Extracellular vimentin is a novel axonal growth facilitator for functional recovery in spinal cord-injured mice.

Vimentin, an intermediate filament protein, is an intracellular protein that is involved in various cellular processes. Several groups have recently reported that vimentin also appears in the extracellular space and shows novel protein activity. We previously reported that denosomin improved motor dysfunction in mice with a contusive spinal cord injury (SCI). At the injured area, astrocytes expressing and secreting vimentin were specifically increased, and axonal growth occurred in a vimentin-dependent manner in denosomin-treated mice. However, the axonal growth that was induced by extracellular vimentin was only investigated in vitro in the previous study. Here, we sought to clarify whether increased extracellular vimentin can promote the axonal extension related to motor improvement after SCI in vivo. Extracellular vimentin treatment in SCI mice significantly ameliorated motor dysfunction. In vimentin-treated mice, 5-HT-positive axons increased significantly at the rostral and central areas of the lesion, and the total axonal densities increased in the central and caudal parts of the lesioned area. This finding suggests that increased axonal density may contribute to motor improvement in vimentin-treated mice. Thus, our in vivo data indicate that extracellular vimentin may be a novel neurotrophic factor that enhances axonal growth activity and motor function recovery after SCI.

NKX6.1 functions as a metastatic suppressor through epigenetic regulation of the epithelial-mesenchymal transition.

The transcription factor NKX6.1 (NK6 homeobox 1) is important in the development of pancreatic ß-cells and neurons. Although recent publications show that NKX6.1 is hypermethylated and downregulated during tumorigenesis, the function of NKX6.1 in carcinogenesis remains elusive. Here, we address the metastasis suppressor function of human NKX6.1 using cell, animal and clinical analyses. Our data show that NKX6.1 represses tumor formation and metastatic ability both in vitro and in vivo. Mechanistically, NKX6.1 suppresses cell invasion by inhibiting the epithelial-to-mesenchymal transition (EMT). NKX6.1 directly enhances the mRNA level of E-cadherin by recruiting BAF155 coactivator and represses that of vimentin and N-cadherin by recruiting RBBP7 (retinoblastoma binding protein 7) corepressor. Clinical cancer tumors with metastasis show low NKX6.1 protein expression coinciding with low E-cadherin and high vimentin expression. Our results demonstrate that NKX6.1 functions as an EMT suppressor by interacting with different epigenetic modifiers, making it a potential novel therapeutic option.

Positive expression of pro-opiomelanocortin (POMC) is a novel independent poor prognostic marker in surgically resected non-small cell lung cancer.

This study aims to investigate the expression level of pro-opiomelanocortin (POMC) and its prognostic value in non-small cell lung cancer (NSCLC). Immunohistochemical staining was used to detect the expression level of POMC. Correlations between POMC expression and clinical and pathological characteristics were evaluated with the chi-square test, and the prognostic value was determined with the Kaplan-Meier method and COX proportional hazards model, α < 0.05. Of the samples, 48.0% had positive POMC expression. POMC expression was significantly related to poorly differentiated tumors, N-stage, p-stage, postoperative failure pattern, expression of vimentin, and expression of E-cadherin (P < 0.05). Multivariate analysis revealed that POMC-positive expression was an independent risk factor for disease-free survival (hazard ratio (HR) 1.988, 95% confidence interval (CI) 1.094-3.910, P = 0.024) and overall survival (HR 1.892, 95% CI 1.726-3.709, P = 0.036). The addition of POMC protein expression to the prognostic model using pathological stage markedly improved the prognostic potential, and the area under the ROC increased from 0.691 to 0.775. Further study revealed that patients with POMC-negative expression can benefit more from a regimen of paclitaxel and carboplatin chemotherapy than a regimen of vinorelbine and carboplatin compared to patients with POMC-positive expression. We found that POMC-positive expression is a novel, independent poor prognostic marker in patients with NSCLC. Prospective studies are needed to validate the potential prognostic value of POMC in combination with the current staging system and in consideration of adjuvant chemotherapy.

Effects of the mycotoxin nivalenol on bovine articular chondrocyte metabolism in vitro.

OBJECTIVE: Kashin-Beck Disease (KBD) is an endemic, age-related degenerative osteoarthropathy and its cause is hypothesised to involve Fusarium mycotoxins. This study investigated the Fusarium mycotoxin Nivalenol (NIV) on the metabolism of bovine articular chondrocytes in vitro. DESIGN: The effect 0.0-0.5 µg/ml NIV on transcript levels of types I and II collagen, aggrecan, matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) and the tissue inhibitors of MMPs (TIMPs) was investigated using quantitative PCR. Amounts of sulphated glycosaminoglycans, MMPs and TIMPs were assessed using the Dimethylmethylene Blue assay, gelatin zymography and reverse gelatin zymography respectively. Cytoskeletal organisation was analysed using confocal microscopy and cytoskeletal gene and protein levels were measured by quantitative PCR and Western blot analysis, respectively. RESULTS: NIV caused a dose-dependent increase in aggrecan transcription with a concomitant retention of sGAG in the cell lysate. Furthermore, NIV significantly increased MMPs-2, -3 & -9, ADAMTS-4 and -5, and TIMP-2 and -3 transcript levels but inhibited type I collagen, MMP 1 and TIMP 1 mRNA levels. NIV promoted extensive cytoskeletal network remodelling, particularly with vimentin where a dose-dependent peri-nuclear aggregation occurred. CONCLUSION: NIV exposure to chondrocytes decreased matrix deposition, whilst enhancing selective catabolic enzyme production, suggesting its potential for induction of cellular catabolism. This NIV-induced extracellular matrix remodelling may be due to extensive remodelling/disassembly of the cytoskeletal elements. Collectively, these findings support the hypothesis that trichothecene mycotoxins, and in particular NIV, have the potential to induce matrix catabolism and propagate the pathogenesis of KBD.

A rare case of malignant pediatric ectomesenchymoma arising from the falx cerebri.

Malignant ectomesenchymoma is a rare tumor arising from mature ganglion cells with immature myogenous elements, with only 4 pediatric intracranial cases having been previously reported. The authors report a rare case of intracranial malignant ectomesenchymoma originating from the falx cerebri in a 10-year-old boy. The patient presented with a 2-week history of headache, nausea, and blurry vision, with mild lateral gaze diplopia. A CT scan revealed a solitary 7.2 × 3.8-cm dural-based mass that extended along the falx. No metastatic disease was identified, and the lesion was grossly resected without complication. Pathological investigation identified single and small groups of cells in a myxoid background, with polygonal or spindle-shaped cells containing eccentric nuclei and prominent nucleoli. Immunohistochemical staining of some cells was positive for smooth-muscle actin, CD99, and vimentin, whereas other cells (often process forming) were positive for S100 protein, synaptophysin, and neurofilament protein. Staining was negative for CD138, CD45, α-fetoprotein, CK AE1/3, glial fibrillary acidic protein, CK7, CK20, CD31, CD34, myoD, and desmin. Normal immunopositivity was seen for INI-1. The Ki 67 immunostaining had < 25% reactivity. The patient was treated with a sarcoma-based chemotherapy regimen and radiation to the craniospinal axis, and was found to be without recurrence or metastatic disease at 20 months.