@article{DiessnerBruttelBeckeretal.2013,
  author    = {Diessner, Joachim and Bruttel, Valentin and Becker, Kathrin and Pawlik, Miriam and Stein, Roland and H{\"a}usler, Sebastian and Dietl, Johannes and Wischhusen, J{\"o}rg and H{\"o}nig, Arnd},
  title     = {Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells},
  series = {American Journal of Cancer Research},
  volume    = {3},
  journal   = {American Journal of Cancer Research},
  number    = {2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128633},
  pages     = {221-220},
  year      = {2013},
  abstract  = {Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25\% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of \(CD44^{high}CD24^{low}HER2^{low}\) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells.},
  language  = {en}
}
@article{AbuHalimaHaeuslerBackesetal.2017,
  author    = {Abu-Halima, Masood and H{\"a}usler, Sebastian and Backes, Christina and Fehlmann, Tobias and Staib, Claudia and Nestel, Sigrun and Nazarenko, Irina and Meese, Eckart and Keller, Andreas},
  title     = {Micro-ribonucleic acids and extracellular vesicles repertoire in the spent culture media is altered in women undergoing \(In\) \(Vitro\) Fertilization},
  series = {Scientific Reports},
  volume    = {7},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-017-13683-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173632},
  year      = {2017},
  abstract  = {MicroRNAs (miRNAs) are class of small RNA molecules with major impact on gene regulation. We analyzed the potential of miRNAs secreted from pre-implantation embryos into the embryonic culture media as biomarkers to predict successful pregnancy. Using microarray analysis, we profiled the miRNome of the 56 spent culture media (SCM) after embryos transfer and found a total of 621 miRNAs in the SCM. On average, we detected 163 miRNAs in SCM of samples with failed pregnancies, but only 149 SCM miRNAs of embryos leading to pregnancies. MiR-634 predicted an embryo transfer leading to a positive pregnancy with an accuracy of 71\% and a sensitivity of 85\%. Among the 621 miRNAs, 102 (16.4\%) showed a differential expression between positive and negative outcome of pregnancy with miR-29c-3p as the most significantly differentially expressed miRNA. The number of extracellular vehicles was lower in SCM with positive outcomes (3.8 × 10\(^9\)/mL EVs), as compared to a negative outcome (7.35 × 10\(^9\)/mL EVs) possibly explaining the reduced number of miRNAs in the SCM associated with failed pregnancies. The analysis of the miRNome in the SCM of couples undergoing fertility treatment lays the ground towards development of biomarkers to predict successful pregnancy and towards understanding the role of embryonic miRNAs found in the SCM.},
  language  = {en}
}
@article{DiessnerWischnewskyStueberetal.2016,
  author    = {Diessner, Joachim and Wischnewsky, Manfred and St{\"u}ber, Tanja and Stein, Roland and Krockenberger, Mathias and H{\"a}usler, Sebastian and Janni, Wolfgang and Kreienberg, Rolf and Blettner, Maria and Schwentner, Lukas and W{\"o}ckel, Achim and Bartmann, Catharina},
  title     = {Evaluation of clinical parameters influencing the development of bone metastasis in breast cancer},
  series = {BMC Cancer},
  volume    = {16},
  journal   = {BMC Cancer},
  number    = {307},
  doi       = {10.1186/s12885-016-2345-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161173},
  year      = {2016},
  abstract  = {Background The development of metastases is a negative prognostic parameter for the clinical outcome of breast cancer. Bone constitutes the first site of distant metastases for many affected women. The purpose of this retrospective multicentre study was to evaluate if and how different variables such as primary tumour stage, biological and histological subtype, age at primary diagnosis, tumour size, the number of affected lymph nodes as well as grading influence the development of bone-only metastases. Methods This retrospective German multicentre study is based on the BRENDA collective and included 9625 patients with primary breast cancer recruited from 1992 to 2008. In this analysis, we investigated a subgroup of 226 patients with bone-only metastases. Association between bone-only relapse and clinico-pathological risk factors was assessed in multivariate models using the tree-building algorithms "exhausted CHAID (Chi-square Automatic Interaction Detectors)" and CART(Classification and Regression Tree), as well as radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression. Results Multivariate analysis demonstrated that breast cancer subtypes have the strongest influence on the development of bone-only metastases (χ2 = 28). 29.9 \% of patients with luminal A or luminal B (ABC-patients) and 11.4 \% with triple negative BC (TNBC) or HER2-overexpressing tumours had bone-only metastases (p < 0.001). Five different mathematical models confirmed this correlation. The second important risk factor is the age at primary diagnosis. Moreover, BC subcategories influence the overall survival from date of metastatic disease of patients with bone-only metastases. Patients with bone-only metastases and TNBC (p < 0.001; HR = 7.47 (95 \% CI: 3.52-15.87) or HER2 overexpressing BC (p = 0.007; HR = 3.04 (95 \% CI: 1.36-6.80) have the worst outcome compared to patients with luminal A or luminal B tumours and bone-only metastases. Conclusion The bottom line of different mathematical models is the prior importance of subcategories of breast cancer and the age at primary diagnosis for the appearance of osseous metastases. The primary tumour stage, histological subtype, tumour size, the number of affected lymph nodes, grading and NPI seem to have only a minor influence on the development of bone-only metastases.},
  language  = {en}
}
@article{DiessnerWischnewskyBlettneretal.2016,
  author    = {Diessner, Joachim and Wischnewsky, Manfred and Blettner, Maria and H{\"a}usler, Sebastian and Janni, Wolfgang and Kreienberg, Rolf and Stein, Roland and St{\"u}ber, Tanja and Schwentner, Lukas and Bartmann, Catharina and W{\"o}ckel, Achim},
  title     = {Do Patients with Luminal A Breast Cancer Profit from Adjuvant Systemic Therapy? A Retrospective Multicenter Study},
  series = {PLoS ONE},
  volume    = {11},
  journal   = {PLoS ONE},
  number    = {12},
  doi       = {10.1371/journal.pone.0168730},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178217},
  year      = {2016},
  abstract  = {Background Luminal A breast cancers respond well to anti-hormonal therapy (HT), are associated with a generally favorable prognosis and constitute the majority of breast cancer subtypes. HT is the mainstay of treatment of these patients, accompanied by an acceptable profile of side effects, whereas the added benefit of chemotherapy (CHT), including anthracycline and taxane-based programs, is less clear-cut and has undergone a process of critical revision. Methods In the framework of the BRENDA collective, we analyzed the benefits of CHT compared to HT in 4570 luminal A patients (pts) with primary diagnosis between 2001 and 2008. The results were adjusted by nodal status, age, tumor size and grading. Results There has been a progressive reduction in the use of CHT in luminal A patients during the last decade. Neither univariate nor multivariate analyses showed any statistically significant differences in relapse free survival (RFS) with the addition of CHT to adjuvant HT, independent of the nodal status, age, tumor size or grading. Even for patients with more than 3 affected lymph nodes, there was no significant difference (univariate: p = 0.865; HR 0.94; 95\% CI: 0.46-1.93; multivariate: p = 0.812; HR 0.92; 95\% CI: 0.45-1.88). Conclusions The addition of CHT to HT provides minimal or no clinical benefit at all to patients with luminal A breast cancer, independent of the RFS-risk. Consequently, risk estimation cannot be the initial step in the decisional process. These findings-that are in line with several publications-should encourage the critical evaluation of applying adjuvant CHT to patients with luminal A breast cancer.},
  language  = {en}
}
@article{HaeuslerdelBarrioDiessneretal.2014,
  author    = {H{\"a}usler, Sebastian F. M. and del Barrio, Itsaso Montalb{\´a}n and Diessner, Joachim and Stein, Roland G. and Strohschein, Jenny and H{\"o}nig, Arnd and Dietl, Johannes and Wischhusen, J{\"o}rg},
  title     = {Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion},
  series = {American Journal of Translational Research},
  volume    = {6},
  journal   = {American Journal of Translational Research},
  number    = {2},
  issn      = {1943-8141},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120016},
  pages     = {129-139},
  year      = {2014},
  abstract  = {The ectonucleotidases CD39 and CD73 degrade ATP to adenosine which inhibits immune responses via the \(A_{2A}\) adenosine receptor (ADORA2A) on T and NK cells. The current study investigates the potential therapeutic use of the specific anti CD39- and anti CD73-antibodies A1 (CD39) and 7G2 (CD73) as these two ectonucleotidases are overexpressed in ovarian cancer (OvCA). As expected, NK cell cytotoxicity against the human ovarian cancer cell lines OAW-42 or SK-OV-3 was significantly increased in the presence of A1 or 7G2 antibody. While this might partly be due to antibody-dependent cell-mediated cytotoxicity, a luciferase-dependent assay for quantifying biologically active adenosine further showed that A1 and 7G2 can inhibit CD39 and CD73-dependent adenosine-generation. In turn, the reduction in adenosine levels achieved by addition of A1 and 7G2 to OAW-42 or SK-OV-3 cells was found to de-inhibit the proliferation of \(CD4^+\) T cells in coculture with OvCA cells. Likewise, blocking of CD39 and CD73 on OvCA cells via A1 and 7G2 led to an increased cytotoxicity of alloreactive primed T cells. Thus, antibodies like A1 and 7G2 could improve targeted therapy in ovarian cancer not only by specifically labeling overexpressed antigens but also by blocking adenosine-dependent immune evasion in this immunogenic malignancy.},
  language  = {en}
}
@article{MontalbandelBarrioPenskiSchlahsaetal.2016,
  author    = {Montalb{\´a}n del Barrio, Itsaso and Penski, Cornelia and Schlahsa, Laura and Stein, Roland G. and Diessner, Joachim and W{\"o}ckel, Achim and Dietl, Johannes and Lutz, Manfred B. and Mittelbronn, Michel and Wischhusen, J{\"o}rg and H{\"a}usler, Sebastian F. M.},
  title     = {Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages - a self-amplifying, CD39- and CD73-dependent mechanism for tumor immune escape},
  series = {Journal for ImmunoTherapy of Cancer},
  volume    = {4},
  journal   = {Journal for ImmunoTherapy of Cancer},
  number    = {49},
  doi       = {10.1186/s40425-016-0154-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146624},
  year      = {2016},
  abstract  = {Background Ovarian cancer (OvCA) tissues show abundant expression of the ectonucleotidases CD39 and CD73 which generate immunomodulatory adenosine, thereby inhibiting cytotoxic lymphocytes. Little, however, is known about the effect of adenosine on myeloid cells. Considering that tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) constitute up to 20 \% of OvCA tissue, we investigated the effect of adenosine on myeloid cells and explored a possible contribution of myeloid cells to adenosine generation in vitro and ex vivo. Methods Monocytes were used as human blood-derived myeloid cells. After co-incubation with SK-OV-3 or OAW-42 OvCA cells, monocyte migration was determined in transwell assays. For conversion into M2-polarized "TAM-like" macrophages, monocytes were co-incubated with OAW-42 cells. Ex vivo TAMs were obtained from OvCA ascites. Macrophage phenotypes were investigated by intracellular staining for IL-10 and IL-12. CD39 and CD73 expression were assessed by FACS analysis both on in vitro-induced TAM-like macrophages and on ascites-derived ex situ-TAMs. Myeloid cells in solid tumor tissue were analyzed by immunohistochemistry. Generation of biologically active adenosine by TAM-like macrophages was measured in luciferase-based reporter assays. Functional effects of adenosine were investigated in proliferation-experiments with CD4+ T cells and specific inhibitors. Results When CD39 or CD73 activity on OvCA cells were blocked, the migration of monocytes towards OvCA cells was significantly decreased. In vivo, myeloid cells in solid ovarian cancer tissue were found to express CD39 whereas CD73 was mainly detected on stromal fibroblasts. Ex situ-TAMs and in vitro differentiated TAM-like cells, however, upregulated the expression of CD39 and CD73 compared to monocytes or M1 macrophages. Expression of ectonucleotidases also translated into increased levels of biologically active adenosine. Accordingly, co-incubation with these TAMs suppressed CD4+ T cell proliferation which could be rescued via blockade of CD39 or CD73. Conclusion Adenosine generated by OvCA cells likely contributes to the recruitment of TAMs which further amplify adenosine-dependent immunosuppression via additional ectonucleotidase activity. In solid ovarian cancer tissue, TAMs express CD39 while CD73 is found on stromal fibroblasts. Accordingly, small molecule inhibitors of CD39 or CD73 could improve immune responses in ovarian cancer.},
  language  = {en}
}