Evaluation of whole and core genome multilocus sequence typing allele schemes for Salmonella enterica outbreak detection in a national surveillance network, PulseNet USA.

Salmonella enterica is a leading cause of bacterial foodborne and zoonotic illnesses in the United States. For this study, we applied four different whole genome sequencing (WGS)-based subtyping methods: high quality single-nucleotide polymorphism (hqSNP) analysis, whole genome multilocus sequence typing using either all loci [wgMLST (all loci)] and only chromosome-associated loci [wgMLST (chrom)], and core genome multilocus sequence typing (cgMLST) to a dataset of isolate sequences from 9 well-characterized Salmonella outbreaks. For each outbreak, we evaluated the genomic and epidemiologic concordance between hqSNP and allele-based methods. We first compared pairwise genomic differences using all four methods. We observed discrepancies in allele difference ranges when using wgMLST (all loci), likely caused by inflated genetic variation due to loci found on plasmids and/or other mobile genetic elements in the accessory genome. Therefore, we excluded wgMLST (all loci) results from any further comparisons in the study. Then, we created linear regression models and phylogenetic tanglegrams using the remaining three methods. K-means analysis using the silhouette method was applied to compare the ability of the three methods to partition outbreak and sporadic isolate sequences. Our results showed that pairwise hqSNP differences had high concordance with cgMLST and wgMLST (chrom) allele differences. The slopes of the regressions for hqSNP vs. allele pairwise differences were 0.58 (cgMLST) and 0.74 [wgMLST (chrom)], and the slope of the regression was 0.77 for cgMLST vs. wgMLST (chrom) pairwise differences. Tanglegrams showed high clustering concordance between methods using two statistical measures, the Baker's gamma index (BGI) and cophenetic correlation coefficient (CCC), where 9/9 (100%) of outbreaks yielded BGI values ≥ 0.60 and CCCs were ≥ 0.97 across all nine outbreaks and all three methods. K-means analysis showed separation of outbreak and sporadic isolate groups with average silhouette widths ≥ 0.87 for outbreak groups and ≥ 0.16 for sporadic groups. This study demonstrates that Salmonella isolates clustered in concordance with epidemiologic data using three WGS-based subtyping methods and supports using cgMLST as the primary method for national surveillance of Salmonella outbreak clusters.

Evaluation of core genome and whole genome multilocus sequence typing schemes for Campylobacter jejuni and Campylobacter coli outbreak detection in the USA.

Campylobacter is a leading causing of bacterial foodborne and zoonotic illnesses in the USA. Pulsed-field gene electrophoresis (PFGE) and 7-gene multilocus sequence typing (MLST) have been historically used to differentiate sporadic from outbreak Campylobacter isolates. Whole genome sequencing (WGS) has been shown to provide superior resolution and concordance with epidemiological data when compared with PFGE and 7-gene MLST during outbreak investigations. In this study, we evaluated epidemiological concordance for high-quality SNP (hqSNP), core genome (cg)MLST and whole genome (wg)MLST to cluster or differentiate outbreak-associated and sporadic Campylobacter jejuni and Campylobacter coli isolates. Phylogenetic hqSNP, cgMLST and wgMLST analyses were also compared using Baker's gamma index (BGI) and cophenetic correlation coefficients. Pairwise distances comparing all three analysis methods were compared using linear regression models. Our results showed that 68/73 sporadic C. jejuni and C. coli isolates were differentiated from outbreak-associated isolates using all three methods. There was a high correlation between cgMLST and wgMLST analyses of the isolates; the BGI, cophenetic correlation coefficient, linear regression model R 2 and Pearson correlation coefficients were >0.90. The correlation was sometimes lower comparing hqSNP analysis to the MLST-based methods; the linear regression model R 2 and Pearson correlation coefficients were between 0.60 and 0.86, and the BGI and cophenetic correlation coefficient were between 0.63 and 0.86 for some outbreak isolates. We demonstrated that C. jejuni and C. coli isolates clustered in concordance with epidemiological data using WGS-based analysis methods. Discrepancies between allele and SNP-based approaches may reflect the differences between how genomic variation (SNPs and indels) are captured between the two methods. Since cgMLST examines allele differences in genes that are common in most isolates being compared, it is well suited to surveillance: searching large genomic databases for similar isolates is easily and efficiently done using allelic profiles. On the other hand, use of an hqSNP approach is much more computer intensive and not scalable to large sets of genomes. If further resolution between potential outbreak isolates is needed, wgMLST or hqSNP analysis can be used.

Ruminal Protozoal Populations of Angus Steers Differing in Feed Efficiency.

Feed accounts for as much as 70% of beef production costs, and improvement of the efficiency with which animals convert feed to product has the potential to have substantial financial impact on the beef industry. The rumen microbiome plays a key role in determining feed efficiency; however, previous studies of rumen microbiota have not focused on protozoal communities despite the estimation that these organisms represent approximately 50% of rumen content biomass. Protozoal communities participate in the regulation of bacterial populations and nitrogen cycling-key aspects of microbiome dynamics. The present study focused on identifying potential associations of protozoal community profiles with feed efficiency. Weaned steers (n = 50) 7 months of age weighing approximately 260 kg were adapted to a growing ration and GrowSafe for 2 weeks prior to a 70-day feed efficiency trial. The GrowSafe system is a feeding system that monitors feed intake in real time. Body weights were collected on the first day and then every 7 days of the feed efficiency trial, and on the final day, approximately 50 mL of rumen content were collected via orogastric tubing and frozen at -80 °C. Body weight and feed intake were used to calculate residual feed intake (RFI) as a measure of feed efficiency, and steers were categorized as high (n = 14) or low (n = 10) RFI based on ±0.5 standard deviations about the mean RFI. Microbial DNA was extracted, and the eukaryotic component profiled by amplification and sequencing of 18S genes using degenerate primers that can amplify this locus across a range of protists. The taxonomy of protozoal sequences was assigned using QIIME 1.9 and analyzed using QIIME and SAS 9.4 with significance determined at α ≤ 0.05. Greater abundances of unassigned taxa were associated with high-RFI steers (p = 0.03), indicating a need for further study to identify component protozoal species. Differences were observed between low- and high-RFI steers in protozoal community phylogenetic diversity, including weighted beta-diversity (p = 0.04), Faith's phylogenetic diversity (p = 0.03), and observed Operational taxonomic unit (OTU) (p = 0.03). The unassigned taxa and differences in phylogenetic diversity of protozoal communities may contribute to divergences observed in feed efficiency phenotypes in beef steers.

Intranodal Hemangioma in the Pelvic Cavity: A Case Report.

Hemangiomas are benign tumours that commonly develop in the skin, mucosal surfaces, and soft tissues. However, intranodal hemangiomas are extremely rare and are among the benign primary vascular abnormalities of the lymph nodes that include lymphangioma, hemangioendothelioma, angiomyomatous hamartoma and hemangiomas. The hemangioma in the pelvic lymph node has never been reported in the English literature. Herein, we described an extremely rare case of hemangioma in the pelvic lymph node, simulating a benign metastasizing leiomyoma.

Effect of urea cream on sorafenib-associated hand-foot skin reaction in patients with hepatocellular carcinoma: A multicenter, randomised, double-blind controlled study.

BACKGROUND: Hand-foot skin reaction (HFSR) is the most common adverse event during sorafenib treatment in patients with hepatocellular carcinoma (HCC). In the present study, we aimed to investigate the role of urea cream in the prevention of HFSR or amelioration of HFSR severity. PATIENTS AND METHODS: Patients with HCC were treated with either placebo cream or urea cream for 12 weeks concomitantly with sorafenib treatment. HFSR development, the Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire score, and adverse events were assessed at 2, 4, 8 and 12 weeks. RESULTS: Of the 288 patients, 247 patients, with 117 patients in the placebo control group and 130 patients in the urea cream group, were analysed. The urea cream group showed a trend towards a lower cumulative incidence of any-grade HFSR (log-rank, P = 0.247) and severe HFSR of grade II or higher (log-rank, P = 0.394) without statistical significance. In the incidence by time point, the incidence of severe HFSR of grade II or higher was significantly lower in the urea cream group than in the placebo control group at 2 weeks (13.8% versus 23.9%, P = 0.042). The urea cream group showed a significantly better HF-QoL questionnaire score than the placebo control group (11.8 versus 19.7, P = 0.014) at 12 weeks. CONCLUSIONS: Treatment with urea cream showed a lower incidence of severe sorafenib-induced HFSR at 2 weeks and reduced the tendency of HFSR development in HCC patients. Therefore, treatment with urea cream may be considered for prophylaxis or improvement of HFSR grade in HCC patients treated with sorafenib. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03212625).

Features of extrahepatic metastasis after radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND: Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) is associated with poor outcomes. However, the clinical features and risk factors of EHM of HCC after radiofrequency ablation (RFA) remain unclear. AIM: To elucidate the characteristics and risk factors of EHM after RFA for HCC. METHODS: From January 2008 to December 2017, we retrospectively enrolled 661 patients who underwent RFA as first-line treatment for HCC at 2 tertiary hospitals. The inclusion criteria were age ≥ 18 years, a diagnosis of HCC, and treatment-naivety. Abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and alpha-fetoprotein measurements were routinely performed at 1 mo after RFA and followed-up at intervals of 3-6 mo. Univariate analyses were performed using the chi-squared test or Student's t-test, and univariate and multivariate analyses were performed via logistic regression, as appropriate. RESULTS: EHM was diagnosed in 44 patients (6.7%) during a median follow-up period of 1204 days. The 10-year cumulative rate of HCC recurrence and EHM was 92.7% and 33.7%, respectively. Initial recurrence was most often intrahepatic, and the rate of extrahepatic recurrence at initial recurrence was only 1.2%. The median time to the diagnosis of EHM was 2.68 years, and 68.2% of patients developed EHM within 2 years of the first recurrence, regardless of recurrence-free survival and 75.0% of patients developed EHM within 5 years after first recurrence. EHM was mostly diagnosed via abdominal CT/MRI in 33 (75.0%) and 38 of 44 patients (86.4%) with EHM had either positive abdominal CT scan results or serum AFP level elevation. In multivariate analysis, recurrence-free survival < 2 years, ablation zone/tumor size < 2, and alpha-fetoprotein level > 400 IU/mL were associated with a high EHM risk. CONCLUSION: EHM occurs following multiple intrahepatic recurrences after RFA and combined contrast-enhanced abdominal CT and serum AFP were useful for surveillance. Patients especially with high-risk factors require close follow-up for EHM.

Development of in vitro three-dimensional co-culture system for metabolic syndrome therapeutic agents.

AIMS: There are many obstacles to overcome in the development of new drugs for metabolic diseases, including efficacy and toxicity problems in later stages of drug development. To overcome these problems and predict efficacy and toxicity in early stages, we constructed a new model of insulin resistance in terms of communication between 3T3-L1 adipocytes and RAW264.7 macrophages by three-dimensional (3D) culture. RESULTS: In this study, results focused on the functional resemblance between 3D co-culture of adipocytes and macrophages and adipose tissue in diabetic mice. The 3D mono-culture preadipocytes showed good cell viability and induced cell differentiation to adipocytes, without cell confluence or cell-cell contact and interaction. The 3D co-cultured preadipocytes with RAW264.7 macrophages induced greater insulin resistance than two-dimensional and 3D mono-cultured adipocytes. Additionally, we demonstrated that 3D co-culture model had functional metabolic similarity to adipose tissue in diabetic mice. We utilized this 3D co-culture system to screen PPARγ antagonists that might have potential as therapeutic agents for diabetes as demonstrated by an in vivo assay. CONCLUSION: This in vitro 3D co-culture system could serve as a next-generation platform to accelerate the development of therapeutics for metabolic diseases.

Thermal boundary layer limitations on the performance of micromachined microphones.

This work examines the extent to which thermal boundary layer effects limit the performance of micromachined microphones. The acoustic impedance of the cavity formed by the microphone enclosure is calculated using both analytical and finite-element methods. A thermal correction to the cavity impedance is included to account for the transition of compression and expansion within the enclosure from adiabatic to isothermal when the thermal boundary layer that forms at the walls of the enclosure becomes large compared to the enclosure dimensions. The thermal correction to the cavity impedance contains a resistive term that results from thermal relaxation losses and contributes thermal-acoustic noise to the system. A lumped-element network model for the microphone response which includes the thermally corrected enclosure impedance is presented and compared to measured results for a case study device. The relative noise power contribution of each noise source considered in the model is calculated. It is shown that the noise due to the resistive term of the enclosure cavity impedance becomes significant when the enclosure volume is small. This sets a theoretical limit on the noise floor that can be achieved by a micromachined microphone with given enclosure dimensions.

A disposable on-chip microvalve and pump for programmable microfluidics.

In this work, a low-cost PDMS micro-pump and -valve have been designed and developed to control multiple reagents for enzyme-linked immunosorbent assay (ELISA) on a programmable lab-on-a-chip (LOC) platform. The micro pump and valves were precisely controlled by selectively pressurizing the PDMS channels and chamber to actuate the multiple reagents in a controlled manner. Selective pressurizing of the PDMS structures was initiated by a simple system that maneuvered a single roller bar operated by a programmed microprocessor. The performance of the micro-pump was fully characterized and a minimum fluid volume of 1 µL was controlled. Also, the on-chip microvalves were programmed to flow the multiple reagents to automatically process the multi-step ELISA procedures. By applying the proposed platform, 19.40 pg ml-1 cardiac troponin T (cTnT) was successfully detected on the LOC device by using multiple programmed valves as multiple steps of the enzyme-linked sandwich immunoassay. As a result, the developed micro-pump and -valve, which were successfully applied to actuate a series of solutions in a controlled manner, can be widely applied to lab-on-a-chip based bioassays.

Mast cells and exosomes in hyperoxia-induced neonatal lung disease.

Chronic lung disease of prematurity (CLD) is a frequent sequela of premature birth and oxygen toxicity is a major associated risk factor. Impaired alveolarization, scarring, and inflammation are hallmarks of CLD. Mast cell hyperplasia is a feature of CLD but the role of mast cells in its pathogenesis is unknown. We hypothesized that mast cell hyperplasia is a consequence of neonatal hyperoxia and contributes to CLD. Additionally, mast cell products may have diagnostic and prognostic value in preterm infants predisposed to CLD. To model CLD, neonatal wild-type and mast cell-deficient mice were placed in an O2 chamber delivering hyperoxic gas mixture [inspired O2 fraction (FiO2 ) of 0.8] (HO) for 2 wk and then returned to room air (RA) for an additional 3 wk. Age-matched controls were kept in RA (FiO2 of 0.21). Lungs from HO mice had increased numbers of mast cells, alveolar simplification and enlargement, and increased lung compliance. Mast cell deficiency proved protective by preserving air space integrity and lung compliance. The mast cell mediators ß-hexosaminidase (ß-hex), histamine, and elastase increased in the bronchoalveolar lavage fluid of HO wild-type mice. Tracheal aspirate fluids (TAs) from oxygenated and mechanically ventilated preterm infants were analyzed for mast cell products. In TAs from infants with confirmed cases of CLD, ß-hex was elevated over time and correlated with FiO2 Mast cell exosomes were also present in the TAs. Collectively, these data show that mast cells play a significant role in hyperoxia-induced lung injury and their products could serve as potential biomarkers in evolving CLD.

Perirenal fat stranding on CT: is there an association with bladder outlet obstruction?

OBJECTIVE: To determine the association between perirenal fat stranding (PFS) on CT and bladder outlet obstruction (BOO). METHODS: CT scans from 122 patients who had undergone urodynamic study for lower urinary tract symptoms (LUTS) were registered after exclusion of patients with renal or retroperitoneal disease. Images were independently reviewed by two radiologists and compared with those of 244 age- and sex-matched control patients without LUTS. The PFS severity was scored on a four-point scale, and the interobserver agreement was assessed with kappa statistics. The severity score and incidence was compared between the groups, and the association with baseline characteristics was analyzed. For the LUTS group, an association between PFS severity and urodynamic and laboratory data was evaluated. RESULTS: PFS was more frequent and more severe in the LUTS group than in the control group (p-value < 0.001); its presence was significantly associated with male gender and older age (p-value < 0.001). PFS was predominantly bilateral in both groups (80.1-93.2%). In the LUTS group, PFS severity scores were significantly correlated with the maximum flow rate, maximum detrusor pressure and estimated glomerular filtration rate (p-value < 0.001). Interobserver agreements were excellent for PFS presence (κ = 0.883) and severity (κ = 0.816). CONCLUSION: Severe PFS was observed in older, male patients with LUTS. PFS severity was associated with the degree of BOO and impaired renal function. ADVANCES IN KNOWLEDGE: Recognition of PFS on the CT scan may warrant further evaluation of BOO and appropriate management to prevent renal impairment.

A smart pipette for equipment-free separation and delivery of plasma for on-site whole blood analysis.

A novel device of smart pipette has been suggested to extract and deliver plasma from whole blood in a disposable format. By operating an on-chip disposable micropump, approximately 30 µL of plasma was obtained from 100 µL of whole blood within 5 min without any external equipment for point-of-care blood analysis.

Determination of optimal imaging settings for urolithiasis CT using filtered back projection (FBP), statistical iterative reconstruction (IR) and knowledge-based iterative model reconstruction (IMR): a physical human phantom study.

OBJECTIVE: The purpose of this study was to compare CT image quality for evaluating urolithiasis using filtered back projection (FBP), statistical iterative reconstruction (IR) and knowledge-based iterative model reconstruction (IMR) according to various scan parameters and radiation doses. METHODS: A 5 × 5 × 5 mm(3) uric acid stone was placed in a physical human phantom at the level of the pelvis. 3 tube voltages (120, 100 and 80 kV) and 4 current-time products (100, 70, 30 and 15 mAs) were implemented in 12 scans. Each scan was reconstructed with FBP, statistical IR (Levels 5-7) and knowledge-based IMR (soft-tissue Levels 1-3). The radiation dose, objective image quality and signal-to-noise ratio (SNR) were evaluated, and subjective assessments were performed. RESULTS: The effective doses ranged from 0.095 to 2.621 mSv. Knowledge-based IMR showed better objective image noise and SNR than did FBP and statistical IR. The subjective image noise of FBP was worse than that of statistical IR and knowledge-based IMR. The subjective assessment scores deteriorated after a break point of 100 kV and 30 mAs. CONCLUSION: At the setting of 100 kV and 30 mAs, the radiation dose can be decreased by approximately 84% while keeping the subjective image assessment. ADVANCES IN KNOWLEDGE: Patients with urolithiasis can be evaluated with ultralow-dose non-enhanced CT using a knowledge-based IMR algorithm at a substantially reduced radiation dose with the imaging quality preserved, thereby minimizing the risks of radiation exposure while providing clinically relevant diagnostic benefits for patients.

X-Ray-based Kinematic Analysis of Cervical Spine According to Prosthesis Designs: Analysis of the Mobi C, Bryan, PCM, and Prestige LP.

STUDY DESIGN: A retrospective study. OBJECTIVE: To identify significant kinematic changes in the cervical spine after cervical artificial disk replacement (ADR) using prostheses with diverse designs. SUMMARY OF BACKGROUND DATA: Various types of artificial disks are used for cervical ADR. However, few clinical studies with a follow-up of 2 or more years have reported on the change in the curvatures and range of motion (ROM) of the cervical spine after cervical ADR in relation to different designs. METHODS: The cohort comprised 58 patients who underwent single-level cervical ADR for radiculopathy. The patients were divided into 4 groups according to the device they received: Mobi-C, Bryan, PCM, and Prestige LP. The radiographs of the cervical spine were obtained preoperatively and at 12, 24, and 36 months after surgery. Several kinematic parameters, including lordotic angles and ROM of the cervical spine, index level, and superior and inferior adjacent disk levels, were assessed preoperatively and at predefined follow-up time points. RESULTS: Cervical sagittal lordosis in patients who received Bryan and PCM prostheses increased at the last follow-up period. The 4 patient groups showed a trend toward an increase of lordosis in the superior adjacent segment with time. The patients who received the Bryan device lost their preoperative lordotic angle at the inferior adjacent level. The ROM of the cervical spine in patients who received Bryan and PCM prostheses increased at the last follow-up compared with preoperative values. The incidence of adjacent segment degeneration in the Mobi-C, Bryan, Prestige LP, and PCM groups were 14.2%, 25%, 9.0%, and 7.6%, respectively. CONCLUSIONS: These results suggest preservation of sagittal ROM and increased superior adjacent segment kinematics, regardless of prosthesis design. Devices with an unconstrained design may not be beneficial to adjacent segment kinematics compared with semiconstrained prostheses.

The longitudinal changes of retinal nerve fiber layer thickness after panretinal photocoagulation in diabetic retinopathy patients.

PURPOSE: To investigate longitudinal changes in retinal nerve fiber layer (RNFL) thickness after panretinal photocoagulation (PRP) in diabetic retinopathy patients. METHODS: This prospective study examined 31 eyes in 25 patients undergoing PRP, who were diagnosed with severe nonproliferative diabetic retinopathy or non-high-risk proliferative diabetic retinopathy. Optical coherence tomography was conducted before PRP and at 3, 6, 12, and 24 months after PRP to investigate changes in peripapillary RNFL thickness. RESULTS: Superior, nasal, inferior, temporal, and mean peripapillary RNFL thickness increased until 6 months after PRP and then decreased. Superior RNFL thickness increased significantly at 3 and 6 months and decreased significantly at 24 months compared with the baseline RNFL thickness. Nasal RNFL thickness declined significantly at 24 months compared with the baseline RNFL thickness without any significant increase in thickness during the follow-up period. Inferior RNFL thickness increased significantly at 6 months and decreased significantly at 24 months compared with its baseline RNFL thickness. Temporal thickness increased significantly at 3, 6, 12, and 24 months compared with the baseline RNFL thickness. Mean RNFL thickness increased significantly at 6 months and decreased significantly at 24 months. Central subfield thickness increased significantly at 3, 6, 12, and 24 months compared with its baseline thickness. CONCLUSION: Peripapillary RNFL thickness increased at 6 months after PRP and then decreased at 24 months after PRP compared with baseline peripapillary RNFL thickness in diabetic retinopathy patients. This finding suggests that in addition to diabetes itself, diabetic retinopathy, and associated glaucoma, PRP may be a cause of RNFL thickness loss in patients with diabetes.

Factors affecting ocular pulse amplitude in eyes with open angle glaucoma and glaucoma-suspect eyes.

PURPOSE: To investigate the associations between ocular pulse amplitude (OPA) as measured by dynamic contour tonometry (DCT) and ocular and systemic factors in patients with open angle glaucoma (OAG) and in glaucoma suspects. METHODS: One hundred and seventy-three glaucoma-suspect patients were consecutively enrolled. All subjects underwent intraocular pressure (IOP) measurement by DCT and Goldmann applanation tonometry (GAT), OPA measurement by DCT, Humphrey visual field (HVF) examination and central corneal thickness measurements. Arterial pulse amplitude (APA) and ocular perfusion pressure (OPP) were defined as the difference between systolic and diastolic BP and the difference between mean arterial pressure and IOP, respectively. All subjects also completed a systemized questionnaire on systemic vascular morbidities. RESULTS: Seventy-four eyes were diagnosed with OAG, based on HVF results. The overall mean CCT was 538.2±37.6 µm. In all 173 eyes, OPA was associated with spherical equivalent (SE, p<0.001) and with IOP by GAT (p=0.013) by multivariate analysis. Multivariate analysis of the 77 subgroup eyes of patients for whom BP parameters were available also revealed that OPA was associated with SE (p=0.007) and with IOP by GAT (p<0.001). When the subjects were classified into the groups with low, intermediate and high cardiovascular risk based on the questionnaire, there was no difference in OPA among these groups (p>0.05). CONCLUSIONS: Ocular pulse amplitude was associated with IOP measured by GAT and SE in patients with OAG and in glaucoma suspects. There was neither significant correlation between systemic hemodynamic parameters and OPA, nor difference of OPA in patients with different cardiovascular risk. OPA is primarily a measure of pressure, and there are certain limitations towards its use as a hemodynamic index.

NF-κB addiction and its role in cancer: 'one size does not fit all'.

Activation of nuclear factor (NF)-κB, one of the most investigated transcription factors, has been found to control multiple cellular processes in cancer including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance and radioresistance. NF-κB is constitutively active in most tumor cells, and its suppression inhibits the growth of tumor cells, leading to the concept of 'NF-κB addiction' in cancer cells. Why NF-κB is constitutively and persistently active in cancer cells is not fully understood, but multiple mechanisms have been delineated including agents that activate NF-κB (such as viruses, viral proteins, bacteria and cytokines), signaling intermediates (such as mutant receptors, overexpression of kinases, mutant oncoproteins, degradation of IκBα, histone deacetylase, overexpression of transglutaminase and iNOS) and cross talk between NF-κB and other transcription factors (such as STAT3, HIF-1α, AP1, SP, p53, PPARγ, ß-catenin, AR, GR and ER). As NF-κB is 'pre-active' in cancer cells through unrelated mechanisms, classic inhibitors of NF-κB (for example, bortezomib) are unlikely to mediate their anticancer effects through suppression of NF-κB. This review discusses multiple mechanisms of NF-κB activation and their regulation by multitargeted agents in contrast to monotargeted agents, thus 'one size does not fit all' cancers.

Removal of heavy metals in an abandoned mine drainage via ozone oxidation: a pilot-scale operation.

The objective of this study was to evaluate the ozone oxidation of dissolved heavy metals in an abandoned mine drainage (AMD) by conducting a pilot-scale operation at two different ozone doses of 7.5 and 24.0 g O(3)/h into an ozone reactor. A portion of the abandoned mine drainage near the Jungam Mine in Samchuck, Korea was pumped into this pilot-scale plant and used as an influent for the ozone oxidation. Some possible precipitates of metal oxides and hydroxides that resulted from the pilot-scale ozone oxidation of the dissolved Fe and Mn ions in the AMD (with a hydraulic retention time of 106 seconds in the ozone reactor) were effectively removed via sand filtration. A six-hour ozone oxidation with an ozone dose of 24.0 g O(3)/h and subsequent sand filtration, before backwashing the sand filter bed, can meet Korean drinking water quality standards (less than 0.3 mg/L) for Fe and Mn in the sand filter effluent under the operating conditions that were used in this study. The SO(4)(-2) concentrations and alkalinities of the influents were not affected by the ozone oxidation. The pH values of the influents were neutral or slightly alkaline, and after the six-hour oxidation, increased very slightly. These experiment results show that the ozone oxidation of dissolved heavy metals and the subsequent sand filtration of metal precipitates are desirable alternatives to removing heavy metals in an abandoned mine drainage.