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2.
J Eur Acad Dermatol Venereol ; 38(7): 1391-1400, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38400660

RESUMO

BACKGROUND: The Global Research on the Impact of Dermatological Diseases (GRIDD) project is developing the new Patient-Reported Impact of Dermatological Diseases (PRIDD) measure. PRIDD measures the impact of dermatological conditions on the patient's life. OBJECTIVES: This study aimed to seek consensus from patients on which items to prioritize for inclusion in PRIDD. METHODS: A modified, two-round Delphi study was conducted. Adults (≥18 years) with dermatological conditions were recruited. The survey consisted of a demographic's questionnaire and 263 potential impact items in six languages. Quantitative data used Likert-type ranking scales and analysed against consensus criteria. Qualitative data collected free text responses for additional feedback and a framework analysis was conducted. RESULTS: 1154 people representing 90 dermatological conditions from 66 countries participated. Items were either removed (n = 79), edited (n = 179) or added (n = 2), based on consensus thresholds and qualitative feedback. Results generated the first draft of PRIDD with 27 items across five impact domains. CONCLUSION: This Delphi study resulted in the draft version of PRIDD, ready for psychometric testing. The triangulated data helped refine the existing conceptual framework of impact. PRIDD has since been pilot tested with patients and is currently undergoing psychometric testing.


Assuntos
Técnica Delphi , Medidas de Resultados Relatados pelo Paciente , Dermatopatias , Humanos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Consenso , Inquéritos e Questionários , Qualidade de Vida , Idoso , Psicometria
3.
J Clin Nurs ; 33(1): 242-254, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37032642

RESUMO

BACKGROUND: Nurses play an essential role in responding to severe viral disease which bring considerable challenges to their personal and professional well-being. This subsequently can affect the delivery of care and healthcare systems' organisational capacity to respond. Understanding nurses' experiences of these challenges will help inform healthcare policies. AIM: To explore the experiences and coping strategies of nurses caring for patients during severe viral disease pandemics. DESIGN: A mixed-methods systematic review informed by the Joanna Briggs Institute (JBI) methodology. METHODS: A mixed-methods systematic review. Five electronic databases Medline, CINAHL, PsychInfo, ASSIA and Scopus were searched on 4th April 2021. Results were reported in accordance with PRISMA. The findings were analysed and reported in the context of the Self-Regulatory Common-Sense Model. RESULTS: In total, 71 peer-review primary research articles describing nurses' experiences of caring for patients during SARS, MERS, Swine flu H1N1, Avian influenza or SARS-CoV-2 / COVID-19 published in English from 2003 to 2021 were included. We found links between nurses' perception of the health threats, their emotional reactions, and coping strategies. Perceived health threats were influenced by organisational factors including frequent changes in clinical guidelines and workplace protocols, onerous workloads and working hours, unavailability of PPE, and lack of knowledge and training in pandemic management. These impacted nurses' physical, psychological and social well-being. Nurses also reported helpful and unhelpful coping strategies to manage the health threats. CONCLUSIONS: It is vital for stakeholders, policymakers, government and healthcare institutions to recognise and monitor the wider impact on healthcare workers from health emergencies. In addition, support to develop and implement effective systems and individual mechanisms to offset the anticipated impact pre and post pandemics/epidemics is needed. Our findings can inform those strategies for similar future health emergencies. RELEVANCE TO CLINICAL PRACTICE: Nurses are often the first point of contact in providing direct care to patients, hence they are at high risk of being infected. The findings from this review can help managers and policymakers in developing programmes to enhance resilience in the nursing workforce. NO PATIENT OR PUBLIC CONTRIBUTION: This was a literature review study.


Assuntos
Capacidades de Enfrentamento , Enfermeiras e Enfermeiros , Pandemias , Viroses , Humanos , COVID-19/epidemiologia , Emergências , Vírus da Influenza A Subtipo H1N1 , Enfermeiras e Enfermeiros/psicologia , Assistência ao Paciente , Viroses/epidemiologia
4.
Nurs Open ; 10(9): 6014-6032, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37458290

RESUMO

AIM: To examine Registered Nurses (RNs') and nursing students' perspectives on factors contributing to moral distress and the effects on their health, well-being and professional and career intentions. DESIGN: Joanna Briggs Institute mixed-methods systematic review and thematic synthesis. Registered in Prospero (Redacted). METHODS: Five databases were searched on 5 May 2021 for studies published in English since January 2010. Methodological quality assessment was conducted in parallel with data extraction. RESULTS: Searches yielded 2343 hits. Seventy-seven articles were included. Most were correlational design and used convenience sampling. Studies were mainly from North America and Asia and situated in intensive and critical care settings. There were common, consistent sources of moral distress across continents, specialities and settings. Factors related to perceived inability or failure to enact moral agency and responsibility in moral events at individual, team and structural levels generated distress. Moral distress had a negative effect on RNs health and psychological well-being. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution to this systematic review.


Assuntos
Enfermeiras e Enfermeiros , Estudantes de Enfermagem , Humanos , Estudantes de Enfermagem/psicologia , América do Norte , Princípios Morais , Satisfação no Emprego
5.
Front Med (Lausanne) ; 10: 1020523, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37215711

RESUMO

Background: The Global Research on the Impact of Dermatological Diseases (GRIDD) team is developing the new Patient-Reported Impact of Dermatological Diseases (PRIDD) measure of the impact of dermatological conditions on the patient's life, in partnership with patients. To develop PRIDD, we conducted a systematic review, followed by a qualitative interview study with 68 patients worldwide and subsequently a global Delphi survey of 1,154 patients to ensure PRIDD items were meaningful and important to patients. Objective: To pilot test PRIDD with patients with dermatological conditions, focusing on its content validity (comprehensiveness, comprehensibility, and relevance), acceptability, and feasibility. Methods: We conducted a theory-led qualitative study using the Three-Step Test-Interview method of cognitive interviewing. Three rounds of semi-structured interviews were conducted online. Adults (≥ 18 years) living with a dermatological condition and who spoke English sufficiently to take part in the interview were recruited through the International Alliance of Dermatology Patient Organizations' (GlobalSkin) global membership network. The topic guide met the gold-standard COSMIN (Consensus-based Standards for the Selection of Health Measurement Instruments) standards for cognitive interviewing. Analysis followed the thematic analytical model of cognitive interviewing. Results: Twelve people (58% male) representing six dermatological conditions from four countries participated. Overall, patients found PRIDD to be comprehensible, comprehensive, relevant, acceptable, and feasible. Participants were able to discern the conceptual framework domains from the items. Feedback resulted in: the recall period being extended from 1 week to 1 month; removal of the 'not relevant' response option; and changes to the instructions and item ordering and wording to improve clarity and increase respondents' confidence in their ability to respond. These evidence-based adjustments resulted in a 26-item version of PRIDD. Conclusion: This study met the gold-standard COSMIN criteria for the pilot testing of health measurement instruments. The data triangulated our previous findings, in particular the conceptual framework of impact. Our findings illuminate how patients understand and respond to PRIDD and other patient-reported measurement instruments. The results of comprehensibility, comprehensiveness, relevance, acceptability, and feasibility of PRIDD provide evidence of content validity from the target population. The next step in the development and validation of PRIDD is psychometric testing.

6.
Front Med (Lausanne) ; 9: 1024879, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405626

RESUMO

Background: Dermatological conditions can have a substantial impact on psychological as well as physical health yet dedicated face-to-face psychological support for patients is lacking. Thus, individuals may require additional support to self-manage dermatological conditions effectively. Digital technology can contribute to long-term condition management, but knowledge of the effectiveness of digital interventions addressing psychological (cognitive, emotional, and behavioural) aspects of dermatological conditions is limited. Objectives: To identify, determine the effectiveness, and explore people's views and experiences of digital interventions supporting the psychological health of people with dermatological conditions. Methods: A mixed methods systematic review informed by JBI methodology. The protocol was registered on PROSPERO. Eight electronic databases were searched for papers written between January 2002 and October 2021. Data screening and extraction were conducted in Covidence. The methodological quality of studies were scrutinised against JBI critical appraisal tools. Intervention characteristics were captured using the Template for Intervention Description and Replication checklist and guide. Data were synthesised using a convergent segregated approach. The results were reported in a narrative summary. Results: Twenty-three papers were identified from 4,883 references, including 15 randomised controlled trials. Nineteen interventions were condition-specific, 13 were delivered online, 16 involved an educational component, and 7 endorsed established, evidence-based therapeutic approaches. Improvements in knowledge, mood, quality of life, the therapeutic relationship, and reduced disease severity in the short to medium term, were reported, although there was substantial heterogeneity within the literature. Thirteen studies captured feedback from users, who considered various digital interventions as convenient and helpful for improving knowledge, emotion regulation, and personal control, but technical and individual barriers to use were reported. Use of established qualitative methodologies was limited and, in some cases, poorly reported. Conclusion: Some web-based digital psychological interventions seem to be acceptable to people living with mainly psoriasis and eczema. Whilst some digital interventions benefitted cognitive and emotional factors, heterogeneity and inconsistencies in the literature meant definitive statements about their effectiveness could not be drawn. Interdisciplinary and patient-centred approaches to research are needed to develop and test quality digital interventions supporting the psychological health of adults living with common and rare dermatological conditions. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=285435], identifier [CRD42021285435].

7.
Acta Derm Venereol ; 102: adv00823, 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36065743

RESUMO

Existing patient-reported outcome measures cannot comprehensively capture the full impact of living with a dermatological condition. The aim of this study was to develop a conceptual framework on which to build a new Patient-Reported Impact of Dermatological Diseases (PRIDD) measure. Adults (≥ 18 years of age) living with a dermatological condition, worldwide and/or representatives from a patient organization recruited via a global patient organization network, were invited to an individual or group interview. Data were analyzed thematically. Sixty-five people from 29 countries, representing 29 dermatological conditions, participated. Key themes were: (i) impacts at the individual, organizational and societal levels; (ii) impacts were point-in-time and cumulative; and (iii) impact is a multifaceted construct, with two subthemes (iiia) common impacts and (iiib) psychological and social impacts are most significant. The conceptual framework shows that impact is a multifaceted concept presenting across physical, psychological, social, financial, daily functioning and healthcare, and provides the basis for co-constructing the PRIDD with patients.


Assuntos
Medidas de Resultados Relatados pelo Paciente , Pacientes , Adulto , Humanos , Pesquisa Qualitativa , Qualidade de Vida/psicologia
8.
Psychol Health Med ; : 1-14, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941815

RESUMO

The use of remote consultations via telephone or video can contribute to the management of people with psoriasis and has allowed continuity of patient care throughout the SARS-CoV-2 pandemic, though little is known about the patient experience. The present study aimed to provide insights into the views and experiences of people with psoriasis and psoriatic arthritis on their remote consultations during the SARS-CoV-2 pandemic and develop guidance for patients and healthcare professionals on how to optimise future remote consultations. We conducted a cross-sectional, on-line survey of people with psoriasis and psoriatic arthritis. Data were analysed using descriptive statistics and Thematic Analysis. Overall, 126 people reported experiences of telephone (92%) or video (8%) consultations. Most participants were satisfied with (78%), and were happy for, remote consultations to continue (21%); few were not (5%). Others did not always want remote consultations (39%) and preferred alternating with face-to-face consultations (18%). Some wanted remote care during the pandemic only (17%). Five themes were identified: (1) Advantages of Remote Consultations; (2) Disadvantages of Remote Consultations plus sub-themes (2.1) Practical Issues and (2.2) the Absence of Non-Verbal Cues and Emotions; (3) Serving a Purpose; and (4) A 'Good' Remote Consultation; and (5) Advice to Other Patients. Remote consultations form an important part of psoriatic disease management, mainly for routine follow-up appointments in patients with stable disease, and in addition to face-to-face consultations. Additional skills training for clinicians could improve the quality of remote consultations.

10.
Soc Sci Med ; 303: 114946, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35605431

RESUMO

OBJECTIVES: Physical distancing, defined as keeping 1-2m apart when co-located, can prevent cases of droplet or aerosol transmitted infectious diseases such as SARS-CoV2. During the COVID-19 pandemic, distancing was a recommendation or a requirement in many countries. This systematic review aimed to determine which interventions and behavior change techniques (BCTs) are effective in promoting adherence to distancing and through which potential mechanisms of action (MOAs). METHODS: Six databases were searched. The review included studies that were (a) conducted on humans, (b) reported physical distancing interventions, (c) included any comparator (e.g., pre-intervention versus post-intervention; randomized controlled trial), and (d) reported actual distancing or predictors of distancing behavior. Risk of bias was assessed using the Mixed Methods Appraisal Tool. BCTs and potential MoAs were identified in each intervention. RESULTS: Six articles (with seven studies and 19 comparisons) indicated that distancing interventions could successfully change MoAs and behavior. Successful BCTs (MoAs) included feedback on behavior (e.g., motivation); information about health consequences, salience of health consequences (e.g., beliefs about consequences), demonstration (e.g., beliefs about capabilities), and restructuring the physical environment (e.g., environmental context and resources). The most promising interventions were proximity buzzers, directional systems, and posters with loss-framed messages that demonstrated the behaviors. CONCLUSIONS: The evidence indicates several BCTs and potential MoAs that should be targeted in interventions and highlights gaps that should be the focus of future research.


Assuntos
COVID-19 , Doenças Transmissíveis , COVID-19/epidemiologia , COVID-19/prevenção & controle , Humanos , Pandemias/prevenção & controle , Distanciamento Físico , RNA Viral , SARS-CoV-2
11.
BMJ Open ; 12(2): e051575, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35144948

RESUMO

OBJECTIVES: To investigate the impact of SARS-CoV-2 on self-reported mood, coping and health behaviours of people living with existing health conditions in the UK to understand how to improve coping responses to the threat of SARS-CoV-2. DESIGN: Quantitative design using a cross-sectional survey. SETTING: Online survey in the UK. PARTICIPANTS: UK adults (18+ years) were eligible to participate. A total of 9110 people participated. Of these, 4377 (48%) reported at least one existing health condition, 874 (10%) reported having two or more existing conditions, and 715 (8%) reported having an existing mental health condition. PRIMARY AND SECONDARY OUTCOME MEASURES: Multivariable linear regression and sequential multiple mediation analysis were used to estimate differences in average scores for active and avoidant coping response scores due to pre-existing health conditions, and to investigate the extent to which these differences are explained by differences in perceptions, beliefs, concerns and mood. RESULTS: People with pre-existing physical (+1.11 higher; 95% CI 0.88 to 1.34) and especially mental health conditions (3.06 higher; 95% CI 2.65 to 3.48) reported poorer health and used more avoidant coping compared with healthy participants. Under some strong untestable assumptions, we estimate that experiencing low mood or concern related to SARS-CoV-2 mostly explained the relationship between existing health conditions and avoidant coping. CONCLUSION: Psychological support and interventions including behaviour change are required to mitigate the psychological burden of the SARS-CoV-2 pandemic and increase autonomy in people with and without pre-existing conditions during this highly uncertain time. Psychologists are well placed to support clinicians and people with existing health conditions to minimise the psychological impact of SARS-CoV-2, in order to alleviate the subsequent strain on healthcare services.


Assuntos
COVID-19 , SARS-CoV-2 , Adaptação Psicológica , Adulto , Estudos Transversais , Humanos , Reino Unido
12.
Int J Behav Med ; 29(6): 743-751, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35132540

RESUMO

BACKGROUND: There is currently a lack of qualitative research exploring how cognitive and emotional reactions to the threat of SARS-CoV-2 affected the health behaviours of people living with and without pre-existing mental and physical health conditions. We aimed to investigate how the threat of SARS-CoV-2 influenced the thoughts, feelings and health behaviours of people with and without pre-existing health conditions in the UK. METHODS: A cross-sectional online survey of UK adults (aged 18 and over). Free-text responses were analysed using a qualitative framework approach guided by the Common-Sense Model of Self-Regulation. RESULTS: Of the 9110 respondents, 2763 participants provided at least one free-text response. Three main themes were derived from the data. Theme one, locus of control, reports on the extent to which people felt in control during the first wave of the pandemic. Theme two, emotional impact, conveys how individuals felt and how people's personal circumstances made them more vulnerable to experiencing negative emotions during the pandemic. Theme three, coping strategies, describes common health-protective and health-threatening behaviours performed by individuals, as well as the importance of social connectedness, the social context and the need for collective action during the first national lockdown. CONCLUSION: Complex psychological interventions including behaviour change are required to mitigate the psychological burden of the SARS-CoV-2 pandemic and increase autonomy in people with and without pre-existing conditions during this highly uncertain time. Behavioural scientists can support governments and public health agencies to develop evidence-based communication and behaviour change strategies that support people to address unhelpful beliefs and emotions and strengthen coping abilities as the UK moves through and beyond the SARS-CoV-2 pandemic.


Assuntos
COVID-19 , Adulto , Humanos , Adolescente , SARS-CoV-2 , Estudos Transversais , Controle de Doenças Transmissíveis , Adaptação Psicológica , Reino Unido/epidemiologia
13.
Br J Dermatol ; 187(1): 82-88, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35064926

RESUMO

BACKGROUND: The quality of dermatology consultations is partly determined by how clinicians approach patient care. The term 'Personal Models' describes the explanatory frameworks of thoughts, feelings and experiences that drive behaviour. One study found that clinicians' personal models, specifically their beliefs about autonomy and patient self-management, influenced the degree to which clinicians engage patients in shared decision making during consultations. Further research is needed to further explore how clinicians' personal models inform and affect the quality of patient care. OBJECTIVES: To explore how clinicians' personal models inform shared decision making and consultation style in managing people living with psoriasis in the context of a new treatment, Apremilast. METHODS: A framework analysis of qualitative semi-structured telephone interviews with 13 dermatologists from the UK and Germany who participated in a novel medicine trial for psoriasis called APPRECIATE. RESULTS: Two themes were derived from the data. Theme 1, 'personal working models of patient care', comprised two subthemes: 'patient-centredness: a continuum' and 'stereotypes and assumptions'. Theme 2, 'impact of personal working models on patient care', included three subthemes: 'shared decision making: a continuum', 'consultation skills' and 'impact of concerns about Apremilast on prescribing behaviour'. CONCLUSIONS: Although many dermatologists endorsed a patient-centred approach, not all reported working in this way. Clinicians' personal models, their beliefs, stereotypes, personal perceptions and assumptions about patients are likely to affect their prescribing behaviour and shared decision making. Additional specialized training and education could increase patient-centredness and whole-person management.


Assuntos
Dermatologistas , Psoríase , Tomada de Decisões , Humanos , Psoríase/tratamento farmacológico , Pesquisa Qualitativa , Encaminhamento e Consulta , Talidomida/análogos & derivados
14.
Acta Derm Venereol ; 101(4): adv00445, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33856042

RESUMO

The Psoriasis and Well-being (PsoWell)™ training programme, incorporating motivational interviewing, improves clinicians' knowledge and skills to manage complex psoriasis, including behaviour change. The aims of this study were to deliver the PsoWell™ training programme to dermatology specialists, and to evaluate the acceptability and feasibility of implementing the PsoWell™ model across dermatology services. Framework analysis of 19 qualitative semi-structured interviews was performed, following delivery of nine, 1-day PsoWell™ training days involving 119 participants. Two themes were identified: "Perceptions and Priorities" and "Awareness", sub-divided into: "Awareness Not Competence" and "Increasing Awareness". The PsoWell™ model was found to be acceptable and feasible to implement across dermatology settings. Participants were more skilled and motivated to address psycho-logical issues, including behaviour change, but wanted further training to ensure competency. The trainees claimed that scepticism among some colleagues regarding whole-patient management might prevent uptake. Data show-ing the impact on health outcomes are needed and might overcome scepticism. Remote consultation could adopt the PsoWell™ approach.


Assuntos
Entrevista Motivacional , Psoríase , Humanos , Psoríase/diagnóstico , Psoríase/terapia
15.
Psychol Health ; 35(7): 854-871, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31746223

RESUMO

Objective: To determine if a weight gain prevention intervention is acceptable to young women with a normal Body Mass Index and a moderately increased or high risk of breast cancer. Design: Qualitative semi-structured interview study involving 14 women aged 26-35 years who were registered with a Family History Clinic in Manchester, UK, due to family history of breast cancer. Participants' views were analysed thematically. Results: Four themes were produced: (1) perceptions of a healthy lifestyle: women's perceptions included health-related behaviours and subjective wellbeing; (2) construing a healthy weight: women rely on appearance, feelings and others opinions to construe weight instead of quantitative indicators; (3) configuring a useful programme: the idea of a programme that is remotely accessible; provides a point of contact; and promotes general wellbeing was appealing. Women believed information explaining the link between lifestyle and breast cancer would facilitate behaviour change; (4) the importance of will(power): women recognised that commitment to a programme is affected by time, money and readiness to change. Conclusion: A weight gain prevention intervention that focuses on wellbeing and behaviour change appears acceptable to many healthy weight women. Future research should examine whether women's expressed acceptability translates into actual acceptability of such a programme.


Assuntos
Manutenção do Peso Corporal , Neoplasias da Mama/epidemiologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Adolescente , Adulto , Neoplasias da Mama/genética , Estudos Transversais , Feminino , Humanos , Avaliação de Programas e Projetos de Saúde , Pesquisa Qualitativa , Medição de Risco , Adulto Jovem
16.
EMBO J ; 35(7): 724-42, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26848154

RESUMO

Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of pro-inflammatory and pro-oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent-associated changes are dependent on mitochondria, particularly the pro-inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC-1ß-dependent mitochondrial biogenesis, contributing to aROS-mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC-1ß deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.


Assuntos
Envelhecimento/fisiologia , Mitocôndrias/fisiologia , Animais , Linhagem Celular , Humanos , Camundongos , Modelos Biológicos , Fenótipo
17.
Cell Rep ; 12(9): 1483-96, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26299965

RESUMO

Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells.


Assuntos
Senescência Celular , Células Gigantes/citologia , Mitose , Proteínas ras/metabolismo , Linhagem Celular , Células Cultivadas , Células Gigantes/metabolismo , Humanos , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas ras/genética
18.
Genes Dev ; 28(24): 2712-25, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25512559

RESUMO

Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Cellular senescence and associated tumor suppression depend on control of chromatin. Histone chaperone HIRA deposits variant histone H3.3 and histone H4 into chromatin in a DNA replication-independent manner. Appropriately for a DNA replication-independent chaperone, HIRA is involved in control of chromatin in nonproliferating senescent cells, although its role is poorly defined. Here, we show that nonproliferating senescent cells express and incorporate histone H3.3 and other canonical core histones into a dynamic chromatin landscape. Expression of canonical histones is linked to alternative mRNA splicing to eliminate signals that confer mRNA instability in nonproliferating cells. Deposition of newly synthesized histones H3.3 and H4 into chromatin of senescent cells depends on HIRA. HIRA and newly deposited H3.3 colocalize at promoters of expressed genes, partially redistributing between proliferating and senescent cells to parallel changes in expression. In senescent cells, but not proliferating cells, promoters of active genes are exceptionally enriched in H4K16ac, and HIRA is required for retention of H4K16ac. HIRA is also required for retention of H4K16ac in vivo and suppression of oncogene-induced neoplasia. These results show that HIRA controls a specialized, dynamic H4K16ac-decorated chromatin landscape in senescent cells and enforces tumor suppression.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Senescência Celular/fisiologia , Chaperonas de Histonas/metabolismo , Fatores de Transcrição/metabolismo , Animais , Antineoplásicos Hormonais/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular , Proliferação de Células , Senescência Celular/genética , Cromatina/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Marcadores Genéticos , Chaperonas de Histonas/genética , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Camundongos , Papiloma/patologia , Neoplasias Cutâneas/patologia , Tamoxifeno/farmacologia , Fatores de Transcrição/genética
19.
Proc Natl Acad Sci U S A ; 110(40): 16009-14, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24043806

RESUMO

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescence-associated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescence-associated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.


Assuntos
Senescência Celular/fisiologia , Melanócitos/fisiologia , Melanoma/etiologia , Nevo/fisiopatologia , Via de Sinalização Wnt/fisiologia , Animais , Linhagem Celular Tumoral , Primers do DNA/genética , Células HEK293 , Humanos , Immunoblotting , Imuno-Histoquímica , Melanócitos/citologia , Camundongos , Análise em Microsséries , Nevo/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA
20.
Acta Biomater ; 7(7): 2919-25, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21459166

RESUMO

Biomimicry is being used in the next generation of biomaterials. Tuning material surface features such as chemistry, stiffness and topography allow the control of cell adhesion, proliferation, growth and differentiation. Here, microtopographical features with nanoscale depths, similar in scale to osteoclast resorption pits, were used to promote in vitro bone formation in basal medium. Primary human osteoblasts were used to represent an orthopaedically relevant cell type and analysis of adhesions, cytoskeleton, osteospecific proteins (phospho-Runx2 and osteopontin) and mineralisation (alizarin red) was performed. The results further demonstrate the potential for biomimicry in material design and show that the osteoblast response can be tuned from changes in feature size.


Assuntos
Biomimética , Osteogênese/fisiologia , Materiais Biocompatíveis/metabolismo , Adesão Celular/fisiologia , Células Cultivadas , Citoesqueleto/metabolismo , Citoesqueleto/ultraestrutura , Humanos , Osteoblastos/citologia , Osteoblastos/fisiologia , Osteopontina/metabolismo , Propriedades de Superfície
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