[Factors affecting the postoperative prognosis of penile cancer].

OBJECTIVE: To investigate the risk factors affecting the prognosis of penile cancer after surgery. METHODS: We retrospectively analyzed the clinical data on 112 cases of penile cancer treated in Weifang People's Hospital from January 2013 to December 2023. Using the Kaplan-Meier survival curve, χ2 test, Fisher's exact test, and univariate and multivariate Cox risk regression analyses, we compared the clinical characteristics among different groups, and determined the independent prognostic risk factors for cancer-specific survival (CSS) of the patients. RESULTS: The 1-, 3- and 5-year CSS rates of the penile cancer patients were 78.2%, 66.1% and 63.7%, respectively. Kaplan-Meier analysis indicated a significant correlation of a higher neutrophil-to-lymphocyte ratio (NLR) with a lower CSS rate (P < 0.001). Multivariate Cox regression analysis showed high NLR (HR = 2.6; 95% CI: 1.031－6.558; P = 0.043) to be an independent risk factor for CSS. CONCLUSION: Preoperative NLR is an independent risk factor for the prognosis of penile cancer. In addition, older age, farmer or worker occupation, lower education, preoperative lymphocyte-to-monocyte ratio (LMR)≤2.81, preoperative fibrinogen (FIB)≥3.41 g/L, advanced tumor stage and tumor differentiation are associated with the poor prognosis the malignancy.

Uracil removal-inhibited ligase reaction in combination with catalytic hairpin assembly for the sensitive and specific detection of uracil-DNA glycosylase activity.

Sensitive and specific detection of uracil-DNA glycosylase (UDG) activity is crucial in biomedical study and disease diagnosis. Here, we developed a uracil removal-inhibited ligase reaction in combination with catalytic hairpin assembly (CHA) for the sensitive and specific detection of UDG activity. A hairpin probe is specially designed, which contains two uracil bases in the loop and is extended with toehold and branch-migration domains at the ends of the stem. Two short oligonucleotides are separately hybridized to one-half of the loop of the hairpin probe to form a DNA complex with a nick. Under the action of UDG, two uracil bases in the hairpin-loop are removed to generate apurinic/apyrimidinic (AP) sites. The AP sites locating at the 3'-side of the nick inhibit the ligase reaction, leaving the toehold and branch-migration domains at the ends of the hairpin probe still adjacent. The adjacent toehold and branch-migration domains initiate CHA, producing numerous G-quadruplex (G4) structures, which interact with N-methyl-mesoporphyrin IX (NMM) to generate an enhanced fluorescence signal. The excessive probes would be masked by the ligase reaction that closes the nick and forms a long DNA strand fully complementary to the hairpin domain. The probes then get opened and the toehold/branch-migration domains are not associated, prohibiting the CHA reaction and minimizing false-positive interferences. The detection limit is as low as 0.00028 U mL-1, and UDG can be well distinguished from other DNA glycosylases. Furthermore, this method is successfully applied for detecting UDG activity from HeLa cell lysates. Additionally, the inhibition of UDG activity is analyzed, which shows inhibitor dose-dependent activity suppression. This strategy will provide a promising tool for assaying UDG activity in biomedical study and disease diagnosis.

A unique dual recognition hairpin probe mediated fluorescence amplification method for sensitive detection of uracil-DNA glycosylase and endonuclease IV activities.

Uracil-DNA glycosylase (UDG) and endonuclease IV (Endo IV) play cooperative roles in uracil base-excision repair (UBER) and inactivity of either will interrupt the UBER to cause disease. Detection of UDG and Endo IV activities is crucial to evaluate the UBER process in fundamental research and diagnostic application. Here, a unique dual recognition hairpin probe mediated fluorescence amplification method was developed for sensitively and selectively detecting UDG and Endo IV activities. For detecting UDG activity, the uracil base in the probe was excised by the target enzyme to generate an apurinic/apyrimidinic (AP) site, achieving the UDG recognition. Then, the AP site was cleaved by a tool enzyme Endo IV, releasing a primer to trigger rolling circle amplification (RCA) reaction. Finally, the RCA reaction produced numerous repeated G-quadruplex sequences, which interacted with N-methyl-mesoporphyrin IX to generate an enhanced fluorescence signal. Alternatively, for detecting Endo IV activity, the uracil base in the probe was first converted into an AP site by a tool enzyme UDG. Next, the AP site was cleaved by the target enzyme, achieving the Endo IV recognition. The signal was then generated and amplified in the same way as those in the UDG activity assay. The detection limits were as low as 0.00017 U mL(-1) for UDG and 0.11 U mL(-1) for Endo IV, respectively. Moreover, UDG and Endo IV can be well distinguished from their analogs. This method is beneficial for properly evaluating the UBER process in function studies and disease prognoses.

Multimodal deep learning-based drought monitoring research for winter wheat during critical growth stages.

Wheat is a major grain crop in China, accounting for one-fifth of the national grain production. Drought stress severely affects the normal growth and development of wheat, leading to total crop failure, reduced yields, and quality. To address the lag and limitations inherent in traditional drought monitoring methods, this paper proposes a multimodal deep learning-based drought stress monitoring S-DNet model for winter wheat during its critical growth periods. Drought stress images of winter wheat during the Rise-Jointing, Heading-Flowering and Flowering-Maturity stages were acquired to establish a dataset corresponding to soil moisture monitoring data. The DenseNet-121 model was selected as the base network to extract drought features. Combining the drought phenotypic characteristics of wheat in the field with meteorological factors and IoT technology, the study integrated the meteorological drought index SPEI, based on WSN sensors, and deep image learning data to build a multimodal deep learning-based S-DNet model for monitoring drought stress in winter wheat. The results show that, compared to the single-modal DenseNet-121 model, the multimodal S-DNet model has higher robustness and generalization capability, with an average drought recognition accuracy reaching 96.4%. This effectively achieves non-destructive, accurate, and rapid monitoring of drought stress in winter wheat.

Stress sensitivity analysis of vuggy porous media based on two-scale fractal theory.

Interparticle pore space and vugs are two different scales of pore space in vuggy porous media. Vuggy porous media widely exists in carbonate reservoirs, and the permeability of this porous media plays an important role in many engineering fields. It has been shown that the change of effective stress has important effects on the permeability of vuggy porous media. In this work, a fractal permeability model for vuggy porous media is developed based on the fractal theory and elastic mechanics. Besides, a Monte Carlo simulation is also implemented to obtain feasible values of permeability. The proposed model can predict the elastic deformation of the fractal vuggy porous media under loading stress, which plays a crucial role in the variations of permeability. The predicted permeability data based on the present fractal model are compared with experimental data, which verifies the validity of the present fractal permeability model for vuggy porous media. The parameter sensitivity analysis indicates that the permeability of stress-sensitivity vuggy porous media is related to the capillary fractal dimension, capillary fractal tortuosity dimension, Young's modulus, and Poisson's ratio.

A multifunctional DNA tetrahedron for imaging, gene therapy, and chemotherapy-phototherapy combination: Binding affinity and anticancer activity.

Imaging, silencing cancer-related microRNA, and chemotherapy-phototherapy (CTPT) combination therapy are crucial for cancer diagnosis and drug resistance overcoming. In this study, we designed a multifunctional DNA tetrahedron (MB-MUC1-TD) for the targeted delivery of combined daunorubicin (DAU) + toluidine blue O (TBO). The detection limit of miRNA-21 was determined to be 0.91 nM. The intercalation of DAU and TBO into MB-MUC1-TD was proved by spectroscopic and calorimetric methods. The thermodynamic parameters for the interactions of DAU and/or TBO with MB-MUC1-TD confirmed high drug loading. The first addition of TBO in the ternary system achieved a higher loading of both drugs and a more stable complex structure. Deoxyribonuclease I (DNase I) accelerated the release of DAU and/or TBO loaded in MB-MUC1-TD. Confocal laser scanning microscope demonstrated that MB-MUC1-TD exhibited good imaging ability for miRNA-21 to accurately identify cancer cells, and DAU/TBO was predominantly distributed within the nucleus of cancer cells. In vitro cytotoxicity showed better gene therapy efficacy of MB on MCF-7 cells, better biocompatibility of loaded DAU and TBO on LO2 cells, and stronger synergistic cytotoxicity of DAU + TBO on MCF-7/ADR cells. This study may establish a theoretical foundation for co-loading CTPT combination drugs based on multifunctional DNA nanostructures.

Effect of the combined binding of topotecan and catechin/protocatechuic acid to a pH-sensitive DNA tetrahedron on release and cytotoxicity: Spectroscopic and calorimetric studies.

The therapeutic efficacy of chemotherapy drugs can be effectively improved through the dual effects of their combination with natural polyphenols and the delivery of targeted DNA nanostructures. In this work, the interactions of topotecan (TPT), (+)-catechin (CAT), or protocatechuic acid (PCA) with a pH-sensitive DNA tetrahedron (MUC1-TD) in the binary and ternary systems at pHs 5.0 and 7.4 were investigated by fluorescence spectroscopy and calorimetry. The intercalative binding mode of TPT/CAT/PC to MUC1-TD was confirmed, and their affinity was ranked in the order of PCA > CAT > TPT. The effects of the pH-sensitivity of MUC1-TD and different molecular structures of CAT and PCA on the loading, release, and cytotoxicity of TPT were discussed. The weakened interaction under acidic conditions and the co-loading of CAT/PCA, especially PCA, improved the release of TPT loaded by MUC1-TD. The targeting of MUC1-TD and the synergistic effect with CAT/PCA, especially CAT, enhanced the cytotoxicity of TPT on A549 cells. For L02 cells, the protective effect of CAT/PCA reduced the damage caused by TPT. The single or combined TPT loaded by MUC1-TD was mainly concentrated in the nucleus of A549 cells. This work will provide key information for the combined application of TPT and CAT/PCA loaded by DNA nanostructures to improve chemotherapy efficacy and reduce side effects.

Hong Kong Corpus of Chinese Sentence and Passage Reading.

Recent years have witnessed a mushrooming of reading corpora that have been built by means of eye tracking. This article showcases the Hong Kong Corpus of Chinese Sentence and Passage Reading (HKC for brevity), featured by a natural reading of logographic scripts and unspaced words. It releases 28 eye-movement measures of 98 native speakers reading simplified Chinese in two scenarios: 300 one-line single sentences and 7 multiline passages of 5,250 and 4,967 word tokens, respectively. To verify its validity and reusability, we carried out (generalised) linear mixed-effects modelling on the capacity of visual complexity, word frequency, and reading scenario to predict eye-movement measures. The outcomes manifest significant impacts of these typical (sub)lexical factors on eye movements, replicating previous findings and giving novel ones. The HKC provides a valuable resource for exploring eye movement control; the study contrasts the different scenarios of single-sentence and passage reading in hopes of shedding new light on both the universal nature of reading and the unique characteristics of Chinese reading.

Thermodynamic and cellular studies of doxorubicin/daunorubicin loaded by a DNA tetrahedron for diagnostic imaging, chemotherapy, and gene therapy.

The combined diagnostic imaging, chemotherapy, and gene therapy based on DNA nanocarriers can reduce the toxic side effects and overcome multidrug resistance (MDR). In this study, we designed an antisense oligonucleotides (ASOs)-linked DNA tetrahedron (ASOs-TD). The detection limit of ASOs-TD for MDR1 mRNA was 0.05 µM. By using fluorescence spectroscopy and isothermal titration calorimetry (ITC), the interactions between doxorubicin (DOX) /daunorubicin (DAU) and ASOs-TD were investigated. The number of binding sites (n), binding constant (Ka), entropy change (ΔSo), enthalpy change (ΔHo) and Gibbs free energy change (ΔGo) were obtained. The intercalation of DOX/DAU with ASOs-TD was demonstrated by differential scanning calorimetry (DSC) and quenching researches of potassium ferricyanide K4[Fe(CN)6]. The in vitro release rate of DOX/DAU loaded in ASOs-TD was accelerated by deoxyribonuclease I (DNase I). In vitro cytotoxicity proved the good gene therapy effect of ASOs-TD and the increased cytotoxicity of DOX/DAU to MCF-7/ADR cells. The results of confocal laser scanning microscope (CLSM) suggested that ASOs-TD could effectively identify drug-resistant cells due to its good imaging ability for MDR1 mRNA. This work offers theoretical significance for overcoming MDR using DNA nanostructures which combine diagnostic imaging, chemotherapy, and gene therapy.

Effects of combined binding of chlorogenic acid/caffeic acid and gallic acid to trypsin on their synergistic antioxidant activity, enzyme activity and stability.

The combined application of multiple natural polyphenols in functional foods may provide better health benefits. The binding of polyphenols with different structures to proteins will affect their respective functions. Spectroscopy and molecular docking were used to investigate the competitive binding of chlorogenic acid (CGA)/caffeic acid (CA) and gallic acid (GA) to trypsin. The effects of different molecular structures and the order of adding the three phenolic acids on the binding were assessed. The stability of trypsin and its docked complexes with CGA/CA/GA was evaluated by molecular dynamics simulation. The effects of the binding process on the activity and thermal stability of trypsin, as well as on the antioxidant activity and stability of CGA/CA/GA were explored. The competitive binding of CGA/CA and GA to trypsin affected their synergistic antioxidant effects. The results may provide a reference for the combined application of CGA/CA and GA in food and pharmaceutical fields.

Spectroscopic, calorimetric and cytotoxicity studies on the combined binding of daunorubicin and acridine orange to a DNA tetrahedron.

Chemotherapy-phototherapy (CTPT) combination drugs co-loaded by targeted DNA nanostructures can achieve controlled drug delivery, reduce toxic side effects and overcome multidrug resistance. Herein, we constructed and characterized a DNA tetrahedral nanostructure (MUC1-TD) linked with the targeting aptamer MUC1. The interaction of daunorubicin (DAU)/acridine orange (AO) alone and in combination with MUC1-TD and the influence of the interaction on the cytotoxicity of the drugs were evaluated. Potassium ferrocyanide quenching analysis and DNA melting temperature assays were used to demonstrate the intercalative binding of DAU/AO to MUC1-TD. The interactions of DAU and/or AO with MUC1-TD were analyzed by fluorescence spectroscopy and differential scanning calorimetry. The number of binding sites, binding constant, entropy and enthalpy changes of the binding process were obtained. The binding strength and binding sites of DAU were higher than those of AO. The presence of AO in the ternary system weakened the binding of DAU to MUC1-TD. In vitro cytotoxicity studies demonstrated that the loading of MUC1-TD augmented the inhibitory effects of DAU and AO and the synergistic cytotoxic effects of DAU + AO on MCF-7 cells and MCF-7/ADR cells. Cell uptake studies showed that the loading of MUC1-TD was beneficial in promoting the apoptosis of MCF-7/ADR cells due to its enhanced targeting to the nucleus. This study has important guiding significance for the combined application of DAU and AO co-loaded by DNA nanostructures to overcome multidrug resistance.

Closing-upon-repair DNA tetrahedron nanoswitch for FRET imaging the repair activity of 8-oxoguanine DNA glycosylase in living cells.

In situ imaging the repair activity of 8-oxoguanine (8-OG) DNA glycosylase in living cells is important as it is associated with genetic mutation. However, the existing imaging methods confront the interference of intracellular nuclease and resulting in false positive signal. Here, a closing-upon-repair DNA tetrahedron nanoswitch (CRTN) was designed for FRET imaging the repair activity of 8-OG DNA glycosylase in living cells with high specificity and accuracy. CRTN comprised a DNA tetrahedron, a recognition strand modified with 8-OG bases, and a reporting strand designed as hairpin structure and labeled with Cy3/Cy5 dual fluorophores. Initially, the DNA tetrahedron was linked with the reporting strand hybridized to the recognition strand, separating the Cy3 donor and Cy5 acceptor into FRET-invalid distance. Upon repair the 8-OG bases by 8-OG DNA glycosylase, CRTN could undergo a structure change from the open to closed state. Specifically, the reporting strand was dissociated from the recognition strand under the action of 8-OG DNA glycosylase and folded into hairpin structure, bringing the Cy3 donor and Cy5 acceptor into FRET-valid proximity with the generation of FRET signal, which could prevent false positive signal arising from nuclease degradation. CRTN exhibited the feasibility for detecting 8-OG DNA glycosylase activity in vitro with good sensitivity and selectivity. More importantly, CRTN could enter cells without any transfection for FRET imaging the repair activity of intracellular 8-OG DNA glycosylase with high specificity and accuracy. This approach provided a promising tool for deeper understanding 8-OG DNA glycosylase function and further studying genetic mutation-related diseases.

A pH-sensitive DNA tetrahedron for targeted release of anthracyclines: Binding properties investigation and cytotoxicity evaluation.

The anticancer efficacy of chemotherapeutic agents can be enhanced by the loading of DNA nanostructures, which is closely related to their interactions. This study achieved pH-responsive and targeted anthracycline delivery using i-motif and MUC1 aptamer co-modified DNA tetrahedron (MUC1-TD). The thermodynamic parameters for the binding of doxorubicin (DOX) and epirubicin (EPI) to MUC1-TD at pHs 7.4 and 5.0 were obtained. The smaller binding constant and the number of binding sites at pH 5.0 than at pH 7.4 indicated that acidic conditions favored the release of DOX and EPI loaded by MUC1-TD. The binding affinity of DOX was stronger than that of EPI at the same pH value due to their different chemical stereostructures. The intercalative binding mechanism was verified. In vitro release experiments revealed that acid pH and deoxyribonuclease I accelerated the release of DOX and EPI. The faster release rate of EPI than DOX was related to their binding affinity. In vitro cytotoxicity and cell uptake experiments revealed that the cytotoxicity of DOX and EPI loaded by MUC1-TD to MCF-7 cells was significantly higher than that to L02 cells. This work will provide theoretical guidance for the application of pH-responsive MUC1-TD nanocarriers in the field of pharmaceutics.

Multispectroscopic and synergistic antioxidant study on the combined binding of caffeic acid and (-)-epicatechin gallate to lysozyme.

The binding of caffeic acid (CA) and/or (-)-epicatechin gallate (ECG) to lysozyme was investigated by multispectroscopic methods and molecular docking. The effects of the single and combined binding on the structure, activity and stability of lysozyme and the synergistic antioxidant activity of CA and ECG were also studied. Fluorescence quenching spectra, time-resolved fluorescence spectra, and UV-vis absorption difference spectra all ascertained the static quenching mechanism of lysozyme by CA/ECG. Thermodynamic parameters indicated that CA and ECG competitively bound to lysozyme, and CA had a stronger binding affinity, which was consistent with the results of molecular docking. Hydrogen bonding, van der Waals' force and electrostatic interaction were the main driving forces for the binding process. Synchronous fluorescence spectra displayed that the interaction of CA/ECG exposed the tryptophan residues of lysozyme to a more hydrophilic environment. Circular dichroism spectroscopy, Fourier transform infrared spectroscopy and dynamic light scattering indicated that the binding of CA and/or ECG to lysozyme resulted in the change of the secondary structure and increased the particle size of lysozyme. The binding of CA and/or ECG to lysozyme inhibited the enzyme activity and enhanced the thermal stability of lysozyme. The combined application of CA and ECG showed antioxidant synergy which was influenced by the encapsulation of lysozyme and cellular uptake. In summary, this work provides theoretical guidance for lysozyme as a carrier for the combined application of CA and ECG.

Antioxidant activity, stability, in vitro digestion and cytotoxicity of two dietary polyphenols co-loaded by ß-lactoglobulin.

The combination of multiple dietary polyphenols may have synergistic beneficial effects. And the beneficial effects can be further improved by the encapsulation of proteins. The interactions of procyanidin B2 (PB2) and/or dihydromyricetin (DMY) with ß-lactoglobulin (ß-LG) were investigated using multi-spectroscopic techniques and molecular docking. The structural change of ß-LG in the presence of PB2 and/or DMY was demonstrated by dynamic light scattering, Fourier transform infrared spectroscopy and circular dichroism spectroscopy. Response surface analysis was used to optimize the synergistic antioxidant activity between PB2 and DMY. Besides, the antioxidant activity, stability, in vitro digestion and cytotoxicity of PB2 and DMY in the binary and ternary systems were investigated. These studies will elucidate the interaction mechanism of PB2 and/or DMY with ß-LG. The research results can provide theoretical support for the development of functional foods and beverages with synergistic activity, improved stability and bioaccessibility, thereby promoting human health and preventing diseases.

Micro OS-ELISA: Rapid noncompetitive detection of a small biomarker peptide by open-sandwich enzyme-linked immunosorbent assay (OS-ELISA) integrated into microfluidic device.

A novel detection system that combines the merits of open-sandwich (OS) enzyme-linked immunoadsorbent assay (ELISA) and a microfluidic sensor chip system, and which enables rapid and noncompetitive immunodetection of small antigens of less than 1000 in molecular weight, has been proposed. Equipped with a sensitive thermal lens microscope, a minute amount of the carboxyl-terminal peptide of human osteocalcin (BGP), a biomarker for bone metabolism, was quantified utilizing antigen-dependent stabilization of an antibody variable region (OS principle). In a short analysis time (approximately 12 min), we could attain a detection limit comparable to that of the microplate-based OS ELISA (1 microg L(-1)). In addition, the effects of several pretreatments for serum-derived samples were investigated: an albumin absorption resin, addition of a protease inhibitor cocktail and heat treatment. Each pretreatment was found to be effective. Consequently, intrinsic BGP and its fragments could be detected in healthy human serum with a superior detection limit and working range compared to those of the conventional competitive ELISA method.

Amphiphilic block polymer-based self-assembly of high payload nanoparticles for efficient combinatorial chemo-photodynamic therapy.

Combinatorial chemo-photodynamic therapy is regared as effective cancer therapy strategy, which could be realized via multiple nano-drug delivery system. Herein, novel high payload nanoparticles stabilized by amphiphilic block polymer cholesterol-b-poly(ethylene glycol) (PEG)2000 (Chol-PEG2000) were fabricated for loading chemotherapeutic drug 10-hydroxycamptothecin (HCPT) and photosensitizer chlorin e6 (Ce6). The obtained HCPT/Ce6 NPs showed uniform rod-like morphology with a hydration diameter of 178.9 ± 4.0 nm and excellent stability in aqueous solution. HCPT and Ce6 in the NPs displayed differential release profile, which was benefit for preferentially exerting the photodynamic effect and subsequently enhancing the sensitivity of the cells to HCPT. Under laser irradiation, the NPs demonstrated fantastic in vitro and in vivo anticancer efficiency due to combinational chemo-photodynamic therapy, enhanced cellular uptake effectiveness, and superb intracellular ROS productivity. Besides, the NPs were proved as absent of systemic toxicity. In summary, this nanoparticle delivery system could be hopefully utilized as effective cancer therapy strategy for synergistically exerting combined chemo-photodynamic therapy in clinic.

High payload and targeted release of anthracyclines by aptamer-tethered DNA nanotrains - Thermodynamic and release kinetic study.

As one of the most promising drug delivery carriers, self-assembled DNA nanostructures are characterized of well-defined sizes, excellent biocompatibility, high drug loading and ability to control drug release. Studying the interactions between anticancer drugs and DNA nanostructures can help to associate microstructure-drug loading-release rate-therapeutic effect. Herein AS1411 aptamer-tethered DNA nanotrains (AS1411NTrs) were constructed and used as anthracyclines carrier with high payload for targeted delivery. The bindings of doxorubicin (DOX), epirubicin (EPI), and daunorubicin (DAU) to AS1411NTrs were investigated by isothermal titration calorimetry and fluorescence spectroscopy, and thermodynamic parameters were obtained. The high drug payload capacity of AS1411NTrs was verified by the large number of binding sites (~20). The binding mode was determined by differential scanning calorimetry and potassium iodide (KI) quenching experiments. The release experiment data showed that DNase I facilitated drug release and the release followed the first-order kinetic model. MTT cell viability assay demonstrated that the drug-loaded AS1411NTrs had significantly higher cytotoxicity against target HeLa cells than normal human liver L02 cells. These findings revealed that AS1411NTrs had high payload and targeted release capacity for DOX, EPI, and DAU. This result can provide a theoretical basis for constructing reasonable DNA nanostructures based on drug carriers.

Drug-binding albumins forming stabilized nanoparticles for co-delivery of paclitaxel and resveratrol: In vitro/in vivo evaluation and binding properties investigation.

Albumin has been regarded as the ideal drug carrier for delivering hydrophobic agents into cancer cells over decades. Combination therapy of paclitaxel (PTX) with resveratrol (RES) could enhance the sensitivity of multidrug resistance (MDR) cancer cell lines to PTX. In this study, novel paclitaxel/resveratrol co-loaded albumin nanoparticles (PTX/RES NPs) were developed to achieve synergistic anticancer efficacy and conquer paclitaxel resistance. The hybrid NPs had an average diameter of about 150 nm and an apparent negative surface charge of about -33 mV. PTX/RES NPs could be efficiently internalized by cells and exert synergistic combination efficacy of the two drugs, thus resulting in dramatically in vitro cytotoxicity even against MDR cancer cells. In vivo antitumor assay demonstrated that the antitumor effect of the hybrid NPs was superior to that of single drug-loaded NPs or free drug combination. Molecular docking analysis disclosed that the binding of PTX and RES to bovine serum albumin (BSA) was noncompetitive but the binding free energy of BSA/PTX dockings was significantly lower than BSA/RES dockings, which resulted in high encapsulation efficiency and sustained drug release profiles of PTX. In summary, the PTX/RES co-delivery system might be a promising strategy for combined anticancer therapy to overcome tumor drug resistance.

Incorporating layer- and local-scale heterogeneities in numerical simulation of unsaturated flow and tracer transport.

This study characterizes layer- and local-scale heterogeneities in hydraulic parameters (i.e., matrix permeability and porosity) and investigates the relative effect of layer- and local-scale heterogeneities on the uncertainty assessment of unsaturated flow and tracer transport in the unsaturated zone of Yucca Mountain, USA. The layer-scale heterogeneity is specific to hydrogeologic layers with layerwise properties, while the local-scale heterogeneity refers to the spatial variation of hydraulic properties within a layer. A Monte Carlo method is used to estimate mean, variance, and 5th, and 95th percentiles for the quantities of interest (e.g., matrix saturation and normalized cumulative mass arrival). Model simulations of unsaturated flow are evaluated by comparing the simulated and observed matrix saturations. Local-scale heterogeneity is examined by comparing the results of this study with those of the previous study that only considers layer-scale heterogeneity. We find that local-scale heterogeneity significantly increases predictive uncertainty in the percolation fluxes and tracer plumes, whereas the mean predictions are only slightly affected by the local-scale heterogeneity. The mean travel time of the conservative and reactive tracers to the water table in the early stage increases significantly due to the local-scale heterogeneity, while the influence of local-scale heterogeneity on travel time gradually decreases over time. Layer-scale heterogeneity is more important than local-scale heterogeneity for simulating overall tracer travel time, suggesting that it would be more cost-effective to reduce the layer-scale parameter uncertainty in order to reduce predictive uncertainty in tracer transport.