Non-spectral interferences due to the presence of sulfuric acid in inductively coupled plasma mass spectrometry

Results of a systematic study concerning non-spectral interferences from sulfuric acid containing matrices on a large number of elements in inductively coupled plasma–mass spectrometry (ICP-MS) are presented in this work. The signals obtained with sulfuric acid solutions of different concentrations (up to 5% w w− 1) have been compared with the corresponding signals for a 1% w w− 1− nitric acid solution at different experimental conditions (i.e., sample uptake rates, nebulizer gas flows and r.f. powers). The signals observed for 128Te+, 78Se+ and 75As+ were significantly higher when using sulfuric acid matrices (up to 2.2-fold for 128Te+ and 78Se+ and 1.8-fold for 75As+ in the presence of 5 w w-1 sulfuric acid) for the whole range of experimental conditions tested. This is in agreement with previously reported observations. The signal for 31P+ is also higher (1.1-fold) in the presence of sulfuric acid. The signal enhancements for 128Te+, 78Se+, 75As+ and 31P+ are explained in relation to an increase in the analyte ion population as a result of charge transfer reactions involving S+ species in the plasma. Theoretical data suggest that Os, Sb, Pt, Ir, Zn and Hg could also be involved in sulfur-based charge transfer reactions, but no experimental evidence has been found. The presence of sulfuric acid gives rise to lower ion signals (about 10–20% lower) for the other nuclides tested, thus indicating the negative matrix effect caused by changes in the amount of analyte loading of the plasma. The elemental composition of a certified low-density polyethylene sample (ERM-EC681K) was determined by ICP-MS after two different sample digestion procedures, one of them including sulfuric acid. Element concentrations were in agreement with the certified values, irrespective of the acids used for the digestion. These results demonstrate that the use of matrix-matched standards allows the accurate determination of the tested elements in a sulfuric acid matrix.

Wirkungen monetärer Anreize auf Antworten zur eigenen Delinquenz bei postalischer Befragung

Im vorliegenden Beitrag werden die Ergebnisse einer in dieser Zeitschrift erschienen Studie von Skarbek-Kozietulska, Preisendörfer & Wolter (2012) über die Validität der Antworten straffällig gewordener Befragter aufgegriffen. Die Autoren stellten einen negativen Effekt der Antwortlatenz fest, demzufolge spät Antwortende eher dazu neigen, ihre Straftaten zu leugnen. Die Gründe hierfür vermuten die Autoren in den Eigenheiten der TDM (tailored design method), speziell in wiederholten Nachfassaktionen. Wir untersuchen im Rahmen eines Methodenexperimentes, ob ebenfalls monetäre Anreize als weiterer zentraler Bestandteil der TDM diesen negativen Latenzeffekt für die Antwortbereitschaft verursachen können. Die These, dass der Zusammenhang von Latenz und Validität selbstberichteter Delinquenz über monetäre Anreize moderiert wird, wird dabei empirisch widerlegt.

Overexpressed Ca-v beta 3 inhibits N-type (Ca(v)2.2) calcium channel currents through a hyperpolarizing shift of "ultra-slow" and "closed-state" inactivation

It has been shown that P auxiliary subunits increase current amplitude in voltage-dependent calcium channels. In this study, however, we found a hovel inhibitory effect of beta3 Subunit on macroscopic Ba2+ currents through recombinant N- and R-type calcium channels expressed in Xenopus oocytes. Overexpressed beta3 (12.5 ng/ cell cRNA) significantly suppressed N- and R-type, but not L-type, calcium channel currents at physiological holding potentials (HPs) of -60 and -80 mV At a HP of -80 mV, coinjection of various concentrations (0-12.5 ng) of the beta3 with Ca,.2.2alpha(1) and alpha(2)delta enhanced the maximum conductance of expressed channels at lower beta3 concentrations but at higher concentrations (>2.5 ng/cell) caused a marked inhibition. The beta3-induced Current suppression was reversed at a HP of - 120 mV, suggesting that the inhibition was voltage dependent. A high concentration of Ba-2divided by (40 mM) as a charge carrier also largely diminished the effect of P3 at -80 mV Therefore, experimental conditions (HP, divalent cation concentration, and P3 subunit concentration) approaching normal physiological conditions were critical to elucidate the full extent of this novel P3 effect. Steady-state inactivation curves revealed that N-type channels exhibited closed-state inactivation without P3, and that P3 caused an similar to40 mV negative shift of the inactivation, producing a second component with an inactivation midpoint of approximately -85 mV The inactivation of N-type channels in the presence of a high concentration (12.5 ng/cell) of P3 developed slowly and the time-dependent inactivation curve was best fit by the sum of two exponential functions with time constants of 14 s and 8.8 min at -80 mV Similar ultra-slow inactivation was observed for N-type channels Without P3. Thus, P3 can have a profound negative regulatory effect on N-type (and also R-type) calcium channels by Causing a hyperpolarizing shift of the inactivation without affecting ultra-slow and closed-state inactivation properties.

Cardiovascular actions of the venom from the Irukandji (Carukia barnesi) jellyfish: Effects in human, rat and guinea-pig tissues in vitro and in pigs in vivo

1. We have investigated the cardiovascular pharmacology of the crude venom extract (CVE) from the potentially lethal, very small carybdeid jellyfish Carukia barnesi, in rat, guinea-pig and human isolated tissues and anaesthetized piglets. 2. In rat and guinea-pig isolated right atria, CVE (0.1-10 mu g/mL) caused tachycardia in the presence of atropine (I mu mol/L), a response almost completely abolished by pretreatment with tetrodotoxin (TTX; 0.1 mu mol/L). In paced left atria from guinea-pig or rat, CVE (0.1-3 mu g/mL) caused a positive inotropic response in the presence of atropine (1 mu mol/L). 3. In rat mesenteric small arteries, CVE (0.1-30 mu g/mL) caused concentration-dependent contractions that were unaffected by 0.1 mu mol/L TTX, 0.3 mu mol/L prazosin or 0.1 mu mol/L co-conotoxin GVIA. 4. Neither the rat right atria tachycardic response nor the contraction of rat mesenteric arteries to CVE were affected by the presence of box jellyfish (Chironex fleckeri) antivenom (92.6 units/mL). 5. In human isolated driven right atrial trabeculae muscle strips, CVE (10 mu g/mL) tended to cause an initial fall, followed by a more sustained increase, in contractile force. In the presence of atropine (I mu mol/L), CVE only caused a positive inotropic response. In separate experiments in the, presence of propranolol (0.2 mu mol/L), the negative inotropic effect of CVE was enhanced, whereas the positive inotropic response was markedly decreased. 6. In anaesthetized piglets, CVE (67 mu g/kg, i.v.) caused sustained tachycardia and systemic and pulmonary hypertension. Venous blood samples demonstrated a marked elevation in circulating levels of noradrenaline and adrenaline. 7. We conclude that C. barnesi venom may contain a neural sodium channel activator (blocked by TTX) that, in isolated atrial tissue (and in vivo), causes the release of transmitter (and circulating) catecholamines. The venom may also contain a 'direct' vasoconstrictor component. These observations explain, at least in part, the clinical features of the potentially deadly Irukandji syndrome.

Perils of managing the service profit chain:the role of time lags and feedback loops

The tendency of managers to focus on short-term results rather than on sustained company success is of particular importance to retail marketing managers, because marketing activities involve expenditures which may only pay off in the longer term. To address the issue of myopic management, our study shows how the complexity of the service profit chain (SPC) can cause managers to make suboptimal decisions. Hence, our paper departs from past research by recognizing that understanding the temporal interplay between operational investments, employee satisfaction, customer satisfaction, and operating profit is essential to achieving sustained success. In particular, we intend to improve understanding of the functioning of the SPC with respect to time lags and feedback loops. Results of our large-scale longitudinal study set in a multi-outlet retail chain reveal time-lag effects between operational investments and employee satisfaction, as well as between customer satisfaction and performance. These findings, along with evidence of a negative interaction effect of employee satisfaction on the relationship between current performance and future investments, show the substantial risk of mismanaging the SPC. We identify specific situations in which the dynamic approach leads to superior marketing investment decisions, when compared to the conventional static view of the SCP. These insights provide valuable managerial guidance for effectively managing the SPC over time. © 2012 New York University.

Pyrolysis and combustion of municipal solid wastes:evaluation of synergistic effects using TGA-MS

A thermogravimetric methodology was developed to investigate and semi-quantify the extent of synergistic effects during pyrolysis and combustion of municipal solid waste (MSW). Results from TGA-MS were used to compare the pyrolysis and combustion characteristics of single municipal solid waste components (polyvinyl chloride (PVC), polypropylene (PP), polystyrene (PS), branches (BR), leaves (LV), grass (GR), packaging paper (PK), hygienic paper (HP) and cardboard (CB)) and a mixture (MX) of PP, BR and CB. Samples were heated under dynamic conditions at 20°C/min from 25°C to 1000°C with the continuous record of their main evolved fragments. Synergistic effects were evaluated by comparing experimental and calculated weight losses and relative areas of MS peaks. Pyrolysis of the mixture happened in two stages, with the release of H2, CH4, H2O, CO and CO2 between 200 and 415°C and the release of CH4, CxHy, CO and CO2 between 415 and 525°C. Negative synergistic effect in the 1st stage was attributed to the presence of PP where the release of hydrocarbons and CO2 from BR and CB was inhibited, whereas positive synergistic effects were observed during the 2nd degradation stage. In a second part of the study, synergistic effects were related to the dependency of the effective activation energy (Eα) versus the conversion (α). Higher Eαs were obtained for MX during its 1st stage of pyrolysis and lower Eαs for the 2nd stage when compared to the individual components. On the other hand, mostly positive synergistic effects were observed during the combustion of the same mixture, for which lower Eαs were recorded.

A magyar minimálbér-szabályozás és hatása a foglalkoztatásra, különösen 2000-től napjainkig (Minimum-wage regulation in Hungary and its impact on employment, with particular respect to the 2000’s)

Noha az 1990-es évek első felében felbomlott az akadémiai közgazdászok sok évtizeden át örök érvényűnek hitt közmegegyezése a minimálbér szükségképpen negatív foglalkoztatási hatásáról, a túlságosan magas minimálbért minden közgazdász foglalkoztatáscsökkentő hatásúnak jósolja. Tanulmányunkban a magyar minimálbér-szabályozást e hatás szempontjából vizsgáljuk és értékeljük. / === / Although the long-held view of an unambiguously negative employment effect of a binding minimum wage was challenged by empirical findings in the early 1990’s, it is unanimously predicted that if the minimum wage is set too high it will bring about adverse employment effects. Accordingly, our study starts from an evaluation of the magnitude of the Hungarian minimum wage, i.e., of how it relates to minimum wage rates elsewhere, and of how it has developed through time. Next we inspect the main features that characterize the Hungarian system of minimum wage regulation. Theoretical views on the potential employment effect of minimum wage regulation are then surveyed and contrasted to empirical findings. The study concludes by policy recommendations. To sum up the main strand of arguments, we try to demonstrate that even though Hungary’s minimum wage, if assessed by its ratio to average and/or median full-time earnings, does not appear particularly high by international standards, it might rightly be regarded as unreasonably high in light of Hungary’s excessively low relative rate of employment among the least schooled. This diagnose should become particularly evident once one takes into account that, in sharp contrast to established rules elsewhere, a significantly higher wage floor is in effect for those with lower secondary schooling. Abolition of this legally guaranteed premium over the minimum wage as well as more moderation in minimum wage adjustments are thus highly recommended.

Financial constraints on research and development

This dissertation examines whether-there exists financial constraints and, if so, their implications for investment in research and development expenditures. It develops a theoretical model of credit rationing and research and development in which both are determined simultaneously and endogenously. The model provides a useful tool to examine different policies that may help alleviate the negative the effect of financial constraints faced by firms.^ The empirical evidence presented deals with two different cases, namely, the motor vehicle industry in Germany (1970-1990) and the electrical machinery industry In Spain (1975-1990).^ The innovation in the empirical analysis is that it follows a novel approach to identify events that allow us to isolate the effect of financial constraints in the determination of research and development.^ Further, empirical evidence is presented to show that in the above two cases financial constraints affect investment in physical capital as well.^ The empirical evidence presented supports the results of the theoretical model developed in this dissertation, showing that financial constraints negatively affect the rate of growth of innovation by reducing the intensity of research and development activity. ^

Role of Pseudomonas aeruginosa PA4157in Quorum Sensing and Iron Transport Regulation

Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen, is a pnmary contributing factor responsible for the morbidity and mortality in patients with cystic fibrosis. One of the trademarks of P. aeruginosa is its ability to resist antibiotics. P. aeruginosa does so in part through the LysR-type transcription factor, AmpR. To identify additional members of the AmpR regulon, a new algorithm called iterative enhancement of motifs was used to identify putative AmpR binding sites upstream of open reading frames in the P. aeruginosa genome. The surprising primary hit of this analysis was the promoter of an uncharacterized open reading frame, P A 415 7. P A 415 7 is located upstream ofthefep operon, which is known to be involved in iron acquisition. PA4157 shares high homology to the IclR family of transcriptional regulators which are known to regulate quorum sensing (QS), an elaborate cell-cell communication signaling system that uses quoromones. We postulated two hypotheses: 1) AmpR regulation of QS genes is mediated by PA4157, and 2) PA4157 may be involved in iron acquisition. To address the role of P A 415 7 we generated an in-frame chromosomal deletion of P A 415 7 in P. aeruginosa PA01 (PA0 PA4157). We compared PA0 PA4157 with its parent strain P A0 1 for its ability to produce quoromones using Chromobacterium violaceum as an indicator strain and LasA proteases using Staphylococcus aureus. We also tested its role in virulence using a Caenorhabditis elegans killing assay. Growth in iron-deficient media was also examined to determine if P A4157 has a potential role in iron uptake regulation. Our preliminary results suggest that P A 415 7 is not involved in quorum sensing regulation but does seem to exert a negative regulatory effect on iron uptake in P. aeruginosa P A0 1.

Avaliação das características de carcaça e perfil dos ácidos graxos em suínos na fase de terminação, alimentados com dietas contendo farelo de bagaço de caju

Provide healthier meat to consumers of pig farmers has required an adjustment of nutrition and feed management. Nutrition is a primary factor in defining the qualitative aspects of pork, because through it we can modify the fatty acid profile. The objective of this study was to analyze the effects of adding bran bagasse cashew (FBC) in diets for finishing pigs, on carcass traits and meat quality. 20 crossbred barrows with an average initial weight of 57.93 ± 3.67 kg / BW were used Diets were formulated based on corn and soybean meal containing vegetable oil, commercial core and different levels of inclusion of the bran bagasse cashew ( 0.0, 7.5 % , 15.0 % , 22.5 % and 30.0 % ) . The experimental design was a randomized block with 5 treatments and 4 replications. Quantitative, qualitative, fatty acid profile of the longissimus muscle and fat area parameters were evaluated. It was observed that with the inclusion of FBC, the parameters of carcass yield, backfat thickness, fat area had a negative linear effect relationship and meat / fat positive effect. Regarding the profile of fatty acids in fat area, the content of linoleic fatty acid level of 30 % of FBC was 18.2 % higher ( P < 0.05 ) at the level of 0.0 % and the arachidonic level of 22.5 % was higher than 33.3 % and 37.5 % at levels of 0.0 % and 15.0 % ( FBC ) respectively. It is concluded that finishing pigs may be food diets containing up to 30 % of FBC, improving the quality of housing for lower fat deposition and modification in the fatty acid profile.

Factors driving territory size and breeding success in a threatened migratory songbird, the Canada Warbler

Successful conservation of migratory birds demands we understand how habitat factors on the breeding grounds influences breeding success. Multiple factors are known to directly influence breeding success in territorial songbirds. For example, greater food availability and fewer predators can have direct effects on breeding success. However, many of these same habitat factors can also result in higher conspecific density that may ultimately reduce breeding success through density dependence. In this case, there is a negative indirect effect of habitat on breeding success through its effects on conspecific density and territory size. Therefore, a key uncertainty facing land managers is whether important habitat attributes directly influence breeding success or indirectly influence breeding success through territory size. We used radio-telemetry, point-counts, vegetation sampling, predator observations, and insect sampling over two years to provide data on habitat selection of a steeply declining songbird species, the Canada Warbler (Cardellina canadensis). These data were then applied in a hierarchical path modeling framework and an AIC model selection approach to determine the habitat attributes that best predict breeding success. Canada Warblers had smaller territories in areas with high shrub cover, in the presence of red squirrels (Tamiasciurus hudsonicus), at shoreline sites relative to forest-interior sites and as conspecific density increased. Breeding success was lower for birds with smaller territories, which suggests competition for limited food resources, but there was no direct evidence that food availability influenced territory size or breeding success. The negative relationship between shrub cover and territory size in our study may arise because these specific habitat conditions are spatially heterogeneous, whereby individuals pack into patches of preferred breeding habitat scattered throughout the landscape, resulting in reduced territory size and an associated reduction in resource availability per territory. Our results therefore highlight the importance of considering direct and indirect effects for Canada warblers; efforts to increase the amount of breeding habitat may ultimately result in lower breeding success if habitat availability is limited and negative density dependent effects occur.

Leaf Traits, Neighbors, and Abiotic Factors: Ways That Context Can Mediate the Impact of Invasive Species on Nitrogen Cycling

Species invasions are more prevalent than ever before. While the addition of a species can dramatically change critical ecosystem processes, factors that mediate the direction and magnitude of those impacts have received less attention. A better understanding of the factors that mediate invasion impacts on ecosystem functioning is needed in order to target which exotic species will be most harmful and which systems are most vulnerable. The role of invasion on nitrogen (N) cycling is particularly important since N cycling controls ecosystem services that provision human health, e.g. nutrient retention and water quality.

We conducted a meta-analysis and in-depth studies focused on the invasive grass species, Microstegium vimineum, to better understand how (i) plant characteristics, (ii) invader abundance and neighbor identity, and (iii) environmental conditions mediate the impacts of invasion on N pools and fluxes. The results of our global meta-analysis support the concept that invasive species and reference community traits such as leaf %N and leaf C:N are useful for understanding invasion impacts on soil N cycling, but that trait dissimilarities between invaded and reference communities are most informative. Regarding the in-depth studies of Microstegium, we did not find evidence to suggest that invasion increases net nitrification as other studies have shown. Instead, we found that an interaction between its abundance and the neighboring plant identify were important for determining soil nitrate concentrations and net nitrification rates in the greenhouse. In field, we found that variability in environmental conditions mediated the impact of Microstegium invasion on soil N pools and fluxes, primarily net ammonification, between sites through direct, indirect, and interactive pathways. Notably, we detected a scenario in which forest openness has a negative direct effect and indirect positive effect on ammonification in sites with high soil moisture and organic matter. Collectively, our findings suggest that dissimilarity in plant community traits, neighbor identity, and environmental conditions can be important drivers of invasion impacts on ecosystem N cycling and should be considered when evaluating the ecosystem impacts of invasive species across heterogeneous landscapes.

Institutional Persistence in Eastern Europe: Economic and Political Legacies of Empires and Communism

This dissertation seeks to advance our understanding of the roles that institutions play in economic development. How do institutions evolve? What mechanisms are responsible for their persistence? What effects do they have on economic development?

I address these questions using historical and contemporary data from Eastern Europe and Russia. This area is relatively understudied by development economists. It also has a very interesting history. For one thing, for several centuries it was divided between different empires. For another, it experienced wars and socialism in the 20th century. I use some of these exogenous shocks as quasi-natural social experiments to study the institutional transformations and its effects on economic development both in the short and long run.

This first chapter explores whether economic, social, and political institutions vary in their resistance to policies designed to remove them. The empirical context for the analysis is Romania from 1690 to the 2000s. Romania represents an excellent laboratory for studying the persistence of different types of historical institutional legacies. In the 18th and 19th centuries, Romania was split between the Habsburg and Ottoman Empires, where political and economic institutions differed. The Habsburgs imposed less extractive institutions relative to the Ottomans: stronger rule of law, a more stable and predictable state, a more developed civil society, and less corruption. In the 20th century, the Romanian Communist regime tried deliberately to homogenize the country along all relevant dimensions. It was only partially successful. Using a regression discontinuity design, I document the persistence of economic outcomes, social capital, and political attitudes. First, I document remarkable convergence in urbanization, education, unemployment, and income between the two former empires. Second, regarding social capital, no significant differences in organizational membership, trust in bureaucracy, and corruption persist today. Finally, even though the Communists tried to change all political attitudes, significant discontinuities exist in current voting behavior at the former Habsburg-Ottoman border. Using data from the parliamentary elections of 1996-2008, I find that former Habsburg rule decreases by around 6 percentage points the vote share of the major post-Communist left party and increases by around 2 and 5 percentage points the vote shares of the main anti-Communist and liberal parties, respectively.

The second chapter investigates the effects of Stalin’s mass deportations on distrust in central authority. Four deported ethnic groups were not rehabilitated after Stalin’s death; they remained in permanent exile until the disintegration of the Soviet Union. This allows one to distinguish between the effects of the groups that returned to their homelands and those of the groups that were not allowed to return. Using regional data from the 1991 referendum on the future of the Soviet Union, I find that deportations have a negative interim effect on trust in central authority in both the regions of destination and those of origin. The effect is stronger for ethnic groups that remained in permanent exile in the destination regions. Using data from the Life in Transition Survey, the chapter also documents a long-term effect of deportations in the destination regions.

The third chapter studies the short-term effect of Russian colonization of Central Asia on economic development. I use data on the regions of origin of Russian settlers and push factors to construct an instrument for Russian migration to Central Asia. This instrument allows me to interpret the outcomes causally. The main finding is that the massive influx of Russians into the region during the 1897-1926 period had a significant positive effect on indigenous literacy. The effect is stronger for men and in rural areas. Evidently, interactions between natives and Russians through the paid labor market was an important mechanism of human capital transmission in the context of colonization.

The findings of these chapters provide additional evidence that history and institutions do matter for economic development. Moreover, the dissertation also illuminates the relative persistence of institutions. In particular, political and social capital legacies of institutions might outlast economic legacies. I find that most economic differences between the former empires in Romania have disappeared. By the same token, there are significant discontinuities in political outcomes. People in former Habsburg Romania provide greater support for liberalization, privatization, and market economy, whereas voters in Ottoman Romania vote more for redistribution and government control over the economy.

In the former Soviet Union, Stalin’s deportations during World War II have a long-term negative effect on social capital. Today’s residents of the destination regions of deportations show significantly lower levels of trust in central authority. This is despite the fact that the Communist regime tried to eliminate any source of opposition and used propaganda to homogenize people’s political and social attitudes towards the authorities. In Central Asia, the influx of Russian settlers had a positive short-term effect on human capital of indigenous population by the 1920s, which also might have persisted over time.

From a development perspective, these findings stress the importance of institutions for future paths of development. Even if past institutional differences are not apparent for a certain period of time, as was the case with the former Communist countries, they can polarize society later on, hampering economic development in the long run. Different institutions in the past, which do not exist anymore, can thus contribute to current political instability and animosity.

Essays on Economics of Entrepreneurship

This dissertation examines three important issues. The first issue is about the human capital investment and entrepreneurship as a career choice. The standard human capital theory shows that firms (employees) never invest in general (firm-specific) human capital of the employee as they do not extract any return from it. However, when entrepreneurship is introduced as a career option for an innovative employee, both firm’s and employee’s human capital investments change. Employee starts investing in his firm-specific human capital to increase the probability to innovate (and to become an entrepreneur). However, the firm uses general human capital investment to reduce the risk of employee’s departure. The second issue is regarding the factors motivating entry regulations reforms and the possible nonlinear effects of entry regulation reforms. The current literature and the policy recommendations assume that these reforms have linear effects on entrepreneurship. Nevertheless, the anecdotal evidence shows that the outcomes of such reforms vary greatly from country to country. To investigate this issue, I collect a sample data on entry regulations and firm creation from World Bank. The empirical analysis indicates that the effect of entry regulation reforms depends on the pre-reform level of bureaucracy in the country. More specifically, while low-bureaucracy countries benefit from entry regulation reforms, high-bureaucracy countries do not benefit. Moreover, the probability of making a reform increases if the country has reformist neighbors, cumbersome entry regulations, high unemployment rate, or low corruption level. The last issue is related to the individual and joint effects of bureaucracy and corruption on different types of entrepreneurs. The current literature investigates these effects only on unified measures of entrepreneurship. However, entrepreneurs are very different in many senses. To address this issue, I collect the necessity-based and opportunity-based entrepreneurship data from Global Entrepreneurship Monitor. The empirical analysis yield two important results: First, bureaucracy has a direct negative (positive) effect on necessity-based (opportunity-based) entrepreneurs. Second, corruption mitigates the effect of bureaucracy for both groups of entrepreneurs. All three chapters offer useful insights and important implications to academics and policymakers.

Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial.

Background: Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. Patients and methods: We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan–Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results: A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995). Conclusion: This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.