Targeting mitochondrial energetics reverses panobinostat- and marizomib-induced resistance in pediatric and adult high-grade gliomas.

In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high-grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain-penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug-naïve cells. The levels of adenosine 5'-triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat- and marizomib-resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.

Does neighborhood or residence influence continued smoking among cancer patients: a spatial-ecological and descriptive analyses brief report.

PURPOSE: Continued smoking after a cancer diagnosis is causally linked to cancer-specific and all-cause mortality. Additionally, smoking, in particular after a cancer diagnosis, increases risk for poor therapeutic outcomes, chronic disease and even COV19 infection. METHODS: In order to better understand and address continued smoking among cancer patients, this research applied geospatial mapping analysis to explore the potential association of dedicated smoke/vape shops density and smoking among cancer patients. RESULTS: Our findings suggest that there is an association between dedicated smoke/vape shops density and continued tobacco product use among cancer patients who live in areas with greater numbers of smoke/vape shops and higher percentage of African Americans and low socioeconomic persons. In the City of Hope-Antelope Valley Center region with an average of 1.4 dedicated smoke/vape shops per sq ml, cancer patients continue to smoke at a rate of almost 10%. This rate is almost twice the 5.2% cancer patient smoking rate of the main cancer center with an average of < 1 dedicated smoke/vape shops per sq ml. CONCLUSION: Our study may inform cessation-related research, practice and policies so that researchers, clinicians and policymakers are well-aware of these disparities in dedicated smoke/vape shops proliferation that is disproportionately affecting minority patient, in particular cancer population.

Spatial and Descriptive Analysis of Smoke and Vape Shop Locations Focusing on A Cancer Center Neighboring Catchment Area.

Tobacco products cause about 1 in 5 deaths premature deaths each year. With increased retailing of both tobacco and electronic nicotine delivery systems (ENDS) products, cancer centers such as City of Hope are prioritizing tobacco and ENDS control. Therefore, we conducted formative geospatial analyses of dedicated smoke and vape shops linked to neighborhood demographic characteristics. The objective of the study was to analyze local data on smoke and vaping shop locations by age, socio-economic status, and racial/ethnic group. Our geospatial analysis used aggregate data from the U.S. Census, Google Maps, and Yelp. Geospatial maps were created using ArcGIS Pro with American Community Survey and U.S. Census 2010. The distributions of exclusive tobacco and vaping shop locations data were overlaid with data from the U.S. Census 2010 to generate maps of the relative geographic distributions of shops across varying area demographic characteristics. Results showed that a higher concentration of exclusive smoke and vaping shops were in areas with a higher concentration of ethnic minorities and lower income and lower status neighborhoods. These findings suggest that laws and licensing should be evaluated to regulate the placement of these shops to reduce and even prevent targeting of minorities and other vulnerable populations.

Endogenous Hot Spots of De Novo Telomere Addition in the Yeast Genome Contain Proximal Enhancers That Bind Cdc13.

DNA double-strand breaks (DSBs) pose a threat to genome stability and are repaired through multiple mechanisms. Rarely, telomerase, the enzyme that maintains telomeres, acts upon a DSB in a mutagenic process termed telomere healing. The probability of telomere addition is increased at specific genomic sequences termed sites of repair-associated telomere addition (SiRTAs). By monitoring repair of an induced DSB, we show that SiRTAs on chromosomes V and IX share a bipartite structure in which a core sequence (Core) is directly targeted by telomerase, while a proximal sequence (Stim) enhances the probability of de novo telomere formation. The Stim and Core sequences are sufficient to confer a high frequency of telomere addition to an ectopic site. Cdc13, a single-stranded DNA binding protein that recruits telomerase to endogenous telomeres, is known to stimulate de novo telomere addition when artificially recruited to an induced DSB. Here we show that the ability of the Stim sequence to enhance de novo telomere addition correlates with its ability to bind Cdc13, indicating that natural sites at which telomere addition occurs at high frequency require binding by Cdc13 to a sequence 20 to 100 bp internal from the site at which telomerase acts to initiate de novo telomere addition.

Semaphorin 4A is dynamically regulated during thymocyte development in mice.

Semaphorins are important regulators of peripheral T and B-cell mediated immune responses in mice and humans. Modulatory roles of semaphorins in T cell development are also being characterized. We carefully analyzed the gene expression and protein levels of semaphorins 4A, 4D, and 7A at various developmental stages of T cell maturation in the thymus of C57BL/6 mice. Sema7a was expressed at very low levels, while Sema4d was abundant at all developmental stages of mouse thymocytes. We found the most interesting pattern of gene regulation and protein localization for semaphorin 4A. Both semaphorin 4A mRNA and protein were clearly detected on the earliest progenitors and were downregulated through thymic development. SEMA4A protein also showed a distinct cortico-medullary pattern of localization. Our findings contribute to an understanding of the complex roles played by semaphorins in the network of spatially and temporally regulated cues underpinning T cell development in the thymus.