Search PubMed⌕ Search

Biomedical subjects

H L Ford

Publications and source records attributed to H L Ford.

16 recordsLinked to original sources
PubMed2001

Developing a disease-specific quality of life measure for people with multiple sclerosis.

OBJECTIVES: To develop a patient-completed disease-specific measure of quality of life in multiple sclerosis and to validate the measure in a community-based population of people with multiple sclerosis. METHODS: The items in the scale were selected in focus group sessions of people with multiple sclerosis. The initial scale included 25 items and was tested in subgroups of 150 people from a population register of people with multiple sclerosis in Leeds. Following further developmental phases, a restructured 16-item scale was tested on a random sample of 200 people with multiple sclerosis from the population register, stratified according to disease course. This led to a final eight-item unidimensional scale, the Leeds Multiple Sclerosis Quality of Life (LMSQoL) scale. RESULTS: After initial development a 16-item scale was found to be both reliable and valid. Cronbach's alpha for the 16-item scale was 0.86. The test-retest correlation was 0.74, using a two-week retest interval. However, convergent validity with the General Well Being Index was 0.67 and with the SF-36 Physical Function Scale was 0.68. This suggested that the scale straddled these two concepts and was confirmed by fit of the data to the Rasch measurement model. This revealed the potential for a reduced eight-item version of the scale. The eight-item scale had a closer association to well-being (0.83) than to physical function (0.39), had good internal consistency (0.79) and test-retest reliability (0.85). There were virtually no floor or ceiling effects for the scale. CONCLUSIONS: The study presents a disease-specific measure of quality of life in multiple sclerosis, the Leeds Multiple Sclerosis Quality of Life (LMSQoL) scale. The instrument is brief, easy to use and practical to administer in clinic or as a postal questionnaire. It measures a construct related to well-being, and provides an important adjunct to the measurement of outcome in multiple sclerosis.

Adult↗
PubMed2000

Cell cycle-regulated phosphorylation of the human SIX1 homeodomain protein.

Human SIX1 (HSIX1) is a member of the Six class of homeodomain proteins implicated in muscle, eye, head, and brain development. To further understand the role of HSIX1 in the cell cycle and cancer, we developed an HSIX1-specific antibody to study protein expression at various stages of the cell cycle. Our previous work demonstrated that HSIX1 mRNA expression increases as cells exit S phase and that overexpression of HSIX1 can attenuate a DNA damage-induced G(2) cell cycle checkpoint. Overexpression of HSIX1 mRNA was observed in 44% of primary breast cancers and 90% of metastatic lesions. Now we demonstrate that HSIX1 is a nuclear phosphoprotein that becomes hyperphosphorylated at mitosis in both MCF7 cells and in Xenopus extracts. The pattern of phosphorylation observed in mitosis is similar to that seen by treating recombinant HSIX1 with casein kinase II (CK2) in vitro. Apigenin, a selective CK2 inhibitor, diminishes interphase and mitotic phosphorylation of HSIX1. Treatment of MCF7 cells with apigenin leads to a dose-dependent arrest at the G(2)/M boundary, implicating CK2, like HSIX1, in the G(2)/M transition. HSIX1 hyperphosphorylated in vitro by CK2 loses its ability to bind the MEF3 sites of the aldolase A promoter (pM), and decreased binding to pM is observed during mitosis. Because CK2 and HSIX1 have both been implicated in cancer and in cell cycle control, we propose that HSIX1, whose activity is regulated by CK2, is a relevant target of CK2 in G(2)/M checkpoint control and that both molecules participate in the same pathway whose dysregulation leads to cancer.

Amino Acid Sequence↗
PubMed2000

Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer.

A gene related to cell differentiation was identified by differential display as a candidate suppressor of metastases in colon cancer. This gene, with a full-length cDNA of 3 kb, is expressed in normal colon and primary colon cancer tissues and cell lines but not in their metastatic counterparts. A GenBank search found that it is identical to a recently cloned gene, differentiation-related gene-1 (Drg-1), isolated from differentiated HT-29 colon cancer cells. Stable transfection of the SW620 metastatic colon cancer cell line with Drg-1 cDNA induced morphological changes consistent with differentiation and up-regulated the expression of several colonic epithelial cell differentiation markers (alkaline phosphatase, carcinoembryonic antigen, and E-cadherin). Moreover, the expression of Drg-1 is controlled by several known cell differentiation reagents, such as ligands of peroxisome proliferator-activated receptor gamma (troglitazone and BRL46593) and of retinoid X receptor (LG268), and histone deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and tributyrin). A synergistic induction of Drg-1 expression was seen with the combination of tributyrin and a low dose of 5'-aza-2'-dexoycytidine (100 nM), an inhibitor of DNA methylation. Functional studies revealed that overexpression of Drg-1 in metastatic colon cancer cells reduced in vitro invasion through Matrigel and suppressed in vivo liver metastases in nude mice. We propose that Drg-1 suppresses colon cancer metastasis by inducing colon cancer cell differentiation and partially reversing the metastatic phenotype.

Animals↗
PubMed1999

Cancer and the cell cycle.

The purpose of this short review is to provide an overview of mammalian somatic cell cycle events and their controls. Cell cycle-related studies have been under way for only 5% of this millennium, yet since then nearly 20,000 references have appeared. This vast literature cannot be detailed here, nor can fundamental information obtained with other organisms such as yeast and Xenopus, or topics such as the abbreviated cell cycle in early embryonic cells. (General references include Murray and Hunt [1993] The cell cycle, an introduction. New York: Oxford University Press, and Denhardt [1999] In: The molecular basis of cell cycle and growth control. p 225-304. New York: John Wiley & Sons, Inc.) J. Cell Biochem. Suppls. 32/33:166-172, 1999.

Animals↗
PubMed1998

Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis.

While conducting a search for cell cycle-regulated genes in human mammary carcinoma cells, we identified HSIX1, a recently discovered member of a new homeobox gene subfamily. HSIX1 expression was absent at the onset of and increased toward the end of S phase. Since its expression pattern is suggestive of a role after S phase, we investigated the effect of HSIX1 in the G2 cell cycle checkpoint. Overexpression of HSIX1 in MCF7 cells abrogated the G2 cell cycle checkpoint in response to x-ray irradiation. HSIX1 expression was absent or very low in normal mammary tissue, but was high in 44% of primary breast cancers and 90% of metastatic lesions. In addition, HSIX1 was expressed in a variety of cancer cell lines, suggesting an important function in multiple tumor types. These data support the role for homeobox genes in tumorigenesis/tumor progression, possibly through a cell cycle function.

Base Sequence↗
PubMed1998

The prevalence of multiple sclerosis in the Leeds Health Authority.

OBJECTIVES: To determine the prevalence of multiple sclerosis in the Leeds Health District. METHODS: Multiple sources of case ascertainment were used-namely, neurology departments, hospital episode statistics, general practitioners, the Leeds branch of the Multiple Sclerosis Society, the West Yorkshire Multiple Sclerosis Therapy Centre, community physiotherapists and occupational therapists, the Leeds Wheelchair Centre, and the Young Disabled Unit. Data collection was from retrospective analysis of hospital and primary care case records. A population based incidence register was established by prospectively registering all new patients with diagnoses of multiple sclerosis. RESULTS: On prevalence day, 30 April 1996, 712 people with multiple sclerosis were identified living in Leeds (population 732,061), giving a prevalence of 97/10(5). The prevalence for definite and probable multiple sclerosis was 84/10(5), and for suspected multiple sclerosis it was 13/10(5). The sex ratio of prevalent people with multiple sclerosis was 2.79 to 1 women to men. The mean age of prevalent cases was 51 years, the mean age at symptom onset was 34 years, and the mean duration of disease was 16 years. Forty cases were prospectively reported as incident cases from 1 November 1995 to 1 February 1996. CONCLUSIONS: The prevalence of multiple sclerosis in Leeds was found to be similar to that in the south of the United Kingdom but lower than that in Scotland. There is no evidence of a latitudinal gradient of increasing prevalence of multiple sclerosis from the south to the north of England.

Adult↗
PubMed1998

The S phase: beginning, middle, and end: a perspective.

Events in the S phase of the cell cycle have been investigated to a relatively limited extent in comparison with those in G1 and M phases. Four aspects of S are briefly discussed in this report: (1) the final biochemical step permitting initiation of DNA synthesis, (2) determination of replication timing of individual genes and its mechanism, (3) S phase processes that lead to the onset of M phase, and (4) resetting the S-phase machinery.

Animals↗
PubMed1997

Effect of Mts1 on the structure and activity of nonmuscle myosin II.

The mts1 gene codes for a 9 kDa protein belonging to the S100 subfamily of Ca2+-binding proteins and is known to play a role in metastasis. Its role in metastasis may be through cellular locomotion, as transfection of mts1 into mouse mammary adenocarcinoma cells increases cellular motility in modified Boyden chemotaxis chambers. The Mts1 protein interacts with nonmuscle myosin II in the presence of Ca2+ with an affinity of approximately 7.9 x 10(4) M-1 and an approximate stoichiometry of 3 mol of Mts1/mol of myosin heavy chain. No interaction was found with myosin I or myosin V. The binding site of Mts1 on myosin is in the rod region, particularly to the light meromyosin portion of the rod. To understand the mechanism by which Mts1 alters cellular motility, we examined its effect on myosin structure and activity. Cosedimentation analysis and electron microscopy suggest that Mts1 destabilizes myosin filaments. In the presence of Ca2+, Mts1 inhibits the actin-activated MgATPase activity of myosin in vitro. The data demonstrate an effect of Mts1 on both myosin structure and function, and suggest a route through which Mts1 affects motility as well as metastasis.

Binding Sites↗
PubMed1995

Expression of Mts1, a metastasis-associated gene, increases motility but not invasion of a nonmetastatic mouse mammary adenocarcinoma cell line.

The mts1 gene codes for a 101 amino acid protein belonging to the S100 subfamily of Ca(2+)-binding proteins. Mts1 is overexpressed in metastatic cancers as compared to their nonmetastatic counterparts, and although mts1 is known to be involved in the metastatic phenotype (Davies et al., 1993; Grigorian et al., 1993), the role mts1 plays in this process is not clearly understood. In order to determine what role mts1 plays in the process of metastasis, we have performed transfection studies on nonmetastatic and metastatic mouse mammary adenocarcinoma cell lines, CSML0 and CSML100, respectively (Senin et al., 1983, 1984). The metastatic variant, CSML100, expresses high levels of mts1, whereas the nonmetastatic variant, CSML0, expresses almost no mts1. CSML0 cells transfected with mts1 were assessed in in vitro motility and invasion assays, as well as in vivo metastasis assays to determine the role of mts1 in these processes. Cell lines expressing mts1 display an altered morphology as well as increased motility in modified Boyden chemotaxis chambers. However, no significant increase in in vitro invasion or in in vivo metastasis was observed. Therefore, the presence of mts1 may be important for metastasis by increasing motility, but may not be sufficient for invasion in vitro or metastasis in vivo. Very low levels of type IV collagenase activities were observed in CSML0 cells and the transfectants, as opposed to the highly metastatic CSML100 cells, where high levels of type IV collagenase activities were observed. It is possible that the presence of these proteases in addition to mts1 may be responsible for the high metastatic potential of the CSML100 in vivo.

Adenocarcinoma↗
PubMed1995

Interaction of metastasis associated Mts1 protein with nonmuscle myosin.

The mts1 gene codes for a 101 amino acid protein which belongs to the subfamily of S100 Ca(2+)-binding proteins and is overexpressed in metastatic cancers as compared to their nonmetastatic counterparts. While the Mts1 protein is putatively involved in cytoskeletal-membrane interactions, its exact physiological role is not known. In order to gain insight into the biological function of Mts1, its expression was monitored throughout mouse embryogenesis as well as in normal adult mouse tissues. In situ hybridizations of mouse embryos showed expression of mts1 mRNA to be highest in trophoblast cells of a day 8 old embryo. In normal adult mouse tissues, immunocytochemistry revealed Mts1 expression in a T-cell specific pattern in both the thymus and spleen. These results indicate that the expression of mts1 is prevalent in motile cell types, and to further elucidate the role of Mts1, gel overlay and GST-fusion protein experiments were performed to identify proteins that interact with the Mts1 protein. Nonmuscle myosin II was found to interact with Mts1, suggesting a role for Mts1 in the process of motility and lending credence to the hypothesis that Mts1 may enhance metastatic potential by increasing the motility of cancerous cells.

Age Factors↗
PubMed1995

Telling your patient he/she has multiple sclerosis.

It is difficult to tell a person that s/he has multiple sclerosis. The diagnosis is based on clinical findings and often cannot be made on first meeting. In many cases investigations do not help. When the diagnosis is made, the patient should be fully informed in the majority of cases. Guidelines have been developed for imparting the diagnosis. Early diagnosis will become increasingly important with the development of new treatments for multiple sclerosis.

Female↗
PubMed1993

Characterization of a positive regulatory element in the mts1 gene.

The first intron of the mts1 gene, a gene that is selectively expressed in metastatic cells and in normal cells that are motile, was found to be highly homologous to the CD3 delta enhancer element. Because of the homology between the CD3 delta enhancer and the first intron of mts1, we analysed the first intron of the mts1 gene to determine whether it functions as a transcriptional regulatory element. Highly metastatic CSML-100 cells transfected with chloramphenicol acetyl transferase-containing plasmids demonstrated the ability of the mts1 first intron to function as a positive regulatory element. In vitro footprinting analysis using extracts from CSML-0 cells (which express mts1 at low levels) or CSML-100 cells (which express mts1 at high levels) identified a protected 16-nucleotide element in the first intron of mts1, regardless of the extract used. However, in vivo footprinting analysis of the same region identified the protected 16-nucleotide fragment only in the mts1 intron from CSML-100 cells, not from CSML-0 cells. Differences in the methylation pattern of the mts1 gene in CSML-100 cells and CSML-0 cells are known to exist, and may in part be responsible for the mts1 footprinting differences observed in vivo from the different cell lines.

Animals↗
PubMed1992

Transcriptional analysis of the mts1 gene with specific reference to 5' flanking sequences.

The mts1 gene is specifically expressed in certain metastatic tumors but not in their nonmetastatic counterparts. It is also expressed in several normal cell and tissue types that exhibit the ability to be motile. The gene was cloned from both mouse and human sources and the 5' flanking regions were sequenced. The sequencing data revealed a 135-base-pair region of high homology between the mouse and human mts1 gene. This homology was observed in the vicinity of the TATA box. The 5' region of the mts1 gene was also observed to have a high degree of homology to some known promoter and enhancer sequences. To determine the role this region plays in regulating the transcription of mts1, promoter analysis was performed. Sixteen constructs were prepared in which the chloramphenicol acetyltransferase gene was fused to different regions of the mouse mts1 promoter. These constructs were analyzed in transient transfection assays in two related cell lines derived from mouse mammary adenosarcomas: CSML-0, a nonmetastatic cell line with low levels of mts1 expression, and CSML-100, a metastatic cell line with high levels of mts1 expression. Results of our transient transfection assays in conjunction with results obtained from in vitro and in vivo footprinting of the promoter region show no evidence of cis-acting control elements important for the transcriptional regulation of mts1 in these cell lines. A few nucleotides upstream of the TATA box are sufficient for maximal levels of mts1 transcription. Because no cis-acting control elements were found, restriction of mts1 transcription in CSML-0 cells must exist on some other level. mts1 was found to be hypermethylated in CSML-0 cells but not in CSML-100 cells. The possible role of methylation in progression of the nonmetastatic CSML-0 adenosarcoma cell line toward the metastatic CSML-100 adenosarcoma cell line is discussed.

Animals↗