The role of NAD(P)H:quinone oxidoreductase 1 in non-small cell lung cancer tumorigenesis and lung cancer stem cell maintenance

Lung cancer is the leading cause of cancer related deaths worldwide. The five-year survival rates for those patients suffering from non-small cell lung cancer (NSCLC), continues to be an abysmal 15%. One of the major reasons for the poor survival rate amongst NSCLC patients is the lack of early detection and subsequent late stage initial diagnosis. Tumors discovered at later stages are often refractory toward chemotherapy and radiation regimens. One theory as to why tumors become resistant to therapy relies heavily on the cells that make up the cancer stem cell (CSC) niche. This small percentage of cells within the heterogeneous tumor has been reported to be responsible for drug resistance, tumor recurrence, and metastasis. In general, CSCs have been isolated using a number of different markers, including cluster differentiation markers, somatic stem cell markers, as well as a number of functional markers such as the side population and aldehyde dehydrogenase (ALDH) activity. While some cancer types, such as breast and hematologic cancers, have been significantly investigated to identify and define their CSC population, lung cancer researchers have only recently begun to identify CSC markers in lung tumors. In addition to the CSC population, malignant cells can also alter their expression of a number of cytoprotective genes that promote tumorigenesis. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a detoxifying enzyme that has been demonstrated to be highly overexpressed in a number of different malignancies. This overexpression has been utilized as a drug target, as the enzyme is expressed at low levels in normal tissue. To this point, there has been success in using NQO1 as a drug target, however little research has been conducted on understanding why NQO1 is overexpressed in these malignancies. The work presented here investigated the role of NQO1 in tumorigenesis as well as its role in maintaining the CSC population in NSCLC. We demonstrate that NQO1 promotes anchorage-independent growth, invasion, reactive oxygen species regulation, anoikis resistance, proliferation, in vivo tumor growth, survival, and ALDH activity. Secondly, we demonstrate that NQO1 also promotes spheroid formation, both in initial and serial contexts, enhances the CSC frequency, and protects spheroid-cultured cells from chemotherapy. Finally, we provide preliminary data that indicates that NQO1 mRNA may be playing an important signaling role in the promotion of the CSC phenotype. This was demonstrated by CRISPR-Cas9 genetic knockout of NQO1 that resulted in a reemergence of the CSC phenotype that can be reversed with transient knockdown of NQO1 mRNA. In summary, our data demonstrate that NQO1 is playing a vital role in the promotion of NSCLC tumorigenesis, as well as supporting the cancer stem cell population. Interestingly, these results may be due to a novel signaling mechanism by NQO1 mRNA, and not the enzyme itself. Further research will be needed to completely understand the role of NQO1 mRNA in NSCLC tumorigenesis and the CSC phenotype

Feeding the Poor: The Interactions of Not for-Profit Organizations and the Decision Making Process of Food Pantry Leaders

Organizational theorist have studied institutions on a macro level in order understand how these structures operate at a social level, accounting for the nature of the written rules and regulations where the involved individuals act both in the internal and external settings. Recently, scholars have focused on the micro level of interactions of individuals within organizations in which they attempt to identify themselves in their given prescript roles. Attempting to understand the interactions of actors within an organization and studying the formation of relationships between organizations, my investigation will also discuss the nature of food distribution in poor communities. Because much of the restaurant industry have been focused on the cultural aspects of food preparation and the roles of culinary experts, my research will focus on the flow of food resources. In that regard, scholars also have studied food production on a macro level; however, my research would like to show this process on a micro level. Attempting to focus less on the cultural aspect of food, I will show how food distribution and resources are a social issue of combating the issue of hunger in poorer communities. In fact, the interviews with Food Pantry leaders will reveal the processes that allow them to allocate necessary resources. Therefore, my research will investigate the nature of Food Pantries as these organizations attempt to combat hunger and how the importance of these leaders are viable to these organizations in order to obtain food resources for the poor

Interaction of gene effects with environments for malting quality of barley doubled haploids

Abstract. Barley doubled haploids covering a wide range of malting quality, along with their parental cultivars and F 2 , F 3 hybrids, were investigated in six environments (three locations, two years) to study the genotype-environment (G × E) interaction structure and the influence of environments on additive, dominance and epistatic gene effects. Grain and malt characters, such as 1000-grain weight, percentage of plump kernels, malt extract yield, protein content, Kolbach index and malt fine-coarse difference (FCD), were measured. Main effects for genetic parameters were estimated and regression analysis was used to explain the interaction of gene effects with environments. The results show that additive effects had the greatest interaction with environments for all the analysed traits, but only for malt characters this interaction was linear. Interaction of dominance effects was much lower and only in the case of 1000-grain weight, protein content and Kolbach index it proved to be significant. The results suggest that effects of heterozygous loci are more stable in contrasting environments than effects of homozygous loci

Oxidative Stress in Cancer

Contingent upon concentration, reactive oxygen species (ROS) influence cancer evolution in apparently contradictory ways, either initiating/stimulating tumorigenesis and supporting transformation/proliferation of cancer cells or causing cell death. To accommodate high ROS levels, tumor cells modify sulfur-based metabolism, NADPH generation, and the activity of antioxidant transcription factors. During initiation, genetic changes enable cell survival under high ROS levels by activating antioxidant transcription factors or increasing NADPH via the pentose phosphate pathway (PPP). During progression and metastasis, tumor cells adapt to oxidative stress by increasing NADPH in various ways, including activation of AMPK, the PPP, and reductive glutamine and folate metabolism

NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer

Identifying cellular drivers responsible for enhancing cancer cell resistance to therapeutics provides critical information for designing more effective drugs. Populations of slowly growing, self-renewing, chemo-resistant cells purportedly contribute to the development of therapeutic resistance in many solid tumors. In the current study, we implemented a tumor spheroid model to determine whether NAD(P)H quinone oxidoreductase-1 (NQO1) was requisite for self-renewal and promotion of the drug-resistant phenotype in non-small cell lung cancer (NSCLC). We found that stable depletion of NQO1 in A549 and H358 human NSCLC tumor models inhibits self-renewal capabilities, as demonstrated by a reduced ability to form primary, secondary, and tertiary spheroids. In contrast, the rescue of NQO1 expression restored the tumor cells’ ability to form spheroids. Additionally, we discovered that NQO1 depletion renders cisplatin-refractory tumor spheroids highly susceptible to drug treatment. Together, these results suggest that NQO1 loss reduces the self-renewing capabilities of NSCLC cells and enhances their susceptibility to clinically relevant therapeutics. These findings describe a novel role for NQO1 and suggest that combining NQO1-inhibitors with conventional chemotherapeutics may enhance anti-tumor effects

Interaction between HVDC links in low short circuit power conditions

Analiza wybranych zagadnień równoległej pracy dwóch układów przesyłowych prądu stałego (HVDC) o odmiennych technologiach, tj. układu tyrystorowego (LCC – Line Commutated Converter) i tranzystorowego (VSC – Voltage Source Converter) jest przedmiotem niniejszego referatu. Pokazano, że równoległa praca układów jest możliwa w warunkach niskiej mocy zwarciowej tam, gdzie sam układ LCC o równoważnej mocy nie mógłby pracować stabilnie w trybie regulacji mocy. Warunkiem jest praca falownika łącza VSC HVDC w trybie regulacji napięcia AC. Z drugiej strony w określonych okolicznościach to właśnie ten tryb może być przyczyną pogorszenia warunków pracy układu LCC, co wskazuje na potrzebę dokładnej analizy takich przypadków celem właściwego doboru nastaw odpowiednich układów regulacji.This paper describes the results of an analysis of selected problems in the parallel operation of two HVDC systems based on different technologies, namely Line Commutated Converter (LCC HVDC) and Voltage Source Converter (VSC HVDC). Using Maximum Power Curves (MPC) technique it is shown that the parallel operation of the two systems in low short circuit power conditions is possible where a single LCC HVDC scheme of equivalent rated power would fail to operate stably in constant power mode. However, the prerequisite for such operation is active AC voltage control offered by the VSC inverter. It is also shown that the positive influence of the VSC converter is noticeable if the two inverters are a considerable distance apart (e.g. 100 or 200 km). On the other hand, EMTP simulations reveal also adverse effects of the mutual influence, particularly apparent in low ESCR systems where the so-called voltage and power instability problem of the AC/DC systems is be more evident. This phenomenon is the basic cause of the undesirable interaction between the LCC HVDC and VSC HVDC resulting in more difficult return to nominal operating conditions after a commutation failure in the LCC system. The proposed and demonstrated solution is to tune down the PLL and voltage controller gains in order to make the overall system less stiff

Finite Element Analysis Of Influence Of Flank Wear Evolution On Forces In Orthogonal Cutting Of 42CrMo4 Steel

This paper presents analysis of flank wear influence on forces in orthogonal turning of 42CrMo4 steel and evaluates capacity of finite element model to provide such force values. Data about magnitude of feed and cutting force were obtained from measurements with force tensiometer in experimental test as well as from finite element analysis of chip formation process in ABAQUS/Explicit software. For studies an insert with complex rake face was selected and flank wear was simulated by grinding operation on its flank face. The aim of grinding inset surface was to obtain even flat wear along cutting edge, which after the measurement could be modeled with CAD program and applied in FE analysis for selected range of wear width. By comparing both sets of force values as function of flank wear in given cutting conditions FEA model was validated and it was established that it can be applied to analyze other physical aspects of machining. Force analysis found that progression of wear causes increase in cutting force magnitude and steep boost to feed force magnitude. Analysis of Fc/Ff force ratio revealed that flank wear has significant impact on resultant force in orthogonal cutting and magnitude of this force components in cutting and feed direction. Surge in force values can result in transfer of substantial loads to machine-tool interface

DU ROLE DES DYSFONCTIONS DANS LA GENESE DES DSYMORPHOSES DENTO-MAXILLO-FACIALES

CLERMONT FD-BCIU-Santé (631132104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Faults in the DC circuits of high voltage direct current (HVDC) systems

W referacie podjęto problem zwarć w obwodach DC układów przesyłowych prądu stałego na wysokim napięciu (HVDC). Przedstawiono aktualny stan rozwoju technologii HVDC, w tym osiągalne parametry elementów półprzewodnikowych istotne z punktu widzenia wytrzymałości zwarciowej. Opisano różnice w topologiach przekształtników układów tranzystorowych (VSC HVDC) wpływające na możliwości wyłączania prądów zwarciowych oraz przedstawiono wyniki badań symulacyjnych dla wybranych z nich. Poddano analizie i porównano odpowiedzi układu z linią kablową i napowietrzną na zwarcia doziemne w obwodach DC.This paper concerns faults in a DC circuit of high voltage direct current (HVDC) systems. State-of-the-art of HVDC technology is presented, including rated parameters of semiconducting elements important from the short-circuit withstand capability standpoint. Differences in transistor-based (VSC) converter topologies that influence short-circuit clearing capability are described and simulations are performed for selected topologies. Analysed and compared are the responses of an overhead line and cable system to the single pole or both poles fault to ground. The results show that DC faults in a VSC system cause an abrupt rise of short-circuit current reaching very high values, which implies high requirements for still not commonly used DC breakers