Biomedical subjects

J Potter

Publications and source records attributed to J Potter.

At least 55 records · Page 3Linked to original sources

PubMed1999

Developing algorithms to enhance the sensitivity of cancellation tests of visuospatial neglect.

We describe a set of algorithms that enhance the sensitivity of cancellation tests used in assessing visuospatial neglect. The algorithms can be readily implemented on a computer and can provide temporal and nontemporal data on strategies used during cancellation. We also present preliminary results from a group of 68 right-hemisphere brain-damaged patients and 12 age-matched control participants, which demonstrate the clinical significance of the measures we have defined.

Adult↗

PubMed1999

Exercise clinical trials in cancer prevention research: a call to action.

The experimental study design can yield valuable information in measuring the association between physical activity and occurrence of cancers. Randomized clinical exercise trials can provide insight into the avenues through which physical activity might affect cancer development and can provide experience with diffusing an exercise intervention into certain populations. This report describes the potential utility of the randomized clinical trial design in providing answers about bias, mechanisms, behavior change, and dose-response in defining the causal pathway between physical activity and cancer. The challenges and limitations of exercise clinical trial are discussed. The research experience in cardiovascular disease and exercise is used as a model for developing a research agenda to explore the potential role of physical activity as a cancer-prevention modality. We recommend that a series of small clinical trials of exercise interventions be conducted to measure exercise change effects on biomarkers for cancer risk, to learn about exercise behavior change in individuals at risk for cancer, and to serve as feasibility studies for larger randomized controlled trials of cancer and precursor end points and for community intervention studies.

Attitude to Health↗

PubMed1999

Should sexual partners of women with bacterial vaginosis receive treatment?

Bacterial vaginosis is the most prevalent infectious cause of vaginitis. It is associated with significant morbidity, particularly in pregnant women and following gynaecological operations. Cure is difficult. There is some controversy over whether treating sexual partners of affected women can improve cure rates. This paper provides a critical appraisal of the evidence for simultaneously treating the male partner of women affected by bacterial vaginosis. Unfortunately, no evidence was found supporting the treatment of partners of women affected by bacterial vaginosis.

Adolescent↗

PubMed1998

Comparison of the Block and the Willett self-administered semiquantitative food frequency questionnaires with an interviewer-administered dietary history.

The performances of two commonly used diet instruments, the Block and the Willett food frequency questionnaires, were compared with a longer, interviewer-administered diet history. Participants in a case-control study on diet and colon cancer were interviewed between 1990 and 1994 in northern California, Utah, and Minnesota by trained nutritionists using a validated diet history. Two separate subsamples of participants were asked to complete either the Block or the Willett questionnaire exactly 5 days after they completed the original diet history. Data were analyzed separately by subsample comparing either the Block or the Willett questionnaire with the original diet history by using means, correlations, quintile agreement, and odds ratios for the relation between several nutrients and colon cancer. The Block and the Willett questionnaires generally provided lower absolute intake estimates than did the original diet history; however, the Block questionnaire underestimated more than did that by Willett. Both correlations and quintile agreement were slightly better for the Willett questionnaire than for that by Block when compared with the original diet history. In general, point estimates obtained from either the Block or the Willett questionnaire fell within the confidence intervals of the estimates of the odds ratios obtained from the original diet history, and no real difference in significance levels appeared. Although the Block and Willett questionnaires differed slightly from each other and from our original diet history in estimating absolute nutrients and ranking or classifying individuals, they were very similar in their ability to predict disease outcome.

Adult↗

PubMed1998

Improved gene transfer into baboon marrow repopulating cells using recombinant human fibronectin fragment CH-296 in combination with interleukin-6, stem cell factor, FLT-3 ligand, and megakaryocyte growth and development factor.

We have used a competitive repopulation assay in baboons to develop improved methods for hematopoietic stem cell transduction and have previously shown increased gene transfer into baboon marrow repopulating cells using a gibbon ape leukemia virus (GALV)-pseudotype retroviral vector (Kiem et al, Blood 90:4638, 1997). In this study using GALV-pseudotype vectors, we examined additional variables that have been reported to increase gene transfer into hematopoietic progenitor cells in culture for their ability to increase gene transfer into baboon hematopoietic repopulating cells. Baboon marrow was harvested after in vivo administration (priming) of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF). CD34-enriched marrow cells were divided into two equal fractions to directly compare transduction efficiencies under different gene transfer conditions. Transduction by either incubation with retroviral vectors on CH-296-coated flasks or by cocultivation on vector-producing cells was studied in five animals; in one animal, transduction on CH-296 was compared with transduction on bovine serum albumin (BSA)-coated flasks. The highest level of gene transfer was obtained after 24 hours of prestimulation followed by 48 hours of incubation on CH-296 in vector-containing medium in the presence of multiple hematopoietic growth factors (interleukin-6, stem cell factor, FLT-3 ligand, and megakaryocyte growth and development factor). Using these conditions, up to 20% of peripheral blood and marrow cells contained vector sequences for more than 20 weeks, as determined by both polymerase chain reaction and Southern blot analysis. Gene transfer rates were higher for cells transduced on CH-296 as compared with BSA or cocultivation. In one animal, we have used a vector expressing a cell surface protein (human placental alkaline phosphatase) and have detected 10% and 5% of peripheral blood cells expressing the transduced gene 2 and 4 weeks after transplantation as measured by flow cytometry. In conclusion, the conditions described here have resulted in gene transfer rates that will allow detection of transduced cells by flow cytometry to facilitate the evaluation of gene expression. The levels of gene transfer obtained with these conditions suggest the potential for therapeutic efficacy in diseases affecting the hematopoietic system.

Animals↗

PubMed1998

Routine protein energy supplementation in adults: systematic review.

OBJECTIVES: To determine whether routine oral and enteral nutritional supplementation can improve the weight, anthropometry, and survival of adult patients. DESIGN: Systematic review of randomised controlled trials of oral or enteral protein supplementation in adults. Trials were identified from Medline (Silver Platter 3.11, 1966-96), reference lists of identified studies and review articles, and communication with feed manufacturers. SUBJECTS: Randomised controlled trials comparing oral or enteral protein supplementation with no routine supplementation. All trials of adult subjects were included except those addressing nutrition in pregnancy. MAIN OUTCOME MEASURES: Change in body weight and anthropometry (mid-arm muscle circumference), and all cause case fatality recorded at the end of scheduled follow up. Body weight and anthropometry were analysed as the weighted mean difference and 95% confidence intervals of the percentage change in these variables. Case fatality was analysed with odds ratio and 95% confidence intervals. RESULTS: 32 eligible reports (2286 randomised patients) published between February 1979 and July 1996 were identified, of which 30 (93.8%) (2062 randomised patients) reported outcomes of interest. Case fatality data were available for 1670 (81%) patients, and continuous variable data for up to 1607 (78%) patients. The treatment group receiving routine nutritional supplementation showed consistently improved changes in body weight and anthropometry compared with controls; weighted mean difference 2.06% (95% confidence interval 1.63% to 2.49%) and 3.16% (2.43% to 3.89%) respectively. The pooled odds ratio for death in the treatment group was 0.66 (0.48 to 0.91, 2P<0.01). Apparent benefits were observed in several prespecified subgroups of patients, treatment settings, and interventions, but were not evident if trials with less robust methodology were excluded. CONCLUSIONS: Routine oral or enteral supplementation seems to improve the nutritional indices of adult patients, but there are insufficient data in trials which meet strict methodological criteria to be certain if mortality is reduced. Benefits were not restricted to particular patient groups. Further large pragmatic randomised controlled trials of routine nutritional supplementation are justified.

Administration, Oral↗

PubMed1998

Differential requirement for caspase 9 in apoptotic pathways in vivo.

Mutation of Caspase 9 (Casp9) results in embryonic lethality and defective brain development associated with decreased apoptosis. Casp9-/- embryonic stem cells and embryonic fibroblasts are resistant to several apoptotic stimuli, including UV and gamma irradiation. Casp9-/- thymocytes are also resistant to dexamethasone- and gamma irradiation-induced apoptosis, but are surprisingly sensitive to apoptosis induced by UV irradiation or anti-CD95. Resistance to apoptosis is accompanied by retention of the mitochondrial membrane potential in mutant cells. In addition, cytochrome c is translocated to the cytosol of Casp9-/- ES cells upon UV stimulation, suggesting that Casp9 acts downstream of cytochrome c. Caspase processing is inhibited in Casp9-/- ES cells but not in thymocytes or splenocytes. Comparison of the requirement for Casp9 and Casp3 in different apoptotic settings indicates the existence of at least four different apoptotic pathways in mammalian cells.

Animals↗

PubMed1998

Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum.

In lymphocytes, the expression of early immune response genes is regulated by NF-AT transcription factors which translocate to the nucleus after dephosphorylation by the Ca2+-dependent phosphatase, calcineurin. We report here that mice bearing a disruption in the NF-ATc gene fail to develop normal cardiac valves and septa and die of circulatory failure before day 14.5 of development. NF-ATc is first expressed in the heart at day 7.5, and is restricted to the endocardium, a specialized endothelium that gives rise to the valves and septum. Within the endocardium, specific inductive events appear to activate NF-ATc: it is localized to the nucleus only in endocardial cells that are adjacent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia. Treatment of wild-type embryos with FK506, a specific calcineurin inhibitor, prevents nuclear localization of NF-ATc. These data indicate that the Ca2+/calcineurin/NF-ATc signalling pathway is essential for normal cardiac valve and septum morphogenesis; hence, NF-ATc and its regulatory pathways are candidates for genetic defects underlying congenital human heart disease.

Animals↗

PubMed1998

Impact of a risk-based prevention policy on neonatal group B streptococcal disease.

OBJECTIVE: Neonatal group B streptococcal infections can be prevented by intrapartum antibiotic prophylaxis. Beginning in 1992, women with obstetric risk factors at University of Miami-Jackson Memorial Medical Center were targeted to receive intrapartum antibiotic prophylaxis. We evaluated these preventive efforts. STUDY DESIGN: A case was defined as isolation of group B streptococci from a sterile site in an infant <7 days old born during the study period, 1992-1995. We reviewed systematic samples of women with preterm delivery and prolonged rupture of membranes to assess use of intrapartum antibiotic prophylaxis. RESULTS: Group B streptococcal cases declined from 1.7 cases/1000 live births to 0.2 cases/1000 live births (Poisson regression, P =.002). Intrapartum antibiotic prophylaxis use increased from 13% of preterm deliveries in 1992 to 42% in 1995, and from 20% of deliveries with prolonged rupture of membranes in 1992 to 72% in 1995 (chi2 test for linear trend P =.007 and P <.001, respectively). CONCLUSION: Provision of intrapartum antibiotic prophylaxis on the basis of risk factors was associated with decreased group B streptococcal disease.

Antibiotic Prophylaxis↗

PubMed1998

Physical activity and cancer etiology: associations and mechanisms.

OBJECTIVES: This paper reviews the epidemiologic data of associations between physical activity and cancer risk, describes potential mechanisms for a physical activity cancer link, and proposes future directions for research. METHODS: We reviewed English-language published papers on physical activity and cancer through Medline searches for epidemiologic studies, and through references on individual reports. We reviewed general texts on effects of exercise on human biology and applied the concepts to the biology of cancer in humans to describe potential mechanisms for a physical activity-cancer association. RESULTS: Considerable epidemiologic evidence has accrued linking increased physical activity with reduced occurrence of cancers of the breast and colon. The association between physical activity and cancers of other sites is unclear. Potential mechanisms for the association between physical activity and reduced risk for breast and colon cancer are varied: they range from bias due to physical activity's strong correlations with other health factors (e.g., diet, smoking, alcohol use, use of medications) to the metabolic effects resulting from increased physical activity and fitness, such as reduced obesity, hormonal and reproductive effects, mechanical effects, and enhancement of the immune system. CONCLUSIONS: The elucidation of biologic mechanisms for an association between physical activity and cancer may provide biological support for the association. It will contribute information to determine the type, frequency, and duration of exercise needed to maximize protection. This information will be needed before large-scale community interventions are begun, in order to choose the correct interventions for the desired effect of reduced incidence of the most common cancers.

Adult↗

PubMed1998

The process of rehabilitation and discharge planning in stroke: a controlled comparison between stroke units.

BACKGROUND AND PURPOSE: Stroke units improve outcome for stroke patients. Comparative controlled studies between stroke units are required to determine which components of stroke unit rehabilitation influence outcome and which may be investigated further in randomized controlled trials. This study compares 2 stroke units with regard to the effect differences in practice have on functional recovery (Barthel Index score) and discharge planning (length of stay). METHODS: Stroke unit patients with moderate disability (Barthel score of 4 to 10 at week 1) admitted over 18 months were studied. Barthel measurements were obtained weekly from week 1 to discharge. Details of stroke unit function were recorded. The core features of stroke units were in place in both units. Rehabilitation was impairment focused (theoretically driven) on one unit and disability oriented (pragmatic) on the other. RESULTS: Numbers of patients were comparable (85 versus 99). Median Barthel score at week 1 (6 versus 6), time to maximal Barthel score (14 versus 14 weeks), discharge Barthel score (14 versus 14), and institutionalization (32% versus 28%) were similar in both units. Median lengths of stay differed (68 versus 49 days; P<0.001). CONCLUSIONS: Comparisons with regard to the rehabilitation process can be made between stroke units. Differences in rehabilitation process between 2 units showed no effect on the rate of functional recovery. Length of stay was significantly different between units, an effect that cannot be attributed to functional recovery and therefore reflects differences in discharge planning, including postdischarge support.

Aged↗

PubMed1997

Gene transfer into marrow repopulating cells: comparison between amphotropic and gibbon ape leukemia virus pseudotyped retroviral vectors in a competitive repopulation assay in baboons.

Many diseases might be treated by gene therapy targeted to the hematopoietic system, but low rates of gene transfer achieved in humans and large animals have limited the application of this technique. We have developed a competitive hematopoietic repopulation assay in baboons to evaluate methods for improving gene transfer and have used this method to compare gene transfer rates for retroviral vectors having an envelope protein (pseudotype) from amphotropic murine retrovirus with similar vectors having an envelope protein derived from gibbon ape leukemia virus (GALV). We hypothesized that vectors with a GALV pseudotype might perform better based on our previous work with cultured human hematopoietic cells. CD34(+) marrow cells from each of four untreated baboons were divided into two equal portions that were cocultivated for 48 hours with packaging cells producing equivalent titers of either amphotropic or GALV pseudotyped vectors containing the neo gene. The vectors contained small sequence differences to allow differentiation of cells genetically marked by the different vectors. Nonadherent and adherent cells from the cultures were infused into animals after they received a myeloablative dose of total body irradiation. Polymerase chain reaction (PCR) analysis for neo gene-specific sequences in colony-forming unit-granulocyte-macrophage from cell populations used for transplant showed gene transfer rates of 2.7%, 7.1%, <15%, and 3.9% with the amphotropic vectors and 7.1%, 11.3%, <15%, and 26.4% with the GALV pseudotyped vector. PCR analysis of peripheral blood and marrow cells after engraftment showed the neo gene to be present in all four animals analyzed at levels between 0.1% and 5%. Overall gene transfer efficiency was higher with the GALVpseudotyped vector than with the amphotropic vectors. Southern blot analysis in one animal confirmed a gene transfer efficiency of between 1% and 5%. The higher gene transfer efficiency with the GALV-pseudotyped vector correlated with higher levels of GALV receptor RNA compared with the amphotropic receptor in CD34(+) hematopoietic cells. These results show that GALV-pseudotyped vectors are capable of transducing baboon marrow repopulating cells and may allow more efficient gene transfer rates for human gene therapy directed at hematopoietic cells. In addition, our data show considerable differences in gene transfer efficiency between individual baboons, suggesting that a competitive repopulation assay will be critical for evaluation of methods designed to improve gene transfer into hematopoietic stem cells.

Animals↗

PubMed1997

Normal immunologic response to a neoantigen, bacteriophage phiX-174, in baboons with long-term lymphohematopoietic reconstitution from highly purified CD34+ Lin- allogeneic marrow cells.

The CD34 antigen is thought to be expressed by hematopoietic stem cells in adult humans and nonhuman primates. We present data that baboons transplanted with highly purified allogeneic CD34+ marrow cells devoid of detectable mature and immature T and B lymphocytes and myeloid cells, isolated from sex-mismatched mixed lymphocyte culture (MLC) nonreactive siblings, have maintained stable lymphohematopoietic engraftment with donor cells for greater than 4.9, greater than 6.0, and 5.0 years. Cytogenetic analysis of unfractionated marrow and peripheral blood cells at multiple time points after transplantation show virtually all donor cells in two animals and stable mixed chimerism in the third. We used polymerase chain reaction to show that colony-forming unit-granulocyte-macrophage, burst-forming unit-erythroid, and high proliferative potential colony-forming cells (HPP-CFC) were virtually all of donor origin in two animals and present at lower levels in the stable mixed chimera. CD20+ B-lymphoblastoid cell lines derived by Herpesvirus Papio transformation of peripheral blood cells were virtually all donor in two animals and 50% donor in the mixed chimera. CD4+ and CD8+ T cells and neutrophils purified from the peripheral blood of the two female animals also were all donor-derived. To assess immunologic function after transplantation, we immunized the three long-term chimeric animals and two normal control animals with bacteriophage phiX-174, a neoantigen that requires the interaction of antigen-presenting cells, T lymphocytes, and B lymphocytes to mount a normal antibody response. Experimental and control animals, when immunized with bacteriophage, had similar serum Ig levels. The experimental and control animals generated similar titers of antibacteriophage antibodies after primary and secondary immunizations with evidence of amplification and class switching. These findings further support the hypothesis that the CD34+ antigen is expressed on hematopoietic stem cells that can mediate stable long-term lymphohematopoiesis in vivo and, importantly, that normal immunologic function can be reconstituted in vivo after transplantation of the highly purified CD34+ Lin- cells alone.

Animals↗

PubMed1997

Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function.

Lymphocyte-specific interferon regulatory factor (LSIRF) (now called IRF4) is a transcription factor expressed only in lymphocytes. Mice deficient in IRF4 showed normal distribution of B and T lymphocyes at 4 to 5 weeks of age but developed progressive generalized lymphadenopathy. IRF4-deficient mice exhibited a profound reduction in serum immunoglobulin concentrations and did not mount detectable antibody responses. T lymphocyte function was also impaired in vivo; these mice could not generate cytotoxic or antitumor responses. Thus, IRF4 is essential for the function and homeostasis of both mature B and mature T lymphocytes.

Animals↗

PubMed1997

Energy balance and colon cancer--beyond physical activity.

Low levels of physical activity and high levels of energy intake and body mass have all been directly associated with colon cancer. The purpose of this study was to determine how physical inactivity interacts with other components of energy balance (energy intake and body mass) in determining colon cancer risk. Data were obtained from 2073 first primary cases of colon cancer and 2466 age- and sex-matched controls identified from 8 counties in Utah, the Northern California Kaiser Permanente Medical Care Program, and the Twin Cities metropolitan area in Minnesota. Recent and lifetime physical activity was assessed by intensity of activities performed at home, leisure, and at work; energy intake was estimated from an extensive diet history questionnaire; and body mass index (BMI) was calculated from measured height at the time of interview and reported weight for the referent year. For both men and women, lack of lifetime vigorous leisure-time activity was associated with increased risk of colon cancer [odds ratio (OR), 1.63 and 95% confidence interval (CI), 1.26-2.12 for men and OR, 1.59 and 95% CI, 1.21-2.10 for women, comparing the lowest to highest level of activity]. There were no differences in risk associated with physical activity by tumor site within the colon or by age at diagnosis. High levels of energy intake were also associated with increased risk of colon cancer in men and women (OR, 1.74 and 95% CI, 1.14-2.67 for men and OR, 1.70 and 95% CI, 1.07-2.70 for women). A large BMI was more associated with increased risk in men (OR, 1.94 and 95% CI, 1.49-2.54) than in women (OR, 1.45 and 95% CI, 1.08-1.94). Those at greatest risk of colon cancer were those who had the most unfavorable energy balance in that they were physically inactive, had high energy intakes, and had a large BMI (OR, 3.35 and 95% CI, 2.09-5.35). However, when physical activity was high, having a high energy intake and large BMI resulted in a nonsignificant increased colon cancer risk (OR, 1.28 and 95% CI, 0.81-2.03). This pattern was consistent between the sexes, but there was some evidence that men may be at higher risk than women, especially older women, as a result of unfavorable energy balance. These results support previous findings that physical inactivity, high energy intake, and large body mass are associated with increased risk of developing colon cancer. However, energy balance as a whole seems to be associated with risk of colon cancer. These findings suggest systemic metabolic influences on carcinogenesis and have important implications for prevention.

Adult↗

PubMed1997

Population-based family study designs: an interdisciplinary research framework for genetic epidemiology.

Most complex traits such as cancer and coronary heart diseases are attributed either to heritable factors or to environmental factors or to both. Dissecting the genetic and environmental etiology of complex traits thus requires an interdisciplinary research strategy. Genetic studies generally involve families and investigate familial aggregations of traits, segregation of major disease genes, and locations of disease genes on the human genome, the latter of which can be identified via linkage analysis. Epidemiologic studies often use population-based case-control studies to establish the role of specific environmental factors. Integrating both objectives, genetic epidemiology is to assess the associations of environmental factors with disease status, to quantify the aggregation of cases within families, to characterize putative disease genes via segregation analysis, and to localize disease genes via linkage analysis with genetic markers. To accomplish these objectives through designed studies, we propose a class of population-based family study designs, which are formed by choosing among sampling designs at three stages. The objectives of sampling at these three stages are 1) combined aggregation and association analysis, 2) combined segregation, aggregation, and association analysis, and 3) combined linkage, segregation, aggregation, and association analysis. These designs form an interdisciplinary research framework for genetic epidemiology. Our preliminary exploration of this framework and related analytic methods indicates that population-based family study designs retain the efficiency of linkage analysis for localizing disease genes without losing the property of being population-based, and they will therefore allow an assessment of a joint contribution of genetic and environmental factors to complex traits.

Case-Control Studies↗

PubMed1997

Diet diversity, diet composition, and risk of colon cancer (United States).

In this study, we evaluate diet diversity, diet composition, and risk of colon cancer in an incident population-based study of 1,993 cases and 2,410 controls in the Kaiser Permanente Medical Care Program of Northern California, eight counties in Utah, and the Twin Cities area of Minnesota (United States). Ninety-one and one-half percent of the population were non-Hispanic White. Dietary intake was obtained using an adaptation of the CARDIA diet-history questionnaire. Diet diversity was defined as the number of unique food items reported; diversity also was explored within six major food groups. Composition of the diet was described by estimating the proportion of total number of food items contributed by major food groups. Younger individuals, higher educated individuals, and those who lived in larger households reported eating the most diverse diet. Total diet diversity was not associated with colon cancer. However, eating a diet with greater diversity of meats, poultry, fish, and eggs, was associated with a 50 percent increase in risk among all men (95 percent confidence interval [CI] = 1.1-2.0; P trend = 0.01), with slightly stronger associations for younger men and men with distal tumors. A diet with a greater number of refined grain products also was associated with increased risk among men (odds ratio [OR] = 1.7, CI = 1.3-2.3). Women who ate a diet with a more diverse pattern of vegetables were at approximately a 20 percent lower risk than women who had the least diverse diet in vegetables. Assessment of diet composition showed that men who consumed a large proportion of their food items from meat, fish, poultry, and eggs were at an increased risk, with the most marked association being for distal tumors (OR = 1.7, CI = 1.2-2.5). Women who consumed the largest percentage of their food items in the form of plant foods (fruits, vegetables, or whole grains) were at a reduced risk of developing colon cancer (OR = 0.7, CI = 0.5-1.0).

Adult↗

PubMed1997

Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation.

Mutations in the mouse Brca1 gene cause lethality at different embryonic stages. We have shown that Brca1 mutant embryos, in which the fifth and sixth exons of Brca1 are deleted die before E7.5 and show decreased cellular proliferation. Brca1 mutants also show decreased expression of mdm2, a gene encoding an inhibitor of p53 activity. Thus, we have proposed that the reduction in mdm2 expression in Brca1 (5-6) mutants might lead to increased p53 activity. Consistent with this finding, the expression of p21, which encodes a G1 cell cycle inhibitor and is a target for p53 transcriptional activation was dramatically increased in the Brca1 (5-6) mutants, suggesting that impaired cellular proliferation could be due to a G1 cell-cycle arrest, caused by increased p21 levels. To test this hypothesis, we generated mice double mutant for Brca1 (5-6) and p53, or Brca1 (5-6) and p21. Mutation in either p53 or p21 prolonged the survival of Brca1 (5-6) mutant embryos from E7.5 to E9.5. The development of most Brca1 (5-6): p21 double-mutant embryos was comparable to that of their wild-type littermates, although no mutant survived past E10.5. The fact that mutation of neither p53 nor p21 completely rescued Brca1 (5-6) embryos suggests that their lethality is likely due to a multi-factorial process.

Animals↗