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Biomedical subjects

C G Kelly

Publications and source records attributed to C G Kelly.

At least 19 recordsLinked to original sources
PubMed2006

Tumour necrosis factor-alpha production stimulated by heat shock protein 70 and its inhibition in circulating dendritic cells and cells eluted from mucosal tissues in Crohn's disease.

Summaryand interleukin (IL)-12 by dendritic cells (DC) from patients with Crohn's disease. TNF-alpha concentration was increased significantly when DC from Crohn's disease were stimulated with HSP70 or CD40L and this was associated with signalling by the extracellular signal regulated kinase (ERK) 1/2 and p38 mitogen activated protein (MAP) kinase pathway. IL-12 production was also increased when DC were stimulated with HSP70. Cells eluted from inflamed intestinal mucosa from Crohn's disease, stimulated with HSP70, CD40L or lipopolysaccharide produced significantly greater TNF-alpha and IL-12 concentrations than cells from uninflamed mucosa. Significant inhibition of TNF-alpha production was demonstrated when DC from peripheral blood mononuclear cells or cells eluted from intestinal mucosa of Crohn's disease were treated with either the HSP70 inhibitory peptide (aa 457-496) or peptides derived from CD40 and CD40L. These inhibitory peptides target the CD40-CD40L and the emerging CD40-HSP70 co-stimulatory pathway. Our findings offer a novel strategy to prevent excessive production of TNF-alpha in Crohn's disease.

CD40 Antigens↗
PubMed2005

Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules.

AIMS: To determine whether palliation of chest symptoms from a 10 Gy single fraction (regimen 1) was equivalent to that from 30 Gy in 10 fractions (regimen 2). MATERIALS AND METHODS: Patients with cytologically proven, symptomatic lung cancer not amenable to curative therapy, with performance status 0-3, were randomised to receive either 30 Gy in 10 fractions or a 10 Gy single fraction. Local symptoms were scored on a physician-assessed, five-point categorical scale and summed to produce a total symptom score (TSS). This, performance status, Hospital Anxiety and Depression (HAD) score and Spitzer's quality-of-life index were noted before treatment, at 1 month after treatment and every 2 months thereafter. Palliation was defined as an improvement of one point or more in the categorical scale. Equivalence was defined as less than 20% difference in the number achieving an improvement in the TSS. RESULTS: We randomised 149 patients and analysed 74 in each arm. According to the design criteria, palliation was equivalent between the two arms. TSS improved in 49 patients (77%) on regimen 1, and in 57 (92%) patients on regimen 2, a difference of 15% (95% confidence interval [CI] 3-28) in the proportion improving between the two regimens. A complete resolution of all symptoms was achieved in three (5%) on regimen 1, and in 14 (23%) patients on regimen 2 (P < 0.001), a difference in the proportion between the two regimens of 21% (95% CI 10-33). A significantly higher proportion of patients experienced palliation and complete resolution of chest pain and dyspnoea with regimen 2. No differences were observed in toxicity. The median survival was 22.7 weeks for regimen 1 and 28.3 weeks for regimen 2 (P = 0.197). CONCLUSIONS: Although this trial met the pre-determined criteria for equivalence between the two palliative regimens, significantly more patients achieved complete resolution of symptoms and palliation of chest pain and dyspnoea with the fractionated regimen.

Aged↗
PubMed2004

CCR5 targeted SIV vaccination strategy preventing or inhibiting SIV infection.

Cell-surface CCR5 is a major coreceptor with CD4 glycoprotein, mediating cellular entry of CCR5 strains of HIV-1 or SIV. We targeted the SIV CCR5 coreceptor in a combined CCR5-SIV antigen immunization strategy. Rhesus macaques were immunized i.m. with the 70 kDa heat shock protein (HSP70) covalently linked to the CCR5 peptides, SIV gpl20 and p27. Intravenous challenge with SIV mac 8980 prevented SIV infection or decreased the viral load with the CCR5-SIV combined vaccine. CC chemokines and antibodies which block and downmodulateCCR5 were induced, as well as immune responses to the subunit SIV antigens. This novel vaccination strategy complements cognate immunity to SIV with innate immunity to the CCR5 coreceptor of SIV.

Amino Acid Sequence↗
PubMed2004

Functional domains of HSP70 stimulate generation of cytokines and chemokines, maturation of dendritic cells and adjuvanticity.

Microbial HSP70 (heat-shock protein 70) consists of three functionally distinct domains: an N-terminal 44 kDa ATPase portion (amino acids 1-358), followed by an 18 kDa peptide-binding domain (amino acids 359-494) and a C-terminal 10 kDa fragment (amino acids 495-609). Immunological functions of these three different domains in stimulating monocytes and dendritic cells have not been fully defined. However, the C-terminal portion (amino acids 359-610) stimulates the production of CC chemokines, IL-12 (interleukin-12), TNFalpha(tumour necrosis factor alpha), NO and maturation of dendritic cells and also functions as an adjuvant in the induction of immune responses. In contrast, the ATPase domain of microbial HSP70 mostly lacks these functions. Since the receptor for HSP70 is CD40, which with its CD40 ligand constitutes a major co-stimulatory pathway in the interaction between antigen-presenting cells and T-cells, HSP70 may function as an alternative ligand to CD40L. HSP70-CD40 interaction has been demonstrated in non-human primates to play a role in HIV infection, in protection against Mycobacterium tuberculosis and in conversion of tolerance to immunity.

Adaptation, Physiological↗
PubMed2004

Optimizing the assessment of quality of life after laryngeal cancer treatment.

Reports of the impact of larynx cancer treatment modality on quality of life are conflicting, in part due to varying study methodology. The aims of this study were to (1) provide preliminary comparisons of quality of life following radiotherapy or combination therapy; (2) evaluate a number of measures of quality of life and thereby (3) inform future prospective studies. Thirty-six laryngeal cancer patients, 24 following radiotherapy, 12 following radiotherapy and laryngectomy completed the Functional Assessment of Cancer Therapy (FACT) - General/Head and Neck subscale; Nottingham Health Profile (NHP); and the Hospital Anxiety and Depression scale (HAD), three to 12 months post-treatment. Results showed trends towards a less good quality of life in the combined therapy group over a wide range of outcomes, significant for the disease specific FACT head and neck subscale, NHP emotion (p = 0.04) and isolation (p = 0.027). To the authors' knowledge, however, this is the first demonstration of greater impact of laryngeal cancer on quality of life in younger subjects, who had lower scores among others on emotional wellbeing (p = 0.015) and anxiety (p = 0.035). Younger patients thus appear more likely to need more intensive support through treatment. Many of the physical and psychosocial domains derived from the three tools used were highly correlated. In other words, given the known high morbidity of the disease and its treatment, the selection of tools for head and neck quality of life assessment may be much less important than their universal application.

Age Factors↗
PubMed2003

Microvascular histopathology in head and neck oncology.

A histological study of both recipient and flap vessels was performed in 30 patients with head and neck cancer, and relevant preoperative risk factors were assessed. A total of 35 free flaps were transferred in 30 patients; 16 patients had preoperative radiotherapy, 13 were smokers, eight had hypertension and six had peripheral vascular disease. No significant venous pathology was found in either the flap or the neck veins. However, over two-thirds of the neck arteries and one-half of the flap arteries were found to have microscopic arterial pathology. The only pre-existing factor significantly influencing vessel pathology was hypertension (P=0.007). All flaps survived, although in two there was some loss of the skin paddle. This study reveals that the majority of patients undergoing microsurgery in the head and neck region have pre-existing arterial damage in both the flap and the recipient arteries, but this does not have a significant effect on the overall patency of the microvascular anastomoses.

Adult↗
PubMed2002

Head and neck oncology: the UK experience. Who is publishing what?

Using the MEDLINE database (OVID), a retrospective review of the UK literature on head and neck oncology was performed for the period 1994-2000, each publication being categorised by department and first author. Tumours almost exclusively managed by general surgeons, cardiothoracic surgeons and neurosurgeons were excluded. In the years 1994 to 2000, there were a total of 120 UK publications, 72% of which came from non-academic NHS units; 23% of the publications were from ENT units, 23% from oral and maxillofacial (OMF) surgery units and 18% from plastic surgery units. The majority of plastic surgery publications described reconstructive techniques, whereas a wider range of topics was observed in the publications by ENT and OMP surgeons. Several irregularities in the MEDLINE database were discovered and are discussed. The findings of this study may be relevant to the future planning of head and neck oncology services.

Bibliometrics↗
PubMed2001

CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines.

The 70 kDa mycobacterial heat shock protein (Mtb HSP70) stimulates mononuclear cells to release CC-chemokines. We now show that this function of Mtb HSP70, but not human HSP70, is dependent on the cell surface expression of CD40. Deletion of the CD40 cytoplasmic tail abolished, and CD40 antibody inhibited, Mtb HSP70 stimulation of CC-chemokine release. Mtb HSP70 stimulated THP1, KG1 cells, and monocyte-derived dendritic cells to produce RANTES. Specific binding of CD40-transfected HEK 293 cells to Mtb HSP70 was demonstrated by surface plasmon resonance. Coimmunoprecipitation of Mtb HSP70 with CD40 indicates a physical association between these molecules. The results suggest that CD40 is critical in microbial HSP70 binding and stimulation of RANTES production.

Bacterial Proteins↗
PubMed2001

Adenoid cystic carcinoma of the head and neck.

Adenoid cystic carcinoma (ACC) is a rare malignant tumour believed to arise from the epithelial cells of mucous-secreting glands. It is a slow-growing but aggressive tumour with a propensity for perineural invasion. A 10 year review of 45 patients (19 males and 26 females with a median age of 56 years) treated for ACC at a single institution between 1989 and 1999 was performed to analyse factors involved in treatment failure, local control, treatment-related morbidity and mortality. The data collected were treated for survival curves according to the Kaplan-Meier method and the log-rank test was used to assess the statistical significance of the various groups. The overall survivals at 3 years and 5 years were 71% and 65%, respectively, while the disease-free survivals at 3 years and 5 years were 73% and 63% respectively. Out of the 45 patients, only six had local recurrences, yielding an 87% locoregional freedom from relapse; 16 patients (35.6%) developed distant metastases, with the lung (8/16) being the commonest site. Patients treated for tumours of the nose and paranasal sinuses experienced more morbidity than those with tumours at other sites. Positive margins, perineural invasion and solid histology of ACC were associated with increased morbidity and treatment failure. Patients treated with combined therapy did better than those who underwent a single treatment modality.

Adolescent↗
PubMed2000

Cutaneous metastasis to the head and neck from colonic carcinoma.

A case of metastatic facial skin involvement from colonic carcinoma is reported where, despite radiotherapy given preoperatively, the tumour continued to grow. The patient remained disease free for 8 months after excision and reconstruction, but died of pulmonary metastases.

Adenocarcinoma↗
PubMed2000

Head and neck skin involvement by non-cutaneous head and neck cancers: free flap reconstruction.

INTRODUCTION: Patients with skin involvement from head and neck cancer have a poor prognosis, with a median survival time of 2 months. METHOD AND RESULTS: During a 9 year period, 31 patients with skin involvement above the clavicle by non-cutaneous malignant tumours of the head and neck were treated. In 19 males and 12 females with a mean age of 62 years, the parotid gland (32%) and the oral cavity (29%) were the commonest sites of primary disease and 77% of the cases were squamous cell carcinomas. Twenty-six had recurrent disease, 20 had received previous radiotherapy and all underwent surgical resection with free flap reconstruction, the commonest being the radial forearm (78%). Complete histological clearance was achieved in 53% of the cases, and adjuvant post-operative irradiation was given to 60%. With this form of management, palliation was extended to a mean survival of 23 months. Six patients are currently alive and disease free at a mean follow up of 4.5 years. CONCLUSIONS: Patients with head and neck skin involvement by non-cutaneous head and neck malignancies have a very poor prognosis, but surgical resection combined with free microvascular flap reconstruction and planned post-operative radiotherapy, can offer good long-term palliation.

Adult↗
PubMed2000

Anti-adhesive strategies in the prevention of infectious disease at mucosal surfaces.

Binding of microbial cell surface adhesins to host receptor molecules is a critical early step in microbial infection and pathogenesis. Anti-adhesive strategies aimed at blocking this interaction offer an attractive means of preventing infection at an early stage. The strategy should reduce the likelihood of resistant strains of microorganisms emerging, since those that do not bind will not be subjected to sustained selective pressure, as may occur with antibiotic therapy. Three classes of adhesion-blocking agent have been investigated, namely anti-adhesin antibodies, adhesin analogues and receptor analogues. The effectiveness of a number of these adhesion-blocking compounds has been demonstrated in human and animal models of infection. Direct application to the tooth surface of anti-adhesin monoclonal antibody, or a synthetic peptide adhesion epitope, prevented infection with the oral pathogen, Streptococcus mutans in humans. Intranasal administration of a soluble receptor analogue significantly reduced virus production and symptoms following experimental infection with rhinovirus. Similarly, all three types of anti-adhesion agent protected against a variety of infections at other mucosal surfaces in animal models. A common finding from these studies is the long duration of protection, which cannot be due to persistence of the anti-adhesion agent, but may be the result of competitive exclusion by members of the normal flora at specific mucosal surfaces. Development of these novel antimicrobial agents is particularly timely in view of the increasing concern over the spread of antibiotic resistance.

Adhesins, Bacterial↗
PubMed1999

Induction of inhibitory antibodies to the CCR5 chemokine receptor and their complementary role in preventing SIV infection in macaques.

The seven-transmembrane G-protein-linked CCR5 molecule functions as a major coreceptor for HIV or simian immunodeficiency virus (SIV) infection. Antibodies to CCR5 were studied in rhesus macaques immunized with SIV grown in human CD4(+) T cells. These macaques were completely protected against i.v. challenge with live SIV. Sera from the protected macaques showed significantly greater inhibition of SIV replication (p < 0.001) and macrophage inflammatory protein-1beta-generated CCR5-dependent chemotaxis (p < 0.01) than sera from unprotected macaques, in the absence of significant neutralizing antibodies to SIV. These two functional assays demonstrate serum antibodies to the CCR5 receptors which were specifically inhibited by CCR5-transfected HEK-293 cells. We postulate that anti-CCR5 antibodies may be complementary to beta-chemokines in blocking CCR5 coreceptors to HIV or SIV binding and fusion of CD4(+) cells.

Animals↗
PubMed1999

A synthetic peptide adhesion epitope as a novel antimicrobial agent.

The earliest step in microbial infection is adherence by specific microbial adhesins to the mucosa of the oro-intestinal, nasorespiratory, or genitourinary tract. We inhibited binding of a cell surface adhesin of Streptococcus mutans to salivary receptors in vitro, as measured by surface plasmon resonance, using a synthetic peptide (p1025) corresponding to residues 1025-1044 of the adhesin. Two residues within p1025 that contribute to binding (Q1025, E1037) were identified by site-directed mutagenesis. In an in vivo human streptococcal adhesion model, direct application of p1025 to the teeth prevented recolonization of S. mutans but not Actinomyces, as compared with a control peptide or saline. This novel antimicrobial strategy, applying competitive peptide inhibitors of adhesion, may be used against other microorganisms in which adhesins mediate colonization of mucosal surfaces.

Actinomyces↗
PubMed1999

Malignant transformation of oral lichen planus.

AIMS: To investigate the malignant potential of oral lichen planus (OLP), a common mucocutaneous disease of unknown aetiology. The malignant potential of OLP is still controversial, with studies reporting malignant transformation rates of between 0 and 5.6%. We also aimed to identify factors that might be associated with malignant transformation. METHODS: We retrospectively reviewed the records of 832 patients with histologically confirmed OLP treated at the Dental Hospital, Newcastle upon Tyne during the period 1983-1996. RESULTS: Of these 832 patients, a total of seven (0.8%) developed intra-oral squamous cell carcinoma (SCC), including three cases of carcinoma in situ. It was noted that OLP patients with SCC are more likely to be women, relatively young and have a low tobacco and alcohol intake. However, they had a good long-term prognosis. CONCLUSIONS: We conclude that the risk of malignant transformation in OLP is real but not high. Clinicians should have a higher index of suspicion of the possibility of malignancy developing in OLP, because such patients are different from typical patients who develop oral malignancy. Follow-up for at least 6 years is recommended.

Adult↗
PubMed1998

Generation of CD8 suppressor factor and beta chemokines, induced by xenogeneic immunization, in the prevention of simian immunodeficiency virus infection in macaques.

Previous xenogeneic immunization experiments in rhesus macaques with simian immunodeficiency virus (SIV) grown in human CD4(+) T cells consistently elicited protection from challenge with live SIV. However, the mechanism of protection has not been established. We present evidence that xenogeneic immunization induced significant CD8 suppressor factor, RANTES (regulated upon activation, normal T cell expressed and secreted), macrophage inflammatory protein (MIP) 1alpha, and MIP-1beta (P < 0.001 - P < 0.02). The concentrations of these increased significantly in protected as compared with infected macaques (P < 0.001). Xenogeneic stimulation in vitro also up-regulated CD8 suppressor factors (SF; P < 0.001) and the beta chemokines which were neutralized by antibodies to the 3 beta chemokines. Recombinant human RANTES, MIP-1alpha and MIP-1beta which bind to simian CCR5, suppressed SIV replication in a dose-dependent manner, with RANTES being more effective than the other two chemokines. The results suggest that immunization with SIV grown in human CD4(+) T cells induces CD8-suppressor factor, RANTES, MIP-1alpha and MIP-1beta which may block CCR5 receptors and prevent the virus from binding and fusion to CD4(+) cells.

Animals↗
PubMed1998

Malignant tumours of the submandibular salivary gland: a 15-year review.

Malignant tumours of the submandibular salivary gland are rare, difficult to distinguish clinically from benign disease and often only diagnosed after initial excision of the enlarged gland. In this study of 70 patients (46 male, 24 female) with a mean age of 64 years (range 17-94), and an average duration of symptoms of 3 months, a painless submandibular swelling was the most common presentation. Of the 69 primary tumours, the most frequent histological types were adenoid cystic carcinomas (26 patients, 37%) and carcinoma ex-PSA (18 patients, 26%). One tumour was metastatic in origin, arising from a parotid primary. A total of 65 patients were treated by primary excision of the gland while five patients who presented with advanced disease were treated by radiotherapy alone. Adjuvant postoperative radiotherapy was utilised in 53 (75%) of patients. After a mean follow-up of 5 years, 32 (46%) of patients are still alive. Metastatic disease accounted for 21 deaths (30%). The clinical stage at presentation was the most significant factor predicting survival.

Adolescent↗