Effects of Different Feed Additives on Intestinal Metabolite Composition of Weaned Piglets.

To study the effects of different feed additives on the weaning stress of Tibetan piglets, we selected 28 healthy, 30-day-old Tibetan weaned piglets and divided them into four groups, namely, the control group (basal feed without any antibiotic additions) (Nor), the group with the addition of the antibiotic lincomycin (Ant), the group with the addition of fifteen-flavor black pills of Tibetan medicine (Tib), and the group with the addition of fecal bacterial supernatant (Fec). We measured growth performance, blood physiological indexes, and metabolomics. The results showed that the Ant, Tib, and Fec groups significantly reduced the ratio of diarrhea to feed/weight (F/G) and increased the average daily gain (ADG) compared with the Nor group (p < 0.01). The Nor group had significantly lower leukocyte counts, hemoglobin levels, and erythrocyte counts compared with the other three groups at 21 d (p < 0.05). These physiological indexes tended to stabilize at 42 d. We found that there were beneficial metabolites and metabolic pathways for gastrointestinal function. Specifically, the porphyrin metabolic pathway was elevated in the Ant group, and the tryptophan metabolic pathway was significantly elevated in the Tib and Fec groups compared with the Nor group (p < 0.05). In conclusion, adding fecal bacterial supernatant and fifteen-flavor black pills of Tibetan medicine to the feed reduced the rate of diarrhea and improved the growth performance of the piglets. Moreover, it had an effect on the microorganisms and their metabolites and pathways in the gastrointestinal tract of the animals, which might be the main reason for influencing the diarrhea rate of weaned Tibetan piglets and the growth and development of the piglets. This study provides a new approach for anti-stress applications in weaned Tibetan piglets and the development of substitute anti-products.

The effect of music tempo on movement flow.

There has been much controversy over the effects of music tempo on movement flow. In this study, a single-factor repeated-measurement design was used to explore the effect of music tempo (fast, slow, and no music control) on movement flow by measuring both subjective experiences and objective electroencephalographic (EEG) characteristics during brisk walking. In the experiment, 20 college students walked briskly on a treadmill using EEG equipment. Each participant walked for 10 min on three different days. Their brain waves were recorded during brisk walking on a treadmill. After each walk, the participants completed a form of short flow state scale-2 (S FSS-2), which covered nine major aspects of flow. The results showed that music tempo had a significant effect on subjective experiences and objective physiological characteristics; that is, a higher subjective flow level for fast-tempo music in brisk walking and a significant enhancement of mean power values in the subconscious brain waves of the delta, theta, alpha, and beta bands for fast tempo music were observed. A fast tempo facilitated the movement flow. The findings of this study can be instructive for the use of music in exercises to improve sports training outcomes.

Smartphone-assisted colorimetric biosensor for the determination of organophosphorus pesticides on the peel of fruits.

Nowadays, the widespread use of organophosphorus pesticides (OPs) in agricultural production leads to varying degrees of residues in crops, which pose a potential threat to human health. Conventional methods used in national standard for the detection of OPs in fruits and vegetables require expensive instruments or cumbersome sample pretreatment steps for the analysis. To address these challenges, in this work, we took advantage of the peroxidase-like activity of PtCu3 alloy nanocrystals (NCs) for a colorimetric and smartphone assisted sensitive detection of OPs. With the assist of a smartphone, the concentration of OPs on the peel of fruits could be obtained by comparing the B/RG value (the brightness value of blue divided by those of red and green) of a test strip with a calibration curve. This work not only provides a facile and cost-effective method to detect pesticides but also makes a positive contribution to food safety warning.

Do children imitate even when it is costly? New insights from a novel task.

Children have a proclivity to learn through faithful imitation, but the extent to which this applies under significant cost remains unclear. To address this, we investigated whether 4- to 6-year-old children (N = 97) would stop imitating to forego a desirable food reward. We presented participants with a task involving arranging marshmallows and craft sticks, with the goal being either to collect marshmallows or build a tower. Children replicated the demonstrated actions with high fidelity regardless of the goal, but retrieved rewards differently. Children either copied the specific actions needed to build a tower, prioritizing tower completion over reward; or adopted a novel convention of stacking materials before collecting marshmallows, and developed their own method to achieve better outcomes. These results suggest children's social learning decisions are flexible and context-dependent, yet that when framed by an ostensive goal, children imitated in adherence to the goal despite incurring significant material costs.

Children's distinct drive to reproduce costly rituals.

Costly rituals are ubiquitous and adaptive. Yet, little is known about how children develop to acquire them. The current study examined children's imitation of costly rituals. Ninety-three 4-6 year olds (47 girls, 45% Oceanians, tested in 2022) were shown how to place tokens into a tube to earn stickers, using either a ritualistic or non-ritualistic costly action sequence. Children shown the ritualistic actions imitated faithfully at the expense of gaining stickers; conversely, those shown the non-ritualistic actions ignored them and obtained maximum reward. This highlights how preschool children are adept at and motivated to learn rituals, despite significant material cost. This study provides insights into the early development of cultural learning and the adaptive value of rituals in group cognition.

Bioequivalence Study of Miglitol Orally Disintegrating Tablets in Healthy Chinese Volunteers Under Fasting Condition Based on Pharmacodynamic and Pharmacokinetic Parameters.

To investigate the bioequivalence of miglitol orally disintegrating tablets in healthy Chinese volunteers based on pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Additionally, the safety profile was estimated. Two randomized, open-label, single-dose, crossover trials were conducted under fasting conditions. In the PD trial (CTR20191811), 45 healthy volunteers were randomly divided into 3 groups in a 1:1:1 ratio and administered sucrose alone or coadministered with 50 mg of miglitol orally disintegrating tablet test or reference formulation/sucrose. In the PK trial (CTR20191696), 24 healthy volunteers were randomized (1:1) to receive the test or reference formulation (50 mg). Blood samples were collected at 15 and 17 sampling points per cycle in the PD and PK trials, respectively. Plasma miglitol and serum glucose concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry method. Serum insulin concentrations were measured using electrochemiluminescent immunoassay. Statistical analyses for the PD and PK parameters were subsequently performed. The volunteers' physical indicators were monitored and documented during the entire study to estimate drug safety. The PD and PK parameters of the two formulations were similar. The main PD and PK end points were both within the prespecified range of 80%-125%. The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were similar between the test and reference formulation groups, and no serious TEAEs or deaths occurred during the 2 trials. These 2 formulations were demonstrated to be bioequivalent and well tolerated in healthy Chinese volunteers under fasting condition.

Bioequivalence of Celecoxib Capsules in Chinese Healthy Volunteers.

Celecoxib is a sulfanilamide nonsteroidal anti-inflammatory drug that can selectively inhibit cyclooxygenase-2 to inhibit prostaglandin production, achieving anti-inflammatory and analgesic effects. This study investigated the pharmacokinetics, safety, and bioequivalence of a single oral dose of celecoxib capsule (the test or reference preparation) in healthy volunteers under fasting and fed conditions. A single-center, randomized, open, single-dose, double-cycle crossover self-control design was conducted: 40 healthy volunteers were enrolled in the fasting and fed groups, respectively. A completely randomized method was used, with one group taking the test celecoxib preparation (T) and the other taking the reference celecoxib preparation (R). During the administration period, the safety of the drug was evaluated simultaneously, and venous blood was collected at the corresponding time points. The concentration of celecoxib in plasma was measured by liquid chromatography-tandem mass spectrometry. The main pharmacokinetic parameters were logarithmically converted and analyzed for variance. The 90% confidence interval for the bioavailability of the T compared to the R was calculated using maximum drug plasma concentration, area under the plasma concentration-time curve from time zero to the last quantifiable concentration point, and area under the plasma concentration-time curve from time zero to infinity for a single oral dose in volunteers, and the data obtained were all between 80% and 125%, indicating that the T and R have bioequivalence and good safety during fasting and fed administration.

[Pollution and Carbon Reduction Effect of OFDI in China and Its Mechanism].

Under the "Going out" strategy and the Belt and Road Initiatives, the trade in goods and services and flow of production factors between China and the rest of the world have become more frequent, and the total amount of outward foreign direct investment (OFDI) is considerable and growing significantly. Therefore, along with the extensive economic growth and the substantial growth of foreign investment, the environmental impact of OFDI has become noteworthy. Here, through theoretical analysis and logical deduction, three possible pathways of the impact of OFDI in China on the environment were presented as hypotheses, which included the industrial structure, the technological innovation progress, and the economic-scale expansion. Using Chinese provincial data from 2004 to 2019, an environmental load index including main environmental pollutant emissions and carbon emissions was constructed. Taking this as the dependent variable, an intermediary effect method was constructed to analyze the home pollution and carbon reduction effect and the influence mechanism of OFDI in China. The results showed that ① OFDI in China reduced the environmental load, and each 1% increase in OFDI reduced the environmental load by 0.051%-0.076%. ② The OFDI in China reduced the environmental load by advancing the industrial structure and technological innovation progress, and a 1% increase in OFDI resulted in a 0.060% and 0.006% reduction in environmental load through their indirect effects, respectively, whereas OFDI increased the environmental load by 0.009% through the path of economic-scale expansion. The contributions of leading environmental load changes mediated by advancing industrial structure, technological innovation progress, and economic-scale expansion were 65.9%-84.5%, 6.6%-8.5%, and -12.7%- -9.9%, respectively, and the contribution of OFDI directly driving the environmental load to change was 19.7%-37.4%. Based on this, policy recommendations, including promoting Chinese enterprises and capital going abroad, encouraging relatively disadvantaged domestic industries to explore foreign markets, strengthening reverse technology spillover effects, and forming a sustainable low-carbon development mode, have been proposed.

Development of oxoisoaporphine derivatives with topoisomerase I inhibition and reversal of multidrug resistance in breast cancer MCF-7/ADR cells.

A series of oxoisoaporphine derivatives with topoisomerase I inhibition and cytotoxic activities. Among them, compound 14 showed the most potent cytotoxic activity against all cancer cell lines tested, and substantially lower cytotoxicity to LO2 cells. Molecular docking studies, dynamics simulation and a follow-up enzyme inhibition assay indicated that 14 could interfere with DNA and significantly inhibit the activity of topoisomerase I. Further mechanistic studies revealed that 14 could arrest cell cycle at the G1 phase, and finally killed MCF-7 cells via apoptosis. In addition, 14 exhibited remarkable chemoreversal ability on multidrug-resistant MCF-7/ADR breast cancer cells. Some of its mechanisms may be related to inhibition of MCF-7/ADR P-gp-mediated Rhodamine (Rh123) efflux function and expression level, as well as inhibition of ROS, increase of ADR accumulation in MCF7/ADR cells, and enhancement of ADR in inducing apoptosis of MCF7/ADR cells. As 14 has little toxic and side effects, it may have the potential for further research.

A comparative study of stage characteristics and factorial decomposition of CO2 emissions between China and the USA.

CO2 contributes a lot to the greenhouse effect. The total CO2 emissions of the two countries, China and the USA, as the world's top two economies, have exceeded 40% of the total global carbon emissions. In this context, the exploration of the evolution of carbon emissions from energy consumption in China and the USA and the comparison of the characteristics of carbon emission drivers in different periods play a significant role in the policy formulation and climate change cooperation between China and the USA. In this study, the BP structural breakpoint test was used to divide the carbon emission stages of China and the USA from 1970 to 2019. The generalized Divisia index model (GDIM) was developed to decompose the growth of carbon emissions in China and the USA into eight items, GDP, carbon intensity of GDP, energy use, carbon intensity of energy, population, carbon emissions per capita, GDP per capita, and energy intensity, and to analyze the characteristics and cumulative contribution of carbon emission drivers at each stage. Based on the stage and cumulative characteristics of carbon emissions between China and the USA, the USA should take the initiative to assume the legal responsibility of carbon emissions and further deepen the cooperation with other countries in the field of climate change. China should transform the economic growth mode, optimize the energy structure, and improve the efficiency of resource utilization to help achieve the peaking carbon emissions and the carbon neutrality smoothly.

Extracellular vesicles derived from PM2.5-exposed alveolar epithelial cells mediate endothelial adhesion and atherosclerosis in ApoE-/- mice.

Epidemiological studies suggested that PM2.5 (particle matters with an aerodynamic diameter ≤2.5 µm) exposure is associated with atherosclerosis. Extracellular vesicles (EVs) are messengers between intracellular communications which are important in diseases procession. At present, whether EVs derived from PM2.5-exposed alveolar epithelial cells (P-EVs) involve in atherosclerosis has not been clearly understood. This study is performed to investigate the effects of P-EVs on the development of endothelium adhesion and atherosclerosis. Here, ApoE-/- mice were randomized into different groups receiving one of the following treatments, filtered air (FA), PM2.5, PBS, PBS-treated alveolar epithelial cells-derived EVs (EVs), or P-EVs. Then the atherosclerosis level in aortas or aorta sections was evaluated by oil red O staining. The results indicated that ApoE-/- mice treated with P-EVs or PM2.5 showed more obvious atherosclerosis plaques in aortas and aortic arches than those treated with EVs or PBS. Endothelial cells (ECs) were treated with PBS, EVs, P-EVs, or PM2.5. The adhesion property, miRNAs level and expressions of IκBα, phosphorylated IκBα, NF-κB p65, phosphorylated NF-κB p65, and VCAM1 in ECs were determined. It was found that P-EVs activated IκBα-NF-κB-VCAM1 signaling and increased adhesion of ECs, and such effects could be reversed by adalimumab (the TNF-α inhibitor) or miR-326-3p inhibitor. Further study suggested that P-EVs induced upregulation of TNF-α and miR-326-3p in recipient ECs and contributed to the phosphorylation of NF-κB p65. Collectively, EVs derived from PM2.5-exposed alveolar epithelial cells played an important role in the development of atherosclerosis via activating IκBα-NF-κB-VCAM1 signaling.

HIV-Proteins-Associated CNS Neurotoxicity, Their Mediators, and Alternative Treatments.

Human immunodeficiency virus (HIV)-infected people's livelihoods are gradually being prolonged with the use of combined antiretroviral therapy (ART). Conversely, despite viral suppression by ART, the symptoms of HIV-associated neurocognitive disorder (HAND) endure. HAND persists because ART cannot really permanently confiscate the virus from the body. HAND encompasses a variety of conditions based on clinical presentation and severity level, comprising asymptomatic neurocognitive impairment, moderate neurocognitive disorder, and HIV-associated dementia. During the early stages of HIV infection, inflammation compromises the blood-brain barrier, allowing toxic virus, infected monocytes, macrophages, T-lymphocytes, and cellular products from the bloodstream to enter the brain and eventually the entire central nervous system. Since there are no resident T-lymphocytes in the brain, the virus will live for decades in macrophages and astrocytes, establishing a reservoir of infection. The HIV proteins then inflame neurons both directly and indirectly. The purpose of this review is to provide a synopsis of the effects of these proteins on the central nervous system and conceptualize avenues to be considered in mitigating HAND. We used bioinformatics repositories extensively to simulate the transcription factors that bind to the promoter of the HIV-1 protein and possibly could be used as a target to circumvent HIV-associated neurocognitive disorders. In the same vein, a protein-protein interaction complex was also deduced from a Search Tool for the Retrieval of Interacting Genes. In conclusion, this provides an alternative strategy that could be used to avert HAND.

The Value of Brain Imaging and Electrophysiological Testing for Early Screening of Autism Spectrum Disorder: A Systematic Review.

Given the significance of validating reliable tests for the early detection of autism spectrum disorder (ASD), this systematic review aims to summarize available evidence of neuroimaging and neurophysiological changes in high-risk infants to improve ASD early diagnosis. We included peer-reviewed, primary research in English published before May 21, 2021, involving the use of magnetic resonance imaging (MRI), electroencephalogram (EEG), or functional near-infrared spectroscopy (fNIRS) in children with high risk for ASD under 24 months of age. The main exclusion criteria includes diagnosis of a genetic disorder and gestation age of less the 36 weeks. Online research was performed on PubMed, Web of Science, PsycINFO, and CINAHL. Article selection was conducted by two reviewers to minimize bias. This research was funded by Massachusetts General Hospital Sundry funding. IRB approval was not submitted as it was deemed unnecessary. We included 75 primary research articles. Studies showed that high-risk infants had divergent developmental trajectories for fractional anisotropy and regional brain volumes, increased CSF volume, and global connectivity abnormalities on MRI, decreased sensitivity for familiar faces, atypical lateralization during facial and auditory processing, and different spectral powers across multiple band frequencies on EEG, and distinct developmental trajectories in functional connectivity and regional oxyhemoglobin concentrations in fNIRS. These findings in infants were found to be correlated with the core ASD symptoms and diagnosis at toddler age. Despite the lack of quantitative analysis of the research database, neuroimaging and electrophysiological biomarkers have promising value for the screening of ASD as early as infancy with high accuracy, which warrants further investigation.

Adipose mesenchymal stem cell-derived antioxidative extracellular vesicles exhibit anti-oxidative stress and immunomodulatory effects under PM2.5 exposure.

PM2.5 exposure elevates the level of reactive oxygen species (ROS) in the lungs and leads to lung injury or other pulmonary conditions. Nrf2 is a key antioxidative regulator that suppresses ROS production. Extracellular vesicles (EVs) secreted by adipose mesenchymal stem cells (ADSCs) have been identified as therapeutic as well as potential drug/gene/protein carriers. In this study, we established rat (PM2.5, 100 µL, 5 mg/mL) or cell (PM2.5, 50 µg/mL) models to conduct in vivo and in vitro studies on the adverse pulmonary effects of PM2.5. Our findings indicated that the initial responses to PM2.5 exposure were robust oxidative stress and inflammation. EVs and antioxidative EVs (Antioxi-EVs, derived from ADSCs that overexpress Nrf2) had been tested as interventions in PM2.5-treated rat or cell models through tracheal instillation or co-incubation. Treatment with EVs or Antioxi-EVs (3 × 1010 particles in vivo and 1 × 109in vitro) was found to have a suppressive effect on the levels of ROS and inflammatory cytokines, with Antioxi-EVs having a superior effect on anti-oxidative stress. In particular, the occurrence of lung injury or cell apoptosis correlated positively with the ROS level, and inhibition of ROS by upregulating Nrf2 alleviated lung injury and cell apoptosis. Furthermore, treatment with EVs or Antioxi-EVs increased the level of M2-like macrophages as compared to treatment with PBS and further reduced IL-6 and TNF-α levels. Our results suggest that Antioxi-EVs can reduce the severity of oxidative stress, inflammation, and lung injury induced by PM2.5via anti-oxidative stress and immunomodulation pathways.

Melatonin Alleviates Pyroptosis of Retinal Neurons Following Acute Intraocular Hypertension.

BACKGROUND: Glaucoma is a multifactorial optic neuropathy progressively characterized by structural loss of Retinal Ganglion Cells (RGCs) and irreversible loss of vision. High Intraocular Pressure (HIOP) is a high-risk factor for glaucoma. It has been reported that the mechanisms of the loss of RGCs are explored in-depth after acute HIOP injury, such as apoptosis, autophagy, and necrosis. However, pyroptosis, a novel type of pro-inflammatory cell programmed necrosis, is rarely reported after HIOP injury. Research studies also showed that melatonin (MT) possesses substantial anti-inflammatory properties. However, whether melatonin could alleviate retinal neuronal death, especially pyroptosis, by HIOP injury is still unclear. OBJECTIVE: This study explored pyroptosis of retinal neurons and the effects of melatonin in preventing retinal neurons from pyroptosis after acute HIOP injury. METHODS: An acute HIOP model of rats was established by increasing the IOP followed by reperfusion. Western Blot (WB) was adopted to detect molecules related to pyroptosis at the protein level, such as GSDMD, GASMDp32, Caspase-1, and caspase-1 p20, and the products of inflammatory reactions, such as IL -18 and IL-1ß. At the same time, immunofluorescence (IF) was used to co-localize caspase-1 with retinal neurons to determine the position of caspase-1 expression. Morphologically, ethidium homodimer III staining, a method commonly used to evaluate cell death, was carried out to stain dead cells. Subsequently, Lactate Dehydrogenase (LDH) cytotoxicity assay kit was used to quantitatively analyze the LDH released after cell disruption. RESULTS: The results suggested that pyroptosis played a vital role in retinal neuronal death, especially in the Ganglion Cell Layer, by acute HIOP injury and peaked at 6h after HIOP injury. Furthermore, it was found that melatonin (MT) might prevent retinal neurons of pyroptosis via NF-κ B/NLRP3 axis after HIOP injury in rats. CONCLUSION: Melatonin treatment might be considered a new strategy for protecting retinal neurons against pyroptosis following acute HIOP injury.

Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Alleviate PM2.5-Induced Lung Injury and Pulmonary Fibrosis.

BACKGROUND Exposure to PM2.5 (fine particulate matter ≤2.5 µm in aerodynamic diameter) in air increases the risk of lung injury and pulmonary fibrosis (PF). Extracellular vesicles (EVs) derived from adipose mesenchymal stem cells (ADSCs) have been identified as a potential treatment based on the proteins or RNAs delivery and immunomodulatory properties. Here, we assessed the protective effects and mechanisms of ADSCs-EVs on PM2.5-induced lung injury or PF. MATERIAL AND METHODS Rats (male, 6 weeks old) were exposed to PBS or PM2.5 (1.5 mg/kg/day) for 3 days a week for 4 weeks. ADSCs-EVs were extracted by ultracentrifugation. PBS and ADSCs-EVs were administrated through intratracheal instillation. After the end of exposure, the rats were anesthetized and killed. Lung tissues with different treatments were collected for Western blot analysis and HE, IHC, and IF staining analysis. Cells exposed to PM2.5 or "PM2.5+ADSCs-EVs" in vitro were also collected for further Western blotting, qRT-PCR, and IF staining evaluation. RESULTS The results indicated that the initial response of lungs exposed to PM2.5 was lung injury with oxidative stress and inflammation. Long-term PM2.5 exposure resulted in obvious PF in rats. Treatment with ADSCs-EVs decreased PM2.5-induced apoptosis and necrosis in type II alveolar epithelial cells and alleviated lung injury and PF in rats. ADSCs-EVs suppressed reactive oxygen species (ROS) levels and inflammation induced by PM2.5. Furthermore, ADSCs-EVs inhibited TGF-ßRI by transferring let-7d-5p and further mitigated PF. CONCLUSIONS Our results suggest that EVs derived from ADSCs can alleviate PM2.5-induced lung injury and PF.

Performance of Different Risk Indicators in a Multi-Period Polynomial Portfolio Selection Problem Based on the Credibility Measure.

In this paper, we study the portfolio selection problem considering transaction costs under multiple periods. For non-professional investors, it is a critical factor to choose an appropriate model among multiple portfolio selection models in investment. Based on the credibility measure, we formulate a multi-period polynomial portfolio selection model to gather the risk indicators involving variance, semi-variance, entropy, and semi-entropy, helping investors bet on assets. According to the polynomial goal programming (PGP) approach, investors can conquer the fields by combining apposite indicators to build appropriate models. Subsequently, an adjusted genetic algorithm on the foundation of the penalty function is designed to obtain the optimal solution of this multi-period model. The results indicate that the PGP method is suitable for investors to choose the model and assigns the proper models to investors with different risk preferences.

Entropy and Semi-Entropies of LR Fuzzy Numbers' Linear Function with Applications to Fuzzy Programming.

As a crucial concept of characterizing uncertainty, entropy has been widely used in fuzzy programming problems, while involving complicated calculations. To simplify the operations so as to broaden its applicable areas, this paper investigates the entropy within the framework of credibility theory and derives the formulas for calculating the entropy of regular LR fuzzy numbers by virtue of the inverse credibility distribution. By verifying the favorable property of this operator, a calculation formula of a linear function's entropy is also proposed. Furthermore, considering the strength of semi-entropy in measuring one-side uncertainty, the lower and upper semi-entropies, as well as the corresponding formulas are suggested to handle return-oriented and cost-oriented problems, respectively. Finally, utilizing entropy and semi-entropies as risk measures, two types of entropy optimization models and their equivalent formulations derived from the proposed formulas are given according to different decision criteria, providing an effective modeling method for fuzzy programming from the perspective of entropy. The numerical examples demonstrate the high efficiency and good performance of the proposed methods in decision making.

The uptake exploration of 68Ga-labeled NGR in well-differentiated hepatocellular carcinoma xenografts: Indication for the new clinical translational of a tracer based on NGR.

18F-FDG has low uptake and poor diagnostic efficiency in hepatocellular carcinoma (HCC), particularly in well-differentiated HCC. The NGR peptide selectively targets CD13, which is overexpressed in many types of tumor cells as well as neovasculature cells. In the present study, we aimed to evaluate the feasibility of utilizing 68Ga-NGR to image CD13-positive well-differentiated HCC xenografts. The in vitro cellular uptake, in vivo micro-PET/CT imaging and biodistribution studies of 68Ga-NGR and 18F-FDG were quantitatively compared in SMMC-7721-based well­differentiated HCC xenografts. The human fibrosarcoma (HT-1080) and human colorectal adenocarcinoma (HT-29) xenografts were respectively used as positive and negative reference groups for CD13. The expression of CD13 was qualitatively verified by immunofluorescence staining and immunohistostaining studies. The expression levels of CD13 and glucose-6-phosphatase (G6Pase) were semi-quantitatively analyzed by western blotting. The in vitro SMMC-7721 cellular uptake of 68Ga­NGR was significantly higher than that of 18F-FDG (1.23±0.11 vs. 0.515±0.14%; P<0.01). The in vivo micro-PET/CT imaging results revealed that the uptake of 68Ga-NGR in SMMC-7721-derived tumors was 2.17±0.21% ID/g (percentage of injected dose per gram of tissue), which was higher compared to that of 18F-FDG (0.73±0.26% ID/g; P<0.01); however, the tumor/liver ratio of 68Ga-NGR was 2-fold higher than that of 18F-FDG. We concluded that the uptake of 68Ga-NGR was significantly higher both in vitro and in vivo than 18F-FDG in the well­differentiated HCC xenografts and therefore, it is promising for further clinical translation in well-differentiated HCC PET/CT diagnosis.

Inter-heterogeneity and intra-heterogeneity of αvß3 in non-small cell lung cancer and small cell lung cancer patients as revealed by 68Ga-RGD2 PET imaging.

PURPOSE: Integrin αvß3 is the therapeutic target of the anti-angiogenic drug cilengitide. The objective of this study was to compare αvß3 levels in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, by using the positron emission tomography (PET) tracer 68Ga-labeled dimerized-RGD (68Ga-RGD2). METHODS: Thirty-one patients with pathologically confirmed lung cancer were enrolled (21 were NSCLC and 10 were SCLC). PET/CT images were acquired using 68Ga-RGD2.18F-FDG PET/CT images were also acquired on the consecutive day as reference. The standard uptake values (SUV) and the tumor/nontarget (T/NT) values were quantitatively compared. Expression of the angiogenesis marker αvß3 in NSCLC and SCLC lesions was analyzed by immunohistochemistry. RESULTS: The 18F-FDG SUVmax and the SUVmean were not significantly different between NSCLC and SCLC patients. The 68Ga-RGD2 uptake of SCLC patients was at background levels in both SUV and T/NT measurements and was significantly lower than that of NSCLC patients. The range value of 68Ga-RGD2 SUVmean was 4.5 in the NSCLC group and 2.2 in the SCLC group, while the variation coefficient was 36.2% and 39.3% in NSCLC and SCLC primary lesions, respectively. Heterogeneity between primary lesions and putative distant metastases was also observed in some NSCLC cases. Immunostaining showed that αvß3 integrin was expressed in the cells and neovasculature of NSCLC lesions, while SCLC samples had negative expression. CONCLUSIONS: The uptake of 68Ga-RGD2 in SCLC patients is significantly lower than that in NSCLC patients, indicating a lower αvß3 target level for cilengitide in SCLC. Apparent intra-tumor heterogeneities of αvß3 also exist in both NSCLC and SCLC. Such inter- and intra-heterogeneity of αvß3 may potentially improve current applications of αvß3-targeted therapy and diagnostic imaging in lung cancer.