Description: A randomized comparison of a commercially available portion-controlled weight-loss intervention with a diabetes self-management education program Nutrition & Diabetes 3, e63 (March 2013). doi:10.1038/nutd.2013.3 Authors: G D Foster, T A Wadden, C A LaGrotte, S S Vander Veur, L A Hesson, C J Homko, B J Maschak-Carey, N R Barbor, B Bailer, L Diewald, E Komaroff, S J Herring & M L Vetter

Description: EMBO Reports 14, 465 (2013). doi:10.1038/embor.2013.37 Authors: Denise Wätzlich, Ingrid Vetter, Katja Gotthardt, Mandy Miertzschke, Yong-Xiang Chen, Alfred Wittinghofer & Shehab Ismail Defects in primary cilia result in human diseases known as ciliopathies. The retinitis pigmentosa GTPase regulator (RPGR), mutated in the most severe form of the eye disease, is located at the transition zone of the ciliary organelle. The RPGR-interacting partner PDEδ is involved in trafficking

Description: Currently, major limitations for the clinical application of adenovirus-mediated gene therapy are high prevalence of neutralizing antibodies, widespread expression of the coxsackie-adenovirus receptor (CAR), and adenovirus sequestration by the liver. In the current study, we used the sodium iodide symporter (NIS) as a theranostic gene to investigate whether coating of adenovirus with synthetic dendrimers could be useful to overcome these hurdles in order to develop adenoviral vectors for combination of systemic oncolytic virotherapy and NIS-mediated radiotherapy. Methods: We coated replication-deficient (Ad5-CMV/NIS) (CMV is cytomegalovirus) and replication-selective (Ad5-E1/AFP-E3/NIS) adenovirus serotype 5 carrying the h NIS gene with poly(amidoamine) dendrimers generation 5 (PAMAM-G5) in order to investigate transduction efficacy and altered tropism of these coated virus particles by 123 I scintigraphy and to evaluate their therapeutic potential for systemic radiovirotherapy in a liver cancer xenograft mouse model. Results: After dendrimer coating, Ad5-CMV/NIS demonstrated partial protection from neutralizing antibodies and enhanced transduction efficacy in CAR-negative cells in vitro. In vivo 123 I scintigraphy of nude mice revealed significantly reduced levels of hepatic transgene expression after intravenous injection of dendrimer-coated Ad5-CMV/NIS (dcAd5-CMV/NIS). Evasion from liver accumulation resulted in significantly reduced liver toxicity and increased transduction efficiency of dcAd5-CMV/NIS in hepatoma xenografts. After PAMAM-G5 coating of the replication-selective Ad5-E1/AFP-E3/NIS, a significantly enhanced oncolytic effect was observed after intravenous application (virotherapy) that was further increased by additional treatment with a therapeutic dose of 131 I (radiovirotherapy) and was associated with markedly improved survival. Conclusion: These results demonstrate efficient liver detargeting and tumor retargeting of adenoviral vectors after coating with synthetic dendrimers, thereby representing a promising innovative strategy for systemic NIS gene therapy. Moreover, our study—based on the function of NIS as a theranostic gene allowing the noninvasive imaging of NIS expression by 123 I scintigraphy—provides detailed characterization of in vivo vector biodistribution and localization, level, and duration of transgene expression, essential prerequisites for exact planning and monitoring of clinical gene therapy trials that aim to individualize the NIS gene therapy concept.

Description: We evaluated the impact of staging procedures to detect asymptomatic distant metastases (DM) in the management of women with operable invasive breast cancer (BC, entire cohort: n = 866). Out of 472 patients with lymph node (LN)-negative disease (pN0), DM were found in four cases (detection rate: 0.8%). All four patients presented with established risk factors: hormone receptor (HR)-negative status, HER2-positive status, n = 3; ‘triple-negative’ disease, n = 1. Considering the subgroup of LN-negative patients whose tumors showed the risk factor ‘negative HR status’ ( n = 66), the detection rate of DM was 6%. The detection rates of DM in higher pN categories were as follows: pN1:1.7%; pN2:9.5%; pN3:13.5%. We generally support the international guidelines, including those published by the European Society for Medical Oncology (ESMO) which emphasize that patients with early-stage BC do not profit from radiological staging for the detection of DM and recommend refraining from this. However, we would expand these guidelines and propose that screening should be carried out in node-negative patients whose tumors show established tumor-related risk factors (e.g. HR-negative and HER2-positive status), since in this particular subcohort, the detection rate of DM is with 6% similarly high as that of patients with four to nine positive LNs.

Description: EMBO Reports 14, 199 (2013). doi:10.1038/embor.2012.211 Authors: Emerich Mihai Gazdag, Alexandra Streller, Ina Haneburger, Hubert Hilbi, Ingrid R Vetter, Roger S Goody & Aymelt Itzen

Description: Using an in vivo cycling strategy, we selected metastatic cancer cells from the lymph nodes (LN) of mice bearing orthotopic DU145 human prostate tumors. Repeated rounds of metastatic selection (LN1–LN4) progressively increased the epithelial phenotype, resulting in a new model of tumor cell mesenchymal-epithelial transition (MET). DU145-LN4 showed increased cell-cell adhesions, higher expression of multiple epithelial markers, such as E-cadherin, EpCAM and cytokeratin 18, and reduced expression of mesenchymal markers such as vimentin. The MET in DU145-LN4 cells was accompanied by increased expression of the miR-200 family, and antimiRs to miR-200c and miR-141 induced an EMT. MET also correlated with the loss of miR-424. Ectopic transient and stable miR-424 expression induced EMT, with reduced epithelial marker expression and increased cell scattering. Our model provides evidence for spontaneous MET in vivo. We show that this cellular plasticity can be mediated through the combined action of miR-424 and the miR-200 family. Scientific Reports 3 doi: 10.1038/srep03151

Description: GSK3β phosphorylation of the KLF6 tumor suppressor promotes its transactivation of p21 Oncogene 32, 4557 (19 September 2013). doi:10.1038/onc.2012.457 Authors: U E Lang, P Kocabayoglu, G Z Cheng, Z Ghiassi-Nejad, U Muñoz, D Vetter, D A Eckstein, R A Hannivoort, M J Walsh & S L Friedman