Search

Transarterial chemoembolization (TACE) is commonly used for treating advanced hepatocellular carcinoma (HCC). However, the instability of lipiodol-drug emulsion and the altered tumor microenvironment (TME, such as hypoxia-induced autophagy) postembolization are responsible for the unsatisfactory therapeutic outcomes. Herein, pH-responsive poly(acrylic acid)/calcium phosphate nanoparticles (PAA/CaP NPs) were synthesized and used as the carrier of epirubicin (EPI) to enhance the efficacy of TACE therapy through autophagy inhibition. PAA/CaP NPs have a high loading capacity of EPI and a sensitive drug release behavior under acidic conditions. Moreover, PAA/CaP NPs block autophagy through the dramatic increase of intracellular Ca2+content, which synergistically enhances the toxicity of EPI. TACE with EPI-loaded PAA/CaP NPs dispersed in lipiodol shows an obvious enhanced therapeutic outcome compared to the treatment with EPI-lipiodol emulsion in an orthotopic rabbit liver cancer model. This study not only develops a new delivery system for TACE but also provides a promising strategy targeting autophagy inhibition to improve the therapeutic effect of TACE for the HCC treatment.

Aromatic six-membered imides suffer the introduction of bulky substituents at the imide positions due to the formation of isoimides and low reactivity, preventing from the investigation of the intrinsic molecular properties. Here, we found a highly efficient alcohol-promoted rearrangement from isonaphthalimide to naphthalimide under acid or basic nonaqueous conditions, which can be regarded as model compounds for aromatic six-membered imides. We proposed two-step nucleophilic substitutions in the isomerization mechanistic pathways that were verified by the separation of a key intermediate. Furthermore, in-situ1H NMR exhibited the first-order kinetics for the isoimide loss process. Finally, the alcohol-promoted isoimide-imide rearrangement was extended to a palladium-catalyzed one-pot domino carbonylation reaction toward sterically crowded aromatic six-membered imides.

Excellent mechanical properties, including residual stress, ductility and strength, are important requirements for bone implants. In order to achieve this effect, titanium samples were manufactured by selective laser melting, and the prepared parts were subsequently subjected to three different heat treatment, which were 550 °C, 650 °C and 750 °C for 2 h, respectively. The results show that for as-built sample, relatively short lath-shaped α grains and a few needle-shaped α′ grains were present. After heat treatment, the α grains became thicker and longer, and the α′ grains became more. As the heat treatment temperature increases from 550 °C to 750 °C, the size of the lath-shaped α grains gradually decreases, and the small-sized needle-shaped α′ grains become denser. Moreover, the tensile strength, elongation and shrinkage of specimens increased as the heat treatment temperature increased. The fine microstructure of heat-treated samples also significantly promoted the improvement of tensile properties. The fracture mechanism of the specimens changed from brittle fracture to a mixed mode including ductile and brittle fracture, so that the tensile strength and ductility of the heat-treated specimens were well combined.

In this study, the stereoselective bioactivity, acute toxicity, and environmental fate for famoxadone enantiomers were reported for the first time. Five representative pathogens (e.g., Alternaria solani) were used to investigate enantioselective activity, and three non-target organisms (e.g., Selenastrum bibraianum) were used to evaluate acute toxicity. S-Famoxadone was 3.00–6.59 times more effective than R-famoxadone. R-Famoxadone also showed 1.80–6.40 times more toxicity than S-famoxadone toward S. bibraianumand Daphnia magna. The toxicity of R-famoxadone was 100 times more toxic than S-famoxadone toward Danio rerio. Under aerobic conditions, the half-life (t1/2) for famoxadone enantiomer degradation was 46.2–126 days in different soils and the enantiomeric fraction (EF) ranged from 0.435 to 0.470 after 120 days. R-Famoxadone preferentially degraded in three soils, resulting in an enrichment of S-famoxadone. Under anaerobic conditions, t1/2of famoxadone enantiomers was 62.4–147 days in different soils and the EF ranged from 0.489 to 0.495, indicating that famoxadone enantiomers were not enantioselective. This study will be useful for the environmental and health risk assessments for famoxadone enantiomers.

The aim of this paper is to recognise key antecedents which are absolutely necessary to achieving flexibility in maritime logistics industry. Methodologically, personal interview and a three-round Delphi survey are used for data collection. We test the key antecedents and derive a ranking of the importance of these antecedents. These findings allowed us to build a model of key antecedents to flexibility in the industry. The canonical correlation analysis reveals that the interrelationships among sets of key antecedents are positive and strong. The results offer managerial insights for companies in the industry to improve their responsibility to uncertainty.

Background and Objective. To explore the effect of respiratory muscle training on children with bronchiectasis. Methods. Participants underwent respiratory muscle training for 24 weeks. The main results were changes in respiratory muscle strength and pulmonary function indices (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow rate (PEF), forced expiratory flow 25–75% (FEF25–75%), and maximal midexpiratory flow 75/25 (MMEF75/25)) before, 12 weeks after, and 24 weeks after the intervention. The secondary outcomes were changes in the exercise load and work rate, exercise work, Leicester Cough Questionnaire (LCQ) scale, and Fatigue Severity Scale (FSS). Results. Compared with before the intervention, after 24 weeks of respiratory muscle training, the maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were significantly enhanced (P<0.05), while FVC, FEV1, and PEF were significantly increased (P<0.01). FEF25–75 and MMEF75/25 values showed significant improvement compared to those before training (P<0.05). The exercise loading, work, and exercise work rate of expiratory muscle training were significantly improved compared to those before intervention (P<0.05). The LCQ score increased significantly (P< 0.001), and the FSS score decreased significantly (P< 0.001). Conclusion. Incremental load respiratory muscle training effectively improved children’s lung function over the long term, improved the strength of their inspiratory and expiratory muscles, and improved their quality of life.

During storage at 20°C, specific pear cultivars may exhibit a greasy texture and decline in quality due to fruit senescence. Among these varieties, ‘Yuluxaing’ is particularly susceptible to peel greasiness, resulting in significant economic losses. Therefore, there is an urgent need for a preservative that can effectively inhibit the development of greasiness. Previous studies have demonstrated the efficacy of 1-methylcyclopropene (1-MCP) in extending the storage period of fruits. We hypothesize that it may also influence the occurrence of postharvest peel greasiness in the ‘Yuluxiang’ pears. In this study, we treated ‘Yuluxiang’ pears with 1-MCP. We stored them at 20°C while analyzing the composition and morphology of the surface waxes, recording enzyme activities related to wax synthesis, as well as measuring indicators associated with fruit storage quality and physiological characteristics. The results demonstrate that prolonged storage at 20°C leads to a rapid increase in skin greasiness, consistent with the observed elevations in L*, greasiness score, and the content of total wax and greasy wax components. Moreover, there were indications that cuticular waxes underwent melting, resulting in the formation of an amorphous structure. In comparison to controls, the application of 1-MCP significantly inhibited increments in L* values as well as grease scores while also reducing accumulation rates for oily waxes throughout most stages over its shelf period, additionally delaying transitions from flaky-wax structures towards their amorphous counterparts. During the initial seven days of storage, several enzymes involved in the biosynthesis and metabolism of greasy wax components, including lipoxygenase (LOX), phospholipase D (PLD), and β-ketoacyl-CoA synthase (KCS), exhibited an increase followed by a subsequent decline. The activity of LOX during early shelf life (0-7 d) and the KCS activity during middle to late shelf life (14-21 d) were significantly suppressed by 1-MCP. Additionally, 1-MCP effectively maintained firmness, total soluble solid (TSS) and titratable acid (TA) contents, peroxidase (POD), and phenylalanine ammonia-lyase (PAL) activities while inhibiting vitamin C degradation and weight loss. Furthermore, it restrained polyphenol oxidase (PPO) activity, ethylene production, and respiration rate increase. These findings demonstrate that 1-MCP not only delays the onset of peel greasiness but also preserves the overall storage quality of ‘Yuluxiang’ pear at a temperature of 20°C. This study presents a novel approach for developing new preservatives to inhibit pear fruit peel greasiness and provides a theoretical foundation for further research on pear fruit preservation.

We discuss the dynamic impact of industrial cluster on regional innovation capacity from the view of life cycle. To identify an industrial cluster, we propose the location quotient composite indexes with technological innovation as the major consideration. Meanwhile, the entire life cycle evolution of industrial clusters is divided into emerging, growth, maturity and decline stages with the graphical index theory and the agglomeration degree measurement. Referring to Cobb-Douglas production function model and conduction process of ‘industrial cluster, innovation network, regional innovation’, we develop a mathematical model to measure the dynamic impact. The model is quantitatively verified using the general equipment manufacturing industrial cluster of Yangtze River Delta area as empirical study and is deemed to have been validated.

Clinically, many candidates for islet transplantation are already immunized, which increases their risk of graft rejection. Encapsulation of pancreatic islets using the TheraCyte™ device has been shown to protect against allograft rejection in nonimmunized recipients. However, the capacity of the TheraCyte™ device to prevent rejection in immunized recipients has not yet been studied. In this study, the protective capacity of the TheraCyte™ device was evaluated in an allogeneic rat model. Lewis rats were used as islet donors, and nonimmunized (control) and alloimmunized, diabetic Wistar–Furth (WF) rats were used as recipients. Graft survival was shorter in immunized recipients than in nonimmunized recipients (mean survival, 5.3 ± 2.7 and 9.3 ± 1.6 days, respectively, p< 0.01) when nonencapsulated islets were transplanted under the kidney capsule. When islets were transplanted into the TheraCyte™ device, graft function was maintained during the 6-month study period in both immunized and nonimmunized rats. In oral glucose tolerance tests performed at 1 month after transplantation, both groups had similar insulin and blood glucose levels indicating similar metabolic functions. Volume densities and absolute volumes of tissue inside the devices 6 months after transplantation were also comparable between the two groups, indicating that both groups maintained similar amounts of endocrine tissue. A higher number of IFN-γ-producing CD8+T-cells were detected in immunized WF rats compared to control WF rats transplanted with encapsulated islets. This suggests that donor-specific alloreactivity in recipient rats was sustained throughout the study period. This study suggests that the TheraCyte™ device protects islet allografts also in immunized recipients. Our results further highlight the potential for using macroencapsulation to avoid immunosuppressive therapy in clinical islet transplantation.

Pancreatic cancer patients frequently show hyperglycemia, but it is uncertain whether hyperglycemia stimulates pancreatic cancer cells. We have investigated whether excess glucose induces hypoxia-inducible factor-1α (HIF-1α) and stimulates glucose metabolism and cell migration in pancreatic cancer cells. We studied wild-type (wt) MiaPaCa2 pancreatic cancer cells and a MiaPaCa2 subline (namely si-MiaPaCa2) that had HIF-1α-specific small interfering RNA. Wt-MiaPaCa2 cells are known to be HIF-1α-positive in hypoxia and HIF-1α-negative in normoxia, whereas si-MiaPaCa2 cells are devoid of HIF-1α in both normoxia and hypoxia. We incubated these cells with different amounts of glucose and determined HIF-1α mRNA and protein by real-time polymerase chain reaction and western blotting. We determined glucose consumption, lactate production and intracellular hexokinase-II and ATP to assess glucose metabolisms and determined pyruvate dehydrogenase kinase-1, reactive oxygen species and fumarate to assess mitochondrial activities. Further, we studied cell migration using a Boyden chamber. Excess glucose (16.7−22.2mM) increased HIF-1α in hypoxic wt-MiaPaCa2 cells. HIF-1α expression increased ATP contents and inhibited mitochondrial activities. Extracellular glucose and hypoxia stimulated glucose metabolisms independent of HIF-1α. Excess glucose stimulated the migration of wt- and si-MiaPaCa2 cells in both normoxia and hypoxia. Thus, glucose stimulated cell migration independent of HIF-1α. Nevertheless, hypoxic wt-MiaPaCa2 cells showed greater migrating ability than their si-MiaPaCa2 counterparts. We conclude that (1) excess glucose increases HIF-1α and ATP in hypoxic wt-MiaPaCa2 cells, (2) extracellular glucose and hypoxia regulate glucose metabolisms independent of HIF-1α and (3) glucose stimulates cell migration by mechanisms that are both dependent on HIF-1α and independent of it.

In this study, we evaluated the effects of exendin-4 on free and encapsulated islet grafts in a rodent model. We also investigated the role of a transcription factor, hypoxia-inducible factor-1 (HIF-1), in mediating the beneficial effects of exendin-4. Diabetic athymic mice were transplanted with free rat islets under the kidney capsule or with macroencapsulated rat islets SC with or without exendin-4, islet preculture (exendin-4 0.1 nM for 20 h), and/or recipient treatment (IP 100 ng/day, day 0–7). The mice were followed for 4 weeks and the graft function and β-cell volume were evaluated. The effects of exendin-4 on islet HIF-1α mRNA and protein expression and on ATP content in a rat insulinoma cell line (INS-1E) were also examined. Preculture with exendin-4 followed by recipient treatment improved the outcome of both free (73% graft function vs. 26% in controls, p= 0.03) and macroencapsulated islet grafts (100% vs. 25% in controls, p= 0.02). In macroencapsulated grafts, the exendin-4-treated group had significantly larger endocrine volume, less graft necrosis, and more blood vessels around the capsule. In rat islets cultured with exendin-4, HIF-1α mRNA and protein expression were significantly enhanced. ATP content was increased in exendin-4-treated INS-1E cells under hypoxic conditions. The improved functional outcome after transplantation of a marginal islet mass with a brief initial treatment with exendin-4 is related to a larger surviving endocrine cell volume. Exendin-4 may improve islet graft resistance to hypoxia during the peritransplant period by increasing the expression of HIF-1α.