Integration of MRI and somatosensory evoked potentials facilitate diagnosis of spinal cord compression.

This study aimed to integrate magnetic resonance imaging (MRI) and related somatosensory evoked potential (SSEP) features to assist in the diagnosis of spinal cord compression (SCC). MRI scans were graded from 0 to 3 according to the changes in the subarachnoid space and scan signals to confirm differences in SCC levels. The amplitude, latency, and time-frequency analysis (TFA) power of preoperative SSEP features were extracted and the changes were used as standard judgments to detect neurological function changes. Then the patient distribution was quantified according to the SSEP feature changes under the same and different MRI compression grades. Significant differences were found in the amplitude and TFA power between MRI grades. We estimated three degrees of amplitude anomalies and power loss under each MRI grade and found the presence or absence of power loss occurs after abnormal changes in amplitude only. For SCC, few integrated approach combines the advantages of both MRI and evoked potentials. However, integrating the amplitude and TFA power changes of SSEP features with MRI grading can help in the diagnosis and speculate progression of SCC.

Effects of synthetic glucocorticoids on breast cancer progression.

Glucocorticoids (GCs) are widely prescribed as adjuvant therapy for breast cancer patients. Unlike other steroid hormone receptors, the GC receptor is not considered an oncogene. Research in the past few years has revealed the complexity of GC-mediated signaling, but it remains puzzling whether GCs promote or inhibit tumor progression in different cancer types. Here we evaluated the potential of using a synthetic GC, dexamethasone (DEX), in the treatment of breast cancer. We found that the administration of low-dose DEX suppressed tumor growth and distant metastasis in the MCF-7 and MDA-MB-231 xenograft mouse model, whereas treatment with high-dose DEX enhanced tumor growth and metastasis, respectively. Treatment of breast cancer cells with DEX inhibited cell adhesion, migration, and invasion in a dose-dependent manner. The DEX-mediated inhibition of cell adhesion, migration, and invasion is partly through induction of microRNA-708 and subsequent Rap1B-mediated signaling in MDA-MB-231 cells. On the other hand, in MCF-7 cells, DEX-suppressed cell migration is independent from microRNA-708 mediated signaling. Overall, our data reveal that DEX acts as a double-edged sword during breast-cancer progression and metastasis: Lower concentrations inhibit breast cancer tumor growth and metastasis, whereas higher concentrations may play an undesired role to promote breast cancer progression.

Low-dose glucocorticoids suppresses ovarian tumor growth and metastasis in an immunocompetent syngeneic mouse model.

Ovarian cancer has the highest mortality rate among gynecologic malignancies. Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently with a poor prognosis. We previously reported a novel role of glucocorticoids (GCs) in metastatic ovarian cancer by upregulating microRNA-708. In this study, we used an immunocompetent syngeneic mouse model and further evaluated the effect and optimal dosages of GCs in treating metastatic ovarian cancer. The treatment of C57BL/6-derived ovarian cancer ID-8 cells with a synthetic GC, dexamethasone (DEX), induced the expression of microRNA-708, leading to decreased cell migration and invasion through targeting Rap1B. Administration of DEX at a low dose, as low as 5 µg/kg body weight, inhibited the primary tumor size and abdominal metastasis in mice bearing ID-8 cell-derived ovarian tumors. In the treated primary tumors, microRNA-708 was upregulated, whereas some proinflammatory cytokines, namely interleukin (IL)-1ß and IL-18, were downregulated. The number of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment were reduced. Overall, our study shows that low-dose GCs can suppress ovarian cancer progression and metastasis likely through not only the upregulation of the metastasis suppressor microRNA-708, but also the modulation of TAMs and MDSCs in the tumor microenvironment.

Glucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B.

Glucocorticoids are widely used in conjunction with chemotherapy for ovarian cancer to prevent hypersensitivity reactions. Here we reveal a novel role for glucocorticoids in the inhibition of ovarian cancer metastasis. Glucocorticoid treatments induce the expression of miR-708, leading to the suppression of Rap1B, which result in the reduction of integrin-mediated focal adhesion formation, inhibition of ovarian cancer cell migration/invasion and impaired abdominal metastasis in an orthotopic xenograft mouse model. Restoring Rap1B expression reverts glucocorticoid-miR-708 cascade-mediated suppression of ovarian cancer cell invasion and metastasis. Clinically, low miR-708 and high Rap1B are found in late-state ovarian tumours, as compared with normal, and patients with high miR-708 show significantly better survival. Overall, our findings reveal an opportunity for glucocorticoids and their downstream mediators, miR-708 or Rap1B, as therapeutic modalities against metastatic ovarian epithelial cancer.

Enhanced chemotherapy of cancer using pH-sensitive mesoporous silica nanoparticles to antagonize P-glycoprotein-mediated drug resistance.

Multidrug resistance (MDR) is the major clinical obstacle in the management of cancer by chemotherapy. Overexpression of ATP-dependent efflux transporter P-glycoprotein (PGP) is a key factor contributing to multidrug resistance of cancer cells. The purpose of the present study was to use the endosomal pH-sensitive MSN (mesoporous silica nanoparticles; MSN-Hydrazone-Dox) for controlled release of doxorubicin (Dox) in an attempt to overcome the PGP-mediated MDR. In vitro cell culture studies indicate that uptake of MSN-Hydrazone-Dox by the human uterine sarcoma MES-SA/Dox-resistant tumor (MES-SA/Dx-5) cell occurs through endocytosis, thus bypassing the efflux pump resistance. This improves the efficacy of the drug and leads to significant cytotoxicity and DNA fragmentation evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and DNA laddering assays. In vivo studies show that the intratumor injection of MSN-Hydrazone-Dox induces significant apoptosis of MES-SA/Dox-resistant cancer cells. This is validated by active caspase-3 immunohistochemical analysis. However, MSN-Hydrazone, without doxorubicin conjugation, cannot induce apoptosis in vitro and in vivo. In conclusion, both in vitro and in vivo studies show that MSN could serve as an efficient nanocarrier entering cell avidly via endocytosis, thus bypassing the PGP efflux pump to compromise the PGP-mediated MDR. MSN-Hydrazone-Dox could further respond to endosomal acidic pH to release doxorubicin in a sustained manner. Besides the cell study, this is the first report that successfully shows the therapeutic efficacy of using MSN against MDR cancer in vivo.

The protease-mediated nucleus shuttles of subnanometer gold quantum dots for real-time monitoring of apoptotic cell death.

Subnanometer photoluminescent gold quantum dots (GQDs) are functionalized with a peptide moiety that contains both nuclear export signal (NES) and nuclear localization signal (NLS) sequences. By taking advantage of its small size and great photostability, the functionalized GQDs are used to mimic the actions of nucleus shuttle proteins, especially of those activated during cell apoptotic death, to work as protease-mediated cytoplasm-nucleus shuttles for dynamic monitoring of apoptosis. The resulting construct demonstrates activation of the nuclear pore complex (NPC) of cells, for bidirectional transport between nucleus and cytoplasm. A caspase-3 recognition sequence (DEVD), placed within the NLS/NES peptide, serves as a proteolytic site for activated caspase-3. Upon the induction of apoptosis, the activated caspase-3 cleaves the functional peptide on GQDs resulting in changes of subcellular distribution of GQDs. Such changes can be quantified as a function of time, by the ratios of GQDs photoluminescence in nucleus to that in cytoplasm. As such, the NES-linker-DEVD-linker-NLS peptide enables the GQDs to function as molecular probes for the real-time monitoring of cellular apoptosis.