163 research outputs found
KRAS Mutation in Metastatic Pancreatic Ductal Adenocarcinoma: Results of a Multicenter Phase II Study Evaluating Efficacy of Cetuximab plus Gemcitabine/Oxaliplatin (GEMOXCET) in First-Line Therapy
Background: Genetic alterations within the epidermal growth factor receptor (EGFR) pathway, including KRAS mutations, have been demonstrated to be associated with response to EGFR inhibitors like cetuximab in colorectal cancers. Mutations in the KRAS gene have been found in 70–90% of pancreatic cancers. Unfortunately, the addition of cetuximab to chemotherapy did not increase response or survival in patients with advanced pancreatic cancer in phase II and phase III studies. The aim of this study was to evaluate the relationship between KRAS mutations and response or survival in patients with metastatic pancreatic cancer treated with cetuximab plus chemotherapy. Methods: Within a multicenter phase II trial, 64 patients with metastatic pancreatic cancer were treated with cetuximab in combination with gemcitabine and oxaliplatin until disease progression. Analyses of the EGFR pathway, including KRAS mutations, could be performed in 25 patients. Analyses were carried out following microdissection of the tumor. Results: Fourteen (56%) of the 25 patients examined harbored a point mutation in codon 12 of the KRAS gene. No differences between the groups were noted in median progression-free survival (104 days in KRAS wild-type patients vs. 118 days in patients with KRAS mutations). Overall survival was longer in wild-type patients compared to patients with KRAS mutations (263 vs. 162 days), but the difference did not reach statistical significance. A further analysis of our clinical phase II trial showed that the presence of a rash was significantly correlated with overall survival. Conclusions: KRAS mutation in codon 12 may be associated with reduced survival compared to KRAS wild type. The role of KRAS mutations for cetuximab therapy in pancreatic cancer warrants further investigation in larger trials to exclude an epiphenomenon. Furthermore, the development of a rash is indicative of clinical benefit
Development of a method for the detection and confirmation of the alpha-2 agonist amitraz and its major metabolite in horse urine
Amitraz (N′-(2,4-dimethylphenyl)-N-[[(2,4-dimethylphenyl)imino] methyl]-N-methyl-methanimidamide) is an alpha-2 adrenergic agonist used in veterinary medicine primarily as a scabicide- or acaricide-type insecticide. As an alpha-2 adrenergic agonist, it also has sedative/tranquilizing properties and is, therefore, listed as an Association of Racing Commissioners International Class 3 Foreign Substance, indicating its potential to influence the outcome of horse races. We identified the principal equine metabolite of amitraz as N-2,4-dimethylphenyl-N′-methylformamidine by electrospray ionization(+)-mass spectrometry and developed a gas chromatographic-mass spectrometric (GC-MS) method for its detection, quantitation, and confirmation in performance horse regulation. The GC-MS method involves derivatization with t-butyldimethylsilyl groups; selected ion monitoring (SIM) of m/z 205 (quantifier ion), 278, 261, and 219 (qualifier ions); and elaboration of a calibration curve based on ion area ratios involving simultaneous SIM acquisition of an internal standard m/z 208 quantifier ion based on an in-house synthesized d6 deuterated metabolite. The limit of detection of the method is approximately 5 ng/mL in urine and is sufficiently sensitive to detect the peak urinary metabolite at 1 h post dose, following administration of amitraz at a 75-mg/horse intraveneous dose
Detection and Confirmation of Ractopamine and Its Metabolites in Horse Urine after Paylean® Administration
We have investigated the detection, confirmation, and metabolism of the beta-adrenergic agonist ractopamine administered as Paylean to the horse. A Testing Components Corporation enzyme-linked imunosorbent assay (ELISA) kit for ractopamine displayed linear response between 1.0 and 100 ng/ml, with an 1-50 of 10 ng/ml, and an effective screening limit of detection of 50 ng/mL. The kit was readily able to detect ractopamine equivalents in unhydrolyzed urine up to 24 h following a 300-mg oral dose. Gas chromatography-mass spectrometry (GC-MS) confirmation comprised glucuronidase treatment, solid-phase extraction, and trimethylsilyl derivatization, with selected-ion monitoring of ractopamine-tris(trimethylsilane) (TMS) m/z 267, 250, 179, and 502 ions. Quantitation was elaborated in comparison to a 445 Mw isoxsuprine-bis(TMS) internal standard monitored simultaneously. The instrumental limit of detection, defined as that number of ng on column for which signal-to-noise ratios for one or more diagnostic ions fell below a value of three, was 0.1 ng, corresponding to roughly 5 ng/mL in matrix. Based on the quantitation ions for ractopamine standards extracted from urine, standard curves showed a linear response for ractopamine concentrations between 10 and 100 ng/mL with a correlation coefficient r \u3e 0.99, whereas standards in the concentration range of 10-1000 ng/mL were fit to a second-order regression curve with r \u3e 0.99. The lower limit of detection for ractopamine in urine, defined as the lowest concentration at which the identity of ractopamine could be confirmed by comparison of diagnostic MS ion ratios, ranged between 25 and 50 ng/mL. Urine concentration of parent ractopamine 24 h post-dose was measured at 360 ng/mL by GC-MS after oral administration of 300 mg. Urinary metabolites were identified by electrospray ionization (+) tandem quadrupole mass spectrometry and were shown to include glucuronide, methyl, and mixed methyl-glucuronide conjugates. We also considered the possibility that an unusual conjugate added 113 amu to give an observed m/z 415 [M+H] species or two times 113 amu to give an m/z 528 [M+H] species with a daughter ion mass spectrum related to the previous one. Sulfate and mixed methyl-sulfate conjugates were revealed following glucuronidase treatment, suggesting that sulfation occurs in combination with glucuronidation. We noted a paired chromatographic peak phenomenon of apparent ractopamine metabolites appearing as doublets of equivalent intensity with nearly identical mass spectra on GC-MS and concluded that this phenomenon is consistent with Paylean being a mixture of RR, RS, SR, and SS diastereomers of ractopamine. The results suggest that ELISA-based screening followed by glucuronide hydrolysis, parent drug recovery, and TMS derivatization provide an effective pathway for detection and GC-MS confirmation of ractopamine in equine urine
Financial cost of the admissions for simultaneous pancreas-kidney transplant in a Brazilian Hospital
Early peri-operative hyperglycaemia and renal allograft rejection in patients without diabetes
BACKGROUND: Patients with diabetes have an increased risk for allograft rejection, possibly related to peri-operative hyperglycaemia. Hyperglycaemia is also common following transplantation in patients without diabetes. We hypothesise that exposure of allograft tissue to hyperglycaemia could influence the risk for rejection in any patient with high sugars. To investigate the relationship of peri-operative glucose control to acute rejection in renal transplant patients without diabetes, all patients receiving their first cadaveric graft in a single center were surveyed and patients without diabetes receiving cyclosporin-based immunosuppression were reviewed (n = 230). Records of the plasma blood glucose concentration following surgery and transplant variables pertaining to allograft rejection were obtained. All variables suggestive of association were entered into multivariate logistic regression analysis, their significance analysed and modeled. RESULTS: Hyperglycaemia (>8.0 mmol/L) occurs in over 73% of non-diabetic patients following surgery. Glycaemic control immediately following renal transplantation independently predicted acute rejection (Odds ratio=1.08). 42% of patients with a glucose < 8.0 mmol/L following surgery developed rejection compared to 71% of patients who had a serum glucose above this level. Hyperglycaemia was not associated with any delay of graft function. CONCLUSION: Hyperglycaemia is associated with an increased risk for allograft rejection. This is consistent with similar findings in patients with diabetes. We hypothesise a causal link concordant with epidemiological and in vitro evidence and propose further clinical research
Overview of ASDEX Upgrade results
Recent results from the ASDEX Upgrade experimental campaigns 2001 and 2002 are presented. An improved understanding of energy and particle transport emerges in terms of a 'critical gradient' model for the temperature gradients. Coupling this to particle diffusion explains most of the observed behaviour of the density profiles, in particular, the finding that strong central heating reduces the tendency for density profile peaking. Internal transport barriers (ITBs) with electron and ion temperatures in excess of 20 keV (but not simultaneously) have been achieved. By shaping the plasma, a regime with small type II edge localized modes (ELMs) has been established. Here, the maximum power deposited on the target plates was greatly reduced at constant average power. Also, an increase of the ELM frequency by injection of shallow pellets was demonstrated. ELM free operation is possible in the quiescent H-mode regime previously found in DIII-D which has also been established on ASDEX Upgrade. Regarding stability, a regime with benign neoclassical tearing modes (NTMs) was found. During electron cyclotron current drive (ECCD) stabilization of NTMs, βN could be increased well above the usual onset level without a reappearance of the NTM. Electron cyclotron resonance heating and ECCD have also been used to control the sawtooth repetition frequency at a moderate fraction of the total heating power. The inner wall of the ASDEX Upgrade vessel has increasingly been covered with tungsten without causing detrimental effects on the plasma performance. Regarding scenario integration, a scenario with a large fraction of noninductively driven current (≥50%), but without ITB has been established. It combines improved confinement (τE/τITER98 ≈ 1.2) and stability (βN ≤ 3.5) at high Greenwald fraction (ne/nGW ≈ 0.85) in steady state and with type II ELMy edge and would offer the possibility for long pulses with high fusion power at reduced current in ITER
An Ontological Approach to Inform HMI Designs for Minimizing Driver Distractions with ADAS
ADAS (Advanced Driver Assistance Systems) are in-vehicle systems designed to enhance driving
safety and efficiency as well as comfort for drivers in the driving process. Recent studies have
noticed that when Human Machine Interface (HMI) is not designed properly, an ADAS can cause
distraction which would affect its usage and even lead to safety issues. Current understanding of
these issues is limited to the context-dependent nature of such systems. This paper reports the
development of a holistic conceptualisation of how drivers interact with ADAS and how such
interaction could lead to potential distraction. This is done taking an ontological approach to
contextualise the potential distraction, driving tasks and user interactions centred on the use of
ADAS. Example scenarios are also given to demonstrate how the developed ontology can be used
to deduce rules for identifying distraction from ADAS and informing future designs
Impact of initial exposure to calcineurin inhibitors on kidney graft function of patients at high risk to develop delayed graft function
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