Discriminative analysis of early-stage Alzheimer's disease and normal aging with automatic segmentation technique in subcortical gray matter structures: a multicenter in vivo MRI volumetric and DTI study.

BACKGROUND: Previous studies have revealed that amyloid depositions exist in not only the hippocampus but in other subcortical gray matter structures as well. Diffusion-tensor imaging (DTI) parameters might be more sensitive measures of early degeneration in Alzheimer's disease (AD) than conventional magnetic resonance imaging (MRI) techniques. PURPOSE: To evaluate the significance of the volumes and the mean diffusivity (MD) values of subcortical gray matter structures in discrimination between early-stage AD and normal subjects using the Integrated Registration and Segmentation Tool in FMRIB's Software Library. MATERIAL AND METHODS: Fifty-three cases of early-stage AD and 30 normal aging volunteers from two hospitals were scanned with 3D-FSPGRIR and SSSE-EPI sequences using two similar 1.5T MR systems. The mean relative volumes and mean MD values of subcortical gray matter structures were compared between early-stage AD and control groups. Binary logistic regression analysis and receiver-operating characteristic (ROC) curves were applied to assess the diagnostic significance of every structure's relative volume, MD value, and combination of both. RESULTS: The relative volumes of the left hippocampus, right amygdala, bilateral thalamus, right caudate, left putamen, and bilateral pallidum were significantly lower in the early-stage AD group than in the control group (P < 0.05). The MD values of the bilateral hippocampus and pallidum, and of the right thalamus and caudate were significantly elevated in the early-stage AD group (P < 0.05). In binary logistic regression analysis, the relative volume of left hippocampus and age entered the final model of volumetric analysis. The MD values of bilateral hippocampi and pallidums entered the final model of MD analysis. The MD values of bilateral hippocampi and pallidums, and the relative volume of left pallidum, entered the final model of combination analysis. The accuracy of three models was 84.7%, 88.9%, and 93.1%, respectively. CONCLUSION: Pathological changes takes place in the hippocampus and other subcortical gray matter structures in early-stage AD. Diffusive imaging has great diagnostic significance in early-stage AD. The combination of both imaging modalities can lead to better discrimination between early-stage AD and normal aging.

Identification of novel rare mutations of DACT1 in human neural tube defects.

Neural tube defects (NTDs) constitute the second most frequent cause of human congenital abnormalities. Complex multigenetic causes have been suggested to contribute to NTDs. The planar cell polarity (PCP) pathway plays a critical role in neural tube closure in model organisms and in human. Knockout of Dact1 (Dapper, Frodo) leads to deregulated PCP signaling with defective neural tube in mice. Here, we report that five missense heterozygote mutations of the DACT1 gene are specifically identified in 167 stillborn or miscarried Han Chinese fetuses with neural tube defects. Our biochemical analyses revealed that among the five mutations, N356K and R45W show loss-of-function or reduced activities in inducing Dishevelled2 (DVL2) degradation and inhibiting jun-N-terminal kinase (JNK) phosphorylation, implicating mutated DACT1 as a risk factor for human NTDs. Our findings, together with early reports, suggest that rare mutations of the PCP-related genes may constitute a great contribution to human NTDs.

Protein kinase A-mediated 14-3-3 association impedes human Dapper1 to promote dishevelled degradation.

Wnt signaling regulates embryo development and tissue homeostasis, and its deregulation leads to an array of diseases, including cancer. Dapper1 has been shown to be a key negative regulator of Wnt signaling. However, its function and regulation remain poorly understood. In this study, we report that 14-3-3ß interacts with human Dapper1 (hDpr1). The interaction is dependent on protein kinase A (PKA)-mediated phosphorylation of hDpr1 at Ser-237 and Ser-827. 14-3-3ß binding attenuates the ability of hDpr1 to promote Dishevelled (Dvl) degradation, thus enhancing Wnt signaling. We further provide evidence that PKA-mediated Dpr1 phosphorylation may contribute to growth and tumor formation of colon cancer Caco2 cells. Finally, we show that cyclooxygenase-2 expression and PKA activation are positively correlated with Dvl protein levels in colon cancer samples. Together, our findings establish a novel layer of regulation of Wnt signaling by PKA via the 14-3-3-Dpr1-Dvl axis.

The effect of remnant preservation on patterns of gene expression in a rabbit model of anterior cruciate ligament reconstruction.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction with remnant preservation technique had been thought to be a more favorable milieu for graft reinnervation, revascularization, and ligamentization. However, the influence of preserving tibial residual fibers on mRNA expression during the graft remodeling process has never been investigated. MATERIALS AND METHODS: Healthy mature New Zealand white rabbits were randomly assigned to one of four groups: remnant dissected, remnant preserved, sham operated, and normal control. Ligament tissue was dissected at 2, 6, and 12 wk after surgery, and real-time PCR was performed using primers for VEGF, TGF-ß1, COLlAl, COL3A1, GAP-43, and NT-3. RESULTS: In the remnant preservation group, mRNA levels for matrix components COL l Al, COL3A1, growth factor TGF-ß1, and nerve-related genesGAP-43 all increased 6 wk after surgery, compared with the remnant dissection group (P < 0.05). An increased level of VEGF mRNA was also detected in the remnant preservation group 12 wk after operation (P < 0.05). An increased level of NT-3 mRNA was also observed in the remnant preservation group 2 and 12 wk after operation (P < 0.05). CONCLUSIONS: Our results suggest that there is a time dependent alteration of angiogenesis-promoting, repair-related, and nerve-related gene expression after ACL reconstruction during the process of graft remodeling. Furthermore, they demonstrate that remnant preservation in ACL reconstruction determines the different molecular profiles of these target genes, especially during the early stages of graft remodeling, which perhaps explains the potential role in promoting revascularization, reinnervation, and ligamentization.

Immunomodulatory Effect of Lentinan on Aberrant T Subsets and Cytokines Profile in Non-small Cell Lung Cancer Patients.

As a purified active component from traditional Chinese medicine, lentinan administration can be applied as beneficial chemo-immunotherapy for anti-tumor. In this study, the immunomodulatory effects of lentinan on aberrant T subsets and cytokines profile were evaluated for non-small cell lung cancer (NSCLC). Of all NSCLC patients treated with NP chemotherapeutic protocol (combination of vinorelbin and cisplatin), 73 cases were recruited in this retrospective cohort trial study, of which 38 cases received additional lentinan. The changes of aberrant T subsets and cytokines profile were compared between two groups (chemotherapy in combination with lentinan vs. conserved single chemotherapy) by flow cytometry and molecular biology. Higher subset ratio of CD3+CD8+ cytotoxic T cells was confirmed in the peripheral blood of NSCLC patients. Chemo-immunotherapy of lentinan resulted in a significant increase of CD3 + CD56+ NKT cells (15.7 ± 3.1%), compared with 8.6 ± 1.4% of NKT cells in single chemotherapy group, and up-regulated CD3+CD8+ and CD3+CD4+ subsets as well, but caused the decrease of CD4+CD25+ Tregs induction, accompanied by significant alleviation of IL-10 and TGF-ß1, and elevation of IFN-γ, TNF-α, and IL-12 (P < 0.05). It could be confirmed that lentinan could not only enhance the cellular immunity and promote the beneficial of anti-tumor by associated immunotherapy, but also had the ability to inhibit the expansion of immune suppressive Tregs in the NSCLC patients, in whom there was a raised Tregs induction compared to health control. Lentinan-based chemo-immunotherapy is a promising strategy for anti-tumor via enhancing the proliferation of cytotoxic T cells, followed by the elevation of inflammatory chemokines/cytokines. Meanwhile, the percentage of CD4+ CD25+ Tregs is down-regulated, leading to a shift in the inflammatory status from Th2 to Th1 in NSCLC patients treated with lentinan.

Discriminative analysis of mild Alzheimer's disease and normal aging using volume of hippocampal subfields and hippocampal mean diffusivity: an in vivo magnetic resonance imaging study.

BACKGROUND: Studies discovered that the hippocampal subfields are differentially affected by pathological damage, and magnetic resonance (MR) diffusion tensor imaging parameters might be more sensitive measures of early degeneration in Alzheimer's disease (AD) than conventional MR imaging techniques. The purpose of this study was to evaluate the significance of the volume of hippocampal subfields and the mean diffusivity (MD) value of hippocampus in discrimination between mild AD and normal aging. METHODS: A total of 29 patients with mild AD and 30 normal aging were scanned. Binary logistic regression analysis was applied to assess the diagnostic significance of the volumes of hippocampal subfields and the MD value of hippocampus. RESULTS: All hippocampal subfields except right tail atrophied significantly in the mild AD group (P < .05). The relative volumes of right CA1 and subiculum subfields entered the binary logistic regression model. The accuracy was 91.8%, which was improved to 93.9% as the MD value of right hippocampus entered the model. CONCLUSION: Atrophy was present in almost all hippocampal subfields at mild AD stage. The volumes of CA1 and subiculum were of the most diagnostic significance in discrimination of mild AD, which can be improved by the combination of volume and diffusivity analysis.