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[Display omitted] • Advance in engineering retinal organoids (ROs) and organoid-on-a-chip (ROoC) and their recent challenges are summarized. • Recreating microphysiological environments of retina in vitro with microvascular and multi-tissue interactions is detailed. • The integration of biosensors in chip platform for in situ and real-time monitoring of ROs and ROoC platforms is emphasized. • Modeling of intraocular drug delivery and development of innovative strategies based on ROs and ROoC platforms is anticipated. Retinal diseases are a rising concern as major causes of blindness in an aging society; therapeutic options are limited, and the precise pathogenesis of these diseases remains largely unknown. Intraocular drug delivery and nanomedicines offering targeted, sustained, and controllable delivery are the most challenging and popular topics in ocular drug development and toxicological evaluation. Retinal organoids (ROs) and organoid-on-a-chip (ROoC) are both emerging as promising in-vitro models to faithfully recapitulate human eyes for retinal research in the replacement of experimental animals and primary cells. In this study, we review the generation and application of ROs resembling the human retina in cell subtypes and laminated structures and introduce the emerging engineered ROoC as a technological opportunity to address critical issues. On-chip vascularization, perfusion, and close inter-tissue interactions recreate physiological environments in vitro, whilst integrating with biosensors facilitates real-time analysis and monitoring during organogenesis of the retina representing engineering efforts in ROoC models. We also emphasize that ROs and ROoCs hold the potential for applications in modeling intraocular drug delivery in vitro and developing next-generation retinal drug delivery strategies. [ABSTRACT FROM AUTHOR]

Plantar fascia (PF) is a heterogeneous thickness structure across plantar foot. It is important significance to investigate the biomechanical behavior of the medial, middle and lateral PF regions. To investigate the non-uniform macro/micro structures of the different PF regions, the uniaxial tensile test of PF strips were performed to assess the mechanical behavior of PF. A scanning electron microscope (SEM) was used to visualize and measure the micro morphology of PF associated with collagen fibers. A three-dimensional foot finite element (FE) model was developed to quantify the tensile behavior of the internal PF. The elastic modulus of the lateral PF component (1560 MPa) was observed, followed by the medial (701 MPa), the central (1100 MPa) and the lateral (714 MPa) portions in the central component. Elongation of the central portion (0.192) was lower than the medial (0.223) and the lateral (0.227) portions. The corresponding SEM images showed that the fibers of the central portion were more densely packed and thicker compared to the ambilateral portions in the central component. While the FE model prediction also suggested that the greater elastic modulus of the central PF portion had lower strain (0.192) versus the ambilateral portions. Therefore, the lower elongation and greater elastic modulus at the central portion of PF would probably have a high risk of PF injury. The findings showed a relation between the mechanical tension and fibrous morphology of PF. This information would have a better understanding of the PF pathophysiology diseases related to tear and injury of PF. [ABSTRACT FROM AUTHOR]

A new fluorescence nanosensor for sensitive and selective 2,4,6-trinitrophenol (TNP) determination is reported based on (3-chloro-2-hydroxypropyl)trimethylammonium chloride (CTA) functionalized carbon dots (CTA-CDs). Carboxymethyl cellulose sodium (CMC)-4,7,10-trioxa-1,13-tridecanediamine (TTDDA) mixture was heated to prepare passivated CDs. Then CTA was grafted onto the surface of the passivated CDs by esterification reaction to form quaternary ammonium-functionalized CTA-CDs. Therefore, the CTA-CDs are used as a sensor for the detection of 2,4,6-trinitrophenol (TNP) in water via molecular interactions (electrostatic, π−π, and hydrogen bonding interactions) between TNP and CTA-CDs. A limit of detection of the CTA-CDs for TNP in aqueous solution is 7.04 × 10 −7  mol/L, which is lower than that of the passivated CDs for TNP (3.03 × 10 −6  mol/L). In addition, compared with various organic reagents, the CTA-CDs exhibit significantly sensitive and selective sensing towards TNP in aqueous medium. [ABSTRACT FROM AUTHOR]

Cell division cycle 7 (Cdc7) plays important roles in the regulation of the initiation of DNA replication throughout S phase. Whether inhibition of Cdc7 has a direct antitumour effect in oral squamous cell carcinoma (OSCC) remains unclear. In this study, XL413, a novel Cdc7 inhibitor, markedly inhibited the viability of OSCC cells but not that of non-tumour primary cells. There was a synergistic effect between XL413 and DNA-damaging agents (e.g. cisplatin and 5-fluorouracil) on OSCC in vitro and in vivo. Moreover, XL413 exhibited a notable antitumour effect on OSCC patients with high Cdc7 expression in mini patient-derived xenografts model. The proliferation was significantly inhibited in OSCC cells after Cdc7 silencing. Cdc7 knockdown significantly induced apoptosis in OSCC cell lines. Furthermore, we demonstrated that Cdc7 was overexpressed and transcriptionally regulated by E2F1 in OSCC by using chromatin immunoprecipitation and luciferase assays. Our results reveal that XL413 has an excellent antitumour effect in OSCC. Importantly, it does not inhibit the proliferation of non-tumour cells. These findings suggest that the overexpression of Cdc7 promotes progression in OSCC and that inhibition of Cdc7 is a very promising therapy for OSCC patients. [ABSTRACT FROM AUTHOR]

Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson’s disease. Herein we disclose the discovery of a 4-ethoxy-7 H -pyrrolo[2,3- d ]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7 , which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration. [ABSTRACT FROM AUTHOR]

Relaxed calcaneal stance position (RCSP) is an important index in the correctional treatment of foot valgus deformities for cerebral palsy (CP) children. However, patients with similar RCSP showed diverse outcomes when accepting similar treatment, as the corrective resistance of subtalar joint (STJ) could be quite different. This study aimed to investigate the relationship between STJ stiffness and RCSP in different loading conditions. 38 valgus feet of 19 CP subjects were included in the study. A reposition force was applied beneath the STJ and pushed the foot from pronated position to neutral position. The STJ stiffness was calculated as the slope of the line fitting the force-displacement data. Correlations between the STJ stiffness, RCSP, and composite spasticity index (CSI) were analyzed. The spearman correlation coefficient indicated that STJ stiffness had no correlation with RCSPs, yet it had negative correlation with the change of RCSP under difference loading conditions (ΔRCSP1w-0w and ΔRCSP0.5w-0w). STJ stiffness was also correlated with the composite spasticity index (CSI), implying that this index had an advantage in reflecting the mechanism of valgus deformity and should be considered as a necessary measurement of foot valgus in CP children. The present method for quantification of STJ stiffness could improve the accuracy in the diagnosis and classification of foot deformity and may help increase the understanding of the biomechanical factors in foot deformity rehabilitation. [ABSTRACT FROM AUTHOR]

Copper incorporated in Li 3 V 2 (PO 4 ) 3 /C cathode materials for high-rate Li-ion batteries were prepared by a self-catalysed sol-gel approach followed by a sintering process. The effect of copper incorporating amounts on the crystal structure, morphology and related electrochemical properties of Li 3 V 2 (PO 4 ) 3 /C was investigated. It is noteworthy that the impurity Li 3 PO 4 phase can be effectively affected by copper-incorporating without any significant influence on the surface morphology and crystal structure; moreover, the carbon layer coated onto Li 3 V 2 (PO 4 ) 3 -Cu 0.05 /C can be separated into the porous inner layer and the graphene-type outer layer. Benefiting from above two factors, copper-incorporated Li 3 V 2 (PO 4 ) 3 /C composite with improved electrochemical properties has been achieved. In comparison with pure Li 3 V 2 (PO 4 ) 3 /C, the Li 3 V 2 (PO 4 ) 3 -Cu 0.05 /C composite delivers a reversible specific capacity of 123.3 mAh g −1 after 50 cycles at a current rate of 1C and 116.2 mAh g −1 at 10C, maintaining 98.2% and 89.5% of capacity retention, respectively, and even cycled at 20C rate, it still possesses 105.4 mAh g −1 of discharge capacity, demonstrating an excellent rate capability and cycling stability. [ABSTRACT FROM AUTHOR]

The construction of macroscopic 3D sponges is of great technological importance for various applications. An outstanding challenge is the facile fabrication of sponges with the desirable combination of good stability, high electrical conductivity, and absorption ability. Here free-standing 3D OMS-2 sponges are demonstrated, with various densities, which possess a combination of desirable physical properties including high porosity, robustness, permeability, recyclability, high electrical conductivity, and selective water absorption in preference to oil. Some of these properties have systematic trends with various densities. The stress of the OMS-2 sponge, made by nanowire-based freeze-drying process, is four orders of magnitude higher than that made by calcination-related process. These new materials should find practical applications in environmental, catalysis, sensing, absorption, and energy storage, particularly in the removal of water spill cleanup, and beyond. [ABSTRACT FROM AUTHOR]

The large-size graphene-like porous carbon nanosheets (LGPCN) with controllable N-doped surface are successfully prepared by using a simple and effective integrated “self-template” and “designing” strategy through KOH activation. Biomass-sugarcane bagasse pith and chitosan are used as self-template carbon source and controlled nitrogen source, respectively. The relationship between structure of the LGPCN-X (X represents the activation temperature) and its electrochemical performance at different activation temperatures is explored in detail. The large-size multiscale wrinkled nanosheets architecture, high surface area, and appropriate controllable surface nitrogen doping state of the LGPCN-800 shows the best electrochemical performance in 6 M KOH. The largest specific electrode capacitance is about 339 F g −1 (at 0.25 A g −1 ), which still as high as 280 F g −1 at 100 A g −1 . The maximum energy density is about 11.77 Wh kg −1 at a power density of 34.11 W kg −1 . The LGPCN-800 also shows an excellent cycling stability with 97.9% capacitance retention after 10,000 cycles. [ABSTRACT FROM AUTHOR]

Pt decorated RuFeSe/C catalyst is prepared by reduction of Pt precursor on pre-formed RuFeSe/C for oxygen reduction reaction (ORR). The catalyst is characterized by X-ray diffraction (XRD), energy dispersive spectrometer (EDS), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). The catalyst particles are found to disperse on the carbon support with an average particle size of 2.8 nm. Physical characterizations and electrochemical tests confirm that Pt is deposited on the surfaces of RuFeSe particles and RuFeSe@Pt/C catalyst has a core-shell structure. The as-prepared catalyst has high durability and shows high ORR activity through a four-electron transfer process. RuFeSe@Pt/C exhibits 1.3-fold greater specific activity and 1.4-fold greater mass activity for ORR than Pt/C. More importantly, it has excellent tolerance to methanol. Consequently, RuFeSe@Pt/C may be used as fine cathode catalyst in direct methanol fuel cells (DMFCs). [ABSTRACT FROM AUTHOR]

Hallux valgus (HV) was one of the most frequent female foot deformities. The aim of this study was to evaluate mechanical responses and stabilities of the Kirschner, bandage and fiberglass fixations after the distal metatarsal osteotomy in HV treatment. Surface traction of different forefoot regions in bandage fixation and the biomechanical behavior of fiberglass bandage material were measured by a pressure sensor device and a mechanical testing, respectively. A three-dimensional foot finite element (FE) model was developed to simulate the three fixation methods (Kirschner, bandage and fiberglass fixations) in weight bearing. The model included 28 bones, sesamoids, ligaments, plantar fascia, cartilages and soft tissue. The peak Von Mises stress (MS) and compression stress (CS) of the distal fragment were predicted from the three fixation methods: Kirschner fixation (MS = 6.71 MPa, CS = 1.232 MPa); Bandage fixation (MS = 14.90 MPa, CS = 9.642 MPa); Fiberglass fixation (MS = 15.83 MPa, CS = 19.70 MPa). Compared with the Kirschner and bandage fixation, the fiberglass fixation reduced the relative movement of osteotomy fragments and obtained the maximum CS. We concluded that fiberglass fixation in HV treatment was helpful to the bone healing of distal fragment. The findings were expected to guide further therapeutic planning of HV patient. [ABSTRACT FROM AUTHOR]

Investigation of the ethyl acetate extract from the marine derived fungus Penicillium chrysogenum Y19-1 led to the isolation and identification of nine compounds, including ethyl formyltyrosinate (1), ergosterol peroxide (2), ergosterol (3), cerebroside A (4), conidiogenone C (5), dihydroresorcylide (6), 7-hydroxydihydroresorcylide (7), N-(2-hydroxypropanoyl)-2-aminobenzoic acid amide (8), and 4-methyl-5,6-dihydro-2H-pyran-2-one (9). Their chemical structures were determined by NMR analysis, ESIMS experiment and comparison with the reported data in the literature. Among them, compound 1 was identified as a natural product for the first time. All compounds were evaluated for antithrombotic and proangiogenic activities. Compounds 1 , 4 and 5 exhibited antithrombotic activities, while compounds 1 , 2 , 8 and 9 showed proangiogenic activities. Meanwhile, the chemotaxonomic significance of these isolated compounds was also discussed. • Nine compounds were isolated from Penicillium chrysogenum Y19-1. • Ethyl formyltyrosinate was identified as a natural product for the first time. • All compounds were evaluated for antithrombotic and proangiogenic activities. • Chemotaxonomic significance of these compounds was described. [ABSTRACT FROM AUTHOR]

• Building a new mathematical model to predict bleeding risk in VAD and ECMO. • Modeling variation between platelet-vWF binding ability to characterize bleeding risk. • Predicted bleeding risk in HVAD > heartmate II, consistent with clinical statistics. • Narrow and turbulence regions in devices are important contributions for bleeding. The objective of this study is to develop a bleeding risk model for assessing device-induced bleeding risk in patients supported with blood contact medical devices (BCMDs). The mathematical model for evaluating bleeding risk considers the effects of shear stress on von Willebrand factor (vWF) unfolding, high molecular weight multimers-vWF (HMWM-vWF) degradation, platelet activation and receptor shedding and platelet-vWF binding ability. Functions of the effect of shear stress on the above factors are fitted/employed and solved by the Eulerian transport equation. An axial flow-through Couette device and two clinical VADs which are HeartWare Ventricular Assist Device (HVAD) and HeartMate II (HM II) blood pump were employed to perform the simulation to evaluate platelet receptor shedding (GPIbα and GPIIb/IIIa), loss of HWMW-vWF, platelet-vWF binding ability and bleeding risk for validating the accuracy of our model. The platelet-vWF binding ability after being subjected to high shear region in the axial flow-through Couette device predicted by our bleeding model was highly consistent with reported experimental data. As indicated by our CFD simulation results in the axial flow-through Couette device, it can find that an increase in shear stress led to a decrease in the adhesion ability of platelets on vWF, while the binding ability of vWF with platelets first increase and then decrease as shear stress elevates gradually beyond a threshold. The factor of exposure time can enhance the effect of shear stress. Additionally, the shear-induced bleeding risk predicted by our model increases with increasing shear stress and exposure time in an axial flow-through Couette device. As indicated by our numerical model, the bleeding risk in HVAD was higher than HMII, which is highly consistent with the meta-analysis based on clinical statistics. Our simulation investigations in these two clinical VADs also found that HVAD caused a higher rate of platelet receptor shedding and lower damage to HWMW-vWF than HeartMate II. The high shear stress generated in the narrow and turbulent regions of both VADs was the underlying cause of device-induced bleeding. In this study, the shear-induced bleeding risk predicted by our bleeding model in axial flow-through Couette device and two clinical VADs is consistent or highly correlated with experimental and clinical findings, which proves the accuracy of our bleeding model. Our bleeding model can be used to aid the development of new BCMDs with improved functional characteristics and biocompatibility, and help to reduce risk of device-induced adverse events in patients. [ABSTRACT FROM AUTHOR]

Crocetin is a major active constituent of Gardenia jasminoides J. Ellis, and can aid in the prevention of cardiovascular disease. The effect and possible mechanism of crocetin on the migration of vascular smooth muscle cells (VSMCs) induced by advanced glycosylation end products (AGEs) were investigated. VSMCs were pre-incubated with or without crocetin and exposed to AGEs subsequently. The invasion of the cells was investigated using a 24-well Cell Invasion Chamber. The anti-proliferative activity of crocetin was evaluated by MTT assay and VSMCs cell-cycle distribution was examined by flow cytometry. Cytokine TNF-α and IL-6 secreted by VSMCs and the amount of matrix metalloproteinase MMP-2 and MMP-9 in the culture supernatant were detected by ELISA. The expression level of RAGE (AGEs receptor), in cells was analyzed by western blot. The results demonstrated that AGEs increased about two-fold migration of VSMCs compared with control (OD = 0.778 ± 0.191 vs OD = 0.413 ± 0.214, P < 0.01), and the proliferation increased by about 20% (OD = 0.335 ± 0.043 vs OD = 0.281 ± 0.037, P < 0.01). Pre-treatment with crocetin (1.0 μM) or RAGE antibody (10 μg/ml) could inhibit the AGEs triggered migration of VSMCs obviously. Furthermore, both crocetin and RAGE antibody inhibited the increase of RAGE protein in VSMCs stimulated by AGEs. The levels of TNF-α and IL-6 decreased in the crocetin (1.0 μM) pre-treated group compared to the AGEs (without pre-treated) group (37.60 ± 3.08 pg/ml vs 46.59 ± 1.92 pg/ml, 32.11 ± 4.69 pg/ml vs 49.99 ± 8.84 pg/ml, respectively). Crocetin (1.0 μM) also reduced the value of MMP-2 and MMP-9 compared with the AGEs group (2.81 ± 0.35 ng/ml vs 6.40 ± 0.85 ng/ml, 2.69 ± 0.25 ng/ml vs 4.32 ± 0.57 ng/ml, respectively). In summary, crocetin inhibits the migration of VSMCs induced by AGEs through RAGE-dependent signaling pathway. And it is meaningful to diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Polyethyleneimine-capped Cu nanoclusters (PEI-CuNCs) with a mean diameter of 2.5 nm and that emitted blue light at 485 nm were synthesized. The fluorescence of PEI-CuNCs was strongly quenched when Au(III) ions were present. Because of this specific response, a PEI-CuNC-based fluorescent turn-off sensor was developed. Under optimum conditions, a good linear relationship (R 2 =0.993) was found between the relative fluorescence intensity ( F 0 / F ) and the Au(III) ion concentration between 0.5 and 15 µM. The detection limit for Au(III) ions was 0.06 µM. The quenching mechanism was assessed by performing X-ray photoelectron spectroscopy spectra studies. The fluorescence quenching was ascribed to photo-induced electron transfer from the PEI-CuNCs to the AuCl 4 − occur. Using The method described is a new way of quantifying Au(III) ions. [ABSTRACT FROM AUTHOR]

The chemical synthesis of a tetrasaccharide repeating unit of the exopolysaccharide discovered from Burkholderia multivorans with a 3-aminopropyl group linked to the glycan downstream end, α-D-Manp-(1→2)-α-D-Manp-(1→2)-3-O-methyl-α-D-Rhap-(1→3)-α-D-Rhap-O(CH2)3NH2 (1), was described. The target tetrasaccharide was achieved by both a convergent [2 + 2] and a linear glycosylation strategies. The latter synthesis was proved to be more efficient than the former due to the excellent stereocontrol of glycosylation. Furthermore, the 3-aminopropyl group in the target molecule would enable its conjugation with functional biomolecules to explore its biological applications. [ABSTRACT FROM AUTHOR]

Background: Human epidermal growth factor receptor 2 (HER-2) has been found in many malignant tumours including salivary malignancy. HER-2-targeted therapy has been applied in the treatment of HER-2-overexpressing carcinoma. The aim of this study was to determine the status of HER-2 in salivary invasive carcinoma ex pleomorphic adenoma (ICXPA) in a relatively large Chinese sample, which may provide HER-2-targeted therapy with profound support in the future.Methods and Results: We collected 140 ICXPAs and their related clinicopathological and follow-up data. All cases were examined for HER-2 expression by immunohistochemistry and gene amplification by fluorescence in situ hybridization, if necessary. The study showed that the ratio of HER-2 positivity was only 25% (35/140) in all cases, but the positive ratio in ICXPAs with luminal differentiation for malignant component (32/79, 40.5%) was much higher than that in cases with non-luminal differentiation (3/61, 4.9%). The overexpression of HER-2 was closely associated with gender, histological grade and N stage. HER-2-positive tumours conferred short overall survival time (P = 0.036) and short disease-specific survival time (P = 0.042) in patients, but HER-2 status was not an independent predictor of prognosis.Conclusions: Human epidermal growth factor receptor 2 amplification is significantly associated with cell differentiation of the malignant component in ICXPA and it implies an unfavourable prognosis. Although HER-2 positivity is not common in the tumour, HER-2-targeted therapy for those HER-2-positive patients is still worth expecting. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the calcium and orthophosphate ions release during the transformation of amorphous calcium phosphate (ACP) to hydroxyapatite (HA) in aqueous solution. The ACP is prepared by a wet chemical method and further immersed in the distilled water for various time points till 14 d. The release of calcium and orthophosphate ions is measured with calcium and phosphate colorimetric assay kits, respectively. The transition of ACP towards HA is detected by x-ray diffraction (XRD), transmission electron microscopy (TEM), and fourier transform infrared spectroscopy (FTIR). The results indicate that the morphological conversion of ACP to HA occurs within the first 9 h, whereas the calcium and orthophosphate ions releases last for over 7 d. Such sustained calcium and orthophosphate ions release is very useful for ACP as a candidate material for hard tissue regeneration. [ABSTRACT FROM AUTHOR]

β-catenin is a key component of the Wnt/β-catenin signal transduction cascade which is a highly conserved signaling pathway in eukaryotes. Increasing evidence suggests that the Wnt/β-catenin signaling pathway is involved in the infection of many viruses. However, its role in fowl adenovirus serotype 4 (FAdV-4) replication remains unclear. In the present study, we showed that FAdV-4 infection increased the expression of β-catenin and promoted the nuclear translocation of β-catenin. Overexpression of β-catenin and LiCl treatment stimulated the accumulation of β-catenin in the nucleus, and then facilitated FAdV-4 replication. Conversely, repression of β-catenin by inhibitors and siRNA significantly inhibited FAdV-4 replication. Furthermore, inhibition of autophagy by 3-Methyladenine (3-MA) suppressed the FAdV-4 replication, and repression of β-catenin inhibited the FAdV-4-triggered autophagy. In conclusion, the nuclear translocation of β-catenin benefits FAdV-4 replication, and suppression of β-catenin limits FAdV-4 production by inhibiting FAdV-4-induced autophagy. These findings indicated that β-catenin is an important regulator of FAdV-4 replication which can serve as a potential target for anti-FAdV-4 agents. • FAdV-4 infection increases the expression of β-catenin and promotes the nuclear translocation of β-catenin. • The nuclear translocation of β-catenin facilitates FAdV-4 replication. • Suppression of β-catenin limits FAdV-4 production by inhibiting FAdV-4-induced autophagy. [ABSTRACT FROM AUTHOR]

Chitosan nanoparticles functionalized with rhodamine B (called RB–CSN) were synthesized. Au(III) was adsorbed onto the surfaces of the RB–CSN through electrostatic interactions between the AuCl 4 − and the protonated amino groups in the RB–CSN. The nanoparticles with AuCl 4 − adsorbed onto them were easily separated from water by centrifugation. The maximum adsorption capacity of the RB–CSN was about 0.33 mmol/g. The self-assembled AuCl 4 − ions were adsorbed in very close proximities to the RB moieties in the RB–CSN, and this caused photo-induced electron transfer from the RB to the AuCl 4 − to occur efficiently. This meant that changes in the fluorescence of the RB–CSN were able to be used to determine the AuCl 4 − concentration more sensitively than were changes in the fluorescence of free RB. Under optimal conditions, the dynamic range over which RB–CSN can be used to detect Au(III) was 1.9 × 10 −7 mol L −1 to 4.75 × 10 −5 mol L −1 . The detection limit was 1.52 × 10 −8 mol L −1 . The dual-functional RB–CSN material can be completely regenerated using a solution of 0.5 M thiourea and 0.1 M HCl. The reusable dual-functional material that was able to be used to both detect dissolved Au(III) and remove Au(III) from an aqueous solution. [ABSTRACT FROM AUTHOR]

Melanin, a natural biological pigment present in many organisms, has been found to exhibit multiple functions. An important property of melanin is its ability to chelate metal ions strongly, which might be developed as an iron chelator for iron overload therapy. Herein, we prepared the ultrasmall water-soluble melanin nanoparticle (MP) and firstly evaluate the pharmacokinetics of MP in iron-overload mice to provide scientific basis for treating iron-overload. To study the circulation time and biodistribution, MP was labeled with 89 Zr, a long half-life (78.4 h) positron-emitting metal which is suited for the labeling of nanoparticles and large bioactive molecule. MP was chelated with 89 Zr directly at pH 5, resulting in non-decay-corrected yield of 89.6% and a radiochemical purity of more than 98%. The specific activity was at least190 MBq/μmol. The 89 Zr-MP was stable in human plasma and PBS for at least 48 h. The half-life of 89 Zr-MP was about 15.70 ± 1.74 h in iron-overload mice. Biodistribution studies and MicroPET imaging showed that 89 Zr-MP mainly accumulated in liver and spleen, which are the target organ of iron-overload. The results indicate that the melanin nanoparticle is promising for further iron overload therapy. [ABSTRACT FROM AUTHOR]

The article presents the case study of a 45 year old female patient who was born with erythema lesions in the right nuchal and occipital area. The lesions were flat and non-hypertrophic. Recently several nodules began forming above the erythema. The biopsy is performed in the nodules and flat erythema lesion site in the nuchal area and the tissues were sent for pathologic and genetic study.

The molten salt fluid-particles transition state is modelled using KTGF-based TFM and CFD-DEM in fluidized beds. The solid phase constitutive equations are modelled using a low density ratio KTGF model. The normal and tangential forces of discrete particles are simulated using CFD-DEM. Two-equation model is used to characterize molten salt fluid turbulence. Wavy-like flow near the bottom and aggregates/fluid voids flow at the upper part coexist along bed height. The molten salt fluid pressure drops and dominant frequencies of wavy-like flow using TFM agree with simulated results using CFD-DEM. The simulated transition state from TFM and CFD-DEM coincides with predictions using four different criteria in literature. The effect of molten salt temperature on normal and tangential Reynolds stresses is discussed. The predicted expansion height and water volume fractions using TFM and CFD-DEM agree with experimental data in an ambient water fluidized bed. [Display omitted] • A low density ratio-based kinetic theory of granular flow (KTGF) was used. • A transitional fluidization state was observed. • Simulation results of TFM and CFD-DEM were compared. • Effects of molten salt fluid temperature on fluidization state were analyzed. [ABSTRACT FROM AUTHOR]

Background and Aim: Co-activation of EGFR by alternative receptor tyrosine kinases (RTKs) might mediate resistance to EGFR inhibition in head and neck squamous cell carcinoma (HNSCC). Here we found a novel mechanism to improve the efficacy of EGFR inhibitor erlotinib on HNSCC.Method: Immunohistochemistry, western blot, cell migration and invasion assays, cell proliferation, cell cycle analysis and in vivo serial transplantation assays were used to evaluate the role of RET on HNSCC cells.Results: The elevated levels of a rearranged during transfection (RET) are observed in HNSCC and that high levels of RET correlate with increased tumor size, advanced tumor stage and decreased overall survival rate. The HNSCC cell proliferation and invasion were inhibited by RET knockdown in vitro and in vivo. The inhibition of RET expression markedly reduced EGFR phosphorylation and downstream EGFR signaling. The inhibition of RET signaling significantly increased the sensitivity of HNSCC cells to the EGFR inhibitor erlotinib in both in vitro and in vivo models.Conclusion: Our results offer a preclinical proof-of-concept supporting a role for RET signaling inhibition in a targeted therapeutic approach to improve the efficacy of EGFR inhibition in HNSCC. [ABSTRACT FROM AUTHOR]

We explored the application of new bifunctional chelating agent p-SCN-NODA by conjugating to GRPR targeting peptide, MATBBN. p-SCN-NODA can increase the labeling yield to 68.3 ± 1.8 %. F-Al-NODA-MATBBN can be produced within 25 min with a radiochemical purity of more than 98 %. At 30 min post-injection, the tumor uptake for F-Al-NODA-MATBBN was 3.23 ± 0.23 % ID/g. Biodistribution studies revealed that F-Al-NODA-MATBBN was excreted mainly through the kidneys. GRPR-binding specificity was also demonstrated by reduced tumor uptake of F-Al-NODA-MATBBN after co-injection with excess unlabeled MATBBN peptide at 1 h post-injection. It suggests that F-Al-NODA-MATBBN may be a potential PET tracer candidate for monitoring prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose Glucagon-like peptide-1 receptor (GLP-1R) is abundantly expressed on beta cells and may be an ideal target for the pancreas imaging. Monitoring the GLP-1R of pancreas could be benefit for understanding the pathophysiology of diabetes. In the present study, 18 F-Al labeled exendin-4 analog, 18 F-Al-NOTA-MAL-Cys 39 -exendin-4, was evaluated for PET imaging GLP-1R in the pancreas. Methods The targeting of 18 F-Al labeled exendin-4 analog was examined in healthy and streptozotocin induced diabetic rats. Rats were injected with 18 F-Al-NOTA-MAL-Cys 39 -exendin-4 and microPET imaging was performed at 1 h postinjection, followed by ex vivo biodistribution. GLP-1R expression in pancreas was determined through post mortern examinations. Results The pancreas of healthy rats was readily visualized after administration of 18 F-Al-NOTA-MAL-Cys 39 -exendin-4, whereas the pancreas of diabetic rats, as well as those from rats co-injected with excess of unlabeled peptides, was barely visible by microPET. At 60 min postinjection, the pancreatic uptakes were 1.02 ± 0.15%ID/g and 0.23 ± 0.05%ID/g in healthy and diabetic rats respectively. Under block, the pancreatic uptakes of non-diabetic rats reduced to 0.21 ± 0.07%ID/g at the same time point. Biodistribution data and IHC staining confirmed the findings of the microPET imaging. Conclusion The favorable preclinical data indicated that 18 F-Al-NOTA-MAL-Cys 39 -exendin-4may be suitable for non-invasive monitoring functional pancreatic beta cells. [ABSTRACT FROM AUTHOR]

The inhomogeneous stress distribution of biodegradable stents after implantation affects the local degradation rate of the stents, leading to stress concentration and hence stent fracture. The quantitative relationship between the tensile stress and degradation rate of stent polymer is first investigated in this work. To implement the study, an in vitro degradation of poly( l -lactide-co-glycolide) (PLGA) membranes was incubated in deionized water under different applied tensile stress levels from 0.1 MPa to 0.5 MPa. By a special designed device, the tensile stress level can be maintained constant during degradation. The mass loss and mechanical properties of the membranes during the degradation were sampled each week until the membranes broke. The experimental results showed that over a range of tensile stress, higher tensile stress might lead to quicker loss of mechanical properties. Specifically, remarkable decreases of elastic modulus and tensile strength in 0.5 MPa group were observed. As the magnitude of tensile stress increased, more mass loss was observed in the loaded groups. In conclusion, the mass loss rate and mechanical properties of PLGA was sensitive to the tensile stress level during the in vitro degradation. The load dependency of our data demonstrates the importance of quantifying the effects of tensile stress on the degradation of biodegradable polymers. Moreover, this quantification model could be used as a prediction tool for the optimization of biodegradable polymer stents. [ABSTRACT FROM AUTHOR]

A CoO/3D graphene composite synthesized via hydrothermal method was used as an anode material for Li-ion batteries. X-ray diffraction, scanning electron microscopy, thermogravimetry, energy-dispersive X-ray spectroscopy, transmission electron microscope, cyclic voltammetry, electrochemical impedance spectroscopy, and charge/discharge measurement were conducted to evaluate the physical and electrochemical properties of the CoO/3D graphene composite. Results showed that the composite delivered high rate capacities of 1481.1, 657.7, 472.5, 423.8, and 391.2 mAh g −1 , at 50, 100, 200, 300, 400, and 500 mA g −1 , respectively. The capacity after 100 cycles was 860 mAh g −1 at 50 mA g −1 , thereby indicating excellent cycle stability. The excellent electrochemical performance was ascribed to 3D graphene sheets that were formed in the composite structure. [ABSTRACT FROM AUTHOR]

A new designed hybrid peptide FSH-Lytic was synthesized and expected to combine the follicle stimulating hormone receptor (FSHR) targeting and tumor cell membranes disintegration. Through in vitro and vivo study, no significant enhancement on anti-tumor activity was shown compared with Lytic peptide only. We also prepared F-Al-NOTA-MAL-FSH-Lytic and use microPET image to observe the FSHR targeting of FSH-Lytic. No accumulation in the tumor may explain the failure of FSH-Lytic on cancer therapy. In summary, microPET image can provide more accurate and visible information for screening new anti-tumor agents. [ABSTRACT FROM AUTHOR]

Introduction Elevated levels of gelatinases (matrix metalloproteinases 2/9, i.e., MMP2 and MMP9) are associated with tumor progression, invasion and metastasis, so these enzymes are potential targets for tumor imaging. The peptide c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor. Cy5.5-C6 has been visualized in many tumor models in vivo . However, the sensitivity and penetrance of optical imaging are poor. It is well known that positron emission tomography (PET) has a high detection sensitivity and Gallium-68 ( 68 Ga) is an optimal PET radioisotope. Thus, in the present study, we developed a novel ligand, 68 Ga-NOTA-C6, to image MMP2 activity in tumors. Methods C6 was conjugated with the bifunctional chelator NOTA (1,4,7-triazacyclononanetriacetic acid) and labeled with 68 Ga. In vitro uptake and binding analyses were performed by using SKOV3 cell lines, coincubating with or without the MMP inhibitor doxycycline. The biodistribution and PET imaging were conducted on SKOV3 ovarian tumor models. MMP2 expression in tumors was analyzed by immunohistochemistry (IHC). Results The non-decay corrected yield of 68 Ga-NOTA-C6 was 61.8%–63.3%. 68 Ga-NOTA-C6 was stable in both physiological saline and human serum. The uptake of 68 Ga-NOTA-C6 in SKOV3 cells increased with time, and could be blocked by doxycycline in a dose dependent manner. The results of biodistribution and PET imaging showed that high radioactivity concentrations of 68 Ga-NOTA-C6 occurred in tumors. The ratios of tumor to blood, muscle and ovary and oviduct at 30, 60 and 120 min p.i. were 2.78 ± 0.54, 3.86 ± 0.65, 0.48 ± 0.14, and 1.73 ± 0.36, 10.31 ± 3.12, 1.22 ± 0.10, and 2.50 ± 0.78, 7.03 ± 1.85, 0.97 ± 0.25, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. These data support the possibility of using 68 Ga-NOTA-C6 in PET to visualize tumors that overexpress MMP2. Conclusions 68 Ga-NOTA-C6 is a potential radiopharmaceutical for the imaging of in vivo MMP2 activity in tumors. [ABSTRACT FROM AUTHOR]

Background and Objective: The overexpression of gelatinases, that is, matrix metalloproteinase MMP2 and MMP9, has been associated with tumor progression, invasion, and metastasis. To image MMP2 in tumors, we developed a novel ligand termed [18F]AlF-NOTA-C6, with consideration that: c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor; Cy5.5-C6 has been visualized in many in vivo tumor models; positron emission tomography (PET) has a higher detection sensitivity and a wider field of view than optical imaging; fluorine-18 (18F) is the optimal PET radioisotope, and the creation of a [18F]AlF-peptide complex is a simple procedure. Methods: C6 was conjugated to the bifunctional chelator NOTA (1, 4, 7-triazacyclononanetriacetic acid) for radiolabeling [18F]AlF conjugation. The MMP2-binding characteristics and tumor-targeting efficacy of [18F]AlF-NOTA-C6 were tested in vitro and in vivo. Results: The non-decay corrected yield of [18F]AlF-NOTA-C6 was 46.2–64.2%, and the radiochemical purity exceeded 95%. [18F]AlF-NOTA-C6 was favorably retained in SKOV3 and PC3 cells, determined by cell uptake. Using NOTA-C6 as a competitive ligand, the uptake of [18F]AlF-NOTA-C6 in SKOV3 cells decreased in a dose-dependent manner. In biodistribution and PET imaging studies, higher radioactivity concentrations were observed in tumors. Pre-injection of C6 caused a marked reduction in tumor tissue uptake. Immunohistochemistry showed MMP2 in tumor tissues. Conclusions: [18F]AlF-NOTA-C6 was easy to synthesize and has substantial potential as an imaging agent that targets MMP2 in tumors. [ABSTRACT FROM AUTHOR]

Aims To investigate the histopathological predictors of overall survival and metastatic failure of oral mucosal melanoma ( OMM), of which the histopathological classification and microstaging has not been established. Methods and results The pathological data, including cell type ( CT), level of invasion, ulceration, mitotic rate, pigmentation, necrosis, tumour-infiltrating lymphocyte ( TIL) and vascular invasion, of 82 OMM patients from April 2002 to April 2012 were reviewed and analysed retrospectively. CT, ulceration, mitotic rate, pigmentation, necrosis and vascular invasion were found to be of significance in predicting the overall survival of OMM patients. CT was an independent prognostic factor of overall survival in multivariate analysis. In patients with localized OMM, CT, level of invasion, mitotic rate, pigmentation and necrosis were associated with overall survival but none of them proved to be an independent prognostic factor. CT, mitotic rate and TIL were associated with the risk of distant metastasis. TIL was revealed to be an independent factor of distant metastases risk in multivariate analysis. Conclusions CT was an independent prognostic factor of overall survival. Patients with epithelioid cell type OMM had a poor prognosis. Patients without TIL had a higher risk of distant metastasis. [ABSTRACT FROM AUTHOR]

Background: High expression of glucagon-like peptide-1 receptor (GLP-1R) in insulinoma supplies a potential drug target for tumor imaging. Exendin-4 can specifically bind to GLP-1R as an agonist and its analogs are extensively used in receptor imaging studies. Purpose: A new GLP-1R imaging agent, [18F]AlF-NOTA-MAL-Cys39-exendin-4, was designed and prepared for insulinoma imaging. Methods: Cys39-exendin-4 was conjugated with NOTA-MAL, then the compound was radiolabeled with [18F]AlF complex to obtained [18F]AlF-NOTA-MAL-Cys39-exendin-4. The tumor-targeting characters of the tracer were evaluated in INS-1 cells and BALB/c nude mice models. Results: [18F]AlF-NOTA-MAL-Cys39-exendin-4 can be efficiently produced with a yield of 17.5 ± 3.2% (non-decay corrected) and radiochemical purity of >95%. The IC50value of displacement [18F]AlF-NOTA-MAL-Cys39-exendin-4 with Cys39-exendin-4 was 13.52 ± 1.36 nM. PET images showed excellent tumor visualization with high uptake (9.15 ± 1.6%ID/g at 30 min and 7.74 ± 0.87%ID/g at 60 min). The tumor to muscle, pancreas and liver ratios were 63.25, 3.85 and 7.29 at 60 min after injection. GLP-1R binding specificity was demonstrated by co-injection with an excess of unlabeled Cys39-exendin-4 and the tumor uptake was found to be reduced significantly. Conclusion: [18F]AlF-NOTA-MAL-Cys39-exendin-4 shows favorable characteristics for insulinoma imaging and may be translated to clinical studies. [ABSTRACT FROM AUTHOR]

A modular, selection-based method was developed for site-specific integration of transgenes into a genomic locus to create multigene stacks. High-frequency gene targeting was obtained using zinc finger nuclease (ZFN)-mediated double-strand break (DSB) formation at a pre-defined target genomic location using a unique intron directly downstream of a promoter driving a selectable marker gene to facilitate homology between target and donor sequences. In this system, only insertion into the target locus leads to a functional selectable marker, and regeneration from random insertions of the promoterless donor construct are reduced on selection media. A new stack of transgenes can potentially be loaded with each successive cycle of gene targeting by exchanging the selectable marker gene using the intron homology. This system was tested in maize using the pat selectable marker gene, whereby up to 30% of the plants regenerated on Bialaphos-containing medium were observed to have the donor construct integrated into the target locus. Unlike previous gene targeting methods that utilize defective or partial genes for selecting targeted events, the present method exchanges fully functional genes with every cycle of targeting, thereby allowing the recycling of selectable marker genes, hypothetically for multiple generations of gene targeting. [ABSTRACT FROM AUTHOR]

Gastrodia elata Blume (G. elata), a traditional Chinese herb, known as "Tian Ma", is widely used as a common medicine and diet ingredient for treating or preventing neurological disorders for thousands of years in China. However, the anti-depressant effect of G. elata and the underlying mechanism have not been fully evaluated. The study is aimed to investigate the anti-depressant effect and the molecular mechanism of G. elata in vitro and in vivo using PC12 cells and zebrafish model, respectively. Network pharmacology was performed to explore the potential active ingredients and action targets of G. elata Blume extracts (GBE) against depression. The cell viability and proliferation were determined by MTT and EdU assay, respectively. TUNEL assay was used to examine the anti-apoptotic effect of GBE. Immunofluorescence and Western blot were used to detect the protein expression level. In addition, novel tank diving test was used to investigate the anti-depressant effect in zebrafish depression model. RT-PCR was used to analyze the mRNA expression levels of genes. G. elata against depression on the reticulon 4 receptors (RTN4R) and apoptosis-related targets, which were predicted by network pharmacology. Furthermore, GBE enhanced cell viability and inhibited the apoptosis in PC12 cells against CORT treatment. GBE relieved depression-like symptoms in adult zebrafish, included increase of exploratory behavior and regulation of depression related genes. Mechanism studies showed that the GBE inhibited the expression of RTN4R-related and apoptosis-related genes. Our studies show the ameliorative effect of G. elata against depression. The mechanism may be associated with the inhibition of RTN4R-related and apoptosis pathways. [Display omitted] • Network pharmacology was used to reveal the anti-depressant activity of G. elata Blume extracts (GBE) and its pharmacological mechanism. • GBE suppressed depression-like symptoms in zebrafish and cellular depression models. • Ameliorative effect of GBE on depression is associated with the inhibition of RTN4R-related and apoptosis pathways. [ABSTRACT FROM AUTHOR]

• A novel green fluorescence sensor FLN for Hg2+ was developed. • FLN demonstrated a distinct fluorescence enhancing due to the "PET-off". • FLN towards Hg2+ features good selectivity, high sensitivity and eminent photostability. • With low toxicity, FLN was successfully applied for quantitatively monitoring Hg2+ and evaluating its toxicity in living cells. Mercury has complex biological toxicity and can cause a variety of physiological diseases and even death, so it is of great importance to develop novel strategies for detecting trace mercury in environmental and biological sample. In this work, a new type of green fluorescence sensor FLN based on fluorescein-carbazole was developed. FLN demonstrated a distinct fluorescence enhancing at 525 nm towards Hg2+ ions due to the "PET-off" (Photoinduced Electron Transfer-off). The binding modes between FLN with Hg2+ was found to be 1:1 by job plot analysis. The limits of detection of TR for sensing Hg2+ is down to 40 nM. Especially with low toxicity, FLN was successfully applied for detecting Hg2+ in living cells. [ABSTRACT FROM AUTHOR]

Necroptosis, an alternative mode of programmed cell death, has crucial pathophysiological roles in many diseases, but its effect on chronic kidney disease (CKD) is poorly understood. Therefore, we assessed necroptosis and its pathophysiological effects in a widely used remnant-kidney rat model. We found that necroptotic cell death and the highest level of receptor interaction protein kinase 1 (RIP1) and receptor interaction protein kinase 3 (RIP3), critical signalling molecules for necroptosis, appeared 8 weeks after subtotal nephrectomy (SNX) surgery. After treatment with Necrostatin-1 (Nec-1), renal function and renal pathologic changes were significantly improved; the overexpression of RIP1, RIP3, mixed lineage kinase domain-like (MLKL) and dynamin-related protein 1 (Drp1) was reduced; and necroptosis was inhibited. These results indicated that necroptosis mediated by RIP1 and RIP3 participates in the loss of renal cells of subtotal nephrectomised rats and might be one of main causes of the excessive loss of renal cells during the sustained progression of renal fibrosis. [ABSTRACT FROM AUTHOR]

A Bi 2 WO 6 /graphene composite synthesized by sol–gel and sintering processes was investigated as anode material for Li-ion batteries. The morphology and structure of the products were analyzed by SEM, TEM, and XRD. The electrochemical performance of Bi 2 WO 6 /graphene composite was investigated by the galvanostatic charge/discharge method, cyclic voltammetry and electrochemical impedance spectroscopy. Results showed that the first cycle of the reversible specific capacity of Bi 2 WO 6 /graphene composite reached 697.1 mA h g −1 at 50 mA g −1 . Charge/discharge cycling study indicated that the Bi 2 WO 6 /graphene composite had excellent cycling stability and superior rate capability. [ABSTRACT FROM AUTHOR]

SUMMARY The aim of this study is to investigate the dynamic response of a multi-segment model of the thoracolumbar spine and determine how the sitting posture affects the response under the impact of ejection. A nonlinear finite element model of the thoracolumbar-pelvis complex (T9-S1) was developed and validated. A multi-body dynamic model of a pilot was also constructed so an ejection seat restraint system could be incorporated into the finite element model. The distribution of trunk mass on each vertebra was also considered in the model. Dynamics analysis showed that ejection impact induced obvious axial compression and anterior flexion of the spine, which may contribute to spinal injuries. Compared with a normal posture, the relaxed posture led to an increase in stress on the cortical wall, endplate, and intradiscal pressure of 43%, 10%, 13%, respectively, and accordingly increased the risk of inducing spinal injuries. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii ( T. gondii) is a pathogenic protozoan parasite, infection of which in early pregnancy increases the risk of serious sequelae in fetus. The aim of this study is to investigate the effect of T. gondii infection on glucose metabolism in the brain of pregnant rats by microPET using F-fluorodeoxygulcose (F-FDG) as the tracer. Thirty female SD rats were divided into the T. gondii infection and control group. After set for pregnancy, the body weight was assessed, T. gondii infection was identified by PCR, ELISA technology and immunohistochemistry, and glucose metabolism in brain of rats was monitored by microPET scan. Our results showed that brain glucose metabolism was significantly increased in T. gondii-infected group comparing to the control, indicating microPET scan is more sensitive to detect the abnormality than traditional measurements. In addition, bio-distribution of F-FDG in T. gondii-infected rats was assessed by using another twenty female SD rats, which has higher uptake of F-FDG at 30 min after injection in whole brain. Furthermore, the expression profile of GLUT1 was also higher in the brain of pregnant rats of the infected group. Therefore, microPET can be effectively applied to in vivo assessment of small animals and contributes to early diagnosis of T. gondii infection, which also assists in understanding birth defects caused by T. gondii infection. [ABSTRACT FROM AUTHOR]

Purpose: Glucagon-like peptide-1 receptor (GLP-1R) is a specific target for insulinomas imaging since it is overexpressed in the tumor. Exendin-4 exhibits high affinity for the GLP-1R. In this study, a novel F-labeled exendin-4 analog, F-FBEM-Cys-exendin-4, was synthesized and its potentials for GLP-1R imaging were also evaluated. Methods: F-FBEM was synthesized by coupling F-fluorobenzoic acid (F-FBA) with N-(2-aminoethyl) maleimide, and the reaction conditions were optimized. Cys-exendin-4 was then conjugated with F-FBEM to obtain F-FBEM-Cys-exendin-4. The GLP-1R targeting potential and pharmacokinetic profile of the tracer were analyzed in INS-1 insulinoma and MDA-MB-435 breast tumor model, respectively. Results: Under the optimal conditions, the yield of radiolabeled F-FBEM was 49.1 ± 2.0 % (based on F-FBA, non-decay corrected). The yield of F-FBEM-Cys-exendin-4 was 35.1 ± 2.6 % (based on the starting F-FBEM, non-decay corrected). The radiochemical purity of F-FBEM-Cys-exendin-4 is >95 %, and the specific activity was at least 35 GBq/μmol. The GLP-1R-positive INS-1 insulinoma xenograft was clearly visible with good contrast to background, whereas GLP-1R-negative MDA-MB435 breast tumor was barely visible. Low levels of radioactivity were also detected at pancreas and lungs due to few GLP-1R expressions. GLP-1R binding specificity was demonstrated by reduced INS-1 tumor uptake of the tracer after coinjection with an excess of unlabeled Cys-exendin-4 at 1 h postinjection. Conclusion: The thiol-reactive reagent, F-FBEM, was prepared with high yield and successfully conjugated to Cys-exendin-4. Favorable preclinical data showing specific and effective tumor targeting by F-FBEM-Cys-exendin-4 suggest that the tracer may be a potential probe for insulinomas imaging. [ABSTRACT FROM AUTHOR]

Purpose: Follicle-stimulating hormone receptor (FSHR) is overexpressed in primary and metastatic tumor. Molecular imaging of FSHR is beneficial for prognosis and therapy of cancer. FSHβ(33-53) (YTRDLVYKDPARPKIQKTCTF), denoted as FSH1, is a FSHR antagonist. In the present study, maleimide-NOTA conjugate of FSH1 (NOTA-MAL-FSH1) was designed and labeled with [(18)F] aluminum fluoride. The resulting tracer, (18)F-Al-NOTA-MAL-FSH1, was preliminarily evaluated in PET imaging of FSHR-positive tumor.Procedures: NOTA-MAL-FSH1 was synthesized and radiolabeled with Al(18)F complex. The tumor-targeting potential and pharmacokinetic profile of the (18)F-labeled compound were evaluated in vitro and in vivo using a PC3 human prostate tumor model.Results: (18)F-Al-NOTA-MAL-FSH1 can be efficiently produced within 30 min with a non-decay-corrected yield of 48.6 ± 2.1 % and a radiochemical purity of more than 95 %. The specific activity was at least 30 GBq/μmol. The radiotracer was stable in phosphate-buffered saline and human serum for at least 2 h. The IC50 values of displacement (18)F-Al-NOTA-MAL-FSH1 with FSH1 were 252 ± 1.12 nM. The PC3 human prostate tumor xenografts were clearly visible with high contrast after injection of (18)F-Al-NOTA-MAL-FSH1 via microPET. At 30, 60 and 120 min postinjection, the tumor uptakes were 2.98 ± 0.29 % injected dose (ID)/g, 2.53 ± 0.20 %ID/g and 1.36 ± 0.12 %ID/g, respectively. Dynamic PET scanning showed that tumor uptake reached a plateau by about 6 min. Heart peaked earlier and then cleared quickly. Biodistribution studies confirmed that the normal organs except kidney uptakes were all below 1 %ID/g at 1 h p.i. The tumor-to-blood and tumor-to-muscle ratio at 10 min, 0.5, 1, and 2 h after injection were 1.64 ± 0.36, 2.97 ± 0.40, 9.31 ± 1.06, and 13.59 ± 2.33 and 7.05 ± 1.10, 10.10 ± 1.48, 16.17 ± 3.29, and 30.88 ± 4.67, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. FSHR-binding specificity was also demonstrated by reduced tumor uptake of (18)F-Al-NOTA-MAL-FSH1 after coinjection with an excess of unlabeled FSH1 peptide.Conclusion: NOTA-MAL-FSH1 could be labeled rapidly and efficiently with (18)F using one step method. Favorable preclinical data suggest that (18)F-Al-NOTA-MAL-FSH1 may be a suitable radiotracer for the non-invasive visualization of FSHR positive tumor in vivo. [ABSTRACT FROM AUTHOR]

Purpose: Follicle-stimulating hormone receptor (FSHR) is overexpressed in primary and metastatic tumor. Molecular imaging of FSHR is beneficial for prognosis and therapy of cancer. FSHβ(33-53) (YTRDLVYKDPARPKIQKTCTF), denoted as FSH1, is a FSHR antagonist. In the present study, maleimide-NOTA conjugate of FSH1 (NOTA-MAL-FSH1) was designed and labeled with [F] aluminum fluoride. The resulting tracer, F-Al-NOTA-MAL-FSH1, was preliminarily evaluated in PET imaging of FSHR-positive tumor. Procedures: NOTA-MAL-FSH1 was synthesized and radiolabeled with AlF complex. The tumor-targeting potential and pharmacokinetic profile of the F-labeled compound were evaluated in vitro and in vivo using a PC3 human prostate tumor model. Results: F-Al-NOTA-MAL-FSH1 can be efficiently produced within 30 min with a non-decay-corrected yield of 48.6 ± 2.1 % and a radiochemical purity of more than 95 %. The specific activity was at least 30 GBq/μmol. The radiotracer was stable in phosphate-buffered saline and human serum for at least 2 h. The IC values of displacement F-Al-NOTA-MAL-FSH1 with FSH1 were 252 ± 1.12 nM. The PC3 human prostate tumor xenografts were clearly visible with high contrast after injection of F-Al-NOTA-MAL-FSH1 via microPET. At 30, 60 and 120 min postinjection, the tumor uptakes were 2.98 ± 0.29 % injected dose (ID)/g, 2.53 ± 0.20 %ID/g and 1.36 ± 0.12 %ID/g, respectively. Dynamic PET scanning showed that tumor uptake reached a plateau by about 6 min. Heart peaked earlier and then cleared quickly. Biodistribution studies confirmed that the normal organs except kidney uptakes were all below 1 %ID/g at 1 h p.i. The tumor-to-blood and tumor-to-muscle ratio at 10 min, 0.5, 1, and 2 h after injection were 1.64 ± 0.36, 2.97 ± 0.40, 9.31 ± 1.06, and 13.59 ± 2.33 and 7.05 ± 1.10, 10.10 ± 1.48, 16.17 ± 3.29, and 30.88 ± 4.67, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. FSHR-binding specificity was also demonstrated by reduced tumor uptake of F-Al-NOTA-MAL-FSH1 after coinjection with an excess of unlabeled FSH1 peptide. Conclusion: NOTA-MAL-FSH1 could be labeled rapidly and efficiently with F using one step method. Favorable preclinical data suggest that F-Al-NOTA-MAL-FSH1 may be a suitable radiotracer for the non-invasive visualization of FSHR positive tumor in vivo. [ABSTRACT FROM AUTHOR]

• Quantification of hair cell density by counting a subset of hair cells (HCs) in regions of interest (ROIs) reduces the accuracy of HC counts and increases the variability compared to counting all HCs in the utricle. • Manually counting HCs from the entire utricle is time-consuming and labor-intensive. • Pou4f3 immunolabeling results in a highly specific and discrete nuclear signal that allows semi-automated quantification of HCs using an ImageJ macro. • The semi-automated method provides accurate HC counts while significantly reducing the time required to quantify HCs in the entire utricle. • It is essential to confirm HC viability using a secondary method (such as activated caspase 3/7 labeling), since dead HCs can retain both Myosin7a and Pou4f3 immunoreactivity, especially in cisplatin-treated tissue. The mouse utricle model system is the best-characterized ex vivo preparation for studies of mature mammalian hair cells (HCs). Despite the many advantages of this model system, efficient and reliable quantification of HCs from cultured utricles has been a persistent challenge with this model system. Utricular HCs are commonly quantified by counting immunolabeled HCs in regions of interest (ROIs) placed over an image of the utricle. Our data indicate that the accuracy of HC counts obtained using this method can be impacted by variability in HC density across different regions of the utricle. In addition, the commonly used HC marker myosin 7a results in a diffuse cytoplasmic stain that is not conducive to automated quantification and must be quantified manually, a labor-intensive task. Furthermore, myosin 7a immunoreactivity is retained in dead HCs, resulting in inaccurate quantification of live HCs using this marker. Here we have developed a method for semi-automated quantification of surviving HCs that combines immunoreactivity for the HC-specific transcription factor Pou4f3 with labeling of activated caspase 3/7 (AC3/7) to detect apoptotic HCs. The discrete nuclear Pou4f3 signal allowed us to utilize the binary or threshold function within ImageJ to automate HC quantification. To further streamline this process, we created an ImageJ macro that automates the process from raw image loading to a final quantified image that can be immediately evaluated for accuracy. Within this quantified image, the user can manually correct the quantification via an image overlay indicating the counted HC nuclei. Pou4f3-positive HCs that also express AC3/7 are subtracted to yield accurate counts of surviving HCs. Overall, we present a semi-automated method that is faster than manual HC quantification and identifies surviving HCs with high accuracy. [ABSTRACT FROM AUTHOR]

Abstract: Mechano growth factor (MGF) and its C-terminal E-peptide with 24 amino acids, MGF-Ct24E, have superiority in resolving the delayed or failed bone repair derived from shortness of suitable biomechanical stimulation. The chitosan/tripolyphosphate microspheres encapsulated with MGF-Ct24E (CS/TPP/MGF-Ct24E) are prepared using emulsion-ionic cross-linking method in order to achieve the sustained release and preserve the bioactivity of MGF-Ct24E. The microspheres are micron-sized and spherical in shape with smooth surface morphology. The TPP component disintegrates in advance of CS matrix and the MGF-Ct24E maintains sustained delivery during in vitro hydrolytic degradation. With the disappearance of TPP, the total weight loss of CS/TPP/MGF-Ct24E is 32% and the release amount of MGF-Ct24E reaches 84.6% after degrading for 2 weeks. In vitro bioactivity assays reveal that the MGF-Ct24E can accelerate MC3T3-E1 cells proliferation and delay their differentiation as well. The encapsulated MGF-Ct24E shows long-term effects after being loaded in the CS/TPP microspheres and the cells exhibit excellent morphology on the surface of microspheres. The continuous delivery of MGF-Ct24E provides a new perspective on resolving the unsatisfactory bone reconstruction associated with microgravity and stress shielding. [Copyright &y& Elsevier]

Orthodontic treatments not only displace irregular teeth but also induce responses in surrounding bone tissues. Bone remodelling is regarded as the regulatory mechanism triggered by mechanical loading. This study was aimed at investigating the effect of orthodontic loading on both tooth movement and neighbouring bone density distribution. A set of computational algorithms incorporating both external and internal remodelling mechanisms was implemented into a patient-specific 3D finite element (FE) model to investigate and analyse orthodontic treatment under four typical modes of orthodontic loading. The consequence of orthodontic treatment was reproduced numerically by using this FE-based technique. The results indicated that the diverse modes of orthodontic loading would result in different magnitudes of tooth movement and particular morphology of bone density distribution. It is illuminated that the newly developed algorithms may replicate the clinical situation more closely compared with the previous proposed method. [ABSTRACT FROM AUTHOR]

Bombesin (BBN) is a peptide exhibiting high affinity for the gastrin-releasing peptide receptor (GRPR), which is overexpressed on several types of cancers. Various GRPR antagonists and agonists have been labeled with radiometals for positron emission tomography (PET) imaging of GRPR-positive tumors. However, unfavorable hepatobiliary excretion such as high intestinal activity may prohibit their clinical utility for imaging abdominal cancer. In this study, the modified BBN peptide with a new hydrophilic linker was labeled with Ga for PET imaging of GRPR-expressing PC-3 prostate cancer xenograft model. GRPR antagonists, MATBBN (Gly-Gly-Gly-Arg-Asp-Asn- d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCHCH) and ATBBN ( d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCHCH), were conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) and labeled with Ga. Partition coefficient and in vitro stability were also determined. GRPR binding affinity of both tracers was investigated by competitive radioligand binding assay. The in vivo receptor targeting potential and pharmacokinetic of Ga-NOTA-MATBBN were also evaluated in PC-3 prostate tumor model and compared with those of Ga-NOTA-ATBBN. NOTA-conjugated BBN analogs were labeled with Ga within 20 min with a decay-corrected yield ranging from 90 to 95 % and a radiochemical purity of more than 98 %. The specific activity of Ga-NOTA-MATBBN and Ga-NOTA-ATBBN was at least 16.5 and 11.9 GBq/μmol, respectively. The radiotracers were stable in phosphate-buffered saline and human serum. Ga-NOTA-MATBBN was more hydrophilic than Ga-NOTA-ATBBN, as indicated by their log P values (−2.73 ± 0.02 vs. −1.20 ± 0.03). The IC values of NOTA-ATBBN and NOTA-MATBBN were similar (102.7 ± 1.18 and 124.6 ± 1.21 nM). The accumulation of Ga-labeled GRPR antagonists in the subcutaneous PC-3 tumors could be visualized via small animal PET. The tumors were clearly visible, and the tumor uptakes of Ga-NOTA-MATBBN and Ga-NOTA-ATBBN were determined to be 4.19 ± 0.32, 4.00 ± 0.41, 2.93 ± 0.35 and 4.70 ± 0.40, 4.10 ± 0.30, 3.14 ± 0.30 %ID/g at 30, 60, and 120 min, respectively. There was considerable accumulation and retention of Ga-NOTA-ATBBN in the liver and intestines. In contrast, the abdominal area does not have much retention of Ga-NOTA-MATBBN. Biodistribution data were in accordance with the PET results, showing that Ga-NOTA-MATBBN had more favorable pharmacokinetics and higher tumor to background ratios than those of Ga-NOTA-ATBBN. At 1 h postinjection, the tumor to liver and intestine of Ga-NOTA-MATBBN were 8.05 ± 0.56 and 21.72 ± 3.47 and the corresponding values of unmodified counterpart were 0.85 ± 0.23 and 3.45 ± 0.43, respectively. GRPR binding specificity was demonstrated by reduced tumor uptake of radiolabeled tracers after coinjection of an excess of unlabeled BBN peptides. Ga-NOTA-MATBBN exhibited GRPR-targeting properties both in vitro and in vivo. The favorable characterizations of Ga-NOTA-MATBBN such as convenient synthesis, specific GRPR targeting, high tumor uptake, and satisfactory pharmacokinetics warrant its further investigation for clinical cancer imaging. [ABSTRACT FROM AUTHOR]

The usability of Tc-spermine for human breast tumor imaging was evaluated. Mice bearing MDA-MB-231 breast tumor were used for SPECT imaging and biodistribution study. Tumor was imaged clearly after injection with Tc-spermine. The accumulation of Tc-spermine was much lower in chest region than that of general breast tumor imaging agent Tc-MIBI. It suggests that Tc-spermine is promising for breast cancer imaging. [ABSTRACT FROM AUTHOR]