Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery

BACKGROUND: Treatment of cells with the anti-cancer drug 5-fluorouracil (5-FU) causes DNA damage, which in turn affects cell proliferation and survival. Two stable wild-type TP53 5-FU-resistant cell lines, ContinB and ContinD, generated from the HCT116 colon cancer cell line, demonstrate moderate and strong resistance to 5-FU, respectively, markedly-reduced levels of 5-FU-induced apoptosis, and alterations in expression levels of a number of key cell cycle- and apoptosis-regulatory genes as a result of resistance development. The aim of the present study was to determine potential differential responses to 8 and 24-hour 5-FU treatment in these resistant cell lines. We assessed levels of 5-FU uptake into DNA, cell cycle effects and apoptosis induction throughout treatment and recovery periods for each cell line, and alterations in expression levels of DNA damage response-, cell cycle- and apoptosis-regulatory genes in response to short-term drug exposure. RESULTS: 5-FU treatment for 24 hours resulted in S phase arrests, p53 accumulation, up-regulation of p53-target genes on DNA damage response (ATF3, GADD34, GADD45A, PCNA), cell cycle-regulatory (CDKN1A), and apoptosis-regulatory pathways (FAS), and apoptosis induction in the parental and resistant cell lines. Levels of 5-FU incorporation into DNA were similar for the cell lines. The pattern of cell cycle progression during recovery demonstrated consistently that the 5-FU-resistant cell lines had the smallest S phase fractions and the largest G(2)(/M) fractions. The strongly 5-FU-resistant ContinD cell line had the smallest S phase arrests, the lowest CDKN1A levels, and the lowest levels of 5-FU-induced apoptosis throughout the treatment and recovery periods, and the fastest recovery of exponential growth (10 days) compared to the other two cell lines. The moderately 5-FU-resistant ContinB cell line had comparatively lower apoptotic levels than the parental cells during treatment and recovery periods and a recovery time of 22 days. Mitotic activity ceased in response to drug treatment for all cell lines, consistent with down-regulation of mitosis-regulatory genes. Differential expression in response to 5-FU treatment was demonstrated for genes involved in regulation of nucleotide binding/metabolism (ATAD2, GNL2, GNL3, MATR3), amino acid metabolism (AHCY, GSS, IVD, OAT), cytoskeleton organization (KRT7, KRT8, KRT19, MAST1), transport (MTCH1, NCBP1, SNAPAP, VPS52), and oxygen metabolism (COX5A, COX7C). CONCLUSION: Our gene expression data suggest that altered regulation of nucleotide metabolism, amino acid metabolism, cytoskeleton organization, transport, and oxygen metabolism may underlie the differential resistance to 5-FU seen in these cell lines. The contributory roles to 5-FU resistance of some of the affected genes on these pathways will be assessed in future studies

An end to Nordic exceptionalism? Europeanisation and Nordic development policies

The Nordic countries have traditionally been praised for their generous and advanced development policies. Recently, however, it has been claimed that the Nordic model has faded: that the Nordic donors have become more similar to other European donors. One possible reason for such trends is influences from EU policies, that is, Europeanisation. This article critically evaluates such claims by presenting arguments for and against Europeanisation effects. We argue that changes have indeed taken place. The Nordic exceptionalism has been eroded. At the same time, a convergence of European aid policies has occurred. The question is if this is the consequence of Europeanisation – or is it rather a result of Nordicisation (the Nordic countries influencing the EU), or perhaps like-mindisation (a broader set of progressive member states having impact upon EU policies)? We suggest that Europeanisation has been extremely weak while there is strong evidence of Nordicisation but also, and increasingly, of like-mindisation. Today, a core group of mainly northern member states, including the Nordics, are the main driving forces behind European aid convergence

User interfaces for information systems

This paper presents descriptions of four information-system interface projects in progress at ESRIN, each demonstrating a somewhat different approach to interface design, but ali sharing the commonality of responding to user goals, tasks and characteristics. It is suggested that next-generation scientific information systems will have to be designed for direct access by end users to a large variety of information sources, through a commom interface. Design of such systems, including their interfaces, should be based on a multi-level analysis of user goals, tasks and domain views.Se describen cuatro proyectos de interfaces de sistemas de información que se están desarrollando en ESRIN (establecimiento de la Agencia Espacial Europea, en Frascati). Cada uno de ellos muestra un enfoque diferente del diseño de interfaces, pero todos tienen en común el responder a los objetivos, tareas y características de los usuarios. Se sugiere que la próxima generación de sistemas de información científica se tendrá que diseñar para permitir el acceso directo de los usuarios finales a una gran variedad de fuentes de información a través de una interfaz común. El diseño de tales sistemas y de sus interfaces debería basarse en un análisis multinivel de objetivos, tareas y puntos de vista propios de la materia de trabajo de cada usuario

A game-theoretic model of interspecific brood parasitism with sequential decisions

The interaction between hosts and parasites in bird populations has been studied extensively. This paper uses game-theoretic methods to model this interaction. This has been done in previous papers but has not been studied taking into account the detailed sequential nature of this game. We introduce a model allowing the host and parasite to make a number of decisions which will depend on various natural factors. The sequence of events begins with the host forming a nest and laying a number of eggs, followed by the possibility that a parasite bird will arrive at the nest; if it does it can choose to destroy some of the host eggs and lay one of its own. A sequence of events follows, which is broken down into two key stages; firstly the interaction between the host and the parasite adult, and secondly that between the host and the parasite chick. The final decision involves the host choosing whether to raise or abandon the chicks that are in the nest. There are certain natural parameters and probabilities which are central to these various decisions; in particular the host is generally uncertain whether parasitism has taken place, but can assess the likelihood of parasitism based upon certain cues (e.g. how many eggs remain in its nest). We then use this methodology to model two real-world interactions, that of the Reed Warbler with the Common Cuckoo and also the Yellow Warbler with the Brown-headed Cowbird. These parasites have different methods in the way they parasitize the nests of their hosts, and the hosts can in turn have different reactions to these parasites. Our model predictions generally match the real results well, and the model also makes predictions of the effect of changes in various key parameters on the type of parasitic interactions that should occur

Rapid and sustained environmental responses to global warming: the Paleocene–Eocene Thermal Maximum in the eastern North Sea

The Paleocene–Eocene Thermal Maximum (PETM; ∼ 55.9 Ma) was a period of rapid and sustained global warming associated with significant carbon emissions. It coincided with the North Atlantic opening and emplacement of the North Atlantic Igneous Province (NAIP), suggesting a possible causal relationship. Only a very limited number of PETM studies exist from the North Sea, despite its ideal position for tracking the impact of both changing climate and NAIP activity. Here we present sedimentological, mineralogical, and geochemical proxy data from Denmark in the eastern North Sea, exploring the environmental response to the PETM. An increase in the chemical index of alteration and a kaolinite content up to 50 % of the clay fraction indicate an influx of terrestrial input shortly after the PETM onset and during the recovery, likely due to an intensified hydrological cycle. The volcanically derived zeolite and smectite minerals comprise up to 36 % and 90 % of the bulk and clay mineralogy respectively, highlighting the NAIP's importance as a sediment source for the North Sea and in increasing the rate of silicate weathering during the PETM. X-Ray fluorescence element core scans also reveal possible hitherto unknown NAIP ash deposition both prior to and during the PETM. Geochemical proxies show that an anoxic to sulfidic environment persisted during the PETM, particularly in the upper half of the PETM body with high concentrations of molybdenum (MoEF > 30), uranium (UEF up to 5), sulfur (∼ 4 wt %), and pyrite (∼ 7 % of bulk). At the same time, export productivity and organic-matter burial reached its maximum intensity. These new records reveal that negative feedback mechanisms including silicate weathering and organic carbon sequestration rapidly began to counteract the carbon cycle perturbations and temperature increase and remained active throughout the PETM. This study highlights the importance of shelf sections in tracking the environmental response to the PETM climatic changes and as carbon sinks driving the PETM recovery.publishedVersio

Rammer flest – koster mest

Muskel- og skjelettsykdom er den sykdomsgruppen som rammer flest og koster mest i Norge. Over 1 million nordmenn, nesten 1 av 5 innbyggere, har ulike former for muskel- og skjelettsykdom (dette inkluderer revmatisk sykdom). Dette er den største enkeltårsaken til sykefravær i Norge. Folkehelseinstituttet har beregnet at muskel- og skjelettsykdommer utgjør 11 prosent av det samlede «helsetapet» i Norge 2016. Vi har beregnet konsekvensene av dette i kroner og øre og finner at de samlede samfunnskostnadene relatert til muskel- og skjelettsykdommer i 2016 var på over 255 mrd. kroner. Dette inkluderer kostnader til helsetjenester, tap av inntekter til stat og kommune som følge av såkalt «produksjonstap» ved sykefravær og uførhet, samt sykdomsbyrde for den enkelte – tap av kvalitetsjusterte leveår. Disse samfunnskostnadene er høyere enn for mange andre store sykdomsgrupper. For eksempel er de samlede samfunnskostnadene knyttet til kreft anslått å være på 210 milliarder kroner(1). Det spesielle med muskel- og skjelettsykdom er at det koster så mye utenfor helsevesenet: Utgifter i forbindelse med sykefravær og uførhet er vesentlig høyere enn for alle andre sykdomsgrupper. Det kan virke som om det er vanskelig for myndighetene å se de ulike kostnadene i sammenheng og vurdere investeringer i helsetjenesten opp mot reduserte kostnader på arbeids- og velferdsområdet. Denne rapporten forsøker å bidra til et bedre kunnskapsgrunnlag for akkurat denne typen avveininger. Vi har gjennom arbeidsmøter med pasienter, representanter fra helsetjenesten, legemiddelaktører og forskere kartlagt situasjonen for muskel- og skjelettpasienter i alle faser av pasientforløpet. Mange opplever at det går svært lang tid fra man først opplever symptomer til man får riktig diagnose. For enkelte diagnoser er det vanlig at dette tar fra seks til ti år. Én årsak til dette er at det ofte går lang tid før pasientene først blir henvist til spesialist: Hele 43 prosent av revmatiske pasienter går til fastlegen mer enn seks ganger før de blir henvist videre. Det er mangel på kompetanse innen muskel- og skjelettsykdom i både primær- og spesialisthelsetjenesten. Behandlingstilbudet ute i kommunene er underdimensjonert og av svært varierende kvalitet. At variasjonen i tilgangen på et godt behandlingstilbud i kommunene er stor underbygges også av data fra Folkehelseinstituttet. Det er betydelige forskjeller mellom landets fylker hva angår andelen pasienter som legges inn på sykehussom følge av muskel- og skjelettsykdommer. Dette kan være en indikasjon på at førstelinjen», kommunehelsetjenesten, er for svak i deler av landet. Trøndelag har eksempelvis 60 prosent flere sykehusinnleggelser per 1000 innbygger enn Oslo. Både pasienter og helsepersonell trekker videre frem mangelfull samhandling og koordinering i helsetjenesten som en gjennomgående utfordring innen muskel- og skjelettområdet. Konsekvensene av dette er at helsetilbudet ikke gis i en hensiktsmessig sammenheng og rekkefølge, samt at pasientene selv ender opp med en koordineringsrolle i sitt eget behandlingsforløp. Dette er en jobb som bare de mest ressurssterke vil kunne mestre. Den gode nyheten er at mulighetene for å redusere samfunnskostnadene er mange: Et tilbakeblikk på den medisinske utviklingen innen diagnoseverktøy, behandlingsmuligheter og -strategier viser at fremtidsutsiktene for pasienter som diagnostiseres i dag er langt bedre enn hva de var for bare et par tiår siden. En norsk studie finner eksempelvis at andelen personer med diagnosen revmatoid artritt, som i dag lever med lav sykdomsaktivitet, har steget fra i underkant av 40 prosent til over 70 prosent de siste 10 årene. Den sentrale årsaken til denne utviklingen er at det har blitt utviklet flere biologiske medisiner som benyttes på en bedre måte enn før. Selv om utviklingen innen biologiske legemidler har bidratt til at mange i dag kan leve et bedre liv enn hva de kunne tidligere, gjelder dette dessverre ikke for alle diagnoser. I denne rapporten diskuterer vi åtte konkrete tiltak for å redusere dagens utfordringer og de tilhørende kostnadene disse medfører for samfunnet. Disse tiltakene er delt inn i tre tiltaksgrupper: 1. Kompetanse- og kvalitetshevingstiltak 2. Behandlings- og rehabiliteringstiltak 3. Informasjons- og samhandlingstiltak De åtte tiltakene blir alle drøftet i en samfunnsøkonomisk kontekst. Beregninger av samfunnsøkonomisk lønnsomhet er gjennomført der det har vært tilgjengelig statistikk og informasjon til at dette har latt seg gjennomføre. Helsedirektoratet har fått i oppdrag av Helse- og omsorgsdepartementet å utarbeide et pakkeforløp for muskelog skjelettsykdommer. En gjennomgang av forskningen på pakkeforløp (behandlingsforløp, «patient pathways») og erfaringene fra andre land viser at dette ofte er et kostnadseffektivt tiltak, først og fremst ved at det øker helsetjenestens behandlingskapasitet og reduserer kostnadene knyttet til behandling. På denne måten kan flere få riktig behandling. Det er viktig at disse pakkeforløpene inneholder mer enn en overordnet ambisjon om mer forutsigbarhet og mindre ventetid: Vi viser i denne rapporten at en kombinasjon av effektive forløp og økt satsing på behandling som fungerer vil kunne bidra til en betydelig reduksjon i de enorme kostnadene som muskel- og skjelettsykdommer medfører for samfunnet i dag. (1) https://osloeconomics.no/wp-content/uploads/Fremtidens-kreftkostnader.pd

A comparison of lead-based and lead-free bullets for shooting sambar deer (Cervus unicolor) in Australia

Context: In response to the toxic health threats posed by lead (Pb), there is currently a focus on transitioning to lead-free bullets for shooting wild animals. Aim: We aimed to quantify the killing efficiency and animal welfare outcomes of lead-based and lead-free (copper-based) bullets for ground-based shooting of sambar deer (Cervus unicolor) in Victoria, south-eastern Australia. Methods: We used shooter-collected data from recreational diurnal hunting and professional nocturnal culling during 2020–2021. Shooters recorded rifle calibre, cartridge type, bullet mass, bullet type, shooting outcomes (miss, wound or kill), shooting distance, flight distance (the distance between where the animal was shot and where it died) as an assumed positive correlate of time to incapacitation, anatomical zones struck by bullets, and frequency of bullet exit wounds. We used flight distance as our response variable, assuming that it is positively correlated with time to incapacitation. To examine the role of several predictor variables (including bullet type) potentially influencing flight distance, the dataset was reduced to those deer killed with a single thoracic shot. Key results: Our data captured shooting events involving 276 deer, with 124 deer shot at with lead-based bullets and 152 with copper-based bullets. Most (87%) of the deer were killed with a single shot. The frequency of non-fatal wounding was <4% for both bullet types and there was no distinct difference in the probability of a single shot kill for deer shot with either bullet type. For those deer killed with a single thoracic shot (n = 198), there was no evidence that bullet energy or shooting distance influenced flight distance. After accounting for differences in terminal kinetic energy, the mean flight distance of deer shot with lead-free bullets (35 m) was 56% greater than that of deer shot with lead-based bullets (22 m). Conclusions: Lead-based and lead-free bullets produced similar animal welfare outcomes for shooting sambar deer. Implications: A transition to lead-free ammunition for shooting sambar deer would have minimal impact on efficiency or animal welfare outcomes

A comparison of lead-based and lead-free bullets for shooting sambar deer (Cervus unicolor) in Australia

Context. In response to the toxic health threats posed by lead (Pb), there is currently a focus on transitioning to lead-free bullets for shooting wild animals. Aim. We aimed to quantify the killing efficiency and animal welfare outcomes of lead-based and lead-free (copper-based) bullets for ground-based shooting of sambar deer (Cervus unicolor) in Victoria, south-eastern Australia. Methods. We used shooter-collected data from recreational diurnal hunting and professional nocturnal culling during 2020–2021. Shooters recorded rifle calibre, cartridge type, bullet mass, bullet type, shooting outcomes (miss, wound or kill), shooting distance, flight distance (the distance between where the animal was shot and where it died) as an assumed positive correlate of time to incapacitation, anatomical zones struck by bullets, and frequency of bullet exit wounds. We used flight distance as our response variable, assuming that it is positively correlated with time to incapacitation. To examine the role of several predictor variables (including bullet type) potentially influencing flight distance, the dataset was reduced to those deer killed with a single thoracic shot. Key results. Our data captured shooting events involving 276 deer, with 124 deer shot at with lead-based bullets and 152 with copper-based bullets. Most (87%) of the deer were killed with a single shot. The frequency of non-fatal wounding was <4% for both bullet types and there was no distinct difference in the probability of a single shot kill for deer shot with either bullet type. For those deer killed with a single thoracic shot (n = 198), there was no evidence that bullet energy or shooting distance influenced flight distance. After accounting for differences in terminal kinetic energy, the mean flight distance of deer shot with lead-free bullets (35 m) was 56% greater than that of deer shot with lead-based bullets (22 m). Conclusions. Lead-based and lead-free bullets produced similar animal welfare outcomes for shooting sambar deer. Implications. A transition to lead-free ammunition for shooting sambar deer would have minimal impact on efficiency or animal welfare outcomes. animal welfare, culling, human dimensions, invasive species, population control, recreational hunting, toxicology, wildlife management.publishedVersio