Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is more prevalent in males and female patients exhibit a survival advantage. Understanding the ...molecular mechanisms that underlie those sex differences could support novel treatment strategies. Amino acids, such as glutamine and the branched-chain amino acids (leucine, isoleucine, valine; BCAAs), play important roles in GBM as they are involved in biosynthesis, energetics, redox homeostasis, and mTOR signaling. Using murine transformed astrocytes, we recently discovered that male cells are more dependent on glutamine and utilize more glutamine to replenish biosynthetic pathways, including BCAA regeneration. BCAA regeneration (i.e., re-amination of branched-chain ketoacids to BCAA) is catalyzed by branched-chain aminotransferases (BCATs) and requires glutamate as a nitrogen donor. Importantly, BCAA regeneration has been linked to cancer progression and poor outcome. Using stable isotope glutamine labeling we found that male transformed astrocytes exhibit greater nitrogen transfer from glutamate onto branched-chain ketoacids to regenerate BCAAs. In line with increased glutamate utilization for BCAA regeneration via BCAT, we found that male transformed astrocytes exhibit greater BCAT1 protein expression levels. Concordantly, male transformed astrocytes are more sensitive to BCAA deprivation compared to female cells, indicating that BCAA metabolism may play a sex-specific role in GBM. Using human GBM surgical specimens, we found greater BCAA metabolite abundance in male GBM. Importantly, our findings on sex differences in BCAA abundance and dependency in GBM are in line with previous reports that show that BCAA abundance and utilization differ between males and females under normal physiological conditions. Together, these data suggest that male GBM are more dependent on BCAAs and that BCAT1 may play unique roles in male and female GBM metabolism. Our data highlight that GBM metabolism differs between males and females and underline the importance of considering sex in metabolic targeting approaches.
•Industry payments to all physicians have increased since disclosure in the Open Payments Database.•Industry payments to spine surgeons have decreased.•Research funding of spine surgery is very low.
...The ethics of industry payments to physicians and the potential impact on healthcare costs and research outcomes have long been topics of debate. Industry payments to spine surgeons are frequently scrutinized. Transparency of industry relationships with physicians provides insight into their possible impact on clinical decision-making and utilization of care.
: To analyze trends in medical industry payments to spine surgeons and all physicians from 2014 to 2019, and further evaluate whether specific payments to spine surgeons vary based on company size.
Cross-sectional investigation of publicly reported Center for Medicare and Medicaid Services (CMS) Open Payments Database (OPD)
All US providers listed as receiving industry payments with further evaluation of payments to neurosurgeons and orthopedic spine surgeons.
Main measures were the magnitude and trends of industry general and research payments and subcategories of general payments, such as royalty/license and consulting fees, to spine surgeons and comparison to all physicians over the six-year period. Variations in payment patterns among spine device manufacturers with the highest reported level of spine surgeon payments in 2019.
From 2014 to 2019 publicly reported general and research industry payments in the CMS OPD were analyzed. Trends in payments to all physicians were compared to trends in payments to neurosurgeons and orthopedic spine surgeons. Trends in payment patterns among spine device manufacturers with the highest payments in 2019 were determined. Linear regression analysis was completed to find statistically significant outcomes.
Our investigation found an aggregate of $42,710,365,196 general and research payments reported to all physicians over the 6-year period, 2.6% ($1,112,936,203) of which went to spine surgeons. Industry general and research payments to spine surgeons decreased by 17.5% ($195,571,109, 2014; $161,283,683, 2019), while increasing by 8.7% ($6,706,208,391, 2014; $7,288,003,832, 2019) to all physicians. Industry research payments to spine surgeons were notably low each year and decreased to only 0.5% of research payments made to all physicians in 2019. Median payment received by spine surgeons as well as the overall distribution of payments to the 75th and 95th percentile significantly increased over the six-year period in comparison to the stable distribution of payments to all physicians. Top eight spine device manufactures with the highest level of spine surgeon payments accounted for 72.9% payments in 2014 but decreased payments by 17.6% to 2019 ($120,409,083.75, 2014; $99,283,264.49, 2019).
Industry general and research payments to all physicians increased from 2014 to 2019 but decreased to spine surgeons, largely due to decreasing payments from eight device manufacturers with the highest level of surgeon payments. A small subset of spine surgeons continues to receive increasing payments. The implications of decreasing investments in research by industry and of large payments made to a small group of spine surgeons bears cautious oversight, both for the future of the specialty and any impact on patient care outcomes.
Small-molecule drugs and toxicants commonly interact with more than a single protein target, each of which may have unique effects on cellular phenotype. Although untargeted metabolomics is often ...applied to understand the mode of action of these chemicals, simple pairwise comparisons of treated and untreated samples are insufficient to resolve the effects of disrupting two or more independent protein targets. Here, we introduce a workflow for dose-response metabolomics to evaluate chemicals that potentially affect multiple proteins with different potencies. Our approach relies on treating samples with various concentrations of compound prior to analysis with mass spectrometry-based metabolomics. Data are then processed with software we developed called TOXcms, which statistically evaluates dose-response trends for each metabolomic signal according to user-defined tolerances and subsequently groups those that follow the same pattern. Although TOXcms was built upon the XCMS framework, it is compatible with any metabolomic data-processing software. Additionally, to enable correlation of dose responses beyond those that can be measured by metabolomics, TOXcms also accepts data from respirometry, cell death assays, other omic platforms, etc. In this work, we primarily focus on applying dose-response metabolomics to find off-target effects of drugs. Using metformin and etomoxir as examples, we demonstrate that each group of dose-response patterns identified by TOXcms signifies a metabolic response to a different protein target with a unique drug binding affinity. TOXcms is freely available on our laboratory website at http://pattilab.wustl.edu/software/toxcms.
Obesity induces numerous physiological changes that can impact cancer risk and patient response to therapy. Obese patients with cervical cancer have been reported to have superior outcomes following ...chemoradiotherapy, suggesting that free fatty acids (FFA) might enhance response to radiotherapy. Here, using preclinical models, we show that monounsaturated and diunsaturated FFAs (uFFA) radiosensitize cervical cancer through a novel p53-dependent mechanism. UFFAs signaled through PPARγ and p53 to promote lipid uptake, storage, and metabolism after radiotherapy. Stable isotope labeling confirmed that cervical cancer cells increase both catabolic and anabolic oleate metabolism in response to radiotherapy, with associated increases in dependence on mitochondrial fatty acid oxidation for survival. In vivo, supplementation with exogenous oleate suppressed tumor growth in xenografts after radiotherapy, an effect that could be partially mimicked in tumors from high fat diet-induced obese mice. These results suggest that supplementation with uFFAs may improve tumor responses to radiotherapy, particularly in p53 wild-type tumors.
Metabolism of monounsaturated and diunsaturated fatty acids improves the efficacy of radiotherapy in cancer through modulation of p53 activity. See related commentary by Jungles and Green, p. 4513.
Discovery and identification of a new endogenous metabolite are typically hindered by requirements of large sample volumes and multistage purifications to guide synthesis of the standard. Presented ...here is a metabolomics platform that uses chemical tagging and tandem mass spectrometry to determine structure, direct synthesis, and confirm identity. Three new homocysteine metabolites are reported: N-succinyl homocysteine, 2-methyl-1,3-thiazinane-4-carboxylic acid (MTCA), and homolanthinone.Discovery and identification of a new endogenous metabolite are typically hindered by requirements of large sample volumes and multistage purifications to guide synthesis of the standard. Presented here is a metabolomics platform that uses chemical tagging and tandem mass spectrometry to determine structure, direct synthesis, and confirm identity. Three new homocysteine metabolites are reported: N-succinyl homocysteine, 2-methyl-1,3-thiazinane-4-carboxylic acid (MTCA), and homolanthinone.
Patients with cirrhosis exhibit features of circadian disruption. Hyperammonaemia has been suggested to impair both homeostatic and circadian sleep regulation. Here, we tested if hyperammonaemia ...directly disrupts circadian rhythm generation in the central pacemaker, the suprachiasmatic nuclei (SCN) of the hypothalamus. Wheel‐running activity was recorded from mice fed with a hyperammonaemic or normal diet for ~35 days in a 12:12 light–dark (LD) cycle followed by ~15 days in constant darkness (DD). The expression of the clock protein PERIOD2 (PER2) was recorded from SCN explants before, during and after ammonia exposure, ±glutamate receptor antagonists. In LD, hyperammonaemic mice advanced their daily activity onset time by ~1 h (16.8 ± 0.3 vs. 18.1 ± 0.04 h, p = .009) and decreased their total activity, concentrating it during the first half of the night. In DD, hyperammonaemia reduced the amplitude of daily activity (551.5 ± 27.7 vs. 724.9 ± 59 counts, p = .007), with no changes in circadian period. Ammonia (≥0.01 mM) rapidly and significantly reduced PER2 amplitude, and slightly increased circadian period. The decrease in PER2 amplitude correlated with decreased synchrony among circadian cells in the SCN and increased extracellular glutamate, which was rescued by AMPA glutamate receptor antagonists. These data suggest that hyperammonaemia affects circadian regulation of rest‐activity behaviour by increasing extracellular glutamate in the SCN.
Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of ...psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1-5 over 1 year) in 286 subjects (aged 12-32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FA
) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FA
in adolescence, and 4% lower FA
by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p < 0.05). Prospective analysis in CHR-P did not reveal a significant impact of illness onset on regional FA
or FW, suggesting that transition to psychosis is not marked by dramatic change in white matter microstructure. Instead, clinical high risk for psychosis-regardless of transition outcome-is characterized by subtle age-related white matter changes that occur in tandem with development.
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