MicroRNA-17 Modulates Regulatory T Cell Function by Targeting Co-regulators of the Foxp3 Transcription Factor.

Regulatory T (Treg) cells are important in maintaining self-tolerance and immune homeostasis. The Treg cell transcription factor Foxp3 works in concert with other co-regulatory molecules, including Eos, to determine the transcriptional signature and characteristic suppressive phenotype of Treg cells. Here, we report that the inflammatory cytokine interleukin-6 (IL-6) actively repressed Eos expression through microRNA-17 (miR-17). miR-17 expression increased in Treg cells in the presence of IL-6, and its expression negatively correlated with that of Eos. Treg cell suppressive activity was diminished upon overexpression of miR-17 in vitro and in vivo, which was mitigated upon co-expression of an Eos mutant lacking miR-17 target sites. Also, RNAi of miR-17 resulted in enhanced suppressive activity. Ectopic expression of miR-17 imparted effector-T-cell-like characteristics to Treg cells via the de-repression of genes encoding effector cytokines. Thus, miR-17 provides a potent layer of Treg cell control through targeting Eos and additional Foxp3 co-regulators.

Role of SH3GLB1 in the regulation of CD133 expression in GBM cells.

BACKGROUND: Glioblastoma (GBM), a malignant brain tumor, has poor survival outcomes due to recurrence or drug resistance. We found that SH3GLB1 is a crucial factor for cells to evade temozolomide (TMZ) cytotoxicity through autophagy-mediated oxidative phosphorylation, which is associated with CD133 levels. Therefore, we propose that SH3GLB1 participate in the impact on tumor-initiating cells (TICs). METHODS: The parental, the derived resistant cell lines and their CD133+ cells were used, and the levels of the proteins were compared by western blotting. Then RNA interference was applied to observe the effects of the target protein on TIC-related features. Finally, in vitro transcription assays were used to validate the association between SH3GLB1 and CD133. RESULTS: The CD133+ cells from resistant cells with enhanced SH3GLB1 levels more easily survived cytotoxic treatment than those from the parental cells. Inhibition of SH3GLB1 attenuated frequency and size of spheroid formation, and the levels of CD133 and histone 4 lysine 5 (H4K5) acetylation can be simultaneously regulated by SH3GLB1 modification. The H4K5 acetylation of the CD133 promoter was later suggested to be the mediating mechanism of SH3GLB1. CONCLUSIONS: These data indicate that SH3GLB1 can regulate CD133 expression, suggesting that the protein plays a crucial role in TICs. Our findings on the effects of SH3GLB1 on the cells will help explain tumor resistance formation.

Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation.

BACKGROUND: Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. METHODS: RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. RESULTS: Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid ß-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. CONCLUSION: Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.

Reduction in Phosphoribulokinase Amount and Re-Routing Metabolism in Chlamydomonas reinhardtii CP12 Mutants.

The chloroplast protein CP12 is involved in the dark/light regulation of the Calvin-Benson-Bassham cycle, in particular, in the dark inhibition of two enzymes: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK), but other functions related to stress have been proposed. We knocked out the unique CP12 gene to prevent its expression in Chlamydomonas reinhardtii (ΔCP12). The growth rates of both wild-type and ΔCP12 cells were nearly identical, as was the GAPDH protein abundance and activity in both cell lines. On the contrary, the abundance of PRK and its specific activity were significantly reduced in ΔCP12, as revealed by relative quantitative proteomics. Isolated PRK lost irreversibly its activity over-time in vitro, which was prevented in the presence of recombinant CP12 in a redox-independent manner. We have identified amino acid residues in the CP12 protein that are required for this new function preserving PRK activity. Numerous proteins involved in redox homeostasis and stress responses were more abundant and the expressions of various metabolic pathways were also increased or decreased in the absence of CP12. These results highlight CP12 as a moonlighting protein with additional functions beyond its well-known regulatory role in carbon metabolism.

Phase I Dose-Escalation Study of SCB01A, a Microtubule Inhibitor with Vascular Disrupting Activity, in Patients with Advanced Solid Tumors.

LESSONS LEARNED: SCB01A is a novel microtubule inhibitor with vascular disrupting activity. This first-in-human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity. SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity. BACKGROUND: SCB01A, a novel microtubule inhibitor, has vascular disrupting activity. METHODS: In this phase I dose-escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m2 to the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). SCB01A-induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints. RESULTS: Treatment-related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m2 cohort; grade 3 gastric hemorrhage in the 6.5 mg/m2 cohort; grade 2 thromboembolic event in the 24 mg/m2 cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m2 cohort. The MTD was 24 mg/m2 , and average half-life was ~2.5 hours. The area under the curve-dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A-induced neurotoxicity was reversible in vitro. CONCLUSION: The MTD of SCB01A was 24 mg/m2 every 21 days; it is safe and tolerable in patients with solid tumors.

Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma.

Glioblastoma is the most common primary malignant brain tumor that is usually considered fatal even with treatment. This is often a result for tumor to develop resistance. Regarding the standard chemotherapy, the alkylating agent temozolomide is effective in disease control but the recurrence will still occur eventually. The mechanism of the resistance is various, and differs in terms of innate or acquired. To date, aberrations in O6-methylguanine-DNA methyltransferase are the clear factor that determines drug susceptibility. Alterations of the other DNA damage repair genes such as DNA mismatch repair genes are also known to affect the drug effect. Together these genes have roles in the innate resistance, but are not sufficient for explaining the mechanism leading to acquired resistance. Recent identification of specific cellular subsets with features of stem-like cells may have role in this process. The glioma stem-like cells are known for its superior ability in withstanding the drug-induced cytotoxicity, and giving the chance to repopulate the tumor. The mechanism is complicated to administrate cellular protection, such as the enhancing ability against reactive oxygen species and altering energy metabolism, the important steps to survive. In this review, we discuss the possible mechanism for these specific cellular subsets to evade cancer treatment, and the possible impact to the following treatment courses. In addition, we also discuss the possibility that can overcome this obstacle.

A multi-mode Wnt- and stemness-regulatory module dictated by FOXM1 and ASPM isoform I in gastric cancer.

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer mortality globally and a molecularly heterogeneous disease. Identifying the driver pathways in GC progression is crucial to improving the clinical outcome. Recent studies identified ASPM (abnormal spindle-like microcephaly-associated) and FOXM1 (Forkhead box protein M1) as novel Wnt and cancer stem cell (CSC) regulators; their pathogenetic roles and potential crosstalks in GC remain unclarified. METHODS: The expression patterns of ASPM isoforms and FOXM1 were profiled in normal gastric epithelial and GC tissues. The functional roles of ASPM and FOXM1 in Wnt activity, cancer stemness and GC progression, and the underlying signaling processes were investigated. RESULTS: Approximately one third of GC cells upregulate the expression of ASPM isoform I (ASPMiI) in their cytoplasm; the tumors with a high ASPMiI positive score (≥ 10%) are associated with a poor prognosis of the patients. Mechanistically, the molecular interplay among FOXM1, ASPMiI and DVL3 was found to converge on ß-catenin to control the Wnt activity and the stemness property of GC cells. This multi-mode Wnt-regulatory module serves to reinforce Wnt signals in CSCs by transcriptional regulation (FOXM1-ASPM), protein-protein interactions (ASPMiI-DVL3-ß-catenin), and nuclear translocation (FOXM1-ß-catenin). CONCLUSIONS: This study illuminates a novel Wnt- and stemness-regulatory mechanism in GC cells and identifies a novel subset of FOXM1highASPMiIhigh GC with potential to guide Wnt- and stemness-related diagnostics and therapies.

New Insights Into Oral Squamous Cell Carcinoma: From Clinical Aspects to Molecular Tumorigenesis.

Oral squamous cell carcinoma (SCC) is a prevalent malignant disease worldwide, especially so in Taiwan. Early- or even preclinical-stage detection is critical for reducing morbidity and mortality from oral SCC. Epidemiological and genome association studies are useful for identifying clinicopathological risk factors for preventive, diagnostic, and therapeutic approaches of oral SCC. For advanced oral SCC, effective treatments are critical to prolonging survival and enhancing quality of life. As oral SCC is characteristic of regional invasion with lymph node metastases, understanding the aggressive features of oral SCC, particularly in lymphangiogenesis, is essential for determining effective treatments. Emerging evidence has demonstrated that the tumor microenvironment (TME) plays a pivotal role in tumor growth, invasion, and metastases. Recent clinical successes in immune checkpoint inhibitors either alone or combined with chemotherapy have also supported the therapeutic value of immunotherapy in oral SCC. This review summarizes critical advances in basic knowledge of oral SCC from the perspective of clinicopathological risk factors, molecular tumorigenesis, and the TME. We also highlight our recent investigations on the microbiome, genome association studies, lymphangiogenesis, and immunomodulation in oral SCC. This review may provide new insights for oral SCC treatment by systematically interpreting emerging evidence from various preclinical and clinical studies.

Establishment of a Genome Editing Tool Using CRISPR-Cas9 in Chlorella vulgaris UTEX395.

To date, Chlorella vulgaris is the most used species of microalgae in the food and feed additive industries, and also considered as a feasible cell factory for bioproducts. However, the lack of an efficient genetic engineering tool makes it difficult to improve the physiological characteristics of this species. Therefore, the development of new strategic approaches such as genome editing is trying to overcome this hurdle in many research groups. In this study, the possibility of editing the genome of C. vulgaris UTEX395 using clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) has been proven to target nitrate reductase (NR) and adenine phosphoribosyltransferase (APT). Genome-edited mutants, nr and apt, were generated by a DNA-mediated and/or ribonucleoprotein (RNP)-mediated CRISPR-Cas9 system, and isolated based on the negative selection against potassium chlorate or 2-fluoroadenine in place of antibiotics. The null mutation of edited genes was demonstrated by the expression level of the correspondent proteins or the mutation of transcripts, and through growth analysis under specific nutrient conditions. In conclusion, this study offers relevant empirical evidence of the possibility of genome editing in C. vulgaris UTEX395 by CRISPR-Cas9 and the practical methods. Additionally, among the generated mutants, nr can provide an easier screening strategy during DNA transformation than the use of antibiotics owing to their auxotrophic characteristics. These results will be a cornerstone for further advancement of the genetics of C. vulgaris.

SOD2 Enhancement by Long-Term Inhibition of the PI3K Pathway Confers Multi-Drug Resistance and Enhanced Tumor-Initiating Features in Head and Neck Cancer.

The phosphoinositide-3-kinase (PI3K) pathway has widely been considered as a potential therapeutic target for head and neck cancer (HNC); however, the application of PI3K inhibitors is often overshadowed by the induction of drug resistance with unknown mechanisms. In this study, PII3K inhibitor resistant cancer cells were developed by prolonged culturing of cell lines with BEZ235, a dual PI3K and mammalian target of rapamycin (mTOR) inhibitor. The drug resistant HNC cells showed higher IC50 of the proliferation to inhibitors specifically targeting PI3K and/or mTOR, as compared to their parental cells. These cells also showed profound resistance to drugs of other classes. Molecular analysis revealed persistent activation of phosphorylated AKT at threonine 308 in the drug resistant cells and increased expression of markers for tumor-initiating cells. Interestingly, increased intra-cellular ROS levels were observed in the drug resistant cells. Among anti-oxidant molecules, the expression of SOD2 was increased and was associated with the ALDH-positive tumor-initiating cell features. Co-incubation of SOD inhibitors and BEZ235 decreased the stemness feature of the cells in vitro, as shown by results of the spheroid formation assay. In conclusion, dysregulation of SOD2 might contribute to the profound resistance to PI3K inhibitors and the other drugs in HNC cells.

Using World Health Organization Disability Assessment Schedule 2.0 in people with schizophrenia: a 4-year follow-up.

Little is known about the changes of people with schizophrenia disability in Taiwan who receive routine treatments under the current mental healthcare system. The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) was used to assess and track changes in the degree of disability in people with schizophrenia before and after 4 years of follow-up. Data on 4497 people with schizophrenia were acquired from the Taiwan Data Bank of Persons with Disability. The WHODAS 2.0 was used for disability assessment, and the chi-square test, logistic regression and generalised estimating equations were adopted for statistical analysis. People with schizophrenia exhibited improvement in cognition, mobility and participation among the six domains as well as in the overall score. The degree of disability in all domains remained mild to moderate among people aged 18-64 years; the degree of disability in cognition declined from moderate to severe among patients aged ≥65 years. The degree of disability in all domains remained mild to moderate among people with mild to moderate impairment; among those with severe impairment, the degree of disability in the domains of cognition and life activities declined from moderate to severe and the degree of disability in the domain of mobility declined from mild to moderate. Community-dwelling patients exhibited less degree of disability in all domains than their institutionalised peers. Early detection and treatment and an emphasis on communication and social problem-solving skills in rehabilitation programmes are recommended for people with schizophrenia.

Enrichment of superoxide dismutase 2 in glioblastoma confers to acquisition of temozolomide resistance that is associated with tumor-initiating cell subsets.

BACKGROUND: Intratumor subsets with tumor-initiating features in glioblastoma are likely to survive treatment. Our goal is to identify the key factor in the process by which cells develop temozolomide (TMZ) resistance. METHODS: Resistant cell lines derived from U87MG and A172 were established through long-term co-incubation of TMZ. Primary tumors obtained from patients were maintained as patient-derived xenograft for studies of tumor-initating cell (TIC) features. The cell manifestations were assessed in the gene modulated cells for relevance to drug resistance. RESULTS: Among the mitochondria-related genes in the gene expression databases, superoxide dismutase 2 (SOD2) was a significant factor in resistance and patient survival. SOD2 in the resistant cells functionally determined the cell fate by limiting TMZ-stimulated superoxide reaction and cleavage of caspase-3. Genetic inhibition of the protein led to retrieval of drug effect in mouse study. SOD2 was also associated with the TIC features, which enriched in the resistant cells. The CD133+ specific subsets in the resistant cells exhibited superior superoxide regulation and the SOD2-related caspase-3 reaction. Experiments applying SOD2 modulation showed a positive correlation between the TIC features and the protein expression. Finally, co-treatment with TMZ and the SOD inhibitor sodium diethyldithiocarbamate trihydrate in xenograft mouse models with the TMZ-resistant primary tumor resulted in lower tumor proliferation, longer survival, and less CD133, Bmi-1, and SOD2 expression. CONCLUSION: SOD2 plays crucial roles in the tumor-initiating features that are related to TMZ resistance. Inhibition of the protein is a potential therapeutic strategy that can be used to enhance the effects of chemotherapy.

Accuracy of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) score as an objective assessment tool for predicting return-to-work status after head and neck cancer in male survivors.

PURPOSE: The objective of this nationwide study in Taiwan was to predict work participation by using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) score as an objective assessment tool. METHOD: Data from between July 2012 and July 2017 regarding 1206 male head and neck cancer (HNC) survivors with disability aged < 50 years were obtained from the Taiwan Data Bank of Persons with Disability (TDPD). Demographic data and the WHODAS 2.0 scores were analyzed to compare employment statuses among HNC survivors. RESULTS: The WHODAS 2.0 scores in all the domains were lower in unemployed than in employed HNC survivors (p < 0.001). The receiver operating characteristic (ROC) curve revealed that the summary WHODAS 2.0 score (area under curve > 0.8) was an extremely accurate predictive tool. Binary logistic regression revealed that the severity levels of impairment and standardized WHODAS 2.0 summary scores less than the cutoff value (27.81) were predictors for the return-to-work (RTW) status of HNC survivors with disability in the working age group. CONCLUSIONS: The WHODAS 2.0 score is an objective quantitative assessment tool for evaluating the RTW possibility among these patient groups.

[Transfection of Leishmania tropica with green fluorescent protein (gfp) gene and investigation of the in vitro drug effect]. / Leishmania tropica'nin yesil floresan protein (gfp) geni ile transfeksiyonu ve in vitro ilaç etkisinin arastirilmasi.

Cutaneous leishmaniasis (CL) is a parasitic disease transmitted by vector sand flies Phlebotomus and Lutzomyia. This disease is characterized by long time non-healing skin lesions, and caused by Leishmania species. CL is the most common infection in Eastern and Southeastern Anatolia in Turkey and L.tropica is known as the main agent of the disease. Number of cases is increasing in our country in time because of malnutrition, migration, travel, low socioeconomic level and ecological changes. For the treatment, the pentavalent antimonials are often used as intralesionally for many years, and it was reported that resistant cases have increased in recent years. New treatment methods and anti-Leishmanial activity of new agents have been investigated because of side effects, resistance development and toxic reactions of the present drugs. These studies are first carried out in vitro and afterwards with in vivo experimental animal models. Reporter gene technology has been used to investigate a variety of purposes like biological events in microorganisms and the efficacy and resistance of drugs in recent years. The major areas that green fluorescent protein (gfp) used are that they can be incorporated into different genes to determine the amount of expression of these genes in different organisms and can be used as markers in living cells. Especially gfp gene, which encodes the green fluorescent protein, is widely used nowadays. Gene-based assays have several advantages like being easy to follow-up, inexpensive and have improved biosecurity. The aim of the present study was to perform the transfection of L.tropica with "enhanced gfp (egfp)" and in vitro usefulness of gfp-transfectants as a drug screening model in comparison to the conventional methods. Promastigotes of L.tropica were transfected with p6.5/egfp by electroporation and selected for tunicamycin-resistance as previously described. L.tropica promastigotes transfected with gfp and in vitro effect of meglumine animoniate was assessed using different methods such as fluorescence microscopy, fluorometer and XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxyanilide) assay. The use of gfp-transfected Leishmania strains was found more rapid and more sensitive by fluorescent microscopy and fluorometry than conventional assays for the evaluation of potential anti-leishmanial agents. Consequently, stable gfp-transfected Leishmania species will be used in vitro and in vivo for screening of anti-leishmanial drugs and vaccine development as well as for understanding the biology of the host-parasite interactions at the cellular level. As a result ot this study, gfp transfected model using a Turkish L.tropica isolate was established to be used in further studies.

Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 expression enhances head and neck squamous cell carcinoma metastasis via up-regulation of fibronectin.

Epidermal growth factor receptor (EGFR) activation is a major cause of metastasis in such cancers as head and neck squamous cell carcinoma (HNSCC); however, whether the metabolic enzyme, pyruvate dehydrogenase kinase 1 (PDK1), mediates EGF-enhanced HNSCC metastasis remains unclear. Of interest, we found that EGF induced PDK1 expression in HNSCC. Tumor cell transformation induced by EGF was repressed by PDK1 knockdown, and the down-regulation of PDK1 expression or inhibition of its activity significantly blocked EGF-enhanced cell migration and invasion. In addition, depletion of PDK1 impeded EGF-enhanced binding of HNSCC cells to endothelial cells as well as the metastatic seeding of tumor cells in lungs. PDK1 depletion inhibited EGF-induced matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. Furthermore, PDK1 overexpression induced MMP-1, MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. Of interest, depletion of fibronectin inhibited PDK1-enhanced MMP-1-3 and MMP-9 expression as well as Rac1/cdc42 activation and tumor invasion. These results demonstrate that EGF-induced PDK1 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway. Inhibition of PDK1 may be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis.-Hsu, J.-Y., Chang, J.-Y., Chang, K.-Y., Chang, W.-C., Chen B.-K. Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 expression enhances head and neck squamous cell carcinoma metastasis via up-regulation of fibronectin.

Assessment of functioning and disability in patients with schizophrenia using the WHO Disability Assessment Schedule 2.0 in a large-scale database.

Schizophrenia is a common mental disorder characterized by deficits in multiple domains of functioning. This study is arguably the first of its kind in Taiwan to examine, in a multifaceted and objective manner, the disability of patients with schizophrenia and the factors affecting it. A cross-sectional design was adopted to gather data from 24,299 patients with schizophrenia who were listed in the Taiwan Databank of Persons with Disabilities. The level of disability in these patients was measured using the World Health Organization Disability Assessment Schedule 2.0. Statistical analyses were conducted through the χ 2 statistic and Poisson regression. The highest level of disability was in participation and the lowest was in self-care. An analysis of disability in all six domains of functioning on the basis of sex, age, type of residence, and socioeconomic status (SES) showed significant differences (P < 0.05). Significant factors (P < 0.05) affecting disability in these domains were female gender, age, educational attainment, SES, type of residence, and employment status. The overall degree of disability in schizophrenia patients was moderate. Six domains were measured in this study. The degrees of disability in mobility and self-care were mild while cognition, getting along, life activities, and participation were moderate. Moreover, female gender, an age of 45 or older, low educational attainment, middle to low SES, staying at healthcare institutions, and unemployment were crucial factors affecting disability of the participants. Preventive and rehabilitation programs should be developed to delay disability and functional degeneration in schizophrenic patients with these characteristics.

Non-elastic taping, but not elastic taping, provides benefits for patients with knee osteoarthritis: systemic review and meta-analysis.

OBJECTIVE: To determine whether therapeutic taping, which includes elastic (Kinesio tape) and non-elastic (Leukotape) taping, is superior to control taping in improving pain and functions for patients with knee arthritis. To understand whether both elastic and non-elastic taping are beneficial. METHODS: We searched the PubMed and Scopus databases from their earliest record to 31 May 2017 for randomized controlled and cross-over studies that used taping to treat knee osteoarthritis. We extracted the mean differences and SD between baseline and posttreatment for selected outcomes measured in the experimental and control groups for subsequent meta-analyses. RESULTS: In total, 11 studies were included in the review. Of which, five Leukotaping and five Kinesio taping studies involving 379 participants were used in the meta-analysis. PEDro scores of the Leukotaping and Kinesio taping studies were 4.2 and 7.8, respectively. Overall, therapeutic taping exhibited significantly greater pain reduction than control taping with a significant weighted mean difference of 12.8 mm on a 0- to 100-mm visual analogue scale. Compared to control taping, Leukotaping produced a significant weighted mean difference of 11.6 mm regarding pain with a large effect size of 0.89 and I2 = 0%, while Kinesio taping produced a non-significant weighted mean difference of 12.1 mm and I2 = 93%. Leukotaping also exhibited a large and significant standard mean difference of 0.82, while Kinesio taping exhibited a non-significant standard mean difference of 1.34 regarding climbing stairs and stepping. CONCLUSION: Therapeutic taping seemed to be superior to control taping in pain control for knee osteoarthritis. Non-elastic taping, but not elastic taping, provides benefits in pain reduction and functional performance.

Fluid structure interaction simulations of the upper airway in obstructive sleep apnea patients before and after maxillomandibular advancement surgery.

INTRODUCTION: The purpose of this study was to analyze pharyngeal airflow using both computational fluid dynamics (CFD) and fluid structure interactions (FSI) in obstructive sleep apnea patients before and after maxillomandibular advancement (MMA) surgery. The airflow characteristics before and after surgery were compared with both CFD and FSI. In addition, the presurgery and postsurgery deformations of the airway were evaluated using FSI. METHODS: Digitized pharyngeal airway models of 2 obstructive sleep apnea patients were generated from cone-beam computed tomography scans before and after MMA surgery. CFD and FSI were used to evaluate the pharyngeal airflow at a maximum inspiration rate of 166 ml per second. Standard steady-state numeric formulations were used for airflow simulations. RESULTS: Airway volume increased, pressure drop decreased, maximum airflow velocity decreased, and airway resistance dropped for both patients after the MMA surgery. These findings occurred in both the CFD and FSI simulations. The FSI simulations showed an area of marked airway deformation in both patients before surgery, but this deformation was negligible after surgery for both patients. CONCLUSIONS: Both CFD and FSI simulations produced airflow results that indicated less effort was needed to breathe after MMA surgery. The FSI simulations demonstrated a substantial decrease in airway deformation after surgery. These beneficial changes positively correlated with the large improvements in polysomnography outcomes after MMA surgery.

Stress stimuli induce cancer-stemness gene expression via Sp1 activation leading to therapeutic resistance in glioblastoma.

It has been suggested that stress stimuli from the microenvironment maintain a subset of tumor cells with stem-like properties, including drug resistance. Here, we investigate whether Sp1, a stress-responsive factor, regulates stemness gene expression and if its inhibition sensitizes cancer cells to chemotherapy. Hydrogen peroxide- and serum deprivation-induced stresses were performed in glioblastoma (GBM) cells and patient-derived cells, and the effect of the Sp1 inhibitor mithramycin A (MA) on these stress-induced stem cells and temozolomide (TMZ)-resistant cells was evaluated. Sp1 and stemness genes were not commonly overexpressed in clinical GBM samples. However, their expression was highly induced by stress stimuli. Using MA, we demonstrated Sp1 as a critical stemness-related transcriptional factor protecting GBM cells against stress- and TMZ-induced death. Thus, Sp1 inhibition may prevent recurrence of malignant cells persisting after primary therapy.