Predicting Dying: Metabolomic Changes, a Model and the Dying Process in Patients with Lung Cancer

Coyle, Séamus; Chapman, Elinor A; Hughes, David; Baker, James E.; Slater, Rachael; Davison, Andrew S.; Norman, Brendan P.; Roberts, Ivayla; Nwosu, Amara Callistus; Boyd, Mark T.; Mayland, Catriona; Kell, Douglas B.; Masson, Steven; Ellershaw, John; Probert, Chris

doi:10.2139/ssrn.4453379

Cited by 1 publication

(7 citation statements)

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“…[20][21][22] In our lung cancer cohort, we previously showed changes in a number of our bone markers in the last weeks of life. 13 Two of the COL1A1-specific collagen peptides reported here progressively increased in urine over the course of time leading up to death, from greater than three months up to the last week before death; these were the dipeptide phenylalanyl-hydroxyproline and the highest molecular weight COL1A1 fragment observed here (marker #22; Table 1). Another unidentified bone marker (marker #13) decreased leading up to death.…”

Section: Discussionmentioning

confidence: 63%

“…Human urine data were obtained as part of a study investigating the metabolic changes that occur during the dying process in patients with incurable lung cancer (patients N = 112). 13 Serial urine samples were collected from patients at various hospitals/hospices in North West England between 2016-2018 at various time points leading up to death (>12 weeks to <1 week before death); total samples N = 234. Among the 112 patients in the urine study, 29 patients had bone metastasis confirmed by CT, PET or bone scintigraphy; the other 83 patients had lung cancer but without known bone metastasis.…”

Section: Human Metabolomic Datamentioning

confidence: 99%

“…Gly-Pro-Hyp and an unidentified compound with m/z 308.122 (compound #13; Table 1) were more abundant (P <0.05, fold change >2) in urine from patients with bone metastasis among the lung cancer cohort; n = 29 patients with lung cancer and bone metastasis; n = 83 patients with lung cancer but without known bone metastasis (Figure 3B). 13 Replicate injections of each pooled sample were randomly interspersed across the entire analytical run which comprised 297 injections. For all peptide fragments, CV was <25% across replicate injections for each pooled sample.…”

Section: Detection Of Novel Oligopeptide Markers In Human Serum and U...mentioning

confidence: 99%

“…N = 29 patients with lung cancer and bone metastasis (mets), n = 83 patients with lung cancer but without known bone metastasis. 13 Table 1. Summary of bone resorption products observed from LC/MS analysis.…”

Section: Detection Of Novel Oligopeptide Markers In Human Serum and U...mentioning

confidence: 99%

“…All remaining urinary oligopeptides detected showed no significant difference (P >0.05 and fold change <2) between patient groups (grey dots). N = 29 patients with lung cancer and bone metastasis (mets), n = 83 patients with lung cancer but without known bone metastasis 13.…”

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confidence: 99%

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Identification of novel bone-resorption markers by osteoclastsin vitroandin vivo

Norman,

Dillon,

Alkharabsheh

et al. 2024

Preprint

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Bone resorption involves dissolution of mineral and enzymatic degradation of bone matrix. The primary enzyme is cathepsin K but other proteases including matrix metalloproteinases are involved. Some cleavage products of cathepsin K have been partially identified, including crossed-linked telopeptides of type I collagen. However, the pathway of type I bone collagen degradation has not been fully elucidated. The aim of this study was to comprehensively characterise the entire complement of bone breakdown products resulting from osteoclast action under controlled conditions in vitro. Complete characterisation of these breakdown products will advance understanding of osteoclast biology and has the potential to reveal new biomarkers of bone resorption. We analysed extracellular media from osteoclasts cultured on dentine substrates, using untargeted liquid chromatography mass spectrometry. We discovered 22 breakdown products resulting from osteoclastic action. These products were peptide fragment sequences that mapped to various collagen proteins present in bone and dentine matrix. Nine peptide fragments mapped exclusively to collagen I alpha-1 chain (COL1A1), the most abundant protein in bone. Analysis of the reported cleavage sites in the COL1A1 protein sequence indicated 7/9 COL1A1-specific fragments not explained by known proteolytic events. We subsequently showed that 14 of the fragment products were present in human serum and/or urine from metabolomic datasets obtained from patients with the inherited metabolic disease alkaptonuria (serum) and lung cancer (urine). Two products were at higher concentration (P <0.05, fold change >2) in urine from patients with bone metastasis (29/112) from the lung cancer cohort. The range of collagen peptide fragments we discovered as a direct result of osteoclast activity indicates a complexity of bone resorption pathways not previously known. Monitoring the concentrations of these novel bone markers in biofluids has the potential to capture multiple pathways of bone resorption activity beyond the existing assays based on Cathepsin K.

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Section: Discussionmentioning

confidence: 63%

Section: Human Metabolomic Datamentioning

confidence: 99%

Section: Detection Of Novel Oligopeptide Markers In Human Serum and U...mentioning

confidence: 99%

Section: Detection Of Novel Oligopeptide Markers In Human Serum and U...mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Identification of novel bone-resorption markers by osteoclastsin vitroandin vivo

Norman,

Dillon,

Alkharabsheh

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Predicting Dying: Metabolomic Changes, a Model and the Dying Process in Patients with Lung Cancer

Cited by 1 publication

References 0 publications

Identification of novel bone-resorption markers by osteoclastsin vitroandin vivo

Identification of novel bone-resorption markers by osteoclastsin vitroandin vivo

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