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1.
Cutis ; 111(5): 254-258, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37406330

RESUMO

Early diagnosis of melanoma drastically reduces morbidity and mortality; however, most skin lesions are not initially evaluated by dermatologists, and some patients may require a referral. This study sought to determine the performance of an artificial intelligence (AI) application in classifying lesions as benign or malignant to determine whether AI could assist in screening potential melanoma cases. One hundred dermoscopic images (80 benign nevi and 20 biopsy-verified malignant melanomas) were assessed by an AI application as well as 23 dermatologists, 7 family physicians, and 12 primary care mid-level providers. The AI's high accuracy and positive predictive value (PPV) demonstrate that this AI application could be a reliable melanoma screening tool for providers.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Inteligência Artificial , Sensibilidade e Especificidade , Melanoma/diagnóstico , Melanoma/patologia , Biópsia , Dermoscopia/métodos
2.
J Drugs Dermatol ; 22(5): 440-444, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37133468

RESUMO

IMPORTANCE: Actinic keratosis (AK) is a premalignant lesion that has a1% to 10% potential of progression to squamous cell carcinoma (SCC), but it is not possible to determine which lesions are at higher risk. OBJECTIVE: This study examined the epidermal genetic profiles of actinic keratosis and SCC through non-invasive techniques seeking to develop a biopsy-free method for AK monitoring and aid in the early diagnosis of developing SCC. DESIGN: Ribonucleic acid (RNA) was collected from adhesive tape strips and gene expression levels were measured. A threshold fold change >2 and adjusted P-value <0.05 were used to determine differentially expressed genes. SETTING: Single center dermatology clinic. PARTICIPANTS: Patients who presented to the clinic with lesions suspicious of non-melanoma skin cancer that had never been previously biopsied. MAIN OUTCOME AND MEASURE: RNA was extracted via non-invasive biopsy and sequenced. Low quality samples were filtered out and the remaining samples underwent differential gene expression analysis by DESeq2 in R package. A threshold of fold change >2 and adjusted P-value <0.05 was used for determination of differentially expressed genes. The differentially expressed genes that overlapped between the corrected and uncorrected groups were the most significant for analysis. RESULTS: From 47 lesions, 6 significant differentially expressed genes were found between AK and SCC, and 25 significant differentially expressed genes between in-situ SCC and invasive SCC. Individual samples showed similarities based on diagnosis, suggesting mutations were specific to the disease and not the individual. CONCLUSIONS AND RELEVANCE: These findings highlight which genes may play a role in AK progression to SCC. The genomic differences between in-situ and invasive squamous cell carcinoma open an opportunity for early diagnosis of squamous cell carcinoma and risk prediction of actinic keratosis. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7097.


Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Humanos , Ceratose Actínica/diagnóstico , Ceratose Actínica/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Epiderme/patologia , RNA
3.
J Drugs Dermatol ; 22(5): 465-470, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37133479

RESUMO

BACKGROUND: Ultraviolet (UV) radiation leads to deoxyribonucleic acid (DNA) damage and changes in gene expression. Topical DNA repair enzymes in liposomes are capable of undoing this damage. OBJECTIVE: To evaluate gene expression changes induced by ultraviolent B-rays (UVB) light and assess the effect of topical DNA repair enzymes extracted from Micrococcus luteus (M. luteus) and photolyase in modifying these changes. METHODS: Non-invasive, adhesive patch collection kits were used to sample skin on the right and left post-auricular areas before and 24 hours after UVB exposure (n=48). Subjects applied topical DNA repair enzymes to the right post-auricular area daily for 2 weeks. Subjects returned 2 weeks later for repeat non-invasive skin sample collection. RESULTS: Eight of 18 tested genes demonstrated significant changes 24 hours following UVB exposure. DNA repair enzymes from M. luteus or photolyase had no significant effect on genetic expression compared with the control at 2 weeks post UV exposure. CONCLUSION: UVB exposure causes acute changes in gene expression, which may play roles in photo-aging damage and skin cancer growth and regulation. While non-invasive gene expression testing can detect UV damage, additional genomic studies investigating recovery from UV damage at different time periods are needed to establish the potential of DNA repair enzymes to minimize or reverse this damage. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7070.


Assuntos
Desoxirribodipirimidina Fotoliase , Neoplasias Cutâneas , Humanos , Dano ao DNA , Desoxirribodipirimidina Fotoliase/genética , Reparo do DNA , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Enzimas Reparadoras do DNA/genética
4.
Dermatol Clin ; 41(1): 231-238, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36410981

RESUMO

Chemoprophylaxis against nonmelanoma skin cancer (NMSC) should be considered in high-risk populations such as those with certain genetic disorders, immunosuppressive states, chronic radiation, excessive UV exposure, or extensive personal or family history of NMSC. The methods for chemoprevention have progressed beyond traditional sunscreen into more effective strategies including DNA repair enzymes, nicotinamide, systemic retinoids, and nonsteroidal anti-inflammatory drugs. Other therapies are still being investigated and include treatments that target premalignant lesions, capecitabine, hedgehog inhibitors, difluoromethylornithine, metformin, and nutritional factors.


Assuntos
Proteínas Hedgehog , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/prevenção & controle , Neoplasias Cutâneas/patologia , Quimioprevenção , Retinoides/uso terapêutico , Niacinamida
5.
Br J Oral Maxillofac Surg ; 60(10): 1303-1320, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36446645

RESUMO

Managing the physical sequelae of facial trauma is routine for the maxillofacial surgeon. However, managing the psychological consequences is more challenging. The often violent mechanism of injury, changes in appearance, altered self-perception, and self-confidence can significantly impact daily life. This review summarises the literature regarding post-traumatic stress disorder (PTSD) and facial trauma, highlighting evidence to guide clinical practice. PubMed and MEDLINE were searched for relevant keywords and MeSH headings. Articles between 2000-2022 were independently reviewed by two authors. Articles were excluded if the full text was not available in English, did not relate to facial trauma, or was not related to PTSD/psychological sequelae. A total of 211 articles were retrieved. The most common reasons for exclusion were papers not reporting psychological outcomes (n = 68) or not relating to facial trauma (n = 35). Articles were sub-categorised to enable evaluation of key themes. Categories included children and adolescents, cross sectional, longitudinal studies, and interventional studies. Whilst there were potential confounders such as socioeconomic factors, overall, patients who had experienced facial trauma (regardless of the mechanism of injury) had an increased risk of PTSD and anxiety/depression. PTSD following facial injury is increasingly recognised as an important issue. A robust evidence base is desirable to inform clinical practice and provide holistic care to often vulnerable patients. Identifying those at increased risk of negative psychological sequelae is essential. We have appraised the literature relevant to OMFS trauma clinicians.


Assuntos
Traumatismos Maxilofaciais , Transtornos de Estresse Pós-Traumáticos , Criança , Adolescente , Humanos , Estudos Transversais , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Depressão/etiologia , Agressão , Traumatismos Maxilofaciais/complicações
6.
Disabil Rehabil ; 44(11): 2372-2384, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-33126821

RESUMO

BACKGROUND: Stroke is a leading cause of disability in adults and third cause of death in the United States. Survivors face challenges postdischarge, including risks in self-management (SM) following prescribed regimens. Although SM education can help develop skills to control risk factors for stroke recurrence, little is known about lived experiences of patients adopting SM. AIMS: To examine Veterans' lived poststroke experiences after discharge and their experiences in SM goal setting/attainment. METHODS: Patients within one year of discharge from a Veterans Administration Medical Center in the United States with two risk factors for stroke recurrence were enrolled and received an SM workbook. Eight patients were interviewed (six males, two females; mean age 62: range 45-80). Part I concerned lived experience. Part II described experiences with goal setting and attainment. Data were analyzed inductively, identifying common experiences. Deductive analysis described goal setting and attainment. Transcript reviews identified SM themes and strategies. RESULTS: Lived experiences included 1) uncertainty about life, 2) anger and frustration, and 3) healthcare system challenges. Coping skills and setting goals to manage risks were critical for physical and emotional functioning. CONCLUSIONS: SM coping and goal setting aided recovery and improved life quality among Veterans after stroke. SM interventions assisted in regaining physical and emotional function. Findings may help in design of interventions for survivors, using SM and goal setting and attainment.IMPLICATIONS FOR REHABILITATIONSeveral implications for clinical practice were identified:Providers should acknowledge Veterans' challenges and struggles after their stroke and help Veterans to re-establish social identity, enhance self-esteem and improve mood.More emphasis should be given to the Veterans' caregivers' availability and willingness to help with their loved one's recovery, work reinstatement status and financial struggles.Recognition of the importance of the social context of recovery after a stroke is important, as nonmedical social interaction is often overlooked.Improvements are needed in the area of providers working with social workers and physical, occupational and mental health therapists to arrange more inpatient and outpatient treatments, including more frequent home visits.Veterans should be strongly encouraged to attend self-management diabetes education classes and smoking cessation and weight-loss programs offered for free within the Veterans Health Administration system.Self-management strategies using goal-setting and attainment concepts may assist individuals with stroke to regain physical and emotional functions, subsequently preventing another stroke.


Assuntos
Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Veteranos , Adulto , Assistência ao Convalescente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Acidente Vascular Cerebral/psicologia , Sobreviventes , Estados Unidos
7.
Hematol Oncol Clin North Am ; 34(2): 475-489, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32089224

RESUMO

Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes are rare types of chronic myeloid hematologic neoplasms. Patients with overlap syndrome have similar clinical features, mutations, and disease course, to other chronic myeloid malignancies. Limited data also suggests that overlap syndromes patients experience long standing and at times poorly controlled symptoms that may be underrecognized. In this article, we discuss the etiologies of symptoms in patients with overlap syndromes and currently available symptom burden assessment tools. Overall, symptom burden is an important consideration in patients with overlap syndrome, and efforts are ongoing to further investigate symptom burden and quality of life in this population.


Assuntos
Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/diagnóstico , Avaliação de Sintomas/métodos , Biomarcadores , Biópsia , Medula Óssea , Terapia Combinada , Diagnóstico Diferencial , Gerenciamento Clínico , Humanos , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/terapia , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/terapia , Prognóstico , Avaliação de Sintomas/normas , Resultado do Tratamento
8.
PLoS One ; 14(8): e0220108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31408476

RESUMO

BACKGROUND: It is cost-effective to perform an HIV test in people with specific indicator conditions (IC) with an undiagnosed HIV prevalence of at least 0.1%. Our aim was to determine the HIV prevalence for 14 different conditions across 20 European countries. METHODS: Individuals aged 18-65 years presenting for care with one of 14 ICs between January 2012 and June 2014 were included and routinely offered an HIV test. Logistic regression assessed factors associated with testing HIV positive. Patients presenting with infectious mononucleosis-like syndrome (IMS) were recruited up until September 2015. RESULTS: Of 10,877 patients presenting with an IC and included in the analysis, 303 tested positive (2.8%; 95% CI 2.5-3.1%). People presenting with an IC in Southern and Eastern Europe were more likely to test HIV positive as were people presenting with IMS, lymphadenopathy and leukocytopenia/ thrombocytopenia. One third of people diagnosed with HIV after presenting with IMS reported a negative HIV test in the preceding 12 months. Of patients newly diagnosed with HIV where data was available, 92.6% were promptly linked to care; of these 10.4% were reported lost to follow up or dead 12 months after diagnosis. CONCLUSION: The study showed that 10 conditions had HIV prevalences > 0.1%. These 10 ICs should be adopted into HIV testing and IC specialty guidelines. As IMS presentation can mimic acute HIV sero-conversion and has the highest positivity rate, this IC in particular affords opportunities for earlier diagnosis and public health benefit.


Assuntos
Diagnóstico Precoce , Infecções por HIV/diagnóstico , HIV/isolamento & purificação , Programas de Rastreamento , Testes Sorológicos/métodos , Adolescente , Adulto , Idoso , Europa Oriental/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Prevalência , Adulto Jovem
9.
AIDS ; 33(12): 1871-1880, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259766

RESUMO

AIMS: To assess associations of comorbidity patterns observed in people living with HIV (PLWH) with risk factors and health outcomes. METHODS: Common patters of comorbidities in PLWH participating in the Pharmacokinetic and Clinical Observations in People Over Fifty study were determined using principal component analysis and a severity score for each pattern was derived. Associations between each pattern's severity score and risk factors were assessed using median regression. The independent associations of patterns' severity scores with self-reported physical and mental health (SF-36 summary scores) were assessed using linear regression, with functional impairment (Lawton IADL < 8) and hospitalization in last year using logistic regression and with number of general practitioner visits using Poisson regression. RESULTS: A total of 1073 PLWH were analysed: 85.2% male, median (interquartile range) age 52 (47-59) years, 98% on therapy. Duration of HIV was associated with higher severity in 4/6 of patterns: cardiovascular diseases, mental health problems, metabolic disorders and chest/other infections (all P ≤ 0.001). Prior AIDS was associated with higher severity scores for the same patterns and for the pattern of cancers (P < 0.001). The pattern of cardiovascular diseases was associated with poorer physical health (P = 0.02), higher risk of functional impairment (P = 0.02) and hospitalization (P < 0.001) and with higher number of general practitioner visits (P < 0.001). Severity of mental health (all P < 0.001) and of chest/other infections patterns negatively affected all the five health outcomes. CONCLUSION: Common patterns of comorbidities seen in PLWH appear to have different risk factors and to differently affect health outcomes. These findings may assist the development of targeted intervention to prevent, treat and manage the increasingly prevalent multimorbidity in PLWH.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Transmissíveis/epidemiologia , Infecções por HIV/complicações , Transtornos Mentais/epidemiologia , Doenças Metabólicas/epidemiologia , Adolescente , Adulto , Doenças Cardiovasculares/patologia , Doenças Transmissíveis/patologia , Comorbidade , Feminino , Humanos , Masculino , Transtornos Mentais/patologia , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
10.
Antivir Ther ; 24(3): 193-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30700636

RESUMO

BACKGROUND: Polypharmacy (use of ≥ five medications) increases the risk of drug-drug interactions and can lead to negative health outcomes. This study aimed to review the medications of people living with HIV (PLWH) and HIV-negative controls in the POPPY study and evaluate the frequency of polypharmacy and potential drug-drug interactions (PDDIs). METHODS: PDDIs between non-antiretroviral (ARV) drugs were analysed using the Lexicomp® database, and PDDIs between non-ARV and ARV drugs using the Liverpool drug interaction database. Between-group differences were assessed using χ2, Mann-Whitney U and Kruskal-Wallis tests. RESULTS: This analysis included 698 PLWH ≥50 years, 374 PLWH <50 years and 304 HIV-negative controls ≥50 years. The prevalence of polypharmacy was 65.8% in older PLWH, 48.1% in younger PLWH and 13.2% in the HIV-negative group. When ARVs were excluded, 29.8% of older PLWH and 14.2% of younger PLWH had polypharmacy. The prevalence of ≥1 PDDI involving non-ARV drugs was 36.1%, 20.3% and 16.4%, respectively, in older PLWH, younger PLWH and HIV-negative controls. In PLWH the prevalence of ≥1 PDDI involving ARV and non-ARV drugs was 57.3% in older PLWH and 32.4% in younger PLWH. CONCLUSIONS: Polypharmacy and PDDIs involving non-ARV/ARV drugs and non-ARV/non-ARV drugs were common among older PLWH, highlighting the need for increased awareness and additional research on all types of PDDI.


Assuntos
Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Polimedicação , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antirretrovirais/administração & dosagem , Antirretrovirais/efeitos adversos , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido/epidemiologia , Carga Viral , Adulto Jovem
11.
Nat Cell Biol ; 20(11): 1328, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30190576

RESUMO

In the version of this Article originally published, in ref. 34 the first author's name was spelled incorrectly. The correct reference is: Rodón, L. et al. Active CREB1 promotes a malignant TGFß2 autocrine loop in glioblastoma. Cancer Discov. 10, 1230-1241 (2014). This has now been amended in all online versions of the Article.

12.
Nat Cell Biol ; 20(10): 1228, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30089841

RESUMO

In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article.

13.
Nat Cell Biol ; 20(7): 823-835, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29915361

RESUMO

Stress is integral to tumour evolution, and cancer cell survival depends on stress management. We found that cancer-associated stress chronically activates the bioenergetic sensor AMP kinase (AMPK) and, to survive, tumour cells hijack an AMPK-regulated stress response pathway conserved in normal cells. Analysis of The Cancer Genome Atlas data revealed that AMPK isoforms are highly expressed in the lethal human cancer glioblastoma (GBM). We show that AMPK inhibition reduces viability of patient-derived GBM stem cells (GSCs) and tumours. In stressed (exercised) skeletal muscle, AMPK is activated to cooperate with CREB1 (cAMP response element binding protein-1) and promote glucose metabolism. We demonstrate that oncogenic stress chronically activates AMPK in GSCs that coopt the AMPK-CREB1 pathway to coordinate tumour bioenergetics through the transcription factors HIF1α and GABPA. Finally, we show that adult mice tolerate systemic deletion of AMPK, supporting the use of AMPK pharmacological inhibitors in the treatment of GBM.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias Encefálicas/enzimologia , Proliferação de Células , Metabolismo Energético , Glioblastoma/enzimologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/genética , Animais , Antineoplásicos/farmacologia , Apoptose , Autofagia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Fator de Transcrição de Proteínas de Ligação GA/genética , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Fatores de Tempo , Transcrição Gênica , Carga Tumoral , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
BMJ Open ; 7(12): e018163, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29247095

RESUMO

INTRODUCTION: HIV remains underdiagnosed. Guidelines recommend routine HIV testing in primary care, but evidence on implementing testing is lacking. In a previous study, the Rapid HIV Assessment 2 (RHIVA2) cluster randomised controlled trial, we showed that providing training and rapid point-of-care HIV testing at general practice registration (RHIVA2 intervention) in Hackney led to cost-effective, increased and earlier diagnosis of HIV. However, interventions effective in a trial context may be less so when implemented in routine practice. We describe the protocol for an MRC phase IV implementation programme, evaluating the impact of rolling out the RHIVA2 intervention in a post-trial setting. We will use a longitudinal study to examine if the post-trial implementation in Hackney practices is effective and cost-effective, and a cross-sectional study to compare Hackney with two adjacent boroughs providing usual primary care (Newham) and an enhanced service promoting HIV testing in primary care (Tower Hamlets). METHODS AND ANALYSIS: Service evaluation using interrupted time series and cost-effectiveness analyses. We will include all general practices in three contiguous high HIV prevalence East London boroughs. All adults aged 16 and above registered with the practices will be included. The interventions to be examined are: a post-trial RHIVA2 implementation programme (including practice-based education and training, external quality assurance, incentive payments for rapid HIV testing and incorporation of rapid HIV testing in the sexual health Local Enhanced Service) in Hackney; the general practice sexual health Network Improved Service in Tower Hamlets and usual care in Newham. Coprimary outcomes are rates of HIV testing and new HIV diagnoses. ETHICS AND DISSEMINATION: The chair of the Camden and Islington NHS Research Ethics Committee, London, has endorsed this programme as an evaluation of routine care. Study results will be published in peer-reviewed journals and reported to commissioners.


Assuntos
Medicina Geral/educação , Infecções por HIV/diagnóstico , Programas de Rastreamento/métodos , Atenção Primária à Saúde/economia , Análise Custo-Benefício , Estudos Transversais , Diagnóstico Precoce , Feminino , Infecções por HIV/epidemiologia , Humanos , Análise de Séries Temporais Interrompida , Londres/epidemiologia , Estudos Longitudinais , Masculino , Programas de Rastreamento/economia , Análise de Regressão , Projetos de Pesquisa
15.
PLoS One ; 12(9): e0184841, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28931051

RESUMO

The tumour immune microenvironment is considered to influence cancer behaviour and outcome. Using a panel of markers for innate and adaptive immune cells we set out to characterise and understand the bladder tumour microenvironment of 114 patients from a prospective multicentre cohort of newly-diagnosed bladder cancer patients, followed-up for 4.33±1.71 years. We found IL-17-positive cells were significantly increased in primary and concomitant carcinoma in situ (CIS), p<0.0001, a highly malignant lesion which is the most significant single risk factor for disease progression. Further characterisation of the tumour immunophenotype identified IL-17+ cells as predominantly mast cells rather than T-cells, in contrast to most other tumour types. Expression of the IL-17-receptor in bladder tumours, and functional effects and gene expression changes induced by IL-17 in bladder tumour cells in vitro suggest a role in tumour behaviour. Finally, we assessed the effects of IL-17 in the context of patient outcome, following intravesical BCG immunotherapy which is the standard of care; higher numbers of IL-17+ cells were associated with improved event-free survival (p = 0.0449, HR 0.2918, 95% CI 0.08762-0.9721) in patients with primary and concomitant CIS (n = 41), we propose a model of IL-17+ Mast cells mechanism of action. Thus, in the context of bladder CIS, IL-17+ mast cells predict favourable outcome following BCG immunotherapy indicative of a novel mechanism of BCG immunotherapy in UBC and could form the basis of a stratified approach to treatment.


Assuntos
Vacina BCG/uso terapêutico , Carcinoma in Situ/imunologia , Imunoterapia , Interleucina-17/farmacologia , Mastócitos/metabolismo , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/imunologia , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Estudos Prospectivos , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
16.
Lancet HIV ; 4(10): e465-e474, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28768604

RESUMO

BACKGROUND: Early HIV diagnosis reduces morbidity, mortality, the probability of onward transmission, and their associated costs, but might increase cost because of earlier initiation of antiretroviral treatment (ART). We investigated this trade-off by estimating the cost-effectiveness of HIV screening in primary care. METHODS: We modelled the effect of the four-times higher diagnosis rate observed in the intervention arm of the RHIVA2 randomised controlled trial done in Hackney, London (UK), a borough with high HIV prevalence (≥0·2% adult prevalence). We constructed a dynamic, compartmental model representing incidence of infection and the effect of screening for HIV in general practices in Hackney. We assessed cost-effectiveness of the RHIVA2 trial by fitting model diagnosis rates to the trial data, parameterising with epidemiological and behavioural data from the literature when required, using trial testing costs and projecting future costs of treatment. FINDINGS: Over a 40 year time horizon, incremental cost-effectiveness ratios were £22 201 (95% credible interval 12 662-132 452) per quality-adjusted life-year (QALY) gained, £372 207 (268 162-1 903 385) per death averted, and £628 874 (434 902-4 740 724) per HIV transmission averted. Under this model scenario, with UK cost data, RHIVA2 would reach the upper National Institute for Health and Care Excellence cost-effectiveness threshold (about £30 000 per QALY gained) after 33 years. Scenarios using cost data from Canada (which indicate prolonged and even higher health-care costs for patients diagnosed late) suggest this threshold could be reached in as little as 13 years. INTERPRETATION: Screening for HIV in primary care has important public health benefits as well as clinical benefits. We predict it to be cost-effective in the UK in the medium term. However, this intervention might be cost-effective far sooner, and even cost-saving, in settings where long-term health-care costs of late-diagnosed patients in high-prevalence regions are much higher (≥60%) than those of patients diagnosed earlier. Screening for HIV in primary care is cost-effective and should be promoted. FUNDING: NHS City and Hackney, UK Department of Health, National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care.


Assuntos
Análise Custo-Benefício/economia , Infecções por HIV/prevenção & controle , Programas de Rastreamento/economia , Modelos Econômicos , Atenção Primária à Saúde/economia , Adulto , Análise Custo-Benefício/métodos , Diagnóstico Precoce , Infecções por HIV/economia , Infecções por HIV/epidemiologia , Custos de Cuidados de Saúde , Humanos , Londres/epidemiologia , Áreas de Pobreza , Prevalência , Atenção Primária à Saúde/estatística & dados numéricos , Anos de Vida Ajustados por Qualidade de Vida
17.
Neuro Oncol ; 19(8): 1068-1078, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28339768

RESUMO

Background: Diffuse intrinsic pontine glioma (DIPG) is a high-grade brainstem glioma of children with dismal prognosis. There is no single unifying model about the cell of origin of DIPGs. Proliferating cells in the developing human and mouse pons, the site of DIPGs, express neural stem/progenitor cell (NPC) markers, including Sox2, nestin, vimentin, Olig2, and glial fibrillary acidic protein, in an overlapping and non-overlapping manner, suggesting progenitor cell heterogeneity in the pons. It is thought that during a restricted window of postnatal pons development, a differentiation block caused by genetic/epigenetic changes leads to unrestrained progenitor proliferation and DIPG development. Nearly 80% of DIPGs harbor a mutation in the H3F3A or the related HIST1H3B gene. Supporting the impaired differentiation model, NPCs derived from human induced pluripotent stem cells expressing the H3F3A mutation showed complete differentiation block. However, the mechanisms regulating an altered differentiation program in DIPG are unknown. Methods: We established syngeneic serum-dependent and independent primary DIPG lines, performed molecular characterization of DIPG lines in vitro and in an orthotopic xenograft model, and used small hairpin RNA to examine Olig2 function in DIPG. Results: The transcription factor Olig2 is highly expressed in 70%-80% of DIPGs. Here we report that Olig2 expression and DIPG differentiation are mutually exclusive events in vitro, and only DIPG cells that retained Olig2 in vitro formed robust Olig2-positive brainstem glioma with 100% penetrance in a xenograft model. Conclusion: Our results indicate Olig2 as an onco-requisite factor in DIPG and propose investigation of Olig2 target genes as novel candidates in DIPG therapy.


Assuntos
Astrocitoma/metabolismo , Neoplasias do Tronco Encefálico/metabolismo , Glioma/metabolismo , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Animais , Neoplasias do Tronco Encefálico/genética , Pré-Escolar , Regulação da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo
18.
Cancer Res ; 76(8): 2314-26, 2016 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-26921326

RESUMO

The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma, or colorectal liver metastasis. We identified a panel of genes consistently upregulated by tumor blood vessels, of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and colorectal carcinoma blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in colorectal carcinoma. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting. Cancer Res; 76(8); 2314-26. ©2016 AACR.


Assuntos
Carcinoma de Células Renais/irrigação sanguínea , Neoplasias Renais/irrigação sanguínea , Laminina/metabolismo , Animais , Antígeno CD146/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Camundongos , Metástase Neoplásica , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/farmacologia
19.
Dysphagia ; 31(1): 104-10, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26519043

RESUMO

Screening patients admitted with stroke symptoms for risk of aspiration is often the responsibility of registered nurses (RNs). Simulation technology has become a widely used evidence-based form of training for healthcare professionals. The purpose of this study was to determine if the use of medical simulation mannequins as a training component is feasible when training and evaluating nurses administering swallowing screenings to stroke patients. A total of 32 RNs were divided into one of two training groups: didactic training only or didactic training plus simulation. Acquisition of skills was assessed immediately post-training and compared between the groups revealing significant differences between simulation group and didactic-only group for interpretation (p = 0.01) and administration (p = 0.05) accuracies. Following training to 100 % accuracy for post-training baseline competency, maintenance of skills across participants was assessed three more times over 6 weeks with the third follow-up screening completed with a standardized patient (live patient actor). While interpretation performance at each subsequent trial never equaled the baseline 100 % post-training accuracy (p = 0.001), steady improvement in performance was observed with each follow-up assessment. For screening administration, no significant differences in skills were evident between post-training baseline competency and the 6-week follow-up (p = 0.269) further confirming improvement in skills over time. Extension of screening administration and interpretation skills to the standardized patient was evident. Findings indicate that simulation training using medical mannequins can be used to train and evaluate nurses for obtainment and maintenance of swallowing screening competency.


Assuntos
Competência Clínica , Transtornos de Deglutição/diagnóstico , Educação Continuada em Enfermagem/métodos , Treinamento por Simulação/métodos , Acidente Vascular Cerebral/complicações , Adulto , Transtornos de Deglutição/etiologia , Feminino , Humanos , Masculino , Manequins , Programas de Rastreamento , Pessoa de Meia-Idade
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