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Mechanical interaction between cells - specifically distortion of tensional homeostasis-emerged as an important aspect of breast cancer genesis and progression. We investigated the biophysical characteristics of mechanosensitive ion channels (MSCs) in the malignant MCF-7 breast cancer cell line. MSCs turned out to be the most abundant ion channel species and could be activated by negative pressure at the outer side of the cell membrane in a saturable manner. Assessing single channel conductance (GΛ) for different monovalent cations revealed an increase in the succession: Li⁺ < Na⁺ < K⁺ ≈Rb⁺ ≈ Cs⁺. Divalent cations permeated also with the order: Ca²⁺ < Ba²⁺. Comparison of biophysical properties enabled us to identify MSCs in MCF-7 as ion channels formed by the Piezo1 protein. Using patch clamp technique no functional MSCs were observed in the benign MCF-10A mammary epithelial cell line. Blocking of MSCs by GsMTx-4 resulted in decreased motility of MCF-7, but not of MCF-10A cells, underscoring a possible role of Piezo1 in invasion and metastatic propagation. The role of Piezo1 in biology and progression of breast cancer is further substantiated by markedly reduced overall survival in patients with increased Piezo1 mRNA levels in the primary tumor.
Background Overexpression the KCNJ3, a gene that encodes subunit 1 of G-protein activated inwardly rectifying K+ channel (GIRK1) in the primary tumor has been found to be associated with reduced survival times and increased lymph node metastasis in breast cancer patients. Methods In order to survey possible tumorigenic properties of GIRK1 overexpression, a range of malignant mammary epithelial cells, based on the MCF-7 cell line that permanently overexpress different splice variants of the KCNJ3 gene (GIRK1a, GIRK1c, GIRK1d and as a control, eYFP) were produced. Subsequently, selected cardinal neoplasia associated cellular parameters were assessed and compared. ResultsAdhesion to fibronectin coated surface as well as cell proliferation remained unaffected. Other vital parameters intimately linked to malignancy, i.e. wound healing, chemoinvasion, cellular velocities / motilities and angiogenesis were massively affected by GIRK1 overexpression. Overexpression of different GIRK1 splice variants exerted differential actions. While GIRK1a and GIRK1c overexpression reinforced the affected parameters towards malignancy, overexpression of GIRK1d resulted in the opposite. Single channel recording using the patch clamp technique revealed functional GIRK channels in the plasma membrane of MCF-7 cells albeit at very low frequency. DiscussionWe conclude that GIRK1d acts as a dominant negative constituent of functional GIRK complexes present in the plasma membrane of MCF-7 cells, while overexpression of GIRK1a and GIRK1c augmented their activity. The core component responsible for the cancerogenic action of GIRK1 is apparently presented by a segment comprising aminoacids 235–402, that is present exclusively in GIRK1a and GIRK1c, but not GIRK1d (positions according to GIRK1a primary structure). Conclusions The current study provides insight into the cellular and molecular consequences of KCNJ3 overexpression in breast cancer cells and the mechanism upon clinical outcome in patients suffering from breast cancer.
The chemical and physical properties of [AgO2C(CH2OCH2)3H] (3) and its use as an aqueous, ligand-free MOD ink (MOD = metal−organic decomposition) for piezo inkjet printing is discussed. The printed, thermal, or photochemical sintered silver features are electrically conductive on glass (2.7 × 107 S m−1) and PET (PET = polyethylene terephthalate) substrates (1.1 × 107 S m−1) corresponding to 43% and 18% of the bulk silver conductivity. Conducted tape tests show the suitability of the ink for particularly polymer substrates. TG-MS studies demonstrate a two-step decomposition for the conversion of 3 to elemental silver. The structure of 3 in the solid state was determined by single X-ray structure determination.
The use of silver(I)-2-[2-(2-methoxyethoxy)ethoxy]acetate, [AgO2C(CH2OCH2)3H], and its application as an aqueous metal-organic decomposition (MOD) inkjet ink is reported. The chemical and physical properties of the silver carboxylate and the ink formulated thereof are discussed. The ink meets all requirements of piezo driven inkjet printing. The printed features were converted into electrically conducting silver patterns by thermal or photo-thermal treatment. The conversion of [AgO2C(CH2OCH2)3H] to elemental silver follows a two-step decomposition as demonstrated by thermogravimetry–mass spectrometry (TG–MS) measurements. The measured conductivities of the printed features on glass and polyethylene-terephthalate (PET) are 2.7 × 107 S m−1 and 1.1 × 107 S m−1, respectively, which correspond to 43% (glass) and 18% (PET) of the bulk silver conductivity.
Der Klimawandel hat Auswirkungen auf die Umwelt, die Menschen und ihre Lebensbedingungen, aber auch auf ihre Gestaltungsmöglichkeiten für die Zukunft. Die Bundesregierung hat deshalb klare und weit reichende Ziele für den Klimaschutz vorgegeben. Die Forschung mit ihren naturwissenschaftlich-technischen Lösungen und ihren gesellschaftswissenschaftlichen Erkenntnissen trägt zur Umsetzung dieser Ziele bei. Eine kohlenstofffreie Energiegewinnung und -nutzung zu fördern und weiterzuentwickeln sowie die vorhandenen Potenziale von energieeffizienten Techniken zu erschließen, kann einen entscheidenden Beitrag zur Senkung von Treibhausgasemissionen leisten. Verdeutlicht man sich jedoch die Herausforderungen, die mit dem Ziel einer Begrenzung des Temperaturanstiegs auf maximal zwei Grad verbunden sind, so ist unabweisbar, dass durch technologische Innovationen allein die Probleme des Klimawandels nicht gelöst werden können.
Die Broschüre "Klimaschutz erfordert Handeln" des Bundesministeriums für Bildung und Forschung zeigt Ergebnisse aus Forschungsvorhaben des Förderschwerpunktes "Sozial-ökologische Forschung", die eine lösungsorientierte Wissensbasis der dynamischen Wechselwirkungen zwischen Gesellschaften und ihrer natürlichen Umwelt geschaffen haben.
Eye movements and balance
(2003)
Increased expression levels of KCNJ3 have been correlated with lymph node metastases and poor prognosis in patients with breast cancer, suggesting a prognostic role of KCNJ3. We aimed to establish protocols for the detection of KCNJ3 in formalin-fixed, paraffin-embedded (FFPE) breast cancer tissue. Several antibodies were tested for sensitivity and specificity by western blot, followed by optimisation of the immunohistochemistry (IHC) procedure and establishment of KCNJ3 mRNA in situ hybridisation (ISH). Methods were validated by processing 15 FFPE breast cancer samples for which microarray data were available. Spearman's rank correlation analysis resulted in borderline significant correlation for IHC versus ISH (rS: 0.625; p<0.05) and IHC versus microarray (rS: 0.668; p<0.01), but in significant correlation for ISH versus microarray (rS: 0.861; p<0.001). The ISH method was superior to IHC, regarding robustness, sensitivity and specificity and will aid to further study expression levels of KCNJ3 in both malignant and physiological conditions.
KCNJ3 is a new independent prognostic marker for estrogen receptor positive breast cancer patients
(2016)
Numerous studies showed abnormal expression of ion channels in different cancer types. Amongst these, the potassium channel gene KCNJ3 (encoding for GIRK1 proteins) has been reported to be upregulated in tumors of patients with breast cancer and to correlate with positive lymph node status. We aimed to study KCNJ3 levels in different breast cancer subtypes using gene expression data from the TCGA, to validate our findings using RNA in situ hybridization in a validation cohort (GEO ID GSE17705), and to study the prognostic value of KCNJ3using survival analysis. In a total of > 1000 breast cancer patients of two independent data sets we showed a) that KCNJ3 expression is upregulated in tumor tissue compared to corresponding normal tissue (p < 0.001), b) that KCNJ3 expression is associated with estrogen receptor (ER) positive tumors (p < 0.001), but that KCNJ3 expression is variable within this group, and c) that ER positive patients with high KCNJ3 levels have worse overall (p < 0.05) and disease free survival probabilities (p < 0.01), whereby KCNJ3 is an independent prognostic factor (p <0.05). In conclusion, our data suggest that patients with ER positive breast cancer might be stratified into high risk and low risk groups based on the KCNJ3 levels in the tumor.
Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real-world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post-resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three-dimensional video-oculography in brightness and darkness conditions, each following two 2-h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P < 0.01). The clinical relevance is to advise patients with DBN to rest in darkness.
Objective: The presence and intensity of symptoms vary in patients with unilateral vestibular hypofunction. We aimed to determine which saccadic and vestibulo-ocular reflex parameters best predict the presence of symptoms in unilateral vestibular hypofunction in order to better understand vestibular compensation and its implications for rehabilitation therapy.
Methods: Video head impulse test data were analyzed from a subpopulation of 23 symptomatic and 10 currently symptom-free participants with unilateral vestibular hypofunction, embedded in the KORA (Cooperative Health Research in the Region of Augsburg) FF4 study, the second follow-up of the KORA S4 population-based health survey (2,279 participants).
Results: A higher number of catch-up saccades, a higher percentage of covert saccades, and a larger retinal error at 200 ms after the onset of the head impulse were associated with relevant symptoms in participants with unilateral vestibular hypofunction (p = 0.028, p = 0.046, and p = 0.038, respectively). After stepwise selection, the number of catch-up saccades and retinal error at 200 ms remained in the final logistic regression model, which was significantly better than a null model (p = 0.014). Age, gender, saccade amplitude, saccade latency, and VOR gain were not predictive of the presence of symptoms.
Conclusion: The accuracy of saccadic compensation seems to be crucial for the presence of symptoms in unilateral vestibular hypofunction, highlighting the role of specific gaze stabilization exercises in rehabilitation. Early saccades, mainly triggered by the vestibular system, do not seem to compensate accurately enough, resulting in a relevant retinal error and the need for more as well as more accurate catch-up saccades, probably triggered by the visual system.