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81.
82.
Freeman BD Kennedy CR Bolcic-Jankovic D Eastman A Iverson E Shehane E Celious A Barillas J Clarridge B 《Journal of empirical research on human research ethics》2012,7(1):58-70
Clinical studies conducted in intensive care units are associated with logistical and ethical challenges. Diseases investigated are precipitous and life-threatening, care is highly technological, and patients are often incapacitated and decision-making is provided by surrogates. These investigations increasingly involve collection of genetic data. The manner in which the exigencies of critical illness impact attitudes regarding genetic data collection is unstudied. Given interest in understanding stakeholder preferences as a foundation for the ethical conduct of research, filling this knowledge gap is timely. The conduct of opinion research in the critical care arena is novel. This brief report describes the development of parallel patient/surrogate decision-maker quantitative survey instruments for use in this environment. Future research employing this instrument or a variant of it with diverse populations promises to inform research practices in critical illness gene variation research. 相似文献
83.
84.
DNA damage induces cell cycle arrest through both Chk1 and the p53 tumor suppressor protein, the latter arresting cells through induction of p21waf1 protein. Arrest permits cells to repair the damage and recover. The frequent loss of p53 in tumor cells makes them more dependent on Chk1 for arrest and survival. However, some p53 wild type tumor cell lines, such as HCT116 and U2OS, are also sensitive to inhibition of Chk1 due to attenuated p21waf1 induction upon DNA damage. The purpose of this study is to determine the cause of this attenuated p21waf1 protein induction. We find that neither the induction of p21waf1 mRNA nor protein half-life is sufficient to explain the low p21waf1 protein levels in HCT116 and U2OS cells. The induced mRNA associates with polysomes but little protein is made suggesting these two cell lines have a reduced rate of p21waf1 mRNA translation. This represents a novel mechanism for disruption of the p53-p21waf1 pathway as currently known mechanisms involve either mutation of p53 or reduction of p53 protein levels. As a consequence, this attenuated p21waf1 expression may render some p53 wild type tumors sensitive to a combination of DNA damage plus checkpoint inhibition. 相似文献
85.
Lorey F Cunningham G Vichinsky EP Lubin BH Witkowska HE Matsunaga A Azimi M Sherwin J Eastman J Farina F Waye JS Chui DH 《Genetic testing》2001,5(2):93-100
Newborn screening is an accepted public health measure to ensure that appropriate health care is provided in a timely manner to infants with hereditary/metabolic disorders. Alpha-thalassemia is a common hemoglobin (Hb) disorder, and causes Hb H (beta4) disease, and usually fatal homozygous alpha(0)-thalassemia, also known as Hb Bart's (gamma4) hydrops fetalis syndrome. In 1996, the State of California began to investigate the feasibility of universal newborn screening for Hb H disease. Initial screening was done on blood samples obtained by heel pricks from newborns, and stored as dried blood spots on filter paper. Hb Bart's levels were measured as fast-moving Hb by automated high-performance liquid chromatography (HPLC) identical to that currently used in newborn screening for sickle cell disease. Subsequent confirmation of Hb H disease was done by DNA-based diagnostics for alpha-globin genotyping. A criterion of 25% or more Hb Bart's as determined by HPLC detects most, if not all cases of Hb H disease, and few cases of alpha-thalassemia trait. From January, 1998, through June, 2000, 89 newborns were found to have Hb H disease. The overall prevalence for Hb H disease among all newborns in California is approximately 1 per 15,000. Implementation of this program to existing newborn hemoglobinopathy screening in populations with significant proportions of southeast Asians is recommended. The correct diagnosis would allow affected infants to be properly cared for, and would also raise awareness for the prevention of homozygous alpha(0)-thalassemia or Hb Bart's hydrops fetalis syndrome. 相似文献
86.
A Eastman 《Biochemistry》1986,25(13):3912-3915
Intrastrand cross-links represent the majority of modifications in DNA resulting from interaction with the cancer chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-DDP). These adducts were recently characterized although several discrepancies remained to be resolved. In these studies, [3H]-cis-dichloro(ethylenediamine)platinum(II) (cis-DEP) was used because of the convenience of the radiolabel; this analogue produces adducts at identical sites in DNA as cis-DDP. Both drugs platinate the following sequences in DNA: GG, 65%; AG, 25%; GNG, 6%. The adduct at AG sequences invariably has adenine on the 5'-terminus of the dimer. The present enzyme digestion protocol included P1 nuclease, which produced complete digestion rather than as previously reported. The frequency of platination at GG was too high to be explained by an initial monofunctional platination at any guanine. However, direct bifunctional attack preferentially at GG was obviated because monofunctional adducts could be trapped with thiourea at short time periods. After short incubations, with cis-DEP and removal of unreacted drug, the monofunctional adducts slowly rearranged to bifunctional adducts. It is suggested that this evolution of adducts may result from the drug "walking" along the double helix, a phenomenon that does not appear to occur in single-stranded DNA. 相似文献
87.
DNA repair in cells sensitive and resistant to cis-diamminedichloroplatinum(II): host cell reactivation of damaged plasmid DNA 总被引:6,自引:0,他引:6
cis-Diamminedichloroplatinum(II) (cis-DDP) has a broad clinical application as an effective anticancer drug. However, development of resistance to the cytotoxic effects is a limiting factor. In an attempt to understand the mechanism of resistance, we have employed a host cell reactivation assay of DNA repair using a cis-DDP-damaged plasmid vector. The efficiency of DNA repair was assayed by measuring the activity of an enzyme coded for by the plasmid vector. The plasmid expression vector pRSVcat contains the bacterial gene coding for chloramphenicol acetyltransferase (CAT) in a configuration which permits expression in mammalian cells. The plasmid was transfected into repair-proficient and -deficient Chinese hamster ovary cells, and CAT activity was subsequently measured in cell lysates. In the repair-deficient cells, one cis-DDP adduct per cat gene was sufficient to eliminate expression. An equivalent inhibition of CAT expression in the repair-proficient cells did not occur until about 8 times the amount of damage was introduced into the plasmid. These results implicate DNA intrastrand cross-links as the lesions responsible for the inhibition of CAT expression. This assay was used to investigate the potential role of DNA repair in mediating cis-DDP resistance in murine leukemia L1210 cells. The parent cell line L1210/0 resembled repair-deficient cells in that about one adduct per cat gene eliminated expression. In three resistant L1210 cell lines, 3-6-fold higher levels of damage were required to produce an equivalent inhibition. This did not correlate with the degree of resistance as these cells varied from 10- to 100-fold resistant.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
88.
Deoxyribonuclease II (DNase II) has been implicated in diverse functions including degradation of foreign DNA, genomic instability, and in mediating the DNA digestion associated with apoptosis. The production of a mouse deleted for DNase II would clearly help to discriminate these functions. We have cloned and sequenced the mouse gene encoding DNase II. It was found to have a similar intron/exon structure to the human gene, although introns 3 and 5 are considerably shorter. The gene is located on mouse chromosome 8. The order of genes at this locus is mGCDH, mEKLF, mDNase II, mSAST, which is the same order that these genes are found on human chromosome 19. The GenBank database contains incorrect expressed sequence tags (ESTs) for the 3' end of the mouse mRNA. Furthermore, the gene structure of two of the three homologs in C. elegans is also incorrectly predicted in the database. We have established the correct intron/exon structure for these genes and show the conserved sequence and structure of the C. elegans, murine and human genes. 相似文献
89.
Poon SF Eastman BW Chapman DF Chung J Cramer M Holtz G Cosford ND Smith ND 《Bioorganic & medicinal chemistry letters》2004,14(22):5477-5480
Structure-activity relationship studies performed around 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile for the purpose of developing novel mGlu5 receptor antagonists are described. Synthesis of a series of four-ring tetrazoles led to the discovery of 3-[3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine, a highly potent, brain penetrant, azole-based mGlu5 receptor antagonist. 相似文献
90.
We present an algorithm for simulating the long time scale dynamics of proteins and other macromolecules. Our method applies the concept of multiple time step integration to the diffusive Langevin equation, in which short time scale dynamics are replaced by friction and noise. The macromolecular force field is represented at atomic resolution. Slow motions are modeled by constrained Langevin dynamics with very large time steps, while faster degrees of freedom are kept in local thermal equilibrium. In the limit of a sufficiently large molecule, our algorithm is shown to reduce the CPU time required by two orders of magnitude. We test the algorithm on two systems, alanine dipeptide and bovine pancreatic trypsin inhibitor (BPTI), and find that it accurately calculates a variety of equilibrium and dynamical properties. In the case of BPTI, the CPU time required is reduced by nearly a factor of 60 compared to a conventional, unconstrained Langevin simulation using the same force field. Proteins 30:215–227, 1998. © 1998 Wiley-Liss, Inc. 相似文献