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"Cooke, L"
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Spatial and Temporal Heterogeneity in High-Grade Serous Ovarian Cancer: A Phylogenetic Analysis
The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease.
Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22-46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66-1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy.
This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.
Journal Article
Genome Analyses of an Aggressive and Invasive Lineage of the Irish Potato Famine Pathogen
Pest and pathogen losses jeopardise global food security and ever since the 19(th) century Irish famine, potato late blight has exemplified this threat. The causal oomycete pathogen, Phytophthora infestans, undergoes major population shifts in agricultural systems via the successive emergence and migration of asexual lineages. The phenotypic and genotypic bases of these selective sweeps are largely unknown but management strategies need to adapt to reflect the changing pathogen population. Here, we used molecular markers to document the emergence of a lineage, termed 13_A2, in the European P. infestans population, and its rapid displacement of other lineages to exceed 75% of the pathogen population across Great Britain in less than three years. We show that isolates of the 13_A2 lineage are among the most aggressive on cultivated potatoes, outcompete other aggressive lineages in the field, and overcome previously effective forms of plant host resistance. Genome analyses of a 13_A2 isolate revealed extensive genetic and expression polymorphisms particularly in effector genes. Copy number variations, gene gains and losses, amino-acid replacements and changes in expression patterns of disease effector genes within the 13_A2 isolate likely contribute to enhanced virulence and aggressiveness to drive this population displacement. Importantly, 13_A2 isolates carry intact and in planta induced Avrblb1, Avrblb2 and Avrvnt1 effector genes that trigger resistance in potato lines carrying the corresponding R immune receptor genes Rpi-blb1, Rpi-blb2, and Rpi-vnt1.1. These findings point towards a strategy for deploying genetic resistance to mitigate the impact of the 13_A2 lineage and illustrate how pathogen population monitoring, combined with genome analysis, informs the management of devastating disease epidemics.
Journal Article
Evolution of platinum resistance in high-grade serous ovarian cancer
High-grade serous ovarian cancers account for most ovarian-cancer mortality. Although this disease initially responds well to platinum-based chemotherapy, relapse and progression to chemotherapy resistance are frequently seen. Time to relapse after first-line therapy is a predictor of response to secondary platinum treatment: more than 12 months is associated with high chance of a secondary response, whereas relapses within 6 months generally indicate platinum resistance. In this Personal View we discuss whether patterns of response, relapse, and the development of drug resistance in high-grade serous ovarian cancers are related to distinct underlying molecular and cellular biological characteristics. In particular, we propose that rapid relapse with platinum-resistant disease is due to minor subpopulations of intrinsically resistant cancer cells at presentation.
Journal Article
Environmental and individual determinants of core and non-core food and drink intake in preschool-aged children in the United Kingdom
Background/Objectives:
Strategies to achieve healthier diets for children are likely to benefit from an understanding of the determinants. We examined environmental and individual predictors of children's intake of ‘core’ foods (fruit and vegetables) and ‘non-core’ foods (snacks and sweetened beverages). Predictors included parental intake, home availability, parental feeding styles (Encouragement and Monitoring) and children's food preferences. Based on research with older children, we expected intake of both food types to be associated with maternal intake, core foods to be more associated with children's preferences and non-core food intake more with the home environment.
Subjects/Methods:
Primary caregivers (
n
=434) of children (2–5 years) from preschools and Children's Centres in London, UK, completed a self-report survey in 2008.
Results:
Multiple regression analyses indicated children's fruit intake was associated with maternal fruit intake (
B
=0.29;
P
=0.000), children's liking for fruit (
B
=0.81;
P
=0.000) and a Monitoring style of parental feeding (
B
=0.13;
P
=0.021). Children's vegetable intake was similarly associated with maternal intake (
B
=0.39;
P
=0.000), children's liking for vegetables (
B
=0.77;
P
=0.000), Encouragement (
B
=0.19;
P
=0.021) and Monitoring (
B
=0.11;
P
=0.029). Non-core snack intake was associated with maternal intake (
B
=0.25;
P
=0.029), Monitoring (
B
=−0.16;
P
=0.010), home availability (
B
=0.10;
P
=0.022) and television viewing (TV) (
B
=0.28;
P
=0.012). Non-core drink intake was associated with maternal intake (
B
=0.32;
P
=0.000) and TV (
B
=0.20;
P
=0.019).
Conclusions:
Results indicate commonalities and differences in the predictors of core and non-core food intake, with only maternal intake being important across all types. Effective interventions to improve young children's diets may need to call on different strategies for different foods.
Journal Article
Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone
Adrienne Flanagan and colleagues identify distinct driver mutations in
H3F3A
and
H3F3B
in chondroblastoma and giant cell tumor of bone. The mutations occur in over 90% of tumors and exhibit a high degree of tumor type specificity.
It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in
H3F3B
, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in
H3F3A
, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported
H3F3A
mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.
Journal Article
A Review of Intraocular Lens Power Calculation Formulas Based on Artificial Intelligence
Purpose: The proper selection of an intraocular lens power calculation formula is an essential aspect of cataract surgery. This study evaluated the accuracy of artificial intelligence-based formulas. Design: Systematic review. Methods: This review comprises articles evaluating the exactness of artificial intelligence-based formulas published from 2017 to July 2023. The papers were identified by a literature search of various databases (Pubmed/MEDLINE, Google Scholar, Crossref, Cochrane Library, Web of Science, and SciELO) using the terms “IOL formulas”, “FullMonte”, “Ladas”, “Hill-RBF”, “PEARL-DGS”, “Kane”, “Karmona”, “Hoffer QST”, and “Nallasamy”. In total, 25 peer-reviewed articles in English with the maximum sample and the largest number of compared formulas were examined. Results: The scores of the mean absolute error and percentage of patients within ±0.5 D and ±1.0 D were used to estimate the exactness of the formulas. In most studies the Kane formula obtained the smallest mean absolute error and the highest percentage of patients within ±0.5 D and ±1.0 D. Second place was typically achieved by the PEARL DGS formula. The limitations of the studies were also discussed. Conclusions: Kane seems to be the most accurate artificial intelligence-based formula. PEARL DGS also gives very good results. Hoffer QST, Karmona, and Nallasamy are the newest, and need further evaluation.
Journal Article
Mutational signatures of ionizing radiation in second malignancies
Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following
in vivo
exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1–100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.
Ionizing radiation may induce irreparable DNA damage leading to cancer. Here, the authors identify a specific signature of mutations arising in patients exposed to ionizing radiation and suggest that radiation-induced tumorigenesis is associated with higher rates of genome-wide deletions and balanced inversions.
Journal Article
Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma
Resistance to chemotherapy in ovarian cancer is poorly understood. Evolutionary models of cancer predict that, following treatment, resistance emerges either because of outgrowth of an intrinsically resistant sub-clone or evolves in residual disease under the selective pressure of treatment. To investigate genetic evolution in high-grade serous (HGS) ovarian cancers, we first analysed cell line series derived from three cases of HGS carcinoma before and after platinum resistance had developed (PEO1, PEO4 and PEO6; PEA1 and PEA2; and PEO14 and PEO23). Analysis with 24-colour fluorescence
in situ
hybridisation and single nucleotide polymorphism (SNP) array comparative genomic hybridisation (CGH) showed mutually exclusive endoreduplication and loss of heterozygosity events in clones present at different time points in the same individual. This implies that platinum-sensitive and -resistant disease was not linearly related, but shared a common ancestor at an early stage of tumour development. Array CGH analysis of six paired pre- and post-neoadjuvant treatment HGS samples from the CTCR-OV01 clinical study did not show extensive copy number differences, suggesting that one clone was strongly dominant at presentation. These data show that cisplatin resistance in HGS carcinoma develops from pre-existing minor clones but that enrichment for these clones is not apparent during short-term chemotherapy treatment.
Journal Article
Cecal Ligation and Puncture Results in Long-Term Central Nervous System Myeloid Inflammation
Survivors of sepsis often experience long-term cognitive and functional decline. Previous studies utilizing lipopolysaccharide injection and cecal ligation and puncture in rodent models of sepsis have demonstrated changes in depressive-like behavior and learning and memory after sepsis, as well as evidence of myeloid inflammation and cytokine expression in the brain, but the long-term course of neuroinflammation after sepsis remains unclear. Here, we utilize cecal ligation and puncture with greater than 80% survival as a model of sepsis. We found that sepsis survivor mice demonstrate deficits in extinction of conditioned fear, but no acquisition of fear conditioning, nearly two months after sepsis. These cognitive changes occur in the absence of neuronal loss or changes in synaptic density in the hippocampus. Sepsis also resulted in infiltration of monocytes and neutrophils into the CNS at least two weeks after sepsis in a CCR2 independent manner. Cellular inflammation is accompanied by long-term expression of pro-inflammatory cytokine and chemokine genes, including TNFα and CCR2 ligands, in whole brain homogenates. Gene expression analysis of microglia revealed that while microglia do express anti-microbial genes and damage-associated molecular pattern molecules of the S100A family of genes at least 2 weeks after sepsis, they do not express the cytokines observed in whole brain homogenates. Our results indicate that in a naturalistic model of infection, sepsis results in long-term neuroinflammation, and that this sustained inflammation is likely due to interactions among multiple cell types, including resident microglia and peripherally derived myeloid cells.
Journal Article