Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration

Abstract

Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using ¹¹C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, ¹¹C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater ¹¹C-PBR28 binding. Minocycline reduced ¹¹C-PBR28 binding (mean Δwhite matter binding = −23.30%, 95% confidence interval −40.9 to −5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.

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Secreted Factors from Metastatic Prostate Cancer Cells Stimulate Mesenchymal Stem Cell Transition to a Pro-tumourigenic ‘Activated' State that Enhances Prostate Cancer Cell Migration

Abstract

Mesenchymal stem cells (MSCs) are a heterogeneous population of multipotent cells that are capable of differentiating into osteocytes, chondrocytes and adipocytes. Recently, MSCs have been found to home to the tumour site and engraft in the tumour stroma. However, it is not yet known whether they have a tumour promoting or suppressive function. We investigated the interaction between prostate cancer cell lines 22Rv1, DU145 and PC3, and bone marrow-derived MSCs. MSCs were 'educated' for extended periods in prostate cancer cell conditioned media and PC3-educated MSCs were found to be the most responsive with a secretory profile rich in pro-inflammatory cytokines. PC3-educated MSCs secreted increased osteopontin (OPN), interleukin-8 (IL-8) and fibroblast growth factor-2 (FGF-2) and decreased soluble fms-like tyrosine kinase-1 (sFlt-1) compared to untreated MSCs. PC3-educated MSCs showed a reduced migration and proliferation capacity that was dependent on exposure to PC3-conditioned medium. Vimentin and α-smooth muscle actin (αSMA) expression was decreased in PC3-educated MSCs compared to untreated MSCs. PC3 and DU145 education of healthy donor and prostate cancer patient derived MSCs led to a reduced proportion of FAP+ αSMA+ cells contrary to characteristics commonly associated with cancer associated fibroblasts (CAFs). The migration of PC3 cells was increased towards both PC3-educated and DU145-educated MSCs compared to untreated MSCs, while DU145 migration was only enhanced towards patient derived MSCs In summary, MSCs developed an altered phenotype in response to prostate cancer conditioned medium which resulted in increased secretion of pro-inflammatory cytokines, modified the functional activity and the chemoattraction of prostate cancer cells. This article is protected by copyright. All rights reserved.

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Telomerase reverse transcriptase mutations are independent predictor of disease-free survival in middle eastern papillary thyroid cancer

Abstract

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Tumor recurrence occurs in approximately 20% of PTCs and some reach advanced stages. Promoter mutation in the telomerase reverse transcriptase (TERT) gene is identified to be a prognostic marker in PTC. However, the contribution of TERT promoter mutation to cancer progression in PTC patients is still not fully understood. In this study we investigated the incidence of TERT promoter mutations and TERT protein expression and their association with clinicopathological outcomes in a large cohort of PTC samples using direct sequencing technology and immunohistochemistry. Furthermore, two PTC cell lines were utilized to investigate role of TERT mutations in mediating metastasis. Two promoter hotspot mutations C228T and C250T were identified in 18.0% (167/927) of our cohort and were significantly associated with poor 5 years disease-free survival and distant metastasis of PTC. TERT protein over-expression was noted in 20.1% of our PTC cohort and was significantly associated with poor prognostic markers such as older age, extra-thyroidal extension and Stage IV tumors. A significant association was also found between TERT over-expression and epithelial–mesenchymal transition (EMT) markers. Functional analysis showed that TERT inhibition reduced cell growth, invasion, migration and angiogenesis in PTC via suppression of EMT in PTC cells. Our results suggest TERT promoter mutation is an independent predictor of disease-free survival and might drive the metastasis, and downregulation of TERT could potentiate anti-tumor and anti-metastatic activities in PTC. This article is protected by copyright. All rights reserved.

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Serum Concentration of Macro-, Micro-, and Trace Elements in Silver Fox ( Vulpes vulpes ) and Their Interrelationships with Morphometric, Densitometric, and Mechanical Properties of the Mandible

Abstract

The optimal content of macro-, micro-, and trace elements in tissues ensures proper systemic growth and development and optimal health status in animals and humans. However, very little is known on the elemental content in the plasma compartment in Silver fox. The aim of this study was to determine the content of selected elements in serum obtained from 8-month-old female (N = 8) and male (N = 7) silver foxes. Moreover, relationships of the evaluated elements with the morphological, densitometric, and mechanical parameters of the mandible were determined. Serum content of 12 different elements was measured using inductively coupled plasma-atomic emission spectrometry. The morphometric and densitometric properties of the mandible were determined using quantitative computed tomography method, while mechanical endurance was tested using a three-point bending test. Serum concentration of calcium was significantly higher by 20% in male foxes (P = 0.01), while manganese concentration was significantly lower in males by over 17% (P = 0.03). Positive correlations of serum concentration of calcium, phosphorus, and magnesium with the morphological traits of the mandible such as weight, length, and bone volume were stated (P < 0.05). In the group of elements playing regulatory functions, the positive relationships between serum concentrations of selenium, chromium, manganese, copper, and cobalt were found (P < 0.05). The elaborated experimental model may serve for further studies on foxes, especially focused on nutritional factors affecting elemental homeostasis, whole-body metabolism, and systemic growth and development. Daily diet formulation and precise delivery for farm foxes, together with relatively large animal population maintained at the same environmental conditions, regularly subjected to slaughter procedure, enable economical experimentation with various dietary and pharmacological manipulations.

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Identifying a combined biomarker for bisphosphonate-related osteonecrosis of the jaw

Abstract

Background

For this study, the aim was to identify combined biomarkers associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ).

Materials and methods

Microarray data for GSE7116 were downloaded from the Gene Expression Omnibus database, which contains 26 samples, including without ONJ, and 5 healthy volunteers. The combined biomarkers were identified using principal component analysis, and the pathway enrichment analyses were performed using the DAVID online tool.

Results

Two hundred differently expressed genes between groups were detected according to the significances. From functional annotation, Y-box binding protein 1 and heterogeneous nuclear ribonucleoprotein C were found to be included in the most significant 10 pathways. Ten combined gene sets were identified that were effective in classifying multiple myeloma (MM) with ONJ and MM without ONJ.

Conclusion

Identifying combined gene expression profiles is expected to contribute to more personalized management of BRONJ and to improve existing therapies, and it will be helpful in finding new therapies by identifying more predictive biomarkers.

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Is Esophageal Temperature Better to Estimate Brain Temperature during Target Temperature Management in a Porcine Model of Cardiopulmonary Resuscitation?

Brain temperature monitoring is important in target temperature management for comatose survivors after cardiac arrest. Since acquisition of brain temperature is invasive and unrealistic in scene of resuscitation, we tried to sought out surrogate sites of temperature measurements that can precisely reflect cerebral temperature. Therefore, we designed this controlled, randomized animal study to investigate whether esophageal temperature can better predict brain temperature in two different hypothermia protocols. The results indicated that esophageal temperature had a stronger correlation with brain temperature in the early phase of hypothermia in both whole and regional body cooling protocols. It means that esophageal temperature was considered as priority method for early monitoring once hypothermia is initiated. This clinical significance of this study is as follows. Since resuscitated patients have unstable hemodynamics, collecting temperature data from esophagus probe is cost-efficient and easier than the catheter in central vein. Moreover, it can prevent the risk of iatrogenic infection comparing with deep vein catheterization, especially in survivors with transient immunoexpressing in hypothermia protocol.

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Clinicopathological Characteristics, Treatment, and Prognosis of Rarely Primary Epididymal Adenocarcinoma: A Review and Update

Primary epididymal adenocarcinoma (PEA) is exceedingly rare. Only 22 cases had been published worldwide by 2008; nearly 80% of these cases were reported before 2007. In order to investigate the current clinical status of PEA, we search for relevant literatures with "epididymis and adenocarcinoma" and "epididymal and adenocarcinoma" as keywords published between January 1997 and November 2017 in PubMed. As a result, 17 cases are identified. We review these cases and summarize new and important perspectives about the clinicopathological characteristics, diagnosis, treatment, and prognosis of PEA in the present review.

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