@article{MoenchGrimmigKannenetal.2016, author = {Moench, Romana and Grimmig, Tanja and Kannen, Vinicius and Tripathi, Sudipta and Faber, Marc and Moll, Eva-Maria and Chandraker, Anil and Lissner, Reinhard and Germer, Christoph-Thomas and Waaga-Gasser, Ana Maria and Gasser, Martin}, title = {Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {42}, doi = {10.18632/oncotarget.11899}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176910}, pages = {68749-68767}, year = {2016}, abstract = {Platelet-derived growth factor (PDGF) and signaling via its receptors plays a crucial role in tumor cell proliferation and thus may represent an attractive target besides VEGF/EGFR-based antibody therapies. In this study we analyzed the influence of PDGF in colorectal cancer. PDGF was expressed intensively in early and even more intensively in late stage primary CRCs. Like VEGF, PDGF enhanced human colon cancer proliferation, and increased oxidative glycolytic activity, and activated HIF1α and c-Myc in vitro. PDGF activated the PI3K/Akt/mTOR pathway while leaving MAPK signaling untouched. Further dissection showed that inhibition of Akt strongly impeded cancer cell growth while inhibition of PI3K did not. MAPK analysis suggested an inhibitory crosstalk between both pathways, thus explaining the different effects of the Akt and PI3K inhibitors on cancer cell proliferation. PDGF stimulates colon cancer cell proliferation, and prevents inhibitor induced apoptosis, resulting in tumor growth. Therefore inhibition of PDGF signaling seems to be a promising target in colorectal cancer therapy. However, due to the multifaceted nature of the intracellular PDGF signaling, careful intervention strategies are needed when looking into specific signaling pathways like PI3K/Akt/mTOR and MAPK.}, language = {en} } @article{MarxSchindlerMoschetal.2016, author = {Marx, Gernot and Schindler, Achim W. and Mosch, Christoph and Albers, Joerg and Bauer, Michael and Gnass, Irmela and Hobohm, Carsten and Janssens, Uwe and Kluge, Stefan and Kranke, Peter and Maurer, Tobias and Merz, Waltraut and Neugebauer, Edmund and Quintel, Michael and Senninger, Norbert and Trampisch, Hans-Joachim and Waydhas, Christian and Wildenauer, Rene and Zacharowski, Kai and Eikermann, Michaela}, title = {Intravascular volume therapy in adults guidelines from the association of the scientific medical societies in Germany}, series = {European Journal of Anaesthesiology}, volume = {33}, journal = {European Journal of Anaesthesiology}, number = {7}, doi = {10.1097/EJA.0000000000000447}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188223}, pages = {488-521}, year = {2016}, abstract = {No abstract available.}, language = {en} } @article{NietzerBaurSieberetal.2016, author = {Nietzer, Sarah and Baur, Florentin and Sieber, Stefan and Hansmann, Jan and Schwarz, Thomas and Stoffer, Carolin and H{\"a}fner, Heide and Gasser, Martin and Waaga-Gasser, Ana Maria and Walles, Heike and Dandekar, Gudrun}, title = {Mimicking metastases including tumor stroma: a new technique to generate a three-dimensional colorectal cancer model based on a biological decellularized intestinal scaffold}, series = {Tissue Engineering Part C-Methods}, volume = {22}, journal = {Tissue Engineering Part C-Methods}, number = {7}, doi = {10.1089/ten.tec.2015.0557}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188202}, pages = {621-635}, year = {2016}, abstract = {Tumor models based on cancer cell lines cultured two-dimensionally (2D) on plastic lack histological complexity and functionality compared to the native microenvironment. Xenogenic mouse tumor models display higher complexity but often do not predict human drug responses accurately due to species-specific differences. We present here a three-dimensional (3D) in vitro colon cancer model based on a biological scaffold derived from decellularized porcine jejunum (small intestine submucosa+mucosa, SISmuc). Two different cell lines were used in monoculture or in coculture with primary fibroblasts. After 14 days of culture, we demonstrated a close contact of human Caco2 colon cancer cells with the preserved basement membrane on an ultrastructural level as well as morphological characteristics of a well-differentiated epithelium. To generate a tissue-engineered tumor model, we chose human SW480 colon cancer cells, a reportedly malignant cell line. Malignant characteristics were confirmed in 2D cell culture: SW480 cells showed higher vimentin and lower E-cadherin expression than Caco2 cells. In contrast to Caco2, SW480 cells displayed cancerous characteristics such as delocalized E-cadherin and nuclear location of beta-catenin in a subset of cells. One central drawback of 2D cultures-especially in consideration of drug testing-is their artificially high proliferation. In our 3D tissue-engineered tumor model, both cell lines showed decreased numbers of proliferating cells, thus correlating more precisely with observations of primary colon cancer in all stages (UICC I-IV). Moreover, vimentin decreased in SW480 colon cancer cells, indicating a mesenchymal to epithelial transition process, attributed to metastasis formation. Only SW480 cells cocultured with fibroblasts induced the formation of tumor-like aggregates surrounded by fibroblasts, whereas in Caco2 cocultures, a separate Caco2 cell layer was formed separated from the fibroblast compartment beneath. To foster tissue generation, a bioreactor was constructed for dynamic culture approaches. This induced a close tissue-like association of cultured tumor cells with fibroblasts reflecting tumor biopsies. Therapy with 5-fluorouracil (5-FU) was effective only in 3D coculture. In conclusion, our 3D tumor model reflects human tissue-related tumor characteristics, including lower tumor cell proliferation. It is now available for drug testing in metastatic context-especially for substances targeting tumor-stroma interactions.}, language = {en} } @article{KlementChampOttoetal.2016, author = {Klement, Rainer J. and Champ, Colin E. and Otto, Christoph and K{\"a}mmerer, Ulrike}, title = {Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0155050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167036}, pages = {e0155050}, year = {2016}, abstract = {Background Currently ketogenic diets (KDs) are hyped as an anti-tumor intervention aimed at exploiting the metabolic abnormalities of cancer cells. However, while data in humans is sparse, translation of murine tumor models to the clinic is further hampered by small sample sizes, heterogeneous settings and mixed results concerning tumor growth retardation. The aim was therefore to synthesize the evidence for a growth inhibiting effect of KDs when used as a monotherapy in mice. Methods We conducted a Bayesian random effects meta-analysis on all studies assessing the survival (defined as the time to reach a pre-defined endpoint such as tumor volume) of mice on an unrestricted KD compared to a high carbohydrate standard diet (SD). For 12 studies meeting the inclusion criteria either a mean survival time ratio (MR) or hazard ratio (HR) between the KD and SD groups could be obtained. The posterior estimates for the MR and HR averaged over four priors on the between-study heterogeneity τ\(^{2}\) were MR = 0.85 (95\% highest posterior density interval (HPDI) = [0.73, 0.97]) and HR = 0.55 (95\% HPDI = [0.26, 0.87]), indicating a significant overall benefit of the KD in terms of prolonged mean survival times and reduced hazard rate. All studies that used a brain tumor model also chose a late starting point for the KD (at least one day after tumor initiation) which accounted for 26\% of the heterogeneity. In this subgroup the KD was less effective (MR = 0.89, 95\% HPDI = [0.76, 1.04]). Conclusions There was an overall tumor growth delaying effect of unrestricted KDs in mice. Future experiments should aim at differentiating the effects of KD timing versus tumor location, since external evidence is currently consistent with an influence of both of these factors.}, language = {en} } @article{GrimmigMoenchKreckeletal.2016, author = {Grimmig, Tanja and Moench, Romana and Kreckel, Jennifer and Haack, Stephanie and Rueckert, Felix and Rehder, Roberta and Tripathi, Sudipta and Ribas, Carmen and Chandraker, Anil and Germer, Christoph T. and Gasser, Martin and Waaga-Gasser, Ana Maria}, title = {Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer}, series = {International Journal of Molecular Sciences}, volume = {17}, journal = {International Journal of Molecular Sciences}, number = {12}, doi = {10.3390/ijms17122060}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165743}, pages = {2060}, year = {2016}, abstract = {Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer.}, language = {en} } @article{KrajinovicReimerKudlichetal.2016, author = {Krajinovic, K. and Reimer, S. and Kudlich, T. and Germer, C. T. and Wiegering, A.}, title = {"Rendezvous technique" for intraluminal vacuum therapy of anastomotic leakage of the jejunum}, series = {Surgical Case Reports}, volume = {2}, journal = {Surgical Case Reports}, number = {114}, doi = {10.1186/s40792-016-0243-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147883}, year = {2016}, abstract = {Background Anastomotic leakage (AL) is one of the most common and serious complications following visceral surgery. In recent years, endoluminal vacuum therapy has dramatically changed therapeutic options for AL, but its use has been limited to areas easily accessible by endoscope. Case presentation We describe the first use of endoluminal vacuum therapy in the small intestine employing a combined surgical and endoscopic "rendezvous technique" in which the surgeon assists the endoscopic placement of an endoluminal vacuum therapy sponge in the jejunum by means of a pullback string. This technique led to a completely closed AL after 27 days and 7 changes of the endosponge. Conclusion The combined surgical and endoscopic rendezvous technique can be useful in cases of otherwise difficult endosponge placement.}, language = {en} } @article{BuschHoffjanBergmannetal.2016, author = {Busch, Albert and Hoffjan, Sabine and Bergmann, Frauke and Hartung, Birgit and Jung, Helena and Hanel, Daniela and Tzschach, Andeas and Kadar, Janos and von Kodolitsch, Yskert and Germer, Christoph-Thomas and Trobisch, Heiner and Strasser, Erwin and Wildenauer, Ren{\´e}}, title = {Vascular type Ehlers-Danlos syndrome is associated with platelet dysfunction and low vitamin D serum concentration}, series = {Orphanet Journal of Rare Diseases}, volume = {11}, journal = {Orphanet Journal of Rare Diseases}, number = {111}, doi = {10.1186/s13023-016-0491-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147757}, year = {2016}, abstract = {Background The vascular type represents a very rare, yet the clinically most fatal entity of Ehlers-Danlos syndrome (EDS). Patients are often admitted due to arterial bleedings and the friable tissue and the altered coagulation contribute to the challenge in treatment strategies. Until now there is little information about clotting characteristics that might influence hemostasis decisively and eventually worsen emergency situations. Results 22 vascular type EDS patients were studied for hemoglobin, platelet volume and count, Quick and activated partial thromboplastin time, fibrinogen, factor XIII, von Willebrand disease, vitamin D and platelet aggregation by modern standard laboratory methods. Results show a high prevalence of over 50 \% for platelet aggregation disorders in vascular type EDS patients, especially for collagen and epinephrine induced tests, whereas the plasmatic cascade did not show any alterations. Additionally, more than half of the tested subjects showed low vitamin D serum levels, which might additionally affect vascular wall integrity. Conclusion The presented data underline the importance of detailed laboratory screening methods in vascular type EDS patients in order to allow for targeted application of platelet-interacting substances that might be of decisive benefit in the emergency setting.}, language = {en} } @article{LichthardtKerscherDietzetal.2016, author = {Lichthardt, Sven and Kerscher, Alexander and Dietz, Ulrich A. and Jurowich, Christian and Kunzmann, Volker and von Rahden, Burkhard H. A. and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Original article: role of adjuvant chemotherapy in a perioperative chemotherapy regimen for gastric cancer}, series = {BMC Cancer}, volume = {16}, journal = {BMC Cancer}, number = {650}, doi = {10.1186/s12885-016-2708-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147743}, year = {2016}, abstract = {Background Multimodal treatment strategies - perioperative chemotherapy (CTx) and radical surgery - are currently accepted as treatment standard for locally advanced gastric cancer. However, the role of adjuvant postoperative CTx (postCTx) in addition to neoadjuvant preoperative CTx (preCTx) in this setting remains controversial. Methods Between 4/2006 and 12/2013, 116 patients with locally advanced gastric cancer were treated with preCTx. 72 patients (62 \%), in whom complete tumor resection (R0, subtotal/total gastrectomy with D2-lymphadenectomy) was achieved, were divided into two groups, one of which receiving adjuvant therapy (n = 52) and one without (n = 20). These groups were analyzed with regard to survival and exclusion criteria for adjuvant therapy. Results Postoperative complications, as well as their severity grade, did not correlate with fewer postCTx cycles administered (p = n.s.). Long-term survival was shorter in patients receiving postCTx in comparison to patients without postCTx, but did not show statistical significance. In per protocol analysis by excluding two patients with perioperative death, a shorter 3-year survival rate was observed in patients receiving postCTx compared to patients without postCTx (3-year survival: 71.2 \% postCTx group vs. 90.0 \% non-postCTx group; p = 0.038). Conclusion These results appear contradicting to the anticipated outcome. While speculative, they question the value of post-CTx. Prospectively randomized studies are needed to elucidate the role of postCTx.}, language = {en} } @article{BaurRitterGermeretal.2016, author = {Baur, Johannes and Ritter, Christian O. and Germer, Christoph-Thomas and Klein, Ingo and Kickuth, Ralph and Steger, Ulrich}, title = {Transarterial chemoembolization with drug-eluting beads versus conventional transarterial chemoembolization in locally advanced hepatocellular carcinoma}, series = {Hepatic Medicine}, volume = {2016}, journal = {Hepatic Medicine}, number = {8}, doi = {10.2147/HMER.S105395}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146553}, pages = {69-74}, year = {2016}, abstract = {Purpose: In hepatocellular carcinoma patients with large or multinodal tumors, where curative treatment options are not feasible, transarterial therapies play a major role. Transarterial chemoembolization (TACE) with drug-eluting beads (DEB-TACE) is a promising new approach due to higher intratumoral and lower systemic concentration of the chemotherapeutic agent compared to conventional TACE (cTACE). Patients and methods: In a retrospective analysis, 32 patients with hepatocellular carcinoma who received either DEB or a cTACE were compared regarding survival time, disease recurrence, and side effects such as pain and fever. Results: No significant differences could be detected between the cTACE and DEB-TACE groups with regard to mean hospital stay, appearance of postinterventional fever, or 30-day mortality. However, the application of intravenous analgesics as postinterventional pain medication was needed more often in patients treated with DEB-TACE (57.1\% vs 12.5\%, P=0.0281). The overall median survival after the initial procedure was 10.8 months in the cTACE group and 9.2 months in the DEB-TACE group, showing no significant difference. Conclusion: No survival benefit for patients treated with either DEB-TACE or cTACE was observed. Surprisingly, a higher rate of postinterventional pain could be detected after DEB-TACE.}, language = {en} } @article{BuschBuschScholzetal.2016, author = {Busch, Albert and Busch, Martin and Scholz, Claus-J{\"u}rgen and Kellersmann, Richard and Otto, Christoph and Chernogubova, Ekaterina and Maegdefessel, Lars and Zernecke, Alma and Lorenz, Udo}, title = {Aneurysm miRNA Signature Differs, Depending on Disease Localization and Morphology}, series = {International Journal of Molecular Science}, volume = {17}, journal = {International Journal of Molecular Science}, number = {1}, issn = {International Journal of Molecular Science}, doi = {10.3390/ijms17010081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146422}, pages = {81}, year = {2016}, abstract = {Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b-1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways.}, language = {en} }