Radiomics-Based Deep Learning Prediction of Overall Survival in Non-Small-Cell Lung Cancer Using Contrast-Enhanced Computed Tomography.

Patient outcomes of non-small-cell lung cancer (NSCLC) vary because of tumor heterogeneity and treatment strategies. This study aimed to construct a deep learning model combining both radiomic and clinical features to predict the overall survival of patients with NSCLC. To improve the reliability of the proposed model, radiomic analysis complying with the Image Biomarker Standardization Initiative and the compensation approach to integrate multicenter datasets were performed on contrast-enhanced computed tomography (CECT) images. Pretreatment CECT images and the clinical data of 492 patients with NSCLC from two hospitals were collected. The deep neural network architecture, DeepSurv, with the input of radiomic and clinical features was employed. The performance of survival prediction model was assessed using the C-index and area under the curve (AUC) 8, 12, and 24 months after diagnosis. The performance of survival prediction that combined eight radiomic features and five clinical features outperformed that solely based on radiomic or clinical features. The C-index values of the combined model achieved 0.74, 0.75, and 0.75, respectively, and AUC values of 0.76, 0.74, and 0.73, respectively, 8, 12, and 24 months after diagnosis. In conclusion, combining the traits of pretreatment CECT images, lesion characteristics, and treatment strategies could effectively predict the survival of patients with NSCLC using a deep learning model.

Evaluation of Time-of-Flight Secondary Ion Mass Spectrometry Spectra of Peptides by Random Forest with Amino Acid Labels: Results from a Versailles Project on Advanced Materials and Standards Interlaboratory Study.

We report the results of a VAMAS (Versailles Project on Advanced Materials and Standards) interlaboratory study on the identification of peptide sample TOF-SIMS spectra by machine learning. More than 1000 time-of-flight secondary ion mass spectrometry (TOF-SIMS) spectra of six peptide model samples (one of them was a test sample) were collected using 27 TOF-SIMS instruments from 25 institutes of six countries, the U. S., the U. K., Germany, China, South Korea, and Japan. Because peptides have systematic and simple chemical structures, they were selected as model samples. The intensity of peaks in every TOF-SIMS spectrum was extracted using the same peak list and normalized to the total ion count. The spectra of the test peptide sample were predicted by Random Forest with 20 amino acid labels. The accuracy of the prediction for the test spectra was 0.88. Although the prediction of an unknown peptide was not perfect, it was shown that all of the amino acids in an unknown peptide can be determined by Random Forest prediction and the TOF-SIMS spectra. Moreover, the prediction of peptides, which are included in the training spectra, was almost perfect. Random Forest also suggests specific fragment ions from an amino acid residue Q, whose fragment ions detected by TOF-SIMS have not been reported, in the important features. This study indicated that the analysis using Random Forest, which enables translation of the mathematical relationships to chemical relationships, and the multi labels representing monomer chemical structures, is useful to predict the TOF-SIMS spectra of an unknown peptide.

Characterizing protein G B1 orientation and its effect on immunoglobulin G antibody binding using XPS, ToF-SIMS, and quartz crystal microbalance with dissipation monitoring.

Controlling how proteins are immobilized (e.g., controlling their orientation and conformation) is essential for developing and optimizing the performance of in vitro protein-binding devices, such as enzyme-linked immunosorbent assays. Characterizing the identity, orientation, etc., of proteins in complex mixtures of immobilized proteins requires a multitechnique approach. The focus of this work was to control and characterize the orientation of protein G B1, an immunoglobulin G (IgG) antibody-binding domain of protein G, on well-defined surfaces and to measure the effect of protein G B1 orientation on IgG antibody binding. The surface sensitivity of time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to distinguish between different proteins and their orientation on both flat and nanoparticle gold surfaces by monitoring intensity changes of characteristic amino acid mass fragments. Amino acids distributed asymmetrically were used to calculate peak intensity ratios from ToF-SIMS data to determine the orientation of protein G B1 cysteine mutants covalently attached to a maleimide surface. To study the effect of protein orientation on antibody binding, multilayer protein films on flat gold surfaces were formed by binding IgG to the immobilized protein G B1 films. Quartz crystal microbalance with dissipation monitoring and x-ray photoelectron spectroscopy analysis revealed that coverage and orientation affected the antibody-binding process. At high protein G B1 coverage, the cysteine mutant immobilized in an end-on orientation with the C-terminus exposed bound 443 ng/cm2 of whole IgG (H + L) antibodies. In comparison, the high coverage cysteine mutant immobilized in an end-on orientation with the N-terminus exposed did not bind detectable amounts of whole IgG (H + L) antibodies.

Versailles Project on Advanced Materials and Standards Interlaboratory Study on Measuring the Thickness and Chemistry of Nanoparticle Coatings Using XPS and LEIS.

We report the results of a VAMAS (Versailles Project on Advanced Materials and Standards) inter-laboratory study on the measurement of the shell thickness and chemistry of nanoparticle coatings. Peptide-coated gold particles were supplied to laboratories in two forms: a colloidal suspension in pure water and; particles dried onto a silicon wafer. Participants prepared and analyzed these samples using either X-ray photoelectron spectroscopy (XPS) or low energy ion scattering (LEIS). Careful data analysis revealed some significant sources of discrepancy, particularly for XPS. Degradation during transportation, storage or sample preparation resulted in a variability in thickness of 53 %. The calculation method chosen by XPS participants contributed a variability of 67 %. However, variability of 12 % was achieved for the samples deposited using a single method and by choosing photoelectron peaks that were not adversely affected by instrumental transmission effects. The study identified a need for more consistency in instrumental transmission functions and relative sensitivity factors, since this contributed a variability of 33 %. The results from the LEIS participants were more consistent, with variability of less than 10 % in thickness and this is mostly due to a common method of data analysis. The calculation was performed using a model developed for uniform, flat films and some participants employed a correction factor to account for the sample geometry, which appears warranted based upon a simulation of LEIS data from one of the participants and comparison to the XPS results.

A Technique for Calculation of Shell Thicknesses for Core-Shell-Shell Nanoparticles from XPS Data.

This paper extends a straightforward technique for the calculation of shell thicknesses in core-shell nanoparticles to the case of core-shell-shell nanoparticles using X-ray Photoelectron Spectroscopy (XPS) data. This method can be applied by XPS analysts and does not require any numerical simulation or advanced knowledge, although iteration is required in the case where both shell thicknesses are unknown. The standard deviation in the calculated thicknesses vs simulated values is typically less than 10%, which is the uncertainty of the electron attenuation lengths used in XPS analysis.

Quantifying the Impact of Nanoparticle Coatings and Nonuniformities on XPS Analysis: Gold/Silver Core-Shell Nanoparticles.

Spectral modeling of photoelectrons can serve as a valuable tool when combined with X-ray photoelectron spectroscopy (XPS) analysis. Herein, a new version of the NIST Simulation of Electron Spectra for Surface Analysis (SESSA 2.0) software, capable of directly simulating spherical multilayer NPs, was applied to model citrate stabilized Au/Ag-core/shell nanoparticles (NPs). The NPs were characterized using XPS and scanning transmission electron microscopy (STEM) to determine the composition and morphology of the NPs. The Au/Ag-core/shell NPs were observed to be polydispersed in size, nonspherical, and contain off-centered Au-cores. Using the average NP dimensions determined from STEM analysis, SESSA spectral modeling indicated that washed Au/Ag-core-shell NPs were stabilized with a 0.8 nm layer of sodium citrate and a 0.05 nm (one wash) or 0.025 nm (two wash) layer of adventitious hydrocarbon, but did not fully account for the observed XPS signal from the Au-core. This was addressed by a series of simulations and normalizations to account for contributions of NP nonsphericity and off-centered Au-cores. Both of these nonuniformities reduce the effective Ag-shell thickness, which effect the Au-core photoelectron intensity. The off-centered cores had the greatest impact for the particles in this study. When the contributions from the geometrical nonuniformities are included in the simulations, the SESSA generated elemental compositions that matched the XPS elemental compositions. This work demonstrates how spectral modeling software such as SESSA, when combined with experimental XPS and STEM measurements, advances the ability to quantitatively assess overlayer thicknesses for multilayer core-shell NPs and deal with complex, nonideal geometrical properties.

Accelerated neuronal differentiation toward motor neuron lineage from human embryonic stem cell line (H9).

Motor neurons loss plays a pivotal role in the pathoetiology of various debilitating diseases such as, but not limited to, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, and spinal muscular atrophy. However, advancement in motor neuron replacement therapy has been significantly constrained by the difficulties in large-scale production at a cost-effective manner. Current methods to derive motor neuron heavily rely on biochemical stimulation, chemical biological screening, and complex physical cues. These existing methods are seriously challenged by extensive time requirements and poor yields. An innovative approach that overcomes prior hurdles and enhances the rate of successful motor neuron transplantation in patients is of critical demand. Iron, a trace element, is indispensable for the normal development and function of the central nervous system. Whether ferric ions promote neuronal differentiation and subsequently promote motor neuron lineage has never been considered. Here, we demonstrate that elevated iron concentration can drastically accelerate the differentiation of human embryonic stem cells (hESCs) toward motor neuron lineage potentially via a transferrin mediated pathway. HB9 expression in 500 nM iron-treated hESCs is approximately twofold higher than the control. Moreover, iron treatment generated more matured and functional motor neuron-like cells that are ∼1.5 times more sensitive to depolarization when compared to the control. Our methodology renders an expedited approach to harvest motor neuron-like cells for disease, traumatic injury regeneration, and drug screening.

Activated charcoal composite biomaterial promotes human embryonic stem cell differentiation toward neuronal lineage.

Transplantation of biomaterial scaffolds encasing human embryonic stem cells (hESCs) has been proposed as a clinical therapy for various neurological lesions and disorders. In light of recent developments, artificially synthesized carbon-based biomaterials such as carbon nanotubes and graphene have demonstrated feasibility in supporting stem cell attachment and differentiation. However, the applicability is significantly hampered by evidence of nanotoxic effects on multiple cell types. Thus, an emergent drive for an innovative carbonaceous biomaterial calls for a safer platform with comparable advantageous characteristics. Here, we showed for the first time, a natural coal-based activated charcoal (AC) composite biosubstrate can support and promote neuronal differentiation in hESCs. The bio-friendly AC composite biomatrices resulted in more matured neuron-like cells. Both of axonal length and density were at least twice as long and abundant, respectively, when compared with control groups. A functional assay demonstrated that the derived neuron-like cells responded to depolarization-dependent synaptic recycling and may contain active synapses. In addition, the AC composite substrate can serve to concentrate growth factors and cell adhesion proteins, further encouraging attachment and hESC differentiation. Moreover, the AC composite biomaterial can potentially be economically manufactured as implantable three-dimensional bioscaffolds, facilitating the regeneration of damaged neural and other tissues.

Functionalized carboxyl nanoparticles enhance mucus dispersion and hydration.

Luminal accumulation of viscous, poorly hydrated, and less transportable mucus has been associated with altered mucus rheology and reduced mucociliary clearance. These symptoms are some of the cardinal clinical manifestations found throughout major respiratory diseases as well as gastrointestinal and digestive disorders. Applications of current mucolytics may yield short-term improvements but are continuously challenged by undesirable side-effects. While nanoparticles (NPs) can interact with mucin polymers,whether functionalized NPs can rectify mucus rheology is unknown. Herein, we report that carboxyl-functionalized NPs (24 nm and 120 nm) dramatically reduced mucin gel size and accelerated mucin matrix hydration rate (diffusivity). Our results suggest that carboxyl-functionalized NPs disperse mucin gels possibly by enhancing network hydration. This report highlights the prospective usages of carboxyl-functionalized NPs as a novel mucus dispersant or mucolytic agent in adjusting mucus rheological properties and improving mucociliary transport to relieve clinical symptoms of patients suffering from relevant diseases.

A mixture of anatase and rutile TiO2 nanoparticles induces histamine secretion in mast cells.

BACKGROUND: Histamine released from mast cells, through complex interactions involving the binding of IgE to FcεRI receptors and the subsequent intracellular Ca²âº signaling, can mediate many allergic/inflammatory responses. The possibility of titanium dioxide nanoparticles (TiO2 NPs), a nanomaterial pervasively used in nanotechnology and pharmaceutical industries, to directly induce histamine secretion without prior allergen sensitization has remained uncertain. RESULTS: TiO2 NP exposure increased both histamine secretion and cytosolic Ca²âº concentration ([Ca²âº]C) in a dose dependent manner in rat RBL-2H3 mast cells. The increase in intracellular Ca²âº levels resulted primarily from an extracellular Ca²âº influx via membrane L-type Ca²âº channels. Unspecific Ca²âº entry via TiO2 NP-instigated membrane disruption was demonstrated with the intracellular leakage of a fluorescent calcein dye. Oxidative stress induced by TiO2 NPs also contributed to cytosolic Ca²âº signaling. The PLC-IP3-IP3 receptor pathways and endoplasmic reticulum (ER) were responsible for the sustained elevation of [Ca²âº]C and histamine secretion. CONCLUSION: Our data suggests that systemic circulation of NPs may prompt histamine release at different locales causing abnormal inflammatory diseases. This study provides a novel mechanistic link between environmental TiO2 NP exposure and allergen-independent histamine release that can exacerbate manifestations of multiple allergic responses.

Mucin secretion induced by titanium dioxide nanoparticles.

Nanoparticle (NP) exposure has been closely associated with the exacerbation and pathophysiology of many respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma. Mucus hypersecretion and accumulation in the airway are major clinical manifestations commonly found in these diseases. Among a broad spectrum of NPs, titanium dioxide (TiO(2)), one of the PM10 components, is widely utilized in the nanoindustry for manufacturing and processing of various commercial products. Although TiO(2) NPs have been shown to induce cellular nanotoxicity and emphysema-like symptoms, whether TiO(2) NPs can directly induce mucus secretion from airway cells is currently unknown. Herein, we showed that TiO(2) NPs (<75 nm) can directly stimulate mucin secretion from human bronchial ChaGo-K1 epithelial cells via a Ca(2+) signaling mediated pathway. The amount of mucin secreted was quantified with enzyme-linked lectin assay (ELLA). The corresponding changes in cytosolic Ca(2+) concentration were monitored with Rhod-2, a fluorescent Ca(2+) dye. We found that TiO(2) NP-evoked mucin secretion was a function of increasing intracellular Ca(2+) concentration resulting from an extracellular Ca(2+) influx via membrane Ca(2+) channels and cytosolic ER Ca(2+) release. The calcium-induced calcium release (CICR) mechanism played a major role in further amplifying the intracellular Ca(2+) signal and in sustaining a cytosolic Ca(2+) increase. This study provides a potential mechanistic link between airborne NPs and the pathoetiology of pulmonary diseases involving mucus hypersecretion.

Functionalized positive nanoparticles reduce mucin swelling and dispersion.

Multi-functionalized nanoparticles (NPs) have been extensively investigated for their potential in household and commercial products, and biomedical applications. Previous reports have confirmed the cellular nanotoxicity and adverse inflammatory effects on pulmonary systems induced by NPs. However, possible health hazards resulting from mucus rheological disturbances induced by NPs are underexplored. Accumulation of viscous, poorly dispersed, and less transportable mucus leading to improper mucus rheology and dysfunctional mucociliary clearance are typically found to associate with many respiratory diseases such as asthma, cystic fibrosis (CF), and COPD (Chronic Obstructive Pulmonary Disease). Whether functionalized NPs can alter mucus rheology and its operational mechanisms have not been resolved. Herein, we report that positively charged functionalized NPs can hinder mucin gel hydration and effectively induce mucin aggregation. The positively charged NPs can significantly reduce the rate of mucin matrix swelling by a maximum of 7.5 folds. These NPs significantly increase the size of aggregated mucin by approximately 30 times within 24 hrs. EGTA chelation of indigenous mucin crosslinkers (Ca(2+) ions) was unable to effectively disperse NP-induced aggregated mucins. Our results have demonstrated that positively charged functionalized NPs can impede mucin gel swelling by crosslinking the matrix. This report also highlights the unexpected health risk of NP-induced change in mucus rheological properties resulting in possible mucociliary transport impairment on epithelial mucosa and related health problems. In addition, our data can serve as a prospective guideline for designing nanocarriers for airway drug delivery applications.

Spiral biphasic contrast-enhanced computerized tomography in the diagnosis of hepatocellular carcinoma.

Advances in spiral computerized tomography (CT) have made rapid biphasic contrast-enhanced CT possible. This study evaluated the capability of biphasic contrast-enhanced spiral CT to detect hepatocellular carcinoma (HCC). A total of 125 patients (68 men and 57 women) with proven HCC underwent preliminary noncontrast (NC) scanning, followed by hepatic arterial phase (HAP) and portal venous phase (PVP) imaging. Contrast medium (80 mL, 300 mgI/mL) was administered routinely at a rate of 2 mL/second using an automated contrast injector under guidance software monitoring. Study of NC and PVP images without concurrent study of HAP images detected 131/171 (76.6%) cases of HCC. In contrast, combined study of NC, PVP, and HAP images detected 153/171 (89.5%) cases of HCC. Thus, combined study of NC and biphasic images was able to detect an additional 12.9% of HCC cases in comparison with conventional study of NC and PVP images only. All HCCs that were detectable only on HAP imaging were enhanced homogeneously with contrast medium during the arterial phase.