Drugs that Kill Cancer Stem-like Cells

The hallmarks of cancer include processes like self-sufficiency for growth signals, insensitivity to growth-inhibitory (anti-growth) signals, evasion of programmed cell death (apoptosis), unlimited replicative potential, sustained angiogenesis, and tissue invasion and metastasis (Hanahan & Weinberg, 2000). Recent research dictates that these definitions, while valid, ought to be enriched. That is, we should also consider tumours as a heterogeneous ‘collection of cancer cells’ with a hierarchy. This ‘hierarchical hypothesis’ tells us that tumours contain a minute (sometimes very small) sub-set of cells with distinct properties from the bulk of the tumour mass (D’Amour & Gage, 2002; Visvader & Lindeman, 2008; Visvader, 2009). These cells feature certain characteristics inherent to stem cells, including the capacity of self-renewal, asymmetric division and differentiation. They have also a very high propensity to form tumours. Therefore these cells are referred to as cancer stem cells (CSC) or cancer stem-like cells or, better, tumour-initiating cells (TICs). The terminology, while not too important, may be misleading though, since the term ‘cancer stem cells’ implies that we are dealing with true stem cells, which is not possible to reconcile with at this stage, perhaps even more so, since the origin of CSCs is not exactly known.Griffith Health, School of Medical ScienceFull Tex

The assembly factor SDHAF2 is dispensable for flavination of the catalytic subunit of mitochondrial complex II in breast cancer cells

Mitochondrial complex II or succinate dehydrogenase (SDH) is at the crossroads of oxidative phosphorylation and the tricarboxylic acid cycle. It has been shown that Sdh5 (SDHAF2/SDH5 in mammals) is required for flavination of the subunit Sdh1 (SDHA in human cells) in yeast. Here we demonstrate that in human breast cancer cells, SDHAF2/SDH5 is dispensable for SDHA flavination. In contrast to yeast, CRISPR-Cas9 nickase-mediated SDHAF2 KO breast cancer cells feature flavinated SDHA and retain fully assembled and functional complex II, as well as normal mitochondrial respiration. Our data show that SDHA flavination is independent of SDHAF2 in breast cancer cells, employing an alternative mechanism

Расчет электротермического конденсатора для электротермических установок

Актуальность данной работы заключается в том, что электротермический конденсатор предназначен для повышения коэффициента мощности электротермических установок частотой от 0,5 до 10 кГц, поэтому он находит широкое применение в электроэнергетике, а также в машиностроении, на металлургических заводах везде, где возникает необходимость использования индукционного нагрева металлов токами высокой частоты. Существующие на данный момент электротермические конденсаторы выполняются с различной изоляцией и на различное напряжение. Постепенно производство электротермических конденсаторов переходит с бумажной на пленочную или бумажно-пленочную изоляцию, что позволяет уменьшить габариты в связи с более высокой электрической прочностью пленки и улучшить экологичность конденсатора.Die Relevanz dieser Arbeit liegt in der Tatsache, dass die elektroKondensator entwickelt, um die Leistung elektrothermische Anlagen Koeffizient Frequenz von 0,5 bis 10 kHz zu erhöhen, so ist es weit verbreitet in der Energiewirtschaft sowie im Maschinenbau, Hüttenwerke überall dort, wo es einen Bedarf für die Induktionserwärmung Metalle der hochfrequenten Ströme. Bestehende an den Moment elektro Kondensatoren hergestellt mit verschiedenen Isolation und für verschiedene Spannungen. Nach und nach elektro Herstellung von Kondensatoren geht das Papier auf der Papierfolie oder Isolationsfolie, wodurch die Größe auf einen hohen elektrischen Schichtwiderstand aufgrund zu reduzieren und die Umweltfreundlichkeit des Kondensators zu verbessern

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model

BackgroundFast adaptation of glycolytic and mitochondrial energy pathways to changes in the tumour microenvironment is a hallmark of cancer. Purely glycolytic ρ0 tumour cells do not form primary tumours unless they acquire healthy mitochondria from their micro-environment. Here we explored the effects of severely compromised respiration on the metastatic capability of 4T1 mouse breast cancer cells.Methods4T1 cell lines with different levels of respiratory capacity were generated; the Seahorse extracellular flux analyser was used to evaluate oxygen consumption rates, fluorescent confocal microscopy to assess the number of SYBR gold-stained mitochondrial DNA nucleoids, and the presence of the ATP5B protein in the cytoplasm and fluorescent in situ nuclear hybridization was used to establish ploidy. MinION nanopore RNA sequence analysis was used to compare mitochondrial DNA transcription between cell lines. Orthotopic injection was used to determine the ability of cells to metastasize to the lungs of female Balb/c mice.ResultsOXPHOS-deficient ATP5B-KO3.1 cells did not generate primary tumours. Severely OXPHOS compromised ρ0D5 cells generated both primary tumours and lung metastases. Cells generated from lung metastasis of both OXPHOS-competent and OXPHOS-compromised cells formed primary tumours but no metastases when re-injected into mice. OXPHOS-compromised cells significantly increased their mtDNA content, but this did not result in increased OXPHOS capacity, which was not due to decreased mtDNA transcription. Gene set enrichment analysis suggests that certain cells derived from lung metastases downregulate their epithelial-to-mesenchymal related pathways.ConclusionIn summary, OXPHOS is required for tumorigenesis in this orthotopic mouse breast cancer model but even very low levels of OXPHOS are sufficient to generate both primary tumours and lung metastases

Exosomal transfer of miR-126 promotes the anti-tumour response in malignant mesothelioma: Role of miR-126 in cancer-stroma communication

none11MiR-126 has been shown to suppress malignant mesothelioma (MM) by targeting cancer-related genes without inducing toxicity or histopathological changes. Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. Here, a tumour stromal model composed of endothelial cells (HUVECs), fibroblasts (IMR-90 cells), non-malignant mesothelial cells (Met-5A cells) and MM cells (H28 and MM-B1 cells) was used. The cells were treated with exosomes from HUVECs carrying endogenous (exo-HUVEC) and enriched miR-126 (exo-HUVECmiR-126), and the uptake/turnover of exosomes; miR-126 distribution within the stroma; and effect of miR-126 on cell signalling, angiogenesis and cell proliferation were evaluated. Based on the sensitivity of MM cells to exo-HUVEC miR-126 treatment, miR-126 was distributed differently across stromal cells. The reduced miR-126 content in fibroblasts in favour of endothelial cells reduced angiogenesis and suppressed cell growth in an miR-126-sensitive environment. Conversely, the accumulation of miR-126 in fibroblasts and the reduced level of miR-126 in endothelial cells induced tube formation in an miR-126-resistant environment via VEGF/EGFL7 upregulation and IRS1-mediated cell proliferation. These findings suggest that transfer of miR-126 via HUVEC-derived exosomes represents a novel strategy to inhibit angiogenesis and cell growth in MM.noneMonaco, Federica; Gaetani, Simona; Alessandrini, Federica; Tagliabracci, Adriano; Bracci, Massimo; Valentino, Matteo; Neuzil, Jiri; Amati, Monica; Bovenzi, Massimo; Tomasetti, Marco; Santarelli, LoryMonaco, Federica; Gaetani, Simona; Alessandrini, Federica; Tagliabracci, Adriano; Bracci, Massimo; Valentino, Matteo; Neuzil, Jiri; Amati, Monica; Bovenzi, Massimo; Tomasetti, Marco; Santarelli, Lor

Мотивационное управление персоналом на примере компании ООО "Мобител"

Цель дипломной работы: анализ системы мотивационного управления в организации и разработка направлений его совершенствования. В ходе работы проводились практические исследования персонала, выявлялся мотивационный тип, определялась степень информативности персонала организации о системе мотивации (мотивационная среда). Был проведен практический анализ соотношения типов мотивации с формами. В ходе исследования применялось несколько практических методик по формированию мотивационной программы в компании. Степень внедрения: ряд рекомендаций по совершенствованию мотивационного управления персоналом были внедрены в практику управления ООО "Мобител".The purpose of the thesis: analysis of the system of motivational management in the organization and development of directions for its improvement. In the course of the work, practical research of personnel was carried out, the motivational type was revealed, the degree of information of the personnel of the organization about the system of motivation (motivational environment) was determined. A practical analysis of the relationship between types of motivation and forms was carried out. In the course of the research, several practical methods were used to form a motivational program in the company. Degree of implementation: a number of recommendations for improving motivational management of personnel were introduced into the practice of the management of LLC "Mobitel"