Classifying youth with bipolar disorder versus healthy youth using cerebral blood flow patterns.

BACKGROUND: Clinical neuroimaging studies often investigate group differences between patients and controls, yet multivariate imaging features may enable individual-level classification. This study aims to classify youth with bipolar disorder (BD) versus healthy youth using grey matter cerebral blood flow (CBF) data analyzed with logistic regressions. METHODS: Using a 3 Tesla magnetic resonance imaging (MRI) system, we collected pseudo-continuous, arterial spin-labelling, resting-state functional MRI (rfMRI) and T 1-weighted images from youth with BD and healthy controls. We used 3 logistic regression models to classify youth with BD versus controls, controlling for age and sex, using mean grey matter CBF as a single explanatory variable, quantitative CBF features based on principal component analysis (PCA) or relative (intensity-normalized) CBF features based on PCA. We also carried out a comparison analysis using rfMRI data. RESULTS: The study included 46 patients with BD (mean age 17 yr, standard deviation [SD] 1 yr; 25 females) and 49 healthy controls (mean age 16 yr, SD 2 yr; 24 females). Global mean CBF and multivariate quantitative CBF offered similar classification performance that was above chance. The association between CBF images and the feature map was not significantly different between groups (p = 0.13); however, the multivariate classifier identified regions with lower CBF among patients with BD (ΔCBF = -2.94 mL/100 g/min; permutation test p = 0047). Classification performance decreased when considering rfMRI data. LIMITATIONS: We cannot comment on which CBF principal component is most relevant to the classification. Participants may have had various mood states, comorbidities, demographics and medication records. CONCLUSION: Brain CBF features can classify youth with BD versus healthy controls with above-chance accuracy using logistic regression. A global CBF feature may offer similar classification performance to distinct multivariate CBF features.

[Development of Portable Bowel Sound Monitor].

This paper designs and implements a low power portable bowel sound monitor, which adopts bone conduction transducer to collect bowel sound continuously for long time and transmit to phone by Bluetooth. Then the phone application can record, play and analyse the bowel sound digital data in real time. This paper also designs an experiment to collect bowel sound from healthy people and patients with intestinal obstruction. It is verified by clinicians that this monitor can accurately record and preserve the bowel sound of the detected people, and is not disturbed by the external environment.

Phosphatase of regenerating liver-3 induces angiogenesis by increasing extracellular signal-regulated kinase phosphorylation in endometrial adenocarcinoma.

OBJECTIVE: The aim of this study was to investigate the mechanism by which phosphatase of regenerating liver-3 (PRL-3) induces angiogenesis in endometrial adenocarcinoma tissues and cells. METHODS: We investigated the expression of PRL-3 and vascular endothelial growth factor (VEGF) in samples from 124 patients with endometrial adenocarcinoma using immunohistochemical staining. The relationship between PRL-3 expression and microvessel density (MVD), clinicopathological factors and surgical treatment outcome was also studied. Following this, we studied the effect on cell lines of blocking or upregulating PRL-3. RESULTS: PRL-3 expression in endometrial adenocarcinoma was high, and this overexpression is correlated with advanced clinical stage (p=0.008), lymph node metastasis (p=0.016) and poor postoperative survival. PRL-3 overexpression was associated with VEGF (p=0.001) expression and MVD (p=0.005). Upregulating PRL-3 expression promoted VEGF and phosphorylated extracellular signal-regulated kinase (pERK) expression. Blocking PRL-3 expression inhibited VEGF and pERK expression. Following inhibition of pERK, VEGF expression was downregulated. CONCLUSIONS: PRL-3 induces microvascular vessel formation by facilitating VEGF expression in endometrial adenocarcinoma tissues. PRL-3 upregulates pERK expression and activity, facilitating VEGF expression and accelerating angiogenesis.

A Blood-Based Lipid Profile Associated With Hippocampal Volume and Brain Resting-State Activation Within Obese Adults from the UK Biobank.

Objectives: Obesity and dyslipidemia may be associated with hippocampal alterations and may increase the risk of neurodegeneration. This study studied hippocampal anatomical and functional association with a lipid profile based on high-density lipoprotein, low-density lipoprotein, and triglyceride related to dyslipidemia in obese and nonobese adults. A whole-brain analysis was also conducted to examine the effect of dyslipidemia on resting-state function across the brain. Participants and Methods: In total, 553 UK Biobank participants comprised three groups based on body mass index (BMI) rankings: obese adults with high BMI (OHigh, n = 184, 32.7 kg/m2 ≤ BMI ≤53.4 kg/m2), obese adults with a lower BMI (OLow, n = 182, 30.3 kg/m2 ≤ BMI ≤32.6 kg/m2), and nonobese controls (n = 187). Structural MRI and functional MRI data were accessed. The fractional amplitude of low-frequency fluctuations (fALFFs) maps was calculated to reflect resting-state brain activity. A lipid health factor was created using principal component analysis. Linear models tested for associations between the lipid health score and hippocampal MRI readouts. Results: With a higher lipid health factor corresponding to a lower dyslipidemia risk, we found a positive correlation between hippocampal volume with the lipid health factor exclusively in group OLow (p = 0.01). We also found a positive association between the lipid health factor and hippocampal fALFF in group OHigh (p = 0.02). Additional fALFF voxel-wise analysis to group OHigh also implicated that the premotor cortex, amygdala, thalamus, subcallosal cortex, temporal fusiform cortex, and middle temporal gyrus brain regions are related with lipid. Conclusion: The study finds novel associations among circulating lipid, hippocampal structure, and hippocampal function exclusively in the obese adults.

Effects of inflammatory factors on mesenchymal stem cells and their role in the promotion of tumor angiogenesis in colon cancer.

Mesenchymal stem cells (MSCs), which are modulated by cytokines present in the tumor microenvironment, play an important role in tumor progression. It is well documented that inflammation is an important part of the tumor microenvironment, so we investigated whether stimulation of MSCs by inflammatory cytokines would contribute to their ability to promote tumor growth. We first showed that MSCs could increase C26 colon cancer growth in mice. This growth-promoting effect was further accelerated when the MSCs were pre-stimulated by inflammatory factors IFN-γ and TNF-α. At the same time, we demonstrated that MSCs pre-stimulated by both inflammatory factors could promote tumor angiogenesis in vivo to a greater degree than untreated MSCs or MSCs pre-stimulated by either IFN-γ or TNF-α alone. A hen egg test-chorioallantoic membrane (HET-CAM) assay showed that treatment of MSC-conditioned medium can promote chorioallantoic membrane angiogenesis in vitro, especially treatment with conditioned medium of MSCs pretreated with IFN-γ and TNF-α together. This mechanism of promoting angiogenesis appears to take place via an increase in the expression of vascular endothelial growth factor (VEGF), which itself takes place through an increase in signaling in the hypoxia-inducible factor 1α (HIF-1α)-dependent pathway. Inhibition of HIF-1α in MSCs by siRNA was found to effectively reduce the ability of MSC to affect the growth of colon cancer in vivo in the inflammatory microenviroment. These results indicate that MSCs stimulated by inflammatory cytokines such as IFN-γ and TNF-α in the tumor microenvironment express higher levels of VEGF via the HIF-1α signaling pathway and that these MSCs then enhance tumor angiogenesis, finally leading to colon cancer growth in mice.

Interleukin-7 up-regulates cyclin D1 via activator protein-1 to promote proliferation of cell in lung cancer.

Interleukin-7 is a potent regulator of lymphocyte proliferation, but it inducing growth of solid tumors is few known. We study the relationship between Interleukin-7 and the regulator of the cell cycle, cyclin D1 and the mechanism of Interleukin-7 regulating cell growth in human lung cancer. We detected expression of cyclin D1 and its impact on the prognosis of lung cancer patients. Using Western blot, reverse transcriptase-PCR, Co-Immunoprecipitation, and Chromatin Immunoprecipitation, we investigated how Interleukin-7 regulated cyclin D1 in vitro and in nude mice. We found that, in lung cancer cell lines and in nude mice, Interleukin-7/Interleukin-7 receptor increased the expression of cyclin D1 and phosphorylation of c-Fos/c-Jun, induce c-Fos and c-Jun heterodimer formation, and enhanced c-Fos/c-Jun DNA-binding activity to regulate cyclin D1. In addition, lymph node metastasis, tumor stage, and cyclin D1 were the strongest predictors of survival in 100 human non-small cell lung cancer specimens analyzed. Taken together, our results provided evidence that Interleukin-7/Interleukin-7 receptor induced cyclin D1 up-regulation via c-Fos/c-Jun pathway to promote proliferation of cells in lung cancer.

[Interleukin 7 and its receptor promote cell proliferation and induce lymphangiogenesis in non-small cell lung cancer].

OBJECTIVE: To study the mechanism of interleukin 7/interleukin 7 receptor (IL-7/IL-7R) in promoting cell proliferation and inducing lymphangiogenesis of non-small cell lung cancer (NSCLC) in vivo and in vitro. METHODS: Immunohistochemical study for IL-7, IL-7R, cyclin D1 and vascular endothelial growth factor-D (VEGF-D) was carried out in NSCLC tissues from 95 patients. The relationship between IL-7/IL-7R expression and various parameters was analyzed. The mechanism of IL-7/IL-7R in promoting cell proliferation and inducing lymphangiogenesis was studied by methylthiazolyldiphenyl-tetrazolium bromide, fluorescence-activated cell sorting, reverse transcriptase-PCR, Western blot, co-immunoprecipitation, chromatin immunoprecipitation and nude mice experiments with xenograft tumors. RESULTS: IL-7 (63.2%, 60/95), IL-7R (61.1%, 58/95), cyclin D1 (52.6%, 50/95) and VEGF-D (58.9%, 56/95) showed that high level of expression in NSCLC. IL-7/IL-7R over-expression correlated with cyclin D1 expression (P < 0.01, P < 0.01), VEGF-D expression (P < 0.01, P < 0.01), increased lymphovascular density (P = 0.005, P = 0.013), advanced clinical stage (P = 0.008, P = 0.005) and presence of lymph node metastasis (P < 0.01, P < 0.01). IL-7/IL-7R could promote proliferation of A549 cell, increase cyclin D1 and VEGF-D expression, and enhance c-Fos/c-Jun expression and phosphorylation, resulting in formation of heterodimer. Furthermore, IL-7/IL-7R could induce binding of c-Fos/c-Jun to cyclin D1/VEGF-D promoters and regulate their transcription. IL-7/IL-7R could also promote proliferation and lymphangiogenesis of lung cancer xenograft tumors. CONCLUSIONS: IL-7/IL-7R promotes c-Fos/c-Jun expression and activity in NSCLC. This further facilitates cyclin D1 expression and accelerates proliferation of cells and VEGF-D-induced lymphovascular formation.

Immunosuppressive effect of bone marrow-derived mesenchymal stem cells in inflammatory microenvironment favours the growth of B16 melanoma cells.

Mesenchymal stem cells (MSCs) are studied for their potential clinical use in regenerative medicine, tissue engineering and tumour therapy. However, the therapeutic application of MSCs in tumour therapy still remains limited unless the immunosuppressive role of MSCs for tumour growth in vivo is better understood. In this study, we investigated the mechanism of MSCs favouring tumour escape from immunologic surveillance in inflammatory microenvironment. We first compared the promotive capacity of bone marrow-derived MSCs on B16 melanoma cells growth in vivo, pre-incubated or not with the inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We showed that the development of B16 melanoma cells is faster when co-injected with MSCs pre-incubated with IFN-γ and TNF-α compared with control groups. Moreover, tumour incidence increases obviously in allogeneic recipients when B16 melanoma cells were co-injected with MSCs pre-incubated with IFN-γ and TNF-α. We then demonstrated that the immunosuppressive function of MSCs was elicited by IFN-γ and TNF-α. These cytokine combinations provoke the expression of inducible nitric oxide synthase (iNOS) by MSCs. The impulsive effect of MSCs treated with inflammatory cytokines on B16 melanoma cells in vivo can be reversed by inhibitor or short interfering RNA of iNOS. Our results suggest that the MSCs in tumour inflammatory microenvironment may be elicited of immunosuppressive function, which will help tumour to escape from the immunity surveillance.

Elevated expression of the stem cell marker CD133 associated with Line-1 demethylation in hepatocellular carcinoma.

BACKGROUND: The relationship of Line-1 demethylation and the CD133 expression of cancer stem cells were discussed in hepatocellular carcinoma (HCC). METHODS: In 95 HCC and matched nontumor tissues, we analyzed the methylation level of Line-1 by quantitative real-time methylation-specific polymerase chain reaction, and the expression of CD133 by real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: Unmethylation of Line-1 increased from nontumor tissues (1.23 × 10(7) copies/µg DNA) toward HCC tissues (2.99 × 10(7) copies/µg DNA), but methylation of Line-1 kept 2 × 10(8) copies/µg DNA around in HCC and nontumor tissues. The methylation index (MI) of Line-1 decreased from 0.919 in nontumor samples to 0.755 in HCC. Results showed that cumulative survival was significantly shorter in HCC patients with MI < 0.76 than that in patients with MI ≥ 0.76. CD133 mRNA expression were higher in HCC tissues (mean -∆(Ct) = -5.751) than that in nontumor tissues (mean -∆(Ct) = -6.742). A total of 73 (76.8%) patients had demethylation of Line-1 (∆MI < 0), and 22 (23.2%) patients had hypermethylation of Line-1 (∆MI ≥ 0). HCC with demethylation of Line-1 had elevated CD133 expression in tumor rather than matched nontumor tissues (mean -∆(∆Ct) = 1.101), but HCC with hypermethylation of Line-1 was considered to be lower with CD133 expression in tumor (mean -∆(∆Ct) = -0.409). CONCLUSIONS: Line-1 hypomethylation is the most common molecular abnormality during the carcinogenic process. Elevated expression of CD133 was associated with demethylation of Line-1 in HCC.

Tumor necrosis factor-alpha promotes tumor growth by inducing vascular endothelial growth factor.

Tumor necrosis factor (TNF)-α has been proved as an adjuvant therapy for tumor by FDA. However, the effect of chronic TNF-α expression for tumor is still controversial. In this study, we investigated the effect of low-dose TNF-α on tumor growth. We confirmed that low-dose TNF-α promoted angiogenesis of tumor in vivo, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α, the transcription factor of VEGF, were both upregulated. Our results suggested that low-dose TNF-α was a powerful activator of angiogenesis in tumor and HIF-1α-VEGF pathway seemed to be the most important molecular mechanism.

Correlation of CpG island methylator phenotype with poor prognosis in hepatocellular carcinoma.

CpG island methylator phenotype (CIMP), in which multiple genes are concurrently methylated, is an important mechanism in hepatocellular carcinoma development. We determined a hypermethylation profile in hepatocellular carcinoma (HCC). We examined the promoter methylation status of 10 genes in 60 cases of hepatocellular carcinoma (HCC), 60 cases of paired non-tumor tissues, and 6 cases of normal tissues by methylation-specific PCR. The average methylated gene numbers were significantly different between HCC and nontumor tissues (p<0.001). We found metastasis, gamma-glutamyl transpeptidase (GGT) and tumor node metastasis (TNM) stage were significantly different among patients with different CIMP status. Patients with high frequency CIMP tumors had significantly worse survival than patients with intermediate frequency or no CIMP tumors (p<0.01 and p<0.05, respectively). Our results suggested that CIMP could serve as a molecular marker of late stage and poorly prognostic HCC development.

CpG island methylator phenotype association with upregulated telomerase activity in hepatocellular carcinoma.

CpG island methylator phenotype (CIMP) involves the targeting of multiple genes by promoter hypermethylation. Telomerase plays an important role in the development of cellular immortality and oncogenesis. To gain insight into the role of epigenetic aberration of telomerase-related genes in hepatocarcinogenesis, we determined a hypermethylation profile in HCC. We examined the promoter methylation status of 9 genes associated with telomerase activity in 120 HCC, 120 cirrhosis tissues and 10 normal liver tissues by methylation-specific PCR. Assay of telomerase activity was by TRAP-ELISA. The frequency of promoter methylation of each gene was P21 63.3%, P15 42.5%, P16 62.5%, P53 14.2%, RB 32.5%, P27 48.3%, WTI 54.2%, E2F-1 70.8% and P300 65.8% of 120 HCC. Methylation status of P21, P15, P16, WTI and E2F-1 was significantly associated with HCC and nontumor tissues (p < 0.05). CIMP+ was detected in 61.7% (74/120) HCC and 15% (18/120) cirrhosis tissues, no CIMP+ was present in normal liver tissues (p < 0.001). A significant difference between CIMP status and metastasis was been found in HCC (p < 0.001). Results showed that 94.6% (70/74) HCC and 55.6% (10/18) cirrhosis patients with CIMP+ show expression of high telomerase activity than 45.5% (10/22) HCC and 6.25% (1/16) cirrhosis patients with CIMP- (p < 0.001). CIMP lead to high levels of expression of telomerase activity through the simultaneous inactivation of multiple genes associated with telomerase activity by concordant methylation.

Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells.

BACKGROUND: Chemoresistance is one of the main obstacles to successful cancer therapy and is frequently associated with Multidrug resistance (MDR). Many different mechanisms have been suggested to explain the development of an MDR phenotype in cancer cells. One of the most studied mechanisms is the overexpression of P-glycoprotein (P-gp), which is a product of the MDR1 gene. Tumor cells often acquire the drug-resistance phenotype due to upregulation of the MDR1 gene. Overexpression of MDR1 gene has often been reported in primary gastric adenocarcinoma. METHODS: This study investigated the role of p38-MAPK signal pathway in vincristine-resistant SGC7901/VCR cells. P-gp and MDR1 RNA were detected by Western blot analysis and RT-PCR amplification. Mitgen-activated protein kinases and function of P-gp were demonstrated by Western blot and FACS Aria cytometer analysis. Ap-1 activity and cell apoptosis were detected by Dual-Luciferase Reporter Assay and annexin V-PI dual staining. RESULTS: The vincristine-resistant SGC7901/VCR cells with increased expression of the multidrug-resistance 1 (MDR1) gene were resistant to P-gp-related drug and P-gp-unrelated drugs. Constitutive increases of phosphorylated p38-MAPK and AP-1 activities were also found in the drug-resistant cells. Inhibition of p38-MAPK by SB202190 reduced activator protein-1 (AP-1) activity and MDR1 expression levels and increased the sensitivity of SGC7901/VCR cells to chemotherapy. CONCLUSION: Activation of the p38-MAPK pathway might be responsible for the modulation of P-glycoprotein-mediated and P-glycoprotein-unmediated multidrug resistance in the SGC7901/VCR cell line.

Mesenchymal stem cells in inflammation microenvironment accelerates hepatocellular carcinoma metastasis by inducing epithelial-mesenchymal transition.

In response to inflammation, mesenchymal stem cells (MSCs) are known to migrate to tissue injury sites to participate in immune modulation, tissue remodeling and wound healing. Tumors apply persistent mechanical and pathological stress to tissues and causes continual infiltration of MSCs. Here, we demonstrate that MSCs promote human hepatocellular carcinoma (HCC) metastasis under the influence of inflammation. The metastasis promoting effect could be imitated with the supernatant of MSCs pretreated with IFNγ and TNFα. Interestingly, treatment of HCC cells with the supernatant leads to epithelial-mesenchymal transition (EMT), an effect related to the production of TGFß by cytokines stimulated MSCs. Importantly, the levels of MSCs expressing SSEA4 in clinical HCC samples significantly correlated with poor prognosis of HCC, and EMT of HCC was strongly associated with a shorter cancer-free interval (CFI) and a worse overall survival (OS). Therefore, our results suggest that MSCs in tumor inflammatory microenvironment could promote tumor metastasis through TGFß-induced EMT.