5728 research outputs found
Sort by
Mendelian randomization of immune cell phenotypes to discover potential drug targets for B-cell malignancy.
No full textAlthough treatment options for B-cell malignancies have expanded, many patients continue to face limited response rates, highlighting an urgent need for new therapeutic targets. To prioritize candidate drug targets for B-cell malignancies, we employed Mendelian Randomization to estimate potentially causal relationships between 445 immune cell traits and six B-cell cancers: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), totaling 22,922 cases and 394,204 controls. 163 traits showed a suggestive association with at least one B-cell malignancy (P < 0.05), with 34 traits being significant after correction for multiple testing (P < 2 × 10-4). By integrating findings with observational data and clinical trial evidence to support drug target candidacy, 24 cell surface markers were identified as druggable targets. In addition to established therapeutic targets such as CD3, CD20 and CD38, our analysis highlights BAFF-R and CD39 in HL, CD25 in MM, CD27 in CLL, CD80/86 in DLBCL, and CCR2 in FL and MZL as promising candidates for therapeutic inhibition. Our findings provide further support for the potential of human genetics to guide the identification of drug targets and address a productivity-limiting step
The development of an in silico imaging pipeline for the simulation and deep learning-based tumour segmentation of spectral photon-counting CT brain images
No full textPhoton-counting CT (PCCT) is an emerging technology employing photon-counting detectors instead of the energy-integrating detectors (EIDs) used in conventional CT. Previous studies have shown benefits of PCCT for neuroimaging, including improved contrast to noise ratio (CNR) and soft tissue contrast. The impact of these advancements on radiotherapy treatment planning is currently unclear and the unmet need this work aims to address. The increased soft tissue contrast makes PCCT a promising candidate for a single-modality approach in stereotactic radiosurgery (SRS). Current clinical practice relies on an MRI scan for soft tissue differentiation in addition to the conventional CT required for dose calculation, however PCCT could achieve both aims with a single scan. This work assesses the feasibility of using PCCT for tumour delineation in SRS.
Recent studies have also shown the benefit of deep learning-based tumour segmentation for treatment planning as opposed to manual delineation. Therefore, the potential of using PCCT as single modality in combination with deep learning for SRS treatment planning is evaluated. An in-silico imaging pipeline is developed simulating PCCT brain images based on computational phantoms derived from clinical data. The images are used as input to a deep learning model for tumour segmentation.
The results demonstrate improved CNR within the tumour region on the PCCT images compared to their EID counterparts, showing the potential of a single-modality approach. Moreover, PCCT image quality was more robust towards an increase in electronic noise. Automatic tumour segmentation on the simulated images is feasible, but a larger number of patients is required to determine the impact of the improved image quality on segmentation performance.
The developed in-silico pipeline is of great benefit to the research community, as it offers a cost- and time-effective way to evaluate feasibility and methodologies of research studies on the implementation of PCCT in neuro-oncology and beyond
SPIRIT-DEFINE explanation and elaboration: recommendations for enhancing quality and impact of early phase dose-finding clinical trials protocols.
No full textUNLABELLED: Transparent and accurate reporting in early phase dose-finding (EPDF) clinical trials is crucial for informing subsequent larger trials. The SPIRIT statement, designed for trial protocol content, does not adequately cover the distinctive features of EPDF trials. Recent findings indicate that the protocol contents in past EPDF trials frequently lacked completeness and clarity. To address this gap, the international consensus-driven SPIRIT-DEFINE checklist was developed through a robust methodological framework for guideline development, with the aim to improve completeness and clarity in EPDF trial protocols. The checklist builds on the SPIRIT statement, adding 17 new items and modifying 15 existing ones.The SPIRIT-DEFINE explanation and elaboration (E&E) document provides comprehensive information to enhance understanding and usability of the SPIRIT-DEFINE checklist when writing an EPDF trial protocol. Each new or modified checklist item is accompanied by a detailed description, its rationale with supportive evidence, and examples of good reporting curated from EPDF trial protocols covering a range of therapeutic areas and interventions. We recommend utilising this paper alongside the SPIRIT statement, and any relevant extensions, to enhance the development and review of EPDF trial protocols.By facilitating adoption of the SPIRIT-DEFINE statement for EPDF trials, this E&E document can promote enhancement of methodological rigour, patient safety, transparency, and facilitate the generation of high-quality, reproducible evidence that will strengthen the foundation of early phase research and ultimately improve patient outcomes. FUNDING: This work is a further extension of the SPIRIT-DEFINE study, which obtained no external funding. The principal investigator (CY) used internal staff resources, together with additional resources from external partners, to conduct this study. The SPIRIT-DEFINE study is a component of the DEFINE project, which also developed the MRC/NIHR funded CONSORT-DEFINE guidance. ICR-CTSU receives programmatic infrastructure funding from Cancer Research UK (C1491/A25351; CTUQQR-Dec22/100004), which has contributed to accelerating the advancement and successful completion of this work
Genomic landscape of diffuse glioma revealed by whole genome sequencing.
No full textDiffuse gliomas are the commonest malignant primary brain tumour in adults. Herein, we present analysis of the genomic landscape of adult glioma, by whole genome sequencing of 403 tumours (256 glioblastoma, 89 astrocytoma, 58 oligodendroglioma; 338 primary, 65 recurrence). We identify an extended catalogue of recurrent coding and non-coding genetic mutations that represents a source for future studies and provides a high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and extrachromosomal DNA. Finally, we relate these to clinical outcome. As well as identifying drug targets for treatment of glioma our findings offer the prospect of improving treatment allocation with established targeted therapies
Investigating Hypoxia and the Potential for Atovaquone in Rhabdomyosarcoma
No full textRhabdomyosarcomas (RMS) are rare aggressive childhood cancers with particularly poor prognosis at relapse. Hypoxia is a negative prognostic factor in cancer and is associated with cancer progression and resistance to radio- and chemotherapy. Hypoxia in RMS remains relatively unexplored. This project is aimed to assess the effect of hypoxia on RMS patient outcomes and test a novel therapeutic strategy based on hypoxia alleviation in RMS. To confirm the presence of hypoxia and assess blood vessel distribution, 40 diagnostic RMS samples were stained for hypoxia and endothelial cells. Hypoxia was present in more than half of the samples, and the location of hypoxia in relation to blood vessels was consistent with a diffusion-limited pattern of hypoxia. To evaluate the clinical relevance of hypoxia, a hypoxia gene signature was assessed in two RMS patient gene expression datasets. Overexpression of the signature significantly correlated with poorer patient outcomes in fusion negative RMS. To characterise the effect of hypoxia on chemotherapy response, eight RMS cell lines cultured in 2D were treated with vincristine and irinotecan, drugs used at relapse, under controlled oxygen conditions. This revealed a marked resistance to irinotecan in hypoxia. Atovaquone, an antimalarial being investigated for cancer treatment, was shown to alleviate hypoxia in 3D cultures of RMS cells. Combining atovaquone with irinotecan in these 3D cultures demonstrated potential therapeutic benefit and a variable but predominantly additive response in a panel of six RMS cell lines and an RMS patient-derived xenograft (PDX) cell culture. Cell lines that were most sensitive to the combination had higher levels of DNA damage with treatment compared to less sensitive cell lines. Lastly, it was shown that atovaquone inhibits RMS cell migration and that this effect may be associated with changes in actin fibres. This research underscores the role of hypoxia in influencing RMS patient outcomes and resistance to irinotecan. It also demonstrates the clinical potential of atovaquone, as a chemosensitiser and migration inhibitor, and that optimal response depends on multiple factors, including hypoxia
Mimicking women's endocrine milieu in mice for women's health-related studies.
No full textTo improve preclinical studies and their translation, patient-derived xenografts (PDXs) are increasingly used. They have human-specific tumor characteristics and reflect intra and inter-tumor heterogeneity. However, the endocrine milieu differs between humans and host mice. In light of sex-specific cancer biology and a rise in endocrine-related cancers there is an urgent need to correctly reflect the hormonal milieu in PDX models. We show that female mice of NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) strain widely used for PDXs has 17-β-estradiol (E2) and testosterone (T) levels comparable to C57Bl6 females but higher progesterone (P4) levels. E2 levels are comparable, T levels are lower and P4 levels higher than those observed in postmenopausal women. Ovariectomy increases T to levels observed in postmenopausal women. Subcutaneous E2 and combined E2/P4 silicon pellets provide NSG females with premenopausal ovarian hormone levels. These procedures humanize the endocrine environment of experimental animals, improving PDX relevance in women's health-related research
Developing therapeutic strategies to target MCL1 and BCLXL in lethal prostate cancer.
No full textTargeting anti-apoptotic BCL2 family proteins is an attractive therapeutic strategy to drive prostate cancer (PCa) cell death. Here, we show that MCL1 is highly expressed in castration-resistant PCa, associating with worse clinical outcome. We demonstrate that targeting MCL1 with BH3 mimetics triggers apoptotic cell death in a subset of PCa cell line models. Furthermore, siRNA targeting of UCHL3, a deubiquitinating enzyme, downregulates MCL1 expression to synergize with BCLXL blockade; however, its impact on MCL1 is driven through an off-target effect, raising an important methodological consideration when studying MCL1 biology. Finally, we demonstrate that co-targeting MCL1 and BCLXL in patient-derived and mouse PCa models drives apoptotic PCa cell death. Taken together, targeting the intrinsic apoptosis pathway remains an attractive therapeutic strategy for lethal PCa. Future studies should focus on identifying strategies and technologies that can deliver cancer specific kill, to improve the outcome for men with this lethal disease
The Effects of Hyperthermic Intraperitoneal Chemotherapy on the Peritoneal Microenvironment of High-Grade Serous Ovarian Cancer
No full textHyperthermic intraperitoneal chemotherapy (HIPEC) given at the time of interval cytoreductive surgery for high-grade serous ovarian
cancer (HGSOC) improves patient survival. The mechanism underlying this eBect has not been determined. Previous work has shown that
systemic chemotherapy alters the tumour microenvironment of HGSOC. To date, the eBect of HIPEC on the peritoneal microenvironment
has not been studied.
In this thesis, I assessed the eBects of HIPEC on the peritoneal microenvironment of HGSOC using human peritoneal samples obtained
pre and post HIPEC at the time of interval cytoreductive surgery.
I investigated immune cell population levels, intercellular distances and localisation to the peritoneal surface using
immunohistochemistry and multiplex imaging with the Cell DIVE platform. I used real-time tissue imaging and Imaris analysis to assess
the immune cell movement within the peritoneum pre and post HIPEC. Furthermore, I evaluated the changes in the extracellular matrix
with Masson’s Trichome staining and TWOMBLI analysis, and cytokine alterations using Meso Scale Discovery assays following HIPEC.
I found no change in immune cell levels following HIPEC, but Cell DIVE analysis showed that immune cells moved closer to the peritoneal
surface, with reduced intercellular distances, after HIPEC. This change in tissue localisation was particularly noticeable for CD68+
macrophages and CD8+ T cells. Real-time imaging analysis demonstrated that CD14+ macrophages and CD8+ T cells moved significantly
faster, further and straighter post HIPEC. There was no change in collagen architecture, collagen percentage or fibronectin percentage
after HIPEC. HIPEC, however, significantly upregulated predominantly pro-inflammatory cytokines.
I conclude that the alterations in immune cell location and movement after HIPEC may be explained by the modulation of cytokine
networks in the peritoneal tissue
Variation within and between digital pathology and light microscopy for the diagnosis of histopathology slides: blinded crossover comparison study.
No full textBACKGROUND: Digital pathology refers to the conversion of histopathology slides to digital image files for examination on computer workstations as opposed to conventional microscopes. Prior to adoption, it is important to demonstrate pathologists provide equivalent reports when using digital pathology in comparison to bright-field and immunofluorescent light microscopy, the current standard of care. OBJECTIVE: A multicentre comparison of digital pathology with light microscopy for reporting of histopathology slides, measuring variation within and between pathologists on both modalities. DESIGN: A blinded crossover 2000-case study estimating clinical management concordance (identical diagnoses plus differences not affecting patient management). Each sample was assessed twice by four pathologists (once using light microscopy, once using digital pathology, the order randomly assigned and a 6-week gap between viewings). Random-effects logistic regression models, including crossed random-effects terms for case and pathologist, estimated percentage clinical management concordance. Findings were interpreted with reference to 98.3% concordance (Azam AS, Miligy IM, Kimani PKU, Maqbool H, Hewitt K, Rajpoot NM, Snead DRJ. Diagnostic concordance and discordance in digital pathology: a systematic review and meta-analysis. J Clin Pathol 2021;74:448-55. https://doi.org/10.1136/jclinpath-2020-206764). SETTING: Sixteen consultant pathologists, four for each specialty, from six National Health Service laboratories. Experience ranged from 3 to 35 years. Some were early adopters of digital pathology, but the majority were new to digital pathology. INTERVENTIONS: Eight viewings per sample (four pathologists with light microscopy and with digital pathology), culminating in a consensus ground truth, enabling measurement of agreement within and between readers. Samples enrolled reflected routine practice, included cancer screening biopsies, and were enriched for areas of difficulty [e.g. dysplasia (7, 10, 11)]. State-of-the-art digital pathology equipment designed for diagnosis, and holding either Conformité Européene or Food and Drug Administration approval, was used. MAIN OUTCOME: Intra-pathologist variation between reports issued on digital pathology and light microscopy, inter-pathologist variation against ground-truth diagnosis using light microscopy and digital pathology. SECONDARY OUTCOMES: Pathologist-recorded reporting times, along with their confidence in diagnosis, analysis of eye-tracking evaluating examination techniques, and a qualitative study examining attitudes of pathologists and laboratory staff to digital pathology adoption. RESULTS: Two thousand and twenty-four cases (608 breast, 607 gastrointestinal, 609 skin, 200 renal) were recruited, with breast and gastrointestinal including screening samples [207 (34%) breast, 250 (41%) gastrointestinal]. Overall, in light microscopy versus digital pathology comparisons, clinical management concordance levels were 99.95% (95% confidence interval 99.91 to 99.97). Similar results were observed within specialties [breast: 99.40% (95% confidence interval 99.06 to 99.62); gastrointestinal 99.96% (95% confidence interval 99.89 to 99.99); skin 99.99% (95% confidence interval 99.92 to 100.0); renal 99.99% (95% confidence interval 99.57 to 100.0)], and within screening cases [98.96% (95% confidence interval 98.42 to 99.32), breast 96.27% (94.63 to 97.43), gastrointestinal 99.93% (95% confidence interval 99.68 to 99.98)]. Reporting time between digital pathology and light microscopy was similar, but pathologists became faster on digital pathology with familiarity. Pathologists recorded high levels of confidence in their diagnosis with light microscopy, significantly higher than digital pathology. LIMITATIONS: Cytology cases and specialty groups outside those tested were not examined. The study used two digital pathology scanning systems. Other systems available on the market were not tested. CONCLUSIONS: Clinical management concordance levels between the two modalities exceed the reference 98.3% in breast, gastrointestinal, skin and renal specialties, and pooled breast and large bowel cancer screening cases. Subgroup analysis of clinically significant differences revealed a range of differences including areas where interobserver variability is known to be high, which were distributed between reads performed with both platforms and without apparent trends to either. FUTURE WORK: The use of digital pathology for cytology samples remains an area for further research. STUDY REGISTRATION: This study is registered as ISRCTN14513591. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/84/07) and is published in full in Health Technology Assessment; Vol. 29, No. 30. See the NIHR Funding and Awards website for further award information
BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress.
No full textBH3 mimetic drugs that inhibit BCL-2, BCL-XL, or MCL-1 have limited activity in solid tumors. Through assessment of xenograft-derived 3D prostate cancer models and cell lines we find that tumors with RB1 loss are sensitive to BCL-XL inhibition. In parallel, drug screening demonstrates that disruption of nucleotide pools by agents including thymidylate synthase inhibitors sensitizes to BCL-XL inhibition, together indicating that replication stress increases dependence on BCL-XL. Mechanistically we establish that replication stress sensitizes to BCL-XL inhibition through TP53/CDKN1A-dependent suppression of BIRC5 expression. Therapy with a BCL-2/BCL-XL inhibitor (navitoclax) in combination with thymidylate synthase inhibitors (raltitrexed or capecitabine) causes marked and prolonged tumor regression in prostate and breast cancer xenograft models. These findings indicate that BCL-XL inhibitors may be effective as single agents in a subset of solid tumors with RB1 loss, and that pharmacological induction of replication stress may be a broadly applicable approach for sensitizing to BCL-XL inhibitors