Designing End-of-life Recyclable Polymers via Diels-Alder Chemistry:A Review on the Kinetics of Reversible Reactions

The purpose of this review is to critically assess the kinetic behaviour of the furan/maleimide Diels-Alder click reaction. The popularity of this reaction is evident and still continues to grow, which is likely attributed to its reversibility at temperatures above 100°C, and due to its bio-based "roots" in terms of raw materials. This chemistry has been used to form thermo-reversible crosslinks in polymer networks, and thus allows the polymer field to design strong, but also end-of-life recyclable thermosets and rubbers. In this context, the rate at which the forward reaction (Diels-Alder for crosslinking) and its reverse (retro Diels-Alder for de-crosslinking) proceed as function of temperature is of crucial importance in assessing the feasibility of the design in real-life products. Differences in kinetics based from various studies are not well understood, but are potentially caused by chemical side groups, mass transfer limitations, and on the analysis methods being employed. In this work we attempt to place all the relevant studies in perspective with respect to each other, and thereby offer a general guide on how to assess their recycling kinetics. This review sheds light on the kinetics on the furan/maleimide Diels-Alder reaction. This popular reaction opens up a path to develop end-of-life recyclable polymer networks with self-healing properties. The factors affecting reaction kinetics are discussed, and the importance of accurate reaction kinetics in the context of polymer reprocessing is highlighted. This article is protected by copyright. All rights reserved

Hyperthermia-induced degradation of BRCA2 : from bedside to bench and back again

Local hyperthermia, a method during which the temperature of a tumor is elevated, clinically increases the efficacy of radiotherapy and chemotherapy, without increasing side-effects. One of the reasons that explains why hyperthermia increases effectivity of these therapies is that it induces degradation of BRCA2. BRCA2 is an essential protein for double strand break DNA repair via homologous recombination (HR). Double strand breaks are the types of damage that occur after radiotherapy and specific types of chemotherapy, and are the basis for the anti-cancer effects of these therapies. By inhibiting HR, hyperthermia prevents repair of these breaks, and therefore increases anti-cancer efficacy of radiotherapy and chemotherapy. This thesis describes the journey of hyperthermia-mediated BRCA2 degradation, from bedside to bench and back again. In the __Prequel__ we describe bedside to bench research that has provided biological explanation for why hyperthermia sensitizes to radiotherapy through hyperthermia-mediated degradation of BRCA2. By taking __a Step Back__ we identify the thermal doses and the hyperthermia-radiotherapy sequencing necessary to best exploit heat-mediated BRCA2 degradation in the clinical setting. Next, with a Bench to Bedside approach, we explore what hyperthermia-mediated BRCA2 degradation and the resulting HR-deficiency can currently contribute to clinical hyperthermia treatment. Lastly, we close the __Bedside to Bench__-circle by addressing how clinical hyperthermia can be improved by exploring new targets for increasing effectiveness of hyperthermia-mediated BRCA2 degradation, using laboratory experiments

Hyperthermia-induced degradation of BRCA2 : from bedside to bench and back again

Local hyperthermia, a method during which the temperature of a tumor is elevated, clinically increases the efficacy of radiotherapy and chemotherapy, without increasing side-effects. One of the reasons that explains why hyperthermia increases effectivity of these therapies is that it induces degradation of BRCA2. BRCA2 is an essential protein for double strand break DNA repair via homologous recombination (HR). Double strand breaks are the types of damage that occur after radiotherapy and specific types of chemotherapy, and are the basis for the anti-cancer effects of these therapies. By inhibiting HR, hyperthermia prevents repair of these breaks, and therefore increases anti-cancer efficacy of radiotherapy and chemotherapy. This thesis describes the journey of hyperthermia-mediated BRCA2 degradation, from bedside to bench and back again. In the __Prequel__ we describe bedside to bench research that has provided biological explanation for why hyperthermia sensitizes to radiotherapy through hyperthermia-mediated degradation of BRCA2. By taking __a Step Back__ we identify the thermal doses and the hyperthermia-radiotherapy sequencing necessary to best exploit heat-mediated BRCA2 degradation in the clinical setting. Next, with a Bench to Bedside approach, we explore what hyperthermia-mediated BRCA2 degradation and the resulting HR-deficiency can currently contribute to clinical hyperthermia treatment. Lastly, we close the __Bedside to Bench__-circle by addressing how clinical hyperthermia can be improved by exploring new targets for increasing effectiveness of hyperthermia-mediated BRCA2 degradation, using laboratory experiments

Shaping the BRCAness mutational landscape by alternative double-strand break repair, replication stress and mitotic aberrancies

Tumours with mutations in the BRCA1/BRCA2 genes have impaired double-stranded DNA break repair, compromised replication fork protection and increased sensitivity to replication blocking agents, a phenotype collectively known as 'BRCAness'. Tumours with a BRCAness phenotype become dependent on alternative repair pathways that are error-prone and introduce specific patterns of somatic mutations across the genome. The increasing availability of next-generation sequencing data of tumour samples has enabled identification of distinct mutational signatures associated with BRCAness. These signatures reveal that alternative repair pathways, including Polymerase θ-mediated alternative end-joining and RAD52-mediated single strand annealing are active in BRCA1/2-deficient tumours, pointing towards potential therapeutic targets in these tumours. Additionally, insight into the mutations and consequences of unrepaired DNA lesions may also aid in the identification of BRCA-like tumours lacking BRCA1/BRCA2 gene inactivation. This is clinically relevant, as these tumours respond favourably to treatment with DNA-damaging agents, including PARP inhibitors or cisplatin, which have been successfully used to treat patients with BRCA1/2-defective tumours. In this review, we aim to provide insight in the origins of the mutational landscape associated with BRCAness by exploring the molecular biology of alternative DNA repair pathways, which may represent actionable therapeutic targets in in these cells

Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases. We modeled oncogene-induced replication stress using inducible expression of Cyclin E1 or Cdc25A in non-transformed RPE-1 cells, either in a TP53 wild-type or TP53-mutant background. DNA fiber analysis showed Cyclin E1 or Cdc25A overexpression to slow replication speed. The resulting replication-derived DNA lesions were transmitted into mitosis causing chromosome segregation defects. Single cell sequencing revealed that replication stress and mitotic defects upon Cyclin E1 or Cdc25A overexpression resulted in genomic instability. ATR or WEE1 inhibition exacerbated the mitotic aberrancies induced by Cyclin E1 or Cdc25A overexpression, and caused cytotoxicity. Both these phenotypes were exacerbated upon p53 inactivation. Conversely, downregulation of Cyclin E1 rescued both replication kinetics, as well as sensitivity to ATR and WEE1 inhibitors. Taken together, Cyclin E1 or Cdc25A-induced replication stress leads to mitotic segregation defects and genomic instability. These mitotic defects are exacerbated by inhibition of ATR or WEE1 and therefore point to mitotic catastrophe as an underlying mechanism. Importantly, our data suggest that Cyclin E1 overexpression can be used to select patients for treatment with replication checkpoint inhibitors

Multimodality in galaxy clusters from SDSS DR8: substructure and velocity distribution

We search for the presence of substructure, a non-Gaussian, asymmetrical velocity distribution of galaxies, and large peculiar velocities of the main galaxies in galaxy clusters with at least 50 member galaxies, drawn from the SDSS DR8. We employ a number of 3D, 2D, and 1D tests to analyse the distribution of galaxies in clusters: 3D normal mixture modelling, the Dressler-Shectman test, the Anderson-Darling and Shapiro-Wilk tests and others. We find the peculiar velocities of the main galaxies, and use principal component analysis to characterise our results. More than 80% of the clusters in our sample have substructure according to 3D normal mixture modelling, the Dressler-Shectman (DS) test shows substructure in about 70% of the clusters. The median value of the peculiar velocities of the main galaxies in clusters is 206 km/s (41% of the rms velocity). The velocities of galaxies in more than 20% of the clusters show significant non-Gaussianity. While multidimensional normal mixture modelling is more sensitive than the DS test in resolving substructure in the sky distribution of cluster galaxies, the DS test determines better substructure expressed as tails in the velocity distribution of galaxies. Richer, larger, and more luminous clusters have larger amount of substructure and larger (compared to the rms velocity) peculiar velocities of the main galaxies. Principal component analysis of both the substructure indicators and the physical parameters of clusters shows that galaxy clusters are complicated objects, the properties of which cannot be explained with a small number of parameters or delimited by one single test. The presence of substructure, the non-Gaussian velocity distributions, as well as the large peculiar velocities of the main galaxies, shows that most of the clusters in our sample are dynamically young.Comment: 15 pages, 11 figures, 2 online tables, accepted for publication in Astronomy and Astrophysic