Cytokine release syndrome and cancer immunotherapies - historical challenges and promising futures.

Cancer is the leading cause of death worldwide. Cancer immunotherapy involves reinvigorating the patient\u27s own immune system to fight against cancer. While novel approaches like Chimeric Antigen Receptor (CAR) T cells, bispecific T cell engagers, and immune checkpoint inhibitors have shown promising efficacy, Cytokine Release Syndrome (CRS) is a serious adverse effect and remains a major concern. CRS is a phenomenon of immune hyperactivation that results in excessive cytokine secretion, and if left unchecked, it may lead to multi-organ failure and death. Here we review the pathophysiology of CRS, its occurrence and management in the context of cancer immunotherapy, and the screening approaches that can be used to assess CRS and de-risk drug discovery earlier in the clinical setting with more predictive pre-clinical data. Furthermore, the review also sheds light on the potential immunotherapeutic approaches that can be used to overcome CRS associated with T cell activation

"Our people has got to come to terms with that": changing perceptions of the digital rectal examination as a barrier to prostate cancer diagnosis in African-Caribbean men

Objective: African‐Caribbean men in the United Kingdom in comparison with other ethnicities have the highest incidence rate of prostate cancer. Psychosocial aspects related to screening and presentation impact on men's behavior, with previous studies indicating a range of barriers. This study explores one such barrier, the digital rectal examination (DRE), due to its prominence within UK African‐Caribbean men's accounts. Methods: African‐Caribbean men with prostate cancer (n = 10) and without cancer (n = 10) were interviewed about their perceptions of DRE. A synthetic discursive approach was employed to analyze the data. Results: Findings illustrate that an interpretative repertoire of homophobia in relation to the DRE is constructed as having an impact upon African‐Caribbean men's uptake of prostate cancer screening. However, the discursive focus on footing and accountability highlight deviations from this repertoire that are built up as pragmatic and orient to changing perceptions within the community. Conclusions: Health promotion interventions need to address the fear of homophobia and are best designed in collaboration with the community

Fluorescent protein tagging confirms the presence of ribosomal proteins atDrosophilapolytene chromosomes

\ud \ud Most ribosomal proteins (RPs) are stoichiometrically incorporated into ribosomal subunits and play essential roles in ribosome biogenesis and function. However, a number of RPs appear to have non-ribosomal functions, which involve direct association with pre-mRNA and transcription factors at transcription sites. The consensus is that the RPs found at these sites are off ribosomal subunits, but observation that different RPs are usually found together suggests that ribosomal or ribosomal-like subunits might be present. Notably, it has previously been reported that antibodies against 20 different RPs stain the same Pol II transcription sites in Drosophila polytene chromosomes. Some concerns, however, were raised about the specificity of the antibodies. To investigate further whether RPs are present at transcription sites in Drosophila, we have generated several transgenic flies expressing RPs (RpS2, RpS5a, RpS9, RpS11, RpS13, RpS18, RpL8, RpL11, RpL32, and RpL36) tagged with either green or red fluorescent protein. Imaging of salivary gland cells showed that these proteins are, as expected, abundant in the cytoplasm as well as in the nucleolus. However, these RPs are also apparent in the nucleus in the region occupied by the chromosomes. Indeed, polytene chromosome immunostaining of a representative subset of tagged RPs confirms the association with transcribed loci. Furthermore, characterization of a strain expressing RpL41 functionally tagged at its native genomic locus with YFP, also showed apparent nuclear accumulation and chromosomal association, suggesting that such a nuclear localization pattern might be a shared feature of RPs and is biologically important. We anticipate that the transgenes described here should provide a useful research tool to visualize ribosomal subunits in Drosophila tissues and to study the non-ribosomal functions of RPs.\u

Clustering of multiple specific genes and gene-rich R-bands around SC-35 domains: evidence for local euchromatic neighborhoods

Typically, eukaryotic nuclei contain 10–30 prominent domains (referred to here as SC-35 domains) that are concentrated in mRNA metabolic factors. Here, we show that multiple specific genes cluster around a common SC-35 domain, which contains multiple mRNAs. Nonsyntenic genes are capable of associating with a common domain, but domain “choice” appears random, even for two coordinately expressed genes. Active genes widely separated on different chromosome arms associate with the same domain frequently, assorting randomly into the 3–4 subregions of the chromosome periphery that contact a domain. Most importantly, visualization of six individual chromosome bands showed that large genomic segments (∼5 Mb) have striking differences in organization relative to domains. Certain bands showed extensive contact, often aligning with or encircling an SC-35 domain, whereas others did not. All three gene-rich reverse bands showed this more than the gene-poor Giemsa dark bands, and morphometric analyses demonstrated statistically significant differences. Similarly, late-replicating DNA generally avoids SC-35 domains. These findings suggest a functional rationale for gene clustering in chromosomal bands, which relates to nuclear clustering of genes with SC-35 domains. Rather than random reservoirs of splicing factors, or factors accumulated on an individual highly active gene, we propose a model of SC-35 domains as functional centers for a multitude of clustered genes, forming local euchromatic “neighborhoods.

PROCEE: a PROstate Cancer Evaluation and Education serious game for African Caribbean men

Purpose – Prostate cancer is the most common cancer diagnosed in men in the UK. Black men are in a higher prostate cancer risk group possibly due to inherent genetic factors. The purpose of this paper is to introduce PROstate Cancer Evaluation and Education (PROCEE), an innovative serious game aimed at providing prostate cancer information and risk evaluation to black African-Caribbean men. Design/methodology/approach – PROCEE has been carefully co-designed with prostate cancer experts, prostate cancer patients and members of the black African-Caribbean community in order to ensure that it meets the real needs and expectations of the target audience. Findings – During the co-design process, the users defined an easy to use and entertaining game which can effectively raise awareness, inform users about prostate cancer and their risk, and encourage symptomatic men to seek medical attention in a timely manner. Originality/value – During focus group evaluations, users embraced the game and emphasised that it can potentially have a positive impact on changing user behaviour among high risk men who are experiencing symptoms and who are reluctant to visit their doctor