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Biomedical subjects

Michael R Johnston

Publications and source records attributed to Michael R Johnston.

14 recordsLinked to original sources
PubMed2006

Targeting colloidal particulates to thoracic lymph nodes.

BACKGROUND: Thoracic lymphatics and lymph nodes can be affected by cancer and other diseases. Micro- or nanoparticulates are used as carriers for therapeutic agents. We investigated the lymphatic distribution after intrapleural administration of three different particulates. METHODS: Various micro- and nanoparticles of charcoal, polystyrene and poly(lactide-co-glycolide) were administered into the pleural space of rats to study the lymphatic distribution of particles from the pleural cavity to the thoracic lymph nodes. Experimental animal models included healthy rats, rats following pneumonectomy and rats bearing orthotopic lung cancer to mimic relevant clinical scenarios and pathophysiology. Macroscopic examination, light microscopy, fluorescence microscopy complemented by transmission electron microscopy analysis of the lymphatic tissue allowed precise mapping and detection of the particulates in the thoracic lymphatic system. RESULTS: We found that (1) the particles studied are cleared by the regional thoracic lymphatic system when placed in the pleural space; (2) the lymphatic uptake occurred as early as 3h after injection and is primarily through the parietal pleura; (3) the transport of particles to regional lymph nodes was consistently found in all three animal models; (4) particles of 0.7-2 microm in size give the best lymphatic distribution. CONCLUSIONS: Regional thoracic lymphatics and lymph nodes can be accessed by colloidal particles injected into the pleural space.

Animals↗
PubMed2005

Preoperative assessment: an anesthesiologist's perspective.

Advances in anesthesia and surgery have made it so that almost any patient with a resectable lung malignancy is now an operative candidate given a full understanding of the risks and after appropriate investigation. This situation necessitates a change in the paradigm that anesthesiologists use for preoperative assessment. Understanding and stratifying the perioperative risks allows the anesthesiologist to develop a systematic focused approach to these patients at the time of the initial contact and immediately before induction, which can be used to guide anesthetic management.

Anesthesia↗
PubMed2004

Modeling of lung cancer by an orthotopically growing H460SM variant cell line reveals novel candidate genes for systemic metastasis.

Endobronchial implantation of NCI-H460 cells into the nude rat generates a primary lung tumor with mediastinal lymph node spread, but rarely systemic metastases. We isolated tumor cells from mediastinal nodes, orthotopically reimplanted the cells into nude rats and repeated this four times to derive a cell line, designated H460SM, that spontaneously metastasizes to bone, kidney, brain, soft tissue and contralateral lung. H460SM cells demonstrated higher invasive activity in vitro than parental NCI-H460 cells. Spectral karyotyping revealed a new inversion within 17q and loss of an extra normal copy of chromosome 14 present in parental NCI-H460 cells. Expression profiling of orthotopic primary tumors revealed differential expression of 360 genes. Of these, 173 were represented in the probe set of a 19.2K OCI cDNA microarray previously used to profile the gene expression of surgically resected lung cancer specimens. We have computationally validated clinical importance of these genes by using in silico analysis of 18 cases of pulmonary adenocarcinoma, which were split into two patient groups with markedly different clinical outcome. The model identifies additional novel candidate genes for the progression of lung cancer to systemic metastases and poor prognosis.

Animals↗
PubMed2004

Expression of chicken ovalbumin upstream promoter-transcription factor II enhances invasiveness of human lung carcinoma cells.

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) plays an essential role in angiogenesis and development. It is differentially expressed in tumor cell lines, but its role in carcinogenesis is largely unknown. We demonstrate here that noninvasive human lung cancer cells become invasive when COUP-TFII was expressed. The expression of extracellular matrix degrading proteinases, such as matrix metalloproteinase 2 and urokinase-type plasminogen activator, was up-regulated in these cells. This finding was confirmed by transduction of different human lung cancer cell lines with COUP-TFII protein and also by using antisense expression. We observed disorganization of actin filaments and focal adhesion kinase phosphorylation in COUP-TFII-transfected human lung cancer cells in addition to the increase in extracellular metalloproteinase activity. These results suggest that COUP-TFII may be considered as a new target for anticancer therapies.

Actins↗
PubMed2004

Validating the prognostic value of marker genes derived from a non-small cell lung cancer microarray study.

We previously reported that our cDNA microarray analysis of primary non-small cell lung carcinoma (NSCLC) could predict for patients at increased risk of cancer recurrence. From the result of this analysis, we selected 11 genes that were considered candidate prognostic marker genes and used the realtime reverse transcription polymerase chain reaction (RT-PCR) to investigate their expression in the same set of NSCLC cases used in the microarray study. Cluster analysis of the realtime RT-PCR data separated these patients into two groups with significantly different disease-free survivals (log-rank test, P < 0.017). In contrast, cluster analysis failed to confirm the prognostic significance of the realtime RT-PCR results for these 11 genes in a validation series of 92 NSCLC cases. In univariate analysis, hypoxia inducible factor 1alpha, Rho-GDP dissociation inhibitor (GDI) alpha (RhoGDI) and Citron/rho-interacting serine-threonine kinase 21 (Citron K21) were significant prognostic factors for disease-free survival in the entire cohort of 130 NSCLC patients, but none were significant in multivariate analysis. The results demonstrate that the prognostic significance of microarray (SAM) results can be partially validated using realtime RT-PCR, but secondary validation using larger and independent series of tumors is necessary to identify true prognostic marker genes.

Carcinoma, Non-Small-Cell Lung↗
PubMed2003

Early combined treatment with carboplatin and the MMP inhibitor, prinomastat, prolongs survival and reduces systemic metastasis in an aggressive orthotopic lung cancer model.

We studied the synthetic matrix metalloproteinase inhibitor (MMPI) prinomastat (AG3340) in a well-established NCI-H460 orthotopic lung cancer model that exhibits highly predictable regional and systemic metastatic patterns. Both primary and metastatic tumors express the matrix metalloproteinases (MMP-2), MT1-MMP (MMP-14) and tissue inhibitor of metalloproteinases (TIMP-2). The anti-tumor activity of prinomastat was investigated both as a single agent and in combination therapy with carboplatin. Treatment with both carboplatin (at two dose levels) and prinomastat commenced when the primary lung cancer was approximately 200-300 mg in size and without gross or microscopic evidence of metastases. As single agents, prinomastat significantly reduced the incidence of kidney metastasis, but had no effect on metastatic frequency to other organs. As single agents neither drug enhanced length of survival over control animals, although microvessel counts in prinomastat-treated tumors were lower than in tumors from control animals (P<0.01). In combination prinomastat and the lower dose of carboplatin significantly enhanced survival over control animals, and over animals treated with carboplatin alone (P<0.05). Tolerance to this combination was assessed with body weight and serum biochemistries. At the higher carboplatin dose, toxicity became evident both as a single agent and in combination with prinomastat. Our results suggest that the administration of prinomastat in combination with standard cytotoxic chemotherapy during early stages of tumor growth and metastasis may prolong survival in non-small cell lung cancer (NSCLC) patients.

Animals↗
PubMed2003

Predicting length of stay out of hospital following lung resection using preoperative health status measures.

Studies evaluating predictors of operative outcome for lung resection have focused on physiological measures of cardiorespiratory impairment, but these have proved inadequate. This study evaluated the predictive abilities of six preoperative variables: the global quality of life (QL), social function (SF), and emotional function (EF) scales of the European Organization for the Research and Treatment of Cancer's (EORTC) QLQ-C30 questionnaire, 6-min walk distance (6MWD), forced expiratory volume (FEV1), and diffusion capacity (DLCO). Operative outcome was represented by the surrogate measure length of stay, out of hospital within the first 30 days (LOSOH). A single-centre prospective cohort study evaluating 70 subjects was conducted using multiple regression. LOSOH was bimodally distributed, therefore analysis was undertaken for the entire sample and for two separate groups (A and B). Group B (n = 4) experienced severe complications (LOSOH = 0-5 days) and was too small for statistical analysis. Group A (n = 66) suffered fewer and less severe complications (LOSOH = 14-26 days). For the entire sample, age was the sole predictor of LOSOH (R2 = 0.123, p = 0.003). In Group A, the strongest predictors of LOSOH were global QL score and 6MWD (R2 = 0.224, p < 0.001). LOSOH was inversely correlated with complications. While it remains difficult to predict severe complications in this population, within Group A, health status measures demonstrated a limited ability to predict LOSOH.

Aged↗
PubMed2002

Novel candidate tumor marker genes for lung adenocarcinoma.

Using the representational difference analysis (RDA) technique on pooled mRNA of five primary lung adenocarcinomas and their corresponding non-neoplastic lung tissues, we identified six genes that were putatively overexpressed in this type of lung cancer. Five corresponded to previously isolated genes, while one (Lc19) matched with the sequence of an unannotated EST. Real-time RT-PCR analyses of expression levels in a panel of 34 paired primary non-small cell lung cancer (NSCLC) and corresponding grossly normal appearing lung tissues confirmed the common overexpression of these genes in non-small cell lung cancer. Among these genes, overexpression of Lc19, hyaluronan binding protein 2 (HABP2) and crystalline-mu appeared more specific to adenocarcinoma, whereas ceruloplasmin, integrin alpha-11 and collagen type XI alpha 1 were overexpressed at high frequency among both adenocarcinoma and squamous cell carcinoma. These genes represent novel candidate tumor biomarker genes for NSCLC and its histological subtypes.

Adenocarcinoma↗
PubMed2002

Animal models for studying lung cancer and evaluating novel intervention strategies.

The pathogenesis of lung cancer progression, invasion and metastasis remains undefined. Clinically relevant laboratory models of the disease could greatly facilitate its clarification. Model systems of lung cancer that accurately reflect different biologic properties and disease stages are necessary to ensure proper experimental design of studies aimed at increasing our understanding of the disease. Such models are also essential tools to accelerate development of new therapies for lung cancer. In this review we summarize the available lung cancer model systems in use today and define both their utility and limitations.

Animals↗
PubMedDate not supplied

Stability and heterogeneity of expression profiles in lung cancer specimens harvested following surgical resection.

One of the major concerns in microarray profiling studies of clinical samples is the effect of tissue sampling and RNA extraction on data. We analyzed gene expression in lung cancer specimens that were serially harvested from tumor mass and snap-frozen at several intervals up to 120 minutes after surgical resection. Global gene expression was profiled on cDNA microarrays, and selected stress and hypoxia-activated genes were evaluated using real-time reverse transcription polymerase chain reaction (RT-PCR). Remarkably, similar gene expression profiles were obtained for the majority of samples regardless of the time that had elapsed between resection and freezing. Real-time RT-PCR studies showed significant heterogeneity in the expression levels of stress and hypoxia-activated genes in samples obtained from different areas of a tumor specimen at one time point after resection. The variations between multiple samplings were significantly greater than those of elapsed time between sampling/freezing. Overall samples snap-frozen within 30 to 60 minutes of surgical resection are acceptable for gene expression studies, thus making sampling and snap-freezing of tumor samples in a routine surgical pathology laboratory setting feasible. However, sampling and pooling from multiple sites of each tumor may be necessary for expression profiling studies to overcome the molecular heterogeneity present in tumor specimens.

Carcinoma, Non-Small-Cell Lung↗