Most solid tumours contain regions of sub-optimal oxygen concentration (hypoxia). Hypoxic cancer cells are more resistant to radiotherapy and represent the most aggressive fraction of a tumour. It is ...therefore essential that strategies continue to be developed to target hypoxic cancer cells. Inhibition of the DNA damage response (DDR) might be an effective way of sensitising hypoxic tumour cells to radiotherapy.
Here, we describe the cellular effects of pharmacological inhibition of the apical DDR kinase ATR (Ataxia Telangiectasia and Rad 3 related) with a highly selective inhibitor, VE-821, in hypoxic conditions and its potential as a radiosensitiser.
VE-821 was shown to inhibit ATR-mediated signalling in response to replication arrest induced by severe hypoxia. In these same conditions, VE-821 induced DNA damage and consequently increased Ataxia Telangiectasia Mutated-mediated phosphorylation of H2AX and KAP1. Consistently, ATR inhibition sensitised tumour cell lines to a range of oxygen tensions. Most importantly, VE-821 increased radiation-induced loss of viability in hypoxic conditions. Using this inhibitor we have also demonstrated for the first time a link between ATR and the key regulator of the hypoxic response, HIF-1. HIF-1 stabilisation and transcriptional activity were both decreased in response to ATR inhibition.
These findings suggest that ATR inhibition represents a novel strategy to target tumour cells in conditions relevant to pathophysiology and enhance the efficacy of radiotherapy.
The efficacy of radiotherapy, a mainstay of cancer treatment, is strongly influenced by both cellular and non-cellular features of the tumor microenvironment (TME). Tumor-associated macrophages ...(TAMs) are a heterogeneous population within the TME and their prevalence significantly correlates with patient prognosis in a range of cancers. Macrophages display intrinsic radio-resistance and radiotherapy can influence TAM recruitment and phenotype. However, whether radiotherapy alone can effectively "reprogram" TAMs to display anti-tumor phenotypes appears conflicting. Here, we discuss the effect of radiation on macrophage recruitment and plasticity in cancer, while emphasizing the role of specific TME components which may compromise the tumor response to radiation and influence macrophage function. In particular, this review will focus on soluble factors (cytokines, chemokines and components of the complement system) as well as physical changes to the TME. Since the macrophage response has the potential to influence radiotherapy outcomes this population may represent a drug target for improving treatment. An enhanced understanding of components of the TME impacting radiation-induced TAM recruitment and function may help consider the scope for future therapeutic avenues to target this plastic and pervasive population.
Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis ...that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.
Emergency mapping makes it possible to manage an emergency situation and even to analyze the catastrophic event, a posteriori, in order to improve action protocols for Civil Protection. The emergency ...maps are produced from the analysis of calls to the Emergency Coordination Centre (911 or 112). Thus, the concept of integral risk mapping arises, in which risk mapping and aspects that allow for more realistic analysis and mapping through the analysis of emergency calls in the event of a natural event converge. In this case, the analysis is focused on the floods that occurred from 12 to 15 September 2019 in the Vega Baja del Segura district (Alicante, Spain). The results obtained show that this is the flooding episode with the highest number of emergency calls in Valencian region and Vega Baja del Segura district (2010–2022). Likewise, the spatial-temporal analysis of the geolocation of the calls and their reasons, have allowed us to draw up a much more detailed map of flooding or affected areas in 2019 than the official maps. In conclusion, the analysis of emergency calls makes it possible to identify problems and vulnerable areas where proposals can be made to reduce the impact of floods and increase the resilience of a territory. At the same time, it is presented as a novel field of research for the analysis of natural and anthropic risks.
Historical cartography is one of the principal tools used in correct flood adaptation and management based on territorial planning. In fact, Directive 2007/60/EC on the assessment and management of ...flood risks includes the analysis and inventory of historical floods in a river basin for assessing the flood hazard and risk existing in a geographical space. This study seeks to analyse the largest flood registered in the Segura basin, occurring on 14–15 October 1879, which attracted enormous interest on a national and international level. The methodology applied is based on the consultation of historical sources and historical cartography, and the elaboration of maps using GIS, enabling comparisons to be made with current flood zones. The results show that the Santa Teresa flood was very similar to the Spanish National Cartographic Systems for Flood Areas (SNCZI) map for a 500-year return period. Furthermore, it allows the identification of the sensitive points along the course of the river or those prone to burst banks or overflowing, which practically coincide with the current maps and modelling conducted by the official bodies. Furthermore, the buildings in the floodable area in the historical cartography have been counted and reconstructed on a GIS map and the SNCZI. Massive anthropic occupation through the construction of settlements and infrastructures (hospitals, schools, centers for the elderly, roads and railways) in the Guadalentín valley and the Segura River increases the risk of flooding in the study area, despite the numerous control and regulation works carried out in the Segura River basin.
Emergency mapping makes it possible to manage an emergency situation and even to analyze the catastrophic event, a posteriori, in order to improve action protocols for Civil Protection. The emergency ...maps are produced from the analysis of calls to the Emergency Coordination Centre (911 or 112). Thus, the concept of integral risk mapping arises, in which risk mapping and aspects that allow for more realistic analysis and mapping through the analysis of emergency calls in the event of a natural event converge. In this case, the analysis is focused on the floods that occurred from 12 to 15 September 2019 in the Vega Baja del Segura district (Alicante, Spain). The results obtained show that this is the flooding episode with the highest number of emergency calls in Valencian region and Vega Baja del Segura district (2010–2022). Likewise, the spatial-temporal analysis of the geolocation of the calls and their reasons, have allowed us to draw up a much more detailed map of flooding or affected areas in 2019 than the official maps. In conclusion, the analysis of emergency calls makes it possible to identify problems and vulnerable areas where proposals can be made to reduce the impact of floods and increase the resilience of a territory. At the same time, it is presented as a novel field of research for the analysis of natural and anthropic risks.
Consumer digital technology is rapidly evolving, allowing users to manage their health in a simple, non-invasive manner. However, there are few studies revealing if using digital technology as part ...of an intervention really has an impact in consumer health compared with traditional strategies. The objective of the current study is to compare two groups (MTB;
= 18, 46.1 ± 10.4 years and MTBAPP;
= 19, 45.3 ± 6.40 years) of overweight, prehypertensive individuals in losing weight and lowering their blood pressure. Both were provided with nutritionist-guided recommendations, a wearable tracking device and a dietary supplement that has previously been proven to help lose body weight and lower blood pressure. In addition, one of the groups (MTBAPP) used a mobile app specifically designed for the intervention. Blood pressure, body composition, triglyceride level, peak expiratory flow, forced expiratory volume in the first second and maximum oxygen volume were measured at different time points. In addition, participants were monitored with an activity bracelet throughout the intervention. As a result, both groups significantly lost body weight, while the group using the app additionally improved blood pressure levels and lowered fat mass. Furthermore, the app users significantly increased the number of daily steps and decreased sedentary time. In conclusion, the addition of a mobile app with daily reminders to follow healthy lifestyle recommendations increased physical activity and overall improved blood pressure and fat mass levels when compared with a group performing the same intervention but in absence of the mobile application.
The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole ...derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.
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