Documents published in Scipedia

• “Universal Flu Vaccine”: Can NK Cell-mediated ADCC Tip the Scales?

  M. Hassane, C. Paget

  Collection of EBioMedicine (2017).

  
  

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• Gap Junctions and Epileptogenesis: No Laughing Matter

  E. Gazzerro, P. Striano

  Collection of EBioMedicine (2017).

  
  

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• Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer

  T. Friedrich, M. Söhn, T. Gutting, K. Janssen, H. Behrens, C. Röcken, M. Ebert, E. Burgermeister

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p = 0.001, n = 1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments.

  Abstract
  Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human [...]

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• Tissue Microbiome Profiling Identifies an Enrichment of Specific Enteric Bacteria in Opisthorchis viverrini Associated Cholangiocarcinoma

  K. Chng, S. Chan, A. Ng, C. Li, A. Jusakul, D. Bertrand, A. Wilm, S. Choo, D. Tan, K. Lim, R. Soetinko, C. Ong, D. Duda, S. Dima, I. Popescu, C. Wongkham, Z. Feng, K. Yeoh, B. Teh, P. Yongvanit, S. Wongkham, V. Bhudhisawasdi, N. Khuntikeo, P. Tan, C. Pairojkul, J. Ngeow, N. Nagarajan

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Cholangiocarcinoma (CCA) is the primary cancer of the bile duct system. The role of bile duct tissue microbiomes in CCA tumorigenesis is unestablished. To address this, sixty primary CCA tumors and matched normals, from both liver fluke (Opisthorchis viverrini ) associated (OVa, n = 28) and non-O. viverrini associated (non-OVa, n = 32) cancers, were profiled using high-throughput 16S rRNA sequencing. A distinct, tissue-specific microbiome dominated by the bacterial families Dietziaceae, Pseudomonadaceae and Oxalobacteraceae was observed in bile duct tissues. Systemic perturbation of the microbiome was noted in tumor and paired normal samples (vs non-cancer normals) for several bacterial families with a significant increase in Stenotrophomonas species distinguishing tumors vs paired normals. Comparison of parasite associated (OVa) vs non-associated (non-OVa) groups identified enrichment for specific enteric bacteria (Bifidobacteriaceae, Enterobacteriaceae and Enterococcaceae ). One of the enriched families, Bifidobacteriaceae, was found to be dominant in the O. viverrini microbiome, providing a mechanistic link to the parasite. Functional analysis and comparison of CCA microbiomes revealed higher potential for producing bile acids and ammonia in OVa tissues, linking the altered microbiota to carcinogenesis. These results define how the unique microbial communities resident in the bile duct, parasitic infections and the tissue microenvironment can influence each other, and contribute to cancer.

  Abstract
  Cholangiocarcinoma (CCA) is the primary cancer of the bile duct system. The role of bile duct tissue microbiomes in CCA tumorigenesis is unestablished. To address this, sixty [...]

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• Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production

  C. Brégnard, J. Guerra, S. Déjardin, F. Passalacqua, M. Benkirane, N. Laguette

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4FANCP deficiency as a working model, we questioned the trigger for chronic inflammation in FA. We found that absence of SLX4 caused cytoplasmic DNA accumulation, including sequences deriving from active Long INterspersed Element-1 (LINE-1), triggering the cGAS-STING pathway to elicit interferon (IFN) expression. In agreement, absence of SLX4 leads to upregulated LINE-1 retrotransposition. Importantly, similar results were obtained with the FANCD2 upstream activator of SLX4. Furthermore, treatment of FA cells with the Tenofovir reverse transcriptase inhibitor (RTi), that prevents endogenous retrotransposition, decreased both accumulation of cytoplasmic DNA and pro-inflammatory signaling. Collectively, our data suggest a contribution of endogenous RT activities to the generation of immunogenic cytoplasmic nucleic acids responsible for inflammation in FA. The additional observation that RTi decreased pro-inflammatory cytokine production induced by DNA replication stress-inducing drugs further demonstrates the contribution of endogenous RTs to sustaining chronic inflammation. Altogether, our data open perspectives in the prevention of adverse effects of chronic inflammation in tumorigenesis.

  Abstract
  Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4FANCP deficiency as a working [...]

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• Cognitive Enhancement in Infants Associated with Increased Maternal Fruit Intake During Pregnancy: Results from a Birth Cohort Study with Validation in an Animal Model

  F. Bolduc, A. Lau, C. Rosenfelt, S. Langer, N. Wang, L. Smithson, D. Lefebvre, R. Alexander, C. Dickson, A. Li, A. Becker, P. Subbarao, S. Turvey, J. Pei, M. Sears, P. Mandhane

  Collection of EBioMedicine (2017).

  
  

  Abstract

  In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton sub-cohort subjects, 688 (85%) had 1-year cognitive outcome data. We found that each maternal daily serving of fruit (sum of fruit plus 100% fruit juice) consumed during pregnancy was associated with a 2.38 point increase in 1-year cognitive development (95% CI 0.39, 4.37, p < 0.05). Consistent with this, we found 30% higher learning Performance index (PI) scores in Drosophila offspring from parents who consumed 30% fruit juice supplementation prenatally (PI: 85.7, SE 1.8, p < 0.05) compared to the offspring of standard diet parents (PI: 65.0 SE 3.4). Using the Drosophila model, we also show that the cyclic adenylate monophosphate (cAMP) pathway may be a major regulator of this effect, as prenatal fruit associated cognitive enhancement was blocked in Drosophila rutabaga mutants with reduced Ca2 + -Calmodulin-dependent adenylyl cyclase. Moreover, gestation is a critical time for this effect as postnatal fruit intake did not enhance cognitive performance in either humans or Drosophila . Our study supports increased fruit consumption during pregnancy with significant increases in infant cognitive performance. Validation in Drosophila helps control for potential participant bias or unmeasured confounders.

  Abstract
  In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton [...]

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• Non-specific Effects of Vaccines and Stunting: Timing May Be Essential

  M. Berendsen, J. Smits, M. Netea, A. Ven

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Bacillus Calmette-Guérin (BCG) vaccination possesses effects on health beyond its target disease, the so called “non-specific effects”. We evaluate these effects, as well as the effect of timing of BCG and other vaccinations, on stunting in Sub-Saharan African (SSA) children under five. We use a Big Data design, including cross-sectional data for 368, 450 children from 33 SSA countries. Logistic regression analysis is used with control factors at child, mother, household and context level. Overall, BCG vaccination did not affect stunting in SSA children (OR 1.00 [0.98–1.03]). Timing of BCG vaccination was of importance (βtime = 0.067 [0.061–0.073]): compared to unvaccinated children, BCG was associated with lower odds on stunting for children vaccinated early in life (OR 0.92 [0.89–0.94]) and higher odds for children vaccinated later in infancy (OR 1.64 [1.53–1.76]). Similar findings were done for diphtheria-tetanus-pertussis (DTP)1 and measles vaccination, and when hemoglobin concentration was used as outcome variable. We found a general time-dependent pattern of non-specific effects of vaccination, with positive associations for vaccinations given early in life and negative associations for vaccinations given later in infancy. If confirmed in further research, our findings may provide a new perspective on the non-specific effects of vaccination.

  Abstract
  Bacillus Calmette-Guérin (BCG) vaccination possesses effects on health beyond its target disease, the so called “non-specific effects”. We evaluate these effects, as [...]

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• Nanobodies as Versatile Tools to Understand, Diagnose, Visualize and Treat Cancer

  I. Audenhove, J. Gettemans

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Since their discovery, nanobodies have been used extensively in the fields of research, diagnostics and therapy. These antigen binding fragments, originating from Camelid heavy-chain antibodies, possess unusual hallmarks in terms of (small) size, stability, solubility and specificity, hence allowing cost-effective production and sometimes outperforming monoclonal antibodies. In this review, we evaluate the current status of nanobodies to study, diagnose, visualize or inhibit cancer-specific proteins and processes. Nanobodies are highly adaptable tools for cancer research as they enable specific modulation of targets, enzymatic and non-enzymatic proteins alike. Molecular imaging studies benefit from the rapid, homogeneous tumor accumulation of nanobodies and their fast blood clearance, permitting previously unattainable fast tumor visualization. Moreover, they are endowed with considerable therapeutic potential as inhibitors of receptor-ligand pairs and deliverers of drugs or drug-loaded nanoparticles towards tumors. More in vivo and clinical studies are however eagerly awaited to unleash their full potential.

  Abstract
  Since their discovery, nanobodies have been used extensively in the fields of research, diagnostics and therapy. These antigen binding fragments, originating from Camelid [...]

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• Leaving History Behind: CD4/CD8 Ratio as a Diagnostic Tool in Sarcoidosis

  W. James

  Collection of EBioMedicine (2017).

  
  

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• Gut Bacteria Metabolism Impacts Immune Recovery in HIV-infected Individuals

  S. Serrano-Villar, D. Rojo, M. Martínez-Martínez, S. Deusch, J. Vázquez-Castellanos, R. Bargiela, T. Sainz, M. Vera, S. Moreno, V. Estrada, M. Gosalbes, A. Latorre, J. Seifert, C. Barbas, A. Moya, M. Ferrer

  Collection of EBioMedicine (2017).

  
  

  Abstract

  While changes in gut microbial populations have been described in human immuno-deficiency virus (HIV)-infected patients undergoing antiretroviral therapy (ART), the mechanisms underlying the contributions of gut bacteria and their molecular agents (metabolites and proteins) to immune recovery remain unexplored. To study this, we examined the active fraction of the gut microbiome, through examining protein synthesis and accumulation of metabolites inside gut bacteria and in the bloodstream, in 8 healthy controls and 29 HIV-infected individuals (6 being longitudinally studied). We found that HIV infection is associated to dramatic changes in the active set of gut bacteria simultaneously altering the metabolic outcomes. Effects were accentuated among immunological ART responders, regardless diet, subject characteristics, clinical variables other than immune recovery, the duration and type of ART and sexual preferences. The effect was found at quantitative levels of several molecular agents and active bacteria which were herein identified and whose abundance correlated with HIV immune pathogenesis markers. Although, we cannot rule out the possibility that some changes are partially a random consequence of the disease status, our data suggest that most likely reduced inflammation and immune recovery is a joint solution orchestrated by both the active fraction of the gut microbiota and the host.

  Abstract
  While changes in gut microbial populations have been described in human immuno-deficiency virus (HIV)-infected patients undergoing antiretroviral therapy (ART), the mechanisms [...]

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