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K Mercer

Publications and source records attributed to K Mercer.

14 recordsLinked to original sources
PubMed2001

Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.

Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras. Here we show that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation. Through the ability to synchronize tumor initiation in these mice, we have been able to characterize the stages of tumor progression. Of particular significance, this system has led to the identification of a new cell type contributing to the development of pulmonary adenocarcinoma.

Adenocarcinoma↗
PubMed2001

Somatic activation of the K-ras oncogene causes early onset lung cancer in mice.

About 30% of human tumours carry ras gene mutations. Of the three genes in this family (composed of K-ras, N-ras and H-ras), K-ras is the most frequently mutated member in human tumours, including adenocarcinomas of the pancreas ( approximately 70-90% incidence), colon ( approximately 50%) and lung ( approximately 25-50%). To construct mouse tumour models involving K-ras, we used a new gene targeting procedure to create mouse strains carrying oncogenic alleles of K-ras that can be activated only on a spontaneous recombination event in the whole animal. Here we show that mice carrying these mutations were highly predisposed to a range of tumour types, predominantly early onset lung cancer. This model was further characterized by examining the effects of germline mutations in the tumour suppressor gene p53, which is known to be mutated along with K-ras in human tumours. This approach has several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.

Alleles↗
PubMed2001

MEK kinase activity is not necessary for Raf-1 function.

Raf-1 protein kinase has been identified as an integral component of the Ras/Raf/MEK/ERK signalling pathway in mammals. Activation of Raf-1 is achieved by RAS:GTP binding and other events at the plasma membrane including tyrosine phosphorylation at residues 340/341. We have used gene targeting to generate a 'knockout' of the raf-1 gene in mice as well as a rafFF mutant version of endogenous Raf-1 with Y340FY341F mutations. Raf-1(-/-) mice die in embryogenesis and show vascular defects in the yolk sac and placenta as well as increased apoptosis of embryonic tissues. Cell proliferation is not affected. Raf-1 from cells derived from raf-1(FF/FF) mice has no detectable activity towards MEK in vitro, and yet raf-1(FF/FF) mice survive to adulthood, are fertile and have an apparently normal phenotype. In cells derived from both the raf-1(-/-) and raf-1(FF/FF) mice, ERK activation is normal. These results strongly argue that MEK kinase activity of Raf-1 is not essential for normal mouse development and that Raf-1 plays a key role in preventing apoptosis.

Animals↗
PubMed1999

Comparison of functional state between bilateral lung volume reduction surgery and pulmonary rehabilitation: a six-month followup study.

STUDY OBJECTIVE: The effectiveness of bilateral lung volume reduction surgery (BLVRS) in the improvement of functional state in severe chronic obstructive pulmonary disease (COPD) has not been reported. This study examined the effects of BLVRS on subjective and objective measures of functional state (FS) and compared these effects with those gained from pulmonary rehabilitation (PR). METHODS: Twenty-eight consecutive patients were studied. Of 13 BLVRS and 15 PR patients enrolled in the study, 12 and 13 patients, respectively, completed the 6-month protocol. Pulmonary function (FEV1, FVC, and FEF25-75) was measured by spirometry. Subjective FS was measured with the activity component of the Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ) and objective FS was determined as the 6-min walk distance (6mwD). Additionally, the maximal dyspnea intensity measured with the Borg scale during the 6-min test was recorded. All outcomes were recorded prior to, and six months following treatment. RESULTS: In patients undergoing BLVRS, FEV1 and FVC increased (17.3% and 16.8%) while in those treated with PR alone, FEV1 and FVC decreased (7.6% and 16.1%,p < 0.05). The subjective functional state (PFSDQ) was also significantly different between BLVRS and PR alone (PFSDQ = -49.4% vs. +4.7%, p < 0.05). Although the absolute distance walked over 6 min did not reach statistical significance, the BLVRS group increased the distance by 20% while the PR alone group had a decrease (-28%). Both groups demonstrated a reduction in dyspnea with exercise but the volume reduction patients showed a significantly greater reduction (PR = -1.0; BLVRS = -2.6, p < 0.05). CONCLUSION: BLVRS results in greater improvement in pulmonary function, dyspnea with exercise, and subjective FS when compared to PR 6 months after surgery.

Aged↗
PubMed1998

Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors.

A role for the membrane/cytoskeleton interface in the development and progression of cancer is established, yet poorly understood. The neurofibromatosis type II (NF2) tumor suppressor gene encodes a member of the ezrin/radixin/moesin (ERM) family of membrane/cytoskeleton linker proteins thought to be important for cell adhesion and motility. We report that in contrast to the narrow spectrum of benign tumors in human NF2 patients, Nf2 heterozygous mice develop a variety of malignant tumors. Using the fact that Nf2 is linked to the p53 tumor suppressor locus in the mouse we have also investigated the effects of genetic linkage of cancer-predisposing mutations on tumorigenesis and examined the genetic pathway to tumor formation involving Nf2 loss. Importantly, we observed a very high rate of metastasis associated with Nf2 deficiency, with or without loss of p53 function, and we provide experimental evidence supporting a role for Nf2 loss in metastatic potential. Together, our results suggest an important role for the NF2 tumor suppressor, and perhaps the ERM family in tumor formation and metastasis.

Animals↗
PubMed1998

Perception of fatigue and quality of life in patients with COPD.

INTRODUCTION: Although dyspnea is considered the primary activity-limiting symptom in patients with COPD, other symptoms, such as fatigue, are frequently reported. The purpose of this study was to determine the relationship between fatigue and pulmonary function, exercise tolerance, depression, and quality of life in patients with COPD. METHODS: Forty-one patients (age = 62+/-8 years; FEV1 = 1.08+/-0.55 L; FEV1 percent predicted = 35.8+/-17%) from two sites participated in the study. Spirometric measures of pulmonary function were carried out in each patient. The Multidimensional Fatigue Inventory was used to measure five subscales of fatigue: general, physical and mental fatigue, reduction in activity, and reduction in motivation. The St. George Respiratory Questionnaire, used to measure quality of life, has three subscale dimensions (symptom, activity, and impact), as well as an overall or total quality of life score. Depression was measured with the Centers of Epidemiological Studies Depression Scale. In 19 patients, exercise tolerance was determined with the 6-min walking distance. RESULTS: General fatigue correlated with FEV1, percent predicted (r = -0.32, p < 0.05), exercise tolerance (r = -0.55, p < 0.05), depression (r = 0.44, p < 0.01), and overall quality of life (r = 0.75, p < 0.01). Among the dimensions of fatigue, depression correlated with general and mental fatigue only. Physical dimensions of fatigue correlated with an increase in the severity of pulmonary impairment and reduction in exercise tolerance. The cognitive components of fatigue, such as reduction in motivation and mental fatigue, were not found to be highly correlated with physical dimensions of quality of life. All five subscales of fatigue showed relationship to the functional impact dimension and total impairment score in quality of life. CONCLUSIONS: These data show a relationship between dimensions of fatigue and pulmonary function, exercise tolerance, and quality of life in COPD. Based on these results, fatigue is an important symptom requiring evaluation and management in patients with COPD. These data clarified also the relationship between depression and fatigue in this patient population.

Exercise Tolerance↗
PubMed1997

K-ras is an essential gene in the mouse with partial functional overlap with N-ras.

Mammalian ras genes are thought to be critical in the regulation of cellular proliferation and differentiation and are mutated in approximately 30% of all human tumors. However, N-ras and H-ras are nonessential for mouse development. To characterize the normal role of K-ras in growth and development, we have mutated it by gene targeting in the mouse. On an inbred genetic background, embryos homozygous for this mutation die between 12 and 14 days of gestation, with fetal liver defects and evidence of anemia. Thus, K-ras is the only member of the ras gene family essential for mouse embryogenesis. We have also investigated the effect of multiple mutations within the ras gene family. Most animals lacking N-ras function and heterozygous for the K-ras mutation exhibit abnormal hematopoietic development and die between days 10 and 12 of embryogenesis. Thus, partial functional overlap appears to occur within the ras gene family, but K-ras provides a unique and essential function.

Anemia↗
PubMed1991

Electrochemical detection of human brain transmitter amino acids by high-performance liquid chromatography of stable o-phthalaldehyde-sulphite derivatives.

A simple, sensitive, reliable and reproducible isocratic HPLC technique for the measurement of OPA/sulphite derivatives of human brain amino acid neurotransmitters is described. This employs a sample preparation that is also compatible with the concurrent determination of monoamines and their metabolites on a separate HPLC system. The method has been applied to the determination of GABA and glutamate in brain tissue taken post-mortem from patients with Huntington's disease and control subjects.

Amino Acids↗
PubMedDate not supplied

Gastroenteritis causing critical limb ischaemia.

Six days after admission to hospital with Salmonella gastroenteritis, this patient presented with a critically ischaemic leg, having developed an iliac occlusion, and a subcutaneous Salmonella abscess in the anterior compartment of the leg. Critical limb ischaemia and abscess formation can be added to infective aortic aneurysm as vascular complications of Salmonella gastroenteritis.

Abscess↗