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1.
Water Sci Technol ; 82(11): 2545-2551, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33339807

ABSTRACT

Saprolite, weathered bedrock, is being used to dispose of domestic sewage through septic system drainfields, but its ability to remove coliforms is unknown. This study determined if Escherichia coli could be removed by a sandy loam saprolite material. Triplicate columns containing saprolite were prepared with lengths of 30, 45, and 60 cm. A 215-mL solution containing 1 × 105 CFU/100 mL of non-toxic E. coli was applied to the top of each column for 5 days/week for 13 weeks, and selected outflow samples were analyzed for E. coli. Control columns had only tap water applied to them at the same time. Significantly higher (p ≤ 0.10 compared to controls) E. coli concentrations were only detected in samples collected at the end of week 3 for the 30-cm columns and week 4 for the 45-cm columns. E. coli concentrations were small and ranged from approximately 2 to 3 MPN/100 mL. No E. coli were detected in any outflow from the 60-cm columns. From weeks 5 to 13, E. coli concentrations from all columns were either undetectable or not significantly different from the control. The results showed that 60 cm of sandy loam saprolite was sufficient for the removal of E. coli from simulated wastewater.


Subject(s)
Escherichia coli , Wastewater , Sewage
3.
World Dev ; 121: 163-177, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31481824

ABSTRACT

Over the last few decades rapid advances in processes to collect, monitor, disclose, and disseminate information have contributed towards the development of entirely new modes of sustainability governance for global commodity supply chains. However, there has been very little critical appraisal of the contribution made by different transparency initiatives to sustainability and the ways in which they can (and cannot) influence new governance arrangements. Here we seek to strengthen the theoretical underpinning of research and action on supply chain transparency by addressing four questions: (1) What is meant by supply chain transparency? (2) What is the relevance of supply chain transparency to supply chain sustainability governance? (3) What is the current status of supply chain transparency, and what are the strengths and weaknesses of existing initiatives? and (4) What propositions can be advanced for how transparency can have a positive transformative effect on the governance interventions that seek to strengthen sustainability outcomes? We use examples from agricultural supply chains and the zero-deforestation agenda as a focus of our analysis but draw insights that are relevant to the transparency and sustainability of supply chains in general. We propose a typology to distinguish among types of supply chain information that are needed to support improvements in sustainability governance, and illustrate a number of major shortfalls and systematic biases in existing information systems. We also propose a set of ten propositions that, taken together, serve to expose some of the potential pitfalls and undesirable outcomes that may result from (inevitably) limited or poorly designed transparency systems, whilst offering guidance on some of the ways in which greater transparency can make a more effective, lasting and positive contribution to sustainability.

4.
Urol Oncol ; 36(7): 345, 2018 07.
Article in English | MEDLINE | ID: mdl-29880459

ABSTRACT

BACKGROUND: Carcinoma in situ (CIS) is a poor prognostic finding in urothelial carcinoma. However, its significance in muscle-invasive urothelial carcinoma (MIUC) treated with neoadjuvant chemotherapy (NAC) is uncertain. We assessed the effect of CIS found in pretreatment transurethral resection of bladder tumor (TURBT) biopsies on the pathologic and clinical outcomes. MATERIALS AND METHODS: Subjects with MIUC treated with NAC before cystectomy were identified. The pathologic complete response (pCR) rates stratified by TURBT CIS status were compared. The secondary analyses included tumor response, progression-free survival (PFS), overall survival (OS), and an exploratory post hoc analysis of patients with pathologic CIS only (pTisN0) at cystectomy. RESULTS: A total of 137 patients with MIUC were identified. TURBT CIS was noted in 30.7% of the patients. The absence of TURBT CIS was associated with a significantly increased pCR rate (23.2% vs. 9.5%; odds ratio = 4.08; 95% CI: 1.19-13.98; P = 0.025). Stage pTisN0 disease was observed in 19.0% of the TURBT CIS patients. TURBT CIS status did not significantly affect the PFS or OS outcomes. Post hoc analysis of the pTisN0 patients revealed prolonged median PFS (104.5 vs. 139.9 months; P = 0.055) and OS (104.5 vs. 152.3 months; P = 0.091) outcomes similar to those for the pCR patients. CONCLUSION: The absence of CIS on pretreatment TURBT in patients with MIUC undergoing NAC was associated with increased pCR rates, with no observed differences in PFS or OS. Isolated CIS at cystectomy was frequently observed, with lengthy PFS and OS durations similar to those for pCR patients. Further studies aimed at understanding the biology and clinical effect of CIS in MIUC are warranted.


Subject(s)
Carcinoma, Transitional Cell/surgery , Neoadjuvant Therapy , Carcinoma in Situ , Cystectomy , Humans , Prognosis , Retrospective Studies , Treatment Outcome , Urinary Bladder Neoplasms/surgery
6.
Environ Sci Process Impacts ; 19(1): 50-58, 2017 Jan 25.
Article in English | MEDLINE | ID: mdl-27942631

ABSTRACT

Manganese oxides, which may be biogenically produced in both pristine and contaminated environments, have a large affinity for many trace metals. In this study, water and Mn oxide-bearing biofilm samples were collected from the components of a pump and treat remediation system at a superfund site. To better understand the factors leading to their formation and their effects on potentially toxic metal fate, we conducted a chemical, microscopic, and spectroscopic characterization of these biofilm samples. Scanning electron microscopy revealed the presence of Mn oxides in close association with biological structures with morphologies consistent with fungi. X-ray absorption spectroscopy (XAS) and X-ray diffraction (XRD) revealed the oxides to be a mixture of layer and tunnel structure Mn(iv) oxides. In addition, XAS suggested that Ba, Co, and Zn all primarily bind to oxides in the biofilm in a manner that is analogous to synthetic or laboratory grown bacteriogenic Mn oxides. The results indicate that Mn oxides produced by organisms in the system may effectively scavenge metals, thus highlighting the potential utility of these organisms in designed remediation systems.


Subject(s)
Biofilms , Environmental Pollutants/chemistry , Environmental Restoration and Remediation/methods , Manganese Compounds/chemistry , Metals/chemistry , Oxides/chemistry , Fungi/chemistry , Fungi/metabolism , Manganese Compounds/metabolism , Microscopy, Electron, Scanning , Oxidation-Reduction , Oxides/metabolism , X-Ray Absorption Spectroscopy , X-Ray Diffraction
7.
Epidemiol Infect ; 145(4): 787-795, 2017 03.
Article in English | MEDLINE | ID: mdl-27927265

ABSTRACT

Australian abattoir workers, farmers, veterinarians and people handling animal birthing products or slaughtering animals continue to be at high risk of Q fever despite an effective vaccine being available. National Notifiable Diseases Surveillance System data were analysed for the period 1991-2014, along with enhanced risk factor data from notified cases in the states of New South Wales and Queensland, to examine changes in the epidemiology of Q fever in Australia. The national Q fever notification rate reduced by 20% [incident rate ratio (IRR) 0·82] following the end of the National Q fever Management Program in 2006, and has increased since 2009 (IRR 1·01-1·34). Highest rates were in males aged 40-59 years (5·9/100 000) and 87% of Q fever cases occurred in New South Wales and Queensland. The age of Q fever cases and proportion of females increased over the study period. Based on the enhanced risk factor data, the most frequently listed occupation for Q fever cases involved contact with livestock, followed by 'no known risk' occupations. More complete and comparable enhanced risk factor data, at the State/Territory and national levels, would aid in further understanding of the epidemiology of Q fever.


Subject(s)
Q Fever/epidemiology , Adolescent , Adult , Age Factors , Aged , Animals , Child , Child, Preschool , Female , Humans , Incidence , Infant , Infant, Newborn , Male , Middle Aged , New South Wales/epidemiology , Occupational Exposure , Queensland/epidemiology , Risk Factors , Sex Factors , Young Adult
8.
J Evol Biol ; 30(2): 244-256, 2017 02.
Article in English | MEDLINE | ID: mdl-27696584

ABSTRACT

Phenotypic traits such as ornaments and armaments are generally shaped by sexual selection, which often favours larger and more elaborate males compared to females. But can sexual selection also influence the brain? Previous studies in vertebrates report contradictory results with no consistent pattern between variation in brain structure and the strength of sexual selection. We hypothesize that sexual selection will act in a consistent way on two vertebrate brain regions that directly regulate sexual behaviour: the medial preoptic nucleus (MPON) and the ventromedial hypothalamic nucleus (VMN). The MPON regulates male reproductive behaviour whereas the VMN regulates female reproductive behaviour and is also involved in male aggression. To test our hypothesis, we used high-resolution magnetic resonance imaging combined with traditional histology of brains in 14 dragon lizard species of the genus Ctenophorus that vary in the strength of precopulatory sexual selection. Males belonging to species that experience greater sexual selection had a larger MPON and a smaller VMN. Conversely, females did not show any patterns of variation in these brain regions. As the volumes of both these regions also correlated with brain volume (BV) in our models, we tested whether they show the same pattern of evolution in response to changes in BV and found that the do. Therefore, we show that the primary brain nuclei underlying reproductive behaviour in vertebrates can evolve in a mosaic fashion, differently between males and females, likely in response to sexual selection, and that these same regions are simultaneously evolving in concert in relation to overall brain size.


Subject(s)
Brain/anatomy & histology , Lizards/anatomy & histology , Mating Preference, Animal , Animals , Female , Male , Sex Characteristics , Sexual Behavior , Sexual Behavior, Animal
9.
Eye (Lond) ; 30(6): 825-32, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27034201

ABSTRACT

PurposeTo quantify early neuroretinal alterations in patients with type 1 diabetes mellitus (T1DM) and to assess whether glycemic variability contributes to alterations in neuroretinal structure or function.MethodsThirty patients with T1DM and 51 controls underwent comprehensive ophthalmic examination and assessment of retinal function or structure with frequency doubling perimetry (FDP), contrast sensitivity, dark adaptation, fundus photography, and optical coherence tomography (OCT). Diabetic participants wore a subcutaneous continuous glucose monitor for 5 days, from which makers of glycemic variability including the low blood glucose index (LGBI) and area under the curve (AUC) for hypoglycemia were derived.ResultsSixteen patients had no diabetic retinopathy (DR), and 14 had mild or moderate DR. Log contrast sensitivity for the DM group was significantly reduced (mean±SD=1.63±0.06) compared with controls (1.77±0.13, P<0.001). OCT analysis revealed that the inner temporal inner nuclear layer (INL) was thinner in patients with T1DM (34.9±2.8 µm) compared with controls (36.5±2.9 µm) (P=0.023), although this effect lost statistical significance after application of the Bonferroni correction for multiple comparisons. Both markers of glycemic variability, the AUC for hypoglycemia (R=-0.458, P=0.006) and LGBI (R=-0.473, P=0.004), were negatively correlated with inner temporal INL thickness.ConclusionsPatients with T1DM and no to moderate DR exhibit alterations in inner retinal structure and function. Increased glycemic variability correlates with retinal thinning on OCT imaging, suggesting that fluctuations in blood glucose may contribute to neurodegeneration.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 1/physiopathology , Diabetic Retinopathy/physiopathology , Glycemic Index/physiology , Retina/physiopathology , Adult , Contrast Sensitivity/physiology , Dark Adaptation/physiology , Diabetes Mellitus, Type 1/diagnosis , Diabetic Retinopathy/diagnosis , Female , Glycated Hemoglobin/metabolism , Humans , Male , Middle Aged , Tomography, Optical Coherence , Visual Field Tests
10.
Cell Stress Chaperones ; 20(3): 461-72, 2015 May.
Article in English | MEDLINE | ID: mdl-25618331

ABSTRACT

Heat shock protein 72 (Hsp72) protects cells against a variety of stressors, and multiple studies have suggested that Hsp72 plays a cardioprotective role. As skeletal muscle Hsp72 overexpression can protect against high-fat diet (HFD)-induced insulin resistance, alterations in substrate metabolism may be a mechanism by which Hsp72 is cardioprotective. We investigated the impact of transgenically overexpressing (Hsp72 Tg) or deleting Hsp72 (Hsp72 KO) on various aspects of cardiac metabolism. Mice were fed a normal chow (NC) or HFD for 12 weeks from 8 weeks of age to examine the impact of diet-induced obesity on metabolic parameters in the heart. The HFD resulted in an increase in cardiac fatty acid oxidation and a decrease in cardiac glucose oxidation and insulin-stimulated cardiac glucose clearance; however, there was no difference in Hsp72 Tg or Hsp72 KO mice in these rates compared with their respective wild-type control mice. Although HFD-induced cardiac insulin resistance was not rescued in the Hsp72 Tg mice, it was preserved in the skeletal muscle, suggesting tissue-specific effects of Hsp72 overexpression on substrate metabolism. Comparison of two different strains of mice (BALB/c vs. C57BL/6J) also identified strain-specific differences in regard to HFD-induced cardiac lipid accumulation and insulin resistance. These strain differences suggest that cardiac lipid accumulation can be dissociated from cardiac insulin resistance. Our study finds that genetic manipulation of Hsp72 does not lead to alterations in metabolic processes in cardiac tissue under resting conditions, but identifies mouse strain-specific differences in cardiac lipid accumulation and insulin-stimulated glucose clearance.


Subject(s)
Diet, High-Fat/adverse effects , HSP72 Heat-Shock Proteins/metabolism , Heart Diseases/metabolism , Animals , Body Composition , Feeding Behavior , Glucose/metabolism , HSP72 Heat-Shock Proteins/genetics , Heart Diseases/etiology , Insulin Resistance , Lipid Metabolism , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Oxidation-Reduction , Palmitic Acid/metabolism
12.
Minerva Gastroenterol Dietol ; 60(4): 227-45, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25288203

ABSTRACT

AIM: Since its introduction, endoscopic ultrasonography (EUS) has been increasingly gaining more attention for diagnosing various gastrointestinal conditions. We aim to systematically review the literature and highlight the benefit of using EUS in different pancreatic diseases by primarily reviewing its importance in diagnosing, treating pancreatic pathologies, comparing its accuracy to other modalities and determining its limitations and complications. METHODS: Using defined (MeSH) terms and keywords; two reviewers conducted a MEDLINE search through August 2014, in addition to manually searching relevant bibliographies cited in the included studies. All case reports, case series, letters, non-English and non-human articles were excluded. RESULTS: Total of (N.=2144) potentially relevant citations were identified and screened, of which (N.=525) fulfilled eligibility criteria and grouped into seven pancreatic disease categories: chronic pancreatitis (N.=72), acute pancreatitis (N.=75), autoimmune pancreatitis (N.=31), pancreatic cancer (N.=179), neuroendocrine pancreatic tumors (N.=48), pancreatic cysts (N.=111) and pancreatic divisum (N.=9). CONCLUSION: EUS sensitivity to diagnose chronic pancreatitis is greater than endoscopic retrograde cholangiopancreatography and CT, but using EUS-guided fine needle aspiration (EUS-FNA) is not diagnostic. In acute biliary pancreatitis, EUS is superior to CT and to magnetic resonance cholangiopancreatography (MRCP) for detection of microlithiasis. EUS-guided pseudocyst drainage is safe with a high success rate. Contrast-enhanced EUS is more valuable than EUS in autoimmune pancreatitis and EUS-FNA is not recommended. EUS is superior to MRCP and multiple detector CT in evaluating pancreatic divisum. Cystic carcinoembryonic antigen level obtained using EUS-FNA is the most accurate test to exclude malignant pancreatic cyst.


Subject(s)
Endosonography , Pancreatic Diseases/diagnostic imaging , Acute Disease , Algorithms , Evidence-Based Medicine , Humans , Meta-Analysis as Topic , Pancreatic Cyst/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Pancreatitis/diagnostic imaging , Pancreatitis, Chronic/diagnostic imaging , Predictive Value of Tests , Randomized Controlled Trials as Topic , Sensitivity and Specificity
13.
Braz J Microbiol ; 44(1): 97-103, 2013.
Article in English | MEDLINE | ID: mdl-24159289

ABSTRACT

Forty-six bottled water samples representing 16 brands from Dhaka, Bangladesh were tested for the numbers of total coliforms, fecal indicator bacteria (i.e., thermotolerant Escherichia coli and Enterococcus spp.) and potential bacterial pathogens (i.e., Aeromonas hydrophila, Pseudomonas aeruginosa, Salmonella spp., and Shigella spp.). Among the 16 brands tested, 14 (86%), ten (63%) and seven (44%) were positive for total coliforms, E. coil and Enterococcus spp., respectively. Additionally, a further nine (56%), eight (50%), six (37%), and four (25%) brands were PCR positive for A. hydrophila lip, P. aeruginosa ETA, Salmonella spp. invA, and Shigella spp. ipaH genes, respectively. The numbers of bacterial pathogens in bottled water samples ranged from 28 ± 12 to 600 ± 45 (A. hydrophila lip gene), 180 ± 40 to 900 ± 200 (Salmonella spp. invA gene), 180 ± 40 to 1,300 ± 400 (P. aeruginosa ETA gene) genomic units per L of water. Shigella spp. ipaH gene was not quantifiable. Discrepancies were observed in terms of the occurrence of fecal indicators and bacterial pathogens. No correlations were observed between fecal indicators numbers and presence/absence of A. hydrophila lip (p = 0.245), Salmonella spp. invA (p = 0.433), Shigella spp. ipaH gene (p = 0.078), and P. aeruginosa ETA (p = 0.059) genes. Our results suggest that microbiological quality of bottled waters sold in Dhaka, Bangladesh is highly variable. To protect public health, stringent quality control is recommended for the bottled water industry in Bangladesh.

14.
Int J Nanomedicine ; 8: 1637-43, 2013.
Article in English | MEDLINE | ID: mdl-23637532

ABSTRACT

BACKGROUND: To address the challenge of treating critical sized intercalary defects, we hypothesized that under physiologic cyclic loading, autografts, allografts, and scaffolds loaded with and without human mesenchymal stem cells (hMSCs) would have different biomechanical characteristics. METHODS: Using a rat femoral defect model, 46 rats were assigned to four groups, ie, autograft (n = 12), allograft (n = 10), scaffold (n = 13), and scaffold with hMSCs (n = 11). The scaffold groups used a 5 mm segment of scaffold composed of 80% poly-ε-caprolactone and 20% hydroxyapatite. Rats were sacrificed 4 months postoperatively, and the repairs were assessed radiographically and biomechanically. RESULTS: Autograft and allograft groups exhibited the most bridging callus, while the scaffold/hMSCs group had more callus than the scaffold repairs. Although signs of radiographic healing did not accurately reflect restoration of mechanical properties, addition of hMSCs on the scaffold enhanced bone formation. The scaffold alone group had significantly lower elastic and viscous stiffness and higher phase angles than other repairs and the contralateral controls. Addition of hMSCs increased the elastic and viscous stiffness of the repair, while decreasing the phase angle. CONCLUSION: Further comparative analysis is needed to optimize clinical use of scaffolds and hMSCs for critical sized defect repairs. However, our results suggest that addition of hMSCs to scaffolds enhances mechanical simulation of native host bone.


Subject(s)
Femoral Fractures/therapy , Fracture Healing/physiology , Tissue Engineering/instrumentation , Tissue Engineering/methods , Transplantation/methods , Analysis of Variance , Animals , Biomechanical Phenomena , Bone Substitutes/chemistry , Durapatite/chemistry , Female , Femoral Fractures/pathology , Femoral Fractures/physiopathology , Femur/injuries , Femur/pathology , Femur/physiology , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/physiology , Polyesters/chemistry , Rats , Rats, Sprague-Dawley , Tissue Scaffolds/chemistry , Weight-Bearing/physiology
16.
Water Sci Technol ; 67(2): 446-51, 2013.
Article in English | MEDLINE | ID: mdl-23168648

ABSTRACT

Increases in the impervious area due to urbanisation have been shown to have negative impacts on the physical and ecological condition of streams, primarily through increased volume and frequency of runoff. The harvesting and detention of runoff has a potential to decrease this impact. This paper describes the effects of urbanisation on catchment flow and of stormwater harvesting on reducing those adverse impacts on a stream in South East Queensland (SEQ), Australia. A largely undeveloped catchment located southeast of Brisbane city was calibrated and validated using the Stormwater Management Model (SWMM). This model was used to investigate the effect of a range of future increases in urbanisation (represented by impervious area) on stream hydrology as well as the potential of stormwater harvesting to return the catchments to predevelopment flow conditions. Stormwater harvesting was modelled according to flow frequency measures specified in current SEQ development guidelines. These guidelines stipulate the capture of the first 10 mm of runoff from impervious areas of 0-40% and the first 15 mm from impervious areas of 40% or greater for urban developments. We found that increases in the impervious area resulted in increases in the mean, frequency and duration of high flows, and an increase in the mean rate of rise and fall for storm events in the catchment. However, the predevelopment (non-urbanised) flow distribution was very flashy in comparison with all urbanised scenarios; i.e. it had the quickest response to rainfall indicated by a high rate of rise to and fall from peak flow volume, followed by a return to zero flow conditions. Capturing the runoff according to the development guidelines resulted in a reduction in flow towards the flow distribution of a lower impervious area, however this was insufficient to meet predevelopment conditions. This suggests a stronger influence of impervious areas in this catchment on the volume of runoff than flow frequency measures are able to ameliorate.


Subject(s)
Cities , Cyclonic Storms , Rain , Water Movements , Queensland , Urbanization , Water
17.
Braz. j. microbiol ; 44(1): 97-103, 2013. tab
Article in English | LILACS | ID: lil-676899

ABSTRACT

Forty-six bottled water samples representing 16 brands from Dhaka, Bangladesh were tested for the numbers of total coliforms, fecal indicator bacteria (i.e., thermotolerant Escherichia coli and Enterococcus spp.) and potential bacterial pathogens (i.e., Aeromonas hydrophil, Pseudomonas aeruginos, Salmonella spp., and Shigella spp.). Among the 16 brands tested, 14 (86%), ten (63%) and seven (44%) were positive for total coliforms, E. coil and Enterococcus spp., respectively. Additionally, a further nine (56%), eight (50%), six (37%), and four (25%) brands were PCR positive for A. hydrophila lip, P. aeruginosa ETA, Salmonella spp. invA, and Shigella spp. ipaH genes, respectively. The numbers of bacterial pathogens in bottled water samples ranged from 28 ± 12 to 600 ± 45 (A. hydrophila lip gene), 180 ± 40 to 900 ± 200 (Salmonella spp. invA gene), 180 ± 40 to 1,300 ± 400 (P. aeruginosa ETA gene) genomic units per L of water. Shigella spp. ipaH gene was not quantifiable. Discrepancies were observed in terms of the occurrence of fecal indicators and bacterial pathogens. No correlations were observed between fecal indicators numbers and presence/absence of A. hydrophila lip (p = 0.245), Salmonella spp. invA (p = 0.433), Shigella spp. ipaH gene (p = 0.078), and P. aeruginosa ETA (p = 0.059) genes. Our results suggest that microbiological quality of bottled waters sold in Dhaka, Bangladesh is highly variable. To protect public health, stringent quality control is recommended for the bottled water industry in Bangladesh.


Subject(s)
Male , Anti-Bacterial Agents , Drinking Water/prevention & control , Coliforms/methods , Coliforms/prevention & control , Enterobacteriaceae Infections , Enterobacteriaceae/isolation & purification , Enterobacteriaceae/pathogenicity , In Vitro Techniques , Polymerase Chain Reaction , Water Pollution , Methods , Virulence , Water Samples
19.
Diabetologia ; 55(10): 2769-2778, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22832498

ABSTRACT

AIMS/HYPOTHESIS: Although skeletal muscle insulin resistance has been associated with activation of c-Jun N-terminal kinase (JNK), whether increased JNK activity causes insulin resistance in this organ is not clear. In this study we examined the metabolic consequences of isolated JNK phosphorylation in muscle tissue. METHODS: Plasmids containing genes encoding a wild-type JNK1 (WT-JNK) or a JNK1/JNKK2 fusion protein (rendering JNK constitutively active; CA-Jnk) were electroporated into one tibialis anterior (TA) muscle of C57Bl/6 mice, with the contralateral TA injected with an empty vector (CON) to serve as a within-animal control. RESULTS: Overproduction of WT-JNK resulted in a modest (~25%) increase in phosphorylation (Thr(183)/Tyr(185)) of JNK, but no differences were observed in Ser(307) phosphorylation of insulin receptor substrate 1 (IRS-1) or total IRS-1 protein, nor in insulin-stimulated glucose clearance into the TA muscle when comparing WT-JNK with CON. By contrast, overexpression of CA-Jnk, which markedly increased the phosphorylation of CA-JNK, also increased serine phosphorylation of IRS-1, markedly decreased total IRS-1 protein, and decreased insulin-stimulated phosphorylation of the insulin receptor (Tyr(1361)) and phosphorylation of Akt at (Ser(473) and Thr(308)) compared with CON. Moreover, overexpression of CA-Jnk decreased insulin-stimulated glucose clearance into the TA muscle compared with CON and these effects were observed without changes in intramuscular lipid species. CONCLUSIONS/INTERPRETATION: Constitutive activation of JNK in skeletal muscle impairs insulin signalling at the level of IRS-1 and Akt, a process which results in the disruption of normal glucose clearance into the muscle.


Subject(s)
Insulin Resistance/physiology , JNK Mitogen-Activated Protein Kinases/metabolism , Muscle, Skeletal/metabolism , Animals , Insulin Receptor Substrate Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Models, Animal , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism
20.
Ann Oncol ; 23(11): 2820-2827, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22571859

ABSTRACT

BACKGROUND: Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC. EXPERIMENTAL DESIGN: Treatment consisted of cetuximab load at 400 mg/m(2) followed by cetuximab 250 mg/m(2) weekly and gemcitabine 50 mg/m(2) twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection. RESULTS: Thirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status. CONCLUSIONS: Neoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.


Subject(s)
Adenocarcinoma/therapy , Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Pancreatic Neoplasms/therapy , Radiotherapy, Intensity-Modulated , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cetuximab , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , ErbB Receptors/biosynthesis , Female , Humans , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Radiotherapy, Intensity-Modulated/adverse effects , Treatment Outcome , Gemcitabine
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