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Lipids in Health and Disease Nov 2022Due to the contribution of coronary artery disease (CAD) to serious cardiovascular events, determining biomarkers that could robustly predict its risk would be of utmost...
Evaluating the use of novel atherogenicity indices and insulin resistance surrogate markers in predicting the risk of coronary artery disease: a case‒control investigation with comparison to traditional biomarkers.
BACKGROUND
Due to the contribution of coronary artery disease (CAD) to serious cardiovascular events, determining biomarkers that could robustly predict its risk would be of utmost importance. Thus, this research was designed to assess the value of traditional cardio-metabolic indices, and more novel atherogenicity indices and insulin resistance surrogate markers in the identification of individuals at risk of CAD.
METHODS
A case‒control survey was conducted, in which 3085 individuals were enrolled. Their clinical and biochemical data were gathered at baseline. The investigated indices included the atherogenic index of plasma (AIP), triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), lipoprotein combine index (LCI), cholesterol index (CHOLINDEX), Castelli's risk indices-I, II (CRI-I, CRI-II), and metabolic score for insulin resistance (METS - IR). To examine the relationship between these variables and CAD risk, multiple regression analyses adjusted for potential confounders were conducted.
RESULTS
Overall, 774 angiographically confirmed CAD patients (mean age = 54 years) were compared with 3085 controls (mean age = 51 years). Higher triglyceride, total cholesterol and fasting blood sugar levels and lower HDL-C levels were related to an elevated risk of CAD (P-for-trend < 0.001), while the direct association between increased serum LDL-C concentrations and a greater risk of CAD only became apparent when excluding those with diabetes, and statin users. Among novel indices, greater values of the majority of these markers, including AIP, CRI-I, and -II, CHOLINDEX, LCI, and TyG-index, in comparison to the lower values, significantly elevated CAD risk (P-for-trend < 0.001).
CONCLUSION
According to the current findings, novel atherogenicity indices and insulin resistance surrogate markers, in particular, AIP, CRI-I and II, CHOLINDEX, LCI, and TyG-index, may be useful in predicting CAD risk.
Topics: Humans; Middle Aged; Insulin Resistance; Coronary Artery Disease; Blood Glucose; Biomarkers; Triglycerides; Case-Control Studies; Glucose; Risk Factors
PubMed: 36435770
DOI: 10.1186/s12944-022-01732-9 -
Journal of Cachexia, Sarcopenia and... Jun 2023Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor...
INTRODUCTION
Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia.
METHODS
Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-ras ; p53 ) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.
RESULTS
Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (-13.7 ± 5.7%; P < 0.01), muscle mass (-13.8 ± 8.1%; P < 0.01) and muscle strength (-25.5 ± 10.5%; P < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32 and Trim63) and autophagy-lysosomal pathway (Gabarapl1 and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (P < 0.001) and CXCL1/KC (P < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal muscle strongly mirrored alterations observed in muscle biopsies of patients with lung cancer cachexia.
CONCLUSIONS
We developed an orthotopic model of lung cancer cachexia in immune competent mice. Because this model simulates key aspects specific to cachexia in lung cancer patients, it is highly suitable to further investigate the underlying mechanisms of lung cancer cachexia and to test the efficacy of novel intervention strategies.
Topics: Animals; Male; Mice; Biomarkers; Cachexia; Lung Neoplasms; Muscle Strength; Muscle, Skeletal; Muscular Atrophy
PubMed: 37025071
DOI: 10.1002/jcsm.13222 -
Liver International : Official Journal... Sep 2021Non-alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non-alcoholic steatohepatitis cirrhosis is projected to increase by... (Review)
Review
Non-alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non-alcoholic steatohepatitis cirrhosis is projected to increase by 64%-156% by 2030. The threat is aggravated by the fact that are currently no approved drugs for the treatment of non-alcoholic steatohepatitis. In this paper, we review the main challenges to drug development in patients with non-alcoholic steatohepatitis cirrhosis, and describe the opportunities brought by the advances in the understanding of the clinical and pathophysiological nuances of cirrhosis. The design of therapeutic regimens for non-alcoholic steatohepatitis cirrhosis will vary according to the specific cirrhosis substage (compensated vs decompensated), and the specific mechanistic basis of therapy, targeted either at improving aetiology-specific pathways and/or at more general aetiology-agnostic processes. The understanding of the probabilistic expectations for the whole range of potential outcomes, rooted at different mechanistic drivers at each specific substage, will be essential in order to choose adequate estimands and therapeutic strategies for clinical trials and individual patients with non-alcoholic steatohepatitis cirrhosis. Finally, we provide a summary of the main pitfalls and uncertainties in the design of clinical trials for non-alcoholic steatohepatitis cirrhosis and discuss potential biomarkers for use in trials and practice for these patients.
Topics: Biomarkers; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease
PubMed: 34242466
DOI: 10.1111/liv.15013 -
Nature Communications Jun 2023The secreted products of cells drive many functions in vivo; however, methods to link this functional information to surface markers and transcriptomes have been...
The secreted products of cells drive many functions in vivo; however, methods to link this functional information to surface markers and transcriptomes have been lacking. By accumulating secretions close to secreting cells held within cavity-containing hydrogel nanovials, we demonstrate workflows to analyze the amount of IgG secreted from single human B cells and link this information to surface markers and transcriptomes from the same cells. Measurements using flow cytometry and imaging flow cytometry corroborate the association between IgG secretion and CD38/CD138. By using oligonucleotide-labeled antibodies we find that upregulation of pathways for protein localization to the endoplasmic reticulum and mitochondrial oxidative phosphorylation are most associated with high IgG secretion, and uncover surrogate plasma cell surface markers (e.g., CD59) defined by the ability to secrete IgG. Altogether, this method links quantity of secretion with single-cell sequencing (SEC-seq) and enables researchers to fully explore the links between genome and function, laying the foundation for discoveries in immunology, stem cell biology, and beyond.
Topics: Humans; Plasma Cells; B-Lymphocytes; Cell Membrane; Biomarkers; Immunoglobulin G
PubMed: 37322036
DOI: 10.1038/s41467-023-39367-8 -
Respirology (Carlton, Vic.) Jun 2024
Topics: Humans; Biomarkers; Breath Tests; Exhalation; Respiratory Tract Diseases
PubMed: 38650380
DOI: 10.1111/resp.14726 -
Journal of Clinical Pathology Jun 2023Ki67 expression is one of the most important and cost-effective surrogate markers to assess for tumour cell proliferation in breast cancer (BC). The Ki67 labelling index... (Review)
Review
Ki67 expression is one of the most important and cost-effective surrogate markers to assess for tumour cell proliferation in breast cancer (BC). The Ki67 labelling index has prognostic and predictive value in patients with early-stage BC, particularly in the hormone receptor-positive, HER2 (human epidermal growth factor receptor 2)negative (luminal) tumours. However, many challenges exist in using Ki67 in routine clinical practice and it is still not universally used in the clinical setting. Addressing these challenges can potentially improve the clinical utility of Ki67 in BC. In this article, we review the function, immunohistochemical (IHC) expression, methods for scoring and interpretation of results as well as address several challenges of Ki67 assessment in BC. The prodigious attention associated with use of Ki67 IHC as a prognostic marker in BC resulted in high expectation and overestimation of its performance. However, the realisation of some pitfalls and disadvantages, which are expected with any similar markers, resulted in an increasing criticism of its clinical use. It is time to consider a pragmatic approach and weigh the benefits against the weaknesses and identify factors to achieve the best clinical utility. Here we highlight the strengths of its performance and provide some insights to overcome the existing challenges.
Topics: Humans; Female; Breast Neoplasms; Ki-67 Antigen; Receptor, ErbB-2; Prognosis; Cell Proliferation; Biomarkers, Tumor
PubMed: 36813558
DOI: 10.1136/jcp-2022-208731 -
Cancer Science Jul 2023Lung adenocarcinoma is classified morphologically into five histological subtypes according to the WHO classification. While each histological subtype correlates with a...
Lung adenocarcinoma is classified morphologically into five histological subtypes according to the WHO classification. While each histological subtype correlates with a distinct prognosis, the molecular basis has not been fully elucidated. Here we conducted DNA methylation analysis of 30 lung adenocarcinoma cases annotated with the predominant histological subtypes and three normal lung cases using the Infinium BeadChip. Unsupervised hierarchical clustering analysis revealed three subgroups with different methylation levels: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME). Micropapillary pattern (MPP)-predominant cases and those with MPP components were significantly enriched in HME (p = 0.02 and p = 0.03, respectively). HME cases showed a significantly poor prognosis for recurrence-free survival (p < 0.001) and overall survival (p = 0.006). We identified 365 HME marker genes specifically hypermethylated in HME cases with enrichment of "cell morphogenesis" related genes; 305 IME marker genes hypermethylated in HME and IME, but not in LME, with enrichment "embryonic organ morphogenesis"-related genes; 257 Common marker genes hypermethylated commonly in all cancer cases, with enrichment of "regionalization"-related genes. We extracted surrogate markers for each epigenotype and designed pyrosequencing primers for five HME markers (TCERG1L, CXCL12, FAM181B, HOXA11, GAD2), three IME markers (TBX18, ZNF154, NWD2) and three Common markers (SCT, GJD2, BARHL2). DNA methylation profiling using Infinium data was validated by pyrosequencing, and HME cases defined by pyrosequencing results also showed the worse recurrence-free survival. In conclusion, lung adenocarcinomas are stratified into subtypes with distinct DNA methylation levels, and the high-methylation subtype correlated with MPP-predominant cases and those with MPP components and showed a poor prognosis.
Topics: Humans; DNA Methylation; Adenocarcinoma of Lung; Prognosis; Biomarkers; Lung Neoplasms; Neoplasm Staging; Kruppel-Like Transcription Factors
PubMed: 37082886
DOI: 10.1111/cas.15817 -
Nihon Yakurigaku Zasshi. Folia... 2022Alzheimer's disease (AD) is one of the most common causes of dementia in the world. Neurodegeneration, gliosis, and misfolded proteins such as amyloid plaques and tau... (Review)
Review
Alzheimer's disease (AD) is one of the most common causes of dementia in the world. Neurodegeneration, gliosis, and misfolded proteins such as amyloid plaques and tau tangles are neuropathological hallmarks in AD. In vivo imaging of these neuropathological lesions would be good biomarkers to understand pathophysiology as well as surrogate markers for clinical trials. We developed THK tau radiotracers including [F]THK-5351 and tested them in humans. Validations studies identified monoamine oxidase-B (MAO-B) as the off-target binding substrate of [F]THK-5351. Since the elevation of MAO-B, which is highly expressed in reactive astrocytes, were observed in various neurological conditions, MAO-B would be a promising target for imaging reactive astrogliosis. In fact, [F]THK-5351 PET studies demonstrated that high tracer uptake in site susceptible regions to occur astrogliosis in various neurological disorders. However, the lack of binding selectivity affects the interpretation of PET images. Therefore, we performed lead optimization from [F]THK-5351 generating a selective and reversible MAO-B PET tracer, [F]SMBT-1. These translational and reverse translational studies, from the development of PET tracers to validation of PET images, led to the generation of new biomarkers. In this review, we will introduce the development of [F]THK-5351, identification of off-target binding substrates, imaging-autopsy validations, new tracer development ([F]SMBT-1), and finally recent clinical studies of [F]SMBT-1.
Topics: Humans; Positron-Emission Tomography; Gliosis; Brain; Quinolines; Alzheimer Disease; Monoamine Oxidase; Biomarkers; tau Proteins
PubMed: 36328560
DOI: 10.1254/fpj.22061 -
JAMA May 2024Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals.
IMPORTANCE
Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals.
OBJECTIVE
To systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases.
DATA SOURCES
The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023.
STUDY SELECTION
Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded.
DATA EXTRACTION AND SYNTHESIS
Two reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes.
MAIN OUTCOMES AND MEASURES
Correlation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized.
RESULTS
Thirty-seven surrogate markers listed in FDA's table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker-clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result.
CONCLUSIONS AND RELEVANCE
Most surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.
Topics: Humans; Biomarkers; Chronic Disease; Clinical Trials as Topic; Meta-Analysis as Topic; Treatment Outcome; United States; Drug Approval
PubMed: 38648042
DOI: 10.1001/jama.2024.4175 -
Journal of Biochemistry Feb 2022Substrate-derived biomarkers are necessary in slowly progressing monogenetic diseases caused by single-enzyme deficiencies to identify affected patients and serve as...
Substrate-derived biomarkers are necessary in slowly progressing monogenetic diseases caused by single-enzyme deficiencies to identify affected patients and serve as surrogate markers for therapy response. N-glycanase 1 (NGLY1) deficiency is an ultra-rare autosomal recessive disorder characterized by developmental delay, peripheral neuropathy, elevated liver transaminases, hyperkinetic movement disorder and (hypo)-alacrima. We demonstrate that N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA), is the analyte most closely associated with NGLY1 deficiency, showing consistent separation in levels between patients and controls. GNA accumulation is directly linked to the absence of functional NGLY1, presenting strong potential for its use as a biomarker. In agreement, a quantitative liquid chromatography with tandem mass spectrometry assay, developed to assess GNA from 3 to 3000 ng/ml, showed that it is conserved as a marker for loss of NGLY1 function in NGLY1-deficient cell lines, rodents (urine, cerebrospinal fluid, plasma and tissues) and patients (plasma and urine). Elevated GNA levels differentiate patients from controls, are stable over time and correlate with changes in NGLY1 activity. GNA as a biomarker has the potential to identify and validate patients with NGLY1 deficiency, act as a direct pharmacodynamic marker and serve as a potential surrogate endpoint in clinical trials.
Topics: Asparagine; Biomarkers; Congenital Disorders of Glycosylation; Humans; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
PubMed: 34697629
DOI: 10.1093/jb/mvab111