Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, ...the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this review, we outline the importance of tumor-associated macrophages (TAM), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs, and their role in blunting the efficacy of cancer treatment by radiation and anticancer drugs, both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally, we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy.
.
Pushing a pressure standard
A challenge for understanding systems at extreme conditions is knowing the exact pressure at which exotic behaviors occur. This situation is caused by the lack of an ...absolute pressure-density relationship of standard pressure calibrants. Fratanduono
et al.
conducted a series of dynamic compression observations on platinum and gold to establish a high-pressure scale for these metals up to terapascal conditions (see the Perpsective by Jeanloz). This work provides a robust calibration when using these standards in high-pressure devices such as diamond anvil cells.
Science
, abh0364, this issue p.
1063
; see also abi8015, p.
1037
Dynamic compression of platinum and gold provides an experimentally calibrated pressure scale up to terapascal conditions.
New techniques are advancing the frontier of high-pressure physics beyond 1 terapascal, leading to new discoveries and offering stringent tests for condensed-matter theory and advanced numerical methods. However, the ability to absolutely determine the pressure state remains challenging, and well-calibrated pressure-density reference materials are required. We conducted shockless dynamic compression experiments at the National Ignition Facility and the Z machine to obtain quasi-absolute, high-precision, pressure-density equation-of-state data for gold and platinum. We derived two experimentally constrained pressure standards to terapascal conditions. Establishing accurate experimental determinations of extreme pressure will facilitate better connections between experiments and theory, paving the way toward improving our understanding of material response to these extreme conditions.
Waste-to-energy systems can play an important role in diverting organic waste from landfills. However, real-world waste management can differ from idealized practices, and emissions driven by ...microbial communities and complex chemical processes are poorly understood. This study presents a comprehensive life-cycle assessment, using reported and measured data, of competing management alternatives for organic municipal solid waste including landfilling, composting, dry anaerobic digestion (AD) for the production of renewable natural gas (RNG), and dry AD with electricity generation. Landfilling is the most greenhouse gas (GHG)-intensive option, emitting nearly 400 kg CO2e per tonne of organic waste. Composting raw organics resulted in the lowest GHG emissions, at −41 kg CO2e per tonne of waste, while upgrading biogas to RNG after dry AD resulted in −36 to −2 kg CO2e per tonne. Monetizing the results based on social costs of carbon and other air pollutant emissions highlights the importance of ground-level NH3 emissions from composting nitrogen-rich organic waste or post-AD solids. However, better characterization of material-specific NH3 emissions from landfills and land-application of digestate is essential to fully understand the trade-offs between alternatives.
Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound
-acyltransferase domain-containing 7 (
) and transmembrane channel-like 4 (
) that associate with ...increased risk of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related cirrhosis, and liver fibrosis in those infected with viral hepatitis (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017). Based on hepatic expression quantitative trait loci analysis, it has been suggested that
loss of function promotes liver disease progression (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017), but this has never been formally tested. Here we show that
loss, but not
, in mice is sufficient to promote the progression of NAFLD in the setting of high fat diet.
loss of function is associated with accumulation of its substrate lysophosphatidylinositol (LPI) lipids, and direct administration of LPI promotes hepatic inflammatory and fibrotic transcriptional changes in an
-dependent manner. These studies reveal a novel role for MBOAT7-driven acylation of LPI lipids in suppressing the progression of NAFLD.
Abstract
The nondetection of companion stars in SN Ia progenitor systems lends support to the notion of double-degenerate systems and explosions triggered by the merging of two white dwarfs. This ...very asymmetric process should lead to a conspicuous polarimetric signature. By contrast, observations consistently find very low continuum polarization as the signatures from the explosion process largely dominate over the pre-explosion configuration within several days. Critical information about the interaction of the ejecta with a companion and any circumstellar matter is encoded in the early polarization spectra. In this study, we obtain spectropolarimetry of SN 2018gv with the ESO Very Large Telescope at −13.6 days relative to the
B
-band maximum light, or ∼5 days after the estimated explosion—the earliest spectropolarimetric observations to date of any SN Ia. These early observations still show a low continuum polarization (≲0.2%) and moderate line polarization (0.30% ± 0.04% for the prominent Si
ii
λ
6355 feature and 0.85% ± 0.04% for the high-velocity Ca component). The high degree of spherical symmetry implied by the low-line and continuum polarization at this early epoch is consistent with explosion models of delayed detonations and is inconsistent with the merger-induced explosion scenario. The dense UV and optical photometry and optical spectroscopy within the first ∼100 days after the maximum light indicate that SN 2018gv is a normal SN Ia with similar spectrophotometric behavior to SN 2011fe.
Abstract Despite the approval of antiangiogenic therapy for glioblastoma multiforme (GBM) patients, survival benefits are still limited. One of the resistance mechanisms for antiangiogenic therapy is ...the induction of hypoxia and subsequent recruitment of macrophages by stromal-derived factor (SDF)-1α (CXCL-12). In this study, we tested whether olaptesed pegol (OLA-PEG, NOX-A12), a novel SDF-1α inhibitor, could reverse the recruitment of macrophages and potentiate the antitumor effect of anti–vascular endothelial growth factor (VEGF) therapy. We also tested whether magnetic resonance imaging (MRI) with ferumoxytol as a contrast agent could provide early information on macrophage blockade. Orthotopic human G12 glioblastomas in nude mice and rat C6 glioblastomas were employed as the animal models. These were treated with bevacizumab or B-20, both anti-VEGF antibodies. Rats were MR imaged with ferumoxytol for macrophage detection. Tumor hypoxia and SDF-1α expression were elevated by VEGF blockade. Adding OLA-PEG to bevacizumab or B-20 significantly prolonged the survival of rodents bearing intracranial GBM compared with anti-VEGF therapy alone. Intratumoral CD68+ tumor associated macrophages (TAMs) were increased by VEGF blockade, but the combination of OLA-PEG + VEGF blockade markedly lowered TAM levels compared with VEGF blockade alone. MRI with ferumoxytol as a contrast agent noninvasively demonstrated macrophage reduction in OLA-PEG + anti-VEGF–treated rats compared with VEGF blockade alone. In conclusion, inhibition of SDF-1 with OLA-PEG inhibited the recruitment of TAMs by VEGF blockage and potentiated its antitumor efficacy in GBM. Noninvasive MRI with ferumoxytol as a contrast agent provides early information on the effect of OLA-PEG in reducing TAMs.
We present ultraviolet (UV) observations of six nearby Type Ia supernovae (SNe Ia) obtained with the Hubble Space Telescope, three of which were also observed in the near-IR (NIR) with Wide-Field ...Camera 3. UV observations with the Swift satellite, as well as ground-based optical and NIR data provide complementary information. The combined data set covers the wavelength range 0.2–2 μm. By also including archival data of SN 2014J, we analyse a sample spanning observed colour excesses up to E(B − V) = 1.4 mag. We study the wavelength-dependent extinction of each individual SN and find a diversity of reddening laws when characterized by the total-to-selective extinction R
V
. In particular, we note that for the two SNe with E(B − V) ≳ 1 mag, for which the colour excess is dominated by dust extinction, we find R
V
= 1.4 ± 0.1 and R
V
= 2.8 ± 0.1. Adding UV photometry reduces the uncertainty of fitted R
V
by ∼50 per cent allowing us to also measure R
V
of individual low-extinction objects which point to a similar diversity, currently not accounted for in the analyses when SNe Ia are used for studying the expansion history of the Universe.
Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in ...which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma.
We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors.
Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 μg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months 95% confidence interval (CI), 15.9-NA with a progression-free survival of 14.5 months (95% CI, 11.9-NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization.
Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.
PDF
