Abstract Purpose Health care professionals (HCP) play a vital role in effectiveness of prehabilitation programs, but information is limited about what assists HCP deliver an effective service. This study evaluated HCP perceptions of enablers and barriers to two behaviours: referral for, and delivery of, multidisciplinary prehabilitation prior to autologous stem cell transplant. Methods Based on the Theoretical Domains Framework (TDF) of behaviour change, we conducted semi-structured interviews, purposively sampling 14 participants (from various healthcare disciplines) at a tertiary cancer centre. Discipline-specific topic guides were created based on the TDF and the behaviours appropriate to each discipline. Interviews were audio-recorded, transcribed verbatim, anonymised, content analysed (grouping, then labelling, thematically similar responses) and classified into theoretical domains. Structured decision rules were used to classify themes as high, medium or low priority. Results Fifty enablers and 31 barriers were identified; of these 26 enablers and 16 barriers classified as high priority. Four domains had the most frequent high-priority enablers: Social professional role and identity (e.g., multidisciplinary teamwork); Beliefs about consequences (e.g., patient benefit); Memory, attention and decision processes (e.g., refer as early as possible); and Environmental context and resources (e.g., electronic medical records are beneficial). High-priority barriers were most frequent in four domains: Memory, attention and decision processes (e.g., conflicting views about who should be referred); Environmental context and resources (e.g., lack of time); Social influences (e.g., families); and Emotions (e.g., patient distress). Conclusion Participants reported more enablers than barriers. Findings can support delivery of prehabilitation programs in hospital settings where uptake remains low.
<p>Significant dermatological toxicities associated with CX-5461 treatment</p>
Abstract Background Although MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer. Methods Using small interfering RNA (siRNA), MYC expression was depleted in 26 human breast cancer cell lines and cell proliferation evaluated by BrdU incorporation. MYC-dependent and MYC-independent cell lines were classified based on their sensitivity to siRNA-mediated MYC knockdown. We then inhibited CDKs including CDK4/6, CDK2 and CDK1 individually using either RNAi or small molecule inhibitors, and compared sensitivity to CDK inhibition with MYC dependence in breast cancer cells. Results Breast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC protein expression and MYC phosphorylation level. Sensitivity to siRNA-mediated MYC knockdown did not parallel sensitivity to the CDK4/6 inhibitor PD0332991; instead MYC-independent cell lines were generally sensitive to PD0332991. Cell cycle arrest induced by MYC knockdown was accompanied by a decrease in CDK2 activity, but inactivation of CDK2 did not selectively affect the viability of MYC-dependent breast cancer cells. In contrast, CDK1 inactivation significantly induced apoptosis and reduced viability of MYC-dependent cells but not MYC- independent cells. This selective induction of apoptosis by CDK1 inhibitors was associated with up-regulation of the pro-apoptotic molecule BIM and was p53-independent. Conclusions Overall, these results suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer is warranted.
This paper aims to optimise a bulk scale design of a novel auxetic structure, the hourglass structure (HGS), through a multi-objective optimisation model to improve its protection performance. A 3D numerical model of the HGS under an in-plane quasi-static compression was developed and validated with experimental results. Based on the validated numerical model, a series of numerical analyses were conducted by automating the HGS design process with randomly generated design variables. The automated numerical analyses built a dataset of the selected protective performance indicators (namely, peak elastic stress, plateau stress, and energy absorption capacity). Then, the dataset was used to develop a high-accuracy surrogate model using a radial basis function (RBF) neural network. Afterward, the Pareto optimal solutions were searched with the non-dominated sorting genetic algorithm (NSGA-II). The best compromise design out of the Pareto optimal set was determined with the ideal point method. The performance of the optimum design was simulated under both quasi-static and blast loadings to comprehensively explore the protective performance. In addition, a correlation matrix was constructed to investigate the effects of each design parameter on the protective performance indicators quantitatively. The results showed that the obtained optimum design outperformed the baseline structure under both quasi-static and blast loadings. The optimum HGS design displayed a higher and more stable negative Poisson's ratio along with two deformation modes leading to two plateau stress levels. The optimised HGS design is applicable as the core of high-performance protective sandwich structures.
<title>Abstract</title> The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PI) has revolutionized the treatment of MM. However, resistance to PI is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461 has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here we show that CX-5461 has potent antimyeloma activity in PI-resistant MM preclinical models in vitro and in vivo. In addition to inhibiting ribosome biogenesis, CX-5461 causes topoisomerase II trapping and replication-dependent DNA damage, leading to G2/M cell cycle arrest and apoptotic cell death. Surprisingly, the addition of PI does not enhance the therapeutic benefit of CX-5461. In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk*MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.
