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Objective: The aim of this study is to investigate the specific links that the Dark Triad traits have with subjective and psychological well-being through a meta-analysis of the existing literature., Background: Over the past few years, associations between the Dark Triad traits and well-being have been a stimulating but understudied topic in personality research., Method: Cross-sectional, correlational studies examining these relationships were searched in the PsycINFO, PubMed, and Web of Science databases. Meta-analyses were performed at the dimension- and facet-level to account for the multidimensional structure of the Dark Triad traits., Results: A total of 55 studies were included (n = 26,252). In general, grandiose narcissism and boldness/dominance related to higher well-being, while vulnerable narcissism, antagonism, disinhibition, and Machiavellianism related to lower levels of well-being. Age and gender moderated few of these associations., Conclusions: We recommend including multidimensional measures of the Dark Triad traits as an essential step to move the field forward., (© 2023 The Authors. Journal of Personality published by Wiley Periodicals LLC.)

Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil., Competing Interests: Declaration of interests H.H. is co-founder of Omniscope, SAB member of Nanostring and MiRXES, and consultant to Moderna and Singularity. J.C.N. is consultant to Omniscope., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study examines the efficacy of positive psychology interventions (PPIs) for patients with chronic pain through a systematic review and meta-analysis. PPIs are defined as strategies that involve focusing on positive emotions, thoughts, and behaviors that improve mental health by increasing mental well-being and reducing psychological distress., Design: The search was conducted using the PubMed, Scopus, PsycINFO, and Cochrane Library databases., Main Outcome Measures: Subjective, psychological, and social well-being were used as indicators of mental well-being, and depression, anxiety, and stress symptoms were used as indicators of psychological distress. Results: Nine studies were included. Eight studies evaluated subjective well-being, seven evaluated depression, and three evaluated anxiety symptoms. No studies examined psychological well-being, social well-being, or stress. PPIs were found to be effective in promoting subjective well-being post-treatment (Hedges' g  = 0.40; 95% CI [0.06, 0.73]) and reducing anxiety (Hedges' g = -0.32, 95% CI [-0.59, -0.06]), but no significant results were found for depression (Hedges' g = -0.23, 95% CI [-0.50, 0.04])., Conclusion: The included investigations, while limited, suggest the utility of PPIs in mitigating the psychological consequences of chronic pain. Researchers and practitioners are encouraged to implement PPI practices.

The extraembryonic yolk sac (YS) ensures delivery of nutritional support and oxygen to the developing embryo but remains ill-defined in humans. We therefore assembled a comprehensive multiomic reference of the human YS from 3 to 8 postconception weeks by integrating single-cell protein and gene expression data. Beyond its recognized role as a site of hematopoiesis, we highlight roles in metabolism, coagulation, vascular development, and hematopoietic regulation. We reconstructed the emergence and decline of YS hematopoietic stem and progenitor cells from hemogenic endothelium and revealed a YS-specific accelerated route to macrophage production that seeds developing organs. The multiorgan functions of the YS are superseded as intraembryonic organs develop, effecting a multifaceted relay of vital functions as pregnancy proceeds.

The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The effectiveness of multicomponent positive psychology interventions (MPPIs) on adolescents' mental health has been studied with the use of standard procedures throughout the scientific literature. However, little is known about the potential mechanisms underlying the network structure of mental health following the dual-factor model after an MPPI. We relied on network analysis to explore the reorganization of the connections between mental health indicators after a school-based MPPI. Adolescents from two high schools in Spain were randomly allocated to the 6-week intervention group (n = 85) or to the control group (n = 135). Network analysis showed that the relations between the two differentiated network dimensions of mental health (i.e. well-being and psychological distress) changed after the intervention. Unlike control participants, emotional well-being was negatively associated with depression and stress, while psychological well-being was positively related to stress after the intervention. The present study supports the viability of the network approach in analyzing the connections between mental health indicators as defined by the dual-factor model and the contribution of MPPIs to change the complex pattern of relations between the dimensions of well-being and psychological distress., (© 2022 The Authors. Applied Psychology: Health and Well-Being published by John Wiley & Sons Ltd on behalf of International Association of Applied Psychology.)

The proliferation of mental health research is orienting its efforts towards the exploration of psychological well-being. One of the main burdens is the measurement challenges reported by the widely used Psychological Well-Being Scale (PWBS), which has often been criticized for inconsistencies between the theoretical and the empirical model. A potential alternative to understand the structure of psychological well-being is network models, which conceptualizes psychological phenomena as emerging systems of mutually connected variables. Employing exploratory graph analysis, we examined the network structure of the Spanish 29-item PWBS in a random sample of 1,404 adults. We estimated a regularized partial correlation network using the graphical LASSO algorithm in the item and dimension level. We tested the stability of both networks and identified the most important variables of the network. The PWBS network model revealed four dimensions, with self-acceptance, life purpose and environmental mastery clustering together. Node strength centrality suggested that self-acceptance is the most central dimension in the psychological well-being structure as measured by the PWBS. Despite the network model of psychological well-being did not replicate the theoretical structure of Ryff's model, it provides a novel conceptualization of psychological well-being and proposes target indicators for mental health interventions., (© 2022 The Authors. Scandinavian Journal of Psychology published by Scandinavian Psychological Associations and John Wiley & Sons Ltd.)

Myeloid cells are central to homeostasis and immunity. Characterising in vitro myelopoiesis protocols is imperative for their use in research, immunotherapies, and understanding human myelopoiesis. Here, we generate a >470K cells molecular map of human induced pluripotent stem cells (iPSC) differentiation into macrophages. Integration with in vivo single-cell atlases shows in vitro differentiation recapitulates features of yolk sac hematopoiesis, before definitive hematopoietic stem cells (HSC) emerge. The diversity of myeloid cells generated, including mast cells and monocytes, suggests that HSC-independent hematopoiesis can produce multiple myeloid lineages. We uncover poorly described myeloid progenitors and conservation between in vivo and in vitro regulatory programs. Additionally, we develop a protocol to produce iPSC-derived dendritic cells (DC) resembling cDC2. Using CRISPR/Cas9 knock-outs, we validate the effects of key transcription factors in macrophage and DC ontogeny. This roadmap of myeloid differentiation is an important resource for investigating human fetal hematopoiesis and new therapeutic opportunities., (© 2022. The Author(s).)

Time attitudes, which refer to positive and negative feelings towards the past, present, and future, are a salient phenomenon in the developmental stage of adolescence and have been related to better well-being. Positive feelings towards time can be promoted in the school setting through empirically validated positive psychology interventions. However, the extent to which these interventions impact the time attitudes of adolescents remains unknown. The current study investigated the influence of a multicomponent positive psychology intervention on adolescents' transitions between time attitude profiles and how these transitions are related to their emotional, social, and psychological well-being. Participants consisted of 220 (M = 14.98; 47.3% female) adolescents from two Spanish high schools who participated in the six-week Get to Know Me+ program. Adolescents' time attitudes and well-being were measured via the Adolescents and Adult Time Inventory-Time Attitudes and the Mental Health Continuum-Short Form, respectively, at pre- and postintervention. Participants were clustered in different profiles through a latent profile analysis, and the transitions were analyzed using a latent transition analysis. Five profiles were identified (negative, present/future negative, past negative, optimistic, and positive), and results indicated that adolescents who participated in the intervention were more likely to transition to positive profiles (optimistic and positive) and generally reported higher well-being, especially those in the negative, present/future negative, and optimistic profiles. Preliminary evidence showed that school-based multicomponent positive psychology interventions can have a positive impact on adolescents' feelings towards time and well-being., (© 2021. The Author(s).)

The COVID-19 pandemic has constituted a global health crisis that has threatened the mental health of individuals worldwide. The present paper sought to systematically review and meta-analyze studies reporting the prevalence during the COVID-19 pandemic of well-being and psychological distress as defined by the dual-continua model, which includes (absence of) psychological distress and (presence of) well-being among the general population and healthcare workers. Systematic searches were conducted in various databases: PubMed, PsycINFO, Scopus, and Web of Science from inception until 6 December 2020. From a total of 158 studies (N = 880,352) included in the meta-analysis, only seven reported the prevalence of well-being. A random-effect model was used to estimate the pooled prevalence among the general population and healthcare workers on depression (25%; 31%), anxiety (27%; 31%), stress (35%; 32%), and well-being (52%; 45%), respectively. Sub-group analyses based on region, income, percentage of women, preparedness of country to respond to COVID-19, and economic vulnerabilities were conducted in order to examine sources of heterogeneity in psychological distress. Results revealed differences among the two groups and indicated that disparities in terms of preparedness to fight the pandemic can distinctly affect mental health in the general population and healthcare workers. Addressing mental health during and after a health crisis should be in the spotlight of the international and national public health agenda. Considering the protective role of well-being to minimize psychological symptoms, mental health policies during the COVID-19 should include strategies to combat the psychological consequences of the pandemic by promoting well-being practices., Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-02913-6., (© The Author(s) 2022.)

The study of cardiovascular risk factors has been deeply described in recent years, but the findings on the complex role of psychological indicators (i.e. happiness and depression) on cardiovascular health are mixed. The primary goal of our study was to examine the extent to which certain psychological aspects, namely happiness and depression, can predict cardiovascular risk. A sample of 173 ( M age  = 44.9, SD  = 14; 62% females) individuals from the general population who attended a public hospital of Lleida (Spain) participated voluntarily in the study. We measured happiness, depression and different clinical and sociodemographic variables. The sample reported low levels of depression and moderate levels of happiness, overweight levels of body mass index and mainly low levels of cardiovascular risk. Happiness was correlated positively to cardiovascular risk and negatively to depression. Increases in happiness, but not in depression, were associated with people being in a higher group of cardiovascular risk. Despite a body of literature indicates that subjective well-being has a protective role over cardiovascular health, the contradictory findings of our study might be explained by several factors. The present findings invite to consider the complex and indirect influence of happiness on physical health. Future research should investigate the potential biological and behavioral processes of happiness linked with increases in cardiovascular risk.

Objective: Two studies were conducted to investigate fear of happiness through the lens of the dual continua model of mental health., Methods: In Study 1, we examined whether depression (indicator of mental illness) and happiness (indicator of mental health) predicted fear of happiness through a Structural Equation Model. In Study 2, we ran a quasi-experimental design to examine differences in affect (positive and negative), happiness and depression when engaging in either fearless or fearful beliefs of happiness., Results: Fear of happiness was positively and negatively predicted by depression and happiness, respectively. Fearless individuals reported higher positive affect and happiness, and lower negative affect and depression, than fearful individuals., Conclusions: Fearing happiness might act as a maladaptive self-verifying motive to enhance one's perspective of the world. Given the likelihood of modifying maladaptive cognitive patterns, we highlight different psychological interventions that can address the negative impact of fearful beliefs of happiness., (© 2021 The Authors. Journal of Clinical Psychology published by Wiley Periodicals LLC.)

Introduction: Time attitudes refer to the way individuals feel about their past, present, and future and have been associated with adolescent-specific developmental, social, and emotional changes. The dual-factor model of mental health proposes that optimal functioning entails high levels of emotional, social, and psychological well-being, as well as low levels of psychopathology. Since previous research has suggested that time attitudes can assist in understanding the development of adolescents, the primary objective of this study was to examine the relationship between time attitudes and mental health according to the dual-factor model., Methods: A total of 317 Spanish high school students aged between 14 and 16 years (45.1% females) participated in the study. Time attitudes were assessed with the Adolescent and Adult Time Inventory-Time Attitudes Scale, and profiles were identified through person-centered analysis. Data were also gathered on well-being and psychological distress measures, which were analyzed as distal outcomes., Results: Four time attitude profiles were identified - negatives, positives, past negatives, and present/future negatives. Adolescents belonging to the positive profile reported higher scores on well-being and lower scores on psychological distress. The psychological well-being and depression constructs had higher (positive and negative, respectively) scores across all profiles. These results suggested an association between time attitude profiles and mental health according to the dual-factor model., Conclusions: We suggest that positive psychology interventions may nudge adolescents towards a more positive appraisal of the past, present, and future and promote their mental health and positive development. Further practical implications are discussed., (Copyright © 2021 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.)

Background: Charisma can be understood as a personality trait that allows one to influence other people. Research on charisma has predominately focused on leadership, but it can also be successfully studied in the general population. The General Charisma Inventory (GCI) has not yet been analysed in different cultures. The current study represents the first attempt to examine and validate this instrument in a Spanish-speaking population., Participants and Procedure: The GCI was administered in a series of three studies to a large adult community sample ( N 1 = 756, N 2 = 96, N 3 = 149). A multigroup confirmatory factor analysis was conducted to verify the structure of the GCI. Factorial and criterion validity was examined in the context of well-being and the Dark Triad traits. Measurement invariance across age and gender of the GCI in a Spanish-speaking sample was also analysed., Results: The results confirmed the hypothesised two-factorial structure and therefore the Spanish version of the GCI is a structurally valid and reliable measure, and its dimensions relate to different outcomes such as well-being and the Dark Triad., Conclusions: The Spanish GCI could be used in general research on charisma and applied to a wide range of age groups within the Spanish-speaking context, providing economic screening for research and practice., (Copyright © Institute of Psychology, University of Gdansk.)

Multicomponent positive psychology interventions are increasing in the general population but the study of its effectiveness in adolescents is still scarce, especially in the school context. Previous meta-analyses have reported that multicomponent positive psychology interventions increase well-being and reduce distress outcomes. However, the results on these outcomes limit their samples to adult populations. The aim of the current systematic review and meta-analysis is to evaluate and compare the immediate but also long-lasting effects of school-based multicomponent positive psychology interventions aimed at increasing well-being indicators of mental health (i.e., subjective and psychological well-being) and reducing the most common psychological distress indicators (i.e., depression, anxiety, and stress) in adolescents. A total of 9 randomized and non-randomized controlled trials from the searched literature met inclusion criteria for the meta-analysis. The results showed small effects for subjective well-being (g = 0.24), psychological well-being (g = 0.25), and depression symptoms (g = 0.28). Removing low-quality studies led to a slight decrease in the effect sizes for subjective well-being and a considerable increase for psychological well-being and depression symptoms. The relevant moderation analyses had an effect on subjective well-being and depression symptoms. The present systematic review and meta-analysis found evidence for the efficacy of school-based multicomponent positive psychology interventions in improving mental health in the short and long-term. Small effects for subjective well-being, psychological well-being, and depression symptoms were identified. Effects for psychological well-being and depression symptoms remained significant over time. In light of our results, education policy-makers and practitioners are encouraged to include positive practices within the schools' curriculum as effective and easily implemented tools that help to enhance adolescents' mental health. Further research is needed in order to strengthen the findings about school-based multicomponent positive psychology interventions in adolescents.

Each year, more than 25,000 people succumb to liver cancer in the United States, and this neoplasm represents the second cause of cancer-related death globally. R-spondins (RSPOs) are secreted regulators of Wnt signaling that function in development and promote tissue stem cell renewal. In cancer, RSPOs 2 and 3 are oncogenes first identified by insertional mutagenesis screens in tumors induced by mouse mammary tumor virus and by transposon mutagenesis in the colonic epithelium of rodents. RSPO2 has been reported to be activated by chromosomal rearrangements in colorectal cancer and overexpressed in a subset of hepatocellular carcinoma. Using human liver tumor gene expression data, we first discovered that a subset of liver cancers were characterized by high levels of RSPO2 in contrast to low levels in adjacent nontumor tissue. To determine if RSPOs are capable of inducing liver tumors, we used an in vivo model from which we found that overexpression of RSPO2 in the liver promoted Wnt signaling, hepatomegaly, and enhanced liver tumor formation when combined with loss of transformation-related protein 53 ( Trp53 ). Moreover, the Hippo/yes-associated protein (Yap) pathway has been implicated in many human cancers, influencing cell survival. Histologic and gene expression studies showed activation of Wnt/β-catenin and Hippo/Yap pathways following RSPO2 overexpression. We demonstrate that knockdown of Yap1 leads to reduced tumor penetrance following RSPO2 overexpression in the context of loss of Trp53. Conclusion: RSPO2 overexpression leads to tumor formation in the mouse liver in a Hippo/Yap-dependent manner. Overall, our results suggest a role for Yap in the initiation and progression of liver tumors and uncover a novel pathway activated in RSPO2-induced malignancies. We show that RSPO2 promotes liver tumor formation in vivo and in vitro and that RSPO2's oncogenic activity requires Hippo/Yap activation in hepatocytes. Both RSPO2 and YAP1 are suggested to represent novel druggable targets in Wnt-driven tumors of the liver., (© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

The DNA mutation produced by cellular repair of a CRISPR-Cas9-generated double-strand break determines its phenotypic effect. It is known that the mutational outcomes are not random, but depend on DNA sequence at the targeted location. Here we systematically study the influence of flanking DNA sequence on repair outcome by measuring the edits generated by >40,000 guide RNAs (gRNAs) in synthetic constructs. We performed the experiments in a range of genetic backgrounds and using alternative CRISPR-Cas9 reagents. In total, we gathered data for >10 9 mutational outcomes. The majority of reproducible mutations are insertions of a single base, short deletions or longer microhomology-mediated deletions. Each gRNA has an individual cell-line-dependent bias toward particular outcomes. We uncover sequence determinants of the mutations produced and use these to derive a predictor of Cas9 editing outcomes. Improved understanding of sequence repair will allow better design of gene editing experiments.

Free time is considered to be a very important aspect of adolescents' psychosocial development. One of the instruments that has been developed to explore motivation in relation to free time activities is Baldwin and Caldwell's (2003) Free Time Motivation Scale for Adolescents (FTMS-A), based on Ryan and Deci (2000) Self-Determination Theory. The main aim of this study is to explore the psychometric properties of the FTM S-A after its translation and adaptation to Catalan, administering it to a sample of 2,263 adolescents aged between 11 and 18 (M = 14.99; SD = 1.79) from Catalonia, Spain. To explore structural validity we follow two steps: Firstly, we analyze how the scale fits with the original model by conducting a CFA on the whole sample; secondly, we conduct an EFA on one half of the sample and a CFA on the other half in order to identify which structure best suits the sample. We also analyze convergent validity using three indicators of subjective well-being: The Personal Well-Being Index (PWI), the Satisfaction with Life scale (SWLS) and the Overall Life Satisfaction scale (OLS). The initial CFA produces a 5-factor model like the original, but with goodness of fit indices that do not reach the acceptable minimum. The EFA and the second CFA show a good fit for a 3-dimensional model (χ2(90) = 320.293; RMSEA = .048; NNFI = .92; CFI = .94) comprising introjected motivation, intrinsic motivation and amotivation. The correlations obtained between the FTMS-A and the three measures of subjective well-being scales show an association between free time motivations and this construct. Due to the model of scale used in the present study differs from the original, it is proposed that the new scale structure with 16 items be tested in the future in different cultural contexts.

Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance., Design: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts., Results: Sorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC)., Conclusions: Acquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background & Aims: Effective treatments are urgently needed for hepatocellular carcinoma (HCC), which is usually diagnosed at advanced stages. Signaling via the insulin-like growth factor (IGF) pathway is aberrantly activated in HCC by IGF2 overexpression. We aimed to elucidate the mechanism of IGF2 overexpression and its oncogenic activities and evaluate the anti-tumor effects of reducing IGF2 signaling., Methods: We obtained 228 HCC samples from patients who underwent liver resection, 168 paired non-tumor adjacent cirrhotic liver samples, and 10 non-tumor liver tissues from patients undergoing resection for hepatic hemangioma. We analyzed gene expression, microRNA, and DNA methylation profiles for all samples, focusing on genes in the IGF signaling pathway. IGF2 was expressed in SNU449 and PLC5 HCC cells and knocked down with small hairpin RNAs in Hep3B and Huh7 cell lines. We analyzed these cells for proliferation, apoptosis, migration, and colony formation. We performed studies in mice engineered to express Myc and Akt1 in liver, which develop liver tumors, with or without hepatic expression of Igf2. Mice with xenograft tumors grown from HCC cells were given a monoclonal antibody against IGF1 and IGF2 (xentuzumab), along with sorafenib; tumor growth was measured and tissues were analyzed by immunohistochemistry and immunoblots., Results: Levels of IGF2 messenger RNA and protein were increased >20-fold in 15% of human HCC tissues compared with non-tumor liver tissues. Methylation at the fetal promoters of IGF2 was reduced in the HCC samples and cell lines that overexpressed IGF2, compared with those that did not overexpress this gene, and non-tumor tissues. Tumors that overexpressed IGF2 had gene expression patterns significantly associated with hepatic progenitor cell features, stellate cell activation, NOTCH signaling, and an aggressive phenotype (P < .0001). In mice engineered to express Myc and Akt1 in liver, co-expression of Igf2 accelerated formation of liver tumors, compared to mice with livers expressing only Myc and Akt1, and shortened survival times (P = .02). The antibody xentuzumab blocked phosphorylation of IGF1 receptor in HCC cell lines and reduced their proliferation and colony formation. In mice with xenograft tumors, injection of xentuzumab, with or without sorafenib, slowed tumor growth and increased survival times compared to vehicle or sorafenib alone. Xentuzumab inhibited phosphorylation of IGF1 receptor and AKT and reduced decreased tumor vascularization compared with vehicle., Conclusions: A large proportion of HCC samples were found to overexpress IGF2, via demethylation of its fetal promoter. Overexpression of IGF2 accelerates formation of liver tumors in mice with hepatic expression of MYC and AKT1, via activation of IGF1 receptor signaling. An antibody against IGF1 and IGF2 slows growth of xenograft tumors and increases survival of these mice., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors., Methods: By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort., Results: Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC., Conclusions: In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: Therapy resistance and associated liver disease make hepatocellular carcinomas (HCC) difficult to treat with traditional cytotoxic therapies, whereas newer targeted approaches offer only modest survival benefit. We focused on DNA-dependent protein kinase, DNA-PKcs, encoded by PRKDC and central to DNA damage repair by nonhomologous end joining. Our aim was to explore its roles in hepatocarcinogenesis and as a novel therapeutic candidate., Experimental Design: PRKDC was characterized in liver tissues from of 132 patients [normal liver (n = 10), cirrhotic liver (n = 13), dysplastic nodules (n = 18), HCC (n = 91)] using Affymetrix U133 Plus 2.0 and 500 K Human Mapping SNP arrays (cohort 1). In addition, we studied a case series of 45 patients with HCC undergoing diagnostic biopsy (cohort 2). Histological grading, response to treatment, and survival were correlated with DNA-PKcs quantified immunohistochemically. Parallel in vitro studies determined the impact of DNA-PK on DNA repair and response to cytotoxic therapy., Results: Increased PRKDC expression in HCC was associated with amplification of its genetic locus in cohort 1. In cohort 2, elevated DNA-PKcs identified patients with treatment-resistant HCC, progressing at a median of 4.5 months compared with 16.9 months, whereas elevation of activated pDNA-PK independently predicted poorer survival. DNA-PKcs was high in HCC cell lines, where its inhibition with NU7441 potentiated irradiation and doxorubicin-induced cytotoxicity, whereas the combination suppressed HCC growth in vitro and in vivo., Conclusions: These data identify PRKDC/DNA-PKcs as a candidate driver of hepatocarcinogenesis, whose biopsy characterization at diagnosis may impact stratification of current therapies, and whose specific future targeting may overcome resistance., (©2014 American Association for Cancer Research.)

Deep-sequencing of a primary tumor and metastasis from a single patient, and functional validation in culture, reveals that TGFBR2 and FGFR2 act as drivers of gastric cancer.

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential regulator of DNA methylation that is highly expressed in many cancers. Here, we use transgenic zebrafish, cultured cells, and human tumors to demonstrate that UHRF1 is an oncogene. UHRF1 overexpression in zebrafish hepatocytes destabilizes and delocalizes Dnmt1 and causes DNA hypomethylation and Tp53-mediated senescence. Hepatocellular carcinoma (HCC) emerges when senescence is bypassed. tp53 mutation both alleviates senescence and accelerates tumor onset. Human HCCs recapitulate this paradigm, as UHRF1 overexpression defines a subclass of aggressive HCCs characterized by genomic instability, TP53 mutation, and abrogation of the TP53-mediated senescence program. We propose that UHRF1 overexpression is a mechanism underlying DNA hypomethylation in cancer cells and that senescence is a primary means of restricting tumorigenesis due to epigenetic disruption., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Induction of angiogenesis represents one of the major hallmarks of cancer. The growth of new vessels is crucial to provide malignant cells with an adequate supply of oxygen and nutrients. It is generally accepted that vascular endothelial growth factor (VEGF) is a major driver of the angiogenic process in physiological and pathological processes in both embryo and adult. VEGF is often found overexpressed in tumors, as well as its receptors VEGFR1 and VEGFR2. Hence, several different strategies have been designed to target VEGF signal transduction. In the last decades, multiple inhibitors have been therapeutically validated in preclinical models and several clinical trials. Neutralizing monoclonal antibodies against VEGF and small molecule tyrosine kinase inhibitors targeting VEGFRs have been shown to block its angiogenic activity, resulting in tumor vascular regression, anti-tumor effects and improvements in patient survival. However, side effects and lack of efficacy in some instances challenge the potential clinical impact of these therapies. This review examines the role of VEGF signaling in cancer and outlines the current status of anti-angiogenic therapies against VEGF pathway.

Background & Aims: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients., Methods: We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC)., Results: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation-based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P < .001)., Conclusions: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Hepatocellular carcinoma (HCC) is one of the deadliest solid cancers and is the third leading cause of cancer-related death. There is a universal estimated male/female ratio of 2.5, but the reason for this is not well understood. The Sleeping Beauty (SB) transposon system was used to elucidate candidate oncogenic drivers of HCC in a forward genetics screening approach. Sex bias occurrence was conserved in our model, with male experimental mice developing liver tumors at reduced latency and higher tumor penetrance. In parallel, we explored sex differences regarding genomic aberrations in 235 HCC patients. Liver cancer candidate genes were identified from both sexes and genotypes. Interestingly, transposon insertions in the epidermal growth factor receptor (Egfr) gene were common in SB-induced liver tumors from male mice (10/10, 100%) but infrequent in female mice (2/9, 22%). Human single-nucleotide polymorphism data confirmed that polysomy of chromosome 7, locus of EGFR, was more frequent in males (26/62, 41%) than females (2/27, 7%) (P = 0.001). Gene expression-based Poly7 subclass patients were predominantly male (9/9) compared with 67% males (55/82) in other HCC subclasses (P = 0.02), and this subclass was accompanied by EGFR overexpression (P < 0.001)., Conclusion: Sex bias occurrence of HCC associated with EGFR was confirmed in experimental animals using the SB transposon system in a reverse genetic approach. This study provides evidence for the role of EGFR in sex bias occurrences of liver cancer and as the driver mutational gene in the Poly7 molecular subclass of human HCC., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background & Aims: The Notch signaling pathway is activated in leukemia and solid tumors (such as lung cancer), but little is known about its role in liver cancer., Methods: The intracellular domain of Notch was conditionally expressed in hepatoblasts and their progeny (hepatocytes and cholangiocytes) in mice. This was achieved through Cre expression under the control of an albumin and α-fetoprotein (AFP) enhancer and promoter (AFP-Notch intracellular domain [NICD]). We used comparative functional genomics to integrate transcriptome data from AFP-NICD mice and human hepatocellular carcinoma (HCC) samples (n = 683). A Notch gene signature was generated using the nearest template prediction method., Results: AFP-NICD mice developed HCC with 100% penetrance when they were 12 months old. Activation of Notch signaling correlated with activation of 3 promoters of insulin-like growth factor 2; these processes appeared to contribute to hepatocarcinogenesis. Comparative functional genomic analysis identified a signature of Notch activation in 30% of HCC samples from patients. These samples had altered expression in Notch pathway genes and activation of insulin-like growth factor signaling, despite a low frequency of mutations in regions of NOTCH1 associated with cancer. Blocking Notch signaling in liver cancer cells with the Notch activation signature using γ-secretase inhibitors or by expressing a dominant negative form of mastermind-like 1 reduced their proliferation in vitro., Conclusions: Notch signaling is activated in human HCC samples and promotes formation of liver tumors in mice. The Notch signature is a biomarker of response to Notch inhibition in vitro., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with active Wnt signaling. Underlying biologic mechanisms remain unclear and no drug targeting this pathway has been approved to date. We aimed to characterize Wnt-pathway aberrations in HCC patients, and to investigate sorafenib as a potential Wnt modulator in experimental models of liver cancer., Experimental Design: The Wnt-pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs), and CTNNB1-mutation data (91 HCCs). Effects of sorafenib on Wnt signaling were evaluated in four liver cancer cell lines with active Wnt signaling and a tumor xenograft model., Results: Evidence for Wnt activation was observed for 315 (49.1%) cases, and was further classified as CTNNB1 class (138 cases [21.5%]) or Wnt-TGFβ class (177 cases [27.6%]). CTNNB1 class was characterized by upregulation of liver-specific Wnt-targets, nuclear β-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature, whereas Wnt-TGFβ class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear β-catenin. Sorafenib decreased Wnt signaling and β-catenin protein in HepG2 (CTNNB1 class), SNU387 (Wnt-TGFβ class), SNU398 (CTNNB1-mutation), and Huh7 (lithium-chloride-pathway activation) cell lines. In addition, sorafenib attenuated expression of liver-related Wnt-targets GLUL, LGR5, and TBX3. The suppressive effect on CTNNB1 class-specific Wnt-pathway activation was validated in vivo using HepG2 xenografts in nude mice, accompanied by decreased tumor volume and increased survival of treated animals., Conclusions: Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt-related molecular classes (CTNNB1 and Wnt-TGFβ), accounting for half of all HCC patients. Sorafenib modulates β-catenin/Wnt signaling in experimental models that harbor the CTNNB1 class signature., (©2012 AACR.)

Clinical management of hepatocellular carcinoma (HCC) is a complex process. Currently existing prognostic staging systems have substantially improved the clinical outcome of patients by guiding treatment decision and allocation of medical resources. However, there is still room to refine many aspects of the framework based on more precise clinical outcome prediction and understanding of HCC molecular pathogenesis. Recent development of genomic technologies has enabled survey of molecular aberrations and deregulations directly from patient specimens in a comprehensive manner. This also has provided clues to therapeutic/preventive targets that could also serve as prognostic/predictive biomarkers. Structural alterations and chemical modifications of genomic DNA have been shown to be useful to guide molecular targeted therapies in some cancers. Gene expression signatures also hold promise as a way to probe functional biological status of the tumor specimen. However, accumulated studies have revealed roadblocks toward the goal to utilize the information in clinic. In this review, we discuss the gene signature's potential application, its pros and cons as a clinical test, technical issues in assay development, and strategies for clinical deployment in the context of HCC management. Recent updates of HCC gene signatures as well as emerging alternative modalities are also overviewed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background & Aims: Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer., Methods: Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in three liver cancer cell lines and a murine xenograft model., Results: Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and HDAC5 mRNAs was significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat and sorafenib significantly decreased vessel density, and most significantly decreased tumor volume and increased survival in HCC xenografts., Conclusions: Aberrant expression of several HDACs and copy number gains of HDAC3 and HDAC5 occur in HCC. Treatment with panobinostat combined with sorafenib demonstrated the highest preclinical efficacy in HCC models, providing the rationale for clinical studies with this novel combination., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We sampled nine different sections from three tumors and seven more sections from the adjacent nontumor tissues.Selected sections were subjected to exon as well as whole-genome sequencing. Putative somatic mutations were then individually validated across all nine tumor and seven nontumor sections. Among the mutations validated, 24 were amino acid changes; in addition, 22 large indels/copy number variants (>1 Mb) were detected. These somatic mutations define four evolutionary lineages among tumor cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein coding mutation. Hence, by using a cell-population genetic definition,this approach identified three coding changes (CCNG1, P62,and an indel/fusion gene) as tumor driver mutations. These three mutations, affecting cell cycle control and apoptosis, are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. These distinct functions of mutations at different stages may reflect the genetic interactions underlying tumor growth.

Recently, interest in hepatocellular carcinoma (HCC) has grown due to its high mortality and increased incidence. Unlike other malignancies, HCC mainly arises in the context of chronic liver injury, complicating its management and the prediction of prognosis. The Barcelona Clinic Liver Cancer (BCLC) staging classification currently offers an efficient decision-making guide in these patients. However, preoperative identification of patients with a higher risk of recurrence after resection and of those who could benefit from liver transplantation despite not meeting the Milan criteria would be useful. New high-throughput genomic technologies that can be applied to paraffin-embedded tissue have facilitated the identification of gene signatures and other biomarkers able to predict prognosis in HCC patients. None of these biomarkers, based on transcriptome, microRNAs or metilome, has been incorporated into clinical practice, although in future they may be able to complement the prognostic value of clinical and pathologic variables., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the major causes of death among cirrhotic patients, being viral hepatitis and alcohol abuse, the main risk factors for its development. The introduction of highly sophisticated genomic technologies has spurred extensive research on the molecular pathogenesis of this devastating disease. Several signaling cascades have been consistently found dysregulated in HCC (e.g., WNT-β-catenin, PI3K/AKT/MTOR, RAS/MAPK, IGF, HGF/MET, VEGF, EGFR, and PDGF). In addition, there have been numerous molecular classifications proposed for this disease, what provides an additional hint about its genomic complexity. The importance of knowing the molecular drivers of HCC is underscored by the positive results of a molecular targeted agent, sorafenib, able to improve survival in patients with advanced disease. This review will briefly outline key concepts in alcohol-related hepatocarcinogenesis, and provide some insight regarding current trends in translating HCC genomics into clinical management of the disease., (Copyright © 2011 by the Research Society on Alcoholism.)