The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the ...resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
ABSTRACT
Supernova remnants (SNRs) are known to accelerate cosmic rays from the detection of non-thermal emission in radio waves, X-rays, and gamma-rays. However, the ability to accelerate cosmic ...rays up to PeV energies has yet to be demonstrated. The presence of cut-offs in the gamma-ray spectra of several young SNRs led to the idea that PeV energies might only be achieved during the first years of a remnant’s evolution. We use our time-dependent acceleration-code RATPaC to study the acceleration of cosmic rays in supernovae expanding into dense environments around massive stars. We performed spherically symmetric one-dimensional (1D) simulations in which we simultaneously solve the transport equations for cosmic rays, magnetic turbulence, and the hydrodynamical flow of the thermal plasma in the test-particle limit. We investigated typical circumstellar-medium (CSM) parameters expected around red supergiant (RSG) and luminous blue variable (LBV) stars for freely expanding winds and accounted for the strong γγ absorption in the first days after explosion. The maximum achievable particle energy is limited to below $600\,$TeV even for the largest considered values of the magnetic field and mass-loss rates. The maximum energy is not expected to surpass $\approx 200\,$ and $\approx 70\,$TeV for LBVs and RSGs that experience moderate mass-loss prior to the explosion. We find gamma-ray peak-luminosities consistent with current upper limits and evaluate that current-generation instruments are able to detect the gamma-rays from Type-IIP explosions at distances up to $\approx 60\,$ kpc and Type-IIn explosions up to $\approx 1.0\,$ Mpc. We also find a good agreement between the thermal X-ray and radio synchrotron emission predicted by our models with a range of observations.
Triple-negative breast cancer (TNBC) is a distinct subset of breast cancer (BC) defined by the lack of immunohistochemical expression of the estrogen and progesterone receptors and human epidermal ...growth factor receptor 2. It is highly heterogeneous and displays overlapping characteristics with both basal-like and BC susceptibility gene 1 and 2 mutant BCs. This review evaluates the activity of emerging targeted agents in TNBC.
A systematic review of PubMed and conference databases was carried out to identify randomised clinical trials reporting outcomes in women with TNBC treated with targeted and platinum-based therapies.
Our review identified TNBC studies of agents with different mechanisms of action, including induction of synthetic lethality and inhibition of angiogenesis, growth, and survival pathways. Combining targeted agents with chemotherapy in TNBC produced only modest gains in progression-free survival, and had little impact on survival. Six TNBC subgroups have been identified and found to differentially respond to specific targeted agents. The use of biological preselection to guide therapy will improve therapeutic indices in target-bearing populations.
Ongoing clinical trials of targeted agents in unselected TNBC populations have yet to produce substantial improvements in outcomes, and advancements will depend on their development in target-selected populations.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
starbench: the D-type expansion of an H ii region Bisbas, T. G; Haworth, T. J; Williams, R. J. R ...
Monthly notices of the Royal Astronomical Society,
10/2015, Volume:
453, Issue:
2
Journal Article
Peer reviewed
Open access
starbench is a project focused on benchmarking and validating different star formation and stellar feedback codes. In this first starbench paper we perform a comparison study of the D-type expansion ...of an H ii region. The aim of this work is to understand the differences observed between the 12 participating numerical codes against the various analytical expressions examining the D-type phase of H ii region expansion. To do this, we propose two well-defined tests which are tackled by 1D and 3D grid- and smoothed particle hydrodynamics-based codes. The first test examines the ‘early phase’ D-type scenario during which the mechanical pressure driving the expansion is significantly larger than the thermal pressure of the neutral medium. The second test examines the ‘late phase’ D-type scenario during which the system relaxes to pressure equilibrium with the external medium. Although they are mutually in excellent agreement, all 12 participating codes follow a modified expansion law that deviates significantly from the classical Spitzer solution in both scenarios. We present a semi-empirical formula combining the two different solutions appropriate to both early and late phases that agrees with high-resolution simulations to ≲ 2 per cent. This formula provides a much better benchmark solution for code validation than the Spitzer solution. The present comparison has validated the participating codes and through this project we provide a data set for calibrating the treatment of ionizing radiation hydrodynamics codes.
Orthology detection is critically important for accurate functional annotation, and has been widely used to facilitate studies on comparative and evolutionary genomics. Although various methods are ...now available, there has been no comprehensive analysis of performance, due to the lack of a genomic-scale 'gold standard' orthology dataset. Even in the absence of such datasets, the comparison of results from alternative methodologies contains useful information, as agreement enhances confidence and disagreement indicates possible errors. Latent Class Analysis (LCA) is a statistical technique that can exploit this information to reasonably infer sensitivities and specificities, and is applied here to evaluate the performance of various orthology detection methods on a eukaryotic dataset. Overall, we observe a trade-off between sensitivity and specificity in orthology detection, with BLAST-based methods characterized by high sensitivity, and tree-based methods by high specificity. Two algorithms exhibit the best overall balance, with both sensitivity and specificity>80%: INPARANOID identifies orthologs across two species while OrthoMCL clusters orthologs from multiple species. Among methods that permit clustering of ortholog groups spanning multiple genomes, the (automated) OrthoMCL algorithm exhibits better within-group consistency with respect to protein function and domain architecture than the (manually curated) KOG database, and the homolog clustering algorithm TribeMCL as well. By way of using LCA, we are also able to comprehensively assess similarities and statistical dependence between various strategies, and evaluate the effects of parameter settings on performance. In summary, we present a comprehensive evaluation of orthology detection on a divergent set of eukaryotic genomes, thus providing insights and guides for method selection, tuning and development for different applications. Many biological questions have been addressed by multiple tests yielding binary (yes/no) outcomes but no clear definition of truth, making LCA an attractive approach for computational biology.
Freshwater ecosystems are considered hotspots of biodiversity in Antarctic polar deserts. Anticipated warming is expected to change the hydrology of these systems due to increased meltwater and ...reduction of ice cover, with implications for environmental conditions and physical connectivity between habitats. Using 16S rRNA gene sequencing, we evaluated microbial mat and planktonic communities within a connected freshwater system in the McMurdo Wright Valley, Antarctica, to determine the roles of connectivity and habitat conditions in controlling microbial assemblage composition. We examined communities from glacial Lake Brownworth, the perennially ice-covered Lake Vanda and the Onyx River, which connects the two. In Lake Vanda, we found distinct microbial assemblages occupying sub-habitats at different lake depths, while the communities from Lake Brownworth and Onyx River were structurally similar. Despite the higher physical connectivity and dispersal opportunities between bacterial communities in the shallow parts of the system, environmental abiotic conditions dominated over dispersal in driving community structure. Functional metabolic pathway predictions suggested differences in the functional gene potential between the microbial mat communities located in shallower and deeper water depths. The findings suggest that increasing temperatures and meltwater due to future climate change will affect bacterial diversity and functioning in Antarctic freshwater ecosystems.
Supernova (SN) blast waves inject energy and momentum into the interstellar medium (ISM), control its turbulent multiphase structure and the launching of galactic outflows. Accurate modelling of the ...blast wave evolution is therefore essential for ISM and galaxy formation simulations. We present an efficient method to compute the input of momentum, thermal energy, and the velocity distribution of the shock-accelerated gas for ambient media (densities of 0.1 ≥ n
0 cm− 3 ≥ 100) with uniform (and with stellar wind blown bubbles), power-law, and turbulent (Mach numbers
$\mathcal {M}$
from 1to100) density distributions. Assuming solar metallicity cooling, the blast wave evolution is followed to the beginning of the momentum conserving snowplough phase. The model recovers previous results for uniform ambient media. The momentum injection in wind-blown bubbles depend on the swept-up mass and the efficiency of cooling, when the blast wave hits the wind shell. For power-law density distributions with n(r) ∼ r
−2 (for n(r) > n
floor) the amount of momentum injection is solely regulated by the background density n
floor and compares to n
uni = n
floor. However, in turbulent ambient media with lognormal density distributions the momentum input can increase by a factor of 2 (compared to the homogeneous case) for high Mach numbers. The average momentum boost can be approximated as
$p_{{\rm turb}}/{p_{{0}}}\ =23.07\, \left(\frac{n_{{0,\rm turb}}}{1\,{\rm cm}^{-3}}\right)^{-0.12} + 0.82 (\ln (1+b^{2}\mathcal {M}^{2}))^{1.49}\left(\frac{n_{{0,\rm turb}}}{1\,{\rm cm}^{-3}}\right)^{-1.6}$
. The velocity distributions are broad as gas can be accelerated to high velocities in low-density channels. The model values agree with results from recent, computationally expensive, three-dimensional simulations of SN explosions in turbulent media.
Luminous blue variables (LBVs) are hot, very luminous massive stars displaying large quasi-periodic variations in brightness, radius, and photospheric temperature on timescales of years to decades. ...The physical origin of this variability, called S Doradus cycle after its prototype, has remained elusive. We study the feedback of stellar wind mass-loss on the envelope structure in stars near the Eddington limit. We calculated a time-dependent hydrodynamic stellar evolution, applying a stellar wind mass-loss prescription with a temperature dependence inspired by the predicted systematic increase in mass-loss rates below 25 kK. We find that when the wind mass-loss rate crosses a well-defined threshold, a discontinuous change in the wind base conditions leads to a restructuring of the stellar envelope. The induced drastic radius and temperature changes, which occur on the thermal timescale of the inflated envelope, in turn impose mass-loss variations that reverse the initial changes, leading to a cycle that lacks a stationary equilibrium configuration. Our proof-of-concept model broadly reproduces the typical observational phenomenology of the S Doradus variability. We identify three key physical ingredients that are required to trigger the instability: inflated envelopes in close proximity to the Eddington limit, a temperature range where decreasing opacities do not lead to an accelerating outflow, and a mass-loss rate that increases with decreasing temperature, crossing a critical threshold value within this temperature range. Our scenario and model provide testable predictions, and open the door for a consistent theoretical treatment of the LBV phase in stellar evolution, with consequences for their further evolution as single stars or in binary systems.
Full text
Available for:
FMFMET, NUK, UL, UM, UPUK
ToxoDB (http://ToxoDB.org) is a genome and functional genomic database for the protozoan parasite Toxoplasma gondii. It incorporates the sequence and annotation of the T. gondii ME49 strain, as well ...as genome sequences for the GT1, VEG and RH (Chr Ia, Chr Ib) strains. Sequence information is integrated with various other genomic-scale data, including community annotation, ESTs, gene expression and proteomics data. ToxoDB has matured significantly since its initial release. Here we outline the numerous updates with respect to the data and increased functionality available on the website.
Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to ...cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.
PDF
