The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions

: Solid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy

An Open-Source Web Platform for 3D Documentation and Storytelling of Hidden Cultural Heritage

The rapid evolution of the urban landscape highlights the need to digitally document the state and historical transformations of heritage sites in densely urbanised areas through the combination of different geomatics survey approaches. Moreover, it is necessary to raise awareness of sites by developing strategies for their dissemination to a diverse audience through engaging, interactive, and accessible 3D web platforms. This work illustrates a methodology for the digital documentation and narration of a cultural heritage site through the implementation of a lightweight and replicable 3D navigation platform based on open-source technologies. Such a solution aims to be an easy-to-implement low-cost approach. The methodology is applied to the case study of the Farnese Castle in Piacenza (Italy), describing the data collection and documentation carried out with an in situ survey and illustrating how the resulting products were integrated into the web platform. The exploration functionalities of the platform and its potential for different types of audiences, from experts to users not familiar with 3D objects and geomatics products, were evaluated and documented on a ReadTheDocs website, allowing interested users to reproduce the project for other applications thanks to the template code available on GitHub

Gastric Adenocarcinomas and Signet-Ring Cell Carcinoma: Unraveling Gastric Cancer Complexity through Microbiome Analysis—Deepening Heterogeneity for a Personalized Therapy

Gastric cancer (GC) is the fifth most prevalent cancer worldwide and the third leading cause of global cancer mortality. With the advances of the omic studies, a heterogeneous GC landscape has been revealed, with significant molecular diversity. Given the multifaceted nature of GC, identification of different patient subsets with prognostic and/or predictive outcomes is a key aspect to allow tailoring of specific treatments. Recently, the involvement of the microbiota in gastric carcinogenesis has been described. To deepen this aspect, we compared microbiota composition in signet-ring cell carcinoma (SRCC) and adenocarcinoma (ADC), two distinct GC subtypes. To this purpose, 10 ADC and 10 SRCC and their paired non-tumor (PNT) counterparts were evaluated for microbiota composition through 16S rRNA analysis. Weighted and unweighted UniFrac and Bray–Curtis dissimilarity showed significant community-level separation between ADC and SRCC. Through the LEfSe (linear discriminant analysis coupled with effect size) tool, we identified potential microbial biomarkers associated with GC subtypes. In particular, SRCCs were significantly enriched in the phyla Fusobacteria, Bacteroidetes, Patescibacteria, whereas in the ADC type, Proteobacteria and Acidobacteria phyla were found. Overall, our data add new insights into GC heterogeneity and may contribute to deepening the GC classification

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. Methods: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Findings: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Funding: Bayer and Janssen