Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide ...therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.
The European Union’s Green Deal emphasises the importance of improving the efficiency of the energy sector in its countries, which is why the issues involved are relevant in both scientific and ...practical terms. The article sets out the hypothesis that conveying the state of the economic efficiency of energy development by grades does not reflect the real situation. Instead of ranks, it is proposed to form homogeneous groups of some countries based on non-linear data normalisation instead of today’s universally used linearisation. Grouping the euro area countries in the European Union on the basis of the value of the cost-effectiveness indicator for the energy development of their industrial sector confirmed the appropriateness of the proposed method-ology. In this way, three groups of countries were formed according to the level of cost-effectiveness achieved. The proposed methodology for grouping countries is universal and can be used for international comparisons of any kind.
Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by ...utilizing a gene co‐expression network of transcriptomics data in addition to laser‐microdissected proteomics from human and murine prostate FFPE samples. We show up‐regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up‐regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis.
Synopsis
Transcriptomic and proteomic analyses in prostate cancer (PCa) reveal high TCA/OXPHOS activity and low PDK4 expression in low STAT3 tumors. PDK4 is a promising independent predictor of biochemical recurrence in PCa.
Low STAT3 tumors show enhanced TCA/OXPHOS and ribosome activity in a gene co‐expression network and in transcriptomic and proteomic analyses.
Enhanced ribosome‐ and metabolic activity is found in mice with a deletion of Pten and Stat3 in the prostate epithelium.
Low STAT3 is associated with low PDK4 expression.
PDK4 is an important regulator of TCA/OXPHOS. Analysis of patient data indicates that low PDK4 correlates with earlier biochemical recurrence in PCa.
Transcriptomic and proteomic analyses in prostate cancer (PCa) reveal high TCA/OXPHOS activity and low PDK4 expression in low STAT3 tumors. PDK4 is a promising independent predictor of biochemical recurrence in PCa.
Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one ...of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.
Prostate cancer is one of the most prevalent forms of cancer in men worldwide. It remains a clinical challenge to identify lethal metastatic prostate cancers, which escape standard therapeutic ...intervention. Aberrant interleukin-6 (IL-6) / signal transducer and activator of transcription-3 (STAT3) signalling and loss of p53 occur during prostate cancer progression to metastatic disease. The abnormality of the IL-6/STAT3/p53 axis is frequently accompanied by other genetic alterations; however, its potential role as an important mediator of oncogenic reprogramming, invasion and metastatic transformation remains unknown. The failure of anti-IL-6 treatments is still unexplained and may be due to an incomplete understanding of the mechanism of the in vivo role of IL-6/STAT3 in prostate cancer. The identification of the alternative reading frame protein (ARF) / murine double minute protein (MDM2) / p53 tumour suppressor pathway potentially involving the IL-6/STAT3 axis as a restricting factor in prostate cancer deficient in the tumour suppressor phosphatase and tensin homologue (PTEN) opened new avenues to currently available therapies. This review summarises the current knowledge on the role of crucial pathways driving prostate cancer progression as well as metastatic disease and discusses the potential use of novel specific target molecules and how it can be exploited to avoid overtreatment and increase quality of life.
We aimed to identify novel markers for aggressive prostate cancer in a STAT3-low proteomics-derived dataset of mitochondrial proteins by immunohistochemical analysis and correlation with ...transcriptomic data and biochemical recurrence in a STAT3 independent PCa cohort. Formalin-fixed paraffin-embedded tissue (FFPE) sample selection for proteomic analysis and tissue-microarray (TMA) generation was conducted from a cohort of PCa patients. Retrospective data analysis was performed with the same cohort. 153 proteins differentially expressed between STAT3-low and STAT3-high samples were identified. Out of these, 46 proteins were associated with mitochondrial processes including oxidative phosphorylation (OXPHOS), and 45 proteins were upregulated, including NDUFS1/ATP5O. In a STAT3 independent PCa cohort, high expression of NDUFS1/ATP5O was confirmed by immunocytochemistry (IHC) and was significantly associated with earlier biochemical recurrence (BCR). mRNA expression levels for these two genes were significantly higher in intra-epithelial neoplasia and in PCa compared to benign prostate glands. NDUFS1/ATP5O levels are increased both at the mRNA and protein level in aggressive PCa. Our results provide evidence that NDUFS1/ATP5O could be used to identify high-risk PCa patients.
Since publication of the article, the authors became aware that Figure 6(A,D) contained errors in the bands and loading controls. The newly compiled Figure 6A and 6D is given below.
Purpose
This paper presents life cycle assessment of planned mass production of the thermal insulation blocks (TIB) made of thermal insulation composite material (TICM) from secondary raw ...materials—glass and plastic. This material is being developed at Brno University of Technology, Faculty of Civil Engineering for use in structural details of (especially low energy or passive) buildings subjected to higher compressive loads. Two production modes depending on the quality of the input materials are compared.
Methods
The assessment is conducted using GaBi 4 software tool with inbuilt Ecoinvent database. The results of the assessment are presented in individual impact categories according to used characterization model (CML 2001—Dec. 07). All the necessary energy and material flows are specified in detail for the purpose of the assessment. Cut-off allocation method is used for allocating the environmental impacts of recycled materials. Part of the assessment is sensitivity analysis of one variable parameter—amount of TIB produced per year.
Results and discussion
The results of the assessment show decisive impact of used electricity source on the overall results—86.2 and 94.3 %, respectively, for both production modes. This is closely connected with quality of used secondary raw materials and design of the production line. Use of higher-quality materials, as well as changes of the designed production line can reduce the overall environmental impacts by almost 30 %.
Conclusions
The results show possible improvements in the planned mass production of the TIB. They also find that further investigation will be required before the start of mass production, especially in connection with improving the environmental impacts of used electricity sources.
The prefabricated roller blind lintels have become common solution, particularly for the single-leaf masonry structures without external thermal insulation system. These lintels, representing simple ...system solution, are designed to interrupt thermal bridges in a place of above the window lintel and simultaneously to provide sufficient reliability of load transfer. The actual outdoor blinds contribute to increase the thermal stability in the room in summer and winter season. They prevent overheating of the room in the summer months and reduce heat transmission through a window in the winter. This paper is focused on the design and numerical modelling of the prefabricated roller blind carrier lintels solutions. Methods of elimination of the thermal bridge are demonstrated on the example of a real produced prefabricated lintel. At the same time this paper deals with its structural analysis. Analyses were carried out using the method of numerical modelling, using finite element method and computing software ANSYS.
The paper deals with determination and classification of the mechanical parameters of cement fibre boards (CFB) with cellulose and PVA reinforcing fibres. The cement fibre material with reinforcing ...fibres is produced using the Hatschek process, where the fibres are arranged in the production direction and the curing is subsequently verified. Test experimental samples, specimens are created from the same production batch, and are produced orienting all of them in the production direction to determine the characteristic for an orthotropic material. The fracture mechanical parameters such as fracture energy and work of fracture were then determined and verified as well. Records will be made for the determined crack mouth opening displacement (CMOD) and displacement (d) of test specimens. The loading directions are given to cover the determination of the mechanical parameters of the material. These measurements are intended to complement the mathematical model that uses FEA modelling for subsequent implementation of the material into civil engineering structures or details.
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•Determination of fracture properties of CFB with cellulose and PVA fibre.•A new CMOD measurement method was developed for smaller test specimens.•The obtained fracture energy values were implemented in the FE Analysis.•Validation of the numerical model with fracture parameters via experimental tests.
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