Chronic Hepatitis B with Spontaneous Severe Acute Exacerbation

Chronic hepatitis B virus (HBV) infection is a major global health problem with an estimated 400 million HBV carriers worldwide. In the natural history of chronic hepatitis B (CHB), spontaneous acute exacerbation (AE) is not uncommon, with a cumulative incidence of 10%–30% every year. While exacerbations can be mild, some patients may develop hepatic decompensation and even die. The underlying pathogenesis is possibly related to the activation of cytotoxic T lymphocyte-mediated immune response against HBV. An upsurge of serum HBV DNA usually precedes the rise of alanine aminotransferase (ALT) and bilirubin. Whether antiviral treatment can benefit CHB with severe AE remains controversial, but early nucleos(t)ide analogues treatment seemed to be associated with an improved outcome. There has been no randomized study that compared the effects of different nucleos(t)ide analogues (NA) in the setting of CHB with severe AE. However, potent NAs with good resistance profiles are recommended. In this review, we summarized current knowledge regarding the natural history, pathogenetic mechanisms, and therapeutic options of CHB with severe AE.     

Asthma in the Precision Medicine Era: Biologics and Probiotics

Asthma is a major global health issue. Over 300 million people worldwide suffer from this chronic inflammatory airway disease. Typical clinical symptoms of asthma are characterized by a recurrent wheezy cough, chest tightness, and shortness of breath. The main goals of asthma management are to alleviate asthma symptoms, reduce the risk of asthma exacerbations, and minimize long-term medicinal adverse effects. However, currently available type 2 T helper cells (Th2)-directed treatments are often ineffective due to the heterogeneity of the asthma subgroups, which manifests clinically with variable and poor treatment responses. Personalized precision therapy of asthma according to individualized clinical characteristics (phenotype) and laboratory biomarkers (endotype) is the future prospect. This mini review discusses the molecular mechanisms underlying asthma pathogenesis, including the hot sought-after topic of microbiota, add-on therapies and the potential application of probiotics in the management of asthma.     

Environmentally persistent free radicals induce airway hyperresponsiveness in neonatal rat lungs

Background  

Increased asthma risk/exacerbation in children and infants is associated with exposure to elevated levels of ultrafine particulate matter (PM). The presence of a newly realized class of pollutants, environmentally persistent free radicals (EPFRs), in PM from combustion sources suggests a potentially unrecognized risk factor for the development and/or exacerbation of asthma.     

Comprehensive Targeted Metabolomic Study in the Lung,Plasma, and Urine of PPE/LPS-Induced COPD Mice Model

(1) Background: Progression of chronic obstructive pulmonary disease (COPD) leads to irreversible lung damage and inflammatory responses; however, biomarker discovery for monitoring of COPD progression remains challenging. (2) Methods: This study evaluated the metabolic mechanisms and potential biomarkers of COPD through the integrated analysis and receiver operating characteristic (ROC) analysis of metabolic changes in lung, plasma, and urine, and changes in morphological characteristics and pulmonary function in a model of PPE/LPS-induced COPD exacerbation. (3) Results: Metabolic changes in the lungs were evaluated as metabolic reprogramming to counteract the changes caused by the onset of COPD. In plasma, several combinations of phenylalanine, 3-methylhistidine, and polyunsaturated fatty acids have been proposed as potential biomarkers; the α-aminobutyric acid/histidine ratio has also been reported, which is a novel candidate biomarker for COPD. In urine, a combination of succinic acid, isocitric acid, and pyruvic acid has been proposed as a potential biomarker. (4) Conclusions: This study proposed potential biomarkers in plasma and urine that reflect altered lung metabolism in COPD, concurrently with the evaluation of the COPD exacerbation model induced by PPE plus LPS administration. Therefore, understanding these integrative mechanisms provides new insights into the diagnosis, treatment, and severity assessment of COPD.     

Associations between dietary factors and obesity-related biomarkers in healthy children and adolescents - a systematic review

Background

The obesity prevalence in children and adolescents has increased worldwide during the past 30 years. Although diet has been identified as one risk factor for developing obesity in this age group, the role of specific dietary factors is still unclear. One way to gain insight into the role of these factors might be to detect biomarkers that reflect metabolic health and to identify the associations between dietary factors and these biomarkers. This would enable nutrition-related metabolic changes to be detected early in life, which might be a promising strategy to prevent childhood obesity. However, existing literature offers only inconclusive evidence for diet and some of these obesity-related biomarkers (e.g., blood lipids). We thus conducted a systematic literature review to further examine eligible studies that investigate associations between dietary factors and 12 obesity-related biomarkers in healthy children and adolescents aged 3-18 years.

Methods

We searched the scientific databases PubMed/Medline and Web of Science Core Collection for potentially eligible articles. Our final literature search resulted in 2727 hits. After the selection process, we included 81 articles that reported on 1111 single observations on dietary factors and any of the obesity-related biomarkers.

Results

Around 81% of the total observations showed nonsignificant results. For many biomarkers we did not find enough observations to draw clear conclusions on possible associations between a dietary factor and the respective biomarker. In cases where we identified enough observations, the results were contradictory. Since these nonsignificant and inconclusive findings may impede the development of effective strategies against childhood obesity, this article takes a closer look at possible reasons for such findings. In addition, it provides action points for future research efforts.

Conclusions

In conclusion, current evidence on associations between dietary factors and obesity-related biomarkers is inconclusive. We thus provided an overview on which specific limitations may impede current research. Such knowledge is necessary to enable future research efforts to better elucidate the role of diet in the early stages of obesity development.

     

Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions

Idiopathic pulmonary fibrosis (IPF), the most lethal form of interstitial pneumonia of unknown cause, is associated with a specific radiological and histopathological pattern (the so-called “usual interstitial pneumonia” pattern) and has a median survival estimated to be between 3 and 5 years after diagnosis. However, evidence shows that IPF has different clinical phenotypes, which are characterized by a variable disease course over time. At present, the natural history of IPF is unpredictable for individual patients, although some genetic factors and circulating biomarkers have been associated with different prognoses. Since in its early stages, IPF may be asymptomatic, leading to a delayed diagnosis. Two drugs, pirfenidone and nintedanib, have been shown to modify the disease course by slowing down the decline in lung function. It is also known that 5–10% of the IPF patients may be affected by episodes of acute and often fatal decline. The acute worsening of disease is sometimes attributed to identifiable conditions, such as pneumonia or heart failure; but many of these events occur without an identifiable cause. These idiopathic acute worsenings are termed acute exacerbations of IPF. To date, clinical biomarkers, diagnostic, prognostic, and theranostic, are not well characterized. However, they could become useful tools helping facilitate diagnoses, monitoring disease progression and treatment efficacy. The aim of this review is to cover molecular mechanisms underlying IPF and research into new clinical biomarkers, to be utilized in diagnosis and prognosis, even in patients treated with antifibrotic drugs.     

Molecular Biomarkers for Pediatric Depressive Disorders: A Narrative Review

Depressive disorder in childhood and adolescence is a highly prevalent mood disorder that tends to recur throughout life. Untreated mood disorders can adversely impact a patient’s quality of life and cause socioeconomic loss. Thus, an accurate diagnosis and appropriate treatment is crucial. However, until now, diagnoses and treatments were conducted according to clinical symptoms. Objective and biological validation is lacking. This may result in a poor outcome for patients with depressive disorder. Research has been conducted to identify the biomarkers that are related to depressive disorder. Cumulative evidence has revealed that certain immunologic biomarkers including brain-derived neurotrophic factor (BDNF) and cytokines, gastrointestinal biomarkers, hormones, oxidative stress, and certain hypothalamus-pituitary axis biomarkers are associated with depressive disorder. This article reviews the biomarkers related to the diagnosis and treatment of pediatric depressive disorders. To date, clinical biomarker tests are not yet available for diagnosis or for the prediction of treatment prognosis. However, cytokines such as Interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and BDNF have shown significant results in previous studies of pediatric depressive disorder. These biomarkers have the potential to be used for diagnosis, prognostic assessment, and group screening for those at high risk.     

The Role of Biomarkers in Atherothrombotic Stroke—A Systematic Review

Stroke represents the primary debilitating disease in adults and is the second-highest cause of death worldwide. Atherosclerosis, the most prevalent etiology for vascular conditions, is a continuous process that gradually creates and develops endothelial lesions known as atherosclerotic plaques. These lesions lead to the appearance of atherothrombotic stroke. In the last decades, the role of biological biomarkers has emerged as either diagnostic, prognostic, or therapeutic targets. This article aims to create a list of potential biomarkers related to atherothrombotic stroke by reviewing the currently available literature. We identified 23 biomarkers and assessed their roles as risk factors, detection markers, prognostic predictors, and therapeutic targets. The central aspect of these biomarkers is related to risk stratification, especially for patients who have not yet suffered a stroke. Other valuable data are focused on the predictive capabilities for stroke patients regarding short-term and long-term prognosis, including their influence over the acute phase treatment, such as rt-PA thrombolysis. Although the role of biomarkers is anticipated to be of extreme value in the future, they cannot yet compete with traditional stroke neuroimaging markers but could be used as additional tools for etiological diagnosis.     

Oral Corticosteroids Dependence and Biologic Drugs in Severe Asthma: Myths or Facts? A Systematic Review of Real-World Evidence

Airway inflammation represents an important characteristic in asthma, modulating airflow limitation and symptom control, and triggering the risk of asthma exacerbation. Thus, although corticosteroids represent the cornerstone for the treatment of asthma, severe patients may be dependent on oral corticosteroids (OCSs). Fortunately, the current humanised monoclonal antibodies (mAbs) benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab have been proven to induce an OCS-sparing effect in randomized controlled trials (RCTs), thus overcoming the problem of OCS dependence in severe asthma. Nevertheless, a large discrepancy has been recognized between selected patients enrolled in RCTs and non-selected asthmatic populations in real-world settings. It is not possible to exclude that the OCS-sparing effect of mAbs resulting from the RCTs could be different than the real effect resulting in clinical practice. Therefore, we performed a systematic review and correlation analysis to assess whether mAbs are effective in eliciting an OCS-sparing effect and overcoming the OCS dependence in severe asthmatic patients in real-world settings. Overall, real-world studies support the evidence that OCS dependence is a real condition that, however, can be found only in a small number of really severe asthmatic patients. In most patients, the dependence on OCS can be related to modifying factors that, when adequately modulated, may lead to a significant reduction or suspension of OCS maintenance. Conversely, in severe asthmatics in whom OCS resistance is proved by a high daily dose intake, mAbs allow reversion of the OCS dependence, leading to the suspension of OCS therapy in most patients or >50% reduction in the daily OCS dose.     

Platelet-activating factor detected in bronchoalveolar lavage fluids from an asthmatic patient

It recently has been recognized that platelet-activating factor (PAF) may be a mediator of asthma exacerbation. We had the opportunity to analyze bronchoalveolar lavage fluids from an asthmatic infant, which were characterized by neutrophil infiltration. The patient's lungs were washed on three occasions with saline during asthmatic attacks. PAF was found in each case on the basis of its ability to cause the immediate aggregation of washed rabbit platelets. The PAF detected was equivalent to 1–1.4 pmol of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine, three quarters of which were recovered in cell-associated form. By contrast, we did not detect PAF in bronchoalveolar exudates from patients with larungeal stenosis or with respiratory distress syndrome. LysoPAF, the direct precursor as well as initial metabolite of PAF, was also analyzed after being converted to PAF by acetylation. There was a wide variation in the amount of lysoPAF present in individual patients, suggesting that lysoPAF levels cannot be taken as an indicator for the presence of PAF. Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl Ether Lipids, Tokyo, Japan, May 1989.     

Impact of Stilbenes as Epigenetic Modulators of Breast Cancer Risk and Associated Biomarkers

With the recent advancement of genetic screening for testing susceptibility to mammary oncogenesis in women, the relevance of the gene−environment interaction has become progressively apparent in the context of aberrant gene expressions. Fetal exposure to external stressors, hormones, and nutrients, along with the inherited genome, impact its traits, including cancer susceptibility. Currently, there is increasing interest in the role of epigenetic biomarkers such as genomic methylation signatures, plasma microRNAs, and alterations in cell-signaling pathways in the diagnosis and primary prevention of breast cancer, as well as its prognosis. Polyphenols like natural stilbenes have been shown to be effective in chemoprevention by exerting cytotoxic effects that can stall cell proliferation. Besides possessing antioxidant properties against the DNA-damaging effects of reactive oxygen species, stilbenes have also been observed to modulate cell-signaling pathways. With the increasing trend of early-life screening for hereditary breast cancer risks, the potency of different phytochemicals in harnessing the epigenetic biomarkers of breast cancer risk demand more investigation. This review will explore means of exploiting the abilities of stilbenes in altering the underlying factors that influence breast cancer risk, as well as the appearance of associated biomarkers.     

Asthma and Allergy: Unravelling a Tangled Relationship with a Focus on New Biomarkers and Treatment

Asthma is a major driver of health care costs across ages. Despite widely disseminated asthma-treatment guidelines and a growing variety of effective therapeutic options, most patients still experience symptoms and/or refractoriness to standard of care treatments. As a result, most patients undergo a further intensification of therapy to optimize symptom control with a subsequent increased risk of side effects. Raising awareness about the relevance of evaluating aeroallergen sensitizations in asthmatic patients is a key step in better informing clinical practice while new molecular tools, such as the component resolved diagnosis, may be of help in refining the relationship between sensitization and therapeutic recommendations. In addition, patient care should benefit from reliable, easy-to-measure and clinically accessible biomarkers that are able to predict outcome and disease monitoring. To attain a personalized asthma management and to guide adequate treatment decisions, it is of paramount importance to expand clinicians’ knowledge about the tangled relationship between asthma and allergy from a molecular perspective. Our review explores the relevance of allergen testing along the asthma patient’s journey, with a special focus on recurrent wheezing children. Here, we also discuss the unresolved issues regarding currently available biomarkers and summarize the evidence supporting the eosinophil-derived neurotoxin as promising biomarker.     

Mitochondria in the Center of Human Eosinophil Apoptosis and Survival

Eosinophils are abundantly present in most phenotypes of asthma and they contribute to the maintenance and exacerbations of the disease. Regulators of eosinophil longevity play critical roles in determining whether eosinophils accumulate into the airways of asthmatics. Several cytokines enhance eosinophil survival promoting eosinophilic airway inflammation while for example glucocorticoids, the most important anti-inflammatory drugs used to treat asthma, promote the intrinsic pathway of eosinophil apoptosis and by this mechanism contribute to the resolution of eosinophilic airway inflammation. Mitochondria seem to play central roles in both intrinsic mitochondrion-centered and extrinsic receptor-mediated pathways of apoptosis in eosinophils. Mitochondria may also be important for survival signalling. In addition to glucocorticoids, another important agent that regulates human eosinophil longevity via mitochondrial route is nitric oxide, which is present in increased amounts in the airways of asthmatics. Nitric oxide seems to be able to trigger both survival and apoptosis in eosinophils. This review discusses the current evidence of the mechanisms of induced eosinophil apoptosis and survival focusing on the role of mitochondria and clinically relevant stimulants, such as glucocorticoids and nitric oxide.     

Extracellular Vesicles from Airway Secretions: New Insights in Lung Diseases

Lung diseases (LD) are one of the most common causes of death worldwide. Although it is known that chronic airway inflammation and excessive tissue repair are processes associated with LD such as asthma, chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF), their specific pathways remain unclear. Extracellular vesicles (EVs) are heterogeneous nanoscale membrane vesicles with an important role in cell-to-cell communication. EVs are present in general biofluids as plasma or urine but also in secretions of the airway as bronchoalveolar lavage fluid (BALF), induced sputum (IS), nasal lavage (NL) or pharyngeal lavage. Alterations of airway EV cargo could be crucial for understanding LD. Airway EVs have shown a role in the pathogenesis of some LD such as eosinophil increase in asthma, the promotion of lung cancer in vitro models in COPD and as biomarkers to distinguishing IPF in patients with diffuse lung diseases. In addition, they also have a promising future as therapeutics for LD. In this review, we focus on the importance of airway secretions in LD, the pivotal role of EVs from those secretions on their pathophysiology and their potential for biomarker discovery.     

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies characterized by abnormal proliferation of immature lymphoid cells. It is the most commonly diagnosed childhood cancer with an almost 80% cure rate. Despite favorable survival rates in the pediatric population, a significant number of patients develop resistance to therapy, resulting in poor prognosis. ALL is a heterogeneous disease at the genetic level, but the intensive development of sequencing in the last decade has made it possible to broaden the study of genomic changes. New technologies allow us to detect molecular changes such as point mutations or to characterize epigenetic or proteomic profiles. This process made it possible to identify new subtypes of this disease characterized by constellations of genetic alterations, including chromosome changes, sequence mutations, and DNA copy number alterations. These genetic abnormalities are used as diagnostic, prognostic and predictive biomarkers that play an important role in earlier disease detection, more accurate risk stratification, and treatment. Identification of new ALL biomarkers, and thus a greater understanding of their molecular basis, will lead to better monitoring of the course of the disease. In this article, we provide an overview of the latest information on genomic alterations found in childhood ALL and discuss their impact on patients’ clinical outcomes.     

Advances and Challenges of Antibody Therapeutics for Severe Bronchial Asthma

Asthma is a disease that consists of three main components: airway inflammation, airway hyperresponsiveness, and airway remodeling. Persistent airway inflammation leads to the destruction and degeneration of normal airway tissues, resulting in thickening of the airway wall, decreased reversibility, and increased airway hyperresponsiveness. The progression of irreversible airway narrowing and the associated increase in airway hyperresponsiveness are major factors in severe asthma. This has led to the identification of effective pharmacological targets and the recognition of several biomarkers that enable a more personalized approach to asthma. However, the efficacies of current antibody therapeutics and biomarkers are still unsatisfactory in clinical practice. The establishment of an ideal phenotype classification that will predict the response of antibody treatment is urgently needed. Here, we review recent advancements in antibody therapeutics and novel findings related to the disease process for severe asthma.     

HIV-Associated Cancer Biomarkers: A Requirement for Early Diagnosis

Globally, HIV/AIDS and cancer are increasingly public health problems and continue to exist as comorbidities. The sub-Saharan African region has the largest number of HIV infections. Malignancies previously associated with HIV/AIDS, also known as the AIDS-defining cancers (ADCs) have been documented to decrease, while the non-AIDS defining cancer (NADCs) are on the rise. On the other hand, cancer is a highly heterogeneous disease and precision oncology as the most effective cancer therapy is gaining attraction. Among HIV-infected individuals, the increased risk for developing cancer is due to the immune system of the patient being suppressed, frequent coinfection with oncogenic viruses and an increase in risky behavior such as poor lifestyle. The core of personalised medicine for cancer depends on the discovery and the development of biomarkers. Biomarkers are specific and highly sensitive markers that reveal information that aid in leading to the diagnosis, prognosis and therapy of the disease. This review focuses mainly on the risk assessment, diagnostic, prognostic and therapeutic role of various cancer biomarkers in HIV-positive patients. A careful selection of sensitive and specific HIV-associated cancer biomarkers is required to identify patients at most risk of tumour development, thus improving the diagnosis and prognosis of the disease.     

Immunodiagnostic Biomarkers for Hepatocellular Carcinoma (HCC): The First Step in Detection and Treatment

Hepatocellular carcinoma (HCC) exerts huge effects on the health burden of the world because of its high mortality and poor prognosis. HCC is often clinically detected late in patients. If HCC could be detected and treated earlier, the survival rate of patients will be greatly improved. Therefore, identifying specific biomarkers is urgent and important for HCC. The liver is also recognized as an immune organ. The occurrence of HCC is related to exacerbation of immune tolerance and/or immunosurveillance escape. The host immune system plays an important role in the recognition and targeting of tumor cells in cancer immunotherapy, as can be seen from the clinical success of immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Thus, there is a pressing medical need to discover immunodiagnostic biomarkers specific to HCC for understanding the pathological mechanisms of HCC, especially for immunotherapy targets. We have reviewed the existing literature to summarize the immunodiagnostic markers of HCC, including autoantibodies against tumor-associated antigens (TAAs) and exosomes, to provide new insights into HCC and early detection of this deadly cancer.     

Exacerbation of allergic inflammation in mice exposed to diesel exhaust particles prior to viral infection

Background  

Viral infections and exposure to oxidant air pollutants are two of the most important inducers of asthma exacerbation. Our previous studies have demonstrated that exposure to diesel exhaust increases the susceptibility to influenza virus infections both in epithelial cells in vitro and in mice in vivo. Therefore, we examined whether in the setting of allergic asthma, exposure to oxidant air pollutants enhances the susceptibility to respiratory virus infections, which in turn leads to increased virus-induced exacerbation of asthma. Ovalbumin-sensitized (OVA) male C57BL/6 mice were instilled with diesel exhaust particles (DEP) or saline and 24 hours later infected with influenza A/PR/8. Animals were sacrificed 24 hours post-infection and analyzed for markers of lung injury, allergic inflammation, and pro-inflammatory cytokine production.