Inhibition of key DNA double strand break repair protein kinases enhances radiosensitivity of head and neck cancer cells to X-ray and proton irradiation.

Ionising radiation (IR) is widely used in cancer treatment, including for head and neck squamous cell carcinoma (HNSCC), where it induces significant DNA damage leading ultimately to tumour cell death. Among these lesions, DNA double strand breaks (DSBs) are the most threatening lesion to cell survival. The two main repair mechanisms that detect and repair DSBs are non-homologous end joining (NHEJ) and homologous recombination (HR). Among these pathways, the protein kinases ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR) and the DNA dependent protein kinase catalytic subunit (DNA-Pkcs) play key roles in the sensing of the DSB and subsequent coordination of the downstream repair events. Consequently, targeting these kinases with potent and specific inhibitors is considered an approach to enhance the radiosensitivity of tumour cells. Here, we have investigated the impact of inhibition of ATM, ATR and DNA-Pkcs on the survival and growth of six radioresistant HPV-negative HNSCC cell lines in combination with either X-ray irradiation or proton beam therapy, and confirmed the mechanistic pathway leading to cell radiosensitisation. Using inhibitors targeting ATM (AZD1390), ATR (AZD6738) and DNA-Pkcs (AZD7648), we observed that this led to significantly decreased clonogenic survival of HNSCC cell lines following both X-ray and proton irradiation. Radiosensitisation of HNSCC cells grown as 3D spheroids was also observed, particularly following ATM and DNA-Pkcs inhibition. We confirmed that the inhibitors in combination with X-rays and protons led to DSB persistence, and increased micronuclei formation. Cumulatively, our data suggest that targeting DSB repair, particularly via ATM and DNA-Pkcs inhibition, can exacerbate the impact of ionising radiation in sensitising HNSCC cell models.

Dynamite plots in surgical research over 10 years: a meta-study using machine-learning analysis.

PURPOSE: Bar charts of numerical data, often known as dynamite plots, are unnecessary and misleading. Their tendency to alter the perception of mean's position through the within-the-bar bias and their lack of information on the distribution of the data are two of numerous reasons. The machine learning tool, Barzooka, can be used to rapidly screen for different graph types in journal articles.We aim to determine the proportion of original research articles using dynamite plots to visualize data, and whether there has been a change in their use over time. METHODS: Original research articles in nine surgical fields of research were sampled based on MeSH terms and then harvested using the Python-based biblio-glutton-harvester tool. After harvesting, they were analysed using Barzooka. Over 40 000 original research articles were included in the final analysis. The results were adjusted based on previous validation data with 95% confidence bounds. Kendall τ coefficient with the Mann-Kendall test for significance was used to determine the trend of dynamite plot use over time. RESULTS: Eight surgical fields of research showed a statistically significant decrease in use of dynamite plots over 10 years. Oral and maxillofacial surgery showed no significant trend in either direction. In 2022, use of dynamite plots, dependent on field and 95% confidence bounds, ranges from ~30% to 70%. CONCLUSION: Our results show that the use of dynamite plots in surgical research has decreased over time; however, use remains high. More must be done to understand this phenomenon and educate surgical researchers on data visualization practices.