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The microtubule-targeting taxanes are important in breast cancer therapy, but no predictive biomarkers have yet been identified with sufficient scientific evidence to allow clinical routine use. The purposes of the present study were to develop a cell-culture-based discovery platform for docetaxel resistance and thereby identify key molecular mechanisms and predictive molecular characteristics to docetaxel resistance. Two docetaxel-resistant cell lines, MCF7RES and MDARES, were generated from their respective parental cell lines MCF-7 and MDA-MB-231 by stepwise selection in docetaxel dose increments over 15 months. The cell lines were characterized regarding sensitivity to docetaxel and other chemotherapeutics and subjected to transcriptome-wide mRNA microarray profiling. MCF7RES and MDARES exhibited a biphasic growth inhibition pattern at increasing docetaxel concentrations. Gene expression analysis singled out ABCB1, which encodes permeability glycoprotein (Pgp), as the top upregulated gene in both MCF7RES and MDARES. Functional validation revealed Pgp as a key resistance mediator at low docetaxel concentrations (first-phase response), whereas additional resistance mechanisms appeared to be prominent at higher docetaxel concentrations (second-phase response). Additional resistance mechanisms were indicated by gene expression profiling, including genes in the interferon-inducible protein family in MCF7RES and cancer testis antigen family in MDARES. Also, upregulated expression of various ABC transporters, ECM-associated proteins, and lysosomal proteins was identified in both resistant cell lines. Finally, MCF7RES and MDARES presented with cross-resistance to epirubicin, but only MDARES showed cross-resistance to oxaliplatin. In conclusion, Pgp was identified as a key mediator of resistance to low docetaxel concentrations with other resistance mechanisms prominent at higher docetaxel concentrations. Supporting Pgp upregulation as one major mechanism of taxane res

Vitamin C (vitC) er en vigtig antioxidant og beskytter mod reaktive oxygen species i pattedyr. Mennesker og nogle andre arter, så som marsvin, kan ikke biosyntetisere dette næringsstof og er derfor afhængige af tilstrækkelig tilførsel via kosten. Humane epidemiologiske studier har vist, at utilstrækkeligt indtag af vitC er almindeligt i den vestlige verden, inklusiv hos gravide kvinder. I hjernen er vitaminet specielt vigtigt, pga. dette organs følsomhed overfor oxidativt stress, hvilket specielt gør sig gældende i den udviklende hjerne. Derudover har vitC flere andre vigtige funtioner i hjernen; så som neuromodulation og vedligholdelse af vaskulaturen. Vigtigheden understreges af hjernens formidable retentive kapacitet ved vitC mangel. Der er derfor bekymring for om udviklingen af hjernen i børn af mødre med vitC mangel foregår korrekt. Et specielt interessant område i hjernen er hippocampus, da denne har et højt indhold af vitC. Forsøg i marsvin udsat for prenatal vitC mangel har vist kompromomiteret spatial hukommelse, samt formindsket volumen af hippocampus og et reduceret antal neuroner. Dette studie er udført på marsvin på gestationsdag 56 udsat for vitC mangel. Målet var at se, om der kunne måles en reduktion i volume af hippocampus, og i hvilke regioner denne volumenændring var mest udtalt. I modsætning til forventet kunne der ikke detekteres nogen statistisk signifikant effekt af vitC mangel på volumen i nogen af regionerne af hippocampus. Der var dog en tendens til en højere biologisk variation i de deficiente dyr, hvilken endda nåede et signifikant niveau i Cornu ammonis 1+2 (p = 0.002). Statistisk analyse viste, at der var en kuldeffekt i studiet, og forskellen i den biologiske variation skyldes derfor måske mødrenes arvelige forskelle i at sikre tilstrækkelig tilførsel af vitC til fostrene. Bemærkelsesværdigt var det, at på trods af tydelig indflydelse af maternelle plasmavæ, Vitamin C (vitC) is a crucial antioxidant and fighter of reactive oxygen species in the mammalian body. Humans and other species such as the guinea pig are not capable of biosynthesising this nutrient and rely on adequate dietary ingestion. Human epidemiological studies have shown that inadequate dietary intake of vitC is common in the western world, including in pregnant women. In the brain the vitamin is especially important due to the vulnerability of this organ to oxidative stress, which especially applies to the developing brain. Furthermore, vitC has several other important functions in the brain such as neuromodulation and maintaining vasculature. The importance is highlighted by the remarkable retentive capacity of the brain in face of deficiency. Thus, there is concern for the development of the brain in children of vitC deficient mothers. A brain area of specific interest is the hippocampus, since it has a high content of vitC. Research in guinea pigs prenatally exposed to vitC deficiency have shown impairment of spatial memory, as well as reduced hippocampal volume and decreased neuron numbers. The present study was conducted in guinea pigs on gestational day 56 subjected to vitC deficiency. The aim was to see, whether a reduction in hippocampal volume could be detected and in which regions of the hippocampus this reduction was most abundant. Unlike expectations, no statistical significant effect of deficiency on hippocampal volume could be detected in any region of the hippocampus. However, a tendency towards a higher biological variance in deficient pups was observed and reached significance in Cornu ammonis 1+2 (p = 0.002). Statistical analysis showed that there was a litter effect in the study and the difference in biological variance may be due to hereditary difference of the dams in ensuring adequate foetal vitC supply. Curiously, it seemed that despite clear effect of m

We sequenced the D21S11 locus in 77 individuals from Danish paternity cases using 454 FLX next generation sequencing (NGS) technology. All samples were also typed with the AmpFlSTR(®) Profiler Plus(®) or the AmpFlSTR(®) Identifiler(®) PCR Amplification kits as part of paternity investigations. In 18 of the confirmed trios, a genetic inconsistency was observed between one of the parents and the child at the D21S11 locus. NGS of the D21S11 locus revealed which allele had mutated from which parent to the child in 13 of these trios. All characterized mutations could be explained by single-step mutations in the longest sub-repeat of D21S11. A total of 53 of the 77 sequenced samples originated from unrelated individuals. Twenty different D21S11 alleles were detected by NGS in these individuals whereas only 13 different alleles were observed with fragment analysis. Several alleles had the same lengths but different sequences, e.g. four and three different alleles were detected by NGS with lengths determined by CE corresponding to allele 30 and allele 31, respectively.

Vitamin C is a pivotal antioxidant in the brain and has been reported to have numerous functions, including reactive oxygen species scavenging, neuromodulation, and involvement in angiogenesis. Absence of vitamin C in the brain has been shown to be detrimental to survival in newborn SVCT2(-/-) mice and perinatal deficiency have shown to reduce hippocampal volume and neuron number and cause decreased spatial cognition in guinea pigs, suggesting that maternal vitamin C deficiency could have severe consequences for the offspring. Furthermore, vitamin C deficiency has been proposed to play a role in age-related cognitive decline and in stroke risk and severity. The present review discusses the available literature on effects of vitamin C deficiency on the developing and aging brain with particular focus on in vivo experimentation and clinical studies.

Several measuring campaigns with focus on deposition behavior have been conducted at full-scale power plants firing biomass in Denmark. These measuring campaigns have been reviewed in this work. The focus of the review is the obtained experiences on deposit formation, chemistry and shedding. Corresponding samples of fuels, ash deposits and fly ash have provided information on the transformation of inorganics in the boiler. Generally, grate fired boilers provide a fly ash containing high contents of K, Cl and S compared to the fuel ash, while suspension fired boilers fly ash has a composition nearly similar to the fuel ash. Inner most biomass deposits are always salt-rich, while thicker deposit layers also contain some Si and Ca. Deposit probe formation rate measurements have been performed in different ways on several boilers. Grate and suspension fired boilers seems to cause similar deposit formation rates. Suspension fired boilers generate more fly ash, while grate boilers form a fly ash with a higher fraction of melt formation (and thereby a higher sticking probability) at similar temperatures. For suspension fired units it is observed that wood with a lower ash content than straw gives rise to lower deposit formation rates. The flue gas temperature is an important parameter in the deposit behavior of biomass-fired boilers. Increases in the flue gas temperature of both grate and suspension fired boilers leads to increased deposition rates and deposits with higher contents of Si and Ca. This can be explained by increased deposition by inertial impaction due to higher melt fractions of ash particles (containing Si and Ca) at increased temperatures. The shedding behavior is influenced by exposure time, probe surface temperature, flue gas temperature and deposits chemistry. The influence of temperature on the degree of sintering varies with the fuel type. Possibly, increased contents of Si and Ca will lead to increases in the sintering temperature

Several measuring campaigns with focus on deposition behavior have been conducted at full-scale power plants firing biomass in Denmark. These campaigns have been reviewed in this work. The focus is the obtained experiences on deposit formation, shedding and chemistry. When comparing results from grate- and suspension-firing, it is found that the rates of deposit formation are comparable, while the chemical composition of the fly ashes are quite different, even for the same type of fuel. The flue gas temperature is considered to be an important parameter in the deposit behavior. Increasing the flue gas temperature leads to increased deposition rates and deposits with higher contents of Si and Ca and lower contents of K and Cl. The shedding behavior is influenced by both probe surface temperature, flue gas temperature and deposits chemistry. The influence of temperature on the degree of sintering varies with the fuel type. Possibly, increased contents of Si and Ca leads to increases in the sintering temperature and thus altered shedding behavior.