Capra hircus) are one of the oldest livestock domesticated species, and have been used for their milk, meat, hair and skins over much of the world. Detection of selection footprints in genomic regions can provide potential insights for understanding the genetic mechanism of specific phenotypic traits and better guide in animal breeding. The study presented here has generated 192.747G raw data and identified more than 5.03 million single-nucleotide polymorphisms (SNPs) and 334,151 Indels (insertions and deletions). In addition, we identified 155 and 294 candidate regions harboring 86 and 97 genes based on allele frequency differences in Dazu black goats (DBG) and Inner Mongolia cashmere goats (IMCG), respectively. Populations differentiation reflected by Fst values detected 368 putative selective sweep regions including 164 genes. The top 1% regions of both low heterozygosity and high genetic differentiation contained 239 (135 genes) and 176 (106 genes) candidate regions in DBG and IMCG, respectively. These genes were related to reproductive and productive traits, such as “neurohypophyseal hormone activity” and “adipocytokine signaling pathway”. These findings may be conducive to molecular breeding and the long-term preservation of the valuable genetic resources for this species.Goats ( Capra hircus) in the world, which are distributed over all types of ecological areas with more concentrated in the tropics, dry zones and developing countries. Goats have been used for their milk, meat, hair, or cashmere and skins over much of the world. In 2011, there were more than 1.4 billion live goats around the globe, according to the UN Food and Agriculture Organization (http://kids.fao.org/glipha/). China is rich in goat genetic resources, and there are about 69 goat breeds in this country, including 58 local breeds, 8 improved breeds and 3 introduced breeds. Especially, Inner Mongolia cashmere goat (IMCG), mainly lived in Alashan, Inner Mongolia, in the north of China (~1304 m) coated white long hair, which produced primarily cashmere and had relatively low fecundity (~105%) compared with Duzu black goat , black short hair, which are raised in Dazu County of Chongqing in the southwest of China (267~934 m) and are primarily used for meat productionThere are over 300 distinct breeds of goat (Capra aegagrus)3Goat is one of the earliest animals domesticated by humans. The most recent genetic analysis confirms the archaeological evidence that the wild Bezoar ibex of the Zagros Mountains are the likely origin of almost all domestic goats today. But the morphologicaland behavioral characteristics of modern domestic goats have greatly changed compared with wild progenitor, the Bezoar goat  and feed efficiency et al. identified some of less-known genes under positive selection correlated with milk production traits such as LAP3 and SAR1B, associated with hair length, namely, FGF5TSHR, GHR and BMP157Based on populations differentiation reflected by Fst statistic, Gibbs The genomes of 12 goats from two genetically diverse and geographically distinct indigenous breeds consists of DBG and IMCG  were seqAfter assembly and mapping of clean reads, we identified 5.03 million SNPs and 334,151 Indels (insertions and deletions) as average. Furthermore, the distributions of the SNPs were determined in the goat genome that there were 37,684 (0.75%) and 38,976 (0.77%) SNPs in the exon in DBG and IMCG, respectively, while the intronic regions contained 28.39% and 28.04% of the SNPs in DBG and IMCG, respectively. SNPs within intergenic regions accounted for up to 69.51% and 68.09% of the SNPs in DBG and IMCG, respectively . The resPopulation substructure was investigated using Clustering, MEGA and ADMIXTURE softwares based on using genomic SNPs. We ran Admixture 1.22 for determining genetic backgrounds of samples and indicated two breeds been almost diverged but there is a little gene introgression in DBG when K = 2 . The resP < 0.05 GO terms and KEGG pathways were deposited in Those genomic regions with ZHp value exceeding the empirical threshold level of −5 across the two populations were obtained, that contain 155 and 294 candidate regions in the DBG and IMCG populations, respectively. The top regions were located on chromosome 8 in DBG goats (41890001–41950001 bp) and on chromosome 2 in IMCG goats (113850001–113900001 bp), respectively . To obtaPAIP2B, CCDC64, EPB41L5), “photoreceptor activity” and “blue light photoreceptor activity” (BIRC6) in DBG goats; “meiosis” and “meiotic cell cycle” , “meiosis I”  in IMCG population; (2) Fst values: “sex determination” and “mating type determination” , “pheromone activity” . (3) Combination |ZHp| with Fst values: “gamete generation” , “neurohypophyseal hormone activity” ,“spermatid development”, “spermatid nucleus differentiation”,“sperm chromatin condensation”, “spermatid differentiation” and “spermatid differentiation” , “spermatogenesis” and “male gamete generation”  (Reproduction trait is an important component of efficiency in goat production system PARD3B) .IKBKG, LOC102190823), “ether lipid metabolism” , “Glycosphingolipid biosynthesis-ganglio series” (SLC33A1), and 8 GO terms, such as, glycosphingolipid/galactolipid metabolic process (LOC102171901), galactolipid/glycolipid/sphingolipid/membrane lipid/glycosylceramide/glycosphingolipid catabolic process (LOC102171901) associated with putative lipid metabolic pathways. In addition, There were “Ras signaling pathway” , “ubiquitin mediated proteolysis” , “VEGF signaling pathway” , “MAPK signaling pathway” , “glutathione metabolism” , “ribosome” , “RNA polymerase” , “purine metabolism” , “biosynthesis of amino acids” , “pyrimidine metabolism”  and “metabolic pathways”   . Our stuSelection, which appear to have left detectable signatures of selection within the animal genomes is a vital driving force of evolution. Since the dawn of agriculture, artificial selection has continuously added to the existing pool of phenotypic variation as same as natural selection fuels the generation of biodiversity on earth. The programs of selection signature have identified hundreds of regions or genes targeted by important traits that formed by natural or artificial selection inchickenFOXI3FGF13, Trps1, Sox914ABCA5FGF5, in many kinds of mammals17181920FGF5 have been included in the candidate genes sets based on low heterozygosity and high genetic differentiation in IMCG population  used in this study is significantly longer than DBG (3.92 ± 0.76 cm). Hair growth was considered to be regulated by hairless gene, pulation . We deteBIRC6 gene acted as “photoreceptor activity” or “blue light photoreceptor activity” was obtained based on heterozygosity as a result of differences of annual insolation duration between two populations BIRC6 gene were associated with hereditary eye diseases, pseudoexfoliative glaucomaBIRC6 would result in abnormal embryonic development26et al. determined blue light was indeed associated with melatonin expression in horses29The seasonal reproduction is one of the most conspicuous characters in goats, which is archived by alternation between long day and short day. Light information received by photoreceptor organ uniquely positioned to eye in mammals is transmitted to the pineal gland through the suprachiasmatic nucleus and then give rise to hormone secretion, especially melatoninIKBKG9, LOC102190823 , which is responsible for animal care and use in China. The experimental conditions were approved by the Committee on the Ethics of Animal Experiments of Southwest University (No. [2007] 3). All experimental goats were fed a daily ration of 300–500 gconcentrate and were allowed to an unrestricted access to straw, mineral saltlick and water.We collected a total of 12 blood samples of unrelated individuals from 6 Dazu black female goats (DBG) and 6 Inner Mongolia cashmere female goats (IMCG) . All theEach DNA sample was used to construct 350 bp paired-end sequencing libraries. Each library was sequenced with Illumina HiSeq PE150 platform according to the manufacturer’s instructions at Novogene . Raw data were processed to filter out the adaptors and low quality reads resulted in clean reads using BWA softwareWe used the Cluster 3.0 software for performing PCA analysis with the population scale SNPs3740Selective sweep analyses were performed by calculating heterozygosity (Hp) and population differentiation (Fst). The Hp and Fst values, respectively were converted to a standard normal distribution, denoted as ZHp and ZFst as described42How to cite this article: Guan, D. et al. Scanning of selection signature provides a glimpse into important economic traits in goats (Capra hircus). Sci. Rep.6, 36372; doi: 10.1038/srep36372 (2016).Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps andinstitutional affiliations.


Smoking has been reported to be associated with peripheral blood DNA methylation, but the causal aspects of the association have rarely been investigated. We aimed to investigate the association and underlying causation between smoking and blood methylation.The methylation profile of DNA from the peripheral blood, collected as dried blood spots stored on Guthrie cards, was measured for 479 Australian women including 66 monozygotic twin pairs, 66 dizygotic twin pairs, and 215 sisters of twins from 130 twin families using the Infinium HumanMethylation450K BeadChip array. Linear regression was used to estimate associations between methylation at ~ 410,000 cytosine-guanine dinucleotides (CpGs) and smoking status. A regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess putative causation.AHRR, F2RL3, 2q37.1 and 6p21.33, were found to be differentially methylated across never, former and current smokers. For all 39 CpG sites, current smokers had the lowest methylation level. Our study provides the first replication for two previously reported CpG sites, cg06226150 (SLC2A4RG) and cg21733098 (12q24.32). From the ICE FALCON analysis with smoking status as the predictor and methylation score as the outcome, a woman’s methylation score was associated with her co-twin’s smoking status, and the association attenuated towards the null conditioning on her own smoking status, consistent with smoking status causing changes in methylation. To the contrary, using methylation score as the predictor and smoking status as the outcome, a woman’s smoking status was not associated with her co-twin’s methylation score, consistent with changes in methylation not causing smoking status.At a 5% false discovery rate, 39 CpGs located at 27 loci, including previously reported For middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with smoking. Our study suggests that smoking has a causal effect on peripheral blood DNA methylation, but not vice versa.The online version of this article (10.1186/s13148-018-0452-9) contains supplementary material, which is available to authorized users. Epigenetics is a mechanism modifying gene expression without changing underlying DNA sequence. DNA methylation, a phenomenon that typically a methyl group (-CH3) is added to a cytosine-guanine dinucleotide (CpG) at which the cytosine is converted to a 5-methylcytosine, has been proposed to play a role in the aetiology of complex traits and diseases , 2.AHRR, F2RL3, GPR15, GFI1, 2q37.1 and 6p21.33, have been consistently reported, and a systematic review published in 2015 found that associations for 62 CpGs had been reported at least three times [At least 21 epigenome-wide association studies (EWASs) have reported that methylation in the blood of adults at a great many CpGs is associated with smoking status –23. A reee times . Apart fee times , 20, 22 ee times , 20, 22 F2RL3 and GPR15 genes.Most of the reported associations are from cross-sectional designs; thus, the causal nature of the association, i.e. whether DNA methylation has a causal effect on smoking or vice versa, is unknown. There is also a possibility that cross-sectional epigenetic associations are due to familial confounding . StudiesIn this study, we aimed to investigate association between smoking and blood DNA methylation, to replicate associations previously reported and to investigate putative causal nature of the association using regression methods for related individuals.The sample comprised women from the Australian Mammographic Density Twins and Sisters Study . A totalA telephone-administered questionnaire was used to collect participants’ self-reported information on smoking. Participants were asked the question ‘Have you ever smoked at least one cigarette per day for 3 months or longer?’ Participants who answered ‘No’ were classified as never smokers, and the rest ever smokers. Ever smokers were further questioned for age at starting smoking, the average number of cigarettes smoked per day, and age at stopping smoking, if any. Ever smokers who had stopped smoking before the interview were classified as former smokers, and the rest current smokers.minfi package [preprocessIllumina) and subset-quantile within array normalisation (preprocessSWAN) [ComBat [P value> 0.01) in one or more samples, with documented SNPs at the target CpG, with beadcount < 3 in more than 5% samples, binding to multiple locations [DNA was extracted from dried blood spots stored on Guthrie cards using a method previously described . Methyla package , which iessSWAN)  for type [ComBat  was applocations  or bindiocations  for moreM value, a logit transformation of the percentage of methylation, as the outcome and smoking status  as the predictor. The model was adjusted for age and estimated cell-type proportions [lmer function from the R package lme4 [P value was calculated based on that, twice the difference in the log likelihoods between the full and nested models approximately follows the chi-squared distribution with two degrees of freedom. To account for multiple testing, associations with a false discovery rate (FDR) [We investigated the association using a linear mixed-effects model in which the methylation portions  as fixedage lme4 . The likte (FDR)  < 0.05 wFor identified CpGs, we investigated their associations with cumulative smoke exposure indicated by pack-years for ever smokers and with years since quitting for former smokers. Pack-years were calculated as the average number of cigarettes smoked per day divided by 20 and multiplied by the number of years smoked, and were log-transformed to be approximately normal distributed. Years since quitting were calculated as age at interview minus age at stopping smoking. The covariates adjusted and statistical inference were the same as those for smoking status, except that the model for pack-years was additionally adjusted for smoking status (former and current smokers) to investigate associations independent of smoking status.P < 0.05 and the same direction as that reported by Joehanes et al. were considered to be replicated, and the corresponding CpGs were referred to as ‘replicated CpGs’.After quality control, 18,671 CpGs reported from the largest meta-analysis performed by Joehanes et al.  were incFor the identified CpGs and replicated CpGs, we performed between- and within-sibship analyses , 42 to iM values, smoking exposures and covariates were orthogonally transformed within sibships to obtain sibship means and within-sibship differences for these variables; see Stone et al. [βB) and within-sibship coefficient (βW). When βB ≠ βW and βW ≈ 0, i.e. the association disappears when familial factors are adjusted, the observation is consistent with the association being due to familial confounding. When βB ≈ βW ≠ 0, i.e. the association is similar regardless of whether familial factors are adjusted, the observation is consistent with absence of evidence for familial confounding; see Carlin et al. [B and βW.In the analysis, the methylation e et al.  for moren et al.  for moreWe performed causal inference between smoking status and methylation using Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON), a regression-based methodology for analysing twin data –48. By cX and Y, measured for pairs of twins, and for example, let X refer to smoking status and Y refer to methylation. Assume that X and Y are positively associated within an individual. Let S denote the unmeasured familial factors that affect both twins, SX represents those factors that influence X values only, SY those that influence Y values only, and SXY those that influence both X and Y values. For the purpose of explanation, let ‘self’ refer to an individual and ‘co-twin’ refer to the individual’s twin, but recognise that these labels can be exchanged and both twins within a pair are used in the analysis.As shown in Fig. Yself and Xco-twin, it might be due to a familial confounder, SXY , fitted using the  geepack , to takeE(Yself) = α + βselfXselfModel 1: E(Yself) = α + βco-twinXco-twinModel 2: E(Yself) = α + β′selfXself + β′co-twinXco-twinModel 3: Yself and Xco-twin is solely due to familial confounders  and the marginal association between Yself and Xco-twin (βco-twin in model 2) must both be non-zero. Adjusting for Xself, however, the conditional association between Yself and Xco-twin (β′co-twin in model 3) is expected to attenuate from βco-twin in model 2 towards the null. Similarly, adjusting for Xco-twin (model 3), the conditional association between Yself and Xself (β′self in model 3) is expected to attenuate from βself in model 1 towards the null.If the correlation between ers Fig. a, the maYself and Xco-twin is solely due to a causal effect from X to Y . Conditioning on Yco-twin induces a negative correlation between Xco-twin and Yself , so that βco-twin in model 2 depends on the within-pair correlations in X (ρX) and in Y (ρY): if ρX > ρY, βco-twin is expected to be positive; otherwise βco-twin to be negative. Conditioning on Xself (model 3), both pathways are blocked and the conditional association (β′co-twin in model 3) is expected to attenuate towards the null.If the correlation between o Y Fig. b, Yself Yself and Xco-twin is solely due to a causal effect from Y to X  age for the 479 women was 56.4 (7.9) years. The women included 291 (60.8%) never smokers, 147 (30.7%) former smokers and 41 (8.5%) current smokers. Ever smokers had a median (interquartile range) of 7.0 (13.8) pack-years. Former smokers had an average (SD) of 21.5 (11.4) years since quitting.SLC2A4RG) and cg21733098 (12q24.32), have only been reported from the meta-analysis performed by Joehanes et al. [AHRR (9 CpGs), 2q37.1 (3 CpGs), 6p21.33 (3 CpGs), and F2RL3 (1 CpG).Methylation at 39 CpGs located at 27 loci was found to be associated with smoking status . The same results were found from the analyses of pack-years and years since quitting .For the 1882 replicated CpGs, no evidence for a difference between Within twin pairs, the correlation in smoking status was 0.11  − 0.06, 0.27), smaller than the correlations in methylation scores for the replicated CpGs and for the identified CpGs, which were 0.37  and 0.22 , respectively.βself = 74.6, 95% CI 55.3, 93.9), and negatively associated with her co-twin’s smoking status . Conditioning on her co-twin’s smoking status (model 3), β′self remained unchanged (P = 0.41) compared with βself in model 1, while conditioning on her own smoking status (model 3), βco-twin in model 2 attenuated by 123.3%  to be β′co-twin of 2.5 . From the analysis in which methylation score was the predictor and smoking status the outcome, a woman’s smoking status was associated with her own methylation score , but not with her co-twin’s methylation score . In model 3, β′self and β′co-twin remained unchanged (both P > 0.1) compared with βself in model 1 and βco-twin in model 2, respectively. These results were consistent with that smoking has a causal effect on the overall methylation level at these CpGs, but not in the opposite direction. Similar results were found and a similar causality was inferred for smoking status and the overall methylation level at the identified CpGs  and cg21733098 (12q24.32), reported by the largest meta-analysis [We performed an EWAS of smoking for a sample of middle-aged women and found 39 CpGs at which methylation was associated with smoking status. Our study confirmed the associations for several previously consistently reported loci including analysis  so far. SLC2A4RG (solute carrier family 2 member 4 regulator gene). SLC2A4RG is involved in the Gene Ontology pathway for regulation of transcription (GO:0006355). Protein encoded by SLC2A4RG regulates the activation of SLC2A4 (solute carrier family 2 member 4). SLC2A4 is involved in the glucose transportation across cell membranes stimulated by insulin. Genetic variants at SLC2A4RG have been found to be associated with inflammatory bowel disease [12q24.32. The region contains several long non-coding RNA genes. Little is known about the regulatory function of cg21733098. The biological relevance of smoking to blood methylation at these two CpGs is largely unknown, and more research are warranted.To the best of our knowledge, our study is the first study to confirm the associations for cg06226150 and cg21733098. cg06226150 is located at the promoter of, and potentially regulates the expression of,  disease . cg21733We found evidence that 18 and 20 of the identified CpGs were also associated with pack-years and years since quitting, respectively. Given that smokers have lower methylation levels at the identified CpGs, the negative associations with pack-years imply that there appear to be dose-relationships between smoking and methylation at the 18 CpGs, and the positive associations with years quitting smoking imply that methylation changes at the 20 CpGs tend to reverse after cessation. The dose-relationship and reversion have also been reported by several studies , 20, 22.AHRR and F2RL3, are observed across Europeans [F2RL3) and cg19859270 (GPR15) between current and never smokers are consequential to smoking under the assumptions of MR.Our study, as one of the first studies, provides insights into the causality underlying the cross-sectional association between smoking and blood DNA methylation. Our results are inconsistent with the proposition that the cross-sectional association is due to familial confounding, e.g. shared genes and/or environment. The roles of shared genes and/or environment are also in part unsupported by that certain smoking-related loci, such as uropeans , 20, 22,uropeans , Arabianuropeans , East Asuropeans , 23, anduropeans , 13, 18,uropeans  also sugAHRR and GFI1, and maternal smoking in pregnancy [AHRR gene encodes a repressor of the aryl hydrocarbon receptor (AHR) gene, the protein encoded by which is involved in the regulation of biological response to planar aromatic hydrocarbons. Polycyclic aromatic hydrocarbons, one main smoking-related toxic and carcinogenic substance, trigger AHR signalling cascade [AHR gene activates the expression of the AHRR gene, which in turn represses the function of AHR through a negative feedback mechanism [AHRR gene caused by smoking is biologically plausible.That smoking causes changes in methylation is also supported to some extent by other evidence. The ‘reversion’ phenomenon is in line with the ‘experimental evidence’ criterion proposed by Bradford Hill, i.e. ‘reducing or eliminating a putatively harmful exposure and seeing if the frequency of disease subsequently declines’ . The assregnancy  also imp cascade , 22. Proechanism . That hyThat smoking causes changes in blood methylation has great clinical and etiological implications: methylation might mediate the effects of smoking on smoking-related health outcomes. As introduced above, there have been a few studies –29 invesOur study shows the value of ICE FALCON in causality assessment for observational associations. Associations from observational studies can be due to confounding and, although analyses of measured potential confounders can eliminate some confounding, there is always the possibility of unmeasured confounding, even with prospective studies. With recent discoveries of genetic markers that predict variation in risk factors, the MR concept has been explored by epidemiologists. MR uses measured genetic variants as the instrumental variable and the results of MR might be biased due to several factors such as strengthen of instrumental variable, directional pleiotropy, and unmeasured confounding . ICE FALWe found evidence that in the peripheral blood from middle-aged women, DNA methylation at several loci is associated with smoking. By investigating causation underlying the association, our study found evidence consistent with smoking having a causal effect on methylation, but not vice versa.Additional file 1:Table S1. This file includes Table S1: Associations for the 1882 replicated CpGs. (XLSX 156 kb)Additional file 2:Table S2. This file includes Table S2: Associations of methylation at the 1882 replicated CpGs with smoking status from the between- and within-sibship analyses. (XLSX 100 kb)


Specifications TableValue of the data•+2, Mg+2, Na+, K+ , F−, Cl−, Determination of hydro-geochemical characterization such, T (°C), EC (µS/cm), pH TDS, SA, TH, •The chemistry of groundwater is an important factor determining its use for domestic, irrigation and industrial purposes. Due to limited literature available for the study area, this data can help to better understand the quality of groundwater and provide information for further studies in the field of purification and better water quality management.•The occurrence of scaling and corrosion may create staining and blocking of piping systems leading to economic and safety problems. In addition, corrosion products contaminate the water resulting in health problems. Therefore, corrosion control is an important aspect of safe drinking water supplies.•Corrosion indices calculated are important in the monitoring of water supply distribution networks.1+2, Mg+2, Na+, K+, Cl−, F−, This dataset contains 5 Tables and 6 Figures that represent quality as well as corrosion and scaling potential of groundwater of the South West Delhi, India. 22.1The South West District of N.C.T. of Delhi is situated between latitude 28 40′ and 28 29′ and longitude between 76 50′ and 77 14′. The South West district has a varied character with Kapashera Sub Division as predominantly rural and the Dwarka Sub Division as mostly urban and Najafgarh Sub Divisions as a mix of both urban and rural population.2.2+2, Mg+2 were measured by EDTA titrimetric method. Na+, K+ were measured using Flame photometer . Cl−1 contents were measured by ergonometric titration. F− was determined using SPANDS method, The concentration of The samples were collected in thoroughly cleaned 2 L capacity bottles and stored at a suitable temperature with necessary precautions till the analysis was done. All sampling sites were selected with a view to cover the entire area of study. Parameters such as pH, EC, SA, and TDS were measured in the field and crosschecked in the laboratory using water analysis kit . Other parameters such as TH, Ca


Convergence stagnation is the chief difficulty to solve hard optimization problems for most particle swarm optimization variants. To address this issue, a novel particle swarm optimization using multi-information characteristics of all personal-best information is developed in our research. In the modified algorithm, two positions are defined by personal-best positions and an improved cognition term with three positions of all personal-best information is used in velocity update equation to enhance the search capability. This strategy could make particles fly to a better direction by discovering useful information from all the personal-best positions. The validity of the proposed algorithm is assessed on twenty benchmark problems including unimodal, multimodal, rotated and shifted functions, and the results are compared with that obtained by some published variants of particle swarm optimization in the literature. Computational results demonstrate that the proposed algorithm finds several global optimum and high-quality solutions in most case with a fast convergence speed. Particle swarm optimization (PSO) is a bio-inspired optimization algorithm introduced by Eberhart and Kennedy , and is Some researchers got insight into three control parameters, named after acceleration coefficients and inertia weight, to develop PSO variants . t is the current generation. According to the theory of PSO, the personal experience and global experience make the particle move closer to them to get a new promising position.Particle swarm optimizer is inspired by fish’s and birds’ foraging behaviors, which are simplified as a swarm of particles by mimicking their key behaviors. As a swarm of mentclass2pt{minimω can benefit the global search while small value can contribute to local exploitation. Linearly decreasing inertia weight adopted in PSO (LPSO) significantly improves the performance of PSO for solving various optimization problems and the inertia weight ω is advised by the Eq.  and 0.4  are suggested Schewefel’s Problem 2.22 Schewefel’s Problem 1.2 Schewefel’s Problem 2.21 Step Function Quartic Function, i.e. Noise Generalized Rastrigin’s Function Non-continuous Rastrigin’s Function Ackley’s Function Generalized Griewank Function Weierstrass Function Generalized Penalized Function Cosine mixture Problem Rotated Rastrign Function Rotated Salomon Function Rotated Rosenbrock Function Rotated Elliptic Function Shifted Schewefel’s Problem 2.21 Shifted Rotated Ackley’s Function Shifted Rotated Weierstrass Function In order to assess the performance of the proposed algorithm, twenty benchmark problems including unimodal, multimodal, rotated and shifted functions selected from the literature , Wilcoxon’s rank sum test is commonly used to analyze whether two data sets are statistically different from each other, and mentclasspt{minimamentclasspt{minimamentclasspt{minimaFrom 20, 30 and 50 dimensions’ results in Tables For three different dimensions, final rank obtained by LPSO-API algorithm all takes the first place and that obtained by PSO-API algorithm are all the second. The final rank can reflect the comprehensive performance of algorithm on a suite of benchmark problems. From the rank, it is clearly seen that LPSO-API algorithm and PSO-API algorithm shows the superiority than LPSO algorithm and PSO algorithm in high-quality solutions.From the data in Tables f5(x), two multimodal problems f7(x) and Six representative benchmark problems, two unimodal problems f1(x), f2(x), f3(x), f5(x), f6(x), f7(x), f8(x), f9(x), f10(x) and f12(x) in section “5 and dimension number is 30. The size of population is 20. All the problems are optimized 30 times. Parameters settings of PSO-API and other settings are identical to that in last section. The comparisons of these PSO algorithms are shown in Table In recent literatures, various PSO algorithms are also developed and perform well on numerical experiments. To compare with these PSO algorithms, eight PSO variants (PSO-cf (Kennedy and Mendes f1(x), f2(x), f3(x), f5(x), f7(x), f8(x), f9(x), f10(x) and performs worst on f6(x) and f12(x). Table From Table Time complexity of algorithm also should be considered and a computational experiment of six PSO variants [PSO-cf , f7(x), f9(x), f10(x) in section “f21(x), and the expression of f21(x) is shown as follows.In order to compare with FSS , f10(x), f21(x) with 30 dimensions are used. The generations is 2000. The population has four sizes of 20, 40, 80, 160. Each experiment will perform 100 runs. Average best fitness (Avg. best fitness) and standard deviation (SD) of PSO-API, FSS and CenterPSO are presented in Tables Population size of PSO-API sets as 30. 30 runs are conducted for each problem and each run will perform 1 × 10From the data in Table In this work, to make full use of multi-information characteristics of all personal-best information, an improved PSO algorithm using three positions with all personal-best information has been adopted to enhance the performance. In proposed algorithm, an improved cognition term using the personal-best position, the centroid position and the median position is introduced in velocity update process of PSO. To validate this strategy, a set of benchmark functions including unimodal, multimodal, rotated and shifted benchmark functions with 20, 30 and 50 dimensions have been optimized. Experimental results show that the strategy using multi-information characteristics of all personal-best information is a valid strategy for the purposes of improving the PSO’s performance. Moreover, PSO-API algorithm has also been used to compare with several PSO variants and some similar algorithms of the proposed algorithm. Numerical results show that the PSO-API algorithm has higher precision and satisfied performance. To sum up, the proposed strategy enhances the search ability of PSO and PSO-API algorithm is an efficient PSO variant to obtain promising solution for most of benchmark functions.


In the original article, there was an error in the CpG oligo-dinucleotide sequence used as adjuvant.A correction has been made to the section “Materials and Methods”, paragraph “Antibodies and adjuvants”: CpG oligo-dinucleotides 5′-ggTGCATCGATTTATCGATTATCGATGCAGggggg-3′ with lower case letters for phosphorothioate linkages and upper case letters for phosphodiester linkages previously shown to be efficient in pigs (26) were bought from Sigma.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.CL, PS, and OS are inventors of the issued patent “A versatile delivery system for antigens or biologically active molecules.” EP 09290987.8-1222, 21.12.09. No license nor royalties. The other authors declare no conflict of interest.


Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments. Integrins are heterodimeric cell-surface adhesion molecules found on all nucleated cells. They integrate processes in the intracellular compartment with the extracellular environment. The 18 α- and 8 β-subunits form 24 different heterodimers each having functional and tissue specificity  deficient for αvβ3 and/or αvβ5 discovered that neither were essential for tumor angiogenesis. In fact, lack of αvβ3 could l growth ,26. Furtl growth . Despitel growth . This apl growth ,30. Thoul growth ).In fact, so far few anti-integrin drugs designed to target epithelial or endothelial cells have significantly benefited patients, whereas several that target leukocytes or platelets have succeeded . WhetheTGFβs are pleiotropic cytokines that are locally activated during tissue remodeling to conduct a concert of repair processes including trans-differentiating fibroblasts into a contractile, collagen-producing myofibroblast phenotype; promoting angiogenesis; and suppressing immune response ,33,34. TTGFβ is deposited by somatic and tumor cells in an inactive form, latent-TGFβ (LTGFβ). This is bound to the extracellular matrix (ECM) in a protein complex (reviewed in ). The inActivated TGFβ is implicated in promoting late-stage cancer development and spread. Cancer cells often accumulate mutations or deletions in biochemical pathways that protect them from its growth inhibitory effects ,33,34. IWhat of therapeutic targeting β1 integrins expressed by solid cancers? Many β1 integrins have been pre-clinically implicated as promoting cancer-associated processes. Some β1 integrins have successfully been targeted pre-clinically, including αvβ1 , α2β1 5, α5β1 6, and α6βNineteen of the 24 integrin heterodimers, alone or as multi-chain families , have been therapeutic targets for drug discovery. Integrins which have been targeted are indicated in https://clinicaltrials.gov/) identifier locating the trial at ClinicalTrials.gov (NCTxxxxxxxx).We have identified some 480 drugs targeting integrins (the cut-off for our survey was July 2017). Where several companies have licensed a drug, target indication and stage of development may vary, with trials discontinued in one indication but still in progress in others. Here, we note the latest stage of clinical development, rather than stating that development has been discontinued. Since our last review , severalIntegrins have also been targeted for diagnostic imaging. Apticitide (Tc-99m-P280), imaging gpIIbIIIa for acute deep-vein thrombosis in lower extremities, has been launched. (99m)Tc-maraciclatide, for identifying fibrosis in hypertrophic cardiomyopathy and acute coronary syndrome, and [18F]FPPRGD2 as a positron emission tomography (PET) imaging agent, for diagnosis of vascular inflammation diseases such as aortic aneurysm or carotid atherosclerosis, both imaging αvβ3, are in PH2 trials. 14 others imaging agents are reported to be in early development ,67.The four β1-series integrin collagen receptors  have each been therapeutically targeted, and for α2β1 there seems to be a clinical basis for further effort . Only on• α1α1β1 is a collagen-laminin receptor seen both as a target for inhibition of tumor angiogenesis and growth , and for• α2α2β1 is seen as an anti-thrombotic target , being rThe biology of α2β1 makes it an interesting therapeutic target, and as well-characterized inhibitors are known future clinical trials in oncology may be warranted.Three β1 integrins  and three αv integrins  are receptors for fibronectin . Five ca• α4®) in therapy of MS. A fatal, virally-induced demyelination disease, progressive multifocal leukoencephalopathy (PML), rare in the immune-competent, arose in natalizumab-treated patients [α4β1 binds VCAM-1 in addition to fibronectin ,84. Subspatients . This chpatients , and ledpatients , only an• Natalizumab®; Antegren) is a humanized mouse monoclonal IgG4κ antibody recognizing the human α4 chain in both α4β1 and α4β7 [Natalizumab  and PH2 trials had similar side effects to placebo, and in multi-center trials as a monotherapy for MS it strongly reduced the numbers of new lesions and relapses over placebo-treated patients ,96. It wA Cochrane report concluded that there was benefit from natalizumab in Crohn’s disease trials, and it was successfully registered in this indication in January 2008 . Biogen’• α5β1Volociximab (EOS-200-4) is a humanized chimeric IgG4 antibody inhibiting the α5β1 integrin, and seen as an anti-angiogenic therapy for solid tumors and wet age-related macular degenerative disease. It was developed by PDL  and subsequently licensed to Biogen-Idec, Ophthotech  and Abbott , but development was stopped after lack of efficacy in PH2 trials ,104. AntA pan- β1 murine monoclonal antibody, P5 ), claimed to predominantly act at α5β1, is reported in PH3 trials for NSCLC . Developαv integrins can control cancer biologies like tumor angiogenesis, growth, metastasis and immunomodulation . They alTwo pan-αv integrin antibodies have been evaluated in late-stage clinical trials, abituzumab )  and inte• AbituzumabAbituzumab from Merck KGaA is a humanized, de-immunized monoclonal IgG2 antibody. It is deglycosylated, so it is expected to not induce antibody dependent cellular cytotoxicity. In PH1 trials in progressive castration-resistant prostate cancer (CRPC) patients with bone metastases after chemotherapy, it showed a favorable safety profile and some evidence of clinical activity . In the ανβ5 and ανβ6 integrins are expressed in CRC cells ,120, andIn the POSEIDON PH1/2 trial, abituzumab was evaluated in mCRC . The triBeside cancer, abituzumab is being investigated in a PH2 trial in patients with systemic-sclerosis-associated interstitial lung disease (SSc-ILD) (NCT02745145), to evaluate safety and efficacy (immune response). As in other fibrotic diseases, in SSc-associated fibrosis the data emphasize a role for TGFβ ,124. Loc• IntetumumabIntetumumab (CNTO-95) from Centocor is also a pan-αv integrin inhibitor. It is a fully human IgG1 and can induce ADCC, in contrast to abituzumab, an effector-negative IgG2. Several PH1 trials demonstrated a favorable safety profile for intetumumab. A PH2 trial in melanoma, as monotherapy and as combination with dacarbazine, demonstrated no statistically significant efficacy, but a trend for an improved OS . Another• αvβ3αvβ3 integrin has been preclinically implicated in tumor angiogenesis, macular degenerative eye disease, bone resorption, and in the progression of several tumors including melanoma and glioblastoma, where its expression is a negative prognostic indicator. Vitaxin ), and efatucizumab ) are humanized higher affinity variants derived from murine antibody LM609. They have been tested in multiple PH2 oncology trials, for example in prostate (NCT00072930) and lung carcinomas, CRC (NCT00027729) and in melanoma , in combinations with standard of care . But theSeveral other αvβ3 inhibitors are in PH2 trial in diverse non-oncological indications. SF-0166 ) is a fluorinated small molecule inhibitor in PH2 trial (NCT02914613) for topical treatment of wet age-related macular degeneration and diabetic macular edema. VPI-2690B  with Janssen ) is a monoclonal antibody in PH2 trial (NCT02251067) for diabetic nephropathy. MK-0429 ) is a small molecule in development both for hormone refractory prostate cancer and for osteoporosis , but no • αvβ5αvβ5 is a vitronectin receptor which has been implicated in resorption of rod cell membranes , and as • αvβ3 and αvβ5O6-methylguanine DNA methyltransferase (MGMT) gene promoter (a stratification marker for sensitivity to temozolimide), while a parallel PH2 study (CORE: NCT00813943) examined the temozolimide-insensitive MGMT-unmethylated population. Both trials showed that cilengitide had no clinical benefit. A PH2 trial (ADVANTAGE: NCT00705016) in first-line SCCHN patients, in combination with cetuximab and platinum-based chemotherapy also failed to give a clear positive outcome. A PH2 trial in first-line NSCLC (CERTO: NCT00842712), in combination with cetuximab and cisplatin, also failed its primary endpoint and development was stopped [Cilengitide (EMD121974) from Merck KGaA is a constrained cyclic pentapeptide based on the RGD-sequence, that specifically inhibits αvβ3 and αvβ5 ,131. Pre stopped ,141,142. stopped , with ce stopped , in chil stopped  were com stopped .1/2 = 3–5 h) [Cilengitide is rapidly cleared from serum (t= 3–5 h) , but con= 3–5 h) . Preclin= 3–5 h) , and on = 3–5 h) . This le= 3–5 h) ). We shoThe lack of efficacy of cilengitide in GBM trials was a surprise, as well as a disappointment , for the• αvβ6αvβ6, originally identified on airway epithelial cells, and as a fibronectin receptor on colon carcinoma cells, was shown in a landmark study to be a local activator of latent TGFβ, and lack of αvβ6 in mice startlingly phenocopied the TGFβ1 knock-out mouse   from Biogen-Idec ,154 is i• αvβ1 and αvβ8αvβ8 is a LTGFβ activator, but its tissue distribution differs markedly from αvβ6 ,156. EffThree β1 integrins , and α6β4 are laminin receptors; two collagen receptors  see . may as Over the past decade many structural details of the conformational activation cycles that integrins experience have been revealed. Here, cytoplasmic signals trigger the transformation of integrin structures which cannot bind extracellular ligands, to high-affinity states that can  ,162,163.4-fold higher affinity in response to local cytokine signals [β2-series integrins are restricted to leukocyte lineages, where they regulate cell-cell interactions involved in innate and adaptive immunity. The low-affinity state on leukocytes in the circulation is rapidly converted to a 10 signals ,165. β2- signals . Other t signals ). Inhibi signals .• Lifitegrast®; SAR 1118) is a low-molecular weight tetrahydroisoquinoline antagonist of αLβ2 [1/2 = 47 min in rat; <4 h in human). This, and its low potency in CYP450 inhibition assays and ether-a-go-go studies, predicted the observed good drug tolerance in humans —without the side-effects of systemic inhibitors of B- and T-cell adhesion [Lifitegrast  is a humanized anti LFA-1 (αLβ2) antibody targeting the αL (CD11a) chain of the complex. Discovered by Genentech, it was developed and launched by Serono  in November 2003 for treatment of plaque psoriasis, where it was an effective therapy [Efalizumab  for targeting LFA-1 to prevent delayed graft function. It reached PH3 trial in the clinic. Although preclinical studies support the efficacy of anti-LFA-1 antibodies in suppressing graft rejection ,174, Odu• Rovelizumab®) is a humanized anti-αL antibody (Hu23F2G) developed by ICOS  which entered PH3 trial for cerebral ischemia. Development appears to have been stopped [Rovelizumab . It failed its PH2 trial endpoints, and development was stopped. BMS-587101, a small molecular weight inhibitor of αLβ2 designed for topical use in psoriasis, was stopped after showing signs of hepatotoxicity .2+ ions at the β2 MIDAS site [Inhibitors of β2 integrins work by specifically inhibiting cell adhesion and trapping of white blood cell lineages, mechanisms distinct from those of other immunosuppressive drugs: thus they are potentially attractive therapeutics, as summarized above. However, obviously therapeutic strategies must avoid life-threatening systemic side-effects. The success of Lifitegrast indicates one possible approach: topical application combined with short systemic half-life to limit exposure to the drug. Where this is not possible, focusing the therapeutic effect to a precisely defined activation state of the target integrins may also prove a successful way of minimizing undesired toxicities in future, and to enable the design of inhibitors which do not induce pro-adhesive alterations ,178,179.DAS site , and it • Vedolizumab®) is a humanized antibody IgG inhibitor of integrin α4β7, originally developed by Millenium pharmaceuticals  as MLN002, and launched in May 2014 after successful PH3 trials in patients with TNF-resistant Crohn’s disease and UC [Vedolizumab  is concentrated on dendritic cells (DCs) in the intestine, and on intraepithelial T-cells, where it mediates T-cell adhesion and DC directed retention in the gut . EtrolizAbrilumab (AMG-181: MEDI-7183) is a human IgG inhibitor of integrin α4β7, developed by Amgen  with AstraZeneca , for treating UC and Crohn’s disease, and considered for CRC . DevelopA meta-analysis of opportunistic infection and malignancy, which are a concern where immune suppressive strategies are used, in 12 Crohn’s disease and UC clinical trials using α4 and β7 inhibitors found no significant enhanced risk .The integrins gpIIbIIIa (αIIbβ3) and αvβ3 have been therapeutic targets. GpIIbIIIa for its role on platelets during thrombosis ,186, and• GpIIbIIIa InhibitorsAnti-thrombotics fall into three major classes: fibrinolytics, anti-coagulants, and platelet aggregation inhibitors (PAIs), targeting surface proteins . GpIIbIIAs noted earlier, integrins function bidirectionally, being activated inside-out by intracellular signaling, and by outside-in by extracellular stimuli . IntegriDespite concerns that competitive gpIIbIIIa antagonists might induce thrombosis or enhance bleeding, this has not been a major issue for gpIIbIIIa inhibitors in the clinic . Bleedin• Abciximab ®, was the first integrin inhibitor to reach the therapeutic market. It was registered by Centocor and Eli Lilly  in January 1995 for prevention of clot formation during high-risk coronary angioplasty. The murine progenitor acts allosterically at the gpIIIa chain (integrin β3 subunit) [The pan-β3 inhibitory humanized antibody Fab fragment, Reoprosubunit) ,200. Thesubunit) . However® [Abciximab was originally launched as a surgical-adjunct therapy for anti-thrombotic prophylaxis during percutaneous coronary intervention (PCI) (high-risk coronary angioplasty). As it was well tolerated in the clinic, its use was extended to all angioplasty, and to unstable angina patients due for angioplasty. It was registered for use in unstable angina, and subsequently a biosimilar was also launched for acute myocardial infarction by ISU-ABXIS  under the name Clotinab® .Following the clinical success of Abciximab many companies attempted to develop low-molecular weight orally-available inhibitors of gpIIbIIIa. This seemed straightforward given the existing knowledge of integrin biology. However, orally available drugs that inhibited activated gpIIbIIIa receptors often increased bleeding events, leading to severe thrombocytopenia ,203. Nev®)• Tirofiban (AggrastatN-(butylsulfonyl)-O-(4-(4-piperidinyl)butyl)-L-tyrosine mono hydrochloride monohydrate) was launched by Merck and Co. in August 1998 for use in acute coronary syndrome. It was subsequently registered for prevention of myocardial infarction in unstable angina or non-Q-wave myocardial infarction. It has recently been approved for use in percutaneous coronary intervention, and has been sold under license by a number of companies. It has a short plasma half-life of 2 h [Tirofiban • Eptifibatide ) which is an active-site mimetic of the snake venom disintegrin Barbourin ,206. In The structural basis for Tirofiban and Eptifibatide inhibition was elegantly revealed using X-ray crystallography . Althoug®) is a gpIIbIIIa-binding peptide launched in 1998 for the imaging of deep vein thromboses. It is the only approved reagent for this indication. It is supplied as a kit for use with a Technicium-99 generator, so its usage may be constrained by current difficulties in the supply of molybdenum-99 [Tc-99m-P280  and a low volume of distribution. It has a high affinity for its target (Kd~5 nM), and is rapidly sequestered by circulating platelets (~50% bound within 10 min). Yet 13–29% of available gpIIbIIIa is still blocked by Reopro® a week following infusion, likely due to the depot-effect from the gpIIbIIIa pool on platelets, which hinders more rapid systemic clearance [Reoprolearance ,210. The®, and with an accessible chemistry, a burst of low-molecular weight inhibitors of gpIIbIIIa were discovered, both orally available and parenteral, but development of these (66 programs) has halted. The oral inhibitors often agonized gpIIbIIIa [After the enthusiastic reception of ReopropIIbIIIa .The future for gpIIbIIIa inhibitors is uncertain, due the use of effective anti-thrombotics from other drug classes. Factor Xa-and thrombin- inhibitors are competing in the market for gpIIbIIIa inhibitors . Orally Integrins control complex biologies that modulate cell-cell and cell-extracellular matrix interactions, and also the activation of some TGFβ family members. Integrins are exposed at the cell surface, and accessible to many forms of therapeutic intervention. Furthermore, their expression is regulated, often dramatically, during human malignancies, and during fibrotic and inflammatory diseases. This has made them seductive therapeutic targets. Yet nearly 30 years of interaction has cooled the ardor of therapeutic developers for many of these previously desirable partners.Both our knowledge and our ignorance of integrin biology have grown with time. There are several reasons for this. First, surprisingly, we still lack a reliable quantitative normal and pathological tissue distribution for many integrins. We have been restricted by a lack of antibodies which reliably function in immunohistochemistry (IHC) of formalin-fixed-paraffin embedded (FFPE) material, the material that makes up the majority of human pathology collections. The collection, storage and archiving of frozen tissues, where many antibodies do reliably function, is challenging, not least in the context of a multi-center, multi-continent clinical trial. We have been restricted by the persistence of archaic analytical modalities, rather than quantitative digital image analysis for enumerating relative expression levels in situ. Integrin RNA expression-profiling is a poor surrogate, as integrins are heterodimers. Furthermore, antibodies capable of detecting integrins in FFPE material rarely reveal the activation state of integrins in situ. Yet this defines whether they are drug targets helping drive a pathology , or whether they are by-standers sustaining homeostasis . The availability of antibodies that can recognize different activation states of gpIIbIIIa have greatly helped interpret therapeutic responses . Second,What has started to emerge from the nearly 70,000 papers referring to integrins in MEDLINE, is a theme replaying a current trend in cancer biology. Reagents that have effectively targeted biological mechanisms driving in vitro and in vivo models have not translated to efficacious therapeutics in the clinic—though it must be remembered that this statement is based largely on combination therapies with chemotherapeutics, rather than on modern immunotherapies. This includes biologies like angiogenesis, targeting endothelial cells or podocytes , or cell proliferation, targeting tumor cells or fibroblast lineages . Whereas drugs that have targeted immune-cell-cell interaction targeting T-cells or B-cells  have clear clinical efficacy. In total, the statistically valid numbers of clinical trials on which this comment is based is still quite low, and this might be a chance observation. Clarification will await further studies. Predictive biomarker for patient stratification could also be a major step forward for the integrin field to translate preclinical efficacy into a beneficial treatment for patients.Despite substantial effort, only seven drugs targeting integrins have actually reached the clinical market: abciximab; tirofiban; eptifibatibe; natalizumab; vedolizumab; and lifitegrast; with efalizumab being withdrawn. This seems somewhat below par for drug development, as 10% of drugs entering PH1 trails are reckoned on average to successfully pass PH3 into the market. As mentioned, some 480 drugs have entered integrin clinical trials, and some have been tested in multiple indications. Why this apparent lack of success? On one hand, animal models and especially systemic knock-out mouse models have been misleading for the integrins—excepting, perhaps, the models where overt immune function was involved. Embryonal function of an integrin need not reflect its function either in the normal or the ill adult. For example, the αv-integrin constitutive knockout mouse was 100% embryonal-perinatal lethal : meanwhiProspective cancer therapies have often been investigated using xenograft models. The limited translatability of such cell-line derived tumor models to human disease has been extensively discussed, and is one of the many contributory factors to the lack of reproducibility of preclinical cancer studies . The selThe pharmaceutical industry appears conservative. This is understandable as getting a cancer medication from concept to market typically costs over a billion euros, dollars or pounds. This has left a number of interesting technologies relatively untested in the field of integrin therapeutics. For example antibody-drug conjugates, small-molecule-drug conjugates, co-therapy with immune-modulators, and more exotic antibody technologies, using smaller and so more tissue permeable single chain antibodies. Intrabodies, bi- or multi-paratopic antibodies to alter multiple functions simultaneously, or the use of alternative-binder technologies, like the knottins, DARPins and affimers  have yet• Health Economics: Will New Integrin-Targeting Drugs Be Affordable?As we have described here, there have been several therapeutic anti-integrin successes. As antibody-based therapeutics are seen as transforming treatment success rates, especially in cancer , the posConsider this: NCI cancer-incidence figures  estimateDoes this make development of anti-integrin therapies pointless? Hopefully not. The spiraling cost of drugs (increasing 10% per year till 2013 ) is forcThis is undoubtedly neither a mutually desirable, nor an acceptable, nor even a necessary outcome.Thus, even though the development costs of drugs is still expected to rise for the foreseeable future, the increased availability and approval of cheaper generic drugs  and biosimilars (for biotherapeutics) (discussed in ) and espIntegrins have been a focus of therapeutic development for nearly 30 years, but despite some outstanding therapeutic successes, their complex biology has often confounded drug development. This is especially true in cancer therapy. While “simple” cell-cell interactions have been effectively targeted, a drug designed to target other specific biological mechanism may be useless when faced with less obvious functions driven by an integrin target. For example, the discovery of exosomes as controlling elements in cancer occurred after most current integrin cancer trials were initiated. Their significance and what the consequences of inhibiting their function might be, or might have been in past trials, remains a blank page. Now that knowledge of integrin structure can enable the design of drugs specific to given integrin activation states, we may see more successful future developments, including in cancer therapy targeting integrins.


No survival difference was observed between the “neoadjuvant chemoradiation followed by surgery” protocol and the “upfront surgery and pathological stage-based adjuvant chemoradiation” strategy.Adjuvant chemoradiation is reported to have a survival benefit for esophageal squamous cell carcinoma (ESCC). We evaluated the “upfront surgery and pathological stage-based adjuvant chemoradiation” strategy, in which adjuvant therapy is guided by pathological stage, in locally advanced ESCC. Data from 2976 clinical stage II/III ESCC patients, including 1735 in neoadjuvant chemoradiation and 1241 in upfront surgery groups, were obtained from a nationwide database. Patients in the upfront surgery group were further categorized into the “upfront surgery and pathological stage-based adjuvant chemoradiation” and “upfront surgery only” groups. The 3-year overall survival (OS) rates in the “neoadjuvant chemoradiation”, “upfront surgery and pathological stage-based adjuvant chemoradiation”, and “upfront surgery only” groups were 41.5%, 45.8%, and 28.5%, respectively. In propensity score matched patients, the 3-year OS rate was 41.7% in the neoadjuvant chemoradiation group, compared to 35.6% in the “upfront surgery and pathological stage-based adjuvant chemoradiation” group ( The strategy of neoadjuvant chemoradiation followed by surgery has been well recognized as an efficient approach. In the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS), the survival of patients with clinical stage T1N1 or T2-3N0-1 could be enhanced with the implementation of neoadjuvant chemoradiotherapy compared to surgery alone3. On the other hand, the strategy of upfront surgery followed by adjuvant treatment guided by pathologic findings has also been proposed by several retrospective studies. For adenocarcinoma, Zahoor et al. reported that upfront minimally invasive esophagectomy may be a reasonable approach, improving stage-based prognostication and potentially minimizing overtreatment in patients with clinical stage II or higher tumors4. For squamous cell carcinoma, Matsuda et al. reported that no significant survival difference was observed between “neoadjuvant chemotherapy” and “upfront surgery plus adjuvant chemotherapy for pN + stage” approaches in patients with clinical stage III tumors5.Multidisciplinary therapy comprising surgery, chemotherapy, and radiotherapy is currently widely introduced in the treatment of esophageal cancer in an attempt to improve prognosis7. Moreover, in patients who completed trimodal treatments, which included surgery and chemoradiotherapy, there was no difference in overall survival or disease-free survival between neoadjuvant (preoperative) and adjuvant (postoperative) chemoradiation groups8. Supported by these data, we aimed to evaluate the “upfront surgery and pathological stage-based adjuvant chemoradiation” strategy and compare it to the “neoadjuvant chemoradiation followed by surgery” approach in locally advanced ESCC. We hypothesized that upfront surgery can avoid unnecessary chemoradiation in patients who are clinically overstaged and that the outcome after adjuvant chemoradiation can be comparable to that after neoadjuvant chemoradiation.We have previously evaluated the role of adjuvant chemoradiation in esophageal squamous cell carcinoma (ESCC) and found that surgery followed by adjuvant chemoradiation is significantly more effective than surgery alone at increasing the overall survival and decreasing recurrence ratesA total of 2976 patients were included in this study Fig. . The clip = 0.986, Fig. p = 0.010) and those in the “upfront surgery only” group (28.5% and 16.4 (95%CI: 14.5–18.7) months, respectively, p < 0.001, Fig. In the survival analysis, the median follow-up time was 37.1 : 21.8–82.5) months for the surviving patients. There was no difference in overall survival between groups A and B. The 3-year overall survival rates and median survival were 41.5% and 24.8 (95%CI: 22.9–28.1) months in group A, versus 41.2% and 26.0 (95%CI: 23.5–29.3) months in group B (p = 0.002) for worse overall survival. In contrast, the “upfront surgery and pathological stage-based adjuvant chemoradiation” strategy was not a significant prognostic factor  compared to the “neoadjuvant chemoradiation followed by surgery” group.In the Cox regression model Table , the sigp < 0.001, Fig. p = 0.147) between the neoadjuvant chemoradiation followed by surgery group and the “upfront surgery and pathological stage-based adjuvant chemoradiation” group, with 3-year overall survival rates and median overall survival of 35.6% and 22.3 (95%CI: 18.5–26.3) months. In contrast, the upfront surgery only group had the worst overall survival, with 3-year overall survival rates and median overall survival of 20.3% and 12.7 (95%CI: 9.7–15.1) months  and larger tumor lengths . However, higher age  and CCI  in the upfront surgery only group might be the reasons that interfered with the decision for adjuvant chemoradiation.The patient characteristics of the “upfront surgery and pathological stage-based adjuvant chemoradiation” group and the “upfront surgery only” group are shown in Table p = 0.005 and E vs. F, p < 0.001 in Fig. p = 0.803). These observations lead to our next question: the impact of different treatment strategies on clinical T3N0 and T1-3N1 tumors.In the upfront surgery group, patients were also classified based on pathological stage and the use of adjuvant chemoradiation (CRT), namely, “T1-2N0 tumors without adjuvant CRT”, “relatively good prognosis advanced cancer with or without adjuvant CRT” and the “most advanced cancer with or without adjuvant CRT”. Whereas the “relatively good prognosis advanced cancer” included T3N0 and T1-3N1 stages, the “most advanced cancer” referred to T4, N2-3, and M1 stages. In the survival curve analysis, patients with T1-2N0 tumors obviously had the best overall survival . In other words, 22.3% (161/723) of patients with clinical T3N0 and T1-3N1 tumors were found to have pathological T1-2N0 tumors. The upfront surgery strategy avoids unnecessary chemoradiation in these patients. In addition, the overall survival in patients with non-pCR after neoadjuvant chemoradiation was similar to that in patients with relatively good prognosis advanced cancer and receiving no adjuvant CRT , but worse than that in those with adjuvant CRT . In our cohort, 53.5% (387/723) of patients with clinical T3N0 and T1-3N1 tumors had similar pathological stages, and their survival, with the use of adjuvant CRT, was non-inferior to the neoadjuvant chemoradiation protocol. Finally, 24.2% (175/723) of patients with clinical T3N0 and T1-3N1 tumors were actually with the most advanced cancer, which means pT4, pN2-3, and pM1 stages. Even with adjuvant CRT, the outcome was very poor after upfront surgery  or non-pCR (n = 618). According to pathological stage and the use of adjuvant chemoradiation, patients in group B were further classified as T1-2N0 tumors without adjuvant CRT (n = 161)”, “relatively good prognosis advanced cancer with (n = 194) or without (n = 193) adjuvant CRT” and the “most advanced cancer with (n = 130) or without (n = 45) adjuvant CRT”. The first observation in the survival curves analysis  and adjuvant (postoperative) chemoradiation groups8. All these observations motivate us to evaluate the impact of “upfront surgery and pathological stage-based adjuvant chemoradiation” strategy, which means the indication for chemoradiotherapy is based on pathological stage after upfront esophagectomy. Whereas no further treatments for pathological T1-2N0 tumors, patients with poor prognostic factors, i.e., pathological stage higher than T1-2N0 tumors, would receive adjuvant chemoradiation. We found that a significant portion of clinical stage II/III patients were actually with pathological stage I (T1-2N0), in which unnecessary chemoradiotherapy could be avoided with an upfront surgery strategy. In both original and matched cohorts, the survival of the “upfront surgery and pathological stage-based adjuvant chemoradiation” group was not inferior to that of the “neoadjuvant chemoradiation followed by surgery” group. Our findings echo with reports in the literature. In a retrospective study of patients with clinical stage II or higher esophageal adenocarcinoma, minimally invasive esophagectomy was performed regardless of tumor stage or the use of neoadjuvant therapy. Guided by pathological stage, adjuvant treatment was administered to 49% of upfront esophagectomy patients. The authors reported that primary minimally invasive esophagectomy followed by adjuvant chemotherapy does not negatively influence survival compared with patients treated with neoadjuvant therapy4. In another study of the multimodal treatment combination of upfront surgery followed by adjuvant chemotherapy for esophageal squamous cell carcinoma, 45% of patients with positive lymph node involvement received adjuvant treatment, and the completion rate was as high as 91%. Patients who received adjuvant chemotherapy showed longer survival than those who underwent surgery alone. However, no significant difference in overall survival was observed between the neoadjuvant treatment and upfront surgery groups5. In contrast, in the pivotal CROSS study, no further treatment was administered to patients in the surgery alone group, even as high as 75% of patients had pathologically positive lymph node metastasis3. To some extent, the CROSS study compared the neoadjuvant chemoradiation group to an undertreated group. A randomized controlled trial comparing different combinations of multimodal treatments is justified.According to the analysis of the Taiwan Cancer Registry database, we have previously suggested pT3/4 stage, positive lymph node involvement, larger tumor size, poorly differentiated tumors, and R1/2 resection as indications for adjuvant chemoradiation12. Additionally, patients who underwent surgery only without adjuvant treatment had a higher age and CCI compared to those who underwent adjuvant chemoradiation in our study, implying that patient age and comorbidities are critical reasons that interfere with the decision for adjuvant chemoradiation. Second, in the analysis based on pathological stage, patients who received upfront surgery but had the “most advanced cancer,” i.e., the most advanced cancer. The pT4, pN2-3, and pM1 stages were associated with dismal prognosis despite the use of adjuvant chemoradiation. Compared to pT3N0 and pT1-3N1 stages, which have limited lymph node involvement and no adjacent organ invasion, the most advanced cancers are at high risk for incomplete resection; thus, they should be avoided in the upfront surgery strategy. In the current study, nearly one-fourth of patients with clinical T3N0 and T1-3N1 tumors actually had the most advanced cancer. The accuracy of clinical staging should be improved to decrease the proportion of clinically under-staged patients.Although the “upfront surgery and pathological stage-based adjuvant chemoradiation” strategy seems to be a reasonable approach in our study, there are several caveats. First, the indications for adjuvant chemoradiation were not randomized in our study. Whereas some hospitals in Taiwan recommend adjuvant chemoradiation for patients with pathologically poor prognostic factors, some stick to the NCCN guideline and just suggest surveillance as long as there is no residual tumor13. In this study, pretreatment tumor factors and patient comorbidities were included in the propensity score matching to decrease potential bias caused by factors that may interfere with treatment decisions. However, we have no data regarding neoadjuvant chemoradiation-related toxicities and surgical complications. Patients who failed to survive neoadjuvant chemoradiotherapy were not included. Similarly, patients who failed to survive upfront surgery and could not receive adjuvant chemoradiation were categorized in the upfront surgery only group. In addition, the toxicity of adjuvant chemoradiation was not evaluated in this study. However, it has been shown that the completion rates of adjuvant therapy are between 65 and 91%14. In our previous study, less than 10% of patients in the adjuvant chemoradiation group received radiation doses less than 40 Gy, suggesting that most patients could complete the entire course of adjuvant treatments6. Indeed, it has been adopted that early recovery after minimally invasive esophagectomy will improve the delivery of adjuvant therapy, whose role needs to be reappraised in the era of minimally invasive surgery. Furthermore, the Taiwan Cancer Registry database lacks detailed information on staging workup studies, chemoradiation regimens, radiation fields, and surgical techniques, which constitute the limitations of this study.The Taiwan Cancer Registry database has standardized definitions of terminology, coding and procedures of the registry’s reporting system. There are also several corrigendum procedures applied to ensure the completeness and accuracy of cancer registration data, e.g., hospitals are required to carry out a self-check procedure using standardized logic algorithms and software provided by the central office to identify and correct potential errors before the data submissionIn conclusion, there was no significant difference in overall survival between the standard neoadjuvant chemoradiation followed by surgery protocol and the “upfront surgery and pathological stage-based adjuvant chemoradiation” strategy, in which adjuvant chemoradiation was administered to patients with poor prognostic pathological factors. However, patients with higher age and comorbidity scores may not be able to complete adjuvant treatments. In addition, patients with pathological T4, N2-3, and M1 had very poor outcomes even after adjuvant chemoradiation. Therefore, patient selection and accurate clinical staging are prerequisites when adopting upfront surgery strategies.8. In brief, patient data were obtained from the Taiwan Cancer Registry database, which is a national population-based database organized by the Health Promotion Administration, Ministry of Health and Welfare (MOHW), Taiwan. Confidentiality was ensured by the Health and Welfare Data Science Center (HWDC), MOHW, Taiwan, which encrypted individual identifiers to protect privacy before releasing information to investigators for research purposes. The diagnosis was based on their International Classification of Diseases for Oncology (ICD-O-3) site codes  and morphology codes . The staging results were determined according to the seventh edition of the American Joint Committee on Cancer TNM classification system. The inclusion criteria for this study were patients with clinical stage II and III ESCC diagnosed between 2008 and 2014 who had undergone neoadjuvant chemoradiation followed by surgical resection (group A) or upfront esophagectomy  as the initial treatment modalities. The exclusion criteria included incomplete clinicopathological information, which precluded statistical analysis. Individual patient-level data were linked with the National Register of Deaths Database for survival status confirmation and the date of death and the National Health Insurance database for comorbidities identification. Charlson’s comorbidity index (CCI) was calculated using ICD-9-CM codes, excluding cancer-related disease, in the year before starting initial treatment15.This study was carried out in accordance with the relevant guidelines and regulations. The Institutional Review Board of Taipei-Veterans General Hospital approved this study and granted a waiver of the informed consent process (IRB_2015-06-001BC). Data source acquisition was as described previouslyp value < 0.05 was considered statistically significant.Categorical and continuous variables were compared with the chi-square test and Student’s t-test, respectively. Propensity score matching was performed to decrease confounding effects due to nonrandomized assignment. First, a propensity score for each patient was calculated by logistic regression using the variables of age, sex, clinical stage, tumor location, differentiation grade, tumor length, and comorbidity score. Then, a 1:1 matched study group was created using a greedy matching algorithm. After matching, 562 well-balanced pairs of patients in groups A and B, respectively, were identified for outcome comparison. Univariable and multivariable survival analyses were analyzed using the Cox proportional hazards regression model. Survival curves were plotted using the Kaplan–Meier method and compared with the log-rank test. The overall survival was calculated as the period between the date of initial treatment and the date of death. Patients who survived to the end of the follow-up period  were censored. All statistical calculations were performed with Statistical Analysis System  and Statistical Product and Service Solutions . A Patient enrollment


During adulthood, personality characteristics may contribute to the individual capacity to compensate the impact of developing cerebral Alzheimer’s disease (AD) pathology on cognitive impairment in later life. In this study we aimed to investigate whether and how premorbid personality traits interact with cerebrospinal fluid (CSF) markers of AD pathology to predict cognitive performance in subjects with mild cognitive impairment or mild AD dementia and in participants with normal cognition.1–42, phosphorylated tau and total-tau). Participants’ proxies completed the Revised NEO Personality Inventory, Form R to retrospectively assess subjects’ premorbid personality.One hundred and ten subjects, of whom 66 were patients with mild cognitive impairment or mild AD dementia and 44 were healthy controls, had a comprehensive medical and neuropsychological examination as well as lumbar puncture to measure CSF biomarkers of AD pathology (amyloid betaIn hierarchical multivariate regression analyses, including age, gender, education, APOEε4 status and cognitive level, premorbid neuroticism, conscientiousness and agreeableness modulated the effect of CSF biomarkers on cognitive performance. Low premorbid openness independently predicted lower levels of cognitive functioning after controlling for biomarker concentrations.Our findings suggest that specific premorbid personality traits are associated with cerebral AD pathology and modulate its impact on cognitive performance. Considering personality characteristics may help to appraise a person’s cognitive reserve and the risk of cognitive decline in later life. Patients with MCI are characterized by a noticeable decline in cognitive abilities, which is relatively greater than normal age-related change observed in the healthy population, and have an increased risk of developing AD dementia during the following year. The underlying pathologies are heterogeneous and only some patients have cerebral AD pathology as the main cause of cognitive impairment. Cerebrospinal fluid (CSF) AD biomarkers reflect the cerebral accumulation of specific pathology; that is, the extracellular plaques containing amyloid beta (Aβ) , 2 and ts in CSF , 6. Studs in CSF , 8, and The risk of dementia has been reported to be associated with specific premorbid personality characteristics . PersonaIn Alzheimer’s type of dementia, the age of onset and the magnitude of cognitive impairment may depend on the individual’s capacity to compensate cerebral pathology and dysfunction, referred to as cognitive reserve . Beginni to explore the relationship between premorbid personality traits and cognitive functioning in cognitively impaired patients and healthy older subjects; and to investigate whether specific personality traits modulate the relationship between cognitive performance and cerebral AD pathology as measured by CSF biomarkers in subjects with MCI or mild dementia and in subjects with normal cognition.Information regarding personality traits is accessible through questionnaires completed by patients’ relatives, and does not involve any invasive techniques. Evaluating subjects’ personality may add significant information on the risk of AD dementia and favour the prevention of cognitive decline. The possible influence of premorbid personality characteristics on the relationship between cognitive functioning and AD pathology, as measured by CSF biomarkers at early clinical disease stages, has not yet been questioned. With this study we aim:n = 57) or mild dementia AD (n = 9)  and was made at a consensus conference of psychiatrists, neuropsychologists and/or neurologists prior to inclusion into the study. MCI was diagnosed according to widely used consensus recommendations . ParticiThe CDR is a semi-structured, clinician-rated interview with the patient and an appropriate informant, widely used to assess the progression of dementia. It is based on the ratings of the patient’s cognitive and functional impairment in six domains usually affected in AD: memory, orientation, judgement and problem-solving, community affairs, home and hobbies, and personal care . Scores 1–42, tau and ptau-181 concentrations with ELISA kits, using commercially available assays . Carrying the APOEε4 allele may influence the relationships between personality, AD pathology, age and clinical manifestations [Venous and lumbar punctures were performed between 8:30 and 9:30 am after overnight fasting at the recruiting memory centres. CSF was collected by lumbar puncture using a standardized technique with a 22 G “atraumatical” spinal needle while the patient was sitting or lying . Samplesstations  at very stations , 30. AccNeuropsychological tests were used to assess cognitive performance in the domains of memory , executPsychosocial and functional assessment included the ADL  and instPatients’ proxies were asked to complete the Revised NEO Personality Inventory, Form R (NEO-PI-R ), which t tests for independent samples. Comparison of premorbid personality traits between clinical and control subjects was performed using Welch’s t test [Data were analysed using SPSS version 20 and R . To chars t test . To scres t test  to be inThe descriptive statistics of the sample are presented in Table t test performed on the informant-report data for each of the five personality dimensions yielded a significant difference in openness to experience scores in both the control  and CI  groups (t(92.12) = 15.318, p < 0.001). Premorbid personality traits in domains of neuroticism, extraversion, agreeableness and conscientiousness did not differ between the two experimental groups (t(87.41) = 0.96, p = 0.33; t(107.61) = 1.58, p = 0.21; t(101.16) = 0.09, p = 0.76; and t(90.06) = 1.19, p = 0.28 respectively). Moreover, among the personality domains, only openness to experience was significantly correlated with MMSE score  and CDR SoB score  in the group with cognitive impairment.Welch’s ptau-181, tau/Aβ1–42 and ptau-181/Aβ1–42. Likewise, premorbid extraversion correlated negatively with tau, ptau-181, tau/Aβ1–42 and ptau-181/Aβ1–42 biomarker concentrations.We applied Kendall’s tau  correlat1–42 concentrations , high tau/Aβ1–42 levels  and high ptau-181/Aβ1–42 levels  contributed significantly in predicting the CDR SoB score. The concentrations of tau and ptau-181 did not reach any significance in model loading.Hierarchical multiple regressions revealed that, after controlling for age, gender, education level, APOEε4 expression and cognitive status, the low Aβ1–42 , β = –0.19, p < 0.05; with ptau and Aβ1–42 , β = –0.266, p < 0.01; with tau/Aβ1–42 , β = –0.193, p < 0.05; with ptau/Aβ1–42 , β = –0.252, p < 0.01). More precisely, after controlling for age, gender, education level, APOEε4 expression, cognitive status (Controls/CI) and biomarker concentrations, low premorbid openness to experience was associated with high CDR SoB score, and thus low cognitive performance.In the third step, where ratings of each personality domain were considered, only openness to experience contributed significantly in predicting the CDR SoB score , premorbid neuroticism and tau/Aβ1–42 , and premorbid neuroticism and ptau-181/Aβ1–42  concentrations negatively correlated with CDR SoB score. At high levels of neuroticism  higher concentrations of tau, tau/Aβ1–42 and ptau-181/Aβ1–42 were related to low CDR SoB score. With low neuroticism (1 SD below mean), higher levels of the same biomarkers were associated with high CDR SoB score, and thus poor cognitive functioning  and between agreeableness and ptau-181/Aβ1–42 concentrations  contributed significantly to cognitive performance  and conscientiousness and ptau-181/Aβ1–42  interactions were shown to be significant in predicting CDR SoB. At high conscientiousness, lower CDR SoB score was predicted by higher ptau-181/Aβ1–42 levels and lower Aβ1–42 levels; while at low conscientiousness, greater ptau-181/Aβ1–42 levels and lower Aβ1–42 levels predicted a higher CDR SoB score, and thus worse cognitive functioning. Figure ptau-181/Aβ1–42 as well as CDR SoB score as examples of premorbid personality and biomarkers’ interaction effect on cognitive performance.Finally, premorbid conscientiousness and AβWe have found that interactions between levels of premorbid neuroticism, conscientiousness and agreeableness and CSF biomarkers of AD pathology predict cognitive performance in healthy older participants and in subjects with MCI and mild AD dementia. Furthermore, lower premorbid openness independently predicted lower cognitive functioning after controlling for biomarker concentrations. To our knowledge, our study is the first to investigate the impact of premorbid personality on the relationship between cognitive functioning and CSF biomarkers of AD pathology.ptau-181, tau/Aβ1–42 and ptau-181/Aβ1–42 ratios, but we did not find any association with the Aβ1–42 level. While tau/Aβ1–42 and ptau-181/Aβ1–42 ratios may be considered markers of concomitant cerebral amyloid pathology and tau-related neurodegeneration, their associations with personality traits seem to be largely due to associations with the tau and ptau-181 levels. One possible explanation for these findings is that, in the clinical stages of AD, pathological changes of CSF Aβ1–42 may have reached the maximum level and remain relatively stable, while changes in tau and ptau-181 concentrations are still ongoing and more closely associated with cognitive performance [There were associations between specific premorbid personality traits and tau, 1–42 and ptau-181/Aβ1–42 ratios predicted poorer cognitive performance. At low premorbid conscientiousness, higher Aβ1–42 and lower ptau-181/Aβ1–42 ratios predicted worse cognitive functioning, suggesting a protective effect of conscientiousness. These findings are partly in line with a clinical and autopsy study [1–42 and ptau-181/Aβ1–42 ratios are relatively low (i.e. suggesting the absence of an AD biomarker profile). This might suggest that there is a “cutoff point” related to cerebral pathology after which the interaction effect on cognitive performance reverses. Finally, premorbid agreeableness moderated the biomarker–cognitive performance relationship so that the high tau/Aβ1–42 and ptau-181/Aβ1–42 concentrations predicted worse cognitive functioning when agreeableness was high. Different results might be due to different study designs applied. Moreover, our sample was comprised of controls and patients with MCI or mild AD dementia unlike in the clinical-autopsy study, where non-demented subjects were compared with participants with dementia. Noteworthily, premorbid neuroticism, conscientiousness and agreeableness considered independently did not predict cognitive functioning and the observed interaction effects on cognition were weak. This finding may be due to the fact that participants with cognitive impairment were at different stages of cognitive impairment and the age of clinical onset was not considered. Overall, the effects found in our sample need confirmation in further studies.Furthermore, we observed that the effect of CSF biomarkers on cognitive performance change depending on the level of specific premorbid personality traits. More precisely, at low levels of neuroticism, higher concentrations of tau and higher tau/Aβsy study , reportisy study . In our Our study also reveals a substantial premorbid personality role in distinguishing between the CI and control groups because the two groups differed significantly in the domain of openness. This finding may seem less expected because clinical AD symptoms, such as troublesome behaviour  and anxiMoreover, our results revealed that premorbid openness predicts cognitive performance beyond the subject’s cognitive status, demographic variables, APOEε4 status and CSF biomarker level. In our study, openness was the only personality domain from the FFM which contributed independently to cognitive performance. This finding is in line with results from some previous studies. For instance, Terry et al.  showed tInheritance of the APOEε4 allele is considered a major genetic risk factor for non-familial AD –68. As fThe main strengths of our study are the use of validated instruments, the comprehensive personality and clinical assessment, and the inclusion of factors with established effects on the relationship between cerebral pathology and clinical manifestations. Neuroticism, conscientiousness and extraversion—the domains widely described in the literature to differ between cognitively impaired subjects and healthy controls—did not predict cognitive performance alone. The absence of associations may be due to a small sample size and thus having a reduced statistical power compared with results obtained from larger cohorts. Furthermore, the assessment of personality characteristics was made by the subjects’ proxies and might have been biased by their relationship with the participants. It should be noted that there is a good agreement between self-report and informant-report ratings , but infThe interaction between premorbid neuroticism, conscientiousness and agreeableness and cerebral pathology as measured by CSF biomarkers predicts cognitive functioning. Subjects with MCI and mild dementia have lower premorbid openness compared with healthy controls. Premorbid openness predicts cognitive impairment independently of cerebral AD pathology. Further studies with larger samples are needed in order to confirm these findings and their potential implications for prevention of cognitive decline, and to better understand the nature of premorbid personality in relation to brain pathology and cognitive performance.