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J. Pers. Med., Volume 10, Issue 4 (December 2020) – 118 articles

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Open AccessFeature PaperReview
Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back
J. Pers. Med. 2020, 10(4), 258; https://doi.org/10.3390/jpm10040258 (registering DOI) - 28 Nov 2020
Abstract
Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenarios, life [...] Read more.
Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenarios, life threatening. Amongst other causes, they can be genetically inherited through mutations in more than 500 different genes. In the last 20 years, specific pharmacological treatments have been approved for human usage. However, these “à-la-carte” therapies cover only a very small portion of the clinical needs and are often partially efficient in alleviating the symptoms of the disease, even less so in curing it. Recombinant adeno-associated virus vector-mediated gene transfer is a more general strategy that could be adapted for a large majority of these diseases and has proved very efficient in rescuing the symptoms in many neuropathological animal models. On this solid ground, several clinical trials are currently being conducted with the whole-body delivery of the therapeutic vectors. This review recapitulates the state-of-the-art tools for neuron and muscle-targeted gene therapy, and summarises the main findings of the spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM) trials. Despite promising efficacy results, serious adverse events of various severities were observed in these trials. Possible leads for second-generation products are also discussed. Full article
Open AccessArticle
The Synergistic Effect of Plasminogen Activator Inhibitor-1 (PAI-1) Polymorphisms and Metabolic Syndrome on Coronary Artery Disease in the Korean Population
J. Pers. Med. 2020, 10(4), 257; https://doi.org/10.3390/jpm10040257 - 28 Nov 2020
Abstract
The most common type of cardiovascular disease is coronary artery disease (CAD), in which a plaque builds up inside the coronary arteries that can lead to a complete blockage of blood flow to the heart, resulting in a heart attack. The CAD may [...] Read more.
The most common type of cardiovascular disease is coronary artery disease (CAD), in which a plaque builds up inside the coronary arteries that can lead to a complete blockage of blood flow to the heart, resulting in a heart attack. The CAD may be affected by various factors including age, gender, and lipoprotein disposition as well as genetic factors and metabolic syndrome. In this study, we investigated whether three PAI-1 polymorphisms (-844 G>A, -675 4G>5G, and +43 G>A) and CAD-related clinical parameters are associated with CAD susceptibility. Genotyping of 463 CAD patients and 401 controls was performed using polymerase chain reaction restriction fragment length polymorphism analysis. We report that the 4G5G genotype (crude odds ratio(COR), 1.392; 95% confidence interval (CI), 1.036–1.871; p = 0.028) and dominant model (4G4G vs. 4G5G + 5G5G; COR, 1.401; 95% CI, 1.060–1.850; p = 0.018; adjust odds ratio, 1.371; 95% CI, 1.027–1.831; p = 0.032) of PAI-1 -675 polymorphisms were associated with increased CAD risk. Haplotype and genotype combinations of PAI-1 -675 and +43 polymorphisms show an increased risk of CAD according to alterations of the -675 polymorphism allele or genotype. Moreover, the PAI-1 -675 polymorphisms show a synergistic effect with the metabolic syndrome component of CAD risk. This study suggests that polymorphisms in the PAI-1 genes along with the metabolic syndrome component of CAD can be useful biomarkers for CAD diagnosis and treatment. Full article
Open AccessArticle
Impact of Drug-Gene-Interaction, Drug-Drug-Interaction, and Drug-Drug-Gene-Interaction on (es)Citalopram Therapy: The PharmLines Initiative
J. Pers. Med. 2020, 10(4), 256; https://doi.org/10.3390/jpm10040256 - 28 Nov 2020
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Abstract
We explored the association between CYP2C19/3A4 mediated drug-gene-interaction (DGI), drug-drug-interaction (DDI) and drug-drug-gene-interaction (DDGI) and (es)citalopram dispensing course. A cohort study was conducted among adult Caucasians from the Lifelines cohort (167,729 participants) and linked dispensing data from the IADB.nl database as part of [...] Read more.
We explored the association between CYP2C19/3A4 mediated drug-gene-interaction (DGI), drug-drug-interaction (DDI) and drug-drug-gene-interaction (DDGI) and (es)citalopram dispensing course. A cohort study was conducted among adult Caucasians from the Lifelines cohort (167,729 participants) and linked dispensing data from the IADB.nl database as part of the PharmLines Initiative. Exposure groups were categorized into (es)citalopram starters with DGI, DDI and DDGI. The primary outcome was drug switching and/or dose adjustment, and the secondary was early discontinuation after the start of (es)citalopram. Logistic regression modeling was applied to estimate adjusted odd ratios with their confidence interval. We identified 316 (es)citalopram starters with complete CYP2C19/3A4 genetic information. The CYP2C19 IM/PM and CYP3A4 NM combination increased risks of switching and/or dose reduction (OR: 2.75, 95% CI: 1.03–7.29). The higher effect size was achieved by the CYP2C19 IM/PM and CYP3A4 IM combination (OR: 4.38, 95% CI: 1.22–15.69). CYP2C19/3A4 mediated DDIs and DDGIs showed trends towards increased risks of switching and/or dose reduction. In conclusion, a DGI involving predicted decreased CYP2C19 function increases the need for (es)citalopram switching and/or dose reduction which might be enhanced by co-presence of predicted decreased CYP3A4 function. For DDI and DDGI, no conclusions can be drawn from the results. Full article
(This article belongs to the Special Issue Pharmacogenetics to Avoid Adverse Drug Reactions)
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Open AccessReview
The Emerging Role of CD24 in Cancer Theranostics—A Novel Target for Fluorescence Image-Guided Surgery in Ovarian Cancer and Beyond
J. Pers. Med. 2020, 10(4), 255; https://doi.org/10.3390/jpm10040255 - 27 Nov 2020
Viewed by 177
Abstract
Complete cytoreductive surgery is the cornerstone of the treatment of epithelial ovarian cancer (EOC). The application of fluorescence image-guided surgery (FIGS) allows for the increased intraoperative visualization and delineation of malignant lesions by using fluorescently labeled targeting biomarkers, thereby improving intraoperative guidance. CD24, [...] Read more.
Complete cytoreductive surgery is the cornerstone of the treatment of epithelial ovarian cancer (EOC). The application of fluorescence image-guided surgery (FIGS) allows for the increased intraoperative visualization and delineation of malignant lesions by using fluorescently labeled targeting biomarkers, thereby improving intraoperative guidance. CD24, a small glycophosphatidylinositol-anchored cell surface receptor, is overexpressed in approximately 70% of solid cancers, and has been proposed as a prognostic and therapeutic tumor-specific biomarker for EOC. Recently, preclinical studies have demonstrated the benefit of CD24-targeted contrast agents for non-invasive fluorescence imaging, as well as improved tumor resection by employing CD24-targeted FIGS in orthotopic patient-derived xenograft models of EOC. The successful detection of miniscule metastases denotes CD24 as a promising biomarker for the application of fluorescence-guided surgery in EOC patients. The aim of this review is to present the clinical and preclinically evaluated biomarkers for ovarian cancer FIGS, highlight the strengths of CD24, and propose a future bimodal approach combining CD24-targeted fluorescence imaging with radionuclide detection and targeted therapy. Full article
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Open AccessReview
Liquid Biomarkers for Pediatric Brain Tumors: Biological Features, Advantages and Perspectives
J. Pers. Med. 2020, 10(4), 254; https://doi.org/10.3390/jpm10040254 - 27 Nov 2020
Viewed by 91
Abstract
Tumors of the central nervous system are the most frequent solid tumor type and the major cause for cancer-related mortality in children and adolescents. These tumors are biologically highly heterogeneous and comprise various different entities. Molecular diagnostics are already well-established for pediatric brain [...] Read more.
Tumors of the central nervous system are the most frequent solid tumor type and the major cause for cancer-related mortality in children and adolescents. These tumors are biologically highly heterogeneous and comprise various different entities. Molecular diagnostics are already well-established for pediatric brain tumors and have facilitated a more accurate patient stratification. The availability of targeted, biomarker-driven therapies has increased the necessity of longitudinal monitoring of molecular alterations within tumors for precision medicine-guided therapy. Nevertheless, diagnosis is still primarily based on analyses of the primary tumor and follow-up is usually performed by imaging techniques which lack important information on tumor biology possibly changing the course of the disease. To overcome this shortage of longitudinal information, liquid biopsy has emerged as a promising diagnostic tool representing a less-invasive source of biomarkers for tumor monitoring and therapeutic decision making. Novel ultrasensitive methods for detection of allele variants, genetic alterations with low abundance, have been developed and are promising tools for establishing and integrating liquid biopsy techniques into clinical routine. Pediatric brain tumors harbor multiple molecular alterations with the potential to be used as liquid biomarkers. Consequently, studies have already investigated different types of biomarker in diverse entities of pediatric brain tumors. However, there are still certain pitfalls until liquid biomarkers can be unleashed and implemented into routine clinical care. Within this review, we summarize current knowledge on liquid biopsy markers and technologies in pediatric brain tumors, their advantages and drawbacks, as well as future potential biomarkers and perspectives with respect to clinical implementation in patient care. Full article
(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)
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Open AccessArticle
Cognitive Insight in First-Episode Psychosis: Changes during Metacognitive Training
J. Pers. Med. 2020, 10(4), 253; https://doi.org/10.3390/jpm10040253 - 27 Nov 2020
Viewed by 141
Abstract
Background: Metacognitive training (MCT) has demonstrated its efficacy in psychosis. However, the effect of each MCT session has not been studied. The aim of the study was to assess changes in cognitive insight after MCT: (a) between baseline, post-treatment, and follow-up; (b) after [...] Read more.
Background: Metacognitive training (MCT) has demonstrated its efficacy in psychosis. However, the effect of each MCT session has not been studied. The aim of the study was to assess changes in cognitive insight after MCT: (a) between baseline, post-treatment, and follow-up; (b) after each session of the MCT controlled for intellectual quotient (IQ) and educational level. Method: A total of 65 patients with first-episode psychosis were included in the MCT group from nine centers of Spain. Patients were assessed at baseline, post-treatment, and 6 months follow-up, as well as after each session of MCT with the Beck Cognitive Insight Scale (BCIS). The BCIS contains two subscales: self-reflectiveness and self-certainty, and the Composite Index. Statistical analysis was performed using linear mixed models with repeated measures at different time points. Results: Self-certainty decreased significantly (p = 0.03) over time and the effect of IQ was negative and significant (p = 0.02). From session 4 to session 8, all sessions improved cognitive insight by significantly reducing self-certainty and the Composite Index. Conclusions: MCT intervention appears to have beneficial effects on cognitive insight by reducing self-certainty, especially after four sessions. Moreover, a minimum IQ is required to ensure benefits from MCT group intervention. Full article
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Open AccessArticle
Establishment of a Molecular Tumor Board (MTB) and Uptake of Recommendations in a Community Setting
J. Pers. Med. 2020, 10(4), 252; https://doi.org/10.3390/jpm10040252 - 27 Nov 2020
Viewed by 157
Abstract
In the precision medicine era, molecular testing in advanced cancer is foundational to patient management. Molecular tumor boards (MTBs) can be effective in processing comprehensive genomic profiling (CGP) results and providing expert recommendations. We assessed an MTB and its role in a community [...] Read more.
In the precision medicine era, molecular testing in advanced cancer is foundational to patient management. Molecular tumor boards (MTBs) can be effective in processing comprehensive genomic profiling (CGP) results and providing expert recommendations. We assessed an MTB and its role in a community setting. This retrospective analysis included patients with MTB recommendations at a community-based oncology practice January 2015 to December 2018; exclusions were death within 60 days of the MTB and/or no metastatic disease. Potentially actionable genomic alterations from CGP (immunohistochemistry, in-situ hybridization, next-generation sequencing) were reviewed bi-weekly by MTB practice experts, pathologists, genetic counselors, and other support staff, and clinical care recommendations were provided. Subsequent chart reviews determined implementation rates of recommendations. In 613 patients, the most common cancers were lung (23%), breast (19%), and colorectal (17%); others included ovarian, endometrial, bladder, and melanoma. Patients received 837 actionable recommendations: standard therapy (37%), clinical trial (31%), germline testing and genetic counseling (17%), off-label therapy (10%), subspecialty multidisciplinary tumor board review (2%), and advice for classifying tumor of unknown origin (2%). Of these recommendations, 36% to 78% were followed by the treating physician. For clinical trial recommendations (n = 262), 13% of patients enrolled in a clinical trial. The median time between CPG result availability and MTB presentation was 12 days. A community oncology-based comprehensive and high-throughput MTB provided useful clinical guidance in various treatment domains within an acceptable timeframe for patients with cancer in a large community setting. Full article
(This article belongs to the Special Issue Personalized Medicine in Oncology)
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Open AccessArticle
Aetiology and 30-Year Long-Term Outcome of Children with Cardiomyopathy Necessitating Heart Transplantation
J. Pers. Med. 2020, 10(4), 251; https://doi.org/10.3390/jpm10040251 - 27 Nov 2020
Viewed by 180
Abstract
Studies assessing the long-term outcome after heart transplantation HTX in patients with cardiomyopathy (CM) in the paediatric age range are rare. The aim of this study was to determine the survival rate of children with CM undergoing HTX and to analyse how aetiology [...] Read more.
Studies assessing the long-term outcome after heart transplantation HTX in patients with cardiomyopathy (CM) in the paediatric age range are rare. The aim of this study was to determine the survival rate of children with CM undergoing HTX and to analyse how aetiology of cardiomyopathy influenced morbidity and mortality. We retrospectively analysed the medical records of children; who were transplanted in our centre between June 1988 and October 2019. 236 heart transplantations were performed since 1988 (9 re-transplants). 98 of 227 patients (43.2%) were transplanted because of CM. Survival rates were 93% after 1; 84% after 10 and 75% after 30 years. Overall; the aetiology of CM could be clearly identified in 37 subjects (37.7%). This rate increased up to 66.6% (12/19) by applying a comprehensive diagnostic workup since 2016. The survival rate was lower (p < 0.05) and neurocognitive deficits were more frequent (p = 0.001) in subjects with systemic diseases than in individuals with cardiac-specific conditions. These data indicate that the long-term survival rate of children with CM after HTX in experienced centers is high. A comprehensive diagnostic workup allows unraveling the basic defect in the majority of patients with CM undergoing HTX. Aetiology of CM affects morbidity and mortality in subjects necessitating HTX. Full article
(This article belongs to the Special Issue Genetic Basis and Clinical Determinants of Inherited Heart Disease)
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Open AccessArticle
Clinical Outcomes Based on Measurable Residual Disease Status in Patients with Core-Binding Factor Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis
J. Pers. Med. 2020, 10(4), 250; https://doi.org/10.3390/jpm10040250 - 26 Nov 2020
Viewed by 103
Abstract
Measurable residual disease (MRD) response during acute myeloid leukemia (AML) treatment is a gold standard for determining treatment strategy, especially in core-binding factor (CBL) AML. The aim of this study was to critically review the literature on MRD status in the CBF-AML to [...] Read more.
Measurable residual disease (MRD) response during acute myeloid leukemia (AML) treatment is a gold standard for determining treatment strategy, especially in core-binding factor (CBL) AML. The aim of this study was to critically review the literature on MRD status in the CBF-AML to determine the overall impact of MRD status on clinical outcomes. Published studies in the MEDLINE and EMBASE databases from their inception up to 1 June 2019 were searched. The primary end-point was either overall survival (OS) or recurrence-free survival (RFS) between MRD negative and MRD positive CBF-AML patients. The secondary variable was cumulative incidence of relapse (CIR) between groups. Of the 736 articles, 13 relevant studies were included in this meta-analysis. The MRD negative group displayed more favorable recurrence-free survival (RFS) than those with MRD positivity, with a pooled odds ratio (OR) of 4.5. Moreover, OS was also superior in the MRD negative group, with a pooled OR of 7.88. Corroborating this, the CIR was statistically significantly lower in the MRD negative group, with a pooled OR of 0.06. The most common cutoff MRD level was 1 × 10−3. These results suggest that MRD assessment should be a routine investigation in clinical practice in this AML subset. Full article
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Open AccessReview
Visualization and Measurements of Blood Cells Flowing in Microfluidic Systems and Blood Rheology: A Personalized Medicine Perspective
J. Pers. Med. 2020, 10(4), 249; https://doi.org/10.3390/jpm10040249 - 26 Nov 2020
Viewed by 109
Abstract
Hemorheological alterations in the majority of metabolic diseases are always connected with blood rheology disturbances, such as the increase of blood and plasma viscosity, cell aggregation enhancement, and reduction of the red blood cells (RBCs) deformability. Thus, the visualizations and measurements of blood [...] Read more.
Hemorheological alterations in the majority of metabolic diseases are always connected with blood rheology disturbances, such as the increase of blood and plasma viscosity, cell aggregation enhancement, and reduction of the red blood cells (RBCs) deformability. Thus, the visualizations and measurements of blood cells deformability flowing in microfluidic devices (point-of-care devices) can provide vital information to diagnose early symptoms of blood diseases and consequently to be used as a fast clinical tool for early detection of biomarkers. For instance, RBCs rigidity has been correlated with myocardial infarction, diabetes mellitus, hypertension, among other blood diseases. In order to better understand the blood cells behavior in microfluidic devices, rheological properties analysis is gaining interest by the biomedical committee, since it is strongly dependent on the interactions and mechanical cells proprieties. In addition, the development of blood analogue fluids capable of reproducing the rheological properties of blood and mimic the RBCs behavior at in vitro conditions is crucial for the design, performance and optimization of the microfluidic devices frequently used for personalized medicine. By combining the unique features of the hemorheology and microfluidic technology for single-cell analysis, valuable advances in personalized medicine for new treatments and diagnosis approach can be achieved. Full article
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Open AccessArticle
Sex Differences in Time-Series Changes in Pseudo-R2 Values Regarding Hyperuricemia in Relation to the Kidney Prognosis
J. Pers. Med. 2020, 10(4), 248; https://doi.org/10.3390/jpm10040248 - 26 Nov 2020
Viewed by 108
Abstract
Studies on sex differences in time-series changes in pseudo-R2 values regarding hyperuricemia (HU) in relation to the kidney prognosis among patients with chronic kidney disease (CKD) are scant. The kidney prognosis was evaluated in 200 patients with CKD (median follow-up, 12.3 [...] Read more.
Studies on sex differences in time-series changes in pseudo-R2 values regarding hyperuricemia (HU) in relation to the kidney prognosis among patients with chronic kidney disease (CKD) are scant. The kidney prognosis was evaluated in 200 patients with CKD (median follow-up, 12.3 years). Survival analyses and logistic regression analyses were conducted, generating time-series pseudo-R2 values. We used four definitions of HU according to serum uric acid (SUA) levels (HU6, SUA ≥ 6.0 mg/dL; HU7, SUA ≥ 7.0 mg/dL; HU8, SUA ≥ 8.0 mg/dL) and antihyperuricemic agent use to calculate the mean and percentage of the change in pseudo-R2 values from the 6th year until the end of the study (6Y–End Mean and 6Y–End Change, respectively). The multivariable Cox regression analysis showed that HU7 was significantly associated with kidney outcomes. When stratified by sex, the 6Y–End Mean was clearly higher in women than in men for all HU definitions, with the highest value (0.1755) obtained for HU7 in women. The pseudo-R2 values for HU6 in women showed an increasing pattern, with a 6Y–End Change of 11.4%/year. Thus, it may be clinically meaningful to consider sex differences in the time-series pseudo-R2 values regarding HU and kidney outcomes. Full article
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Open AccessReview
What Can Machine Learning Approaches in Genomics Tell Us about the Molecular Basis of Amyotrophic Lateral Sclerosis?
J. Pers. Med. 2020, 10(4), 247; https://doi.org/10.3390/jpm10040247 - 26 Nov 2020
Viewed by 263
Abstract
Amyotrophic Lateral Sclerosis (ALS) is the most common late-onset motor neuron disorder, but our current knowledge of the molecular mechanisms and pathways underlying this disease remain elusive. This review (1) systematically identifies machine learning studies aimed at the understanding of the genetic architecture [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is the most common late-onset motor neuron disorder, but our current knowledge of the molecular mechanisms and pathways underlying this disease remain elusive. This review (1) systematically identifies machine learning studies aimed at the understanding of the genetic architecture of ALS, (2) outlines the main challenges faced and compares the different approaches that have been used to confront them, and (3) compares the experimental designs and results produced by those approaches and describes their reproducibility in terms of biological results and the performances of the machine learning models. The majority of the collected studies incorporated prior knowledge of ALS into their feature selection approaches, and trained their machine learning models using genomic data combined with other types of mined knowledge including functional associations, protein-protein interactions, disease/tissue-specific information, epigenetic data, and known ALS phenotype-genotype associations. The importance of incorporating gene-gene interactions and cis-regulatory elements into the experimental design of future ALS machine learning studies is highlighted. Lastly, it is suggested that future advances in the genomic and machine learning fields will bring about a better understanding of ALS genetic architecture, and enable improved personalized approaches to this and other devastating and complex diseases. Full article
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Open AccessArticle
Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer
J. Pers. Med. 2020, 10(4), 246; https://doi.org/10.3390/jpm10040246 - 26 Nov 2020
Viewed by 113
Abstract
Objective: The objective of this study is to identify and validate novel therapeutic target(s) in ovarian cancer. Background: Development of targeted therapeutics in ovarian cancer has been limited by molecular heterogeneity. Although gene expression datasets are available, most of them lack appropriate pair-matched [...] Read more.
Objective: The objective of this study is to identify and validate novel therapeutic target(s) in ovarian cancer. Background: Development of targeted therapeutics in ovarian cancer has been limited by molecular heterogeneity. Although gene expression datasets are available, most of them lack appropriate pair-matched controls to define the alterations that result in the transformation of normal ovarian cells to cancerous cells. Methods: We used microarray to compare the gene expression of treatment-naïve ovarian cancer tissue samples to pair-matched normal adjacent ovarian tissue from 24 patients. Ingenuity Pathway Analysis (IPA) was used to identify target pathways for further analysis. Integrin-linked kinase (ILK) expression in SKOV3 and OV90 cells was determined using Western blot. ILK was knocked down using CRISPR/Cas9 constructs. Subcutaneous xenograft study to determine the effect of ILK knockdown on tumor growth was performed in NOD SCID gamma mice. Results: Significant upregulation of the ILK pathway was identified in 22 of the 24 cancer specimens, identifying it as a potential player that could contribute to the transformation of normal ovarian cells to cancerous cells. Knockdown of ILK in SKOV3 cells resulted in decreased cell proliferation and tumor growth, and inhibition of downstream kinase, AKT (protein kinase B). These results were further validated using an ILK-1 chemical inhibitor, compound 22. Conclusion: Our initial findings validate ILK as a potential therapeutic target for molecular inhibition in ovarian cancer, which warrants further investigation. Full article
(This article belongs to the Special Issue Personalized Medicine in Oncology)
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Open AccessReview
An Overview of the Application of Systems Biology in an Understanding of Chronic Rhinosinusitis (CRS) Development
J. Pers. Med. 2020, 10(4), 245; https://doi.org/10.3390/jpm10040245 - 26 Nov 2020
Viewed by 118
Abstract
Chronic rhinosinusitis (CRS) is an inflammatory disease of the paranasal sinuses. It is defined as the presence of a minimum of two out of four main symptoms such as hyposmia, facial pain, nasal blockage, and discharge, which last for 8–12 weeks. CRS significantly [...] Read more.
Chronic rhinosinusitis (CRS) is an inflammatory disease of the paranasal sinuses. It is defined as the presence of a minimum of two out of four main symptoms such as hyposmia, facial pain, nasal blockage, and discharge, which last for 8–12 weeks. CRS significantly impairs a patient’s quality of life. It needs special treatment mainly focusing on preventing local infection/inflammation with corticosteroid sprays or improving sinus drainage using nasal saline irrigation. When other treatments fail, endoscopic sinus surgery is considered an effective option. According to the state-of-the-art knowledge of CRS, there is more evidence suggesting that it is more of an inflammatory disease than an infectious one. This condition is also treated as a multifactorial inflammatory disorder as it may be triggered by various factors, such as bacterial or fungal infections, airborne irritants, defects in innate immunity, or the presence of concomitant diseases. Due to the incomplete understanding of the pathological processes of CRS, there is a continuous search for new indicators that are directly related to the pathogenesis of this disease—e.g., in the field of systems biology. The studies adopting systems biology search for possible factors responsible for the disease at genetic, transcriptomic, proteomic, and metabolomic levels. The analyses of the changes in the genome, transcriptome, proteome, and metabolome may reveal the dysfunctional pathways of inflammatory regulation and provide a clear insight into the pathogenesis of this disease. Therefore, in the present paper, we have summarized the state-of-the-art knowledge of the application of systems biology in the pathology and development of CRS. Full article
(This article belongs to the Special Issue Integrative Multi-Omics for Novel Clinical Insights)
Open AccessArticle
Helpful Criteria When Implementing NGS Panels in Childhood Lymphoblastic Leukemia
J. Pers. Med. 2020, 10(4), 244; https://doi.org/10.3390/jpm10040244 - 26 Nov 2020
Viewed by 137
Abstract
The development of Next-Generation Sequencing (NGS) has provided useful diagnostic, prognostic, and therapeutic strategies for individualized management of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Consequently, NGS is rapidly being established in clinical practice. However, the technology’s complexity, bioinformatics analysis, and the different [...] Read more.
The development of Next-Generation Sequencing (NGS) has provided useful diagnostic, prognostic, and therapeutic strategies for individualized management of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Consequently, NGS is rapidly being established in clinical practice. However, the technology’s complexity, bioinformatics analysis, and the different available options difficult a broad consensus between different laboratories in its daily routine introduction. This collaborative study among Spanish centers was aimed to assess the feasibility, pros, and cons of our customized panel and other commercial alternatives of NGS-targeted approaches. The custom panel was tested in three different sequencing centers. We used the same samples to assess other commercial panels (OncomineTM Childhood Cancer Research Assay; Archer®FusionPlex® ALL, and Human Comprehensive Cancer Panel GeneRead Panel v2®). Overall, the panels showed a good performance in different centers and platforms, but each NGS approach presented some issues, as well as pros and cons. Moreover, a previous consensus on the analysis and reporting following international guidelines would be preferable to improve the concordance in results among centers. Our study shows the challenges posed by NGS methodology and the need to consider several aspects of the chosen NGS-targeted approach and reach a consensus before implementing it in daily practice. Full article
(This article belongs to the Special Issue Clinical Application of Personalized Genomic Medicine)
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Open AccessArticle
Molecular Genetic Architecture of Monogenic Pediatric IBD Differs from Complex Pediatric and Adult IBD
J. Pers. Med. 2020, 10(4), 243; https://doi.org/10.3390/jpm10040243 - 26 Nov 2020
Viewed by 138
Abstract
Inflammatory bowel disease (IBD) manifests as a complex disease resulting from gene–environment interactions or as a monogenic disease resulting from deleterious mutations. While monogenic IBD is predominantly pediatric, only one-quarter of complex IBD is pediatric. In this study, we were the first to [...] Read more.
Inflammatory bowel disease (IBD) manifests as a complex disease resulting from gene–environment interactions or as a monogenic disease resulting from deleterious mutations. While monogenic IBD is predominantly pediatric, only one-quarter of complex IBD is pediatric. In this study, we were the first to systematically compare genetic architecture between monogenic and complex pediatric and adult IBD on genetic and molecular pathway levels. Genes reported as causal for monogenic pediatric IBD and related syndromes and as risk factors for pediatric and adult complex IBD were analyzed using CytoScape and ClueGO software tools to elucidate significantly enriched Gene Ontology (GO) terms. Despite the small overlap (seven genes) between monogenic IBD genes (85) and complex IBD loci (240), GO analysis revealed several enriched GO terms shared between subgroups (13.9%). Terms Th17 cell differentiation and Jak/STAT signaling were enriched in both monogenic and complex IBD subgroups. However, primary immunodeficiency and B-cell receptor signaling pathway were specifically enriched only for pediatric subgroups, confirming existing clinical observations and experimental evidence of primary immunodeficiency in pediatric IBD patients. In addition, comparative analysis identified patients below 6 years of age to significantly differ from complex pediatric and adult IBD and could be considered a separate entity. Full article
(This article belongs to the Section Mechanisms of Diseases)
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Open AccessArticle
Amorphous Ropinirole-Loaded Mucoadhesive Buccal Film: A Potential Patient-Friendly Tool to Improve Drug Pharmacokinetic Profile and Effectiveness
J. Pers. Med. 2020, 10(4), 242; https://doi.org/10.3390/jpm10040242 - 25 Nov 2020
Viewed by 138
Abstract
Nowadays the therapeutic strategies to manage Parkinson’s Disease are merely symptomatic and consist of administering L-DOPA and/or dopamine receptor agonists. Among these, Ropinirole (ROP) is a widely orally-administered molecule, although it is extensively susceptible to hepatic metabolism. Since literature reports the buccal mucosa [...] Read more.
Nowadays the therapeutic strategies to manage Parkinson’s Disease are merely symptomatic and consist of administering L-DOPA and/or dopamine receptor agonists. Among these, Ropinirole (ROP) is a widely orally-administered molecule, although it is extensively susceptible to hepatic metabolism. Since literature reports the buccal mucosa as a potentially useful route to ROP administration, the development of novel, effective, and comfortable oromucosal formulations should prove desirable in order to both enhance the therapeutic efficacy of the drug and allow a personalized therapeutic strategy able to meet the patient’s needs. The results of the proposed ROP film as a new dosage form show that it is flexible; uniform; and characterized by suitable surface pH; good mucoadhesiveness; low swelling degree; and fast, complete drug release. Moreover, after ex vivo evaluation on a film having an area of 0.282 cm2 and dose of 2.29 mg, the results of drug flux through the buccal mucosa are closely comparable to the amount of ROP that reaches the bloodstream at the steady-state condition after ROP-PR 4 mg oral administration, calculated according to the literature (0.237 mg/cm2·h−1 vs. 0.243 mg/h, respectively). Moreover, drug flux and ROP dose could be accurately modulated time-by-time depending on the patient’s need, by varying the administered disk area. In addition, the proposed ROP film displays no lag time, producing an immediate drug input in the bloodstream, which could result in a prompt therapeutic response. These findings make ROP film a potentially comfortable and patient-friendly formulation, and a promising candidate for further clinical trials. Full article
(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)
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Open AccessArticle
Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry
J. Pers. Med. 2020, 10(4), 241; https://doi.org/10.3390/jpm10040241 - 23 Nov 2020
Viewed by 386
Abstract
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder generally caused by out-of-frame mutations in the DMD gene. In contrast, in-frame mutations usually give rise to the milder Becker muscular dystrophy (BMD). However, this reading frame rule does not always hold true. Therefore, [...] Read more.
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder generally caused by out-of-frame mutations in the DMD gene. In contrast, in-frame mutations usually give rise to the milder Becker muscular dystrophy (BMD). However, this reading frame rule does not always hold true. Therefore, an understanding of the relationships between genotype and phenotype is important for informing diagnosis and disease management, as well as the development of genetic therapies. Here, we evaluated genotype–phenotype correlations in DMD and BMD patients enrolled in the Canadian Neuromuscular Disease Registry from 2012 to 2019. Data from 342 DMD and 60 BMD patients with genetic test results were analyzed. The majority of patients had deletions (71%), followed by small mutations (17%) and duplications (10%); 2% had negative results. Two deletion hotspots were identified, exons 3–20 and exons 45–55, harboring 86% of deletions. Exceptions to the reading frame rule were found in 13% of patients with deletions. Surprisingly, C-terminal domain mutations were associated with decreased wheelchair use and increased forced vital capacity. Dp116 and Dp71 mutations were also linked with decreased wheelchair use, while Dp140 mutations significantly predicted cardiomyopathy. Finally, we found that 12.3% and 7% of DMD patients in the registry could be treated with FDA-approved exon 51- and 53-skipping therapies, respectively. Full article
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Open AccessArticle
Evaluation of a Home Monitoring Application for Follow Up after Lung Transplantation—A Pilot Study
J. Pers. Med. 2020, 10(4), 240; https://doi.org/10.3390/jpm10040240 - 21 Nov 2020
Viewed by 190
Abstract
Home spirometry after lung transplantation is common practice, to monitor graft function. However, there is little experience with online home monitoring applications with direct data transfer to the hospital. We evaluated the feasibility and patient experiences with a new online home monitoring application, [...] Read more.
Home spirometry after lung transplantation is common practice, to monitor graft function. However, there is little experience with online home monitoring applications with direct data transfer to the hospital. We evaluated the feasibility and patient experiences with a new online home monitoring application, integrated with a Bluetooth-enabled spirometer and real-time data transfer. Consecutive lung transplant recipients were asked to evaluate this home monitoring application for three months in a pilot study. Home spirometry measurements were compared with in-hospital lung function tests (the forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) at the end of the study. Ten patients participated. The home and hospital spirometry measurements showed a high correlation, for both the FEV1 (r = 0.99, p < 0.01) and FVC (r = 0.99, p < 0.01). The adherence and patient satisfaction were high, and the patients preferred the home monitoring application over the current home spirometer, with a difference of 1.4 ± 1.5 points on a scale from 0 to 10 (p = 0.02). Online home monitoring with direct data transfer is feasible and reliable after lung transplantation and results in high patient satisfaction. Whether the implementation of online home monitoring enables the earlier detection of lung function decline and improves patient and graft outcomes will be the subject of future research. Full article
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Open AccessReview
Genetic Risk Score for Coronary Heart Disease: Review
J. Pers. Med. 2020, 10(4), 239; https://doi.org/10.3390/jpm10040239 - 20 Nov 2020
Viewed by 207
Abstract
The present review deals with the stages of creation, methods of calculation, and the use of a genetic risk score for coronary heart disease in various populations. The concept of risk factors is generally recognized on the basis of the results of epidemiological [...] Read more.
The present review deals with the stages of creation, methods of calculation, and the use of a genetic risk score for coronary heart disease in various populations. The concept of risk factors is generally recognized on the basis of the results of epidemiological studies in the 20th century; according to this concept, the high prevalence of diseases of the circulatory system is due to lifestyle characteristics and associated risk factors. An important and relevant task for the healthcare system is to identify the population segments most susceptible to cardiovascular diseases (CVDs). The level of individual risk of an unfavorable cardiovascular prognosis is determined by genetic factors in addition to lifestyle factors. Full article
(This article belongs to the Special Issue Genetic Basis and Clinical Determinants of Inherited Heart Disease)
Open AccessEditorial
Biomarkers for Alzheimer’s Disease: Where Do We Stand and Where Are We Going?
J. Pers. Med. 2020, 10(4), 238; https://doi.org/10.3390/jpm10040238 - 20 Nov 2020
Viewed by 319
Abstract
Alzheimer’s disease (AD) is an age-related neurodegenerative and progressive disorder representing the most common form of dementia in older adults [...] Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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Open AccessReview
The Road so Far in Colorectal Cancer Pharmacogenomics: Are We Closer to Individualised Treatment?
J. Pers. Med. 2020, 10(4), 237; https://doi.org/10.3390/jpm10040237 - 19 Nov 2020
Viewed by 252
Abstract
In recent decades, survival rates in colorectal cancer have improved greatly due to pharmacological treatment. However, many patients end up developing adverse drug reactions that can be severe or even life threatening, and that affect their quality of life. These remain a limitation, [...] Read more.
In recent decades, survival rates in colorectal cancer have improved greatly due to pharmacological treatment. However, many patients end up developing adverse drug reactions that can be severe or even life threatening, and that affect their quality of life. These remain a limitation, as they may force dose reduction or treatment discontinuation, diminishing treatment efficacy. From candidate gene approaches to genome-wide analysis, pharmacogenomic knowledge has advanced greatly, yet there is still huge and unexploited potential in the use of novel technologies such as next-generation sequencing strategies. This review summarises the road of colorectal cancer pharmacogenomics so far, presents considerations and directions to be taken for further works and discusses the path towards implementation into clinical practice. Full article
(This article belongs to the Special Issue Pharmacogenetics to Avoid Adverse Drug Reactions)
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Open AccessArticle
Multi-Omics Identifies Circulating miRNA and Protein Biomarkers for Facioscapulohumeral Dystrophy
J. Pers. Med. 2020, 10(4), 236; https://doi.org/10.3390/jpm10040236 - 19 Nov 2020
Viewed by 489
Abstract
The development of therapeutics for muscle diseases such as facioscapulohumeral dystrophy (FSHD) is impeded by a lack of objective, minimally invasive biomarkers. Here we identify circulating miRNAs and proteins that are dysregulated in early-onset FSHD patients to develop blood-based molecular biomarkers. Plasma samples [...] Read more.
The development of therapeutics for muscle diseases such as facioscapulohumeral dystrophy (FSHD) is impeded by a lack of objective, minimally invasive biomarkers. Here we identify circulating miRNAs and proteins that are dysregulated in early-onset FSHD patients to develop blood-based molecular biomarkers. Plasma samples from clinically characterized individuals with early-onset FSHD provide a discovery group and are compared to healthy control volunteers. Low-density quantitative polymerase chain reaction (PCR)-based arrays identify 19 candidate miRNAs, while mass spectrometry proteomic analysis identifies 13 candidate proteins. Bioinformatic analysis of chromatin immunoprecipitation (ChIP)-seq data shows that the FSHD-dysregulated DUX4 transcription factor binds to regulatory regions of several candidate miRNAs. This panel of miRNAs also shows ChIP signatures consistent with regulation by additional transcription factors which are up-regulated in FSHD (FOS, EGR1, MYC, and YY1). Validation studies in a separate group of patients with FSHD show consistent up-regulation of miR-100, miR-103, miR-146b, miR-29b, miR-34a, miR-454, miR-505, and miR-576. An increase in the expression of S100A8 protein, an inflammatory regulatory factor and subunit of calprotectin, is validated by Enzyme-Linked Immunosorbent Assay (ELISA). Bioinformatic analyses of proteomics and miRNA data further support a model of calprotectin and toll-like receptor 4 (TLR4) pathway dysregulation in FSHD. Moving forward, this panel of miRNAs, along with S100A8 and calprotectin, merit further investigation as monitoring and pharmacodynamic biomarkers for FSHD. Full article
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Open AccessArticle
Evaluation of the Role of Circulating Tumor Cells and Microsatellite Instability Status in Predicting Outcome of Advanced CRC Patients
J. Pers. Med. 2020, 10(4), 235; https://doi.org/10.3390/jpm10040235 - 18 Nov 2020
Viewed by 242
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related death due to its high metastatic potential. This study aimed to investigate the detection and heterogeneity of circulating tumor cells (CTCs) and the microsatellite instability (MSI) status in advanced CRC patients prior [...] Read more.
Colorectal cancer (CRC) remains one of the leading causes of cancer-related death due to its high metastatic potential. This study aimed to investigate the detection and heterogeneity of circulating tumor cells (CTCs) and the microsatellite instability (MSI) status in advanced CRC patients prior to any systemic front-line treatment. Peripheral whole blood was obtained from 198 patients. CTCs were detected using double immunofluorescence and a real time-polymerase chain reaction assay; whereas MSI status was evaluated using fragment analysis. Median age of the patients was 66 years, 63.1% were males, 65.2% had a colon/sigmoid tumor location and 90.4% had a good performance status (PS). MSI-High status was detected in 4.9% of the patients; 33.3%, 56.1% and 8.6% patients had at least one detectable CEACAM5+/EpCAM+, CEACAM5+/EpCAM and CEACAM5/EpCAM+ CTC, respectively, and 9.1% of the patients had CEACAM5mRNA-positive CTCs. Following multivariate analysis, age, PS and MSI were confirmed as independent prognostic factors for decreased time to progression, whereas age, PS and CTC presence were confirmed as independent prognostic factors for decreased overall survival. In conclusion, our data support the use of CEACAM5 as a dynamic adverse prognostic CTC biomarker in patients with metastatic CRC and MSI-High is considered an unfavorable prognostic factor in metastatic CRC patient tumors. Full article
(This article belongs to the Special Issue Immunology and Immunogenetics)
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Open AccessCase Report
A Novel Kindred with Familial Gastrointestinal Stromal Tumors Caused by a Rare KIT Germline Mutation (N655K): Clinico-Pathological Presentation and TKI Sensitivity
J. Pers. Med. 2020, 10(4), 234; https://doi.org/10.3390/jpm10040234 - 17 Nov 2020
Viewed by 370
Abstract
Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age [...] Read more.
Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a KIT germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this KIT variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant KIT mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs. Full article
(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)
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Open AccessArticle
An Integrated Imaging and Circulating Biomarker Approach for Secondary Tricuspid Regurgitation
J. Pers. Med. 2020, 10(4), 233; https://doi.org/10.3390/jpm10040233 - 16 Nov 2020
Viewed by 239
Abstract
Secondary tricuspid regurgitation (sTR) is frequent among patients with heart failure with reduced ejection fraction (HFrEF), however it confers considerable diagnostic challenges. The assessment of neurohumoral activation may constitute a valuable supplement to the current imaging-based diagnostic process. This study sought to investigate [...] Read more.
Secondary tricuspid regurgitation (sTR) is frequent among patients with heart failure with reduced ejection fraction (HFrEF), however it confers considerable diagnostic challenges. The assessment of neurohumoral activation may constitute a valuable supplement to the current imaging-based diagnostic process. This study sought to investigate the expression of complementary biomarkers in sTR and to evaluate the effectiveness of integrating their assessment into the diagnostic process. We enrolled 576 HFrEF patients recording echocardiographic and biochemical measurements, i.e., N-terminal pro-B-type natriuretic peptide, mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin, C-terminal pro-endothelin-1 (CT-pro-ET1), and copeptin. Plasma levels of the aforementioned neurohormones were significantly elevated with increasing sTR severity (p < 0.001 for all). CT-pro-ET1 and MR-proANP were the closest related to severe sTR (adj. OR 1.46; 95%CI 1.11–1.91, p = 0.006 and adj. OR 1.45, 95%CI 1.13–1.87, p = 0.004, respectively). In patients with moderate-to-severe sTR, adding selected biomarkers (i.e., CT-pro-ET1 and MR-proANP) resulted in a substantial improvement in the discriminatory power regarding long-term mortality (C-statistic: 0.54 vs. 0.65, p < 0.001; continuous NRI 57%, p < 0.001). Circulating biomarkers closely relate to sTR severity and correlate with hemodynamic and morphologic mechanisms of sTR. Specifically, MR-proANP and CT-pro-ET1 are closely linked to the presence of severe sTR, and a combined assessment with the guideline recommended echocardiographic grading significantly improves individual risk stratification. Full article
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Open AccessArticle
Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-β in Human Skin Fibroblasts from Familial Alzheimer’s Disease
J. Pers. Med. 2020, 10(4), 232; https://doi.org/10.3390/jpm10040232 - 16 Nov 2020
Viewed by 288
Abstract
Alzheimer’s disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aβ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous [...] Read more.
Alzheimer’s disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aβ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, Aβ and 37/67kDa laminin receptor (LR), finding the possibility to regulate intracellular APP localization and maturation through modulation of the receptor. Here, we report that in fibroblasts from familial AD (fAD), APP was prevalently expressed as an immature isoform and accumulated preferentially in the transferrin-positive recycling compartment rather than in the Golgi apparatus. Moreover, besides the altered mitochondrial network exhibited by fAD patient cells, the levels of pAkt and pGSK3 were reduced in respect to healthy control fibroblasts and were accompanied by an increased amount of secreted Aβ in conditioned medium from cell cultures. Interestingly, these features were reversed by inhibition of 37/67kDa LR by NSC47924 a small molecule that was able to rescue the “typical” APP localization in the Golgi apparatus, with consequences on the Aβ level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and Aβ levels with implications in Alzheimer’s disease. Full article
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Open AccessArticle
Ocular Vascular Changes in Mild Alzheimer’s Disease Patients: Foveal Avascular Zone, Choroidal Thickness, and ONH Hemoglobin Analysis
J. Pers. Med. 2020, 10(4), 231; https://doi.org/10.3390/jpm10040231 - 15 Nov 2020
Viewed by 413
Abstract
In Alzheimer’s disease (AD), vascular changes could be caused by amyloid beta (Aβ) aggregates replacing the contractile smooth musculature of the arteriole walls. These changes happen in the brain vascular network, but also in the eye, and are related to decreased vascular density [...] Read more.
In Alzheimer’s disease (AD), vascular changes could be caused by amyloid beta (Aβ) aggregates replacing the contractile smooth musculature of the arteriole walls. These changes happen in the brain vascular network, but also in the eye, and are related to decreased vascular density and low blood flow. In patients with Alzheimer’s disease, thinning of the choroid and the retina has been shown. The aim of this prospective study was to assess the retinal and choroidal vascular systems, analyzing the choroidal thickness with optical coherence tomography (OCT), the foveal avascular zone (FAZ) with OCT-angiography (OCTA), and the optic nerve head (ONH) hemoglobin with the Laguna ONhE program, to evaluate which of the two ocular vascular systems shows earlier changes in mild AD patients. These patients, compared to controls, showed a significantly thinner choroid at all the analyzed points, with the exception of the temporal macula (at 1000 and 1500 µm from the fovea). On the other hand, the FAZ and ONH hemoglobin did not show significant differences. In conclusion, a thinner choroid was the main ocular vascular change observed in mild AD patients, while the retinal vessels were not yet affected. Therefore, choroidal thickness could be used an early biomarker in AD. Full article
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Open AccessArticle
Dynamic Prognostication in Transplant Candidates with Acute-on-Chronic Liver Failure
J. Pers. Med. 2020, 10(4), 230; https://doi.org/10.3390/jpm10040230 - 15 Nov 2020
Viewed by 217
Abstract
We aimed to extensively investigate clinical markers that are sufficiently dynamic for prognosis of acute-on-chronic liver failure (ACLF). Defined by the Asian Pacific Association for the Study of the Liver (APASL) criteria, patients with ACLF on the liver transplant waitlist in a tertiary [...] Read more.
We aimed to extensively investigate clinical markers that are sufficiently dynamic for prognosis of acute-on-chronic liver failure (ACLF). Defined by the Asian Pacific Association for the Study of the Liver (APASL) criteria, patients with ACLF on the liver transplant waitlist in a tertiary center were retrospectively reviewed. Laboratory results and severity scores at three time points (days 1, 7, and 14 after admission) were analyzed. From 2015 to 2019, 64 patients with ACLF were enrolled, of which 24 received a liver transplant from 22 live donors. The hospital mortality rate was 31% (8% for transplant; 45% for nontransplant groups), and the 3-month survival was crucial for determining long-term outcomes. The number of significant variables for mortality, and, specifically, the hazards of international normalized ratio of prothrombin time (INR) and APASL ACLF Research Consortium (AARC) score were increased within two weeks. In multivariable analysis, INR and AARC score (D-14) were associated with poor survival and liver transplant was a protective factor in all patients, while AARC score (D-14) was significant in the nontransplant group. AARC score at day 14 is an independent risk factor for mortality in ACLF. Liver transplant from live donors reversed poor outcomes in patients with ACLF in a timely manner. Full article
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Open AccessArticle
Metabolic Profiles of Whole Serum and Serum-Derived Exosomes Are Different in Head and Neck Cancer Patients Treated by Radiotherapy
J. Pers. Med. 2020, 10(4), 229; https://doi.org/10.3390/jpm10040229 - 13 Nov 2020
Viewed by 265
Abstract
Background: In general, the serum metabolome reflects the patient’s body response to both disease state and implemented treatment. Though serum-derived exosomes are an emerging type of liquid biopsy, the metabolite content of these vesicles remains under researched. The aim of this pilot study [...] Read more.
Background: In general, the serum metabolome reflects the patient’s body response to both disease state and implemented treatment. Though serum-derived exosomes are an emerging type of liquid biopsy, the metabolite content of these vesicles remains under researched. The aim of this pilot study was to compare the metabolite profiles of the whole serum and serum-derived exosomes in the context of differences between cancer patients and healthy controls as well as patients’ response to radiotherapy (RT). Methods: Serum samples were collected from 10 healthy volunteers and 10 patients with head and neck cancer before and after RT. Metabolites extracted from serum and exosomes were analyzed by the gas chromatography–mass spectrometry (GC–MS). Results: An untargeted GC–MS-based approach identified 182 and 46 metabolites in serum and exosomes, respectively. Metabolites that differentiated cancer and control samples, either serum or exosomes, were associated with energy metabolism. Serum metabolites affected by RT were associated with the metabolism of amino acids, sugars, lipids, and nucleotides. Conclusions: cancer-related features of energy metabolism could be detected in both types of specimens. On the other hand, in contrast to RT-induced changes observed in serum metabolome, this pilot study did not reveal a specific radiation-related pattern of exosome metabolites. Full article
(This article belongs to the Special Issue Radiation Response Biomarkers for Individualised Cancer Treatments)
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