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Effective intracellular delivery of oligonucleotides in order to make sense of antisense. 总被引:5,自引:0,他引:5
For more than two decades, antisense oligonucleotides (ODNs) have been used to modulate gene expression for the purpose of applications in cell biology and for development of novel sophisticated medical therapeutics. Conceptually, the antisense approach represents an elegant strategy, involving the targeting to and association of an ODN sequence with a specific mRNA via base-pairing, resulting in an impairment of functional and/or harmful protein expression in normal and diseased cells/tissue, respectively. Apart from ODN stability, its efficiency very much depends on intracellular delivery and release/access to the target side, issues that are still relatively poorly understood. Since free ODNs enter cells relatively poorly, appropriate carriers, often composed of polymers and cationic lipids, have been developed. Such carriers allow efficient delivery of ODNs into cells in vitro, and the mechanisms of delivery, both in terms of biophysical requirements for the carrier and cell biological features of uptake, are gradually becoming apparent. To become effective, ODNs require delivery into the nucleus, which necessitates release of internalized ODNs from endosomal compartments, an event that seems to depend on the nature of the delivery vehicle and distinct structural shape changes. Interestingly, evidence is accumulating which suggests that by modulating the surface properties of the carrier, the kinetics of such changes can be controlled, thus providing possibilities for programmable release of the carrier contents. Here, consideration will also be given to antisense design and chemistry, and the challenge of extra- and intracellular barriers to be overcome in the delivery process. 相似文献
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Can Electrocardiographic Criteria Predict Adverse Cardiac Events and Positive Cardiac Markers? 总被引:5,自引:0,他引:5
Andra L. Blomkalns MD Christopher J. Lindsell PhD Abhinav Chandra MD Mary E. Osterlund MD W. Brian Gibler MD Charles V. Pollack MS MD Brian R. Tiffany MD PhD Judd E. Hollander MD James W. Hoekstra MD 《Academic emergency medicine》2003,10(3):205-210
OBJECTIVES: To determine electrocardiogram (ECG) predictors of positive cardiac markers and short-term adverse cardiac events in an undifferentiated chest pain population presenting to emergency departments (EDs). The authors hypothesized that specific ECG findings, other than those previously identified in higher-risk populations, would be predictive of cardiac outcomes and positive cardiac markers. METHODS: This study used data from a prospectively collected, retrospectively analyzed Internet-based data registry of undifferentiated chest pain patients (i*trACS). Logistic regression modeling was performed to determine the ECG findings that were predictive of 1) positive cardiac markers and 2) short-term adverse cardiac events. RESULTS: ST-segment elevation (STE), ST-segment depression (STD), pathological Q-waves (PQW), and T-wave inversion were associated with increased odds of percutaneous coronary intervention or catheterization, myocardial infarction, or coronary artery bypass grafting. The odds of creatine kinase-MB (CK-MB) measuring positive were increased if STE, STD, or PQW were present [odds ratio (OR) 2.495, 2.582, and 1.295, respectively]. A right bundle branch block tended to decrease the odds of CK-MB measuring positive (OR 0.658). A similar pattern of results was observed for troponin I (OR 3.608 for STE, 3.72 for STD, 1.538 for PQW). Troponin T showed an increased odds of measuring positive if any of STE, STD, left bundle branch block, or T-wave inversion were evident (OR 2.313, 2.816, 1.80, and 1.449, respectively). CONCLUSIONS: Initial ECG criteria can be used to predict short-term cardiac outcomes and positive cardiac markers. These findings can be important aids in the risk-stratification and aggressive treatment regimens of chest pain patients presenting to EDs. 相似文献
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Specific MR imaging of human lymphocytes by monoclonal antibody-guided dextran-magnetite particles. 总被引:4,自引:0,他引:4
J W Bulte Y Hoekstra R L Kamman R L Magin A G Webb R W Briggs K G Go C E Hulstaert S Miltenyi T H The 《Magnetic resonance in medicine》1992,25(1):148-157
Human lymphocytes were labeled with biotinylated anti-lymphocyte-directed monoclonal antibodies, to which streptavidin and subsequently biotinylated dextran-magnetite particles were coupled. This labeling resulted in a strong and selective negative contrast enhancement of lymphocyte suspensions at 2.0 T, caused predominantly by the specific increase of R2 with a small but significant specific increase of R1. The R1 was found to decrease with increasing field strength. The immunolabeling procedure described here may be used for the selective signal depletion of target cells in MR imaging. 相似文献
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Annemieke C. Kole MD Omgo E. Nieweg MD PhD Robert J. van Ginkel MD Jan Pruim MD PhD Harald J. Hoekstra MD PhD Anne M. J. Paans PhD Willem Vaalburg PhD Dr. Heimen Schraffordt Koops MD PhD 《Annals of surgical oncology》1997,4(1):57-63
Background: It is often difficult to detect a local recurrence of soft-tissue sarcomas due to disturbance of the normal anatomy by previous
surgery and radiotherapy. The aim of this study was to assess the value of positron emission tomography (PET) with [18F]fluoro-2-deoxy-d-glucose (FDG) for detecting local recurrences.
Methods: In the period 1992–1995, 17 patients with proven or suspected local recurrence of soft-tissue sarcoma were examined using
FDG-PET. Fifteen of these patients were ultimately proven to have a recurrence.
Results: Recurrence was visualized in 14 patients (93%). Small tumors (maximum diameter 0.5 cm) were as easily visible as large lesions
(maximum diameter 20 cm). In one patient the PET scan was positive, but the recurrence could not be proven histologically.
Recurrence was proven 1 year later. A recurrent low-grade liposarcoma was not visualized. The two patients with benign lesions
had a negative PET scan. The mean glucose metabolic rate was calculated to be 13.2 μmol/100 g/min (range 1.9–28.4). A correlation
was found between the histological malignancy grade and the metabolic rate (p<0.05; Kruskal-Wallis).
Conclusion: PET with FDG is a useful addition to the diagnostic armamentarium for detecting local recurrence of soft-tissue sarcomas
and provides an indication of the malignancy grade of the recurrent lesion.
Presented at the 47th Annual Meeting of The Society for Surgical Oncology, Houston, Texas, March 17–20, 1994. 相似文献
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Optimization of localized 19F magnetic resonance spectroscopy for the detection of fluorinated drugs in the human liver. 总被引:1,自引:0,他引:1
Dennis W J Klomp Hanneke W M Van Laarhoven Arno P M Kentgens Arend Heerschap 《Magnetic resonance in medicine》2003,50(2):303-308
Fluorine MR spectroscopy ((19)F MRS) is an indispensable tool for assessing the pharmacokinetics of fluorinated drugs. Since the metabolism of 5-fluorouracil (5FU), a frequently used cytotoxic drug, is expected to be different in normal liver and in tumor tissue, spatial localization is required for detection by MRS. In this study, three independent signal-to-noise ratio (SNR) optimizations were combined to enable chemical shift imaging (CSI) as a localization method in the detection of 5FU and its metabolites in tumor tissue. First, the hardware was optimized by using circularly polarized coils together with integrated preamplifiers. Second, the optimal pulse angle (Ernst angle) was determined on the basis of T(1) relaxation time measurements of 5FU. Finally, averaging of CSI phase-encoding steps was optimized by using the applied Hamming filter as a weighting function. The combination of these three methods enables the in vivo detection of 5FU and alpha-fluoro-beta-alanine (FBAL) by (19)F MRS, localized in three dimensions in tumor and liver tissue at a time resolution of 4 min at 1.5 Tesla. 相似文献
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Arend Bökenkamp Bettina Bohnhorst Christian Beier Norbert Albers Gisela Offner Johannes Brodehl 《Pediatric nephrology (Berlin, Germany)》1994,8(2):181-185
Gingival hyperplasia is a common side-effect of immunosuppression with cyclosporine A. Nifedipine is often used to control hypertension in kidney graft recipients. Analysis of gingival status in 106 children transplanted at our centre, and treated either with azathioprine, cyclosporine A or both, revealed significantly higher degrees of gingival overgrowth in those children receiving a combination of cyclosporine A and nifedipine compared with those children treated with cyclosporine A or nifedipine alone. Seven children undergoing gingivectomy at our centre over the past few years had received this combination. After a change in the antihypertensive regimen, avoiding long-term nifedipine medication, and improved dental care with chlorhexidine gel, we noted a reduction in the degree of gingival hyperplasia. In the majority of patients, nifedipine could be replaced by a single drug, usually hydralazine. We therefore recommend avoiding calcium channel blockers in the long-term management of hypertension in patients receiving cyclosporine. 相似文献