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The recent manufacturing trend toward mass customization and further personalization of products requires factories to be smarter than ever before in order to: (1) quickly respond to customer requirements, (2) resiliently retool machinery and adjust operational parameters for unforeseen system failures and product quality problems, and (3) retrofit old systems with upcoming new technologies. Furthermore, product lifecycles are becoming shorter due to unbounded and unpredictable customer requirements, thereby requiring reconfigurable and versatile manufacturing systems that underpin the basic building blocks of smart factories. This study introduces a modular factory testbed, emphasizing transformability and modularity under a distributed shop-floor control architecture. The main technologies and methods, being developed and verified through the testbed, are presented from the four aspects of rapid factory transformation: self-layout recognition, rapid workstation and robot reprogramming, inter-layer information sharing, and configurable software for shop-floor monitoring.

Four hundred and sixty-seven hematopoietic stem cell transplantations (HSCTs) (217 autologous and 250 allogeneic HSCT) were performed in 374 children at four pediatric HSCT centers in Korea from January 2005 to December 2007. Among 467 transplants, veno-occlusive disease (VOD) developed in 72 transplants (15.4%) at a median of 10 days after HSCT. Multivariate analysis showed that BU or TBI-containing regimen ( P =0.002), VOD prophylaxis without lipo-prostaglandin E1 (PGE1) ( P =0.012), number of previous HSCT ( P =0.014), and pretransplant serum ferritin ( P =0.018) were independent risk factors for developing VOD. Mean serum ferritin levels were significantly higher in HSCT with VOD (2109.6±2842.5 ng/ml) than in HSCT without VOD (1315.9±1094.4 ng/ml) ( P <0.001). The relative risk of death within 100 days of HSCT in transplants with VOD compared with transplants without VOD was 3.39 (confidence interval: 1.78–6.45). Our results suggest that lipo-PGE1 might have a protective effect against the development of VOD, and pretransplant serum ferritin could act as a risk factor for VOD. A larger prospective study is needed to confirm a possible role of lipo-PGE1 and iron chelation therapy in reducing the incidence of VOD.

Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug–induced liver injury (iDILI), a phenomenon that occurs with many drugs including β-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI.

Background: This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer. Patients and methods: A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II–IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m −2 , followed by oral doxifluridine 460–600 mg m −2 per day for 3 months) or MFP (MMC 20 mg m −2 , followed by oral doxifluridine 460–600 mg m −2 per day for 12 months with 6 monthly infusions of 60 mg m −2 of cisplatin) chemotherapy. Results: With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89–1.35); P =0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89–1.39); P =0.33). Conclusion: Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.

Salinomycin has been shown to control breast cancer stem cells, although the mechanisms underlying its anticancer effects are not clear. Deregulation of cell cycle regulators play critical roles in tumorigenesis, and they have been considered as anticancer targets. In this study, we investigated salinomycin effect on cell cycle progression using OVCAR-8 ovarian cancer cell line and multidrug-resistant NCI/ADR-RES and DXR cell lines that are derived from OVCAR-8. Parental OVCAR-8 cells are sensitive to several anticancer drugs, but NCI/ADR-RES and DXR cells are resistant to several anticancer drugs. However, salinomycin caused cell growth inhibition and apoptosis via cell cycle arrest at G1 in all three cell lines. Salinomycin inhibited signal transducer and activator of transcription 3 (Stat3) activity and thus decreased expression of Stat3-target genes, including cyclin D1, Skp2, and survivin. Salinomycin induced degradation of Skp2 and thus accumulated p27Kip1. Knockdown of Skp2 further increased salinomycin-induced G1 arrest, but knockdown of p27Kip1 attenuated salinomycin effect on G1 arrest. Cdh1, an E3 ligase for Skp2, was shifted to nuclear fractions upon salinomycin treatment. Cdh1 knockdown by siRNA reversed salinomycin-induced Skp2 downregulation and p27Kip1 upregulation, indicating that salinomycin activates the APC Cdh1 –Skp2–p27Kip1 pathway. Concomitantly, si-Cdh1 inhibited salinomycin-induced G1 arrest. Taken together, our data indicate that salinomycin induces cell cycle arrest and apoptosis via downregulation or inactivation of cell cycle-associated oncogenes, such as Stat3, cyclin D1, and Skp2, regardless of multidrug resistance.

Background: High levels of S100A6 have been associated with poor outcome in pancreatic cancer patients. The functional role of S100A6 is, however, poorly understood. Methods: Immunoprecipitation followed by two-dimensional gel electrophoresis and mass spectrometry were undertaken to identify S100A6 interacting proteins in pancreatic cancer cells. Immunohistochemistry and coimmunofluorescence were performed to examine expression or colocalisation of proteins. siRNA was used to deplete specific proteins and effects on motility were measured using Boyden Chamber and wound healing assays. Results: Our proteomic screen to identify S100A6 interacting proteins revealed annexin 11, annexin 2, tropomyosin β and a candidate novel interactor lamin B1. Of these, annexin 2 was considered particularly interesting, as, like S100A6, it is expressed early in the development of pancreatic cancer and overexpression occurs with high frequency in invasive cancer. Reciprocal immunoprecipitation confirmed the interaction between annexin 2 and S100A6 and the proteins colocalised, particularly in the plasma membrane of cultured pancreatic cancer cells and primary pancreatic tumour tissue. Analysis of primary pancreatic cancer specimens ( n =55) revealed a strong association between high levels of cytoplasmic S100A6 and the presence of annexin 2 in the plasma membrane of cancer cells ( P =0.009). Depletion of S100A6 was accompanied by diminished levels of membrane annexin 2 and caused a pronounced reduction in the motility of pancreatic cancer cells. Conclusion: These findings point towards a functional role for S100A6 that may help explain the link between S100A6 expression in pancreatic cancer and aggressive disease.

High rate algal ponds (HRAPs) provide improved wastewater treatment over conventional wastewater stabilisation ponds; however, algal production and recovery of wastewater nutrients as algal biomass is limited by the low carbon:nitrogen ratio of wastewater. This paper investigates the influence of CO2 addition (to augment daytime carbon availability) on wastewater treatment performance and algal production of two pilot-scale HRAPs operated with different hydraulic retention times (4 and 8 days) over a New Zealand Summer (November–March, 07/08). Weekly measurements were made of influent and effluent flow rate and water qualities, algal and bacterial biomass production, and the percentage of algae biomass harvested in gravity settling units. This research shows that the wastewater treatment HRAPs with CO2 addition achieved a mean algal productivity of 16.7 g/m2/d for the HRAP4d (4 d HRT, maximum algae productivity of 24.7 g/m2/d measured in January 08) and 9.0 g/m2/d for the HRAP8d (8 d HRT)). Algae biomass produced in the HRAPs was efficiently harvested by simple gravity settling units (mean harvested algal productivity: 11.5 g/m2/d for the HRAP4d and 7.5 g/m2/d for the HRAP8d respectively). Higher bacterial composition and the larger size of algal/bacterial flocs of the HRAP8d biomass increased harvestability (83%) compared to that of HRAP4d biomass (69%).

Wastewater treatment High Rate Algal Ponds with CO2 addition could provide cost-effective and efficient tertiary-level wastewater treatment with the co-benefit of algal biomass production for biofuel use. Wastewater grown algal biomass can have a lipid content of 10–30% of dry weight, which could be used to make biodiesel. This research investigated algal biomass and total lipid production by two pilot-scale wastewater treatment HRAPs (4-day HRT) with and without CO2 addition under New Zealand mid summer (Nov–Jan) conditions. The influence of CO2 addition on wastewater treatment performance was also determined. CO2 was added to one of the HRAPs (the HRAPE) by maintaining the maximum pH of the pond below 8. Measurements of HRAP influent and effluent water qualities, total lipid content and algal biomass production were made twice a week over the experimental period. Both HRAPs achieved high levels of organic compound and nutrient removal, with >85% SBOD5, >92 NH4+-N and >70% DRP removal. Algal/bacterial biomass production in the HRAPE (15.2 g/m2/d) was improved by CO2 addition by ∼30% compared with that of the control HRAPW (10.6 g/m2/d). Total lipid content of the biomass grown on both HRAPs was slightly reduced (from 25% to 20%) with CO2 addition and the maximum total lipid content of ∼40% was observed in the HRAPW when low NH4+-N concentration (<0.5 mg/L) and high maximum pH (>10.0) occurred. Total lipid content of the biomass increased by ∼15% under nitrogen limiting conditions, however, overall algal/bacterial biomass production was reduced by half during the period of nitrogen limitation. More research is required to maintain algal production under near nitrogenlimiting conditions.

Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10–15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.