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Photodynamic Diagnosis-guided Transurethral Resection of Bladder Tumour in Participants with a First Suspected Diagnosis of Intermediate- or High-risk Non-muscle-invasive Bladder Cancer: Cost-effectiveness Analysis Alongside a Randomised Controlled Trial.
No full textBACKGROUND: Recurrence of non-muscle-invasive bladder cancer (NMIBC) is common after transurethral resection of bladder tumour (TURBT). Photodynamic diagnosis (PDD) may reduce recurrence. PDD uses a photosensitiser in the bladder that causes the tumour to fluoresce to guide resection. PDD provides better diagnostic accuracy and allows more complete tumour resection. OBJECTIVE: To estimate the economic efficiency of PDD-guided TURBT (PDD-TURBT) in comparison to white light-guided TURNT (WL-TURBT) in individuals with a suspected first diagnosis of NMIBC at intermediate or high risk of recurrence on the basis of routine visual assessment before being scheduled for TURBT. DESIGN SETTING AND PARTICIPANTS: This is a health economic evaluation alongside a pragmatic, open-label, parallel-group randomised trial from a societal perspective. A total of 493 participants (aged ≥16 yr) were randomly allocated to PDD-TURBT (n = 244) or WL-TURBT (n = 249) in 22 UK National Health Service hospitals. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cost effectiveness ratios were based on the use of health care resources associated with PDD-TURBT and WL-TURBT and quality-adjusted life years (QALYs) gained within the trial. Uncertainties in key parameters were assessed using sensitivity analyses. RESULTS AND LIMITATIONS: On the basis of the use of resources driven by the trial protocol, the incremental cost effectiveness of PDD-TURBT in comparison to WL-TURBT was not cost saving. At 3 yr, the total cost was £12 881 for PDD-TURBT and £12 005 for WL-TURBT. QALYs at three years were 2.087 for PDD-TURBT and 2.094 for WL-TURBT. The probability that PDD-TURBT is cost effective was never >30% above the range of societal cost-effectiveness thresholds. CONCLUSIONS: There was no evidence of a difference in either costs or QALYs over 3-yr follow-up between PDD-TURBT and WL-TURBT in individuals with suspected intermediate- or high-risk NMIBC. PDD-TURBT is not supported for the management of primary intermediate- or high-risk NMIBC. PATIENT SUMMARY: We assessed overall costs for two approaches for removal of bladder tumours in noninvasive cancer and measured quality-adjusted life years gained for each. We found that use of a photosensitiser in the bladder was not more cost effective than use of white light only during tumour removal
Systems biology of the motif-mediated cell cycle interactome
No full textThe eukaryotic cell cycle is a tightly controlled series of events leading to cell division. It relies on a complex network of regulatory proteins, serving as checkpoints to oversee DNA replication and ensure orderly cell division. Disruption of this system can lead to uncontrolled cell growth, as seen in diseases like cancer. Cell cycle regulation occurs at multiple levels yet largely depends on protein and phosphorylation abundance dynamics. Protein abundance is defined by the balance between transcription and protein degradation at different cycle stages. Whereas, kinases and phosphatases manage protein phosphorylation, further modulating cell cycle progression.
The primary objective of this project is to study the spatiotemporal dynamics of the cell cycle machinery. To achieve this goal, cell cycle analysis methods have been developed and applied to create a high-confidence dataset of proteins and phosphorylation sites oscillating in a cell cycle-dependent manner. These data were integrated with available information on protein, phosphorylation site, and mRNA abundance, and enriched with complementary annotations of protein half-life, localisation, cancer dependency, complexes, and interaction interfaces. This comprehensive approach aims to link cell cycle-dependent abundance dynamics to functional changes, illuminating the biological role of oscillating proteins and phosphorylation events. An online database, Cell Cycle Database (CCdb), has been created to disseminate this data, providing an in-depth resource for the cell cycle community.
Next, I focussed on characterising the short linear motifs (SLiMs)-based interactome of the cell cycle. SLiMs are short peptides that mediate transient and low affinity protein-protein interactions. SLiMs are particularly crucial for cell cycle progression, and the functions of most cell cycle regulators are coordinated directly or indirectly through SLiMs. A motif specificity comparison method has been developed and applied to create two novel tools: CompariPSSM, which quantifies the similarity between motifs binding determinants, and SLiMScan, which searches with motifs binding determinants to discover uncharacterised SLiMs. These tools were applied to discover cell cycle state-specific motif-mediated interactions, cell cycle motifs, and the mechanisms that control the conditionality of these motifs on a proteome-wide scale
Using Mendelian Randomisation to search for modifiable risk factors influencing the development of clonal haematopoiesis.
No full textDNA-PK controls Apollo's access to leading-end telomeres.
No full textThe complex formed by Ku70/80 and DNA-PKcs (DNA-PK) promotes the synapsis and the joining of double strand breaks (DSBs) during canonical non-homologous end joining (c-NHEJ). In c-NHEJ during V(D)J recombination, DNA-PK promotes the processing of the ends and the opening of the DNA hairpins by recruiting and/or activating the nuclease Artemis/DCLRE1C/SNM1C. Paradoxically, DNA-PK is also required to prevent the fusions of newly replicated leading-end telomeres. Here, we describe the role for DNA-PK in controlling Apollo/DCLRE1B/SNM1B, the nuclease that resects leading-end telomeres. We show that the telomeric function of Apollo requires DNA-PKcs's kinase activity and the binding of Apollo to DNA-PK. Furthermore, AlphaFold-Multimer predicts that Apollo's nuclease domain has extensive additional interactions with DNA-PKcs, and comparison to the cryo-EM structure of Artemis bound to DNA-PK phosphorylated on the ABCDE/Thr2609 cluster suggests that DNA-PK can similarly grant Apollo access to the DNA end. In agreement, the telomeric function of DNA-PK requires the ABCDE/Thr2609 cluster. These data reveal that resection of leading-end telomeres is regulated by DNA-PK through its binding to Apollo and its (auto)phosphorylation-dependent positioning of Apollo at the DNA end, analogous but not identical to DNA-PK dependent regulation of Artemis at hairpins
Association between endocrine adjuvant therapy intake timing and disease-free survival in patients with high-risk early breast cancer: results of a sub-study of the UCBG- UNIRAD trial.
No full textBACKGROUND: Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271). METHODS: 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), or 24:00-05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here. FINDINGS: ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n = 465, 54.4%) or afternoon (n = 45, 5.4%) ET intake were older than those declaring evening (n = 339, 39.6%) or nighttime (n = 5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n = 30) or metastasis relapse (n = 84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR = 0.77, 95% CI [0.53-1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR = 0.43, 95% CI [0.22-0.85]), while no association was found for AI intake (HR = 1.07, 95% CI [0.68-1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR = 0.38 [0.16-0.91]). INTERPRETATION: Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies. FUNDING: UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis
Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
No full textTumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets
A preclinical model to investigate the role of surgically-induced inflammation in tumor responses to intraoperative photodynamic therapy.
No full textOBJECTIVE: Inflammation is a well-known consequence of surgery. Although surgical debulking of tumor is beneficial to patients, the onset of inflammation in injured tissue may impede the success of adjuvant therapies. One marker for postoperative inflammation is IL-6, which is released as a consequence of surgical injuries. IL-6 is predictive of response to many cancer therapies, and it is linked to various molecular and cellular resistance mechanisms. The purpose of this study was to establish a murine model by which therapeutic responses to photodynamic therapy (PDT) can be studied in the context of surgical inflammation. MATERIALS AND METHODS: Murine models with AB12 mesothelioma tumors were treated with either surgical resection or sham surgery with tumor incision but no resection. The timing and extent of IL-6 release in the tumor and/or serum was measured using enzyme-linked immunosorbent assay (ELISA) and compared to that measured in the serum of 27 consecutive, prospectively enrolled patients with malignant pleural mesothelioma (MPM) who underwent macroscopic complete resection (MCR). RESULTS: MPM patients showed a significant increase in IL-6 at the time MCR was completed. Similarly, IL-6 increased in the tumor and serum of mice treated with surgical resections. However, investigations that combine resection with another therapy make it necessary to grow tumors for resection to a larger volume than those that receive secondary therapy alone. As the larger size may alter tumor biology independent of the effects of surgical injury, we assessed the tumor incision model. In this model, tumor levels of IL-6 significantly increased after tumor incision. CONCLUSION: The tumor incision model induces IL-6 release as is seen in the surgical setting, yet it avoids the limitations of surgical resection models. Potential mechanisms by which surgical induction of inflammation and IL-6 could alter the nature and efficacy of tumor response to PDT are reviewed. These include a wide spectrum of molecular and cellular mechanisms through which surgically-induced IL-6 could change the effectiveness of therapies that are combined with surgery. The tumor incision model can be employed for novel investigations of the effects of surgically-induced, acute inflammation on therapeutic response to PDT (or potentially other therapies). Lasers Surg. Med. 50:440-450, 2018. © 2018 Wiley Periodicals, Inc
Prediction of lymph node metastases using immunohistochemical analysis of primary oral tongue squamous cell carcinomas
No full textWe studied archival tissue samples of oral tongue squamous cell carcinoma (OTSCC) for the expression of genes that have been identified, by cDNA microarray studies and previous studies, to be highly discriminatory for lymph node spread. We performed immunohistochemistry on samples from 186 patients with squamous cell carcinoma using the following antibodies: CD44V9, COL5A1, DSG3, FAS, FTH1, IL22RA1, Ivl, KIF2A, Laminin 5, Llgl2, MMP8, MRP2, ODC1, P4HA1, P16, P53, S100a9, SRP19, and VEGF A.
VEGF expression, in the periphery of a tumour, predicted worse overall survival (60 vs 80% 5-year survival p=0.001). SRP19 expression in the centre (56% vs 78% 5-year survival p = 0.004) and periphery of tumour (60% vs 78% 5-year survival p = 0.015) predicted significantly worse overall survival.
VEGF and MMP8 positivity, in the periphery of a tumour, and P4HA1 negativity, in the centre of a tumour, were associated with lymph node metastases.
We constructed a logistic regression model which is far superior to the standard model of using tumour thickness above 5mm to decide on a neck dissection. It incorporates VEGF peripheral cores (+), P4HA1 central cores (-), MMP8 peripheral (+) and tumour thickness (Amen signature) to provide overall accuracy of prediction of 69.1% vs 58.1% for tumour thickness alone in the full sample. Combining our antibody predictors with tumour thickness increases accuracy to 69.1% from 65.7% using the three antibodies alone.
The superiority is particularly pronounced when comparing our signature’s accuracy of 73.0% in positive prediction of metastasis compared with tumour thickness of greater than 5mm with 53.2% accuracy in predicting metastasis. The use of the traditional tumour thickness predictor would result in an unnecessary neck dissection in 46.5% of patients, predicted to have nodal metastasis, vs 27.0% using the Amen signature
ELM-the Eukaryotic Linear Motif resource-2024 update.
No full textShort Linear Motifs (SLiMs) are the smallest structural and functional components of modular eukaryotic proteins. They are also the most abundant, especially when considering post-translational modifications. As well as being found throughout the cell as part of regulatory processes, SLiMs are extensively mimicked by intracellular pathogens. At the heart of the Eukaryotic Linear Motif (ELM) Resource is a representative (not comprehensive) database. The ELM entries are created by a growing community of skilled annotators and provide an introduction to linear motif functionality for biomedical researchers. The 2024 ELM update includes 346 novel motif instances in areas ranging from innate immunity to both protein and RNA degradation systems. In total, 39 classes of newly annotated motifs have been added, and another 17 existing entries have been updated in the database. The 2024 ELM release now includes 356 motif classes incorporating 4283 individual motif instances manually curated from 4274 scientific publications and including >700 links to experimentally determined 3D structures. In a recent development, the InterPro protein module resource now also includes ELM data. ELM is available at: http://elm.eu.org