Epidermal growth factor receptor mutations and treatment of non-small-cell lung cancer

Petletno preživetje bolnikov s pljučnim rakom je slabo, samo 12-odstotno, in se v zadnjih 15 letih ni bistveno izboljšalo. Standardno zdravljenje razsejanega nedrobnoceličnega raka pljuč (NDRP), ki je danes najpogostejši tip raka pljuč, je kemoterapija na osnovi citostatika cisplatina. S tem je citostatsko zdravljenje razsejanega NDRP najbrž doseglo največ, kar je lahko. V zadnjih letih pa smo tudi pri zdravljenju NDRP priča razmahu tarčnega zdravljenja. Kot učinkovita so se izkazala tarčna zdravila, ki delujejo na receptor za epidermalni rastni dejavnik (EGFR), in to predvsem mali molekuli, zaviralca tirozinske kinaze (TKI) erlotinib in gefitinib. EGFR je transmembranski glikoprotein, ki se nahaja tako na površini zdravih kot tudi tumorskih celic različnih rakov. Pripada družini proteinov ErbB, ki vključuje 4 receptorje. Od vseh določanj izraženosti EGFR se je določitev aktivirajočih mutacij gena za EGFR v primarnem tumorju izkazala za najboljši pozitivni napovedni dejavnik odgovora na zdravljenje s proti EGFR usmerjenimi TKI. Čeprav je bila povezava med mutacijami gena za EGFR ter nekaterimi kliničnimi in patološkimi značilnostmi NDRP dokazana, pa na podlagi kliničnih in patoloških značilnosti bolnikov ne moremo zanesljivo prepoznati tistih, ki bodo imeli največjo korist od zdravljenja s TKI. Samo z določitvijo aktivirajočih mutacij gena za EGFR je mogoče prepoznati bolnike, ki bodo značilno bolje odgovorili na zdravljenje s TKI kot na kemoterapijo in pri katerih je ob zdravljenju s proti EGFR usmerjenimi TKI utemeljeno pričakovati razmeroma dolgo preživetje in dobro kakovost življenja. Zato je danes pri vseh bolnikih s pljučnim adenokarcinomom pred uvedbo prvega sistemskega zdravljenja napredovale bolezni priporočeno določanje mutacij gena za EGFR v primarnem tumorju. Na podlagi tega podatka je namreč mogoča ustreznejša izbira prvega in tudi poznejših redov sistemskega zdravljenja pri vsakem bolniku.The 5-year relative survival rates of patients with lung cancer are approximately 12%, and have increased only by 2.2% during the last 15 years. Third generation chemotherapy based on platinum derivates is currently a standard treatment for the advanced non-small-cell lung cancer (NSCLC) but has probably reached a plateau. With the advent of targeted therapy it has been introduced into the clinical management of advanced NSCLC as well. Epidermal growth factor (EGFR) is a transmembrane glycoprotein which is expressed on the cell surface of a tumor as well as on normal cells. It belongs to the ErbB receptor family, which includes four types of receptors. In the article only EGFR (HER1/ErbB1) will be considered. Treatment with two small molecules, tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR), namely gefintib and erlotinib, already proved to be an effective treatment strategy in patients with advanced NSCLC. Among different methods used for EGFR status determination, only identification of activating mutations in the EGFR gene domain proved to be a very reliable and significant predictor for the response to EGFRdirected TKIs therapy in NSCLC. Even though the activating EGFR mutations were found to be more frequent in patients with particular clinico-pathological characteristics, such as females, non-smokers, those with adenocarcinoma histology, a selection of patients based on these characteristics does not allow for a proper selection of patients for EGFR-directed TKI therapy. Only by determining the activating EGFR mutations in the primary tumor can the identification of NSCLC patients with expected high response rates to EGFR-directed TKI therapy leading to long survival and a good quality of life be achieved. Personalized medicine for NSCLC patients is now reality, and EGFR mutation status should be determined in the primary tumor of all patients prior to any systemic therapy for advanced disease, thus allowing us a tailored first-line and subsequent lines of systemic therapy in each individual patient

Toward a Systemic Understanding of Listeria monocytogenes Metabolism during Infection

Listeria monocytogenes is a foodborne human pathogen that can cause invasive infection in susceptible animals and humans. For proliferation within hosts, this facultative intracellular pathogen uses a reservoir of specific metabolic pathways, transporter, and enzymatic functions whose expression requires the coordinated activity of a complex regulatory network. The highly adapted metabolism of L. monocytogenes strongly depends on the nutrient composition of various milieus encountered during infection. Transcriptomic and proteomic studies revealed the spatial–temporal dynamic of gene expression of this pathogen during replication within cultured cells or in vivo. Metabolic clues are the utilization of unusual C2- and C3-bodies, the metabolism of pyruvate, thiamine availability, the uptake of peptides, the acquisition or biosynthesis of certain amino acids, and the degradation of glucose-phosphate via the pentose phosphate pathway. These examples illustrate the interference of in vivo conditions with energy, carbon, and nitrogen metabolism, thus affecting listerial growth. The exploitation, analysis, and modeling of the available data sets served as a first attempt to a systemic understanding of listerial metabolism during infection. L. monocytogenes might serve as a model organism for systems biology of a Gram-positive, facultative intracellular bacterium

Exploring Causal Relationships Among Emotional and Topical Trajectories in Political Text Data

We explore relationships between dynamics of emotion (arousal and valence) and topical stability in political discourse in two diachronic corpora of Austrian German. In doing so, we assess interactions among emotional and topical dynamics related to political parties as well as interactions between two different domains of discourse: debates in the parliament and journalistic media. Methodologically, we employ unsupervised techniques, time-series clustering and Granger-causal modeling to detect potential interactions. We find that emotional and topical dynamics in the media are only rarely a reflex of dynamics in parliamentary discourse

Izbrisani slovarski sestavki iz druge, dopolnjene in deloma prenovljene izdaje Slovarja slovenskega knjižnega jezika

Iz druge, dopolnjene in deloma prenovljene izdaje Slovarja slovenskega knjižnega jezika smo morali zaradi zahteve imetnikov blagovnih znamk Cockta, Superga, Teflon in Tetra Pak po drugačni slovarski obravnavi umakniti slovarske sestavke, ki prikazujejo iz navedenih blagovnih znamk izpeljane občnoimenske besede

Single and multiple dose pharmacokinetics of maritime pine bark extract (Pycnogenol) after oral administration to healthy volunteers

BACKGROUND: Since plant extracts are increasingly used as phytotherapeutics or dietary supplements information on bioavailability, bioefficacy and safety are warranted. We elucidated the plasma kinetics of genuine extract components and metabolites after single and multiple ingestion of the standardized maritime pine bark extract Pycnogenol (USP quality) by human volunteers. METHODS: Eleven volunteers received a single dose of 300 mg pine bark extract, five volunteers ingested 200 mg daily for five days to reach steady state concentrations. Plasma samples were obtained before and at defined time points after intake of the extract. Samples were analyzed by HPLC with ion-pair reagents and simultaneous UV and electrochemical detection. RESULTS: We quantified total plasma concentrations of catechin, caffeic acid, ferulic acid, taxifolin and the metabolite M1 (δ-(3,4-dihydroxy-phenyl)-γ-valerolactone). Additionally, we describe plasma time courses and steady state appearance of ten so far unknown compounds, U1 to U10. After single ingestion, compounds derived from the extract were rapidly absorbed and the majority of them were detectable over whole experimental period of 14 h. The analysis of steady state plasma samples revealed significant phase II metabolism. CONCLUSION: We present the first systematic pharmacokinetic analysis of compounds derived from maritime pine bark extract. Beyond the known constituents and metabolites we uncovered the plasma time courses of ten unknown compounds. In concert with our previous detection of anti-inflammatory bioefficacy of these plasma samples ex vivo we suggest that constituents and metabolites of Pycnogenol bear potential for disclosure of novel active principles

Reduced Efficacy of Natural Selection on Codon Usage Bias in Selfing Arabidopsis and Capsella Species

Population genetic theory predicts that the efficacy of natural selection in a self-fertilizing species should be lower than its outcrossing relatives because of the reduction in the effective population size (Ne) in the former brought about by inbreeding. However, previous analyses comparing Arabidopsis thaliana (selfer) with A. lyrata (outcrosser) have not found conclusive support for this prediction. In this study, we addressed this issue by examining silent site polymorphisms (synonymous and intronic), which are expected to be informative about changes in Ne. Two comparisons were made: A. thaliana versus A. lyrata and Capsella rubella (selfer) versus C. grandiflora (outcrosser). Extensive polymorphism data sets were obtained by compiling published data from the literature and by sequencing 354 exon loci in C. rubella and 89 additional loci in C. grandiflora. To extract information from the data effectively for studying these questions, we extended two recently developed models in order to investigate detailed selective differences between synonymous codons, mutational biases, and biased gene conversion (BGC), taking into account the effects of recent changes in population size. We found evidence that selection on synonymous codons is significantly weaker in the selfers compared with the outcrossers and that this difference cannot be fully accounted for by mutational biases or BGC

An arrhythmogenic metabolite in atrial fibrillation

Abstract Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF

Ethical issues in autologous stem cell transplantation (ASCT) in advanced breast cancer: A systematic literature review

BACKGROUND: An effectiveness assessment on ASCT in locally advanced and metastatic breast cancer identified serious ethical issues associated with this intervention. Our objective was to systematically review these aspects by means of a literature analysis. METHODS: We chose the reflexive Socratic approach as the review method using Hofmann's question list, conducted a comprehensive literature search in biomedical, psychological and ethics bibliographic databases and screened the resulting hits in a 2-step selection process. Relevant arguments were assembled from the included articles, and were assessed and assigned to the question list. Hofmann's questions were addressed by synthesizing these arguments. RESULTS: Of the identified 879 documents 102 included arguments related to one or more questions from Hofmann's question list. The most important ethical issues were the implementation of ASCT in clinical practice on the basis of phase-II trials in the 1990s and the publication of falsified data in the first randomized controlled trials (Bezwoda fraud), which caused significant negative effects on recruiting patients for further clinical trials and the doctor-patient relationship. Recent meta-analyses report a marginal effect in prolonging disease-free survival, accompanied by severe harms, including death. ASCT in breast cancer remains a stigmatized technology. Reported health-related-quality-of-life data are often at high risk of bias in favor of the survivors. Furthermore little attention has been paid to those patients who were dying. CONCLUSIONS: The questions were addressed in different degrees of completeness. All arguments were assignable to the questions. The central ethical dimensions of ASCT could be discussed by reviewing the published literature