Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Argon Fluoride (ArF) Excimer laser is currently used for experimental reshaping of the front surface of the cornea for the correction of myopic refractive error (photorefractive keratectomy, PRK) and for smoothing corneal irregularities (phototherapeutic keratectomy, PTK). Both PRK and PTK are in FDA clinical trials, but are more readily available outside the U.S.A. These techniques have achieved reasonable success in spite of early reports that deeper ablation procedures can cause reduced corneal clarity (haze) or a result which is less accurate or tends to regress. We studied how different depths of excimer tissue removal affect the smoothness of the ablation zone of the rabbit cornea. Dutch belted rabbits were immediately sacrificed by pentobarbital overdose. Their corneas were de-epithelialized with a knife or by the excimer laser and then were photoablated. A 4.5-mm circular ablation beam was delivered to each denuded area, but the beam was masked by positioning a steel blade to partially block the laser beam, thus creating variable ablation depths corresponding to 0.0, 12.5, 37.5, and 62.5 microns. The eyes were fixed in situ by topical and anterior chamber application of glutaraldehyde and the corneas were excised after 5 min and placed in glutaraldehyde for tissue processing. The corneas were whole-mounted and examined by scanning electron microscopy (SEM). The resultant micrographs show increasing irregularity of the ablated surface as a function of depth. The irregularity appeared to be due largely to the inhomogeneities of the anterior stroma, which is known to be layered by alternately directed collagen fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of depth upon the smoothness of excimer laser corneal ablation. 815 41

A useful synthetic methodology was developed to synthesize and radiolabel a series of (E)-5-(2-[125I]iodovinyl)uracil nucleoside substrates for herpes simplex virus type-1 thymidine kinase (HSV-1 TK). (E)-5-(2-[125I]Iodovinyl)-2'-deoxyuridine ([125I]IVDU, 10), (E)-5-(2-[125I]iodovinyl)-2'-fluoro-2'-deoxyuridine ([125I]IVFRU, 11), (E)-5-(2-[125I]iodovinyl)-2'-fluoro-2'-deoxyarabinouridine ([125I]IVFAU, 12), and (E)-5-(2-[125I]iodovinyl)arabinouridine ([125I]IVAU, 13) were synthesized in 63-83% radiochemical yield by reaction of the unprotected (E)-5-(2-(trimethylsilyl)vinyl) precursors (6-9) with [125I]ICl. Cellular uptake of these labeled compounds (10-13) was evaluated in vitro. All compounds showed minimal uptake in the KBALB cell line. However, increased uptake was observed for all compounds in KBALB-STK cells which are transduced with a replication incompetent Moloney murine leukemia virus vector encoding the HSV-1 TK gene. The results indicate that uptake of these compounds in KBALB-STK cells is variable and highly dependent on the nature of the sugar 2'-substituent. When a fluoro (12) or a hydroxy (13) substituent is present in the arabinofuranosyl (up) configuration at the 2'-position, there is diminished cellular uptake in KBALB-STK cells relative to hydrogen (10) or fluorine (11) in the ribofuranosyl (down) configuration at the 2'-position. Our results indicate that radiolabeled IVFRU (11) is most promising for further in vivo studies.
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PMID:Synthesis and cellular uptake of 2'-substituted analogues of (E)-5-(2-[125I]iodovinyl)-2'-deoxyuridine in tumor cells transduced with the herpes simplex type-1 thymidine kinase gene. Evaluation as probes for monitoring gene therapy. 921 37

A series of substituted 4-anilinoquinazolines and related compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that a narrow structure-activity relationship (SAR) existed for the bicyclic ring system, with quinazolines, quinolines, and cinnolines having activity and with quinazolines and quinolines generally being preferred. Substitution of the aniline was investigated and clearly indicated that small lipophilic substituents such as halogens or methyl were preferred at the C-4' position. Small substituents such as hydrogen and fluorine are preferred at the C-2' position. Introduction of a hydroxyl group at the meta position of the aniline produced the most potent inhibitors of Flt and KDR tyrosine kinases activity with IC(50) values in the nanomolar range (e.g. 10, 12, 13, 16, and 18). Investigation of the quinazoline C-6 and C-7 positions indicates that a large range of substituents are tolerated at C-7, whereas variation at the C-6 is more restricted. At C-7, neutral, basic, and heteroaromatic side chains led to very potent compounds, as illustrated by the methoxyethoxy derivative 13 (IC(50) < 2 nM). Our inhibitors proved to be very selective inhibitors of Flt and KDR tyrosine kinase activity when compared to that associated with the FGF receptor (50- to 3800-fold). Observed enzyme profiles translated well with respect to potency and selectivity for inhibition of growth factor stimulated proliferation of human umbilical vein endothelial cells (HUVECs). Oral administration of selected compounds to mice produced total plasma levels 6 h after dosing of between 3 and 49 microM. In vivo efficacy was demonstrated in a rat uterine oedema assay where significant activity was achieved at 60 mg/kg with the meta hydroxy anilinoquinazoline 10. Inhibition of growth of human tumors in athymic mice has also been demonstrated: compound 34 inhibited the growth of established Calu-6 lung carcinoma xenograft by 75% (P < 0.001, one tailed t-test) following daily oral administration of 100 mg/kg for 21 days.
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PMID:Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors. 1063 80

Increasingly hospitals are showing an interest in developing their imaging services to include positron emission tomography (PET). There is therefore a need to be aware of the radiation doses to critical groups. To assess the effective whole-body dose received by technologists within our dedicated PET centre, each staff member was issued with a dose rate meter, and was instructed to record the time spent in contact with any radioactive source, the dose received per working day and the daily injected activity. On average each technologist administered 831 MBq per day. The mean whole-body dose per MBq injected was 0.02 microSv/MBq(-1). The average time of close contact (<2.0 m) with a radioactive source per day was 32 min. The average effective dose per minute close contact was 0.5 microSv/min(-1), which resulted in a mean daily effective dose of 14.4 microSv. No technologist received greater than 60 microSv (the current UK limit for non-classified workers) in any one day, and in general doses received were less than 24 microSv, the daily dose corresponding to the proposed new annual limit for non-classified workers of 6.0 mSv per annum. However, we recognise that the layout of nuclear medicine departments will not mirror our own. We therefore measured the instantaneous dose rates at 0.1, 0.5, 1.0 and 2.0 m from the mid-thorax on 115 patients immediately after injection, to provide estimates of the likely effective doses that might be received by technologists operating dual-headed coincidence detection systems, and others coming into contact in the waiting room with patients who have been injected with fluorine-18 fluorodeoxyglucose. The mean (95th percentile) dose rates measured at the four aforementioned distances were 391.7 (549.5), 127.0 (199.8), 45.3 (70.0) and 17.1 (30.0) microSv/h(-1), respectively. A number of situations have been modelled showing that, with correct planning, FDG studies should not significantly increase the effective doses to technologists. However, one possible area of concern is that, depending on the number of patients in a waiting area at any one time, accompanying persons may approach the limits set by the new UK IRR 1999 regulations for members of the public.
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PMID:Radiation dose rates from patients undergoing PET: implications for technologists and waiting areas. 1085 15

Several studies have shown that the prognosis of oligodendrogliomas is dependent on their histological grade. In order to identify a non-invasive method for the primary diagnosis and follow-up of these tumours, we investigated the relationship between their in vivo metabolism, assessed by positron emission tomography (PET), and their histological grade assessed at the same time. Forty-seven patients with histologically confirmed oligodendrogliomas were investigated. Conventional neuroradiological assessment by computed tomography and magnetic resonance imaging (MRI) was performed in all the patients. All the histology slices were reviewed by the same pathologist after referral from various pathology laboratories. The PET investigation included a carbon-1 methionine (11C-MET) uptake study and, in the majority of cases, a fluorine-18 fluorodeoxyglucose (18F-FDG) uptake study, in order to investigate at the same time both amino acid metabolism and glycolysis. The sampled tumour region of interest (ROI) was defined from the T1-weighted 3D MR scan matched with the PET scan. Tracer concentration in each voxel of the tumour ROI was divided by the mean concentration in an ROI of the same size located in the healthy brain tissue. For each tumour and each tracer, we characterized the metabolic pattern on the basis of the mean and the maximum tumour to healthy tissue concentration ratio, and also the standard deviation and range of the ratios, which indicate the degree of metabolic heterogeneity of the tumour. The histological criteria for differentiating between high- and low-grade tumours were those of the WHO and, partially, of the Sainte-Anne-Daumas-Duport classification. Highly significant differences between high- and low-grade oligodendrogliomas (Mann-Whitney test: P<0.0001) were observed for all the assessed parameters of 11C-MET uptake. On the other hand, the pattern of 18F-FDG uptake showed only moderate differences between the two tumour groups.
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PMID:Non-invasive grading of oligodendrogliomas: correlation between in vivo metabolic pattern and histopathology. 1095 89

Substitution of two fluorine atoms on organic molecules is expected to alter both chemical reactivity and biological activity due to the strong electron-withdrawing nature of fluorine. The synthesis of partly gem-difluorinated compounds remains a significant challenge to synthetic organic chemists. We report that [2,3]-Wittig rearrangement of 1,1,2-trifluoroallylic ether gave a new type of partly gem-difluorinated allylic alcohol: 6-methyl-4,4,5-trifluorohept-1,5-dien-3-ol, 3, in a highly stereoselective fashion, and optical resolution of alcohol 3 was accomplished via lipase PS(PCL)-catalyzed reaction. Using this alcohol as the starting material, the first asymmetric synthesis of both enantiomers of point-fluorinated-eldanolides, 2,2,5,5,6-pentafluoroeldanolide 1 and 5,5,6-trifluoroeldanolide 2, analogues of the sex pheromone of the male African sugarcane borer, has been demonstrated.
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PMID:Asymmetric synthesis of both enantiomers of point-difluorinated-eldanolide, analogues of insect sex pheromone. 1143 40

Over the last two decades the large volume of research involving various brain tracers has shed invaluable light on the pathophysiology of cerebral neoplasms. Yet the question remains as to how best to incorporate this newly acquired insight into the clinical context. Thallium is the most studied radiotracer with the longest track record. Many, but not all studies, show a relationship between (201)Tl uptake and tumor grade. Due to the overlap between tumor uptake and histologic grades, (201)Tl cannot be used as the sole noninvasive diagnostic or prognostic tool in brain tumor patients. However, it may help differentiating a high-grade tumor recurrence from radiation necrosis. MIBI is theoretically a better imaging agent than (201)Tl but it has not convincingly been shown to differentiate tumors according to grade. MDR-1 gene expression as demonstrated by MIBI does not correlate with chemoresistance in high grade gliomas. Currently, MIBI's clinical role in brain tumor imaging has yet to be defined. IMT, a radio-labeled amino acid analog, may be useful for identifying postoperative tumor recurrence and, in this application, appears to be a cheaper, more widely available tool than positron emission tomography (PET). However, its ability to accurately identify tumor grade is limited. 18 F-2-Fluoro-2-deoxy-d-glucose (FDG) PET predicts tumor grade, and the metabolic activity of brain tumors has a prognostic significance. Whether FDG uptake has an independent prognostic value above that of histology remains debated. FDG-PET is effective in differentiating recurrent tumor from radiation necrosis for high-grade tumors, but has limited value in defining the extent of tumor involvement and recurrence of low-grade lesions. Amino-acid tracers, such as MET, perform better for this purpose and thus play a complementary role to FDG. Given the poor prognosis of patients with gliomas, particularly with high-grade lesions, the overall clinical utility of single photon emission computed tomography (SPECT) and PET in characterizing recurrent lesions remains dependent on the availability of effective treatments. These tools are thus mostly suited to the evaluation of treatment response in experimental protocols designed to improve the patients' outcome.
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PMID:Imaging gliomas with positron emission tomography and single-photon emission computed tomography. 1275 47

This report describes the synthesis, spectroscopy, and photochemistry of a new fluorescein-derivatized iron sulfur nitrosyl compound, the Roussin's red salt ester bis-((mu-S,mu-S')-fluorescein-2-thioethyl-ester)-tetranitrosyldiiron (Fluor-RSE). Under continuous photolysis Fluor-RSE decomposes with moderate quantum yields (0.0036 +/- 0.0005 at lambda(irr) = 436 nm) with the corresponding release of most of the NO carried by the Fe2S2NO4 cluster. Large changes in the optical absorptivity occur upon photolysis of the Fluor-RSE, and these changes have been attributed to the different protic forms available to the fluorescein chromophore as it is separated from the cluster. Steady-state luminescence experiments have shown that the fluorescence of Fluor-RSE is about 85% quenched relative to the model compound ethyl fluorescein (Fluor-Et). Thus, it is clear that excitation of the fluorescein chromophore antennae is followed by energy transfer to the Fe/S/NO cluster at a rate at least comparable to fluorescence. However, the effect of the iron-sulfur core on the fluorescent lifetimes from fluorescein chromophore is much smaller. A single-exponential decay (tau = 3.3 ns) was seen for Fluor-RSE that is only modestly shorter than that for Fluor-Et (tau = 4.5 ns), and this is the effect of the smaller radiative rate constant (k(r)) for the former. These systems further demonstrate that attachment of a pendant dye chromophore as an antenna significantly improves the effective rate for photochemical NO generation from the Roussin's red salt esters at longer excitation wavelengths.
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PMID:Toward development of water soluble dye derivatized nitrosyl compounds for photochemical delivery of NO. 1644 Nov 30

Investigations of the basic pathological, cellular, and molecular mechanisms of traumatic brain injury (TBI) over the past two decades have been carried out primarily in rodents. Unfortunately, these studies have not translated into improved outcome in patients with TBI. To better model human TBI, a swine model of controlled cortical impact (CCI) was developed. A CCI device was used to generate a focal lesion in 23 anesthetized male Yorkshire swine. In 10 swine, CCI parameters of velocity and dwell time were varied to achieve a consistent injury (3.5 m/sec, 400 msec, respectively). In 13 swine, depth of depression was varied from 9 to 12 mm. Physiological data, including heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP), were collected for 10 h after injury. Following injury, ICP and HR increased above baseline values in all swine, with a more pronounced elevation in animals impacted to a depth of depression of 12 mm. An 11-mm depth of depression was found to most closely mimic pathological features of human TBI with edema, infiltration of inflammatory cells, pericapillary hemorrhage, and petechial hemorrhages in the white matter. Injury to a depth of depression of 12 mm resulted in cortical laceration obscuring these features. Immunohistological staining with Neu-N, MAP-2, and Fluoro Jade B revealed evidence of degenerating neurons, axonal disruption, and impending cell death. These results indicate that the swine model of CCI results in a defined and reproducible injury with pathological features similar to human TBI. Physiological parameters after injury are readily monitored in a setting mimicking conditions of an intensive care unit, establishing a more clinically relevant experimental model for future investigations.
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PMID:Controlled cortical impact in swine: pathophysiology and biomechanics. 1650 97

The experiments described here demonstrate the use of two-photon excitation (TPE) to sensitize nitric oxide (NO) release from a dye-derivatized iron/sulfur/nitrosyl cluster Fe2(mu-RS)2(NO)4 (Fluor-RSE, RS = 2-thioethyl ester of fluorescein) with near-infrared (NIR) light in the form of femtosecond pulses from a Ti:sapphire laser. TPE at 800 nm leads both to weak fluorescence from the organic chromophore at lambda(max) = 532 nm and to NO labilization from the cluster. Since the emission from the reference compound Fluor-Et (the ethyl ester of fluorescein) under identical conditions (50/50 CH3CN/phosphate buffer (1 mM) at pH 7.4) is considerably more intense, the weaker emission from Fluor-RSE and the NO generation indicate that the fluorescein excited states initially formed by TPE are largely quenched by energy transfer to the cluster core. The two-photon absorption (TPA) cross section of Fluor-RSE at 800 nm was determined to be delta = 63 +/- 7 GM via the TPA photoluminescence technique. This can be compared to the TPA cross section of 36 GM reported for fluorescein dye in pH 11 aqueous solution and of 32 +/- 3 GM for Fluor-Et measured under conditions comparable to those used for Fluor-RSE. Pulse intensity dependence studies showed that the quantity of NO released from the latter as the result of NIR photoexcitation follows a quadratic relationship to excitation intensity, consistent with the expectation for a TPE process. These studies demonstrate the potential utility of a two-photon antenna for sensitization of the photochemical release of an active agent (in this case, NO) from a photoactive pro-drug.
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PMID:A two-photon antenna for photochemical delivery of nitric oxide from a water-soluble, dye-derivatized iron nitrosyl complex using NIR light. 1653 59


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