IKK/NF-κB signaling contributes to glioblastoma stem cell maintenance

// Amanda L. Rinkenbaugh 1,2 , Patricia C. Cogswell 2,3 , Barbara Calamini 4 , Denise E. Dunn 4 , Anders I. Persson 5,6 , William A. Weiss 5,6 , Donald C. Lo 4 and Albert S. Baldwin 2 1 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA 2 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA 3 Chordoma Foundation, Durham, NC, USA 4 Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC, USA 5 Helen Diller Family Comprehensive Cancer Center and Department of Neurology, University of California, San Francisco, CA, USA 6 Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, CA, USA Correspondence to: Albert Baldwin, email: // Keywords : NF-κB, glioblastoma, cancer stem cells, tumor-initiating cells Received : March 14, 2016 Accepted : September 24, 2016 Published : October 06, 2016 Abstract Glioblastoma multiforme (GBM) carries a poor prognosis and continues to lack effective treatments. Glioblastoma stem cells (GSCs) drive tumor formation, invasion, and drug resistance and, as such, are the focus of studies to identify new therapies for disease control. Here, we identify the involvement of IKK and NF-κB signaling in the maintenance of GSCs. Inhibition of this pathway impairs self-renewal as analyzed in tumorsphere formation and GBM expansion as analyzed in brain slice culture. Interestingly, both the canonical and non-canonical branches of the NF-κB pathway are shown to contribute to this phenotype. One source of NF-κB activation in GBM involves the TGF-β/TAK1 signaling axis. Together, our results demonstrate a role for the NF-κB pathway in GSCs and provide a mechanistic basis for its potential as a therapeutic target in glioblastoma

Shale Oil Value Enhancement Research. Quarterly Report, March 1 - May 31, 1996

The overall objective is to develop a new technology for manufacturing valuable marketable products from shale oil. Phase I objectives are to identify desirable components in shale oil, develop separations techniques for those components, identify market needs and to identify plausible products manufacturable from raw shale oil to meet those needs. The quarter`s efforts were concentrated on (a) compound type analysis of shale oil and its extraction products, (b) thermal hydrodealkylation of the >290{degrees}C polar fraction, (c) reaction of pyridinic type compounds to form secondary products, (d) updating SPX economic analysis, and (e) preparation of a business plan for presentation before the Dawnbreaker Commercial Assistance Program. The subcontract on the thermal hydrodealkylation work at the University of Utah ended at May 3 1, 1996. We have obtained valuable information from the batch experiments. The progress on the flow reactor proved somewhat limited because of the restriction of the existing reactor configuration. The liaison with potential industrial partners is continuing. An additional company has reached agreement to proceed with a geochemical testing of shale oil derived products

Shale Oil Value Enhancement Research. Quarterly Report, June 1 - August 31, 1996

The overall objective is to develop a new technology for manufacturing valuable marketable products from shale oil. The quarter`s efforts were concentrated on (a) THDA and reaction of alkylpyridines at elevated conditions, (b) compound type analysis of kerogen oil and its derived products, (b) thermal hydrodealkylation of the > 290{degrees}C polar fraction, (c) secondary reactions of pyridinic type compounds to form marketable products, and (d) preparation of presentation to the Dawnbreaker Commercial Assistance Program. Excellent progress is being made in all cases. Our market analysis and industrial feedback indicate that the low molecular weight pyridines are the main market driving force. We are concentrating our effort toward increasing the yield of ``light`` pyridines before the end of Phase II(a). Our current laboratory set-up can only produce analytical quantity of samples, which is not sufficient for marketing purpose. However, the completion of a secondary flow THDA unit for a pilot-scale production depends on the availability of the Phase-II(b) and Phase-III funding

Shale Oil Value Enhancement Research. Quarterly Report, September 1 - November 30, 1995

Activities during this quarter focused on compound type analysis of shale oil extraction products and improvement of the continuous extraction process. We have installed a walk-in fume hood to improve the ventilation of our working environment while handling of larger amounts of shale oil and volatile solvents in our Phase-II(a) work. The fume hood accommodates the distillation column, rotary evaporator, and the CLLX column. During the construction period, experimental work was carried on at a smaller scale. Modifications to the thermal hydrodealkylation process unit at the University of Utah have been completed. The higher boiling polar fraction of shale oil was fed and the preliminary ran showed promising results. The search for potential industrial partners is continuing. During this period, the prijcipal investigator has visited six industrial companies that are candidates for partner/buyer relationship. Currently, we are pursuing confidentiality agreements with four of them. It is the intent to focus our research toward addressing the objectives of those companies who show sufficient interest in the shale oil value enhancement project to enter the next level of discussions

Evidence for a Fourteenth mtDNA-Encoded Protein in the Female-Transmitted mtDNA of Marine Mussels (Bivalvia: Mytilidae)

BACKGROUND: A novel feature for animal mitochondrial genomes has been recently established: i.e., the presence of additional, lineage-specific, mtDNA-encoded proteins with functional significance. This feature has been observed in freshwater mussels with doubly uniparental inheritance of mtDNA (DUI). The latter unique system of mtDNA transmission, which also exists in some marine mussels and marine clams, is characterized by one mt genome inherited from the female parent (F mtDNA) and one mt genome inherited from the male parent (M mtDNA). In freshwater mussels, the novel mtDNA-encoded proteins have been shown to be mt genome-specific (i.e., one novel protein for F genomes and one novel protein for M genomes). It has been hypothesized that these novel, F- and M-specific, mtDNA-encoded proteins (and/or other F- and/or M-specific mtDNA sequences) could be responsible for the different modes of mtDNA transmission in bivalves but this remains to be demonstrated. METHODOLOGY/PRINCIPAL FINDINGS: We investigated all complete (or nearly complete) female- and male-transmitted marine mussel mtDNAs previously sequenced for the presence of ORFs that could have functional importance in these bivalves. Our results confirm the presence of a novel F genome-specific mt ORF, of significant length (>100aa) and located in the control region, that most likely has functional significance in marine mussels. The identification of this ORF in five Mytilus species suggests that it has been maintained in the mytilid lineage (subfamily Mytilinae) for ∼13 million years. Furthermore, this ORF likely has a homologue in the F mt genome of Musculista senhousia, a DUI-containing mytilid species in the subfamily Crenellinae. We present evidence supporting the functionality of this F-specific ORF at the transcriptional, amino acid and nucleotide levels. CONCLUSIONS/SIGNIFICANCE: Our results offer support for the hypothesis that "novel F genome-specific mitochondrial genes" are involved in key biological functions in bivalve species with DUI

KEROGEN OIL VALUE ENHANCEMENT RESEARCH

Task 13 (a) was approved on December 21, 2001. Minimal work was performed for the quarter during the approval process. Laboratory and equipment facilities have been maintained in anticipation of the work to be done. The PI communicated with DOE and Estonia researchers during this period, providing advice and direction for the startup of the Estonia research, and preparing a Draft Teaming Agreement. The PI participated in an industrial liaison meeting with DOE personnel. This meeting is expected to lead to formal cooperation between industry and government

KEROGEN OIL VALUE ENHANCEMENT RESEARCH

Three general categories of products from the Estonia Kukersite kerogen oil were defined: pure compounds, broad range concentrates, and sweet refinery feedstock. Product development and market research center on these three categories. Further attempts were made to identify and test chemical approaches for producing lower alkyl resorcinols (what the market requires) from higher alkyl resorcinols. The approaches and process conditions tested have not yet produced satisfactory results. Progress was made to interest industry in the phenolic products producible. A sample of oil from the Galoter retort was received from Estonia and characterization of this sample was initiated. The sample was batch extracted and results of yields and selectivity are reported

IKK/NF-κB signaling contributes to glioblastoma stem cell maintenance.

Glioblastoma multiforme (GBM) carries a poor prognosis and continues to lack effective treatments. Glioblastoma stem cells (GSCs) drive tumor formation, invasion, and drug resistance and, as such, are the focus of studies to identify new therapies for disease control. Here, we identify the involvement of IKK and NF-κB signaling in the maintenance of GSCs. Inhibition of this pathway impairs self-renewal as analyzed in tumorsphere formation and GBM expansion as analyzed in brain slice culture. Interestingly, both the canonical and non-canonical branches of the NF-κB pathway are shown to contribute to this phenotype. One source of NF-κB activation in GBM involves the TGF-β/TAK1 signaling axis. Together, our results demonstrate a role for the NF-κB pathway in GSCs and provide a mechanistic basis for its potential as a therapeutic target in glioblastoma