C-Terminal Peptide of γ-Enolase Impairs Amyloid-β-Induced Apoptosis Through p75NTR Signaling

γ-Enolase acts as a neurotrophic-like factor promoting growth, differentiation, survival and regeneration of neurons. It is shown in this study to exert a protective effect against amyloid-β-peptide (Aβ)-induced neurotoxicity in rat pheochromocytoma PC12 cells. Aβ-induced toxicity was abolished in the presence of the active C-terminal peptide of γ-enolase (γ-Eno) as measured by cell viability, lactate dehydrogenase release, sub-G1 cell population, intracellular reactive oxygen species, mitochondrial functions and apoptotic morphology. γ-Eno caused downregulation of the pro-apoptotic protein Bax and upregulation of the anti-apoptotic protein Bcl-2, as well as reduced caspase-3 activation. Exposure to Aβ increased surface expression of p75 neurotrophin receptor (p75^NTR), and the increase was abolished in the presence of γ-Eno peptide. Further, pretreatment with γ-Eno suppressed the activation of mitogen-activated protein kinases p38 and Jun-N-terminal kinase, which are p75^NTR downstream effectors in apoptotic signaling. Moreover, Aβ triggered γ-enolase co-immunoprecipitation with p75^NTR as well as their strong association in the perimembrane region as shown by confocal microscopy, which further supports the interaction between these two proteins in cells insulted by Aβ peptide. Our results indicate the possible use of γ-enolase C-terminal peptide for treating or preventing Alzheimer’s disease.     

γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia

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Dental diseases and loss of teeth in a group of Finnish alcoholics: a radiological study

A total of 85 Finnish alcohol-dependent subjects and 53 controls were studied with panoramic radiography. The aim was to study the possible associations between prolonged alcohol consumption and dental health. The mean number of teeth, caries lesions, endodontic treatments, periapical lesions, marginal bone loss, and periodontal infrabony pockets was studied. The subjects met the diagnostic criteria of alcohol dependence as set out in DSM-IV and ICD-10. The control group comprised social drinking volunteers with an AUDIT score &#104 8. For the final results the subjects were divided into groups on the basis of sex and age. The social backgrounds of the subjects were similar, except for employment and smoking. The results show significantly fewer teeth and more caries in the alcoholic group. There was a tendency for the alcoholics <45 years of age to have more endodontically treated teeth than the controls, but no difference in the number of periapical lesions in endodontically treated teeth was found. Horizontal bone loss and the presence of calculus were more frequent in alcoholic men than in alcoholic women. Significantly more horizontal bone loss was observed in the group of alcoholic nonsmokers than in nonalcoholic nonsmokers. In the nonsmoking groups alcoholics had significantly more periodontal destruction than the nonsmoking controls. We conclude that radiological dental health among individuals dependent on alcohol is weakened by more caries, more horizontal bone loss, and more numerous vertical infrabony pockets than social drinkers.     

Circulating Fibronectin Controls Tumor Growth

Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.     

Top–down signal transmission and global hyperconnectivity in auditory‐visual synesthesia: Evidence from a functional EEG resting‐state study

Auditory‐visual (AV) synesthesia is a rare phenomenon in which an auditory stimulus induces a “concurrent” color sensation. Current neurophysiological models of synesthesia mainly hypothesize “hyperconnected” and “hyperactivated” brains, but differ in the directionality of signal transmission. The two‐stage model proposes bottom–up signal transmission from inducer‐ to concurrent‐ to higher‐order brain areas, whereas the disinhibited feedback model postulates top–down signal transmission from inducer‐ to higher‐order‐ to concurrent brain areas. To test the different models of synesthesia, we estimated local current density, directed and undirected connectivity patterns in the intracranial space during 2 min of resting‐state (RS) EEG in 11 AV synesthetes and 11 nonsynesthetes. AV synesthetes demonstrated increased parietal theta, alpha, and lower beta current density compared to nonsynesthetes. Furthermore, AV synesthetes were characterized by increased top–down signal transmission from the superior parietal lobe to the left color processing area V4 in the upper beta frequency band. Analyses of undirected connectivity revealed a global, synesthesia‐specific hyperconnectivity in the alpha frequency band. The involvement of the superior parietal lobe even during rest is a strong indicator for its key role in AV synesthesia. By demonstrating top–down signal transmission in AV synesthetes, we provide direct support for the disinhibited feedback model of synesthesia. Finally, we suggest that synesthesia is a consequence of global hyperconnectivity. Hum Brain Mapp 39:522–531, 2018. © 2017 Wiley Periodicals, Inc.     

A novel niche for skin derived precursors in non-follicular skin

BackgroundSkin derived precursors (SKP) comprise a subset of specialized dermal cells that can be distinguished from fibroblast by their capacity for spheroidal growth. Recent investigations have shown that hair follicles constitute a niche for this cell type, but their localization and their definite function in non-follicular skin remains largely unknown.ObjectiveTo identify the dermal niche of non-follicular SKPs and to analyze whether functional aspects correlate with this localization.MethodsSKPs were isolated from separate anatomical regions of human abdominal skin. Fluorescence activated cell sorting then was used to obtain a pure population of non-follicular SKPs. Functional characterization of these cells was performed applying differentiation and proliferation assays. Information on specific in vivo functions was derived from histological evaluation of quantity and localization patterns.ResultsSphere forming capacity and differentiation assays show that SKPs reside in the papillary part of the dermis. Further delineation revealed that the dermal capillaries represent a niche for these cells which subsequently could be isolated by FACS utilizing a perivascular marker. Whereas functional properties described for follicular SKPs could also be detected in the perivascular SKP population, histological analyses additionally point to a cross-talk with epidermal stem cells and a reduction during chronological aging.ConclusionOur data show that SKPs isolated from non-follicular skin originate from a perivascular niche. Compared to their follicular counterparts, no functional differences could be observed upon cultivation, but ex vivo analyses also point to unique functions and a contribution to the phenotype of aged skin.     

Fas expression by tumor stroma is required for cancer eradication

The contribution of molecules such as perforin, IFN-γ (IFNγ), and particularly Fas ligand (FasL) by transferred CD8⁺ effector T (T_E) cells to rejection of large, established tumors is incompletely understood. Efficient attack against large tumors carrying a surrogate tumor antigen (mimicking a “passenger” mutation) by T_E cells requires action of IFNγ on tumor stroma cells to avoid selection of antigen-loss variants. Because “cancer-driving” antigens (CDAs) are rarely counterselected, IFNγ may be expected to be dispensable in elimination of cancers by targeting a CDA. Here, initial regression of large, established tumors required neither IFNγ, FasL, nor perforin by transferred CD8⁺ T_E cells targeting Simian Virus (SV) 40 large T as CDA. However, cytotoxic T_E cells lacking IFNγ or FasL could not prevent relapse despite retention of the rejection antigen by the cancer cells. Complete tumor rejection required IFNγ-regulated Fas by the tumor stroma. Therefore, T_E cells lacking IFNγ or FasL cannot prevent progression of antigenic cancer because the tumor stroma escapes destruction if its Fas expression is down-regulated.     

Label retaining cells in cancer – The dormant root of evil?

The phenomenon of cellular dormancy has been observed in normal adult stem cells in many different tissues such as the skin, the intestine and the hematopoietic system. These dormant cells have been proposed to be important for life-long self-renewal and for the generation of the different cellular lineages. As tumor cells can share properties with normal stem cells, dormant cells might also exist within a tumor. The term tumor dormancy has evolved from the clinical observation in cancer patients that relapse can occur years to decades after apparently successful treatment, suggesting that some cancer cells might resist chemotherapy and persist in a dormant state. Several studies investigating the role of cellular dormancy in normal stem cells and in cancer hint towards a complex network involving different pools of cells. These cells might interact with each other or even dynamically switch their phenotypes dependent upon so far unknown endogenous and microenvironmental stimuli. In this review, we will discuss the recent findings related to cellular dormancy in normal adult stem cells and in cancer. Furthermore, the clinical relevance of dormancy and its dynamic regulation in tumor cells will be highlighted.