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New Applications in the Diagnosis and Therapy of Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 21486

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Dr. Miguel Hueso

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Department of Nephrology, Hospital Universitari de Bellvitge, 08907 L’Hospitalet de Llobregat, Spain
Interests: kidney pathology; dialysis; vascular pathology; molecular medicine; predictive medicine; personalized medicine; inflammation; ncRNAs
Special Issues, Collections and Topics in MDPI journals

Dr. Alfredo Vellido

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IDEAI_UPC Research Center, Universitat Politècnica de Catalunya (UPC BarcelonaTech), 08034 Barcelona, Spain
Interests: machine learning; data science; medical applications of artificial intelligence
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Personalized Medicine is an emerging field that promotes the use of novel diagnostic tests to offer the right treatment at the right time for each patient. Personalized medicine unavoidable leads us towards a data-centric view of health, as data from expensive multicenter, randomized, controlled clinical trials (evidence-based medicine) are required to demonstrate that a treatment is effective, but the results can be disappointing in population minorities. Therefore, an analysis of retrospective data collected in large databases (Big Data) can help to explore its usefulness in population minorities and benefit patients and health systems. However, data must usually be obtained from heterogeneous sources and in different modalities (individual medical history, high-resolution images, omics data, diagnostic tests, etc.) and their analysis may become complex due to non-linear behaviour, or changing dynamics. Therefore, modelling such complexity is a major challenge that requires powerful new tools and technologies. This is a natural challenge and pursuit for data science in the form of data collection, storage, curation of databases, processing, and analysis. Challenges that require a joint effort of medical experts and data scientists with a multidisciplinary approach were the core of the discussion in our recent “Science for Dialysis 4” workshop (YouTube recording of the session: https://youtu.be/e2PZrLEE1to). We argue that the knowledge generated by data science approaches will have a positive impact on clinical practice through personalized treatments and we would like to dedicate a special issue to collect experiences in the diagnosis and personalized treatment of diseases from a data science perspective. Review papers and work in progress putting forward new and groundbreaking ideas are also welcomed.

Dr. Miguel Hueso
Dr. Alfredo Vellido
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

personalized medicine
systems biology
high-throughput technologies
molecular imaging
omics
pharmacogenomics
monitoring responses
data visualization
theranostics

Published Papers (8 papers)

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Research

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12 pages, 1127 KiB

Open AccessArticle

Soluble ST2 in Patients with Carotid Artery Stenosis—Association with Plaque Morphology and Long-Term Outcome

by Stefan Stojkovic, Stephanie Kampf, Olesya Harkot, Maja Nackenhorst, Mira Brekalo, Kurt Huber, Christian Hengstenberg, Christoph Neumayer, Johann Wojta and Svitlana Demyanets

Int. J. Mol. Sci. 2023, 24(10), 9007; https://doi.org/10.3390/ijms24109007 - 19 May 2023

Viewed by 1040

Abstract

Interleukin (IL-33) and the ST2 receptor are implicated in the pathogenesis of atherosclerosis. Soluble ST2 (sST2), which negatively regulates IL-33 signaling, is an established biomarker in coronary artery disease and heart failure. Here we aimed to investigate the association of sST2 with carotid atherosclerotic plaque morphology, symptom presentation, and the prognostic value of sST2 in patients undergoing carotid endarterectomy. A total of 170 consecutive patients with high-grade asymptomatic or symptomatic carotid artery stenosis undergoing carotid endarterectomy were included in the study. The patients were followed up for 10 years, and the primary endpoint was defined as a composite of adverse cardiovascular events and cardiovascular mortality, with all-cause mortality as the secondary endpoint. The baseline sST2 showed no association with carotid plaque morphology assessed using carotid duplex ultrasound (B 0.051, 95% CI −0.145–0.248, p = 0.609), nor with modified histological AHA classification based on morphological description following surgery (B −0.032, 95% CI −0.194–0.130, p = 0.698). Furthermore, sST2 was not associated with baseline clinical symptoms (B −0.105, 95% CI −0.432–0.214, p = 0.517). On the other hand, sST2 was an independent predictor for long-term adverse cardiovascular events after adjustment for age, sex, and coronary artery disease (HR 1.4, 95% CI 1.0–2.4, p = 0.048), but not for all-cause mortality (HR 1.2, 95% CI 0.8–1.7, p = 0.301). Patients with high baseline sST2 levels had a significantly higher adverse cardiovascular event rate as compared to patients with lower sST2 (log-rank p < 0.001). Although IL-33 and ST2 play a role in the pathogenesis of atherosclerosis, sST2 is not associated with carotid plaque morphology. However, sST2 is an excellent prognostic marker for long-term adverse cardiovascular outcomes in patients with high-grade carotid artery stenosis. Full article

(This article belongs to the Special Issue New Applications in the Diagnosis and Therapy of Diseases)

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22 pages, 1725 KiB

Open AccessArticle

Layer-Wise Relevance Analysis for Motif Recognition in the Activation Pathway of the β2-Adrenergic GPCR Receptor

by Mario A. Gutiérrez-Mondragón, Caroline König and Alfredo Vellido

Int. J. Mol. Sci. 2023, 24(2), 1155; https://doi.org/10.3390/ijms24021155 - 06 Jan 2023

Cited by 1 | Viewed by 1804

Abstract

G-protein-coupled receptors (GPCRs) are cell membrane proteins of relevance as therapeutic targets, and are associated to the development of treatments for illnesses such as diabetes, Alzheimer’s, or even cancer. Therefore, comprehending the underlying mechanisms of the receptor functional properties is of particular interest in pharmacoproteomics and in disease therapy at large. Their interaction with ligands elicits multiple molecular rearrangements all along their structure, inducing activation pathways that distinctly influence the cell response. In this work, we studied GPCR signaling pathways from molecular dynamics simulations as they provide rich information about the dynamic nature of the receptors. We focused on studying the molecular properties of the receptors using deep-learning-based methods. In particular, we designed and trained a one-dimensional convolution neural network and illustrated its use in a classification of conformational states: active, intermediate, or inactive, of the $β 2$ -adrenergic receptor when bound to the full agonist BI-167107. Through a novel explainability-oriented investigation of the prediction results, we were able to identify and assess the contribution of individual motifs (residues) influencing a particular activation pathway. Consequently, we contribute a methodology that assists in the elucidation of the underlying mechanisms of receptor activation–deactivation. Full article

(This article belongs to the Special Issue New Applications in the Diagnosis and Therapy of Diseases)

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13 pages, 2475 KiB

Open AccessArticle

Development of the Chromatographic Method for Simultaneous Determination of Azaperone and Azaperol in Animal Kidneys and Livers

by Izabella Kośka and Paweł Kubalczyk

Int. J. Mol. Sci. 2023, 24(1), 100; https://doi.org/10.3390/ijms24010100 - 21 Dec 2022

Cited by 1 | Viewed by 1085

Abstract

A precise and accurate method for the simultaneous determination of azaperone and azaperol in meat tissues has been developed. This paper describes the first method to be so fast, simple, and useful, especially for many laboratories that do not have sophisticated equipment. This method is based on LC separation and UV-Vis detection. During the sample preparation, the meat tissue was homogenized in acetonitrile at a ratio of 1:4 (tissue weight:acetonitrile volume). The homogenate was centrifuged, the supernatant was evaporated in a lyophilizator, and then the evaporation residue was dissolved in 20 µL of ethanol. For deproteinization, 15 µL of perchloric acid was added, and the sample prepared in this way was injected into a chromatographic column and analyzed using reversed-phased HPLC. The mobile phase consisted of 0.05 mol/L phosphate buffer pH 3.00 (component A) and acetonitrile (component B). UV detection was conducted at 245 nm. The experimentally determined LOQs were 0.25 µg/kg for azaperone and 0.12 µg/kg for azaperol. For both analytes, the calibration curves showed linearity in the tested concentration range from 50 to 300 µg/kg of tissue. The accuracy of the presented method did not exceed 15%, and the recovery was in the range of 85–115%. A validated analytical procedure was implemented for the analysis of various animal tissues for their content of azaperone and azaperol. Full article

(This article belongs to the Special Issue New Applications in the Diagnosis and Therapy of Diseases)

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10 pages, 635 KiB

Open AccessArticle

Antibodies against HSV-1 and Curli Show the Highest Correlation in Parkinson’s Disease Patients in Comparison to Healthy Controls

by Seyedesomaye Jasemi, Kai Paulus, Marta Noli, Elena Rita Simula, Stefano Ruberto and Leonardo A. Sechi

Int. J. Mol. Sci. 2022, 23(23), 14816; https://doi.org/10.3390/ijms232314816 - 26 Nov 2022

Cited by 5 | Viewed by 1709

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder involving the accumulation of alpha-synuclein (α-syn)/Lewy bodies in the brain and -enteric nervous system. The etiology of the disease is not well understood, but bacterial and viral infections may contribute to the pathogenesis of PD. It has been suggested that the gastrointestinal (GI) complications observed in PD patients may arise from bacterial dysbiosis, leading to curli/α-syn deposits in the enteric nervous system. Enteric bacteria secrete curli, a functional amyloid peptide involved in adhesion to surfaces, cell invasion, and biofilm formation. However, these bacterial amyloids can initiate additional α-syn deposits through immune system activation and cross-seeding. In this study, we investigate the humoral response against α-syn, curli peptides, and various bacterial and viral immunogen peptides in PD patients, and compare them with those in healthy controls (HCs). Polyclonal IgG antibodies (Abs) were detected against peptides derived from α-syn (α-syn_100–114), curli (Curli_133–141), Porphyromonas gingivalis Pg (RgpA_800–812, Kpg_328–339), Aggregatibacter actinomycetemcomitans (LtxA1_429–445, LtxA2_64–80), Mycobacterium avium subsp. paratuberculosis (MAP3865c_125–133, MAP1,4-a-gbp_157–173 and MAP_4027_18–32), Epstein–Barr virus (EBNA1_400–413, BOLF1_305–320), and Herpes Simplex virus 1 (UI42_22–36), as investigated by indirect ELISA of 51 serum samples from PD and 58 sex and age-matched HCs. Significant differences in OD (optical density) values and Abs positivity between PD patients and HCs were observed for Kpg (82.3% vs. 10.3%), followed by RgpA (60.7% vs. 24.1%), curli (51% vs. 22.4%), and UI42 (43.1% vs. 25.8%) in PD, compared to HCs sera (p < 0.001). No significant difference was found in the ODs obtained from other tested peptides in PD patients, compared to HCs. Significant positive correlations between OD values obtained by ELISA were observed for UI42 and curli (r = 0.811, p < 0.0001), Kpg and RgpA (r = 0.659, p < 0.0001), followed by LtxA1 and LtxA2 (r = 0.653, p < 0.0001). The correlation between the HY scale (Hoehn and Yahr Scale) and LtxA1 (r = 0.306, p < 0.028) and HY and Kpg (r = 0.290, p < 0.038) were significantly positive. This study reports a significantly increased humoral response against curli, Pg, and HSV-1 in PD patients, implying that they could be important factors in the pathogenesis of the disease. In addition, the high positive correlation between UI42 and curli may suggest the involvement of HSV-1 in GI dysbiosis. Therefore, the role of each individual pathogen and curli in PD needs to be further investigated. Full article

(This article belongs to the Special Issue New Applications in the Diagnosis and Therapy of Diseases)

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17 pages, 4339 KiB

Open AccessArticle

A Novel Nanobody-Horseradish Peroxidase Fusion Based-Competitive ELISA to Rapidly Detect Avian Corona-Virus-Infectious Bronchitis Virus Antibody in Chicken Serum

by Kui Gu, Zengxu Song, Peng Ma, Ziwei Liao, Ming Yang, Changyu Zhou, Chao Li, Yu Zhao, Hao Li, Xin Yang, Changwei Lei and Hongning Wang

Int. J. Mol. Sci. 2022, 23(14), 7589; https://doi.org/10.3390/ijms23147589 - 08 Jul 2022

Cited by 5 | Viewed by 2590

Abstract

Avian coronavirus-infectious bronchitis virus (AvCoV-IBV) is the causative agent of infectious bronchitis (IB) that has brought great threat and economic losses to the global poultry industry. Rapid and accurate diagnostic methods are very necessary for effective disease monitoring. At the present study, we screened a novel nanobody against IBV-N protein for development of a rapid, simple, sensitive, and specific competitive ELISA for IBV antibody detection in order to enable the assessment of inoculation effect and early warning of disease infection. Using the phage display technology and bio-panning, we obtained 7 specific nanobodies fused with horseradish peroxidase (HRP) which were expressed in culture supernatant of HEK293T cells. Out of which, the nanobody of IBV-N-Nb66-vHRP has highly binding with IBV-N protein and was easily blocked by the IBV positive serums, which was finally employed as an immunoprobe for development of the competitive ELISA (cELISA). In the newly developed cELISA, we reduce the use of enzyme-conjugated secondary antibody, and the time of whole operation process is approximately 1 h. Moreover, the IBV positive serums diluted at 1:1000 can still be detected by the developed cELISA, and it has no cross reactivity with others chicken disease serums including Newcastle disease virus, Fowl adenovirus, Avian Influenza Virus, Infectious bursal disease virus and Hepatitis E virus. The cut-off value of the established cELISA was 36%, and the coefficient of variation of intra- and inter-assay were 0.55–1.65% and 2.58–6.03%, respectively. Compared with the commercial ELISA (IDEXX kit), the agreement rate of two methods was defined as 98% and the kappa value was 0.96, indicating the developed cELISA has high consistency with the commercial ELISA. Taken together, the novel cELISA for IBV antibody detection is a simple, rapid, sensitive, and specific immunoassay, which has the potential to rapidly test IBV antibody contributing to the surveillance and control of the disease. Full article

(This article belongs to the Special Issue New Applications in the Diagnosis and Therapy of Diseases)

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Review

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15 pages, 584 KiB

Open AccessReview

Extracellular Matrix-Based Approaches in Cardiac Regeneration: Challenges and Opportunities

by Thi Van Anh Vu, Daniela Lorizio, Roman Vuerich, Melania Lippi, Diana S. Nascimento and Serena Zacchigna

Int. J. Mol. Sci. 2022, 23(24), 15783; https://doi.org/10.3390/ijms232415783 - 13 Dec 2022

Cited by 3 | Viewed by 2412

Abstract

Cardiac development is characterized by the active proliferation of different cardiac cell types, in particular cardiomyocytes and endothelial cells, that eventually build the beating heart. In mammals, these cells lose their regenerative potential early after birth, representing a major obstacle to our current capacity to restore the myocardial structure and function after an injury. Increasing evidence indicates that the cardiac extracellular matrix (ECM) actively regulates and orchestrates the proliferation, differentiation, and migration of cardiac cells within the heart, and that any change in either the composition of the ECM or its mechanical properties ultimately affect the behavior of these cells throughout one’s life. Thus, understanding the role of ECMs’ proteins and related signaling pathways on cardiac cell proliferation is essential to develop effective strategies fostering the regeneration of a damaged heart. This review provides an overview of the components of the ECM and its mechanical properties, whose function in cardiac regeneration has been elucidated, with a major focus on the strengths and weaknesses of the experimental models so far exploited to demonstrate the actual pro-regenerative capacity of the components of the ECM and to translate this knowledge into new therapies. Full article

(This article belongs to the Special Issue New Applications in the Diagnosis and Therapy of Diseases)

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24 pages, 1584 KiB

Open AccessReview

Role of Transposable Elements in Genome Stability: Implications for Health and Disease

by Audesh Bhat, Trupti Ghatage, Sonali Bhan, Ganesh P. Lahane, Arti Dhar, Rakesh Kumar, Raj K. Pandita, Krishna M. Bhat, Kenneth S. Ramos and Tej K. Pandita

Int. J. Mol. Sci. 2022, 23(14), 7802; https://doi.org/10.3390/ijms23147802 - 15 Jul 2022

Cited by 13 | Viewed by 6769

Abstract

Most living organisms have in their genome a sizable proportion of DNA sequences capable of mobilization; these sequences are commonly referred to as transposons, transposable elements (TEs), or jumping genes. Although long thought to have no biological significance, advances in DNA sequencing and analytical technologies have enabled precise characterization of TEs and confirmed their ubiquitous presence across all forms of life. These findings have ignited intense debates over their biological significance. The available evidence now supports the notion that TEs exert major influence over many biological aspects of organismal life. Transposable elements contribute significantly to the evolution of the genome by giving rise to genetic variations in both active and passive modes. Due to their intrinsic nature of mobility within the genome, TEs primarily cause gene disruption and large-scale genomic alterations including inversions, deletions, and duplications. Besides genomic instability, growing evidence also points to many physiologically important functions of TEs, such as gene regulation through cis-acting control elements and modulation of the transcriptome through epigenetic control. In this review, we discuss the latest evidence demonstrating the impact of TEs on genome stability and the underling mechanisms, including those developed to mitigate the deleterious impact of TEs on genomic stability and human health. We have also highlighted the potential therapeutic application of TEs. Full article

(This article belongs to the Special Issue New Applications in the Diagnosis and Therapy of Diseases)

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20 pages, 593 KiB

Open AccessReview

Challenges and Future of Drug-Induced Liver Injury Research—Laboratory Tests

by Sabine Weber and Alexander L. Gerbes

Int. J. Mol. Sci. 2022, 23(11), 6049; https://doi.org/10.3390/ijms23116049 - 27 May 2022

Cited by 12 | Viewed by 3229

Abstract

Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes. Full article

(This article belongs to the Special Issue New Applications in the Diagnosis and Therapy of Diseases)

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