A domain needed for the catalytic efficiency of an enzyme model of simple processivity and domain–domain interactions has been characterized by NMR. This domain 4 from phosphomannomutase/phosphoglucomutase (PMM/PGM) closes upon glucose phosphate and mannose phosphate ligands in the active site, and can modestly reconstitute activity of enzyme truncated to domains 1–3. This enzyme supports biosynthesis of the saccharide-derived virulence factors (rhamnolipids, lipo-polysaccharides, and alginate) of the opportunistic bacterial pathogen Pseudomonas aeruginosa. 1H, 13C, and 15N NMR chemical shift assignments of domain 4 of PMM/PGM suggest preservation and independence of its structure when separated from domains 1–3. The face of domain 4 that packs with domain 3 is perturbed in NMR spectra without disrupting this fold. The perturbed residues overlap both the most highly coevolved positions in the interface and residues lining a cavity at the domain interface.
Domain interactions; NMR spectroscopy; Multi-domain enzyme; Phosphomannomutase; Phosphoglucomutase
Cloud workflow system is a kind of platform service based on cloud computing. It facilitates the automation of workflow applications. Between cloud workflow system and its counterparts, market-oriented business model is one of the most prominent factors. The optimization of task-level scheduling in cloud workflow system is a hot topic. As the scheduling is a NP problem, Ant Colony Optimization (ACO) and Particle Swarm Optimization (PSO) have been proposed to optimize the cost. However, they have the characteristic of premature convergence in optimization process and therefore cannot effectively reduce the cost. To solve these problems, Chaotic Particle Swarm Optimization (CPSO) algorithm with chaotic sequence and adaptive inertia weight factor is applied to present the task-level scheduling. Chaotic sequence with high randomness improves the diversity of solutions, and its regularity assures a good global convergence. Adaptive inertia weight factor depends on the estimate value of cost. It makes the scheduling avoid premature convergence by properly balancing between global and local exploration. The experimental simulation shows that the cost obtained by our scheduling is always lower than the other two representative counterparts.
AIM: To assess the influence of SLIT and NTRK-like family member 3 (SLITRK3) on the prognosis of gastrointestinal stromal tumor (GIST) and determine whether SLITRK3 can help improve current risk stratification systems.
METHODS: We hypothesized that SLITRK3 could be used as a prognostic molecular biomarker for GIST. 35 fresh tumor samples and 417 paraffin-embedded specimens from GIST patients were utilized. SLITRK3 mRNA expression in GIST tumor tissue was detected by real-time polymerase chain reaction, and SLITRK3 protein levels were estimated by immunohistochemistry. The correlation of SLITRK3 expression with various tumor clinicopathological characteristics and follow-up data were analyzed.
RESULTS: GIST tumors had high expression of SLITRK3 compared with adjacent normal tissues and the expression level gradually increased with risk grade. SLITRK3 protein expression was closely associated with gastrointestinal bleeding, tumor site, tumor size, mitotic index, and National Institutes of Health (NIH) classification. Survival analysis showed that SLITRK3 expression was closely correlated with overall survival and disease-free survival of GIST patients. Multivariate analysis also identified SLITRK3 expression, mitotic index, and NIH stage as significant risk factors of GIST recurrence.
CONCLUSION: SLITRK3 expression is a highly significant predictor of GIST recurrence and metastasis. Combinations of SLITRK3 and NIH stage have strong predictive and prognostic value, and are feasible markers for clinical practice in gastrointestinal stromal tumor.
SLITRK3; Gastrointestinal stromal tumor; Biomarkers; Non-epithelial tumors; Risk stratification
The seventh AJCC TNM classification defines rules for classifying adenocarcinomas of esophagogastric junction (AEG II and III) as a part of esophageal cancer. But there are still many controversies over the classification system. The study aims to evaluate and compare whether AEG should be classified as cancers of esophagus or stomach. A single-center cohort of patients with AEG or proximal third gastric adenocarcinoma underwent surgical resection with curative intent in Shanghai from November 2004 to July 2011. We compared the clinicopathologic features between AEG (n=291) and proximal third gastric adenocarcinoma (n=176) and analyzed overall survival probabilities of AEG using the latest seventh AJCC TNM classification for cancers. Patients with AEG not only show more advanced diseases, but also have a significantly worse 5-year survival rate than those with proximal third gastric adenocarcinoma (P=0.027). In 291 patients with AEG, the gastric T classification is monotone but indistinct except for pT2 versus pT3 (P=0.001) and pT4a versus pT4b (P=0.012). The esophageal T classification is neither monotone nor distinct. For the N classification, both schemes are monotone and distinct. The gastric scheme is indistinctive for stages IA versus IB (P=0.428), for IIA versus IIB (P=0.376), for IIB versus IIIA (P=0.086), for IIIA versus IIIB (P=0.087), and for IIIC versus IV (P=0.928). The esophageal scheme is indistinct only except for IIIB versus IIIC (P=0.002). The gastric scheme includes one heterogeneous stage group (stage IIIC, P<0.001), whereas all stage groups are homogeneous in the esophageal scheme. Although AEG shows different clinicopathological features and surgical outcomes of patients, the current seventh AJCC TNM classification which stages the AEG in the esophageal scheme does not demonstrate the advantages in the assessment of the patient prognosis. We propose a revised staging system to clarify the AEG with esophageal invasion.
TNM classification; esophagogastric junction; esophageal cancer; gastric cancer
We aimed to investigate whether 1-deoxynojirimycin (DNJ) modulates glycometabolism and has toxicity in Eri silkworm (Samia cynthia ricini, Saturniidae). In this paper, hemolymph metabolites were used to explore metabolic changes after oral administration of DNJ or mulberry latex and to characterize the biological function of DNJ at the metabolic and systemic levels. Hemolymph samples were collected from fourth-instar larvae of Eri silkworm and ex-vivo high-resolution 1H nuclear magnetic resonance (NMR) spectra were acquired from the collected hemolymph samples. Then the obtained spectra were analyzed by principal component analysis (PCA) and independent-samples t-test. Metabolic pattern recognition analysis of hemolymph samples indicated that the groups of 0.25% DNJ, latex, and the mixture of 0.5% DNJ and latex (1:1) were significantly different from the control group. Moreover, compared to the control group, the groups of 0.25% DNJ, latex, and the mixture of 0.5% DNJ and latex (1:1) showed the decreased levels of citrate, succinate, fumarate, malate, and glutamine in hemolymph, the groups of 0.25% DNJ and the mixture of 0.5% DNJ and latex (1:1) showed the increased levels of trehalose and lactate. In addition, mulberry leaves exude latex was highly toxic to Eri silkworm because rich unidentified high-molecular-weight factor (s) acted as toxic substances. In our results, latex caused 20 deaths among 50 fourth-instar larvae of Eri silkmoth, but DNJ or the mixture did not caused death. All these results suggest that DNJ has a positive impact on the reverse glycometabolism by modulating glycometabolism and inhibiting glucogenesis and energy metabolism. DNJ is a secure substance as a single-ingredient antidiabetic medicine due to its nontoxicity and bioactivity.
Several studies have reported the favorable effect of leucine supplementation on insulin resistance or insulin sensitivity. However, whether or not leucine supplementation improves leptin sensitivity remains unclear.
Forty-eight male Sprague-Dawley rats were fed with either a high-fat diet (HFD) or HFD supplemented with 1.5, 3.0, and 4.5% leucine for 16 weeks. At the end of the experiment, serum leptin level was measured by ELISA, and leptin receptor (ObR) in the hypothalamus was examined by immunohistochemistry. The protein expressions of ObR and leptin-signaling pathway in adipose tissues were detected by western blot.
No significant differences in body weight and food/energy intake existed among the four groups. Serum leptin levels were significantly lower, and ObR expression in the hypothalamus and adipose tissues was significantly higher in the three leucine groups than in the control group. These phenomena suggested that leptin sensitivity was improved in the leucine groups. Furthermore, the expressions of JAK2 and STAT3 (activated by ObR) were significantly higher, and that of SOCS3 (inhibits leptin signaling) was significantly lower in the three leucine groups than in the control group.
Leucine supplementation improves leptin sensitivity in rats on HFD likely by promoting leptin signaling.
leptin sensitivity; leptin signaling; leucine; high-fat diet
Matrix metalloproteinases (MMPs) regulate tissue remodeling, inflammation, and disease progression. Some soluble MMPs are inexplicably active near cell surfaces. Here, we demonstrate binding of MMP-12 directly to bilayers and cellular membranes using paramagnetic NMR and fluorescence. Opposing sides of the catalytic domain engage spin-labeled membrane mimics. Loops project from the β-sheet interface to contact the phospholipid bilayer with basic and hydrophobic residues. The distal membrane interface comprises loops on the other side of the catalytic cleft. Both interfaces mediate MMP-12 association with vesicles and cell membranes. MMP-12 binds plasma membranes and is internalized to hydrophobic perinuclear features, the nuclear membrane, and inside the nucleus within minutes. While binding of TIMP-2 to MMP-12 hinders membrane interactions beside the active site, TIMP-2-inhibited MMP-12 binds vesicles and cells, suggesting compensatory rotation of its membrane approaches. MMP-12 association with diverse cell membranes may target its activities to modulate innate immune responses and inflammation.
peripheral membrane protein; protein-bilayer interactions; pericellular proteolysis; NMR; paramagnetic relaxation enhancement; live cell imaging; metzincin; metalloproteinase
Sacrococcygeal teratoma (SCT) is a sacrococcygeal neoplasm derived from more than one primitive germ layer and is only occasionally encountered in adults. The primary treatment for all primary SCTs is surgical excision. The present study reports the case of a giant SCT in a middle-aged female with a history lasting >3 decades. Multi-staged surgical treatment was performed, including ileostomy plus tumor excision, four debridement plus flap repair procedures, and closure of the ileostomy. Follow-up showed improved quality of life without evidence of local recurrence after resection. The study also presents a brief overview of the relevant literature. To the best of our knowledge, this is the first report of multi-staged surgical treatment for giant SCT in an adult patient.
sacrococcygeal teratoma; presacral tumor; presacral teratoma; teratoma; adult
Instance checking is considered a central tool for data retrieval from description logic (DL) ontologies. In this paper, we propose a revised most specific concept (MSC) method for DL SHI, which converts instance checking into subsumption problems. This revised method can generate small concepts that are specific-enough to answer a given query, and allow reasoning to explore only a subset of the ABox data to achieve efficiency. Experiments show effectiveness of our proposed method in terms of concept size reduction and the improvement in reasoning efficiency.
Data retrieval; Description Logic; Ontology; MSC; SHI; Algorithms
Gastric cancer (GC) remains the second leading cause of cancer-related death worldwide. Owing to the lack of early diagnostic techniques, GC is often diagnosed at advanced stage and that leading to low survival rate. Growing evidences have been suggesting that circulating microRNAs play an important role in earlier diagnostic of disease. In the present study, we analyze the circulating miRNAs expression in plasma of volunteers with/without GC aiming to identifying early diagnostic biomarkers. Plasma samples were collected form 6 volunteers including 3 early patients with GC and 3 healthy adults. And then miRNAs microarrays were performed to detect the expression profile of miRNAs in these plasma samples. For further validate the results from miRNAs microarray, qRT-PCR was performed. Finally, target genes of miRNAs were predicted by bioinformatic means. Compared to control plasma, 11 up-regulated and 13 down-regulated miRNAs were detected in the plasma from earlier patients with GC (fold change ≥ 2, P < 0.05). Then, 5 differential expression miRNAs (miR-223, miR-19b-2*, miR-194*, miR-141, miR-1233) were chose to confirm by qRT-PCR. The result is nearly consistent with previous data from miRNAs microarray. Finally, 53 target genes of the 5 miRNAs are predicted by bioinformatics. These differential expression miRNAs may be used as biomarker candidates for minimally invasive diagnosis of early patients with GC in the future.
Gastric cancer; miRNAs; early diagnosis; biomarkers; plasma
Effective therapy for visual loss caused by optic nerve injury or diseases has not been achieved even though the optic nerve has the regeneration potential after injury. This study was designed to modify amniotic epithelial cells (AECs) with basic fibroblast growth factor (bFGF) gene, preliminarily investigating its effect on transected optic nerve.
A human bFGF gene segment was delivered into rat AECs (AECs/hbFGF) by lentiviral vector, and the gene expression was examined by RT-PCR and ELISA. The AECs/hbFGF and untransfected rat AECs were transplanted into the transected site of the rat optic nerve. At 28 days post transplantation, the survival and migration of the transplanted cells was observed by tracking labeled cells; meanwhile retinal ganglion cells (RGCs) were observed and counted by employing biotin dextran amine (BDA) and Nissl staining. Furthermore, the expression of growth associated protein 43 (GAP-43) within the injury site was examined with immunohistochemical staining.
The AECs/hbFGF was proven to express bFGF gene and secrete bFGF peptide. Both AECs/hbFGF and AECs could survive and migrate after transplantation. RGCs counting implicated that RGCs numbers of the cell transplantation groups were significantly higher than that of the control group, and the AECs/hbFGF group was significantly higher than that of the AECs group. Moreover GAP-43 integral optical density value in the control group was significantly lower than that of the cell transplantation groups, and the value in the AECs/hbFGF group was significantly higher than that of the AECs group.
AECs modified with bFGF could reduce RGCs loss and promote expression of GAP-43 in the rat optic nerve transected model, facilitating the process of neural restoration following injury.
The gut microbiota is hypothesized to have a critical role in metabolic diseases, including type 2 diabetes (T2D). A traditional Chinese herbal formula, Gegen Qinlian Decoction (GQD), can alleviate T2D. To find out whether GQD modulates the composition of the gut microbiota during T2D treatment, 187 T2D patients were randomly allocated to receive high (HD, n=44), moderate (MD, n=52), low dose GQD (LD, n=50) or the placebo (n=41) for 12 weeks in a double-blinded trial. Patients who received the HD or MD demonstrated significant reductions in adjusted mean changes from baseline of fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) compared with the placebo and LD groups. Pyrosequencing of the V3 regions of 16S rRNA genes revealed a dose-dependent deviation of gut microbiota in response to GQD treatment. This deviation occurred before significant improvement of T2D symptoms was observed. Redundancy analysis identified 47 GQD-enriched species level phylotypes, 17 of which were negatively correlated with FBG and 9 with HbA1c. Real-time quantitative PCR confirmed that GQD significantly enriched Faecalibacterium prausnitzii, which was negatively correlated with FBG, HbA1c and 2-h postprandial blood glucose levels and positively correlated with homeostasis model assessment of β-cell function. Therefore, these data indicate that structural changes of gut microbiota are induced by Chinese herbal formula GQD. Specifically, GQD treatment may enrich the amounts of beneficial bacteria, such as Faecalibacterium spp. In conclusion, changes in the gut microbiota are associated with the anti-diabetic effects of GQD.
Whey supplementation is beneficial for human health, possibly by reducing the circulating C-reactive protein (CRP) level, a sensitive marker of inflammation. Thus, a meta-analysis of randomized controlled trials was conducted to evaluate their relationship. A systematic literature search was conducted in July, 2014, to identify eligible studies. Either a fixed-effects model or a random-effects model was used to calculate pooled effects. The meta-analysis results of nine trials showed a slight, but no significant, reduction of 0.42 mg/L (95% CI −0.96, 0.13) in CRP level with the supplementation of whey protein and its derivates. Relatively high heterogeneity across studies was observed. Subgroup analyses showed that whey significantly lowered CRP by 0.72 mg/L (95% CI −0.97, −0.47) among trials with a daily whey dose ≥20 g/day and by 0.67 mg/L (95% CI −1.21, −0.14) among trials with baseline CRP ≥3 mg/L. Meta-regression analysis revealed that the baseline CRP level was a potential effect modifier of whey supplementation in reducing CRP. In conclusion, our meta-analysis did not find sufficient evidence that whey and its derivates elicited a beneficial effect in reducing circulating CRP. However, they may significantly reduce CRP among participants with highly supplemental doses or increased baseline CRP levels.
whey protein; C-reactive protein; randomized controlled trial; meta-analysis
A Pseudomonas fluorescens strain ZY2, isolated from swine wastewater, was used to investigate the synergistic effects of five heavy metals (Pb, Cu, Zn, Cr(VI) and Hg) on bacterial resistance to antibiotics. Results indicate that the combined effects of antibiotic type, heavy metal type and concentration were significant (p < 0.01). Cross-resistance to Hg and antibiotics was the most noticeable. Moreover, the resistance to Hg and cefradine or amoxicillin, and Cr and amoxicillin were synergistic for low heavy metal concentrations, and turned antagonistic with increasing concentrations, while the resistances to Cr or Cu and cefradine, Pb or Cu and amoxicillin, Cu and norfloxacin showed reverse effects. In addition, resistance to Zn and amoxicillin were always synergetic, while resistance to Pb and cefradine or norfloxacin, Cr or Hg and norfloxacin as well as all the heavy metals and tetracycline were antagonistic. These results indicate that bacterial resistance to antibiotics can be affected by the type and concentration of co-exposed heavy metals and may further threaten people’s health and ecological security severely via horizontal gene transfer.
Pseudomonas fluorescens; resistance; antibiotic; heavy metal; swine wastewater
Background: Upper lumbar disc herniation (ULDH) is easy to be misdiagnosed due to its special anatomical and atypical clinical features. Few studies have identified the relationship between ULDH and adjacent wedge-shaped vertebrae (WSV). Hypothesis: WSV may have some indicative relations withULDH. Patients and methods: Between January 2003 and October 2013, 47 patients (27 males and 20 females; mean age, 41.2 years) with single-level ULDH (as study group) and 47 sex- and age-matched healthy volunteers (as control group) were studied by radiograph. The two groups were compared with respect to age, sexual proportion, body mass index (BMI), kyphotic angle, and the proportion of WSV. Also, correlative analyses were conducted in the study group to investigate the relation between the kyphotic angle of target vertebrae and other factors including age, BMI, Cobb angle, JOA score and bone mineral density (BMD). Results: The average kyphotic angle in the study group was 11° (4°-22°), while the average kyphotic angle in the control group was 2° (0°-7°). Obviously, the mean kyphotic angle in the study group was statistically larger than that in the control group (t=13.797, P<0.001). The proportion of WSV in the study group was significantly larger than that in the control group (x2=36.380, P<0.0001). The correlations between kyphotic angles and other items (i.e., age, BMI, BMD, Cobb angle and JOA score) in the study group and the control group were low or uncorrelated. Conclusions: WSV are indicatively associated with adjacent ULDH. Thus, ULDH should be alerted when WSV are first found in radiograph and accompanied by clinical symptoms.
Disc herniation; upper lumbar spine; wedge-shaped vertebrae; correlative analysis
Pim-1 (Provirus integration site for Moloney murine leukemia virus 1) belongs to the Ser/Thr kinase family and plays a pivotal role in occurrence and development of oncogenesis. Recent studies have demonstrated that Pim-1 phosphorylates RUNX3 and alters its subcellular localization. However, few studies have concerned the implications of Pim-1 in the salivary gland adenoid cystic carcinoma (ACC). In this study, we aimed to clarify the function of Pim-1 in ACC in vitro. Meanwhile, we measured the levels of Pim-1 and RUNX3 in the ACC tissues. The correlations between Pim-1/RUNX3 levels and clinical parameters were also analyzed.
SACC-83 and SACC-LM cells were transfected with the Pim-1 siRNA. Pim-1 mRNA and protein expression were measured using real-time PCR and immnuoblot, respectively. Cell proliferation was analyzed by CCK-8 assay. Cell cycle, apoptosis, and mitochondrial membrane potential were detected by flow cytometry. Effects of Pim-1 on cells’ invasion were evaluated by transwell migration assay. Pim-1 and RUNX3 levels in ACC tissues were examined by immunohistochemistry.
Pim-1 siRNA reduces cell proliferation, induces apoptosis, causes cell cycle arrest through cell cycle related proteins (Cyclin D1 and CDK4), mitochondrial depolarization, and decreases invasive ability in SACC-83 and SACC-LM cells. Pim-1 and RUNX3 levels are significantly relevant and associated with T-stage and nerve invasion in the ACC tissues.
This study demonstrates the oncogenic role of Pim-1 in ACC. The findings also suggest that Pim-1 may serve as a neoteric therapeutic target and potential prognostic marker for ACC cancer.
Salivary gland adenoid cystic carcinoma; Pim-1; RUNX3
Bombyx mori nucleopolyhedrovirus (BmNPV) is a primary pathogen of silkworm (B. mori) that causes severe economic losses each year. However, the molecular mechanisms of silkworm-BmNPV interactions, especially the silkworm proteins that can interact with the virus, are still largely unknown. In this study, the total and membrane proteins of silkworm midguts were displayed using one- and two-dimensional electrophoresis. A virus overlay assay was used to detect B. mori proteins that specifically bind to BmNPV particles. Twelve proteins were located and identified using mass spectrometry, and the different expression of the corresponding genes in BmNPV susceptible and resistant silkworm strains also indicated their involvement in BmNPV infection. The 12 proteins are grouped based on their potential roles in viral infection, for example, endocytosis, intracellular transportation, and host responses. Based on these results, we hypothesize the following: I) vacuolar ATP synthase catalytic subunit A and subunit B may be implicated in the process of the membrane fusion of virus and the release of the nucleocapsid into cytoplasm; II) actin, enolase and phosphoglycerate kinase are cytoskeleton associated proteins and may play an important role in BmNPV intracellular transportation; III) mitochondrial prohibitin complex protein 2, ganglioside-induced differentiation-associated protein, calreticulin, regucalcin-like isoform X1 and 60 kDa heat shock protein are involved in cell apoptosis regulation during BmNPV infection in larvae midguts; IV) ribosomal P0 may be associated with BmNPV infection by regulating gene expression of BmNPV; V) arginine kinase has a role in the antiviral activities against BmNPV. Our work should prove informative by providing multiple protein targets and a novel direction to investigate the molecular mechanisms of the interactions between silkworms and BmNPV.
The liver plays a central role in cholesterol homeostasis. It exclusively receives and metabolizes oxysterols, which are important metabolites of cholesterol and are more cytotoxic than free cholesterol, from all extrahepatic tissues. Hepatocellular carcinomas (HCCs) impair certain liver functions and cause pathological alterations in many processes including cholesterol metabolism. However, the link between an altered cholesterol metabolism and HCC development is unclear. Human ACAT2 is abundantly expressed in intestine and fetal liver. Our previous studies have shown that ACAT2 is induced in certain HCC tissues. Here, by investigating tissue samples from HCC patients and HCC cell lines, we report that a specific cholesterol metabolic pathway, involving induction of ACAT2 and esterification of excess oxysterols for secretion to avoid cytotoxicity, is established in a subset of HCCs for tumor growth. Inhibiting ACAT2 leads to the intracellular accumulation of unesterified oxysterols and suppresses the growth of both HCC cell lines and their xenograft tumors. Further mechanistic studies reveal that HCC-linked promoter hypomethylation is essential for the induction of ACAT2 gene expression. We postulate that specifically blocking this HCC-established cholesterol metabolic pathway may have potential therapeutic applications for HCC patients.
ACAT2; CpG methylation; oxysterol secretion; inhibition of tumor growth; HCC
Acute myocardial infarction (AMI) concomitant with aortic dissection (AD) is rare but a devastating situation if misdiagnosed as simply AMI, followed by anticoagulant or thrombolytic therapy. In such cases, Standford type B AD was extremely infrequent.
To present a case with apparent concordance with the patient's history, symptoms, cardiac enzymes that lead to diagnostic error.
An 85-year-old man with chronic hypertension and coronary atherosclerotic heart disease presented in our emergency department with squeezing retrosternal chest pain and dyspnea. Elevated cardiac enzymes and electrocardiography result suggested acute non-ST-segment elevation myocardial infarction. Emergency coronary angiography demonstrated a 50–90% diffuse stenosis of the proximal and mid right coronary artery also confirmed the diagnosis. Stents were deployed thereafter. However, the patient was found to be concomitant with Standford type B AD by computed tomography angiography due to unrelieved chest pain and new onset of abdominal pain after the operation. The patient refused to have endovascular operation and died of hemorrhagic shock one week later.
AD may cause AMI due to some indirect mechanisms, and it is of utmost importance to search for the existence of AD before reperfusion therapy in AMI patients. Aortic dissection detection risk score, transthoracic echocardiography and D-dimer help early identification of AD.
Acute myocardial infarction; Aortic dissection; Misdiagnosis
The objective of this study was to develop quantitative models to delineate the net efficacy of taspoglutide on fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) from the response of placebo in type 2 diabetes patients, and further find pharmacodynamic potency of taspoglutide and FPG for half of maximum reduction responses of FPG and HbA1c, respectively. Several PD data about taspoglutide treatments for type 2 diabetes patients were digitalized from the published papers related with the clinical development of taspoglutide. The model based meta-analysis (MBMA) studies for FPG and HbA1c were performed with Monolix 4.2 software. The MBMA successfully described the effects of placebo and taspoglutide on pharmacological indexes of FPG and HbA1c through mono and multiple combination therapies in clinical trials. The pharmacodynamic potency (25.3 pmol/l) produced 50% of maximum responses of FPG (−2.39 mmol/l) from the responses of placebo for FPG (−0.371 mmol/l); the response change of FPG (−1.81 mmol/l) affected 50% of maximum response change (−1.74%) for HbA1c from the response of placebo (−0.253%). The leveraging prior knowledge from the longitudinal MBMA will be utilized to guide clinical development of taspoglutide and further support study designs including optimization of dose and duration of therapy.
FPG; HbA1c; Taspoglutide; Glucagon-like peptide-1; Pharmacodynamics; Meta-analysis
Somatostatin receptors (SSTRs) already act as important roles in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with high expression levels for prognosis predicting and octreotide LAR treatment purposes but less noticed in gastrointestinal stromal tumors (GISTs). Our study aims to fully evaluate the expression levels and prognostic values of SSTRs in GIST patients. For SSTRs expression detection, qPCR were used in 25 fresh GIST specimens, and then, 453 GIST samples (405 GISTs with operation only and 48 with imatinib adjuvant therapy after surgery) were collected for tissue microarrays (TMAs) construction and confirmed by immunohistochemistry (IHC). Clinicopathological data were confirmed by pathological diagnosis and clinical recorders, recurrence-free survivals (RFS) were evaluated in 453 GIST patients. With IHC performed, SSTR1 and SSTR2 present high positive proportion (81.9% and 87.6%) in 453 GISTs in our study, and positive expression rates of SSTR3, SSTR4 and SSTR5 are 56.1%, 8.8% and 47.2%, respectively. SSTR2 and SSTR5 negative expression are associated with decreased RFS when compared to positive cases by Kaplan-Meier survival analyses with log-rank test and univariate analysis in GISTs, furthermore, SSTR2 was an independent prognostic indicator for GISTs by multivariate analysis. In our study, detection of SSRT2 and SSTR5 expression helps to predict different prognosis in GIST patients. SSTR2 is a novel independent prognostic biomarker for GISTs. With high expression performance of SSTRs in GISTs, new therapeutic strategies such as octreotide or pasireotide LAR could be taken into consideration in selected advanced GIST patients.
Gastrointestinal stromal tumor; somatostatin receptor; octreotide; pasireotide; prognosis
HER family has been implicated in a number of malignant tumors for predicting prognosis and potential targeted therapy purposes, however, the prognostic roles of HER family in GISTs have not been elaborated yet. Our study aims to fully evaluate the prognostic value of HER family in GIST patients and efficacy of imatinib adjuvant therapy. For HER family expression detection, qPCR were used in 33 flesh GIST specimens, and then, 453 GIST samples (405 GISTs with operation only and 48 with imatinib adjuvant therapy after radical surgery) were collected for tissue microarrays construction and immunohistochemistry (IHC). Clinicopathological data were confirmed by pathological diagnosis and clinical recorders, recurrence-free survivals (RFS) were evaluated in 453 GIST patients. With qPCR and IHC performed, EGFR, HER2 and HER4 are focused on examining prognostic value in remainder of our study by high positive expression rates in GISTs. In high-risk GISTs with or without imatinib adjuvant therapy, EGFR negative expression are associated with decreased RFS when compared to positive cases. HER2 present no relationship with GIST patients’ prognosis. HER4 positive expression significantly associated with disease recurrence in GISTs. Further subgroup studies revealed HER4 was an independent prognostic indicator especially for gastric GISTs, and also for gastric high-risk GISTs. In our study, detection of EGFR expression helps to precisely subdivide high-risk GISTs for different prognosis and probably predict outcomes for imatinib treatment. HER4 is a novel independent prognostic biomarker for gastric GISTs specifically, which could be potential therapeutic target in GISTs originated from stomach.
Gastrointestinal stromal tumor; EGFR; HER2; HER4; prognosis
Gastrointestinal stromal tumor (GIST) is known for its wide variability in biological behaviors and it is difficult to predict its malignant potential. The aim of this study is to explore the characteristics and prognostic factors of GIST.
Clinical and pathological data of 497 GIST patients in our center between 1997 and 2012 were reviewed.
Patients were categorized into very low-, low-, intermediate- and high-risk groups according to modified National Institutes of Health (NIH) consensus classification system. Among the 401 patients untreated with imatinib mesylate (IM), 5-year overall survival (OS) in very low-, low-, intermediate- and high-risk groups was 100%, 100%, 89.6% and 65.9%; and 5-year relapse-free survival (RFS) was 100%, 98.1%, 90.9% and 44.5%, respectively. Univariate analysis revealed that sex, tumor size, mitotic rate, risk grade, CD34 expression, and adjacent involvement were predictors of OS or RFS. COX hazard proportional model (Forward LR) showed that large tumor size, high mitotic rate, and high risk grade were independent risk factors to OS, whereas high mitotic rate, high risk grade and adjacent organ involvement were independent risk factors to RFS. The intermediate-high risk patients who received IM adjuvant therapy (n = 87) had better 5-year OS and RFS than those who did not (n = 188) (94.9% vs. 72.1; 82.3% vs. 56.3%, respectively). Similarly, advanced GIST patients underwent IM therapy (n = 45) had better 3-year OS and 1-year progression-free survival (PFS) than those who didn’t (n = 42) (75.6% vs. 6.8%; 87.6% vs. 12.4%, respectively).
Very low- and low-risk GISTs can be treated with surgery alone. Large tumor size, high mitotic rate, high risk grade, and adjacent organ involvement contribute to the poor outcome. IM therapy significantly improves the survival of intermediate-high risk or advanced GIST patients.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2482-14-93) contains supplementary material, which is available to authorized users.
Gastrointestinal stromal tumor; Survival; Imatinib
Long non-coding RNAs (lncRNAs) have been regarded as the primary genetic regulators of several important biological processes. However, the biological functions of lncRNAs in radiation-induced lung damage remain largely unknown. The present study aimed to investigate the potential effects of lncRNAs on radiation-induced lung injury (RILI). Female C57BL/6 mice were exposed to 12 Gy single doses of total body irradiation (TBI). LncRNA microarray screening was conducted at 24 h post-irradiation (IR) to investigate the differentially-expressed lncRNAs during RILI. Following the subsequent bioinformatics analysis and reverse transcription-polymerase chain reaction (RT-PCR) validation, one of the verified differentially-expressed long intergenic radiation-responsive ncRNAs (LIRRs), LIRR1, was selected for further functional study. The normal human bronchial epithelial BEAS-2B cell line was used as the cell model. The recombinant eukaryotic expression vector for the lncRNA was designed, constructed and transfected using lipofectamine. RT-PCR, clonogenic and flow cytometry assays, immunofluorescence detection and western blot analysis were performed to reveal the role of the lncRNA in the radiosensitivity regulation of the RILI target cells. In lung tissues 24 h after 12 Gy TBI, six of the identified differentially-expressed LIRRs near the coding genes were validated using quantitative (q)PCR. The upregulation of two LIRRs was observed and confirmed using qPCR. LIRR1 was chosen for further functional study. Following the stable transfection of LIRR1, identified through G418 screening, increased radiosensitivity, evident cell cycle G1 phase arrest and increased γ-H2AX foci formation were observed in the bronchial epithelial BEAS-2B cell line subsequent to IR. LIRR1 overexpression also led to decreased expression of the KU70, KU80 and RAD50 DNA repair proteins, marked activation of p53, decreased mouse double minute 2 homolog (MDM2) expression, and substantially induced p21 and suppressed cyclin-dependent kinase 2 in BEAS-2B following IR. Subsequent to the use of Pifithrin-α, a specific inhibitor of p53 activation, increased MDM2 expression was observed in the LIRR1-overexpressing cells, suggesting that LIRR1 could mediate the DNA damage response (DDR) signaling in a p53-dependent manner. The present study provides a novel mechanism for RILI, using the concept of lncRNAs.
long non-coding RNA; radiation-induced lung injury; radiosensitivity; cell cycle; DNA damage response; p53
We recast the Cosegmentation problem using Random Walker
(RW) segmentation as the core segmentation algorithm, rather than the
traditional MRF approach adopted in the literature so far. Our formulation is
similar to previous approaches in the sense that it also permits Cosegmentation
constraints (which impose consistency between the extracted objects from
≥ 2 images) using a nonparametric model. However, several previous
nonparametric cosegmentation methods have the serious limitation that they
require adding one auxiliary node (or variable) for every pair of pixels that
are similar (which effectively limits such methods to describing only those
objects that have high entropy appearance models). In contrast, our proposed
model completely eliminates this restrictive dependence –the resulting
improvements are quite significant. Our model further allows an optimization
scheme exploiting quasiconvexity for model-based segmentation with no dependence
on the scale of the segmented foreground. Finally, we show that the optimization
can be expressed in terms of linear algebra operations on sparse matrices which
are easily mapped to GPU architecture. We provide a highly specialized CUDA
library for Cosegmentation exploiting this special structure, and report
experimental results showing these advantages.