IL-1 and senescence: Friends and foe of EGFR neutralization and immunotherapy

Historically, senescence has been considered a safe program in response to multiple stresses in which cells undergo irreversible growth arrest. This process is characterized by morphological and metabolic changes, heterochromatin formation, and secretion of inflammatory components, known as senescence-associated secretory phenotype (SASP). However, recent reports demonstrated that anti-cancer therapy itself can stimulate a senescence response in tumor cells, the so-called therapy-induced senescence (TIS), which may represent a temporary bypass pathway that promotes drug resistance. In this context, several studies have shown that EGFR blockage, by TKIs or moAbs, promotes TIS by increasing IL-1 cytokine production, thus pushing cells into a "pseudo-senescent" state. Today, senotherapeutic agents are emerging as a potential strategy in cancer treatment thanks to their dual role in annihilating senescent cells and simultaneously preventing their awakening into a resistant and aggressive form. Here, we summarize classic and recent findings about the cellular processes driving senescence and SASP, and we provide a state-of-the-art of the anti-cancer strategies available so far that exploits the activation and/or blockade of senescence-based mechanisms

Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies

ERBB4 is a tyrosine kinase receptor reported to exert both oncogenic and tumor suppressor activities. These paradoxical effects were suggested to stem from different ERBB4 homo-/hetero-dimers and/or isoforms. By stratifying breast cancer patients for clinical and molecular subtypes and ERBB4 mRNA abundance, we here report that higher ERBB4 levels correlate with longer relapse-free survival in breast cancer patients of HER2-enriched and luminal A molecular subtypes, proposing a cancer-protecting role for this receptor in these specific subgroups. We also observed that HER2-enriched breast cancers express intermediate ERBB4 mRNA levels compared to luminal and triple-negative/basal-like subgroups, which displayed the highest and the lowest levels, respectively. Inspired by these clinical data, we tested the activation of ERBB4 by Neuregulins as a potential anticancer strategy for HER2+ breast cancers. To this end, we employed two HER2+ breast cancer cellular models (BT474 and SKBR3), which express intermediate/high and low ERBB4 levels, respectively. Cell proliferation and motility were evaluated on these cellular models following treatments with Neuregulin 1 (NRG1), which activates both ERBB3 and ERBB4, or Neuregulin 4 (NRG4), which specifically activates ERBB4. Both NRG1 and NRG4 were used alone or in combination with anti-ERBB2 neutralizing antibodies, namely trastuzumab and pertuzumab. In vitro treatment with NRG1 on BT474 cells restrained cell growth and reduced the anti-proliferative efficacy of trastuzumab. In contrast, treatment with NRG1 on SKBR3 cells increased cell proliferation and migration, and partially or completely impaired the anti-proliferative/anti-migratory action of trastuzumab and/or pertuzumab. Importantly, in both the cell lines, treatment with NRG4 robustly potentiated the anti-proliferative action of trastuzumab and pertuzumab. Collectively, our data in HER2+ breast cancer cells highlight that NRG1 may exert both pro- and anti-proliferative effects, and may reduce the efficacy of anti-HER2 agents, whereas NRG4 may boost the anti-proliferative effects of anti-ERBB2 agents. We propose a provocative paradigm shift in the field of growth factors in cancer progression, suggesting the administration of ERBB4 ligands, such as Neuregulin 4, as a strategy to improve the efficacy of anti-ERBB2 agents

Neonatal Apex Resection Triggers Cardiomyocyte Proliferation, Neovascularization and Functional Recovery Despite Local Fibrosis

So far, opposing outcomes have been reported following neonatal apex resection in mice, questioning the validity of this injury model to investigate regenerative mechanisms. We performed a systematic evaluation, up to 180 days after surgery, of the pathophysiological events activated upon apex resection. In response to cardiac injury, we observed increased cardiomyocyte proliferation in remote and apex regions, neovascularization, and local fibrosis. In adulthood, resected hearts remain consistently shorter and display permanent fibrotic tissue deposition in the center of the resection plane, indicating limited apex regrowth. However, thickening of the left ventricle wall, explained by an upsurge in cardiomyocyte proliferation during the initial response to injury, compensated cardiomyocyte loss and supported normal systolic function. Thus, apex resection triggers both regenerative and reparative mechanisms, endorsing this injury model for studies aimed at promoting cardiomyocyte proliferation and/or downplaying fibrosis. In this article, Nascimento and colleagues demonstrate that neonatal apex resection stimulates cardiomyocyte proliferation and permanent scarring in the apex. Newly formed cardiomyocytes compensate muscle loss by resection, and resected hearts recover functional competence in adulthood. These findings endorse this model for studies aiming to block cardiac fibrosis and/or favoring CM proliferation

DTM to NURBS—A Parametric Approach to Landscape Modeling for an Environmentally-Conscious Design

This research aims to develop a methodology for geometric analysis of the territory, which, by means of a specially designed digital tool, allows quantitative assessments useful for drawing up sustainability policies. The difficulty of working with this type of procedure is the sectorialisation of technical skills among those who deal with design at the architectural scale and those who work at territorial scale. The undertaken methodology establishes a workflow that can export data from a GIS tool and import it into a three-dimensional modeler. To do this you need an intermediate tool, a parametric software. The explained procedure aims to have maximum freedom of model geometries processing. Therefore, it has been based on Nurbs mathematical models. The application tested with this is the solar radiation analysis in the territory of Ortona, Italy, on the Adriatic coast. Starting from the cartographic data of the Abruzzo Region, the three-dimensional model has been developed and it has built a base for further analysis. This working methodology ensures efficient results with a low amount of human iteration to generate the final model. Some of the procedure’s limitations have been explained in detail, mainly due to the structure of the used components

Slow mobility-based representation of coastal territoryThe Costa dei Trabucchi case study

This research explores the relationships between the representation of digital models and mobility flows related to a coastal territory. The aim is creating a synergy between travel data and their representation, in order to optimize the territorial development strategies of soft mobility. A combination of GIS and Computational design digital tools has been used to achieve this goal. The case study selected is the set of municipalities on the Abruzzo coast, ranging north to south from the territory of Ortona to San Salvo. The choice of a case study limited to the coast was determined by the need to make different flows coexist between the summer and winter seasons. In the analysed territorial ecosystem, a useful strategy was developed to integrate private transport with an apparatus that facilitates soft mobility. To this purpose, seasonally adjusted isochrones were developed from the urban centres of the eight municipalities considered. The calibration of the isochrone was elaborated (Schantz and others, 2017) by calculating an area reachable by bike with a travel time of 25 minutes. The overlap between the isochrone of contiguous municipalities provides information about the areas where the cycling network needs to be implemented in intra-municipal and inter-municipal mobility. Finally, the studies carried out show that these overlapping areas are not localised as would be conceivable on administrative borders