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Purpose: Enzymolysis clearance strategy, characterized by releasing the non-reabsorbable radioactive fragment under the specific cleavage of enzymes, is confirmed to be a safe and effective way to reduce the renal radioactivity accumulation in mice. However, the effectiveness of this strategy in humans remains unknown. Human epidermal growth factor receptor 2 (HER2) is overexpressed in various types of tumors, and radiolabeled HER2 Affibody is believed to be an attractive tool for HER2-targeted theranostics. However, its wide application is limited by the high and persistent renal uptake. In this study, we intend to validate the effectiveness of enzymolysis clearance strategy in reducing renal accumulation by using a modified HER2 Affibody. Materials and methods: A new HER2 Affibody ligand, NOTA-MVK-ZHER2:2891, containing a cleavable Met-Val-Lys (MVK) linker was synthesized and labeled with 68Ga. The microPET imaging study was performed in SKOV-3 tumor mice to assess the uptakes of the control ligand and the MVK one in tumors and kidneys. Seven healthy volunteers were included for biodistribution and dosimetric studies with both the control and MVK ligands performed 1 week apart. Urine and blood samples from healthy volunteers were collected for in vivo metabolism study of the two ligands. Four HER2-positive and two HER2-negative patients were recruited for [68Ga]Ga-NOTA-MVK-ZHER2:2891 PET/CT imaging at 2 and 4 h post-injection (p.i.). Results: [68Ga]Ga-NOTA-MVK-ZHER2:2891 was stable both in PBS and in mouse serum. MicroPET images showed that the tumor uptake of [68Ga]Ga-NOTA-MVK-ZHER2:2891 was comparable to that of [68Ga]Ga-NOTA-ZHER2:2891 at all the time points, while the kidney uptake was significantly reduced 40 min p.i. (P < 0.05). The biodistribution study in healthy volunteers showed that the kidney uptake of MVK ligand was significantly lower than that of the control ligand at 1 h p.i. (P < 0.05), with the SUVmean of 34.3 and 45.8, respectively, while the uptakes of the two ligands in the other organs showed negligible difference. The effective doses of the MVK ligand and the control one were 26.1 and 28.7 µSv/MBq, respectively. The enzymolysis fragment of [68Ga]Ga-NOTA-Met-OH was observed in the urine samples of healthy volunteers injected with the MVK ligand, indicating that the enzymolysis clearance strategy worked in humans. The PET/CT study of patients showed that the range of SUVmax of HER2-positive lesions was 9.4–21, while that of HER2-negative lesions was 2.7–6.2, which suggested that the MVK modification did not affect the ability of ZHER2:2891 structure to bind with HER2. Conclusion: We for the first time demonstrated that enzymolysis clearance strategy can effectively reduce renal radioactivity accumulation in humans. This strategy is expected to decrease renal radiation dose of peptide and small protein-based radiotracers, especially in the field of radionuclide therapy. [ABSTRACT FROM AUTHOR]

Metallic barrier layer is a key component in thermoelectric (TE) devices, but it is rarely investigated for the recently discovered inorganic ductile TE materials. In this work, we demonstrate that tungsten (W) is the excellent metallic barrier layer for Ag2S1−xSex ductile thermoelectric materials. The phase composition, microstructure, adhesive strength, and interfacial contact resistivity (ρC) of the W/Ag2S1−xSex joint have been systematically investigated. The sputtered W film has high adhesive strength and little interdiffusion/reaction with Ag2S1−xSex. The ρC decreases with increasing the Se content, which can be understood by the Thermionic-field Emission model. This work would guide the development of high-performance flexible TE devices based on ductile TE materials. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective hematopoiesis. Accumulating evidence has shown that macrophages (MΦs) are important components in the regulation of tumor progression and hematopoietic stem cells (HSCs). However, the roles of bone marrow (BM) MΦs in regulating normal and malignant hematopoiesis in different clinical stages of MDS are largely unknown. Age‐paired patients with lower‐risk MDS (N = 15), higher‐risk MDS (N = 15), de novo acute myeloid leukemia (AML) (N = 15), and healthy donors (HDs) (N = 15) were enrolled. Flow cytometry analysis showed increased pro‐inflammatory monocyte subsets and a decreased classically activated (M1) MΦs/alternatively activated (M2) MΦs ratio in the BM of patients with higher‐risk MDS compared to lower‐risk MDS. BM MФs from patients with higher‐risk MDS and AML showed impaired phagocytosis activity but increased migration compared with lower‐risk MDS group. AML BM MΦs showed markedly higher S100A8/A9 levels than lower‐risk MDS BM MΦs. More importantly, coculture experiments suggested that the HSC supporting abilities of BM MΦs from patients with higher‐risk MDS decreased, whereas the malignant cell supporting abilities increased compared with lower‐risk MDS. Gene Ontology enrichment comparing BM MΦs from lower‐risk MDS and higher‐risk MDS for genes was involved in hematopoiesis‐ and immunity‐related pathways. Our results suggest that BM MΦs are involved in ineffective hematopoiesis in patients with MDS, which indicates that repairing aberrant BM MΦs may represent a promising therapeutic approach for patients with MDS. [ABSTRACT FROM AUTHOR]

Plant essential oils are unstable due to high volatility and easy oxidation, while microencapsulation provides a potentially effective strategy for increasing the stability of natural essential oils and preserving their function. This study examined the effects of feeding coated oregano essential oil and cinnamaldehyde (COEC) compounds on growth, immune organ development, intestinal morphology, mucosal immune function, and the cecal microbiota populations of broilers. Three hundred one-day-old male Arbor Acres broiler chicks were organized into 5 groups: 1) negative control fed basal diet alone (NC), 2) positive control receiving basal diet plus 50 mg/kg of chlortetracycline (CTC), 3) basal diet plus 150 mg/kg COEC (COEC 150 ), 4) plus 300 mg/kg COEC (COEC 300 ), and 5) plus 450 mg/kg COEC (COEC 450 ). The supplement trial was continued for 42 d. The results showed that CTC, COEC300, and COEC450 treatments decreased the feed conversion ratio of broilers both in the starter and whole experiment phases, increased the height of jejunal villi at 21 d and the number of goblet cells and IgA-producing cells at 21 or 42 d compared with NC group (P  < 0.05). Members of the COEC300 treatment group had a higher thymus weight index and jejunum length index than birds of NC or CTC groups at 21 d (P  < 0.05). CTC and all COEC treatments decreased malondialdehyde content in jejunal mucosa at 42 d (P  < 0.05). The population of Escherichia coli (E. coli) in the cecal digesta at 21 d was lower in the CTC, COEC300, and COEC450 treatment groups compared with the NC group (P  < 0.05). In contrast to the CTC group, COEC supplementation dose-dependently accelerated body weight gain, improved jejunal morphology, decreased malondialdehyde content in jejunal mucosa, increased numbers of jejunal goblet cells and IgA-producing cells, and decreased the E. coli population in cecal digesta at 21 or 42 d (P  < 0.05). Thus, we concluded that feeding broiler chickens with 300 or 450 mg/kg in antibiotic-free diets can improve growth performance, enhance immune responses, and inhibit the proliferation of cecal pathogenic bacteria. [ABSTRACT FROM AUTHOR]

This study was purposed to investigate the efficacy of dietary creatine nitrate (CrN) supplementation on redox status and mitochondrial function in pectoralis major (PM) muscle of broilers that experienced preslaughter transport. A total of 288 Arbor Acres broilers (28-day-old) were randomly assigned into five dietary treatments, including a basal diet or the basal diet supplemented with 600 mg/kg guanidinoacetic acid (GAA), 300, 600, or 900 mg/kg CrN for 14 days, respectively. On the transportation day, the basal diet group was divided into two groups on average, resulting in six groups. The control group was transported for 0.5 h and the other groups for 3 h (identified as Control, T3h, GAA600, CrN300, CrN600, and CrN900 group, respectively), and all crates were randomly placed on the truck travelling at an average speed of 80 km/h. Our results showed that GAA600 and CrN treatments decreased the muscle ROS level and MDA content (P < 0.05) and increased the mitochondrial membrane potential (P < 0.001), as well as a higher mRNA expression of avUCP (P < 0.001) and lower mRNA expressions of Nrf2 (P < 0.001), Nrf2 and PGC-1α (P < 0.05) compared with T3h group. Meanwhile, the mRNA and protein expressions of Nrf1, TFAM, and PGC-1α in CrN600 and CrN900 groups were lower than those in the T3h group (P < 0.05). Conclusively, dietary supplementation with GAA and CrN decreased muscle oxidative products and enhanced mitochondrial uncoupling mechanism and mtDNA copy number, which relieved muscle oxidative damage and maintained mitochondrial function. [ABSTRACT FROM AUTHOR]