Funding Opportunity RFA-RM-17-014 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) solicits applications to establish a Stakeholder Engagement and Program Coordination Center (SEPCC) to coordinate the required activities of the Common Fund Metabolomics Program Consortium; to engage the stakeholder community in identifying and developing strategies to address outstanding concerns in the application of metabolomics to biomedical research; and to promote use of Consortium resources by the greater biomedical research community. The Common Fund Metabolomics Program views community engagement and multi-directional communication as essential to overcome challenges in realizing the potential of metabolomics in biomedical research.

Notice NOT-DA-17-051 from the NIH Guide for Grants and Contracts

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Activity of Pazopanib and Trabectedin in Advanced Alveolar Soft Part Sarcoma.

Oncologist. 2017 Jul 28;:

Authors: Stacchiotti S, Mir O, Le Cesne A, Vincenzi B, Fedenko A, Maki RG, Somaiah N, Patel S, Brahmi M, Blay JY, Boye K, Sundby Hall K, Gelderblom H, Hindi N, Martin-Broto J, Kosela H, Rutkowski P, Italiano A, Duffaud F, Kobayashi E, Casali PG, Provenzano S, Kawai A

Abstract
BACKGROUND: Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin.
MATERIALS AND METHODS: From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method.
RESULTS: Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6-32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached.Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7-109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months.
CONCLUSION: The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS.
IMPLICATIONS FOR PRACTICE: This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.

PMID: 28754721 [PubMed - as supplied by publisher]

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BDNF Genotype is Associated with Hippocampal Volume in Mild Traumatic Brain Injury.

Genes Brain Behav. 2017 Jul 28;:

Authors: Hayes JP, Reagan A, Logue MW, Hayes SM, Sadeh N, Miller DR, Verfaellie M, Wolf EJ, McGlinchey RE, Milberg WP, Stone A, Schichman SA, Miller MW

Abstract
The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507, and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non-Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 who had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Further, exploratory analysis of functional resting state data revealed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.

PMID: 28755387 [PubMed - as supplied by publisher]

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The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer.

Int J Mol Sci. 2017 Jul 21;18(7):

Authors: Senthebane DA, Rowe A, Thomford NE, Shipanga H, Munro D, Mazeedi MAMA, Almazyadi HAM, Kallmeyer K, Dandara C, Pepper MS, Parker MI, Dzobo K

Abstract
Chemoresistance is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Chemoresistance is influenced by genetic and epigenetic alterations which affect drug uptake, metabolism and export of drugs at the cellular levels. While most research has focused on tumor cell autonomous mechanisms of chemoresistance, the tumor microenvironment has emerged as a key player in the development of chemoresistance and in malignant progression, thereby influencing the development of novel therapies in clinical oncology. It is not surprising that the study of the tumor microenvironment is now considered to be as important as the study of tumor cells. Recent advances in technological and analytical methods, especially 'omics' technologies, has made it possible to identify specific targets in tumor cells and within the tumor microenvironment to eradicate cancer. Tumors need constant support from previously 'unsupportive' microenvironments. Novel therapeutic strategies that inhibit such microenvironmental support to tumor cells would reduce chemoresistance and tumor relapse. Such strategies can target stromal cells, proteins released by stromal cells and non-cellular components such as the extracellular matrix (ECM) within the tumor microenvironment. Novel in vitro tumor biology models that recapitulate the in vivo tumor microenvironment such as multicellular tumor spheroids, biomimetic scaffolds and tumor organoids are being developed and are increasing our understanding of cancer cell-microenvironment interactions. This review offers an analysis of recent developments on the role of the tumor microenvironment in the development of chemoresistance and the strategies to overcome microenvironment-mediated chemoresistance. We propose a systematic analysis of the relationship between tumor cells and their respective tumor microenvironments and our data show that, to survive, cancer cells interact closely with tumor microenvironment components such as mesenchymal stem cells and the extracellular matrix.

PMID: 28754000 [PubMed - in process]

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Mycobacterium abscessus displays fitness for fomite transmission.

Appl Environ Microbiol. 2017 Jul 28;:

Authors: Malcolm KC, Caceres SM, Honda JR, Davidson RM, Epperson LE, Strong M, Chan ED, Nick JA

Abstract
Mycobacterium abscessus (Mab) is a rapidly growing nontuberculous mycobacterium (NTM) increasingly reported in soft tissue infections and chronic lung diseases, including cystic fibrosis. The environmental source of Mab has not been definitively identified, but NTM have been detected in soil and water. To determine the potential of soil-derived Mab as an infectious source we explored the association, growth, and survival of Mab with defined mineral particulates, including kaolin, halloysite, and silicone dioxide, and house dust as possible Mab fomites. Mab physically associated with particulates and growth of Mab was enhanced in the presence of both kaolin and house dust. Mab survived desiccation for two weeks but was not viable after three weeks. The rate of decline of Mab viability during desiccation was reduced in the presence of house dust. Evidence for enhanced growth and survival of Mab during alternating growth and drying periods suggest that dissemination could occur when in wet or dry environments. These studies are important to understand environmental survival and acquisition of NTM.Importance The environmental source of pulmonary Mycobacterium abscessus (Mab) infections is not known. Fomites are non-living carriers of infectious agents and may contribute to acquisition of Mab This study provides evidence that Mab growth is enhanced in the presence of particulates, using kaolin, an abundant natural clay mineral, and house dust, as experimental fomites. Moreover, Mab survived desiccation for up to two weeks in the presence of house dust, kaolin and several chemically defined mineral particulates; mycobacterial viability during extended periods in a dry condition was enhanced by the presence of house dust. The growth characteristics of Mab with particulates suggest a fomite mechanism of transmission may contribute the Mab acquisition, and suggest strategies to better control infections by Mab and related organisms.

PMID: 28754702 [PubMed - as supplied by publisher]

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Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium.

Biochim Biophys Acta. 2017 Jul 25;:

Authors: Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E, Scirpo R, Fabris L

Abstract
The most studied physiological function of biliary epithelial cells (cholangiocytes) is to regulate bile flow and composition, in particular the hydration and alkalinity of the primary bile secreted by hepatocytes. After almost three decades of studies it is now become clear that cholangiocytes are also involved in epithelial innate immunity, in inflammation, and in the reparative processes in response to liver damage. An increasing number of evidence highlights the ability of cholangiocyte to undergo changes in phenotype and function in response to liver damage. By participating actively to the immune and inflammatory responses, cholangiocytes represent a first defense line against liver injury from different causes. Indeed, cholangiocytes express a number of receptors able to recognize pathogen- or damage-associated molecular patterns (PAMPs/DAMPs), such as Toll-like receptors (TLR), which modulate their pro-inflammatory behavior. Cholangiocytes can be both the targets and the initiators of the inflammatory process. Derangements of the signals controlling these mechanisms are at the basis of the pathogenesis of different cholangiopathies, both hereditary and acquired, such as cystic fibrosis-related liver disease and sclerosing cholangitis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

PMID: 28754453 [PubMed - as supplied by publisher]

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Relevance of multidrug-resistant Pseudomonas aeruginosa infections in cystic fibrosis.

Int J Med Microbiol. 2017 Jul 19;:

Authors: Stefani S, Campana S, Cariani L, Carnovale V, Colombo C, Lleo MM, Iula VD, Minicucci L, Morelli P, Pizzamiglio G, Taccetti G

Abstract
Multidrug-resistant (MDR) Pseudomonas aeruginosa is an important issue for physicians who take care of patients with cystic fibrosis (CF). Here, we review the latest research on how P. aeruginosa infection causes lung function to decline and how several factors contribute to the emergence of antibiotic resistance in P. aeruginosa strains and influence the course of the infection course. However, many aspects of the practical management of patients with CF infected with MDR P. aeruginosa are still to be established. Less is known about the exact role of susceptibility testing in clinical strategies for dealing with resistant infections, and there is an urgent need to find a tool to assist in choosing the best therapeutic strategy for MDR P. aeruginosa infection. One current perception is that the selection of antibiotic therapy according to antibiogram results is an important component of the decision-making process, but other patient factors, such as previous infection history and antibiotic courses, also need to be evaluated. On the basis of the known issues and the best current data on respiratory infections caused by MDR P. aeruginosa, this review provides practical suggestions to optimize the diagnostic and therapeutic management of patients with CF who are infected with these pathogens.

PMID: 28754426 [PubMed - as supplied by publisher]

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Age-related levels of fecal M2-pyruvate kinase in children with cystic fibrosis and healthy children 0 to 10years old.

J Cyst Fibros. 2017 Jul 25;:

Authors: Garg M, Leach ST, Pang T, Needham B, Coffey MJ, Katz T, Strachan R, Widger J, Field P, Belessis Y, Chuang S, Day AS, Jaffe A, Ooi CY

Abstract
BACKGROUND: The pathogenesis of gut inflammation, bacterial dysbiosis and increased rates of malignancy in CF is unclear. Fecal M2-pyruvate kinase (M2-PK) is a biomarker indicative of cellular proliferation that may be raised in intestinal malignancy and inflammation. Biomarkers, including M2-PK, may be useful in assessing effects of novel therapies on the gastrointestinal tract.
METHODS: M2-PK was measured in stools collected from patients with CF and HC (0-10years). Linear mixed model analysis was used.
RESULTS: M2-PK levels did not significantly change in children with CF (36 patients, 77 samples) (P=0.998) or HC (45 patients, 45 samples) (P=0.21), over the age range 0-10years. Patients with CF had elevated M2-PK compared to HC (median [IQR; range]: 10.7 [5.7-28.6; 1.0-239.1] (n=77) vs. 1.0 [1.0-1.0; 1.0-50.0] (n=45) U/mL, respectively; P=0.001).
CONCLUSIONS: Fecal M2-PK was elevated in children with CF compared with HC during infancy and throughout childhood suggesting abnormalities in the CF gut exist in early life.

PMID: 28754328 [PubMed - as supplied by publisher]

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Mitochondrial Encephalopathy and Transient 3-Methylglutaconic Aciduria in ECHS1 Deficiency: Long-Term Follow-Up.

JIMD Rep. 2017 Jul 29;:

Authors: Huffnagel IC, Redeker EJW, Reneman L, Vaz FM, Ferdinandusse S, Poll-The BT

Abstract
We report the major diagnostic challenge in a female patient with signs and symptoms suggestive of an early-onset mitochondrial encephalopathy. Motor and cognitive development was severely delayed and brain MRI showed signal abnormalities in the putamen and caudate nuclei. Metabolic abnormalities included 3-methylglutaconic aciduria and elevated lactate levels in plasma and cerebrospinal fluid, but were transient. Whole exome sequencing at the age of 25 years finally revealed compound heterozygous mutations c.[229G>C];[563C>T], p.[Glu77Gln];[Ala188Val] in the ECHS1 gene. Activity of short-chain enoyl-CoA hydratase, a mitochondrial enzyme encoded by the ECHS1 gene, was markedly decreased in lymphocytes. Retrospective urine analysis confirms that elevated levels of S-(2-carboxypropyl)cysteamine, S-(2-carboxypropyl)cysteine, and N-acetyl-S-(2-carboxypropyl)cysteine can be a diagnostic clue in the disease spectrum of ECHS1 mutations.

PMID: 28755360 [PubMed - as supplied by publisher]

Towards an evidence based approach for the development of adjuvanted vaccines.

Curr Opin Immunol. 2017 Jul 26;47:93-102

Authors: O'Hagan DT, Friedland LR, Hanon E, Didierlaurent AM

Abstract
In the last two decades, several vaccines formulated with a new generation of adjuvants have been licensed or approved to target diseases such as influenza, hepatitis B, cervical cancer, and malaria. These new generation adjuvants appear to work by delivering a localized activation signal to the innate immune system, which in turn promotes antigen-specific adaptive immunity. Advances in understanding of the innate immune system together with high-throughput discovery of synthetic immune potentiators are now expanding the portfolio of new generation adjuvants available for evaluation. Meanwhile, omics and systems biology are providing molecular benchmarks or signatures to assess vaccine safety and effectiveness. This accumulating knowledge and experience raises the prospect that the future selection of the right antigen/adjuvant combination can be more evidence based and can speed up the clinical development program for new adjuvanted vaccines.

PMID: 28755542 [PubMed - as supplied by publisher]

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Date Fruit Proteomics During Development and Ripening Stages.

Methods Mol Biol. 2017;1638:381-398

Authors: Marondedze C

Abstract
Gel-based comparative proteomics approach is a valuable technique for studying the changes in abundance of proteins in any given system. The combination of this technique with mass spectrometry has provided immense insight into protein dynamics during fruit development and ripening. This chapter describes, informatively, the procedures for carrying out comparative proteomics analysis of date palm (Phoenix dactylifera L.) fruits at different developmental stages using a combination of two-dimensional gel electrophoresis (2-DE) and mass spectrometry. A comparative proteomics approach provides an overview of protein abundances during fruit maturation and insights into proteins that play key roles during fruit maturation. Moreover, 2-DE technique enables the visualization of total protein distribution and abundance in addition to providing a comparative platform following separation of complex proteins based on their molecular weight and isoelectric point. Overall, this chapter describes methodologies for extraction of proteins from a high carbohydrate-containing fruit, protein quality assessment using one-dimensional gel electrophoresis (1-DE), separation using 2-DE, comparative analysis using Delta2D v4.6, processing of spots of interest, and protein identification using mass spectrometry. This protocol is important for studies aiming at comparative proteomics to gain insights into changes of protein abundances in tissues and organs in general and date palm fruits, in particular.

PMID: 28755236 [PubMed - in process]

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A comparative study on the WCRF International/University of Bristol methodology for systematic reviews of mechanisms underpinning exposure-cancer associations.

Cancer Epidemiol Biomarkers Prev. 2017 Jul 28;:

Authors: Ertaylan G, Le Cornet C, van Roekel EH, Jung AY, Bours MJL, Damms-Machado A, van den Brandt PA, Schock H, de Kok TM, Theys J, Arts ICW, Kaaks R, Weijenberg MP, Fortner RT

Abstract
The World Cancer Research Fund International and the University of Bristol have developed a novel framework for providing an overview of mechanistic pathways and conducting a systematic literature review of the biologically plausible mechanisms underlying exposure-cancer associations. Two teams independently applied the two-stage framework on mechanisms underpinning the association between body fatness and breast cancer to test the framework feasibility and reproducibility as part of a WCRF-Commissioned validation study. In Stage 1, a "hypothesis-free" approach was used to provide an overview of potential intermediate mechanisms between body fatness and breast cancer. Dissimilar rankings of potential mechanisms were observed between the two teams due to different applications of the framework. In Stage 2, a systematic review was conducted on the insulin-like growth factor 1 receptor chosen as intermediate mechanism. Although the studies included differed, both teams found inconclusive evidence for the body fatness-IGF1R association and modest evidence linking IGF1R to breast cancer, therefore concluded that there is currently weak evidence for IGF1R as mechanism linking body fatness to breast cancer. The framework is a good starting point for conducting systematic review by integrating evidence from mechanistic studies on exposure-cancer associations. Based on our experience, we provide recommendations for future users.

PMID: 28754794 [PubMed - as supplied by publisher]

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NRF1 coordinates with DNA methylation to regulate spermatogenesis.

FASEB J. 2017 Jul 28;:

Authors: Wang J, Tang C, Wang Q, Su J, Ni T, Yang W, Wang Y, Chen W, Liu X, Wang S, Zhang J, Song H, Zhu J, Wang Y

Abstract
Spermatogenesis is a highly coordinated process that requires tightly regulated gene expression programmed by transcription factors and epigenetic modifiers. In this study, we found that nuclear respiratory factor (NRF)-1, a key transcription factor for mitochondrial biogenesis, cooperated with DNA methylation to directly regulate the expression of multiple germ cell-specific genes including Asz1 In addition, conditional ablation of NRF1 in gonocytes dramatically down-regulated these germline genes, blocked germ cell proliferation, and subsequently led to male infertility in mice. Our data highlight a precise crosstalk between transcriptional regulation by NRF1 and epigenetic modulation during germ cell development and unequivocally demonstrate a novel role of NRF1 in spermatogenesis.-Wang, J., Tang, C., Wang, Q., Su, J., Ni, T., Yang, W., Wang, Yo., Chen, W., Liu, X., Wang, S., Zhang, J., Song, H., Zhu, J., Wang, Yu. NRF1 coordinates with DNA methylation to regulate spermatogenesis.

PMID: 28754714 [PubMed - as supplied by publisher]

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Direct interaction of ezrin and AQP2 and its role in AQP2 trafficking.

J Cell Sci. 2017 Jul 28;:

Authors: Li W, Jin WW, Tsuji K, Chen Y, Nomura N, Su L, Yui N, Arthur J, Cotecchia S, Păunescu TG, Brown D, Lu HAJ

Abstract
The water channel aquaporin-2 (AQP2) is a major regulator of water homeostasis in response to vasopressin (VP). Dynamic trafficking of AQP2 relies on its close interaction with trafficking machinery proteins and the actin cytoskeleton. Here, we report the identification of ezrin, an actin binding protein from the ezrin/radixin/moesin (ERM) family as an AQP2 interacting protein. Ezrin was first detected in a co-immunoprecipitation (co-IP) complex using an anti-AQP2 antibody by proteomic analysis. Immunofluorescence staining revealed the co-expression of ezrin and AQP2 in collecting duct principal cells, and VP treatment caused redistribution of both proteins to the apical membrane. The ezrin-AQP2 interaction was confirmed by co-IP experiments using an anti-ezrin antibody, and by pull-down assays using purified full-length and FERM (four-point one/ezrin/radixin/moesin) domain-containing recombinant ezrin. Using purified recombinant proteins, we showed that ezrin directly interacts with AQP2 C-terminus through its N-terminal FERM domain. Knocking down ezrin expression with shRNA resulted in increased membrane accumulation of AQP2 and reduced AQP2 endocytosis. Therefore, through direct interaction with AQP2, ezrin facilitates AQP2 endocytosis, thus linking the dynamic actin cytoskeleton network with AQP2 trafficking.

PMID: 28754689 [PubMed - as supplied by publisher]

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Deciphering the regulation of metabolism with dynamic optimization: an overview of recent advances.

Biochem Soc Trans. 2017 Jul 28;:

Authors: Ewald J, Bartl M, Kaleta C

Abstract
Understanding optimality principles shaping the evolution of regulatory networks controlling metabolism is crucial for deriving a holistic picture of how metabolism is integrated into key cellular processes such as growth, adaptation and pathogenicity. While in the past the focus of research in pathway regulation was mainly based on stationary states, more recently dynamic optimization has proved to be an ideal tool to decipher regulatory strategies for metabolic pathways in response to environmental cues. In this short review, we summarize recent advances in the elucidation of optimal regulatory strategies and identification of optimal control points in metabolic pathways. We discuss biological implications of the discovered optimality principles on genome organization and provide examples how the derived knowledge can be used to identify new treatment strategies against pathogens. Furthermore, we briefly discuss the variety of approaches for solving dynamic optimization problems and emphasize whole-cell resource allocation models as an important emerging area of research that will allow us to study the regulation of metabolism on the whole-cell level.

PMID: 28754658 [PubMed - as supplied by publisher]

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Magnetic resonance T2 mapping and diffusion-weighted imaging for early detection of cystogenesis and response to therapy in a mouse model of polycystic kidney disease.

Kidney Int. 2017 Jul 26;:

Authors: Franke M, Baeßler B, Vechtel J, Dafinger C, Höhne M, Borgal L, Göbel H, Koerber F, Maintz D, Benzing T, Schermer B, Persigehl T

Abstract
Polycystic kidney disease (PKD) is among the leading causes of end-stage renal disease. Increasing evidence exists that molecular therapeutic strategies targeted to cyst formation and growth might be more efficacious in early disease stages, highlighting the growing need for sensitive biomarkers. Here we apply quantitative magnetic resonance imaging techniques of T2 mapping and diffusion-weighted imaging in the jck mouse model for PKD using a clinical 3.0 T scanner. We tested whether kidney T2 values and the apparent diffusion coefficient (ADC) are superior to anatomical imaging parameters in the detection of early cystogenesis, as shown on macro- and histopathology. We also tested whether kidney T2 values and ADC have the potential to monitor early treatment effects of therapy with the V2 receptor antagonist Mozavaptane. Kidney T2 values and to a lesser degree ADC were found to be highly sensitive markers of early cystogenesis and superior to anatomical-based imaging parameters. Furthermore, kidney T2 values exhibited a nearly perfect correlation to the histological cystic index, allowing a clear separation of the two mouse genotypes. Additionally, kidney T2 values and ADC were able to monitor early treatment effects in the jck mouse model in a proof-of-principle experiment. Thus, given the superiority of kidney T2 values and ADC over anatomical-based imaging in mice, further studies are needed to evaluate the translational impact of these techniques in patients with PKD.

PMID: 28754558 [PubMed - as supplied by publisher]

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Manatee invariants reveal functional pathways in signaling networks.

BMC Syst Biol. 2017 Jul 28;11(1):72

Authors: Amstein L, Ackermann J, Scheidel J, Fulda S, Dikic I, Koch I

Abstract
BACKGROUND: Signal transduction pathways are important cellular processes to maintain the cell's integrity. Their imbalance can cause severe pathologies. As signal transduction pathways feature complex regulations, they form intertwined networks. Mathematical models aim to capture their regulatory logic and allow an unbiased analysis of robustness and vulnerability of the signaling network. Pathway detection is yet a challenge for the analysis of signaling networks in the field of systems biology. A rigorous mathematical formalism is lacking to identify all possible signal flows in a network model.
RESULTS: In this paper, we introduce the concept of Manatee invariants for the analysis of signal transduction networks. We present an algorithm for the characterization of the combinatorial diversity of signal flows, e.g., from signal reception to cellular response. We demonstrate the concept for a small model of the TNFR1-mediated NF- κB signaling pathway. Manatee invariants reveal all possible signal flows in the network. Further, we show the application of Manatee invariants for in silico knockout experiments. Here, we illustrate the biological relevance of the concept.
CONCLUSIONS: The proposed mathematical framework reveals the entire variety of signal flows in models of signaling systems, including cyclic regulations. Thereby, Manatee invariants allow for the analysis of robustness and vulnerability of signaling networks. The application to further analyses such as for in silico knockout was shown. The new framework of Manatee invariants contributes to an advanced examination of signaling systems.

PMID: 28754124 [PubMed - in process]

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A Janus tale of the two faces of corticosteroid therapy: A potential for adverse effects versus a steroid-sparing benefit of certain therapies.

Allergy Asthma Proc. 2016 Nov;37(6):423-425

Authors: Bellanti JA, Settipane RA

PMID: 27931295 [PubMed - indexed for MEDLINE]

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Captivity Shapes the Gut Microbiota of Andean Bears: Insights into Health Surveillance.

Front Microbiol. 2017;8:1316

Authors: Borbón-García A, Reyes A, Vives-Flórez M, Caballero S

Abstract
The Andean bear is an endemic species of the tropical Andes who has an almost exclusively plant-based diet. Since herbivorous mammals do not carry enzymes for fiber degradation, the establishment of symbiosis with cellulolytic microorganisms in their gastrointestinal (GI) tract is necessary to help them fulfill their nutritional needs. Furthermore, as described for other mammals, a stable, diverse, and balanced gut microbial composition is an indicator of a healthy status of the host; under disturbances this balance can be lost, leading to potential diseases of the host. The goal of this study was to describe the gut microbiota of wild and captive Andean bears and determine how habitat status influences the composition and diversity of the gut symbiotic community. Fecal samples from wild (n = 28) and captive (n = 8) Andean bears were collected in "Reserva Pantano de Martos" and "Fundación Bioandina", Colombia. Composition and diversity analyses were performed using amplicons from the V4 region of the 16S rDNA gene sequenced using the Ion PGM platform. PICRUSt algorithm was applied to predict the gene content of the gut microbiome of wild and captive Andean bears. A total of 5,411 and 838 OTUs were identified for wild and captive bears, respectively. Captive bears contained a lower number of bacterial phyla (n = 7) compared to wild individuals (n = 9). Proteobacteria (59.03%) and Firmicutes (14.03%) were the phyla that contributed the most to differences between wild and captive bears (overall dissimilarity = 87.72%). At family level, Enterobacteriaceae drove the main differences between the two groups (13.7%). PICRUSt metagenomics predictions suggested a similar pattern of relative abundance of gene families associated with the metabolism of carbohydrates across samples in wild individuals, despite the taxonomic differences of their gut microbiota. Captivity alters the availability and diversity of food resources, which likely reduces microbiota richness and diversity compared to wild individuals. Further considerations should be taken into account for nutritional schemes improving ex-situ conservation and its potential as a surveillance tool of endangered populations of wild Andean bears.

PMID: 28751883 [PubMed]