Tumor-vascular interactions promote STING-driven inflammation in the tumor microenvironment

The recruitment of T cells following intratumoral administration of Stimulation of Interferon Genes (STING) agonists in the tumor microenvironment (TME) is a critical event in the STING-driven antitumor immune response, a pathway with great relevance in the context of cancer immunotherapy. We have previously demonstrated that LKB1 mutation is associated with suppression of tumor cell STING levels and reduced production of T-cell chemoattractants such as CXCL10 in KRAS-driven non-small cell lung cancer (NSCLC). Consistent with this, immunohistochemical staining of patient samples showed poor infiltration of CD3, CD4, and CD8 T cells into LKB1 negative versus LKB1 intact cancer epithelium, and instead, retention of T-cells in stroma. To examine how LKB1 alters immune cell recruitment in a STING-dependent manner, we used a 3-D microfluidic co-culture system to study interactions between vasculature and tumor spheroids derived from a KRAS/LKB1 mutated (KL) cell line with LKB1 reconstitution +/- STING deletion. To form the vasculature, we co-cultured tumor spheroids with fibroblasts and endothelial cells for 7 days, and identified changes in morphology, cytokine production, and gene expression that occur in co-culture. We first observed that co-culture induced synergistic production of multiple immune cell chemo-attractants such as CXCL10, CCL2, CCL5, and G-CSF. Interestingly, this more physiologic ex vivo tumor model of LKB1 reconstitution revealed particularly strong cooperative production of STING-dependent cytokines such as CXCL10 in the vasculature. Moreover, STING depletion in LKB1 reconstituted tumor cells did not significantly attenuate production of CXCL10 and other cytokines in co-culture, suggesting that tumor/vessel interaction may promote STING activation in the vasculature regardless of cancer cell-intrinsic STING function. Furthermore, although there was no appreciable response after treatment of KL cancer cells with cGAMP based STING agonists, treatment of isolated 3-D vascular networks with cGAMP enhanced vascular permeability and increased production of CXCL10 and CCL5, possibly contributing to defective chemokine gradients that retain T cells near the vasculature. Thus, developing these more complex models that incorporate the vasculature may elucidate important aspects of STING biology and may ultimately aid further development of effective immunotherapies targeting this signaling axi

Simulation of Guided Wave Propagation in Isotropic and Composite Structures using LISA

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97117/1/AIAA2012-1387.pd

Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium falciparum

Malaria parasites use hemoglobin (Hb) as a major nutrient source in the intraerythrocytic stage, during which heme is converted to hemozoin (Hz). The formation of Hz is essential for parasite survival, but to date, the underlying mechanisms of Hb degradation and Hz formation are poorly understood. We report the presence of a ∼200-kDa protein complex in the food vacuole that is required for Hb degradation and Hz formation. This complex contains several parasite proteins, including falcipain 2/2', plasmepsin II, plasmepsin IV, histo aspartic protease, and heme detoxification protein. The association of these proteins is evident from coimmunoprecipitation followed by mass spectrometry, coelution from a gel filtration column, cosedimentation on a glycerol gradient, and in vitro protein interaction analyses. To functionally characterize this complex, we developed an in vitro assay using two of the proteins present in the complex. Our results show that falcipain 2 and heme detoxification protein associate with each other to efficiently convert Hb to Hz. We also used this in vitro assay to elucidate the modes of action of chloroquine and artemisinin. Our results reveal that both chloroquine and artemisinin act during the heme polymerization step, and chloroquine also acts at the Hb degradation step. These results may have important implications in the development of previously undefined antimalarials

Quantum-mechanical effects in photoluminescence from thin crystalline gold films

Luminescence constitutes a unique source of insight into hot carrier processes in metals, including those in plasmonic nanostructures used for sensing and energy applications. However, being weak in nature, metal luminescence remains poorly understood, its microscopic origin strongly debated, and its potential for unravelling nanoscale carrier dynamics largely unexploited. Here, we reveal quantum-mechanical effects emanating in the luminescence from thin monocrystalline gold flakes. Specifically, we present experimental evidence, supported by first-principles simulations, to demonstrate its photoluminescence origin when exciting in the interband regime. Our model allows us to identify changes to the measured gold luminescence due to quantum-mechanical effects as the gold film thickness is reduced. Excitingly, such effects are observable in the luminescence signal from flakes up to 40 nm in thickness, associated with the out-of-plane discreteness of the electronic band structure near the Fermi level. We qualitatively reproduce the observations with first-principles modelling, thus establishing a unified description of luminescence in gold and enabling its widespread application as a probe of carrier dynamics and light-matter interactions in this material. Our study paves the way for future explorations of hot-carriers and charge-transfer dynamics in a multitude of material systems.Comment: Main text 21 pages and 4 figures. Supplemental Information 33 pages and 17 figure

The quest for effective pain control during suture adjustment after strabismus surgery: a study evaluating supplementation of 2% lidocaine with 0.4% ropivacaine

PURPOSE: To determine whether the addition of 0.4% ropivacaine to the standard 2% lidocaine peribulbar anesthetic block improves pain scores during suture adjustment in patients undergoing strabismus surgery with adjustable sutures. METHODS: Prospective, double-blind study of 30 adult patients aged 21–84 years scheduled for elective strabismus surgery with adjustable sutures. Patients were divided into two groups of 15 patients each based on the local anesthetic. Group A received 2% lidocaine and Group B received 2% lidocaine/0.4% ropivacaine. Pain was assessed using the visual analog scale (VAS) preoperatively and at 2, 4, and 6 hours postoperatively. The Lancaster red-green test was used to measure ocular motility at the same time points. RESULTS: The pain scores in the two groups were low and similar at all measurement intervals. The VAS for Group A versus Group B at 2 hours (1.7 versus 2.4, P=0.5) and 4 hours (3.5 versus 3.7, P=0.8) showed no benefit from the addition of ropivacaine. At 6 hours, the VAS (3.7 versus 2.7) was not statistically significant, but the 95% confidence interval indicated that ropivacaine may provide some benefit. A repeated measures ANOVA did not find a statistically significant difference in VAS scores over time (P=0.9). In addition, the duration of akinesia was comparable in both groups (P=0.7). CONCLUSION: We conclude that the 50:50 mixture of 2% lidocaine with 0.4% ropivacaine as compared to 2% lidocaine in peribulbar anesthetic blocks in adjustable-suture strabismus surgery does not produce significant improvements in pain control during the postoperative and adjustment phases. In addition, ropivacaine did not impair return of full ocular motility at 6 hours, which is advantageous in adjustable-suture strabismus surgery

Structure and vibrational properties of carbon tubules

The structure of multilayered carbon tubules has been investigated by electron microscopy and X-ray diffraction. The structure of tubules is characterized by disorder in the stacking of cylindrical graphene sheets. Raman scattering measurements have been carried out in tubules and compared with graphite. The observed features in the Raman spectra in tubules can be understood in terms of the influence of disorder. The additional Raman modes predicted for single layer carbon tubules have not been observed

1D-confined crystallization routes for tungsten phosphides

Topological materials confined in one-dimension (1D) can transform computing technologies, such as 1D topological semimetals for nanoscale interconnects and 1D topological superconductors for fault-tolerant quantum computing. As such, understanding crystallization of 1D-confined topological materials is critical. Here, we demonstrate 1D-confined crystallization routes during template-assisted nanowire synthesis where we observe diameter-dependent phase selectivity for topological metal tungsten phosphides. A phase bifurcation occurs to produce tungsten monophosphide and tungsten diphosphide at the cross-over nanowire diameter of ~ 35 nm. Four-dimensional scanning transmission electron microscopy was used to identify the two phases and to map crystallographic orientations of grains at a few nm resolution. The 1D-confined phase selectivity is attributed to the minimization of the total surface energy, which depends on the nanowire diameter and chemical potentials of precursors. Theoretical calculations were carried out to construct the diameter-dependent phase diagram, which agrees with experimental observations. Our find-ings suggest a new crystallization route to stabilize topological materials confined in 1D.Comment: 5 figure