Acquisition of temozolomide (TMZ) resistance is a major factor leading to the failure of glioblastoma (GBM) treatment. The exact mechanism by which GBM evades TMZ toxicity is not always related to ...the expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), and so remains unclear. In this study, TMZ-resistant variants derived from MGMT-negative GBM clinical samples and cell lines were studied, revealing there to be increased specificity protein 1 (Sp1) expression associated with reduced reactive oxygen species (ROS) accumulation following TMZ treatment. Analysis of gene expression databases along with cell studies identified the ROS scavenger superoxide dismutase 2 (SOD2) as being disease-related. SOD2 expression was also increased, and it was found to be co-expressed with Sp1 in TMZ-resistant cells. Investigation of the SOD2 promoter revealed Sp1 as a critical transcriptional activator that enhances SOD2 gene expression. Co-treatment with an Sp1 inhibitor restored the inhibitory effects of TMZ, and decreased SOD2 levels in TMZ-resistant cells. This treatment strategy restored susceptibility to TMZ in xenograft animals, leading to prolonged survival in an orthotopic model. Thus, our results suggest that Sp1 modulates ROS scavengers as a novel mechanism to increase cancer malignancy and resistance to chemotherapy. Inhibition of this pathway may represent a potential therapeutic target for restoring treatment susceptibility in GBM.
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•Sp1 levels increase in TMZ resistance of MGMT-deficient cells.•Sp1 upregulation enables GBM cells to escape TMZ-mediated toxicity.•Sp1 is a critical transcriptional activator to enhance SOD2 gene expression.•Sp1-SOD2 pathway raises GBM malignancy and chemotherapy resistance.•Inhibition of Sp1-SOD2 pathway restores treatment susceptibility in GBM.
Extracapsular dissection (ECD) is thought to be effective in treating benign tumors and minimally invasive. Nonetheless, its application and feasibility in treating benign parapharyngeal space (PPS) ...tumor, the neoplasm located in the complex anatomical space, have never been investigated. The aim of this study is to evaluate the utility and efficacy of transcervical ECD in treating benign PPS tumors. From 1996 to 2009, 54 patients with PPS tumors were treated by the designated surgeon. Excluding nine patients who were initially regarded as the potential candidates for ECD treatment but failed to meet the inclusion criteria, 22 patients who received the procedure were retrospectively analyzed. In 22 enrolled patients, 10 had pleomorphic adenoma while 6 had neurilemmoma. There were 13 PPS tumors located in the prestyloid space and 9 in the poststyloid space. The median volume of PPS tumors was 22.6 cm
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, and the median distance from tumor to skull base was 2.3 cm. The median length of incision was 4.5 cm with the ECD intervention. No major intra- or post-operative complications were noted and post-operative courses were unremarkable in long-term follow-up. This study demonstrates that ECD is an effective and safe treatment for selected benign PPS tumors. It has a favorable clinical outcome and an acceptable aesthetic result, and can be performed in a minimally invasive fashion. Therefore, it is suggested that ECD be included in the treatment modalities of benign PPS tumors.
Background: Metatarsalgia due to increased plantar pressure under the metatarsal head (MTH) is often seen with wearing high-heeled shoes. However, the concomitant soft tissue strain has not been well ...discussed. The objective of our study was to explore the standing plantar pressure and corresponding soft tissue strain under the metatarsal heads (MTHs) with different heel heights. Materials and Methods: Twenty-one healthy subjects (10 male and 11 female) participated. The plantar pressure and soft-tissue thicknesses were measured simultaneously with a load cell and a 10-MHz linear-array ultrasound (US) transducer respectively. The changes in plantar pressure and soft tissue strain under the MTHs were analyzed for different heel heights. Results: As hypothesized, plantar metatarsal pressure significantly increased and shifted to the first and second MTHs with increasing heel height from 2 cm to 4 cm(p < 0.05). However, the change in soft tissue strain under the medial forefoot became insignificant when the heel height was greater than 2 cm (p = 0.473 and 0.517). Conclusions: Increased heel height resulted in increasing medial forefoot loading pressure; however, the soft tissue exhibited stationary compressibility when the heel height was greater than 2 cm. Clinical Relevance: Our finding provides an understanding of the biomechanical changes with wearing high-heeled shoes and suggests possible strategies to reducing discomfort and risk of injury, such as limiting heel height to no greater than 2 cm and using medial padding under MTHs.
There is a distinct lack of knowledge on the prevalence of skin disorders in Tuvalu. The aim of the current study was to assess the prevalence of cutaneous diseases and to evaluate access ...dermatological care in Tuvalu. Cutaneous disorders in the people of Tuvalu between 2009 and 2012 were examined. The most common skin conditions were eczema/dermatitis, superficial fungal infections, impetigo, carbuncles, furuncles, folliculitis, acne, scabies, warts and keloids. Infrequent skin conditions included infectious granulomatous disease, albinism, actinic keratosis, skin cancer, cutaneous lupus erythematosus and mammary Paget's disease, which required medical attention. This is the first epidemiological report on skin disorders in the southwest Pacific Island, Tuvalu.
Summary The objective of this study was to clarify the expression and epigenetic regulation of DLEC1 , a candidate tumor suppressor gene (TSG) located at 3p21.3-p22, in oral squamous cell carcinoma ...(OSCC) and the clinical relevance of its down-expression. Quantitative RT-PCR was performed to exam the expression level of DLEC1 in matched OSCC and normal oral samples from 57 prospectively enrolled patients (with additional matched leukoplakia samples from 9 patients). We defined DLEC1 down-expression as a 2-fold decrease in expression of DLEC1 between normal tissues and tumors, and determined its correlation with clinical characteristics. Methylation-specific PCR (MSP) and bisulfite sequencing were used to evaluate the promoter methylation status of DLEC1 in 19 OSCC, 19 oral leukoplakia (OL), and 17 normal oral tissues. A statistically significant association between DLEC1 down-expression and invasive depth of OSCC was observed ( P = 0.026). Besides, expression of DLEC1 decreased sequentially from normal tissues to OL and then to OSCC ( P < 0.05), which was inversely correlated with methylation status of the DLEC1 promoter. Promoter methylation of DLEC1 increased progressively among normal tissues, OL, and OSCC, as revealed by MSP, and confirmed by sequencing. Treatment of OSCC cell lines with 5-aza-2′-deoxycytidine (5-Aza-dC) reversed the methylation and restored DLEC1 expression. Our results demonstrating that down-expression and promoter methylation of DLEC1 increased from normal tissues to premalignancies and then to malignancies. Furthermore, its transcriptional repression is associated with the depth of tumor invasion.
Background Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the ...regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear. Methodology and Principal Findings In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3sigma isoform. Knockdown of 14-3-3sigma with siRNA reduced embryonic stem cell proliferation, while only 14-3-3sigma transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3sigma was abrogated by beta-catenin knockdown, we investigated the influence of 14-3-3sigma overexpression on beta-catenin/GSK-3beta. 14-3-3sigma bound GSK-3beta and increased GSK-3beta phosphorylation in a PI-3K/Akt-dependent manner. It disrupted beta-catenin binding by the multiprotein destruction complex. 14-3-3sigma overexpression attenuated beta-catenin phosphorylation and rescued the decline of beta-catenin induced by retinoid acid. Furthermore, 14-3-3sigma enhanced Wnt3a-induced beta-catenin level and GSK-3beta phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3beta/14-3-3sigma binding. Significance Our findings show for the first time that 14-3-3sigma plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3beta and enhancing Wnt-signaled GSK-3beta inactivation. 14-3-3sigma is a novel target for embryonic stem cell expansion.
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