Intermuscular coherence as a biomarker of subthalamic nucleus deep brain stimulation efficacy in Parkinson's disease

OBJECTIVE: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established treatment in advanced Parkinson's disease (PD). However, the clinical outcome after STN-DBS is variable. The aim of this study was to explore the coherence of antagonistic muscles measured with electromyography (EMG) as novel biomarker of STN-DBS efficacy in PD. METHODS: EMG of bilateral wrist and upper arm antagonistic muscles of 21 PD patients was recorded during three standardized motor tasks. Patients were measured one day prior to DBS surgery (pre-DBS) and 6 months afterwards (post-DBS). Coherence analyses were performed on the antagonistic muscle pairs. Pearson correlations between intermuscular coherence and clinical performance were calculated. RESULTS: Intermuscular coherence during each of the different co-contraction tasks significantly correlated to UPDRS-III bradykinesia scores (p < 0.01). In other words, higher intermuscular coherence is associated with more severe PD symptoms. Moreover, coherence changes (pre-DBS - post-DBS coherence) correlated to clinical score changes after DBS (p < 0.01) and pre-DBS coherence correlated to this clinical score change as well (p < 0.01). CONCLUSIONS: Higher pre-DBS coherence of antagonistic arm muscles is correlated to worsening of clinical PD state and higher intermuscular coherence predicts enhanced clinical improvement. SIGNIFICANCE: We propose that pre-DBS intermuscular coherence could be developed into a predictor of STN-DBS clinical outcome. It could aid patient selection and adaptive stimulation algorithms for DBS

Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression

Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets.Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)-educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography.Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFβ, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFβ-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFβ are increased in osteosarcoma patients.Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFβ-blocking agents as new therapeutic options for osteosarcoma patients

Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression

Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets.Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)-educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography.Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGF\u3b2, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGF\u3b2-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGF\u3b2 are increased in osteosarcoma patients.Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGF\u3b2-blocking agents as new therapeutic options for osteosarcoma patients. Clin Cancer Res; 23(14); 3721-33. \ua92017 AACR

Circulating β-endorphin, adrenocorticotrophic hormone and cortisol levels of stallions before and after short road transport: stress effect of different distances

<p>Abstract</p> <p>Background</p> <p>Since transport evokes physiological adjustments that include endocrine responses, the objective of this study was to examine the responses of circulating β-endorphin, adrenocorticotrophic hormone (ACTH) and cortisol levels to transport stress in stallions.</p> <p>Methods</p> <p>Forty-two healthy Thoroughbred and crossbred stallions were studied before and after road transport over distances of 100, 200 and 300 km. Blood samples were collected from the jugular vein: first in a single box immediately before loading (pre-samples), then immediately after transport and unloading on arrival at the breeding stations (post-samples).</p> <p>Results</p> <p>An increase in circulating β-endorphin levels after transport of 100 km (<it>P </it>< 0.01), compared to basal values was observed. Circulating ACTH levels showed significant increases after transport of 100 km (<it>P </it>< 0.001) and 200 km (<it>P </it>< 0.001). Circulating cortisol levels showed significant increases after road transport over distances of 100, 200 and 300 km (<it>P </it>< 0.001). An effect of transport on β-endorphin, ACTH and cortisol variations was therefore evident for the different distances studied. No significant differences (<it>P </it>> 0.05) between horses of different ages and different breeds were observed for β-endorphin, ACTH and cortisol levels.</p> <p>Conclusion</p> <p>The results obtained for short term transportation of stallions showed a very strong reaction of the adrenocortical system. The lack of response of β-endorphin after transport of 200–300 km and of ACTH after transport of 300 km seems to suggest a soothing effect of negative feedback of ACTH and cortisol levels.</p

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

Acid susceptibility at various depths of pH-cycled enamel and dentine specimens

pH-cycling and in situ studies have shown that fluctuations in de-/remineralisation conditions or in fluoride usage can lead to laminations inside enamel or dentine lesions. Layers with different mineral content are thought to reflect the history of fluoride administrations. Studying the dissolution properties of such lesions at various depths - using bulk specimens - is presumably hampered by limited diffusion of acids through the lesion pores. Therefore, in this study the acid susceptibility of enamel and dentine lesions and the underlying sound tissues was studied by exposing sections to acid buffers from the cut rather than from the external surface. Specimens were obtained from a previous study of the effects of high-fluoride (0, 1,000, 2,000, 3,000/5,000 ppm F) toothpastes on enamel and dentine de-/remineralisation. Sections were subjected to acid buffers for 3 and 7 days and the changes in mineral content were monitored by contact microradiography. For enamel lesions a significant difference in dissolution over depth was observed between the groups subjected to the different fluoride schemes. At 7 days a dose response was found between the different fluoride groups and the lesion parameters. In the no-fluoride group dissolution in the original lesion and the sound tissue were similar. All dentine lesions which had been treated with fluoride showed inhibition of dissolution, but the inhibition did not increase with higher fluoride concentrations. Deeper into the dentine tissue there was some protection, but it was not statistically significant. We conclude that penetration of fluoride through the lesion pores determines the dissolution pattern of a lesion at various depths

Remineralisation of enamel lesions with daily applications of a high-concentration fluoride gel and a fluoridated toothpaste: An in situ study

The inhibition of enamel demineralisation and the enhancement of remineralisation are positively but not linearly related to the concentration of fluoride, especially when high fluoride concentrations are used. The aim of this in situ experiment was to determine the maximum amount of enamel remineralisation that can be achieved with daily applications of very high concentrations of fluoride. For this purpose we compared the efficacy of a daily application of fluoridated topical gel (12,500 ppm F, partly as NaF, Olafluor and Dectafluor, pH 4.5) in combination with a fluoridated toothpaste (1,450 ppm F as NaF), with fluoridated toothpaste alone. Participants (n = 26, with partial dentures) were fitted with a demineralised enamel specimen (mean mineral loss of 1,674 vol%·μm) and were instructed to use one of the two fluoride treatments. After 4 weeks of treatment, the specimens were retrieved, a section was cut and analysed with microradiography. The remainder of each of the specimens was used for analysis of the 'loosely bound' and 'bound' fluoride. Fluoride was measured with gas-liquid chromatography. After 4 weeks in the mouth, the original lesion was reduced in size by 54% in the toothpaste + gel group (n = 14) and by 44% in the toothpaste-only group (n = 12), but the difference between the groups was not statistically significant. The mineral content profiles showed remineralisation of the lesions throughout the depth of the lesion. The enhancement of remineralisation by the high amounts of fluoride was most pronounced in the surface layer. For both the 'loosely bound' and 'bound' fluoride, a statistically significant increase in fluoride concentration could be found in the toothpaste + gel group. In the 4-week in situ period the use of high amounts of fluoride resulted in a maximum remineralisation rate. This is illustrated by an increase in remineralisation and higher fluoride concentrations in the toothpaste + gel group compared to the toothpaste-only group