Microscopic heterogeneity in ulcerative colitis: implications for microscopic measurement of disease activity

Growing interest in histological measurements of inflammatory  activity to determine therapeutic efficacy and endpoints in IBD has been accompanied by progress in developing and validating scoring instruments for this purpose.1–5 Four histological grading instruments, the Geboes score, Nancy index, Robarts Histological Index (RHI) and modified Riley score, have recently demonstrated responsiveness to clinical changes based on data from a phase II trial of ozanimod.6 Further refinement of the operating characteristics of these instruments and definition of threshold values for remission can be expected.7

Less attention has been given to pre-analytical factors which might affect the histological assessment of disease activity and the definition of therapeutic endpoints, such as biopsy sampling density and target selection. Clinical consensus guidelines have thus far provided only empirical guidance. The European Crohn's and Colitis Organisation (ECCO) guidelines for initial IBD diagnosis recommend two...

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TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function

Objective

We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability.

Design

Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied.

Results

In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C- activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice.

Conclusion

The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.

http://bit.ly/2DVcJ2a

NKX2.2 immunohistochemistry in the distinction of Ewing sarcoma from cytomorphologic mimics: Diagnostic utility and pitfalls—Comment on Russell‐Goldman et al

http://bit.ly/2Gn1OzQ

Cancers, Vol. 11, Pages 186: Virus-Based Immunotherapy of Glioblastoma

Cancers, Vol. 11, Pages 186: Virus-Based Immunotherapy of Glioblastoma

Cancers doi: 10.3390/cancers11020186

Authors: Martikainen Essand

Glioblastoma (GBM) is the most common type of primary brain tumor in adults. Despite recent advances in cancer therapy, including the breakthrough of immunotherapy, the prognosis of GBM patients remains dismal. One of the new promising ways to therapeutically tackle the immunosuppressive GBM microenvironment is the use of engineered viruses that kill tumor cells via direct oncolysis and via stimulation of antitumor immune responses. In this review, we focus on recently published results of phase I/II clinical trials with different oncolytic viruses and the new interesting findings in preclinical models. From syngeneic preclinical GBM models, it seems evident that oncolytic virus-mediated destruction of GBM tissue coupled with strong adjuvant effect, provided by the robust stimulation of innate antiviral immune responses and adaptive anti-tumor T cell responses, can be harnessed as potent immunotherapy against GBM. Although clinical testing of oncolytic viruses against GBM is at an early stage, the promising results from these trials give hope for the effective treatment of GBM in the near future.

http://bit.ly/2RGh3WL

Cancers, Vol. 11, Pages 187: SOURCE: A Registry-Based Prediction Model for Overall Survival in Patients with Metastatic Oesophageal or Gastric Cancer

Cancers, Vol. 11, Pages 187: SOURCE: A Registry-Based Prediction Model for Overall Survival in Patients with Metastatic Oesophageal or Gastric Cancer

Cancers doi: 10.3390/cancers11020187

Authors: Héctor van den Boorn Ameen Abu-Hanna Emil ter Veer Jessy van Kleef Florian Lordick Michael Stahl Jaffer Ajani Rosine Guimbaud Se Park Susan Dutton Yung-Jue Bang Narikazu Boku Nadia Mohammad Mirjam Sprangers Rob Verhoeven Aeilko Zwinderman Martijn van Oijen Hanneke van Laarhoven

Prediction models are only sparsely available for metastatic oesophagogastric cancer. Because treatment in this setting is often preference-based, decision-making with the aid of a prediction model is wanted. The aim of this study is to construct a prediction model, called SOURCE, for the overall survival in patients with metastatic oesophagogastric cancer. Data from patients with metastatic oesophageal (n = 8010) or gastric (n = 4763) cancer diagnosed during 2005–2015 were retrieved from the nationwide Netherlands cancer registry. A multivariate Cox regression model was created to predict overall survival for various treatments. Predictor selection was performed via the Akaike Information Criterion and a Delphi consensus among experts in palliative oesophagogastric cancer. Validation was performed according to a temporal internal-external scheme. The predictive quality was assessed with the concordance-index (c-index) and calibration. The model c-indices showed consistent discriminative ability during validation: 0.71 for oesophageal cancer and 0.68 for gastric cancer. The calibration showed an average slope of 1.0 and intercept of 0.0 for both tumour locations, indicating a close agreement between predicted and observed survival. With a fair c-index and good calibration, SOURCE provides a solid foundation for further investigation in clinical practice to determine its added value in shared decision making.

http://bit.ly/2WL5bGS

Cancers, Vol. 11, Pages 185: In Vivo Cell Fusion between Mesenchymal Stroma/Stem-Like Cells and Breast Cancer Cells

Cancers, Vol. 11, Pages 185: In Vivo Cell Fusion between Mesenchymal Stroma/Stem-Like Cells and Breast Cancer Cells

Cancers doi: 10.3390/cancers11020185

Authors: Melzer von der Ohe Hass

Cellular communication within the tumor microenvironment enables important interactions between cancer cells and recruited adjacent populations including mesenchymal stroma/stem-like cells (MSC). These interactions were monitored in vivo following co-injection of GFP-labeled human MSC together with mcherry-labeled MDA-MB-231 breast cancer cells in NODscid mice. Within 14 days of tumor development the number of initially co-injected MSC had significantly declined and spontaneous formation of breast cancer/MSC hybrid cells was observed by the appearance of double fluorescing cells. This in vivo fusion displayed a rare event and occurred in less than 0.5% of the tumor cell population. Similar findings were observed in a parallel in vitro co-culture. Characterization of the new cell fusion products obtained after two consecutive flow cytometry cell sorting and single cell cloning revealed two populations, termed MDA-hyb3 and MDA-hyb4. The breast cancer fusion cells expressed both, GFP and mcherry and displayed more characteristics of the MDA-MB-231 cells than of the parental MSC. While little if any differences were determined in the proliferative capacity, a significant delay of MDA-hyb3 cells in tumor formation was observed when compared to the parental MDA-MB-231 cells. Moreover, MDA-hyb3 cells developed an altered pattern of distant organ metastases. These findings demonstrated dynamic tumor changes by in vivo and in vitro fusion with the development of new breast cancer hybrid cells carrying altered tumorigenic properties. Consequently, cancer cell fusion contributes to progressively increasing tumor heterogeneity which complicates a therapeutic regimen.

http://bit.ly/2RIEJdf

Cancers, Vol. 11, Pages 184: The Diverse Consequences of FOXC1 Deregulation in Cancer

Cancers, Vol. 11, Pages 184: The Diverse Consequences of FOXC1 Deregulation in Cancer

Cancers doi: 10.3390/cancers11020184

Authors: Gilding Somervaille

Forkhead box C1 (FOXC1) is a transcription factor with essential roles in mesenchymal lineage specification and organ development during normal embryogenesis. In keeping with these developmental properties, mutations that impair the activity of FOXC1 result in the heritable Axenfeld-Rieger Syndrome and other congenital disorders. Crucially, gain of FOXC1 function is emerging as a recurrent feature of malignancy; FOXC1 overexpression is now documented in more than 16 cancer types, often in association with an unfavorable prognosis. This review explores current evidence for FOXC1 deregulation in cancer and the putative mechanisms by which FOXC1 confers its oncogenic effects.

http://bit.ly/2WLs9xB