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Biomedical subjects

P Jackson

Publications and source records attributed to P Jackson.

At least 19 recordsLinked to original sources
PubMed2006

Androgen decreases osteoprotegerin expression in prostate cancer cells.

Osteoprotegerin (OPG), a key regulator of bone resorption, is hypothesized to have a role in prostate cancer (CaP) bone metastasis. As advanced CaP is treated by androgen ablation, we examined if androgen modulates OPG expression by CaP cell lines in vitro. Basal levels of secreted OPG protein were significantly greater in androgen-independent PC-3 cells compared with androgen-responsive LNCaP-FGC cells (P<0.001); OPG was not detected in the androgen-responsive CaP cell lines LAPC-4 or DuCaP. Treatment with 5alpha-dihydrotestosterone (5alpha-DHT) significantly decreased OPG protein levels in both PC-3 and LNCaP-FGC, with maximal suppression using 10(-9)-10(-7) M 5alpha-DHT in PC-3 (P<0.01; day 3), and using 10(-10)-10(-9) M 5alpha-DHT in LNCaP-FGC cells (P<0.01; day 6). OPG messenger RNA levels were not significantly altered by this 5alpha-DHT treatment. Co-treatment with 10(-6) M flutamide blocked 5alpha-DHT inhibition of OPG protein expression in LNCaP-FGC cells. These data suggest that androgen may modulate OPG protein levels in CaP cell lines in vitro using a post-transcriptional mechanism.

5-alpha-Dihydroprogesterone↗
PubMed2006

Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo.

This study has investigated the impact of three specific dominant-negative p53 mutants (F134L, M237L, and R273H) on tumorigenesis by LNCaP prostate cancer cells. Mutant p53 proteins were associated with an increased subcutaneous "take rate" in NOD-SCID mice, and increased production of PSA. Tumors expressing F134L and R273H grew slower than controls, and were associated with decreased necrosis and apoptosis, but not hypoxia. Interestingly, hypoxia levels were increased in tumors expressing M237L. There was less proliferation in F134L-bearing tumors compared to control, but this was not statistically significant. Angiogenesis was decreased in tumors expressing F134L and R273H compared with M237L, or controls. Conditioned medium from F134L tumors inhibited growth of normal human umbilical-vein endothelial cells but not telomerase-immortalized bone marrow endothelial cells. F134L tumor supernatants showed lower levels of VEGF and endostatin compared with supernatants from tumors expressing other mutants. Our results support the possibility that decreased angiogenesis might account for reduced growth rate of tumor cells expressing the F134L p53 mutation.

Apoptosis↗
PubMed2004

Efficacy and safety of sequential moxifloxacin for treatment of community-acquired pneumonia associated with atypical pathogens.

In two prospective, randomized studies intravenous (IV)/oral (PO) moxifloxacin (400 mg q.i.d.) was compared to IV/PO antimicrobial comparator agents for the treatment of hospitalized patients with community-acquired pneumonia. Reported here are the pooled data for the sub-population with atypical pathogens. Of 101 intent-to-treat patients with atypical pathogens, a total of 39 moxifloxacin-treated and 47 comparator-treated subjects were microbiologically valid and included in the analysis. Clinical and bacteriological success rates were 95% for the moxifloxacin-treated and 94% for the comparator-treated subjects at the test-of-cure visit. The results indicate IV/PO moxifloxacin (400 mg q.i.d.) is an effective monotherapy for patients with CAP due to atypical pathogens.

Administration, Oral↗
PubMed2004

Retrospective characterization of Newcastle Disease Virus Antrim '73 in relation to other epidemics, past and present.

In November 1973 Newcastle disease suddenly appeared in Northern Ireland, where the viscerotropic disease had not been seen in 3 1/2 years and the two Irelands had been regarded as largely disease free for 30 years. It was successfully controlled with only 36 confirmed affected layer flocks, plus 10 more slaughtered as 'dangerous contacts'. Contemporary investigations failed to reveal the source of the Irish epidemic. Using archival virus samples from most of the affected flocks, RT PCR was conducted with primers selected for all six NDV genes. Phylogenetic analyses of three genes, HN, M and F, confirmed vaccine as the cause of one of the outbreaks. The other six samples were identical and closely related to previous outbreaks in the United States and western Europe initiated by infected imported Latin American parrots. The probable cause of the epidemic followed from the importation from The Netherlands of bulk feed grains contaminated with infected pigeon faeces.

HN Protein↗
PubMed2004

Testing for HER2 in breast cancer.

HER2 is a paradigm of a molecular target whose appropriate assessment is pivotal in the targeting of novel therapies for breast cancer, notably including Herceptin/Trastuzumab. Determining the correct levels requires immunohistochemical and molecular biological skills that are reproducible and measurable, coupled with a knowledge of the appropriate morphological and pathobiological context. Attaining these goals is not easy and laboratories testing for HER2 should maintain a high level of throughput of tests and engage in a recognized external quality assurance scheme. Fluorescence in-situ hybridization testing remains a particular challenge and there is a range of testing strategies. This testing forms the model for the identification of other novel molecular targets. In the future rapid throughput techniques such as real-time quantitative polymerase chain reaction (rqPCR), tissue microarrays or both should bring significant economies of cost and scale.

Breast Neoplasms↗
PubMed2003

Downregulation of KAI1 mRNA in localised prostate cancer and its bony metastases does not correlate with p53 overexpression.

Recent data have proposed that transcription of the KAI1 metastasis suppressor gene is directly mediated by p53 and that loss of KAI1 expression in advanced prostate cancer is simply due to loss of p53 function after mutation. To investigate this possibility, we have examined KAI1 mRNA (by in situ hybridisation) and p53 protein expression (by immunohistochemistry) as an indicator of wildtype or mutant p53, in a series of 77 paraffin-embedded prostate tissue samples, including post-mortem normal prostates (2), benign prostatic hyperplasia (10), localised cancer (grades 4-6, 25; grades 7-9, 21) and prostate-derived bony metastases (19). Overall, we confirmed that expression of KAI1 mRNA decreased from normal tissue, through localised cancer to bony metastases (P=0.055, tending to significance), while levels of p53 staining significantly increased with cancer progression (P=0.046). These were consistent with the possibility that loss of p53 function might be responsible for loss of KAI1 mRNA. However, by close examination of KAI1 and p53 in adjacent tissue sections, we found no correlation between decreased levels of KAI1 mRNA and overexpression of p53 protein (P=0.497). In addition, high levels of KAI1 mRNA could be identified in samples irrespective of p53 staining. Our data suggest that mutation of p53 is independent of the loss of KAI1 mRNA, and do not support a role for p53 in regulating the expression of KAI1.

Adult↗
PubMed2003

Acute effects of winter air pollution on respiratory function in schoolchildren in southern England.

AIM: To investigate the acute health effects of winter outdoor air pollution (nitrogen dioxide (NO(2)), ozone (O(3)), sulphur dioxide (SO(2)), sulphate (SO(4)(2-)),and particles (PM(10))) on schoolchildren in an area of southern England where levels of SO(2) had been reported to be high. METHODS: A total of 179 children, aged 7-13, from three schools (two urban and one rural location), were included. Peak expiratory flow rate (PEFR) and presence or absence of upper respiratory infections were recorded on 63 school days from 1 November 1996 to 14 February 1997. Air pollution and meteorological data were taken from monitors at each school site. The analysis regressed daily PEFR on pollutant level adjusting for confounders and serial correlation and calculated a weighted pooled estimate of effect overall for each pollutant. In addition, large decrements in PEFR were analysed as a binary outcome. Same day, lag 1, lag 2, and a five day average of pollutant levels were used. RESULTS: There were no clear effects of any pollutant on mean PEFR. In addition, we analysed large PEFR decrements (a binary outcome), observing consistent negative associations with NO(2), SO(4)(2-), and PM(10), although few lag/pollutant combinations were significant: odds ratios (95% CI) for five day average effect: NO(2) 24 h average 1.043 (1.000 to 1.089), SO(4)(2-) 1.090 (0.898 to 1.322), PM(10) 1.037 (0.992 to 1.084). The observed effects of PM(10) (only) were stronger in wheezy children (1.114 (1.057 to 1.174)). There were no consistent negative associations between large decrements and ozone or SO(2). CONCLUSIONS: There is no strong evidence for acute effects of winter outdoor air pollution on mean PEFR overall in this area, but there is evidence for negative effects on large PEFR decrements.

Adolescent↗
PubMed2001

Selection criteria among gastroenterologists and surgeons for laparoscopic antireflux surgery.

BACKGROUND: Symptomatic gastroesophageal reflux disease (GERD) affects a substantial proportion of the American population. The diagnosis and treatment of GERD has advanced tremendously over the past 30 years. However, there remains a lack of understanding about the differences and advantages that laparoscopic antireflux surgery offers and a lack of agreement on the ideal surgical candidate. The purpose of this study was to determine whether a significant difference exists in the practice habits and selection criteria for surgery between gastroenterologists and laparoscopic surgeons. METHODS: Surveys were sent to 1,000 randomly selected members of the American Gastroenterological Association (AGA) and to 1,000 randomly selected members of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES). As a result, 20% of the AGA surveys and 33% of the SAGES surveys were completed and returned. RESULTS: The AGA group considered patients whose symptoms are not well controlled, those who have complications of disease, and those who require significant lifestyle changes to control their symptoms as the best candidates for surgical evaluation. As a group, gastroenterologists remain somewhat hesitant to refer patients for laparoscopic antireflux surgery. Surgeons considered patients whose symptoms have been well controlled with medical therapy, those who have complications of disease, and those who require significant lifestyle changes to control their symptoms as ideal candidates for fundoplication. CONCLUSION: A consensus should be reached between surgeons and gastroenterologists in establishing criteria for surgical intervention to manage GERD.

Gastroenterology↗
PubMed2001

Lipid activation of CTP: phosphocholine cytidylyltransferase alpha: characterization and identification of a second activation domain.

The CTP:phosphocholine cytidylyltransferase (CCT) governs the rate of phosphatidylcholine (PtdCho) biosynthesis, and its activity is governed by interaction with membrane lipids. The carboxy-terminus was dissected to delineate the minimum sequences required for lipid responsiveness. The helical domain is recognized as a site of lipid interaction, and all three tandem alpha-helical repeats from residues 257 through 290 were found to be required for regulation of enzymatic activity by this domain. Truncation of the carboxy-terminus to remove one or more of the alpha-helical repeats yielded catalytically compromised proteins that were not responsive to lipids but retained sufficient activity to accelerate PtdCho biosynthesis when overexpressed in vivo. The role of the helical region in lipid-activation was tested further by excising residues 257 through 309 to yield a protein that retained a 57-residue carboxy terminal domain fused to the catalytic core. This construct tested the hypothesis that the helical region inhibits activity in the absence of lipid rather than activates the enzyme in the presence of lipid. This hypothesis predicts constitutive activity for CCTalpha[Delta257-309]; however, this protein was tightly regulated by lipid with activities comparable to the full-length CCTalpha, in both the absence and presence of lipid. Activation of CCTalpha[Delta257-309] was dependent exclusively on anionic lipids, whereas full-length CCTalpha responded to either anionic or neutral lipids. Phosphatidic acid delivered in Triton X-100 micelles was the preferred activator of the second lipid-activation domain. These data demonstrate that CCTalpha can be regulated by lipids by two independent domains: (i) the three amphipathic alpha-helical repeats that interact with both neutral and anionic lipid mixtures and (ii) the last 57 residues that interact with anionic lipids. The results show that both domains are inhibitory in the absence of lipid and activating in the presence of lipid. Removal of both domains results in a nonresponsive, dysregulated enzyme with reduced activity. The data also demonstrate for the first time that the 57-residue carboxy-terminal domain in CCTalpha participates in lipid-mediated regulation and is sufficient for maximum activation of enzyme activity.

Amino Acid Sequence↗
PubMed2001

The importance of dihydrogen complexes HnGe(H2)+ (n=0,1) to the chemistry of cationic germanium hydrides: advanced theoretical and mass spectrometric analysis.

Investigations of [Ge,Hn]-/0/- (n = 2,3) have been performed using a four-sector mass spectrometer. The results reveal that the complexes HnGe(H2)+ (n = 0,1) play an important role in the unimolecular dissociation of the metastable cations. Theoretical calculations support the experimental observations in most instances, and the established view that the global minimum of [Ge,H2]+ is an inserted structure may need reexamination; CCSD(T,full)/cc-pVTZ//CCSD(T)/6-311 ++ G(d,p) and B3LYP/cc-pVTZ studies of three low-lying cation states (2A1 HGeH+, 2B2 Ge(H2)+ and 2B1 Ge(H2)+) indicate a very small energy difference (ca. 4 kcal mol(-1)) between 2A1 HGeH+ and 2B2 Ge(H2)+; B3LYP favours the ion-molecule complex, whereas coupled-cluster calculations favour the inserted structure for the global minimum. Single-point multireference (MR) averaged coupled-pair functional and MR-configuration interaction calculations give conflicting results regarding the global minimum. We also present theoretical evidence indicating that the orbital-crossing point implicated in the spin-allowed metastable dissociation HGeH+* --> Ge(H2)+* --> Ge+ + H2 lies above the H-loss asymptote. Thus, a quantum-mechanical tunneling mechanism is invoked to explain the preponderance of the H2-loss signal for the metastable ion.

Journal Article↗
PubMed2001

A unique charge-coupled device/xenon arc lamp based imaging system for the accurate detection and quantitation of multicolour fluorescence.

In recent years the use of fluorescent dyes in biological applications has dramatically increased. The continual improvement in the capabilities of these fluorescent dyes demands increasingly sensitive detection systems that provide accurate quantitation over a wide linear dynamic range. In the field of proteomics, the detection, quantitation and identification of very low abundance proteins are of extreme importance in understanding cellular processes. Therefore, the instrumentation used to acquire an image of such samples, for spot picking and identification by mass spectrometry, must be sensitive enough to be able, not only, to maximise the sensitivity and dynamic range of the staining dyes but, as importantly, adapt to the ever changing portfolio of fluorescent dyes as they become available. Just as the available fluorescent probes are improving and evolving so are the users application requirements. Therefore, the instrumentation chosen must be flexible to address and adapt to those changing needs. As a result, a highly competitive market for the supply and production of such dyes and the instrumentation for their detection and quantitation have emerged. The instrumentation currently available is based on either laser/photomultiplier tube (PMT) scanning or lamp/charge-coupled device (CCD) based mechanisms. This review briefly discusses the advantages and disadvantages of both System types for fluorescence imaging, gives a technical overview of CCD technology and describes in detail a unique xenon/are lamp CCD based instrument, from PerkinElmer Life Sciences. The Wallac-1442 ARTHUR is unique in its ability to scan both large areas at high resolution and give accurate selectable excitation over the whole of the UV/visible range. It operates by filtering both the excitation and emission wavelengths, providing optimal and accurate measurement and quantitation of virtually any available dye and allows excellent spectral resolution between different fluorophores. This flexibility and excitation accuracy is key to multicolour applications and future adaptation of the instrument to address the application requirements and newly emerging dyes.

Computers↗
PubMed2001

Mutations within the tumour suppressor gene p53 are not confined to a late event in prostate cancer progression. a review of the evidence.

Mutations in the p53 tumour suppressor gene are generally believed to be a late event in the progression of prostate cancer, and are associated with androgen independence, metastasis, and a worse prognosis. In this review, we examine the current literature available on p53 mutations and focus on stages A (T1) and B (T2) of prostate cancer. We report here that p53 mutations can be found in approximately one third of prostate cancers that are clinically localized to the prostate. In addition, high levels of p53 mutation are found in normal prostate tissue of prostate cancer patients, prostatic intraepithelial neoplasia, and benign prostatic hyperplasia. The limitations of techniques used to determine p53 mutations are discussed, as well as other modes of p53 loss in early stage prostate cancer.

Journal Article↗
PubMed2001

SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity.

Hepatocellular carcinoma (HCC) is a major cause of cancer death, but the molecular mechanism for its development beyond its initiation has not been well characterized. Suppressor of cytokine signaling (SOCS-1; also known as JAB and SSI-1) switches cytokine signaling 'off' by means of its direct interaction with Janus kinase (JAK). We identified aberrant methylation in the CpG island of SOCS-1 that correlated with its transcription silencing in HCC cell lines. The incidence of aberrant methylation was 65% in the 26 human primary HCC tumor samples analyzed. Moreover, the restoration of SOCS-1 suppressed both growth rate and anchorage-independent growth of cells in which SOCS-1 was methylation-silenced and JAK2 was constitutively activated. This growth suppression was caused by apoptosis and was reproduced by AG490, a specific, chemical JAK2 inhibitor that reversed constitutive phosphorylation of STAT3 in SOCS-1 inactivated cells. The high prevalence of the aberrant SOCS-1 methylation and its growth suppression activity demonstrated the importance of the constitutive activation of the JAK/STAT pathway in the development of HCC. Our results also indicate therapeutic strategies for the treatment of HCC including use of SOCS-1 in gene therapy and inhibition of JAK2 by small molecules, such as AG490.

Antineoplastic Agents↗