Abstract. Given the important role of CXCR4 in cancer metastasis, microenvironmental factors that modulate CXCR4 may have an impact on the process of tumor expansion. Hypoxia is a common feature of solid tumors and a significant microenvironmental factor that drives aggressive behavior. CXCR4 is upregulated in several cancer cells under hypoxic conditions, suggesting a relationship between tumor hypoxia and CXCR4. However, the role of hypoxia in regulating CXCR4 in gastric cancer remains poorly understood. KATO III gastric cancer cells were exposed to hypoxia or normoxia. CXCR4 expression in cells transfected with shRNA specific for HIF-1α was investigated by western blotting and flow cytometry. Wound healing, migration and invasion assays were used to assess cell motility and the chemotactic response to CXCL12, a major CXCR4 ligand. CXCR4 expression at the protein level and in the cell membrane was significantly increased in KATO III cells following exposure to hypoxia. This upregulation of CXCR4 was implicated in increased cell motility and enhanced chemotactic responses (migration and invasion) to CXCL12 treatment in vitro. The increases in CXCR4 expression and metastatic potential in gastric cancer cells exposed to hypoxia were blocked by HIF-1α-specific shRNA. Our results indicate that hypoxia upregulates CXCR4 in gastric cancer cells in a HIF-1α-dependent manner, and that upregulation of CXCR4 plays a role in cancer cell migration and invasion. Thus, disrupting the hypoxia-HIF-1α-CXCR4 axis could be an attractive therapeutic strategy for the treatment of gastric cancer.

PurposeAMD3100, an antagonist of the CXCR4 chemokine receptor is soon to be used clinically for the peripheral mobilization of hematopoietic stem cells (HSCs) in patients with multiple myeloma. AMD3100 has been shown to activate a G protein coupled with CXCR4 and thus acts as a partial CXCR4 agonist in vitro. Thus, we explored whether AMD3100 affected the survival and proliferation of myeloma cells in vitro.Materials and MethodsThe effects of AMD3100 on survival and proliferation of two myeloma cell lines (RPMI8226 and U266) as well as CD138+ cells obtained from several patients with multiple myeloma were analyzed by flow cytometry using annexin V and a colorimetric cell proliferation assay (CCK-8 assay).ResultsAMD3100, but not T140, another CXCR4 antagonist, stimulated the proliferation of myeloma cell lines and CD138+ primary human myeloma cells (-2-fold increase) in a dose-dependent manner in serum-free culture for up to 5 days, which was inhibited by pretreating the cells with pertussis toxin. AMD3100 enhanced the proliferation of U266 cells induced by interleukin-6 and partially reversed AG490-mediated growth inhibition and apoptosis induced by serum deprivation in RPMI8226 cells. AMD3100 induced the phosphorylation of Akt and MAPK p44/p42 in U266 cells and MAPK p44/p42 in RPMI8226 cells. In contrast, AMD3100 markedly increased the cell apoptosis and reduced the number of RPMI8226 cells after 5 to 7 days of culture under serum-free conditions.ConclusionAMD3100 exerts dual effects, initially enhancing and subsequently inhibiting the survival and proliferation of myeloma cells, signaling via CXCR4 in vitro.

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Purpose: Although recent studies have suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) is important in the progression of various malignancies, its role in gallbladder carcinoma (GBC) remains unknown. We investigated CXCL12 expression in GBC and its biologic and prognostic role in GBC tumorigenesis.Experimental Design: We examined CXCL12 expression in tumor specimens from 72 patients with GBC by immunohistochemistry and analyzed the correlation between CXCL12 expression and clinicopathologic factors or survival. The functional significance of CXCL12 expression was investigated by CXCL12 treatment and suppression of CXCR4, a major receptor of CXCL12, as well as by CXCL12 overexpression in in vitro and in vivo studies.Results: CXCL12 was differentially expressed in GBC tissues. CXCL12 expression was significantly associated with a high histologic grade (P ¼ 0.042) and nodal metastasis (P ¼ 0.015). Multivariate analyses showed that CXCL12 expression (HR, 8.675; P ¼ 0.014) was an independent risk factor for patient survival. CXCL12 significantly increased anchorage-dependent and -independent growth, migration, invasion, adhesiveness, and survival of GBC cells in vitro, and these effects were dependent on CXCR4. Consistent with these results, overexpression of CXCL12 significantly promoted GBC tumorigenicity in a xenograft model.Conclusions: Our results indicate that GBC cells express both CXCL12 and its receptor CXCR4, and CXCL12 may have a role in GBC progression through an autocrine mechanism. In addition, CXCL12 is a novel independent poor prognostic factor in patients with GBCs. Thus, targeting CXCL12 and CXCR4 may provide a novel therapeutic strategy for GBC treatment.

Background Metallic dental prostheses may degrade image quality on head and neck computed tomography (CT). However, there is little information available on the use of dual-energy CT (DECT) and metal artifact reduction software (MARS) in the head and neck regions to reduce metallic dental artifacts. Purpose To assess the usefulness of DECT with virtual monochromatic imaging and MARS to reduce metallic dental artifacts. Material and Methods DECT was performed using fast kilovoltage (kV)-switching between 80-kV and 140-kV in 20 patients with metallic dental prostheses. CT data were reconstructed with and without MARS, and with synthesized monochromatic energy in the range of 40-140-kiloelectron volt (keV). For quantitative analysis, the artifact index of the tongue, buccal, and parotid areas was calculated for each scan. For qualitative analysis, two radiologists evaluated 70-keV and 100-keV images with and without MARS for tongue, buccal, parotid areas, and metallic denture. The locations and characteristics of the MARS-related artifacts, if any, were also recorded. Results DECT with MARS markedly reduced metallic dental artifacts and improved image quality in the buccal area ( P < 0.001) and the tongue ( P < 0.001), but not in the parotid area. The margin and internal architecture of the metallic dentures were more clearly delineated with MARS ( P < 0.001) and in the higher-energy images than in the lower-energy images ( P = 0.042). MARS-related artifacts most commonly occurred in the deep center of the neck. Conclusion DECT with MARS can reduce metallic dental artifacts and improve delineation of the metallic prosthesis and periprosthetic region.

We compared two series of benzimidazole (BI)-grafted polyurethane (PU), one of which was water-compatible, to compare their antifungal activities. The water-compatible PU series had an additional 2,2-bis(hydroxymethyl)propanoic acid group in the PU backbone. The water-compatible PU series had a lower crosslinking density and tensile strength compared to the other PU series with increasing BI content. Although ordinary PU did not suppress fungal growth (Chaetomium globosum), the water-compatible PU completely suppressed the growth even though it contained half as many BI groups.

A series of polyurethanes (PUs) containing grafted cholesterol (UA series) and a control series blended with free cholesterol (UB series) were prepared: the spectroscopic, thermal, tensile, shape memory, and low temperature flexibility properties of these series were compared with those of unmodified PU. For both the UA and UB series, the soft segment melting temperature (T m ) was not affected by the cholesterol content. Differential scanning calorimetry (DSC) results showed that the crystallization of the hard segment of the UA series was completely inhibited as the grafted cholesterol content increased, which were supported by dynamic mechanical analysis (DMA) results for the storage modulus. As the cholesterol content increased, the glass transition temperature (T g ) of the UA series increased and remained the same for the UB series. The tensile strength in the UA series sharply increased with the cholesterol content, unlike that of the UB series. The strain at break in the UA series remained the same as the cholesterol content increased, whereas that of the UB series decreased significantly. As the cholesterol content increased, the shape recovery of the UA series remained above 90% at 45 o C and sharply increased at 0 o C. Finally, the UA series containing grafted cholesterol demonstrated excellent low temperature flexibilities compared to the UB series and unmodified PU.

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