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  • Protocol to study the inheritance and propagation of non-genetically encoded states using barcode decay lineage tracing

    Shlyakhtina, Yelyzaveta; Bloechl, Bloechl; Moran, Katherine L; Portal, Maximiliano M; Cell Plasticity & Epigenetics Lab, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK; (2024)
    Here, we present a protocol to perform barcode decay lineage tracing followed by single-cell transcriptome analysis (BdLT-Seq). We describe steps for BdLT-Seq experimental design, building barcoded episome reporters, performing episome transfection, and barcode retrieval. We then describe procedures for sequencing library construction while providing options for sample multiplexing and data analysis. This BdLT-Seq technique enables the assessment of clonal evolution in a directional manner while preserving isogeneity, thus allowing the comparison of non-genetic molecular features between isogenic cell lineages. For complete details on the use and execution of this protocol, please refer to Shlyakhtina et al. (2023).(1).
  • Scavenging of cation radicals of the visual cycle retinoids by lutein, zeaxanthin, taurine, and melanin

    Rozanowska, M.; Edge, R.; Land, Edward J; Navaratnam, S.; Sarna, T.; Truscott, T. G.; The Paterson Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. (2023)
    In the retina, retinoids involved in vision are under constant threat of oxidation, and their oxidation products exhibit deleterious properties. Using pulse radiolysis, this study determined that the bimolecular rate constants of scavenging cation radicals of retinoids by taurine are smaller than 2 x 10(7) M(-1)s(-1) whereas lutein scavenges cation radicals of all three retinoids with the bimolecular rate constants approach the diffusion-controlled limits, while zeaxanthin is only 1.4-1.6-fold less effective. Despite that lutein exhibits greater scavenging rate constants of retinoid cation radicals than other antioxidants, the greater concentrations of ascorbate in the retina suggest that ascorbate may be the main protectant of all visual cycle retinoids from oxidative degradation, while alpha-tocopherol may play a substantial role in the protection of retinaldehyde but is relatively inefficient in the protection of retinol or retinyl palmitate. While the protection of retinoids by lutein and zeaxanthin appears inefficient in the retinal periphery, it can be quite substantial in the macula. Although the determined rate constants of scavenging the cation radicals of retinol and retinaldehyde by dopa-melanin are relatively small, the high concentration of melanin in the RPE melanosomes suggests they can be scavenged if they are in proximity to melanin-containing pigment granules.
  • Precision medicine for childhood cancer: current limitations and future perspectives

    McCabe, Martin G; Geoerger, B.; Chesler, L.; Hargrave, D.; Parsons, D. W.; van Tilburg, C. M.; Schleiermacher, G.; Hickman, J. A.; George, S. L.; Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom. (2024)
    Greater collaboration needed to realize potential of molecular profiling initiatives for pediatric cancers.
  • Frequency of naevus cells in lymph nodes of melanoma and breast cancer patients

    Green, Adele C; Mundra, Piyushkumar A; Grant, Megan; Marais, Richard; Cook, Martin G; Molecular Oncology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK (2024)
    INTRODUCTION: We aimed to study the frequency (prevalence) and histology of benign melanocytic naevus cells in regional lymph nodes in relation to age and sex and nodal location. MATERIAL AND METHODS: Histopathology reports of sentinel lymph node (SLN) biopsies from melanoma patients, 2002 - 2014, and from breast cancer patients, 2010- 2019, were obtained from records of a single hospital in England. All sections were similarly processed and examined. For standardisation, presence of naevus cells was assessed in a single node per patient: the first SLN biopsied (melanoma) or the node nearest the first SLN (breast cancer). RESULTS: Associations were tested using Fisher's exact test. Naevus cells were found in 10% (60/585) of melanoma patients' index SLNs. Frequency varied significantly by anatomic region: 13% in axillary to 0% cervical SLNs (p = 0.03), but not by sex or age. Within nodes, naevus cells were present in capsular or pericapsular tissue (93%), or trabeculae (7%). In breast cancer patients' index axillary nodes, 6% (11/196) contained naevus cells, all intracapsular. In the predominant 40-69 years age-group, prevalence was similar in breast cancer (7%) and female melanoma (9%) patients, but in those aged 70-100, prevalence was lower in breast cancer (2%) than in female melanoma (15%) patients (p = 0.05). CONCLUSIONS: Standard methods of assessment yielded no clear pattern of naevus cell frequency in lymph nodes by age or sex, but confirmed naevus cell location as mostly intracapsular.
  • Gradual and synergistic correlation of tumor thickness and histological grade in penile invasive carcinomas

    Alvarado-Cabrero, I.; Fernández-Nestosa, M. J.; Valencia-Cedillo, R.; Urizar, C.; Cañete-Portillo, S.; Sánchez, D. F.; Cubilla, Antonio L; Cancer Research UK Manchester Institute, University of Manchester, Manchester Cancer Research Centre, Manchester, M20 4GJ, UK. (2024)
    Histological grade and depth of invasion are among the best outcome pathological predictors in penile cancer. The TNM system is based on a combination of both for some stages. It is assumed that high-grade and deep tumors carry the worst prognosis, and the opposite occurs with superficial and low-grade neoplasms. However, there is no systematic evaluation of the phenomenon. We studied 147 patients from the Hospital de Oncologia - Instituto Mexicano del Seguro Social (period 2000 to 2013). They were treated by total or partial penectomies. Lymph node involvement was evaluated by bilateral inguinal node dissection (126 cases) or ultrasonography (21 cases). Tumor thickness was measured in mm from tumor surface to deepest invasion point, using a cut-point for superficial (≤10 mm) vs deep (>10 mm) tumors. Histological grade was from 1 to 3 according to WHO and AFIP criteria and considering G1 and G2 as low-grade and G3 as high-grade. Average age was 62 (26-98) years old. Tumor thickness mean was 15 mm (2-30 mm). G1, G2 and G3 tumors corresponded to 19 (13 %), 48 (33 %), and 80 (54 %) cases, respectively. Follow-up ranged from 10 to 82 months (median: 57 months). Fifty-three (36 %) patients died of disease. There was an overall correlation of tumor thickness and grade in most of the cases. Low-grade tumors were encountered in 92 % (12/13 cases) of superficial tumors. Deep tumors showed high-grade in 75 % of cases (73/97 cases). Superficial tumors with low histological grade had negative inguinal nodes and no mortality whereas deep tumors showing high histological grade were associated with high metastatic risk to lymph nodes (62/73 cases) and mortality (52/73 cases). Out of 24 deep tumors with low histological grade, seven had nodal spread (29 %) but only one died of disease. No outcome difference was found in HPV associated vs HPV independent tumors. Tumor thickness and grade are important synergistic and predictive pathological factors in relation to prognosis.
  • Linking African ancestral substructure to prostate cancer health disparities

    Gheybi, K.; Mmekwa, N.; Lebelo, M. T.; Patrick, S. M.; Campbell, R.; Nenzhelele, M.; Soh, P. X. Y.; Obida, M.; Loda, M.; Shirindi, J.; et al. (2023)
    Prostate cancer (PCa) is a significant health burden in Sub-Saharan Africa, with mortality rates loosely linked to African ancestry. Yet studies aimed at identifying contributing risk factors are lacking within the continent and as such exclude for significant ancestral diversity. Here, we investigate a series of epidemiological demographic and lifestyle risk factors for 1387 men recruited as part of the multi-ethnic Southern African Prostate Cancer Study (SAPCS). We found poverty to be a decisive factor for disease grade and age at diagnosis, with other notably significant PCa associated risk factors including sexually transmitted diseases, erectile dysfunction, gynaecomastia, and vertex or complete pattern balding. Aligned with African American data, Black ethnicity showed significant risk for PCa diagnosis (OR = 1.44, 95% CI 1.05-2.00), and aggressive disease presentation (ISUP ≥ 4: OR = 2.25, 95% CI   1.49-3.40). New to this study, we demonstrate African ancestral population substructure associated PCa disparity, observing increased risk for advanced disease for the southern African Tsonga people (ISUP ≥ 4: OR = 3.43, 95% CI   1.62-7.27). Conversely, South African Coloured were less likely to be diagnosed with aggressive disease overall (ISUP ≥ 3: OR = 0.38, 95% 0.17-0.85). Understanding the basis for PCa health disparities calls for African inclusion, however, lack of available data has limited the power to begin discussions. Here, focusing on arguably the largest study of its kind for the African continent, we draw attention to the contribution of within African ancestral diversity as a contributing factor to PCa health disparities within the genetically diverse region of southern Africa.
  • One versus three weeks hypofractionated whole breast radiotherapy for early breast cancer treatment: the FAST-Forward phase III RCT

    Brunt, A. M.; Haviland, J. S.; Wheatley, D. A.; Sydenham, M. A.; Bloomfield, D. J.; Chan, C.; Cleator, S.; Coles, C. E.; Donovan, E.; Fleming, H.; et al. (2023)
    BACKGROUND: FAST-Forward aimed to identify a 5-fraction schedule of adjuvant radiotherapy delivered in 1 week that was non-inferior in terms of local cancer control and as safe as the standard 15-fraction regimen after primary surgery for early breast cancer. Published acute toxicity and 5-year results are presented here with other aspects of the trial. DESIGN: Multicentre phase III non-inferiority trial. Patients with invasive carcinoma of the breast (pT1-3pN0-1M0) after breast conservation surgery or mastectomy randomised (1 : 1 : 1) to 40 Gy in 15 fractions (3 weeks), 27 Gy or 26 Gy in 5 fractions (1 week) whole breast/chest wall (Main Trial). Primary endpoint was ipsilateral breast tumour relapse; assuming 2% 5-year incidence for 40 Gy, non-inferiority pre-defined as < 1.6% excess for 5-fraction schedules (critical hazard ratio = 1.81). Normal tissue effects were assessed independently by clinicians, patients and photographs. SUB-STUDIES: Two acute skin toxicity sub-studies were undertaken to confirm safety of the test schedules. Primary endpoint was proportion of patients with grade ≥ 3 acute breast skin toxicity at any time from the start of radiotherapy to 4 weeks after completion. Nodal Sub-Study patients had breast/chest wall plus axillary radiotherapy testing the same three schedules, reduced to the 40 and 26 Gy groups on amendment, with the primary endpoint of 5-year patient-reported arm/hand swelling. LIMITATIONS: A sequential hypofractionated or simultaneous integrated boost has not been studied. PARTICIPANTS: Ninety-seven UK centres recruited 4096 patients (1361:40 Gy, 1367:27 Gy, 1368:26 Gy) into the Main Trial from November 2011 to June 2014. The Nodal Sub-Study recruited an additional 469 patients from 50 UK centres. One hundred and ninety and 162 Main Trial patients were included in the acute toxicity sub-studies. RESULTS: Acute toxicity sub-studies evaluable patients: (1) acute grade 3 Radiation Therapy Oncology Group toxicity reported in 40 Gy/15 fractions 6/44 (13.6%); 27 Gy/5 fractions 5/51 (9.8%); 26 Gy/5 fractions 3/52 (5.8%). (2) Grade 3 common toxicity criteria for adverse effects toxicity reported for one patient. At 71-month median follow-up in the Main Trial, 79 ipsilateral breast tumour relapse events (40 Gy: 31, 27 Gy: 27, 26 Gy: 21); hazard ratios (95% confidence interval) versus 40 Gy were 27 Gy: 0.86 (0.51 to 1.44), 26 Gy: 0.67 (0.38 to 1.16). With 2.1% (1.4 to 3.1) 5-year incidence ipsilateral breast tumour relapse after 40 Gy, estimated absolute differences versus 40 Gy (non-inferiority test) were -0.3% (-1.0-0.9) for 27 Gy (p = 0.0022) and -0.7% (-1.3-0.3) for 26 Gy (p = 0.00019). Five-year prevalence of any clinician-assessed moderate/marked breast normal tissue effects was 40 Gy: 98/986 (9.9%), 27 Gy: 155/1005 (15.4%), 26 Gy: 121/1020 (11.9%). Across all clinician assessments from 1 to 5 years, odds ratios versus 40 Gy were 1.55 (1.32 to 1.83; p < 0.0001) for 27 Gy and 1.12 (0.94-1.34; p = 0.20) for 26 Gy. Patient and photographic assessments showed higher normal tissue effects risk for 27 Gy versus 40 Gy but not for 26 Gy. Nodal Sub-Study reported no arm/hand swelling in 80% and 77% in 40 Gy and 26 Gy at baseline, and 73% and 76% at 24 months. The prevalence of moderate/marked arm/hand swelling at 24 months was 10% versus 7% for 40 Gy compared with 26 Gy. INTERPRETATION: Five-year local tumour incidence and normal tissue effects prevalence show 26 Gy in 5 fractions in 1 week is a safe and effective alternative to 40 Gy in 15 fractions for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. FUTURE WORK: Ten-year Main Trial follow-up is essential. Inclusion in hypofractionation meta-analysis ongoing. A future hypofractionated boost trial is strongly supported. TRIAL REGISTRATION: FAST-Forward was sponsored by The Institute of Cancer Research and was registered as ISRCTN19906132. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/01/47) and is published in full in Health Technology Assessment; Vol. 27, No. 25. See the NIHR Funding and Awards website for further award information.
  • Senescent cells in giant cell arteritis display an inflammatory phenotype participating in tissue injury via IL-6-dependent pathways

    Veroutis, D; Argyropoulou, OD; Goules, AV; Kambas, K; Palamidas, DA; Evangelou, K; Havaki, S; Polyzou, A; Valakos, D; Xingi, E; et al. (2023)
    OBJECTIVES: Age is the strongest risk factor of giant cell arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multimarker algorithm in temporal artery biopsies (TABs) of GCA patients. METHODS: 75(+) TABs from GCA patients, 22(-) TABs from polymyalgia rheumatica (PMR) patients and 10(-) TABs from non-GCA/non-PMR patients were retrospectively retrieved and analysed. Synovial tissue specimens from patients with inflammatory arthritis and aorta tissue were used as disease control samples. Senescent cells and their histological origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype by triple costaining. GCA or PMR artery culture supernatants were applied to fibroblasts, HUVECs and monocytes with or without IL-6R blocking agent to explore the induction of IL-6-associated cellular senescence. RESULTS: Senescent cells were present in GCA arteries at higher proportion compared with PMR (9.50% vs 2.66%, respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts, and macrophages while MMP-9 by senescent fibroblasts only. IL-6(+) senescent cells were associated with the extension of vascular inflammation (transmural inflammation vs adventitia limited disease: 10.02% vs 4.37%, respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6R blockade. CONCLUSIONS: Senescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk, suggesting a potential implication in disease pathogenesis.
  • Prostate cancer genetic risk and associated aggressive disease in men of African ancestry

    Soh, PXY; Mmekwa, N; Petersen, DC; Gheybi, K; van Zyl, S; Jiang, J; Patrick, SM; Campbell, R; Jaratlerdseri, W; Mutambirwa, SBA; et al. (2023)
    African ancestry is a significant risk factor for prostate cancer and advanced disease. Yet, genetic studies have largely been conducted outside the context of Sub-Saharan Africa, identifying 278 common risk variants contributing to a multiethnic polygenic risk score, with rare variants focused on a panel of roughly 20 pathogenic genes. Based on this knowledge, we are unable to determine polygenic risk or differentiate prostate cancer status interrogating whole genome data for 113 Black South African men. To further assess for potentially functional common and rare variant associations, here we interrogate 247,780 exomic variants for 798 Black South African men using a case versus control or aggressive versus non-aggressive study design. Notable genes of interest include HCP5, RFX6 and H3C1 for risk, and MKI67 and KLF5 for aggressive disease. Our study highlights the need for further inclusion across the African diaspora to establish African-relevant risk models aimed at reducing prostate cancer health disparities.
  • The ISMRM Open Science Initiative for Perfusion Imaging (OSIPI): Results from the OSIPI-Dynamic Contrast-Enhanced challenge

    Shalom, ES; Kim, H; van der Heijden, RA; Ahmed, Z; Patel, R; Hormuth, D A, 2nd; DiCarlo, J C; Yankeelov, T E; Sisco, N J; Dortch, R D; et al. (2023)
    PURPOSE: Ktrans has often been proposed as a quantitative imaging biomarker for diagnosis, prognosis, and treatment response assessment for various tumors. None of the many software tools for Ktrans quantification are standardized. The ISMRM Open Science Initiative for Perfusion Imaging-Dynamic Contrast-Enhanced (OSIPI-DCE) challenge was designed to benchmark methods to better help the efforts to standardize Ktrans measurement. METHODS: A framework was created to evaluate Ktrans values produced by DCE-MRI analysis pipelines to enable benchmarking. The perfusion MRI community was invited to apply their pipelines for Ktrans quantification in glioblastoma from clinical and synthetic patients. Submissions were required to include the entrants' Ktrans values, the applied software, and a standard operating procedure. These were evaluated using the proposed OSIPIgold score defined with accuracy, repeatability, and reproducibility components. RESULTS: Across the 10 received submissions, the OSIPIgold score ranged from 28% to 78% with a 59% median. The accuracy, repeatability, and reproducibility scores ranged from 0.54 to 0.92, 0.64 to 0.86, and 0.65 to 1.00, respectively (0-1 = lowest-highest). Manual arterial input function selection markedly affected the reproducibility and showed greater variability in Ktrans analysis than automated methods. Furthermore, provision of a detailed standard operating procedure was critical for higher reproducibility. CONCLUSIONS: This study reports results from the OSIPI-DCE challenge and highlights the high inter-software variability within Ktrans estimation, providing a framework for ongoing benchmarking against the scores presented. Through this challenge, the participating teams were ranked based on the performance of their software tools in the particular setting of this challenge. In a real-world clinical setting, many of these tools may perform differently with different benchmarking methodology.
  • Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial

    Cuzick, J.; Chu, K.; Keevil, B.; Brentnall, A. R.; Howell, Anthony; Zdenkowski, N.; Bonanni, B.; Loibl, S.; Holli, K.; Evans, D. G.; et al. (2024)
    BACKGROUND: An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. METHODS: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. FINDINGS: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]). INTERPRETATION: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. FUNDING: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.
  • Feasibility of dynamic T(2) *-based oxygen-enhanced lung MRI at 3T

    Kim, M.; Naish, J. H.; Needleman, S. H.; Tibiletti, M.; Taylor, Y.; O'Connor, James P B; Parker, G. J. M.; Division of Cancer Sciences, University of Manchester, Manchester, UK. (2024)
    PURPOSE: To demonstrate proof-of-concept of a T(2) *-sensitized oxygen-enhanced MRI (OE-MRI) method at 3T by assessing signal characteristics, repeatability, and reproducibility of dynamic lung OE-MRI metrics in healthy volunteers. METHODS: We performed sequence-specific simulations for protocol optimisation and acquired free-breathing OE-MRI data from 16 healthy subjects using a dual-echo RF-spoiled gradient echo approach at 3T across two institutions. Non-linear registration and tissue density correction were applied. Derived metrics included percent signal enhancement (PSE), ∆R(2) * and wash-in time normalized for breathing rate (τ-nBR). Inter-scanner reproducibility and intra-scanner repeatability were evaluated using intra-class correlation coefficient (ICC), repeatability coefficient, reproducibility coefficient, and Bland-Altman analysis. RESULTS: Simulations and experimental data show negative contrast upon oxygen inhalation, due to substantial dominance of ∆R(2) * at TE > 0.2 ms. Density correction improved signal fluctuations. Density-corrected mean PSE values, aligned with simulations, display TE-dependence, and an anterior-to-posterior PSE reduction trend at TE(1) . ∆R(2) * maps exhibit spatial heterogeneity in oxygen delivery, featuring anterior-to-posterior R(2) * increase. Mean T(2) * values across 32 scans were 0.68 and 0.62 ms for pre- and post-O(2) inhalation, respectively. Excellent or good agreement emerged from all intra-, inter-scanner and inter-rater variability tests for PSE and ∆R(2) *. However, ICC values for τ-nBR demonstrated limited agreement between repeated measures. CONCLUSION: Our results demonstrate the feasibility of a T(2) *-weighted method utilizing a dual-echo RF-spoiled gradient echo approach, simultaneously capturing PSE, ∆R(2) * changes, and oxygen wash-in during free-breathing. The excellent or good repeatability and reproducibility on intra- and inter-scanner PSE and ∆R(2) * suggest potential utility in multi-center clinical applications.
  • Multi-omic diagnostics of prostate cancer in the presence of benign prostatic hyperplasia

    Spick, M; Muazzam, Ammara; Pandha, H; Michael, A; Gethings, LA; Hughes, C J; Munjoma, N; Plumb, R S; Wilson, I D; Whetton, Anthony D; et al. (2023)
    There is an unmet need for improved diagnostic testing and risk prediction for cases of prostate cancer (PCa) to improve care and reduce overtreatment of indolent disease. Here we have analysed the serum proteome and lipidome of 262 study participants by liquid chromatography-mass spectrometry, including participants diagnosed with PCa, benign prostatic hyperplasia (BPH), or otherwise healthy volunteers, with the aim of improving biomarker specificity. Although a two-class machine learning model separated PCa from controls with sensitivity of 0.82 and specificity of 0.95, adding BPH resulted in a statistically significant decline in specificity for prostate cancer to 0.76, with half of BPH cases being misclassified by the model as PCa. A small number of biomarkers differentiating between BPH and prostate cancer were identified, including proteins in MAP Kinase pathways, as well as in lipids containing oleic acid; these may offer a route to greater specificity. These results highlight, however, that whilst there are opportunities for machine learning, these will only be achieved by use of appropriate training sets that include confounding comorbidities, especially when calculating the specificity of a test.
  • Clinical, histological, and molecular differences in melanoma due to different TERT promoter mutations subtypes. a retrospective cross-sectional study in 684 melanoma patients

    Manrique-Silva, E.; David, M. E.; Maider, A. M.; García-Casado, Z.; Moro, R.; Requena, C.; Través, V.; Virós, Amaya; Kumar, R.; Nagore, E.; et al. (2023)
    Differences in survival according to the pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT) have been observed. The present study aimed to describe the clinical as the histopathological and molecular cutaneous melanoma features according to the presence of the three most prevalent pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT). A retrospective cross-sectional study including 684 patients was designed, and a Partial Least-Squares Discriminant Analysis (PLS-DA) was performed. After the PSL-DA, it was observed that the tandem -138_139CC > TT subtype differs from the other subtypes. The model demonstrated that the -124C > T and the -138_139 CC > TT subtypes were associated with fast-growing melanomas (OR 0.5, CI 0.29-0.86, p = .012) and with Breslow >2 mm (OR 0.6, CI 0.37-0.97, p = .037), compared to the -146C > T mutation. Finally, the -124C > T appeared to be more associated with the presence of TILs (non-brisk) than the -146C > T (OR 0.6, CI 0.40-1.01, p = .05). These findings confirmed that the -124C > T and the tandem -138_139 CC > TT subtypes are both highly associated with the presence of features of aggressiveness; however, only the -124C > T was highly associated with TILs. This difference could explain the worse survival rate associated with the tandem -138_139CC > TT mutations.
  • POTEE promotes breast cancer cell malignancy by inducing invadopodia formation through the activation of SUMOylated Rac1

    Martínez-López, A.; García-Casas, A.; Infante, G.; González-Fernández, M.; Salvador, N.; Lorente, M.; Mendiburu-Eliçabe, M.; Gonzalez-Moreno, S.; Villarejo-Campos, P.; Velasco, G.; et al. (2023)
    The small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1) has been implicated in cancer progression and in the poor prognosis of various types of tumors. Rac1 SUMOylation occurs during epithelial-mesenchymal transition (EMT), and it is required for tumor cell migration and invasion. Here we identify POTEE (POTE Ankyrin domain family member E) as a novel Rac1-SUMO1 effector involved in breast cancer malignancy that controls invadopodium formation through the activation of Rac1-SUMO1. POTEE activates Rac1 in the invadopodium by recruiting TRIO-GEF (triple functional domain protein), and it induces tumor cell proliferation and metastasis in vitro and in vivo. We found that the co-localization of POTEE with Rac1 is correlated with more aggressive breast cancer subtypes. Given its role in tumor dissemination, the leading cause of cancer-related deaths, POTEE could represent a potential therapeutic target for these types of cancer.
  • Prostaglandin E₂ impacts multiple stages of the natural killer cell antitumor immune response

    Patterson, C.; Hazime, K. S.; Zelenay, S.; Davis, Daniel M; Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom. (2023)
    Tumor immune escape is a major factor contributing to cancer progression and unresponsiveness to cancer therapies. Tumors can produce prostaglandin E(2) (PGE(2) ), an inflammatory mediator that directly acts on Natural killer (NK) cells to inhibit antitumor immunity. However, precisely how PGE(2) influences NK cell tumor-restraining functions remains unclear. Here, we report that following PGE₂ treatment, human NK cells exhibited altered expression of specific activating receptors and a reduced ability to degranulate and kill cancer targets. Transcriptional analysis uncovered that PGE₂ also differentially modulated the expression of chemokine receptors by NK cells, inhibiting CXCR3 but increasing CXCR4. Consistent with this, PGE₂-treated NK cells exhibited decreased migration to CXCL10 but increased ability to migrate toward CXCL12. Using live cell imaging, we showed that in the presence of PGE(2) , NK cells were slower and less likely to kill cancer target cells following conjugation. Imaging the sequential stages of NK cell killing revealed that PGE₂ impaired NK cell polarization, but not the re-organization of synaptic actin or the release of perforin itself. Together, these findings demonstrate that PGE₂ affects multiple but select NK cell functions. Understanding how cancer cells subvert NK cells is necessary to more effectively harness the cancer-inhibitory function of NK cells in treatments.
  • Overweight-years and cancer risk: a prospective study of the association and comparison of predictive performance with body mass index (atherosclerosis risk in communities study)

    Hawwash, Nadin K; Sperrin, M.; Martin, G. P.; Joshu, C. E.; Florido, R.; Platz, E. A.; Renehan, A. G.; Cancer Research UK, Manchester Cancer Research Centre, Manchester, UK. (2023)
    Excess body mass index (BMI) is associated with a higher risk of at least 13 cancers, but it is usually measured at a single time point. We tested whether the overweight-years metric, which incorporates exposure time to BMI ≥25 kg/m(2) , is associated with cancer risk and compared this with a single BMI measure. We used adulthood BMI readings in the Atherosclerosis Risk in Communities (ARIC) study to derive the overweight-years metric. We calculated associations between the metric and BMI and the risk of cancers using Cox proportional hazards models. Models that either included the metric or BMI were compared using Harrell's C-statistic. We included 13,463 participants, with 3,876 first primary cancers over a mean of 19 years (SD 7) of cancer follow-up. Hazard ratios for obesity-related cancers per standard deviation overweight-years were 1.15 (95% CI: 1.05-1.25) in men and 1.14 (95% CI: 1.08-1.20) in women. The difference in the C-statistic between models that incorporated BMI, or the overweight-years metric was non-significant in men and women. Overweight-years was associated with the risk of obesity-related cancers but did not outperform a single BMI measure in association performance characteristics.
  • The management of myelofibrosis: a british society for haematology guideline

    McLornan, D. P.; Psaila, B.; Ewing, J.; Innes, A.; Arami, S.; Brady, J.; Butt, N. M.; Cargo, C.; Cross, N. C. P.; Francis, S.; et al. (2024)
  • Association of diet quality and weight increase in adult heart transplant recipients

    Miura, K.; Yu, R.; Entwistle, T. R.; McKenzie, S. C.; Green, Adele C; CRUK Manchester Institute and University of Manchester, Manchester, UK. (2023)
    BACKGROUND: Understanding the quality of the diet of heart transplant recipients (HTRs) is essential to developing effective dietary interventions for weight control, but relevant evidence is scarce. We investigated diet quality and its association with post-transplant increase in weight adjusted for height (body mass index [BMI]) in Australian HTRs. METHODS: We recruited adult HTRs from Queensland's thoracic transplant clinic, 2020-2021. Study participants completed a 3-day food diary using a smart-phone app. Socio-demographic information was collected by self-administered questionnaire, and height, serial weight and clinical information were obtained from medical records. We calculated the Dietary Approaches to Stop Hypertension (DASH) index based on nine food groups and nutrients (index of 90 indicates highest possible quality), and any changes in BMI (≤ 0 kg m(-2) or >0 kg m(-2) ) post-transplantation. Median DASH index values were assessed in relation to sex and BMI change using Mann-Whitney U test. RESULTS: Among 49 consented HTRs, 25 (51%) completed the food diary (median age 48 years, 52% females). Median BMI at enrolment was 27.2 kg m(-2) ; median BMI change since transplant was +3.7 kg m(-2) . Fruit, vegetable, and whole grain intakes were generally lower than recommended, giving a low overall median DASH index of 30 with no sex differences. HTRs for which the BMI increased post-transplant had significantly lower median DASH indices than those whose BMI did not increase (30 vs. 45, p = 0.013). CONCLUSIONS: The diet quality of HTRs appears suboptimal overall, with fruit and vegetable intakes especially low. HTRs whose BMI increased post-transplant had substantially lower quality diets than HTRs whose BMI did not increase.
  • Zanubrutinib in patients with relapsed/refractory marginal zone lymphoma (MZL): final analysis of MAGNOLIA (BGB-3111-214)

    Linton, Kim M; Trotman, J; McKay, P; Ardeshna, K; Iyengar, S; Tedeschi, A; Hu, B; Leitch, S; Jin, J; Sun, M; et al. (2023)

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