Biomarker Insights最新文献

Background: Prostanoids are a family of lipid mediators formed from arachidonic acid by cyclooxygenase enzymes and serve as biomarkers of vascular function. Prostanoid production may be different in males and females indicating that different therapeutic approaches may be required during disease.

Objectives: We examined sex-dependent differences in COX-related metabolites in genetically modified mice that produce a cyclooxygenase-2 (COX2) enzyme containing a tyrosine 385 to phenylalanine (Y385F) mutation. This mutation renders the COX2 enzyme unable to form a key intermediate radical required for complete arachidonic acid metabolism and provides a model of selective COX2 inhibition.

Design and methods: Mice heterozygous for the Y385F mutation in COX2 were mated to produce cohorts of wild-type, heterozygous, and COX2 mutant mice. We investigated whether the genotype distribution followed Mendelian genetics and studied whether sex-specific differences could be found in certain prostanoid levels measured in peritoneal macrophages and in urinary samples.

Results: The inheritance of the COX2 mutation displayed a significant deviation with respect to Mendel's laws of genetics, with a lower-than-expected progeny of weaned COX2 mutant pups. In macrophages, prostaglandin E₂ (PGE₂) production following lipopolysaccharide (LPS) and interferon gamma (IFNγ) stimulation was COX2-dependent in both males and females, and data indicated that crosstalk between the nitric oxide (NO) and COX2 pathways may be sex specific. We observed significant differences in urinary PGE₂ production by male and female COX2 mutant mice, with the loss of COX2 activity in male mice decreasing their ability to produce urinary PGE₂. Finally, female mice across all 3 genotypes produced similar levels of urinary thromboxane (measured as 11-dehydro TxB₂) at significantly higher levels than males, indicating a sex-related difference that is likely COX1-derived.

Conclusions: Our findings clearly demonstrate that sex-related differences in COX-derived metabolites can be observed, and that other pathways (such as the NO pathway) are affected.

Background: MicroRNAs are short nucleotide sequences that contribute to the regulation of various biological functions and therefore their roles have been investigated in many pathologic conditions such as epithelial to mesenchymal transition in cancer and fibrosis; among them, miR-138 has been mostly studied in cancer biology and is well-known for its suppressing effect on cancer progression. Being able to suppress major pathways involved in EMT, miR-138 could be a good candidate to be investigated in fibrotic responses too. Based on our previous studies, and the capability of miR-138 to target and regulate several components of the EMT pathway; we hypothesized a role for miR-138 in systemic sclerosis. Accordingly, the gene expression of miR-138 was assessed to find any alterations in the whole blood of the SSc patients.

Methods: Blood was collected from 70 patients with systemic sclerosis (equally divided between 2 groups of limited and diffuse categories) and 30 healthy individuals as controls. RNA was immediately isolated from the fresh whole blood; afterward, the resulting RNA was reverse transcribed into cDNA and then the relative expression of miR-138 was compared between the patients and the controls by the means of qPCR, and specific TaqMan primer and probes.

Results: The relative expression of miR-138 was significantly lower in patients with systemic sclerosis compared to the controls. No significant difference was observed between the limited and diffuse patient groups. ROC curve analysis showed an appropriate diagnostic value of miR-138 in effectively differentiating SSc patients from the healthy controls.

Conclusion: miR-138 is likely involved in the pathogenesis of SSc and with further evaluations may be utilized as a diagnostic biomarker in SSc. Also, targeting miR-138 in future studies could be promising for finding a novel treatment option for patients with SSc.

Clinical management of gynecological cancer begins by optimal debulking with first-line platinum-based chemotherapy. However, in ~80% patients, ovarian cancer will recur and is lethal. Prognostic gene signature panel identifying platinum-resistance enables better patient stratification for precision therapy. Retrospectively collected serum from 11 "poor" (<6 months progression free interval [PFI]) and 22 "favorable" (>24 months PFI) prognosis patients, were evaluated using circulating cell-free DNA (cfDNA). DNA from both groups showed 50 to 10 000 bp fragments. Pairwise analysis of sequenced cfDNA from patients showed that gene dosages were higher for 29 genes and lower for 64 genes in poor than favorable prognosis patients. Gene ontology analysis of higher dose genes predominantly grouped into cytoskeletal proteins, while lower dose genes, as hydrolases and receptors. Higher dosage genes searched for cancer-relatedness in Reactome database indicated 15 genes were referenced with cancer. Among them 3 genes, TGFBR2, ZMIZ2, and NRG2, were interacting with more than 4 cancer-associated genes. Protein expression analysis of tumor samples indicated that TGFBR2 was downregulated and ZMIZ2 was upregulated in poor prognosis patients. Our results indicate that the cfDNA gene dosage combined with protein expression in tumor samples can serve as gene signature panel for prognosis determination amongst ovarian cancer patients.

Introduction: Serum neurofilament light (NfL) is an emerging biomarker of traumatic brain injury (TBI). However, the effect of peripheral injuries such as long bone fracture and skeletal muscle injury on serum NfL levels is unknown. Therefore, the aim of this study was to determine whether serum NfL levels can be used as a biomarker of TBI in the presence of concomitant peripheral injuries.

Methods: Rats were randomly assigned to one of four injury groups: polytrauma (muscle crush + fracture + TBI; n = 11); peripheral injuries (muscle crush + fracture + sham-TBI; n = 12); TBI-only (sham-muscle crush + sham-fracture + TBI; n = 13); and triple-sham (n = 7). At 2-days post-injury, serum levels of NfL were quantified using a Simoa HD-X Analyzer.

Results: Compared to triple-sham rats, serum NfL concentrations were higher in rats with peripheral injuries-only, TBI-only, and polytrauma. When compared to peripheral injury-only rats, serum NfL levels were higher in TBI-only and polytrauma rats. No differences were found between TBI-only and polytrauma rats.

Conclusion: Serum NfL levels did not differ between TBI-only and polytrauma rats, indicating that significant peripheral injuries did not affect the sensitivity and specificity of serum NfL as a biomarker of moderate TBI. However, the finding of elevated serum NfL levels in rats with peripheral injuries in the absence of a TBI suggests that the presence of such injuries may limit the utility of NfL as a biomarker of less severe TBI (eg, concussion).

Companion diagnostics (CDx) hail promise of improving the drug development process and precision medicine. However, there are various challenges involved in the clinical development and regulation of CDx, which are considered high-risk in vitro diagnostic medical devices given the role they play in therapeutic decision-making and the complications they may introduce with respect to their sensitivity and specificity. The European Union (E.U.) is currently in the process of bringing into effect in vitro Diagnostic Medical Devices Regulation (IVDR). The new Regulation is introducing a wide range of stringent requirements for scientific validity, analytical and clinical performance, as well as on post-market surveillance activities throughout the lifetime of in vitro diagnostics (IVD). Compliance with General Safety and Performance Requirements (GSPRs) adopts a risk-based approach, which is also the case for the new classification system. This changing regulatory framework has an impact on all stakeholders involved in the IVD Industry, including Authorized Representatives, Distributors, Importers, Notified Bodies, and Reference Laboratories and is expected to have a significant effect on the development of new CDx.

Biobanking efforts, to establish and grow the pool of available tissue from which evidence on aetiology, therapeutic susceptibility and prognosis of various diseases, have been underway for decades. This is illustrated nowhere better than in cancer. High incidence cancers such as breast, colorectal and lung have seen massive increases in their requisite formularies that have yielded improved prognoses. These discoveries, on a very fundamental level, were made by scientists who had access to tumour tissue and associated clinical data from patient donors. As the research space for higher incidence malignancies became increasingly crowded, attention has turned towards those malignancies with lower incidence. In the same time span, technology has continued to evolve, allowing the next generation of scientists and clinicians to ask more nuanced questions. Inquiries are no longer limited to the -omics of tumour tissue but also include biomarkers of blood and excretory products, concurrent disease status and composition of the gut microbiome. The impact of these new technologies and the questions now facing researchers in low-incidence cancers will be summarized and discussed. Our experience with pancreatic ductal adenocarcinoma will be used as a model for this review.

Purpose: Neutrophil-lymphocyte ratio has been explored as a prognosticator in several cancer types, but its association with larynx cancer outcomes is not well known. We aimed to identify an optimal NLR cutoff point and examine the prognostic utility of this biomarker in patients with locoregionally advanced larynx cancer treated with curative intent.

Methods: In the Veterans Affairs' (VA) national database, we identified patients with locoregionally advanced (T3-4N0-3M0) laryngeal squamous cell carcinoma diagnosed between 2000 and 2017 and treated with curative intent. NLR cutoff points were calculated using Contal/O'Quigley's method. Outcomes of larynx cancer-specific survival (CSS), overall survival (OS), and non-larynx cancer survival (NCS) were evaluated in multivariable Cox and Fine-Gray models.

Results: In 1047 patients, the optimal pretreatment NLR cutoff was identified as 4.17 - 722 patients with NLR ⩽ 4.17, 325 patients with NLR > 4.17. The elevated NLR cohort had a higher proportion of T4 disease (39.4% vs 28.4%), node positive disease (52.3% vs 43.1%), and surgical treatment (43.7% vs 35.2%). In multivariable analysis, NLR > 4.17 was independently associated with worse OS (HR 1.31, 95% CI 1.12-1.54, P = .001) and worse CSS (HR 1.46, 95% CI 1.17-1.83, P < .001), but not with NCS (HR 0.94, 95% CI 0.75-1.18, P = .58).

Conclusion: In locoregionally advanced larynx cancer treated with curative intent, we identified elevated NLR to be associated with inferior OS and CSS. Further prospective studies are needed to investigate pretreatment NLR and our identified 4.17 cutoff as a potential larynx cancer-specific marker for this high risk population.