GLI1-mediated regulation of side population is responsible for drug resistance in gastric cancer

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Chemotherapy is frequently used for gastric cancer treatment. Most patients with advanced gastric cancer eventually succumb to the disease despite some patients responded initially to chemotherapy. Thus, identifying molecular mechanisms responsible for cancer relapse following chemotherapy will help design new ways to treat gastric cancer. In this study, we revealed that the residual cancer cells following treatment with chemotherapeutic reagent cisplatin have elevated expression of hedgehog target genes GLI1, GLI2 and PTCH1, suggestive of hedgehog signaling activation. We showed that GLI1 knockdown sensitized gastric cancer cells to CDDP whereas ectopic GLI1 expression decreased the sensitivity. Further analyses indicate elevated GLI1 expression is associated with an increase in tumor sphere formation, side population and cell surface markers for putative cancer stem cells. We have evidence to support that GLI1 is critical for maintenance of putative cancer stem cells through direct regulation of ABCG2. In fact, GLI1 protein was shown to be associated with the promoter fragment of ABCG2 through a Gli-binding consensus site in gastric cancer cells. Disruption of ABCG2 function, through ectopic expression of an ABCG2 dominant negative construct or a specific ABCG2 inhibitor, increased drug sensitivity of cancer cells both in culture and in mice. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high ABCG2 expression was associated with poor survival in the gastric cancer patients who underwent chemotherapy. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain chemotherapy resistance

Energetic stability, structural transition, and thermodynamic properties of ZnSnO[sub 3]

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98679/1/ApplPhysLett_98_091914.pd

Clinical Application of Exosome Components

Exosomes belong to a subpopulation of EVs that carry different functional molecular cargoes, including proteins, nucleic acids, metabolites, and lipids. Notably, evidence has demonstrated that exosomes participate in bidirectional cell–cell communication and act as critical molecular vehicles in regulating numerous physiological and pathological processes. Since the specific contents within exosomes carry the information from their cells of origin, this property permits exosomes to act as valuable biomarkers. This chapter summarizes the potential use of exosome components in diagnosing, prognosis, or monitoring and treating multiple cancers and other non-neoplastic diseases. We also discuss the deficiency of basic applications, including the limitations of research methods and different research institutions and the differences generated by specimen sources. Thus, a better understanding of the problem of exosome detection may pave the way to promising exosome-based clinical applications

Activation of the hedgehog pathway in advanced prostate cancer

BACKGROUND: The hedgehog pathway plays a critical role in the development of prostate. However, the role of the hedgehog pathway in prostate cancer is not clear. Prostate cancer is the second most prevalent cause of cancer death in American men. Therefore, identification of novel therapeutic targets for prostate cancer has significant clinical implications. RESULTS: Here we report that activation of the hedgehog pathway occurs frequently in advanced human prostate cancer. We find that high levels of hedgehog target genes, PTCH1 and hedgehog-interacting protein (HIP), are detected in over 70% of prostate tumors with Gleason scores 8–10, but in only 22% of tumors with Gleason scores 3–6. Furthermore, four available metastatic tumors all have high expression of PTCH1 and HIP. To identify the mechanism of the hedgehog signaling activation, we examine expression of Su(Fu) protein, a negative regulator of the hedgehog pathway. We find that Su(Fu) protein is undetectable in 11 of 27 PTCH1 positive tumors, two of them contain somatic loss-of-function mutations of Su(Fu). Furthermore, expression of sonic hedgehog protein is detected in majority of PTCH1 positive tumors (24 out of 27). High levels of hedgehog target genes are also detected in four prostate cancer cell lines (TSU, DU145, LN-Cap and PC3). We demonstrate that inhibition of hedgehog signaling by smoothened antagonist, cyclopamine, suppresses hedgehog signaling, down-regulates cell invasiveness and induces apoptosis. In addition, cancer cells expressing Gli1 under the CMV promoter are resistant to cyclopamine-mediated apoptosis. All these data suggest a significant role of the hedgehog pathway for cellular functions of prostate cancer cells. CONCLUSION: Our data indicate that activation of the hedgehog pathway, through loss of Su(Fu) or overexpression of sonic hedgehog, may involve tumor progression and metastases of prostate cancer. Thus, targeted inhibition of hedgehog signaling may have significant implications of prostate cancer therapeutics

Effects of yeast extract supplemented in diet on growth performance, digestibility, intestinal histology, and the antioxidant capacity of the juvenile turbot (Scophthalmus maximus)

An 8-week feeding experiment was conducted on the juvenile turbot (Scophthalmus maximus) to evaluate the influence of yeast extract (YE) supplementation in the diet on growth performance, feed utilization, body composition, nutrient digestibility, intestinal histology, and antioxidant capacity. Four experimental diets were formulated with graded levels of yeast extract 0 (YE0), 1% (YE1), 3% (YE3), and 5% (YE5) and fed to turbots (initial body weight: 4.2 ± 0.1 g) with three replicates per diet and 200 fish in each replicate, respectively. The results showed that turbots fed with diets YE1 and YE3 displayed a significantly higher specific growth rate and protein efficiency rate than those fed with diets YE0 and YE5, while the feed conversion ratios in YE1 and YE3 groups were lower than those in YE0 and YE5. Fish fed with diets YE3 and YE5 showed higher body crude protein contents than those in groups YE0 and YE1. The highest apparent digestibility coefficients for dry matter and crude protein, digestive enzyme activities (trypsin, lipase, and amylase), and the height of the intestinal fold were observed in the YE3 group. YE3 treatment displayed a significantly higher superoxide dismutase (SOD) activity than the YE0 group, while the malondialdehyde (MDA) content in YE1 was significantly lower than those in YE0 and YE5. No significant difference was observed in serum physiological and biochemical parameters among all treatments. Overall, appropriate dietary supplementation of the yeast extract could improve the growth performance, digestibility, and antioxidant capacity of the juvenile turbot, and the recommended yeast extract level in the feed is 2.47%

A Novel Human Microbe-Disease Association Prediction Method Based on the Bidirectional Weighted Network

The survival of human beings is inseparable from microbes. More and more studies have proved that microbes can affect human physiological processes in various aspects and are closely related to some human diseases. In this paper, based on known microbe-disease associations, a bidirectional weighted network was constructed by integrating the schemes of normalized Gaussian interactions and bidirectional recommendations firstly. And then, based on the newly constructed bidirectional network, a computational model called BWNMHMDA was developed to predict potential relationships between microbes and diseases. Finally, in order to evaluate the superiority of the new prediction model BWNMHMDA, the framework of LOOCV and 5-fold cross validation were implemented, and simulation results indicated that BWNMHMDA could achieve reliable AUCs of 0.9127 and 0.8967 ± 0.0027 in these two different frameworks respectively, which is outperformed some state-of-the-art methods. Moreover, case studies of asthma, colorectal carcinoma, and chronic obstructive pulmonary disease were implemented to further estimate the performance of BWNMHMDA. Experimental results showed that there are 10, 9, and 8 out of the top 10 predicted microbes having been confirmed by related literature in these three kinds of case studies separately, which also demonstrated that our new model BWNMHMDA could achieve satisfying prediction performance

Synthesis of single-crystal La0.67Sr0.33MnO3 freestanding films with different crystal-orientation

We report the synthesis of single-crystal La0.67Sr0.33MnO3 (LSMO) freestanding films with different crystal orientations. By using pulsed laser deposition, water soluble perovskite-like sacrificial layers Sr3Al2O6 (SAO) followed by LSMO films are grown on differently oriented SrTiO3 substrates. Freestanding LSMO films with different orientations are obtained by etching the SAO in pure water. All the freestanding films show room-temperature ferromagnetism and metallicity, independent of the crystal orientation. Intriguingly, the Curie temperature (TC) of the freestanding films is increased due to strain relaxation after releasing from the substrates. Our results provide an additional degree of freedom to tailor the properties of freestanding perovskite oxide heterostructures by crystal orientation and an opportunity to further integrate different oriented films together

Identification of Anti-Malarial Compounds as Novel Antagonists to Chemokine Receptor CXCR4 in Pancreatic Cancer Cells

Despite recent advances in targeted therapies, patients with pancreatic adenocarcinoma continue to have poor survival highlighting the urgency to identify novel therapeutic targets. Our previous investigations have implicated chemokine receptor CXCR4 and its selective ligand CXCL12 in the pathogenesis and progression of pancreatic intraepithelial neoplasia and invasive pancreatic cancer; hence, CXCR4 is a promising target for suppression of pancreatic cancer growth. Here, we combined in silico structural modeling of CXCR4 to screen for candidate anti-CXCR4 compounds with in vitro cell line assays and identified NSC56612 from the National Cancer Institute's (NCI) Open Chemical Repository Collection as an inhibitor of activated CXCR4. Next, we identified that NSC56612 is structurally similar to the established anti-malarial drugs chloroquine and hydroxychloroquine. We evaluated these compounds in pancreatic cancer cells in vitro and observed specific antagonism of CXCR4-mediated signaling and cell proliferation. Recent in vivo therapeutic applications of chloroquine in pancreatic cancer mouse models have demonstrated decreased tumor growth and improved survival. Our results thus provide a molecular target and basis for further evaluation of chloroquine and hydroxychloroquine in pancreatic cancer. Historically safe in humans, chloroquine and hydroxychloroquine appear to be promising agents to safely and effectively target CXCR4 in patients with pancreatic cancer

Biodegradable Thermosensitive Hydrogel for SAHA and DDP Delivery: Therapeutic Effects on Oral Squamous Cell Carcinoma Xenografts

Background: OSCC is one of the most common malignancies and numerous clinical agents currently applied in combinative chemotherapy. Here we reported a novel therapeutic strategy, SAHA and DDP-loaded PECE (SAHA-DDP/PECE), can improve the therapeutic effects of intratumorally chemotherapy on OSCC cell xenografts. Objective/Purpose: The objective of this study was to evaluate the therapeutic efficacy of the SAHA-DDP/PECE in situ controlled drug delivery system on OSCC cell xenografts. Methods: A biodegradable and thermosensitive hydrogel was successfully developed to load SAHA and DDP. Tumorbeared mice were intratumorally administered with SAHA-DDP/PECE at 50 mg/kg (SAHA) +2 mg/kg (DDP) in 100 ul PECE hydrogel every two weeks, SAHA-DDP at 50 mg/kg(SAHA) +2 mg/kg(DDP) in NS, 2 mg/kg DDP solution, 50 mg/kg SAHA solution, equal volume of PECE hydrogel, or equal volume of NS on the same schedule, respectively. The antineoplastic actions of SAHA and DDP alone and in combination were evaluated using the determination of tumor volume, immunohistochemistry, western blot, and TUNEL analysis. Results: The hydrogel system was a free-flowing sol at 10uC, become gel at body temperature, and could sustain more than 14 days in situ. SAHA-DDP/PECE was subsequently injected into tumor OSCC tumor-beared mice. The results demonstrated that such a strategy as this allows the carrier system to show a sustained release of SAHA and DDP in vivo, and coul