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A Systematic Review of Absorbed Doses and Response in Patients Treated with Radioiodine for Differentiated Thyroid Cancer.
No full textBackground: Treatment of patients with thyroid cancer with Na[131I]I is routinely performed with empirical activity levels. Treatment success may be expected to correlate with the absorbed doses delivered to targets (thyroid remnants or metastatic lesions), but no systematic review or meta-analysis of absorbed dose-effect relationships has yet been performed. Methods: A systematic review and meta-analysis of reports published before August 22, 2025, was performed using PubMed, Web of Science, and OVID MEDLINE. Studies were included if they reported the proportion of patients achieving successful outcome as defined in individual publications and the absorbed doses delivered to targets. The study is registered with PROSPERO (CRD42024554956). Results: In total, 3723 studies were identified of which 18 were eligible for analysis. Number of patients in the included studies ranged from 4 to 509. For patients treated with Na[131I]I for thyroid remnant ablation, the reported success rates ranged from 60% to 100%, while lower success rates of 43-58% were found for patients with metastatic lesions. Success rates for patients with a thyroid remnant absorbed dose of 300 Gy or more ranged from 78% to 96%, while patients with metastatic lesions receiving at least 80 Gy had success rates ranging from 46% to 98%. Conclusions: While individual studies have demonstrated the importance of absorbed doses from Na[131I]I for differentiated thyroid cancer, no conclusive absorbed dose-effect relationship has been established in this review. A lack of standardization of dosimetry methodologies and follow-up criteria in the studies obscures the relationship. Large-scale observational prospective studies are required to determine the absorbed doses required for successful personalized treatments of patients with thyroid cancer with Na[131I]I
The prognostic role of Claudin 18.2 in advanced gastric or gastroesophageal junction adenocarcinoma: a systematic literature review
No full textRetreatment, rechallenge, and escalation with subsequent immune checkpoint inhibitor therapies across cancers after initial failure.
No full textBACKGROUND: Immune checkpoint inhibitors (ICIs) are used across many tumor types in perioperative and advanced settings. However, most patients discontinue treatment due to disease progression, adverse events, or other reasons. Clinical benefit of using ICIs following discontinuation is not well defined. METHODS: We analyzed the literature examining ICI treatment outcomes after progression or discontinuation in different tumor types. We extracted data from 51 studies, assessed the strength of the evidence, summarized treatment options, and identified gaps in our understanding. RESULTS: We proposed definitions for the different scenarios of subsequent treatment with ICIs. In melanoma, studies frequently reported complete response (CR), partial response (PR), and stable disease (SD) following subsequent ICI therapy. In renal cell carcinoma, discordant results have been reported following subsequent ICI treatment; some trials reported CR/PR cases, whereas others did not show any CR/PR. In non-small-cell lung cancer, we found frequent reports of PR or SD but not CR following subsequent ICI treatment, although studies had small patient cohorts. Subsequent ICI treatment showed efficacy in some patients with urothelial carcinoma, but the small cohort sizes limited the strength of the evidence. One cross-tumor study investigated subsequent ICI treatment after initial discontinuation and reported a few PR and SD without any CR. CONCLUSIONS: Evidence supporting the efficacy of subsequent ICI treatment is strongest in melanoma, but the level of evidence remains low overall. Prospective studies and improved reporting of subsequent ICI therapy in existing trials investigating long-term outcomes, standardized predictive factors, and treatment modalities are warranted
Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer.
No full textMetastatic castration-resistant prostate cancer (mCRPC) is a lethal disease requiring additional therapeutic strategies. MCL1, an anti-apoptotic BCL2 family member, promotes cancer-cell survival, but its role in mCRPC remains poorly understood. Here, we characterise MCL1 in multiple mCRPC biopsy cohorts and patient-derived models, assessing responses to MCL1 inhibition. MCL1 copy number gain (14%-34%) correlates with increased MCL1 expression and worse outcomes. MCL1 inhibition exhibits anti-tumour effects in MCL1-gained mCRPC models. Co-inhibition of MCL1 and AKT induces cancer-specific cell death in PTEN-loss/PI3K-activated models in vitro and in vivo, modulating BAD-BCLXL and BIM-MCL1 interactions, with durable anti-tumour activity in models with AKT inhibitor acquired resistance. Finally, CDK9-mediated MCL1 downregulation combined with AKT inhibition recapitulates these findings, providing further opportunities for clinical translation. These data support early phase clinical trials targeting MCL1, both as monotherapy for MCL1-gained mCRPC, and in combination with AKT inhibition for PTEN-loss/PI3K-activated mCRPC
NSD2-epigenomic reprogramming and maintenance of plasma cell phenotype in t(4;14) myeloma.
No full textOverexpression of the H3K36 histone methyltransferase NSD2 in t(4;14) multiple myeloma (MM) is an early, oncogenic event, and understanding its impact on genomic organisation and expression is relevant to understanding MM biology. We performed epigenetic, transcriptional and phenotypic profiling of the t(4;14) KMS11 myeloma cell line and its isogenic translocation knock out (TKO) to characterise the sequelae of NSD2 overexpression. We found a marked global impact of NSD2 on gene expression and DNA organisation implicating cell identity genes; notably the early lymphocyte regulator, LAIR1 and MM cell surface markers, including CD38, a classical marker of plasma cells which was reduced in TKO cells. Plasma cell transcription factors such as PRDM1, IRF4 and XBP1 were unaffected, suggesting a downstream direct gene effect of NSD2 on cell identity. Changes in cell surface markers suggest an altered surface immunophenotype. Our findings suggest a role for NSD2 in maintaining MM cell identity, with potential implications for future therapeutic strategies based on targeting of NSD2
Fluorescent Probes for Imaging Reactive Cell Metabolites
No full textThis thesis reports the design and development of activity-based sensors (ABS) form vitro imaging of reactive oxygen (ROS) and nitrogen species (RNS). The ABS have been designed on
established boronic pinacol ester sensing moieties and a range of reporters including: 4-nitroaniline, 4-methyl-7-amino-coumarin, and 1,8-naphthalimide. Chapter 1 includes: a thesis introduction,
background to reactive intracellular metabolites such as hydrogen peroxide and peroxynitrite,
current methods of ROS/RNS imaging, fluorescence imaging, and a history of activity-based
sensing. Chapter 2 comprises an in-depth investigation into known and novel proof-of-concept
based ABS. their synthesis, and all non-biological fluorescence testing, including the selectivity,
stability. and sensitivity of such compounds. Chapters 3 and 4 include two strategies to enhance the intracellular retention time of fluorescent reporters for ABS. The first hypothesis for improving the intracellular retention time of reporters relies on lowering passive permeability, a concept termed ''the polarity switch". This chapter investigates the entrapment of positively charged reporters
unmasked via ROS/RNS mediated mechanisms. The second strategy and the following chapter explore using covalent warheads for the promiscuous covalent attachment of ABS within the cell. This chapter also includes the design and development of a novel masked covalent warhead which is unreactive until activation by ROS/RNS. Lastly, chapter 5 includes all biological and imaging
data of the compounds generated as part of this thesis, including a discussion on the permeability and stability of ABS under biological conditions
Circulating tumour DNA to direct the management of patients with gastrointestinal malignancies
No full textBackground
Management of patients with gastrointestinal (GI) malignancies requires a personalised approach to improve survival while minimising risk. Colorectal and oesophagogastric (OG) malignancies account for 20% of all cancer deaths, with significant global socioeconomic impact. Novel technologies are required to customise treatment. Circulating tumour DNA (ctDNA) is emerging as a prognostic biomarker and predictive biomarker of treatment response and can be used to guide management.
Hypotheses
ctDNA can be used to predict recurrence and guide adjuvant chemotherapy (ACT) treatment decisions in patients with resected early-stage colorectal cancer (CRC) and evaluate response to therapies in metastatic CRC and OGA.
Aims and objectives
1. Determine the association between detectable ctDNA and recurrence free survival (RFS) in patients with resected CRC using a tissue-free approach to ctDNA detection.
2. Assess the feasibility of using a tissue-free (versus tumour-informed) ctDNA assay to detect minimal residual disease (MRD) and guide a de-escalation strategy of ACT in patients with curatively resected CRC who are ctDNA negative post-operatively.
3. Determine the use of serial ctDNA monitoring and immune profiling to detect biomarkers of response and resistance to immunotherapy combinations in metastatic GI cancers.
Methodology
1. Clinical validity of ctDNA to detect MRD based on a tissue-free ctDNA assay from TRACC Part B UK-based multi-centre observational translational study data of curatively treated CRC patients.
2. Clinical utility of ctDNA to guide adjuvant management of CRC by means of development of the TRACC Part C interventional randomised MRD study, involving additional clinical validation and process implementation and evaluation.
3. ctDNA and immune profiling in immunotherapy response monitoring in an academic phase II study of anti-PD1 and an HDAC inhibitor (EMERGE study) in patients with metastatic OG and CRC
Significance
ctDNA has potential for wide ranging applications in early and metastatic GI malignancies to directly impact patient care
CRISPR base editing and proteomic analysis reveal novel tankyrase regulatory mechanisms in Wnt/β-catenin signalling
No full textTankyrase (with paralogues TNKS and TNKS2) is an ADP-ribosyltransferase (ART) that plays important roles in numerous cellular processes. These include Wnt/β-catenin and Hippo signalling, telomere length maintenance, sister telomere resolution in mitosis, proteostasis, and glucose homeostasis. While the regulatory mechanisms of the ART family members PARP1 and PARP2 are well understood, tankyrase regulation beyond NAD+ concentrations, substrate binding, and filamentous polymerisation, remain inadequately characterised. Pharmacologic inhibition of tankyrase (TNKSi) prevents Wnt/β-catenin signalling in a subset of colorectal cancer cells and animal models but can be associated with intestinal toxicity. A lack of understanding regarding the biomarkers and complex molecular impacts produced by TNKSi impedes further therapeutic development. This highlights the need to understand the molecular mechanisms governing tankyrase regulation and function.
Here, CRISPR-driven base editor screens are established and employed to identify missense mutations in tankyrase that disrupt Wnt/β-catenin signalling and reduce cell fitness. Using a fluorescence-based Wnt/β-catenin reporter and cell fitness as readouts, clusters of mutations in various tankyrase domains were identified to impair β-catenin signalling, revealing novel regulatory mechanisms. By overlaying these findings with quantitative mass-spectrometry and a protein interaction screen on a peptide matrix (PRISMA), mutation sites are associated to the stabilisation of specific tankyrase substrates and cellular interactors, including a phosphorylation site for Polo-like kinase 1 (PLK1). In vitro PLK1 can phosphorylate tankyrase at two sites that are important for β-catenin signalling. This integrated approach combines high-resolution genomics and proteomics to uncover novel tankyrase regulatory mechanisms and candidate regulators across different biological contexts
Geometric deep learning and multiple-instance learning for 3D cell-shape profiling.
No full textThe three-dimensional (3D) morphology of cells emerges from complex cellular and environmental interactions, serving as an indicator of cell state and function. In this study, we used deep learning to discover morphology representations and understand cell states. This study introduced MorphoMIL, a computational pipeline combining geometric deep learning and attention-based multiple-instance learning to profile 3D cell and nuclear shapes. We used 3D point-cloud input and captured morphological signatures at single-cell and population levels, accounting for phenotypic heterogeneity. We applied these methods to over 95,000 melanoma cells treated with clinically relevant and cytoskeleton-modulating chemical and genetic perturbations. The pipeline accurately predicted drug perturbations and cell states. Our framework revealed subtle morphological changes associated with perturbations, key shapes correlating with signaling activity, and interpretable insights into cell-state heterogeneity. MorphoMIL demonstrated superior performance and generalized across diverse datasets, paving the way for scalable, high-throughput morphological profiling in drug discovery. A record of this paper's transparent peer review process is included in the supplemental information
PBRM1 directs PBAF to pericentromeres and protects centromere integrity.
No full textThe specialised structure of the centromere is critical for effective chromosome segregation, but its repetitive nature makes it vulnerable to rearrangements. Centromere fragility can drive tumorigenesis, but protective mechanisms preventing fragility are still not fully understood. The PBAF chromatin remodelling complex is frequently misregulated in cancer, but its role in cancer is incompletely characterized. Here, we identify PBAF as a protector of centromere and pericentromere structure with profound consequences for genome stability. A conserved feature of isogenic cell lines lacking PBRM1, a subunit of PBAF, is compromised centromere and pericentromere integrity. PBAF is present at these regions, and binding patterns of PBAF and H3K9 methylation change when PBRM1 is absent. PBRM1 loss creates a dependence on the spindle assembly checkpoint, which represents a therapeutic vulnerability. Importantly, we find that even in the absence of any perturbations, PBRM1 loss leads to centromere fragility, thus identifying a key player in centromere protection