Tumor penetration of nanoparticles is crucial in nanomedicine, but the mechanisms of tumor penetration are poorly understood. This work presents a multidimensional, quantitative approach to ...investigate the tissue penetration behavior of nanoparticles, with focuses on the particle size effect on penetration pathways, in an MDA‐MB‐231 tumor spheroid model using a combination of spectrometry, microscopy, and synchrotron beamline techniques. Quasi‐spherical gold nanoparticles of different sizes are synthesized and incubated with 2D and 3D MDA‐MB‐231 cells and spheroids with or without an energy‐dependent cell uptake inhibitor. The distribution and penetration pathways of nanoparticles in spheroids are visualized and quantified by inductively coupled plasma mass spectrometry, two‐photon microscopy, and synchrotron X‐ray fluorescence microscopy. The results reveal that 15 nm nanoparticles penetrate spheroids mainly through an energy‐independent transcellular pathway, while 60 nm nanoparticles penetrate primarily through an energy‐dependent transcellular pathway. Meanwhile, 22 nm nanoparticles penetrate through both transcellular and paracellular pathways and they demonstrate the greatest penetration ability in comparison to other two sizes. The multidimensional analytical methodology developed through this work offers a generalizable approach to quantitatively study the tissue penetration of nanoparticles, and the results provide important insights into the designs of nanoparticles with high accumulation at a target site.
This work presents a multidimensional, quantitative approach to investigate the tissue penetration behavior of nanoparticles in tumor spheroids. The results reveal that 15 nm nanoparticles penetrate spheroids mainly through an energy‐independent transcellular pathway, while 60 nm nanoparticles penetrate primarily through an energy‐dependent transcellular pathway. Meanwhile, 22 nm nanoparticles penetrate through both transcellular and paracellular pathways.
Real-time monitoring of cancer cells' phenotypic evolution during therapy can provide vital tumour biology information for treatment management. Circulating tumour cell (CTC) analysis has emerged as ...a useful monitoring tool, but its routine usage is restricted by either limited multiplexing capability or sensitivity. Here, we demonstrate the use of antibody-conjugated and Raman reporter-coated gold nanoparticles for simultaneous labelling and monitoring of multiple CTC surface markers (named as "cell signature"), without the need for isolating individual CTCs. We observe cell heterogeneity and phenotypic changes of melanoma cell lines during molecular targeted treatment. Furthermore, we follow the CTC signature changes of 10 stage-IV melanoma patients receiving immunological or molecular targeted therapies. Our technique maps the phenotypic evolution of patient CTCs sensitively and rapidly, and shows drug-resistant clones having different CTC signatures of potential clinical value. We believe our proposed method is of general interest in the CTC relevant research and translation fields.
Cancer-derived small extracellular vesicles (sEVs) may be a promising drug delivery system that targets cancer cells due to their unique features, such as native homing ability, biological barrier ...crossing capability, and low immune response. However, the oncogenic cargos within them pose safety concerns, hence limiting their application thus far. We proposed using an electroporation-based strategy to extract the endogenous cargos from cancer-derived sEVs and demonstrated that their homing ability was still retained. A membrane fusion technique was used to fuse these sEVs with liposomes to form hybrid particles, which possessed both benefits of sEVs and liposomes. Anti-EGFR monoclonal antibodies were modified on the hybrid particles to improve their targeting ability further. The engineered hybrid particles showed higher drug loading ability that is 33.75 and 43.88% higher than that of liposomes and sEVs, respectively, and improved targeting ability by 52.23% higher than hybrid particles without modification. This delivery system showed >90% cell viability and enhanced treatment efficiency with 91.58 and 79.26% cell migration inhibition rates for the miR-21 inhibitor and gemcitabine, respectively.
Knowledge on the prevalence of sex chromosome abnormalities (SCAs) is limited, and delayed diagnosis or non-diagnosis of SCAs are a continuous concern. We aimed to investigate change over time in ...incidence, prevalence and age at diagnosis among Turner syndrome (TS), Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y).
This study is a nationwide cohort study in a public health care system. The Danish Cytogenetic Central Registry (DCCR) holds information on all karyotypes performed in Denmark since 1961. We identified all individuals in the DCCR with a relevant SCA during 1961-2014; TS: n = 1156; KS: n = 1235; Triple X: n = 197; and Double Y: n = 287. From Statistics Denmark, which holds an extensive collection of data on the Danish population, complete data concerning dates of death and migrations in and out of Denmark were retrieved for all individuals.
The prevalence among newborns was as follows: TS: 59 per 100,000 females; KS: 57 per 100,000 males; Triple X: 11 per 100,000 females; and Double Y: 18 per 100,000 males. Compared with the expected number among newborns, all TS, 38% of KS, 13% of Triple X, and 18% of Double Y did eventually receive a diagnosis. The incidence of TS with other karyotypes than 45,X (P < 0.0001), KS (P = 0.02), and Double Y (P = 0.03) increased during the study period whereas the incidence of 45,X TS decreased (P = 0.0006). The incidence of Triple X was stable (P = 0.22).
The prevalence of TS is higher than previously identified, and the karyotypic composition of the TS population is changing. Non-diagnosis is extensive among KS, Triple X and Double Y, whereas all TS seem to become diagnosed. The diagnostic activity has increased among TS with other karyotypes than 45,X as well as among KS and Double Y.
The Navy Global Environmental Model HOGAN, TIMOTHY F.; LIU, MING; RIDOUT, JAMES A. ...
Oceanography,
09/2014, Letnik:
27, Številka:
3
Journal Article
Recenzirano
Odprti dostop
On February 13, 2013, the US Navy's weather forecast system reached a milestone when the NAVy Global Environmental Model (NAVGEM) replaced the Navy Operational Global Atmospheric Prediction System ...(NOGAPS) for operational global weather prediction. The new operational system NAVGEM 1.1 combines a semi-Lagrangian/semi-implicit dynamical core together with advanced parameterizations of subgrid-scale moist processes, convection, ozone, and radiation. The NAVGEM dynamical core allows for much higher spatial resolutions without the need for the small time steps that would be necessary in NOGAPS. The increased computational efficiency is expected to enable significant increases in resolution in future NAVGEM releases. Model physics improvements in the NAVGEM 1.1 transition include representations of cloud liquid water, cloud ice water, and ozone as fully predicted constituents. Following successful testing of a new mass flux scheme, a second transition to NAVGEM 1.2 occurred on November 6, 2013. Addition of this mass flux parameterization to the eddy diffusion vertical mixing parameterization resulted in a reduction of the cold temperature bias of the lower troposphere over ocean and further increased the forecast skill of NAVGEM.
Sensitive and accurate identification of specific DNA mutations can influence clinical decisions. However accurate diagnosis from limiting samples such as circulating tumour DNA (ctDNA) is ...challenging. Current approaches based on fluorescence such as quantitative PCR (qPCR) and more recently, droplet digital PCR (ddPCR) have limitations in multiplex detection, sensitivity and the need for expensive specialized equipment. Herein we describe an assay capitalizing on the multiplexing and sensitivity benefits of surface-enhanced Raman spectroscopy (SERS) with the simplicity of standard PCR to address the limitations of current approaches. This proof-of-concept method could reproducibly detect as few as 0.1% (10 copies, CV < 9%) of target sequences thus demonstrating the high sensitivity of the method. The method was then applied to specifically detect three important melanoma mutations in multiplex. Finally, the PCR/SERS assay was used to genotype cell lines and ctDNA from serum samples where results subsequently validated with ddPCR. With ddPCR-like sensitivity and accuracy yet at the convenience of standard PCR, we believe this multiplex PCR/SERS method could find wide applications in both diagnostics and research.
Spatially resolved transcriptomics of tissue sections enables advances in fundamental and applied biomedical research. Here, we present Multiplexed Deterministic Barcoding in Tissue (xDBiT) to ...acquire spatially resolved transcriptomes of nine tissue sections in parallel. New microfluidic chips were developed to spatially encode mRNAs over a total tissue area of 1.17 cm
with a 50 µm resolution. Optimization of the biochemical protocol increased read and gene counts per spot by one order of magnitude compared to previous reports. Furthermore, the introduction of alignment markers allowed seamless registration of images and spatial transcriptomic spots. Together with technological advances, we provide an open-source computational pipeline to prepare raw sequencing data for downstream analysis. The functionality of xDBiT was demonstrated by acquiring 16 spatially resolved transcriptomic datasets from five different murine organs, including the cerebellum, liver, kidney, spleen, and heart. Factor analysis and deconvolution of spatial transcriptomes allowed for in-depth characterization of the murine kidney.
Vibration assistance has increasing applications in metal removal processes. This method induces high-frequency and low-amplitude vibration in the feed direction during cutting, and has the potential ...to reduce cutting forces leading to improved surface quality and reduced tool wear. Note that this cutting process is distinct from ultrasonic machining. This paper presents a thrust force model to predict the thrust force during vibration-assisted drilling of aluminum 6061-T6. This model incorporates plowing force and strain rate-dependent shear strength to provide more accurate predictions than the existing model. The results of 72 drilling experiments with TiN-coated standard twist drills are reported. The predictions from the developed thrust force model are compared with the experimental results. The comparison demonstrates that the maximum deviation between the predictions and the averaged values of the experimental measurements is 20% using the existing model and only 7% using the proposed model.
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