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Biomedical subjects

K Howe

Publications and source records attributed to K Howe.

At least 19 recordsLinked to original sources
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↗
PubMed1997

Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is typified by the reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of PML-RARalpha and RARalpha-PML fusion genes. We have characterized 7 cases of morphologic APL found to lack the t(15; 17) on conventional cytogenetic assessment. In 6 of 7 cases, cryptic PML-RARalpha rearrangements were identified by reverse transcriptase-polymerase chain reaction and fluorescent in situ hybridization (FISH); whereas, in the remaining patient, APL was associated with the variant translocation, t(11; 17)(q23; q12-21), leading to the formation of PLZF-RARalpha and RARalpha-PLZF fusion genes. In each of the cases with cryptic PML-RARalpha rearrangements, PML-RARalpha transcripts were detected in the absence of RARalpha-PML, consistent with the concept that PML-RARalpha is the critical oncogenic fusion protein. In 4 of these cases with evaluable metaphase spreads, the occurrence of a nonreciprocal translocation was confirmed by FISH with sole formation of the PML-RARalpha fusion gene; in 3 cases with morphologically normal chromosomes 15 and 17, RARalpha was inserted into PML on 15q, whereas in the remaining patient the PML-RARalpha fusion arose due to insertion of 15q-derived material including PML into RARalpha on 17q. Immunofluorescence studies were performed using antibodies raised against PML and PIC 1, a ubiquitin-homology domain protein previously identified as an interaction partner of PML. In acute myeloid leukemia (AML) of subtypes other than M3, PIC 1 was localized to the nuclear membrane and colocalized with PML within discrete nuclear bodies. In APL cases with cryptic PML-RARalpha rearrangements, the characteristic microparticulate pattern of PML staining was detected with partial colocalization with PIC 1, indicative of disruption of the nuclear bodies; whereas in t(11; 17)-associated APL, PML and PIC 1 remained colocalized within discrete nuclear bodies, as observed in non-APL cases. Although deregulation of the putative growth suppressor PML and delocalization of other nuclear body constituents have been advocated to play a key role in the development of t(15; 17)-associated APL, the present study shows that disruption of PML nuclear bodies per se is not a prerequisite for the pathogenesis of APL.

Chromosomes, Human, Pair 15↗
PubMed1997

The management of cervical carcinoma within the south west region of England. Expert Tumour Panel.

OBJECTIVE: 1. To audit the management of cervical carcinoma in the South West Region with the aim of identifying and addressing deficiencies. 2. To determine whether recent NHS restructuring has affected the provision of cancer care. DESIGN: Retrospective review of hospital case notes. SETTING: All hospitals in the South West Region of England. POPULATION: Three hundred and twenty-four women with a diagnosis of cervical carcinoma: 191 were diagnosed in 1989 and 133 in 1993. MAIN OUTCOME MEASURES: Documentation of patient assessment and management. RESULTS: There was a mean delay of 17 days (range 0-66) from cervical smear to cytology report and 34 days (range 1-380) from general practitioner referral to attendance at a hospital clinic. Overall, 175 women (54%) had evidence of cytological assessment prior to treatment and 137 (42%) had a colposcopic assessment; 49% had cytological assessment and 37% had colposcopy in 1989, compared with 60% and 50%, respectively, in 1993. Excluding 49 cases of micro-invasive carcinoma, 238 case notes (86%) contained evidence of clinical examination; 195 women (71%) had had an examination under anaesthesia, 115 (42%) a chest radiograph, 123 (45%) an intravenous urogram or renal ultrasound, and 92 (33%) cystoscopy. One hundred and forty-seven women (53%) had FIGO staging recorded in the notes. As first line treatment, 69 had conservative surgery (39 for Stage IA), 138 had radiotherapy, and 107 had radical surgery. Ten had radical surgery for Stage IA but eight had a > 3 mm invasion or lymphatic/vascular spread. Thirty-one had Stage IB treated with radiotherapy of whom 14 were younger than 50 years of age. Following radical surgery 30% had evidence of sampling > or = 10 nodes, and 9% had tumour extending to the resection margins. CONCLUSIONS: Record keeping was inadequate but appeared to indicate inconsistent cytological, clinical, colposcopic and radiological assessment, leading to inappropriate clinical delays and conservative surgery. Radical surgery often appeared inadequate, but poor node sampling rates may also reflect insufficient histopathological preparation or reporting. There was a reduction in the number of new cases of cervical carcinoma diagnosed in 1993, perhaps reflecting an observed increase in cytological surveillance. No other alterations in clinical practice were observed over the four-year period. We feel it is imperative to standardise assessment throughout the region with a minimum clinical and histopathological dataset.

Adult↗
PubMed1996

PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia.

Acute promyelocytic leukaemia (APL) arises following a reciprocal translocation t(15;17) that fuses PML with retinoic acid receptor alpha (RARA). The PML-RARA fusion protein targets and disrupts nuclear multiprotein complexes called PODs, ND10 or NBs, a process which is associated with a block in myeloid differentiation leading to APL. A human B-cell cDNA library was screened for PML-interacting clones and a single positive clone (PIC1) was isolated. The sequence of PIC1 shows 52% identity to a S. cerevisiae ubiquitin-like protein that was cloned as a suppressor of mutations in MIF2, a protein required for mitotic spindle integrity during anaphase. Transient transfection of NIH3T3 cells with PIC1 results in a nuclear staining pattern coincident with that of endogenous mouse PML. Further, cotransfection of PIC1 with human PML produces a completely overlapping staining pattern between the two proteins. An antibody raised against PIC1 detects a punctate staining pattern in HeLa cells that is coincident with endogenous human PML. There is no significant colocalisation observed between the staining of PML/ PML-RARA and PIC1 in an APL-derived cell line NB4, as compared to cells expressing only wild type PML. However, following all trans retinoic acid treatment of NB4 cells a significant relocalisation of PIC1 and PML is observed. PIC1 is the first identified NB-associated protein that interacts with PML, the function of which may lead to a fuller understanding of the molecular events leading to APL.

3T3 Cells↗
PubMed1996

Fibrinolytic abnormalities in two different cutaneous manifestations of venous disease.

BACKGROUND: Chronic venous insufficiency may be associated with lipodermatosclerosis or atrophie blanche. Coagulation abnormalities may be related to these cutaneous disorders. OBJECTIVE: Our purpose was to determine whether fibrinolytic abnormalities exist in patients with lipodermatosclerosis or atrophie blanche. METHODS: A case control study of patients with venous disease and atrophie blanche or lipodermatosclerosis was performed. Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in a resting and venous occluded state were measured. RESULTS: Plasma levels of PAI-1 were different between the two groups of patients. The lipodermatosclerosis group had significantly higher levels of PAI-1 in both the resting and venous occluded states (p < 0.001). Patients with atrophie blanche had milder elevations of PAI-1 in the resting and venous occluded state (p = 0.06). CONCLUSION: Fibrinolytic abnormalities are present in patients with venous disease. These abnormalities are different between patients with lipodermatosclerosis and patients with atrophie blanche.

Aged↗
PubMed1996

A retrospective study of the investigation and management of muscle-invasive bladder cancer in the South West Region.

OBJECTIVE: To evaluate the present management of muscle-invasive bladder cancer in the South West Region and to assess the workload resulting from the rationalization of treatment in specific centres. METHODS: A retrospective survey was undertaken in all the hospitals in the South West Region, to assess the management of all patients presenting with muscle-invasive bladder cancer in the years 1989 and 1993. Data were collected from histopathology records and hospital in-patients' notes. The optimum standard of assessment and treatment were defined by a panel of specialists in urological tumours. The management of patients was compared against these defined standards. RESULTS: A total of 186 and 199 patients in 1989 and 1993, respectively, were evaluated. When comparing their assessment against the defined standard, only 69% of patients in 1989 and 58% in 1993 had an intravenous urogram, with 7% and 4%, respectively, having no upper tract imaging (the remainder undergoing ultrasonography). Evidence from an examination under anaesthetic (EUA) was found for 80% of patients in 1989 and 84% of patients in 1993. Only 23% of patients in 1989 and 36% in 1993 were staged by either computed tomography or magnetic resonance imaging. In both 1989 and 1993, 54% of patients had definitive treatment, 31% had an endoscopic follow-up only and 15% had no treatment; there were no differences in age or co-morbidity among these groups. The median time elapsed between referral and diagnosis was 59 days (1989) and 52 days (1993), and the median delay to definitive treatment was 114 and 96 days, respectively. CONCLUSION: There was insufficient upper tract imaging, poor clinical staging in the EUA and too few investigations for staging. The low rate of definitive treatment may be a consequence of the delays in management, allowing the tumour to progress, and suggesting the need for a more rapid assessment of haematuria.

Adult↗
PubMed1996

Glycolic acid modulation of collagen production in human skin fibroblast cultures in vitro.

BACKGROUND: Glycolic acid has been used extensively for the treatment of photoaging and wrinkles. Suggestions have been made that glycolic acid may have specific dermal effects, although biochemical studies are limited. OBJECTIVE: This study's purpose was to examine the effect of glycolic acid on the radioactively labeled collagen production in human skin fibroblasts in culture. METHODS: Normal dermal fibroblasts were grown to semi-confluence and incubated in the presence of glycolic acid for 24 hours. Radioactive proline was added to the cultures. Using a specific amino acid assay, the amount of radioactive hydroxyproline was measured and was used as an accurate index of collagen production. RESULTS: Results show that glycolic acid caused an elevated collage production in the fibroblasts. CONCLUSION: These results demonstrate a specific stimulatory effect by the glycolic acid and could explain some of the positive benefits from the clinical use of glycolic acid.

Cells, Cultured↗
PubMed1996

Pityriasis rubra pilaris with acantholysis.

Two patients developed a papulosquamous eruption in a widespread distribution which progressed with islands of sparing of uninvolved skin characteristic clinically of adult-onset pityriasis rubra pilaris (PRP). Biopsies from both patients showed multiple areas of nonfollicular and follicular suprabasilar and intra-epidermal acantholysis with minimal dyskeratosis. They also showed the usual histologic features of PRP with a thickened orthokeratosis and parakeratosis, a retained and sometimes thickened granular cell layer, and psoriasiform epidermal hyperplasia with a perivascular lymphohistiocytic infiltrate in the superficial dermis. Two previous patients with PRP have been reported with nonfollicular, focal acantholytic dyskeratosis and both were interpreted as most likely representing an incidental finding. We believe the acantholysis in these two cases is related to the disease process, and in our second patient, was helpful in establishing the diagnosis.

Acantholysis↗