Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance

Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.1668F is a founder variant among Ashkenazi Jews (allele frequency of -.2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.Genetics of disease, diagnosis and treatmen

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

NEOShield: the physical properties of the most frequent impactors

NEOShield is a consortium of 13 research institutes, universities and industrial partners from 6 countries. The aim of the project is to explore mitigation options in the event that a NEO is found to be on a potential collision course with Earth, and to pave the way for demonstration missions to test proposed mitigation techniques. Finding an accessible and appropriate target NEO for a demonstration mission is an important aspect of mission design. We are carrying out a statistical investigation of the properties of the known NEO population, using the latest published data, with the aim of estimating the most likely mitigation-relevant physical properties of the first NEO to trigger a space-borne mitigation action. Our investigation focuses on the physical properties of the most frequent serious impactors. We define a serious impactor to be one with the potential to lead to major loss of life and damage to infrastructure. At the low end of the size range our definition includes atmospheric events such as the 1908 Tunguska explosion, caused by a body with a diameter, D, of around 50 m. We consider the upper limit of our size-range of interest to be around D = 200 m, because for objects above this size the impact frequency drops below 1 per 10 000 years. However as there are large uncertainties related to the calculation of diameter, we include NEOs with H > 20 mag (D < 300 m). Another reason for considering objects larger than 200 m is the fact that present guidance, navigation, and control (GNC) technology may dictate a minimum size larger than 200 m for the target of a feasible demonstration mission to ensure a high chance of success (although research to improve GNC performance is part of the NEOShield project). Very little is known about NEOs with D < 300 m, as only 2% of the more than 5400 discovered NEOs in this size range have had any physical properties measured besides H magnitudes. Our investigation includes recently published data from the NEOWISE and Warm Spitzer ExploreNEOs surveys, without which this fraction would be much smaller

Characterizing the near-Earth asteroid population in the framework of the NEOShield project

Knowledge of the physical characteristics of near-Earth asteroids (NEAs) is fundamental to assessing the impact risk on our planet and designing efficient mitigation strategies. In the framework of the NEOShield project, financed by the European Commission, the activity of Work Package 2 (January 2012 – July 2014) was aimed at improving our knowledge of NEA physical properties

Laminin And Collagen Iv Distribution And Ultrastructure Of The Basement Membrane Of The Gingiva Of The Rat Incisor

[No abstract available]30534935

A global response roadmap to the asteroid impact threat: The NEOShield perspective

Besides being of great scientific interest, near-Earth objects represent a well-founded threat to life on our planet. Nonetheless, up to now there has been no concerted international plan on how to deal with the impact threat, and how to prepare and implement mitigation measures. The NEOShield project is funded by the European Commission to address such issues, to investigate the feasibility of techniques to prevent a potentially catastrophic impact on Earth by an asteroid or a comet, and to develop detailed designs of appropriate space missions to test deflection techniques. In this work we present and discuss the scientific and strategic aspects of the asteroid impact threat, highlighting the necessary steps so as to be ready to react to future hazardous objects

Requirements for mitigation precursor reconnaissance, a study from the NEOShield project

The NEOShield project (Harris et al. 2012, Acta Astronautica, in press), which commenced in January 2012, is being funded by the European Union for a period of 3.5 years. The primary aim of the project is to study in detail the three most promising techniques to mitigate the NEO impact risk: the kinetic impactor, blast deflection, and the gravity tractor, and to devise feasible demonstration missions. NEOShield also aims to address the issue of an international strategy to deal with the impact threat and how to organize, prepare, and implement mitigation plans. Our contributions to NEOShield include the study of NEO physical and dynamical properties. We are currently investigating the issue of how best to obtain the information required to design an effective mitigation mission once a hazardous asteroid has been discovered. Pre-mitigation reconnaissance plays a central role in any asteroid deflection scenario, as it is vital in providing the necessary orbital and physical data of a potential impactor to instigate a successful deflection mission. The assessment of the true impact probability for the hazardous asteroid is the first important aspect in this regard, since it can render an expensive mitigation mission obsolete. Hence all of the available techniques (like optical astrometry and radar ranging), as well as the effect of non-gravitational forces and keyholes, have to be considered in the orbit refinement process. If the impact threat is confirmed, the prevention of a collision with the Earth would require either the destruction of the object (ensuring that the fragments would not be hazardous themselves) or, more realistically, deflecting it slightly from its catastrophic trajectory (ensuring that the deflection operation does not simply move the object to another hazardous orbit). In either case, the final aim of the mitigation mission is to modify the trajectory of the impacting NEO. The mass is one of the primary parameters governing the design of an effective mitigation mission; it also provides an upper bound on the amount of damage that would be caused by the object should it impact on Earth. In order to mount an effective mission to destroy or deflect a hazardous object, knowledge of several other physical properties is also required, such as composition, and internal structure and strength. Information on the object’s elemental composition and internal strength is particularly important for the planning of a mitigation attempt involving a standoff explosion. The magnitude and positioning of an impulse, in the case of a kinetic impactor, or the application of a continuous or periodic thrust, may also depend on the mass distribution throughout the irregularly-shaped body, the body’s surface characteristics, and its spin vector. A large degree of porosity (e.g., due to internal fractures or a rubble pile structure), or a binary nature, would add significant complexity to the planning of a mitigation mission. Possibilities for mitigation precursor rendezvous or fly-by missions, including the dynamical accessibility of the NEO with a spacecraft, are further considerations for the selection of the best mitigation strategy. It should be noted that the information requirements from a mitigation point of view are different to those of purely scientific investigations. Hence we address purely mitigation-relevant aspects: I. Assessment of the true impact probability through the orbit refinement, including the necessity for a reconnaissance mission. II. Identification of what physical properties are relevant to a particular type of mitigation method. III. Examination of the relevance and accuracy of a variety of observational techniques and data types, and ways in which this crucial information can be provided. IV. Consideration of a programme of reconnaissance observations, in particular the balance between Earth-based remotely-sensed observations and in-situ investigations from a spacecraft, including the onboard instrumentation. Our goal is to develop a precursor reconnaissance strategy based on a prioritised list of observational requirements (in terms of wavelength, resolution, precision, et

NEOShield: a global approach to mitigate the asteroid impact hazard

Besides being objects of great scientific interest, Near Earth Objects (NEOs) also represent a well-founded threat to life on our planet. However, up to now there has been no a concerted international plan on how to deal with the impact threat and how to organize, prepare, and implement mitigation measures. The European NEOShield project aims to address this problem. NEOShield is a consortium of 13 research institutes, universities, and industrial partners and includes leading US and Russian space organizations. The primary aim of the project is to study in detail the three most promising mitigation techniques: the kinetic impactor, blast deflection, and the gravity tractor, and to devise feasible demonstration missions. The NEOShield project is funded by the European Union with a total of 5.8 million Euros for a period of 3.5 years. The kick-off meeting took place at the DLR Institute of Planetary Research, Berlin, in January 2012, while the first progress meeting was scheduled on May 31 - June 1 at the Paris Observatory. While we will give particular emphasis on the NEOShield activity carried out at the Paris Observatory, we will present and discuss the whole proposed 42 months work plan, which includes the tasks listed in the following section