[Research on classification method of multimodal magnetic resonance images of Alzheimer's disease based on generalized convolutional neural networks].

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. Neuroimaging based on magnetic resonance imaging (MRI) is one of the most intuitive and reliable methods to perform AD screening and diagnosis. Clinical head MRI detection generates multimodal image data, and to solve the problem of multimodal MRI processing and information fusion, this paper proposes a structural and functional MRI feature extraction and fusion method based on generalized convolutional neural networks (gCNN). The method includes a three-dimensional residual U-shaped network based on hybrid attention mechanism (3D HA-ResUNet) for feature representation and classification for structural MRI, and a U-shaped graph convolutional neural network (U-GCN) for node feature representation and classification of brain functional networks for functional MRI. Based on the fusion of the two types of image features, the optimal feature subset is selected based on discrete binary particle swarm optimization, and the prediction results are output by a machine learning classifier. The validation results of multimodal dataset from the AD Neuroimaging Initiative (ADNI) open-source database show that the proposed models have superior performance in their respective data domains. The gCNN framework combines the advantages of these two models and further improves the performance of the methods using single-modal MRI, improving the classification accuracy and sensitivity by 5.56% and 11.11%, respectively. In conclusion, the gCNN-based multimodal MRI classification method proposed in this paper can provide a technical basis for the auxiliary diagnosis of Alzheimer's disease.

Mild changes in the mucosal microbiome during terminal ileum inflammation.

Patients with inflammation in the terminal ileum have high morbidity. In genetically susceptible hosts, chronic intestinal inflammation targeting the resident intestinal microbiota develops, but the microbial signature of the terminal ileum is poorly studied. To improve understanding of the mechanisms underlying the high prevalence of terminal ileum inflammation, we used 16S rRNA sequencing to analyse the mucosa-associated microbiota of the terminal ileum under intestinal homeostasis and inflammation conditions. Mucosal biopsy is the most commonly used sampling technique for assessing microbial communities associated with the intestinal mucosa. Thirty patients (15 with terminal ileum inflammation and 15 controls) underwent colonoscopy and biopsies were taken from the terminal ileum. Diagnosis depended on a combination of endoscopic and histological factors. To determine the composition and diversity of the microbiota, the 16S rRNA was analysed, and a variety of bioinformatics analyses were performed. Among the patients, composition analysis showed that the most abundant phyla identified in the terminal ileum samples were Fusobacteria, Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria. At the phylum level, the relative proportion of Bacteroidetes was lower in patients with inflammation than in control patients. In addition, there was an increase in the abundance of the phyla Proteobacteria and Lentisphaerae in patients with inflammation. The abundances of the dominant microbes in the terminal ileum were not significantly different between patients in an inflammatory state and controls. These results confirm that partial dysbiosis of the intestinal mucosa-associated microbiota composition is associated with terminal ileum inflammation.

Sanguinarine inhibits growth and invasion of gastric cancer cells via regulation of the DUSP4/ERK pathway.

Sanguinarine, a bioactive benzophenanthridine alkaloid extracted from plants of the Papaveraceae family, has shown antitumour effects in multiple cancer cells. But the therapeutic effects and regulatory mechanisms of sanguinatine in gastric cancer (GC) remain elusive. This study was aimed to investigate the correlation of dual-specificity phosphatase 4 (DUSP4) expression with clinicopathologic features and overall survival in patients with GC and explore the effects of sanguinarine on tumour growth and invasion in GC cells (SGC-7901 and HGC-27) and underlying molecular mechanisms. Immunohistochemical analysis showed that decreased DUSP4 expression was associated with the sex, tumour size, depth of invasion and distant metastasis in patients with GC. Functional experiments including CCK-8, Transwell and flow cytometry analysis indicated that sanguinarine or DUSP4 overexpression inhibited GC cell viability and invasive potential, and induced cell apoptosis and cycle arrest in S phase, but DUSP4 knockdown attenuated the antitumour activity of sanguinarine. Further observation demonstrated that sanguinarine up-regulated the expression of DUSP4 and Bcl-2-associated X protein (Bax), but down-regulated phosphorylated extracellular signal-regulated kinase (p-ERK), proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP-2) and B-cell lymphoma 2 (Bcl-2) expression. Taken together, our findings indicate that sanguinarine inhibits growth and invasion of GC cells through regulation of the DUSP4/ERK pathway, suggesting that sanguinarine may have potential for use in GC treatment.

Potent Anti-Inflammatory Activity of Tetramethylpyrazine Is Mediated through Suppression of NF-k.

The purpose of the current study was to evaluate the anti-inflammatory activity of tetramethlpyrazine on oxazolone-induced colitis mice. Spleen mononuclear cells (SMC), lamina propria mononuclear cells (LPMC) and peripheral blood mononuclear cells (PBMC) were isolated from oxazolone-induced colitis and normal mice. The colitis cells treated by oxazolone were randomly divided into model, low dose, middle dose and high dose groups treated with 0, 0.5, 1.0 and 2.0 g/L tetramethlpyrazine, respectively. The apoptotic rate of SMC and LPMC in the oxazolone-induced group was lower than that in the normal group. Compared with model group, apoptotic rate of SMC was significantly increased in the high dose group, while the apoptotic rate of LPMC in the middle dose group was increased. Compared with SMC, LPMC and PBMC of normal group, the mRNA level of nuclear factor kappa B (NF-kB), transcription factor-activated protein-1 (AP-1) and nuclear factor of activated T cells (NF-AT) were higher in model group. Tetramethylpyrazine inhibited the increase of NF-kB, AP-1 and NF-AT mRNA induced by oxazolone. For SMC, LPMC and PBMC there was significant difference in the mRNA level of AP-1 among the three different doses of tetramethylpyrazine treated groups. However, no significant difference was observed in the mRNA levels of NF-AT and NF-κB between normal and middle groups. Tetramethylpyrazine promoted the apoptotic rate of SMC and LPMC in-vitro, and suppressed the expression of transcription factors in SMC, LPMC and PBMC isolated from oxazolone-induced colitis mice. The study provides a novel insight into the mechanism behind the effect of etramethylpyrazine on colitis.

MicroRNA-203 suppresses gastric cancer growth by targeting PIBF1/Akt signaling.

BACKGROUND: MicroRNAs (miRNAs) have been proved involved in many tumorigenic behaviors including tumor growth. But, the clinical significance and functions of miRNA-203 in gastric cancer (GC) remain elusive. RESULTS: Decreased expression of miRNA-203 was correlated with tumor size, poor prognosis and recurrence in GC patients. Overexpression of miR-203 or knockdown of its target progesterone immunomodulatory binding factor 1 (PIBF1) inhibited GC growth in vitro and in vivo, while miR-203 knockdown promoted GC proliferation. In addition, PIBF1 overexpression attenuated the inhibitory effects of miR-203 on GC growth and enhanced that effect on p-Akt expression. CONCLUSIONS: MiR-203 as a tumor biomarker suppresses GC growth through targeting the PIBF1/Akt signaling, suggesting that it may have the important therapeutic potential for the treatment of GC.

Loss of large tumor suppressor 1 promotes growth and metastasis of gastric cancer cells through upregulation of the YAP signaling.

Accumulating evidence shows that large tumor suppressor 1 (LATS1) as a novel resident governor of cellular homeostasis is implicated in multiple tumorigenic properties including cell growth, apoptosis and metastasis. However, the contribution of LATS1 to gastric carcinoma (GC) remains unclear. The correlation of LATS1 expression with clinicopathologic characteristics, GC prognosis and recurrence was analyzed by immunohistochemistry, Univariate and Kaplan-Meier analysis. Functional experiments were performed to investigate biological behaviors of GC cells and underlying molecular mechanisms. Tumor growth and metastasis was assessed in vivo using orthotopic implantation GC models in severe combined immune deficiency (SCID) mice. Consequently, decreased LATS1 expression was significantly associated with the lymph node metastasis, poor prognosis and recurrence. Ectopic expression of LATS1 decreased GC cell proliferation and invasion in vitro and inhibited tumor growth and liver metastasis in vivo, but depletion of LATS1 expression restored the invasive phenotype. Further observation indicated that YAP pathway was required for LATS1-induced inhibition of cell growth and invasion, and LATS1 restrained nuclear transfer of YAP, downregulated YAP, PCNA, CTGF, MMP-2, MMP-9, Bcl-2 and CyclinD1 expression and upregulated p-YAP and Bax expression. Our findings suggest that LATS1 is a potential candidate tumor suppressor and inhibits the growth and metastasis of GC cells via downregulation of the YAP signaling.

Eriocalyxin B blocks human SW1116 colon cancer cell proliferation, migration, invasion, cell cycle progression and angiogenesis via the JAK2/STAT3 signaling pathway.

Eriocalyxin B, a natural ent-kaurene diterpene compound, has been shown to prevent carcinogenesis and tumor development. However, little is known regarding the mechanism underlying the antitumor activity of Eriocalyxin B in human colon cancer. The aim of the present study was to examine the role of Eriocalyxin B in SW1116 cells, and to verify the hypothesis that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway may serve as a therapeutic target in human colon cancer treatment. Cell proliferation was measured with a Cell Counting kit­8 assay, and the cell cycle was assessed by flow cytometry. Cell migration and invasion were measured by Transwell analysis. In addition, western blot analysis was performed to detect the protein expression levels in SW1116 cells treated with various concentrations of Eriocalyxin B. The results demonstrated that 1 µmol/l Eriocalyxin B was effective at inhibiting JAK2 and STAT3 phosphorylation, followed by the downregulation of JAK2 and STAT3 downstream target expression, which resulted in the inhibition of cell proliferation, migration, invasion and angiogenesis. Eriocalyxin B also suppressed the expression of proliferation­associated protein (proliferating cell nuclear antigen) and angiogenesis­associated proteins (vascular endothelial growth factor and vascular endothelial growth factor receptor 2), as well as that of migration- and invasion­associated proteins (matrix metalloproteinase 2 and 9). These results suggested that Eriocalyxin B may suppress JAK2/STAT3 signaling, and thus act as a therapeutic or preventive agent in the treatment of human colon cancer.

Silencing of MAP4K4 by short hairpin RNA suppresses proliferation, induces G1 cell cycle arrest and induces apoptosis in gastric cancer cells.

Gastric cancer (GC) is the second most common cause of cancer­associated mortality worldwide. Previous studies suggest that mitogen­activated protein kinase kinase kinase kinase isoform 4 (MAP4K4) is involved in cancer cell growth, apoptosis and migration. In the present study, bioinformatics analysis and reverse transcription­quantitative polymerase chain reaction were performed to determine if MAP4K4 was overexpressed in GC. The knockdown of MAP4K4 by RNA interference in GC cells markedly inhibited cell proliferation, which may be mediated by cell cycle arrest in the G1 phase. The silencing of MAP4K4 also induced cell apoptosis by increasing the ratio of Bax/Bcl­2. In addition, Notch signaling was markedly reduced by MAP4K4 silencing. The results of the present study suggested that inhibition of MAP4K4 may be a therapeutic strategy for GC.

Effect of RTKN on progression and metastasis of colon cancer in vitro.

Like many epithelial-derived cancers, colon cancer results from a multistep tumorigenic process. However, the detailed mechanisms involved in colon cancer formations are poorly characterized. In the present study, we investigated the role of RTKN in colon cancer and explored underlying mechanisms. The results showed that RTKN expression was significantly increased in colon cancer tissues when compared with the adjacent tissues of patients in Shanghai People's hospital and in TCGA independent dataset. Furthermore, silencing of RTKN inhibited cell proliferation, migration, invasion, and arrested cell cycle at G1 phase in LOVO cells. Bioinformatics analysis demonstrated that DNA replication and cell cycle were involved in the regulation of RTKN. MCM2/3/5, CDK1/2 and PCNA expression had a direct relationship with the reduction of RTKN. RTKN could affect the proliferation and metastasis of colon cancer by reducing expression of MCM2/3/5, CDK1/2 and PCNA, suggesting that RTKN was a potential target for treating colon cancer.

Toosendanin inhibits growth and induces apoptosis in colorectal cancer cells through suppression of AKT/GSK-3ß/ß-catenin pathway.

AKT/GSK-3ß/ß-catenin signaling pathway plays an important role in the progression of colorectal cancer (CRC). Toosendanin (TSN) is a triterpenoid extracted from the bark or fruits of Melia toosendan Sieb et Zucc and possesses antitumour effects on various human cancer cells. However, its effect on CRC remains poorly understood. The present study investigated the effect of TSN on CRC SW480 cells and the AKT/GSK-3ß/ß-catenin signaling. Proliferation assay, flow cytometry and Hoechst 33342 nuclear staining demonstrated TSN dose-dependently inhibited cell viability and induced cell apoptosis as well as cell cycle arrest in S phase. Confocal laser scanning microscope showed ß-catenin transferred to the outside of the nucleus in TSN-treated cells. Quantitative real-time PCR and western blot analysis found that TSN effectively modulated molecules related to apoptosis and AKT/GSK-3ß/ß-catenin signaling. Moreover, TSN administration significantly inhibited CRC growth in a mouse tumor xenograft model. In conclusion, our findings indicate that TSN inhibits growth and induces apoptosis in CRC cells through suppression of AKT/GSK-3ß/ß-catenin pathway, suggesting that TSN may have potential for use in CRC treatment.

Ponicidin induces apoptosis via JAK2 and STAT3 signaling pathways in gastric carcinoma.

Ponicidin has a variety of biological effects such as immunoregulatory and anti-inflammatory functions as well as anti-viral functions especially in the upper respiratory tract infection. This study was aimed to elucidate the antitumor effect of ponicidin in gastric carcinoma MKN28 cells and the possible molecular mechanism involved. Cell viability was measured by the Cell Count Kit-8 (CCK8). Cell apoptosis was assessed by flow cytometry as well as cell cycle and reactive oxygen species (ROS) analysis. Western blot analysis was used to detect the active form of caspase-3 as well as Bax and B-cell lymphoma-2 (Bcl-2) expressions after cells were treated with different concentrations of ponicidin. The results revealed that ponicidin could inhibit the growth of MKN28 cells significantly in both a time- and dose-dependent manner. The cell cycle was blocked and ROS generation was increased after the cells were treated with ponicidin. Bcl-2 expression was down-regulated remarkably while Bax expression and the active form of caspase-3 were increased after apoptosis occurred. We therefore conclude that ponicidin exhibited significant growth inhibition of gastric carcinoma cell line MKN28 and induced apoptosis of MKN28 cells via the signaling pathway regulated by Janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). Ponicidin may serve as a potential therapeutic agent for gastric carcinoma.

Oleanolic acid induces apoptosis of MKN28 cells via AKT and JNK signaling pathways.

CONTEXT: Oleanolic acid (OA) belongs to the triterpenoid compound group existing widely in food, medicinal herbs and other plants. Its effects on gastric cancer cells and the mechanisms involved have not been investigated. OBJECTIVE: This study aimed to substantiate whether OA induces apoptosis of gastric cancer cell line (MKN28) and to elucidate the molecular mechanism involved. MATERIALS AND METHODS: Cell viability was assessed by MTT assay within the range of 0-160 µg/mL. The effects of OA (5, 10 and 20 µg/mL) on apoptosis of MKN28 cells were evaluated by flow cytometry, DNA fragmentation and mitochondrial membrane potential assays. Western blot and FQRT-PCR assays were used to investigate the mechanism of cell apoptosis induced by OA (5 and 10 µg/mL). RESULTS: OA evidently inhibited cell viability with IC50 of 44.8 and 15.9 µg/mL at 12 and 24 h, respectively. Furthermore, OA increased JNK phosphorylation, decreased AKT phosphorylation, but did not affect p38 and ERK phosphorylation in MKN28 cells. In contrast, OA also significantly enhanced the mRNA expression levels of caspase 3, caspase 9 and Apaf-1 in MKN28 cells. CONCLUSION: OA induces apoptosis of MKN28 cells via the mitochondrial pathway regulated by AKT and JNK signaling pathways.

Tetramethylpyrazine improves oxazolone-induced colitis by inhibiting the NF-κB pathway.

PURPOSE: Tetramethylpyrazine (TMP) is an effective Chinese plant-derived medicine for colitis in the clinic, but the underlying molecular mechanisms of its use remain poorly understood. The purpose of this study was to investigate the mechanisms involved in its therapeutic action. METHODS: A colitis mouse model was induced by oxazolone enema. TMP was administered at 80 mg/kg/day and sulphasalazine (SASP) was used as positive control and administered at 100 mg/kg/day for the treatment of colitis. On the fourth day after enema, mice were sacrificed. The inflammatory response was assessed by the disease activity index and histology. Colon mucosa was isolated and biochemically analyzed. In addition, in vitro studies were performed to evaluate the activity of TMP in Caco-2 cells. RESULTS: Our results showed that TMP improved the colonic inflammatory status as evidenced by histological findings, as well as SASP. These effects were associated with a decrease in nucleus translocation of NF-κB. Paired with this inhibitive activity, there was a decrease in downstream signaling, such as C-MYC, iNOS and COX-2. In vitro assays revealed that TMP inhibited NF-κB translocation and its downstream production of inflammatory factors, such as TNF-α, IL-6 and IL-8, and that ROS production that was induced by LPS in Caco-2 cells. CONCLUSION: TMP improved the colitis induced by oxazoline, and its activity was associated with inhibition of NF-κB translocation, and subsequent inhibition of pro-inflammatory factor production and oxidative stress.

Adalimumab for Crohn's disease after infliximab treatment failure: a systematic review.

The tumor necrosis factor inhibitors infliximab and adalimumab are effective treatments for Crohn's disease (CD); however, some patients treated with infliximab experience a loss of efficacy. There is a lack of high-quality evidence available on whether adalimumab is an effective treatment for patients who have failed infliximab treatment. A systematic review was carried out to examine the efficacy and safety of adalimumab for the treatment of CD in patients who have failed infliximab treatment. PubMed, Google Scholar, and the Cochrane Library were searched using the terms 'adalimumab AND infliximab AND Crohn's'. Randomized-controlled trials and cohort studies were included if they involved patients treated with adalimumab after failing infliximab. Outcomes were response and remission rates, adverse event (AE) rate, and the rate of discontinuations because of AEs. Ten studies (one randomized-controlled trial and nine cohort studies) involving 1009 patients were included. Luminal disease remission rates ranged from 12 to 67% during induction and 29 to 72% during maintenance therapy. Fistulizing disease remission rates ranged from 5 to 50% during induction and 27 to 68% during maintenance therapy. Luminal disease response rates ranged from 29 to 83% during induction and 31 to 59% during maintenance therapy. Fistulizing disease response rates ranged from 15 to 44% during induction and 41 to 56% during maintenance therapy. The overall AE rate ranged from 13 to 69%. Most AEs were mild to moderate in severity. The rate of discontinuation because of AEs ranged from 0 to 14%. The findings reported in the current literature support adalimumab as an efficacious and safe treatment for CD in patients who have failed infliximab treatment.

Efficacy and safety of certolizumab pegol for Crohn's disease: a systematic review and meta-analysis.

INTRODUCTION: The authors performed a systematic review and meta-analysis of data from randomized controlled trials (RCTs) to evaluate the efficacy and safety of certolizumab pegol. METHODS: The authors searched PubMed, MEDLINE via Medscape, BioMed Central, Google Scholar, China National Knowledge Infrastructure (CNKI), the Cochrane library, and the Directory of Open Access Journals. The outcomes of interest were response and remission rates and the treatment-related toxicity rate. RESULTS: A total of five RCTs, involving 1,891 participants, were included. The meta-analysis revealed that certolizumab significantly increased the overall (induction + maintenance therapy) response [odds ratio (OR) 1.565, 95% CI 1.056-2.321, P = 0.026] and remission rates (OR 1.626, 95% CI 1.297-2.038, P < 0.001) compared with placebo. Certolizumab significantly increased the response and remission rates when given as maintenance therapy (OR 2.171, 95% CI 1.644-2.866, P < 0.001 and OR 1.888, 95% CI 1.390-2.565, P < 0.001), but not as induction therapy (OR 1.234, 95% CI 0.912-1.671, P = 0.173 and OR 1.361, 95% CI 0.974-1.901, P = 0.071). Certolizumab (induction + maintenance therapy) did not significantly increase the treatment-related toxicity rate compared with placebo (OR 0.985, 95% CI 0.799-1.214, P = 0.887). CONCLUSION: Certolizumab may be an efficacious treatment for Crohn's disease as maintenance therapy and appears to have a favorable safety profile.

Tetramethylpyrazine attenuates PPAR-γ antagonist-deteriorated oxazolone-induced colitis in mice.

Tetramethylpyrazine (TMP) is suggested to have anti-inflammatory activity. The aim of this study was to determine the role of peroxisome proliferator activated receptor γ (PPAR-γ) signaling in the pharmacologic effect of TMP on oxazolone (OXZ)-induced colitis. TMP (80 mg/kg/day i.p.) was administered daily 48 h after intrarectal instillation of OXZ, with or without PPAR-γ inhibitor [bisphenol A diglycidyl ether (BADGE) 30 mg/kg] during the 4 days before sacrifice. The inflammatory response was assessed by the disease activity index, macroscopy, histology and myeloperoxidase (MPO) activity. Expression levels of PPAR-γ, NF-κB p65, COX-2, iNOS and TNF-α mRNA in colon mucosa were determined by FQ-PCR, levels of PPAR-γ and NF-κB p65 protein were analyzed by immunohistochemistry, and the total and phosphorylated levels of p38 MAPK were assessed by western blotting. TMP significantly attenuated the damage caused by OXZ and substantially reduced the rise in MPO activity, TNF-α, iNOS, NF-κB p65 and COX-2 expression, as well as the increase in PPAR-γ production; however, no changes in the activation of p38 MAPK were observed. Inhibition of PPAR-γ signaling aggravated inflammation of colon mucosa, and increased p38 phosphrylation. TMP counteracted the effect of inhibition of PPAR-γ. We suggest that the effect of TMP treatment in ulcerative colitis may be related to PPAR-γ signaling, but is independent of PPAR-γ.