NFκB signalling in colorectal cancer: Examining the central dogma of IKKα and IKKß signalling.

The NFκB pathway, known as the central regulator of inflammation, has a well-established role in colorectal cancer (CRC) initiation, progression, and therapy resistance. Due to the pathway's overarching roles in CRC, there have been efforts to characterise NFκB family members and target the pathway for therapeutic intervention. Initial research illustrated that the canonical NFκB pathway, driven by central kinase IKKß, was a promising target for drug intervention. However, dose limiting toxicities and specificity concerns have resulted in failure of IKKß inhibitors in clinical trials. The field has turned to look at targeting the less dominant kinase, IKKα, which along with NFκB inducing kinase (NIK), drives the lesser researched non-canonical NFκB pathway. However prognostic studies of the non-canonical pathway have produced conflicting results. There is emerging evidence that IKKα is involved in other signalling pathways, which lie outside of canonical and non-canonical NFκB signalling. Evidence suggests that some of these alternative pathways involve a truncated form of IKKα, and this may drive poor cancer-specific survival in CRC. This review aims to explore the multiple components of NFκB signalling, highlighting that NIK may be the central kinase for non-canonical NFκB signalling, and that IKKα is involved in novel pathways which promote CRC.

TAK1 expression is associated with increased PD-L1 and decreased cancer-specific survival in microsatellite-stable colorectal cancer.

BACKGROUND: Transforming growth factor ß-activated protein kinase-1 (TAK1) plays an important role in MAPK and NFκB pathways and has been associated with colorectal cancer. The aim of this study was to determine how cytoplasmic and juxtanuclear punctate staining of TAK1 relates to immune checkpoint expression and cancer specific survival in colorectal cancer. METHODS: Protein expression was assessed by immunohistochemistry on tissue microarrays from primary curative colorectal cancer resected specimens. Expression levels of cytoplasmic TAK1 by QuPath digital quantification and punctate TAK1 staining was scored using a manual point scoring technique and correlated with clinicopathological features, immune checkpoint expression and cancer-specific survival. Bulk RNA sequencing was performed in specimens to determine mutational profiles and differentially expressed genes. RESULTS: A cohort of 875 patients who had undergone colorectal cancer resection were assessed for TAK1 expression. Higher levels of cytoplasmic TAK1 expression correlated with elevated PD1 and PD-L1 expression (p < 0.010). High punctate TAK1 expression was more commonly identified in poorly differentiated colorectal cancers (p = 0.036), had dysregulated mutational and transcriptional profiles with decreased insulin-like growth factor 2(IGF2) expression (p < 0.010), and independently predicted poor cancer-specific survival (HR 2.690, 95% CI 1.419-5.100, p = 0.002). The association of punctate TAK1 expression and recurrence remained after subgroup analysis for microsatellite-stable colorectal cancer (p = 0.028). DISCUSSION: Punctate TAK1 expression is associated with worse cancer specific survival. TAK1 signalling may be an important pathway to investigate underlying mechanisms for recurrence in microsatellite-stable colorectal cancer.

WNT Signalling Promotes NF-κB Activation and Drug Resistance in KRAS-Mutant Colorectal Cancer.

Approximately 40% of colorectal cancer (CRC) cases are characterized by KRAS mutations, rendering them insensitive to most CRC therapies. While the reasons for this resistance remain incompletely understood, one key aspect is genetic complexity: in CRC, oncogenic KRAS is most commonly paired with mutations that alter WNT and P53 activities ("RAP"). Here, we demonstrate that elevated WNT activity upregulates canonical (NF-κB) signalling in both Drosophila and human RAS mutant tumours. This upregulation required Toll-1 and Toll-9 and resulted in reduced efficacy of RAS pathway targeted drugs such as the MEK inhibitor trametinib. Inhibiting WNT activity pharmacologically significantly suppressed trametinib resistance in RAP tumours and more genetically complex RAP-containing 'patient avatar' models. WNT/MEK drug inhibitor combinations were further improved by targeting brm, shg, ago, rhoGAPp190 and upf1, highlighting these genes as candidate biomarkers for patients sensitive to this duel approach. These findings shed light on how genetic complexity impacts drug resistance and proposes a therapeutic strategy to reverse this resistance.

Neutron-activated theranostic radionuclides for nuclear medicine.

Theranostics in nuclear medicine refers to personalized patient management that involves targeted therapy and diagnostic imaging using a single or combination of radionuclide (s). The radionuclides emit both alpha (α) or beta (ß-) particles and gamma (γ) rays which possess therapeutic and diagnostic capabilities, respectively. However, the production of these radionuclides often faces difficulties due to high cost, complexity of preparation methods and that the products are often sourced far from the healthcare facilities, hence losing activity due to radioactive decay during transportation. Subject to the availability of a nuclear reactor within an accessible distance from healthcare facilities, neutron activation is the most practical and cost-effective route to produce radionuclides suitable for theranostic purposes. Holmium-166 (166Ho), Lutetium-177 (177Lu), Rhenium-186 (186Re), Rhenium-188 (188Re) and Samarium-153 (153Sm) are some of the most promising neutron-activated radionuclides that are currently in clinical practice and undergoing clinical research for theranostic applications. The aim of this paper is to review the physical characteristics, current clinical applications and future prospects of these neutron activated radionuclides in theranostics. The production, physical properties, validated clinical applications and clinical studies for each neutron-activated radionuclide suitable for theranostic use in nuclear medicine are reviewed in this paper.

Improving the mental wellbeing of Arabic speaking refugees: an evaluation of a mental health promotion program.

BACKGROUND: Refugee populations have particularly high rates of mental health problems, including Posttraumatic Stress Disorder (PTSD) and depression. However, uptake of mental health care may be low even when severe depression and PTSD symptoms are present in individuals following resettlement. This is likely due, at least in part, to cultural influences on refugees' knowledge and beliefs about mental health problems and their treatment. We sought to provide preliminary evidence for the effectiveness of a culturally tailored mental health promotion program for Arabic-speaking refugees. METHODS: A total of 33 Arabic-speaking refugees resettled in South Western Sydney were recruited and completed intervention which consisted of weekly three-hour sessions for 4 weeks delivered in Arabic. Key aspects of mental health literacy, help-seeking intentions and levels of general psychological distress were assessed, by means of a self-report survey, pre-intervention, (immediately) post-intervention and 3 months following intervention. RESULTS: Of the 33 participants that completed the intervention, 31 completed the immediate post-intervention survey and 29 completed the 3 months follow-up survey. Improvements in most aspects of mental health literacy assessed were found immediately post-intervention and at follow-up, although only changes relating to stigmatising attitudes were statistically significant. Additionally, a statistically significant decrease in participants' levels of general psychological distress was observed immediately following the intervention, and this decrease was sustained at follow-up. CONCLUSION: While further research employing a more rigorous study design and larger sample size will be needed, results of this initial trial suggest that a culturally tailored mental health promotion program targeting key aspects of mental health literacy can improve the mental health of Arabic-speaking refugees resettled in a Western nation.