Click-Capable Phenanthriplatin Derivatives as Tools to Study Pt(II)-Induced Nucleolar Stress.

It is well established that oxaliplatin, one of the three Pt(II) anticancer drugs approved worldwide, and phenanthriplatin, an important preclinical monofunctional Pt(II) anticancer drug, possess a different mode of action from that of cisplatin and carboplatin, namely, the induction of nucleolar stress. The exact mechanisms that lead to Pt-induced nucleolar stress are, however, still poorly understood. As such, studies aimed at better understanding the biological targets of both oxaliplatin and phenanthriplatin are urgently needed to expand our understanding of Pt-induced nucleolar stress and guide the future design of Pt chemotherapeutics. One approach that has seen great success in the past is the use of Pt-click complexes to study the biological targets of Pt drugs. Herein, we report the synthesis and characterization of the first examples of click-capable phenanthriplatin complexes. Furthermore, through monitoring the relocalization of nucleolar proteins, RNA transcription levels, and DNA damage repair biomarker γH2AX, and by investigating their in vitro cytotoxicity, we show that these complexes successfully mimic the cellular responses observed for phenanthriplatin treatment in the same experiments. The click-capable phenanthriplatin derivatives described here expand the existing library of Pt-click complexes. Significantly they are suitable for studying nucleolar stress mechanisms and further elucidating the biological targets of Pt complexes.

A protocol for a scoping review to identify methods used in clinical practice to assess wound odour.

Objective: The objective of this scoping review is to map, from wound assessment tools and other literature, the current methods used to assess wound odour in order to answer the following question: Which methods of assessment, validated or otherwise, are currently used in wound assessment tools to assess wound odour? Introduction: Wound assessment includes not only details of the condition of the wound bed but also evaluation of symptoms associated with the wound including that of odour. Odour is cited by clinicians, patients and carers as one of the most distressing wound symptoms. However, there is no consensus on a preferred method to assess odour thus negatively impacting the internal and external validity of many clinical trials and minimising the ability to perform meta-analysis. Eligibility criteria: Any wound assessment tool or framework that includes assessment of wound odour in any wound aetiology and in any care setting. Any systematic or scoping review that includes assessment of wound odour in any wound aetiology and in any care setting. No limits on date of publication or language will be applied. Methods: We will employ the Preferred Reporting Items for Systematic Review and Meta-Analyses extension for scoping reviews (PRISMA-ScR) guidelines for this scoping review and base its structure on the framework proposed by Arksey and O'Malley. Results: A narrative format will summarise extracted data and provide an overview of tools used to assess wound odour. A PRISMA diagram will outline the results of the search strategy. The identified tools will be summarised in table format and stratified according to methods used. Conclusion: The result of this scoping review will be a list of methods used to assess odour in wounds and will be used to inform a subsequent Delphi study to gain consensus on the preferred method to assess wound odour.

BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival.

Malignant melanoma is one of the most difficult cancers to treat due to its resistance to chemotherapy. Despite recent successes with BRAF inhibitors and immune checkpoint inhibitors, many patients do not respond or become resistant to these drugs. Hence, alternative treatments are still required. Due to the importance of the BCL-2-regulated apoptosis pathway in cancer development and drug resistance, it is of interest to establish which proteins are most important for melanoma cell survival, though the outcomes of previous studies have been conflicting. To conclusively address this question, we tested a panel of established and early passage patient-derived cell lines against several BH3-mimetic drugs designed to target individual or subsets of pro-survival BCL-2 proteins, alone and in combination, in both 2D and 3D cell cultures. None of the drugs demonstrated significant activity as single agents, though combinations targeting MCL-1 plus BCL-XL, and to a lesser extent BCL-2, showed considerable synergistic killing activity that was elicited via both BAX and BAK. Genetic deletion of BFL-1 in cell lines that express it at relatively high levels only had minor impact on BH3-mimetic drug sensitivity, suggesting it is not a critical pro-survival protein in melanoma. Combinations of MCL-1 inhibitors with BRAF inhibitors also caused only minimal additional melanoma cell killing over each drug alone, whilst combinations with the proteasome inhibitor bortezomib was more effective in multiple cell lines. Our data show for the first time that therapies targeting specific combinations of BCL-2 pro-survival proteins, namely MCL-1 plus BCL-XL and MCL-1 plus BCL-2, could have significant benefit for the treatment of melanoma.