TAZ, a transcriptional modulator, has a key role in cell proliferation, differentiation and stem cell self-renewal. TAZ activity is regulated by several signalling pathways, including Hippo, GPCR and ...Wnt signalling, but the regulatory mechanisms of TAZ activation are not yet clearly understood. In this report, we show that TAZ is regulated by canonical Wnt signalling during osteogenic differentiation. Wnt3a increases TAZ expression and an inhibitor of GSK3β, a downstream effector of Wnt signalling, induces TAZ. Wnt3a facilitates the dephosphorylation of TAZ, which stabilises TAZ and prevents it from binding 14-3-3 proteins, thus inducing the nuclear localisation of TAZ. Dephosphorylation of TAZ occurs via PP1A, and depletion of PP1A blocks Wnt3a-induced TAZ stabilisation. Wnt3a-induced TAZ activates osteoblastic differentiation and siRNA-induced TAZ depletion decreases Wnt3a-induced osteoblast differentiation. Taken together, these results show that TAZ mediates Wnt3a-stimulated osteogenic differentiation through PP1A, suggesting that the Wnt signal regulates the Hippo pathway.
Several studies have shown physiological functions of interleukin (IL)-32, a novel cytokine. However, the role of IL-32 in cancer development has not been reported. In this study, we showed that ...IL-32γ inhibited tumor growth in IL-32γ-overexpressing transgenic mice inoculated with melanoma as well as colon tumor growth in xenograft nude mice inoculated with IL-32γ-transfected colon cancer cells (SW620). The inhibitory effect of IL-32γ on tumor growth was associated with the inhibition of constitutive activated nuclear transcription factor-κB (NF-κB) and of signal transducer and activator of transcription 3 (STAT3). The expression of antiapoptotic, cell proliferation and tumor-promoting genes (bcl-2, X-chromosome inhibitor of apoptosis protein (IAP), cellular IAP and cellular FADD-like IL-1β-converting enzyme-inhibitory protein, cyclin D), cyclin-dependent kinase 4, cycolooxygenase-2 and inducible nitric oxide synthase was decreased, whereas the expression of apoptotic target genes (caspase-3 and -9, bax) increased. In tumor, spleen and blood, the number of cytotoxic CD8(+) T cells and CD57(+) natural killer cells and the levels of IL-10 increased, but that of tumor necrosis factor-α (TNF-α), IL-1β and IL-6 decreased. We also found that forced overexpression of IL-32γ inhibited colon cancer cell (SW620 and HCT116) growth accompanied with the inhibition of activated NF-κB and STAT3 in vitro. In addition, when IL-32γ was knocked down by small interfering RNA (siRNA) or neutralized with an anti-IL-32γ antibody, IL-32γ-induced colon cancer cell growth inhibition, the IL-32γ-induced decrease of TNF-α, IL-1 and IL-6 production, and the increase of IL-10 production were abolished. However, siRNA of NF-κB and STAT3 augmented IL-32γ-induced colon cancer cell growth inhibition. These findings indicate significant pathophysiological roles of IL-32γ in cancer development.
Summary
Background
Chronic low back pain (CLBP) is one of the most common musculoskeletal disorders, and thus effective treatments are required. Recently, a real horseback riding has been reported to ...be beneficial for the patients. However, it has some limitations, such as limited approaches and safety issues.
Objective
The purpose of this study was to investigate the effect of horse simulator riding on back pain, body composition and trunk strength in the patients with CLBP.
Participants
Forty‐seven men with CLBP (mean age 20.55 ± 1.38 years) were randomly divided into a control group (n = 23) and a horse simulator riding group (n = 24), and visual analogue scale (VAS), body composition and isokinetic trunk strength were measured after 8 weeks for which subjects in a horse simulator riding group had performed the horse simulator exercise (HSE).
Results
Horse simulator exercise significantly reduced pain scores of VAS and enhanced isokinetic torques of trunk at 30 and 90°/s. There were also significantly increased muscle mass and decreased fat mass in horse simulator riding group.
Conclusion
It can be inferred that HSE may be helpful in relief of back pain and recovery of back function through developing trunk strength and balancing the ratio of trunk flexor/extensor muscles.
Linked Comment: Citrome Int J Clin Pract 2014; 68: 931.
Cells establish and sustain structural and functional integrity of the genome to support cellular identity and prevent malignant transformation. In this review, we present a strategic overview of ...epigenetic regulatory mechanisms including histone modifications and higher order chromatin organization (HCO) that are perturbed in breast cancer onset and progression. Implications for dysfunctions that occur in hormone regulation, cell cycle control, and mitotic bookmarking in breast cancer are considered, with an emphasis on epithelial‐to‐mesenchymal transition and cancer stem cell activities. The architectural organization of regulatory machinery is addressed within the contexts of translating cancer‐compromised genomic organization to advances in breast cancer risk assessment, diagnosis, prognosis, and identification of novel therapeutic targets with high specificity and minimal off target effects.
Aim: Individuals requiring insulin therapy for type 2 diabetes often require escalation of their regimen to achieve glycaemic control. Optimal management strategies for uncontrolled type 2 diabetes ...would improve glycaemic control without hypoglycaemia and weight gain. This study compared the efficacy and tolerability of adding sitagliptin, an oral dipeptidyl peptidase‐4 inhibitor, and an up to 20% increase in insulin dose in patients with uncontrolled type 2 diabetes on insulin therapy.
Methods: We conducted a 24‐week, randomized, active‐competitor, parallel‐group study in subjects with uncontrolled type 2 diabetes haemoglobin A1c (HbA1c) = 7.5–11% currently using insulin therapy. Subjects were randomly assigned to either the sitagliptin adding (100 mg daily, n = 70) or an insulin‐increasing arm (≥10% at week 12 and ≥10% at week 24, n = 70) while continuing other medications.
Results: Average baseline HbA1c was 9.2% in both groups. HbA1c decreased more at 24 weeks in the sitagliptin adding than the insulin‐increasing arm (−0.6 ± 0.1% vs. −0.2 ± 0.1%, p < 0.01). Insulin was increased by 25% at 24 weeks in the insulin‐increasing group. Hypoglycaemic events were less common and less severe in sitagliptin adding arm than insulin‐increasing arm (7.0 vs. 14.3 events per patient‐year, p < 0.05). Weight was stable in the sitagliptin adding subjects (68.6 ± 11.6 vs. 68.1 ± 11.4 kg) but increased in the insulin‐increasing subjects (66.2 ± 10.6 vs. 67.4 ± 9.7 kg, p < 0.05). Other adverse events occurred at similar rates in both arms.
Conclusions: Compared to a 25% increase in insulin dose, adding sitagliptin to an insulin‐based regimen was more effective at lowering HbA1c and associated with less hypoglycaemia and weight gain over 24 weeks. Clinical trial number: NCT01100125.
The aim of this study is to investigate the prognostic role of phosphorylated AMP-activated protein kinase (pAMPK) in surgically resected non-small-cell lung cancer (NSCLC).
Immunohistochemical ...staining of pAMPK was carried out on tissue microarrays containing 463 samples obtained from patients with NSCLC and correlated with clinicopathological characteristics and survival.
pAMPK expression levels were significantly higher in never smokers versus former smokers versus current smokers (P=0.045). A positive pAMPK expression was associated with increased overall survival (OS) and recurrence-free survival (RFS) (P=0.0009 and P=0.0007, respectively). OS and RFS were statistically superior in pAMPK-positive than in pAMPK-negative patients with adenocarcinoma (ADC; median OS: 5.6 and 4.2 years, respectively, P=0.0001; median RFS: 5.0 and 2.4 years, respectively, P=0.001), whereas they were similar in those patients with squamous cell carcinoma. Multivariate analysis confirmed that pAMPK positivity was associated with OS hazard ratio (HR) = 0.574, 95% confidence interval (CI) 0.418–0.789, P = 0.0006) and RFS (HR = 0.608, 95% CI 0.459–0.807, and P = 0.0006), independent of clinical covariates.
High pAMPK expression levels are associated with increased survival in patients with NSCLC, especially those with ADC. Our results support further evaluation of AMP-activated protein kinase as a potential prognostic and therapeutic target for lung cancer.
Background: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose ...isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We conducted a phase III randomized trial of low-dose isotretinoin versus placebo in early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival. Methods: We randomly assigned 1190 patients who had been treated for stage I or II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years. The patients were monitored for up to 4 more years. Survival was analyzed by the Kaplan–Meier method, and Cox proportional hazards models were used for multivariable survival analysis. All statistical tests were two-sided. Results: Isotretinoin did not statistically significantly reduce the rate of second primary tumors (hazard ratio HR = 1.06, 95% confidence interval CI = 0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared with placebo in patients with early-stage HNSCC. Current smokers had a higher rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to 2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of death from any cause for current smokers versus never smokers was 2.51 (95% CI = 1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI = 1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung (31%), oral cavity (17%), larynx (8%), and pharynx (5%). Conclusions: Low-dose isotretinoin was not effective in reducing the rate of second primary tumors or death or smoking-related disease. Smoking statistically significantly increased the rate of second primary tumors and death. Ongoing trials are testing higher doses of isotretinoin as part of combination bioadjuvant therapeutic methods for patients with locally advanced HNSCC.
A metal-organic framework (MOF), copper trimesate (Cu3(BTC)2), was selectively functionalized with aminopropylisooctyl polyhedral oligomeric silsesquioxane (O-POSS) to make the external surface of ...Cu3(BTC)2 hydrophobic and thereby enhance the stability of the material against humidity. POSS modification was also successfully applied to other MOFs such as MOF-74 and MIL-100.
Schizophrenia and nicotine addiction are both highly heritable phenotypes. Because individuals with schizophrenia have a higher rate of smoking than those in the general population, one could ...hypothesize that genes associated with smoking might be overrepresented in schizophrenia and thus help explain their increased smoking incidence. Although a number of genes have been proposed to explain the increased smoking risk in schizophrenia, none of them have been consistently linked to smoking and schizophrenia, and thus difficult to explain the increased smoking in schizophrenia. A functional smoking‐related nicotinic acetylcholine receptor α5 subunit gene (CHRNA5) nonsynonymous single nucleotide polymorphism (SNP) rs16969968 (Asp398Asn) has recently been discovered and replicated. As such, we tested whether this variant contributes to smoking in schizophrenia in a sample of 313 schizophrenia patients and 525 controls. The Asp398Asn risk allele is significantly associated with smoking severity independently in schizophrenia patient smokers (P = 0.001) and control smokers (P = 0.029). Furthermore, the same risk allele is significantly associated with schizophrenia in both Caucasian (P = 0.022) and African‐American (P = 0.006) nonsmoker schizophrenia patients compared with control nonsmokers. Intriguingly, this SNP was not significantly associated with smoking status (smokers vs. nonsmokers) in either schizophrenia patients or controls. Therefore, our study identifies a genetic variant that is simultaneously linked to smoking and schizophrenia in the same cohort, but whether this SNP contributes to the increased smoking prevalence in schizophrenia patients requires additional studies.
Endometriosis is the most common cause of pelvic pain and affects an estimated 5 million women in the US. The biologically active estrogen estradiol (E
2) is the best-defined mitogen for the growth ...and inflammation processes in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Progesterone and progestins may relieve pain by limiting growth and inflammation in endometriosis but a portion of patients with endometriosis and pelvic pain do not respond to treatment with progestins. Moreover, progesterone-induced molecular changes in the eutopic (intrauterine) endometrial tissue of women with endometriosis are either blunted or undetectable. These in vivo observations are indicative of resistance to progesterone action in endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptors (PRs) and the lack of the PR isoform named progesterone receptor B (PR-B). In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factor(s). These unknown factor(s) act on neighboring epithelial cells to induce the expression of the enzyme 17β-hydroxysteriod dehydrogenase type 2 (17β-HSD-2), which metabolizes the biologically active estrogen E
2 to estrone (E
1). In endometriotic tissue, progesterone does not induce epithelial 17β-HSD-2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate 17β-HSD-2 may be due to the lack of PR-B and very low levels of progesterone receptor A (PR-A) observed in vivo in endometriotic tissue. The end result is deficient metabolism of E
2 in endometriosis giving rise to high local concentrations of this local mitogen. The cellular and molecular mechanisms underlying progesterone resistance and failure to metabolize E
2 in endometriosis are reviewed.
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