Regulation fo mTOR and its Role in Reproduciton: Invasion-related Signal Transduction in Human Trophoblast Cells

Ziel der Arbeit war es die Rolle des Signalmoleküls mTOR in der Invasion humaner Trophoblastzellen und dessen Regulation durch Nährstoffe (Serumpräsenz im Kulturmedium) und der upstream gelegenen GTPase Rheb näher zu analysieren. Als Modell diente die immortalisierte Trophoblastzelllinie HTR8/SVneo. Funktionelle Regulation von mTOR durch Rheb wurde durch Generierung eines Sets an Rheb-Mutanten und deren Fähigkeit an mTOR zu binden in der Zelllinie HEK293T näher untersucht. Generell konnte gezeigt werden, dass mTOR hauptsächlich die Proliferation- und Apoptoserate in der gewählten Trophoblastzelllinie beeinflusst. Es konnte auch nachgewiesen werden, dass mTOR die Trophoblastinvasion durch Regulation der Sekretion von uPA and PAI-1 beeinflußt. Die Frage, ob diese Regulation über mTORC1 oder mTORC2 vermittelt wird, konnte nicht vollständig geklärt werden. Die Ergebnisse deuten auf eine größere Rolle für mTORC1. Zusätzlich konnte ein Cross-talk zwischen mTOR und Stat3 in humanen Trophoblasten bestätigt werden. Die Expression von mTOR konnte in humanen Plazenten aus dem ersten und dritten Trimester nachgewiesen werden. Immunhistochemische Analysen zeigten eine erhöhte mTOR Expression in extravillösen und synzytialen Trophoblasten für beide Zeitpunkte. Es wird vorgeschlagen, dass mTOR die Invasivität von Trophoblasten über Regulation der Sekretion von uPA und PAI-1 reguliert, vermutlich in Abhängigkeit der Nährstoffverfügbarkeit. Ist genügend Energie in Form von Nährstoffen und Aminosäuren vorhanden, vermittelt mTOR eher eine Zellantwort im metabolischen Sinn (in synzytialen Trophoblasten), während bei zu geringem Energieangebot, mTOR die Invasivität induziert (in extra-villösen Trophoblasten)

Agrivoltaic: Solar Radiation for Clean Energy and Sustainable Agriculture with Positive Impact on Nature

Climate change and land use conflicts represent two of the greatest challenges worldwide. Climate change affects agricultural production by more frequent and more intense extreme weather events besides the continuing temperature and carbon dioxide increase. The most important climate mitigation measure is the abolishment of fossil fuels, and climate change adaptation is needed for sustainable crop production. The concept of agrivoltaics (AV) combines the installation of a photovoltaic (PV) system for clean energy generation with an agricultural use on the same area, increasing land use efficiency and creating synergy effects to adapt agriculture to climate change by protecting crops from extreme weather events. Recently, interest in AV systems is booming in many countries with an estimate 14 GW of electricity being produced by AV worldwide. Latest technical options of AV systems are described, and the advantage for crops is evaluated. Additionally, environmental effects are reviewed, in terms of influences on microclimate, biodiversity, soil conditions and water management. Optimal technical options for installation and management of AV and results of life cycle analyses are presented. Economic comparison showed that if electricity is directly consumed on-farm, an amortization could be achieved after 3.22 years, based on the present electricity costs in Germany

Downregulation of miR-92a Is Associated with Aggressive Breast Cancer Features and Increased Tumour Macrophage Infiltration

BACKGROUND: MicroRNAs are small non-coding RNAs involved in the regulation of gene expression on a posttranscriptional level. These regulatory RNAs have been implicated in numerous cellular processes and are further deregulated in different cancer types, including breast cancer. MiR-92a is part of the miR-17∼92 cluster, which was first reported to be linked to tumourigenesis. However, little is known about the expression of miR-92a in breast cancer and potential associations to tumour properties. The expression of miR-92a was therefore characterized in 144 invasive breast cancer samples using in situ hybridization and related to clinico-pathological data as well as to selected key properties of the tumour stroma, including the presence of macrophages (CD68) and cancer activated fibroblasts (alpha-SMA). METHODOLOGY/PRINCIPAL FINDINGS: To measure miR-92a levels, an in situ hybridisation protocol was developed and validated using cell lines and miR-92a inhibitors. The expression in the tumour samples was objectively evaluated using digital image analysis program subtracting background activities. We found that the miR-92a expression varied between tumours and was inversely correlated to tumour grade (r = -0.276, p = 0.003) and recurrence-free survival (p = 0.008) and provided independent prognostic information in multivariate Cox analysis (HR: 0.375, CI: 0.145-0.972, p = 0.043). MiR-92a was moreover inversely correlated to the number of infiltrating macrophages in the tumour stroma (r = -0.357, p<0.001), and downregulation of miR-92a promoted cell migration (p<0.01). CONCLUSIONS/SIGNIFICANCE: This study demonstrates that downregulation of miR-92a in breast cancer is linked to key epithelial and stromal properties as well as clinical outcome

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-85202 Low ERK Phosphorylation in Cancer-Associated Fibroblasts Is Associated with Tamoxifen Resistance in Pre-Menopausal Breast Cancer

Purpose: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. Patients and Methods: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMAa) in cancerassociated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated. Results: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despit

Low ERK Phosphorylation in Cancer-Associated Fibroblasts Is Associated with Tamoxifen Resistance in Pre-Menopausal Breast Cancer

Purpose: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. less thanbrgreater than less thanbrgreater thanPatients and Methods: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMA alpha) in cancer-associated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated. less thanbrgreater than less thanbrgreater thanResults: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ER alpha-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis). In both clinical materials we further show a significant association between pERK and SMA alpha, a characteristic marker for activated fibroblasts. SMA alpha expression however was not linked to treatment-predictive information but instead had prognostic qualities. less thanbrgreater than less thanbrgreater thanConclusion: The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer.Funding Agencies|Swedish Cancer Society and Breakthrough Breast Cancer UK||</p

Loss of TGFβ Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance.

One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease. (C)2015 AACR

The Effect of Happiness Enhancing Strategies on Subjective Well Being Indicators

Bakalaura darba mērķis bija apkopot šobrīd zināmās laimes izjūtu paaugstinošās stratēģijas un realizēt eksperimentālu pētījumu, lai noskaidrotu vai pēc dalības 4 nedēļu ilgā laimes izjūtu paaugstinošu stratēģiju intervencē būs vērojama laimes izjūtas līmeņa paaugstināšanās. Pētījumā piedalījās 145 respondenti (kontroles grupa n=75, eksperimentālā grupa n=70) vecumā no 18 līdz 74 gadiem. Eksperimentālās grupas dalībnieki 4 nedēļu garumā realizēja laimes izjūtu paaugstinošās stratēģijas. Abās grupās tika veikti subjektīvās laimes izjūtas mērījumi pirms un pēc dalības pētījumā. Izmantotais instrumentārijs – Subjektīvās laimes skala. Pētījuma rezultāti liecina, ka ir vērojamas statistiski nozīmīgas, pozitīvas izmaiņas laimes izjūtas radītājos pēc dalības laimes intervencē eksperimentālajā grupā (W+=415,50). Var izvirzīt pieņēmumu, ka dalība laimes intervencē ir paaugstinājusi subjektīvās laimes izjūtas eksperimentālajā grupā līmeni. Kontroles grupas laimes izjūtas līmeņa rādītājos nav statistiski nozīmīgu izmaiņu (t = - 0,80). Būtiski, ka nav statistiski nozīmīgu atšķirību starp kontroles un eksperimentālās grupas pirmajiem mērījumiem, kas liecina, ka grupu laimes izjūtas līmenis eksperimenta sākumā ir bijis līdzīgs.The aim of the Bachelor's was to summarize currently known happiness enhancing strategies and to conduct an experimental study to discover if the participation in 4-week happiness enhancing strategy intervention will boost the level of happiness scores in a subject taking the experiment. The study included 145 respondents (control group n= 75, experimental group n= 70) from the age of 18 to 74 years. The experimental group members were subjected to 4 weeks happiness enhancing strategies. Both group’s measurements were obtained before and after participating in the study. The used measures - Subjective happiness scale. The results of the study in the experimental group shows that there is a statistically significant, positive changes in Subjective happiness scale’s scores after participating in a happiness intervention (W+=415,50). This suggests that the participation in happiness enhancing intervention has raised the level of subjective happiness. There are no statistically significant changes in Subjective happiness scale’s scores in control group (t = - 0,80). It is important to highlight that there was statistically no significant difference between the control and experimental group first measurements – both groups Subjective happiness scale’s scores at the beginning of the experiment was similar

Kaplan-Meier plots.

<p>Recurrence-free survival according to CAF-pERK level (A-C) and CAF-SMAα expression (D-F) of patients in cohort I (ERα-positive patients). Plots represent prognostic (A, D) or tamoxifen treatment-predictive information (B, C and E, F) (<i>P</i>-value: Univariate Cox regression, HR: Hazard Ratio, CI: Confidence Interval, RFS: Recurrence-Free Survival).</p