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N Maitland

Publications and source records attributed to N Maitland.

At least 19 recordsLinked to original sources
PubMed2006

Use of the PSA enhancer core element to modulate the expression of prostate- and non-prostate-specific basal promoters in a lentiviral vector context.

Composite promoters combining the prostate-specific antigen (PSA) enhancer core element with promoter elements derived from gene coding for human prostate-specific transglutaminase gene, prostate-specific membrane antigen gene, prostate-specific antigen, rat probasin or phosphoglycerate kinase were characterized for their ability to specifically express the enhanced green fluorescent protein (EGFP) gene in prostate versus non-prostate cancer cell lines when transferred with a human immunodeficiency virus-1-based lentiviral vector. By themselves minimal proximal promoter elements were found to inefficiently promote relevant tissue-specific expression; in all the vectors tested, addition of the PSA enhancer core element markedly improved EGFP expression in LnCaP, a cancer prostate cell line used as a model for prostate cancer. The composite promoter was inactive in HuH7, a hepatocarcinoma cell line used as a model of neighboring non-prostate cancer cells. Among the promoters tested, the combination of the PSA enhancer and the rat probasin promoter showed both high specificity and a strong EGFP expression. Neither a high viral input nor the presence of the cPPT/CTS sequence affected composite promoter behavior. Our data suggest that composite prostate-specific promoters constructed by combining key elements from various promoters can improve and/or confer tissue specific expression in a lentiviral vector context.

Cell Line, Tumor↗
PubMed2006

Gene therapy for prostate cancer: current strategies and new cell-based approaches.

Prostate cancer is the most commonly diagnosed cancer in adult males in the Western world. It accounts for one in ten cancer cases and is the second leading cause of cancer death in men, after lung cancer. A number of curative treatments are available for patients with localized prostate cancer such as radical prostatectomy, radiotherapy, or brachytherapy. However, a proportion of these men will develop progressive disease, and some will present de novo with advanced and metastatic prostate cancer, which is amenable to palliation only with androgen-withdrawal therapy. Most of these patients will eventually develop hormone refractory disease which is incurable, and for whom gene therapy, if feasible may develop as an alternative treatment option. In this review we discuss the gene therapy vectors and strategies that are currently in use, new cell-based approaches, discuss their advantages and disadvantages, and review the potential or proven pre-clinical and clinical efficacy in prostate cancer models/patients.

Adult↗
PubMed2003

Expression of a model gene in prostate cancer cells lentivirally transduced in vitro and in vivo.

In a preclinical model for prostate cancer gene therapy, we have tested lentiviral vectors as a practical possibility for the transfer and long-term expression of the EGFP gene both in vitro and in vivo. The human prostate cancer cell lines DU145 and PC3 were transduced using experimental conditions which permitted analysis of the expression from a single proviral vector per cell. The transduced cells stably expressed the EGFP transgene for 4 months. After injection of the transduced cell populations into Nod-SCID mice a decrease in EGFP was only observed in a minority of cases, while the majority of tumors maintained transgene expression at in vitro levels. In vivo injection of viral vector preparations directly into pre-established subcutaneous or orthotopic tumor masses, obtained by implantation of untransduced PC3 and DU145 cells led to a high transduction efficiency. While the efficiency of direct intratumoral transduction was proportional to the dose of virus injected, the results indicated some technical limitations inherent in these approaches to prostate cancer gene therapy.

Animals↗
PubMed2002

Macrophages in gene therapy: cellular delivery vehicles and in vivo targets.

The appearance and activation of macrophages are thought to be rapid events in the development of many pathological lesions, including malignant tumors, atherosclerotic plaques, and arthritic joints. This has prompted recent attempts to use macrophages as novel cellular vehicles for gene therapy, in which macrophages are genetically modified ex vivo and then reintroduced into the body with the hope that a proportion will then home to the diseased site. Here, we critically review the efficacy of various gene transfer methods (viral, bacterial, protozoan, and various chemical and physical methods) in transfecting macrophages in vitro, and the results obtained when transfected macrophages are used as gene delivery vehicles. Finally, we discuss the use of various viral and nonviral methods to transfer genes to macrophages in vivo. As will be seen, definitive evidence for the use of macrophages as gene transfer vehicles has yet to be provided and awaits detailed trafficking studies in vivo. Moreover, although methods for transfecting macrophages have improved considerably in efficiency in recent years, targeting of gene transfer specifically to macrophages in vivo remains a problem. However, possible solutions to this include placing transgenes under the control of macrophage-specific promoters to limit expression to macrophages or stably transfecting CD34(+) precursors of monocytes/macrophages and then differentiating these cells into monocytes/macrophages ex vivo. The latter approach could conceivably lead to the bone marrow precursor cells of patients with inherited genetic disorders being permanently fortified or even replaced with genetically modified cells.

Adenoviridae↗
PubMed1998

Metastasis-associated Mts1 (S100A4) protein modulates protein kinase C phosphorylation of the heavy chain of nonmuscle myosin.

Mts1 protein (S100A4 according to a new classification) has been implicated in the formation of the metastatic phenotype via regulation of cell motility and invasiveness. Previously we have demonstrated that Mts1 protein interacted with the heavy chain of nonmuscle myosin in a calcium-dependent manner. To elucidate the role of the Mts1-myosin interaction, we mapped the Mts1-binding region on the myosin heavy chain molecule. We prepared proteolytically digested platelet myosin and a series of overlapped myosin heavy chain protein fragments and used them in a blot overlay with Mts1 protein. Here we report that the Mts1-binding site is located within a 29-amino acid region, at the C-terminal end of the myosin heavy chain (between 1909-1937 amino acids). Two-dimensional phosphopeptide analysis showed that Mts1 protein inhibits protein kinase C phosphorylation of the platelet myosin heavy chain at Ser-1917. We hypothesize that Mts1 protein regulates cytoskeletal dynamics of the metastatic cells through modulation of the myosin phosphorylation by protein kinase C in calcium-dependent fashion.

Binding Sites↗
PubMed1998

Detection of Epstein-Barr virus in oral scrapes in HIV infection, in hairy leukoplakia, and in healthy non-HIV-infected people.

Epstein Barr virus (EBV) has been implicated in the pathogenesis of oral hairy leukoplakia (OHL). EBV is normally detected by lesional biopsy. The objectives of this study were to examine oral scrapes containing squamous epithelial cells (squames) from HIV-infected people with and without clinical lesions of OHL, and from healthy non-HIV-infected controls, for EBV-DNA by the polymerase chain reaction (PCR). EBV-DNA was detected in 65% of HIV-infected people and 20% of healthy HIV-negative controls but in HIV-infected individuals it was found as frequently in those without OHL as in those with. Moreover, EBV-DNA was not detected in all HIV-infected individuals, nor in all OHL. The results suggest that the presence or absence of detectable EBV-DNA in oral scrapes, though a guide, cannot be regarded as absolutely reliable in the diagnosis or exclusion of OHL.

Adult↗
PubMed1996

Development and preliminary evaluation of VISLAN, a surgical planning and guidance system using intra-operative video imaging.

VISLAN is an integrated neurosurgical planning and guidance system. New segmentation and rendering techniques have been incorporated. A stereo video system is used intra-operatively and fulfils four roles. First, the video display is overlaid with graphical outlines showing the position of the planned craniotomy or the target (enhanced reality displays). Second, a skin surface patch is reconstructed from the stereo video images using patterned light (mean errors of surface point location are < 0.15 mm). Third, a freely mobile, hand-held localizer is tracked in real time (position errors are < 0.5 mm and with improved calibration < 0.2 mm), with its position superimposed on the pre-operative patient representation to assist surgical guidance. Fourth, markers fixed to the skull bone next to the cranial opening are used to detect intra-operative movement and to update registration. Initial results from phantom experiments show an overall system accuracy of better than 0.9 mm for intra-operative localization of features defined in pre-operative images. The prototype system has been tested during six neurosurgical operations with very good results.

Astrocytoma↗
PubMed1996

Craniotomy guidance using a stereo-video-based tracking system.

In open intracranial neurosurgery, it is desirable to minimize exposure and to approach the target in the most accurate way possible. The VISLAN system described here employs a completely passive hand-held locator which is tracked by a video system and does not require a mechanical linkage nor cables. The system also tracks easily recognizable, constant, anatomical landmarks of the patient. By this means the initial registration of pre-operative imaging and the detection of, and correction for, patient movement can be accomplished. High-resolution MRI segmented interactively is used to define external surface and brain anatomy. Thus, a pre-operative patient representation (POPR) is planned. During the surgical procedure the patient's head is illuminated by structured light and stereo-video pictures obtained from two television cameras mounted above the head. The system is calibrated and registered with the POPR using a chamfered matching algorithm. The locator is also tracked in space by the video system, and its tip position shown in relation to the POPR on the video monitor.

Craniotomy↗
PubMed1995

Demonstration of smoking-related DNA damage in cervical epithelium and correlation with human papillomavirus type 16, using exfoliated cervical cells.

Smoking is a known aetiological risk factor for cervical cancer. Smoking-related DNA damage (DNA adducts), in cervical epithelial cells, has recently been demonstrated to suggest a causal role in the development of cervical cancer. Human papillomavirus 16 (HPV 16) is a known oncogenic virus and is also implicated as a cause of cervical cancer. It has been suggested that both smoking and HPV may act synergistically in the development of cervical cancer. We have investigated the cervical DNA adduct level and the prevalence of HPV 16 (using polymerase chain reaction) in women who had normal cervical cytology. Both the DNA adduct assay and the HPV assay were carried out on exfoliated cervical cells recovered from cervical scrapes. In 87% of the cases there was enough DNA from the exfoliative cervical cells to analyse for DNA adducts. Smokers had higher DNA adduct levels than non-smokers (P = 0.002), confirming the previous data from cervical biopsy samples. Forty-two per cent of the specimens were found to be HPV 16 positive. There was no significant difference in smoking-related DNA damage (DNA adduct levels) between HPV-positive and HPV-negative smokers. This suggests that smoking DNA damage does not augment HPV infectivity. These results do not, therefore, support the molecular synergism theory.

Adolescent↗
PubMed1995

Detection of cytomegalovirus and Epstein-Barr virus in labial salivary glands in Sjogren's syndrome and non-specific sialadenitis.

To investigate the role of herpes viruses in Sjogren's syndrome, minor (labial) salivary gland tissues from Sjogren's syndrome and from non-specific sialadenitis were examined for Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) DNA by the polymerase chain reaction. Almost half of all salivary glands studied contained EBV and/or HCMV. There was, however, no significant difference between the detection of EBV or HCMV in salivary glands from patients with Sjogren's syndrome or non-specific sialadenitis. The findings are consistent with the persistence of EBV and HCMV in minor salivary glands following primary infection, but do not indicate a direct role for either virus in the aetiology of Sjogren's syndrome, and do not exclude reactivation of the viruses in this disease.

Base Sequence↗
PubMed1993

Human herpes simplex-1 and papillomavirus type 16 homologous DNA sequences in normal, potentially malignant and malignant oral mucosa.

We have tested a range of normal, potentially malignant and malignant oral mucosal biopsies tissues by Southern blot hybridisation analysis for the simultaneous presence of HSV-1 and HPV type 16 DNA sequences, both of which have been implicated as risk factors in oral carcinogenesis. The results show that: (1) 2/4 patients with lichen planus, 2/4 patients with non-specific keratosis, 1/8 patients with oral carcinoma and 3/5 biopsy specimens of normal oral mucosa contained DNA sequences homologous to the HSV-1, Bam HI-G fragment. (2) HPV-16 homologous DNA sequences were detected in 3/4 patients with lichen planus, 4/4 non-specific keratosis, 4/8 oral carcinomas and in 3/5 biopsy specimens of normal oral mucosa. (3) Overall, only 5 patient biopsy specimens were positive for both HSV-1 and HPV-16 homologous DNA sequences; 2 lichen planus, 2 non-specific keratosis and 1 normal. The data cannot exclude a "hit and run" oncogenic mechanism for HSV but suggest that if HSV-1 and HPV-16 play a synergistic role in the development of oral cancer this may be an early event. Indeed, the data suggest HSV might be more frequently found in potentially malignant lesions than in carcinoma.

Adolescent↗
PubMed1992

Human papillomavirus type 16 DNA in oral white sponge nevus.

White sponge nevus (WSN) is a benign hereditary lesion of the mucous membranes. DNA extracted from a biopsy specimen of oral WSN was assayed for the presence of DNA sequences homologous to human papillomavirus (HPV) types 1, 2, 4, 6, 11, 13, 16, and 18 by Southern blot hybridization. Only HPV-16 homologous DNA sequences were detected at a copy number of approximately 200 to 250 genome copies per diploid cell. The viral DNA sequences did not appear to be integrated into the host cell chromosome. The finding of HPV-16 in an inherited lesion such as WSN indicates that caution must be exercised in ascribing a causal association in relation to the demonstration of HPV in other mucosal disorders.

DNA, Viral↗
PubMed1991

Viruses in the aetiology of oral carcinoma? Examination of the evidence.

This paper examines the evidence for an aetiological role for viruses in the development of oral carcinoma. Several viruses have been sought in oral cancer and evidence found for some, particularly herpes simplex and human papillomavirus. However, the evidence also suggests that these viruses are ubiquitous agents and a number of criteria must be met before these potentially oncogenic agents can reliably be implicated in human carcinogenesis. In contrast, there is no evidence that viruses such as adenovirus, Epstein-Barr virus, and retroviruses play any role in oral carcinogenesis.

Humans↗
PubMed1985

Papillomaviruses: their possible role in oral disease.

Papillomaviruses are ubiquitous DNA viruses that are epitheliotropic and produce a range of epithelial neoplasms, both benign and malignant, in animals and man. Human papillomaviruses are associated with a variety of rare and uncommon oral lesions, and there has been increasing suspicion that they may be implicated also in some premalignant and malignant oral lesions.

Animals↗
PubMed1982

Adenovirus-related RNA sequences in human neurogenic tumours.

Thirty two human tumours, mainly neurogenic, have been investigated for the presence of adenovirus-related RNA sequences. 3H-labelled tumour virus DNA probes derived from human adenoviruses types 2 and 12, bovine adenovirus type 3, and avian adenovirus CELO were hybridized in-situ on tumour kryostat sections under conditions that detect complementary RNA. Tumour virus-related RNA was detected in 62% of all tumours tested, but was not detectable in normal human brain tissues. Expression of tumour virus-related RNA was found in 2/4 astrocytomas, 2/4 metastatic brain carcinomas, 2/2 glioblastomas, 1/1 melanoma, 5/7 meningiomas, 4/4 neurinomas, 1/2 oligodendrogliomas, and 1/1 rhabdomyosarcoma. The presence of adenovirus-related RNA in the majority of human neurogenic tumours may reflect a viral involvement in the pathogenesis of these tumours.

Adenoviridae↗