| 1. |
- Anney, Richard, et al.
(författare)
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A genome-wide scan for common alleles affecting risk for autism.
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
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Tidskriftsartikel (refereegranskat)abstract
- Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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| 2. |
- Anney, Richard, et al.
(författare)
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Individual common variants exert weak effects on the risk for autism spectrum disorders.
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:21, s. 4781-92
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Tidskriftsartikel (refereegranskat)abstract
- While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating association of individual SNPs, we also sought evidence that common variants, en masse, might affect risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest p-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. By contrast, allele-scores derived from the transmission of common alleles to Stage 1 cases significantly predict case-status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
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| 3. |
- Bellomo, Rinaldo, et al.
(författare)
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Early acid-base and blood pressure effects of continuous renal replacement therapy intensity in patients with metabolic acidosis
- 2013
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Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 39:3, s. 429-436
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:In acute kidney injury patients, metabolic acidosis is common. Its severity, duration, and associated changes in mean arterial pressure (MAP) and vasopressor therapy may be affected by the intensity of continuous renal replacement therapy (CRRT). We aimed to compare key aspects of acidosis and MAP and vasopressor therapy in patients treated with two different CRRT intensities.METHODS:We studied a nested cohort of 115 patients from two tertiary intensive care units (ICUs) within a large multicenter randomized controlled trial treated with lower intensity (LI) or higher intensity (HI) CRRT.RESULTS:Levels of metabolic acidosis at randomization were similar [base excess (BE) of -8 ± 8 vs. -8 ± 7 mEq/l; p = 0.76]. Speed of BE correction did not differ between the two groups. However, the HI group had a greater increase in MAP from baseline to 24 h (7 ± 3 vs. 0 ± 3 mmHg; p < 0.01) and a greater decrease in norepinephrine dose (from 12.5 to 3.5 vs. 5 to 2.5 μg/min; p < 0.05). The correlation (r) coefficients between absolute change in MAP and norepinephrine (NE) dose versus change in BE were 0.05 and -0.37, respectively.CONCLUSIONS:Overall, LI and HI CRRT have similar acid-base effects in patients with acidosis. However, HI was associated with greater improvements in MAP and vasopressor requirements (clinical trial no. NCT00221013).
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| 4. |
- Bloomfield, Madeleine, et al.
(författare)
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European Autism GEnomics Registry (EAGER): protocol for a multicentre cohort study and registry
- 2024
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Ingår i: BMJ OPEN. - 2044-6055. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants' genetic profiles.Methods and analysis EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms.Ethics and dissemination To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).
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| 5. |
- Bölte, Sven, et al.
(författare)
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Sex and gender in neurodevelopmental conditions
- 2023
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Ingår i: Nature Reviews Neurology. - : Springer Science and Business Media LLC. - 1759-4758 .- 1759-4766. ; 19:3, s. 136-159
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Tidskriftsartikel (refereegranskat)abstract
- Health-related conditions often differ qualitatively or quantitatively between individuals of different birth-assigned sexes and gender identities, and/or with different gendered experiences, requiring tailored care. Studying the moderating and mediating effects of sex-related and gender-related factors on impairment, disability, wellbeing and health is of paramount importance especially for neurodivergent individuals, who are diagnosed with neurodevelopmental conditions with uneven sex/gender distributions. Researchers have become aware of the myriad influences that sex-related and gender-related variables have on the manifestations of neurodevelopmental conditions, and contemporary work has begun to investigate the mechanisms through which these effects are mediated. Here we describe topical concepts of sex and gender science, summarize current knowledge, and discuss research and clinical challenges related to autism, attention-deficit/hyperactivity disorder and other neurodevelopmental conditions. We consider sex and gender in the context of epidemiology, behavioural phenotypes, neurobiology, genetics, endocrinology and neighbouring disciplines. The available evidence supports the view that sex and gender are important contributors to the biological and behavioural variability in neurodevelopmental conditions. Methodological caveats such as frequent conflation of sex and gender constructs, inappropriate measurement of these constructs and under-representation of specific demographic groups (for example, female and gender minority individuals and people with intellectual disabilities) limit the translational potential of research so far. Future research and clinical implementation should integrate sex and gender into next-generation diagnostics, mechanistic investigations and support practices.
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| 6. |
- Casey, Jillian P, et al.
(författare)
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A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
- 2012
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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| 7. |
- Dykes, Charlotta, et al.
(författare)
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Women's perceptions of factors needed to encourage a culture of public breastfeeding : a cross-sectional study in Sweden, Ireland and Australia
- 2023
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Ingår i: International Breastfeeding Journal. - 1746-4358. ; 18, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Breastfeeding in the public sphere is known to be experienced as a problem for many women. It has been shown to arouse negative feelings among the public, depending on the attitude of those in the immediate surroundings. This contributes to the fact that many women hesitate to breastfeed in public and prepare themselves for potential adverse comments.METHODS: An online survey was used for an international cross-sectional study including women living in Sweden (n = 1252), Australia (n = 7602) and Ireland (n = 1597). Women who had breastfed within the previous two years were invited to participate through Facebook. One key open-ended question was presented, inviting women to respond to: "What do you think is important or needed to encourage a breastfeeding culture where breastfeeding in public is seen as normal?" During 2018, data were collected during a four-week period. A thematic analysis of women's responses was conducted separately in each country and then comparison and negotiation occurred once similarities between themes and subthemes were confirmed. Frequencies of subthemes were then determined and compared between the three countries.RESULTS: Seven subthemes developed from the data; 'Make breastfeeding visible in society'; 'Healthcare professionals support and knowledge regarding breastfeeding'; 'Education of the public'; 'Inviting environment'; 'Zero tolerance to other's unwanted opinions'; 'Focusing on the needs and rights of the breastfeeding dyad'; and 'Desexualize breastfeeding and women's' bodies in society'. Subthemes were integrated under two themes; 'Active supportive interventions needed for breastfeeding' and 'The obvious right of breastfeeding women and children to take a seat in the public sphere'.CONCLUSION: The common experience that exists today regarding public breastfeeding requires change towards normalization. Further collaborative research is recommended to meet the expressed requirements from women who wish to breastfeed in public.
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| 8. |
- Gallagher, Louise, et al.
(författare)
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Australian, Irish, and Swedish women’s comfort levels when breastfeeding in public
- 2023
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Ingår i: BMC Public Health. - 1471-2458. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDespite a flux of global initiatives to increase and sustain breastfeeding rates, challenges persist. The decision to commence and sustain breastfeeding is influenced by multiple, complex factors. Feelings of social embarrassment, shame, fear of judgement, and lack of confidence when breastfeeding in public, compound women’s decisions to breastfeed and may result in formula feeding or early cessation of breastfeeding. A greater understanding of where and how women feel most comfortable when breastfeeding in public can assist in designing interventions to support the initiation and continuation of breastfeeding.MethodsA cross-sectional survey was conducted with women living in Australia (n = 10,910), Sweden (n = 1,520), and Ireland (n = 1,835), who were currently breastfeeding or who had breastfed within the previous two years. Our aim was to explore where, and how often women breastfeed in public and to compare their levels of comfort when breastfeeding in public. Data were collected in 2018 using an anonymous online survey over a four-week period in Ireland, Australia, and Sweden, and were analyzed using SPSS Version 25.ResultsMost respondents were highly educated, with over 70% in each country reporting having a university or college degree. Observing women breastfeeding in public was more commonly reported to be a weekly or daily occurrence in Sweden (24.5%) and Australia (28%), than in Ireland (13.3%). Women in the participating countries reported breastfeeding in public most commonly whenever their babies needed feeding. Very few women never or rarely breastfed publicly. Coffee shops/cafes, restaurants, and parks were the most popular locations. In all three countries, partners were reported to be very supportive of breastfeeding in public, which enhanced breastfeeding women’s comfort levels. When asked to score out of a maximum comfort level of 10, women reported higher mean levels of comfort when breastfeeding in front of strangers (Ireland M = 7.33, Australia M = 6.58, Sweden M = 6.75) than with those known to them, particularly in front of their father-in-law (Ireland M = 5.44, Australia M = 5.76, Sweden M = 6.66 out of 10), who scored lowest in terms of women’s comfort levels.ConclusionThis study offers important insights into the experiences and comfort levels of women breastfeeding in public. Limitations include the anonymous nature of the surveys, thus preventing follow-up, and variances in terminology used to describe locations across the three settings. Recommendations are made for research to determine the relationships between the frequency of breastfeeding in public and breastfeeding women’s perceived comfort levels, the influence of family members’ perceptions of breastfeeding in public and women’s experiences, and the experience of women who feel uncomfortable while breastfeeding in public, with a view to developing support measures.
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| 9. |
- Gallagher, Robyn, et al.
(författare)
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Social Support and Self-care in Heart Failure
- 2011
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Ingår i: Journal of Cardiovascular Nursing. - : Lippincott, Williams & Wilkins. - 0889-4655 .- 1550-5049. ; 26:6, s. 439-445
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVE:: Self-care by heart failure (HF) patients is essential for optimal disease management of their condition. However, as the nature of HF is unrelenting and burdensome, self-care is usually achieved with the support of partners. It is not clear what role the level of social support by partners plays in HF self-care; therefore, this study sets out to determine the types of social support provided to HF patients and the impact of differing levels of social support on HF patients' self-care. SUBJECTS AND METHOD:: This is secondary analysis of a subgroup of patients experiencing their second hospital admission for HF at baseline in the COACH study, a multisite trial conducted in the Netherlands. Measures included the European Heart Failure Self-care Behaviour Scale and a multiple component assessment of social support, which categorized patients into low, moderate, and high levels of social support according to the presence of a partner and their perception of support they received from their partner. RESULTS AND CONCLUSIONS:: Patients (n = 333) had an average age of 72 (SD, 11) years, and 92% belonged to New York Heart Association class III or greater. Of the patients with partners (56%), only 49% had a high level of support from their partner. No demographic or clinical characteristic was associated with self-care behavior. Patients with a high level of support reported significantly better self-care (P = .002) than patients with low or moderate levels of social support. Patients with a high level of social support reported being significantly more likely to consult with a health professional for weight gain (P = .011), to limit the amount of fluids they have (P = .02), take their medication (P = .017), to get a flu shot (P = .001), and to exercise on a regular basis (P < .001) than those with medium or low levels of social support. The presence of social support by a partner is not sufficient to influence HF patients' self-care. Social support provided by partners needs to be of a quality and content that matches HF patients' perception of need to influence self-care. Caregivers, especially partners, should be considered as integral in the treatment and care of HF patients.
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| 10. |
- Hauck, Yvonne, et al.
(författare)
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Australian, Irish and Swedish women's perceptions of what assisted them to breastfeed for six months: exploratory design using critical incidence technique
- 2016
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Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Breastfeeding initiation rates in some developed countries are high (98 % in Sweden and 96 % inAustralia) whereas in others, they are not as favourable (46 % to 55 % in Ireland). Although the World Health Organization recommends exclusively breastfeeding for six months, 15 % of Australian women, 11 % of Swedish women and less than 7 % of Irish women achieve this goal. Awareness of what women in different countries perceive as essential breastfeeding support is a gap in our knowledge.Methods: Our aim was to explore Australian, Irish and Swedish women’s perceptions of what assisted them tocontinue breastfeeding for six months. An exploratory design using critical incident techniques was used. Recruitment occurred through advertisements in local newspapers and on social networking platforms. Initial sampling was purposive, followed by snowball sampling. Telephone interviews were conducted with 64 Irish, 139 Swedish and 153 Australian women who responded to one question “what has assisted you to continue breastfeeding for at least six months?” Content analysis was conducted and common categories determined toallow comparison of frequencies and priority ranking.Results: Categories reflected the individual mother, her inner social network, her outer social network (informal support either face to face or online), and societal support (health professionals, work environment and breastfeeding being regarded as the cultural norm). Categories ranked in the top five across the three countries were ‘informal face to face support’ and ‘maternal determination’. Swedish and Australian women ranked “health professional support” higher (first and third respectively) than Irish women who ranked ‘informal online support’ as second compared to ninth and tenth for Swedish and Australian women.Conclusions: The support required to assist breastfeeding women is complex and multi-faceted. Although common international categories were revealed, the ranking of these supportive categories varied. We must recognize how the cultural context of breastfeeding support can vary for women in differing countries and acknowledge the resourcefulness of women who embrace innovations such as social media where face to face formal and informal support are not as accessible.
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| 11. |
- Hauck, Yvonne L, et al.
(författare)
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Helpful and challenging aspects of breastfeeding in public for women living in Australia, Ireland and Sweden : a cross-sectional study
- 2020
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Ingår i: International Breastfeeding Journal. - : Springer Science and Business Media LLC. - 1746-4358. ; 15:1, s. 38-38
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Breastfeeding in public continues to be contentious with qualitative evidence confirming that women face many challenges. It is therefore important to gain understanding of not only the challenges but also what women perceive is helpful to breastfeed in public.METHODS: A cross-sectional study was conducted with women living in Australia, Ireland or Sweden currently breastfeeding or having breastfed within the previous 2 years. Our objective was to explore and compare what women do when faced with having to breastfeed in the presence of someone they are uncomfortable with and what women think is helpful and challenging when considering whether to breastfeed in public. Data were collected in 2018 from an online survey over a 4 week period in each country. Content analysis revealed data similarity and theme names and definitions were negotiated until consensus was reached. How often each theme was cited was counted to report frequencies. Helpful and challenging aspects were also ranked by women to allow international comparison.RESULTS: Ten themes emerged around women facing someone they were uncomfortable to breastfeed in the presence of with the most frequently cited being: 'made the effort to be discreet'; 'moved to a private location'; 'turned away' and 'just got on with breastfeeding'. Nine themes captured challenges to breastfeed in public with the following ranked in the top five across countries: 'unwanted attention'; 'no comfortable place to sit'; 'environment not suitable'; 'awkward audience' and 'not wearing appropriate clothing'. Nine themes revealed what was helpful to breastfeed in public with the top five: 'supportive network'; 'quiet private suitable environment'; 'comfortable seating'; 'understanding and acceptance of others' and 'seeing other mothers' breastfeed'.CONCLUSIONS: When breastfeeding in public women are challenged by shared concerns around unwanted attention, coping with an awkward audience and unsuitable environments. Women want to feel comfortable when breastfeeding in a public space. How women respond to situations where they are uncomfortable is counterproductive to what they share would be helpful, namely seeing other mothers breastfeed. Themes reveal issues beyond the control of the individual and highlight how the support required by breastfeeding women is a public health responsibility.
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| 12. |
- Lanigan, Fiona, et al.
(författare)
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Delineating Transcriptional Networks of Prognostic Gene Signatures Refines Treatment Recommendations for Lymph Node-negative Breast Cancer Patients.
- 2015
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X. ; 282:18, s. 3455-3473
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Tidskriftsartikel (refereegranskat)abstract
- The majority of women diagnosed with lymph node-negative breast cancer are unnecessarily treated with damaging chemotherapeutics following surgical resection. This highlights the importance of understanding and more accurately predicting patient prognosis. Here, we define the transcriptional networks regulating well-established prognostic gene expression signatures. We find that the same set of transcriptional regulators consistently lie upstream of both 'prognosis' and 'proliferation' gene signatures, suggesting that a central transcriptional network underpins a shared phenotype within these signatures. Strikingly, the master transcriptional regulators within this network predict recurrence risk for lymph node-negative breast cancer better than currently used multi-gene prognostic assays, particularly in lymph node-negative, estrogen receptor-positive patients. Simultaneous examination of p16(INK) (4A ) expression, which predicts tumors that have bypassed cellular senescence, revealed that intermediate levels of p16(INK) (4A) correlate with an intact pRB pathway and improved survival. A combination of these master transcriptional regulators and p16(INK) (4A) , termed the OncoMasTR score, stratifies tumours based on their proliferative and senescence capacity, facilitating a clearer delineation of lymph node-negative breast cancer patients at high risk of recurrence, and thus requiring chemotherapy. Furthermore, OncoMasTR accurately classifies over 60% of patients as 'low risk', an improvement on existing prognostic assays, which has the potential to reduce overtreatment in early-stage patients. Taken together, this study provides new insights into the transcriptional regulation of cellular proliferation in breast cancer and provides an opportunity to enhance and streamline breast cancer prognosis. This article is protected by copyright. All rights reserved.
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| 13. |
- Li, Bo, et al.
(författare)
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Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer
- 2017
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Ingår i: Cancer Research. - 0008-5472. ; 77:14, s. 3834-3845
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Tidskriftsartikel (refereegranskat)abstract
- Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle–related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n ¼ 383) and the METABRIC TNBC dataset (n ¼ 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n ¼ 109) and the METABRIC TNBC cohort (n ¼ 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment.
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| 14. |
- O'Hurley, Gillian, et al.
(författare)
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Investigation of molecular alterations of AKT-3 in triple-negative breast cancer
- 2014
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Ingår i: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 64:5, s. 660-670
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Tidskriftsartikel (refereegranskat)abstract
- Aims Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer (BC) deaths, owing to its intrinsic aggressiveness and a lack of treatment options, especially targeted therapies. Thus, there is an urgent need for the development of better targeted treatments for TNBC. Molecular alteration of AKT-3 was previously reported in oestrogen receptor (ER)-positive BC. AKT-3 has also been suggested to play a role in hormone-unresponsive BC. The aim of this study was to investigate molecular alterations of AKT-3 in TNBC, to perform associated survival analysis, and to compare these findings with the incidence of AKT-3 molecular alterations in ER-positive BC. Results Our study revealed AKT-3 amplification and deletions in 11% (9/82) and 13% (11/82) of TNBCs, respectively. In contrast, 1% (2/209) of ER-positive BCs were found to have AKT-3 amplifications and deletions. A higher prevalence of AKT-3 copy number gains was observed in TNBC [26% (21/82)] than in ER-positive BC [9% (19/209)]. AKT-3 amplification together with Akt-3 protein expression was negatively associated with recurrence-free survival in TNBC. Furthermore, a negative association between high AKT-3 copy number and recurrence-free survival was observed. Conclusion AKT-3 amplification could represent a potentially relevant oncogenic event in a subset of TNBCs that may, in turn, select cells sensitive to Akt-3 inhibitors.
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| 15. |
- Pinto, Dalila, et al.
(författare)
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Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.
- 2014
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Ingår i: American journal of human genetics. - : Elsevier BV. - 1537-6605 .- 0002-9297. ; 94:5, s. 677-694
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Tidskriftsartikel (refereegranskat)abstract
- Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0× 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7× 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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| 16. |
- Pinto, Dalila, et al.
(författare)
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Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
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Tidskriftsartikel (refereegranskat)abstract
- The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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| 17. |
- Robinne, Francois-Nicolas, et al.
(författare)
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Scientists' warning on extreme wildfire risks to water supply
- 2021
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Ingår i: Hydrological Processes. - : John Wiley & Sons. - 0885-6087 .- 1099-1085. ; 35:5
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Tidskriftsartikel (refereegranskat)abstract
- 2020 is the year of wildfire records. California experienced its three largest fires early in its fire season. The Pantanal, the largest wetland on the planet, burned over 20% of its surface. More than 18 million hectares of forest and bushland burned during the 2019-2020 fire season in Australia, killing 33 people, destroying nearly 2500 homes, and endangering many endemic species. The direct cost of damages is being counted in dozens of billion dollars, but the indirect costs on water-related ecosystem services and benefits could be equally expensive, with impacts lasting for decades. In Australia, the extreme precipitation ("200 mm day-1 in several location") that interrupted the catastrophic wildfire season triggered a series of watershed effects from headwaters to areas downstream. The increased runoff and erosion from burned areas disrupted water supplies in several locations. These post-fire watershed hazards via source water contamination, flash floods, and mudslides can represent substantial, systemic long-term risks to drinking water production, aquatic life, and socio-economic activity. Scenarios similar to the recent event in Australia are now predicted to unfold in the Western USA. This is a new reality that societies will have to live with as uncharted fire activity, water crises, and widespread human footprint collide all-around of the world. Therefore, we advocate for a more proactive approach to wildfire-watershed risk governance in an effort to advance and protect water security. We also argue that there is no easy solution to reducing this risk and that investments in both green (i.e., natural) and grey (i.e., built) infrastructure will be necessary. Further, we propose strategies to combine modern data analytics with existing tools for use by water and land managers worldwide to leverage several decades worth of data and knowledge on post-fire hydrology.
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| 18. |
- Salomone, Erica, et al.
(författare)
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Use of early intervention for young children with autism spectrum disorder across Europe
- 2016
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Ingår i: Autism. - : SAGE PUBLICATIONS LTD. - 1362-3613 .- 1461-7005. ; 20:2, s. 233-249
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about use of early interventions for autism spectrum disorder in Europe. Parents of children with autism spectrum disorder aged 7 years or younger (N = 1680) were recruited through parent organisations in 18 European countries and completed an online survey about the interventions their child received. There was considerable variation in use of interventions, and in some countries more than 20% of children received no intervention at all. The most frequently reported interventions were speech and language therapy (64%) and behavioural, developmental and relationship-based interventions (55%). In some parts of Europe, use of behavioural, developmental and relationship-based interventions was associated with higher parental educational level and time passed since diagnosis, rather than with child characteristics. These findings highlight the need to monitor use of intervention for children with autism spectrum disorder in Europe in order to contrast inequalities.
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| 19. |
- Sumaila, U. Rashid, et al.
(författare)
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WTO must ban harmful fisheries subsidies
- 2021
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 20. |
- Walsh, Louise, et al.
(författare)
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BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer
- 2019
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 25:23, s. 7139-7150
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor-positive breast cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are effective in diverse types of breast cancer but they have not yet been assessed in ILC.EXPERIMENTAL DESIGN: We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing (RNA-seq) to identify transcriptional reprograming enabling resistance to JQ1-induced apoptosis. As part of the RATHER study, we obtained copy-number alterations and RNA-seq on 61 ILC patient samples.RESULTS: Certain ILC cell lines were sensitive to JQ1, while others were intrinsically resistant to JQ1-induced apoptosis. JQ1 treatment led to an enhanced dependence on antiapoptotic proteins and a transcriptional rewiring inducing fibroblast growth factor receptor 1 (FGFR1). This increase in FGFR1 was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitors was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% had FGFR1 amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC.CONCLUSIONS: We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.
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