Effective therapeutic strategies for in vivo siRNA delivery to knockdown genes in cells outside the liver are needed to harness RNA interference for treating cancer. EpCAM is a tumor-associated ...antigen highly expressed on common epithelial cancers and their tumor-initiating cells (TIC, also known as cancer stem cells). Here, we show that aptamer-siRNA chimeras (AsiC, an EpCAM aptamer linked to an siRNA sense strand and annealed to the siRNA antisense strand) are selectively taken up and knock down gene expression in EpCAM(+) cancer cells in vitro and in human cancer biopsy tissues. PLK1 EpCAM-AsiCs inhibit colony and mammosphere formation (in vitro TIC assays) and tumor initiation by EpCAM(+) luminal and basal-A triple-negative breast cancer (TNBC) cell lines, but not EpCAM(-) mesenchymal basal-B TNBCs, in nude mice. Subcutaneously administered EpCAM-AsiCs concentrate in EpCAM(+) Her2(+) and TNBC tumors and suppress their growth. Thus, EpCAM-AsiCs provide an attractive approach for treating epithelial cancer.
It is widely believed that magnetic excitations become increasingly incoherent as the temperature is raised due to random collisions which limit their lifetime. This picture is based on spin-wave ...calculations for gapless magnets in 2 and 3 dimensions and is observed experimentally as a symmetric Lorentzian broadening in energy. Here, we investigate a three-dimensional dimer antiferromagnet and find unexpectedly that the broadening is asymmetric-indicating that far from thermal decoherence, the excitations behave collectively like a strongly correlated gas. This result suggests that a temperature activated coherent state of quasiparticles is not confined to special cases like the highly dimerized spin-1/2 chain but is found generally in dimerized antiferromagnets of all dimensionalities and perhaps gapped magnets in general.
Background
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, causing approximately 660,000 deaths worldwide annually. The preferred treatment of HCC is surgical resection or ...orthotopic liver transplantation (OLT) for patients meeting specific criteria. For patients outside these criteria, options are limited and include medical therapy, radiofrequency ablation, chemoembolization, or palliative measures, and these result in poor outcomes. Various centers at Baylor are elucidating the genomics of HCC to improve treatment options, with a focus on three etiologies: hepatitis C virus, hepatitis B virus, and non-viral.
Methods
Through collaborative efforts, we have established an effective specimen biobanking protocol, and we are using several techniques to analyze HCC, including whole genome sequencing, whole exome sequencing, gene-specific analysis, gene expression, and epigenetic analysis.
Results
We have completed whole genome sequencing on two patient samples, whole exome sequencing on 47 patient samples, gene-specific analysis on 94 patient samples, gene expression on 4 patient samples, and epigenetic analysis on 1 patient sample.
Conclusions
We hope to use these results to define novel genetic therapeutic strategies that may work in conjunction with surgical approaches to improve long-term patient and graft survival rates in patients with HCC. We also aim to provide a functional framework of a comprehensive program for genomic analysis that may be imitated by other institutions and for other tumors in the global quest toward personalized genomic medicine.
Effects of interchain couplings and anisotropy on a Haldane chain have been investigated by single-crystal inelastic neutron scattering and density functional theory (DFT) calculations on the model ...compound SrNi sub(2) V sub(2) O sub(8). Significant effects on low-energy excitation spectra are found where the Haldane gap ( Delta sub(0) approximately 0.41J, where J is the intrachain exchange interaction) is replaced by three energy minima at different antiferromagnetic zone centers due to the complex interchain couplings. Further, the triplet states are split into two branches by single-ion anisotropy. Quantitative information on the intrachain and interchain interactions as well as on the single-ion anisotropy is obtained from the analyses of the neutron scattering spectra by the random-phase approximation method. The presence of multiple competing interchain interactions is found from the analysis of the experimental spectra and is also confirmed by the DFT calculations. The interchain interactions are two orders of magnitude weaker than the nearest-neighbor intrachain interaction J = 8.7 meV. The DFT calculations reveal that the dominant intrachain nearest-neighbor interaction occurs via nontrivial extended superexchange pathways Ni-O-V-O-Ni involving the empty d orbital of V ions. The present single-crystal study also allows us to correctly position SrNi sub(2) V sub(2) O sub(8) in the theoretical D-J sub(perpendicular) phase diagram T. Sakai and M. Takahashi, Phys. Rev. B 42, 4537 (1990) (http://dx.doi.org/10.1103/PhysRevB.42.4537), showing where it lies within the spin-liquid phase.
Forest fires are major contributors of reactive gas- and particle-phase organic compounds to the atmosphere. We used offline high-resolution tandem mass spectrometry to perform a molecular-level ...speciation of gas- and particle-phase compounds sampled via aircraft from an evolving boreal forest fire smoke plume in Saskatchewan, Canada. We observed diverse multifunctional compounds containing oxygen, nitrogen, and sulfur (CHONS), whose structures, formation, and impacts are understudied. The dilution-corrected absolute ion abundance of particle-phase CHONS compounds increased with plume age by a factor of 6.4 over the first 4 h of downwind transport, and their relative contribution to the observed functionalized organic aerosol (OA) mixture increased from 19 % to 40 %. The dilution-corrected absolute ion abundance of particle-phase compounds with sulfide functional groups increased by a factor of 13 with plume age, and their relative contribution to observed OA increased from 4 % to 40 %. Sulfides were present in up to 75 % of CHONS compounds and the increases in sulfides were accompanied by increases in ring-bound nitrogen; both increased together with CHONS prevalence. A complex mixture of intermediate- and semi-volatile gas-phase organic sulfur species was observed in emissions from the fire and depleted downwind, representing potential precursors to particle-phase CHONS compounds. These results demonstrate CHONS formation from nitrogen- and oxygen-containing biomass burning emissions in the presence of reduced sulfur species. In addition, they highlight chemical pathways that may also be relevant in situations with elevated emissions of nitrogen- and sulfur-containing organic compounds from residential biomass burning and fossil fuel use (e.g., coal), respectively.
Background
Since the advent of the human genome, the era of personalized genomic medicine is indisputably in progress.
Methods
In an effort to contribute to the evolving knowledge of genomic ...medicine, we have aimed directly at building a bioresource bank for hepatocellular carcinoma. This tumor bank is based on the rigorous guidelines set forth by the National Cancer Institute, and it offers analytes to help elucidate the mechanisms of progression from cirrhosis to malignancy, risk factors for recurrence, and applicability of current treatment options to a diverse group of people.
Conclusions
Surgeons have a privileged position between patients (and their cancer) and the benches of basic science. Thus, we offer a primer based on our own experiences, from which surgeons may take elements to build their own bioresource bank for use in collaboration with others. We highlight some practicalities and pitfalls that could be overlooked, as well as a discussion of possible solutions.
In this work we report the airborne aerosol optical depth (AOD) from measurements within freshly emitted anthropogenic plumes arising from mining and processing operations in the Athabasca Oil Sands ...Region (AOSR) in the context of ground-based AERONET climatological daily averaged AODs at Fort McMurray (Alberta, Canada). During two flights on 9 and 18 June 2018, the NASA airborne 4STAR (Spectrometers for Sky-Scanning, Sun-Tracking Atmospheric Research) Sun photometer registered high fine-mode (FM, <1 µm) in-plume AODs of up to 0.4 and 0.9, respectively, in the vicinity of the plume source (<20 km). Particle composition shows that the plumes were associated with elevated concentrations of sulfates and ammonium. These high AODs significantly exceed climatological averages for June and were not captured by the nearby AERONET instrument (mean daily AODs of 0.10±0.01 and 0.07±0.02, maximum AOD of 0.12) due possibly to horizontal inhomogeneity of the plumes, plume dilution and winds which in certain cases were carrying the plume away from the ground-based instrument. The average 4STAR out-of-plume (background) AODs deviated only marginally from AERONET daily averaged values. While 4STAR AOD peaks were generally well correlated in time with peaks in the in situ-measured particle concentrations, we show that differences in particle size are the dominant factor in determining the 4STAR-derived AOD. During the two flights of 24 June and 5 July 2018 when plumes likely travelled distances of 60 km or more, the average 4STAR FM AOD increased by 0.01–0.02 over ∼50 km of downwind particle evolution, which was supported by the increases in layer AODs calculated from the in situ extinction measurements. Based on these observations as well as the increases in organic mass, we attribute the observed AOD increase, at least in part, to secondary organic aerosol formation. The in-plume and out-of-plume AODs for this second pair of flights, in contrast to clear differences in in situ optical and other measurements, were practically indistinguishable and compared favourably to AERONET within 0.01–0.02 AOD. This means that AERONET was generally successful in capturing the background AODs, but missed some of the spatially constrained high-AOD plumes with sources as close as 30–50 km, which is important to note since the AERONET measurements are generally thought to be representative of the regional AOD loading. The fact that industrial plumes can be associated with significantly higher AODs in the vicinity of the emission sources than previously reported from AERONET can potentially have an effect on estimating the AOSR radiative impact.
The concomitant occurrence of a vasculitic glomerulonephritis and membranous nephropathy in the same patient is unusual. We report data on 10 patients with this unusual combination.
Ten patients ...(nine males/one female; median age 63.5 years, range 30-70 years) presented between 1981 and 1995 with: acute renal failure (n = 3), nephrotic syndrome (n = 4), non-nephrotic range proteinuria and renal insufficiency (n = 3). The median serum creatinine at presentation was 296 mumol/l (range 65-1749 mumol/l). One patient had a vasculitic transformation from membranous nephropathy 5 years after the original presentation, coincident with an acute deterioration of renal function requiring dialysis; in all other patients the two glomerular disorders were seen together at presentation. Treatment was with oral prednisolone and cyclophosphamide (eight patients), of whom one also had plasma exchange; and oral prednisolone and azathioprine (one patient). Specific immunosuppressive treatment was withheld in one patient with histological evidence of chronic renal damage. Sera from four patients out of nine tested were positive for ANCA.
After a median follow-up of 3.5 years (range 2 months-10 years), renal function had improved in three patients and remained stable in two. Two patients required renal replacement therapy. Three patients had died: one was ANCA-negative and died of a systemic vasculitis, and the other two died of sepsis.
Membranous nephropathy complicated by a vasculitic glomerulonephritis: (1) has a more aggressive clinical course than membranous nephropathy alone, (2) appears to have an association with ANCA, (3) should be considered in those patients with an accelerated decline in renal function, and (4) may respond to treatment with immunosuppressive drugs.
Ultrasound velocity measurements of the orbital-degenerate frustrated spinel MgV2O4 are performed in the disorder-free high-purity single crystal which exhibits successive structural and ...antiferromagnetic phase transitions, and in the disorder-introduced single crystal which exhibits spin-glass-like behavior. The measurements reveal coexisting two types of anomalous temperature dependence of the elastic moduli in the cubic paramagnetic phase: Curie-type softening with decreasing temperature, and softening with a characteristic minimum with decreasing temperature. These elastic anomalies should respectively originate from the coexisting orbital fluctuations and spin-cluster excitations.
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