Into the blue...Using mouse models to uncover genes driving tumorigenesis and therapy resistance in human breast cancer

To improve cancer treatments, personalized medicine approaches have aimed to identify exactly which mutations are driving tumor development in a given patient and specifically target these mutations using precision therapies. However, one of the main challenges of this approach is identifying which mutations are true drivers, as tumors typically contain many additional passenger mutations that do not actually contribute to tumor development. Besides this, many patients often relapse after prolonged treatment due to the emergence of acquired resistance, limiting the clinical effectiveness of targeted treatments. In this thesis, we focussed on using genetically engineered mouse models to identify candidate cancer genes and therapy resistance mechanisms in two different breast cancers: invasive lobular carcinoma (ILC) and triple-negative breast cancer (TNBC). For ILC, we used transposon-based insertional mutagenesis (TIM) to uncover several novel cancer genes driving ILC development. Besides this, we also developed a novel computational approach (IM-Fusion) for improving the discovery of cancer genes from TIM screens and explored mechanisms of resistance in Fgfr2-driven ILC. For TNBC, we used CRISPR-based iterative mouse modeling combined with comparative oncogenomics to identify novel drivers of BRCA1-deficient TNBC. Finally, using combined in-vivo/in-vitro screens, we identified Parg as a driver of treatment resistance in BRCA2-deficient TNBC. Divisions of Molecular Pathology and Molecular Carcinogenesis, Netherlands Cancer InstituteToxicolog

Using local and historical data to enhance understanding of spatial and temporal rainfall patterns

Farmers face uncertainty in their businesses from many factors, but rainfall is a key determinant of both the nature of the production system and variation in financial returns. Currently, various weather forecasting services are available from the Australian Bureau of Meteorology (BoM) based on about 7000 stations covering all of Australia. Seasonal Climate Forecasts are seen as another tool that can help to improve farm productivity. It is well known that many farmers keep their own rainfall records, and likely that the farmers have a high degree of confidence in their own records. Australian Bureau of Statistics figures indicate that there were possibly 7000 grain related ‘agricultural businesses’ in NSW alone in 2009/10 indicating that there is the potential to increase data density by up to an order of magnitude. This project is part of a broader study to improve rainfall predictions for grain farmers using data collected locally to the users (crowd sourcing). The data is collected directly on farm, and from other sources which may be available. The focus is on the historical data, its collection and analysis, in terms of discerning patterns in time and space which may help provide a local framework, within which coarser scale forecasts can be interpreted and understood. Data will be stored on secure database systems at the University of Sydney. Results indicate that farm data does provide more local detail, temporally and spatially. Deficit and surplus analysis demonstrates the predictive capacity of the local temporal data, despite limited data precluding the definition of ideal criteria and parameters for predictive ‘similar year’ selection. The spatial data demonstrates quantifiable site specific differences from institutional data. Testing across more climate types may allow these differences to be defined within and across regions. Tests for an indicator time period show that farm rainfall in the early part of the growing season (April and May) may indeed be indicative of seasonal condtions, while more data is needed to confirm this. The use of southern oscillation life cycle information to select appropriate years considerably improved the relationships revealed, with a doubling of relationship strength across all climatic types, although the strength of the relationships differed across the climatic types, and the strongest relationships were split between the months of April and May. More extensive analysis, with more data across more BoM districts (and therefore climate classes) will be required to confirm this conclusion, but it appears that farm rainfall records and SOI information can provide an indicator time period to help farmers interpret, refine and utilise seasonal forecasts

Publiek-private samenwerking bij waterberging

In Nederland neemt door klimaatsveranderingen de behoefte voor waterberging sterk toe. Om de problemen structureel aan te pakken acht de Commissie Waterbeheer 21e eeuw het nood-zakelijk dat het watersysteem over ruimte beschikt voor het bergen en vasthouden van water. Deze waterberging hoeft niet alleen door waterschappen te worden gerealiseerd, maar kan ook door grondeigenaren in de vorm van meervoudig ruimtegebruik worden gerealiseerd. Dit kan leiden tot publiek-private samenwerkingsconstructies (pps). In dit rapport is aan de hand van de beleidsarrangemententheorie geanalyseerd welke pps-constructies voor waterberging kansrijk zij

Relativistic models of two low-luminosity radio jets: B2 0326+39 and B2 1553+24

We apply the intrinsically symmetrical, decelerating relativistic jet model developed by Laing & Bridle for 3C 31 to deep, full-synthesis 8.4-GHz VLA imaging of the two low-luminosity radio galaxies B2 0326+39 and B2 1553+24. After some modifications to the functional forms used to describe the geometry, velocity, emissivity and magnetic-field structure, these models can accurately fit our data in both total intensity and linear polarization. We conclude that the jets in B2 0326+39 and B2 1553+24 are at angles of 64 +/- 5 deg and 7.7 +/- 1.3 deg to the line of sight, respectively. In both objects, we find that the jets decelerate from 0.7 - 0.8c to <0.2c over a distance of approximately 10 kpc, although in B2 1553+24 this transition occurs much further from the nucleus than in B2 0326+39 or 3C 31. The longitudinal emissivity profiles can be divided into sections, each fit accurately by a power law; the indices of these power laws decrease with distance from the nucleus. The magnetic fields in both objects are dominated by the longitudinal component in the high-velocity regions close to the nucleus and by the toroidal component further out, but B2 0326+39 also has a significant radial component at large distances, whereas B2 1553+24 does not. Simple adiabatic models fail to fit the emissivity variations in the regions of high velocity but provide good descriptions of the emissivity after the jets have decelerated. Given the small angle to the line of sight inferred for B2 1553+24, there should be a significant population of similar sources at less extreme orientations. Such objects should have long (>200 kpc), straight, faint jets and we show that their true sizes are likely to have been underestimated in existing images. (Slightly abridged.)Comment: 27 pages, 21 figures, accepted for publication in MNRA

Phase 1 study of chemoradiotherapy combined with nivolumab +/- Ipilimumab for the curative treatment of muscle-invasive bladder cancer

Background: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. Objective: To determine the safety of iCRT for MIBC. Design, setting, and participants: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 x 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. Intervention: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). Outcome measurements and statistical analysis: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). Results and limitations: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade >= 3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. Conclusions: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. Patient summary: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combiningimmunecheckpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials

Sub-arcsecond imaging with the International LOFAR Telescope I. Foundational calibration strategy and pipeline

The International LOFAR Telescope is an interferometer with stations spread across Europe. With baselines of up to ~2000 km, LOFAR has the unique capability of achieving sub-arcsecond resolution at frequencies below 200 MHz. However, it is technically and logistically challenging to process LOFAR data at this resolution. To date only a handful of publications have exploited this capability. Here we present a calibration strategy that builds on previous high-resolution work with LOFAR. It is implemented in a pipeline using mostly dedicated LOFAR software tools and the same processing framework as the LOFAR Two-metre Sky Survey (LoTSS). We give an overview of the calibration strategy and discuss the special challenges inherent to enacting high-resolution imaging with LOFAR, and describe the pipeline, which is publicly available, in detail. We demonstrate the calibration strategy by using the pipeline on P205+55, a typical LoTSS pointing with an 8 h observation and 13 international stations. We perform in-field delay calibration, solution referencing to other calibrators in the field, self-calibration of these calibrators, and imaging of example directions of interest in the field. We find that for this specific field and these ionospheric conditions, dispersive delay solutions can be transferred between calibrators up to ~1.5° away, while phase solution transferral works well over ~1°. We also demonstrate a check of the astrometry and flux density scale with the in-field delay calibrator source. Imaging in 17 directions, we find the restoring beam is typically ~0.3′′ ×0.2′′ although this varies slightly over the entire 5 deg2 field of view. We find we can achieve ~80–300 μJy bm−1 image rms noise, which is dependent on the distance from the phase centre; typical values are ~90 μJy bm−1 for the 8 h observation with 48 MHz of bandwidth. Seventy percent of processed sources are detected, and from this we estimate that we should be able to image roughly 900 sources per LoTSS pointing. This equates to ~ 3 million sources in the northern sky, which LoTSS will entirely cover in the next several years. Future optimisation of the calibration strategy for efficient post-processing of LoTSS at high resolution makes this estimate a lower limit

Standardized outcome measures for pregnancy and childbirth, an ICHOM proposal

Background: Value-based health care aims to optimize the balance of patient outcomes and health care costs. To improve value in perinatal care using this strategy, standard outcomes must first be defined. The objective of this work was to define a minimum, internationally appropriate set of outcome measures for evaluating and improving perinatal care with a focus on outcomes that matter to women and their families. Methods: An interdisciplinary and international Working Group was assembled. Existing literature and current measurement initiatives were reviewed. Serial guided discussions and validation surveys provided consumer input. A series of nine teleconferences, incorporating a modified Delphi process, were held to reach consensus on the proposed Standard Set. Results: The Working Group selected 24 outcome measures to evaluate care during pregnancy and up to 6 months postpartum. These include clinical outcomes such as maternal and neonatal mortality and morbidity, stillbirth, preterm birth, birth injury and patient-reported outcome measures (PROMs) that assess health-related quality of life (HRQoL), mental health, mother-infant bonding, confidence and success with breastfeeding, incontinence, and satisfaction with care and birth experience. To support analysis of these outcome measures, pertinent baseline characteristics and risk factor metrics were also defined. Conclusions: We propose a set of outcome measures for evaluating the care that women and infants receive during pregnancy and the postpartum period. While validation and refinement via pilot implementation projects are needed, we view this as an important initial step towards value-based improvements in care

Astronomical Distance Determination in the Space Age: Secondary Distance Indicators

The formal division of the distance indicators into primary and secondary leads to difficulties in description of methods which can actually be used in two ways: with, and without the support of the other methods for scaling. Thus instead of concentrating on the scaling requirement we concentrate on all methods of distance determination to extragalactic sources which are designated, at least formally, to use for individual sources. Among those, the Supernovae Ia is clearly the leader due to its enormous success in determination of the expansion rate of the Universe. However, new methods are rapidly developing, and there is also a progress in more traditional methods. We give a general overview of the methods but we mostly concentrate on the most recent developments in each field, and future expectations. © 2018, The Author(s)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Sub-arcsecond imaging with the International LOFAR Telescope. I.: Foundational calibration strategy and pipeline

InstrumentationGalaxie