Dynamic density functional theory with inertia and background flow.

We present dynamic density functional theory (DDFT) incorporating general inhomogeneous, incompressible, time-dependent background flows and inertia, describing externally driven passive colloidal systems out of equilibrium. We start by considering the underlying nonequilibrium Langevin dynamics, including the effect of the local velocity of the surrounding liquid bath, to obtain the nonlinear, nonlocal partial differential equations governing the evolution of the (coarse-grained) density and velocity fields describing the dynamics of colloids. In addition, we show both with heuristic arguments, and by numerical solution, that our equations and solutions agree with existing DDFTs in the overdamped (high friction) limit. We provide numerical solutions that model the flow of hard spheres, in both unbounded and confined domains, and compare with previously derived DDFTs with and without the background flow.

Let the river erode! Enabling lateral migration increases geomorphic unit diversity.

River restoration practice frequently employs conservative designs that create and maintain prescribed, static morphology. Such approaches ignore an emerging understanding of resilient river systems that typically adjust their morphology in response to hydrologic, vegetative and sediment supply changes. As such, using increased dynamism as a restoration design objective will arguably yield more diverse and productive habitats, better managed expectations, and more self-sustaining outcomes. Here, we answer the following question: does restoring lateral migration in a channelised river that was once a wandering gravel-bed river, result in more diverse in-channel geomorphology? We acquired pre- and post-restoration topographic surveys on a segment of the Allt Lorgy, Scotland to quantify morphodynamics and systematically map geomorphic units, using Geomorphic Unit Tool (GUT) software. GUT implements topographic definitions to discriminate between a taxonomy of fluvial landforms that have been developed from an extension of the River Styles framework, using 3-tiered hierarchy: (1) differentiation based on stage or elevation relative to channel; (2) classification of form based on shape (mound, bowl, trough, saddle, plane, wall); and (3) mapping geomorphic units based on attributes (e.g., position and orientation). Results showed restoration increased geomorphic unit diversity, with the Shannon Diversity Index increasing from 1.40 pre-restoration (2012) to 2.04 (2014) and 2.05 (2016) after restoration. Channel widening, due to bank erosion, caused aerial coverage of in-channel geomorphic units to increase 23% after restoration and 6% further in the two-years following restoration. Once bank protection was removed, allowing bank erosion yieled a local supply of sediment to enable the formation and maintenance of lateral and point bars, riffles and diagonal bar complexes, and instream wood created structurally-forced pools and riffles. The methodology used systematically quantifies how geomorphic unit diversity increases when a river is given back its freedom space. The framework allows for testing restoration design hypotheses in post-project appraisal.

Assessment of a numerical model to reproduce event-scale erosion and deposition distributions in a braided river.

Numerical morphological modeling of braided rivers, using a physics-based approach, is increasingly used as a technique to explore controls on river pattern and, from an applied perspective, to simulate the impact of channel modifications. This paper assesses a depth-averaged nonuniform sediment model (Delft3D) to predict the morphodynamics of a 2.5 km long reach of the braided Rees River, New Zealand, during a single high-flow event. Evaluation of model performance primarily focused upon using high-resolution Digital Elevation Models (DEMs) of Difference, derived from a fusion of terrestrial laser scanning and optical empirical bathymetric mapping, to compare observed and predicted patterns of erosion and deposition and reach-scale sediment budgets. For the calibrated model, this was supplemented with planform metrics (e.g., braiding intensity). Extensive sensitivity analysis of model functions and parameters was executed, including consideration of numerical scheme for bed load component calculations, hydraulics, bed composition, bed load transport and bed slope effects, bank erosion, and frequency of calculations. Total predicted volumes of erosion and deposition corresponded well to those observed. The difference between predicted and observed volumes of erosion was less than the factor of two that characterizes the accuracy of the Gaeuman et al. bed load transport formula. Grain size distributions were best represented using two φ intervals. For unsteady flows, results were sensitive to the morphological time scale factor. The approach of comparing observed and predicted morphological sediment budgets shows the value of using natural experiment data sets for model testing. Sensitivity results are transferable to guide Delft3D applications to other rivers.

Exogenous Carbohydrate Reduces Cortisol Response from Combined Mental and Physical Stress.

Combined mental and physical stress is associated with exacerbated cortisol production which may increase risk for the progression of cardiovascular disease in individuals working in high-stress occupations (e.g., firefighters, military personnel, etc.). Carbohydrate (CHO) ingestion prior to physical stress may attenuate cortisol concentrations. This project was the first to investigate the effect of CHO ingestion on cortisol response from combined mental and physical stress. 16 men 21-30 years old were randomly assigned a 6.6% CHO beverage or non-CHO control 15 min prior to performing a dual-concurrent-stress challenge. This consisted of physical stress (i.e., steady state exercise) combined with computerized mental challenges. Blood was sampled 70, 40, and 15 min before exercise, immediately at onset of exercise, 10, 20, 30, 35 min during exercise, and 15, 30, 45, and 60 min after exercise. There was a significant main effect for treatment regarding mean cortisol concentrations (F=5.30, P=0.0219). The total area under curve for cortisol was less when CHO was ingested (T7=4.07, P=0.0048). These findings suggest that CHO ingestion immediately prior to combined mental and physical stress may attenuate cortisol responses.

Bochdalek Congenital Diaphragmatic Hernia in an Adult Sheep.

Congenital diaphragmatic hernia (CDH) is a rare condition. The aetiology of CDH is often unclear. In our case, a hollow mass was noted on MRI. Cardiac ejection fraction was diminished (47.0%) compared to 60.5% (average of 10 other normal animals, P < 0.05). The final diagnosis of congenital diaphragmatic hernia (Bochdalek type) was made when the sheep underwent surgery. The hernia was right-sided and contained the abomasum. Lung biopsy demonstrated incomplete development with a low number of bronchopulmonary segments and vessels. The likely cause of this hernia was genetic malformation.

Liquid jet delivery method featuring S100A1 gene therapy in the rodent model following acute myocardial infarction.

The S100A1 gene is a promising target enhancing contractility and survival post myocardial infarction (MI). Achieving sufficient gene delivery within safety limits is a major translational problem. This proof of concept study evaluates viral mediated S100A1 overexpression featuring a novel liquid jet delivery (LJ) method. Twenty-four rats after successful MI were divided into three groups (n = 8 ea.): saline control (SA); ssAAV9.S100A1 (SS) delivery; and scAAV9.S100A1 (SC) delivery (both 1.2 × 10¹¹ viral particles). For each post MI rat, the LJ device fired three separate 100 µl injections into the myocardium. Following 10 weeks, all rats were evaluated with echocardiography, quantitative PCR (qPCR) and overall S100A1 and CD38 immune protein. At 10 weeks all groups demonstrated a functional decline from baseline, but the S100A1 therapy groups displayed preserved left ventricular function with significantly higher ejection fraction %; SS group (60 ± 3) and SC group (57 ± 4) versus saline (46 ± 3), P < 0.05. Heart qPCR testing showed robust S100A1 in the SS (10,147 ± 3993) and SC (35,155 ± 5808) copies per 100 ng DNA, while off-target liver detection was lower in both SS (40 ± 40), SC (34,841 ± 3164), respectively. Cardiac S100A1 protein expression was (4.3 ± 0.2) and (6.1 ± 0.3) fold higher than controls in the SS and SC groups, respectively, P < 0.05.

A needleless liquid jet injection delivery method for cardiac gene therapy: a comparative evaluation versus standard routes of delivery reveals enhanced therapeutic retention and cardiac specific gene expression.

This study evaluates needleless liquid jet method and compares it with three common experimental methods: (1) intramuscular injection (IM), (2) left ventricular intracavitary infusion (LVIC), and (3) LV intracavitary infusion with aortic and pulmonary occlusion (LVIC-OCCL). Two protocols were executed. First (n = 24 rats), retention of dye was evaluated 10 min after delivery in an acute model. The acute study revealed the following: significantly higher dye retention (expressed as % myocardial cross-section area) in the left ventricle in both the liquid jet [52 ± 4] % and LVIC-OCCL [58 ± 3] % groups p < 0.05 compared with IM [31 ± 8] % and LVIC [35 ± 4] %. In the second (n = 16 rats), each animal received adeno-associated virus encoding green fluorescent protein (AAV.EGFP) at a single dose with terminal 6-week endpoint. In the second phase with AAV.EGFP at 6 weeks post-delivery, a similar trend was found with liquid jet [54 ± 5] % and LVIC-OCCL [60 ± 8] % featuring more LV expression as compared with IM [30 ± 9] % and LVIC [23 ± 9] %. The IM and LVIC-OCCL cross sections revealed myocardial fibrosis. With more detailed development in future model studies, needleless liquid jet delivery offers a promising strategy to improve direct myocardial delivery.

Gain of 1q is a marker of poor prognosis in Wilms' tumors.

Wilms' tumor (WT) trials aim to better tailor treatment intensity to the risk of relapse and death. Currently, stage, histology, age (< or > 24 months), and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs are the only risk factors used for treatment stratification. However, they predict only less than one-third of all relapsing patients, implying that other factors are involved in treatment failure. Previous studies have associated 1q gain with adverse outcome. Therefore, in this study, the role of 1q gain and other common cytogenetic aberrations (CAs) in WTs was investigated and related to follow-up data from patients with WT treated in the United Kingdom; 19% (64/331) had 1q gain. Gain of 1q was significantly associated with 16q loss (P < 0.001) and 1p loss (P < 0.001). In multivariate analysis taking account of age, tumor stage, anaplasia, and common CA (e.g., 1p loss and 16q loss), 1q gain was independently associated with adverse event-free survival [EFS; hazard ratio (HR) = 2.45, P = 0.02] and overall survival (HR = 4.28, P = 0.004). Loss of 14q was independently associated with an adverse EFS (HR = 4.0, P = 0.04). Gain of 1q is a marker of poor prognosis in WTs, independent of high tumor stage and anaplasia which remain the overarching adverse prognostic factors. Confirmation in other studies is necessary before future therapeutic studies can incorporate 1q gain into new risk stratification schema.

Phase II trial of pemetrexed-based induction chemotherapy followed by concomitant chemoradiotherapy in previously irradiated patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Concurrent chemoreirradiation therapy (CRRT) offers a therapeutic option for patients with locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that response to induction chemotherapy (IC) would improve outcome and predict increased survival. PATIENTS AND METHODS: Subjects with recurrent SCCHN not amenable to standard therapy were eligible. IC consisted of two 28-day cycles of gemcitabine and pemetrexed on days 1 and 14, followed by surgical resection, if appropriate, and/or CRRT consisting of carboplatin, pemetrexed, and single daily fractionated radiotherapy. RESULTS: Thirty-five subjects were enrolled, 31 were assessable for response, with 11 responders [response rate = 35%; 95% confidence interval (CI) 19.2-54.6]. Among 24 subjects who started CRRT, 11 were assessable for radiographic response, 4 complete response, 2 partial response, and 5 progressive disease. Median progression-free survival and overall survival (OS) were 5.5 months (95% CI 3.6-8.3) and 9.5 months (95% CI 7.2-15.4), respectively. One-year OS was 43% (95% CI 26% to 58%). Subjects who responded to IC had improved survival (P = 0.02). Toxic effects included mucositis, dermatitis, neutropenia, infection, hemorrhage, dehydration, and pain. CONCLUSIONS: The combination of pemetrexed plus gemcitabine was active and well tolerated in recurrent SCCHN. Response to IC may help stratify prognosis and offer an objective and dynamic metric in recurrent SCCHN patients being considered for CRRT.

Long-term efficacy and safety of bimatoprost for intraocular pressure lowering in glaucoma and ocular hypertension: year 4.

BACKGROUND: Bimatoprost 0.03% has been shown to consistently reduce mean intraocular pressure (IOP) more than timolol 0.5% over 2 years. To further evaluate long-term safety and efficacy, once-daily bimatoprost 0.03% was compared with timolol 0.5% twice daily through year 4. METHODS: In this multicentre, double-masked, randomised, controlled trial, glaucoma and ocular hypertension patients (n = 152) who completed phase III bimatoprost trials through month 36 were enrolled in a study extension through month 48. Patients randomised to bimatoprost once daily (n = 78) or timolol twice daily (n = 35) continued on the same regimen for a fourth year. Patients randomised to bimatoprost twice daily had been switched to bimatoprost once daily dosing at month 24 (bimatoprost twice daily/once daily treatment group), and continued with once daily dosing through month 48 (n = 39). IOP was measured at 08:00 and 10:00 at months 39, 42, 45 and 48. Safety measures included adverse events, biomicroscopy, ophthalmoscopy, visual acuity and visual field. RESULTS: Baseline IOP was comparable among groups. During year 4, mean IOP reductions from baseline were 7.0 to 8.1 mm Hg with bimatoprost once daily and 6.5 to 7.9 mm Hg with bimatoprost twice daily/once daily, significantly greater than with timolol twice daily (3.8 to 5.8 mm Hg, p< or =0.035) at all measurements. Over 4 years, the mean IOP reduction from baseline at 08:00 and 10:00 was 1.9 to 3.9 mm Hg (35% to 100%) greater with bimatoprost once daily than with timolol (p< or =0.013). Low IOPs were achieved by more bimatoprost than timolol patients (p< or =0.042). No safety concerns developed during long-term bimatoprost treatment; two patients in the timolol treatment group discontinued after month 36 because of adverse events. The most common treatment-related adverse event in the bimatoprost treatment groups was conjunctival hyperaemia. CONCLUSION: Bimatoprost once daily provided sustained IOP lowering greater than timolol twice daily and was well tolerated over long-term use.

Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

Array CGH profiling of favourable histology Wilms tumours reveals novel gains and losses associated with relapse.

Despite the excellent survival of Wilms tumour patients treated with multimodality therapy, approximately 15% will suffer from tumour relapse, where response rates are markedly reduced. We have carried out microarray-based comparative genomic hybridisation on a series of 76 Wilms tumour samples, enriched for cases which recurred, to identify changes in DNA copy number associated with clinical outcome. Using 1Mb-spaced genome-wide BAC arrays, the most significantly different genomic changes between favourable histology tumours that did (n = 37), and did not (n = 39), subsequently relapse were gains on 1q, and novel deletions at 12q24 and 18q21. Further relapse-associated loci included losses at 1q32.1, 2q36.3-2q37.1, and gain at 13q31. 1q gains correlated strongly with loss of 1p and/or 16q. In 3 of 11 cases with concurrent 1p(-)/1q(+), a breakpoint was identified at 1p13. Multiple low-level sub-megabase gains along the length of 1q were identified using chromosome 1 tiling-path arrays. One such recurrent region at 1q22-q23.1 included candidate genes RAB25, NES, CRABP2, HDGF and NTRK1, which were screened for mRNA expression using quantitative RT-PCR. These data provide a high-resolution catalogue of genomic copy number changes in relapsing favourable histology Wilms tumours.

Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase.

PDE10A is a recently identified phosphodiesterase that is highly expressed by the GABAergic medium spiny projection neurons of the mammalian striatum. Inhibition of PDE10A results in striatal activation and behavioral suppression, suggesting that PDE10A inhibitors represent a novel class of antipsychotic agents. In the present studies we further elucidate the localization of this enzyme in striatum of rat and cynomolgus monkey. We find by confocal microscopy that PDE10A-like immunoreactivity is excluded from each class of striatal interneuron. Thus, the enzyme is restricted to the medium spiny neurons. Subcellular fractionation indicates that PDE10A is primarily membrane bound. The protein is present in the synaptosomal fraction but is separated from the postsynaptic density upon solubilization with 0.4% Triton X-100. Immuno-electron microscopy of striatum confirms that PDE10A is most often associated with membranes in dendrites and spines. Immuno-gold particles are observed on the edge of the postsynaptic density but not within this structure. Our studies indicate that PDE10A is associated with post-synaptic membranes of the medium spiny neurons, suggesting that the specialized compartmentation of PDE10A enables the regulation of intracellular signaling from glutamatergic and dopaminergic inputs to these neurons.

Group based training for self-management strategies in people with type 2 diabetes mellitus.

BACKGROUND: It has been recognised that adoption of self-management skills by the person with diabetes is necessary in order to manage their diabetes. However, the most effective method for delivering education and teaching self-management skills is unclear. OBJECTIVES: To assess the effects of group-based, patient-centred training on clinical, lifestyle and psychosocial outcomes in people with type 2 diabetes. SEARCH STRATEGY: Studies were obtained from computerised searches of multiple electronic bibliographic databases, supplemented by hand searches of reference lists of articles, conference proceedings and consultation with experts in the field. Date of last search was February 2003. SELECTION CRITERIA: Randomised controlled and controlled clinical trials which evaluated group-based education programmes for adults with type 2 diabetes compared with routine treatment, waiting list control or no intervention. Studies were only included if the length of follow-up was six months or more and the intervention was at least one session with the minimum of six participants. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed study quality. A meta-analysis was performed if there were enough homogeneous studies reporting an outcome at either four to six months, 12-14 months, or two years, otherwise the studies were summarised in a descriptive manner. MAIN RESULTS: Fourteen publications describing 11 studies were included involving 1532 participants. The results of the meta-analyses in favour of group-based diabetes education programmes were reduced glycated haemoglobin at four to six months (1.4%; 95% confidence interval (CI) 0.8 to 1.9; P < 0.00001), at 12-14 months (0.8%; 95% CI 0.7 to 1.0; P < 0.00001) and two years (1.0%; 95% CI 0.5 to 1.4; P < 0.00001); reduced fasting blood glucose levels at 12 months (1.2 mmol/L; 95% CI 0.7 to 1.6; P < 0.00001); reduced body weight at 12-14 months (1.6 Kg; 95% CI 0.3 to 3.0; P = 0.02); improved diabetes knowledge at 12-14 months (SMD 1.0; 95% CI 0.7 to 1.2; P < 0.00001) and reduced systolic blood pressure at four to six months (5 mmHg: 95% CI 1 to 10; P = 0.01). There was also a reduced need for diabetes medication (odds ratio 11.8, 95% CI 5.2 to 26.9; P < 0.00001; RD = 0.2; NNT = 5). Therefore, for every five patients attending a group-based education programme we could expect one patient to reduce diabetes medication. AUTHORS' CONCLUSIONS: Group-based training for self-management strategies in people with type 2 diabetes is effective by improving fasting blood glucose levels, glycated haemoglobin and diabetes knowledge and reducing systolic blood pressure levels, body weight and the requirement for diabetes medication.

PAX7 expression in embryonal rhabdomyosarcoma suggests an origin in muscle satellite cells.

Rhabdomyosarcoma (RMS) is a common paediatric soft tissue sarcoma that resembles developing foetal skeletal muscle. Tumours of the alveolar subtype frequently harbour one of two characteristic translocations that juxtapose PAX3 or PAX7, and the forkhead-related gene FKHR (FOXO1A). The embryonal subtype of RMS is not generally associated with these fusion genes. Here, we have quantified the relative levels of chimaeric and wild-type PAX transcripts in various subtypes of RMS (n=34) in order to assess the relevance of wild-type PAX3 and PAX7 gene expression in these tumours. We found that upregulation of wild-type PAX3 is independent of the presence of either fusion gene and is unlikely to contribute to tumorigenesis. Most strikingly, upregulated PAX7 expression is almost entirely restricted to cases without PAX3-FKHR or PAX7-FKHR fusion genes and may contribute to tumorigenesis in the absence of chimaeric PAX transcription factors. Furthermore, as myogenic satellite cells are known to express PAX7, this pattern of PAX7 expression suggests this cell type as the origin of these tumours. This is corroborated by the detection of MET (c-met) expression, a marker for the myogenic satellite cell lineage, in all RMS samples expressing wild-type PAX7.

CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours.

We have recently shown that the CHEK2*1100delC mutation acts as a low penetrance breast cancer susceptibility allele. To investigate if other CHEK2 variants confer an increased risk of breast cancer, we have screened an affected individual with breast cancer from 68 breast cancer families. Five of these individuals were found to harbour germline variants in CHEK2. Three carried the 1100delC variant (4%). One of these three individuals also carried the missense variant, Arg180His. In the other two individuals, missense variants, Arg117Gly and Arg137Gln, were identified. These two missense variants reside within the Forkhead-associated domain of CHEK2, which is important for the function of the expressed protein. None of these missense variants were present in 300 healthy controls. Microdissected tumours with a germline mutation showed loss of the mutant allele suggesting a mechanism for tumorigenesis other than a loss of the wild type allele. This study provides further evidence that sequence variation in CHEK2 is associated with an increased risk of breast cancer, and implies that tumorigenesis in association with CHEK2 mutations does not involve loss of the wild type allele.

Statistical processing for gastric slow-wave identification.

Successful identification of gastric slow waves in canine gastric electrical activity (GEA) data was achieved using a statistical data-processing procedure based on the multiple linear regression (MLR) curve fitting technique. Both distal and proximal waveforms were identified, first by construction of separate orthonormal bases from pre-selected sets of representative distal and proximal gastric slow waves (GSWs). Respective basis matrices were used to fit proximal and distal data to an MLR data model. Residual waveforms were computed from the original and 'fitted' waveforms and used in identifying GSWs in the data. Canine GEA data were split into 1,800-point blocks, and each 245-point data segment in a block was processed to identify the GSWs. Gastric slow waves were located in the data using a residual mean-squared error (MSE) threshold and, for distal GEA data, the minimum value of the main distal waveform peak. All threshold values were determined empirically and were set to detect GSWs while limiting false matches. Identification rates of 95% and 99% for proximal and distal GSWs, respectively, represent a significant improvement over those obtained in a previous study in which the same data were analysed using linear signal-processing methods. The use of the method presented in this paper for real-time identification of GSWs in conjunction with an implantable gastric pacer unit appears promising. Because the technique is inherently customisable, results obtained in this study should also be applicable to human subjects.

Using resonance Raman spectroscopy to examine vibrational barriers to electron transfer and electronic delocalization.

A time-dependent approach to the interpretation of resonance Raman scattering intensities has been used to obtain quantitative vibrational mode displacement information from scattering intensities associated with charge-transfer excitation. The displacements and associated frequencies are the key parameters needed to understand Franck-Condon effects in electron-transfer kinetics, and to delineate in a mode-specific way the composition of vibrational reorganization energies. Application of the approach to a number of types of electron-transfer reactions is described, including symmetrical and unsymmetrical intervalence electron transfers in inorganic and organic redox systems, metal-to-ligand charge-transfer reactions, and interfacial electron-transfer reactions. Also described is how the approach can be used to elucidate mechanisms for valence delocalization in strongly interacting redox systems.

Isofenphos induced metabolic changes in K562 myeloid blast cells.

The organophosphate pesticide, isofenphos, is associated with human myeloid leukemia. In this study we describe metabolic changes in K562 myeloid blast cells from exposure to varying concentrations of isofenphos using the stable [1,2-13C(2)]glucose isotope as the single tracer and biological mass spectrometry. Isofenphos (1, 10, 100 microg/ml/72 h) treated K562 cells showed increases of 10.7, 33.8 and 39.7% in lactate production as well as a 14.2% increase (1 microg/ml/72 h) in 13C incorporation into nucleic acid ribose from glucose. Concomitantly, we observed a decrease in glucose oxidation and the synthesis of glutamate, palmitate and stearate from glucose. Our results demonstrate that this organophosphate pesticide exerts a leukemogenic effect by the recruitment of glucose carbons for nucleic acid synthesis thus promoting proliferation simultaneous with poor differentiation. The imbalanced metabolic phenotype with a severe defect in glucose oxidation, lipid and amino acid synthesis concurrent with de novo synthesis of nucleic acids in response to isofenphos treatment conforms to the invasive proliferating phenotype observed in TGF-beta treated lung epithelial carcinoma cells.