A major goal of the analysis of high-dimensional RNA expression data from tumor tissue is to identify prognostic signatures for discriminating patient subgroups. For this purpose genome-wide identification of bimodally expressed genes from gene array data is relevant because distinguishability of high and low expression groups is easier compared to genes with unimodal expression distributions.Recently, several methods for the identification of genes with bimodal distributions have been introduced. A straightforward approach is to cluster the expression values and score the distance between the two distributions. Other scores directly measure properties of the distribution. The kurtosis, e.g., measures divergence from a normal distribution. An alternative is the outlier-sum statistic that identifies genes with extremely high or low expression values in a subset of the samples.

We recently reported that nuclear grading in prostate cancer is subject to a strong confirmation bias induced by the tumor architecture. We now wondered whether a similar bias governs nuclear grading in breast carcinoma. An unannounced test was performed at a pathology conference. Pathologists were asked to grade nuclei in a PowerPoint presentation. Circular high power fields of 27 invasive ductal carcinomas were shown, superimposed over low power background images of either tubule-rich or tubule-poor carcinomas. We found (a) that diagnostic reproducibility of nuclear grades was poor to moderate (weighed kappa values between 0.07 and 0.54, 27 cases, 44 graders), but (b) that nuclear grades were not affected by the tumor architecture. We speculate that the categorized grading in breast cancer, separating tubule formation, nuclear pleomorphism, and mitotic figure counts in a combined three tier score, prevents the bias that architecture exerts on nuclear grades in less well-controlled situations.

Integration of trees in agroforestry systems can increase the system sustainability compared to monocultures. The resulting increase in system complexity is likely to affect soil-N cycling by altering soil microbial community structure and functions. Our study aimed to assess the abundance of genes encoding enzymes involved in soil-N cycling in paired monoculture and agroforestry cropland in a Phaeozem soil, and paired open grassland and agroforestry grassland in Histosol and Anthrosol soils. The soil fungi-to-bacteria ratio was greater in the tree row than in the crop or grass rows of the monoculture cropland and open grassland in all soil types, possibly due to increased input of tree residues and the absence of tillage in the Phaeozem (cropland) soil. In the Phaeozem (cropland) soil, gene abundances of amoA indicated a niche differentiation between archaeal and bacterial ammonia oxidizers that distinctly separated the influence of the tree row from the crop row and monoculture system. Abundances of nitrate (napA and narG), nitrite (nirK and nirS) and nitrous oxide reductase genes (nosZ clade I) were largely influenced by soil type rather than management system. The soil types' effects were associated with their differences in soil organic C, total N and pH. Our findings show that in temperate regions, conversion of monoculture cropland and open grassland to agroforestry systems can alter the abundance of soil bacteria and fungi and soil-N-cycling genes, particularly genes involved in ammonium oxidation.

Amplification and/or overexpression of the human epidermal growth factor 2 (HER2) oncogene occurs in about 13-15% of invasive breast cancer and triggers breast cancer cell proliferation, survival and metastatic progression. Around half of all breast cancers with HER2 overexpression co-express hormone receptors (HR) such as those for estrogen and progesterone. Aberrant signaling through HER2 and other members of the HER-family mediates endocrine-resistance in estrogen receptor alpha (ERα) positive breast cancer. On the other hand, ERα co-expression has been shown to attenuate the efficiency of anti-HER2 therapies. These findings indicate that HER2 and ERα synergize to escape from both anti-ERα and anti-HER2-targeted therapies. Rationally designed clinical trials that combine endocrine therapy with anti-HER2 agents to interfere with HER2/ERα cross-talk have been conducted. However, the outcome of these trials suggests that novel therapeutic approaches are needed to further improve inhibition of HER2 and other HER-family members in conjunction with a more efficient ERα blockade. Here, we demonstrate that carfilzomib and bortezomib stabilize the HER2-specific protein tyrosine phosphatase BDP1 leading to decreased HER2 autophosphorylation, reduced HER2 activity and subsequently attenuated activation of the PI3K/Akt-pathway, together with blockade of ERα expression. We further observed that proteasome inhibitors (PIs) reverse autophosphorylation and thereby inhibit the activity of constitutively active mutant HER2. We also demonstrate that PIs cause cell death in lapatinib and endocrine-resistant HER2+/ER+ breast cancer cells. These findings suggest that PIs might have the potential to improve the management of HER2+/ER+ breast cancer patients by efficiently disrupting the bi-directional HER2/ERα cross-talk.

Informed consent is required prior to any medical procedure. In the context of cancer treatment, special efforts are needed to inform cancer patients properly about treatment, potential sequelae and alternative therapies. Little is known about the effectiveness of current informed consent strategies and patients' individual satisfaction. Given the heterogeneity in terms of age, education, sex and other factors, detailed understanding of patients' comprehension and perception is the basis for further optimization of the informed consent process, which was the aim of the current investigation.

Mechanisms of acquired endocrine resistance and late recurrence in patients with ER+/HER2- breast cancer are complex and not fully understood. Here, we evaluated mechanisms of acquired resistance in circulating tumor cells (CTCs) from an ER+/HER2- breast cancer patient who initially responded but later progressed under endocrine treatment. We found a switch from ERα-dependent to HER2-dependent and ERα-independent expression of FOXM1, which may enable disseminated ER+/HER2- cells to re-initiate tumor cell growth and metastasis formation in the presence of endocrine treatment. Our results also suggest a role for HER2 in resistance, even in ER+ breast cancer cells that have neither HER2 amplification nor activating HER2 mutations. We found that NFkB signaling sustains HER2 and FOXM1 expression in CTCs in the presence of ERα inhibitors. Inhibition of NFkB signaling blocked expression of HER2 and FOXM1 in the CTCs, and induced apoptosis. Thus, targeting of NFkB and FOXM1 might be an efficient therapeutic approach to prevent late recurrence and to treat endocrine resistance. Collectively our data show that CTCs from patients with endocrine resistance allow mechanisms of acquired endocrine resistance to be delineated, and can be used to test potential drug regimens for combatting resistance.

The placenta-specific 1 (PLAC1) gene encodes a membrane-associated protein which is selectively expressed in the placental syncytiotrophoblast and in murine fetal tissues during embryonic development. In contrast to its transcriptional repression in all other adult normal tissues, PLAC1 is frequently activated and highly expressed in a variety of human cancers, in particular breast cancer, where it associates with estrogen receptor α (ERα) positivity. In a previous study, we showed that ERα-signaling in breast cancer cells transactivates PLAC1 expression in a non-classical pathway. As the members of the p160/nuclear receptor co-activator (NCOA) family, NCOA1, NCOA2 and NCOA3 are known to be overexpressed in breast cancer and essentially involved in estrogen-mediated cancer cell proliferation we asked if these proteins are involved in the ERα-mediated transactivation of PLAC1 in breast cancer cells.

It has long been known that specific visual frequencies result in greater blood flow to the striate cortex. These peaks are thought to reflect synchrony of local neuronal firing that is reflective of local cortical networks. Since disrupted neural connectivity is a possible etiology for schizophrenia, our goal was to investigate whether localized connectivity, as measured by aberrant synchrony, is abnormal in children and adolescents with schizophrenia. Subjects included 25 children and adolescents with schizophrenia and 39 controls matched for age and gender. Subjects were scanned on a Siemens 3 Tesla Trio scanner while observing flashing checkerboard presented at either 1, 4, 8, or 12 Hz. Image processing included both a standard GLM model and a Fourier transform analysis. Patients had significantly smaller volume of activation in the occipital lobe compared to controls. There were no differences in the integral or percent signal change of the hemodynamic response function for each of the four frequencies. Occipital activation was stable during development between childhood and late adolescence. Finally, both patients and controls demonstrated an increased response between 4 and 8 Hz consistent with synchrony or entrainment in the neuronal response. Children and adolescents with schizophrenia had a significantly lower volume of activation in the occipital lobe in response to the flashing checkerboard task. However, features of intact local connectivity in patients, such as the hemodynamic response function and maximal response at 8 Hz, were normal. These results are consistent with abnormalities in regional connectivity with preserved local connectivity in early-onset schizophrenia.

Strongly increased uptake of glucose is a hallmark of solid malignant tumors. This phenotype can be triggered by hypoxia-induced gene expression changes or can occur independently of hypoxia as a consequence of malignant transformation itself, and is often referred to as the Warburg effect. The glycolytic phenotype has been associated with malignant progression and resistance to radio- and chemotherapy.

The epithelial to mesenchymal transition (EMT) is a biological process in which cells lose cell-cell contacts and become motile. EMT is used during development, for example, in triggering neural crest migration, and in cancer metastasis. Despite progress, the dynamics of JNK signaling, its role in genomewide transcriptional reprogramming, and involved downstream effectors during EMT remain largely unknown. Here, we show that JNK is not required for initiation, but progression of phenotypic changes associated with EMT. Such dependency resulted from JNK-driven transcriptional reprogramming of critical EMT genes and involved changes in their chromatin state. Furthermore, we identified eight novel JNK-induced transcription factors that were required for proper EMT. Three of these factors were also highly expressed in invasive cancer cells where they function in gene regulation to maintain mesenchymal identity. These factors were also induced during neuronal development and function in neuronal migration in vivo. These comprehensive findings uncovered a kinetically distinct role for the JNK pathway in defining the transcriptome that underlies mesenchymal identity and revealed novel transcription factors that mediate these responses during development and disease.

An important application of high dimensional gene expression measurements is the risk prediction and the interpretation of the variables in the resulting survival models. A major problem in this context is the typically large number of genes compared to the number of observations (individuals). Feature selection procedures can generate predictive models with high prediction accuracy and at the same time low model complexity. However, interpretability of the resulting models is still limited due to little knowledge on many of the remaining selected genes. Thus, we summarize genes as gene groups defined by the hierarchically structured Gene Ontology (GO) and include these gene groups as covariates in the hazard regression models. Since expression profiles within GO groups are often heterogeneous, we present a new method to obtain subgroups with coherent patterns. We apply preclustering to genes within GO groups according to the correlation of their gene expression measurements.

Current prognostic gene signatures for breast cancer mainly reflect proliferation status and have limited value in triple-negative (TNBC) cancers. The identification of prognostic signatures from TNBC cohorts was limited in the past due to small sample sizes.

The purpose of this work was to study the prognostic influence in breast cancer of thioredoxin reductase 1 (TXNRD1) and thioredoxin interacting protein (TXNIP), key players in oxidative stress control that are currently evaluated as possible therapeutic targets.

Frailty is a frequent and underdiagnosed multidimensional age-related syndrome, involving decreased physiological performance reserves and marked vulnerability against major stressors. To standardize the preoperative frailty assessment and identify patients at risk of adverse surgical outcomes, commonly used global health assessment tools were evaluated. We aimed to assess three interdisciplinary preoperative screening assessments to investigate the influence of frailty status with in-hospital complications irrespective of surgical complexity and radicality in older women with ovarian cancer (OC).

Background: Intermittent fasting (IF) is defined as an eating pattern without calorie restrictions, alternating between periods of fasting and eating. In the past decades IF has not only become a popular weight-reducing diet but is thought to improve Quality of Life (QoL) and fatigue. However, very little evidence exists for the general population. Thus, we aimed to assess the impact of a 16-h fasting period per day over a three-month study period on QoL and especially fatigue in healthy people. Methods: We conducted a prospective cohort study including healthy subjects. All participants fasted 16 h for at least five days a week while maintaining their normal lifestyle. In the study, we analysed blood samples as well as QoL through standardized questionnaires (WHO-5 questionnaire, Short Form Health 36). Furthermore, we measured the degree of fatigue with the Fatigue Assessment Scale (FAS) and Fatigue Severity Scale (FSS) as well as compliance, activity records, and weight alterations. All endpoints were evaluated at baseline, after two weeks, four weeks, and three months of IF. Results: A total of 30 participants fasted for the entire study period. The results of the WHO-5 questionnaire (15.6 ± 4.6 vs. 18 ± 3.6, p < 0.0019) demonstrated a significant increase in QoL. For long-term QoL six out of eight domains measured by the Short Form Health 36 (SF-36) significantly improved (e.g., physical health: 92.3 ± 11.6 vs. 96.5 ± 6.3, p = 0.015; mental health: 75.5 ± 12.0 vs. 81.7 ± 9.0; p < 0.001 and body pain: 74.1 ± 31.8 vs. 89.5 ± 14.9; p = 0.008) after three months. Fatigue significantly decreased from 10.3 ± 3.2 to 8.4 ± 2.5; p = 0.002 for mental fatigue and from 12.6 ± 3.8 to 10.7 ± 3.3; p = 0.002 measured by the FAS. The mean FSS-Score at baseline was 3.5 ± 1.2 compared to 2.9 ± 1.1 (scale 1−7) after three months (p < 0.001). Notably, the proliferation marker IGF-1 was significantly reduced. No clinically significant changes in laboratory parameters were observed that would have endangered a participant’s safety. Conclusions: IF according to the 16:8 regime over a fasting period of three months significantly improved several aspects of the QoL and decreased fatigue in healthy people, while maintaining a good safety profile. The practicability of this diet was also demonstrated for shift workers and people with a high percentage of active labour. Apart from the improvement in QoL and fatigue, the significant reduction in IGF-1, which can act as an accelerator of tumour development and progression, might be an indicator of the potential benefits of IF for patients with cancer.

Integrins may be involved in the metastatic spread of high-grade serous ovarian cancer (HGSOC) which determines the therapeutical approach and prognosis. We investigated the integrin expression in primary tumor and metastases of advanced HGSOC.

Endothelial lipase (LIPG) is a cell surface associated lipase that displays phospholipase A1 activity towards phosphatidylcholine present in high-density lipoproteins (HDL). LIPG was recently reported to be expressed in breast cancer and to support proliferation, tumourigenicity and metastasis. Here we show that severe oxidative stress leading to AMPK activation triggers LIPG upregulation, resulting in intracellular lipid droplet accumulation in breast cancer cells, which supports survival. Neutralizing oxidative stress abrogated LIPG upregulation and the concomitant lipid storage. In human breast cancer, high LIPG expression was observed in a limited subset of tumours and was significantly associated with shorter metastasis-free survival in node-negative, untreated patients. Moreover, expression of PLIN2 and TXNRD1 in these tumours indicated a link to lipid storage and oxidative stress. Altogether, our findings reveal a previously unrecognized role for LIPG in enabling oxidative stress-induced lipid droplet accumulation in tumour cells that protects against oxidative stress, and thus supports tumour progression.

Intrinsic or acquired resistance to HER2-targeted therapy is often a problem when small molecule tyrosine kinase inhibitors or antibodies are used to treat patients with HER2 positive breast cancer. Therefore, the identification of new targets and therapies for this patient group is warranted. Activated choline metabolism, characterized by elevated levels of choline-containing compounds, has been previously reported in breast cancer. The glycerophosphodiesterase EDI3 (GPCPD1), which hydrolyses glycerophosphocholine to choline and glycerol-3-phosphate, directly influences choline and phospholipid metabolism, and has been linked to cancer-relevant phenotypes in vitro. While the importance of choline metabolism has been addressed in breast cancer, the role of EDI3 in this cancer type has not been explored.

Few studies including contradictory results have addressed the acute effects of the 11+ on motor performance, indicating a potentially reduced applicability of the program for warming up before competitions. This study aims to compare the acute effects of a soccer-specific warm-up (Football+) and the 11+ on motor performance.

Noninvasive biomarkers are urgently needed for early detection of breast cancer since the risk of recurrence, morbidity and mortality are closely related to disease stage at the time of primary surgery. In the past decade, many proteomics-based approaches were developed that utilize the protein profiling of human body fluids or identification of putative biomarkers to obtain more knowledge on the effects of cancer emergence and progression. Herein, we report on an analysis of proteins in the tear fluid from breast carcinoma patients and healthy women using a de novo proteomic approach and 25 mixed samples from each group. This study included 25 patients with primary invasive breast carcinoma and 25 age-matched healthy controls. We performed a MALDI-TOF-TOF-driven semi-quantitative comparison of tear protein levels in cancer (CA) and control (CTRL) using a de novo approach in pooled samples. Over 150 proteins in the tear fluid of CTRL and CA were identified. Using an in-house-developed algorithm we found more than 20 proteins distinctly upregulated or downregulated in the CTRL and CA groups. We identified several proteins that had modified expression in breast cancer patients. These proteins are involved in host immune system pathways (e.g., C1Q1 or S100A8) and different metabolic cascades (ALDH3A or TPI). Further validation of the results in an independent population combined with individual protein profiling of participants is needed to confirm the specificity of our findings and may lead to a better understanding of the pathological mechanism of breast cancer.