Peptides can offer the versatility needed for a successful oncology drug discovery approach. Peptide-drug conjugates (PDCs) are an emerging targeted therapeutic that present increased tumour ...penetration and selectivity. Despite these advantages, there are still limitations for the use of peptides as therapeutics exemplified through their slow progression to get into the clinic and limited oral bioavailability. New approaches to address these problems have been studied and successfully implemented to enhance the stability of peptides and their constructs. There is great promise for the future of PDCs with two molecules already on the market and many variations currently undergoing clinical trials, such as bicycle-toxin conjugates and peptide-dendrimer conjugates. This review summarises the entire process needed for the design and successful development of an oncology PDC including chemical and nanomaterial strategies to enhance peptide stability within circulation, the function of each component of a PDC construct, and current examples in clinical trials.
A tutorial review showcasing how peptide-drug conjugates can offer the versatility needed for a successful drug discovery approach, their problems and future opportunities.
Motivated by observational studies that report associations between schizophrenia and traits, such as poor diet, increased body mass index and metabolic disease, we investigated the genetic ...contribution to dietary intake in a sample of 335,576 individuals from the UK Biobank study. A principal component analysis applied to diet question item responses generated two components: Diet Component 1 (DC1) represented a meat-related diet and Diet Component 2 (DC2) a fish and plant-related diet. Genome-wide association analysis identified 29 independent single-nucleotide polymorphisms (SNPs) associated with DC1 and 63 SNPs with DC2. Estimated from over 35,000 3rd-degree relative pairs that are unlikely to share close family environments, heritabilities for both DC1 and DC2 were 0.16 (standard error (s.e.) = 0.05). SNP-based heritability was 0.06 (s.e. = 0.003) for DC1 and 0.08 (s.e = 0.004) for DC2. We estimated significant genetic correlations between both DCs and schizophrenia, and several other traits. Mendelian randomisation analyses indicated a negative uni-directional relationship between liability to schizophrenia and tendency towards selecting a meat-based diet (which could be direct or via unidentified correlated variables), but a bi-directional relationship between liability to schizophrenia and tendency towards selecting a fish and plant-based diet consistent with genetic pleiotropy.
Engaging with children and adolescents in mental health settings who are exhibiting behaviours that challenge can often result in the use of seclusion, restraint and coercive practices. It is ...recognised that more therapeutic ways to engage this population are needed, adopting trauma informed interventions may provide a solution. The aim of this systematic review is to synthesize the evidence in relation to the effect of trauma-informed interventions on coercive practices in child and adolescent residential settings. The review is guided by elements of the Cochrane Handbook for Systematic Reviews of Interventions and reported using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist. Results were synthesized and reported narratively. Nine studies met the eligibility criteria for this review. There was a lack of homogeneity amongst the studies. The trauma-informed interventions used were typically multi-faceted, underpinned by a variety of approaches and sought to bring about changes to clinical practice
.
Most studies (n = 8) reported significant reductions in the use of restrictive practices following the implementation of a trauma informed approach. The use of a trauma-informed approach, underpinned by an organisational change or implementation strategy, have the potential to reduce coercive practices with children and adolescents. However, the included interventions were insufficiently described to draw strong conclusions.
Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage
. The FA repair pathway protects against ...endogenous and exogenous carcinogenic aldehydes
. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas
(SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus
(HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.
High-risk behaviours are sometimes encountered in Child and Adolescent inpatient mental health units and can prompt the use of coercive practices to maintain safety. Coercive practices may lead to ...re-traumatisation of young people and deteriorating therapeutic relationships. Trauma-informed practice (TIP) has successfully reduced coercive practices. While education is identified as foundational to implementation, evaluations of programmes remain minimal. The aim of this study was to explore mental health professionals' views and experiences of a trauma-informed education programme and its likely impact on their approach to practice. Five mental health professionals agreed to participate, four contributed in a focus group and one in an individual interview. Data were analysed thematically using the Braun and Clarke Framework. Three main themes were identified. Firstly, shifting attitudes and perceptions of trauma-informed practice. Participants believed they had developed more compassion towards clients and these attitudes were reflected in their clinical practice. Secondly, challenges associated with trauma-informed practice educational intervention. Staffing issues and shift work made it difficult for participants to attend education sessions regularly. Participants identified barriers to practicing in a trauma-informed manner in the current clinical environment. Finally, the need for interdisciplinary communication and support was identified. Participants saw the need for all professionals, not only nurses, to take responsibility for changing practice, and for stronger support at the organisational level. Trauma-informed practice is crucial to recovery-focused mental health nursing practice. These findings highlight the importance of TIP education and suggest areas for further improvement to enhance positive mental health outcomes for young people.
Platelets are blood cells with numerous crucial pathophysiological roles in hemostasis, cardiovascular thrombotic events and cancer metastasis. Platelet activation requires the engagement of ...intracellular signalling pathways that involve protein-protein interactions (PPIs). A better understanding of these pathways is therefore crucial for the development of selective anti-platelet drugs. New strategies for studying PPIs in human platelets are required to overcome limitations associated with conventional platelet research methods. For example, small molecule inhibitors can lack selectivity and are often difficult to design and synthesise. Additionally, development of transgenic animal models is costly and time-consuming and conventional recombinant techniques are ineffective due to the lack of a nucleus in platelets. Herein, we describe the generation of a library of novel, functionalised stapled peptides and their first application in the investigation of platelet PPIs. Moreover, the use of platelet-permeable stapled Bim BH3 peptides confirms the part of Bim in phosphatidyl-serine (PS) exposure and reveals a role for the Bim protein in platelet activatory processes. Our work demonstrates that functionalised stapled peptides are a complementary alternative to conventional platelet research methods, and could make a significant contribution to the understanding of platelet signalling pathways and hence to the development of anti-platelet drugs.
Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify ...functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (P
= 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.
PDF
