IntroductionThe objective of this study was to investigate the effects of moderate-to-high intensity Nordic walking (NW) on functional capacity and pain in fibromyalgia (FM).MethodsA total of 67 women with FM were recruited to the study and randomized either to moderate-to-high intensity Nordic Walking (n = 34, age 48 ± 7.8 years) or to a control group engaging in supervised low-intensity walking (LIW, n = 33, age 50 ± 7.6 years). Primary outcomes were the six-minute walk test (6MWT) and the Fibromyalgia Impact Questionnaire Pain scale (FIQ Pain). Secondary outcomes were: exercise heart rate in a submaximal ergometer bicycle test, the FIQ Physical (activity limitations) and the FIQ total score.ResultsA total of 58 patients completed the post-test. Significantly greater improvement in the 6MWT was found in the NW group (P = 0.009), as compared with the LIW group. No between-group difference was found for the FIQ Pain (P = 0.626). A significantly larger decrease in exercise heart rate (P = 0.020) and significantly improved scores on the FIQ Physical (P = 0.027) were found in the NW group as compared with the LIW group. No between-group difference was found for the change in the FIQ total. The effect sizes were moderate for the above mentioned outcomes.ConclusionsModerate-to-high intensity aerobic exercise by means of Nordic walking twice a week for 15 weeks was found to be a feasible mode of exercise, resulting in improved functional capacity and a decreased level of activity limitations. Pain severity did not change over time during the exercise period.Trial registrationClinicaltrials.gov identifier NCT00643006.

The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor-associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase-9 (MMP-9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell-derived tumors. SW480 colon cancer cells exposed to M2-like macrophage-conditioned medium (M2-medium) exhibited increased MMP-9 mRNA, protein expression and gelatinase activity. A similar effect was obtained by the addition of tumor necrosis factor-α (TNFα) and leukotriene D (LTD ). MMP-9 expression and activity were reduced by a TNFα blocking antibody adalimumab and a cysteinyl leukotriene receptor 1 (CysLTR1, the receptor for LTD ) antagonist montelukast. M2-medium also induced changes in the epithelial-mesenchymal transition (EMT) markers E-cadherin, β-catenin, vimentin, and snail in SW480 cells. We also found that both M2-medium and TNFα and LTD induced stabilization/nuclear translocation of β-catenin. Furthermore, we also observed an elongated phenotype that may indicate increased invasiveness, as confirmed in a collagen I invasion assay. M2-medium increased the invasive ability, and a similar effect was also obtained by the addition of TNFα and LTD . The specific MMP inhibitor I or adalimumab and montelukast reduced the number of invasive cells. In conclusion, our findings show that M2-medium enriched in TNFα and LTD promote colon cancer cell invasion via MMP-9 expression and activation and the induction of EMT.

SummaryBackground BRAF and NRAS mutations are frequently found in melanoma tumours, and recently developed BRAF-targeted therapies demonstrate significant clinical benefit. Objectives We sought to investigate the clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort. Methods In total, 237 tumours, mostly metastatic lesions, from 203 patients were screened for mutations in exon 15 of BRAF and exon 2 of NRAS using Sanger sequencing. BRAF and NRAS mutation status was analysed in relation to clinical and histopathological characteristics, and outcome. Results Mutation in BRAF and NRAS was present in 43% (88% V600E, 10% V600K) and 30% (48% Q61K, 40% Q61R) of metastatic melanomas, respectively. We found consistent BRAF and NRAS mutation status in all but one of 27 patients with multiple metastases. BRAF mutation was associated with younger age at primary diagnosis (P = 0Á02). Among patients with distant metastatic melanoma, patients with BRAF-mutant tumours without BRAF inhibitor treatment had inferior survival compared with patients with BRAF inhibitor treatment [hazard ratio (HR) 2Á35, 95% confidence interval (CI) 1Á10-5Á01, P = 0Á03]. We also observed a trend towards better prognosis for patients with wild-type and NRASmutant tumours compared with BRAF V600E-mutant tumours (HR 0Á64, 95% CI 0Á39-1Á04, P = 0Á07; and HR 0Á76, 95% CI 0Á48-1Á21, P = 0Á25, respectively). Conclusions We were able to confirm the effect of BRAF inhibitor treatment in a single clinical institution. The results suggest further that BRAF mutation is a weak prognostic factor but a strong predictive factor and that BRAF-mutant melanoma might constitute one or more distinct subtypes of the disease with certain aetiology and clinical outcome.

Extensive research has demonstrated a tumor‐promoting role of increased WNT5A expression in malignant melanoma. However, very little light has been shed upon how WNT5A expression is up‐regulated in melanoma. A potential regulator of WNT5A expression is the pro‐inflammatory cytokine Interleukin (IL)‐6, which shares the ability of WNT5A to increase melanoma cell invasion. Here, we investigate whether IL‐6 can promote melanoma cell motility through an increased expression of WNT5A. We clearly demonstrate that the WNT5A‐antagonistic peptide Box5 could inhibit IL‐6‐induced melanoma cell migration and invasion. Furthermore, IL‐6 stimulation of the human melanoma cell lines HTB63 and A375 increased the expression of WNT5A in a dose‐dependent manner. To identify the signaling mechanism responsible for this up‐regulation, we explored the involvement of the three main signals induced by IL‐6; STAT3, Akt and ERK 1/2. Of these, only STAT3 was activated by IL‐6 in the melanoma cell lines tested. However, the STAT3 inhibitor S3I‐201 failed to inhibit IL‐6‐induced WNT5A up‐regulation in HTB63 and A375 cells. Nor did STAT3 siRNA silencing affect the expression of WNT5A. In search of an alternative signaling mechanism, we detected IL‐6‐induced activation of p38‐MAPK in HTB63 and A375 cells. The p38‐MAPK inhibitor SB203580 abolished the IL‐6‐induced WNT5A up‐regulation and blocked IL‐6‐induced melanoma cell invasion. The latter effect could be rescued by the addition of recombinant WNT5A. Notably, immunoprecipitation analysis revealed that only the p38α‐MAPK isoform was activated by IL‐6, and subsequent siRNA silencing of p38α‐MAPK abolished the IL‐6‐induced up‐regulation of WNT5A. Taken together, we demonstrate a novel link between the two melanoma pro‐metastatic agents IL‐6 and WNT5A explaining how IL‐6 can increase melanoma cell invasion and thus promote the metastatic process. This finding provides a basis for future therapeutic intervention of melanoma progression.