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L Flaherty

Publications and source records attributed to L Flaherty.

At least 19 recordsLinked to original sources
PubMed2006

Localization of two new X-linked quantitative trait loci controlling corpus callosum size in the mouse.

Corpus callosum (CC) size is a complex trait, characterized by a gradation of values within a normal range, as well as abnormalities that include a small or totally absent CC. Among inbred mouse strains with defects of the CC, BTBR T(+)tf/J (BTBR) mice have the most extreme phenotype; all animals show total absence of the CC and severe reduction of the hippocampal commissure (HC). In contrast, the BALB/cByJ (BALB) strain has a low frequency of small CC and consistently normal HC. Reciprocal F(1) crosses between BTBR and BALB suggest the presence of X-linked quantitative trait loci (QTLs) affecting CC size. Through linkage analysis of backcross male progeny, we have localized two regions on the X chromosome, having peaks at 68.5 Mb (approximately 29.5 cM) and at 134.5 Mb (approximately 60.5 cM) that are largely responsible for the reciprocal differences, with the BTBR allele showing X-linked dominant inheritance associated with CC defects.

Agenesis of Corpus Callosum↗
PubMed2003

The math of making mutant mice.

More than ten large-scale mutagenesis projects are now generating hundreds of novel mouse mutants. Projects employ a wide variety of strategies and screens: targeting as much as the whole genome, part of a chromosome or just single genes. In this commentary, we consider the pros and cons of different tactics. We highlight issues of cost, efficiency and defend the impact of this mutagenesis program in an era of sophisticated conditional knockouts and advanced transgenic lines. Given the significant difficulties of adequately phenotyping and mapping randomly generated mutations that cover the whole genome, we tend to favor regional and gene-targeted screens. Whatever the choice of method, whole genome sequence data combined with detailed transcriptome and proteome surveys promise to significantly improve the efficiency with which series of mutations in a large subset of mammalian genes can be generated and cloned.

Animals↗
PubMed2003

Genetic analysis of the psychomotor stimulant effect of ethanol.

Genetic influences on the psychomotor stimulant effect of ethanol may be a key feature of abuse liability. While earlier work has shown the activational effects of ethanol to be under the influence of a relatively uncomplicated additive genetic system, preliminary data from our laboratory suggested the possibility of nonadditive genetic variance. In the present study, a full Mendelian cross was conducted to further characterize gene action and search for quantitative trait loci (QTL) influencing the psychomotor stimulant properties of ethanol. We tested 3062 mice of the six Mendelian cross genotypes (P1, P2, F1, F2, BC1 and BC2) derived from a cross between the C57BL/6J (B6) and C3H/HeJ (C3H) inbred strains of mice. On day 1, mice were injected with saline, put in a holding cage for 5 min, then placed in an activity monitor for 5 min. On day 2, mice were injected with 1.5 g/kg ethanol, and activity again monitored for 5 min. Analysis showed the expected activation in the C3H strain and little activation in the B6 strain, with no effect of sex. Biometrical genetic analysis showed a best-fit model that included the mean (m), additive effect (a), and an epistatic parameter (i = homozygote by homozygote interaction). Analysis showed good evidence for QTL on chromosomes 1 (logarithm of odds (LOD) 3.4-7.5, 88-100 cM), 6 (LOD 9.1-10.4, 46-50 cM) and 15 (LOD 7.3-8.8, 28-32 cM). While the regions on chromosomes 1 and 6 have previously been implicated in several different ethanol-related phenotypes, this is the first report of a QTL influencing the psychomotor stimulant properties of ethanol on chromosome 15. Other studies have identified QTL in this region of chromosome 15 mediating locomotor activation caused by other psychostimulants, including cocaine, amphetamine and phencyclidine.

Animals↗
PubMed2003

Differences among eight inbred strains of mice in motor ability and motor learning on a rotorod.

The rotorod is commonly used to assess motor ability in mice. We examined a number of inbred strains to determine whether there is genetic variability in rotorod performance and motor learning. Mice received three trials per day for three days in a modified accelerating rotorod paradigm, and active rotation performance was calculated for each day. Male and female 129S1/SvlmJ, A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J and FVB/NJ mice were tested. Strain and sex differences were observed in motor performance. Motor learning also differed across strains, as some strains showed an improvement in performance over the three days while other strains did not. In certain strains the weight and body length of the mouse correlated with rotorod performance. The role of vision in motor performance on the rotorod was assessed by a comparison of C3H/HeJ mice (with retinal degeneration) and congenic C3A.BLiA-Pde6b+ (Pdeb+) mice (without retinal degeneration). The sight-impaired C3H mice stayed on the rotorod longer than did their sighted Pdeb+ partners, although both strains improved across days. Thus, we have demonstrated a genetic component in rotorod performance, and we have shown that factors other than inherent motor ability can contribute to rotorod performance in mice.

Animals↗
PubMed2002

Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group.

PURPOSE: To evaluate the antitumor effects and toxicities of whole brain irradiation (WBI) with temozolomide (TMZ) administered by prolonged oral dosing in patients with melanoma metastatic to the brain. BACKGROUND: Patients with melanoma metastatic to the central nervous system (CNS) have an extremely poor prognosis and appear to benefit little from WBI. TMZ is an alkylating agent chemically similar to dacarbazine (DTIC) with good oral bioavailability and CNS penetration. TMZ has broad preclinical antitumor activity which in melanoma is comparable to that of DTIC. The combination of TMZ and WBI may provide enhanced antitumor activity against CNS metastasis from melanoma. PATIENTS AND METHODS: Patients with measurable CNS metastases with or without systemic disease were treated with WBI, 30 Gray over ten fractions (days 1-5 and 8-12). TMZ, 75 mg small middle dotm(2 small middle dot)day, was started on day 1, continued daily for 6 weeks and repeated every 10 weeks. RESULTS: Thirty-one patients were treated. There was one CNS complete response of 4.5 months and two CNS partial responses of 2 months and 7 months duration; the latter patient also had a 4-month complete remission of systemic metastases. Toxicities were limited to a single episode of grade 3 transaminase elevation and two episodes of grade 3 neutropenia, one complicated by fatal sepsis. The median progression-free interval for both CNS and extracranial sites was 2 months (range 1 week-11 months), and median survival 6 months (range 2-12 months). CONCLUSIONS: WBI has lower than expected activity in CNS metastasis of malignant melanoma. Although TMZ can be safely administered with WBI, the combination has limited anti-tumor activity.

Administration, Oral↗
PubMed2002

Characterization of the region containing the jcpk PKD gene on mouse Chromosome 10.

The jcpk gene on mouse Chromosome 10 causes a severe, early onset form of polycystic kidney disease (PKD) when inherited in an autosomal recessive manner. In order to positionally clone this gene, high resolution genetic and radiation hybrid maps were generated along with a detailed physical map of the approximately 500-kb region containing the jcpk gene. Additionally, sixty-nine kidney-specific ESTs were evaluated as candidates for jcpk and subsequently localized throughout the mouse genome by radiation hybrid mapping analysis. Previous studies indicating non-complementation of the jcpk mutation and 67Gso, a new PKD translocation mutant had suggested that 67Gso represents a new allele of jcpk. Fluorescence in situ hybridization (FISH) analysis using key bacterial artificial chromosome clones from the jcpk critical region, refined the 67Gso breakpoint and provided support for the allelism of jcpk and 67Gso.

Animals↗
PubMed2001

Phase II evaluation of paclitaxel, alpha-interferon, and cis-retinoic acid in advanced renal cell carcinoma.

BACKGROUND: Interferon and 13-cis-retinoic acid (13-CRA) therapy showed clinical response rates of 30% in advanced renal cell carcinoma (RCC). This combination also enhanced sensitivity to paclitaxel in a bcl-2 and mutant p53 expressing renal carcinoma cell line. Based on this, the authors conducted a Phase II clinical trial of the combination of interferon, 13-CRA, and weekly paclitaxel, in advanced RCC. METHODS: The eligibility criteria consisted of unresectable or metastatic RCC, measurable disease, a Southwest Oncology Group performance status of 0-2, and adequate bone marrow, hepatic, and renal function. Prior cytotoxic or immunologic treatment including interferon was permitted. Paclitaxel was administered at a dose of 80 mg/m(2) as a 1-hour intravenous infusion on Days 1, 8, and 15 of each 28-day cycle. Interferon was administered at a dose of 3 million units subcutaneously daily and 13-CRA at 1 mg/kg/day orally in 2 divided doses for the first 21 days of each cycle. RESULTS: Twenty-one patients were enrolled with a median age of 52 years, 16 males and 5 females, 10 patients with no prior therapy, 5 each with prior interleukin-2 or interferon therapy, and 1 patient with both. Four patients had also received prior investigational chemotherapy. A total of 61 cycles were administered with a median of 2 per patient. Grade 3 and 4 toxicities were neutropenia in three patients, anemia in four patients, and asthenia, skin rash, and hypersensitivity reaction in one case each. Of the 20 evaluable patients, one objective partial response was observed for a duration of 7+ months. Seven patients had disease stabilization. The median survival of the entire population was 9.5 months (range, 4-18+ months). CONCLUSIONS: The combination of 13-CRA, interferon, and weekly paclitaxel was well tolerated and had minimal efficacy in advanced RCC.

Adult↗
PubMed2001

Inbred strain variation in contextual and cued fear conditioning behavior.

A number of commonly used inbred strains were surveyed in a fear-conditioning paradigm conducted with an automated computer-controlled system. Control studies were used to verify the automated system. Response to shock was also monitored to determine if it was associated with contextual and/or cued conditioning behavior. After three pairings of tone with shock, fear conditioning was measured 24 h later in 129S1/SvImJ (129), A/J (A), BALB/cByJ (BALB), C3H/HeJ (C3H), C57BL/6J (B6), CBA/J (CBA), DBA/2J (D2), and FVB/NJ (FVB) male and female mice. There were both significant strain and sex differences in response. To determine the effects of vision on this behavior, C3H mice (with retinal degeneration) were compared with C3.BLiA-+Pde6b congenics (without retinal degeneration). Here, vision was found to play a minimal role in responsiveness in this paradigm. Because this fear-conditioning test is automated, it can be used for the rapid screening of a large number of mice, such as required for mutagenesis studies.

Animals↗
PubMed2001

Chronic oral administration of CI-994: a phase 1 study.

OBJECTIVES: CI-994 (N-acetyl dinaline, PD 123654) is a novel oral agent active in a broad variety of murine and human tumor xenografts. While cytotoxic in the Brown Norway (BN) rat leukemia model, growth inhibition in other murine and human tumor xenografts is predominantly cytostatic. Its specific mechanism of action remains unknown. Following CI-994 administration, inhibition of both histone deacetylation and cellular proliferation at the G1 to S transition phase of the cell cycle are observed. This Phase 1 study in patients with solid tumors was carried out to determine a maximum tolerated daily oral dose (MTD) for CI-994 administered on a chronic basis. METHODS: Fifty-three patients received CI-994 daily for treatment durations ranging from 2 to 10 weeks. Dosage escalation proceeded in 2 phases; an Acute Dosing Phase (n = 11) to define the MTD for CI-994 administered over 2 weeks and a Chronic Dosing Phase (n = 29) to define the MTD for daily administration for 8 weeks. Upon completion of the Chronic Dosing Phase, a third cohort of patients (n = 13) received CI-994 at the recommended Phase 2 dose and schedule with 2 additional single doses of drug administered separated by a 1-week washout to assess the effect of food on CI-994 pharmacokinetics. RESULTS: Thrombocytopenia was dose limiting at the MTD of 8 mg/m2/day for 8 weeks. Other toxicities included fatigue and gastrointestinal effects such as nausea, vomiting, diarrhea, constipation and mucositis. Pharmacokinetic studies revealed that peak plasma levels and AUC's generally increased with dose and that food intake did not affect the rate or extent of drug absorption. One patient with heavily pre-treated adenocarcinoma of the lung achieved a Partial Response (PR) lasting over 2 years and 3 additional patients achieved Stable Disease (SD), 1 each with non-small cell lung, colorectal, and renal cancer. CONCLUSIONS: The recommended Phase 2 starting dose is 8 mg/m2/day for 8 weeks repeated after a 2-week drug-free interval.

Administration, Oral↗
PubMed2001

LPS-hyporesponsiveness of mnd mice is associated with a mutation in Toll-like receptor 4.

Toll-like receptors (Tlrs) are transmembrane proteins that have recently been shown to play a critical role in the innate immune recognition of microbial constituents. Among this family, Tlr4 is a crucial signal transducer for lipopolysaccharide (LPS), the major component of the Gram-negative bacteria outer cell membrane. In this paper, we report that C57BL/6.KB2-mnd mice, a model of neuronal ceroid lipofuscinosis, do not respond to LPS. This defect is associated with a spontaneous mutation in Tlr4 consisting of a large insertion within exon 2 predicting a frameshift mutation and a truncated protein.

Animals↗
PubMed2001

Mapping of quantitative trait loci with knockout/congenic strains.

Recently we have explored the use of knockout/congenic mouse strains for isolating and mapping quantitative trait loci (QTLs). Because most knockout strains have been bred to be B6.129 congenic strains, they can be used to test for QTLs in the targeted chromosomal area as long as there is a genetic difference between B6 and 129. Thus, we have tested a number of knockout/congenic strains in a series of behavioral tests in which mouse performance has a significant genetic component. We have also developed a breeding scheme for distinguishing the effects of background flanking genes from the targeted ablation. In screening several knockout/congenics, we have found at least one that harbors a behavioral QTL in the 129 chromosomal segment. The position of this QTL was confirmed subsequently by several F1 crosses.

Animals↗
PubMed2001

Anxiety-related behaviors in the elevated zero-maze are affected by genetic factors and retinal degeneration.

Anxiety levels were tested in an elevated zero-maze for 8 inbred strains of mice that are used widely in biomedical and behavioral research. Strain differences were observed for activity, latency to enter an open quadrant, open time, and defecation, demonstrating that genetic factors mediate anxiety in this paradigm. Three of the strains have the rdl mutation that causes retinal degeneration and were less anxious in the maze. To discern whether visual acuity is a source of difference on the maze, anxiety levels were tested in a congenic strain in which the rdl allele has been replaced with the wild-type allele. The congenic strain, with normal vision, had higher levels of anxiety. This study provides baseline data for the selection and use of any of these strains in pharmacological challenges in the maze, and provides a starting point for the identification of strains that may have appropriate backgrounds for targeted mutation studies.

Alleles↗
PubMed2000

List of transgenic and knockout mice: behavioral profiles.

A list of transgenic and knockout mice, having behavioral profiles, has been compiled. Behavioral and genetic information has been assembled in a simplified fashion so that the reader can easily determine the possible usefulness of each transgenic or knockout strain. Brief descriptions of the behavioral tests are given. A discussion is also presented of the effects of genetic backgrounds on these behavioral profiles.

Animals↗
PubMed2000

From the feds

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Journal Article↗
PubMed2000

From the feds

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Journal Article↗
PubMed2000

Habituation of activity in an open field: A survey of inbred strains and F1 hybrids.

To determine if there is genetic variability in habituation of activity in an open field, we examined a number of inbred strains and F1 hybrids. Using 5-min exposures to a dark open field, we measured changes in exploratory behavior over 3 consecutive days in 129S3/SvImJ, A/J, BALB/ cByJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J, FVB/NJ, (B6 x 129)F1/J, and (B6 x C3H) F1/J male and female mice. Strain differences in open-field activity and in habituation were evident. Some of the strain differences were further modified by sex. The strains and F1's could be separated into groups that increased, decreased, or did not modify their activities across testing sessions. In a second study, the effects of altering the floor surface on habituation were examined in male 129S3/SvImJ, C57BL/6J, DBA/2J, and (B6 x 129)F1/J mice. When the floor was altered after 3 consecutive days of habituation, increased activity levels were evident. There were strain differences in the responsiveness to the changes in the floor. These results confirm a genetic role in intersession habituation to an open field.

Animals↗
PubMed2000

From the feds

Explore the source record for details and available documents.

Journal Article↗