The primary somatosensory cortex largely contributes to the early part of the cortical response elicited by nociceptive stimuli.

Research on the cortical sources of nociceptive laser-evoked brain potentials (LEPs) began almost two decades ago (Tarkka and Treede, 1993). Whereas there is a large consensus on the sources of the late part of the LEP waveform (N2 and P2 waves), the relative contribution of the primary somatosensory cortex (S1) to the early part of the LEP waveform (N1 wave) is still debated. To address this issue we recorded LEPs elicited by the stimulation of four limbs in a large population (n=35). Early LEP generators were estimated both at single-subject and group level, using three different approaches: distributed source analysis, dipolar source modeling, and probabilistic independent component analysis (ICA). We show that the scalp distribution of the earliest LEP response to hand stimulation was maximal over the central-parietal electrodes contralateral to the stimulated side, while that of the earliest LEP response to foot stimulation was maximal over the central-parietal midline electrodes. Crucially, all three approaches indicated hand and foot S1 areas as generators of the earliest LEP response. Altogether, these findings indicate that the earliest part of the scalp response elicited by a selective nociceptive stimulus is largely explained by activity in the contralateral S1, with negligible contribution from the secondary somatosensory cortex (S2).

Interacting controls on innate sources of CO2 efflux from a calcareous arid zone soil under experimental acidification and wetting

More than half of global soil carbon is stored as carbonates, primarily in arid and semi-arid zones. Climate change models predict more frequent and severe rainfall events in some parts of the globe, many of which are dominated by calcareous soils. Such events trigger substantial increases in soil CO2 efflux. We hypothesised that the primary source of CO2 emissions from calcareous, arid zone soil during a single wetting event is abiotic and that soil acidification and wetting have a positive, potentially interacting, effect. We manipulated soil pH, soil moisture, and controlled soil respiration by gamma irradiating half of an 11 day incubation experiment. All manipulated experimental treatments had a rapid and enormous effect on CO2 emission. Respiration contributed ca. 5% of total CO2 efflux; the major source (carbonate buffering) varied depending on the extent of acidification and wetting. Maximum CO2 efflux occurred when pH was lowest and at intermediate matric potential. CO2 efflux was lowest at native pH when soil was air dry. Our data suggest that there may be an underestimate of soil-atmosphere carbon fluxes in arid ecosystems with calcareous soils. There is also a clear potential that these soils may become net carbon sources depending on changes in rainfall patterns, rainfall acidity, and future land management. Our findings have major implications for carbon cycling in arid zone soil and further study of carbon dynamics in these terrestrial systems at a landscape level will be required if we are to improve global climate and carbon cycling models.

The influence of macroeconomic factors on primary issues in the Brazilian market

This research analyses the influence of the macroeconomic factors on the primary issue of stocks and debentures in the Brazilian market. Previous studies have agreed on the importance of aspects of the economic situation on a company’s capital structure, but have not established a relationship between the macroeconomic variables and the level of aggregate debt; we can mention Procianoy and Caselani (1997) and Terra (2003) as examples of this. According to Leal (2000), the limitations of the Brazilian capital market suggest that management takes advantage of moments of euphoria in the market - whether caused by a reduction in the rate of interest or by the return being offered by the equity market - to raise funds at rates that are more advantageous to the company. This characterizes the first evidence we have of opportunistic behavior influencing a company’s financing decisions. Eid Jr. (1996) provides us with the first evidence of this opportunistic behavior in his research in which 47% of those interviewed said that they chose fund sources that are economically more advantageous.

Carbon sources and trophic position of the main species of fishes of Baía River, Paraná River floodplain, Brazil

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Sources of atmospheric acidity in an agricultural-industrial region of São Paulo State, Brazil

[1] Surface-based measurements of atmospheric formic acid (HCOOH), acetic acid (CH3COOH), sulfur dioxide (SO2), hydrogen chloride (HCl), and nitric acid (HNO3) were made in central São Paulo State, Brazil, between April 1999 and March 2000. Mean concentrations were 9.0 ppb (HCOOH), 1.3 ppb (CH3COOH), 4.9 ppb (SO2), 0.3 ppb (HCl), and 0.5 ppb (HNO3). Concentrations in sugar cane burning plumes were 1160-4230 ppb (HCOOH), 360-1750 ppb (CH3COOH), 10-630 ppb (SO2), 4-210 ppb (HCl), and 14-90 ppb (HNO3). Higher ambient concentrations of SO2, HCl and HNO3 were measured during the burning season (May-November). Concentrations of SO2 and HCl increased during the evening, and of HCOOH and CH3COOH were lowest in the morning, with peak levels in the afternoon. Ratios obtained between different species showed either nighttime maxima (SO2/HCOOH, SO2/CH3COOH, SO2/HNO3, CH3COOH/HNO3, SO2/HCl and HCOOH/HNO3), daytime maxima (HCOOH/HCl, CH3COOH/HCl and HNO3/HCl), or no clear trends (HCOOH/CH3COOH). Correlation analysis showed that SO2 and HCl were primary emissions from biomass burning and road transport; HCOOH, HNO3 and CH3COOH were products of photochemistry; HCOOH and CH3COOH were emitted directly during combustion as well as from biogenic sources. Biomass burning affected atmospheric acidity on a regional scale, while vehicular emissions had greater impact in urban and adjacent areas. Atmospheric ammonia levels were insufficient to neutralize atmospheric acidity, which was mainly removed by deposition to the surface.

Economic growth in Latin America: the role of investment and other growth sources

Includes bibliography

Effect of Nd:YAG laser combined with fluoride on the prevention of primary tooth enamel demineralization

Most studies dealing with the caries preventive action of Nd:YAG laser have been done in permanent teeth and studies on primary teeth are still lacking. The aim of this study was to evaluate in vitro the effect of Nd:YAG laser combined or not with fluoride sources on the acid resistance of primary tooth enamel after artificial caries induction by assessing longitudinal microhardness and demineralization depth. Sixty enamel blocks obtained from the buccal/lingual surface of exfoliated human primary molars were coated with nail polish/wax, leaving only a 9 mm² area exposed on the outer enamel surface, and randomly assigned to 6 groups (n=10) according to the type of treatment: C-control (no treatment); APF: 1.23% acidulated phosphate fluoride gel; FV: 5% fluoride varnish; L: Nd:YAG laser 0.5 W/10 Hz in contact mode; APFL: fluoride gel + laser; FVL: fluoride varnish + laser. After treatment, the specimens were subjected to a des-remineralization cycle for induction of artificial caries lesions. Longitudinal microhardness data (%LMC) were analyzed by the Kruskal-Wallis test and demineralization depth data were analyzed by oneway ANOVA and Fisher’s LSD test (á=0.05). APFL and APF groups presented the lowest percentage of microhardness change (p<0.05). Demineralization depth was smaller in all treated groups compared with the untreated control. In conclusion, Nd:YAG laser combined or not with fluoride gel/varnish was not more effective than fluoride alone to prevent enamel demineralization within the experimental period.

Semantic integration of gene expression analysis tools and data sources using software connectors

Abstract Background The study and analysis of gene expression measurements is the primary focus of functional genomics. Once expression data is available, biologists are faced with the task of extracting (new) knowledge associated to the underlying biological phenomenon. Most often, in order to perform this task, biologists execute a number of analysis activities on the available gene expression dataset rather than a single analysis activity. The integration of heteregeneous tools and data sources to create an integrated analysis environment represents a challenging and error-prone task. Semantic integration enables the assignment of unambiguous meanings to data shared among different applications in an integrated environment, allowing the exchange of data in a semantically consistent and meaningful way. This work aims at developing an ontology-based methodology for the semantic integration of gene expression analysis tools and data sources. The proposed methodology relies on software connectors to support not only the access to heterogeneous data sources but also the definition of transformation rules on exchanged data. Results We have studied the different challenges involved in the integration of computer systems and the role software connectors play in this task. We have also studied a number of gene expression technologies, analysis tools and related ontologies in order to devise basic integration scenarios and propose a reference ontology for the gene expression domain. Then, we have defined a number of activities and associated guidelines to prescribe how the development of connectors should be carried out. Finally, we have applied the proposed methodology in the construction of three different integration scenarios involving the use of different tools for the analysis of different types of gene expression data. Conclusions The proposed methodology facilitates the development of connectors capable of semantically integrating different gene expression analysis tools and data sources. The methodology can be used in the development of connectors supporting both simple and nontrivial processing requirements, thus assuring accurate data exchange and information interpretation from exchanged data.

Characterization of primary biogenic aerosol particles by DNA analysis: Diversity of airborne Ascomycota and Basidiomycota

Primary biogenic aerosol (PBA) particles account for large proportions of air particulate matter, and they can influence the hydrological cycle and climate as nuclei for water droplets and ice crystals in clouds, fog, and precipitation. Moreover, they can cause or enhance human, animal, and plant diseases. The actual abundance and properties of PBA particles and components in the atmosphere are, however, still poorly understood and quantified. rnIn this study, the identity, diversity, and frequency of occurrence of PBA particles were investigated by DNA analysis. Methods for the extraction, amplification, and analysis of DNA from aerosol filter samples were developed and optimized for different types of organisms, including fungi, bacteria, and plants. The investigations were focused on fungal DNA, and over 2500 sequences were obtained from air samples collected at different locations and climatic zones around the world (tropical, mid-latitude, sub-polar; continental, marine). rnNearly all fungal DNA sequences could be attributed to the phyla of Ascomycota and Basidiomycota. With regard to species richness, the ratio of Basidiomycota to Ascomycota was much higher in continental air samples (~60:40) than in marine air samples (~30:70). Pronounced differences in the relative abundance and seasonal cycles of various groups of fungi were detected in coarse and fine particulate matter from continental air, with more plant pathogens in the coarse and more human pathogens and allergens in the respirable fine particle fraction (<3 µm). The results of this study provide new information and insights into the sources of PBA particles and the interactions of the biosphere with the atmosphere, climate, and public health. rn

Water-soluble organic compounds in air particulate matter analyzed by HPLC-DAD-MS and HPLC-MS/MS: abundance, sources and transformation of carboxylic acids, nitrophenols and nitrated proteins

Wasserlösliche organische Verbindungen (WSOCs) sind Hauptbestandteile atmosphärischer Aerosole, die bis zu ~ 50% und mehr der organischen Aerosolfraktion ausmachen. Sie können die optischen Eigenschaften sowie die Hygroskopizität von Aerosolpartikeln und damit deren Auswirkungen auf das Klima beeinflussen. Darüber hinaus können sie zur Toxizität und Allergenität atmosphärischer Aerosole beitragen.In dieser Studie wurde Hochleistungsflüssigchromatographie gekoppelt mit optischen Diodenarraydetektion und Massenspektrometrie (HPLC-DAD-MS und HPLC-MS/MS) angewandt, um WSOCs zu analysieren, die für verschiedene Aerosolquellen und -prozesse charakteristisch sind. Niedermolekulare Carbonsäuren und Nitrophenole wurden als Indikatoren für die Verbrennung fossiler Brennstoffe und die Entstehung sowie Alterung sekundärer organischer Aerosole (SOA) aus biogenen Vorläufern untersucht. Protein-Makromoleküle wurden mit Blick auf den Einfluss von Luftverschmutzung und Nitrierungsreaktionen auf die Allergenität primärer biologischer Aerosolpartikel – wie Pollen und Pilzsporen – untersucht.rnFilterproben von Grob- und Feinstaubwurden über ein Jahr hinweg gesammelt und auf folgende WSOCs untersucht: die Pinen-Oxidationsprodukte Pinsäure, Pinonsäure und 3-Methyl-1,2,3-Butantricarbonsäure (3-MBTCA) sowie eine Vielzahl anderer Dicarbonsäuren und Nitrophenole. Saisonale Schwankungen und andere charakteristische Merkmale werden mit Blick auf Aerosolquellen und -senken im Vergleich zu Daten anderen Studien und Regionen diskutiert. Die Verhätlnisse von Adipinsäure und Phthalsäure zu Azelainsäure deuten darauf hin, dass die untersuchten Aerosolproben hauptsächlich durch biogene Quellen beeinflusst werden. Eine ausgeprägte Arrhenius-artige Korrelation wurde zwischen der 3-MBTCA-¬Konzentration und der inversen Temperatur beobachtet (R2 = 0.79, Ea = 126±10 kJ mol-1, Temperaturbereich 275–300 K). Modellrechnungen zeigen, dass die Temperaturabhängigkeit auf eine Steigerung der photochemischen Produktionsraten von 3-MBTCA durch erhöhte OH-Radikal-Konzentrationen bei erhöhten Temperaturen zurückgeführt werden kann. Im Vergleich zur chemischen Reaktionskinetik scheint der Einfluss von Gas-Partikel-Partitionierungseffekten nur eine untergeordnete Rolle zu spielen. Die Ergebnisse zeigen, dass die OH-initiierte Oxidation von Pinosäure der geschwindigkeitsbestimmende Schritt der Bildung von 3-MBTCA ist. 3-MBTCA erscheint somit als Indikator für die chemische Alterung von biogener sekundärer organischer Aerosole (SOA) durch OH-Radikale geeignet. Eine Arrhenius-artige Temperaturabhängigkeit wurde auch für Pinäure beobachtet und kann durch die Temperaturabhängigkeit der biogenen Pinen-Emissionen als geschwindigkeitsbestimmender Schritt der Pinsäure-Bildung erklärt werden (R2 = 0.60, Ea = 84±9 kJ mol-1).rn rnFür die Untersuchung von Proteinnitrierungreaktionen wurde nitrierte Protein¬standards durch Flüssigphasenreaktion von Rinderserumalbumin (BSA) und Ovalbumin (OVA) mit Tetranitromethan (TNM) synthetisiert.Proteinnitrierung erfolgt vorrangig an den Resten der aromatischen Aminosäure Tyrosin auf, und mittels UV-Vis-Photometrie wurde der Proteinnnitrierungsgrad (ND) bestimmt. Dieser ist definiert als Verhältnis der mittleren Anzahl von Nitrotyrosinresten zur Tyrosinrest-Gesamtzahl in den Proteinmolekülen. BSA und OVA zeigten verschiedene Relationen zwischen ND und TNM/Tyrosin-Verhältnis im Reaktionsgemisch, was vermutlich auf Unterschiede in den Löslichkeiten und den molekularen Strukturen der beiden Proteine zurück zu führen ist.rnDie Nitrierung von BSA und OVA durch Exposition mit einem Gasgemisch aus Stickstoffdioxid (NO2) und Ozon (O3) wurde mit einer neu entwickelten HPLC-DAD-¬Analysemethode untersucht. Diese einfache und robuste Methode erlaubt die Bestimmung des ND ohne Hydrolyse oder Verdau der untersuchten Proteine und ernöglicht somit eine effiziente Untersuchung der Kinetik von Protein¬nitrierungs-Reaktionen. Für eine detaillierte Produktstudien wurden die nitrierten Proteine enzymatisch verdaut, und die erhaltenen Oligopeptide wurden mittels HPLC-MS/MS und Datenbankabgleich mit hoher Sequenzübereinstimmung analysiert. Die Nitrierungsgrade individueller Nitrotyrosin-Reste (NDY) korrelierten gut mit dem Gesamt-Proteinnitrierungsgrad (ND), und unterschiedliche Verhältnisse von NDY zu ND geben Aufschluss über die Regioselektivität der Reaktion. Die Nitrierungmuster von BSA und OVA nach Beahndlung mit TNM deuten darauf hin, dass die Nachbarschaft eines negativ geladenen Aminosäurerestes die Tyrosinnitrierung fördert. Die Behandlung von BSA durch NO2 und O3 führte zu anderend Nitrierungemustern als die Behandlung mit TNM, was darauf hindeutet, dass die Regioselektivität der Nitrierung vom Nitrierungsmittel abhängt. Es zeigt sich jedoch, dass Tyrosinreste in Loop-Strukturen bevorzugt und unabhängig vom Reagens nitriert werden.Die Methoden und Ergebnisse dieser Studie bilden eine Grundlage für weitere, detaillierte Untersuchungen der Reaktionskinetik sowie der Produkte und Mechanismen von Proteinnitrierungreaktionen. Sie sollen helfen, die Zusammenhänge zwischen verkehrsbedingten Luftschadstoffen wie Stickoxiden und Ozon und der Allergenität von Luftstaub aufzuklären.rn

Fossil versus contemporary sources of fine elemental and organic carbonaceous particulate matter during the DAURE campaign in Northeast Spain

We present results from the international field campaign DAURE (Detn. of the sources of atm. Aerosols in Urban and Rural Environments in the Western Mediterranean), with the objective of apportioning the sources of fine carbonaceous aerosols. Submicron fine particulate matter (PM1) samples were collected during Feb.-March 2009 and July 2009 at an urban background site in Barcelona (BCN) and at a forested regional background site in Montseny (MSY). We present radiocarbon (14C) anal. for elemental and org. carbon (EC and OC) and source apportionment for these data. We combine the results with those from component anal. of aerosol mass spectrometer (AMS) measurements, and compare to levoglucosan-based ests. of biomass burning OC, source apportionment of filter data with inorg. compn. + EC + OC, submicron bulk potassium (K) concns., and gaseous acetonitrile concns. At BCN, 87 % and 91 % of the EC on av., in winter and summer, resp., had a fossil origin, whereas at MSY these fractions were 66 % and 79 %. The contribution of fossil sources to org. carbon (OC) at BCN was 40 % and 48 %, in winter and summer, resp., and 31 % and 25 % at MSY. The combination of results obtained using the 14C technique, AMS data, and the correlations between fossil OC and fossil EC imply that the fossil OC at Barcelona is ∼47 % primary whereas at MSY the fossil OC is mainly secondary (∼85 %). Day-to-day variation in total carbonaceous aerosol loading and the relative contributions of different sources predominantly depended on the meteorol. transport conditions. The estd. biogenic secondary OC at MSY only increased by ∼40 % compared to the order-of-magnitude increase obsd. for biogenic volatile org. compds. (VOCs) between winter and summer, which highlights the uncertainties in the estn. of that component. Biomass burning contributions estd. using the 14C technique ranged from similar to slightly higher than when estd. using other techniques, and the different estns. were highly or moderately correlated. Differences can be explained by the contribution of secondary org. matter (not included in the primary biomass burning source ests.), and/or by an over-estn. of the biomass burning OC contribution by the 14C technique if the estd. biomass burning EC/OC ratio used for the calcns. is too high for this region. Acetonitrile concns. correlate well with the biomass burning EC detd. by 14C. K is a noisy tracer for biomass burning. [on SciFinder(R)]

Vitellogenin synthesis in primary cultures of fish liver cells as endpoint for in vitro screening of the (anti)estrogenic activity of chemical substances

Concern over possible adverse effects of endocrine-disrupting compounds on fish has caused the development of appropriate testing methods. In vitro screening assays may provide initial information on endocrine activities of a test compound and thereby may direct and optimize subsequent testing. Induction of vitellogenin (VTG) is used as a biomarker of exposure of fish to estrogen-active substances. Since VTG induction can be measured not only in vivo but also in fish hepatocytes in vitro, the use of VTG induction response in isolated fish liver cells has been suggested as in vitro screen for identifying estrogenic-active substances. The main advantages of the hepatocyte VTG assay are considered its ability to detect effects of estrogenic metabolites, since hepatocytes in vitro remain metabolically competent, and its ability to detect both estrogenic and anti-estrogenic effects. In this article, we critically review the current knowledge on the VTG response of cultured fish hepatocytes to (anti)estrogenic substances. In particular, we discuss the sensitivity, specificity, and variability of the VTG hepatocyte assay. In addition, we review the available data on culture factors influencing basal and induced VTG production, the response to natural and synthetic estrogens as well as to xenoestrogens, the detection of indirect estrogens, and the sources of assay variability. The VTG induction in cultured fish hepatocytes is clearly influenced by culture conditions (medium composition, temperature, etc.) and culture system (hepatocyte monolayers, aggregates, liver slices, etc.). The currently available database on estrogen-mediated VTG induction in cultured teleost hepatocytes is too small to support conclusive statements on whether there exist systematic differences of the VTG response between in vitro culture systems, VTG analytical methods or fish species. The VTG hepatocyte assay detects sensitively natural and synthetic estrogens, whereas the response to xenoestrogens appears to be more variable. The detection of weak estrogens can be critical due to the overshadow with cytotoxic concentrations. Moreover, the VTG hepatocyte assay is able to detect antiestrogens as well as indirect estrogens, i.e substances which require metabolic activation to induce an estrogenic response. Nevertheless, more chemicals need to be analysed to corroborate this statement. It will be necessary to establish standardized protocols to minimize assay variability, and to develop a set of pass-fail criteria as well as cut-offs for designating positive and negative responses.

Upper ocean vertical supply: A neglected primary factor controlling the distribution of neodymium concentrations of open ocean surface waters?

Neodymium (Nd) isotopes are an important geochemical tool to trace the present and past water mass mixing as well as continental inputs. The distribution of Nd concentrations in open ocean surface waters (0�100 m) is generally assumed to be controlled by lateral mixing of Nd from coastal surface currents and by removal through reversible particle scavenging. However, using 228Ra activity as an indicator of coastal water mass influence, surface water Nd concentration data available on key oceanic transects as a whole do not support the above scenario. From a global compilation of available data, we find that more stratified regions are generally associated with low surface Nd concentrations. This implies that upper ocean vertical supply may be an as yet neglected primary factor in determining the basin-scale variations of surface water Nd concentrations. Similar to the mechanism of nutrients supply, it is likely that stratification inhibits vertical supply of Nd from the subsurface thermocline waters and thus the magnitude of Nd flux to the surface layer. Consistently, the estimated required input flux of Nd to the surface layer to maintain the observed concentrations could be nearly two orders of magnitudes larger than riverine/dust flux, and also larger than the model-based estimation on shelf-derived coastal flux. In addition, preliminary results from modeling experiments reveal that the input from shallow boundary sources, riverine input, and release from dust are actually not the primary factors controlling Nd concentrations most notably in the Pacific and Southern Ocean surface waters.

Responses of lung cells to realistic exposure of primary and aged carbonaceous aerosols

Diesel exhaust and wood burning are important sources of ambient atmospheric particles due to increasing numbers of diesel cars and the importance of wood as a source of renewable energy. Inhalation is the predominant route of entry and uptake for fine and ultrafine particles into the body. Health effects of atmospheric particles are still not completely understood. There is consistent evidence from epidemiology that particle exposure contributes to respiratory and cardiovascular diseases. This study aimed at examining acute responses of airway epithelial cells and luminal macrophages after exposure to freshly emitted and photochemically aged carbonaceous aerosols under realistic atmospheric conditions. In addition to a bronchial epithelial cell line advanced cell cultures namely fully differentiated respiratory epithelia and primary surface macrophages were used. Our results demonstrate that a single exposure of the cells to realistic particle doses of 0.3–3 ng diesel or 3–9 ng wood aerosol per cm2 cell surface induces small, particle-specific responses. The release of interleukin-6 and -8 was found to be decreased in differentiated airway epithelia but not in the other cell models studied. Aerosol exposure decreased macrophage phagocytic activity by 45–90%. Cell and tissue integrity remained unaffected. Overall, primary and aged particles from the same combustion induced similar responses in the cell models tested, whereby particles from diesel exhaust affected the cells more than those from wood combustion.

Inherited and noninherited sources of variation in metastasis and the growth rate of tumors: Implications for tumor evolution and therapy

I have undertaken measurements of the genetic (or inherited) and nongenetic (or noninherited) components of the variability of metastasis formation and tumor diameter doubling time in more than 100 metastatic lines from each of three murine tumors (sarcoma SANH, sarcoma SA4020, and hepatocarcinoma HCA-I) syngeneic to C3Hf/Kam mice. These lines were isolated twice from lung metastases and analysed immediately thereafter to obtain the variance to spontaneous lung metastasis and tumor diameter doubling time. Additional studies utilized cells obtained from within 4 passages of isolation. Under the assumption that no genetic differences in metastasis formation or diameter doubling time existed among the cells of a given line, the variance within a line would estimate nongenetic variation. The variability derived from differences between lines would represent genetic origin. The estimates of the genetic contribution to the variation of metastasis and tumor diameter doubling time were significantly greater than zero, but only in the metastatic lines of tumor SANH was genetic variation the major source of metastatic variability (contributing 53% of the variability). In the tumor cell lines of SA4020 and HCA-I, however, the contribution of nongenetic factors predominated over genetic factors in the variability of the number of metastasis and tumor diameter doubling time. A number of other parameters examined, such as DNA content, karyotype, and selection and variance analysis with passage in vivo, indicated that genetic differences existed within the cell lines and that these differences were probably created by genetic instability. The mean metastatic propensity of the lines may have increased somewhat during their isolation and isotransplantation, but the variance was only slightly affected, if at all. Analysis of the DNA profiles of the metastatic lines of SA4020 and HCA-I revealed differences between these lines and their primary parent tumors, but not among the SANH lines and their parent tumor. Furthermore, there was a direct correlation between the extent of genetic influence on metastasis formation and the ability of the tumor cells to develop resistance to cisplatinum. Thus although nongenetic factors might predominate in contributing to metastasis formation, it is probably genetic variation and genetic instability that cause the progression of tumor cells to a more metastatic phenotype and leads to the emergence of drug resistance. ^