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Biomedical subjects

K Howe

Publications and source records attributed to K Howe.

At least 19 recordsLinked to original sources
PubMed2006

Ensembl 2007.

The Ensembl (http://www.ensembl.org/) project provides a comprehensive and integrated source of annotation of chordate genome sequences. Over the past year the number of genomes available from Ensembl has increased from 15 to 33, with the addition of sites for the mammalian genomes of elephant, rabbit, armadillo, tenrec, platypus, pig, cat, bush baby, common shrew, microbat and european hedgehog; the fish genomes of stickleback and medaka and the second example of the genomes of the sea squirt (Ciona savignyi) and the mosquito (Aedes aegypti). Some of the major features added during the year include the first complete gene sets for genomes with low-sequence coverage, the introduction of new strain variation data and the introduction of new orthology/paralog annotations based on gene trees.

Animals↗
PubMed2006

The genomic sequence and analysis of the swine major histocompatibility complex.

We describe the generation and analysis of an integrated sequence map of a 2.4-Mb region of pig chromosome 7, comprising the classical class I region, the extended and classical class II regions, and the class III region of the major histocompatibility complex (MHC), also known as swine leukocyte antigen (SLA) complex. We have identified and manually annotated 151 loci, of which 121 are known genes (predicted to be functional), 18 are pseudogenes, 8 are novel CDS loci, 3 are novel transcripts, and 1 is a putative gene. Nearly all of these loci have homologues in other mammalian genomes but orthologues could be identified with confidence for only 123 genes. The 28 genes (including all the SLA class I genes) for which unambiguous orthology to genes within the human reference MHC could not be established are of particular interest with respect to porcine-specific MHC function and evolution. We have compared the porcine MHC to other mammalian MHC regions and identified the differences between them. In comparison to the human MHC, the main differences include the absence of HLA-A and other class I-like loci, the absence of HLA-DP-like loci, and the separation of the extended and classical class II regions from the rest of the MHC by insertion of the centromere. We show that the centromere insertion has occurred within a cluster of BTNL genes located at the boundary of the class II and III regions, which might have resulted in the loss of an orthologue to human C6orf10 from this region.

Animals↗
PubMed2006

Ensembl 2006.

The Ensembl (http://www.ensembl.org/) project provides a comprehensive and integrated source of annotation of large genome sequences. Over the last year the number of genomes available from the Ensembl site has increased from 4 to 19, with the addition of the mammalian genomes of Rhesus macaque and Opossum, the chordate genome of Ciona intestinalis and the import and integration of the yeast genome. The year has also seen extensive improvements to both data analysis and presentation, with the introduction of a redesigned website, the addition of RNA gene and regulatory annotation and substantial improvements to the integration of human genome variation data.

Animals↗
PubMed2005

Influenza immunisation in children with solid tumours.

We assessed response to immunisation with trivalent split virus influenza vaccine in children with non-leukaemic malignant disease. Children with solid tumours and lymphoma received one or two doses of influenza vaccine, according to current UK guidelines, in autumn 2001 and/or 2002. Children were currently receiving chemotherapy or were within 6 months of completing chemotherapy. Pre and post vaccination sera were assessed for antibodies to the prevalent influenza strains by haemagglutination inhibition (HI). Sixty six children were assessed prior to 69 episodes of vaccination. In 30% episodes, children were susceptible to all three circulating influenza viruses (65% to H1N1, 42% to H3N2 and 90% to B) and only one patient showed protective titres (HI32) against all three strains. Seroresponse rates (4-fold rise in HI) for H1N1, H3N2 and B were 52%, 33% and 51% in 65 episodes. Following immunisation protective titres to all three viruses were seen in 25 episodes (38%) and protective responses to one or two viruses were seen in a further 12 (19%) episodes. There was no significant difference in response rates among children on treatment and off treatment and by intensity of chemotherapy. Children with solid tumours and lymphoma are highly susceptible to influenza infection. Influenza vaccine was well tolerated in this patient group and children showed a significant response to immunisation. These findings support the recommendation for annual influenza vaccination in these children.

Adolescent↗
PubMed2005

Ensembl 2005.

The Ensembl (http://www.ensembl.org/) project provides a comprehensive and integrated source of annotation of large genome sequences. Over the last year the number of genomes available from the Ensembl site has increased by 7 to 16, with the addition of the six vertebrate genomes of chimpanzee, dog, cow, chicken, tetraodon and frog and the insect genome of honeybee. The majority have been annotated automatically using the Ensembl gene build system, showing its flexibility to reliably annotate a wide variety of genomes. With the increased number of vertebrate genomes, the comparative analysis provided to users has been greatly improved, with new website interfaces allowing annotation of different genomes to be directly compared. The Ensembl software system is being increasingly widely reused in different projects showing the benefits of a completely open approach to software development and distribution.

Animals↗
PubMed2004

The DNA sequence and comparative analysis of human chromosome 10.

The finished sequence of human chromosome 10 comprises a total of 131,666,441 base pairs. It represents 99.4% of the euchromatic DNA and includes one megabase of heterochromatic sequence within the pericentromeric region of the short and long arm of the chromosome. Sequence annotation revealed 1,357 genes, of which 816 are protein coding, and 430 are pseudogenes. We observed widespread occurrence of overlapping coding genes (either strand) and identified 67 antisense transcripts. Our analysis suggests that both inter- and intrachromosomal segmental duplications have impacted on the gene count on chromosome 10. Multispecies comparative analysis indicated that we can readily annotate the protein-coding genes with current resources. We estimate that over 95% of all coding exons were identified in this study. Assessment of single base changes between the human chromosome 10 and chimpanzee sequence revealed nonsense mutations in only 21 coding genes with respect to the human sequence.

Animals↗
PubMed2001

The surgical management of women with ovarian cancer in the south west of England.

The surgical management of epithelial ovarian cancer in the South West of England was studied in the two years 1997-1998 in order to determine the factors that influence the outcome of surgery and to provide a baseline from which to assess the effect of centralisation of cancer services. All hospitals in the South West region of England participating in the Regional Cancer Organisation's longitudinal study of outcomes in gynaecological malignancies are included. Six hundred and eighty-two patients with epithelial ovarian cancer were registered with the RCO in the two-year study period. Five hundred and ninety-five women were offered primary cytoreductive surgery of which 438 were said to be optimally cytoreduced. Applying multivariate models to analyse the outcome of surgery, older patients (OR = 0.82 per 5-year increase in age, P = 0.0003), patients treated in hospitals managing fewer than ten cases of ovarian cancer per year (OR = 1.92, P = 0.02) and patients with FIGO stage 3 (OR = 0.02, P < 0.0001) or 4 (OR = 0.002, P < 0.0001) disease were less likely to be optimally cytoreduced. Gynaecological oncologists were 2.06 times more likely to attain optimal cytoreduction when compared to general gynaecologists and this was statistically significant (P = 0.01). The results from this study support the argument that limiting surgery for ovarian malignancy to specialised surgeons improves the extent of cytoreductive surgery.

Adult↗
PubMed2001

A prospective regional audit of surgical management of endometrial cancer in the South and West of England.

The results of a prospective audit of surgical management of endometrial cancer in the South and West of England is presented. A minimum data set was defined and information collected prospectively. There was limited tertiary referral to a gynaecological oncologist. The role of centralisation of endometrial cancer care has been questioned, as surgery has traditionally been simple in patients perceived to be at increased risk of more radical surgery. However, this audit demonstrates that standards of even this simple care within the region are often inadequate, with only one-third of patients having basic staging procedures performed fully. This has important implications for patients management, future interpretation of outcome data and clinical governance in endometrial cancer care.

Journal Article↗
PubMed2000

Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies".

Acute promyelocytic leukemia (APL) is typified by the t(15;17), generating the PML-RAR alpha fusion and predicting a beneficial response to retinoids. However, a sizeable minority of APL cases lack the classic t(15;17), prompting the establishment of the European Working Party to further characterize this group. Such cases were referred to a workshop held in Monza, Italy and subjected to morphologic, cytogenetic, and molecular review, yielding 60 evaluable patients. In the majority (42 of 60), molecular analyses revealed underlying PML/RAR alpha rearrangements due to insertions (28 of 42) or more complex mechanisms, including 3-way and simple variant translocations (14 of 42). Metaphase fluorescence in situ hybridization (FISH) demonstrated that insertions most commonly led to formation of the PML-RAR alpha fusion gene on 15q. In 11 of 60 workshop patients, PLZF/RAR alpha rearrangements were identified, including 2 patients lacking the t(11;17)(q23;q21). In one case with a normal karyotype, FISH analysis revealed insertion of RAR alpha into 11q23, and PLZF-RAR alpha was the sole fusion gene formed. Two patients were found to have t(5;17), one with a diffuse nuclear NPM staining pattern and with NPM-RAR alpha and RAR alpha-NPM transcripts detected. In the other with an unbalanced der(5)t(5;17)(q13;q21) and a nucleolar NPM localization pattern, an NPM/RAR alpha rearrangement was excluded, and FISH revealed deletion of one RAR alpha allele. In the remaining 5 workshop patients, no evidence was found for a rearrangement of RAR alpha, indicating that in rare instances, alternative mechanisms could mediate the differentiation block that typifies this disease. This study highlights the importance of combining morphologic, cytogenetic, and molecular analyses for optimal management of APL patients and better understanding of the pathogenesis of the disease. (Blood. 2000;96:1297-1308)

Adult↗
PubMed2000

Dextran sulfate sodium-induced colonic histopathology, but not altered epithelial ion transport, is reduced by inhibition of phosphodiesterase activity.

Inhibition of phosphodiesterase (PDE) activity is beneficial in models of arthritis and airway inflammation. Here we assessed the ability of PDE inhibitors to modulate colitis by exposing mice to 4% (w/v) dextran sulfate sodium (DSS) drinking water for 5 days with or without rolipram, an inhibitor of PDE type 4, or the nonselective PDE inhibitor, pentoxifylline (both at 5 mg/kg, i.p., twice daily). Controls received saline, vehicle, or drug only. Colonic histology, myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-alpha) levels, and epithelial ion transport (baseline and stimulated by electrical nerve stimulation, carbachol, and forskolin) were examined. DSS-treated mice displayed a variable diarrhea, significant histopathology in the mid-distal colon, elevated MPO activity, and reduced (>50%) responses to all three pro-secretory stimuli. Treatment with rolipram, and to a lesser extent pentoxifylline, significantly reduced the severity of the colonic histopathology and MPO levels. Neither PDE inhibitor had any affect on the diminished ion transport events caused by DSS-induced colitis. However, although stimulated ion transport events were still reduced 3 days after DSS treatment, colonic segments from DSS + rolipram-treated mice displayed enhanced recovery in their secretory responsiveness, particularly to carbachol. These findings indicate that specific PDE4 inhibition can significantly reduce the tissue damage that accompanies colitis and enhance recovery of normal colonic function.

Animals↗
PubMed2000

Incidental detection of a malignant hurthle cell carcinoma by Tc-99m sestamibi cardiac imaging.

A 60-year-old man reported chest pain and shortness of breath. His medical history was negative for myocardial infarction but positive for "mini strokes" and type 2 diabetes mellitus. Tc-99m sestamibi cardiac imaging revealed an abnormal focus of increased activity in the left lobe of the thyroid. Although no cardiac abnormalities were found, a I-123 thyroid scan subsequently showed a solitary hypofunctioning nodule involving the middle and inferior aspects of the left lobe of the thyroid, which fine-needle aspiration proved was a Hurthle cell carcinoma.

Adenocarcinoma↗
PubMed2000

The surgical management of cervical carcinoma within the South West of England: progress through an audit loop. Gynaecology Tumour Panel.

OBJECTIVE: To define and use a minimum clinical dataset for prospective data collection in order to audit the surgical management of cervical cancer in the South West of England. To compare this data set with a retrospective audit allowing assessment of the quality of care offered to patients. DESIGN: Prospective collection of a defined dataset on paper forms which were put into a computerised database for analysis. Registrations validated against histopathology databases and hospital coding. SETTING: All 13 hospitals in the South West of England which participated in the retrospective audit. PARTICIPANTS: One hundred and sixty-five women with cervical cancer diagnosed in 1997. MAIN OUTCOME MEASURES: Distribution of cases by hospital and surgeon; workload of individual surgeons; adequacy and accuracy of FIGO staging; adequacy of histological information; and adequacy of surgery. RESULTS: There is a trend to centralisation of cancer care and radical surgery in the region. Prospective collection of data has dramatically improved FIGO staging with 92% of all cases staged. For cases greater than Stage Ia, 98% were staged suggesting that a target of 100% staging is feasible. The histological dimensions of tumours were not measured in a high proportion of cases (20% of tumour diameters and 28% of tumour thicknesses). Apparent inadequacies in surgical management are explored. In 10/165 cases (6%) inappropriate conservative surgery may have been unavoidable, suggesting that a quality standard of 95% for appropriate radical surgical management of cervical cancer can be achieved. An anatomically complete removal of pelvic node-bearing tissue, yielding greater than 10 nodes in more than 95% cases, should be achievable with each surgeon/pathologist achieving a mean of more than 20 nodes. CONCLUSION: Regional audit of cervical cancer management is feasible. It can be used to improve the quality of information on management and guide improved service provision.

England↗
PubMed1999

Acute promyelocytic leukaemia: a retrospective analysis of patients treated at St. Bartholomew's Hospital 1969-1995.

Seventy-two patients with acute promyelocytic leukemia (APML) were treated at St.Bartholomew's Hospital (SBH) over a 25-year period. Improvements in supportive care and the use of more intensive chemotherapy have led to an increase in the complete remission rate from 14 to 58%. Similarly, the median survival has increased from 3 weeks to 2 years; the median duration of remission, which was 7 months in 1974, has not yet been reached. There was also a significant difference in survival from first recurrence, compared with that of patients with other subtypes of acute myeloid leukemia. RT-PCR analysis on bone marrow samples from 14 patients confirmed the presence of the PML/RARA fusion; 13 of the 14 patients achieved 'molecular remission' after therapy. The one patient who remained persistently positive experienced recurrence within 4 months. In seven of the eight patients in whom the disease recurred, the translocation was identified by RT-PCR at the time of relapse, whilst in one patient it was noted 4 months prior to morphological recurrence. These results illustrate the improvement in prognosis that occurred over a 25-year period in patients with APML treated at a single centre.

Adult↗
PubMed1999

SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation.

PML is a nuclear phosphoprotein that was first identified as part of a translocated chromosomal fusion product associated with acute promyelocytic leukaemia (APL). PML localises to distinct nuclear multi-protein complexes termed ND10, Kr bodies, PML nuclear bodies and PML oncogenic domains (PODs), which are disrupted in APL and are the targets for immediate early viral proteins, although little is known about their function. In a yeast two-hybrid screen, we first identified a ubiquitin-like protein named PIC1 (now known as SUMO-1), which interacts and co-localises with PML in vivo. More recent studies have now shown that SUMO-1 covalently modifies a number of target proteins including PML, RanGAP1 and IkappaBalpha and is proposed to play a role in either targeting modified proteins and/or inhibiting their degradation. The precise molecular role for the SUMO-1 modification of PML is unclear, and the specific lysine residues within PML that are targeted for modification and the PML sub-domains necessary for mediating the modification in vivo are unknown. Here we show that SUMO-1 covalently modifies PML both in vivo and in vitro and that the modification is mediated either directly or indirectly by the interaction of UBC9 with PML through the RING finger domain. Using site-specific mutagenesis, we have identified the primary PML-SUMO-1 modification site as being part of the nuclear localisation signal (Lys487 or Lys490). However SUMO-1 modification is not essential for PML nuclear localisation as only nuclear PML is modified. The sequence of the modification site fits into a consensus sequence for SUMO-1 modification and we have identified several other nuclear proteins which could also be targets for SUMO-1. We show that SUMO-1 modification appears to be dependant on the correct subcellular compartmentalisation of target proteins. We also find that the APL-associated fusion protein PML-RARA is efficiently modified in vitro, resulting in a specific and SUMO-1-dependent degradation of PML-RARA. Our results provide significant insights into the role of SUMO-1 modification of PML in both normal cells and the APL disease state.

Consensus Sequence↗
PubMed1998

The ubiquitin-homology gene PIC1: characterization of mouse (Pic1) and human (UBL1) genes and pseudogenes.

The human ubiquitin-homology domain protein PIC1 interacts with the acute promyelocytic leukemia protein PML, and both proteins form part of the large, nuclear, multiprotein complexes known as PML nuclear bodies. The normal punctate immunohistochemical staining pattern of these complexes is disrupted by viral infection or interferon treatment and in blast cells from patients with acute promyelocytic leukemia. We have characterized the murine homologue of PIC1 and have found that the predicted amino acid sequences of the mouse and human proteins are identical. High levels of Pic1 mRNA were detected in a range of mouse tissues. Pic1 genomic clones were isolated, and the organization of the gene was determined. Two processed Pic1 pseudogenes were also isolated and characterized. Through FISH, the chromosomal localizations of the mouse Pic1 gene and the two pseudogenes were determined. Human PIC1 (HGMW-approved symbol UBL1)-related sequences were isolated from human genomic DNA and were shown to represent processed pseudogenes. The role of PIC1 in a variety of cellular processes is discussed.

3T3 Cells↗