MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency

open9siopenFong, Louise Y.; Taccioli, Cristian; Jing, Ruiyan; Smalley, Karl J.; Alder, Hansjuerg; Jiang, Yubao; Fadda, Paolo; Farber, John L.; Croce, Carlo M.Fong, Louise Y.; Taccioli, Cristian; Jing, Ruiyan; Smalley, Karl J.; Alder, Hansjuerg; Jiang, Yubao; Fadda, Paolo; Farber, John L.; Croce, Carlo M

Surface bioactivation through the nanostructured layer on titanium modified by facile HPT treatment

AbstractFacile fabrication of nanostructured surface is of great importance for the use of titanium (Ti) implants in biomedical field. In this study, a low-cost and easy-to-operate method called HPT (hydrothermal &amp; pressure) here has been developed and used to fabricate the expected nanostructured surface on Ti substrates. The effects of experimental parameters on the morphology of Ti surface were investigated and characterized. The results indicated that by altering the hydrothermal pressure, NaOH concentration and treating time, surface nanostructure like nanopetals or nanoflakes could be formed on the surface of Ti substrates. The orthogonal experiments were conducted to demonstrate the optimized operation conditions. A formation mechanism of the nanostructured titanate layer was proposed, revealing that the nanostructured layer could be formed via a special upward and downward co-growth manner. In vitro cell culture showed that the HPT treated Ti substrates, especially the T-10 sample, could greatly enhance the cell-material interactions, i.e. the cell proliferation and differentiation, focal protein adhesion, and osteogenic factor expression. The HPT method paves a new way to modify the surface of Ti implants with better bioactivity and promising prospect for future biomedical applications.</jats:p

Combined Effect of Contact Area, Aperture Variation, and Fracture Connectivity on Fluid Flow through Three-Dimensional Rock Fracture Networks

AbstractIn order to investigate the combined effect of contact area, aperture variation, and fracture connectivity on the fluid flow through a fractured medium, a series of flow simulations were implemented on two types of three-dimensional discrete fracture network (3D DFN) models constituting fractures having spatially variable apertures and parallel plates, respectively. The flow tortuosity within the 3D DFN models was examined by changing the density, aperture distribution, and closure of fractures. The results show that compared with the 3D DFN models constituting parallel plates, the model with variable apertures provides more pronounced 3D preferential flow pathways. At the individual fracture scale, the preferential flow pathways mostly converge within the void spaces of large aperture, and at the network scale, they are located in the most transmissive fractures within the connected networks. The permeability of 3D DFNs depends not only on the contact area and aperture variation within individual fractures but also on the fracture connectivity and the contact at fracture intersections within the fracture network. Increasing the fracture connectivity tends to enhance the permeability, while increasing the contact at fracture intersections would significantly reduce the permeability. A correlation between the equivalent permeability of 3D DFNs constituting fractures with spatially variable apertures and parallel plates is proposed incorporating the effect of network-scale topology. A tortuosity factor for 3D DFNs is defined based on the proposed model, and it can account for two competing effects when the model is upscaled from individual fracture to fracture network: the permeability reduction induced by contact obstacles at fracture intersections and permeability enhancement induced by increasing the fracture connectivity

Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo.

BACKGROUND: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined. METHODS: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter assay. Cellular proliferation, apoptosis, and expression of inflammation genes were determined by immunoblotting, caspase assays, and immunohistochemistry. The miR-31 promoter in Zn-deficient esophagus was identified by ChIP-seq using an antibody for histone mark H3K4me3. Data were analyzed with t test and analysis of variance. All statistical tests were two-sided. RESULTS: In vivo, anti-miR-31 reduced miR-31 overexpression (P = .002) and suppressed the esophageal preneoplasia in Zn-deficient rats. At the same time, the miR-31 target Stk40 was derepressed, thereby inhibiting the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis (caspase 3/7 activities, fold change = 10.7, P = .005). This same connection between miR-31 overexpression and STK40/NF-κΒ expression was also documented in human ESCC cell lines. In Zn-deficient esophagus, the miR-31 promoter region and NF-κΒ binding site were activated. Zn replenishment restored the regulation of this genomic region and a normal esophageal phenotype. CONCLUSIONS: The data define the in vivo signaling pathway underlying interaction of Zn deficiency and miR-31 overexpression in esophageal neoplasia and provide a mechanistic rationale for miR-31 as a therapeutic target for ESCC

Cognitive impairment in Chinese adult patients with type III spinal muscular atrophy without disease-modifying treatment

ObjectiveSpinal muscular atrophy (SMA) is a neurodegenerative disorder characterized by the degeneration of motor neurons in the spinal cord. It remains uncertain whether the cognitive performance of adult patients with SMA is impaired. The objective of this study was to assess the cognitive profile of adult Chinese patients with SMA and the association between clinical features and cognitive ability, particularly executive function.MethodsThis cross-sectional study included 22 untreated adult patients with type III SMA and 20 healthy subjects. The following variables were assessed: general intelligence, memory, attention, language, executive function, depression, anxiety, and other demographic and clinical parameters. In addition, physical function was evaluated using the Hammersmith Functional Motor Scale Expanded (HFMSE), the Revised Upper Limb Module (RULM), and the 6-Minute Walk Test (6MWT).ResultsSMA patients had lower scores than healthy subjects in the Verbal Fluency Test, Stroop effect, Total Errors, Perseverative Responses, Perseverative Errors, and Non-perseverative Errors in the Wisconsin Card Sorting Test, showing impaired abilities of SMA patients in executive function. In the Attention Network Test (ANT), the results indicated that the SMA patients also had selective deficits in their executive control networks. Ambulant patients had better executive function test performance than non-ambulant ones. Compromised executive abilities in patients with SMA were correlated with a younger age at onset, poorer motor function, and higher levels of anxiety and depression.ConclusionOur study presented the distribution of cognitive impairment in a Chinese cohort with SMA. Patients with type III SMA showed selective deficits in executive function, which may be associated with disease severity, physical impairment, depression and anxiety. Future cognitive studies, accounting for motor and emotional impairment, are needed to evaluate if executive impairment is driven by specific brain changes or by those confounding factors

Study on Vibrio Disease of Pseudosciaena crocea and Recognition of the Disease Resistant Group Based on Automatic Detection System for Hemogram

Chemical medicines and antibiotics can kill pathogenic microorganisms in aquiculture animals, but they will lead to environmental pollution and serious food safety problems. Therefore, study on the selection for the disease resistant group of animals is necessary to solve the problem and promote the development of aquaculture. From the view of the relationship between fishes and pathogenic microorganisms, the present paper studies hemogram changes of Pseudosciaena crocea with different disease resistant abilities after artificial infected with the Vibrio harveyi. The results showed that the changes of hemograms of Pseudosciaena crocea after infected with Vibrio harveyi had close relationship with its disease resistant abilities. The hemogram indicators of the high disease resistant group (HDRG) did not change remarkably after infection compared with the control (P >0.05). But in the low disease resistant group (LDRG) or sensitive group, the concentrations of the red blood cells, white blood cells, lymphocytes, monocytes and neutrophil cells, as well as hematocrit and hemoglobin content per litre blood, decreased remarkably compared with the control (p < 0.05). And the white blood cells, monocytes and neutrophil cells of the LDRG also decreased remarkably compared with that of the HDRG (P < 0.05). These indicators of hemogram provide better referrences for the study on the anti-disease ability of Pseudosciaena crocea, and also provide selection basis for the group with high disease resistant abilities. Application of automatic detection system greatly improved the analytical efficiency and would be a better choice for a large number of samples

Zinc deficiency activates S100A8 inflammation in the absence of COX-2 and promotes murine oral-esophageal tumor progression

Zinc (Zn)-deficiency (ZD) is implicated in the pathogenesis of human oral-esophageal cancers. Previously, we showed that in ZD mice genetic deletion of cyclooxygenase-2 (Cox-2) enhances N-nitrosomethylbenzylamine-induced forestomach carcinogenesis. By contrast, Cox-2 deletion offers protection in Zn-sufficient (ZS) mice. We hypothesize that ZD activates pathways insensitive to COX-2 inhibition, thereby promoting carcinogenesis. This hypothesis is tested in a Cox-2−/− mouse tongue cancer model that mimics pharmacologic blockade of COX-2 by firstly examining transcriptome profiles of forestomach mucosa from Cox-2−/− and wild-type mice on a ZD vs. ZS diet, and secondly investigating the roles of identified markers in mouse forestomach/tongue preneoplasia and carcinomas. In Cox-2−/− mice exposed to the tongue carcinogen 4-nitroquinoline 1-oxide, dietary ZD elicited tongue/esophagus/forestomach carcinomas that were prevented by ZS. The precancerous ZD:Cox-2−/−vs. ZS:Cox-2−/− forestomach had an inflammatory signature with upregulation of the proinflammation genes S100a8 and S100a9. Bioinformatics analysis revealed overrepresentation of inflammation processes comprising S100a8/a9 and an nuclear factor (NF)-κB network with connectivity to S100A8. Immunohistochemistry revealed co-overexpression of S100A8, its heterodimeric partner S100A9, the receptor for advanced glycation end-products (RAGE), NF-κB p65, and cyclin D1, in ZD:Cox-2−/− forestomach/tongue preneoplasia and carcinomas, evidence for the activation of a RAGE-S100A8/A9 inflammatory pathway. Accumulation of p53 in these carcinomas indicated activation of additional inflammatory pathways. Zn-replenishment in ZD:Cox-2−/−mice reversed the inflammation and inhibited carcinogenesis. Thus, ZD activates alternative inflammation-associated cancer pathways that fuel tumor progression and bypass the antitumor effect of Cox-2 ablation. These findings have important clinical implications, as combination cancer therapy that includes Zn may improve efficacy

Preparation and biological properties of a novel composite scaffold of nano-hydroxyapatite/chitosan/carboxymethyl cellulose for bone tissue engineering

Abstract In this study, we report the physico-chemical and biological properties of a novel biodegradable composite scaffold made of nano-hydroxyapatite and natural derived polymers of chitosan and carboxymethyl cellulose, namely, n-HA/CS/CMC, which was prepared by freeze-drying method. The physico-chemical properties of n-HA/CS/CMC scaffold were tested by infrared absorption spectra (IR), transmission electron microscope(TEM), scanning electron microscope(SEM), universal material testing machine and phosphate buffer solution (PBS) soaking experiment. Besides, the biological properties were evaluated by MG63 cells and Mesenchymal stem cells (MSCs) culture experiment in vitro and a short period implantation study in vivo. The results show that the composite scaffold is mainly formed through the ionic crossing-linking of the two polyions between CS and CMC, and n-HA is incorporated into the polyelectrolyte matrix of CS-CMC without agglomeration, which endows the scaffold with good physico-chemical properties such as highly interconnected porous structure, high compressive strength and good structural stability and degradation. More important, the results of cells attached, proliferated on the scaffold indicate that the scaffold is non-toxic and has good cell biocompatibility, and the results of implantation experiment in vivo further confirm that the scaffold has good tissue biocompatibility. All the above results suggest that the novel degradable n-HA/CS/CMC composite scaffold has a great potential to be used as bone tissue engineering material.</p