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Objectives We aimed to investigate the role of [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT for the initial assessment of gastric cancer and to explore the factors associated with their uptake. Methods This study enrolled 62 patients with histopathologically confirmed gastric cancer. We compared the diagnostic performance of [68Ga]FAPI-04, [18F]FDG, and combined dual-tracer PET/CT. The standardized uptake value (SUV) and tumor-to-background ratio (TBR) were also measured, and the factors that influence tracer uptake were analyzed. Results [68Ga]FAPI-04 PET/CT detected more primary lesions (90.3% vs 77.4%, p = 0.008) and peritoneal metastases (91.7% vs 41.7%, p = 0.031) and demonstrated higher SUVmax and TBR values (p < 0.001) of primary lesions compared to [18F]FDG PET/CT. Dual-tracer PET/CT significantly improved the diagnostic sensitivity for the detection of distant metastases, compared with stand-alone [18F]FDG (97.1% vs 73.5%, p = 0.008) or [68Ga]FAPI-04 (97.1% vs 76.5%, p = 0.016) PET/CT. Subsequently, treatment strategies were changed in nine patients following [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT. Nevertheless, [68Ga]FAPI-04 uptake was primarily influenced by the size and invasion depth of the tumor. Both [68Ga]FAPI-04 and [18F]FDG PET/CT showed limited sensitivity for detecting early gastric cancer (EGC) (37.5% vs 25.0%, p > 0.05). Conclusions In this initial study, [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT were complementary and improved sensitivity for the detection of distant metastases pre-treatment in gastric cancer and could improve treatment stratification in the future. [68Ga]FAPI-04 had limited efficacy in detecting EGC. Key Points •[68Ga]FAPI-04 and[18F]FDG dual-tracer PET/CT are complementary to each other for improving diagnostic sensitivity in the initial evaluation of distant metastases from gastric cancer. •[68Ga]FAPI-04 PET/CT showed limited sensitivity in detecting EGC. • Need for further validation in a larger multi-centre prospective study.

We aimed to investigate the role of [This study enrolled 62 patients with histopathologically confirmed gastric cancer. We compared the diagnostic performance of [[In this initial study, [• [

The absorption of peptides and proteins delivered orally is minimum because of the intestine epithelial barrier. There are few known active transport mechanisms for macromolecules including the neonatal Fc Receptor (FcRn) for the absorption and secretion of IgGs in infant and adult intestine. We had previously described the FnAb-8 protein that could bind to hFcRn tightly at pH 6.0 but barely at pH 7.4. In this study, we examined its uptake, biodistribution and pharmacokinetics after peroral administration in both wild-type and human FcRn transgenic (Tg) mice. FnAb-8 was modified to contain trans-cyclooctene (TCO) which could interact with 18F labeled tetrazine in situ via the bioorthogonal inverse-electron-demand Diels−Alder reaction. We showed that FnAb-8 had a tendency to distribute and persist in the Tg mice intestine for an extended duration of time. It could also be absorbed into the circulation and distributed systemically over a long period of time up to 172 h. The improvement in oral uptake and concentration in the intestine tissue may be valuable for designing oral delivery of biopharmaceuticals, especially for diseases involving the gastric intestinal tissue., Graphical abstract PET/CT images of FcRn Tg mice after receiving p.o. administration of FnAb-8-TCO and in situ labeling by Tz-NOTA-Al18F injected intravenously.Image, graphical abstract

Background The 68Ga-labelled FAPI provides new oncology imaging option other than 18F-FDG-PET. However, it's unclear about whether the FAPI-PET distinguishes malignancy from benign lesions. Methods We established an AOM/DSS-induced rat colorectal tumor model. A double PET/CT tracer of 68Ga-FAPI-04 and 18F-FDG was used in the rat colorectal tumor model. Histological examination, immunohistochemistry staining, and radioautography were performed in this study. Results 68Ga-FAPI PET imaging distinguishes neoplasia from inflammatory lesions in an AOM/DSS-induced rat colorectal tumor model, and FAPI accumulation gradually increases along with tumor progression. An inflammatory lesion did not interfere with 68Ga-FAPI PET imaging. Conclusion The 68Ga-FAPI-04 PET distinguishes malignant tumors from inflammatory lesions by detecting FAP in a rat colorectal tumor model, suggesting that 68Ga-FAPI-04 PET is a better diagnostic tool than 18F-FDG PET, at least to colorectal cancer patients.

BackgroundPrimary Sjogren’s syndrome (pSS) is a slowly progressive, inflammatory autoimmune disease characterized by lymphocytic infiltration into salivary and lacrimal glands. It becomes more recognized that morphology alterations of epithelial mitochondria are involved in altered cellular bioenergetics in pSS patients. The integrated analysis of the mitochondrial role in the pathogenesis and aberrant immune microenvironment in pSS remains unknown.MethodsThe mitochondria-related genes and gene expression data were downloaded from the MitoMiner, MitoCarta, and NCBI GEO databases. We performed novel transcriptomic analysis and constructed a network between the mitochondrial function and immune microenvironment in pSS-salivary glands by computer-aided algorithms. Subsequently, real-time PCR was performed in clinical samples in order to validate the bioinformatics results. Histological staining and transmission electron microscopy (TEM) were further studied on labial salivary gland samples of non-pSS and pSS patients characterized for mitochondria-related phenotypic observation in the different stages of the disease.ResultsThe bioinformatic analysis revealed that the expression of several mitochondria-related genes was altered in pSS. Quantitative real-time PCR showed that four hub genes, CD38, CMPK2, TBC1D9, and PYCR1, were differentially expressed in the pSS clinical samples. These hub genes were associated with the degree of immune cell infiltration in salivary glands, the mitochondrial respiratory chain complexes, mitochondrial metabolic pathway in gluconeogenesis, TCA cycle, and pyruvate/ketone/lipid/amino acid metabolism in pSS. Clinical data revealed that the gene expression of fission (Fis1, DRP1, and MFF) and fusion (MFN1, MFN2, and OPA1) was downregulated in pSS samples, consistent with the results from the public validation database. As the disease progressed, cytochrome c and Bcl-2 proteins were regionally distributed in salivary glands from pSS patients. TEM revealed cytoplasmic lipid droplets and progressively swollen mitochondria in salivary epithelial cells.ConclusionOur study revealed cross talk between mitochondrial dysfunction and the immune microenvironment in salivary glands of pSS patients, which may provide important insights into SS clinical management based on modulation of mitochondrial function.

Purpose. Extracellular acidity is a marker of highly aggressive breast cancer (BC). pH-low insertion peptides (pHLIPs) target the acidic tumor microenvironment. This study evaluates the distribution and therapeutic efficacy of radioiodine-labeled pHLIP variant 3 (Var3) in a mouse model of BC. Methods. The binding of fluorescein isothiocyanate (FITC)- or radioiodine-125 (125I) labeled Var3-pHLIP to MDA-MB-231, 4T1, and SK-BR-3 BC cell lines under different pH values was evaluated in vitro. The distribution of 125I-labeled Var3-pHLIP and wild-type- (WT-) pHLIP in tumor-bearing mice was analyzed in vivo using micro-SPECT/CT imaging. The therapeutic efficacy of radioiodine-131 (131I)-labeled Var3-pHLIP in MDA-MB-231 xenografts was evaluated by relative tumor volume measurement and immunohistochemical analysis. Results. The binding ability of FITC- or 125I-labeled Var3-pHLIP to tumor cells increased with the decrease in pH. The tumor-to-background ratio of 125I-Var3-pHLIP in BC xenografts showed the best imaging contrast at 24 h or 48 h postinjection. The uptake of 125I-Var3-pHLIP in MDA-MB-231 xenografts at 2 h postinjection was significantly higher than that of 125I-WT-pHLIP ( 3.76 ± 0.37 vs. 2.87 ± 0.60 %ID/g, p = 0.046 ). The relative tumor volume in MDA-MB-231 xenografts was significantly lower in the 131I-Var3-pHLIP-treated group than in the groups treated with Var3-pHLIP ( p = 0.027 ), 131I ( p = 0.001 ), and saline ( p < 0.001 ). The 131I-Var 3-pHLIP group presented a lower expression of Ki67 and a higher expression of caspase 3. Conclusion. Radioiodine-labeled Var3-pHLIP effectively targeted BC cells in an acidic environment and inhibited the growth of MDA-MB-231 xenografts by ionizing radiation.

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Hyaluronan (HA) based biomaterials are widely used as tissue scaffolds, drug formulations, as well as targeting ligands and imaging probes for diagnosis and drug delivery. However, because of the presence of abundant endogenous HA presented in various tissues in vivo, the pharmacokinetic behavior and biodistribution patterns of exogenously administered HAs have not been well characterized. The HA backbone was modified with Diethylenetriamine (DTPA) to enable the chelation of gadolinium (Gd) and aluminum (Al) ions. Series of PET and MR imaging were taken after the injection of HA-DTPA-Gd and HA-DTPA-Al18F while using18F-FDG and Magnevist(DTPA-Gd) as controls. The Tomographic images were analyzed and quantified to reveal the distribution and locations of HA in tumor-bearing mice. The labeled HAs had good stability in plasma. They retained binding affinity towards CD44s on tumor cell surface. The injected HAs distributed widely in various organs, but were found to be cleared quickly except inside tumor tissues where the signals were higher and persisted longer. Medical imaging tools, including MR and PET, can be highly valuable for examining biomaterial distribution non-invasively. The HA tumor accumulation properties may be explored for the development of active targeting drug carriers and molecular probes.

Background: Amnesia in Alzheimer's disease (AD) could be due to disrupted encoding, consolidation dysfunction, or an impairment in the retrieval of stored memory information. The different memory phases relate with different parts of functional brain systems. Methods: We combine task functional magnetic resonance imaging and amyloid positron emission tomography in 72 participants (36 AD and 36 controls), to investigate the relationship between memory performance, memory phase-locked functional connectivity, and cortical β-amyloid deposition.Results: We found that AD was mainly characterized by decreased functional connectivity in a new data-driven Network composed of regions from default mode network, limbic network and frontoparietal network during the memory maintenance and retrieval phase. Within the Network, AD had more regions with reduced connectivity during the retrieval phase than other phases, locating mainly in the medial prefrontal cortex, posterior cingulate cortex, middle temporal and inferior parietal cortex of left hemisphere. Furthermore, functional connectivity in the Network related to memory performance. Crucially, the magnitude of the Network connectivity reduction during retrieval negatively correlated with mean cortical β-amyloid, and this relationship mediated the relationship between cortical β-amyloid and memory performance.Conclusions: Our findings show that memory deficiency in AD relates with decreased connectivity in specific network and cortical β-amyloid only during retrieval phase. These findings help to map impaired functional connectivity during memory phases and explain the relationship between memory deficiency and cortical β-amyloid.

It is widely reported that BAT is more frequently observed in patients during the winter season, and its activities could vary significantly under different conditions. However, whether this phenomenon is entirely caused by low temperature or other factors is not very clear. In this study, we tried to explore the seasonal fluctuation of FDG-PET BAT using mouse models that were from the same genetic breed and raised in a well-controlled environment. We also compared these variations with the effects of fasting and cold stimulation on BAT activities in these mice. In overnight fasted mice, the FDG-PET BAT was the highest in standardized uptake value (SUV) in the winter season. The values were much lower in all other seasons, especially in the summer. Compared to regular feeding, overnight fasting reduced BAT SUV, and refeeding after fasting could fully recover BAT activities. Fasted mice also did not respond to cold environment stimulation. After refeeding, their BAT thermogenic activities became normal. These results suggest that BAT FDG-PET SUV measurements vary significantly with the season and highlight the importance of taking into account the seasonal effect and fasting status in BAT evaluation studies using FDG-PET imaging.

Although RNA interference (RNAi) technology shows great potential in cancer treatment, the tumor target delivery and sufficient cytosolic transport of RNAi agents are still the main obstacles for its clinical applications. Herein, we report a functional supramolecular self-assembled nanoparticle vector for RNAi agent loading and tumor target therapy. Molecular block adamantane-grafted poly(ethylene glycol) (Ad-PEG) was modified with epidermal growth factor receptor (EGFR)-specific binding ligand GE11 or pH-sensitive fusogenic peptide GALA and then used for self-assembly with cyclodextrin-grafted branched polyethylenimine (CD-PEI), adamantane-grafted polyamidoamine dendrimer (Ad-PAMAM), and plasmid DNA containing a small hairpin RNA expression cassette against vascular endothelial growth factor (VEGF) into functional DNA-loaded supramolecular nanoparticles (GE11&GALA-pshVEGF@SNPs) based on molecular recognition and charge interaction. These functional peptides facilitated the target cell binding, internalization, and endosomal escape of GE11&GALA-pshVEGF@SNPs, resulting in increased reporter gene expression and efficient targeted gene silencing. The systemic delivery of the GE11&GALA-pshVEGF@SNPs can efficiently downregulate the intratumoral VEGF protein levels, reduce blood vessel formation, and significantly inhibit A549 xenograft tumor growth. These results reveal the potential of these multifunctional self-assembled nanoparticles as a nucleic acid drug delivery system for the treatment of lung cancer.

Ultrasmall sub-5 nm KGdF4 rare earth nanoparticles were synthesized as multifunctional probes for fluorescent, magnetic, and radionuclide imaging. The cytotoxicity of these nanoparticles in human glioblastoma U87MG and human non-small cell lung carcinoma H1299 cells was evaluated, and their application for in vitro and in vivo tumor targeted imaging has also been demonstrated.

Fluorescent quantum dots (QDs) used for biomedical imaging and diagnostics have attracted considerable attention over the past decade. Here, we report our finding regarding the therapeutic efficacy of the popularly used red/brown, brown or close to black CdTe and CdSe QDs. Upon 671-nm laser irradiation, these QDs can rapidly convert light energy into heat, both in vitro and in vivo. In the present study, the growth of mouse melanoma tumors injected with CdTe(710) QDs coated with a silica shell (SiO(2)) was significantly inhibited after laser irradiation, with eventual disappearance of the tumor. In contrast, tumors injected with the silica-coated QDs without subsequent irradiation continued to grow over time. They had a growth rate close to that of tumors injected with SiO(2) or phosphate-buffered saline, with or without laser irradiation. In conclusion, our data suggest that the popularly used CdTe and CdSe QDs have great potential in the treatment of cancer using photothermal therapy.

The use of non-toxic or low toxicity materials exhibiting dual functionality for use in sentinel lymph node (SLN) mapping and cancer therapy has attracted considerable attention during the past two decades. Herein, we report that the natural black sesame melanin (BSM) extracted from black sesame seeds (Sesamum indicum L.) shows exciting potential for SLN mapping and cancer photothermal therapy. Aqueous solutions of BSM under neutral and alkaline conditions can assemble into sheet-like nanoparticles ranging from 20 to 200 nm in size. The BSM nanoparticles were encapsulated by liposomes to improve their water solubility and the encapsulated and bare BSM nanoparticles were both non-toxic to cells. Furthermore, the liposome-encapsulated BSM nanoparticles (liposome-BSM) did not exhibit any long-term toxicity in mice. The liposome-BSM nanoparticles were subsequently used to passively target healthy and tumor-bearing mice SLNs, which were identified by the black color of the nanoparticles. BSM also strongly absorbed light in the near-infrared (NIR) range, which was rapidly converted to heat energy. Human esophagus carcinoma cells (Eca-109) were killed efficiently by liposome-BSM nanocomposites upon NIR laser irradiation. Furthermore, mouse tumor tissues grown from Eca-109 cells were seriously damaged by the photothermal effects of the liposome-BSM nanocomposites, with significant tumor growth suppression compared with controls. Given that BSM is a safe and nutritious biomaterial that can be easily obtained from black sesame seed, the results presented herein represent an important development in the use of natural biomaterials for clinical SLN mapping and cancer therapy.

The aim of this study is to evaluate the potential of both the Dual-time point PET imaging and the Time Activity Curve (TAC) in dynamic PET imaging in differentiating tumor and inflammation (both subcutaneous and in situ). Methods: Dynamic FDG-PET was performed on 23 female mice inoculated with tumor or inflammation subcutaneously or inside the lung. Values of Retention Index (RI) as a metric in the dual-time analysis and curvature of TAC were obtained. Results: Values of RI showed no significant difference between various experimental groups, while values of curvature showed significant difference between subcutaneous tumor and inflammation, tumors at different locations (subcutaneous and in situ), and inflammations at different locations (subcutaneous and in situ). Conclusions: Dual-time analysis requires more work in deciding the two time points. Compared to the dual-point analysis with current settings, analyzing the shape of TAC has a higher sensitivity for differentiating malignancies from inflammations.

Background [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been widely used in oncologic procedures such as tumor diagnosis and staging. However, false-positive rates have been high, unacceptable and mainly caused by inflammatory lesions. Misinterpretations take place especially when non-subcutaneous inflammations appear at the tumor site, for instance in the lung. The aim of the current study is to evaluate the use of dynamic PET imaging procedure to differentiate in situ and subcutaneous non-small cell lung carcinoma (NSCLC) from inflammation, and estimate the kinetics of inflammations in various locations. Methods Dynamic FDG-PET was performed on 33 female mice inoculated with tumor and/or inflammation subcutaneously or inside the lung. Standardized Uptake Values (SUVs) from static imaging (SUVmax) as well as values of influx rate constant (Ki) of compartmental modeling from dynamic imaging were obtained. Static and kinetic data from different lesions (tumor and inflammations) or different locations (subcutaneous, in situ and spontaneous group) were compared. Results Values of SUVmax showed significant difference in subcutaneous tumor and inflammation (p

Epidemiological and clinico-pathological studies indicate a causal relationship between heart disease and Alzheimer’s disease (AD). To learn whether heart disease causes an onset of AD, mice with myocardial infarction (MI) and congestive heart failure (HF) were used to test neuropsychiatric and cognitive behaviors as well as for measurements of AD related protein markers. To this end, adult mice were subjected to ligation of left anterior descending artery (LAD) and about two weeks later high-frequency echocardiography was performed to exam the resulting cardiac structure and function. Three months after successful induction of chronic heart failure (CHF) these mice showed an impairment of learning in the Morris Water Maze task. In addition, the expression of selected molecules, which are involved in β-amyloid metabolism, apoptosis and inflammation on the level of gene transcription and translation, was altered in CHF mice. Our findings provide a plausible explanation that CHF increases the risk of cognitive impairments and alters cerebral β-amyloid metabolism. In addition, our data indicate that the cerebral compensatory mechanisms in response to CHF are brain area and gender specific.

Objectives Vitamin D deficiency has been associated with incident cardiovascular disease and cardiovascular mortality. Vitamin D receptor (VDR) activation through vitamin D or its analogues attenuates cardiomyocyte hypertrophy and cardiac dysfunction. Whether VDR status influences cardiomyocyte fate in the setting of myocardial ischaemia/reperfusion (MI/R) injury remains unknown. Our aim was to determine effects of cardiac VDR activation on MI/R injury. Methods The mice were randomly assigned to seven groups: sham, vehicle, paricalcitol (PC), In vivo VDR-siRNA + PC, In vivo VDR-siRNA + vehicle, In vivo control siRNA + PC, and In vivo control siRNA + vehicle. PC was administered through intraperitoneal injection at 20 ng/mouse/day for 2 days before MI/R. The last dose was administered at 15 min before reperfusion. The vehicle groups received vehicle injections using the same schedule. In vivo siRNA-mediated cardiac-specific VDR gene silencing was performed 48 h before MI/R. Following 30 minutes of ischaemia, the myocardium was reperfused. The mice were reperfused for 15 min (for protein phosphorylation levels), 3 h (for apoptosis, oxidation, nitration,and inflammation assays), 24 h (for cardiac function and infarct size assays), or 4 weeks (for left ventricular remodelling). The myocardial infarct size was determined using Evans blue-TTC double staining methods. Cardiac function was measured using an echocardiographic imaging system. DHE was used to detect ROS generation within the myocardium in situ . The nitrotyrosine levels were measured using immunostaining and ELISA.caspase-9, caspase-12, cleaved-caspase-8,gp91 phox , iNOS, phospho-JNK, and phospho-p38 MAPK were detected using western blot analysis. ANP, β-MHC, TNFα, IL1β, and IL6 expression were determined using real-time quantitative PCR. Results Low VDR expression was detected in the mouse heart, and MI/R upregulated VDR expression. The activation of VDR through PC reduced myocardial infarct size (23% vs. 44%, p phox and iNOS expression. Moreover, VDR activation suppressed the activation of proinflammatory kinases (p38 and JNK) and inflammatory cytokines [TNFα(-34%, p In vivo cardiac-specific VDR knockdown experiment demonstrated that intact VDR signalling was required for the anti-oxidative/anti-nitrative and anti-inflammatory effect of PC. Conclusions The results obtained in this study demonstrate VDR is a potent cardioprotective receptor against MI/R injury through the inhibition of oxidative/nitrative stress and inflammation and subsequent intrinsic and extrinsic caspase-mediated apoptosis. VDR represents a potential molecular therapeutic target for the treatment of ischaemic heart disease.