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Biomedical subjects

K Fagan

Publications and source records attributed to K Fagan.

At least 19 recordsLinked to original sources
PubMed2005

Beyond the principle of plentitude: a review of terrestrial planet habitability.

We review recent work that directly or indirectly addresses the habitability of terrestrial (rocky) planets like the Earth. Habitability has been traditionally defined in terms of an orbital semimajor axis within a range known as the habitable zone, but it is also well known that the habitability of Earth is due to many other astrophysical, geological, and geochemical factors. We focus this review on (1) recent refinements to habitable zone calculations; (2) the formation and orbital stability of terrestrial planets; (3) the tempo and mode of geologic activity (e.g., plate tectonics) on terrestrial planets; (4) the delivery of water to terrestrial planets in the habitable zone; and (5) the acquisition and loss of terrestrial planet carbon and nitrogen, elements that constitute important atmospheric gases responsible for habitable conditions on Earth's surface as well as being the building blocks of the biosphere itself. Finally, we consider recent work on evidence for the earliest habitable environments and the appearance of life itself on our planet. Such evidence provides us with an important, if nominal, calibration point for our search for other habitable worlds.

Environment↗
PubMed1998

Collection and analysis of peripheral blood mononuclear cells during haemopoietic recovery following PBSCT for CML: autografting as an in vivo purging manoeuvre?

A 47-year-old man with a 2-year history of Philadelphia chromosome-positive chronic phase (CP) chronic myeloid leukaemia (CML) underwent autologous PBSCT. During the period of haemopoietic reconstitution he underwent five leucapheretic (LP) harvests yielding a total of 2.6 x 10(6)/kg CD34+ cells. Cytogenetic analyses revealed 94, 83, 83, 96 and 85% Ph negativity respectively for the five harvests. RT-PCR analyses for BCR-ABL performed on randomly picked CFU-GM from the five LP products were negative in all cases. These observations suggest that the majority of harvested cells, including the more primitive clonogenic cells, were BCR-ABL (Ph) negative and presumably were not part of the leukaemic clone. These findings support the notion that autologous PBSCT in CML whilst serving as a therapeutic manoeuvre may also facilitate the collection of non-leukaemic progenitor cells for further transplantation procedures.

Hematopoiesis↗
PubMed1998

The t(8;13)(p11;q11-12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP.

A recently described atypical myeloproliferative disorder is invariably associated with reciprocal translocations involving 8p11-12. The most common rearrangement is a t(8;13)(p11;q11-12). Here we determine that this translocation results in the fusion of the fibroblast growth factor receptor 1 gene (FGFR1), a member of the receptor tyrosine kinase family at 8p11, to a novel gene at 13q11-12 designated RAMP . The predicted RAMP protein exhibits strong homology to the product of a recently cloned candidate gene for X-linked mental retardation, DXS6673E . We also provide the first report of a novel, putative metal-binding motif, present as five tandem repeats in both RAMP and DXS6673E. RT-PCR detected only one of the two possible fusion transcripts, encoding a product in which the N-terminal 641 amino acids of RAMP become joined to the tyrosine kinase domain of FGFR1. Receptor tyrosine kinases are not commonly involved in the formation of tumour-specific fusion proteins. However, the previous reports of involvement of receptor tyrosine kinases in fusion proteins in non-Hodgkin's lymphoma, chronic myelomonocytic leukaemia and papillary thyroid carcinoma described similar rearrangements. By analogy with these, we propose that the RAMP-FGFR1 fusion product will contribute to progression of this myeloproliferative disorder by constitutive activation of tyrosine kinase function.

Amino Acid Sequence↗
PubMed1997

Construction of a full-length Ca2+-sensitive adenylyl cyclase/aequorin chimera.

Ca2+-sensitive adenylyl cyclases are key integrators of Ca2+ and cAMP signaling. To selectively probe dynamic changes in [Ca2+]i at the plasma membrane where adenylyl cyclases reside, a full-length, Ca2+-inhibitable type VI adenylyl cyclase/aequorin chimera has been constructed by a two-stage polymerase chain reaction method. The expressed adenylyl cyclase/aequorin chimera was appropriately localized to the plasma membrane, as judged by biochemical fractionation and functional analysis. The chimera retained full adenylyl cyclase activity and sensitivity to inhibition by physiological [Ca2+]i elevation. The aequorin portion of the chimeric construct was also capable of measuring changes in [Ca2+] both in vitro and in vivo. When the plasma membrane-tagged aequorin and cytosolic aequorin were compared in their measurement of [Ca2+]i, they showed contrasting sensitivities depending on whether the [Ca2+]i originated from internal stores or capacitative entry. This is the first full-length enzyme-aequorin chimera that retains the full biological properties of both aequorin and a Ca2+-sensitive adenylyl cyclase. This novel chimeric Ca2+ sensor provides the unique ability to directly report the dynamics of [Ca2+]i that regulates this Ca2+-sensitive enzyme under a variety of physiological conditions. Since this chimera is localized to the plasma membrane, it can also be used to assess local changes in [Ca2+]i at the plasma membrane as distinct from global changes in [Ca2+]i within the cytosol.

Adenylyl Cyclases↗
PubMed1997

Supernumerary ring chromosome 17 identified by fluorescent in situ hybridization.

We present a patient with multiple anomalies and severe developmental delay. A small supernumerary ring chromosome was found in 40% of her lymphocyte cells at birth. The origin of the marker chromosome could not be determined by GTG banding, but fluorescent in situ hybridization (FISH) later identified the marker as deriving from chromosome 17.

Abnormalities, Multiple↗
PubMed1997

Anal anomalies: an uncommon feature of velocardiofacial (Shprintzen) syndrome?

We report three cases of velocardiofacial syndrome (VCFS) with anal anomalies who have deletions of the 22q11 region and a further case where the proband has VCFS clinically and her father has an anal anomaly. It is important to consider VCFS in the differential diagnosis of children with anal anomalies and to look for other features of the syndrome, such as asymmetrical crying facies, submucous cleft of the palate, developmental delay, cardiac anomalies, and hypoparathyroidism.

Abnormalities, Multiple↗
PubMed1997

Translocations involving 4p16.3 in three families: deletion causing the Pitt-Rogers-Danks syndrome and duplication resulting in a new overgrowth syndrome.

Three families are reported who have a translocation involving 4p16.3. Nine subjects are described with the clinical features of the Pitt-Rogers-Danks (PRD) syndrome confirming pre- and postnatal growth failure, microcephaly, severe mental retardation, seizures, and a distinctive facial appearance; a deletion of 4p16.3 was seen in all eight patients studied with fluorescence in situ hybridisation (FISH). Eleven subjects had a new syndrome with physical overgrowth, heavy facial features, and mild to moderate mental handicap; a duplication of the chromosome region 4p16.3 was found in the four subjects studied. It is suggested that the growth abnormalities in these two families may be explained by a dosage effect of the fibroblast growth factor receptor gene 3 (FGFR3), which is located at 4p16.3, that is, a single dose leads to growth failure and a triple dose to physical overgrowth. We describe the molecular mapping of the translocation breakpoint and define it to within locus D4S43.

Abnormalities, Multiple↗
PubMed1996

Velo-cardio-facial and partial DiGeorge phenotype in a child with interstitial deletion at 10p13--implications for cytogenetics and molecular biology.

We report on a female with a interstitial deletion of 10p13 and a phenotype similar to that seen with the 22q deletion syndromes (DiGeorge/velo-cardio-facial). She had a posterior cleft palate, perimembranous ventricular septal defect, dyscoordinate swallowing, T-cell subset abnormalities, small ears, maxillary and mandibular hypoplasia, broad nasal bridge, deficient alae nasi, contractures of fingers and developmental delay. This could indicate homology of some developmental genes at 22q and 10p so that patients with the velocardiofacial phenotype who do not prove to be deleted on 22q are candidates for a 10p deletion.

Abnormalities, Multiple↗
PubMed1994

An interstitial deletion of chromosome 7(q35).

We describe a patient with developmental delay, mild dysmorphic features, and monosomy of 7q35. Only one other patient with an interstitial deletion of this band has been previously reported. A review of clinical features of these two children did not show similarities in dysmorphic features. Reports of patients with other 7q interstitial deletions are listed.

Child↗
PubMed1993

Translocation (8;13) and T-cell lymphoma. A case report.

A patient with a myeloproliferative disorder is described with an eosinophilia together with T-cell lymphoma. A unique translocation t(8;13)(p11.2;q12) was present in all bone marrow cells examined at presentation. No evidence of this translocation was found in a peripheral blood lymphocyte culture. Chromosome analysis after 9 months revealed this same translocation as well as an extra chromosome 21 in all cells; 4.5% of cells also had an additional chromosome 9. The morphologic diagnosis at this stage was chronic myelomonocytic leukemia. Immunophenotyping 3 months later was consistent with a stem-cell leukemia.

Bone Marrow↗
PubMed1992

Failure of ondansetron to block the discriminative or reinforcing stimulus effects of cocaine in the rat.

Ondansetron (GR38032F), a serotonin 5HT3 antagonist, is active in numerous behavioral paradigms and neurochemical systems. Since 5HT3 antagonists have been suggested as therapeutic agents for the treatment of drug abuse, the action of ondansetron on cocaine drug discrimination and self-administration paradigms in rats was investigated. Doses of ondansetron (0.001 - 1.0 mg/kg) had no effect on the discriminative stimulus properties of 10 mg/kg cocaine. In contrast SCH23390, a dopamine D1 antagonist known to block cocaine discrimination, acted as previously reported. Ondansetron did not augment the effects of SCH23390, but at higher doses, combinations of ondansetron and SCH23390 produced disruption of lever pressing in the presence of cocaine. Ondansetron (0.001-1.0 mg/kg) had no effect on the self-administration of various doses of cocaine, nor did it have any effect on reacquisition of cocaine self-administration in animals with a history of active administration followed by a period of abstinence. As before, SCH23390, known to block cocaine self-administration, acted as previously reported. Although other 5HT antagonists may prove to be efficacious in cocaine abuse, ondansetron appears unlikely to alter the subjective or rewarding stimulus properties of cocaine.

Animals↗
PubMed1991

A human colon cancer cell line established from collagen matrix cultures transplanted into nude mice.

A new human colon cancer cell line (020588) has been derived by means of a combined in vitro matrix-in vivo xenograft technique. The tumour cell line is carcino-embryonic antigen positive, displays a marker chromosome and proliferates in chemically-defined serum-free culture medium. The chemosensitivity pattern for the tumour cell line was similar to that observed for the parent tumour cells. The novel method used to establish this continuous human tumour cell line may have several advantages over standard techniques.

Animals↗