Antagonism of the mammalian target of rapamycin selectively mediates metabolic effects of epidermal growth factor receptor inhibition and protects human malignant glioma cells from hypoxia-induced cell death

Although inhibition of the epidermal growth factor receptor is a plausible therapy for malignant gliomas that, in vitro, enhances apoptosis, the results of clinical trials have been disappointing. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates starvation signals and generates adaptive responses that aim at the maintenance of energy homeostasis. Antagonism of mTOR has been suggested as a strategy to augment the efficacy of epidermal growth factor receptor inhibition by interfering with deregulated signalling cascades downstream of Akt. Here we compared effects of antagonism of mTOR utilizing rapamycin or a small hairpin RNA-mediated gene silencing to those of epidermal growth factor receptor inhibition or combined inhibition of epidermal growth factor receptor and mTOR in human malignant glioma cells. In contrast to epidermal growth factor receptor inhibition, mTOR antagonism neither induced cell death nor enhanced apoptosis induced by CD95 ligand or chemotherapeutic drugs. However, mTOR inhibition mimicked the hypoxia-protective effects of epidermal growth factor receptor inhibition by maintaining adenosine triphosphate levels. These in vitro experiments thus challenge the current view of mTOR as a downstream target of Akt that mediates antiapoptotic stimuli. Under the conditions of the tumour microenvironment, metabolic effects of inhibition of epidermal growth factor receptor, Akt and mTOR may adversely affect outcome by protecting the hypoxic tumour cell fractio

Replication of an emergency department-based recovery coaching intervention and pilot testing of pragmatic trial protocols within the context of Indiana's Opioid State Targeted Response plan

Solving the opioid crisis requires immediate, innovative, and sustainable solutions. A number of promising strategies are being carried out by U.S. states and territories as part of their Opioid State Targeted Response (STR) plans funded through the 21st Century Cures Act, and they provide an opportunity for researchers to assess effectiveness of these interventions using pragmatic approaches. This paper describes a pilot study of Project Planned Outreach, Intervention, Naloxone, and Treatment (POINT), the intervention that served as the basis for Indiana's STR-funded, emergency department (ED)-based peer specialist expansion that was conducted in preparation for a larger, multisite pragmatic trial. Through the pilot, we identified, documented, and corrected for challenges encountered while implementing planned study protocols. Per the project's funding mechanism, the ability to move to the larger trial was determined by the achievement of 3 milestones: (1) successful replication of the intervention; (2) demonstrated ability to obtain the necessary sample size; and (3) observe a higher level of engagement in medication for addiction treatment in the POINT group compared to standard care. Overall implementation of the study protocols was successful, with only minor refinements to proposed procedures being required in light of challenges with (1) data access, (2) recruitment, and (3) identification of the expansion hospitals. All three milestones were reached. Challenges in implementing protocols and reaching milestones resulted in refinements that improved the study design overall. The subsequent trial will add to the limited but growing evidence on ED-based peer supports. Capitalizing on STR efforts to study an already scaling and promising intervention is likely to lead to faster and more sustainable results with greater generalizability than traditional, efficacy-focused clinical research

Pituitary-hormone secretion by thyrotropinomas

Hormone secretion by somatotropinomas, corticotropinomas and prolactinomas exhibits increased pulse frequency, basal and pulsatile secretion, accompanied by greater disorderliness. Increased concentrations of growth hormone (GH) or prolactin (PRL) are observed in about 30% of thyrotropinomas leading to acromegaly or disturbed sexual functions beyond thyrotropin (TSH)-induced hyperthyroidism. Regulation of non-TSH pituitary hormones in this context is not well understood. We there therefore evaluated TSH, GH and PRL secretion in 6 patients with up-to-date analytical and mathematical tools by 24-h blood sampling at 10-min intervals in a clinical research laboratory. The profiles were analyzed with a new deconvolution method, approximate entropy, cross-approximate entropy, cross-correlation and cosinor regression. TSH burst frequency and basal and pulsatile secretion were increased in patients compared with controls. TSH secretion patterns in patients were more irregular, but the diurnal rhythm was preserved at a higher mean with a 2.5 h phase delay. Although only one patient had clinical acromegaly, GH secretion and IGF-I levels were increased in two other patients and all three had a significant cross-correlation between the GH and TSH. PRL secretion was increased in one patient, but all patients had a significant cross-correlation with TSH and showed decreased PRL regularity. Cross-ApEn synchrony between TSH and GH did not differ between patients and controls, but TSH and PRL synchrony was reduced in patients. We conclude that TSH secretion by thyrotropinomas shares many characteristics of other pituitary hormone-secreting adenomas. In addition, abnormalities in GH and PRL secretion exist ranging from decreased (joint) regularity to overt hypersecretion, although not always clinically obvious, suggesting tumoral transformation of thyrotrope lineage cells

Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy

Background: Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. Methods: To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. Results: The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1alpha (HIF-1alpha) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. Conclusion: In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways

Constraints on axionlike particles with H.E.S.S. from the irregularity of the PKS 2155-304 energy spectrum

Axionlike particles (ALPs) are hypothetical light (sub-eV) bosons predicted in some extensions of the Standard Model of particle physics. In astrophysical environments comprising high-energy gamma rays and turbulent magnetic fields, the existence of ALPs can modify the energy spectrum of the gamma rays for a sufficiently large coupling between ALPs and photons. This modification would take the form of an irregular behavior of the energy spectrum in a limited energy range. Data from the H.E.S.S. observations of the distant BL Lac object PKS 2155-304 (z=0.116) are used to derive upper limits at the 95% C.L. on the strength of the ALP coupling to photons, ggammaa<2.1×10-11GeV-1 for an ALP mass between 15 and 60 neV. The results depend on assumptions on the magnetic field around the source, which are chosen conservatively. The derived constraints apply to both light pseudoscalar and scalar bosons that couple to the electromagnetic fieldFil: Medina, Maria Clementina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Argentino de Radioastronomia (i); ArgentinaFil: H.E.S. S. collaboration

International Asteroid Warning Network Timing Campaign : 2019 XS

Peer reviewe

Apophis planetary defense campaign

We describe results of a planetary defense exercise conducted during the close approach to Earth by the near-Earth asteroid (99942) Apophis during 2020 December–2021 March. The planetary defense community has been conducting observational campaigns since 2017 to test the operational readiness of the global planetary defense capabilities. These community-led global exercises were carried out with the support of NASA's Planetary Defense Coordination Office and the International Asteroid Warning Network. The Apophis campaign is the third in our series of planetary defense exercises. The goal of this campaign was to recover, track, and characterize Apophis as a potential impactor to exercise the planetary defense system including observations, hypothetical risk assessment and risk prediction, and hazard communication. Based on the campaign results, we present lessons learned about our ability to observe and model a potential impactor. Data products derived from astrometric observations were available for inclusion in our risk assessment model almost immediately, allowing real-time updates to the impact probability calculation and possible impact locations. An early NEOWISE diameter measurement provided a significant improvement in the uncertainty on the range of hypothetical impact outcomes. The availability of different characterization methods such as photometry, spectroscopy, and radar provided robustness to our ability to assess the potential impact risk

Simultaneous observations of PKS 2155-304 with H.E.S.S., Fermi, RXTE and ATOM: spectral energy distributions and variability in a low state

We report on the first simultaneous observations that cover the optical, X-ray, and high energy gamma-ray bands of the BL Lac object PKS 2155-304. The gamma-ray bands were observed for 11 days, between 25 August and 6 September 2008, jointly with the Fermi Gamma-ray Space Telescope and the H.E.S.S. atmospheric Cherenkov array, providing the first simultaneous MeV-TeV spectral energy distribution with the new generation of gamma-ray telescopes. The ATOM telescope and the RXTE and Swift observatories provided optical and X-ray coverage of the low-energy component over the same time period. The object was close to the lowest archival X-ray and Very High Energy state, whereas the optical flux was much higher. The light curves show relatively little (~30%$) variability overall when compared to past flaring episodes, but we find a clear optical/VHE correlation and evidence for a correlation of the X-rays with the high energy spectral index. Contrary to previous observations in the flaring state, we do not find any correlation between the X-ray and VHE components. Although synchrotron self-Compton models are often invoked to explain the SEDs of BL Lac objects, the most common versions of these models are at odds with the correlated variability we find in the various bands for PKS 2155-304.Comment: Accepted for publication in the Astrophysical Journa