Research on variable universe fuzzy PID control for semi-active suspension with CDC dampers based on dynamic adjustment functions.

The vehicle suspension system is a complex system with multiple variables, nonlinearity and time-varying characteristics, and the traditional variable universe fuzzy PID control algorithm has the problems of over-reliance on expert experience and non-adaptive adjustment of the contracting-expanding factor parameters, which make it difficult to achieve a better control effect. In this paper, the system error e(t) and its change rate ec(t) are introduced into the contracting-expanding factor as dynamic parameters to realize the adaptive adjustment of the contracting-expanding factor parameters, and propose a variable universe fuzzy PID control based on dynamic adjustment functions (VUFP-DAF), which uses the real-time contracting-expanding factor to realize the adaptive adjustment of the fuzzy universe, so as to improve the ride comfort of vehicles. The research results show that the proposed VUFP-DAF has strong adaptability and can effectively improve the ride comfort and handling stability of vehicles under different speeds and road excitations, providing a certain technical basis for the development of the semi-active suspension system.

Metabolic Labeling of Legionaminic Acid in Flagellin Glycosylation of Campylobacter jejuni Identifies Maf4 as a Putative Legionaminyl Transferase.

Campylobacter jejuni is the major human food-borne pathogen. Its bipolar flagella are heavily O-glycosylated with microbial sialic acids and essential for its motility and pathogenicity. However, both the glycosylation of flagella and the exact contribution of legionaminic acid (Leg) to flagellar activity is poorly understood. Herein, we report the development of a metabolic labeling method for Leg glycosylation on bacterial flagella with probes based on azide-modified Leg precursors. The hereby azido-Leg labeled flagellin could be detected by Western blot analysis and imaged on intact bacteria. Using the probes on C. jejuni and its isogenic maf4 mutant we also further substantiated the identification of Maf4 as a putative Leg glycosyltransferase. Further evidence was provided by UPLC-MS detection of labeled CMP-Leg and an in silico model of Maf4. This method and the developed probes will facilitate the study of Leg glycosylation and the functional role of this modification in C. jejuni motility and invasiveness.

FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer.

BACKGROUND: Low expression of FOXE1, a member of Forkhead box (FOX) transcription factor family that plays vital roles in cancers, contributes to poor prognosis of colorectal cancer (CRC) patients. However, the underlying mechanism remains unclear. MATERIALS AND METHODS: The effects of FOXE1 on the growth of colon cancer cells and the expression of glycolytic enzymes were investigated in vitro and in vivo. Molecular biological experiments were used to reveal the underlying mechanisms of altered aerobic glycolysis. CRC tissue specimens were used to determine the clinical association of ectopic metabolism caused by dysregulated FOXE1. RESULTS: FOXE1 is highly expressed in normal colon tissues compared with cancer tissues and low expression of FOXE1 is significantly associated with poor prognosis of CRC patients. Silencing FOXE1 in CRC cell lines dramatically enhanced cell proliferation and colony formation and promoted glucose consumption and lactate production, while enforced expression of FOXE1 manifested the opposite effects. Mechanistically, FOXE1 bound directly to the promoter region of HK2 and negatively regulated its transcription. Furthermore, the expression of FOXE1 in CRC tissues was negatively correlated with that of HK2. CONCLUSION: FOXE1 functions as a critical tumor suppressor in regulating tumor growth and glycolysis via suppressing HK2 in CRC.

Selective Activation of a Prodrug by Thioredoxin Reductase Providing a Strategy to Target Cancer Cells.

Elevated reactive oxygen species and antioxidant defense systems have been recognized as one of the hallmarks of cancer cells. As a major regulator of the cellular redox homeostasis, the selenoprotein thioredoxin reductase (TrxR) is increasingly considered as a promising target for anticancer drug development. The current approach to inhibit TrxR predominantly relies on the modification of the selenocysteine residue in the C-terminal active site of the enzyme, in which it is hard to avoid the off-target effects. By conjugating the anticancer drug gemcitabine with a 1,2-dithiolane scaffold, an unprecedented prodrug strategy is disclosed that achieves a specific release of gemcitabine by TrxR in cells. As overexpression of TrxR is frequently found in different types of tumors, the TrxR-dependent prodrugs are promising for further development as cancer chemotherapeutic agents.

Correlation between clinicopathological features and KRAS, NRAS, and BRAF mutation status in Chinese colorectal cancer patients.

This study was retrospectively performed to analyze correlations between clinicopathological features of colorectal cancer (CRC) and mutations in KRAS, NRAS, and BRAF in Chinese patients, and to assess the importance of detecting additional mutations in KRAS exons 3 and 4 and NRAS in patients with CRC. RAS (KRAS and NRAS) and BRAF mutations were detected in 715 and 655 patients respectively. The mutation rate of RAS (KRAS or NRAS) was 45.6% (326/715). KRAS exon 2 mutations were evaluated in 36.6% of patients (262/715). Additional mutations in RAS exons occurred in 9.0% of patients (64/715), including KRAS exons 3 and 4 in 5.6% (40/715) and NRAS exons 2, 3, or 4 in 3.4% (24/715). Among 453 patients with wild-type KRAS exon 2, 14.1% (64/453) had other mutations in RAS exons. The most frequent sites of mutations were codons 12, 13, 61, and 146 in KRAS and codons 12 and 61 in NRAS. The mutation rate of BRAF (exon 15) was 4.0% (26/655), and the most frequent mutation site was codon 600. Among 440 patients with CRC who had a primary tumor resection at our center, those with mucinous or signet ring cell CRC were more likely to harbor KRAS mutations than those with adenocarcinoma (62.7% vs. 43.6%, P=0.006 and 59.3% vs. 39.6%, P=0.004, respectively). Female patients had a higher BRAF (exon 15) mutation rate than male patients (5.1% vs. 1.1%, P=0.017). Detection of both KRAS and NRAS mutations is useful for selecting patients who will benefit from anti-EGFR monoclonal antibody therapy. KRAS mutations were more frequent in patients with mucinous adenocarcinoma/signet ring cell CRC, whereas BRAF mutations were more common in female patients with CRC.

Does tumor size have its prognostic role in colorectal cancer? Re-evaluating its value in colorectal adenocarcinoma with different macroscopic growth pattern.

BACKGROUND: Few previous studies have taken the growth pattern into consideration when analyzing the prognostic value of tumor size in colorectal cancer (CRC). OBJECTIVE: We sought to reveal the prognostic role of tumor size in different macroscopic growth patterns of CRC. MATERIALS AND METHODS: Using Cancer Center datasets, we identified 4057 cases with colorectal adenocarcinoma treated with curative resection. Macroscopic growth patterns of tumors were classified into three types: infiltrative, ulcerative and expansive types based on tumor gross appearance. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic factors for overall survival (OS) and disease-free survival (DFS). RESULTS: In whole cohort, tumor size was an independent factor for OS (HR 1.10, 95%CI 1.04-1.16, p < 0.001). Subgroup analysis based on macroscopic growth pattern suggested that tumor size was an independent factor for OS both in the infiltrative (HR 1.37, 95%CI 1.12-1.66, p = 0.002) group and ulcerative group (HR 1.08, 95%CI 1.00-1.16, p = 0.044) and tumor size (HR 1.22, 95%CI 1.06-1.40, p = 0.004) was found as an independent factor for DFS only in infiltrative group. CONCLUSIONS: Tumor size is an independent factor for OS and DFS in patients with colorectal adenocarcinoma of infiltrative type, while only for OS in patients of ulcerative type.

A study of peritoneal metastatic xenograft model of colorectal cancer in the treatment of hyperthermic intraperitoneal chemotherapy with Raltitrexed.

Peritoneal metastasis of colorectal cancer is one of the most incident and fateful diseases among relapse cases. It shows a certain resistance to systemic chemotherapy. The perfusion system in clinic is complex and hard to be used in fundamental researches. This study aims at evaluating the effect of an improved hyperthermic intraperitoneal chemotherapy with Raltitrexed used in tumor-bearing mice with peritoneal metastatic colorectal carcinoma. The results showed that no severe adverse effect was observed. All control animals developed extensive peritoneal and mesenteric metastatic nodes. Tumor sites in the treatment groups were reduced significantly. The administration dose of Raltitrexed influenced concentration in systemic blood and peritoneal tissues. Temperature promoted the intracellular absorption of Raltitrexed significantly. Our findings reveal that hyperthermic intraperitoneal chemotherapy is an efficient therapy in treating peritoneal metastatic carcinoma in nude mice. It can effectively reduce the extension of carcinoma cells from macro and micro examination. The combination of hyperthermia and Raltitrexed resulted in an improved therapeutic effect on animal models.

High preoperative peripheral blood neutrophil predicts poor outcome in rectal cancer treated with neoadjunctive chemoradiation therapy.

Distant metastasis impaired the value of neoadjunctive chemoradiation therapy (NCRT) for patients who were not pathological completed response. The objective of this study was to evaluate whether the absolute counts of preoperative neutrophils (pN) could predict survival outcomes of patients treated with NCRT. In this study, 289 locally advanced rectal cancer patients receiving NCRT and radical surgery were recruited between January 2006 and December 2012 at the Fudan University Shanghai Cancer Center. The absolute counts of pN were gathered and analyzed. Survival analysis was used to evaluate the prognostic value of pN. As results, a pN 3.00 was elected as the optimal cutoff points in term of survival by X-tile program. There were 112 patients (38.8%) in high-pN group and 177 patients (61.2%) in low pN group. The 4-year rectal cancer-specific survival (RCSS) and disease free survival (DFS) rate was 48.5% and 80.6%, 50.9% and 76.7% in high and low pN group, respectively. Univariate and multivariate analysis revealed that high-pN predicted poor RCSS and DFS. In conclusion, an elevated pN level was a significantly risk factor for locally advanced rectal cancer patient treated with NCRT, which may serve as a valuable marker to predict the outcomes of those patients.

miR-139-5p Inhibits the Epithelial-Mesenchymal Transition and Enhances the Chemotherapeutic Sensitivity of Colorectal Cancer Cells by Downregulating BCL2.

MicroRNAs (miRNAs) are important regulators involved in various cancers, including colorectal cancer (CRC). The functions and mechanisms of the miRNAs involved in CRC progress and metastasis are largely unknown. In this study, miRNA microarray analysis was performed to screen crucial miRNAs involved in CRC progress, and miR-139-5p was chosen for further study. The functional roles of miR-139-5p in colon cancer were demonstrated by CCK-8 proliferation assay, cell invasion and migration, cell apoptosis and in a KO mouse study. miR-139-5p expression was significantly decreased in cancer tissues compared to normal tissues. The miR-139-5p expression level was associated with tumour stage (P < 0.01). Function studies revealed that miR-139-5p was significantly correlated with the metastasis potential and drug resistance of colon cancer cells by affecting the epithelial-mesenchymal transition (EMT). Then, we identified BCL2 as a direct target of miR-139-5p cells in vitro. The patient samples and KO mice model showed that BCL2 expression was inversely correlated with the expression of miR-139-5p. In conclusion, we found that miR-139-5p targeted the BCL2 pathway to reduce tumour metastasis and drug sensitivity in CRC. This axis provided insight into the mechanism underlying miRNA regulation of CRC metastasis and a novel therapeutic target for CRC therapy.

High preoperative serum globulin in rectal cancer treated with neoadjunctive chemoradiation therapy is a risk factor for poor outcome.

An elevated serum albumin (ALB) and albumin/globulin ratio (AGR) has been reported to be associated with a favorable prognosis for certain malignancies; however, little is known about the prognostic significance of globulin (GLB) in rectal cancer treated with neoadjuvant chemoradiation therapy (NCRT). The purpose of this study was to evaluate whether GLB analysis could predict the prognosis of patients received NCRT. A retrospective cohort of 293 locally advanced rectal cancer patients receiving NCRT followed by radical surgery was recruited between January 2006 and December 2012 at Fudan University Shanghai Cancer Center. Levels for preoperative GLB and ALB were obtained and used to calculate the AGR. Survival analysis was used to evaluate the predictive value of GLB. X-tile program determined 28.50, 36.20 and 1.20 as optimal cut-off value for GLB, ALB and AGR in terms of survival. Univariate and multivariate analysis revealed that low GLB levels were significantly associated with favorable rectal cancer-specific survival (RCSS) (P < 0.05). Conversely, low ALB levels were associated with a significantly worse RCSS (P = 0.010). Collectively, high preoperative GLB level was a significantly unfavorable factor for rectal cancer patients treated with NCRT. This easily obtained variable may serve as a valuable marker to predict the outcomes of such patient population.

Synthesis of piperlongumine analogues and discovery of nuclear factor erythroid 2-related factor 2 (Nrf2) activators as potential neuroprotective agents.

The cellular antioxidant system plays key roles in blocking or retarding the pathogenesis of adult neurodegenerative disorders as elevated oxidative stress has been implicated in the pathophysiology of such diseases. Molecules with the ability in enhancing the antioxidant defense thus are promising candidates as neuroprotective agents. We reported herein the synthesis of piperlongumine analogues and evaluation of their cytoprotection against hydrogen peroxide- and 6-hydroxydopamine-induced neuronal cell oxidative damage in the neuron-like PC12 cells. The structure-activity relationship was delineated after the cytotoxicity and protection screening. Two compounds (4 and 5) displayed low cytotoxicity and confer potent protection of PC12 cells from the oxidative injury via upregulation of a panel of cellular antioxidant molecules. Genetically silencing the transcription factor Nrf2, a master regulator of the cellular stress responses, suppresses the cytoprotection, indicating the critical involvement of Nrf2 for the cellular action of compounds 4 and 5 in PC12 cells.