DataSheet_1_Polymer Nanoformulation of Sorafenib and All-Trans Retinoic Acid for Synergistic Inhibition of Thyroid Cancer.pdf

Part of differentiated thyroid cancer will relapse or develop into dedifferentiated thyroid cancer after standard therapy, such as surgery or radionuclide therapy. Sorafenib (SOR) is recommended for the treatment of advanced or radioiodine-refractory thyroid cancer. The monotherapy using SOR is often hampered by its modest efficacy, serve systemic toxicity, and high occurrence of drug resistance. In order to enhance the antitumor effect of SOR and reduce its side effects, SOR and all-trans retinoic acid (ATRA), a differentiation-promoting drug, were loaded into poly(ethylene glycol)–poly(lactide-co-glycolide) (PEG–PLGA) polymer micelles in this study. The drug-loaded micelles, PM/(SOR+ATRA), exhibited relatively slow drug release and effective cell uptake. Compared with other treatment groups, the PM/(SOR+ATRA) treatment group showed the most significant antitumor effect and minimal systemic toxicity toward the FTC-133 thyroid cancer-bearing BALB/c nude mouse model. Immunofluorescence analysis confirmed that PM/(SOR+ATRA) could significantly promote apoptosis and re-differentiation of tumor cells. All the results demonstrated that polymer micelles loaded with SOR and ATRA could treat thyroid cancer more effectively and safely.</p

DataSheet1_Predictive Simulations in Preclinical Oncology to Guide the Translation of Biologics.PDF

Preclinical in vivo studies form the cornerstone of drug development and translation, bridging in vitro experiments with first-in-human trials. However, despite the utility of animal models, translation from the bench to bedside remains difficult, particularly for biologics and agents with unique mechanisms of action. The limitations of these animal models may advance agents that are ineffective in the clinic, or worse, screen out compounds that would be successful drugs. One reason for such failure is that animal models often allow clinically intolerable doses, which can undermine translation from otherwise promising efficacy studies. Other times, tolerability makes it challenging to identify the necessary dose range for clinical testing. With the ability to predict pharmacokinetic and pharmacodynamic responses, mechanistic simulations can help advance candidates from in vitro to in vivo and clinical studies. Here, we use basic insights into drug disposition to analyze the dosing of antibody drug conjugates (ADC) and checkpoint inhibitor dosing (PD-1 and PD-L1) in the clinic. The results demonstrate how simulations can identify the most promising clinical compounds rather than the most effective in vitro and preclinical in vivo agents. Likewise, the importance of quantifying absolute target expression and antibody internalization is critical to accurately scale dosing. These predictive models are capable of simulating clinical scenarios and providing results that can be validated and updated along the entire development pipeline starting in drug discovery. Combined with experimental approaches, simulations can guide the selection of compounds at early stages that are predicted to have the highest efficacy in the clinic.</p

Polychlorinated naphthalene concentrations and profiles in cheese and butter, and comparisons with polychlorinated dibenzo-<i>p</i>-dioxin, polychlorinated dibenzofuran and polychlorinated biphenyl concentrations

<div><p>Polychlorinated naphthalenes (PCNs) are candidates for inclusion in the Stockholm Convention on persistent organic pollutants. PCNs are structurally and toxicologically similar to 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin (2,3,7,8-TCDD) and its analogues. Intake in food is considered to be an important human exposure pathway for PCNs. In this preliminary study, cheese and butter samples were analysed for PCNs, polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) using an isotope dilution gas chromatography high-resolution mass spectrometry method. The aim of this study was to evaluate the PCN concentrations in the cheese and butter samples and to compare them with the PCDD, PCDF and PCB concentrations. The PCN concentrations were 5.6–103 pg g⁻¹ of wet weight in the seven cheese samples tested and 5.0–199 pg g⁻¹ of wet weight in the seven butter samples tested. The mass concentrations of lower chlorinated congeners were greater than those of the higher chlorinated congeners. Congeners of CN45/36, CN27/30 and CN33/34/37 were much more abundant than other congeners found in tetrachlorinated PCNs. Congeners of CN51, CN66/67 and CN73 were determined to be the predominant congeners in penta-, hexa- and heptachlorinated homologs, respectively. The PCNs contributed around 5% of the total PCN, PCDD, PCDF and PCB toxic equivalence (TEQ) values. CN73 was found to be the dominant PCN congener and contributed more than 40% to the PCN TEQ value. Congeners CN66/67, CN69 and CN63 were also found at relatively high levels. The PCB congener CB118 was the predominant congener (by mass-based concentration) of the 12 dioxin-like PCBs (dl-PCBs). The PCBs contributed 53.8% of the total TEQ, and congener CB126 contributed more than any other compound that was analysed to the total TEQ. The PCDDs and PCDFs contributed 11.6% and 29.7% of the total TEQ values, respectively.</p></div

Stress Response in the Honeybee (Apis mellifera L.) Gut Induced by Chlorinated Paraffins at Residue Levels Found in Bee Products

Chlorinated paraffins (CPs) have become global pollutants and are of considerable concern as a result of their persistence and long-distance transmission in the environment and toxicity to mammals. However, their risks to pollinating insects are unknown. Honeybees are classical pollinators and sensitive indicators of environmental pollution. Herein, the effects of CPs on the gut microenvironment and underlying mechanisms were evaluated and explored using Apis mellifera L. Both short- and medium-chain CPs had significant sublethal effects on honeybees at a residue dose of 10 mg/L detected in bee products but did not significantly alter the composition or diversity of the gut microbiota. However, this concentration did induce significant immune, detoxification, and antioxidation responses and metabolic imbalances in the midgut. The mechanisms of CP toxicity in bees are complicated by the complex composition of these chemicals, but this study indicated that CPs could substantially affect intestinal physiology and metabolic homeostasis. Therefore, CPs in the environment could have long-lasting impacts on bee health. Future studies are encouraged to identify novel bioindicators of CP exposure to detect early contamination and uncover the detailed mechanisms underlying the adverse effects of CPs on living organisms, especially pollinating insects

Occupational Exposure to Polychlorinated Dibenzo‑<i>p</i>‑dioxins and Dibenzofurans, Dioxin-like Polychlorinated Biphenyls, and Polychlorinated Naphthalenes in Workplaces of Secondary Nonferrous Metallurgical Facilities in China

The concentrations of polychlorinated dibenzo-<i>p</i>-dioxins and dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (dl-PCBs), and polychlorinated naphthalenes (PCNs) were determined in workplace air from eight secondary nonferrous metal processing plants to investigate occupational exposure to these toxic compounds. The total estimated daily intakes of PCDD/Fs and dl-PCBs for workers by inhalation in the workplace were in the range of 0.15–9.91 and 0.13–8.59 pg of WHO-TEQ/kg of body weight (bw) for moderate and light activities, respectively. The daily inhalation doses for workers in the workplaces of three investigated plants exceeded the tolerable daily intake recommended by the World Health Organization. These results indicate that the risk of occupational exposure to dioxins by inhalation in the workplace of plants investigated was considerably high. For PCNs, the daily inhalation doses for workers in the workplace were in the range of 0.005–4.46 and 0.004–3.87 pg of TEQ/kg of bw for moderate and light activities, respectively, which were lower than those of dioxins. To identify the source of PCDD/Fs, PCBs, and PCNs in workplace air, their homologue profiles were compared with those in stack gas from the plants investigated. It was found that significant dioxin contamination in workplace air was mainly attributed to the emission of fugitive gas from smelting furnaces during reclamation processes

Comparative In Vitro and In Vivo Hydroxylation Metabolization of Polychlorinated Biphenyl 101 in Laying Hens: A Pilot Study

Polychlorinated biphenyls (PCBs) can be metabolized into hydroxylated PCBs (OH-PCBs) that exhibit greater toxicity than their parent compounds. In particular, 2,2′,4,5,5′-pentachlorobiphenyl (PCB 101) is commonly found in chicken feeds and breeding environments, although information on the biotransformation of this PCB in chickens is lacking. In this study, the hydroxylation metabolization of PCB 101 was assessed based on in vitro trials with Sanhuang chicken liver microsomes and in vivo experiments with Hy-Line Brown hens. The para-substituted metabolite 4′-OH-PCB 101 is the predominant metabolite of PCB 101. 4′-OH-PCB 101 is preferentially retained in the chicken bloodstream and partly distributed into different tissues of laying hens. The blood–brain barrier can effectively prevent the OH-PCB from entering the brain, and the adipose tissue contains a relatively low residue concentration of the OH-PCB. The laying hen can deplete the OH-PCB via laying eggs and excrement. The ratio of 4′-OH-PCB 101/PCB 101 in egg yolk is about 1:2. These results first provide definite evidence for the previous hypothesis of the PCB 101 metabolism by chickens. They could assist in predicting the environmental fate of PCBs, and in the risk assessment of PCBs and OH-PCBs in chicken-based foodstuffs

Remarkable Uptake of Deoxynivalenol in Stable Metal–Organic Frameworks

Deoxynivalenol (DON), which is known as one of the most harmful mycotoxins, has contaminated food and feed and attracted concerns worldwide. However, the effective adsorptive removal of DON to ensure food safety still is a challenge, which is ascribed to the poor planarity and larger steric hindrance of DON molecules. Here, a new Zr­(IV)-based metal–organic framework, entitled BUT-16 with one-dimensional channels and N-atom-decorated pore surface, is designed, prepared, and utilized for the adsorptive removal of DON. It exhibits excellent adsorption ability with an adsorption capacity of 46 mg/g higher than all reported adsorbents until now and a rapid adsorption rate of 0.031 g mg–1 min–1. DFT calculation and X-ray photoelectron spectroscopy results of the guest-loaded phase suggest that the record-breaking adsorption could be due to the cooperation of hydrogen bonding and Zr···O interaction between DON molecules and BUT-16 host. Most importantly, BUT-16 can effectively adsorb and remove DON in the simulated gastric fluid, but DON adsorbed on BUT-16 is hardly desorbed in the simulated intestinal fluid. The results demonstrate that BUT-16 has great promising application for the control of DON in foods and feeds

Remarkable Uptake of Deoxynivalenol in Stable Metal–Organic Frameworks

Deoxynivalenol (DON), which is known as one of the most harmful mycotoxins, has contaminated food and feed and attracted concerns worldwide. However, the effective adsorptive removal of DON to ensure food safety still is a challenge, which is ascribed to the poor planarity and larger steric hindrance of DON molecules. Here, a new Zr­(IV)-based metal–organic framework, entitled BUT-16 with one-dimensional channels and N-atom-decorated pore surface, is designed, prepared, and utilized for the adsorptive removal of DON. It exhibits excellent adsorption ability with an adsorption capacity of 46 mg/g higher than all reported adsorbents until now and a rapid adsorption rate of 0.031 g mg–1 min–1. DFT calculation and X-ray photoelectron spectroscopy results of the guest-loaded phase suggest that the record-breaking adsorption could be due to the cooperation of hydrogen bonding and Zr···O interaction between DON molecules and BUT-16 host. Most importantly, BUT-16 can effectively adsorb and remove DON in the simulated gastric fluid, but DON adsorbed on BUT-16 is hardly desorbed in the simulated intestinal fluid. The results demonstrate that BUT-16 has great promising application for the control of DON in foods and feeds

Remarkable Uptake of Deoxynivalenol in Stable Metal–Organic Frameworks

Deoxynivalenol (DON), which is known as one of the most harmful mycotoxins, has contaminated food and feed and attracted concerns worldwide. However, the effective adsorptive removal of DON to ensure food safety still is a challenge, which is ascribed to the poor planarity and larger steric hindrance of DON molecules. Here, a new Zr­(IV)-based metal–organic framework, entitled BUT-16 with one-dimensional channels and N-atom-decorated pore surface, is designed, prepared, and utilized for the adsorptive removal of DON. It exhibits excellent adsorption ability with an adsorption capacity of 46 mg/g higher than all reported adsorbents until now and a rapid adsorption rate of 0.031 g mg–1 min–1. DFT calculation and X-ray photoelectron spectroscopy results of the guest-loaded phase suggest that the record-breaking adsorption could be due to the cooperation of hydrogen bonding and Zr···O interaction between DON molecules and BUT-16 host. Most importantly, BUT-16 can effectively adsorb and remove DON in the simulated gastric fluid, but DON adsorbed on BUT-16 is hardly desorbed in the simulated intestinal fluid. The results demonstrate that BUT-16 has great promising application for the control of DON in foods and feeds