Citation: Dieckow J, Brandt W, Hattermann K, et al. CXCR4 and CXCR7 mediate TFF3-induced cell migration independently from the ERK1/2 signaling pathway. Invest Ophthalmol Vis Sci. 2016;57:56-65. DOI:10.1167/ iovs.15-18129 PURPOSE. Trefoil factor family (TFF) peptides, and in particular TFF3, are characteristic secretory products of mucous epithelia that promote antiapoptosis, epithelial migration, restitution, and wound healing. For a long time, a receptor for TFF3 had not yet been identified. However, the chemokine receptor CXCR4 has been described as a low affinity receptor for TFF2. Additionally, CXCR7, which is able to heterodimerize with CXCR4, has also been discussed as a potential TFF2 receptor. Since there are distinct structural similarities between the three known TFF peptides, this study evaluated whether CXCR4 and CXCR7 may also act as putative TFF3 receptors. METHODS.We evaluated the expression of both CXCR4 and CXCR7 in samples of human ocular surface tissues and cell lines, using RT-PCR, immunohistochemistry, and Western blot analysis. Furthermore, we studied possible binding interactions between TFF3 and the receptor proteins in an x-ray structure-based modeling system. Functional studies of TFF3-CXCR4/CXCR7 interaction were accomplished by cell culture-based migration assays, flow cytometry, and evaluation of activation of the mitogen-activated protein (MAP) kinase signaling cascade. RESULTS.We detected both receptors at mRNA and protein level in all analyzed ocular surface tissues, and in lesser amount in ocular surface cell lines. X-ray structure-based modeling revealed CXCR4 and CXCR7 dimers as possible binding partners to TFF3. Cell culture-based assays revealed enhanced cell migration under TFF3 stimulation in a conjunctival epithelial cell line, which was completely suppressed by blocking CXCR4 and/or CXCR7. Flow cytometry showed increased proliferation rates after TFF3 treatment, while blocking both receptors had no effect on this increase. Trefoil factor family 3 also activated the MAP kinase signaling cascade independently from receptor activity.CONCLUSIONS. Dimers CXCR4 and CXCR7 are involved in TFF3-dependent activation of cell migration, but not cell proliferation. The ERK1/2 pathway is activated in the process, but not influenced by CXCR4 or CXCR7. These results implicate a dependence of TFF3 activity as to cell migration on the chemokine receptors CXCR4 and CXCR7 at the ocular surface.

Summary Background Loss of skeletal muscle mass is a recognised complication with a prognostic impact in patients with cirrhosis. Aim To explore in a retrospective analysis which muscle compartment most reliably predicts the occurrence of cirrhosis‐associated complications and if there are gender‐related differences. Methods 795 patients with cirrhosis listed for liver transplantation between 2001 and 2014 met the inclusion and exclusion criteria including an abdominal CT scan (±200). Controls were 109 patients who underwent a CT scan after polytrauma. The paraspinal muscles index (PSMI), the abdominal wall muscles index (AWMI) and its combination skeletal muscle index (SMI) were assessed at L3/L4, normalised to the height (cm2/m2). Results 62.0% of patients with cirrhosis had alcoholic liver disease, and 70.6% were male. As compared to controls, a reduction in PSMI and SMI but not AWMI was associated with high model of end‐stage liver disease (MELD) score, high Child‐Pugh class, and the presence or history of cirrhosis‐associated complications in males but not females. PSMI independently predicted the occurrence of bacterial infections (HR 0.932), spontaneous bacterial peritonitis (HR 0.901), hepatic encephalopathy (HR 0.961), and hepatorenal syndrome (HR 0.946) by multivariate Cox regression analysis in a gender‐independent manner. Post‐transplant survival was not associated with the PSMI; neither AWMI nor SMI predicted any clinical endpoints. Conclusions This study links muscle wasting in patients with cirrhosis predominantly to males. However, the presence of a low PSMI mass is a gender‐independent predictor of developing cirrhosis‐associated complications and death. Scores combining the MELD with muscle parameters should be re‐validated by utilizing the PSMI.

Our purpose was to analyze associations between positron emission tomography (PET), diffusion weighted imaging (DWI), and dynamic contrast-enhanced (DCE) imaging in patients with head and neck squamous cell carcinoma (HNSCC). The study involved 34 patients (9 women, 25 men, mean age: 56.7 ± 10.2 years). In all patients a simultaneous 18F-FDG-PET/MR was performed. DWI was obtained by using of an axial EPI sequence. Minimal ADC values (ADCmin), mean ADC values (ADCmean), and maximal ADC values (ADCmax) were estimated. DCE MRI was performed by using dynamic T1w DCE sequence. The following parameters were estimated: Ktrans, Ve, and Kep. Spearman's correlation coefficient was used to analyze associations between investigated parameters. In overall sample, ADCmean correlated significantly with Ve and Ktrans, ADCmin correlated with Ve, and ADCmax correlated with Ktrans and Ve. SUVmean tended to correlate slightly with Ktrans. In G1/2 tumors, only Ktrans correlated well with ADCmax and SUVmean. In G3 tumors, Ktrans correlated well with Kep and Ve. Ve showed significant correlations with ADCmean and ADCmax. Ktrans correlated with ADCmax. Kep was higher in cancers with N2/3 stages. Tumor metabolism, water diffusion, and tumor perfusion have complex relationships in HNSCC. Furthermore, these associations depend on tumor grading. Kep may predict lymphonodal metastasizing.

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ADC histogram profiling provides a distinct set of parameters, which help differentiate low-grade versus high-grade meningiomas. Also, histogram metrics correlate significantly with histological surrogates of the respective proliferative potential. More specifically, entropy revealed to be the most promising imaging biomarker for presurgical grading. Both, entropy and skewness were significantly associated with progesterone receptor status and Ki-67 expression and therefore should be investigated further as predictors for prognostically relevant tumor biological features. Since absolute ADC values vary between MRI scanners of different vendors and field strengths, their use is more limited in the presurgical setting.