Loss of p53 triggers Wnt-dependent systemic inflammation to drive breast cancer metastasis

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1β, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1β and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer

Loss of p53 triggers Wnt-dependent systemic inflammation to drive breast cancer metastasis

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1β, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1β and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer

Determinants of station-based round-trip bikesharing demand

First and last mile connectivity of public transport hubs is a key component in promoting multi-modal travel. The Dutch train station operator (NS Stations) promotes the combination of bike and train by offering a train station-based round-trip bikesharing (SBRT) scheme, known as ‘OV-fiets’, located at train stations throughout the country. This scheme allows users to rent a bike to travel between train stations and their destination and vice versa. The round-trip nature of the SBRT makes it unique in comparison to widely applied one-way bikesharing schemes. Little is known about the determinants of demand for round-trip bikesharing, especially when being integrated into an existing PT scheme. This paper aims to fill this gap by identifying potential temporal and weather-related determinants for SBRT-rentals of the Dutch SBRT-system using multiple linear regression (MLR) and an in-depth analysis for selected stations. The results are compared with the findings of one-way bikesharing schemes. The results show that for hourly rentals in an SBRT-system, the highest explanatory power is attributed to the number of train travelers leaving the corresponding train station, followed by temporal and weather-related determinants. Furthermore, the magnitude of the correlation between the determinants and the hourly demand varies considerably across stations, depending on the underlying demand patterns.Transport and Plannin

Understanding the Role of Cycling to Urban Transit Stations through a Simultaneous Access Mode and Station Choice Model

Governments worldwide are aiming to increase sustainable mode use to increase sustainability, livability, and accessibility. Integration of bicycle and transit can increase catchment areas of transit compared with walking and thus provide better competition to non-sustainable modes. To achieve this, effective measures have to be designed that require a better understanding of the factors influencing access mode and station choice. At the national/regional level this has been thoroughly studied, but there is a knowledge gap at the urban level. This study aims to investigate which factors influence the joint decision for tram access mode and tram station choice. The joint investigation can identify trade-offs between the access and transit journeys. Furthermore, the effect of each factor on the bicycle catchment area is investigated. Using data from tram travelers in The Hague, Netherlands, a joint simultaneous discrete choice model is estimated. Generally, walking is preferred to cycling. The findings of this study suggest that access distance is one of the main factors for explaining the choice, where walking distance is weighted 2.1 times cycling distance. Frequent cyclists are more likely also to cycle to the tram station, whereas frequent tram users are less inclined to cycle. Bicycle parking facilities increase the cycling catchment area by 234 m. The transit journey time has the largest impact on the catchment area of cyclists. Improvements to the system, such as fewer stops, higher frequency (like light rail transit), or both, therefore would result in a much longer accepted cycling distance

Exploring attitude-behaviour dynamics during COVID-19: How fear of infection and working from home influence train use and the attitude toward this mode

Research on the relationships between travel-related attitudes and travel behaviour has recently been reinvigorated by new theorizing as well as new empirical models. While traditional theories assume a rather static role of attitudes, i.e. acting as stable predispositions that cause behaviours in a unidirectional manner, recent models assume that attitudes and behaviours mutually influence each other over time. This study aims at better understanding attitude-behaviour dynamics by capitalizing on the circumstances presented by the ongoing COVID-19 pandemic. It assesses how the fear of COVID-19 infection and (the attitude towards) working-from-home influence train use as well as train use attitudes. To explore the (within-person) reciprocal relationships between these variables, random-intercept cross-lagged panel models were estimated using a 4-wave longitudinal dataset collected during the COVID-19 pandemic from a large panel of train travellers in the Netherlands. The results indicate that train use and the attitude towards train use reciprocally influence each other. Those with stronger fears of infection in one wave tend to use the train less in a subsequent wave, but higher use of the train in one wave also reduces the fear of infection in the next. We also found that working from home (WFH) and travelling by train operate as substitutes for one another. Moreover, people who work from home frequently become more fearful of infection. All the findings are consistent with cognitive dissonance theory that people develop attitudes that align with their behaviours. The paper concludes with several policy implications related to changing attitudes and promoting train use.Transport and Logistic

Trip chain complexity: a comparison among latent classes of daily mobility patterns

This paper studies the relationship between trip chain complexity and daily travel behaviour of travellers. While trip chain complexity is conventionally investigated between travel modes, our scope is the more aggregated level of a person’s activity-travel pattern. Using data from the Netherlands Mobility Panel, a latent class cluster analysis was performed to group people with similar mode choice behaviour in distinct mobility pattern classes. All trip chains were assigned to both a travel mode and the mobility pattern class of the traveller. Subsequently, differences in trip chain complexity distributions were analysed between travel modes and between mobility pattern classes. Results indicate considerable differences between travel modes, particularly between multimodal and unimodal trip chains, but also between the unimodal travel modes car, bicycle, walking and public transport trip chains. No substantial differences in trip chain complexity were found between mobility pattern classes. Independently of the included travel modes, the distributions of trip chain complexity degrees were similar across mobility pattern classes. This means that personal circumstances such as the number of working hours or household members are not systematically translated into specific mobility patterns

What Makes a Good Cargo Bike Route? Perspectives from Users and Planners

Cargo bikes—bicycles made to carry both goods and people—are becoming increasingly common as an alternative to automobiles in urban areas. With a wider and heavier body, cargo bikes often face problems even in the presence of cycling infrastructure, thus limiting their possibilities of route choice. Infrastructure quality and the route choices of cyclists have been well studied, but often solely based on a quantitative approach, leading to tools such as BLOS (bicycle level of service). With various designs of cargo bikes being used for a wide range of purposes, the route choice of cargo bike users is difficult to generalize. This study combines quantitative and qualitative approaches in order to explore what is important for cargo bike users’ route choice, and how this knowledge can be effectively used for planning. Our results suggest that while some general preferences exist, route choice involves complex dynamics that cannot be fully explained by quantitative measures alone: in addition to understanding “what” is important for cargo bike users, we need to understand “why” it is important. Furthermore, route choice is also influenced by the city context, making a study tailored to the local context essential