Our research focuses on developing advanced nanoparticles for cancer treatment, with a focus on reducing side effects and improving efficacy. We have developed nanoparticles that can not only... Show moreOur research focuses on developing advanced nanoparticles for cancer treatment, with a focus on reducing side effects and improving efficacy. We have developed nanoparticles that can not only target cancer cells but also serve as imaging agents to monitor treatment. In addition, we have investigated how lipids and immune cells in the tumor environment can be manipulated to improve cancer therapy.Our findings show that the developed nanoparticles can improve drug delivery to tumors while reducing side effects to the rest of the body. Moreover, we have shown that lipids can be used to reprogramme immune cells in the tumor environment, causing them to exhibit anti-tumor activity. In addition, the nanoparticles show excellent delivery capabilities in 3D models of skin cancer, allowing them to kill skin tumor cells more effectively.The societal relevance of our research lies in improving cancer treatment options, particularly by reducing side effects and increasing the effectiveness of therapies. These findings provide new insights and approaches for the development of cancer therapies, which can contribute to a better quality of life for patients.We have achieved these results through a multidisciplinary approach using nanotechnology, chemotherapeutic drugs and knowledge of the tumor environment. Our findings are special because they offer promising new strategies for cancer treatment using cutting-edge technologies and insights into tumor biology. Show less
Wang, Z.; Zhao, K.; He, Y.; Chen, Z.; Ren, P.; Rijke, M. de; Ren, Z. 2023
This thesis focuses on the development of sample-preparation methods for small amounts of samples and applying the developed methods to muscle tissues to investigate the mechanisms involved in... Show moreThis thesis focuses on the development of sample-preparation methods for small amounts of samples and applying the developed methods to muscle tissues to investigate the mechanisms involved in sarcopenia. A fully automated, high-throughput, and high enrichment sample-preparation method, electroextraction, was developed. The metabolomics mechanism analysis of sarcopenia by using mouse models facilitate the understanding of metabolic processes underlying sarcopenia and can help to identify treatment options in the future. Show less
Sample preparation is a labor-intensive and time-consuming procedure, especially for the bioanalysis of small-volume samples with low-abundant analytes. To minimize losses and dilution, sample... Show moreSample preparation is a labor-intensive and time-consuming procedure, especially for the bioanalysis of small-volume samples with low-abundant analytes. To minimize losses and dilution, sample preparation should ideally be hyphenated to downstream on-line analysis such as liquid chromatography-mass spectrometry (LC-MS). In this study, an automated three-phase electro-extraction (EE) method coupled to machine vision was developed, integrated with a robotic autosampler hyphenated to LC-MS. Eight model compounds, i.e. amitriptyline, clemastine, clomipramine, haloperidol, loperamide, propranolol, oxeladin, and verapamil were utilized for the optimization and evaluation of the automated EE setup. The stability of automated EE was evaluated by monitoring the acceptor droplet size by machine vision and recording the current during EE. A Design of Experiment approach (Box-Behnken design) was utilized to optimize the critical parameters of the EE method, i. e., the ratio of formic acid in the sample to acceptor phase, extraction voltage, and extraction time. The developed quadratic models showed good fitness (p < 0.001, R-2 > 0.95). Automated EE could be achieved in less than 2 min with enrichment factors (EF) up to 387 and extraction recoveries (ER) up to 97% for academic samples. Finally, the optimized EE method was successfully applied to both spiked human urine and plasma samples with low-concentration (50 ng mL(-1)) analytes and a low starting sample volume of 20 mu L of plasma and urine in 10-fold diluted samples. The developed automated EE setup is easy to operate, provides a fast extraction method for analytes from volume-limited biological samples, and is hyphenated with on-line LC-MS analysis. Therefore, this method can provide fast and automated sample preparation to solve bottlenecks in high-throughput bioanalysis workflows. Show less
He, Y.; Mever, M. van; Yang, W.; Huang, L.: Ramautar, R.; Rijksen, Y.; Vermeij, W.P.; ... ; Hankemeier, T. 2022
The metabolic profiling of a wide range of chemical classes relevant to understanding sarcopenia under conditions in which sample availability is limited, e.g., from mouse models, small muscles, or... Show moreThe metabolic profiling of a wide range of chemical classes relevant to understanding sarcopenia under conditions in which sample availability is limited, e.g., from mouse models, small muscles, or muscle biopsies, is desired. Several existing metabolomics platforms that include diverse classes of signaling lipids, energy metabolites, and amino acids and amines would be informative for suspected biochemical pathways involved in sarcopenia. The sample limitation requires an optimized sample preparation method with minimal losses during isolation and handling and maximal accuracy and reproducibility. Here, two developed sample preparation methods, BuOH-MTBE-Water (BMW) and BuOH-MTBE-More-Water (BMMW), were evaluated and compared with previously reported methods, Bligh-Dyer (BD) and BuOH-MTBE-Citrate (BMC), for their suitability for these classes. The most optimal extraction was found to be the BMMW method, with the highest extraction recovery of 63% for the signaling lipids and 81% for polar metabolites, and an acceptable matrix effect (close to 1.0) for all metabolites of interest. The BMMW method was applied on muscle tissues as small as 5 mg (dry weight) from the well-characterized, prematurely aging, DNA repair-deficient Ercc1 Delta/-mouse mutant exhibiting multiple-morbidities, including sarcopenia. We successfully detected 109 lipids and 62 polar targeted metabolites. We further investigated whether fast muscle tissue isolation is necessary for mouse sarcopenia studies. A muscle isolation procedure involving 15 min at room temperature revealed a subset of metabolites to be unstable; hence, fast sample isolation is critical, especially for more oxidative muscles. Therefore, BMMW and fast muscle tissue isolation are recommended for future sarcopenia studies. This research provides a sensitive sample preparation method for the simultaneous extraction of non-polar and polar metabolites from limited amounts of muscle tissue, supplies a stable mouse muscle tissue collection method, and methodologically supports future metabolomic mechanistic studies of sarcopenia. Show less
Nanoparticles (NPs), heavy metals and natural organic matter may co-exist in the water bodies. Currently, knowledge on their interaction effects on the behaviors and fates of NPs and heavy metal... Show moreNanoparticles (NPs), heavy metals and natural organic matter may co-exist in the water bodies. Currently, knowledge on their interaction effects on the behaviors and fates of NPs and heavy metal ions is rather limited, which is critical to comprehensively understand their environmental risk. In this study, the aggregation, solubility and Cd-adsorption of CuO NPs co-existing with humic acid (HA) and Cd2+ upon different solution pH and contact sequences were determined. In the ternary systems of CuO NPs, HA and Cd2+, pH was more important than the contact sequence of the components in affecting the NP aggregation, while the contact sequence was a predominant factor in determining the NP solubility. Pre-equilibration of CuO NPs and HA before addition of Cd2+ resulted in the highest solubility and lowest aggregation of the NPs, relative to other sequences of addition of the components. The adsorption capacity of CuO NPs for Cd-ions increased with an increasing pH value from 5 to 9. HA significantly enhanced the Cd-adsorption capacity of CuO NPs at pH 7 and 9, while at pH 5 a non-significant effect was observed. The results are helpful to better estimate the behaviors and fates of CuO NPs and Cd2+ when they coexisting in natural waters. Show less
The hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation... Show moreThe hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation sites during somatic hypermutation, and their presence is predictive for disease development. However, the functional consequences of VDGs on autoreactive B cells remain elusive. Combining crystallography, glycobiology, and functional B cell assays allowed us to dissect key characteristics of VDGs on human B cell biology. Crystal structures showed that VDGs are positioned in the vicinity of the antigen-binding pocket, and dynamic modeling combined with binding assays elucidated their impact on binding. We found that VDG-expressing B cell receptors stay longer on the B cell surface and that VDGs enhance B cell activation. These results provide a rationale on how the acquisition of VDGs might contribute to the breach of tolerance of autoreactive B cells in a major human autoimmune disease. Show less
Sample preparation is a challenge for high-throughput analysis, especially for volume-limited samples with low-abundant analytes. Ideally, sample preparation enriches the analytes of interest while... Show moreSample preparation is a challenge for high-throughput analysis, especially for volume-limited samples with low-abundant analytes. Ideally, sample preparation enriches the analytes of interest while removing the interferents to reduce the matrix effect and improve both sensitivity and quantification. In this study, a three-phase electroextraction (EE) method hyphenated to fast online liquid chromatography -mass spectrometry (LC-MS) was developed. Four model acidic drugs of relevance for drug monitoring in plasma, i.e. naproxen, fenoprofen, flurbiprofen, and ibuprofen, were utilized for the optimization and evaluation of the method. A Design of Experiment approach (Box-Behnken design) was used to optimize the critical parameters of the method, i.e., the type of organic solvent, pH of the sample and acceptor phase, and the extraction voltage and time. Good fitness (P < 0.02, R2 > 0.95) was observed for the developed quadratic model. Extraction could be achieved in less than 2 min (115 s) with enrichment factors (EF) up to 190 and extraction recoveries (ER) up to 38% for academic samples. Additionally, the optimized three-phase EE method was successfully applied to spiked plasma samples with lowabundant (50 ng mL-1) analytes and a low sample volume of 15 mL plasma in 10-fold diluted samples. Finally, two crucial contributors to the matrix effect of three-phase EE application on plasma samples were determined. Specifically, the ion-suppression effect in the MS source was reduced by the fast LC separation, and the matrix effect during extraction was negligible for the diluted protein-precipitated plasma samples. The developed three-phase EE method is easy to operate and provides fast and online extraction of trace-level acidic analytes from volume-limited biological samples. Therefore, this method can provide a potential solution for sample-preparation bottlenecks in high-throughput bioanalysis workflows. (c) 2021 Published by Elsevier B.V. Show less
In conventional superconductors, the phase transition into a zero-resistance and perfectly diamagnetic state is accompanied by a jump in the specific heat and the opening of a spectral gap(1). In... Show moreIn conventional superconductors, the phase transition into a zero-resistance and perfectly diamagnetic state is accompanied by a jump in the specific heat and the opening of a spectral gap(1). In the high-transition-temperature (high-T-c) cuprates, although the transport, magnetic and thermodynamic signatures of T-c have been known since the 1980s(2), the spectroscopic singularity associated with the transition remains unknown. Here we resolve this long-standing puzzle with a high-precision angle-resolved photoemission spectroscopy (ARPES) study on overdoped (Bi,Pb)(2)Sr2CaCu2O8+delta (Bi2212). We first probe the momentum-resolved electronic specific heat via spectroscopy and reproduce the specific heat peak at T-c, completing the missing link for a holistic description of superconductivity. Then, by studying the full momentum, energy and temperature evolution of the spectra, we reveal that this thermodynamic anomaly arises from the singular growth of in-gap spectral intensity across T-c. Furthermore, we observe that the temperature evolution of in-gap intensity is highly anisotropic in the momentum space, and the gap itself obeys both the d-wave functional form and particle-hole symmetry. These findings support the scenario that the superconducting transition is driven by phase fluctuations. They also serve as an anchor point for understanding the Fermi arc and pseudogap phenomena in underdoped cuprates. Show less
Xiao, Y.; Ma, J.; Xian, J.; Peijnenburg, W.J.G.M.; Du, Y.; Tian, D.; ... ; Lihua, T 2022
Copper oxide nanoparticles (CuO NPs) are one of the most widely used materials owing to their excellent properties such as thermal and photochemical stability, superconductivity, and high... Show moreCopper oxide nanoparticles (CuO NPs) are one of the most widely used materials owing to their excellent properties such as thermal and photochemical stability, superconductivity, and high electrochemical activity. Once they enter the environment, Cu2+ may be released in water, which alters the behavior and toxicity of CuO NPs. The present study thus investigated the dissolution of CuO NPs (40 nm) in the presence of tannic acid (TA), a model chemical of dissolved organic matter. The adsorption of TA decreased the hydrodynamic diameter of CuO NPs and increased the zeta potential of the suspension. Although the adsorption of TA on particle surface improved the dispersion of CuO NPs, their dissolution extents were all reduced at TA concentration up to 55.4 mg C L−1. At pH 5, the contributions of TA complexed Cu to the overall dissolution increased up to 37.8% as a function of TA concentrations. All the findings shown above approved that the strong adsorption of TA played a dominant role in preventing the dissolution of CuO NPs. Show less
Xiao, Y.; Du, Y.; Zhang, X.; Wu, J.; Yang, G.; He, Y.; ... ; Luo, L. 2021
Copper (Cu) pollution is common in the soil. Due to the widespread application of TiO2 NPs, there is a high propensity for the co-occurrence of TiO2 nanoparticles (NPs) and Cu in agricultural soils... Show moreCopper (Cu) pollution is common in the soil. Due to the widespread application of TiO2 NPs, there is a high propensity for the co-occurrence of TiO2 nanoparticles (NPs) and Cu in agricultural soils. It is therefore imperative to evaluate the joint effects of TiO2 NPs and Cu on crops. In this study, the mutual effects of TiO2 NPs and Cu on their toxicity and accumulation in soybean seedlings and on their fates in a hydroponic system were determined. When Cu was at levels of 1 and 2 mg/L, the co-occurring TiO2 NPs at a non-toxic concentration (10 mg/L) significantly enhanced the toxicity and accumulation of Cu and Ti in soybeans, and inhibited the translocation of Cu from soybean roots to shoots. However, when the Cu concentration for co-exposure was ≥ 5 mg/L, such mutual effects disappeared. The amount of Cu ions adsorbed onto TiO2 NPs after 48 h of co-exposure gradually increased from 31 to 118 mg/g when the Cu concentration was increased from 1 to 20 mg/L. The aggregation and sedimentation of TiO2 NPs were significantly increased after 48 h of co-exposure with the Cu at a concentration higher than 5 mg/L, as compared to the single TiO2 NPs exposure. The increasing aggregation and sedimentation might reduce the bioavailability of TiO2 NPs associated with the adsorbed Cu to soybeans, and consequently alleviate or even neutralize the enhanced toxicity and accumulation of Cu in soybeans exerted by the co-existing TiO2 NPs. Our results thus suggest that consideration of the impact of TiO2 NPs on the phytotoxicity of heavy metals, and specifically Cu, needs to be interpreted with care, and highlight the importance of integrating the interaction and fates of TiO2 NPs and metals into their risk assessment. Show less
Geloven, N. van; He, Y.; Zwinderman, A.H.; Putter, H. 2021
The incident/dynamic time-dependent AUC (Area Under the ROC Curve) is an appealing measure to express the discriminative value of a dynamic survival model over time. However, estimation of this... Show moreThe incident/dynamic time-dependent AUC (Area Under the ROC Curve) is an appealing measure to express the discriminative value of a dynamic survival model over time. However, estimation of this measure is not straightforward. Four recently proposed estimation approaches are studied. In an extensive simulation study, a head-to-head comparison between these four estimation methods is made. The estimation algorithms of some of the methods are extended. Results are illustrated with a motivating dynamic survival model from Reproductive Medicine. (C) 2020 The Authors. Published by Elsevier B.V. Show less
Childhood trauma fundamentally shapes social cognition and basic processing of social cues, which frequently cascade into adverse behavioral outcomes. Recent studies indicate that epigenetic... Show moreChildhood trauma fundamentally shapes social cognition and basic processing of social cues, which frequently cascade into adverse behavioral outcomes. Recent studies indicate that epigenetic changes in oxytocin functioning might contribute to these long-term effects, although a deeper understanding of the underlying mechanisms is still lacking. The electroencephalographic N170 response to faces might capture a neural response at the core of these interactive effects of oxytocin gene methylation and childhood adversity, given that this response is considered to reflect fundamental face processing, to be susceptible to oxytocin administration and also to be a biomarker of various psychiatric disorders. We assessed the N170 response to neutral faces in relation to participant's (81, women) recalled childhood trauma, methylation of their oxytocin structural (OXTg) and oxytocin receptor (OXTRg) genes, and endogenous levels of cortisol and testosterone. Additionally, we investigated the interactive effect of OXTg methylation and CTQ across three face sets of varying maturity. Methylation of OXTg relates to a weakened N170 response towards adults, children and infants. Moreover, methylation of both OXTRg and OXTg shaped the directionality of adversity effects, predicting a weakened N170 response in those with high methylation and hyper-vigilance with participants with low methylation. Our results are the first to relate OXT(R)g methylation to the N170 response. They shed light on biological processes linking childhood adversity and epigenetic marks to altered behavior and potentially psychopathologies. Show less
The human oxytocin (OXT) system is implicated in the regulation of complex social behaviors, as well as in psychopathologies characterized by social deficits. Emerging evidence suggests that... Show moreThe human oxytocin (OXT) system is implicated in the regulation of complex social behaviors, as well as in psychopathologies characterized by social deficits. Emerging evidence suggests that variation in epigenetic regulation of the oxytocin receptor gene (OXTR) provides the oxytocin system with flexibility in response to environmental events, especially those occurring during early childhood. Changes in DNA methylation patterns of OXTR associated with these events may reflect biological alterations of social sensitivity. This is often related to an increased risk of developing mental disorders later in life. Here, we systematically reviewed all human studies (n = 30) discussing OXTR methylation in relation to socio-behavioral phenotypes. As such, we provide a complete and up-to-date overview of the literature that will aid future research in the interdisciplinary field of epigenetics and socio-behavioral sciences. Show less
He, Y.; Hashimoto, M.; Song, D.; Chen, S.D.; He, J.; Vishik, I.M.; ... ; Zaanen, J. 2018
