Resistance mechanisms during endocrine treatment in breast cancer

Prolonged endocrine therapy is the mainstay of treatment for ER+ breast cancer patients. However, resistance develops in many patients which leads to more aggressive disease. Understanding the mechanisms of acquired resistance that emerge as a consequence of prolonged endocrine treatment remains critical. This study aimed to use gene expression profiling to discover induced mechanisms shared by a panel of MCF7-derived acquired resistant cells that underpin endocrine resistant growth. The in vitro panel represents resistance to oestrogen deprivation, tamoxifen or fulvestrant and includes long-term (3year) models to better-mimic clinical endocrine exposure. Affymetrix 1.0ST microarrays detected 572 genes induced in all resistant models versus MCF7. Over-represented ontologies, pathways and functional classification for these genes revealed induction of oxidative phosphorylation (OxPhos) and TCA cycle enzymes in the resistant models, a finding further confirmed by mass spectrometry. Increased oxygen consumption, NADH dehydrogenase and/or cytochrome C oxidase activity was detected in resistant cells, and targeting with OxPhos inhibitors Metformin or Antimycin A confirmed growth-dependency on OxPhos. Western blotting for AMPK (energy sensor) activity and its downstream anabolic targets (ACC, mTOR/P70S6K) showed Metformin reduced fatty acid and protein synthesis in growth-sensitive endocrine resistant cells. In silico analysis inferred clinical relevance since many TCA/OxPhos genes associated with earlier relapse in ER+ and/or tamoxifen treated patients. Monitoring basal glycolysis (extracellular lactate) and growth impact of 2DG or glutamine restriction demonstrated glycolysis and glutaminolysis also contribute to endocrine resistance. The microarrays furthermore revealed that metabolic kinases PCK2, ALDH18A1 and PFKFB2, and components of cell response to Zn were commonly-induced which may additionally help endocrine resistant growth. This study has revealed increased OxPhos arises as a consequence of prolonged endocrine treatment and is a key bioenergetic pathway sustaining resistance. Since resistant growth is Metformin-sensitive, such targeting of this energy pathway (alongside further antihormones or glycolysis/glutaminolysis inhibitors) could help treat resistance

Sex-specific effects of central adiposity and inflammatory markers on limbic microstructure

Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, obesity-related neuroinflammation may contribute to damage in limbic structures important in LOAD. Here, we investigated the hypothesis that systemic inflammation would mediate central obesity related effects on limbic tissue microstructure in 166 asymptomatic individuals (38–71 years old). We employed MRI indices sensitive to myelin and neuroinflammation [macromolecular proton fraction (MPF) and kf] from quantitative magnetization transfer (qMT) together with indices from neurite orientation dispersion and density imaging (NODDI) to investigate the effects of central adiposity on the fornix, parahippocampal cingulum, uncinate fasciculus (compared with whole brain white matter and corticospinal tract) and the hippocampus. Central obesity was assessed with the Waist Hip Ratio (WHR) and abdominal visceral and subcutaneous fat area fractions (VFF, SFF), and systemic inflammation with blood plasma concentrations of leptin, adiponectin, C-reactive protein and interleukin 8. Men were significantly more centrally obese and had higher VFF than women. Individual differences in WHR and in VFF were negatively correlated with differences in fornix MPF and kf, but not with any differences in neurite microstructure. In women, age mediated the effects of VFF on fornix MPF and kf, whilst in men differences in the leptin and adiponectin ratio fully mediated the effect of WHR on fornix MPF. These results suggest that visceral fat related systemic inflammation may damage myelin-related properties of the fornix, a key limbic structure known to be involved in LOAD

Microbial diversity in waters, sediments and microbial mats evaluated using fatty acid-based methods

The review summarises recent advances towards a greater comprehensive assessment of microbial diversity in aquatic environments using the fatty acid methyl esters and phospholipid fatty acids approaches. These methods are commonly used in microbial ecology because they do not require the culturing of micro-organisms, are quantitative and reproducible and provide valuable information regarding the structure of entire microbial communities. Because some fatty acids are associated with taxonomic and functional groups of micro-organisms, they allow particular groups of micro-organisms to be distinguished. The integration of fatty acid-based methods with stable isotopes, RNA and DNA analyses enhances our knowledge of the role of micro-organisms in global nutrient cycles, functional activity and phylogenetic lineages within microbial communities. Additionally, the analysis of fatty acid profiles enables the shifts in the microbial diversity in pristine and contaminated environments to be monitored. The main objective of this review is to present the use of lipid-based approaches for the characterisation of microbial communities in water columns, sediments and biomats

Die biogeochemische Signifikanz von sorbierten Kohlenwasserstoffgasen in marinen Sedimenten

Sorption of hydrocarbon gases (HCs) to marine sediments is a recognized phenomenon that has been investigated mostly in the context of petroleum exploration. However, little is known about the mechanisms of sorption and the importance of biologically produced HCs. In this study, we sought to constrain quantities and sources of sorbed HCs, its major sorbents and sorption mechanisms and its potential importance for sedimentary biogeochemistry. We applied geochemical and mineralogical analysis to 431 sediment samples from different oceanographic settings and geochemical regimes, integrated efficiency tests of extraction pro-tocols for sorbed HCs, and used high pressure equipment to experimentally infer sorption capacities of clay minerals. Significant amounts of biogenic methane were liberated from all samples, regardless of the pore water geochemistry. Alkaline conditions mostly yielded more HCs than the established acidic extraction, whereas both methods indicated the importance of biological methane production. Ethane to hexane were not restricted to cold seep settings or sulfate-free sediments. C2 HCs were selectively retained according to their carbon number, and therefore showed opposite abundance patterns compared to the dissolved gas phase. Methanogenic sediments with a high quartz/phyllosilicate ratio released particularly high amounts of sorbed methane (up to 2.1 mmol kg-1 dry sediment). Both, clay-rich or sulfate-reducing environments displayed strong partitioning of HCs in favor of the sorbed reservoir. The mineralogical data set did not show significant correlations with inorganic minerals or organic carbon, whereas experimental sorption experiments point to the importance of hydro-phobic siloxane patches of tetrahedral silicate sheets as sorbent sites. Microbial production and consumption of methane, even in sulfate-replete environments, affected the sorbed meth-ane pool with resulting stable isotopic compositions ranging from -44 to -84 per mill vs. VPDB (N=225) for carbon, and from -194 to -203 per mill vs. SMOW (N=7) for hydrogen, respectively

The biogeochemical significance of gaseous hydrocarbons sorbed to marine sediments

Sorption of hydrocarbon gases (HCs) to marine sediments is a recognized phenomenon that has been investigated mostly in the context of petroleum exploration. However, little is known about the mechanisms of sorption and the importance of biologically produced HCs. In this study, we sought to constrain quantities and sources of sorbed HCs, its major sorbents and sorption mechanisms and its potential importance for sedimentary biogeochemistry. We applied geochemical and mineralogical analysis to 431 sediment samples from different oceanographic settings and geochemical regimes, integrated efficiency tests of extraction pro-tocols for sorbed HCs, and used high pressure equipment to experimentally infer sorption capacities of clay minerals. Significant amounts of biogenic methane were liberated from all samples, regardless of the pore water geochemistry. Alkaline conditions mostly yielded more HCs than the established acidic extraction, whereas both methods indicated the importance of biological methane production. Ethane to hexane were not restricted to cold seep settings or sulfate-free sediments. C2 HCs were selectively retained according to their carbon number, and therefore showed opposite abundance patterns compared to the dissolved gas phase. Methanogenic sediments with a high quartz/phyllosilicate ratio released particularly high amounts of sorbed methane (up to 2.1 mmol kg-1 dry sediment). Both, clay-rich or sulfate-reducing environments displayed strong partitioning of HCs in favor of the sorbed reservoir. The mineralogical data set did not show significant correlations with inorganic minerals or organic carbon, whereas experimental sorption experiments point to the importance of hydro-phobic siloxane patches of tetrahedral silicate sheets as sorbent sites. Microbial production and consumption of methane, even in sulfate-replete environments, affected the sorbed meth-ane pool with resulting stable isotopic compositions ranging from -44 to -84 per mill vs. VPDB (N=225) for carbon, and from -194 to -203 per mill vs. SMOW (N=7) for hydrogen, respectively