NBPF1, a tumor suppressor candidate in neuroblastoma, exerts growth inhibitory effects by inducing a G1 cell cycle arrest

Background: NBPF1 (Neuroblastoma Breakpoint Family, member 1) was originally identified in a neuroblastoma patient on the basis of its disruption by a chromosomal translocation t(1;17)(p36.2;q11.2). Considering this genetic defect and the frequent genomic alterations of the NBPF1 locus in several cancer types, we hypothesized that NBPF1 is a tumor suppressor. Decreased expression of NBPF1 in neuroblastoma cell lines with loss of 1p36 heterozygosity and the marked decrease of anchorage-independent clonal growth of DLD1 colorectal carcinoma cells with induced NBPF1 expression further suggest that NBPF1 functions as tumor suppressor. However, little is known about the mechanisms involved. Methods: Expression of NBPF was analyzed in human skin and human cervix by immunohistochemistry. The effects of NBPF1 on the cell cycle were evaluated by flow cytometry. We investigated by real-time quantitative RT-PCR the expression profile of a panel of genes important in cell cycle regulation. Protein levels of CDKN1A-encoded p21(CIP1/WAF1) were determined by western blotting and the importance of p53 was shown by immunofluorescence and by a loss-offunction approach. LC-MS/MS analysis was used to investigate the proteome of DLD1 colon cancer cells with induced NBPF1 expression. Possible biological interactions between the differentially regulated proteins were investigated with the Ingenuity Pathway Analysis tool. Results: We show that NBPF is expressed in the non-proliferative suprabasal layers of squamous stratified epithelia of human skin and cervix. Forced expression of NBPF1 in HEK293T cells resulted in a G1 cell cycle arrest that was accompanied by upregulation of the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) in a p53-dependent manner. Additionally, forced expression of NBPF1 in two p53-mutant neuroblastoma cell lines also resulted in a G1 cell cycle arrest and CDKN1A upregulation. However, CDKN1A upregulation by NBPF1 was not observed in the DLD1 cells, which demonstrates that NBPF1 exerts cell-specific effects. In addition, proteome analysis of NBPF1-overexpressing DLD1 cells identified 32 differentially expressed proteins, of which several are implicated in carcinogenesis. Conclusions: We demonstrated that NBPF1 exerts different tumor suppressive effects, depending on the cell line analyzed, and provide new clues into the molecular mechanism of the enigmatic NBPF proteins

Current lifestyles in the context of future climate targets: analysis of long-term scenarios and consumer segments for residential and transport

The carbon emissions of individuals strongly depend on their lifestyle, both between and within regions. Therefore, lifestyle changes could have a significant potential for climate change mitigation. This potential is not fully explored in long-term scenarios, as the representation of behaviour change and consumer heterogeneity in these scenarios is limited. We explore the impact and feasibility of lifestyle and behaviour changes in achieving climate targets by analysing current per-capita emissions of transport and residential sectors for different regions and consumer segments within one of the regions, namely Japan. We compare these static snapshots to changes in per-capita emissions from consumption and technology changes in long-term mitigation scenarios. The analysis shows less need for reliance on technological solutions if consumption patterns become more sustainable. Furthermore, a large share of Japanese consumers is characterised by consumption patterns consistent with those in scenarios that achieve ambitious climate targets, especially regarding transport. The varied lifestyles highlight the importance of representing consumer heterogeneity in models and further analyses

(Path)ways to sustainable living: The impact of the SLIM scenarios on long-term emissions

Sustainable lifestyles and behaviour changes can be vital in climate change mitigation. Various disciplines analyse the potential for such changes – but without much interaction. Qualitative studies look into the change process (e.g. social practice theory), while quantitative studies often focus on their impact in stylised cases (e.g. energy modelling). A more holistic approach can provide insightful scenarios with diverse lifestyle changes based on informed narratives for quantifying long-term impacts. This research explores how comprehensive sustainable lifestyle scenarios, coined SLIM (Sustainable Living in Models) scenarios, could contribute to transport and residential emission reductions. By translating and quantifying lifestyle scenario narratives through engagements with advisors and policymakers, we modelled two distinct lifestyle scenarios which differ in their degree of access to structural support. In one scenario, governments, corporations and cities leverage existing values and market systems to shape citizen and consumer preferences and everyday practices. In the other scenario, people adopt ambitious sustainable lifestyle behaviours and practices through peer-to-peer interaction and digital technology. We quantified the scenarios based on motivations, contextual factors, extent, and speed of lifestyle adoptions with regional differentiation. Furthermore, we applied heterogenous adopter groups to determine the model inputs. We present the resulting pathways in per capita emissions and more detailed changes in total emissions via decomposition analyses. We conclude that regional differentiation of the scenario narratives and modelling of intra-regional differences allows accounting for equity in lifestyle changes to a certain extent. Furthermore, new technologies are more important for enabling lifestyle change in a scenario with than a scenario without strong structural support. With strong structural support, lifestyle changes reduce transport and residential emissions to a larger degree (about 39% for Global North and 27% for Global South overall in 2050 relative to a “Middle-of-the-Road” SSP2 reference scenario in 2050). Thus, lifestyle changes in larger systems change are essential for effective climate change mitigation

Decomposition analysis of per capita emissions : a tool for assessing consumption changes and technology changes within scenarios

Recent studies show that behaviour changes can provide an essential contribution to achieving the Paris climate targets. Existing climate change mitigation scenarios primarily focus on technological change and underrepresent the possible contribution of behaviour change. This paper presents and applies a methodology to decompose the factors contributing to changes in per capita emissions in scenarios. With this approach, we determine the relative contribution to total emissions from changes in activity, the way activities are carried out, the intensity of activities, as well as fuel choice. The decomposition tool breaks down per capita emissions loosely following the Kaya Identity, allowing a comparison between the contributions of technology and consumption changes among regions and between various scenarios. We illustrate the use of the tool by applying it to three previously-published scenarios; a baseline scenario, a scenario with a selection of behaviour changes, and a 2 degrees C scenario with the same selection of behaviour changes. Within these scenarios, we explore the contribution of technology and consumption changes to total emission changes in the transport and residential sector, for a selection of both developed and developing regions. In doing so, the tool helps identify where specifically (i.e. via consumption or technology factors) different measures play a role in mitigating emissions and expose opportunities for improved representation of behaviour changes in integrated assessment models. This research shows the value of the decomposition tool and how the approach could be flexibly replicated for different global models based on available variables and aims. The application of the tool to previously-published scenarios shows substantial differences in consumption and technology changes from CO2 price and behaviour changes, in transport and residential per capita emissions and between developing and developed regions. Furthermore, the tool's application can highlight opportunities for future scenario development of a more nuanced and heterogeneous representation of behaviour and lifestyle changes in global models.Peer reviewe

Heart failure-induced microbial dysbiosis contributes to colonic tumour formation in mice

Introduction Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive. In colorectal cancer (CRC), gut microbial dysbiosis is linked to cancer progression and recent studies have shown that HF patients display microbial dysbiosis.Aims This current study focussed on the effects of HF-induced microbial dysbiosis on colonic tumour formation.Methods and results C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16 s rRNA sequencing, and pooled for faecal microbiota transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane/Dextran sodium sulphate. The CRC mice were transplanted with faeces from MI or sham mice. MI-induced HF resulted in microbial dysbiosis, characterized by a decreased alpha-diversity and microbial alterations on the genus level, several of which have been associated with CRC. We then performed faecal microbiota transplantation with faeces from HF mice in CRC mice, which resulted in a higher endoscopic disease score and an increase in the number of tumours in CRC mice.Conclusion We demonstrated that MI-induced HF contributes to colonic tumour formation by altering the gut microbiota composition, providing a mechanistic explanation for the observed association between HF and increased risk for cancer. Targeting the microbiome may present as a tool to mitigate HF-associated co-morbidities, especially cancer.Graphical abstrac

Heart failure-induced microbial dysbiosis contributes to colonic tumour formation in mice

Introduction Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive. In colorectal cancer (CRC), gut microbial dysbiosis is linked to cancer progression and recent studies have shown that HF patients display microbial dysbiosis.Aims This current study focussed on the effects of HF-induced microbial dysbiosis on colonic tumour formation.Methods and results C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16 s rRNA sequencing, and pooled for faecal microbiota transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane/Dextran sodium sulphate. The CRC mice were transplanted with faeces from MI or sham mice. MI-induced HF resulted in microbial dysbiosis, characterized by a decreased alpha-diversity and microbial alterations on the genus level, several of which have been associated with CRC. We then performed faecal microbiota transplantation with faeces from HF mice in CRC mice, which resulted in a higher endoscopic disease score and an increase in the number of tumours in CRC mice.Conclusion We demonstrated that MI-induced HF contributes to colonic tumour formation by altering the gut microbiota composition, providing a mechanistic explanation for the observed association between HF and increased risk for cancer. Targeting the microbiome may present as a tool to mitigate HF-associated co-morbidities, especially cancer.Graphical abstrac

The autoinflammation-associated NLRC4V341A mutation increases microbiota-independent IL-18 production but does not recapitulate human autoinflammatory symptoms in mice

BackgroundAutoinflammation with infantile enterocolitis (AIFEC) is an often fatal disease caused by gain-of-function mutations in the NLRC4 inflammasome. This inflammasomopathy is characterized by macrophage activation syndrome (MAS)-like episodes as well as neonatal-onset enterocolitis. Although elevated IL-18 levels were suggested to take part in driving AIFEC pathology, the triggers for IL-18 production and its ensuing pathogenic effects in these patients are incompletely understood.MethodsHere, we developed and characterized a novel genetic mouse model expressing a murine version of the AIFEC-associated NLRC4V341A mutation from its endogenous Nlrc4 genomic locus.ResultsNLRC4V341A expression in mice recapitulated increased circulating IL-18 levels as observed in AIFEC patients. Housing NLRC4V341A-expressing mice in germfree (GF) conditions showed that these systemic IL-18 levels were independent of the microbiota, and unmasked an additional IL-18-inducing effect of NLRC4V341A expression in the intestines. Remarkably, elevated IL-18 levels did not provoke detectable intestinal pathologies in NLRC4V341A-expressing mice, even not upon genetically ablating IL-18 binding protein (IL-18BP), which is an endogenous IL-18 inhibitor that has been used therapeutically in AIFEC. In addition, NLRC4V341A expression did not alter susceptibility to the NLRC4-activating gastrointestinal pathogens Salmonella Typhimurium and Citrobacter rodentium.ConclusionAs observed in AIFEC patients, mice expressing a murine NLRC4V341A mutant show elevated systemic IL-18 levels, suggesting that the molecular mechanisms by which this NLRC4V341A mutant induces excessive IL-18 production are conserved between humans and mice. However, while our GF and infection experiments argue against a role for commensal or pathogenic bacteria, identifying the triggers and mechanisms that synergize with IL-18 to drive NLRC4V341A-associated pathologies will require further research in this NLRC4V341A mouse model

The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration:Insights from the IMPROVE Study

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMT(max); cIMT(mean-max) of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMT(max) and cIMT(mean-max), but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMT(max) or cIMT(mean-max) were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMT(max) and cIMT(mean-max) when the CETP concentration was below the median (HDL-C x CETP interaction, p = 0.001 and p = 0.003 for cIMT(max) and cIMT(mean-max), respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMT(max). rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMT(max). In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMT(max). This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent