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Both autophagy and glycolysis are essential for pancreatic ductal adenocarcinoma (PDAC) survival due to desmoplasia. We investigated whether targeting a hub gene which participates in both processes could be an efficient strategy for PDAC treatment.The expression pattern of glycolysis signatures (GS) and autophagy signatures (AS) and their correlation with cystatin B (CSTB) in PDAC were analysed. It was discovered how CSTB affected the growth, glycolysis, and autophagy of PDAC cells. We assessed competitive binding to cathepsin B (CTSB) between CSTB and cystatin C (CSTC) via immunoprecipitation (IP) and immunofluorescence (IF). Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter gene assays were used to unveil the mechanism underlying CSTB upregulation. The expression pattern of CSTB was examined in clinical samples and KrasG12D/+, Trp53R172H/+, Pdx1-Cre (KPC) mice.GS and AS were enriched and closely associated in PDAC tissues. CSTB increased autophagic flux and provided substrates for glycolysis. CSTB knockdown attenuated the proliferation of PDAC cells and patient-derived xenografts. The liquid chromatography-tandem mass spectrometry assay indicated CSTB interacted with CTSB and contributed to the proteolytic activity of CTSB in lysosomes. IF and IP assays demonstrated that CSTB competed with CSTC to bind to CTSB. Mutation of the key sites of CSTB abolished the interaction between CSTB and CTSB. CSTB was highly expressed in PDAC due to H3K27acetylation and SP1 expression. High expression of CSTB in PDAC was observed in tissue microarray and patients' serum samples.Our work demonstrated the tumorigenic roles of autophagy and glycolysis in PDAC. CSTB is a key role in orchestrating these processes to ensure energy supply of PDAC cells.

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.

An integrin α

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.

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.

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.