Correlation of oncoprotein 18/stathmin expression in human breast cancer with established prognostic factors

Oncoprotein 18/stathmin (Op18) is a conserved cytosolic phosphoprotein that regulates microtubule dynamics. The microtubule destabilizing activity is regulated by phosphorylation, mediated by both growth factor stimulated- and cell-cycle regulating kinases. The protein is highly expressed in a variety of human malignancies. In human breast carcinoma, Op18 has previously been shown to be up-regulated in a subset of the tumours, however, no correlation with clinicopathologic characteristics has been reported so far. In the present study we have examined Op18 protein expression by quantitative Western blot analysis in a panel of 151 semi-consecutive breast carcinoma samples. Op18 levels were negatively correlated with oestrogen receptor (OR) expression and positively correlated with a high fraction of aneuploid cells, proliferation measured by proliferating cell nuclear antigen (PCNA) expression, tumour size and histopathologic grade. Taken together, and in contrast to what has been previously reported, the present study shows that high Op18 expression correlates with general predictive factors and is not restricted to a specific sub-group of breast carcinoma. © 2000 Cancer Research Campaig

Benefit:Risk Profile of Budesonide in Obstructive Airways Disease

Airway inflammation is a major contributing factor in both asthma and chronic obstructive pulmonary disease (COPD) and represents an important target for treatment. Inhaled corticosteroids (ICS) as monotherapy or in combination therapy with long-acting β2-agonists or long-acting muscarinic antagonists are used extensively in the treatment of asthma and COPD. The development of ICS for their anti-inflammatory properties progressed through efforts to increase topical potency and minimise systemic potency and through advances in inhaled delivery technology. Budesonide is a potent, non-halogenated ICS that was developed in the early 1970s and is now one of the most widely used lung medicines worldwide. Inhaled budesonide's physiochemical and pharmacokinetic/pharmacodynamic properties allow it to reach a rapid and high airway efficacy due to its more balanced relationship between water solubility and lipophilicity. When absorbed from the airways and lung tissue, its moderate lipophilicity shortens systemic exposure, and its unique property of intracellular esterification acts like a sustained release mechanism within airway tissues, contributing to its airway selectivity and a low risk of adverse events. There is a large volume of clinical evidence supporting the efficacy and safety of budesonide, both alone and in combination with the fast- and long-acting β2-agonist formoterol, as maintenance therapy in patients with asthma and with COPD. The combination of budesonide/formoterol can also be used as an as-needed reliever with anti-inflammatory properties, with or without regular maintenance for asthma, a novel approach that is already approved by some country-specific regulatory authorities and currently recommended in the Global Initiative for Asthma (GINA) guidelines. Budesonide remains one of the most well-established and versatile of the inhaled anti-inflammatory drugs. This narrative review provides a clinical reappraisal of the benefit:risk profile of budesonide in the management of asthma and COPD

Regulation of Op18 during Spindle Assembly in Xenopus Egg Extracts

Oncoprotein 18 (Op18) is a microtubule-destabilizing protein that is negatively regulated by phosphorylation. To evaluate the role of the three Op18 phosphorylation sites in Xenopus (Ser 16, 25, and 39), we added wild-type Op18, a nonphosphorylatable triple Ser to Ala mutant (Op18-AAA), and to mimic phosphorylation, a triple Ser to Glu mutant (Op18-EEE) to egg extracts and monitored spindle assembly. Op18-AAA dramatically decreased microtubule length and density, while Op18-EEE did not significantly affect spindle microtubules. Affinity chromatography with these proteins revealed that the microtubule-destabilizing activity correlated with the ability of Op18 to bind tubulin. Since hyperphosphorylation of Op18 is observed upon addition of mitotic chromatin to extracts, we reasoned that chromatin-associated proteins might play a role in Op18 regulation. We have performed a preliminary characterization of the chromatin proteins recruited to DNA beads, and identified the Xenopus polo-like kinase Plx1 as a chromatin-associated kinase that regulates Op18 phosphorylation. Depletion of Plx1 inhibits chromatin-induced Op18 hyperphosphorylation and spindle assembly in extracts. Therefore, Plx1 may promote microtubule stabilization and spindle assembly by inhibiting Op18

A possible explanation for non-responders, responders and super-responders to biologics in severe asthma

Response to biologic therapies in severe asthma is variable, with patients being either nonresponders, responders or super-responders. There is currently no explanation for this variation in response. If asthma-specific inflammatory pathways are part of a wider network of pathogenic mechanisms (including systemic inflammation), then the state of this wider network could either help or hinder the effect of the biologic. People with severe asthma are often polysymptomatic with a variable frequency of nonrespiratory symptoms. Application of existing network theory would predict that high systemic inflammation, measurable by the frequency of nonrespiratory symptoms, should decrease the effectiveness of biologics, a prediction consistent with the limited existing data. A detailed examination of the relationship between biologic response and the frequency or profile of nonrespiratory symptoms would provide a testable prediction of this hypothesis. The clinical presentation of super-responders is consistent with biologics sometimes having a positive effect on the pathology (level of dysregulation) in a network system. If that were the case, then network theory predicts the possibility of a short-term increase in nonrespiratory symptoms prior to the improvement reported by super-responders. If biologics lead to less network dysregulation in some patients, then this raises the possibility of new applications for this therapy and of an improved response to biologics if lifestyle improvement is started prior to biologic therap

Predictions for the future of kallikrein-related peptidases in molecular diagnostics

Kallikrein-related peptidases (KLKs) form a cancer-related ensemble of serine proteases. This multigene family hosts the most widely used cancer biomarker that is PSA-KLK3, with millions of tests performed annually worldwide. The present report provides an overview of the biomarker potential of the extended KLK family (KLK1-KLK15) in various disease settings and envisages approaches that could lead to additional KLK-driven applications in future molecular diagnostics. Particular focus is given on the inclusion of KLKs into multifaceted cancer biomarker panels that provide enhanced diagnostic, prognostic and/or predictive accuracy in several human malignancies. Such panels have been described so far for prostate, ovarian, lung and colorectal cancers. The role of KLKs as biomarkers in non-malignant disease settings, such as Alzheimer’s disease and multiple sclerosis, is also commented upon. Predictions are given on the challenges and future directions regarding clinically oriented KLK research

Management of Allergic Rhinitis: Focus on Intranasal Agents

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90304/1/j.1875-9114.1989.tb04148.x.pd

Gene Expression Responses Linked to Reproduction Effect Concentrations (EC10,20,50,90) of Dimethoate, Atrazine and Carbendazim, in Enchytraeus albidus

BACKGROUND: Molecular mechanisms of response to pesticides are scarce and information on such responses from soil invertebrates is almost inexistent. Enchytraeus albidus (Oligochaeta) is a standard soil ecotoxicology model species for which effects of many pesticides are known on survival, reproduction and avoidance behaviour. With the recent microarray development additional information can be retrieved on the molecular effects. METHODOLOGY/PRINCIPAL FINDINGS: Experiments were performed to investigate the transcription responses of E. albidus when exposed to three pesticides - dimethoate (insecticide), atrazine (herbicide) and carbendazim (fungicide) - in a range of concentrations that inhibited reproduction by 10%, 20%, 50% and 90% (EC(10), EC(20), EC(50) and EC(90), respectively). The goal of this study was to further identify key biological processes affected by each compound and if dose-related. All three pesticides significantly affected biological processes like translation, regulation of the cell cycle or general response to stress. Intracellular signalling and microtubule-based movement were affected by dimethoate and carbendazim whereas atrazine affected lipid and steroid metabolism (also by dimethoate) or carbohydrate metabolism (also by carbendazim). Response to DNA damage/DNA repair was exclusively affected by carbendazim. CONCLUSIONS: Changes in gene expression were significantly altered after 2 days of exposure in a dose-related manner. The mechanisms of response were comparable with the ones for mammals, suggesting across species conserved modes of action. The present results indicate the potential of using gene expression in risk assessment and the advantage as early markers

Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors

BackgroundBRCA1- and BRCA2-associated tumors appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers. Methodology Breast tumor RNAs from 7 BRCA1 and 6 BRCA2 mutation carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors. Results Genes more highly expressed in BRCA1-associated tumors included stathmin, osteopontin, TGFβ2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. BRCA2-associated cancers were characterized by the higher relative expression of FGF1 and FGFR2. FGFR2 protein was also more highly expressed in BRCA2-associated cancers (P = 0.004). SignificanceBRCA1-associated tumours demonstrated increased expression of component genes of the Notch and TGFβ pathways whereas the higher expression of FGFR2 and FGF1 in BRCA2-associated cancers suggests the existence of an autocrine stimulatory loop