A Signature of Four Circulating microRNAs as Potential Biomarkers for Diagnosing Early-Stage Breast Cancer

Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation. In this study, we investigated the expression of 12 microRNA (miR-21/miR-155/miR-23a/miR-130a/miR-145/miR-425-5p/miR-139-5p/miR-451/miR-195/miR-125b/miR-100, and miR-182) in the plasma of 41 newly diagnosed Lebanese BC patients with early invasive ductal carcinoma as compared with 32 healthy controls. Total RNA was extracted from plasma, and expression levels of miRNA of interest were measured using RT-qPCR followed by statistical analysis; miR-21, miR-155, miR-23a, miR-130a, miR-145, miR-425-5p, and miR-139-5p were significantly upregulated and miR-451 was significantly downregulated, in the plasma of BC patients as compared with healthy controls. The positively correlated miR-23a, miR-21, and miR-130a had a high diagnostic accuracy (86%). Importantly, the combination of miR-145/miR-425-5p/miR-139-5p/miR-130a scored the highest diagnostic accuracy of 95% with AUC = 0.97 (sensitivity 97% and specificity 91%). MicroRNAs are promising non-invasive diagnostic biomarkers for early-stage BC with the panel of miR-145/miR-425-5p/miR-139-5p/miR-130a having the highest diagnostic accuracy.     

Circulating Exosomal miRNAs as Biomarkers for the Diagnosis and Prognosis of Colorectal Cancer

Colorectal cancer (CRC) is one of the most common malignant tumors in the gastrointestinal tract. It is a multifactorial disease that involves environmental factors, genetic factors, and lifestyle factors. Due to the absence of specific and sensitive biomarkers, CRC patients are usually diagnosed at an advanced stage and consequently suffer from a low 5-year overall survival rate. Despite improvements in surgical resection and adjuvant chemotherapy, the prognosis of patients with CRC remains unfavorable due to local and distant metastases. Several studies have shown that small noncoding RNAs, such as microRNAs packed in exosomes, are potential biomarkers in various types of cancers, including CRC, and that they can be detected in a stable form in both serum and plasma. In this review, we report the potential of circulating exosomal miRNAs to act as biomarkers for the diagnosis and prognosis of CRC.     

Insights into the Pathophysiology of Psychiatric Symptoms in Central Nervous System Disorders: Implications for Early and Differential Diagnosis

Different psychopathological manifestations, such as affective, psychotic, obsessive-compulsive symptoms, and impulse control disturbances, may occur in most central nervous system (CNS) disorders including neurodegenerative and neuroinflammatory diseases. Psychiatric symptoms often represent the clinical onset of such disorders, thus potentially leading to misdiagnosis, delay in treatment, and a worse outcome. In this review, psychiatric symptoms observed along the course of several neurological diseases, namely Alzheimer’s disease, fronto-temporal dementia, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, are discussed, as well as the involved brain circuits and molecular/synaptic alterations. Special attention has been paid to the emerging role of fluid biomarkers in early detection of these neurodegenerative diseases. The frequent occurrence of psychiatric symptoms in neurological diseases, even as the first clinical manifestations, should prompt neurologists and psychiatrists to share a common clinico-biological background and a coordinated diagnostic approach.     

A 4-Gene Signature of CDKN1, FDXR,SESN1 and PCNA Radiation Biomarkers for Prediction of Patient Radiosensitivity

The quest for the discovery and validation of radiosensitivity biomarkers is ongoing and while conventional bioassays are well established as biomarkers, molecular advances have unveiled new emerging biomarkers. Herein, we present the validation of a new 4-gene signature panel of CDKN1, FDXR, SESN1 and PCNA previously reported to be radiation-responsive genes, using the conventional G2 chromosomal radiosensitivity assay. Radiation-induced G2 chromosomal radiosensitivity at 0.05 Gy and 0.5 Gy IR is presented for a healthy control (n = 45) and a prostate cancer (n = 14) donor cohort. For the prostate cancer cohort, data from two sampling time points (baseline and Androgen Deprivation Therapy (ADT)) is provided, and a significant difference (p > 0.001) between 0.05 Gy and 0.5 Gy was evident for all donor cohorts. Selected donor samples from each cohort also exposed to 0.05 Gy and 0.5 Gy IR were analysed for relative gene expression of the 4-gene signature. In the healthy donor cohort, there was a significant difference in gene expression between IR dose for CDKN1, FXDR and SESN1 but not PCNA and no significant difference found between all prostate cancer donors, unless they were classified as radiation-induced G2 chromosomal radiosensitive. Interestingly, ADT had an effect on radiation response for some donors highlighting intra-individual heterogeneity of prostate cancer donors.     

CARS Imaging Advances Early Diagnosis of Cardiac Manifestation of Fabry Disease

Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient’s prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90–96%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD.     

Liquid Biopsies in the Clinical Management of Germ Cell Tumor Patients: State-of-the-Art and Future Directions

Liquid biopsies constitute a minimally invasive means of managing cancer patients, entailing early diagnosis, follow-up and prediction of response to therapy. Their use in the germ cell tumor field is invaluable since diagnostic tissue biopsies (which are invasive) are often not performed, and therefore only a presumptive diagnosis can be made, confirmed upon examination of the surgical specimen. Herein, we provide an overall review of the current liquid biopsy-based biomarkers of this disease, including the classical, routinely used serum tumor markers—the promising microRNAs rapidly approaching the introduction into clinical practice—but also cell-free DNA markers (including DNA methylation) and circulating tumor cells. Finally, and importantly, we also explore novel strategies and challenges for liquid biopsy markers and methodologies, providing a critical view of the future directions for liquid biopsy tests in this field, highlighting gaps and unanswered questions.     

A Systems Biology Approach to Understanding the Mechanisms of Action of Chinese Herbs for Treatment of Cardiovascular Disease

Traditional Chinese Medicine (TCM) involves a broad range of empirical testing and refinement and plays an important role in the health maintenance for people all over the world. However, due to the complexity of Chinese herbs, a full understanding of TCM’s action mechanisms is still unavailable despite plenty of successful applications of TCM in the treatment of various diseases, including especially cardiovascular diseases (CVD), one of the leading causes of death. Thus in the present work, by incorporating the chemical predictors, target predictors and network construction approaches, an integrated system of TCM has been constructed to systematically uncover the underlying action mechanisms of TCM. From three representative Chinese herbs, i.e., Ligusticum chuanxiong Hort., Dalbergia odorifera T. Chen and Corydalis yanhusuo WT Wang which have been widely used in CVD treatment, by combinational use of drug absorption, distribution, metabolism and excretion (ADME) screening and network pharmacology techniques, we have generated 64 bioactive ingredients and identified 54 protein targets closely associated with CVD, of which 29 are common targets (52.7%) of the three herbs. The result provides new information on the efficiency of the Chinese herbs for the treatment of CVD and also explains one of the basic theories of TCM, i.e., “multiple herbal drugs can treat one disease”. The predicted potential targets were then mapped to target-disease and target-signal pathway connections, which revealed the relationships of the active ingredients with their potential targets, diseases and signal systems. This means that for the first time, the action mechanism of these three important Chinese herbs for the treatment of CVD is uncovered, by generating and identifying both their active ingredients and novel targets specifically related to CVD, which clarifies some of the common conceptions in TCM, and thus provides clues to modernize such specific herbal medicines.     

Evaluation of Individual and Combined Applications of Serum Biomarkers for Diagnosis of Hepatocellular Carcinoma: A Meta-Analysis

The clinical value of Serum alpha-fetoprotein (AFP) to detect early hepatocellular carcinoma (HCC) has been questioned due to its low sensitivity and specificity found in recent years. Other than AFP, several new serum biomarkers including the circulating AFP isoform AFP-L3, des-gamma-carboxy prothrombin (DCP) and Golgi protein-73 (GP73) have been identified as useful HCC markers. In this investigation, we review the current knowledge about these HCC-related biomarkers, and sum up the results of our meta-analysis on studies that have addressed the utility of these biomarkers in early detection and prognostic prediction of HCC. A systematic search in PubMed, Web of Science, and the Cochrane Library was performed for articles published in English from 1999 to 2012, focusing on serum biomarkers for HCC detection. Data on sensitivity and specificity of tests were extracted from 40 articles that met the inclusion criteria, and the summary receiver operating characteristic curve (sROC) was obtained. A meta-analysis was carried out in which the area under the curve (AUC) for each biomarker or biomarker combinations (AFP, DCP, GP73, AFP-L3, AFP + DCP, AFP + AFP-L3, and AFP + GP73) was used to compare the diagnostic accuracy of different biomarker tests. The AUC of AFP, DCP, GP73, AFP-L3, AFP + DCP, AFP + AFP-L3, and AFP + GP73 are 0.835, 0.797, 0.914, 0.710, 0.874, 0.748, and 0.932 respectively. A combination of AFP + GP73 is superior to AFP in detecting HCC and differentiating HCC patients from non-HCC patients, and may prove to be a useful marker in the diagnosis and screening of HCC. In addition, the AUC of GP73, AFP + DCP and AFP + GP73 are better than that of AFP. The clinical value of GP73, AFP + DCP, or AFP + GP73 as serological markers for HCC diagnosis needs to be addressed further in future studies.     

Comparative Analysis of Chromatin-Delivered Biomarkers in the Monitoring of Sepsis and Septic Shock: A Pilot Study

Sepsis management remains one of the most important challenges in modern clinical practice. Rapid progression from sepsis to septic shock is practically unpredictable, hence the critical need for sepsis biomarkers that can help clinicians in the management of patients to reduce the probability of a fatal outcome. Circulating nucleoproteins released during the inflammatory response to infection, including neutrophil extracellular traps, nucleosomes, and histones, and nuclear proteins like HMGB1, have been proposed as markers of disease progression since they are related to inflammation, oxidative stress, endothelial damage, and impairment of the coagulation response, among other pathological features. The aim of this work was to evaluate the actual potential for decision making/outcome prediction of the most commonly proposed chromatin-related biomarkers (i.e., nucleosomes, citrullinated H3, and HMGB1). To do this, we compared different ELISA measuring methods for quantifying plasma nucleoproteins in a cohort of critically ill patients diagnosed with sepsis or septic shock compared to nonseptic patients admitted to the intensive care unit (ICU), as well as to healthy subjects. Our results show that all studied biomarkers can be used to monitor sepsis progression, although they vary in their effectiveness to separate sepsis and septic shock patients. Our data suggest that HMGB1/citrullinated H3 determination in plasma is potentially the most promising clinical tool for the monitoring and stratification of septic patients.     

CRISPR Approaches for the Diagnosis of Human Diseases

CRISPR/Cas is a prokaryotic self-defense system, widely known for its use as a gene-editing tool. Because of their high specificity to detect DNA and RNA sequences, different CRISPR systems have been adapted for nucleic acid detection. CRISPR detection technologies differ highly among them, since they are based on four of the six major subtypes of CRISPR systems. In just 5 years, the CRISPR diagnostic field has rapidly expanded, growing from a set of specific molecular biology discoveries to multiple FDA-authorized COVID-19 tests and the establishment of several companies. CRISPR-based detection methods are coupled with pre-existing preamplification and readout technologies, achieving sensitivity and reproducibility comparable to the current gold standard nucleic acid detection methods. Moreover, they are very versatile, can be easily implemented to detect emerging pathogens and new clinically relevant mutations, and offer multiplexing capability. The advantages of the CRISPR-based diagnostic approaches are a short sample-to-answer time and no requirement of laboratory settings; they are also much more affordable than current nucleic acid detection procedures. In this review, we summarize the applications and development trends of the CRISPR/Cas13 system in the identification of particular pathogens and mutations and discuss the challenges and future prospects of CRISPR-based diagnostic platforms in biomedicine.     

A Role for Caveolin-3 in the Pathogenesis of Muscular Dystrophies

Caveolae are the cholesterol-rich small invaginations of the plasma membrane present in many cell types including adipocytes, endothelial cells, epithelial cells, fibroblasts, smooth muscles, skeletal muscles and cardiac muscles. They serve as specialized platforms for many signaling molecules and regulate important cellular processes like energy metabolism, lipid metabolism, mitochondria homeostasis, and mechano-transduction. Caveolae can be internalized together with associated cargo. The caveolae-dependent endocytic pathway plays a role in the withdrawal of many plasma membrane components that can be sent for degradation or recycled back to the cell surface. Caveolae are formed by oligomerization of caveolin proteins. Caveolin-3 is a muscle-specific isoform, whose malfunction is associated with several diseases including diabetes, cancer, atherosclerosis, and cardiovascular diseases. Mutations in Caveolin-3 are known to cause muscular dystrophies that are collectively called caveolinopathies. Altered expression of Caveolin-3 is also observed in Duchenne’s muscular dystrophy, which is likely a part of the pathological process leading to muscle weakness. This review summarizes the major functions of Caveolin-3 in skeletal muscles and discusses its involvement in the pathology of muscular dystrophies.     

A Survey of Autoencoder Algorithms to Pave the Diagnosis of Rare Diseases

Rare diseases (RDs) concern a broad range of disorders and can result from various origins. For a long time, the scientific community was unaware of RDs. Impressive progress has already been made for certain RDs; however, due to the lack of sufficient knowledge, many patients are not diagnosed. Nowadays, the advances in high-throughput sequencing technologies such as whole genome sequencing, single-cell and others, have boosted the understanding of RDs. To extract biological meaning using the data generated by these methods, different analysis techniques have been proposed, including machine learning algorithms. These methods have recently proven to be valuable in the medical field. Among such approaches, unsupervised learning methods via neural networks including autoencoders (AEs) or variational autoencoders (VAEs) have shown promising performances with applications on various type of data and in different contexts, from cancer to healthy patient tissues. In this review, we discuss how AEs and VAEs have been used in biomedical settings. Specifically, we discuss their current applications and the improvements achieved in diagnostic and survival of patients. We focus on the applications in the field of RDs, and we discuss how the employment of AEs and VAEs would enhance RD understanding and diagnosis.     

The Emerging Role of Presepsin (P-SEP) in the Diagnosis of Sepsis in the Critically Ill Infant: A Literature Review

Sepsis causes high rates of morbidity and mortality in NICUs. The estimated incidence varies between 5 and 170 per 1000 births, depending on the social context. In very low birth-weight neonates, the level of mortality increases with the duration of hospitalization, reaching 36% among infants aged 8–14 days and 52% among infants aged 15–28 days. Early diagnosis is the only tool to improve the poor prognosis of neonatal sepsis. Blood culture, the gold standard for diagnosis, is time-consuming and poorly sensitive. C-reactive protein and procalcitonin, currently used as sepsis biomarkers, are influenced by several maternal and fetal pro-inflammatory conditions in the perinatal age. Presepsin is the N-terminal fragment of soluble CD14 subtype (sCD14-ST): it is released in the bloodstream by monocytes and macrophages, in response to bacterial invasion. Presepsin seems to be a new, promising biomarker for the early diagnosis of sepsis in neonates as it is not modified by perinatal confounding inflammatory factors. The aim of the present review is to collect current knowledge about the role of presepsin in critically ill neonates.     

Cardiovascular Disease-Associated MicroRNAs as Novel Biomarkers of First-Trimester Screening for Gestational Diabetes Mellitus in the Absence of Other Pregnancy-Related Complications

We assessed the diagnostic potential of cardiovascular disease-associated microRNAs for the early prediction of gestational diabetes mellitus (GDM) in singleton pregnancies of Caucasian descent in the absence of other pregnancy-related complications. Whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation. This retrospective study involved all pregnancies diagnosed with only GDM (n = 121) and 80 normal term pregnancies selected with regard to equality of sample storage time. Gene expression of 29 microRNAs was assessed using real-time RT-PCR. Upregulation of 11 microRNAs (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-23a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-181a-5p, miR-195-5p, miR-499a-5p, and miR-574-3p) was observed in pregnancies destinated to develop GDM. Combined screening of all 11 dysregulated microRNAs showed the highest accuracy for the early identification of pregnancies destinated to develop GDM. This screening identified 47.93% of GDM pregnancies at a 10.0% false positive rate (FPR). The predictive model for GDM based on aberrant microRNA expression profile was further improved via the implementation of clinical characteristics (maternal age and BMI at early stages of gestation and an infertility treatment by assisted reproductive technology). Following this, 69.17% of GDM pregnancies were identified at a 10.0% FPR. The effective prediction model specifically for severe GDM requiring administration of therapy involved using a combination of these three clinical characteristics and three microRNA biomarkers (miR-20a-5p, miR-20b-5p, and miR-195-5p). This model identified 78.95% of cases at a 10.0% FPR. The effective prediction model for GDM managed by diet only required the involvement of these three clinical characteristics and eight microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-100-5p, miR-125b-5p, miR-195-5p, miR-499a-5p, and miR-574-3p). With this, the model identified 50.50% of GDM pregnancies managed by diet only at a 10.0% FPR. When other clinical variables such as history of miscarriage, the presence of trombophilic gene mutations, positive first-trimester screening for preeclampsia and/or fetal growth restriction by the Fetal Medicine Foundation algorithm, and family history of diabetes mellitus in first-degree relatives were included in the GDM prediction model, the predictive power was further increased at a 10.0% FPR (72.50% GDM in total, 89.47% GDM requiring therapy, and 56.44% GDM managed by diet only). Cardiovascular disease-associated microRNAs represent promising early biomarkers to be implemented into routine first-trimester screening programs with a very good predictive potential for GDM.     

双季铵盐杀菌剂的杀菌试验研究

为解决循环冷却水的微生物问题,克服目前较多使用的一些杀菌剂的若干不足之处。本文在多种杀菌剂研究的基础上,进行了双季铵盐杀菌剂静态实验研究。发现双季铵盐具有高效低毒、作用时效长的特点,是一种优良的杀菌剂。     

Molecular Biological and Clinical Understanding of the Statin Residual Cardiovascular Disease Risk and Peroxisome Proliferator-Activated Receptor Alpha Agonists and Ezetimibe for Its Treatment

Several randomized, double blind, placebo-controlled trials (RCTs) have demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering by using statins, including high-doses of strong statins, reduced the development of cardiovascular disease (CVD). However, among the eight RCTs which investigated the effect of statins vs. placebos on the development of CVD, 56–79% of patients had the residual CVD risk after the trials. In three RCTs which investigated the effect of a high dose vs. a usual dose of statins on the development of CVD, 78–87% of patients in the high-dose statin arms still had the CVD residual risk after the trials. An analysis of the characteristics of patients in the RCTs suggests that elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C), the existence of obesity/insulin resistance, and diabetes may be important metabolic factors which determine the statin residual CVD risk. To understand the association between lipid abnormalities and the development of atherosclerosis, we show the profile of lipoproteins and their normal metabolism, and the molecular and biological mechanisms for the development of atherosclerosis by high TG and/or low HDL-C in insulin resistance. The molecular biological mechanisms for the statin residual CVD risk include an increase of atherogenic lipoproteins such as small dense LDL and remnants, vascular injury and remodeling by inflammatory cytokines, and disturbed reverse cholesterol transport. Peroxisome proliferator-activated receptor alpha (PPARα) agonists improve atherogenic lipoproteins, reverse the cholesterol transport system, and also have vascular protective effects, such as an anti-inflammatory effect and the reduction of the oxidative state. Ezetimibe, an inhibitor of intestinal cholesterol absorption, also improves TG and HDL-C, and reduces intestinal cholesterol absorption and serum plant sterols, which are increased by statins and are atherogenic, possibly contributing to reduce the statin residual CVD risk.     

A Bioinformatics Systems Biology Analysis of the Current Oral Proteomic Biomarkers and Implications for Diagnosis and Treatment of External Root Resorption

External root resorption (ERR) is a silent destructive phenomenon detrimental to dental health. ERR may have multiple etiologies such as infection, inflammation, traumatic injuries, pressure, mechanical stimulations, neoplastic conditions, systemic disorders, or idiopathic causes. Often, if undiagnosed and untreated, ERR can lead to the loss of the tooth or multiple teeth. Traditionally, clinicians have relied on radiographs and cone beam computed tomography (CBCT) images for the diagnosis of ERR; however, these techniques are not often precise or definitive and may require exposure of patients to more ionizing radiation than necessary. To overcome these shortcomings, there is an immense need to develop non-invasive approaches such as biomarker screening methods for rapid and precise diagnosis for ERR. In this review, we performed a literature survey for potential salivary or gingival crevicular fluid (GCF) proteomic biomarkers associated with ERR and analyzed the potential pathways leading to ERR. To the best of our knowledge, this is the first proteomics biomarker survey that connects ERR to body biofluids which represents a novel approach to diagnose and even monitor treatment progress for ERR.