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1.
Nature ; 606(7916): 976-983, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35705807

RESUMO

Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA1. The broad genomic complexity caused by CIN is a hallmark of cancer2; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.


Assuntos
Instabilidade Cromossômica , Neoplasias , Instabilidade Cromossômica/genética , Recombinação Homóloga/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo
2.
Br J Cancer ; 131(3): 457-467, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38902534

RESUMO

BACKGROUND/OBJECTIVES: Pseudo-vascular network formation in vitro is considered a key characteristic of vasculogenic mimicry. While many cancer cell lines form pseudo-vascular networks, little is known about the spatiotemporal dynamics of these formations. METHODS: Here, we present a framework for monitoring and characterising the dynamic formation and dissolution of pseudo-vascular networks in vitro. The framework combines time-resolved optical microscopy with open-source image analysis for network feature extraction and statistical modelling. The framework is demonstrated by comparing diverse cancer cell lines associated with vasculogenic mimicry, then in detecting response to drug compounds proposed to affect formation of vasculogenic mimics. Dynamic datasets collected were analysed morphometrically and a descriptive statistical analysis model was developed in order to measure stability and dissimilarity characteristics of the pseudo-vascular networks formed. RESULTS: Melanoma cells formed the most stable pseudo-vascular networks and were selected to evaluate the response of their pseudo-vascular networks to treatment with axitinib, brucine and tivantinib. Tivantinib has been found to inhibit the formation of the pseudo-vascular networks more effectively, even in dose an order of magnitude less than the two other agents. CONCLUSIONS: Our framework is shown to enable quantitative analysis of both the capacity for network formation, linked vasculogenic mimicry, as well as dynamic responses to treatment.


Assuntos
Neovascularização Patológica , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Linhagem Celular Tumoral , Melanoma/patologia , Melanoma/irrigação sanguínea , Melanoma/tratamento farmacológico , Axitinibe/farmacologia
3.
Stat Med ; 43(5): 833-854, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38115199

RESUMO

Average (bio)equivalence tests are used to assess if a parameter, like the mean difference in treatment response between two conditions for example, lies within a given equivalence interval, hence allowing to conclude that the conditions have "equivalent" means. The two one-sided tests (TOST) procedure, consisting in testing whether the target parameter is respectively significantly greater and lower than some pre-defined lower and upper equivalence limits, is typically used in this context, usually by checking whether the confidence interval for the target parameter lies within these limits. This intuitive and visual procedure is however known to be conservative, especially in the case of highly variable drugs, where it shows a rapid power loss, often reaching zero, hence making it impossible to conclude for equivalence when it is actually true. Here, we propose a finite sample correction of the TOST procedure, the α $$ \alpha $$ -TOST, which consists in a correction of the significance level of the TOST allowing to guarantee a test size (or type-I error rate) of α $$ \alpha $$ . This new procedure essentially corresponds to a finite sample and variability correction of the TOST procedure. We show that this procedure is uniformly more powerful than the TOST, easy to compute, and that its operating characteristics outperform the ones of its competitors. A case study about econazole nitrate deposition in porcine skin is used to illustrate the benefits of the proposed method and its advantages compared to other available procedures.


Assuntos
Equivalência Terapêutica , Tamanho da Amostra
4.
Respirology ; 27(10): 834-843, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35918280

RESUMO

The use of Bayesian adaptive designs for clinical trials has increased in recent years, particularly during the COVID-19 pandemic. Bayesian adaptive designs offer a flexible and efficient framework for conducting clinical trials and may provide results that are more useful and natural to interpret for clinicians, compared to traditional approaches. In this review, we provide an introduction to Bayesian adaptive designs and discuss its use in recent clinical trials conducted in respiratory medicine. We illustrate this approach by constructing a Bayesian adaptive design for a multi-arm trial that compares two non-invasive ventilation treatments to standard oxygen therapy for patients with acute cardiogenic pulmonary oedema. We highlight the benefits and some of the challenges involved in designing and implementing Bayesian adaptive trials.


Assuntos
COVID-19 , Pneumologia , Teorema de Bayes , Ensaios Clínicos como Assunto , Humanos , Oxigênio , Pandemias , Projetos de Pesquisa
5.
Br J Cancer ; 124(1): 156-160, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33024263

RESUMO

Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAFV600, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, p = 0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Melanoma/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Cutâneas/genética , Análise Mutacional de DNA , Humanos , Mutação , Recidiva , Melanoma Maligno Cutâneo
6.
Magn Reson Med ; 85(6): 3027-3035, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33421253

RESUMO

PURPOSE: To compare carbon-13 (13 C) MRSI of hyperpolarized [1-13 C]pyruvate metabolism in a murine tumor model with mass spectrometric (MS) imaging of the corresponding tumor sections in order to cross validate these metabolic imaging techniques and to investigate the effects of pyruvate delivery and tumor lactate concentration on lactate labeling. METHODS: [1-13 C]lactate images were obtained from tumor-bearing mice, following injection of hyperpolarized [1-13 C]pyruvate, using a single-shot 3D 13 C spectroscopic imaging sequence in vivo and using desorption electrospray ionization MS imaging of the corresponding rapidly frozen tumor sections ex vivo. The images were coregistered, and levels of association were determined by means of Spearman rank correlation and Cohen kappa coefficients as well as linear mixed models. The correlation between [1-13 C]pyruvate and [1-13 C]lactate in the MRS images and between [12 C] and [1-13 C]lactate in the MS images were determined by means of Pearson correlation coefficients. RESULTS: [1-13 C]lactate images generated by MS imaging were significantly correlated with the corresponding MRS images. The correlation coefficient between [1-13 C]lactate and [1-13 C]pyruvate in the MRS images was higher than between [1-13 C]lactate and [12 C]lactate in the MS images. CONCLUSION: The inhomogeneous distribution of labeled lactate observed in the MRS images was confirmed by MS imaging of the corresponding tumor sections. The images acquired using both techniques show that the rate of 13 C label exchange between the injected pyruvate and endogenous tumor lactate pool is more correlated with the rate of pyruvate delivery to the tumor cells and is less affected by the endogenous lactate concentration.


Assuntos
Linfoma , Ácido Pirúvico , Animais , Isótopos de Carbono , Ácido Láctico , Linfoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Espectrometria de Massas , Camundongos
7.
Br J Cancer ; 123(5): 793-802, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32555365

RESUMO

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.


Assuntos
PTEN Fosfo-Hidrolase/biossíntese , Adenocarcinoma de Células Claras/enzimologia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Fatores Etários , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/enzimologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Estudos de Coortes , Regulação para Baixo , Feminino , Técnicas de Inativação de Genes , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Estudos Prospectivos , Receptores Androgênicos/biossíntese , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Análise Serial de Tecidos , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/deficiência
8.
Biom J ; 61(2): 333-342, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30003579

RESUMO

In clinical trials one traditionally models the effect of treatment on the mean response. The underlying assumption is that treatment affects the response distribution through a mean location shift on a suitable scale, with other aspects of the distribution (shape/dispersion/variance) remaining the same. This work is motivated by a trial in Parkinson's disease patients in which one of the endpoints is the number of falls during a 10-week period. Inspection of the data reveals that the Poisson-inverse Gaussian (PiG) distribution is appropriate, and that the experimental treatment reduces not only the mean, but also the variability, substantially. The conventional analysis assumes a treatment effect on the mean, either adjusted or unadjusted for covariates, and a constant dispersion parameter. On our data, this analysis yields a non-significant treatment effect. However, if we model a treatment effect on both mean and dispersion parameters, both effects are highly significant. A simulation study shows that if a treatment effect exists on the dispersion and is ignored in the modelling, estimation of the treatment effect on the mean can be severely biased. We show further that if we use an orthogonal parametrization of the PiG distribution, estimates of the mean model are robust to misspecification of the dispersion model. We also discuss inferential aspects that are more difficult than anticipated in this setting. These findings have implications in the planning of statistical analyses for count data in clinical trials.


Assuntos
Bioestatística/métodos , Modelos Estatísticos , Viés , Distribuição Normal , Distribuição de Poisson , Análise de Regressão
9.
Appetite ; 121: 337-347, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29183701

RESUMO

OBJECTIVE: Placing snack-food further away from people consistently decreases its consumption ("proximity effect"). However, given diet-related health inequalities, it is important to know whether interventions that alter food proximity have potential to change behaviour regardless of cognitive resource (capacity for self-control). This is often lower in those in lower socio-economic positions, who also tend to have less healthy diet-related behaviours. Study 1 aims to replicate the proximity effect in a general population sample and estimate whether trait-level cognitive resource moderates the effect. In a stronger test, Study 2 investigates whether the effect is similar regardless of manipulated state-level cognitive resource. METHOD: Participants were recruited into two laboratory studies (Study 1: n = 159; Study 2: n = 246). A bowl of an unhealthy snack was positioned near (20 cm) or far (70 cm) from the participant, as randomised. In Study 2, participants were further randomised to a cognitive load intervention. The pre-specified primary outcome was the proportion of participants taking any of the snack. RESULTS: Significantly fewer participants took the snack when far compared with near in Study 2 (57.7% vs 70.7%, ß = -1.63, p = 0.020), but not in Study 1 (53.8% vs 63.3%, X2 = 1.12, p = 0.289). Removing participants who moved the bowl (i.e. who did not adhere to protocol), increased the effect-sizes: Study 1: 39.3% vs 63.9%, X2 = 6.43, p = 0.011; Study 2: 56.0% vs 73.9%, ß = -2.46, p = 0.003. Effects were not moderated by cognitive resource. CONCLUSIONS: These studies provide the most robust evidence to date that placing food further away reduces likelihood of consumption in general population samples, an effect unlikely to be moderated by cognitive resource. This indicates potential for interventions altering food proximity to contribute to addressing health inequalities, but requires testing in real-world settings. TRIAL REGISTRATION: Both studies were registered with ISRCTN (Study 1 reference no.: ISRCTN46995850, Study 2 reference no.: ISRCTN14239872).


Assuntos
Cognição , Comportamento Alimentar/psicologia , Comportamentos Relacionados com a Saúde , Autocontrole , Lanches/psicologia , Adulto , Índice de Massa Corporal , Dieta , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos , Adulto Jovem
10.
BMC Public Health ; 16: 504, 2016 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-27297225

RESUMO

BACKGROUND: Despite attempts to improve diet at population level, people living in material and social deprivation continue to consume unhealthy diets. Executive function - the ability to regulate behaviour and resist impulses - is weaker in individuals living in deprivation. Dietary interventions that educate and persuade people to reflect on and actively change behaviour may therefore disproportionately benefit individuals who are socioeconomically advantaged and have stronger executive function, thus exacerbating inequalities in health resulting from unhealthy diets. In contrast, manipulating environmental cues, such as how far away a food is placed, does not appeal to reasoned action and is thought to operate largely outside of awareness to influence behaviour. People eat more of a food when it is placed closer to them, an effect seemingly robust to context, food quality and body-weight status. However, previous studies of this 'proximity effect' are limited by small samples consisting mainly of university staff or students, biased towards higher socio-economic position and therefore likely stronger executive function. This study aims to test the hypothesis that placing food further away from a person decreases intake of that food regardless of executive function. METHODS/DESIGN: 156 members of the general public, recruited from low and high socio-economic groups, will be randomised to one of two conditions varying in the proximity of a snack food relative to their position: 20 cm or 70 cm. Participants are told they will be taking part in a relaxation study - and are fully debriefed at the conclusion of the session. The primary outcome is the proportion of participants eating any amount of snack food and the secondary outcome is the mean amount eaten. Executive function is assessed using the Stroop task. DISCUSSION: The proposed study takes a novel step by investigating the effect of proximity on snack food intake in a general population sample consisting of those with high and low executive function, appropriately powered to detect the predicted proximity effect. If this effect occurs irrespective of executive function and socio-economic position, it may have potential to reduce inequalities patterned by socio-economic position if implemented in real-world settings such as shops or restaurants. TRIAL REGISTRATION: Registered with the ISRCTN registry: ISRCTN46995850 on 07 October 2015.


Assuntos
Ingestão de Alimentos/psicologia , Função Executiva , Comportamento Alimentar/psicologia , Comportamentos Relacionados com a Saúde , Lanches/psicologia , Adulto , Sinais (Psicologia) , Feminino , Humanos , Inibição Psicológica , Masculino , Fatores Socioeconômicos , Teste de Stroop
11.
BMC Public Health ; 16: 390, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27268112

RESUMO

BACKGROUND: Wine glass size can influence both perceptions of portion size and the amount poured, but its impact upon purchasing and consumption is unknown. This study aimed to examine the impact of wine glass size on wine sales for on-site consumption, keeping portion size constant. METHODS: In one establishment (with separate bar and restaurant areas) in Cambridge, England, wine glass size (Standard; Larger; Smaller) was changed over eight fortnightly periods. The bar and restaurant differ in wine sales by the glass vs. by the bottle (93 % vs. 63 % by the glass respectively). RESULTS: Daily wine volume purchased was 9.4 % (95 % CI: 1.9, 17.5) higher when sold in larger compared to standard-sized glasses. This effect seemed principally driven by sales in the bar area (bar: 14.4 % [3.3, 26.7]; restaurant: 8.2 % [-2.5, 20.1]). Findings were inconclusive as to whether sales were different with smaller vs. standard-sized glasses. CONCLUSIONS: The size of glasses in which wine is sold, keeping the portion size constant, can affect consumption, with larger glasses increasing consumption. The hypothesised mechanisms for these differential effects need to be tested in a replication study. If replicated, policy implications could include considering glass size amongst alcohol licensing requirements. TRIAL REGISTRATION: ISRCTN registry: ISRCTN12018175 . Registered 12(th) May 2015.


Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Vidro , Restaurantes/economia , Vinho , Consumo de Bebidas Alcoólicas/psicologia , Comércio/estatística & dados numéricos , Inglaterra , Humanos , Tamanho da Porção
12.
Elife ; 122023 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-37166279

RESUMO

High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterized by ubiquitous TP53 mutation, profound chromosomal instability, and heterogeneity. The mutational processes driving chromosomal instability in HGSOC can be distinguished by specific copy number signatures. To develop clinically relevant models of these mutational processes we derived 15 continuous HGSOC patient-derived organoids (PDOs) and characterized them using bulk transcriptomic, bulk genomic, single-cell genomic, and drug sensitivity assays. We show that HGSOC PDOs comprise communities of different clonal populations and represent models of different causes of chromosomal instability including homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype, and whole genome duplication. We also show that these PDOs can be used as exploratory tools to study transcriptional effects of copy number alterations as well as compound-sensitivity tests. In summary, HGSOC PDO cultures provide validated genomic models for studies of specific mutational processes and precision therapeutics.


Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Mutação , Genômica , Instabilidade Cromossômica , Organoides
13.
Trials ; 24(1): 640, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37798805

RESUMO

In the UK, the Medicines and Healthcare products Regulatory Agency consulted on proposals "to improve and strengthen the UK clinical trials legislation to help us make the UK the best place to research and develop safe and innovative medicines". The purpose of the consultation was to help finalise the proposals and contribute to the drafting of secondary legislation. We discussed these proposals as members of the Trials Methodology Research Partnership Adaptive Designs Working Group, which is jointly funded by the Medical Research Council and the National Institute for Health and Care Research. Two topics arose frequently in the discussion: the emphasis on legislation, and the absence of questions on data sharing. It is our opinion that the proposals rely heavily on legislation to change practice. However, clinical trials are heterogeneous, and as a result some trials will struggle to comply with all of the proposed legislation. Furthermore, adaptive design clinical trials are even more heterogeneous than their non-adaptive counterparts, and face more challenges. Consequently, it is possible that increased legislation could have a greater negative impact on adaptive designs than non-adaptive designs. Overall, we are sceptical that the introduction of legislation will achieve the desired outcomes, with some exceptions. Meanwhile the topic of data sharing - making anonymised individual-level clinical trial data available to other investigators for further use - is entirely absent from the proposals and the consultation in general. However, as an aspect of the wider concept of open science and reproducible research, data sharing is an increasingly important aspect of clinical trials. The benefits of data sharing include faster innovation, improved surveillance of drug safety and effectiveness and decreasing participant exposure to unnecessary risk. There are already a number of UK-focused documents that discuss and encourage data sharing, for example, the Concordat on Open Research Data and the Medical Research Council's Data Sharing Policy. We strongly suggest that data sharing should be the norm rather than the exception, and hope that the forthcoming proposals on clinical trials invite discussion on this important topic.


Assuntos
Disseminação de Informação , Projetos de Pesquisa , Humanos , Atenção à Saúde
14.
Nat Commun ; 14(1): 6505, 2023 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-37845213

RESUMO

High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and strongly associated with CIN and genome subclonality. Cell-based studies showed that high-prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel, the commonest treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Centrossomo/metabolismo , Cistadenocarcinoma Seroso/genética
15.
EMBO Mol Med ; 15(6): e16505, 2023 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-37161793

RESUMO

Analysis of circulating tumor DNA (ctDNA) to monitor cancer dynamics and detect minimal residual disease has been an area of increasing interest. Multiple methods have been proposed but few studies have compared the performance of different approaches. Here, we compare detection of ctDNA in serial plasma samples from patients with breast cancer using different tumor-informed and tumor-naïve assays designed to detect structural variants (SVs), single nucleotide variants (SNVs), and/or somatic copy-number aberrations, by multiplex PCR, hybrid capture, and different depths of whole-genome sequencing. Our results demonstrate that the ctDNA dynamics and allele fractions (AFs) were highly concordant when analyzing the same patient samples using different assays. Tumor-informed assays showed the highest sensitivity for detection of ctDNA at low concentrations. Hybrid capture sequencing targeting between 1,347 and 7,491 tumor-identified mutations at high depth was the most sensitive assay, detecting ctDNA down to an AF of 0.00024% (2.4 parts per million, ppm). Multiplex PCR targeting 21-47 tumor-identified SVs per patient detected ctDNA down to 0.00047% AF (4.7 ppm) and has potential as a clinical assay.


Assuntos
Neoplasias da Mama , DNA Tumoral Circulante , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , DNA Tumoral Circulante/genética , Mutação
16.
Int J Biostat ; 18(2): 553-575, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34714982

RESUMO

This paper considers the problem of semi-parametric proportional hazards model fitting where observed survival times contain event times and also interval, left and right censoring times. Although this is not a new topic, many existing methods suffer from poor computational performance. In this paper, we adopt a more versatile penalized likelihood method to estimate the baseline hazard and the regression coefficients simultaneously. The baseline hazard is approximated using basis functions such as M-splines. A penalty is introduced to regularize the baseline hazard estimate and also to ease dependence of the estimates on the knots of the basis functions. We propose a Newton-MI (multiplicative iterative) algorithm to fit this model. We also present novel asymptotic properties of our estimates, allowing for the possibility that some parameters of the approximate baseline hazard may lie on the parameter space boundary. Comparisons of our method against other similar approaches are made through an intensive simulation study. Results demonstrate that our method is very stable and encounters virtually no numerical issues. A real data application involving melanoma recurrence is presented and an R package 'survivalMPL' implementing the method is available on R CRAN.


Assuntos
Algoritmos , Projetos de Pesquisa , Modelos de Riscos Proporcionais , Funções Verossimilhança , Simulação por Computador
17.
Commun Biol ; 5(1): 10, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013537

RESUMO

Hyperpolarized [1-13C]pyruvate enables direct in vivo assessment of real-time liver enzymatic activities by 13C magnetic resonance. However, the technique usually requires the injection of a highly supraphysiological dose of pyruvate. We herein demonstrate that liver metabolism can be measured in vivo with hyperpolarized [1-13C]pyruvate administered at two- to three-fold the basal plasma concentration. The flux through pyruvate dehydrogenase, assessed by 13C-labeling of bicarbonate in the fed condition, was found to be saturated or partially inhibited by supraphysiological doses of hyperpolarized [1-13C]pyruvate. The [13C]bicarbonate signal detected in the liver of fasted rats nearly vanished after treatment with a phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, indicating that the signal originates from the flux through PEPCK. In addition, the normalized [13C]bicarbonate signal in fasted untreated animals is dose independent across a 10-fold range, highlighting that PEPCK and pyruvate carboxylase are not saturated and that hepatic gluconeogenesis can be directly probed in vivo with hyperpolarized [1-13C]pyruvate.


Assuntos
Bicarbonatos/metabolismo , Privação de Alimentos , Gluconeogênese , Fígado/metabolismo , Ácido Pirúvico/metabolismo , Animais , Biomarcadores/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
18.
Chem Commun (Camb) ; 58(12): 1962-1965, 2022 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-35044383

RESUMO

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Imunoconjugados/química , Indicadores e Reagentes/química , Pirimidinas/química , Animais , Antineoplásicos Imunológicos/efeitos adversos , Linhagem Celular Tumoral , Humanos , Imunoconjugados/efeitos adversos , Camundongos , Estudo de Prova de Conceito , Trastuzumab/efeitos adversos , Trastuzumab/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Photoacoustics ; 26: 100357, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35574188

RESUMO

Mesoscopic photoacoustic imaging (PAI) enables non-invasive visualisation of tumour vasculature. The visual or semi-quantitative 2D measurements typically applied to mesoscopic PAI data fail to capture the 3D vessel network complexity and lack robust ground truths for assessment of accuracy. Here, we developed a pipeline for quantifying 3D vascular networks captured using mesoscopic PAI and tested the preservation of blood volume and network structure with topological data analysis. Ground truth data of in silico synthetic vasculatures and a string phantom indicated that learning-based segmentation best preserves vessel diameter and blood volume at depth, while rule-based segmentation with vesselness image filtering accurately preserved network structure in superficial vessels. Segmentation of vessels in breast cancer patient-derived xenografts (PDXs) compared favourably to ex vivo immunohistochemistry. Furthermore, our findings underscore the importance of validating segmentation methods when applying mesoscopic PAI as a tool to evaluate vascular networks in vivo.

20.
Cancer Res ; 82(8): 1658-1668, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35404400

RESUMO

Angiogenesis is an established prognostic factor in advanced breast cancer, yet response to antiangiogenic therapies in this disease remains highly variable. Noninvasive imaging biomarkers could help identify patients that will benefit from antiangiogenic therapy and provide an ideal tool for longitudinal monitoring, enabling dosing regimens to be altered with real-time feedback. Photoacoustic tomography (PAT) is an emerging imaging modality that provides a direct readout of tumor hemoglobin concentration and oxygenation. We hypothesized that PAT could be used in the longitudinal setting to provide an early indication of response or resistance to antiangiogenic therapy. To test this hypothesis, PAT was performed over time in estrogen receptor-positive and estrogen receptor-negative breast cancer xenograft mouse models undergoing treatment with the antiangiogenic bevacizumab as a single agent. The cohort of treated tumors, which were mostly resistant to the treatment, contained a subset that demonstrated a clear survival benefit. At endpoint, the PAT data from the responding subset showed significantly lower oxygenation and higher hemoglobin content compared with both resistant and control tumors. Longitudinal analysis revealed that tumor oxygenation diverged significantly in the responding subset, identifying early treatment response and the evolution of different vascular phenotypes between the subsets. Responding tumors were characterized by a more angiogenic phenotype when analyzed with IHC, displaying higher vessel density, yet poorer vascular maturity and elevated hypoxia. Taken together, our findings indicate that PAT shows promise in providing an early indication of response or resistance to antiangiogenic therapy. SIGNIFICANCE: Photoacoustic assessment of tumor oxygenation is a noninvasive early indicator of response to bevacizumab therapy, clearly distinguishing between control, responding, and resistant tumors within just a few weeks of treatment.


Assuntos
Neoplasias da Mama , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Feminino , Hemoglobinas , Humanos , Camundongos , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Receptores de Estrogênio , Tomografia
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