Preoperative Radiologic and Postoperative Pathologic Risk Factors for Early Intra-Hepatic Recurrence in Hepatocellular Carcinoma Patients Who Underwent Curative Resection

PURPOSE: The risk of hepatocellular carcinoma (HCC) recurrence must be considered ahead of surgery. This study was undertaken to identify pre-operative risk factors for early intrahepatic recurrence of HCC after curative resection in a large-scale. MATERIALS AND METHODS: We retrospectively reviewed the preoperative three-phase multi-detector CT (MDCT) and laboratory data for 240 HCC patients who underwent curative resection; tumor size, number, gross shape, capsule integrity, distinctiveness of tumor margin, portal vein thrombosis (PVT), alpha-fetoprotein level (AFP), and protein induced by vitamin K absence-II (PIVKA-II) levels were assessed. Surgical pathology was reviewed; tumor differentiation, capsule, necrosis, and micro-vessel invasion were recorded. RESULTS: HCC recurred in 61 patients within six months (early recurrence group), but not in 179 patients (control group). In univariate analysis, large tumor size (p = 0.018), shape (p = 0.028), poor capsule integrity (p = 0.046), elevated AFP (p = 0.015), and PIVKA-II (p = 0.008) were significant preoperative risk factors. Among the pathologic features, PVT (p = 0.023), Glisson's capsule penetration (p = 0.033), microvascular invasion (p < 0.001), and poor differentiation (p = 0.001) showed statistical significance. In multivariate analysis, only the histopathologic parameters of microvascular invasion and poor differentiation achieved statistical significance. CONCLUSION: Preoperative CT and laboratory parameters showed limited value, while the presence of microscopic vascular tumor invasion and poorly differentiated HCC correlated with higher risk of early recurrence after curative resection.ope

Engineered Contrast Agents in a Single Structure for T1-T2 Dual Magnetic Resonance Imaging

[EN] The development of contrast agents (CAs) for Magnetic Resonance Imaging (MRI) with T-1-T-2 dual-mode relaxivity requires the accurate assembly of T-1 and T-2 magnetic centers in a single structure. In this context, we have synthesized a novel hybrid material by monitoring the formation of Prussian Blue analogue Gd(H2O)(4)[Fe(CN)(6)] nanoparticles with tailored shape (from nanocrosses to nanorods) and size, and further protection with a thin and homogeneous silica coating through hydrolysis and polymerization of silicate at neutral pH. The resulting Gd(H2O)(4)[Fe(CN)(6)]@SiO2 magnetic nanoparticles are very stable in biological fluids. Interestingly, this combination of Gd and Fe magnetic centers closely packed in the crystalline network promotes a magnetic synergistic effect, which results in significant improvement of longitudinal relaxivity with regards to soluble Gd3+ chelates, whilst keeping the high transversal relaxivity inherent to the iron component. As a consequence, this material shows excellent activity as MRI CA, improving positive and negative contrasts in T-1- and T-2-weighted MR images, both in in vitro (e.g., phantom) and in vivo (e.g., Sprague-Dawley rats) models. In addition, this hybrid shows a high biosafety profile and has strong ability to incorporate organic molecules on the surface with variable functionality, displaying great potential for further clinical application.Financial support of the Spanish Ministry of Economy and Competitiveness (projects TEC2016-80976-R and SEV-2016-0683) is gratefully acknowledged. Dr E. M. Rivero thanks the Cursol Foundation for a post-doctoral scholarship. A. C. G. also thanks the La Caixa Foundation for a Ph.D. scholarship. We fully appreciate the assistance of the Electron Microscopy Service of the UPV and INSCANNER S.L.Cabrera-García, A.; Checa-Chavarria, E.; Pacheco-Torres, J.; Bernabeu-Sanz, A.; Vidal Moya, JA.; Rivero-Buceta, EM.; Sastre Navarro, GI.... (2018). Engineered Contrast Agents in a Single Structure for T1-T2 Dual Magnetic Resonance Imaging. Nanoscale. 10(14):6349-6360. https://doi.org/10.1039/c7nr07948fS634963601014Bolan, P. J., Nelson, M. T., Yee, D., & Garwood, M. (2005). Imaging in breast cancer: Magnetic resonance spectroscopy. Breast Cancer Research, 7(4). doi:10.1186/bcr1202Mitchell, R. E., Katz, M. H., McKiernan, J. M., & Benson, M. C. (2005). The evaluation and staging of clinically localized prostate cancer. Nature Clinical Practice Urology, 2(8), 356-357. doi:10.1038/ncpuro0260Colombo, M., Carregal-Romero, S., Casula, M. F., Gutiérrez, L., Morales, M. P., Böhm, I. B., … Parak, W. J. (2012). Biological applications of magnetic nanoparticles. Chemical Society Reviews, 41(11), 4306. doi:10.1039/c2cs15337hMi, P., Kokuryo, D., Cabral, H., Wu, H., Terada, Y., Saga, T., … Kataoka, K. (2016). A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nature Nanotechnology, 11(8), 724-730. doi:10.1038/nnano.2016.72Cheng, W., Ping, Y., Zhang, Y., Chuang, K.-H., & Liu, Y. (2013). Magnetic Resonance Imaging (MRI) Contrast Agents for Tumor Diagnosis. Journal of Healthcare Engineering, 4(1), 23-46. doi:10.1260/2040-2295.4.1.23Lauffer, R. B. (1987). Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design. Chemical Reviews, 87(5), 901-927. doi:10.1021/cr00081a003Caravan, P., Ellison, J. J., McMurry, T. J., & Lauffer, R. B. (1999). Gadolinium(III) Chelates as MRI Contrast Agents:  Structure, Dynamics, and Applications. Chemical Reviews, 99(9), 2293-2352. doi:10.1021/cr980440xDavis, M. E., Chen, Z., & Shin, D. M. (2008). Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Reviews Drug Discovery, 7(9), 771-782. doi:10.1038/nrd2614Lee, N., & Hyeon, T. (2012). Designed synthesis of uniformly sized iron oxide nanoparticles for efficient magnetic resonance imaging contrast agents. Chem. Soc. Rev., 41(7), 2575-2589. doi:10.1039/c1cs15248cHasebroock, K. M., & Serkova, N. J. (2009). Toxicity of MRI and CT contrast agents. Expert Opinion on Drug Metabolism & Toxicology, 5(4), 403-416. doi:10.1517/17425250902873796Khawaja, A. Z., Cassidy, D. B., Al Shakarchi, J., McGrogan, D. G., Inston, N. G., & Jones, R. G. (2015). Revisiting the risks of MRI with Gadolinium based contrast agents—review of literature and guidelines. Insights into Imaging, 6(5), 553-558. doi:10.1007/s13244-015-0420-2Lee, N., Yoo, D., Ling, D., Cho, M. H., Hyeon, T., & Cheon, J. (2015). Iron Oxide Based Nanoparticles for Multimodal Imaging and Magnetoresponsive Therapy. Chemical Reviews, 115(19), 10637-10689. doi:10.1021/acs.chemrev.5b00112Zhou, Z., Bai, R., Munasinghe, J., Shen, Z., Nie, L., & Chen, X. (2017). T1–T2 Dual-Modal Magnetic Resonance Imaging: From Molecular Basis to Contrast Agents. ACS Nano, 11(6), 5227-5232. doi:10.1021/acsnano.7b03075Shin, T.-H., Choi, Y., Kim, S., & Cheon, J. (2015). Recent advances in magnetic nanoparticle-based multi-modal imaging. Chemical Society Reviews, 44(14), 4501-4516. doi:10.1039/c4cs00345dBae, K. H., Kim, Y. B., Lee, Y., Hwang, J., Park, H., & Park, T. G. (2010). Bioinspired Synthesis and Characterization of Gadolinium-Labeled Magnetite Nanoparticles for Dual ContrastT1- andT2-Weighted Magnetic Resonance Imaging. Bioconjugate Chemistry, 21(3), 505-512. doi:10.1021/bc900424uPeng, Y.-K., Lui, C. N. P., Chen, Y.-W., Chou, S.-W., Raine, E., Chou, P.-T., … Tsang, S. C. E. (2017). Engineering of Single Magnetic Particle Carrier for Living Brain Cell Imaging: A Tunable T1-/T2-/Dual-Modal Contrast Agent for Magnetic Resonance Imaging Application. Chemistry of Materials, 29(10), 4411-4417. doi:10.1021/acs.chemmater.7b00884Choi, J., Lee, J.-H., Shin, T.-H., Song, H.-T., Kim, E. Y., & Cheon, J. (2010). Self-Confirming «AND» Logic Nanoparticles for Fault-Free MRI. Journal of the American Chemical Society, 132(32), 11015-11017. doi:10.1021/ja104503gShin, T.-H., Choi, J., Yun, S., Kim, I.-S., Song, H.-T., Kim, Y., … Cheon, J. (2014). T1andT2Dual-Mode MRI Contrast Agent for Enhancing Accuracy by Engineered Nanomaterials. ACS Nano, 8(4), 3393-3401. doi:10.1021/nn405977tCheng, K., Yang, M., Zhang, R., Qin, C., Su, X., & Cheng, Z. (2014). Hybrid Nanotrimers for Dual T1 and T2-Weighted Magnetic Resonance Imaging. ACS Nano, 8(10), 9884-9896. doi:10.1021/nn500188yZhou, Z., Huang, D., Bao, J., Chen, Q., Liu, G., Chen, Z., … Gao, J. (2012). A Synergistically EnhancedT1-T2Dual-Modal Contrast Agent. Advanced Materials, 24(46), 6223-6228. doi:10.1002/adma.201203169Huang, G., Li, H., Chen, J., Zhao, Z., Yang, L., Chi, X., … Gao, J. (2014). Tunable T1and T2contrast abilities of manganese-engineered iron oxide nanoparticles through size control. Nanoscale, 6(17), 10404. doi:10.1039/c4nr02680bPerrier, M., Kenouche, S., Long, J., Thangavel, K., Larionova, J., Goze-Bac, C., … Guari, Y. (2013). Investigation on NMR Relaxivity of Nano-Sized Cyano-Bridged Coordination Polymers. Inorganic Chemistry, 52(23), 13402-13414. doi:10.1021/ic401710jPerera, V. S., Yang, L. D., Hao, J., Chen, G., Erokwu, B. O., Flask, C. A., … Huang, S. D. (2014). Biocompatible Nanoparticles of KGd(H2O)2[Fe(CN)6]·H2O with Extremely HighT1-Weighted Relaxivity Owing to Two Water Molecules Directly Bound to the Gd(III) Center. Langmuir, 30(40), 12018-12026. doi:10.1021/la501985pCai, X., Gao, W., Ma, M., Wu, M., Zhang, L., Zheng, Y., … Shi, J. (2015). A Prussian Blue-Based Core-Shell Hollow-Structured Mesoporous Nanoparticle as a Smart Theranostic Agent with Ultrahigh pH-Responsive Longitudinal Relaxivity. Advanced Materials, 27(41), 6382-6389. doi:10.1002/adma.201503381Yang, L., Zhou, Z., Liu, H., Wu, C., Zhang, H., Huang, G., … Gao, J. (2015). Europium-engineered iron oxide nanocubes with high T1and T2contrast abilities for MRI in living subjects. Nanoscale, 7(15), 6843-6850. doi:10.1039/c5nr00774gCabrera-García, A., Vidal-Moya, A., Bernabeu, Á., Sánchez-González, J., Fernández, E., & Botella, P. (2015). Gd–Si oxide mesoporous nanoparticles with pre-formed morphology prepared from a Prussian blue analogue template. Dalton Transactions, 44(31), 14034-14041. doi:10.1039/c5dt01928aCabrera-García, A., Vidal-Moya, A., Bernabeu, Á., Pacheco-Torres, J., Checa-Chavarria, E., Fernández, E., & Botella, P. (2016). Gd-Si Oxide Nanoparticles as Contrast Agents in Magnetic Resonance Imaging. Nanomaterials, 6(6), 109. doi:10.3390/nano6060109Botella, P., Corma, A., & Quesada, M. (2012). Synthesis of ordered mesoporous silica templated with biocompatible surfactants and applications in controlled release of drugs. Journal of Materials Chemistry, 22(13), 6394. doi:10.1039/c2jm16291aMascharak, P. K. (1986). Convenient synthesis of tris(tetraethylammonium) hexacyanoferrate(III) and its use as an oxidant with tunable redox potential. Inorganic Chemistry, 25(3), 245-247. doi:10.1021/ic00223a001Clemments, A. M., Muniesa, C., Landry, C. C., & Botella, P. (2014). Effect of surface properties in protein corona development on mesoporous silica nanoparticles. RSC Adv., 4(55), 29134-29138. doi:10.1039/c4ra03277bOyane, A., Kim, H.-M., Furuya, T., Kokubo, T., Miyazaki, T., & Nakamura, T. (2003). Preparation and assessment of revised simulated body fluids. Journal of Biomedical Materials Research, 65A(2), 188-195. doi:10.1002/jbm.a.10482Blüml, S., Schad, L. R., Stepanow, B., & Lorenz, W. J. (1993). Spin-lattice relaxation time measurement by means of a TurboFLASH technique. Magnetic Resonance in Medicine, 30(3), 289-295. doi:10.1002/mrm.1910300304Hennig, J., & Friedburg, H. (1988). Clinical applications and methodological developments of the RARE technique. Magnetic Resonance Imaging, 6(4), 391-395. doi:10.1016/0730-725x(88)90475-4Hennig, J., Nauerth, A., & Friedburg, H. (1986). RARE imaging: A fast imaging method for clinical MR. Magnetic Resonance in Medicine, 3(6), 823-833. doi:10.1002/mrm.1910030602Yamada, M., & Yonekura, S. (2009). Nanometric Metal−Organic Framework of Ln[Fe(CN)6]: Morphological Analysis and Thermal Conversion Dynamics by Direct TEM Observation. The Journal of Physical Chemistry C, 113(52), 21531-21537. doi:10.1021/jp907180eNavarro, M. C., Pannunzio-Miner, E. V., Pagola, S., Gómez, M. I., & Carbonio, R. E. (2005). Structural refinement of Nd[Fe(CN)6]·4H2O and study of NdFeO3 obtained by its oxidative thermal decomposition at very low temperatures. Journal of Solid State Chemistry, 178(3), 847-854. doi:10.1016/j.jssc.2004.11.026Ding, Y., Chu, X., Hong, X., Zou, P., & Liu, Y. (2012). The infrared fingerprint signals of silica nanoparticles and its application in immunoassay. Applied Physics Letters, 100(1), 013701. doi:10.1063/1.3673549Botella, P., Abasolo, I., Fernández, Y., Muniesa, C., Miranda, S., Quesada, M., … Corma, A. (2011). Surface-modified silica nanoparticles for tumor-targeted delivery of camptothecin and its biological evaluation. Journal of Controlled Release, 156(2), 246-257. doi:10.1016/j.jconrel.2011.06.039Na, H. B., Lee, J. H., An, K., Park, Y. I., Park, M., Lee, I. S., … Hyeon, T. (2007). Development of aT1 Contrast Agent for Magnetic Resonance Imaging Using MnO Nanoparticles. Angewandte Chemie International Edition, 46(28), 5397-5401. doi:10.1002/anie.200604775Deng, Y., Li, E., Cheng, X., Zhu, J., Lu, S., Ge, C., … Pan, Y. (2016). Facile preparation of hybrid core–shell nanorods for photothermal and radiation combined therapy. Nanoscale, 8(7), 3895-3899. doi:10.1039/c5nr09102kBottrill, M., Kwok, L., & Long, N. J. (2006). Lanthanides in magnetic resonance imaging. Chemical Society Reviews, 35(6), 557. doi:10.1039/b516376pZhang, W., Martinelli, J., Peters, J. A., van Hengst, J. M. A., Bouwmeester, H., Kramer, E., … Djanashvili, K. (2017). Surface PEG Grafting Density Determines Magnetic Relaxation Properties of Gd-Loaded Porous Nanoparticles for MR Imaging Applications. ACS Applied Materials & Interfaces, 9(28), 23458-23465. doi:10.1021/acsami.7b05912Li, Y., Chen, T., Tan, W., & Talham, D. R. (2014). Size-Dependent MRI Relaxivity and Dual Imaging with Eu0.2Gd0.8PO4·H2O Nanoparticles. Langmuir, 30(20), 5873-5879. doi:10.1021/la500602xT. L. Riss , R. A.Moravec , A. L.Niles , S.Duellman , H. A.Benink , T. J.Worzella and L.Minor , Cell Viability Assays , in Assay Guidance Manual , Eli Lilly & Company and the National Center for Advancing Translational Sciences , Bethesda, MD , 2012Mahmoudi, M., Lynch, I., Ejtehadi, M. R., Monopoli, M. P., Bombelli, F. B., & Laurent, S. (2011). Protein−Nanoparticle Interactions: Opportunities and Challenges. Chemical Reviews, 111(9), 5610-5637. doi:10.1021/cr100440gLu, J., Liong, M., Li, Z., Zink, J. I., & Tamanoi, F. (2010). Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small, 6(16), 1794-1805. doi:10.1002/smll.20100053

Disulfide Bridges Remain Intact while Native Insulin Converts into Amyloid Fibrils

Amyloid fibrils are β-sheet-rich protein aggregates commonly found in the organs and tissues of patients with various amyloid-associated diseases. Understanding the structural organization of amyloid fibrils can be beneficial for the search of drugs to successfully treat diseases associated with protein misfolding. The structure of insulin fibrils was characterized by deep ultraviolet resonance Raman (DUVRR) and Nuclear Magnetic Resonance (NMR) spectroscopy combined with hydrogen-deuterium exchange. The compositions of the fibril core and unordered parts were determined at single amino acid residue resolution. All three disulfide bonds of native insulin remained intact during the aggregation process, withstanding scrambling. Three out of four tyrosine residues were packed into the fibril core, and another aromatic amino acid, phenylalanine, was located in the unordered parts of insulin fibrils. In addition, using all-atom MD simulations, the disulfide bonds were confirmed to remain intact in the insulin dimer, which mimics the fibrillar form of insulin

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV