56 research outputs found
Circulating Cell-Free Tumour DNA for Early Detection of Pancreatic Cancer
No full textPancreatic cancer is a lethal disease, with mortality rates negatively associated with the stage at which the disease is detected. Early detection is therefore critical to improving survival outcomes. A recent focus of research for early detection is the use of circulating cell-free tumour DNA (ctDNA). The detection of ctDNA offers potential as a relatively non-invasive method of diagnosing pancreatic cancer by using genetic sequencing technology to detect tumour-specific mutational signatures in blood samples before symptoms manifest. These technologies are limited by a number of factors that lower sensitivity and specificity, including low levels of detectable ctDNA in early stage disease and contamination with non-cancer circulating cell-free DNA. However, genetic and epigenetic analysis of ctDNA in combination with other standard diagnostic tests may improve early detection rates. In this review, we evaluate the genetic and epigenetic methods under investigation in diagnosing pancreatic cancer and provide a perspective for future developments
Editorial on “Perihilar Cholangiocarcinoma—Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers”
No full textManipulating regulatory T cells: is it the key to unlocking effective immunotherapy for pancreatic ductal adenocarcinoma?
No full textThe five-year survival rates for pancreatic ductal adenocarcinoma (PDAC) have scarcely improved over the last half-century. It is inherently resistant to FDA-approved immunotherapies, which have transformed the outlook for patients with other advanced solid tumours. Accumulating evidence relates this resistance to its hallmark immunosuppressive milieu, which instils progressive dysfunction among tumour-infiltrating effector T cells. This milieu is established at the inception of neoplasia by immunosuppressive cellular populations, including regulatory T cells (Tregs), which accumulate in parallel with the progression to malignant PDAC. Thus, the therapeutic manipulation of Tregs has captured significant scientific and commercial attention, bolstered by the discovery that an abundance of tumour-infiltrating Tregs correlates with a poor prognosis in PDAC patients. Herein, we propose a mechanism for the resistance of PDAC to anti-PD-1 and CTLA-4 immunotherapies and re-assess the rationale for pursuing Treg-targeted therapies in light of recent studies that profiled the immune landscape of patient-derived tumour samples. We evaluate strategies that are emerging to limit Treg-mediated immunosuppression for the treatment of PDAC, and signpost early-stage trials that provide preliminary evidence of clinical activity. In this context, we find a compelling argument for investment in the ongoing development of Treg-targeted immunotherapies for PDAC
Master Regulators of Oncogenic KRAS Response in Pancreatic Cancer: An Integrative Network Biology Analysis.
No full textBackgroundKRAS is the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC), but the mechanisms underlying the transcriptional response to oncogenic KRAS are still not fully understood. We aimed to uncover transcription factors that regulate the transcriptional response of oncogenic KRAS in pancreatic cancer and to understand their clinical relevance.Methods and findingsWe applied a well-established network biology approach (master regulator analysis) to combine a transcriptional signature for oncogenic KRAS derived from a murine isogenic cell line with a coexpression network derived by integrating 560 human pancreatic cancer cases across seven studies. The datasets included the ICGC cohort (n = 242), the TCGA cohort (n = 178), and five smaller studies (n = 17, 25, 26, 36, and 36). 55 transcription factors were coexpressed with a significant number of genes in the transcriptional signature (gene set enrichment analysis [GSEA] p ConclusionsOur results characterize the regulatory mechanisms underlying the transcriptional response to oncogenic KRAS and provide a framework to develop strategies for specific subtypes of this disease using current therapeutics and by identifying targets for new groups
HER2 Expression in Gastric Cancer: Rare, Heterogeneous and of No Prognostic Value – Conclusions from 924 Cases of Two Independent Series
No full textBackground: Patients with gastric cancer (GC) have a poor survival and biologicals such as Trastuzumab have not been used routinely in these patients. Existing data on HER2 expression and its clinical relevance in GC are still limited and controversial
Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma
No full textBackground: Distinguishing benign from malignant pancreaticobiliary disease is challenging because of the absence of reliable biomarkers. Circulating extracellular vesicles (EVs) have emerged as functional mediators between cells. Their cargos, including microRNAs (miRNAs), are increasingly acknowledged as an important source of potential biomarkers. This multicentric, prospective study aimed to establish a diagnostic plasma EV-derived miRNA signature to discriminate pancreatic ductal adenocarcinoma (PDAC) from benign pancreaticobiliary disease. Methods: Plasma EVs were isolated using size exclusion chromatography (SEC) and characterised using nanoparticle tracking analysis, electron microscopy and Western blotting. EV-RNAs underwent small RNA sequencing to discover differentially expressed markers for PDAC (n = 10 benign vs. 10 PDAC). Candidate EV-miRNAs were then validated in a cohort of 61 patients (n = 31 benign vs. 30 PDAC) by RT-qPCR. Logistic regression and optimal thresholds (Youden Index) were used to develop an EV-miR-200 family model to detect cancer. This model was tested in an independent cohort of 95 patients (n = 30 benign, 33 PDAC, and 32 cholangiocarcinoma). Results: Small RNA sequencing and RT-qPCR showed that EV-miR-200 family members were significantly overexpressed in PDAC vs. benign disease. Combined expression of the EV-miR-200 family showed an AUC of 0.823. In an independent validation cohort, application of this model showed a sensitivity, specificity and AUC of 100%, 88%, and 0.97, respectively, for diagnosing PDAC. Conclusions: This is the first study to validate plasma EV-miR-200 members as a clinically-useful diagnostic biomarker for PDAC. Further validation in larger cohorts and clinical trials is essential. These findings also suggest the potential utility in monitoring response and/or recurrence. Graphical Abstract
Stiffness and Strength of an Artificially Cemented Waste-PET-Shred Reinforced Clay
No full textPublisher Copyright: © The Author(s) 2024.This study explores whether the polyethylene terephthalate bottle shreds (PETBS), could be a viable alternative additive in order to reduce the usage of traditional cement in geotechnical and transportation projects. Through a comprehensive study, clayey soil was stabilized with varying quantities (0.1–1% of solid mass) of PETBS of two different size ranges. Optimal dosages were chosen, followed by additional tests incorporating small amounts of (5, 7 and 10% of solid mass) cement enhancement. After curing periods of 7 and 28 days, California bearing ratio (CBR) tests and ultrasonic pulse velocity (UPV) test results revealed that the addition of PETBS enhanced CBR values and initial shear modulus (G0) in both plain and cement treated samples. Scanning electron microscope (SEM) images also affirmed the improvement of strength at the microstructural level. Notably, PETBS of size 2–4.75 mm exhibited superior performance compared to size 0.42–0.841 mm, with an optimal content range of 0.6–0.8%. It was observed that the addition of PETBS to artificially cemented soil improved CBR values by up to 35%, while also modifying stiffness and brittleness, rendering the soil more ductile. Ultimately, a regression model was proposed to facilitate estimates of CBR and G0 in PETBS-reinforced cemented clay, to accommodate varying PETBS grading and content. The suggested approach promotes cost-effective and eco-friendly solutions by reducing pavement thickness and enhancing soil stability, demonstrating the potential of repurposing PET waste as a sustainable strategy in various engineering projects.Peer reviewe
Tumor heterogeneity: does it matter?
No full textIntroduction: It has long been recognized that tumors are composed of a mosaic of cells and numerous methods have been developed to detect tumor heterogeneity, including in situ hybridization, multi-regional sampling, cytological assays, and whole genome and single cell sequencing. Using these methods, heterogeneity has been observed at the genetic, epigenetic, and phenotypic level in numerous cancers. With the advent of deep sequencing technology, we now appreciate a greater complexity of distinct genotypes and phenotypes that drive the biological behavior of cancer. Despite decades of progress in detecting tumor heterogeneity, the question remains: to what extent does it matter?Areas covered: This review explores the evidence for and against the importance of tumor heterogeneity in three main areas: prognostication, development of targeted therapeutics and tumor resistance; summarizing current understanding before evaluating ongoing experimental and clinical developments.Expert opinion: Theoretical understanding and in vitro detection of intratumour heterogeneity promises much but is yet to translate into meaningful clinical benefit. However, the recent emergence of a host of technological innovations and upcoming clinical trials may soon change the landscape of this field
Subtypes show different immune activity.
No full textA. Bar plot showing the Pearson partial correlation t-statistic difference between Hedgehog and Notch for ssGSEA pathway enrichment scores significantly associated with one subtype or the other. B. Boxplots from the ESTIMATE analysis showing the variation in the stromal and immune content between the Hedgehog, Notch, and cell cycle subgroups for both the ICGC and TCGA cohorts. C. Bar plot showing the difference in Pearson partial correlation coefficient difference between Hedgehog and Notch for estimated CIBERSORT leukocyte cell fractions significantly associated with one subtype or the other. A negative difference highlights strong association with Hedgehog, whereas a positive value indicates a strong association with Notch.</p
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