysosomes ; mTOR ; AUTOPHAGY ; lysosome ; Agent-based modeling ; Autophagic flux ; Cell-to-cell variability ; TRANSFER-RNA SYNTHETASE
    Abstract: BackgroundAutophagy is a vesicle-mediated pathway for lysosomal degradation, essential under basal and stressed conditions. Various cellular components, including specific proteins, protein aggregates, organelles and intracellular pathogens, are targets for autophagic degradation. Thereby, autophagy controls numerous vital physiological and pathophysiological functions, including cell signaling, differentiation, turnover of cellular components and pathogen defense. Moreover, autophagy enables the cell to recycle cellular components to metabolic substrates, thereby permitting prolonged survival under low nutrient conditions. Due to the multi-faceted roles for autophagy in maintaining cellular and organismal homeostasis and responding to diverse stresses, malfunction of autophagy contributes to both chronic and acute pathologies.ResultsWe applied a systems biology approach to improve the understanding of this complex cellular process of autophagy. All autophagy pathway vesicle activities, i.e. creation, movement, fusion and degradation, are highly dynamic, temporally and spatially, and under various forms of regulation. We therefore developed an agent-based model (ABM) to represent individual components of the autophagy pathway, subcellular vesicle dynamics and metabolic feedback with the cellular environment, thereby providing a framework to investigate spatio-temporal aspects of autophagy regulation and dynamic behavior. The rules defining our ABM were derived from literature and from high-resolution images of autophagy markers under basal and activated conditions. Key model parameters were fit with an iterative method using a genetic algorithm and a predefined fitness function. From this approach, we found that accurate prediction of spatio-temporal behavior required increasing model complexity by implementing functional integration of autophagy with the cellular nutrient state. The resulting model is able to reproduce short-term autophagic flux measurements (up to 3 hours) under basal and activated autophagy conditions, and to measure the degree of cell-to-cell variability. Moreover, we experimentally confirmed two model predictions, namely (i) peri-nuclear concentration of autophagosomes and (ii) inhibitory lysosomal feedback on mTOR signaling.ConclusionAgent-based modeling represents a novel approach to investigate autophagy dynamics, function and dysfunction with high biological realism. Our model accurately recapitulates short-term behavior and cell-to-cell variability under basal and activated conditions of autophagy. Further, this approach also allows investigation of long-term behaviors emerging from biologically-relevant alterations to vesicle trafficking and metabolic state.
    Type of Publication: Journal article published
    PubMed ID: 25214434
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