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British Journal of Cancer Oct 2023Although genome duplication, or polyploidization, is believed to drive cancer evolution and affect tumor features, its significance in hepatocellular carcinoma (HCC) is...
BACKGROUND
Although genome duplication, or polyploidization, is believed to drive cancer evolution and affect tumor features, its significance in hepatocellular carcinoma (HCC) is unclear. We aimed to determine the characteristics of polyploid HCCs by evaluating chromosome duplication and to discover surrogate markers to discriminate polyploid HCCs.
METHODS
The ploidy in human HCC was assessed by fluorescence in situ hybridization for multiple chromosomes. Clinicopathological and expression features were compared between polyploid and near-diploid HCCs. Markers indicating polyploid HCC were explored by transcriptome analysis of cultured HCC cells.
RESULTS
Polyploidy was detected in 36% (20/56) of HCCs and discriminated an aggressive subset of HCC that typically showed high serum alpha-fetoprotein, poor differentiation, and poor prognosis compared to near-diploid HCCs. Molecular subtyping revealed that polyploid HCCs highly expressed alpha-fetoprotein but did not necessarily show progenitor features. Histological examination revealed abundant polyploid giant cancer cells (PGCCs) with a distinct appearance and frequent macrotrabecular-massive architecture in polyploid HCCs. Notably, the abundance of PGCCs and overexpression of ubiquitin-conjugating enzymes 2C indicated polyploidy in HCC and efficiently predicted poor prognosis in combination.
CONCLUSIONS
Histological diagnosis of polyploidy using surrogate markers discriminates an aggressive subset of HCC, apart from known HCC subgroups, and predict poor prognosis in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; alpha-Fetoproteins; In Situ Hybridization, Fluorescence; Prognosis; Polyploidy
PubMed: 37715023
DOI: 10.1038/s41416-023-02408-6 -
International Journal of Molecular... Apr 2023Kidney transplantation (KT) may improve the neurological status of chronic kidney disease (CKD) patients, reflected by the altered levels of circulating BBB-specific...
Kidney transplantation (KT) may improve the neurological status of chronic kidney disease (CKD) patients, reflected by the altered levels of circulating BBB-specific biomarkers. This study compares the levels of neuron specific enolase (NSE), brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), and circulating plasma extracellular vesicles (EVs) in kidney-failure patients before KT and at a two-year follow up. Using ELISA, NSE, BDNF, and NfL levels were measured in the plasma of 74 living-donor KT patients. Plasma EVs were isolated with ultracentrifugation, and characterized for concentration/size and surface protein expression using flow cytometry from a subset of 25 patients. Lower NSE levels, and higher BDNF and NfL were observed at the two-year follow-up compared to the baseline ( < 0.05). Male patients had significantly higher BDNF levels compared to those of females. BBB biomarkers correlated with the baseline lipid profile and with glucose, vitamin D, and inflammation markers after KT. BBB surrogate marker changes in the microcirculation of early vascular aging phenotype patients with calcification and/or fibrosis were observed only in NSE and BDNF. CD31+ microparticles from endothelial cells expressing inflammatory markers such as CD40 and integrins were significantly reduced after KT. KT may, thus, improve the neurological status of CKD patients, as reflected by changes in BBB-specific biomarkers.
Topics: Female; Male; Humans; Brain-Derived Neurotrophic Factor; Kidney Transplantation; Blood-Brain Barrier; Endothelial Cells; Biomarkers; Renal Insufficiency, Chronic
PubMed: 37047601
DOI: 10.3390/ijms24076628 -
The European Journal of Neuroscience Nov 2022A biomarker associated with cognition in neurodegenerative dementias would aid in the early detection of disease progression, complement clinical staging and act as a...
A biomarker associated with cognition in neurodegenerative dementias would aid in the early detection of disease progression, complement clinical staging and act as a surrogate endpoint in clinical trials. The current systematic review evaluates the association between cerebrospinal fluid protein markers of synapse loss and neuronal injury and cognition. We performed a systematic search which revealed 67 studies reporting an association between cerebrospinal fluid markers of interest and neuropsychological performance. Despite the substantial heterogeneity between studies, we found some evidence for an association between neurofilament-light and worse cognition in Alzheimer's diseases, frontotemporal dementia and typical cognitive ageing. Moreover, there was an association between cerebrospinal fluid neurogranin and cognition in those with an Alzheimer's-like cerebrospinal fluid biomarker profile. Some evidence was found for cerebrospinal fluid neuronal pentraxin-2 as a correlate of cognition across dementia syndromes. Due to the substantial heterogeneity of the field, no firm conclusions can be drawn from this review. Future research should focus on improving standardization and reporting as well as establishing the importance of novel markers such as neuronal pentraxin-2 and whether such markers can predict longitudinal cognitive decline.
Topics: Humans; Amyloid beta-Peptides; tau Proteins; Alzheimer Disease; Cognitive Dysfunction; Cognition; Biomarkers; Aging
PubMed: 35338546
DOI: 10.1111/ejn.15656 -
Epilepsia Sep 2021Stereo-electroencephalography (SEEG)-guided radiofrequency thermocoagulation (RF-TC) aims at modifying epileptogenic networks to reduce seizure frequency. High-frequency...
OBJECTIVE
Stereo-electroencephalography (SEEG)-guided radiofrequency thermocoagulation (RF-TC) aims at modifying epileptogenic networks to reduce seizure frequency. High-frequency oscillations (HFOs), spikes, and cross-rate are quantifiable epileptogenic biomarkers. In this study, we sought to evaluate, using SEEG signals recorded before and after thermocoagulation, whether a variation in these markers is related to the therapeutic effect of this procedure and to the outcome of surgery.
METHODS
Interictal segments of SEEG signals were analyzed in 38 patients during presurgical evaluation. We used an automatized method to quantify the rate of spikes, rate of HFOs, and cross-rate (a measure combining spikes and HFOs) before and after thermocoagulation. We analyzed the differences both at an individual level with a surrogate approach and at a group level with analysis of variance. We then evaluated the correlation between these variations and the clinical response to RF-TC and to subsequent resective surgery.
RESULTS
After thermocoagulation, 19 patients showed a clinical improvement. At the individual level, clinically improved patients more frequently had a reduction in spikes and cross-rate in the epileptogenic zone than patients without clinical improvement (p = .002, p = .02). At a group level, there was a greater decrease of HFOs in epileptogenic and thermocoagulated zones in patients with clinical improvement (p < .05) compared to those with no clinical benefit. Eventually, a significant decrease of all the markers after RF-TC was found in patients with a favorable outcome of resective surgery (spikes, p = .026; HFOs, p = .03; cross-rate, p = .03).
SIGNIFICANCE
Quantified changes in the rate of spikes, rate of HFOs, and cross-rate can be observed after thermocoagulation, and the reduction of these markers correlates with a favorable clinical outcome after RF-TC and with successful resective surgery. This may suggest that interictal biomarker modifications after RF-TC can be clinically used to predict the effectiveness of the thermocoagulation procedure and the outcome of resective surgery.
Topics: Biomarkers; Electrocoagulation; Electroencephalography; Humans; Imaging, Three-Dimensional; Seizures; Treatment Outcome
PubMed: 34272883
DOI: 10.1111/epi.16989 -
Cells Oct 2021Schizophrenia is a neuropsychiatric disorder characterized by dissociation of thoughts, idea, identity, and emotions. It has no central pathophysiological mechanism and... (Review)
Review
Schizophrenia is a neuropsychiatric disorder characterized by dissociation of thoughts, idea, identity, and emotions. It has no central pathophysiological mechanism and precise diagnostic markers. Despite its high heritability, there are also environmental factors implicated in the development of schizophrenia. Epigenetic factors are thought to mediate the effects of environmental factors in the development of the disorder. Epigenetic modifications like DNA methylation are a risk factor for schizophrenia. Targeted gene approach studies attempted to find candidate gene methylation, but the results are contradictory. Genome-wide methylation studies are insufficient in literature and the available data do not cover different populations like the African populations. The current genome-wide studies have limitations related to the sample and methods used. Studies are required to control for these limitations. Integration of DNA methylation, gene expression, and their effects are important in the understanding of the development of schizophrenia and search for biomarkers. There are currently no precise and functional biomarkers for the disorder. Several epigenetic markers have been reported to be common in functional and peripheral tissue. This makes the peripheral tissue epigenetic changes a surrogate of functional tissue, suggesting common epigenetic alteration can be used as biomarkers of schizophrenia in peripheral tissue.
Topics: Biomarkers; DNA Methylation; Epigenesis, Genetic; Genome-Wide Association Study; Humans; Precision Medicine; Schizophrenia
PubMed: 34831111
DOI: 10.3390/cells10112890 -
American Journal of Respiratory and... May 2021
Topics: Biomarkers; Humans; Hypertension, Pulmonary; Lung Neoplasms; Prognosis
PubMed: 33789070
DOI: 10.1164/rccm.202103-0740ED -
World Journal of Gastroenterology May 2017Hepatocellular carcinoma is becoming an increasing indication for liver transplantation, but selection and allocation of patients are challenging because of organ...
Hepatocellular carcinoma is becoming an increasing indication for liver transplantation, but selection and allocation of patients are challenging because of organ shortages. Conventional Milan criteria are the reference for the selection of patients worldwide, but many expanded criteria, like University of California San Francisco criteria and up-to-7 criteria, have demonstrated that survival and recurrence results are lower than those for restricted indications. Correct staging is crucial and should include surrogate markers of biological aggressiveness (α-fetoprotein, response to loco-regional treatments). Successful down-staging can select between patients with tumor burden initially beyond transplantation criteria those with a more favorable biology, provided a 3-mo stability in meeting the transplantation criteria. Allocation rules are constantly adjusted to minimize the imbalance between the priorities of candidates with and without hepatocellular carcinoma, and take into account local donor rate and waitlist dynamics. Recently, Mazzaferro et al proposed a benefit-oriented "adaptive approach", in which the selection and allocation of patients are based on their response to non-transplantation treatments: low priority for transplantation in case of complete response, high priority in case of partial response or recurrence, and no listing in case of progression beyond transplantation criteria.
Topics: Biomarkers; Carcinoma, Hepatocellular; Disease Progression; Europe; Humans; Liver Neoplasms; Liver Transplantation; Neoplasm Recurrence, Local; Neoplasm Staging; Patient Selection; Severity of Illness Index; Treatment Outcome; United States; alpha-Fetoproteins
PubMed: 28566879
DOI: 10.3748/wjg.v23.i18.3195 -
Clinical Trials (London, England) Aug 2015A surrogate marker is a variable commonly used in clinical trials to guide treatment decisions when the outcome of ultimate interest is not available. A good surrogate...
BACKGROUND
A surrogate marker is a variable commonly used in clinical trials to guide treatment decisions when the outcome of ultimate interest is not available. A good surrogate marker is one where the treatment effect on the surrogate is a strong predictor of the effect of treatment on the outcome. We review the situation when there is one treatment delivered at baseline, one surrogate measured at one later time point, and one ultimate outcome of interest and discuss new issues arising when variables are time-varying.
METHODS
Most of the literature on surrogate markers has only considered simple settings with one treatment, one surrogate, and one outcome of interest at a fixed time point. However, more complicated time-varying settings are common in practice. In this article, we describe the unique challenges in two settings, time-varying treatments and time-varying surrogates, while relating the ideas back to the causal-effects and causal-association paradigms.
CONCLUSION
In addition to discussing and extending popular notions of surrogacy to time-varying settings, we give examples illustrating that one can be misled by not taking into account time-varying information about the surrogate or treatment. We hope this article has provided some motivation for future work on estimation and inference in such settings.
Topics: Biomarkers; Clinical Trials as Topic; Humans; Mathematical Concepts; Outcome Assessment, Health Care; Regression Analysis; Therapeutics; Time Factors
PubMed: 25948621
DOI: 10.1177/1740774515583500 -
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 -
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