New NRC patient release guidelines: major quality of life & cost-containment benefits.
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Brachytherapy↗
Biomedical subjects
S M Baker
Publications and source records attributed to S M Baker.
Role of DNA mismatch repair in the cytotoxicity of ionizing radiation.
The DNA mismatch repair (MMR) system in mammalian cells not only serves to correct base mispairs and other replication errors, but it also influences the cellular response to certain forms of DNA damage. Cells that are deficient in MMR are relatively resistant to alkylation damage because, in wild-type cells, the MMR system is thought to promote toxicity via futile repair of alkylated mispairs. Conversely, MMR-deficient cells are sensitive to UV light, possibly due to the requirement for MMR factors in transcription-coupled repair of active genes. MMR deficiency has been associated with familial and sporadic carcinomas of the colon and other sites, and so, we sought to determine the influence of MMR status on cellular response to ionizing radiation, an agent commonly used for cancer therapy. Fibroblast cell lines were established from transgenic mice carrying targeted disruptions of one of three MMR genes in mammalian cells: Pms2, Mlh1, or Msh2. In comparison to wild-type cell lines from related mice, the Pms2-, Mlh1-, or Msh2-nullizygous cell lines were found to exhibit higher levels of clonogenic survival following exposure to ionizing radiation. Because ionizing radiation generates a variety of lesions in DNA, the differences in survival may reflect a role for MMR in processing a subset of these lesions, such as damaged bases. These results both identify a new class of DNA-damaging agents whose effects are modulated by the MMR system and may help to elucidate pathways of radiation response in cancer cells.
Animals↗
The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.
BACKGROUND: Carriers of germ-line mutations in BRCA1 and BRCA2 from families at high risk for cancer have been estimated to have an 85 percent risk of breast cancer. Since the combined frequency of BRCA1 and BRCA2 mutations exceeds 2 percent among Ashkenazi Jews, we were able to estimate the risk of cancer in a large group of Jewish men and women from the Washington, D.C., area. METHODS: We collected blood samples from 5318 Jewish subjects who had filled out epidemiologic questionnaires. Carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 were identified with assays based on the polymerase chain reaction. We estimated the risks of breast and other cancers by comparing the cancer histories of relatives of carriers of the mutations and noncarriers. RESULTS: One hundred twenty carriers of a BRCA1 or BRCA2 mutation were identified. By the age of 70, the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval, 40 to 73 percent); of ovarian cancer, 16 percent (95 percent confidence interval, 6 to 28 percent); and of prostate cancer, 16 percent (95 percent confidence interval, 4 to 30 percent). There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. CONCLUSIONS: Over 2 percent of Ashkenazi Jews carry mutations in BRCA1 or BRCA2 that confer increased risks of breast, ovarian, and prostate cancer. The risks of breast cancer may be overestimated, but they fall well below previous estimates based on subjects from high-risk families.
Adult↗
Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2.
The Pms2 gene has been implicated in hereditary colon cancer and is one of several mammalian homologs of the Escherichia coli mutL DNA mismatch repair gene. To determine the effect of Pms2 inactivation on genomic integrity in vivo, hybrid transgenic mice were constructed that carry targeted disruptions at the Pms2 loci along with a chromosomally integrated mutation reporter gene. In the absence of any mutagenic treatment, mice nullizygous for Pms2 showed a 100-fold elevation in mutation frequency in all tissues examined compared with both wild-type and heterozygous litter mates. The mutation pattern in the nullizygotes was notable for frequent 1-bp deletions and insertions within mononucleotide repeat sequences, consistent with an essential role for PMS2 in the repair of replication slippage errors. Further, the results demonstrate that high rates of mutagenesis in multiple tissues are compatible with normal development and life and are not necessarily associated with accelerated aging. Also, the finding of genetic instability in all tissues tested contrasts with the limited tissue distribution of cancers in the animals, raising important questions regarding the role of mutagenesis in carcinogenesis.
Adenosine Triphosphatases↗
Intestinal stem cell division and genetic diversity. A computer and experimental analysis.
Somatic mutations are expected to arise with age. This process is accelerated in mice lacking the DNA mismatch repair gene Pms2. The distributions of microsatellite alleles present in small patches of normal Pms2 -/- intestines revealed a general increase in genetic diversity or the number of mutations with age. However, the patterns were complex with different distributions and variances present within a single mouse. Computer simulations indicate that the experimental data are consistent with mutation rates between 0.0020 and 0.0025 mutations per division, nonrandom cell death, and an effective population size of 20 or fewer cells. Small numbers of cells exacerbate the random accumulation of mutations expected of a stochastic mutation process. The computer simulations and experimental data are consistent with known patterns of intestinal development and renewal by small numbers of stem cells and demonstrate relatively high mutation rates in histologically normal epithelium. These findings provide background for the analysis of microsatellite mutations in normal and tumor tissue lacking mismatch repair and further support the hypothesis that microsatellite loci can function as molecular tumor clocks.
Adenosine Triphosphatases↗
Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes.
To date, at least four genes involved in DNA mismatch repair (MMR) have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additionally, loss of MMR function has been demonstrated to lead to the phenomenon of microsatellite instability (MIN) in tumors from these patients. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded tumors from 7 patients with MIN+ sporadic cancer, 13 patients with familial colorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between the expression of these two gene products, the presence of germline or somatic mutations, and the presence of tumor MIN was examined. Nineteen of the 28 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eight MIN+/mutation+ cases, the absence of protein expression was observed for the corresponding gene product in all but one case (missense mutation in hMLH1). However, seven MIN+/mutation- cases also showed no expression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), whereas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 9) demonstrated an altered expression pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may be a rapid method for prescreening tumors for mutations in the MMR genes.
Adaptor Proteins, Signal Transducing↗
Brief report: alternative approaches to the development of effective treatments for autism.
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Autistic Disorder↗
Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over.
Mice that are deficient in either the Pms2 or Msh2 DNA mismatch repair genes have microsatellite instability and a predisposition to tumours. Interestingly, Pms2-deficient males display sterility associated with abnormal chromosome pairing in meiosis. Here mice deficient in another mismatch repair gene, Mlh1, possess not only microsatellite instability but are also infertile (both males and females). Mlh1-deficient spermatocytes exhibit high levels of prematurely separated chromosomes and arrest in first division meiosis. We also show that Mlh1 appears to localize to sites of crossing over on meiotic chromosomes. Together these findings suggest that Mlh1 is involved in DNA mismatch repair and meiotic crossing over.
Adaptor Proteins, Signal Transducing↗
Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis.
Using gene targeting in embryonic stem cells, we have derived mice with a null mutation in a DNA mismatch repair gene homolog, PMS2. We observed microsatellite instability in the male germline, in tail, and in tumor DNA of PMS2-deficient animals. We therefore conclude that PMS2 is involved in DNA mismatch repair in a variety of tissues. PMS2-deficient animals appear prone to sarcomas and lymphomas. PMS2-deficient males are infertile, producing only abnormal spermatozoa. Analysis of axial element and synaptonemal complex formation during prophase of meiosis I indicates abnormalities in chromosome synapsis. These observations suggest links among mismatch repair, genetic recombination, and chromosome synapsis in meiosis.
Adenosine Triphosphatases↗
Pertussis toxin export genes are regulated by the ptx promoter and may be required for efficient translation of ptx mRNA in Bordetella pertussis.
The gene products from an 8-kb region adjacent to the 3' end of the ptx operon are required by Bordetella pertussis for the export of pertussis holotoxin. At least one of these gene products (PtlC) is specifically required for the export of assembled holotoxin from the periplasmic space. ptlC mutants exhibit a 20-fold reduction in the amount of holotoxin present in the culture supernatant but have no effect upon the assembly or steady-state level of holotoxin present in the periplasmic space. Impaired export of holotoxin from the ptlC strain blocks expression of toxin at a posttranscriptional level, and wild-type levels of ptx mRNA are detected in the mutant strain. The transcription of ptl is subject to modulation by MgSO4 in the same manner as ptx is; however, in B. pertussis strains containing an E. coli tac promoter in place of the native ptx promoter, wild-type levels of ptx mRNA are present and holotoxin is synthesized and exported even in the presence of MgSO4. Promoter mapping of the region extending from the ptxS3 coding region to the ptlC coding region failed to detect the ptl transcription initiation site. Additional RNase protection experiments with ptx promoter deletion and substitution strains indicate that the ptl operon is transcribed from the ptx promoter as part of a > 11-kb mRNA.
Animals↗
Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer.
The human DNA mismatch repair gene homologue hMSH2, on chromosome 2p is involved in hereditary non-polyposis colon cancer (HNPCC). On the basis of linkage data, a second HNPCC locus was assigned to chromosome 3p21-23 (ref. 3). Here we report that a human gene encoding a protein, hMLH1 (human MutL homologue), homologous to the bacterial DNA mismatch repair protein MutL, is located on human chromosome 3p21.3-23. We propose that hMLH1 is the HNPCC gene located on 3p because of the similarity of the hMLH1 gene product to the yeast DNA mismatch repair protein, MLH1, the coincident location of the hMLH1 gene and the HNPCC locus on chromosome 3, and hMLH1 missense mutations in affected individuals from a chromosome 3-linked HNPCC family.
Adaptor Proteins, Signal Transducing↗
Results of the 1993 survey of the American Association of Academic Chief Residents in Radiology.
RATIONALE AND OBJECTIVES: A survey of chief residents of academic radiology programs is conducted annually on behalf of the American Association of Academic Chief Residents in Radiology (A3CR2). Data are obtained to improve the training of diagnostic radiology residents and to increase the understanding of radiologists and their associates about issues of interest to radiologists in training. METHODS: Questionnaires were mailed to 133 accredited programs in the United States and Canada. A wide variety of demographic and common interest questions were asked. The analysis took into account geographic location of the responders and the size of the residency program. Comparisons were made to the data from prior years. RESULTS: Completed surveys from 93 programs (70%) were returned. The percentage of women residents is increasing. Important regional and size variations exist in several areas including salary, workload, prior clinical training, resident/fellow ratios, post residency plans, and call schedules. Although many chief residents feel knowledgeable about the health care system, opinions about the future of radiology and medical care are tentative. CONCLUSIONS: This survey provides important demographic information about academic radiology residency programs. The summary information regarding plans for fellowship training, resident call schedules, and opinions about socioeconomic issues may be useful for chief residents, program directors, and departmental chairmen.
Canada↗
Dysphoria as a moderator of the relationship between perceived effort and perceived ability.
Although Heiderian logic (F. Heider, 1958) proposes an inverse relationship between ability and effort, research has uncovered dramatic individual differences in the judged relationship between the two. Some view ability and effort as positively related; others view them as negatively related. Study 1 explored dysphoria as a moderator of this relationship by gathering dysphoric and nondysphoric individuals' perceptions of their effort and ability on daily activities. Although ability and effort generally were positively related, dysphorics reported lower ability on high effort tasks. In Study 2, Ss rated their effort as high or low. Dysphorics discounted ability when effort was high; nondysphorics reported the greatest ability when they expended the greatest effort. Collectively, there was no support for an inverse relationship between ability and effort. However, dysphorics infer less ability than nondysphorics following high effort.
Adult↗
Inducible alkyltransferase DNA repair proteins in the filamentous fungus Aspergillus nidulans.
We have investigated the response of the filamentous fungus Aspergillus nidulans to low, non-killing, doses of the alkylating agent MNNG (N-methyl-N'-nitro-N-nitrosoguanidine). Such treatment causes a substantial induction of DNA alkyltransferase activity, with the specific activity in treated cells increasing up to one hundred-fold. Fluorography reveals the two main inducible species as proteins of 18.5 kDa and 21 kDa, both of which have activity primarily against O6-methylguanine (O6-MeG) lesions. In addition, two other alkyltransferase proteins can also be detected. One, of MW 16 kDa, is expressed in non-treated cells, but is not induced to the same extent as the 18.5 and 21 kDa proteins. The other, a protein of 19.5 kDa, is highly inducible and can only be detected in treated cells. Unlike the other three proteins, it acts primarily against methyl-phosphotriester (Me-PT) lesions. This is the first instance in which an MePT alkyltransferase has been detected in a eukaryotic organism and, coupled with the high level of induction of the O6-MeG alkyltransferase enzymes, this indicates that a control system similar to the bacterial adaptive response may be present in filamentous fungi.
Alkyl and Aryl Transferases↗
Color Doppler sonography of ureteral jets in normal volunteers: importance of the relative specific gravity of urine in the ureter and bladder.
OBJECTIVE: Sonographic visualization of ureteral jets is a well-recognized phenomenon. In vitro studies have indicated that detection of fluid flow similar to ureteral jets depends on differences in density between the moving and the stationary fluid. This study was undertaken to determine if differences in density between ureteral urine and urine in the bladder could make a significant impact on the sonographic detectability of ureteral jets in vivo. SUBJECTS AND METHODS: Ten healthy volunteers were vigorously hydrated after an overnight fast. An initial color Doppler sonographic examination of ureteral jets was performed before voiding (while concentrated urine that had accumulated overnight was still in the bladder). A second examination was performed after two cycles of voiding and refilling the bladder (to ensure that dilute urine produced by the hydration was in the bladder). RESULTS: In all subjects, normal ureteral jets were readily identified on the initial examination. The difference in the estimated specific gravity between bladder urine and ureteral urine during the initial examination ranged from 0.002 to 0.016 (mean, 0.008). This was a statistically significant difference (p less than .05). On the second examination, ureteral jets were not detected from either ureter in any subject. The difference in the estimated specific gravity of bladder urine and ureteral urine during the second examination ranged from 0.000 to 0.002 (mean, 0.001). This was not a statistically significant difference (p greater than .05). There was no statistically significant difference in the diuresis rates throughout the course of the examinations. These ranged from 300 to 1218 ml/hr. CONCLUSION: These in vivo results support the hypothesis that detection of ureteral jets depends on density differences between ureteral and bladder urine. This is important clinically, because normal ureteral jets may be undetectable, despite adequate hydration and high rates of diuresis, if the patient is allowed to completely void and refill the bladder before the examination.
Adult↗
HIV: reasons to apply traditional methods of disease control to the spread of HIV.
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AIDS Serodiagnosis↗
Orientation-dependent function of a short CYC1 DNA fragment in directing mRNA 3' end formation in yeast.
We have cloned an 82-base-pair region spanning the site of normal 3' end formation of Saccharomyces cerevisiae CYC1 mRNA into an integrative vector carrying the 5' end of the actin gene (including its intron) fused in frame to HIS4ABC sequences. This vector can confer the ability to grow on histidinol if HIS4C (encoding histidinol dehydrogenase) is sufficiently expressed. With the CYC1 fragment cloned in its wild-type (forward) orientation within the actin intron, transformants cannot grow on histidinol, whereas cells transformed with the vector carrying the reverse orientation of this fragment are able to grow well. RNA transfers demonstrate that transformants containing the forward orientation accumulate less than 40% of the control level of full-length mRNA and reveal the presence of a short, stable (approximately equal to 300 nucleotides) poly(A) RNA that represents 60-70% of the transcripts originating from the same promoter. The reverse orientation of the insert allows near-normal levels of full-length mRNA. Mapping of the 3' end of the truncated RNA indicates that poly(A) addition is variable in length but occurs at the same location as in the normal CYC1 transcript. Dominant and recessive suppressor mutations permit growth on histidinol despite the inserted fragment. Genetic analyses indicate that most of the dominant mutants are cis-acting and that the recessive mutants define a minimum of three complementation groups, indicating that defects in several different genes can restore higher levels of HIS4C expression.
Actins↗
Transcription of multiple copies of the yeast GAL7 gene is limited by specific factors in addition to GAL4.
High levels of the GAL7 gene in the yeast cell appear to titrate regulatory factors and to impair transcription of related sequences. To investigate the role that the GAL regulatory factors GAL4 and GAL80 have in this process we have compared the accumulation of mRNA transcribed from single-copy (plasmid-borne GAL7 and chromosomal GAL10) and high-copy (plasmid-borne GAL7) genes in several GAL regulatory mutants. Our results show that functional GAL4 gene product is required for induction of transcription from the single- and high-copy genes. In a strain containing the GAL4 gene fused to the high expression ADH1 promoter, glucose can replace galactose to induce high levels of transcription of GAL7 and GAL10 genes, although the kinetics of accumulation induced by the two sugars are distinctly different. In the presence of high levels of GAL4, maximum accumulation of mRNA from single and high copy genes is elevated two-fold; disruption of the gal80 gene in combination with high levels of GAL4 results in a further two-fold increase in transcription. In this genetic background, galactose-induced transcription of the high copy GAL7 gene results in a greater than 50-fold increase in the levels of GAL7 mRNA, representing 30%-50% of the total cellular mRNA. Our results are consistent with a cooperative effect of saturation of multiple GAL4 DNA binding sites and with a limiting factor, in addition to GAL4, that is required for transcription of the GAL genes.
Alcohol Dehydrogenase↗