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Biomedicines
Volume 12
Issue 9
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Biomedicines, Volume 12, Issue 9 (September 2024) – 230 articles

Cover Story (view full-size image): Duchenne muscular dystrophy (DMD) is an X-linked, progressive, and lethal muscle-degenerating disease caused by a lack of dystrophin. Currently, there is no cure for DMD, but DT-DEC01 represents a novel breakthrough therapy based on the PEG-mediated fusion of myoblasts from a healthy donor (MBN) and a patient with DMD (MBDMD). Following intraosseous administration, DT-DEC01 expresses critical muscle proteins, dystrophin (DYS), myosin heavy chain (MyHC), and desmin (DES), all essential for muscle repair. DT-DEC01 transfers healthy and chimeric mitochondria to the cells of patients with DMD, enhancing muscle regeneration and function. Donor chimerism confirmed by STR loci analysis combined with myogenic differentiation and myotube formation introduce DT DEC01 as a new, viable therapeutic approach for patients with DMD. View this paper
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25 pages, 2816 KiB  
Article
GastricAITool: A Clinical Decision Support Tool for the Diagnosis and Prognosis of Gastric Cancer
by Rocío Aznar-Gimeno, María Asunción García-González, Rubén Muñoz-Sierra, Patricia Carrera-Lasfuentes, María de la Vega Rodrigálvarez-Chamarro, Carlos González-Muñoz, Enrique Meléndez-Estrada, Ángel Lanas and Rafael del Hoyo-Alonso
Biomedicines 2024, 12(9), 2162; https://doi.org/10.3390/biomedicines12092162 - 23 Sep 2024
Viewed by 957
Abstract
Background/Objective: Gastric cancer (GC) is a complex disease representing a significant global health concern. Advanced tools for the early diagnosis and prediction of adverse outcomes are crucial. In this context, artificial intelligence (AI) plays a fundamental role. The aim of this work was [...] Read more.
Background/Objective: Gastric cancer (GC) is a complex disease representing a significant global health concern. Advanced tools for the early diagnosis and prediction of adverse outcomes are crucial. In this context, artificial intelligence (AI) plays a fundamental role. The aim of this work was to develop a diagnostic and prognostic tool for GC, providing support to clinicians in critical decision-making and enabling personalised strategies. Methods: Different machine learning and deep learning techniques were explored to build diagnostic and prognostic models, ensuring model interpretability and transparency through explainable AI methods. These models were developed and cross-validated using data from 590 Spanish Caucasian patients with primary GC and 633 cancer-free individuals. Up to 261 variables were analysed, including demographic, environmental, clinical, tumoral, and genetic data. Variables such as Helicobacter pylori infection, tobacco use, family history of GC, TNM staging, metastasis, tumour location, treatment received, gender, age, and genetic factors (single nucleotide polymorphisms) were selected as inputs due to their association with the risk and progression of the disease. Results: The XGBoost algorithm (version 1.7.4) achieved the best performance for diagnosis, with an AUC value of 0.68 using 5-fold cross-validation. As for prognosis, the Random Survival Forest algorithm achieved a C-index of 0.77. Of interest, the incorporation of genetic data into the clinical–demographics models significantly increased discriminatory ability in both diagnostic and prognostic models. Conclusions: This article presents GastricAITool, a simple and intuitive decision support tool for the diagnosis and prognosis of GC. Full article
(This article belongs to the Special Issue Advancements in Artificial Intelligence (AI) for Cancer Genomics and Genetics)
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18 pages, 8953 KiB  
Article
Process Development for Fabricating 3D-Printed Polycaprolactone-Infiltrated Hydroxyapatite Bone Graft Granules: Effects of Infiltrated Solution Concentration and Agitating Liquid
by Faungchat Thammarakcharoen, Autcharaporn Srion, Waraporn Suvannapruk, Watchara Chokevivat, Wiroj Limtrakarn and Jintamai Suwanprateeb
Biomedicines 2024, 12(9), 2161; https://doi.org/10.3390/biomedicines12092161 - 23 Sep 2024
Viewed by 594
Abstract
Bone grafts are commonly used in orthopedic and dental surgeries to facilitate bone repair and regeneration. A new type of bone graft, polycaprolactone-infiltrated three dimensionally printed hydroxyapatite (3DP HA/PCL), was previously developed by infiltrating polycaprolactone (PCL) into preformed three-dimensional-printed hydroxyapatite (3DP HA) that [...] Read more.
Bone grafts are commonly used in orthopedic and dental surgeries to facilitate bone repair and regeneration. A new type of bone graft, polycaprolactone-infiltrated three dimensionally printed hydroxyapatite (3DP HA/PCL), was previously developed by infiltrating polycaprolactone (PCL) into preformed three-dimensional-printed hydroxyapatite (3DP HA) that was fabricated using binder jetting technology combined with a low-temperature phase transformation process. However, when producing small granules, which are often used for bone grafting, issues of granule agglomeration emerged, complicating the application of this method. This study aimed to develop a fabrication process for 3DP HA/PCL bone graft granules using solution infiltration and liquid agitation. The effects of varying PCL solution concentrations (40% and 50% w/w) and different agitating liquids (deionized water or DI, N-Methyl-2-Pyrrolidone or NMP, and an NMP-DI mixture) on the properties of the resulting composites were investigated. XRD and FTIR analysis confirmed the coexistence of HA and PCL within the composites. The final PCL content was comparable across all conditions. The contact angles of 3DP HA/PCL were 26.3 and 69.8 degree for 40% and 50% PCL solution, respectively, when using DI, but were zero when using NMP and NMP-DI. The highest compression load resistance and diametral tensile strength were achieved using the 50% PCL solution with DI or the NMP-DI mixture. DI resulted in a dense PCL coating, while NMP and the NMP-DI mixture produced a porous and irregular surface morphology. All samples exhibited a porous internal microstructure due to PCL infiltration into the initial pores of the 3D-printed HA. Biocompatibility tests showed that all samples supported the proliferation of MC3T3-E1 cells, with the greatest OD values observed for the 50% PCL solution with DI or the NMP-DI mixture at each cultured period. Considering the microstructural, mechanical, and biological properties, the 50% PCL solution with the NMP-DI mixture demonstrated overall desirable properties. Full article
(This article belongs to the Special Issue Biomaterials for Bone Regeneration)
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8 pages, 1311 KiB  
Communication
Patients with Taste Disorders in a Hospital’s Dental Department and Strategies for Taste Disorders
by Tatsuki Itagaki, Ken-ichiro Sakata, Taro Okura, Hirokazu Kobayashi, Sadasuke Hayata and Yoshimasa Kitagawa
Biomedicines 2024, 12(9), 2160; https://doi.org/10.3390/biomedicines12092160 - 23 Sep 2024
Viewed by 764
Abstract
Background/Objectives: A retrospective study was conducted to clarify the clinical characteristics of taste disorder cases at the Department of Oral Medicine of Hokkaido University Hospital. The subjects were 322 taste disorder patients (86 male, 236 female, average age: 66 (13.1) years, mean duration [...] Read more.
Background/Objectives: A retrospective study was conducted to clarify the clinical characteristics of taste disorder cases at the Department of Oral Medicine of Hokkaido University Hospital. The subjects were 322 taste disorder patients (86 male, 236 female, average age: 66 (13.1) years, mean duration of disorder: 15.2 (20.0) months) who were treated at our department from 2007 to 2018. Methods: Associations between symptoms and classification were examined. Results: When looking at the taste symptoms, 154 cases of quantitative taste disorder were observed as taste loss, abscission, and dissociative taste disorder, and 168 cases of qualitative taste disorder were observed as spontaneous abnormal taste, dysgeusia, and maltaste. There was no relationship between sex and quantitative/qualitative taste disorders at V = 0.08. When looking at the causes of taste disorders, the majority were psychogenic, idiopathic, and oral diseases. Conclusions: Approximately 20% of taste disorders are caused by oral diseases, so it should be noted that oral diseases such as oral candidiasis and xerostomia can cause taste disorders and that many of them can be improved with oral treatment. Full article
(This article belongs to the Special Issue Advancements in Understanding and Treating Oral Pathologies: From Dry Mouth to Oral Cancer)
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18 pages, 2243 KiB  
Article
The Relationship between Lipoprotein A and the Prevalence of Multivessel Coronary Artery Disease in Young Patients with Acute Myocardial Infarction: An Observational Study
by Ionut Cezar Buciu, Eugen Nicolae Tieranu, Andreea Stefania Pircalabu, Ovidiu Mircea Zlatian, Ionut Donoiu, Constantin Militaru, Sebastian Militaru and Cristian Militaru
Biomedicines 2024, 12(9), 2159; https://doi.org/10.3390/biomedicines12092159 - 23 Sep 2024
Cited by 1 | Viewed by 869
Abstract
Introduction: Cardiovascular diseases are the leading cause of mortality worldwide, with a significant impact on socioeconomic aspects. Various biomarkers have been studied in relation to the diagnosis, progression, and prognosis of atherosclerotic disease, with lipoprotein (a) [Lp (a)] standing out as an important [...] Read more.
Introduction: Cardiovascular diseases are the leading cause of mortality worldwide, with a significant impact on socioeconomic aspects. Various biomarkers have been studied in relation to the diagnosis, progression, and prognosis of atherosclerotic disease, with lipoprotein (a) [Lp (a)] standing out as an important predictor of cardiovascular risk. This observational study aimed to clarify the association between Lp (a) levels and the severity of significant multivessel coronary lesions in acute myocardial infarction (AMI) patients. Materials and Methods: Conducted at the Clinical Emergency County Hospital of Craiova, Romania, the study involved 256 young patients divided into two groups based on Lp (a) levels: Group A (Lp (a) < 30 mg/dL) and Group B (Lp (a) ≥ 30 mg/dL). Patients included young adults up to 55 years for males and 60 years for females, excluding those with familial hypercholesterolemia. Results: The study revealed a significant association between elevated Lp (a) levels and the presence of multivessel coronary lesions. Patients with Lp (a) concentrations ≥ 30 mg/dL exhibited a higher prevalence of multivessel disease compared to those with lower levels. Discussion: The findings suggest that elevated Lp (a) levels are a crucial biomarker for the risk of coronary artery disease, particularly in young patients with AMI. The study emphasizes the need for aggressive lipid management strategies and personalized treatment approaches, considering the significant role of Lp (a) in atherosclerosis and AMI. Conclusions: Lipoprotein A levels above 30 mg/dL are associated with a higher prevalence of multivessel coronary lesions. Multivariate analysis revealed that higher Lp (a) levels and lower HDL levels are linked to an increased risk of multivessel coronary lesions. Full article
(This article belongs to the Special Issue Molecular Insights into Myocardial Infarction)
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26 pages, 952 KiB  
Review
Revolutionizing Cancer Treatment: Recent Advances in Immunotherapy
by Rose Ghemrawi, Lama Abuamer, Sedra Kremesh, Ghadeer Hussien, Rahaf Ahmed, Walaa Mousa, Ghalia Khoder and Mostafa Khair
Biomedicines 2024, 12(9), 2158; https://doi.org/10.3390/biomedicines12092158 - 23 Sep 2024
Viewed by 2806
Abstract
Cancer immunotherapy has emerged as a transformative approach in oncology, utilizing the body’s immune system to specifically target and destroy malignant cells. This review explores the scope and impact of various immunotherapeutic strategies, including monoclonal antibodies, chimeric antigen receptor (CAR)-T cell therapy, checkpoint [...] Read more.
Cancer immunotherapy has emerged as a transformative approach in oncology, utilizing the body’s immune system to specifically target and destroy malignant cells. This review explores the scope and impact of various immunotherapeutic strategies, including monoclonal antibodies, chimeric antigen receptor (CAR)-T cell therapy, checkpoint inhibitors, cytokine therapy, and therapeutic vaccines. Monoclonal antibodies, such as Rituximab and Trastuzumab, have revolutionized treatment paradigms for lymphoma and breast cancer by offering targeted interventions that reduce off-target effects. CAR-T cell therapy presents a potentially curative option for refractory hematologic malignancies, although challenges remain in effectively treating solid tumors. Checkpoint inhibitors have redefined the management of cancers like melanoma and lung cancer; however, managing immune-related adverse events and ensuring durable responses are critical areas of focus. Cytokine therapy continues to play a vital role in modulating the immune response, with advancements in cytokine engineering improving specificity and reducing systemic toxicity. Therapeutic vaccines, particularly mRNA-based vaccines, represent a frontier in personalized cancer treatment, aiming to generate robust, long-lasting immune responses against tumor-specific antigens. Despite these advancements, the field faces significant challenges, including immune resistance, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Future research should address these obstacles through emerging technologies, such as next-generation antibodies, Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-based gene editing, and AI-driven drug discovery. By integrating these novel approaches, cancer immunotherapy holds the promise of offering more durable, less toxic, and highly personalized treatment options, ultimately improving patient outcomes and survival rates. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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25 pages, 19339 KiB  
Article
Identifying Key Genes as Progression Indicators of Prostate Cancer with Castration Resistance Based on Dynamic Network Biomarker Algorithm and Weighted Gene Correlation Network Analysis
by Siyuan Liu, Yi Hu, Fei Liu, Yizheng Jiang, Hongrui Wang, Xusheng Wu and Dehua Hu
Biomedicines 2024, 12(9), 2157; https://doi.org/10.3390/biomedicines12092157 - 23 Sep 2024
Viewed by 882
Abstract
Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for prostate cancer, yet dynamic molecular changes from hormone-sensitive to castration-resistant states in patients treated with ADT remain unclear. Methods: In this study, we combined the dynamic network biomarker (DNB) method and the [...] Read more.
Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for prostate cancer, yet dynamic molecular changes from hormone-sensitive to castration-resistant states in patients treated with ADT remain unclear. Methods: In this study, we combined the dynamic network biomarker (DNB) method and the weighted gene co-expression network analysis (WGCNA) to identify key genes associated with the progression to a castration-resistant state in prostate cancer via the integration of single-cell and bulk RNA sequencing data. Based on the gene expression profiles of CRPC in the GEO dataset, the DNB method was used to clarify the condition of epithelial cells and find out the most significant transition signal DNB modules and genes included. Then, we calculated gene modules associated with the clinical phenotype stage based on the WGCNA. IHC was conducted to validate the expression of the key genes in CRPC and primary PCa patients Results:Nomograms, calibration plots, and ROC curves were applied to evaluate the good prognostic accuracy of the risk prediction model. Results: By combining single-cell RNA sequence data and bulk RNA sequence data, we identified a set of DNBs, whose roles involved in androgen-associated activities indicated the signals of a prostate cancer cell transition from an androgen-dependent state to a castration-resistant state. In addition, a risk prediction model including the risk score of four key genes (SCD, NARS2, ALDH1A1, and NFXL1) and other clinical–pathological characteristics was constructed and verified to be able to reasonably predict the prognosis of patients receiving ADT. Conclusions: In summary, four key genes from DNBs were identified as potential diagnostic markers for patients treated with ADT and a risk score-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions of CRPC. Full article
(This article belongs to the Topic Recent Advances in Anticancer Strategies)
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14 pages, 912 KiB  
Systematic Review
From Voxel to Gene: A Scoping Review on MRI Radiogenomics’ Artificial Intelligence Predictions in Adult Gliomas and Glioblastomas—The Promise of Virtual Biopsy?
by Xavier Maximin Le Guillou Horn, François Lecellier, Clement Giraud, Mathieu Naudin, Pierre Fayolle, Céline Thomarat, Christine Fernandez-Maloigne and Rémy Guillevin
Biomedicines 2024, 12(9), 2156; https://doi.org/10.3390/biomedicines12092156 - 23 Sep 2024
Viewed by 733
Abstract
Background: Gliomas, including the most severe form known as glioblastomas, are primary brain tumors arising from glial cells, with significant impact on adults, particularly men aged 45 to 70. Recent advancements in the WHO (World Health Organization) classification now correlate genetic markers with [...] Read more.
Background: Gliomas, including the most severe form known as glioblastomas, are primary brain tumors arising from glial cells, with significant impact on adults, particularly men aged 45 to 70. Recent advancements in the WHO (World Health Organization) classification now correlate genetic markers with glioma phenotypes, enhancing diagnostic precision and therapeutic strategies. Aims and Methods: This scoping review aims to evaluate the current state of deep learning (DL) applications in the genetic characterization of adult gliomas, addressing the potential of these technologies for a reliable virtual biopsy. Results: We reviewed 17 studies, analyzing the evolution of DL algorithms from fully convolutional networks to more advanced architectures (ResNet and DenseNet). The methods involved various validation techniques, including k-fold cross-validation and external dataset validation. Conclusions: Our findings highlight significant variability in reported performance, largely due to small, homogeneous datasets and inconsistent validation methods. Despite promising results, particularly in predicting individual genetic traits, the lack of robust external validation limits the generalizability of these models. Future efforts should focus on developing larger, more diverse datasets and integrating multidisciplinary collaboration to enhance model reliability. This review underscores the potential of DL in advancing glioma characterization, paving the way for more precise, non-invasive diagnostic tools. The development of a robust algorithm capable of predicting the somatic genetics of gliomas or glioblastomas could accelerate the diagnostic process and inform therapeutic decisions more quickly, while maintaining the same level of accuracy as the traditional diagnostic pathway, which involves invasive tumor biopsies. Full article
(This article belongs to the Special Issue Establishment of State-of-the-Art Methods/Techniques and Identification of Novel Biomarkers in Brain Tumor Diagnosis)
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15 pages, 601 KiB  
Review
In Vitro Models of Cardiovascular Calcification
by Andrea Tóth, Enikő Balogh and Viktória Jeney
Biomedicines 2024, 12(9), 2155; https://doi.org/10.3390/biomedicines12092155 - 23 Sep 2024
Viewed by 920
Abstract
Cardiovascular calcification, characterized by hydroxyapatite deposition in the arterial wall and heart valves, is associated with high cardiovascular morbidity and mortality. Cardiovascular calcification is a hallmark of aging but is frequently seen in association with chronic diseases, such as chronic kidney disease (CKD), [...] Read more.
Cardiovascular calcification, characterized by hydroxyapatite deposition in the arterial wall and heart valves, is associated with high cardiovascular morbidity and mortality. Cardiovascular calcification is a hallmark of aging but is frequently seen in association with chronic diseases, such as chronic kidney disease (CKD), diabetes, dyslipidemia, and hypertension in the younger population as well. Currently, there is no therapeutic approach to prevent or cure cardiovascular calcification. The pathophysiology of cardiovascular calcification is highly complex and involves osteogenic differentiation of various cell types of the cardiovascular system, such as vascular smooth muscle cells and valve interstitial cells. In vitro cellular and ex vivo tissue culture models are simple and useful tools in cardiovascular calcification research. These models contributed largely to the discoveries of the numerous calcification inducers, inhibitors, and molecular mechanisms. In this review, we provide an overview of the in vitro cell culture and the ex vivo tissue culture models applied in the research of cardiovascular calcification. Full article
(This article belongs to the Special Issue In Vitro Models of Cardiovascular Diseases and Toxicity)
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15 pages, 1661 KiB  
Article
Biomarker Profiling of Upper Tract Urothelial Carcinoma Only and with Synchronous or Metachronous Bladder Cancer
by Sara Meireles, Carolina Dias, Diana Martins, Ana Marques, Nuno Dias, Luís Pacheco-Figueiredo, João Silva, Carlos Martins Silva, Miguel Barbosa, Luís Costa, José Manuel Lopes and Paula Soares
Biomedicines 2024, 12(9), 2154; https://doi.org/10.3390/biomedicines12092154 - 23 Sep 2024
Viewed by 648
Abstract
Background: Molecular profiling in upper tract urothelial carcinoma (UTUC) with synchronous or metachronous urothelial bladder cancer (UBC) is scarce. We intended to assess immunohistochemical (IHC) and genetic differences between UTUC-only and UTUC with synchronous or metachronous UBC (UTUC + UBC) and evaluate the [...] Read more.
Background: Molecular profiling in upper tract urothelial carcinoma (UTUC) with synchronous or metachronous urothelial bladder cancer (UBC) is scarce. We intended to assess immunohistochemical (IHC) and genetic differences between UTUC-only and UTUC with synchronous or metachronous UBC (UTUC + UBC) and evaluate the effect of subsequent UBC on the outcome of UTUC patients stratified by luminal-basal subtypes. Methods: A retrospective cohort of UTUC was divided into UTUC-only (n = 71) and UTUC + UBC (n = 43). IHC expression of cytokeratin 5/6 (CK5/6), CK20, GATA3, and p53 was evaluated to assess relevant subtypes. Genetic characterization comprised TERTp, FGFR3, RAS, and TP53 status. Kaplan–Meier and Cox regression analyses estimated the effect of clinicopathological variables and molecular profiles on progression-free survival (PFS) and overall survival (OS) of UTUC patients. Results: No meaningful differences were detected among both subgroups according to luminal-basal stratification and genetic analysis. UTUC + UBC was independently associated with a worse PFS when stratified by luminal-basal phenotype (HR 3.570, CI 95% 1.508–8.453, p = 0.004) but with no impact in OS (HR 1.279, CI 95% 0.513–3.190, p = 0.597). Conclusions: This study reveals that both subgroups exhibited equivalent genomic features and luminal-basal subtypes. The involvement of the bladder relates to shorter PFS but does not seem to influence the survival outcome of UTUC, independently of the IHC phenotype. Full article
(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)
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25 pages, 1432 KiB  
Review
Role of Circulating Biomarkers in Diabetic Cardiomyopathy
by Raluca Diana Ianoș, Angela Cozma, Roxana Liana Lucaciu, Adriana Corina Hangan, Vasile Negrean, Delia Corina Mercea, George Ciulei, Călin Pop and Lucia Maria Procopciuc
Biomedicines 2024, 12(9), 2153; https://doi.org/10.3390/biomedicines12092153 - 23 Sep 2024
Viewed by 888
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that has alarmingly increased in incidence in recent decades. One of the most serious complications of T2DM is diabetic cardiomyopathy (DCM), an often underrecognized yet severe condition that is a leading cause of mortality [...] Read more.
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that has alarmingly increased in incidence in recent decades. One of the most serious complications of T2DM is diabetic cardiomyopathy (DCM), an often underrecognized yet severe condition that is a leading cause of mortality among diabetic patients. In the early stages of DCM, patients typically show no symptoms and maintain normal systolic and diastolic left ventricle function, making early detection challenging. Currently available clinical markers are often not specific enough to detect the early stage of DCM. Conventional biomarkers of cardiac mechanical stress and injury, such as natriuretic peptides (NPs) and cardiac troponin I (cTnI), have shown limited predictive value for patients with T2DM. NPs have proven efficacy in detecting diastolic dysfunction in diabetic patients when used alongside 2D echocardiography, but their utility as biomarkers is limited to symptomatic individuals. While cTnI is a reliable indicator of general cardiac damage, it is not specific to cardiac injury caused by high glucose levels or T2DM. This underscores the need for research into biomarkers that can enable early diagnosis and management of DCM to reduce mortality rates. Promising novel biomarkers that showed good performance in detecting diastolic dysfunction or heart failure in diabetic patients include galectin-3, ST2, FGF-21, IGFBP-7, GDF-15, and TGF-β. This review summarizes the current understanding of DCM biomarkers, aiming to generate new ideas for the early recognition and treatment of DCM by exploring related pathophysiological mechanisms. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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17 pages, 8845 KiB  
Article
Targeting CD47 and Angiogenesis Demonstrates Effective Anti-Tumor Effect in Bladder Cancer
by Xiting Huang, Qian Wang, Yanyang Nan, Xuyao Zhang, Ke Xu, Dianwen Ju and Weihong Ding
Biomedicines 2024, 12(9), 2152; https://doi.org/10.3390/biomedicines12092152 - 23 Sep 2024
Viewed by 904
Abstract
Background: Although immunotherapy has shown potential in cancer treatment, current immunotherapeutics for bladder cancer are limited by a low response rate. Therefore, it is necessary to investigate other suitable immunotherapeutic targets and strategies for bladder cancer. Methods: To evaluate whether CD47 could [...] Read more.
Background: Although immunotherapy has shown potential in cancer treatment, current immunotherapeutics for bladder cancer are limited by a low response rate. Therefore, it is necessary to investigate other suitable immunotherapeutic targets and strategies for bladder cancer. Methods: To evaluate whether CD47 could be a suitable target for bladder cancer immunotherapy, CD47 protein expression levels in 116 bladder cancer tissue samples were assessed by IHC staining. In vitro anti-tumor effect of blocking CD47 was examined by phagocytosis assays. In vivo anti-tumor effects of targeting CD47 and angiogenesis were experimented in the HSPCs-CDX model. Results: We find that CD47 is highly expressed in bladder cancer samples and is associated with poor prognosis. Blocking CD47 could enhance the human PBMC-derived macrophages’ phagocytosis of T24 (from 10.40% to 29.70%) and 5637 (from 5.31% to 33.52%) human bladder cancer cells, as well as demonstrate anti-tumor effects in the HSPCs-CDX model (tumor growth inhibition rate, TGI: 33.05%). During CD47 treatment, we observed that the level of angiogenesis increased after CD47 blockade, and it might undermine the effect of CD47 immunotherapy. We then combined CD47 blockade with anti-angiogenic drugs to treat bladder cancer and discovered that inhibiting angiogenesis could further improve the anti-tumor effect of CD47 blockade (TGI: 76.39%). Finally, we tested the anti-tumor effect of co-targeting CD47 and angiogenesis using a bispecific fusion protein, SIRPα-VEGFR1, which successfully inhibited tumor growth to a similar extent as a combination therapy. Conclusions: Our study suggests that targeting CD47 could inhibit the growth of bladder cancer by promoting macrophage-mediated anti-tumor immunity. Moreover, blocking CD47 and angiogenesis could achieve a potent anti-tumor effect and could be an effective immunotherapy strategy for bladder cancer. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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10 pages, 702 KiB  
Article
Assessing Cardiovascular Risk with Coronary Artery Calcium and Carotid Intima-Media Thickness in Patients with Negative Stress Echocardiography
by Narae Kim, Hui-Jeong Hwang and In-Ho Yang
Biomedicines 2024, 12(9), 2151; https://doi.org/10.3390/biomedicines12092151 - 23 Sep 2024
Viewed by 724
Abstract
Background: The role of treadmill stress echocardiography (TSE) in symptomatic patients may be limited. We evaluated whether carotid intima-media thickness (cIMT) and coronary artery calcium (CAC) scores can predict cardiovascular (CV) outcomes in patients with negative TSE. Methods: Patients who had [...] Read more.
Background: The role of treadmill stress echocardiography (TSE) in symptomatic patients may be limited. We evaluated whether carotid intima-media thickness (cIMT) and coronary artery calcium (CAC) scores can predict cardiovascular (CV) outcomes in patients with negative TSE. Methods: Patients who had negative TSE and measured cIMT or CAC scoring were enrolled and followed up. The primary CV outcome was defined as a composite of acute coronary syndrome, coronary revascularization, heart failure, stroke, and CV death. Results: Overall, 1095 patients participated. The median follow-up duration was 5.8 years. Patients with increased cIMT and CAC scores experienced a high incidence of primary CV outcomes (normal vs. increased group on cIMT and CAC scoring: 4.4% vs. 20.0% and 0.4% vs. 25.0%, respectively, p < 0.001). In the Cox proportional hazard model, increased cIMT and CAC scores were associated with increased primary CV outcomes (adjusted hazard ratio [95% confidence interval], p-value for increased cIMT and increased CAC scores = 2.939 [1.241–6.960], p = 0.014 and 45.192 [5.497–371.505], p < 0.001, respectively). Conclusions: Patients with increased cIMT and CAC scores have poor CV outcomes even though they have negative TSE results, and therefore, they should be carefully monitored. Full article
(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)
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21 pages, 883 KiB  
Review
Retinal Imaging-Based Oculomics: Artificial Intelligence as a Tool in the Diagnosis of Cardiovascular and Metabolic Diseases
by Laura Andreea Ghenciu, Mirabela Dima, Emil Robert Stoicescu, Roxana Iacob, Casiana Boru and Ovidiu Alin Hațegan
Biomedicines 2024, 12(9), 2150; https://doi.org/10.3390/biomedicines12092150 - 23 Sep 2024
Viewed by 1655
Abstract
Cardiovascular diseases (CVDs) are a major cause of mortality globally, emphasizing the need for early detection and effective risk assessment to improve patient outcomes. Advances in oculomics, which utilize the relationship between retinal microvascular changes and systemic vascular health, offer a promising non-invasive [...] Read more.
Cardiovascular diseases (CVDs) are a major cause of mortality globally, emphasizing the need for early detection and effective risk assessment to improve patient outcomes. Advances in oculomics, which utilize the relationship between retinal microvascular changes and systemic vascular health, offer a promising non-invasive approach to assessing CVD risk. Retinal fundus imaging and optical coherence tomography/angiography (OCT/OCTA) provides critical information for early diagnosis, with retinal vascular parameters such as vessel caliber, tortuosity, and branching patterns identified as key biomarkers. Given the large volume of data generated during routine eye exams, there is a growing need for automated tools to aid in diagnosis and risk prediction. The study demonstrates that AI-driven analysis of retinal images can accurately predict cardiovascular risk factors, cardiovascular events, and metabolic diseases, surpassing traditional diagnostic methods in some cases. These models achieved area under the curve (AUC) values ranging from 0.71 to 0.87, sensitivity between 71% and 89%, and specificity between 40% and 70%, surpassing traditional diagnostic methods in some cases. This approach highlights the potential of retinal imaging as a key component in personalized medicine, enabling more precise risk assessment and earlier intervention. It not only aids in detecting vascular abnormalities that may precede cardiovascular events but also offers a scalable, non-invasive, and cost-effective solution for widespread screening. However, the article also emphasizes the need for further research to standardize imaging protocols and validate the clinical utility of these biomarkers across different populations. By integrating oculomics into routine clinical practice, healthcare providers could significantly enhance early detection and management of systemic diseases, ultimately improving patient outcomes. Fundus image analysis thus represents a valuable tool in the future of precision medicine and cardiovascular health management. Full article
(This article belongs to the Special Issue Connections between Diabetes Mellitus, Other Metabolic and Endocrine Dysfunctions and Cardiovascular Pathologies)
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16 pages, 3651 KiB  
Article
Dopamine and Serotonin Transporter Genes Regulation in Highly Sensitive Individuals during Stressful Conditions: A Focus on Genetics and Epigenetics
by Fabio Bellia, Alessandro Piccinini, Eugenia Annunzi, Loreta Cannito, Francesca Lionetti, Bernardo Dell’Osso, Walter Adriani, Enrico Dainese, Alberto Di Domenico, Mariangela Pucci, Riccardo Palumbo and Claudio D’Addario
Biomedicines 2024, 12(9), 2149; https://doi.org/10.3390/biomedicines12092149 - 23 Sep 2024
Viewed by 1108
Abstract
Background: Coping with stress is essential for mental well-being and can be critical for highly sensitive individuals, characterized by a deeper perception and processing of stimuli. So far, the molecular bases characterizing high-sensitivity traits have not been completely investigated and gene × [...] Read more.
Background: Coping with stress is essential for mental well-being and can be critical for highly sensitive individuals, characterized by a deeper perception and processing of stimuli. So far, the molecular bases characterizing high-sensitivity traits have not been completely investigated and gene × environment interactions might play a key role in making some people more susceptible than others. Methods: In this study, 104 young adult university students, subjects that might face overwhelming experiences more than others, were evaluated for the genetics and epigenetics of dopamine (DAT1) and serotonin (SERT) transporter genes, in addition to the expression of miR-132, miR-491, miR-16, and miR-135. Results: We found an increase in DNA methylation at one specific CpG site at DAT1 5’UTR in highly sensitive students reporting high levels of perceived stress when compared to those less sensitive and/or less stressed. Moreover, considering DAT1 VNTR at 3’UTR, we observed that this effect was even more pronounced in university students having the 9/9 genotype when compared to those with the 9/10 genotype. These data are corroborated by the higher levels of miR-491, targeting DAT1, in highly sensitive subjects with high levels of perceived stress. SERT gene DNA methylation at one specific CpG site was reported to instead be higher in subjects reporting lower perceived stress when compared to more stressed subjects. Consistently, miR-135 expression, regulating SERT, was lower in subjects with higher perceived stress. Conclusions: We here suggest that the correlation of DAT1 and SERT genetic and epigenetic data with the analysis of stress and sensitivity might be useful to suggest possible biomarkers to monitor mental health wellness in vulnerable subjects. Full article
(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine)
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4 pages, 183 KiB  
Editorial
Editorial to the Special Issue “Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis”
by Nikita G. Nikiforov
Biomedicines 2024, 12(9), 2148; https://doi.org/10.3390/biomedicines12092148 - 23 Sep 2024
Viewed by 410
Abstract
The current Special Issue, “Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis”, is dedicated to exploring the various mechanisms involved in atherogenesis [...] Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)
23 pages, 6768 KiB  
Article
The Proteasome-Family-Members-Based Prognostic Model Improves the Risk Classification for Adult Acute Myeloid Leukemia
by Guangying Sheng, Jingfen Tao, Peng Jin, Yilu Li, Wen Jin and Kankan Wang
Biomedicines 2024, 12(9), 2147; https://doi.org/10.3390/biomedicines12092147 - 22 Sep 2024
Viewed by 861
Abstract
Background: The accumulation of diverse molecular and cytogenetic variations contributes to the heterogeneity of acute myeloid leukemia (AML), a cluster of hematologic malignancies that necessitates enhanced risk evaluation for prognostic prediction and therapeutic guidance. The ubiquitin–proteasome system plays a crucial role in AML; [...] Read more.
Background: The accumulation of diverse molecular and cytogenetic variations contributes to the heterogeneity of acute myeloid leukemia (AML), a cluster of hematologic malignancies that necessitates enhanced risk evaluation for prognostic prediction and therapeutic guidance. The ubiquitin–proteasome system plays a crucial role in AML; however, the specific contributions of 49 core proteasome family members (PSMs) in this context remain largely unexplored. Methods: The expression and survival significance of 49 PSMs in AML were evaluated using the data from BeatAML2.0, TCGA, and the GEO database, mainly through the K-M plots, differential genes enrichment analysis, and candidate compounds screening via R language and statistical software. Results: we employed LASSO and Cox regression analyses and developed a model comprising three PSMs (PSMB8, PSMG1, and PSMG4) aimed at predicting OS in adult AML patients, utilizing expression profiles from the BeatAML2.0 training datasets. Patients with higher risk scores were predominantly found in the AML–M2 subtype, exhibited poorer ELN stratification, showed no complete remission following induction therapies, and had a higher mortality status. Consistently, significantly worse OS was observed in high-risk patients across both the training and three validation datasets, underscoring the robust predictive capability of the three-PSMs model for AML outcomes. This model elucidated the distinct genetic abnormalities landscape between high- and low-risk groups and enhanced the ELN risk stratification system. Ultimately, the three-PSMs risk score captured AML-specific gene expression signatures, providing a molecular basis for selecting potential therapeutic agents. Conclusions: In summary, these findings manifested the significant potential of the PSM model for predicting AML survival and informed treatment strategies. Full article
(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)
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15 pages, 331 KiB  
Review
The Importance of Predictive Biomarkers and Their Correlation with the Response to Immunotherapy in Solid Tumors—Impact on Clinical Practice
by Raluca Ioana Mihaila, Adelina Silvana Gheorghe, Daniela Luminita Zob and Dana Lucia Stanculeanu
Biomedicines 2024, 12(9), 2146; https://doi.org/10.3390/biomedicines12092146 - 22 Sep 2024
Viewed by 1178
Abstract
Background/Objectives: Immunotherapy has changed the therapeutic approach for various solid tumors, especially lung tumors, malignant melanoma, renal and urogenital carcinomas, demonstrating significant antitumor activity, with tolerable safety profiles and durable responses. However, not all patients benefit from immunotherapy, underscoring the need for [...] Read more.
Background/Objectives: Immunotherapy has changed the therapeutic approach for various solid tumors, especially lung tumors, malignant melanoma, renal and urogenital carcinomas, demonstrating significant antitumor activity, with tolerable safety profiles and durable responses. However, not all patients benefit from immunotherapy, underscoring the need for predictive biomarkers that can identify those most likely to respond to treatment. Methods: The integration of predictive biomarkers into clinical practice for immune checkpoint inhibitors (ICI) holds great promise for personalized cancer treatment. Programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), microsatellite instability (MSI), gene expression profiles and circulating tumor DNA (ctDNA) have shown potential in predicting ICI responses across various cancers. Results: Challenges such as standardization, validation, regulatory approval, and cost-effectiveness must be addressed to realize their full potential. Predictive biomarkers are crucial for optimizing the clinical use of ICIs in cancer therapy. Conclusions: While significant progress has been made, further research and collaboration among clinicians, researchers, and regulatory institutes are essential to overcome the challenges of clinical implementation. However, little is known about the relationship between local and systemic immune responses and the correlation with response to oncological therapies and patient survival. Full article
(This article belongs to the Special Issue Modulation of Anti-tumor Immunity and Tumor Microenvironment)
25 pages, 2418 KiB  
Article
Unraveling the Impact of COVID-19 on Rheumatoid Arthritis: Insights from Two Romanian Hospitals—Preliminary Results
by Andreea-Iulia Vlădulescu-Trandafir, Gelu Onose, Constantin Munteanu, Ioana Iancu, Andra-Rodica Bălănescu, Daniela Opriș-Belinski, Florian Berghea, Cristiana Prefac, Elena Grădinaru, Sorina Aurelian, Vlad Ciobanu and Violeta-Claudia Bojincă
Biomedicines 2024, 12(9), 2145; https://doi.org/10.3390/biomedicines12092145 - 21 Sep 2024
Cited by 1 | Viewed by 1035
Abstract
Background: Rheumatoid arthritis (RA) patients are at heightened risk of Coronavirus Disease—19 (COVID-19) complications due to immune dysregulation, chronic inflammation, and treatment with immunosuppressive therapies. This study aims to characterize the clinical and laboratory parameters of RA patients diagnosed with COVID-19, identify predictive [...] Read more.
Background: Rheumatoid arthritis (RA) patients are at heightened risk of Coronavirus Disease—19 (COVID-19) complications due to immune dysregulation, chronic inflammation, and treatment with immunosuppressive therapies. This study aims to characterize the clinical and laboratory parameters of RA patients diagnosed with COVID-19, identify predictive risk factors for severe forms of this infection for RA patients, and determine if any RA immunosuppressive therapy is associated with worse COVID-19 outcomes. Methods: A retrospective observational case-control study included 86 cases (43 diagnosed with RA and 43 cases without any inflammatory or autoimmune disease) that suffered from SARS-CoV-2 in two Romanian hospitals between March 2020 and February 2024. Data on demographics, RA disease characteristics, COVID-19 severity, treatment regimens, and outcomes were analyzed. Results: RA patients exhibited a distinct symptom profile compared to non-RA controls, with higher incidences of neurological, musculoskeletal, and gastrointestinal symptoms, while the control group showed more respiratory and systemic manifestations. Severe COVID-19 is correlated with age and laboratory markers like erythrocyte sedimentation rate (ESR), leucocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), aspartate aminotransferase (AST), serum creatinine, and urea. Additionally, RA treatments, particularly rituximab (RTX), were associated with more severe COVID-19 outcomes (but with no statistical significance), potentially due to the advanced disease stage and comorbidities in these patients. Post-infection, a significant number of RA patients experienced disease flares, necessitating adjustments in their treatment regimens. Conclusions: This study underscores the complex interplay between RA and COVID-19, highlighting significant clinical heterogeneity and the need for tailored management strategies. Limitations include sample size constraints, possible selection, and information bias, as well as the lack of adjustments for potential confounding variables that hinder the ability to formulate definitive conclusions. Future research plans to expand the research group size and further elucidate these relationships. Full article
(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy (Volume II))
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14 pages, 824 KiB  
Article
Metabolic Dysfunction-Associated Steatotic Liver Disease: The Associations between Inflammatory Markers, TLR4, and Cytokines IL-17A/F, and Their Connections to the Degree of Steatosis and the Risk of Fibrosis
by Sorina-Cezara Coste, Olga Hilda Orășan, Angela Cozma, Vasile Negrean, Adela-Viviana Sitar-Tăut, Gabriela Adriana Filip, Adriana Corina Hangan, Roxana Liana Lucaciu, Mihaela Iancu and Lucia Maria Procopciuc
Biomedicines 2024, 12(9), 2144; https://doi.org/10.3390/biomedicines12092144 - 21 Sep 2024
Viewed by 903
Abstract
Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease) is driven by environmental, genetic, metabolic, immune, and inflammatory factors. IL-17 and TLR4 determine hepatic steatosis, inflammation, and finally fibrosis. Objectives: To explore the associations between the plasma levels of inflammatory [...] Read more.
Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease) is driven by environmental, genetic, metabolic, immune, and inflammatory factors. IL-17 and TLR4 determine hepatic steatosis, inflammation, and finally fibrosis. Objectives: To explore the associations between the plasma levels of inflammatory markers, TLR4, and the cytokines IL17A/F, as well as their connections with the degree of hepatic steatosis and the risk of hepatic fibrosis (defined by the FIB-4 score) in MASLD patients. Methods: The study cohort included 80 patients diagnosed with MASLD. The IL-17A/F and TLR4 serum concentrations were determined using the ELISA method. Results: We found a significant difference in the CAR levels (C-reactive protein to albumin ratio) when comparing MASLD patients with severe steatosis to those with mild/moderate steatosis (Student’s t test, t (71) = 2.32, p = 0.023). The PIV (pan-immune inflammatory value) was positively correlated with the SII (systemic immune inflammation index), (r = 0.86, p < 0.0001) and the CAR (r = 0.41, p = 0.033) in MASLD patients with severe steatosis. In contrast, increased values of the LMR (lymphocyte to monocyte ratio) were significantly associated, with decreased levels of the SII (ρ = −0.38, p = 0.045). We also found a positive correlation between the CAR and the SII (r = 0.41, p = 0.028). In patients with mild/moderate steatosis, a significant positive correlation was observed between the SII and IL17A (r = 0.36, p = 0.010), the PIV and the CAR (r = 0.29, p = 0.011), the PIV and the SII (r = 0.87, p < 0.0001) and the PIV and IL17A (r = 0.3, p = 0.036). A negative correlation was observed between the LMR and the SII (r = −0.55, p < 0.0001) and the CAR and IL17F (r = −0.37, p = 0.011). Regarding the inflammatory markers, the PIV (336.4 vs. 228.63, p = 0.0107), and the SII (438.47 vs. 585.39, p = 0.0238) had significantly lower levels in patients with an intermediate–high risk of hepatic fibrosis as compared with the patients with a low risk of hepatic fibrosis. The PNI (prognostic nutritional index) (47.16 vs. 42.41, p = 0.0392) had significantly different levels in patients with the likelihood of hepatic fibrosis than those with a low risk of hepatic fibrosis. Conclusions: Regarding the inflammatory markers, the PIV and the SII hold promise as biomarkers for discriminating between MASLD patients with an intermediate–high risk and those with a low risk of hepatic fibrosis. Our findings underscore the role of IL-17A and its potential relationship with inflammatory markers in MASLD pathogenesis and the progression to hepatic fibrosis. Full article
(This article belongs to the Special Issue Pancreatic, Liver, Biliary Tract and Intestinal Diseases: Pathogenesis, Diagnostics and Therapy)
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21 pages, 909 KiB  
Article
Reinforcement Learning: A Paradigm Shift in Personalized Blood Glucose Management for Diabetes
by Lehel Dénes-Fazakas, László Szilágyi, Levente Kovács, Andrea De Gaetano and György Eigner
Biomedicines 2024, 12(9), 2143; https://doi.org/10.3390/biomedicines12092143 - 21 Sep 2024
Viewed by 691
Abstract
Background/Objectives: Managing blood glucose levels effectively remains a significant challenge for individuals with diabetes. Traditional methods often lack the flexibility needed for personalized care. This study explores the potential of reinforcement learning-based approaches, which mimic human learning and adapt strategies through ongoing interactions, [...] Read more.
Background/Objectives: Managing blood glucose levels effectively remains a significant challenge for individuals with diabetes. Traditional methods often lack the flexibility needed for personalized care. This study explores the potential of reinforcement learning-based approaches, which mimic human learning and adapt strategies through ongoing interactions, in creating dynamic and personalized blood glucose management plans. Methods: We developed a mathematical model specifically for patients with type IVP diabetes, validated with data from 10 patients and 17 key parameters. The model includes continuous glucose monitoring (CGM) noise and random carbohydrate intake to simulate real-life conditions. A closed-loop system was designed to enable the application of reinforcement learning algorithms. Results: By implementing a Policy Optimization (PPO) branch, we achieved an average Time in Range (TIR) metric of 73%, indicating improved blood glucose control. Conclusions: This study presents a personalized insulin therapy solution using reinforcement learning. Our closed-loop model offers a promising approach for improving blood glucose regulation, with potential applications in personalized diabetes management. Full article
(This article belongs to the Special Issue Diabetes: Pathogenesis, Therapeutics and Outcomes)
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25 pages, 3094 KiB  
Article
Exosome-like Nanoparticles, High in Trans-δ-Viniferin Derivatives, Produced from Grape Cell Cultures: Preparation, Characterization, and Anticancer Properties
by Yury Shkryl, Zhargalma Tsydeneshieva, Ekaterina Menchinskaya, Tatiana Rusapetova, Olga Grishchenko, Anastasia Mironova, Dmitry Bulgakov, Tatiana Gorpenchenko, Vitaly Kazarin, Galina Tchernoded, Victor Bulgakov, Dmitry Aminin and Yulia Yugay
Biomedicines 2024, 12(9), 2142; https://doi.org/10.3390/biomedicines12092142 - 20 Sep 2024
Viewed by 1098
Abstract
Background: Recent interest in plant-derived exosome-like nanoparticles (ENs) has surged due to their therapeutic potential, which includes antioxidant, anti-inflammatory, and anticancer activities. These properties are attributed to their cargo of bioactive metabolites and other endogenous molecules. However, the properties of ENs isolated [...] Read more.
Background: Recent interest in plant-derived exosome-like nanoparticles (ENs) has surged due to their therapeutic potential, which includes antioxidant, anti-inflammatory, and anticancer activities. These properties are attributed to their cargo of bioactive metabolites and other endogenous molecules. However, the properties of ENs isolated from plant cell cultures remain less explored. Methods: In this investigation, grape callus-derived ENs (GCENs) were isolated using differential ultracentrifugation techniques. Structural analysis through electron microscopy, nanoparticle tracking analysis, and western blotting confirmed that GCENs qualify as exosome-like nanovesicles. Results: These GCENs contained significant amounts of microRNAs and proteins characteristic of plant-derived ENs, as well as trans-δ-viniferin, a notable stilbenoid known for its health-promoting properties. Functional assays revealed that the GCENs reduced the viability of the triple-negative breast cancer cell line MDA-MB-231 in a dose-dependent manner. Moreover, the GCENs exhibited negligible effects on the viability of normal human embryonic kidney (HEK) 293 cells, indicating selective cytotoxicity. Notably, treatment with these GCENs led to cell cycle arrest in the G1 phase and triggered apoptosis in the MDA-MB-231 cell line. Conclusions: Overall, this study underscores the potential of grape callus-derived nanovectors as natural carriers of stilbenoids and proposes their application as a novel and effective approach in the management of cancer. Full article
(This article belongs to the Section Nanomedicine and Nanobiology)
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12 pages, 3844 KiB  
Article
Cytocidal Effects of Interstitial Photodynamic Therapy Using Talaporfin Sodium and a Semiconductor Laser in a Rat Intracerebral Glioma Model
by Yuki Saito, Shinjiro Fukami, Kenta Nagai, Emiyu Ogawa, Masahiko Kuroda, Michihiro Kohno and Jiro Akimoto
Biomedicines 2024, 12(9), 2141; https://doi.org/10.3390/biomedicines12092141 - 20 Sep 2024
Viewed by 698
Abstract
This preclinical study was conducted to investigate the efficacy of interstitial PDT (i-PDT) for malignant gliomas arising deep within the brain, which are difficult to remove. C6 glioma cells were implanted into the basal ganglia of rats, and 3 weeks later, the second-generation [...] Read more.
This preclinical study was conducted to investigate the efficacy of interstitial PDT (i-PDT) for malignant gliomas arising deep within the brain, which are difficult to remove. C6 glioma cells were implanted into the basal ganglia of rats, and 3 weeks later, the second-generation photosensitizer talaporfin sodium (TPS) was administered intraperitoneally. Ninety minutes after administration, a prototype fine plastic optical fiber was punctured into the tumor tissue, and semiconductor laser light was irradiated into the tumor from a 2-mm cylindrical light-emitting source under various conditions. The brain was removed 24 h after the i-PDT and analyzed pathologically. The optical fiber was able to puncture the tumor center in all cases, enabling i-PDT to be performed. Histological analysis showed that tumor necrosis was induced in areas close to the light source, correlating with the irradiation energy dose, whereas apoptosis was induced at some distance from the light source. Irradiation using high energy levels resulted in tissue swelling from strong tumor necrosis, and irradiation at 75 J/cm2 was most suitable for inducing apoptosis. An experimental system of i-PDT using TPS was established using malignant glioma cells transplanted into the rat brain. Tumor cell death, which correlated with the light propagation, was induced in tumor tissue. Full article
(This article belongs to the Special Issue Photodynamic Therapy (3rd Edition))
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12 pages, 1330 KiB  
Systematic Review
Breaking the Cycle of Pain: The Role of Graded Motor Imagery and Mirror Therapy in Complex Regional Pain Syndrome
by Danilo Donati, Paolo Boccolari, Federica Giorgi, Lisa Berti, Daniela Platano and Roberto Tedeschi
Biomedicines 2024, 12(9), 2140; https://doi.org/10.3390/biomedicines12092140 - 20 Sep 2024
Viewed by 1108
Abstract
Background: Complex Regional Pain Syndrome (CRPS) is a chronic condition characterized by severe pain and functional impairment. Graded Motor Imagery (GMI) and Mirror Therapy (MT) have emerged as potential non-invasive treatments; this review evaluates the effectiveness of these therapies in reducing pain, improving [...] Read more.
Background: Complex Regional Pain Syndrome (CRPS) is a chronic condition characterized by severe pain and functional impairment. Graded Motor Imagery (GMI) and Mirror Therapy (MT) have emerged as potential non-invasive treatments; this review evaluates the effectiveness of these therapies in reducing pain, improving function, and managing swelling in CRPS patients. Methods: A systematic review was conducted including randomized controlled trials (RCTs) that investigated GMI and MT in CRPS patients. This review was registered in PROSPERO (CRD42024535972) to ensure transparency and adherence to protocols. This review included searches of PubMed, Cochrane, SCOPUS, and Web of Science databases. Out of 81 studies initially screened, 6 were included in the final review. Studies were assessed for quality using the PEDro and RoB-2 scales. The primary outcomes were pain reduction, functional improvement, and swelling reduction. Results: Graded Motor Imagery (GMI) and Mirror Therapy (MT) reduced pain by an average of 20 points on the Neuropathic Pain Scale (NPS) and resulted in functional improvements as measured by the Task-Specific Numeric Rating Scale (NRS). GMI also contributed to some reduction in swelling. MT, particularly in post-stroke CRPS patients, showed significant pain reduction and functional improvements, with additional benefits in reducing swelling in certain studies. However, the included studies had small sample sizes and mixed designs, which limit the generalizability of the findings. The studies varied in sample size and design, with some risk of bias noted. Conclusions: Graded Motor Imagery (GMI) and Mirror Therapy (MT) have proven to be effective interventions for managing Complex Regional Pain Syndrome (CRPS), with significant improvements in pain reduction and functional recovery. These non-invasive treatments hold potential for integration into standard rehabilitation protocols. However, the small sample sizes and variability in study designs limit the generalizability of these findings. Future research should focus on larger, more homogeneous trials to validate the long-term effectiveness of GMI and MT, ensuring more robust clinical application. Full article
(This article belongs to the Special Issue Musculoskeletal Diseases: From Pathophysiology to Clinics, Diagnostics and Treatment)
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17 pages, 1030 KiB  
Article
Analysis of Brain Age Gap across Subject Cohorts and Prediction Model Architectures
by Lara Dular, Žiga Špiclin, for the Alzheimer’s Disease Neuroimaging Initiative and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing
Biomedicines 2024, 12(9), 2139; https://doi.org/10.3390/biomedicines12092139 - 20 Sep 2024
Viewed by 862
Abstract
Background: Brain age prediction from brain MRI scans and the resulting brain age gap (BAG)—the difference between predicted brain age and chronological age—is a general biomarker for a variety of neurological, psychiatric, and other diseases or disorders. Methods: This study examined the differences [...] Read more.
Background: Brain age prediction from brain MRI scans and the resulting brain age gap (BAG)—the difference between predicted brain age and chronological age—is a general biomarker for a variety of neurological, psychiatric, and other diseases or disorders. Methods: This study examined the differences in BAG values derived from T1-weighted scans using five state-of-the-art deep learning model architectures previously used in the brain age literature: 2D/3D VGG, RelationNet, ResNet, and SFCN. The models were evaluated on healthy controls and cohorts with sleep apnea, diabetes, multiple sclerosis, Parkinson’s disease, mild cognitive impairment, and Alzheimer’s disease, employing rigorous statistical analysis, including repeated model training and linear mixed-effects models. Results: All five models consistently identified a statistically significant positive BAG for diabetes (ranging from 0.79 years with RelationNet to 2.13 years with SFCN), multiple sclerosis (2.67 years with 3D VGG to 4.24 years with 2D VGG), mild cognitive impairment (2.13 years with 2D VGG to 2.59 years with 3D VGG), and Alzheimer’s dementia (5.54 years with ResNet to 6.48 years with SFCN). For Parkinson’s disease, a statistically significant BAG increase was observed in all models except ResNet (1.30 years with 2D VGG to 2.59 years with 3D VGG). For sleep apnea, a statistically significant BAG increase was only detected with the SFCN model (1.59 years). Additionally, we observed a trend of decreasing BAG with increasing chronological age, which was more pronounced in diseased cohorts, particularly those with the largest BAG, such as multiple sclerosis (−0.34 to −0.2), mild cognitive impairment (−0.37 to −0.26), and Alzheimer’s dementia (−0.66 to −0.47), compared to healthy controls (−0.18 to −0.1). Conclusions: Consistent with previous research, Alzheimer’s dementia and multiple sclerosis exhibited the largest BAG across all models, with SFCN predicting the highest BAG overall. The negative BAG trend suggests a complex interplay of survival bias, disease progression, adaptation, and therapy that influences brain age prediction across the age spectrum. Full article
(This article belongs to the Special Issue Pathological Biomarkers in Precision Medicine)
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14 pages, 1991 KiB  
Article
COVID-19 Inflammatory Syndrome: Lessons from TNFRI and CRP about the Risk of Death in Severe Disease
by Thaís Soares Farnesi-de-Assunção, Ana Carolina de Morais Oliveira-Scussel, Wellington Francisco Rodrigues, Beatriz Sodré Matos, Djalma Alexandre Alves da Silva, Leonardo Eurípedes de Andrade e Silva, Fabiano Vilela Mundim, Fernanda Rodrigues Helmo, Anna Victória Bernardes e Borges, Chamberttan Souza Desidério, Rafael Obata Trevisan, Malu Mateus Santos Obata, Laís Milagres Barbosa, Marcela Rezende Lemes, Juliana Cristina Costa-Madeira, Rafaela Miranda Barbosa, Andrezza Cristina Cancian Hortolani Cunha, Loren Queli Pereira, Sarah Cristina Sato Vaz Tanaka, Fernanda Bernadelli de Vito, Ivan Borges Monteiro, Yulsef Moura Ferreira, Guilherme Henrique Machado, Hélio Moraes-Souza, Denise Bertulucci Rocha Rodrigues, Carlo José Freire de Oliveira, Marcos Vinicius da Silva and Virmondes Rodrigues Júnioradd Show full author list remove Hide full author list
Biomedicines 2024, 12(9), 2138; https://doi.org/10.3390/biomedicines12092138 - 20 Sep 2024
Viewed by 620
Abstract
Background/Objectives: Cytokine storm in severe COVID-19 is responsible for irreversible tissue damage and death. Soluble mediators from the TNF superfamily, their correlation with clinical outcome, and the use of TNF receptors as a potent predictor for clinical outcome were evaluated. Methods: [...] Read more.
Background/Objectives: Cytokine storm in severe COVID-19 is responsible for irreversible tissue damage and death. Soluble mediators from the TNF superfamily, their correlation with clinical outcome, and the use of TNF receptors as a potent predictor for clinical outcome were evaluated. Methods: Severe COVID-19 patients had the levels of soluble mediators from the TNF superfamily quantified and categorized according to the clinical outcome (death versus survival). Statistical modeling was performed to predict clinical outcomes. Results: COVID-19 patients have elevated serum levels from the TNF superfamily. Regardless of sex and age, the sTNFRI levels were observed to be significantly higher in deceased patients from the first weeks following the onset of symptoms. We analyzed hematological parameters and inflammatory markers, and there was a difference between the groups for the following factors: erythrocytes, hemoglobin, hematocrit, leukocytes, neutrophils, band cells, lymphocytes, monocytes, CRP, IL-8, IFN-γ, IL-10, IL-6, IL-4, IL-2, leptin MIF sCD40L, and sTNFRI (p < 0.05). A post hoc analysis showed an inferential capacity over 70% for some hematological markers, CRP, and inflammatory mediators in deceased patients. sTNFRI was strongly associated with death, and the sTNFRI/sTNFRII ratio differed between outcomes (p < 0.001; power above 90%), highlighting the impact of these proteins on clinical results. The final logistic model, including sTNFRI/sTNFRII and CRP, indicated high sensitivity, specificity, accuracy, and an eight-fold higher odds ratio for an unfavorable outcome. Conclusions: The joint use of the sTNFRI/sTNFRII ratio with CRP proves to be a promising tool to assist in the clinical management of patients hospitalized for COVID-19. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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23 pages, 1543 KiB  
Review
Circulating Tumor Cells: Origin, Role, Current Applications, and Future Perspectives for Personalized Medicine
by Maria Cristina Rapanotti, Tonia Cenci, Maria Giovanna Scioli, Elisa Cugini, Silvia Anzillotti, Luca Savino, Deborah Coletta, Cosimo Di Raimondo, Elena Campione, Mario Roselli, Sergio Bernardini, Luca Bianchi, Anastasia De Luca, Amedeo Ferlosio and Augusto Orlandi
Biomedicines 2024, 12(9), 2137; https://doi.org/10.3390/biomedicines12092137 - 20 Sep 2024
Viewed by 1260
Abstract
Circulating tumor cells (CTCs) currently represent a revolutionary tool offering unique insights for the evaluation of cancer progression, metastasis, and response to therapies. Indeed, CTCs, upon detachment from primary tumors, enter the bloodstream and acquire a great potential for their use for personalized [...] Read more.
Circulating tumor cells (CTCs) currently represent a revolutionary tool offering unique insights for the evaluation of cancer progression, metastasis, and response to therapies. Indeed, CTCs, upon detachment from primary tumors, enter the bloodstream and acquire a great potential for their use for personalized cancer management. In this review, we describe the current understanding of and advances in the clinical employment of CTCs. Although considered rare and fleeting, CTCs are now recognized as key players favoring the development of cancer metastasis and disease recurrence, particularly in malignant melanoma, lung, breast, and colorectal cancer patients. To date, the advancements in technology and the development of several successful approaches, also including immunomagnetic enrichment allow for a reliable and reproducible detection and characterization of CTCs. Those innovative methodologies improved the isolation, quantification, and characterization of CTCs from the blood of cancer patients, providing extremely useful evidence and new insights into the nature of the tumor, its epithelial/mesenchymal profile, and its potential resistance to therapy. In fact, in addition to their prognostic and predictive value, CTCs could serve as a valuable instrument for real-time monitoring of treatment response and disease recurrence, facilitating timely interventions and thus improving patient outcomes. However, despite their potential, several challenges hinder the widespread clinical utility of CTCs: (i) CTCs’ rarity and heterogeneity pose technical limitations in isolation and characterization, as well as significant hurdles in their clinical implementation; (ii) it is mandatory to standardize CTC detection methods, optimize the sample processing techniques, and integrate them with existing diagnostic modalities; and (iii) the need for the development of new techniques, such as single-cell analysis platforms, to enhance the sensitivity and specificity of CTC detection, thereby facilitating their integration into routine clinical practice. In conclusion, CTCs represent a potential extraordinary tool in cancer diagnostics and therapeutics, offering unprecedented opportunities for personalized medicine and precision oncology. Moreover, their ability to provide real-time insights into tumor biology, treatment response, and disease progression underlines a great potential for their clinical application to improve patients’ outcomes and advance our understanding of cancer biology. Full article
(This article belongs to the Special Issue The Biology of Circulating Tumor Cells 2.0)
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13 pages, 2825 KiB  
Article
Outcome Disparities in Patients with Early-Stage Laryngeal Cancer Depending on Localization, Tobacco Consumption, and Treatment Modality
by Theresa Wald, Tim-Jonathan Koppe, Markus Pirlich, Veit Zebralla, Viktor Kunz, Andreas Dietz, Matthaeus Stoehr and Gunnar Wichmann
Biomedicines 2024, 12(9), 2136; https://doi.org/10.3390/biomedicines12092136 - 20 Sep 2024
Viewed by 583
Abstract
Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is among most frequent malignancies of the head and neck. Recent oncologic research focusses on advanced rather than on early stages. Thus, we aimed to improve the knowledge concerning prognostic factors and survival in early glottic (GC) [...] Read more.
Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is among most frequent malignancies of the head and neck. Recent oncologic research focusses on advanced rather than on early stages. Thus, we aimed to improve the knowledge concerning prognostic factors and survival in early glottic (GC) and supraglottic cancer (SGC). Methods: We retrospectively investigated patients diagnosed in 2007 to 2020 with stage I or II GC (ICD-10-C32.0) or SGC (ICD-10-C32.1, C32.8 or C32.9). For precise discrimination of GC and SGC, pathology reports about biopsy and definitive excision were closely examined and information on clinical characteristics and risk factors were collected before analyzing patterns of risk factors for overall survival (OS) in multivariate Cox regression analyses (mvCox). Results: The cohort included 220 patients with early GC (n = 183) and SGC (n = 37). The GC patients showed significantly improved 5-year OS compared to SGC patients (83.6% vs. 64.9%; p = 0.004), whereas survival according to UICC stage (I vs. II) was not different (p = 0.177). Surgical resection was superior to definitive radiotherapy (RT) for 5-year OS (p < 0.001). Cumulative tobacco consumption of greater than 10 pack years drastically impaired OS (p = 0.024), especially in patients receiving RT (p < 0.001). Supraglottic localization, smoking, and re-resection after initial R1 status consistently were independent prognostic factors in mvCox. Conclusions: Our cohort of early LSCC patients demonstrates significant negative impact of supraglottic localization, older age, tobacco consumption, poor tumor differentiation, and re-resection on OS. Further research is required as there is still lack of evidence on optimal decision-making and therapeutic strategies. Full article
(This article belongs to the Special Issue Head and Neck Tumors, 3rd Edition)
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18 pages, 2917 KiB  
Article
Elevated Cellular Uptake of Succinimide- and Glucose-Modified Liposomes for Blood–Brain Barrier Transfer and Glioblastoma Therapy
by Larissa J. Lubitz, Moritz P. Haffner, Harden Rieger and Gero Leneweit
Biomedicines 2024, 12(9), 2135; https://doi.org/10.3390/biomedicines12092135 - 20 Sep 2024
Viewed by 714
Abstract
The uptake of four liposomal formulations was tested with the murine endothelial cell line bEnd.3 and the human glioblastoma cell line U-87 MG. All formulations were composed of DPPC, cholesterol, 5 mol% of mPEG (2000 Da, conjugated to DSPE), and the dye DiD. [...] Read more.
The uptake of four liposomal formulations was tested with the murine endothelial cell line bEnd.3 and the human glioblastoma cell line U-87 MG. All formulations were composed of DPPC, cholesterol, 5 mol% of mPEG (2000 Da, conjugated to DSPE), and the dye DiD. Three of the formulations had an additional PEG chain (nominally 5000 Da, conjugated to DSPE) with either succinimide (NHS), glucose (PEG-bound at C-6), or 4-aminophenyl β-D-glucopyranoside (bound at C-1) as ligands at the distal end. Measuring the uptake kinetics at 1 h and 3 h for liposomal incubation concentrations of 100 µM, 500 µM, and 1000 µM, we calculated the liposomal uptake saturation S and the saturation half-time t1/2. We show that only succinimide has an elevated uptake in bEnd.3 cells, which makes it a very promising and so far largely unexplored candidate for BBB transfer and brain cancer therapies. Half-times are uniform at low concentrations but diversify for high concentrations for bEnd.3 cells. Contrary, U-87 MG cells show almost identical saturations for all three ligands, making a uniform uptake mechanism likely. Only mPEG liposomes stay at 60% of the saturation for ligand-coated liposomes. Half-times are diverse at low concentrations but unify at high concentrations for U-87 MG cells. Full article
(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)
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14 pages, 2995 KiB  
Article
Comparison of Multiple Carbapenemase Tests Based on an Unbiased Colony-Selection Method
by Hsin-Yao Wang, Yi-Ju Tseng, Wan-Ying Lin, Yu-Chiang Wang, Ting-Wei Lin, Jen-Fu Hsu, Marie Yung-Chen Wu, Chiu-Hsiang Wu, Sriram Kalpana and Jang-Jih Lu
Biomedicines 2024, 12(9), 2134; https://doi.org/10.3390/biomedicines12092134 - 20 Sep 2024
Viewed by 843
Abstract
Carbapenemase-producing organisms (CPOs) present a major threat to public health, demanding precise diagnostic techniques for their detection. Discrepancies among the CPO tests have raised concerns, partly due to limitations in detecting bacterial diversity within host specimens. We explored the impact of an unbiased [...] Read more.
Carbapenemase-producing organisms (CPOs) present a major threat to public health, demanding precise diagnostic techniques for their detection. Discrepancies among the CPO tests have raised concerns, partly due to limitations in detecting bacterial diversity within host specimens. We explored the impact of an unbiased colony selection on carbapenemase testing and assessed its relevance to various tests. Using the FirstAll method for unbiased colony selection to reduce bias, we compared the results from different methods, namely the modified carbapenem inactivation method/EDTA-modified carbapenem inactivation method (mCIM/eCIM), the Carba5, the CPO panel, and the multiplex PCR (MPCR). We compared the FirstAll method to the conventional colony selection for MPCR with seven CPO species. In addition, we evaluated the test performance on seven CPO species using MPCR as a reference and the FirstAll method as the colony-selection method. The results revealed that the selections from the FirstAll method have improved rates of carbapenemase detection, in comparison to approximately 11.2% of the CPO isolates that were noted to be false negatives in the conventional colony-selection methods. Both the Carba5 test and the CPO panel showed suboptimal performance (sensitivity/specificity: Carba5 74.6%/89.5%, CPO panel 77.2%/74.4%) in comparison to the FirstAll method. The Carba5 test provided specific carbapenemase class assignments, but the CPO panel failed in 18.7% of the cases. The Carba5 test and the CPO panel results correlated well with ceftazidime–avibactam minimal inhibitory concentrations (MICs). The concordance for Class A/D with MICs was 94.7% for Carba5 and 92.7% for the CPO panel; whereas for Class B, it was 86.5% for Carba5 and 75.9% for the CPO panel. In conclusion, FirstAll, as the unbiased colony-selection method, was shown to impact carbapenemase testing. With FirstAll, the diagnostic performance of both the Carba5 and the CPO panel was found to be lower. Furthermore, the utilization of ceftazidime–avibactam guided by either the CPO panel or Carba5 was appropriate. Full article
(This article belongs to the Section Microbiology in Human Health and Disease)
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16 pages, 506 KiB  
Review
Chemerin in the Spotlight: Revealing Its Multifaceted Role in Acute Myocardial Infarction
by Andreas Mitsis, Elina Khattab, Michael Myrianthefs, Stergios Tzikas, Nikolaos P. E. Kadoglou, Nikolaos Fragakis, Antonios Ziakas and George Kassimis
Biomedicines 2024, 12(9), 2133; https://doi.org/10.3390/biomedicines12092133 - 20 Sep 2024
Viewed by 726
Abstract
Chemerin, an adipokine known for its role in adipogenesis and inflammation, has emerged as a significant biomarker in cardiovascular diseases, including acute myocardial infarction (AMI). Recent studies have highlighted chemerin’s involvement in the pathophysiological processes of coronary artery disease (CAD), where it modulates [...] Read more.
Chemerin, an adipokine known for its role in adipogenesis and inflammation, has emerged as a significant biomarker in cardiovascular diseases, including acute myocardial infarction (AMI). Recent studies have highlighted chemerin’s involvement in the pathophysiological processes of coronary artery disease (CAD), where it modulates inflammatory responses, endothelial function, and vascular remodelling. Elevated levels of chemerin have been associated with adverse cardiovascular outcomes, including increased myocardial injury, left ventricular dysfunction, and heightened inflammatory states post-AMI. This manuscript aims to provide a comprehensive review of the current understanding of chemerin’s role in AMI, detailing its molecular mechanisms, clinical implications, and potential as a biomarker for diagnosis and prognosis. Additionally, we explore the therapeutic prospects of targeting chemerin pathways to mitigate myocardial damage and improve clinical outcomes in AMI patients. By synthesizing the latest research findings, this review seeks to elucidate the multifaceted role of chemerin in AMI and its promise as a target for innovative therapeutic strategies. Full article
(This article belongs to the Special Issue The Role of Chemerin in Human Disease—2nd Edition)
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