Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma.

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations

Duality Cascade in Brane Inflation

We show that brane inflation is very sensitive to tiny sharp features in extra dimensions, including those in the potential and in the warp factor. This can show up as observational signatures in the power spectrum and/or non-Gaussianities of the cosmic microwave background radiation (CMBR). One general example of such sharp features is a succession of small steps in a warped throat, caused by Seiberg duality cascade using gauge/gravity duality. We study the cosmological observational consequences of these steps in brane inflation. Since the steps come in a series, the prediction of other steps and their properties can be tested by future data and analysis. It is also possible that the steps are too close to be resolved in the power spectrum, in which case they may show up only in the non-Gaussianity of the CMB temperature fluctuations and/or EE polarization. We study two cases. In the slow-roll scenario where steps appear in the inflaton potential, the sensitivity of brane inflation to the height and width of the steps is increased by several orders of magnitude comparing to that in previously studied large field models. In the IR DBI scenario where steps appear in the warp factor, we find that the glitches in the power spectrum caused by these sharp features are generally small or even unobservable, but associated distinctive non-Gaussianity can be large. Together with its large negative running of the power spectrum index, this scenario clearly illustrates how rich and different a brane inflationary scenario can be when compared to generic slow-roll inflation. Such distinctive stringy features may provide a powerful probe of superstring theory.Comment: Corrections in Eq.(5.47), Eq (5.48), Eq(5.49) and Fig

Permeability of anti-fouling PEGylated surfaces probed by fluorescence correlation spectroscopy

The present work reports on in situ observations of the interaction of organic dye probe molecules and dye-labeled protein with different poly(ethylene glycol) (PEG) architectures (linear, dendron, and bottle brush). Fluorescence correlation spectroscopy (FCS) and single molecule event analysis were used to examine the nature and extent of probe朠EG interactions. The data support a sieve-like model in which size-exclusion principles determine the extent of probe朠EG interactions. Small probes are trapped by more dense PEG architectures and large probes interact more with less dense PEG surfaces. These results, and the tunable pore structure of the PEG dendrons employed in this work, suggest the viability of electrochemically-active materials for tunable surfaces

Field-Aligned Current Structures during the Terrestrial Magnetosphere's Transformation into Alfven Wings and Recovery

On April 24th, 2023, a CME event caused the solar wind to become sub-Alfvenic, leading to the development of an Alfven Wing configuration in the Earth's Magnetosphere. Alfven Wings have previously been observed as cavities of low flow in Jupiter's magnetosphere, but the observing satellites did not have the ability to directly measure the Alfven Wings' current structures. Through in situ measurements made by the Magnetospheric Multiscale (MMS) spacecraft, the April 24th event provides us with the first direct measurements of current structures during an Alfven Wing configuration. We have found two distinct types of current structures associated with the Alfven Wing transformation as well as the magnetosphere recovery. These structures are observed to be significantly more anti-field-aligned and electron-driven than typical magnetopause currents, indicating the disruptions caused to the magnetosphere current system by the Alfven Wing formation

Turbulence properties and kinetic signatures of electron in Kelvin-Helmholtz waves during a geomagnetic storm

We present a comprehensive study of Magnetospheric Multiscale (MMS) spacecraft encounter with KHI during a geomagnetic storm, focusing on elucidating key turbulence properties and reconnection signatures observed at the edges of KH vortices. The spectral slope for electric field stays approximately constant for frequencies below the ion cyclotron frequency and exhibits a break around the lower hybrid frequency, indicating wave activity. Furthermore, MMS observes a current sheet accompanied by intense electron jets and features consistent with strong guide-field asymmetric reconnection across the magnetopause. Substantial agyrotropy (by a factor of 10) in electron distribution functions is observed in the reconnecting current sheet and at the edges of KH. Our observation presents a multi-scale view into KH turbulence under strongly driven conditions and into the dynamics occurring at electron dissipation scales.Comment: 10 pages, including 4 figure

HIV/AIDS, declining family resources and the community safety net

Families play central roles in the HIV/AIDS pandemic, caring for both orphaned children and the ill. This extra caregiving depletes two family resources essential for supporting children: time and money. We use recent data from published studies in sub-Saharan Africa to illustrate deficits and document community responses. In Botswana, parents caring for the chronically ill had less time for their preschool children (74 versus 96 hours per month) and were almost twice as likely to leave children home alone (53% versus 27%); these children experienced greater health and academic problems. Caregiving often prevented adults from working full time or earning their previous level of income; 47% of orphan caregivers and 64% of HIV/AIDS caregivers reported financial difficulties due to caregiving. Communities can play an important role in helping families provide adequate childcare and financial support. Unfortunately, while communities commonly offer informal assistance, the value of such support is not adequate to match the magnitude of need: 75% of children's families in Malawi received assistance from their social network, but averaging only US$81 annually. We suggest communities can strengthen the capacity of families by implementing affordable quality childcare for 0–6 year olds, after-school programming for older children and youth, supportive care for ill children and parents, microlending to enhance earnings, training to increase access to quality jobs, decent working conditions, social insurance for the informal sector, and income and food transfers when families are unable to make ends meet

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma

The templated zeolite-analogue GaPO-34 (CHA structure type) crystallises from a gel precursor Ga2O3:2H3PO4:1HF:1.7SDA:70H2O (where SDA = structure directing agent), treated hydrothermally for 24 hours at 170 °C using either pyridine or 1-methylimizadole as SDA and one of either poorly crystalline ε-Ga2O3 or γ-Ga2O3 as gallium precursor. If the same gels are stirred for periods shorter than 2 hours but treated under identical hydrothermal conditions, then a second phase crystallises, free of GaPO-34. If β-Ga2O3 is used as a reagent only the second phase is found to crystallise, irrespective of gel aging time. The competing phase, which we denote GaPO-34A, has been structurally characterised using synchrotron powder X-ray diffraction for the pyridine material, GaPO-34A(pyr), and using single-crystal X-ray diffraction for the 1-methylimiazole material, GaPO-34A(mim). The structure of GaPO-34A(pyr), P1 @#x0305;, a = 10.22682(6) Å, b = 12.09585(7) Å, c = 13.86713(8) Å, α = 104.6531(4) °, β = 100.8111(6) °, γ = 102.5228(6) °, contains 7 unique gallium sites and 6 phosphorus sites, with empirical formula [Ga7P6O24(OH)2F3(H2O)2].2(C5NH6). GaPO-34A(mim) is isostructural but is modelled as a half volume unit cell, P1 @#x0305;, a = 5.0991(2) Å, b = 12.0631(6) Å, c = 13.8405(9) Å, α = 104.626(5) °, β = 100.346(5) °, γ = 101.936(4) °, with a gallium and a bridging fluoride partially occupied and two partially occupied SDA sites. Solid-state 31P and 71Ga NMR spectroscopy confirms the structural complexity of GaPO-34A with signals resulting from overlapping lineshapes from multiple Ga and P sites, while 1H and 13C solid-state NMR spectra confirm the presence of the protonated SDA and provide evidence for disorder in the SDA. The protonated SDA is located in 14-ring one-dimensional channels with hydrogen bonding deduced from the SDA nitrogens to framework oxygen distances. Upon thermal treatment to investigate SDA removal, structure collapse occurs, which may be due the large number of bridging hydroxides and fluorides in the as-made material, and the unequal amounts of gallium and phosphorus present

Comparing Brane Inflation to WMAP

We compare the simplest realistic brane inflationary model to recent cosmological data, including WMAP 3-year cosmic microwave background (CMB) results, Sloan Digital Sky Survey luminous red galaxies (SDSS LRG) power spectrum data and Supernovae Legacy Survey (SNLS) Type 1a supernovae distance measures. Here, the inflaton is simply the position of a $D3$-brane which is moving towards a $\bar{D}3$-brane sitting at the bottom of a throat (a warped, deformed conifold) in the flux compactified bulk in Type IIB string theory. The analysis includes both the usual slow-roll scenario and the Dirac-Born-Infeld scenario of slow but relativistic rolling. Requiring that the throat is inside the bulk greatly restricts the allowed parameter space. We discuss possible scenarios in which large tensor mode and/or non-Gaussianity may emerge. Here, the properties of a large tensor mode deviate from that in the usual slow-roll scenario, providing a possible stringy signature. Overall, within the brane inflationary scenario, the cosmological data is providing information about the properties of the compactification of the extra dimensions.Comment: 45 pages 11 figure

Assessing the Effects of Medium Chain Fatty Acids and Fat Sources on Porcine Epidemic Diarrhea Virus Viral RNA Stability and Infectivity

Research has confirmed that chemical treatments, such as medium chain fatty acids (MCFA) and commercial formaldehyde, can be effective to reduce the risk of porcine epidemic diarrhea virus (PEDV) cross-contamination in feed. However, the efficacy of individual MCFA levels are unknown. The objective of this study is to compare the efficacy of commercially-available sources of MCFA and other fat sources versus a synthetic custom blend of MCFA to minimize the risk of PEDV cross-contamination as measured by qRT-PCR and bioassay. Treatments were arranged in a 17 × 4 plus 1 factorial with 17 chemical treatments: 1) Positive control with PEDV and no chemical treatment, 2) 0.3% Sal CURB, 3) 1% medium chain fatty acid blend [caproic, caprylic, and capric acids; 1:1:1] (aerosolized), 4) 1% medium chain fatty acid blend [caproic, caprylic, and capric acids; 1:1:1] (non-aerosolized), 5) 0.66% caproic acid, 6) 0.66% caprylic acid, 7) 0.66% capric acid, 8) 0.66% lauric acid, 9) 1% capric and lauric acid mixture (1:1 ratio), 10) FRA C12, 11) 1% choice white grease, 12) 1% soy oil, 13) 1% canola oil, 14) 2% palm kernel oil, 15) 1% palm kernel oil, 16) 2% coconut oil, and 17) 1% coconut oil; 4 analysis days of 0, 1, 3, and 7 post inoculation; and 1 treatment of PEDV negative, untreated feed. Matrices were first chemically treated, then inoculated with PEDV, and stored at room temperature until being analyzed by qRT-PCR. The analyzed values represent threshold cycle (CT), at which a higher CT value represents less detectable RNA. All main effects and interactions were significant (P \u3c 0.002). The interaction of treatment × day indicated that over time the MCFA treatments, either as a mixture or as individual fatty acids, and Sal CURB had the greatest effect of reducing detectable PEDV RNA, which follows the same trend as the main effect of treatment and the bioassay results. Feed treated with individual synthetic MCFA, MCFA mixture, or Sal CURB had fewer (P \u3c 0.05) detectable viral particles than all other treatments. Day also had a significant impact on quantification of viral RNA, and CT increased from 29.5 to 34.6 CT from day 0 to 7, respectively. In summary, time, Sal CURB, 1% MCFA, 0.66% caproic, 0.66% caprylic, and 0.66% capric acids enhance the RNA degradation of PEDV in swine feed. Notably, the MCFA was equally as successful at mitigating PEDV as a commercially-available formaldehyde product in the complete swine diet at 1% inclusion and as individual fatty acids