Investigating the Efficacy of JAK2/STAT3 and PI3K/mTOR Inhibitory Therapy on Glioblastoma and Basal Breast Cancer Cell Lines

The JAK2/STAT3 and PI3K/mTOR pathways are upregulated in cancer cells. STAT3 promotes a positive feedback loop for the stem program whereas PI3K inhibits FOXOs tumor suppressor role and mTOR promotes tumorigenic advancement. Particularly GBM and BBC are aggressive cancers that have a stem cell population that makes them difficult to treat and metastatic. We investigate the effects of a combination therapy that inhibits JAK2/STAT3 and PI3K/mTOR output aiming to lower stem cell expression and promote apoptosis. Our collected data indicates that the dual inhibition induced apoptosis, but it also increased the stem cell signature. The findings pave way for the future isolation of the remaining stem cells to investigate their intricacies and identify how to target them effectively

NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells

Cancer cells almost universally harbor constitutively active Phosphatidylinositol-3 Kinase (PI3K) Pathway ac-tivity via mutation of key signaling components and/or epigenetic mechanisms. Scores of PI3K Pathway in-hibitors are currently under investigation as putative chemotherapeutics. However, feedback and stem cell mechanisms induced by PI3K Pathway inhibition can lead to reduced treatment efficacy. To address therapeutic barriers, we examined whether JAKi would reduce stem gene expression in a setting of PI3K Pathway inhibition in order to improve treatment efficacy. We targeted the PI3K Pathway with NVP-BEZ235 (dual PI3K and mTOR inhibitor) in combination with the Janus Kinase inhibitor JAKi in glioblastoma (GBM) and basal-like breast cancer (BBC) cell lines. We examined growth, gene expression, and apoptosis in cells treated with NVP-BEZ235 and/or JAKi. Growth and recovery assays showed no significant impact of dual treatment with NVP-BEZ235/ JAKi compared to NVP-BEZ235 treatment alone. Gene expression and flow cytometry revealed that single and dual treatments induced apoptosis. Stem gene expression was retained in dual NVP-BEZ235/JAKi treatment samples. Future in vivo studies may give further insight into the impact of combined NVP-BEZ235/JAKi treat-ment in GBM and BBC

The PI3K pathway impacts stem gene expression in a set of glioblastoma cell lines

Background: The PI3K pathway controls diverse cellular processes including growth, survival, metabolism, and apoptosis. Nuclear FOXO factors were observed in cancers that harbor constitutively active PI3K pathway output and stem signatures. FOXO1 and FOXO3 were previously published to induce stem genes such as OCT4 in embryonic stem cells. Here, we investigated FOXO-driven stem gene expression in U87MG glioblastoma cells. Methods: PI3K-activated cancer cell lines were investigated for changes in gene expression, signal transduction, and clonogenicity under conditions with FOXO3 disruption or exogenous expression. The impact of PI3K pathway inhibition on stem gene expression was examined in a set of glioblastoma cell lines. Results: We found that CRISPR-Cas9-mediated FOXO3 disruption in U87MG cells caused decreased OCT4 and SOX2 gene expression, STAT3 phosphorylation on tyrosine 705 and clonogenicity. FOXO3 over expression led to increased OCT4 in numerous glioblastoma cancer cell lines. Strikingly, treatment of glioblastoma cells with NVP-BEZ235 (a dual inhibitor of PI3K and mTOR), which activates FOXO factors, led to robust increases OCT4 gene expression. Direct FOXO factor recruitment to the OCT4 promoter was detected by chromatin immunoprecipitation analyses using U87MG extracts. Discussion: We show for the first time that FOXO transcription factors promote stem gene expression glioblastoma cells. Treatment with PI3K inhibitor NVP-BEZ235 led to dramatic increases in stem genes in a set of glioblastoma cell lines. Conclusion: Given that, PI3K inhibitors are actively investigated as targeted cancer therapies, the FOXO-mediated induction of stem genes observed in this study highlights a potential hazard to PI3K inhibition. Understanding the molecular underpinnings of stem signatures in cancer will allow refinements to therapeutic strategies. Targeting FOXO factors to reduce stem cell characteristics in concert with PI3K inhibition may prove therapeutically efficacious

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Evaluation of the reliability of space solar cells by means of Sequential Accelerated Life Tests

To evaluate the reliability of space solar cells from Accelerated Life Tests (ALT) in laboratory have important difficulties due the presence in space of stressors that are not present in terrestrial environment and that must be emulated simultaneously in laboratory. To overcome these difficulties in this paper we propose a sequential ALT for space solar cells

Sustainable provision of renewable energy technologies for rural electrification in Brazil An assessment of the photovoltaic option

Im ersten Teil ihrer Untersuchung skizzieren die Verfasser mit dem Einsatz erneuerbarer Energien verbundene oekologische Vorteile, technische Optionen der Elektrifizierung im laendlichen Raum sowie Hindernisse, die einer Elektrifizierung laendlicher Gebiete mit Hilfe photovoltaischer Systeme entgegenstehen. Im zweiten Teil werden typische Strukturen der Elektrizitaetswirtschaft in Entwicklungslaendern und deren Folgen fuer eine Elektrifizierung laendlicher Raeume dargestellt und unterschiedliche Ansaetze zur Elektrifizierung laendlicher Raeume mit Hilfe photovoltaischer Systeme auf der Mikroebene sowie Probleme der Regulierung auf der Makroebene diskutiert. Zudem werden Folgen einer Elektrifizierung vermittels photovoltaischer Systeme fuer die laendliche Entwicklung abgeschaetzt. Der dritte Teil der Untersuchung ist einer empirischen Studie zu der behandelten Thematik am Beispiel Brasiliens gewidmet. Zunaechst werden die einschlaegigen rechtlichen, wirtschaftlichen und politischen Voraussetzungen eroertert und die soziooekonomischen Rahmenbedingungen in den Untersuchungsregionen (Alagoas, Bahia, Minas Gerais) dargestellt. Vor diesem Hintergrund werden vier mit Sonnenenergie arbeitende Elektrifizierungsprojekte vorgestellt und moegliche Folgewirkungen auf Lebensqualitaet, Bildung und Einkommen abgeschaetzt. Abschliessend werden Empfehlungen fuer die deutsche Politik auf dem Gebiet der Entwicklungszusammenarbeit formuliert. (ICE)German title: Nachhaltige Bereitstellung von Technologie fuer erneuerbare Energien zur Elektrifizierung laendlicher Regionen in Brasilien: eine Beurteilung der Option PhotovoltaikAvailable from UuStB Koeln(38)-20040106017 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Influence of concentration and solar cell size on the warranty time of triple junction solar cells

In a previous work the warranty time of commercial lattice-matched GaInP/Ga(In)As/Ge triple junction concentrator solar cells was evaluated under real climatic conditions. The solar cells had a size of 7x7 mm operating with an efficiency of 35% at 820×. For these particular solar cells the warranty time for three locations, Golden (CO-USA), Madrid (Spain), and Tucson AZUSA), exhibits a 4 to 1 ratio, which affects the LCOE (Levelized Cost of Electricity) in an important way. In this work, we go a step further evaluating the influence of concentration and solar cell size on the warranty for a specific thermal design