Biomedicines

18 pages, 2645 KB

Open AccessEditor’s ChoiceArticle

A Deep Learning Methodology for Screening New Natural Therapeutic Candidates for Pharmacological Cardioversion and Anticoagulation in the Treatment and Management of Atrial Fibrillation

by Tim Dong, Rhys D. Llewellyn, Melanie Hezzell and Gianni D. Angelini

Biomedicines 2025, 13(6), 1323; https://doi.org/10.3390/biomedicines13061323 - 28 May 2025

Cited by 1 | Viewed by 1255

Abstract

Background: The treatment and management of atrial fibrillation poses substantial complexity. A delicate balance in the trade-off between the minimising risk of stroke without increasing the risk of bleeding through anticoagulant optimisations. Natural compounds are often associated with low-toxicity effects, and their effects [...] Read more.

Background: The treatment and management of atrial fibrillation poses substantial complexity. A delicate balance in the trade-off between the minimising risk of stroke without increasing the risk of bleeding through anticoagulant optimisations. Natural compounds are often associated with low-toxicity effects, and their effects on atrial fibrillation have yet to be fully understood. Whilst deep learning (a subtype of machine learning that uses multiple layers of artificial neural networks) methods may be useful for drug compound interaction and discovery analysis, graphical processing units (GPUs) are expensive and often required for deep learning. Furthermore, in limited-resource settings, such as low- and middle-income countries, such technology may not be easily available. Objectives: This study aims to discover the presence of any new therapeutic candidates from a large set of natural compounds that may support the future treatment and management of atrial fibrillation anywhere using a low-cost technique. The objective is to develop a deep learning approach under a low-resource setting where suitable high-performance NVIDIA graphics processing units (GPUs) are not available and to apply to atrial fibrillation as a case study. Methods: The primary training dataset is the MINER-DTI dataset from the BIOSNAP collection. It includes 13,741 DTI pairs from DrugBank, 4510 drug compounds, and 2181 protein targets. Deep cross-modal attention modelling was developed and applied. The Database of Useful Decoys (DUD-E) was used to fine-tune the model using contrastive learning. This application and evaluation of the model were performed on the natural compound NPASS 2018 dataset as well as a dataset curated by a clinical pharmacist and a clinical scientist. Results: the new model showed good performance when compared to existing state-of-the-art approaches under low-resource settings in both the validation set (PR AUC: 0.8118 vs. 0.7154) and test set (PR AUC: 0.8134 vs. 0.7206). Tenascin-C (TNC; NPC306696) and deferoxamine (NPC262615) were identified as strong natural compound interactors of the arrhythmogenic targets ADRB1 and HCN1, respectively. A strong natural compound interactor of the bleeding-related target Factor X was also identified as sequoiaflavone (NPC194593). Conclusions: This study presented a new high-performing model under low-resource settings that identified new natural therapeutic candidates for pharmacological cardioversion and anticoagulation. Full article

(This article belongs to the Special Issue Role of Natural Product in Cardiovascular Disease—2nd Edition)

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15 pages, 1195 KB

Open AccessEditor’s ChoiceArticle

Long-Term Outcomes After High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy in Very High-Risk Prostate Cancer: A 24-Year Follow-Up

by Pedro J. Prada Gómez, Ana L. Rivero Pérez, Joaquín Carballido Rodríguez, Javier Anchuelo Latorre, Rosa Fabregat Borrás, Marina Gutiérrez Ruiz, Cristina Rodríguez-Acosta Caballero, Carlos F. Carrascal Gordillo, Maria P. Galdós Barroso and Paola A. Navarrete Solano

Biomedicines 2025, 13(6), 1310; https://doi.org/10.3390/biomedicines13061310 - 27 May 2025

Cited by 3 | Viewed by 3312

Abstract

Purpose: To evaluate the long-term oncological outcomes and toxicity profile based on 24 years of follow-up in patients with localized very high-risk prostate cancer (VHR PCa) treated with a combination of high-dose-rate brachytherapy (HDR-BT) and pelvic external beam radiation therapy (EBRT). Methods [...] Read more.

Purpose: To evaluate the long-term oncological outcomes and toxicity profile based on 24 years of follow-up in patients with localized very high-risk prostate cancer (VHR PCa) treated with a combination of high-dose-rate brachytherapy (HDR-BT) and pelvic external beam radiation therapy (EBRT). Methods: A retrospective analysis was conducted on 87 patients with VHR PCa, classified according to National Comprehensive Cancer Network (NCCN) criteria, who received HDR-BT and EBRT. Androgen deprivation therapy (ADT) was administered to 72 patients (82.8%). The primary endpoints were biochemical control and cancer-specific survival (CSS), while the secondary endpoints included local control rates, tumor-free survival (TFS), overall survival (OS), and treatment-related toxicity. Results: The 24-year biochemical control rate was 68% (standard deviation [SD]: ±4%), while CSS and TFS at 24 years were 82% (SD ±4%) and 78% (SD ±4%), respectively. Local control rates remained at 98% at 24 years. Furthermore, the OS rate at 24 years was 30%. Multivariate Cox regression analysis identified the T category in the TNM classification as the only factor significantly associated with biochemical control, with 24-year rates of 69%, 71%, and 50% for patients with T-classifications of ≤T2c, T3a, and T3b-T4, respectively (p = 0.024). Notably, no grade ≥3 late toxicities were observed during the follow-up period. Conclusions: The 24-year outcomes support the viability and therapeutic efficacy of EBRT combined with a conformal HDR-BT boost for patients with VHR PCa. Full article

(This article belongs to the Special Issue Prostate Cancer Targeted Therapy: Highlighting Advances in Precision Medicine and Rational Combination Approaches)

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11 pages, 1096 KB

Open AccessEditor’s ChoiceCommunication

Exosomal Protein Biomarkers in Arthritis: Deciphering the Inflammatory Profiles of RA and OA

by Claudia M. Brenis Gómez, Chamaida Plasencia-Rodríguez, Marta Novella-Navarro, Ana Martínez-Feito, Alejandro Balsa, Enrique Calvo-Aranda and Borja Hernández-Breijo

Biomedicines 2025, 13(6), 1283; https://doi.org/10.3390/biomedicines13061283 - 23 May 2025

Cited by 3 | Viewed by 1488

Abstract

Background/Objectives: Rheumatoid arthritis (RA) and osteoarthritis (OA) are highly prevalent diseases and their pathophysiology, diagnosis and treatment continue to be challenging. The aim of this study was to characterize and differentiate the profiles of the serum extracellular vesicles (EVs) isolated from RA [...] Read more.

Background/Objectives: Rheumatoid arthritis (RA) and osteoarthritis (OA) are highly prevalent diseases and their pathophysiology, diagnosis and treatment continue to be challenging. The aim of this study was to characterize and differentiate the profiles of the serum extracellular vesicles (EVs) isolated from RA and OA patients. Methods: This study included nine patients diagnosed with RA, eight patients with OA during a flare and five healthy controls (HCs). Blood samples were collected and EVs from the serum were isolated for further performance of flow cytometry and proteomic analysis. Results: The extracellular vesicles from HC samples exhibited smaller sizes and were more concentrated than exosomes from RA and OA samples. Surface protein expression was analyzed by flow cytometry. The results showed an enrichment of exosomes derived from antigen-presenting cells in RA samples; this was evidenced by their expression of CD14 and HLA-DR. Proteomic analysis identified 45 differentially expressed proteins between RA and OA patients. Furthermore, Ingenuity Pathway Analysis (IPA) identified inflammatory pathways such as the IL-1β and IL-6 signaling pathways as being enhanced in RA-derived exosomes, while the MYC and ROCK2 signaling pathways were enhanced in OA-derived exosomes. Conclusions: Our results show serum-derived exosomes from RA and OA patients harbor different surface proteins and cargo profiles, mirroring the different pathophysiologic mechanisms underlying these diseases. These results also highlight the promising use of exosomes as disease biomarkers. Full article

(This article belongs to the Section Cell Biology and Pathology)

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20 pages, 4500 KB

Open AccessEditor’s ChoiceReview

Spatial Heterogeneity of Intratumoral Microbiota: A New Frontier in Cancer Immunotherapy Resistance

by Qiwen Tan, Xiongjing Cao, Falong Zou, Hanwenchen Wang, Lijuan Xiong and Shenghe Deng

Biomedicines 2025, 13(5), 1261; https://doi.org/10.3390/biomedicines13051261 - 21 May 2025

Cited by 9 | Viewed by 3696

Abstract

The intratumoral microbiota, as an important component of the tumor microenvironment, is increasingly recognized as a key factor in regulating responses to cancer immunotherapy. Recent studies have revealed that the intratumoral microbiota is not uniformly distributed but instead exhibits significant spatial heterogeneity, with [...] Read more.

The intratumoral microbiota, as an important component of the tumor microenvironment, is increasingly recognized as a key factor in regulating responses to cancer immunotherapy. Recent studies have revealed that the intratumoral microbiota is not uniformly distributed but instead exhibits significant spatial heterogeneity, with its distribution patterns influenced by factors such as tumor anatomy, local immune status, and therapeutic interventions. This spatial heterogeneity not only alters the interactions between microbes and the host immune system but may also reshape the immunogenic and immunosuppressive landscapes of tumors. The enrichment or depletion of microbiota in different tumor regions can influence immune cell infiltration patterns, metabolic pathway activities, and immune checkpoint molecule expression, thereby driving the development of resistance to immunotherapy. Moreover, certain bacterial metabolites form concentration gradients between the tumor core and margins, thereby regulating immune cell function. Therefore, understanding and manipulating the spatial distribution of intratumoral microbiota, particularly in resistant patients, holds promise for developing new strategies to overcome immunotherapy resistance. In the future, precise modulation strategies targeting microbial spatial heterogeneity, such as engineered bacterial vectors, probiotic combinations, and phage therapy, may open new avenues for immunotherapy. Full article

(This article belongs to the Special Issue Novel Progress in Cancer Immunotherapy)

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28 pages, 1299 KB

Open AccessEditor’s ChoiceReview

Cardiac Amyloidosis: A Narrative Review of Diagnostic Advances and Emerging Therapies

by Dana Emilia Movila, Alexandru Catalin Motofelea, Dragos Cozma, Oana Albai, Alexandra Christa Sima, Minodora Andor, Tudor Ciocarlie and Simona Ruxanda Dragan

Biomedicines 2025, 13(5), 1230; https://doi.org/10.3390/biomedicines13051230 - 19 May 2025

Cited by 4 | Viewed by 4352

Abstract

Background/Objectives: Cardiac amyloidosis (CA) is an underdiagnosed and potentially life-threatening infiltrative cardiomyopathy characterized by the extracellular deposition of misfolded amyloid fibrils in cardiac tissue. It is most commonly associated with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis, either hereditary or wild-type. The [...] Read more.

Background/Objectives: Cardiac amyloidosis (CA) is an underdiagnosed and potentially life-threatening infiltrative cardiomyopathy characterized by the extracellular deposition of misfolded amyloid fibrils in cardiac tissue. It is most commonly associated with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis, either hereditary or wild-type. The disease often presents with non-specific symptoms, leading to delayed diagnosis and treatment. This study aims to provide a comprehensive overview of the pathophysiology, diagnostic strategies, and current therapeutic approaches for cardiac amyloidosis, with a focus on improving early detection and clinical outcomes. Methods: A narrative review was conducted using databases such as PubMed and Scopus, covering the period from September 2016 to March 2025. Keywords such as “cardiac amyloidosis”, “cardiac amyloidosis from transthyretin”, “cardiomyopathy”, “transthyretin”, “immunoglobulin light-chain amyloidosis”, and “familial amyloidosis” were used. Relevant clinical trials and guideline-based management recommendations were also included. Results: This review highlights that non-invasive imaging modalities and serum biomarker analyses are key to reducing diagnostic delays. New therapeutic developments, including gene-editing technologies and RNA-based therapies, show promise in early trials. Multidisciplinary management and increased awareness are crucial for timely diagnosis and treatment optimization. Conclusions: The early recognition of cardiac amyloidosis remains a major clinical challenge. Advances in non-invasive diagnostics and emerging disease-modifying therapies are transforming the prognosis of affected patients. Continued research and heightened clinical suspicion are essential to improve outcomes in this complex and heterogeneous disease. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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25 pages, 840 KB

Open AccessEditor’s ChoiceReview

Stem Cell Therapy for Myocardial Infarction Recovery: Advances, Challenges, and Future Directions

by Nicholas T. Le, Matthew W. Dunleavy, William Zhou, Sumrithbir S. Bhatia, Rebecca D. Kumar, Suyin T. Woo, Gonzalo Ramirez-Pulido, Kaushik S. Ramakrishnan and Ahmed H. El-Hashash

Biomedicines 2025, 13(5), 1209; https://doi.org/10.3390/biomedicines13051209 - 16 May 2025

Cited by 3 | Viewed by 7065

Abstract

Myocardial infarction (MI) is a leading cause of morbidity worldwide, resulting from ischemic damage and necrosis to cardiomyocytes. While the standard treatment regimen for MI can be successful in restoring coronary perfusion, it typically does not resolve myocardial damage, which can leave patients [...] Read more.

Myocardial infarction (MI) is a leading cause of morbidity worldwide, resulting from ischemic damage and necrosis to cardiomyocytes. While the standard treatment regimen for MI can be successful in restoring coronary perfusion, it typically does not resolve myocardial damage, which can leave patients particularly vulnerable to complications such as heart failure or electrical conduction abnormalities. Stem cell therapies offer a promising novel approach aimed at restoring cardiac function and decreasing the incidence of functional complications after an MI. This review used a literature search to evaluate the current landscape of stem cell therapy for post-MI recovery and focuses on the stem cell candidates for MI recovery therapy, delivery methods of such treatment, and their effectiveness. Both preclinical and clinical trials have demonstrated the safety of stem cells, but have struggled with limited cell retention, inconsistent efficacy, and survival. Mechanisms are employed by stem cells to promote regeneration, such as paracrine signaling, angiogenesis, and structural remodeling, in addition to the various stem cell delivery methods, including intracoronary infusion, direct myocardial injection, and intravenous administration. Furthermore, some strategies to combat past challenges in this field are discussed; for instance, extracellular vesicles, bioengineered patches, hydrogels, gene editing, and bioprinting. This article will provide a framework for future research in stem cell therapies and highlight the current progress in the field. Full article

(This article belongs to the Section Gene and Cell Therapy)

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10 pages, 654 KB

Open AccessEditor’s ChoiceArticle

Characterization of Coronary Artery Disease in Sepsis Survivors

by Samuel Malomo, Thomas Oswald, Thomas Alway, Stanislav Hadjivassilev, Steven Coombs, Susan Ellery, Joon Lee, Claire Phillips, Barbara Philips, Rachael James, David Hildick-Smith, Victoria Parish and Alexander Liu

Biomedicines 2025, 13(5), 1181; https://doi.org/10.3390/biomedicines13051181 - 13 May 2025

Cited by 5 | Viewed by 1480

Abstract

Background: Sepsis survivors are at risk of developing myocardial infarction and heart failure. It remains unclear whether coronary artery disease (CAD) is a major contributor to the development of these complications. This study sought to characterize the burden and distribution of significant CAD [...] Read more.

Background: Sepsis survivors are at risk of developing myocardial infarction and heart failure. It remains unclear whether coronary artery disease (CAD) is a major contributor to the development of these complications. This study sought to characterize the burden and distribution of significant CAD in sepsis survivors. Methods: Sepsis survivors who underwent computed tomography coronary angiography (CTCA) or invasive coronary angiography (ICA) in a UK tertiary cardiac center for suspected ischemic heart disease were retrospectively studied. Results: Of the 30 sepsis survivors (age 57 ± 12 years; 50% males), 21 patients underwent CTCA and 9 patients underwent ICA a median 39 days [IQR 12–152] from the sepsis episode. Eight patients (~27%) had angiographically significant CAD (n = 6 severe [>70%] stenosis; n = 2 moderate [50–70%] stenosis). The CT coronary calcium score was higher in patients with significant CAD compared to patients without significant CAD (638 [368–1015] vs. 4 [1–72]; p < 0.001). Of the 8 patients with significant CAD, 3 patients had LV systolic dysfunction (38%) on echocardiography and 8/21 (38%) patients without significant CAD had LV systolic dysfunction (p = 1.00). Long-term adverse complications (all-cause mortality and/or heart failure hospitalization) occurred 3/8 (38%) patients with significant CAD and 4/22 (18%) patients without significant CAD (p = 0.345). Conclusions: A minority of sepsis survivors have significant CAD. The presence of significant CAD cannot fully explain the occurrence of post-sepsis LV systolic dysfunction and adverse outcomes. The ischemic and non-ischemic mechanisms underlying post-sepsis cardiovascular disease require further investigation. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis, and Treatment of Cardiomyopathy)

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18 pages, 1376 KB

Open AccessEditor’s ChoiceReview

Emerging Epigenetic Therapies for the Treatment of Cardiac Fibrosis

by Nerea Garitano, Laura Pilar Aguado-Alvaro and Beatriz Pelacho

Biomedicines 2025, 13(5), 1170; https://doi.org/10.3390/biomedicines13051170 - 11 May 2025

Cited by 7 | Viewed by 3482

Abstract

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis [...] Read more.

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis is particularly relevant due to its impact on cardiovascular diseases (CVDs), which remain the leading cause of morbidity and mortality worldwide. This process is driven by activated cardiac fibroblasts (CFs), which promote ECM accumulation in response to chronic stressors. Epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, are key regulators of fibroblast activation and fibrotic gene expression. Enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs) have emerged as potential therapeutic targets, and epigenetic inhibitors have shown promise in modulating these enzymes to attenuate fibrosis by controlling fibroblast function and ECM deposition. These small-molecule compounds offer advantages such as reversibility and precise temporal control, making them attractive candidates for therapeutic intervention. This review aims to provide a comprehensive overview of the mechanisms by which epigenetic regulators influence cardiac fibrosis and examines the latest advances in preclinical epigenetic therapies. By integrating recent data from functional studies, single-cell profiling, and drug development, it highlights key molecular targets, emerging therapeutic strategies, and current limitations, offering a critical framework to guide future research and clinical translation. Full article

(This article belongs to the Section Molecular Genetics and Genetic Diseases)

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14 pages, 1908 KB

Open AccessEditor’s ChoiceArticle

Safety and Efficacy of Regorafenib and 5-Fluorouracil Combination Therapy in Refractory Metastatic Colorectal Cancer After Third-Line Treatment: An Institutional Experience

by Maen Abdelrahim, Abdullah Esmail, Ebtesam Al-Najjar, Bayan Khasawneh, Godsfavour Umoru, Waseem Abdelrahim, Karen Abboud and Veronica B. Ajewole

Biomedicines 2025, 13(5), 1151; https://doi.org/10.3390/biomedicines13051151 - 9 May 2025

Cited by 1 | Viewed by 1421

Abstract

Background: Colorectal carcinoma (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer. Many patients with CRC present with metastatic disease despite receiving standard first- and second-line therapies; thus emerges the demand for implementing new therapies [...] Read more.

Background: Colorectal carcinoma (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer. Many patients with CRC present with metastatic disease despite receiving standard first- and second-line therapies; thus emerges the demand for implementing new therapies that could improve outcomes among CRC patients. This case series was conducted to assess the efficacy and safety of regorafenib plus 5-fluorouracil (5-FU) in patients with refractory metastatic CRC (mCRC). Methods: We conducted a retrospective analysis of data from adult patients aged 18 and above who were diagnosed with refractory mCRC and received regorafenib plus 5-FU combination therapy at Houston Methodist Hospital between November 2017 and October 2023. Our study focuses on assessing key outcomes, including Overall Survival [OS], Progression-Free Survival [PFS], and safety. Results: Among the 12 patients we included in this study who underwent regorafenib plus 5-FU combination therapy for refractory mCRC after receiving at least three prior lines of treatment, the best response for six patients (50%) was successfully achieved, with disease control within 7–12 weeks from therapy initiation. Patients had an overall good tolerance for this treatment regimen and reported only the most common adverse events, including Hand-Foot Syndrome (HFS), mucositis, and hypertension (HTN), which were mostly resolved with dose adjustment of medications. Conclusions: This study highlights that using a combination of regorafenib plus 5-FU can be a potential treatment option for patients with refractory mCRC. Additional research, including prospective clinical trials, is required to assess the effectiveness and safety of regorafenib and 5-FU combination therapy in comparison to other currently limited treatment options. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)

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34 pages, 2833 KB

Open AccessEditor’s ChoiceReview

Current Status and Future Perspectives of Nuclear Medicine in Prostate Cancer from Imaging to Therapy: A Comprehensive Review

by Joohee Lee and Taejin Kim

Biomedicines 2025, 13(5), 1132; https://doi.org/10.3390/biomedicines13051132 - 7 May 2025

Cited by 9 | Viewed by 7297

Abstract

Nuclear medicine has emerged as a critical modality in the diagnostic and therapeutic management of urological malignancies, particularly prostate cancer. Advances in single-photon emission computed tomography/computed tomography (CT) and positron emission tomography/CT (PET/CT) have enhanced tumor assessment across staging, treatment response, and recurrence [...] Read more.

Nuclear medicine has emerged as a critical modality in the diagnostic and therapeutic management of urological malignancies, particularly prostate cancer. Advances in single-photon emission computed tomography/computed tomography (CT) and positron emission tomography/CT (PET/CT) have enhanced tumor assessment across staging, treatment response, and recurrence settings. Molecular imaging, which offers insights beyond traditional anatomical imaging, is increasingly integral in specific clinical scenarios. Theranostic nuclear medicine, which combines diagnostic imaging with targeted therapy, has become a well-established treatment option, particularly for patients with metastatic castration-resistant prostate cancer (mCRPC). The development of the prostate-specific membrane antigen (PSMA) radioligands has revolutionized clinical management by enabling precise disease staging and delivering effective radioligand therapy (RLT). Ongoing research aims to refine the role of PSMA PET imaging in staging and treatment monitoring, while optimizing PSMA-targeted RLT for broader clinical use. Given that prostate cancer remains highly prevalent, the anticipated increase in the demand for RLT presents both challenges and opportunities for nuclear medicine services globally. Theranostic approaches exemplify personalized medicine by enabling the tailoring of treatments to individual tumor biology, thereby improving survival outcomes and maintaining patients’ quality of life with minimal toxicity. Although the current focus is on advanced disease, future research holds promise for expanding these strategies to earlier stages, potentially enhancing curative prospects. This evolving field not only signifies a paradigm shift in the care of prostate cancer patients but also underscores the growing importance of nuclear medicine in delivering precision oncology. Full article

(This article belongs to the Special Issue Urogenital Cancers: New Molecular and Translational Aspects on Carcinogenesis and Treatments)

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20 pages, 1818 KB

Open AccessEditor’s ChoiceReview

Oligodendroglioma: Advances in Molecular Mechanisms and Immunotherapeutic Strategies

by Yongxin Zhao, Yan Yu, Weizhi Chen, Xiaojun Zhang, Jing Lv and Heping Zhao

Biomedicines 2025, 13(5), 1133; https://doi.org/10.3390/biomedicines13051133 - 7 May 2025

Cited by 2 | Viewed by 5256

Abstract

Oligodendroglioma is a central nervous system tumor defined by IDH1/2 mutations and 1p/19q co-deletion. Current management involves maximal resection followed by radiotherapy/chemotherapy, yielding a 20-year survival rate of 37% for grade 3 tumors according to the WHO 2021 classification. As these tumors primarily [...] Read more.

Oligodendroglioma is a central nervous system tumor defined by IDH1/2 mutations and 1p/19q co-deletion. Current management involves maximal resection followed by radiotherapy/chemotherapy, yielding a 20-year survival rate of 37% for grade 3 tumors according to the WHO 2021 classification. As these tumors primarily affect young to middle-aged patients, novel therapies are urgently needed to improve outcomes. Immunotherapy has revolutionized tumor treatment by modulating immune responses. However, its application in oligodendrogliomas faces two major hurdles, including the immunosuppressive tumor microenvironment (TME) and the blood–brain barrier’s restrictive properties. This review first examines oligodendroglioma’s molecular alterations to refine diagnosis and guide targeted therapies. Next, we focus on the oligodendroglioma TME to evaluate emerging immunotherapies, including oncolytic viruses, immune checkpoint blockade, chimeric antigen receptor (CAR) T-cell therapy, and cancer vaccines. Finally, we discuss current challenges and future directions to overcome therapeutic limitations and advance treatment strategies. Full article

(This article belongs to the Special Issue Feature Reviews in Tumor Immunology)

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18 pages, 2646 KB

Open AccessEditor’s ChoiceArticle

The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids

by Corinna Boden, Laura K. Esser, Leona Dold, Bettina Langhans, Taotao Zhou, Dominik J. Kaczmarek, Maria A. Gonzalez-Carmona, Tobias J. Weismüller, Glen Kristiansen, Jörg C. Kalff, Michael Hölzel, Hanno Matthaei, Marieta I. Toma and Vittorio Branchi

Biomedicines 2025, 13(5), 1083; https://doi.org/10.3390/biomedicines13051083 - 29 Apr 2025

Cited by 3 | Viewed by 2794

Abstract

Background/Objectives: Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its prognostic significance as [...] Read more.

Background/Objectives: Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its prognostic significance as well as explore the potential of organoids derived from PSC and liver tumor patients as an in vitro model for testing novel therapeutic strategies in both PSC and BTC. Methods: Fresh tissue samples obtained from 10 PSC patients through targeted endoscopic retrograde cholangiography (ERC) and biopsy samples from liver tumor patients were used to establish organoid cultures. Organoids were treated with different agents and the therapeutic effect was measured by CellTiterGlo. Treatment with the JAK inhibitor baricitinib was followed by the measurement of cytokine concentrations in the supernatant. Archived formalin-fixed paraffin-embedded (FFPE) samples from 55 surgically resected BTC tumors were analyzed for STAT3 expression using immunohistochemistry. Results: We successfully established organoid cultures from all ERC samples. STAT3 protein expression was detected in 56% of tumor samples and 69% of the immune microenvironment. STAT3 positivity in the immune cell compartment was associated with longer disease-free survival, although the multivariate analysis could not confirm its value as an independent prognostic factor. Chemotherapy testing on liver tumor organoids showed various degrees of decreases in viability after treatment with gemcitabine, cisplatin, and cabozantinib. Baricitinib treatment significantly reduced IL-6 and MCP-1 secretion in cholangiocarcinoma Conclusions: The patient-derived organoid model of PSC and liver tumors is a valuable tool for testing novel and established therapeutic strategies, including JAK inhibitors and chemotherapy regimens. STAT3 expression in the immune microenvironment of BTC may serve as a prognostic marker. Further studies are needed to explore the integration of co-cultured organoid systems with stromal and immune components to improve physiological relevance. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)

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25 pages, 3082 KB

Open AccessEditor’s ChoiceReview

Advancing Head and Neck Cancer Therapies: From Conventional Treatments to Emerging Strategies

by Aleksandra Mordzińska-Rak, Ilona Telejko, Grzegorz Adamczuk, Tomasz Trombik, Andrzej Stepulak and Ewa Błaszczak

Biomedicines 2025, 13(5), 1046; https://doi.org/10.3390/biomedicines13051046 - 25 Apr 2025

Cited by 13 | Viewed by 5372

Abstract

Head and neck cancers (HNCs), particularly head and neck squamous cell carcinoma (HNSCC), are among the most aggressive and prevalent malignancies of the upper aerodigestive tract. As the incidence of HNCs continues to rise, this cancer type presents a significant public health challenge. [...] Read more.

Head and neck cancers (HNCs), particularly head and neck squamous cell carcinoma (HNSCC), are among the most aggressive and prevalent malignancies of the upper aerodigestive tract. As the incidence of HNCs continues to rise, this cancer type presents a significant public health challenge. Despite conventional treatment options, such as surgery, chemotherapy, and radiotherapy, the five-year survival rates remain relatively low due to resistance to these therapies, local recurrence, local lymph node metastasis, and in some advanced cases also distant metastasis. Consequently, patients with HNCs face a high mortality risk and have reduced quality of life due to the side effects of chemo- and radiotherapy. Furthermore, targeted therapies and immunotherapies have also shown limited effectiveness in many cases, with issues related to resistance and the accessibility of these treatments. Therefore, new strategies, such as those based on combination therapies and nanotechnology, are being explored to improve the treatment of HNC patients. The proteolysis-targeting chimeras (PROTACs) also emerged as a promising therapeutic approach, though research is still ongoing to bring this technology into clinical practice. Here, we aim to highlight the current knowledge of HNC therapies, with a focus on recent advancements, including nanomedicine and PROTAC-based strategies. The development and advancement of novel emerging therapies hold promise for the improvement of patients’ survival and quality of life. Full article

(This article belongs to the Special Issue Novel Approaches towards Targeted Head and Neck Cancer Therapies)

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23 pages, 9420 KB

Open AccessEditor’s ChoiceArticle

Druggability Studies of Benzene Sulfonamide Substituted Diarylamide (E3) as a Novel Diuretic

by Hang Zhang, Shuyuan Wang, Nannan Li, Yue Xu, Zhizhen Huang, Yukun Zhang, Jing Li, Yinglin Zuo, Min Li, Runtao Li and Baoxue Yang

Biomedicines 2025, 13(4), 992; https://doi.org/10.3390/biomedicines13040992 - 18 Apr 2025

Cited by 1 | Viewed by 1557

Abstract

Background/Objectives: Urea transporters (UTs) play an important role in the urine-concentrating mechanism and have been regarded as a novel drug target for developing salt-sparing diuretics. Our previous studies found that diarylamides 1H and 25a are specific UT inhibitors and have oral diuretic [...] Read more.

Background/Objectives: Urea transporters (UTs) play an important role in the urine-concentrating mechanism and have been regarded as a novel drug target for developing salt-sparing diuretics. Our previous studies found that diarylamides 1H and 25a are specific UT inhibitors and have oral diuretic activity. However, these compounds necessitate further optimization and comprehensive druggability studies. Methods: The optimal compound was identified through structural optimization. Experiments were conducted to investigate its UT inhibitory activity and evaluate its diuretic effect. Furthermore, disease models were utilized to assess the compound’s efficacy in treating hyponatremia. Pharmacokinetic studies were performed to examine its metabolic stability, and toxicity tests were conducted to evaluate its safety. Results: Based on the chemical structure of compound 25a, we synthesized a novel diarylamide compound, E3, by introducing a benzenesulfonamide group into its side chain. E3 exhibited dose-dependent inhibition of UT at the nanomolar level and demonstrated oral diuretic activity without causing electrolyte excretion disorders in both mice and rats. Experiments on UT-B^−/− and UT-A1^−/− mice indicated that E3 enhances the diuretic effect primarily by inhibiting UT-A1 more effectively than UT-B. Furthermore, E3 displayed good metabolic stability and favorable pharmacokinetic characteristics. E3 significantly ameliorated hyponatremia through diuresis in a rat model. Importantly, E3 did not induce acute oral toxicity, subacute oral toxicity, genotoxicity, or cardiotoxicity. Conclusions: Our study confirms that E3 exerts a diuretic effect by specifically inhibiting UTs and has good druggability, which offers potential for E3 to be developed into a new diuretic for the treatment of hyponatremia. Full article

(This article belongs to the Section Drug Discovery, Development and Delivery)

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21 pages, 645 KB

Open AccessEditor’s ChoiceSystematic Review

A Systematic Review of Pneumonitis Following Treatment with Immune Checkpoint Inhibitors and Radiotherapy

by Melina Yerolatsite, Nanteznta Torounidou, Anna-Lea Amylidi, Iro-Chrisavgi Rapti, George Zarkavelis, Eleftherios Kampletsas and Paraskevi V. Voulgari

Biomedicines 2025, 13(4), 946; https://doi.org/10.3390/biomedicines13040946 - 12 Apr 2025

Cited by 4 | Viewed by 5272

Abstract

Background: Immune checkpoint inhibitors (ICIs) are increasingly included in management guidelines for various types of cancer. However, immune-related adverse events (irAEs) are an inevitable consequence of these therapies. Some of these side effects, such as pneumonitis, can be particularly serious. Additionally, the combination [...] Read more.

Background: Immune checkpoint inhibitors (ICIs) are increasingly included in management guidelines for various types of cancer. However, immune-related adverse events (irAEs) are an inevitable consequence of these therapies. Some of these side effects, such as pneumonitis, can be particularly serious. Additionally, the combination of ICIs with radiotherapy (RT) may further increase the risk of pneumonitis. Objective: The aim of this systematic review is to examine all available studies on pneumonitis following the use of ICIs and RT to assess its appearance and severity. Methods: We systematically searched four different databases (PubMed, Scopus, Cochrane, and DOAJ) to identify all relevant studies within our scope. Additionally, we reviewed the references of the studies we found, as well as those of other systematic reviews and meta-analyses. We assessed the risk of bias using the Cochrane Risk of Bias Tool version 2 for randomized controlled trials and the RTI Risk of Bias Item Bank for non-randomized trials. Finally, we extracted relevant data into an Excel file and presented them in tables throughout this study. Results: A total of 58 articles met our inclusion criteria, comprising 4889 patients across multiple studies and nine case reports. Due to significant heterogeneity in study methodologies and data reporting, a cumulative statistical analysis was not performed. The included studies were published between 2017 and 2025. The incidence of pneumonitis varied, with retrospective studies showing higher rates compared to randomized and non-randomized controlled trials. Case reports described a range of pneumonitis presentations, treatments, and outcomes, with corticosteroids being the primary treatment. Conclusions: The incidence of pneumonitis varied, with retrospective studies showing the highest rates compared to other study designs. Early detection and management of pneumonitis in patients receiving RT and/or ICIs are crucial for improving outcomes. Identifying high-risk patients through predictive models, radiomics, and biomarkers may help tailor treatment strategies and minimize toxicity. Further research is needed to establish the most appropriate diagnostic criteria, optimize management approaches, and refine advanced imaging and biomarker-based risk stratification to improve patient care. Interdisciplinary collaboration is essential for reducing the risk of pneumonitis and improving patient outcomes. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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14 pages, 265 KB

Open AccessEditor’s ChoiceReview

Kidney Transplantation in Congenital Abnormalities of Kidney and Urinary Tract (CAKUT)

by Silvio Maringhini and Lars Pape

Biomedicines 2025, 13(4), 932; https://doi.org/10.3390/biomedicines13040932 - 10 Apr 2025

Cited by 2 | Viewed by 2233

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a common cause of chronic kidney disease in children. Most patients will reach end-stage renal function and dialysis or transplantation in childhood or early adulthood. Patients with CAKUT deserve a careful evaluation before [...] Read more.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a common cause of chronic kidney disease in children. Most patients will reach end-stage renal function and dialysis or transplantation in childhood or early adulthood. Patients with CAKUT deserve a careful evaluation before a kidney transplant; detailed imaging and functional studies are necessary, particularly in the presence of lower urinary tract abnormalities, and surgical procedures are advisable in selected cases. A higher incidence of complications has been reported after a kidney transplant in CAKUT, mainly urinary tract infections. However, in the long term, the prognosis seems to be comparable to other kidney diseases. A large number of reports are available in the literature on medical and surgical management of patients with CAKUT before, during, and after a kidney transplant; almost all recommendations of surgical procedures before a kidney transplantation are based on retrospective not controlled studies or personal opinions; prospective controlled studies are needed. In this narrative, nonsystematic review, we report the results of recently published selected studies and underline questions that should be addressed in future guidelines. Full article

(This article belongs to the Section Molecular and Translational Medicine)

19 pages, 7484 KB

Open AccessEditor’s ChoiceArticle

Comprehensive Integrated Analysis Reveals the Spatiotemporal Microevolution of Cancer Cells in Patients with Bone-Metastatic Prostate Cancer

by Yinghua Feng, Xiuli Zhang, Guangpeng Wang, Feiya Yang, Ruifang Li, Lu Yin, Dong Chen, Wenkuan Wang, Mingshuai Wang, Zhiyuan Hu, Yuan Sh and Nianzeng Xing

Biomedicines 2025, 13(4), 909; https://doi.org/10.3390/biomedicines13040909 - 9 Apr 2025

Cited by 3 | Viewed by 3444

Abstract

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70–85% of prostate cancer patients. Understanding the cellular and molecular mechanisms underlying bone metastasis is essential for developing targeted therapies. This study aimed to systematically characterize the heterogeneity [...] Read more.

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70–85% of prostate cancer patients. Understanding the cellular and molecular mechanisms underlying bone metastasis is essential for developing targeted therapies. This study aimed to systematically characterize the heterogeneity and microenvironmental adaptation of prostate cancer bone metastases using single-cell transcriptomics. Methods: We integrated the largest single-cell transcriptome dataset to date, encompassing 124 samples from primary prostate tumors, various bone metastatic sites, and non-malignant tissues (e.g., benign prostatic hyperplasia, normal bone marrow). After quality control, 602,497 high-quality single-cell transcriptomes were analyzed. We employed unsupervised clustering, gene expression profiling, mutation analysis, and metabolic pathway reconstruction to characterize cancer cell subtypes and tumor microenvironmental remodeling. Results: Cancer epithelial cells dominated the tumor microenvironment but exhibited pronounced heterogeneity, posing challenges for conventional clustering methods. By integrating genetic and metabolic features, we revealed key evolutionary trajectories of epithelial cancer cells during metastasis. Notably, we identified a novel epithelial subpopulation, NEndoCs, characterized by unique differentiation patterns and distinct spatial distribution across metastatic niches. We also observed significant metabolic reprogramming and recurrent mutations linked to prostate-to-bone microenvironmental transitions. Conclusions: This study comprehensively elucidates the mutation patterns, metabolic reprogramming, and microenvironment adaptation mechanisms of bone metastasis in prostate cancer, providing key molecular targets and clinical strategies for the precise treatment of bone metastatic prostate cancer. Full article

(This article belongs to the Special Issue Urogenital Cancers: New Molecular and Translational Aspects on Carcinogenesis and Treatments)

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20 pages, 1979 KB

Open AccessEditor’s ChoiceArticle

TGF-β1 Improves Nerve Regeneration and Functional Recovery After Sciatic Nerve Injury by Alleviating Inflammation

by Maorong Jiang, Zihan Ding, Yuxiao Huang, Taoran Jiang, Yiming Xia, Dandan Gu, Xi Gu, Huiyuan Bai and Dengbing Yao

Biomedicines 2025, 13(4), 872; https://doi.org/10.3390/biomedicines13040872 - 3 Apr 2025

Cited by 8 | Viewed by 1953

Abstract

Background: Peripheral nerves have a certain regenerative ability, but their repair and regeneration after injury is a complex process, usually involving a large number of genes and proteins. In a previous study, we analyzed the gene expression profile in rats after sciatic nerve [...] Read more.

Background: Peripheral nerves have a certain regenerative ability, but their repair and regeneration after injury is a complex process, usually involving a large number of genes and proteins. In a previous study, we analyzed the gene expression profile in rats after sciatic nerve injury and found significant changes in transforming growth factor-beta 1 (TGF-β1) expression, suggesting that TGF-β1 may be involved in the process of nerve regeneration after injury. Methods: In this study, we first detected the time-course expression and localization of TGF-β1 in dorsal root ganglion (DRG) tissues in a rat sciatic nerve transection model via RT-qPCR. Secondly, we investigated the bioactive roles of TGF-β1 in primary cultured DRG neuron cells through a CCK8 assay, TUNEL assay, and immunofluorescence staining. Thirdly, we explored the neuroprotective roles of TGF-β1 in an in vivo model of sciatic nerve regeneration through morphological observation, behavioral, and electrophysiological tests, and a molecular biological measure. Results: We found that TGF-β1 expression was increased after injury and mainly located in the cytoplasm and nuclei of neuron cells in the DRG. TGF-β1 may regulate the viability, apoptosis, and neurite outgrowth of primary DRG neuron cells. In our in vivo model of sciatic nerve regeneration, TGF-β1 improved nerve regeneration and neuronal function recovery after sciatic nerve injury, alleviated the inflammatory response, and relieved neuropathic pain via the TGF-β1/smad2 pathway. Conclusions: This study provides an experimental and theoretical basis for using TGF-β1 as a neuroprotective agent after peripheral nerve injury in clinical practice in the future. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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36 pages, 2379 KB

Open AccessEditor’s ChoiceReview

The Role of NK Cells in Cancer Immunotherapy: Mechanisms, Evasion Strategies, and Therapeutic Advances

by Paula Morcillo-Martín-Romo, Javier Valverde-Pozo, María Ortiz-Bueno, Maurizio Arnone, Laura Espinar-Barranco, Celia Espinar-Barranco and María Eugenia García-Rubiño

Biomedicines 2025, 13(4), 857; https://doi.org/10.3390/biomedicines13040857 - 2 Apr 2025

Cited by 27 | Viewed by 12696

Abstract

Background/Objectives: Natural killer (NK) cells play a crucial role in tumor surveillance by exerting cytotoxic activity and modulating immune responses. However, tumors employ diverse evasion strategies that limit NK cell effectiveness. This review aims to explore the molecular mechanisms of NK cell activation [...] Read more.

Background/Objectives: Natural killer (NK) cells play a crucial role in tumor surveillance by exerting cytotoxic activity and modulating immune responses. However, tumors employ diverse evasion strategies that limit NK cell effectiveness. This review aims to explore the molecular mechanisms of NK cell activation and inhibition in cancer, the influence of the tumor microenvironment, and the latest advancements in NK cell-based immunotherapies, including adoptive NK cell transfer and Chimeric Antigen Receptor-Natural Killer (CAR-NK) cell therapies. Methods: A comprehensive literature review was conducted, prioritizing peer-reviewed studies from the last decade on NK cell biology, tumor immune evasion, and immunotherapeutic applications. The analysis includes data from preclinical models and clinical trials evaluating NK cell expansion strategies, cytokine-based stimulation, and CAR-NK cell therapy developments. Results: NK cells eliminate tumors through cytotoxic granule release, death receptor pathways, and cytokine secretion. However, tumor cells evade NK-mediated immunity by downregulating activating ligands, secreting immunosuppressive molecules, and altering the tumor microenvironment. Novel NK cell-based therapies, such as CAR-NK cells and combination approaches with immune checkpoint inhibitors, enhance NK cell persistence and therapeutic efficacy against both hematologic and solid malignancies. Clinical trials suggest improved safety profiles compared to CAR-T therapies, with reduced cytokine release syndrome and graft-versus-host disease. Conclusions: While NK cell-based immunotherapies hold great promise, challenges remain, including limited persistence and tumor-induced immunosuppression. Addressing these hurdles will be critical for optimizing NK cell therapies and advancing next-generation, off-the-shelf immunotherapeutics for broader clinical applications. Full article

(This article belongs to the Special Issue The Role of NK Cells in Cancer Immunotherapy: Mechanisms, Evasion Strategies, and Therapeutic Advances)

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33 pages, 13491 KB

Open AccessEditor’s ChoiceArticle

Investigating the Prognostic Role of Telomerase-Related Cellular Senescence Gene Signatures in Breast Cancer Using Machine Learning

by Qiong Li and Hongde Liu

Biomedicines 2025, 13(4), 826; https://doi.org/10.3390/biomedicines13040826 - 30 Mar 2025

Cited by 3 | Viewed by 1999

Abstract

Background: Telomeres and cellular senescence are critical biological processes implicated in cancer development and progression, including breast cancer, through their influence on genomic stability and modulation of the tumor microenvironment. Methods: This study integrated bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) [...] Read more.

Background: Telomeres and cellular senescence are critical biological processes implicated in cancer development and progression, including breast cancer, through their influence on genomic stability and modulation of the tumor microenvironment. Methods: This study integrated bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) data to establish a gene signature associated with telomere maintenance and cellular senescence for prognostic prediction in breast cancer. Telomere-related genes (TEGs) and senescence-associated genes were curated from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A comprehensive machine learning framework incorporating 101 algorithmic combinations across 10 survival modeling approaches, including random survival forests and ridge regression, was employed to develop a robust prognostic model. Results: A set of 19 key telomere- and senescence-related genes was identified as the optimal prognostic signature. The model demonstrated strong predictive accuracy and was successfully validated in multiple independent cohorts. Functional enrichment analyses indicated significant associations with immune responses and aging-related pathways. Single-cell transcriptomic analysis revealed marked cellular heterogeneity, identifying distinct subpopulations (fibroblasts and immune cells) with divergent risk scores and biological pathway activity. Additionally, pseudo-time trajectory analysis and intercellular communication mapping provided insights into the dynamic evolution of the tumor microenvironment. Immunohistochemical (IHC) validation using data from the Human Protein Atlas confirmed differential protein expression between normal and tumor tissues for several of the selected genes, reinforcing their biological relevance and clinical utility. Conclusions: This study presents a novel 19-gene telomere- and senescence-associated signature with strong prognostic value in breast cancer. These findings enhance our understanding of tumor heterogeneity and may inform precision oncology approaches and future therapeutic strategies. Full article

(This article belongs to the Section Cell Biology and Pathology)

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19 pages, 1600 KB

Open AccessEditor’s ChoiceReview

Application of the Human Proteome in Disease, Diagnosis, and Translation into Precision Medicine: Current Status and Future Prospects

by Yawen Xie, Xiaoying Chen, Maokai Xu and Xiaochun Zheng

Biomedicines 2025, 13(3), 681; https://doi.org/10.3390/biomedicines13030681 - 10 Mar 2025

Cited by 11 | Viewed by 5156

Abstract

This review summarizes the existing studies of human proteomics technology in the medical field with a focus on the development mechanism of a disease and its potential in discovering biomarkers. Through a systematic review of the relevant literature, we found the significant advantages [...] Read more.

This review summarizes the existing studies of human proteomics technology in the medical field with a focus on the development mechanism of a disease and its potential in discovering biomarkers. Through a systematic review of the relevant literature, we found the significant advantages and application scenarios of proteomics technology in disease diagnosis, drug development, and personalized treatment. However, the review also identifies the challenges facing proteomics technologies, including sample preparation of low-abundance proteins, massive amounts of data analysis, and how research results can be better used in clinical practice. Finally, this work discusses future research directions, including the development of more effective proteomics technologies, strengthening the integration of multi-source omics technologies, and promoting the application of AI in the human proteome. Full article

(This article belongs to the Special Issue The Human Proteome in Disease, Diagnostics and Translation into Precision Medicine: Current Status and Future Prospects)

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17 pages, 268 KB

Open AccessEditor’s ChoiceReview

Severe Asthma and Active SARS-CoV-2 Infection: Insights into Biologics

by Sara Manti, Michela Leotta, Federica D’Amico, Simone Foti Randazzese, Giuseppe Fabio Parisi and Salvatore Leonardi

Biomedicines 2025, 13(3), 674; https://doi.org/10.3390/biomedicines13030674 - 10 Mar 2025

Cited by 2 | Viewed by 1826

Abstract

Since the onset of the COVID-19 pandemic, managing asthma has become significantly more challenging. Both national and international guidelines emphasize the importance of continuing prescribed medications to maintain asthma control and prevent exacerbations. However, the emergence of SARS-CoV-2 infection has raised concerns about [...] Read more.

Since the onset of the COVID-19 pandemic, managing asthma has become significantly more challenging. Both national and international guidelines emphasize the importance of continuing prescribed medications to maintain asthma control and prevent exacerbations. However, the emergence of SARS-CoV-2 infection has raised concerns about the safety of biologic therapies during acute COVID-19 episodes, necessitating a careful and individualized approach to their use. Biologic therapies, including omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, and tezepelumab, which target specific pathways in severe asthma, have revolutionized asthma management by improving symptom control and reducing exacerbation rates. Despite their proven benefits, the intersection of biologic therapy and active SARS-CoV-2 infection has prompted questions regarding potential immunomodulatory effects and risks. This review aimed to synthesize the current literature on the antiviral effects and safety of biologic drugs in severe asthmatic patients with active SARS-CoV-2 infection, encompassing both pediatric and adult populations. Full article

(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma: Second Edition)

17 pages, 805 KB

Open AccessEditor’s ChoiceReview

Personalized Nutrition in Chronic Kidney Disease

by Nishigandha Pradhan, Jennifer Kerner, Luciana A. Campos and Mirela Dobre

Biomedicines 2025, 13(3), 647; https://doi.org/10.3390/biomedicines13030647 - 6 Mar 2025

Cited by 10 | Viewed by 11957

Abstract

A personalized approach to nutrition in patients with chronic kidney disease (CKD) represents a promising paradigm shift in disease management, moving beyond traditional one-size-fits-all dietary recommendations. Patients with CKD often have other comorbidities and face unique nutritional challenges, including protein-energy wasting (PEW), sarcopenia, [...] Read more.

A personalized approach to nutrition in patients with chronic kidney disease (CKD) represents a promising paradigm shift in disease management, moving beyond traditional one-size-fits-all dietary recommendations. Patients with CKD often have other comorbidities and face unique nutritional challenges, including protein-energy wasting (PEW), sarcopenia, and impaired renal excretion of nutrients, which complicate dietary planning. Current guidelines focus primarily on nutrient restrictions—such as limiting protein, sodium, potassium, and phosphorus. However, these generalized recommendations often result in suboptimal adherence and outcomes. Personalized nutrition, which adapts dietary recommendations to individual characteristics, such as genotype, phenotype, and socio-cultural preferences, has gained traction across various chronic diseases. However, its application in nephrology remains underexplored, and despite promising results from studies such as Food4Me, questions remain about the real-world impact of such strategies. The aims of this review are (1) to summarize the evidence on the current state of nutritional recommendations in CKD, (2) to discuss the emerging role of multi-omics approaches in informing personalized nutrition advice in CKD, and (3) to provide an opinion on nutritional challenges faced by patients with CKD and the importance of collaboration with the renal dietician. We conclude that despite barriers, such as the cost and data integration, personalized nutrition holds the potential to improve CKD outcomes, enhance quality of life, and empower patients through tailored dietary strategies for better disease management. Full article

(This article belongs to the Special Issue Pathological Biomarkers in Precision Medicine)

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27 pages, 5680 KB

Open AccessEditor’s ChoiceArticle

Synergistic Effects of Green Nanoparticles on Antitumor Drug Efficacy in Hepatocellular Cancer

by Mirela Claudia Rîmbu, Liliana Popescu, Mirela Mihăilă, Roxana Colette Sandulovici, Daniel Cord, Carmen-Marinela Mihăilescu, Mona Luciana Gălățanu, Mariana Panțuroiu, Carmen-Elisabeta Manea, Adina Boldeiu, Oana Brîncoveanu, Mihaela Savin, Alexandru Grigoroiu, Florin Dan Ungureanu, Emilia Amzoiu, Mariana Popescu and Elena Truță

Biomedicines 2025, 13(3), 641; https://doi.org/10.3390/biomedicines13030641 - 5 Mar 2025

Cited by 7 | Viewed by 4052

Abstract

Background/Objectives: Cancer remains one of the leading causes of mortality worldwide. Despite significant advancements in treatment strategies and drug development, survival rates remain low and the adverse effects of conventional therapies severely impact patients’ quality of life. This study evaluates the therapeutic [...] Read more.

Background/Objectives: Cancer remains one of the leading causes of mortality worldwide. Despite significant advancements in treatment strategies and drug development, survival rates remain low and the adverse effects of conventional therapies severely impact patients’ quality of life. This study evaluates the therapeutic potential of plant-derived extracts in hepatocellular carcinoma treatment, with a focus on minimizing side effects while enhancing efficacy. Methods: This research investigates the in vitro synergistic effect of silver bio-nanoparticles synthesized from Clematis vitalba, Melissa officinalis, and Taraxacum officinale extracts (Clematis vitalbae extractum—CVE, Melissae extractum—ME, Taraxaci extractum—TE) in combination with liver cancer drugs, sunitinib (SNTB) and imatinib (IMTB), on HepG2 (human hepatocellular carcinoma) and HUVEC (human umbilical vein endothelial) cell lines. The silver nanoparticles (AgNPs) were characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), zeta potential analysis, and scanning electron microscopy (SEM). The antitumor effects were evaluated through cell viability assays after 24 and 48 h of exposure, with additional cytotoxicity tests on HUVEC cells. Results: Results indicated that Melissa officinalis-derived silver nanoparticles (ME AgNPs) and Clematis vitalba extract with silver nanoparticles (CVE AgNPs) significantly reduced HepG2 cell viability. Their efficacy improved when combined with conventional therapies (SNTB + ME AgNPs 1:1 vs. SNTB: 20.01% vs. 25.73%, p = 0.002; IMTB + ME AgNPs 1:1 vs. IMTB: 17.80% vs. 18.08%, p = 0.036; SNTB + CVE AgNPs 1:1 vs. SNTB: 18.73% vs. 25.73%, p = 0.000; SNTB + CVE AgNPs 1:2 vs. SNTB: 26.62% vs. 41.00%, p = 0.018; IMTB + CVE AgNPs 1:1 vs. IMTB: 12.99% vs. 18.08%, p = 0.001). Taraxacum extract exhibited similar cytotoxicity to its nanoparticle formulation but did not exceed the efficacy of the extract alone at 24 h. Selectivity index assessments confirmed that AgNPs-based formulations significantly improve cytotoxicity and selectivity to HepG2 cells. Among the tested extracts, CVE demonstrated the strongest antitumor effect, enhancing the efficacy of synthetic drugs (CI < 1). SNTB + TE AgNPs (5% EtOH) also demonstrated consistent synergy at high doses, while SNTB + CVE AgNPs provided broad-range synergy, making it suitable for dose-escalation strategies. Conclusions: These findings underscore the potential of nanoparticle-based formulations in combination therapies with targeted kinase inhibitors such as sunitinib and imatinib. Future research should focus on in vivo validation and clinical trials to confirm these findings. Full article

(This article belongs to the Special Issue Nanoparticle-Based Drug Delivery in Cancer Therapy: Current Progress and Challenges)

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16 pages, 953 KB

Open AccessEditor’s ChoiceArticle

Enhancing Cardiovascular Risk Prediction with a Simplified Carotid IMT Protocol: Evidence from the IMPROVE Study

by Fabrizio Veglia, Anna Maria Malagoni, Mauro Amato, Rona J. Strawbridge, Kai Savonen, Philippe Giral, Antonio Gallo, Matteo Pirro, Bruna Gigante, Per Eriksson, Douwe J. Mulder, Beatrice Frigerio, Daniela Sansaro, Alessio Ravani, Daniela Coggi, Roberta Baetta, Nicolò Capra, Elena Tremoli and Damiano Baldassarre

Biomedicines 2025, 13(3), 584; https://doi.org/10.3390/biomedicines13030584 - 26 Feb 2025

Cited by 3 | Viewed by 2575

Abstract

Background/Objectives: Carotid intima-media thickness (CIMT) has long been used as an index of subclinical atherosclerosis, but its role as a risk modifier in cardiovascular (CV) risk optimization has recently been questioned due to methodological problems, such as lack of protocol standardization and [...] Read more.

Background/Objectives: Carotid intima-media thickness (CIMT) has long been used as an index of subclinical atherosclerosis, but its role as a risk modifier in cardiovascular (CV) risk optimization has recently been questioned due to methodological problems, such as lack of protocol standardization and scanning difficulties. In this multicentre, longitudinal, and observational study, we tested the predictive ability of two new CIMT variables detectable with a simplified, quick, and easy-to-standardize protocol. Methods: CIMT was measured in 3165 subjects from six centers, in five European countries, belonging to the IMPROVE study. The two variables tested were the average of two maximal CIMT measures taken, from a single angle, in the right and left common carotids (1CC-IMT_{mean-of-2-max}) or bifurcations (BIF-IMT_{mean-of-2-max}). The ability to predict CV events, on top of the SCORE2/SCORE2-OP risk algorithm, was quantified by the time-dependent increase in the receiver operating characteristic (ROC) area under the curve (AUC). Results: During a median follow-up of 7.1 years, 367 cardio-, cerebro-, and peripheral-vascular events were registered. Both CIMT variables tested were associated with CV risk, but 1CC-IMT_{mean-of-2-max} was also able to significantly increase the ROC AUC over the risk score (+0.017, p = 0.014). The result was stable after running several sensitivity analyses. Conclusions: 1CC-IMT_{mean-of-2-max} is able to significantly improve the predictive capacity of SCORE2/SCORE2-OP. Being based on a simple and easily standardized measurement protocol, this new variable is a promising candidate for application in mass screening and risk assessment in primary prevention. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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11 pages, 1196 KB

Open AccessEditor’s ChoiceArticle

Circulating Microvesicles Enriched in miR–126–5p and miR–223–3p: Potential Biomarkers in Acute Coronary Syndrome

by José Rubicel Hernández-López, Mirthala Flores-García, Esbeidy García-Flores, Benny Giovanni Cazarín-Santos, Marco Antonio Peña-Duque, Fausto Sánchez-Muñoz, Martha Alicia Ballinas-Verdugo, Hilda Delgadillo-Rodríguez, Marco Antonio Martínez-Ríos, Eduardo Angles-Cano and Aurora de la Peña-Díaz

Biomedicines 2025, 13(2), 510; https://doi.org/10.3390/biomedicines13020510 - 18 Feb 2025

Cited by 5 | Viewed by 2067

Abstract

Background. The molecular mechanisms underlying acute coronary syndrome (ACS) have been extensively investigated, with a particular focus on the role of circulating microvesicles (MVs) as carriers of regulatory elements that influence hemodynamic changes and coronary flow. Endothelial and platelet dysfunction during ACS alters [...] Read more.

Background. The molecular mechanisms underlying acute coronary syndrome (ACS) have been extensively investigated, with a particular focus on the role of circulating microvesicles (MVs) as carriers of regulatory elements that influence hemodynamic changes and coronary flow. Endothelial and platelet dysfunction during ACS alters MV composition, impacting clinical outcomes. This study explores the levels of miR–126–5p and miR–223–3p in circulating MVs and their association with the Thrombolysis in Myocardial Infarction (TIMI) coronary flow classification scale, proposing their potential as biomarkers. Methods. Bioinformatic tools identified miRNAs linked to ACS. Plasma MVs were isolated from ACS patients and healthy controls through high-speed centrifugation. miRNA levels were quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and compared across TIMI 0 and TIMI 3 groups. Diagnostic efficacy was assessed via receiver operating characteristic (ROC) curve analysis. Results. The bioinformatic analysis identified miR–126 and miR–223 present in ACS. miR–126–5p and miR–223–3p were significantly reduced in MVs from TIMI 0 patients compared to TIMI 3. ROC analysis showed high diagnostic accuracy for miR–126–5p (AUC = 0.918; 95% CI: 0.818–1.00; p = 0.001) and miR–223–3p (AUC = 1.00; 95% CI: 1.00–1.00; p < 0.001). Conclusions. Reduced levels of miR–126–5p and miR–223–3p in circulating MVs are strongly associated with impaired coronary flow, positioning these miRNAs as potential biomarkers for ACS risk stratification and therapeutic targeting. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: From Pathophysiology to Novel Therapeutic Approaches)

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19 pages, 2857 KB

Open AccessEditor’s ChoiceArticle

Dupilumab in the Treatment of Severe Uncontrolled Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and Comorbid Asthma—A Multidisciplinary Monocentric Real-Life Study

by Gian Luca Fadda, Chiara Rustichelli, Simone Soccal, Simone Moglio, Alessandro Serrone, Francesca Bertolini, Vitina Carriero, Stefano Pizzimenti, Stefano Levra, Giovanni Cavallo, Fabio Luigi Massimo Ricciardolo and Giuseppe Guida

Biomedicines 2025, 13(2), 501; https://doi.org/10.3390/biomedicines13020501 - 17 Feb 2025

Cited by 8 | Viewed by 4352

Abstract

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma are mutually correlated with Type-2 inflammation. Dupilumab is effective in uncontrolled and relapsing CRSwNP. However, the precise characterization of Type-2 inflammation and the impact of previous surgery on clinical outcomes need clarification. Methods: [...] Read more.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma are mutually correlated with Type-2 inflammation. Dupilumab is effective in uncontrolled and relapsing CRSwNP. However, the precise characterization of Type-2 inflammation and the impact of previous surgery on clinical outcomes need clarification. Methods: We present a prospective observational study on a 38 CRSwNP-patient cohort, whose Type-2 endotype was confirmed after a multidisciplinary approach shared among ENTs, pneumologists and allergologists. Patients were treated with dupilumab and evaluated at 15 days and 1-3-6-12-18-24-30 months, focusing on clinical (VAS, nasal polyp score—NPS), radiological (Lund-Mackay) and quality of life (SNOT-22) parameters, as well olfactory function, asthma control, variation of Type-2 markers and number and extent (ACCESS score) of previous surgeries. Results: We confirmed the efficacy of dupilumab in total and sub-items VAS, NPS, SNOT-22 and sniffing score, as well as Lund–Mackay score improvements, observable and significant after 2 weeks of treatment (p < 0.0001) and long-lasting over 30 months. Good to excellent response criteria to biologic treatment at 6 months was observed in 30/32 patients. Comorbid asthma reached rapid control (p < 0.0001) and exhaled nitric oxide normalization was achieved. One single “not adequate” surgery showed a trend to milder improvement, as well as a higher ACCESS score to better olfactory outcome. Conclusions: The accurate selection of uncontrolled relapsing CRSwNP in terms of Type-2 endotyping by multidisciplinary approach can maximize dupilumab efficacy. The number and extent of previous surgeries may differentiate the response, although this effect is difficult to catch in real life. “Adequate” ESS surgery before dupilumab may drive mostly effective disease control. Full article

(This article belongs to the Special Issue Recent Advances in Chronic Rhinosinusitis and Asthma)

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21 pages, 732 KB

Open AccessEditor’s ChoiceReview

Animal Models for Studying Developmental Origins of Cardiovascular–Kidney–Metabolic Syndrome

by You-Lin Tain, Ying-Jui Lin and Chien-Ning Hsu

Biomedicines 2025, 13(2), 452; https://doi.org/10.3390/biomedicines13020452 - 12 Feb 2025

Cited by 6 | Viewed by 2846

Abstract

Cardiovascular–kidney–metabolic syndrome (CKMS) has become a significant global health challenge. Since CKMS often originates early in life, as outlined by the developmental origins of health and disease (DOHaD) concept, prevention is a more effective strategy than treatment. Various animal models, classified by environmental [...] Read more.

Cardiovascular–kidney–metabolic syndrome (CKMS) has become a significant global health challenge. Since CKMS often originates early in life, as outlined by the developmental origins of health and disease (DOHaD) concept, prevention is a more effective strategy than treatment. Various animal models, classified by environmental exposures or mechanisms, are used to explore the developmental origins of CKMS. However, no single model can fully replicate all aspects of CKMS or its clinical stages, limiting the advancement of preventive and therapeutic strategies. This review aims to assist researchers by comparing the strengths and limitations of common animal models used in CKMS programming studies and highlighting key considerations for selecting suitable models. Full article

(This article belongs to the Special Issue Animal Models for the Study of Cardiovascular Physiology)

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15 pages, 3032 KB

Open AccessEditor’s ChoiceArticle

Antitumor Potential of Different Treatment Approaches Using Cold Atmospheric Pressure Plasma on Oral Squamous Cell Carcinoma Models: In Vitro Study

by Ognjan Pavlović, Miloš Lazarević, Aleksandar Jakovljević, Nikola Škoro, Nevena Puač, Slavko Mojsilović and Maja Miletić

Biomedicines 2025, 13(2), 443; https://doi.org/10.3390/biomedicines13020443 - 11 Feb 2025

Cited by 5 | Viewed by 2382

Abstract

Background/Objectives: Cold atmospheric plasma (CAP) has shown a strong anticancer effect on a variety of tumors, presenting a new approach for the effective treatment of oral squamous cell carcinoma (OSCC), one of the most prevalent malignant neoplasms with a high mortality rate. Here, [...] Read more.

Background/Objectives: Cold atmospheric plasma (CAP) has shown a strong anticancer effect on a variety of tumors, presenting a new approach for the effective treatment of oral squamous cell carcinoma (OSCC), one of the most prevalent malignant neoplasms with a high mortality rate. Here, we aimed to comprehensively investigate the antitumor potential of two approaches of CAP treatment on both two-dimensional and three-dimensional OSCC cell line models, as well as to analyze whether plasma treatment enhances the sensitivity of OSCC to chemotherapy. Methods: An in-house designed plasma needle, with helium as a working gas, was used to treat the SCC-25 cell line directly or indirectly via plasma-treated medium (PTM). The antitumor effect of CAP was assessed by measuring cell viability, apoptosis, adhesion, and migration. In addition, the combined effect of PTM and cisplatin was analyzed in SCC-25 tumor spheroids, as a more complex and reliable in vitro model. Results: Both plasma treatments showed time-dependent antitumor effects affecting their viability, adhesion, and migration. The rate of apoptosis was higher after incubation with PTM and is mediated by the intrinsic pathway. By utilizing the 3D spheroid carcinoma model, we confirmed the antitumor potential of CAP and additionally demonstrated an increased chemosensitivity of PTM-treated carcinoma cells. Conclusions: The results of our study illustrate a promising avenue for the application of CAP as a therapeutic option for OSCC, either as a standalone treatment or in combination with cisplatin. Full article

(This article belongs to the Special Issue Applications and Perspectives of Cold Electric Discharge Plasmas in Biomedicine and Bioengineering)

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20 pages, 1645 KB

Open AccessEditor’s ChoiceReview

Evolution of Light-Sensitive Proteins in Optogenetic Approaches for Vision Restoration: A Comprehensive Review

by Kamil Poboży, Tomasz Poboży, Paweł Domański, Michał Derczyński, Wojciech Konarski and Julia Domańska-Poboża

Biomedicines 2025, 13(2), 429; https://doi.org/10.3390/biomedicines13020429 - 10 Feb 2025

Cited by 14 | Viewed by 7784

Abstract

Retinal degenerations, such as age-related macular degeneration and retinitis pigmentosa, present significant challenges due to genetic heterogeneity, limited therapeutic options, and the progressive loss of photoreceptors in advanced stages. These challenges are compounded by difficulties in precisely targeting residual retinal neurons and ensuring [...] Read more.

Retinal degenerations, such as age-related macular degeneration and retinitis pigmentosa, present significant challenges due to genetic heterogeneity, limited therapeutic options, and the progressive loss of photoreceptors in advanced stages. These challenges are compounded by difficulties in precisely targeting residual retinal neurons and ensuring the sustained efficacy of interventions. Optogenetics offers a novel approach to vision restoration by inducing light sensitivity in residual retinal neurons through gene delivery of light-sensitive opsins. This review traces the evolution of opsins in optogenetic therapies, highlighting advancements from early research on channelrhodopsin-2 (ChR2) to engineered variants addressing key limitations. Red-shifted opsins, including ReaChR and ChrimsonR, reduced phototoxicity by enabling activation under longer wavelengths, while Chronos introduced superior temporal kinetics for dynamic visual tracking. Further innovations, such as Multi-Characteristic Opsin 1 (MCO1), optimized opsin performance under ambient light, bridging the gap to real-world applications. Key milestones include the first partial vision restoration in a human patient using ChrimsonR with light-amplifying goggles and ongoing clinical trials exploring the efficacy of opsin-based therapies for advanced retinal degeneration. While significant progress has been made, challenges remain in achieving sufficient light sensitivity for functional vision under normal ambient lighting conditions in a manner that is both effective and safe, eliminating the need for external light-enhancing devices. As research progresses, optogenetic therapies are positioned to redefine the management of retinal degenerative diseases, offering new hope for millions affected by vision loss. Full article

(This article belongs to the Section Cell Biology and Pathology)

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46 pages, 5484 KB

Open AccessEditor’s ChoiceReview

The Role of Early Risk Factor Modification and Ablation in Atrial Fibrillation Substrate Remodeling Prevention

by Ioanna Koniari, Maria Bozika, Kassiani-Maria Nastouli, Dimitra Tzegka, Anastasios Apostolos, Dimitrios Velissaris, Georgios Leventopoulos, Angelos Perperis, Nicholas G. Kounis, Grigorios Tsigkas and Periklis Davlouros

Biomedicines 2025, 13(2), 405; https://doi.org/10.3390/biomedicines13020405 - 7 Feb 2025

Cited by 3 | Viewed by 6544

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia, contributing to significant morbidity and healthcare burden worldwide. This review evaluates the role of early risk factor modification and timely catheter ablation in preventing AF progression and improving patient outcomes. A comprehensive literature search [...] Read more.

Atrial fibrillation (AF) is the most common sustained arrhythmia, contributing to significant morbidity and healthcare burden worldwide. This review evaluates the role of early risk factor modification and timely catheter ablation in preventing AF progression and improving patient outcomes. A comprehensive literature search was conducted using PubMed, MEDLINE, and Google Scholar, focusing on studies published after the ESC 2020 guidelines for the diagnosis and management of AF up to the release of the updated ESC 2024 guidelines for the management of AF. Keywords included “atrial fibrillation”, “catheter ablation”, “risk factor management”, and “psychological stress”. Relevant clinical trials, randomized controlled trials, systematic reviews, and meta-analyses were included, with particular emphasis on novel studies contributing to the ESC 2024 updated recommendations. Traditional risk factors such as obesity, hypertension, diabetes, sleep apnea, alcohol consumption, and physical exertion are well established in AF progression. Early evidence also suggests a role for psychological stress and mood disorders, including depression and post-traumatic stress disorder (PTSD), in increasing AF susceptibility. Psychological stress and mood disorders are linked to AF primarily through behavioral changes such as poor medication adherence, unhealthy lifestyle choices, and increased substance use. Recent guidelines recommend early catheter ablation in selected patients to reduce AF burden, prevent atrial remodeling, and improve quality of life, particularly in those resistant to antiarrhythmic drugs or individuals with AF-induced cardiomyopathy. Furthermore, we highlight the importance of a patient-centered, multidisciplinary approach, integrating electrophysiologists, cardiologists, and primary care providers with structured risk factor interventions and shared decision-making. Despite these advances, gaps remain in defining optimal timing, patient selection, and long-term benefits of catheter ablation in persistent AF, necessitating the need for further research. By integrating early intervention, personalized treatment strategies, and collaborative care models, we may usher in a paradigm shift in AF management, improving long-term cardiovascular outcomes and patient quality of life. Full article

(This article belongs to the Special Issue Research Trends in Cardiovascular Pathologies: From Mechanisms to Therapies)

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14 pages, 442 KB

Open AccessEditor’s ChoiceArticle

Phenolic Content, Antioxidant Activity and In Vitro Anti-Inflammatory and Antitumor Potential of Selected Bulgarian Propolis Samples

by Yulian Tumbarski, Ivan Ivanov, Mina Todorova, Sonia Apostolova, Rumiana Tzoneva and Krastena Nikolova

Biomedicines 2025, 13(2), 334; https://doi.org/10.3390/biomedicines13020334 - 1 Feb 2025

Cited by 10 | Viewed by 4042

Abstract

Background/objectives: Propolis (bee glue) is a valuable bee product widely used as a natural remedy, a cosmetic ingredient, a nutritional value enhancer and a food biopreservative. The present research aims to investigate the phenolic content, antioxidant activity and in vitro anti-inflammatory and antitumor [...] Read more.

Background/objectives: Propolis (bee glue) is a valuable bee product widely used as a natural remedy, a cosmetic ingredient, a nutritional value enhancer and a food biopreservative. The present research aims to investigate the phenolic content, antioxidant activity and in vitro anti-inflammatory and antitumor potential of six propolis samples from three regions of Bulgaria (Vidin, Gabrovo and Lovech). Methods: the analysis of propolis phenolic compounds was determined by high-performance liquid chromatography (HPLC); the antioxidant activity of ethanolic propolis extracts was assessed by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and ferric-reducing antioxidant power (FRAP) assay; the in vitro anti-inflammatory activity was assessed by the inhibition of albumin denaturation method; the in vitro antitumor activity was determined in human metastatic breast cancer cell line MDA-MB-231 using 3-(4,5-Dimethyl -2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Results: The ethanolic propolis extracts exhibited the total phenolic content from 190.4 to 317.0 mg GAE/g, total flavonoid content from 53.4 to 79.3 mg QE/g and total caffeic acid derivatives content from 5.9 to 12.1 mg CAE/g. The studied propolis extracts showed significant antioxidant capacity (between 1000.3 and 1606.0 mM TE/g determined by the DPPH assay, and between 634.1 and 1134.5 mM TE/g determined by the FRAP assay). The chemical composition analysis indicated high concentrations of caffeic acid benzyl ester, chrysin, pinocembrin and pinobanksin-3-O-propionate, predominantly in three of the propolis samples originating from Gabrovo and Lovech regions. All propolis samples demonstrated promising in vitro anti-inflammatory activity, expressed as the inhibition of thermally induced albumin denaturation by 73.59% to 78.44%, which was higher than that of the conventional anti-inflammatory drugs Aspirin (58.44%) and Prednisolone Cortico (57.34%). The propolis samples exhibited high in vitro cytotoxicity against cancer cells MDA-MB-231 with IC₅₀ values ranging between 9.24 and 13.62 µg/mL as determined by MTT assay. Conclusions: Overall, we can suggest that the high phenolic content of Bulgarian propolis from respective areas contributes to its enhanced antioxidant, anti-inflammatory and antitumor activity. Taken together, our results support the beneficial properties of Bulgarian propolis, with potential application as a promising therapeutic agent. Full article

(This article belongs to the Special Issue Compounds from Natural Products as Sources for Drug Discovery)

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16 pages, 3222 KB

Open AccessEditor’s ChoiceArticle

High-Throughput Microfluidic Production of Ultrasmall Lecithin Nanoliposomes for High-Efficacy Transdermal Delivery and Skin-Aging Treatment

by Xiao Liang, Chan Lu, Fangqiao Zheng, Zhengyi Lan, Haoji Wang, Muhammad Shafiq, Xinxin Pan, Hangrong Chen and Ming Ma

Biomedicines 2025, 13(2), 322; https://doi.org/10.3390/biomedicines13020322 - 30 Jan 2025

Cited by 6 | Viewed by 3429

Abstract

Background: Liposome particles with smaller sizes could increase transdermal drug delivery efficacy for enhanced skin penetration. While microfluidic methods have enabled controlled liposome synthesis, achieving efficient production of ultrasmall nanoliposomes (NLP_US) with a size smaller than 40 nm yet remains an [...] Read more.

Background: Liposome particles with smaller sizes could increase transdermal drug delivery efficacy for enhanced skin penetration. While microfluidic methods have enabled controlled liposome synthesis, achieving efficient production of ultrasmall nanoliposomes (NLP_US) with a size smaller than 40 nm yet remains an unmet challenge. Methods: In this study, we employed a helical-blade-strengthened co-flow focusing (HBSCF) device to efficiently synthesize NLP_US, which demonstrated superior skin permeation and retention. Results: Liposome formulation primarily contains unsaturated lecithin, which endows an unprecedented capacity to NLP_US to scavenge reactive oxygen species (ROS). Moreover, NLP_US can effectively encapsulate a broad spectrum of anti-aging agents, including coenzyme Q10 (CoQ10), while preserving its physical properties. In a photoaged skin model, topical application of CoQ10-loaded NLP_US (CoQ10@NLP_US) inhibited ultraviolet B (UVB)-induced matrix metalloproteinase-1 (MMP-1) production, and promoted collagen type I (Col-I) synthesis in skin cells, thereby effectively rejuvenating the photoaged skin. Conclusions: This study presents a straightforward and efficient method for the production of NLP_US, thereby offering a promising platform for transdermal delivery of diverse therapeutic agents. Full article

(This article belongs to the Section Biomedical Engineering and Materials)

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15 pages, 2993 KB

Open AccessEditor’s ChoiceArticle

Cold vs. Room Temperature: A Comparative Analysis of Platelet Functionality in Cold Storage

by Panagiotis V. Drossos, Sotirios P. Fortis, Alkmini T. Anastasiadi, Efthymia G. Pavlou, Andreas G. Tsantes, Gerasimos A. Spyratos, Effie G. Papageorgiou, Efrosyni G. Nomikou, Konstantinos E. Stamoulis, Georgios Dryllis, Vassilis L. Tzounakas, Marianna Politou, Serena Valsami and Anastasios G. Kriebardis

Biomedicines 2025, 13(2), 310; https://doi.org/10.3390/biomedicines13020310 - 27 Jan 2025

Cited by 6 | Viewed by 4318

Abstract

Background: The platelet functionality of cold-stored platelets remains a subject of debate. Our aim was to investigate the effect of temperature on the hemostatic properties of stored platelets. Methods: Ten split pooled platelets stored at cold and at room temperature were evaluated in [...] Read more.

Background: The platelet functionality of cold-stored platelets remains a subject of debate. Our aim was to investigate the effect of temperature on the hemostatic properties of stored platelets. Methods: Ten split pooled platelets stored at cold and at room temperature were evaluated in vitro on storage days 1, 5, 10, and 15 for metabolic, physiological, and vesiculation parameters, as well as their hemostatic profile using rotational thromboelastometry (ROTEM^®). Results: The integrity profile was better preserved in the cold-stored platelets, as lower lactate dehydrogenase levels were documented (e.g., day 10: 261 ± 46 vs. 572 ± 220 U/L, 4 vs. 22 °C, p = 0.004). A time-dependent decrease in hemostatic capacity was evident regardless of the temperature, but the cold-stored units were linked to shorter clot initiation times and increased elasticity, strength, and firmness parameters, especially during extended storage (e.g., maximum clot firmness, INTEM day 15: 81 ± 2 vs. 19 ± 4 mm, 4 vs. 22 °C, p = 0.0008). Additionally, the aggregation of cold-stored platelets was superior after the addition of any agonist tested. Regarding vesiculation parameters, the extracellular vesicles of the units at 4 °C were characterized by a larger size from day 10 onwards, when they also presented higher procoagulant activity (e.g., phospholipid-dependent clotting time of day 15: 21.4 ± 2.3 vs. 25.0 ± 3.0 s, 4 vs. 22 °C, p = 0.016). Conclusion: Our results indicate that cold-stored platelets perform better than those stored at room temperature, demonstrating superior clot formation and stability. This suggests that cold storage may more effectively preserve platelet function, potentially offering advantages for transfusion therapy and the extension of shelf-life. However, the clinical relevance of these findings requires further investigation. Full article

(This article belongs to the Special Issue Platelets in Health and Disease: From Molecular Mechanisms to Therapeutic Potential)

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26 pages, 1042 KB

Open AccessEditor’s ChoiceReview

Phenotypes and Endotypes in Sarcoidosis: Unraveling Prognosis and Disease Course

by Ilias C. Papanikolaou, Konstantinos Chytopoulos, Dimitrios Kaitatzis, Nikolaos Kostakis, Anastasios Bogiatzis, Paschalis Steiropoulos and Fotios Drakopanagiotakis

Biomedicines 2025, 13(2), 287; https://doi.org/10.3390/biomedicines13020287 - 24 Jan 2025

Cited by 5 | Viewed by 4544

Abstract

Sarcoidosis is a multi-system granulomatous disease of unknown etiology. In genetically susceptible individuals, the precipitating factors generate, via immunity mechanisms, a host granulomatous response. The granuloma, for unknown reasons thus far, may resolve or may persist and lead to organ damage and fibrosis. [...] Read more.

Sarcoidosis is a multi-system granulomatous disease of unknown etiology. In genetically susceptible individuals, the precipitating factors generate, via immunity mechanisms, a host granulomatous response. The granuloma, for unknown reasons thus far, may resolve or may persist and lead to organ damage and fibrosis. Infectious agents, occupational exposure, obesity, smoking and genetic factors are implicated in the pathogenesis of sarcoidosis. Macrophages are important in granuloma formation, and their M1/M2 phenotype is associated with the prognosis of the disease. CD4⁺ T helper cells play a central role in the pathogenesis of sarcoidosis. The major contributors appear to be Th1 and Th17.1 cells, whose microenvironmental behavior is dictated by the secretions of macrophages and dendritic cells. Higher levels of Th1 and Th17.1 cells are associated with chronic disease and resistance to corticosteroid treatment. In recent years, advances in the phenotyping of sarcoidosis with the help of HRCT, PET-CT and lung function tests have provided us with a better understanding of the disease. Genetic phenotyping performed by the GenPhenReSa consortium and the SAGA study has led to the recognition of new, distinct phenotypes. The reconstitution of dysregulated autophagy through persistent m-TORC-1 pathways may be a new treatment target in sarcoidosis. Full article

(This article belongs to the Special Issue Phenotypes and Endotypes in Interstitial Lung Diseases)

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21 pages, 1883 KB

Open AccessEditor’s ChoiceReview

Non-Invasive Retinal Biomarkers for Early Diagnosis of Alzheimer’s Disease

by Snježana Kaštelan, Antonela Gverović Antunica, Velibor Puzović, Ana Didović Pavičić, Samir Čanović, Petra Kovačević, Pia Antonia Franciska Vučemilović and Suzana Konjevoda

Biomedicines 2025, 13(2), 283; https://doi.org/10.3390/biomedicines13020283 - 24 Jan 2025

Cited by 12 | Viewed by 7121

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain associated with ageing and is the most prevalent form of dementia, affecting an estimated 55 million people worldwide, with projections suggesting this number will exceed 150 million by 2050. With its increasing [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain associated with ageing and is the most prevalent form of dementia, affecting an estimated 55 million people worldwide, with projections suggesting this number will exceed 150 million by 2050. With its increasing prevalence, AD represents a significant global health challenge with potentially serious social and economic consequences. Diagnosing AD is particularly challenging as it requires timely recognition. Currently, there is no effective therapy for AD; however, certain medications may help slow its progression. Existing diagnostic methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and biomarker analysis in cerebrospinal fluid tend to be expensive and invasive, making them impractical for widespread use. Consequently, research into non-invasive biomarkers that enable early detection and screening for AD is a crucial area of contemporary clinical investigation. One promising approach for the early diagnosis of AD may be retinal imaging. As an extension of the central nervous system, the retina offers a distinctive opportunity for non-invasive brain structure and function assessment. Considering their shared embryological origins and the vascular and immunological similarities between the eye and brain, alterations in the retina may indicate pathological changes in the brain, including those specifically related to AD. Studies suggest that structural and vascular changes in the retina, particularly within the neuronal network and blood vessels, may act as markers of cerebral changes caused by AD. These retinal alterations have the potential to act as biomarkers for early diagnosis. Since AD is typically diagnosed only after a significant neuronal loss has occurred, identifying early diagnostic markers could enable timely intervention and help prevent disease progression. Non-invasive retinal imaging techniques, such as optical coherence tomography (OCT) and OCT angiography, provide accessible methods for the early detection of changes linked to AD. This review article focuses on the potential of retinal imaging as a non-invasive biomarker for early diagnosis of AD. Investigating the ageing of the retina and its connections to neurodegenerative processes could significantly enhance the diagnosis, monitoring, and treatment of AD, paving the way for new diagnostic and therapeutic approaches. Full article

(This article belongs to the Special Issue Pathological Biomarkers in Precision Medicine)

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22 pages, 16874 KB

Open AccessEditor’s ChoiceArticle

Comprehensive Analysis Reveals Midnolin as a Potential Prognostic, Therapeutic, and Immunological Cancer Biomarker

by Xin-Guo Zhang, Wen-Ting Li, Xin Jin, Chuang Fu, Wen Jiang, Jie Bai and Zhi-Zhou Shi

Biomedicines 2025, 13(2), 276; https://doi.org/10.3390/biomedicines13020276 - 23 Jan 2025

Cited by 7 | Viewed by 4027

Abstract

Background/Objectives: MIDN (midnolin) is newly discovered method for critically regulating a ubiquitin-independent proteasomal degradation pathway. This study aims to examine the expression, prognostic value, genomic changes, interacting proteins, methylation status, and correlations with the tumor immune microenvironment of MIDN in various cancers. [...] Read more.

Background/Objectives: MIDN (midnolin) is newly discovered method for critically regulating a ubiquitin-independent proteasomal degradation pathway. This study aims to examine the expression, prognostic value, genomic changes, interacting proteins, methylation status, and correlations with the tumor immune microenvironment of MIDN in various cancers. Methods: The GTEx, Depmap, GEPIA2, and Kaplan–Meier Plotter databases are applied to evaluate the MIDN level in tumor and normal tissues and the MIDN prognostic value in cancers. The genetic alterations of MIDN in cancers are investigated using the cBioPortal database. The STRING, GeneMANIA, DAVID, and Human Protein Atlas are harnessed to identify and analyze MIDN-interacted proteins. The Sangerbox 3.0 platform (a pan-cancer analysis module) is used to measure the correlations between the MIDN level and the tumor immune microenvironment, stemness, immune cell infiltration, tumor mutational burden, immune checkpoint genes, and RNA modification genes. Immunofluorescence, qRT-PCR, and Western blotting assays were used to evaluate the biological roles of MIDN in breast and gastric cancer cells. Results: MIDN expression was dysregulated in many cancers and associated with prognosis in several cancers, such as esophageal cancer. MIDN was mutated in 1.7% of cancers, and deep deletion was the dominant mutation type. NR4A1, PSMC1, and EGR1 were selected as MIDN-interacted proteins, and these four molecules were co-expressed in pancreatic cancer, liver cancer, urothelial cancer, melanoma, and breast cancer. MIDN expression was significantly correlated with the infiltration of CD8+ T cell, CD4+ T cell, B cell, macrophage, neutrophil, and DC both in prostate adenocarcinoma and liver hepatocellular carcinoma. The MIDN level was correlated with several immune checkpoint genes, such as VEGFA, and RNA modification genes such as YTHDF1, YTHDF2, YTHDF3, and YTHDC1 in cancers. Furthermore, in breast cancer cells, the downregulation of MIDN suppressed the colony formation abilities and lessened cell-cycle-associated and stemness-associated genes; in gastric cancer, the knockdown of MIDN diminished the mRNA levels of Nanog and LDHA. Strikingly, silence of MIDN upregulated FTO protein expression in both breast and gastric cancer cells. Conclusions: Our findings demonstrate the expression, prognostic value, mutation status, interacting proteins, methylation status, and correlations with the tumor immune microenvironment of MIDN. MIDN will be developed as a potential therapeutic target and a prognosis biomarker. Full article

(This article belongs to the Special Issue Morphomolecular Characterization of Neoplastic and Pre-neoplastic Lesions in Solid Tumors)

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15 pages, 5376 KB

Open AccessEditor’s ChoiceArticle

Butyrate Prevents Obesity Accompanied by HDAC9-Mediated Browning of White Adipose Tissue

by Jing Yang, Guoli Li, Shan Wang, Mingqian He, Sijing Dong, Ting Wang, Binyin Shi, Patrick C. N. Rensen and Yanan Wang

Biomedicines 2025, 13(2), 260; https://doi.org/10.3390/biomedicines13020260 - 21 Jan 2025

Cited by 4 | Viewed by 4000

Abstract

Background/Objectives: Mounting evidence indicates that the short-chain fatty acid butyrate protects against obesity and associated comorbidities, partially through the induction of adipose tissue thermogenesis. However, the effects of butyrate on white adipose tissue (WAT) browning and its molecular mechanism are still elusive. The [...] Read more.

Background/Objectives: Mounting evidence indicates that the short-chain fatty acid butyrate protects against obesity and associated comorbidities, partially through the induction of adipose tissue thermogenesis. However, the effects of butyrate on white adipose tissue (WAT) browning and its molecular mechanism are still elusive. The objective of this study was to investigate butyrate-induced thermogenesis in white adipose tissue and its underlying mechanism. Methods: We studied the effects of butyrate on diet-induced obesity in the humanized APOE*3-Leiden.CETP transgenic mouse model and explored factors related to white adipose browning. Specifically, mice were challenged with a high-fat diet supplemented with butyrate. Adiposity was measured to assess obesity development. Energy metabolism was detected using an indirect calorimetry system. RNA-seq analysis was conducted to analyze the transcription landscape of WAT and responsible targets. Furthermore, the revealed molecular mechanism was verified in vitro. Results: Butyrate alleviated high-fat diet-induced obesity and promoted energy expenditure accompanied by brown adipose tissue activation and WAT browning. Mechanistically, RNA-seq analysis revealed that butyrate downregulated HDAC9 in WAT. Additionally, butyrate decreased HDAC9 while increasing thermogenesis in vitro. Inhibition of HDAC9 with TMP269 promoted thermogenic gene expression, mimicking the effects of butyrate. Conclusions: Butyrate protects against diet-induced obesity accompanied by decreasing the expression of HDAC9 in white adipose tissue and inducing browning. This study reveals a new mechanism whereby butyrate activates adaptive thermogenesis and provides new insights for the development of weight-loss drugs targeting adipose HDAC9. Full article

(This article belongs to the Special Issue Adiposity, Inflammation, and Metabolic Regulation: Molecular Mechanisms and Therapeutic Strategies)

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22 pages, 524 KB

Open AccessEditor’s ChoiceReview

Dietary Interventions and Physical Activity as Crucial Factors in the Prevention and Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease

by Paweł Rajewski, Jakub Cieściński, Piotr Rajewski, Szymon Suwała, Alicja Rajewska and Maciej Potasz

Biomedicines 2025, 13(1), 217; https://doi.org/10.3390/biomedicines13010217 - 16 Jan 2025

Cited by 15 | Viewed by 7091

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and affects nearly 30% of the adult population and 10% of the pediatric population. It is estimated that this number will double by 2030. MASLD is one of the [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and affects nearly 30% of the adult population and 10% of the pediatric population. It is estimated that this number will double by 2030. MASLD is one of the leading causes of hepatocellular carcinoma, cirrhosis, and liver transplantation, as well as a significant risk factor for cardiovascular disease and mortality. Due to the ever-increasing number of patients, the long-term asymptomatic course of the disease, serious complications, and lack of preventive programs, as well as insufficient awareness of the disease among patients and doctors themselves, MASLD is a growing interdisciplinary problem and a real challenge for modern medicine. The main cause of MASLD is an inappropriate lifestyle—inadequate nutrition and insufficient physical activity, which lead to various components of metabolic syndrome. Lifestyle changes—appropriate diet, weight reduction, and systematic physical activity—are also the basis for the prevention and treatment of MASLD. Hence, in recent years, so much importance has been attached to lifestyle medicine, to non-pharmacological treatment as prevention of lifestyle diseases. The narrative review presents possible therapeutic options for non-pharmacological management in the prevention and treatment of MASLD. The best documented and available diets used in MASLD were discussed, focusing on the benefits and drawbacks of the Mediterranean, high-protein, ketogenic, and intermittent fasting diets. In addition, the most recent recommendations regarding physical activity are summarized. Full article

(This article belongs to the Special Issue New Insights Into Non-Alcoholic Fatty Liver Diseases)

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17 pages, 2637 KB

Open AccessEditor’s ChoiceArticle

An Analysis of the Effectiveness and Safety of Upadacitinib in the Treatment of Inflammatory Bowel Disease: A Multicenter Real-World Study

by Hongzhen Wu, Tingting Xie, Qiao Yu, Tao Su, Min Zhang, Luying Wu, Xiaoling Wang, Xiang Peng, Min Zhi and Jiayin Yao

Biomedicines 2025, 13(1), 190; https://doi.org/10.3390/biomedicines13010190 - 14 Jan 2025

Cited by 12 | Viewed by 5385

Abstract

Background and Aims: Inflammatory bowel disease (IBD) requires effective treatment options. Upadacitinib, a Janus kinase 1 (JAK1) inhibitor, has shown effectiveness in trials for Crohn’s disease (CD) and ulcerative colitis (UC). This study evaluates its real-world effectiveness and safety. Methods: We conducted a [...] Read more.

Background and Aims: Inflammatory bowel disease (IBD) requires effective treatment options. Upadacitinib, a Janus kinase 1 (JAK1) inhibitor, has shown effectiveness in trials for Crohn’s disease (CD) and ulcerative colitis (UC). This study evaluates its real-world effectiveness and safety. Methods: We conducted a multicenter retrospective cohort study in tertiary care centers, involving patients treated with upadacitinib from January 2023 to September 2024. The study included adult patients aged 18 years or older, diagnosed with UC or CD, who received at least 8 weeks of upadacitinib therapy. Treatment outcomes were evaluated using established clinical, endoscopic, imaging, histological, and laboratory parameters. Results: A total of 236 IBD patients received upadacitinib treatment. In 80 UC patients at 8 weeks, 64.0% achieved steroid-free remission, 57.6% clinical remission, and 81.8% response. Endoscopic remission was 35.8% (p = 0.039), with 63.3% response and 35.8% mucosal healing. Histological remission reached 29.2% (p = 0.009). For 156 CD patients at 12 weeks, 76.8% achieved steroid-free remission (p < 0.001), 77.8% clinical remission (p < 0.001), and 81.0% response. Mean CDAI decreased from 214.9 to 117.5 (p < 0.001). Endoscopic remission was 19.4%, with 48.9% response and 4.9% mucosal healing. Radiological remission was 9.1% with 85.7% response. Intestinal ultrasound showed 5.7% remission and 56.7% response. Conclusions: Upadacitinib demonstrates significant real-world effectiveness and safety in IBD, particularly in biologic-resistant cases, as evidenced by high rates of steroid-free remission and clinical response. These outcomes are likely due to its targeted JAK1 inhibition, which effectively reduces inflammation and promotes mucosal healing. Future research should focus on long-term safety, comparative effectiveness with other biologics, and its application in diverse patient populations. These findings support the integration of upadacitinib into IBD management strategies. Full article

(This article belongs to the Special Issue Feature Reviews in Gastrointestinal Diseases)

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12 pages, 245 KB

Open AccessEditor’s ChoiceArticle

Differentiating Liver Metastases from Primary Liver Cancer: A Retrospective Study of Imaging and Pathological Features in Patients with Histopathological Confirmation

by Laura Andreea Ghenciu, Mirela Loredana Grigoras, Luminioara Maria Rosu, Sorin Lucian Bolintineanu, Laurentiu Sima and Octavian Cretu

Biomedicines 2025, 13(1), 164; https://doi.org/10.3390/biomedicines13010164 - 11 Jan 2025

Cited by 8 | Viewed by 6503

Abstract

Background and Objectives: This study aimed to identify and analyze imaging and pathological features that differentiate liver metastases from primary liver cancer in patients with histopathological confirmation, and to evaluate the diagnostic accuracy of imaging modalities. Materials and Methods: This retrospective study included [...] Read more.

Background and Objectives: This study aimed to identify and analyze imaging and pathological features that differentiate liver metastases from primary liver cancer in patients with histopathological confirmation, and to evaluate the diagnostic accuracy of imaging modalities. Materials and Methods: This retrospective study included 137 patients who underwent liver biopsy or resection between 2016 and 2024, comprising 126 patients with liver metastases and 11 patients with primary liver cancer (hepatocellular carcinoma). Imaging features on contrast-enhanced MRI were evaluated, including lesion number, size, margins, enhancement patterns, presence of capsule, T1/T2 signal characteristics, diffusion-weighted imaging (DWI) signal, and portal vein thrombosis. Laboratory data such as liver function tests and alpha-fetoprotein (AFP) levels were collected. Pathological features recorded included tumor differentiation, vascular invasion, necrosis, and fibrosis. Statistical analyses were performed using chi-squared tests, t-tests, and logistic regression, with a significance level of p < 0.05. The diagnostic accuracy of imaging features was assessed using receiver operating characteristic (ROC) curve analysis. Results: Liver metastases were more likely to present as multiple lesions (82.5% vs. 27.3%, p < 0.001), had irregular margins (78.6% vs. 36.4%, p = 0.002), rim enhancement (74.6% vs. 18.2%, p < 0.001), and were hypointense on T1-weighted images (85.7% vs. 45.5%, p = 0.004). Primary liver cancers were more likely to be solitary (72.7% vs. 17.5%, p < 0.001), have smooth margins (63.6% vs. 21.4%, p = 0.002), exhibit arterial phase hyperenhancement (81.8% vs. 23.8%, p < 0.001), and portal venous washout (72.7% vs. 19.0%, p < 0.001). Vascular invasion was more common in primary liver cancer (45.5% vs. 11.1%, p = 0.01). AFP levels > 400 ng/mL were significantly associated with primary liver cancer (63.6% vs. 4.8%, p < 0.001). ROC curve analysis showed that a combination of imaging features had an area under the curve (AUC) of 0.91 for differentiating the two entities. Conclusions: Imaging features such as lesion number, margin characteristics, enhancement patterns, T1/T2 signal characteristics, and portal venous washout, along with pathological features like vascular invasion and AFP levels, can effectively differentiate liver metastases from primary liver cancer. The diagnostic accuracy of imaging is high when multiple features are combined. Full article

(This article belongs to the Section Cancer Biology and Oncology)

23 pages, 3030 KB

Open AccessEditor’s ChoiceArticle

Evidence of Inflammatory Network Disruption in Chronic Venous Disease: An Analysis of Circulating Cytokines and Chemokines

by Oscar Fraile-Martinez, Cielo García-Montero, Ana María Gomez-Lahoz, Felipe Sainz, Julia Bujan, Silvestra Barrena-Blázquez, Laura López-González, Raul Díaz-Pedrero, Melchor Álvarez-Mon, Natalio García-Honduvilla, Miguel A. Saez, Jorge Monserrat and Miguel A. Ortega

Biomedicines 2025, 13(1), 150; https://doi.org/10.3390/biomedicines13010150 - 9 Jan 2025

Cited by 5 | Viewed by 2547

Abstract

Background: Chronic venous disease (CVD) comprises a set of vascular disorders that affect the venous system with important local and systemic repercussions. A growing body of evidence displays the relationship between suffering from CVD and a marked deregulation of the immune inflammatory system. [...] Read more.

Background: Chronic venous disease (CVD) comprises a set of vascular disorders that affect the venous system with important local and systemic repercussions. A growing body of evidence displays the relationship between suffering from CVD and a marked deregulation of the immune inflammatory system. In this sense, the previous literature has reported some significant changes in the level of various circulating inflammatory parameters in these patients. However, more research is required to detail and deepen this complex relationship. Methods: In this work, we studied, using a multiplex technique, the levels of circulating cytokines and chemokines detectable in the serum of 40 patients with CVD and compared it with 38 healthy controls (HCs). In parallel, we performed Spearman’s correlation analysis to explore potential inflammatory networks in CVD. Results: In this study, we measured circulating cytokines and chemokines in CVD patients using a multiplex assay. Results showed increased levels of several pro-inflammatory mediators (IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-12, IL-17A, IL-23, TNF-α, IFN-γ, fractalkine, ITAC, and GM-CSF) and a decrease in IL-13, with no significant changes in IL-4, IL-10, IL-21, MIP-1α, MIP-1β, or MIP-3α. The Spearman correlation analysis revealed strong, positive correlations among several inflammatory mediators in HC, particularly between TNF-alpha, IL-1β, IL-17A, and IL-23, forming a highly interconnected cytokine network. In contrast, CVD patients showed fewer, weaker, and distinct correlations, with new associations such as IFN-γ with IL-1β and IL-23, suggesting a disrupted inflammatory profile. Conclusions: The distinct inflammatory profile in CVD patients, characterized by altered cytokine and chemokine levels and a less coordinated cytokine network, underscores the reconfiguration of inflammatory pathways in this condition. These findings highlight potential therapeutic targets aimed at restoring immune balance and mitigating chronic inflammation in CVD. Full article

(This article belongs to the Special Issue Unraveling New Horizon in Vascular Diseases: From Pathophysiology to Novel Therapeutic)

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17 pages, 630 KB

Open AccessEditor’s ChoiceArticle

Evidence Gaps and Lessons in the Early Detection of Atrial Fibrillation: A Prospective Study in a Primary Care Setting (PREFATE Study)

by Josep L. Clua-Espuny, Alba Hernández-Pinilla, Delicia Gentille-Lorente, Eulàlia Muria-Subirats, Teresa Forcadell-Arenas, Cinta de Diego-Cabanes, Domingo Ribas-Seguí, Anna Diaz-Vilarasau, Cristina Molins-Rojas, Meritxell Palleja-Millan, Eva M. Satué-Gracia and Francisco Martín-Luján

Biomedicines 2025, 13(1), 119; https://doi.org/10.3390/biomedicines13010119 - 7 Jan 2025

Cited by 5 | Viewed by 3607

Abstract

Background/Objectives: In Europe, the prevalence of AF is expected to increase 2.5-fold over the next 50 years with a lifetime risk of 1 in 3–5 individuals after the age of 55 years and a 34% rise in AF-related strokes. The PREFATE project investigates [...] Read more.

Background/Objectives: In Europe, the prevalence of AF is expected to increase 2.5-fold over the next 50 years with a lifetime risk of 1 in 3–5 individuals after the age of 55 years and a 34% rise in AF-related strokes. The PREFATE project investigates evidence gaps in the early detection of atrial fibrillation in high-risk populations within primary care. This study aims to estimate the prevalence of device-detected atrial fibrillation (DDAF) and assess the feasibility and impact of systematic screening in routine primary care. Methods: The prospective cohort study (NCT 05772806) included 149 patients aged 65–85 years, identified as high-risk for AF. Participants underwent 14 days of cardiac rhythm monitoring using the Fibricheck^® app (CE certificate number BE16/819942412), alongside evaluations with standard ECG and transthoracic echocardiography. The primary endpoint was a new AF diagnosis confirmed by ECG or Holter monitoring. Statistical analyses examined relationships between AF and clinical, echocardiographic, and biomarker variables. Results: A total of 18 cases (12.08%) were identified as positive for possible DDAF using FibriCheck^® and 13 new cases of AF were diagnosed during follow-up, with a 71.4-fold higher probability of confirming AF in FibriCheck^®-positive individuals than in FibriCheck^®-negative individuals, resulting in a post-test odds of 87.7%. Significant echocardiographic markers of AF included reduced left atrial strain (<26%) and left atrial ejection fraction (<50%). MVP ECG risk scores ≥ 4 strongly predicted new AF diagnoses. However, inconsistencies in monitoring outcomes and limitations in current guidelines, particularly regarding AF burden, were observed. Conclusions: The study underscores the feasibility and utility of AF screening in primary care but identifies critical gaps in diagnostic criteria, anticoagulation thresholds, and guideline recommendations. Full article

(This article belongs to the Special Issue Feature Reviews in Cardiovascular Diseases)

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27 pages, 1771 KB

Open AccessEditor’s ChoiceReview

Impact of Early-Life Microbiota on Immune System Development and Allergic Disorders

by Norbert Dera, Katarzyna Kosińska-Kaczyńska, Natalia Żeber-Lubecka, Robert Brawura-Biskupski-Samaha, Diana Massalska, Iwona Szymusik, Kacper Dera and Michał Ciebiera

Biomedicines 2025, 13(1), 121; https://doi.org/10.3390/biomedicines13010121 - 7 Jan 2025

Cited by 12 | Viewed by 6851

Abstract

Introduction: The shaping of the human intestinal microbiota starts during the intrauterine period and continues through the subsequent stages of extrauterine life. The microbiota plays a significant role in the predisposition and development of immune diseases, as well as various inflammatory processes. Importantly, [...] Read more.

Introduction: The shaping of the human intestinal microbiota starts during the intrauterine period and continues through the subsequent stages of extrauterine life. The microbiota plays a significant role in the predisposition and development of immune diseases, as well as various inflammatory processes. Importantly, the proper colonization of the fetal digestive system is influenced by maternal microbiota, the method of pregnancy completion and the further formation of the microbiota. In the subsequent stages of a child’s life, breastfeeding, diet and the use of antibiotics influence the state of eubiosis, which determines proper growth and development from the neonatal period to adulthood. The literature data suggest that there is evidence to confirm that the intestinal microbiota of the infant plays an important role in regulating the immune response associated with the development of allergic diseases. However, the identification of specific bacterial species in relation to specific types of reactions in allergic diseases is the basic problem. Background: The main aim of the review was to demonstrate the influence of the microbiota of the mother, fetus and newborn on the functioning of the immune system in the context of allergies and asthma. Methods: We reviewed and thoroughly analyzed the content of over 1000 articles and abstracts between the beginning of June and the end of August 2024. Over 150 articles were selected for the detailed study. Results: The selection was based on the PubMed National Library of Medicine search engine, using selected keywords: “the impact of intestinal microbiota on the development of immune diseases and asthma”, “intestinal microbiota and allergic diseases”, “the impact of intrauterine microbiota on the development of asthma”, “intrauterine microbiota and immune diseases”, “intrauterine microbiota and atopic dermatitis”, “intrauterine microbiota and food allergies”, “maternal microbiota”, “fetal microbiota” and “neonatal microbiota”. The above relationships constituted the main criteria for including articles in the analysis. Conclusions: In the present review, we showed a relationship between the proper maternal microbiota and the normal functioning of the fetal and neonatal immune system. The state of eubiosis with an adequate amount and diversity of microbiota is essential in preventing the development of immune and allergic diseases. The way the microbiota is shaped, resulting from the health-promoting behavior of pregnant women, the rational conduct of the medical staff and the proper performance of the diagnostic and therapeutic process, is necessary to maintain the health of the mother and the child. Therefore, an appropriate lifestyle, rational antibiotic therapy as well as the way of completing the pregnancy are indispensable in the prevention of the above conditions. At the same time, considering the intestinal microbiota of the newborn in relation to the genera and phyla of bacteria that have a potentially protective effect, it is worth noting that the use of suitable probiotics and prebiotics seems to contribute to the protective effect. Full article

(This article belongs to the Special Issue Advances in Fetal Medicine and Neonatology)

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31 pages, 977 KB

Open AccessEditor’s ChoiceReview

Advances in Therapy for Urothelial and Non-Urothelial Subtype Histologies of Advanced Bladder Cancer: From Etiology to Current Development

by Whi-An Kwon, Ho Kyung Seo, Geehyun Song, Min-Kyung Lee and Weon Seo Park

Biomedicines 2025, 13(1), 86; https://doi.org/10.3390/biomedicines13010086 - 1 Jan 2025

Cited by 13 | Viewed by 5259

Abstract

Urothelial carcinoma (UC) is the most common histological subtype of bladder tumors; however, bladder cancer represents a heterogeneous group of diseases with at least 40 distinct histological subtypes. Among these, the 2022 World Health Organization classification of urinary tract tumors identifies a range [...] Read more.

Urothelial carcinoma (UC) is the most common histological subtype of bladder tumors; however, bladder cancer represents a heterogeneous group of diseases with at least 40 distinct histological subtypes. Among these, the 2022 World Health Organization classification of urinary tract tumors identifies a range of less common subtypes of invasive UC, formerly known as variants, which are considered high-grade tumors, including squamous cell, small-cell, sarcomatoid urothelial, micropapillary, plasmacytoid, and urachal carcinomas, and adenocarcinoma. Their accurate histological diagnosis is critical for risk stratification and therapeutic decision-making, as most subtype histologies are associated with poorer outcomes than conventional UC. Despite the importance of a precise diagnosis, high-quality evidence on optimal treatments for subtype histologies remains limited owing to their rarity. In particular, neoadjuvant and adjuvant chemotherapy have not been well characterized, and prospective data are scarce. For advanced-stage diseases, clinical trial participation is strongly recommended to address the lack of robust evidence. Advances in molecular pathology and the development of targeted therapies and immunotherapies have reshaped our understanding and classification of bladder cancer subtypes, spurring efforts to identify predictive biomarkers to guide personalized treatment strategies. Nevertheless, the management of rare bladder cancer subgroups remains challenging because they are frequently excluded from clinical trials. For localized disease, curative options such as surgical resection or radiotherapy are available; however, treatment options become more limited in recurrence or metastasis, where systemic therapy is primarily used to control disease progression and palliate symptoms. Herein, we present recent advances in the management of urothelial and non-urothelial bladder cancer subtypes and also explore the current evidence guiding their treatment and emphasize the challenges and perspectives of future therapeutic strategies. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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19 pages, 852 KB

Open AccessEditor’s ChoiceArticle

Autoantibodies Targeting G-Protein-Coupled Receptors and RAS-Related Molecules in Post-Acute COVID Vaccination Syndrome: A Retrospective Case Series Study

by Mauro Mantovani, Paolo Bellavite, Serafino Fazio, Giuseppe Di Fede, Marco Tomasi, Daniele Belli and Elisabetta Zanolin

Biomedicines 2024, 12(12), 2852; https://doi.org/10.3390/biomedicines12122852 - 15 Dec 2024

Cited by 4 | Viewed by 26197

Abstract

Background/Objectives: While post-acute COVID-19 syndrome is well known and extensively studied, the post-acute COVID vaccination syndrome (PACVS) is a more recent nosological entity that is poorly defined at the immunopathological level, although it shares many symptoms with the sequelae of viral infections. [...] Read more.

Background/Objectives: While post-acute COVID-19 syndrome is well known and extensively studied, the post-acute COVID vaccination syndrome (PACVS) is a more recent nosological entity that is poorly defined at the immunopathological level, although it shares many symptoms with the sequelae of viral infections. Methods: This single-center retrospective study reports a case series of 17 subjects vaccinated with mRNA or adenoviral vector vaccines who were healthy before vaccination and had never been infected with SARS-CoV-2 but who presented with symptoms similar to PACVS for a median time of 20 months (min 4, max 32). The medical records of all patients referred to our outpatient clinic over a one-year period were retrospectively analyzed. Results: In this group, serological tests showed that, in addition to positivity for anti-spike protein antibodies, a high percentage of subjects were positive for antibodies against G protein-coupled receptors and molecules involved in the response to SARS-CoV-2. In a panel of 16 autoantibodies tested, a few were positively associated with some of the symptoms reported by patients: anti-ATR1 with lymphadenopathy and/or tonsillitis; anti-ACE2 with skin symptoms such as ecchymosis, skin oedema, and rash; anti-MAS1 with widespread burning sensation; and anti-STAB1 with skin oedema and rash. Anti-ADRA2A were negatively associated with memory loss and/or mental fog. ACE2 correlated with the serum levels of anti-S antibodies, supporting the hypothesis of an anti-idiotype mechanism in the immunopathogenesis of PACVS. Conclusions: This exploratory analysis suggests that the levels of autoantibodies directed against ACE2, and probably also MAS1 and STAB1, may serve as biomarkers for PACVS. Full article

(This article belongs to the Special Issue SARS-CoV-2 Infection: Focus on Pathophysiological Characteristics, Complications and Effects of Vaccinations)

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16 pages, 301 KB

Open AccessEditor’s ChoiceReview

Updates on Chimeric Antigen Receptor T-Cells in Large B-Cell Lymphoma

by Khalil Saleh, Nadine Khalife, Ahmadreza Arbab, Rita Khoury, Claude Chahine, Rebecca Ibrahim, Zamzam Tikriti, Nohad Masri, Mohamad Hachem and Axel Le Cesne

Biomedicines 2024, 12(12), 2810; https://doi.org/10.3390/biomedicines12122810 - 11 Dec 2024

Cited by 2 | Viewed by 3066

Abstract

CD19-targeting chimeric antigen receptor (CAR) T-cells have changed the treatment paradigm of patients with large B-cell lymphoma (LBCL). Three CAR T-cells were approved by the Food and Drug Administration (FDA) for patients with relapsed and/or refractory (R/R) LBCL in the third-line setting: tisagenlecleucel [...] Read more.

CD19-targeting chimeric antigen receptor (CAR) T-cells have changed the treatment paradigm of patients with large B-cell lymphoma (LBCL). Three CAR T-cells were approved by the Food and Drug Administration (FDA) for patients with relapsed and/or refractory (R/R) LBCL in the third-line setting: tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), and lisocabtagene maraleucel (liso-cel), with an ORR ranging from 58% to 82%. More recently, axi-cel and liso-cel were approved as second-line treatments for patients with R/R disease up to 12 months after the completion of first-line chemo-immunotherapy. The safety profile was acceptable with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome being the two most frequent acute adverse events. Potential long-term toxicities of CD19-targeting CAR T-cells have also been described. Overall, 30% to 40% of patients are cured with a single infusion of CAR T-cells. However, 60% to 70% of patients relapse after being treated with CAR T-cells and have a dismal prognosis. The advent of bispecific antibodies (BsAb) offers an additional treatment modality for patients with R/R LBCL. The aim of this review is to describe the clinical efficacy of the three CAR T-cells, as well as their safety profile. We also compare these three CAR T-cells in terms of their efficacy and safety profile as well as evaluating the place of CAR T-cells and BsAb in the treatment arsenal of patients with R/R LBCL. Full article

(This article belongs to the Special Issue Advances in CAR-T Cell Therapy)

12 pages, 1920 KB

Open AccessEditor’s ChoiceArticle

Exploration of Novel Biomarkers for Neurodegenerative Diseases Using Proteomic Analysis and Ligand-Binding Assays

by Annalena Kenzelmann, Christina Boch, Ronny Schmidt, Mario Richter and Michael Schulz

Biomedicines 2024, 12(12), 2794; https://doi.org/10.3390/biomedicines12122794 - 9 Dec 2024

Cited by 1 | Viewed by 3005

Abstract

Background/Objectives: Neurodegenerative diseases are a major cause of morbidity and mortality worldwide, and their public health burden continues to increase. There is an urgent need to develop reliable and sensitive biomarkers to aid the timely diagnosis, disease progression monitoring, and therapeutic development for [...] Read more.

Background/Objectives: Neurodegenerative diseases are a major cause of morbidity and mortality worldwide, and their public health burden continues to increase. There is an urgent need to develop reliable and sensitive biomarkers to aid the timely diagnosis, disease progression monitoring, and therapeutic development for neurodegenerative disorders. Proteomic screening strategies, including antibody microarrays, are a powerful tool for biomarker discovery, but their findings should be confirmed using quantitative assays. The current study explored the feasibility of combining an exploratory proteomic strategy and confirmatory ligand-binding assays to screen for and validate biomarker candidates for neurodegenerative disorders. Methods: It analyzed cerebrospinal fluid (CSF) and plasma samples from patients with Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis and healthy controls using an exploratory antibody microarray and validatory ligand-binding assays. Results: The screening antibody microarray identified differentially expressed proteins between patients with neurodegenerative diseases and healthy controls, including cluster of differentiation 14 (CD14), osteopontin, and vascular endothelial growth factor 165b. Quantitative ligand-binding assays confirmed that CD14 levels were elevated in CSF of patients with Alzheimer’s disease (p = 0.0177), whereas osteopontin levels were increased in CSF of patients with Parkinson’s disease (p = 0.0346). Conclusions: The current study demonstrated the potential utility of combining an exploratory proteomic approach and quantitative ligand-binding assays to identify biomarker candidates for neurodegenerative disorders. To further validate and expand these findings, large-scale analyses using well-characterized samples should be conducted. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Mechanisms to Therapeutic Approaches)

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16 pages, 638 KB

Open AccessEditor’s ChoiceArticle

Machine Learning for Early Detection of Cognitive Decline in Parkinson’s Disease Using Multimodal Biomarker and Clinical Data

by Raziyeh Mohammadi, Samuel Y. E. Ng, Jayne Y. Tan, Adeline S. L. Ng, Xiao Deng, Xinyi Choi, Dede L. Heng, Shermyn Neo, Zheyu Xu, Kay-Yaw Tay, Wing-Lok Au, Eng-King Tan, Louis C. S. Tan, Ewout W. Steyerberg, William Greene and Seyed Ehsan Saffari

Biomedicines 2024, 12(12), 2758; https://doi.org/10.3390/biomedicines12122758 - 3 Dec 2024

Cited by 7 | Viewed by 3828

Abstract

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease, primarily affecting the middle-aged to elderly population. Among its nonmotor symptoms, cognitive decline (CD) is a precursor to dementia and represents a critical target for early risk assessment and diagnosis. Accurate [...] Read more.

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease, primarily affecting the middle-aged to elderly population. Among its nonmotor symptoms, cognitive decline (CD) is a precursor to dementia and represents a critical target for early risk assessment and diagnosis. Accurate CD prediction is crucial for timely intervention and tailored management of at-risk patients. This study used machine learning (ML) techniques to predict the CD risk over five-year in early-stage PD. Methods: Data from the Early Parkinson’s Disease Longitudinal Singapore (2014 to 2018) was used to predict CD defined as a one-unit annual decrease or a one-unit decline in Montreal Cognitive Assessment over two consecutive years. Four ML methods—AutoScore, Random Forest, K-Nearest Neighbors and Neural Network—were applied using baseline demographics, clinical assessments and blood biomarkers. Results: Variable selection identified key predictors of CD, including education year, diastolic lying blood pressure, diastolic standing blood pressure, systolic lying blood pressure, Hoehn and Yahr scale, body mass index, phosphorylated tau at threonine 181, total tau, Neurofilament light chain and suppression of tumorigenicity 2. Random Forest was the most effective, achieving an AUC of 0.93 (95% CI: 0.89, 0.97), using 10-fold cross-validation. Conclusions: Here, we demonstrate that ML-based models can identify early-stage PD patients at high risk for CD, supporting targeted interventions and improved PD management. Full article

(This article belongs to the Special Issue Neurodegeneration in Cognitive Impairment and Mood Disorders for Experimental, Clinical, and Translational Neuropsychiatry—Second Edition)

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13 pages, 699 KB

Open AccessEditor’s ChoiceArticle

Pharmacotherapy from Pre-COVID to Post-COVID: Longitudinal Trends and Predictive Indicators for Long COVID Symptoms

by Nadia Baalbaki, Sien T. Verbeek, Harm Jan Bogaard, Jelle M. Blankestijn, Vera C. van den Brink, Merel E. B. Cornelissen, Jos W. R. Twisk, Korneliusz Golebski and Anke H. Maitland-van der Zee

Biomedicines 2024, 12(12), 2694; https://doi.org/10.3390/biomedicines12122694 - 26 Nov 2024

Cited by 1 | Viewed by 2177

Abstract

Background/objectives: A significant number of COVID-19 cases experience persistent symptoms after the acute infection phase, a condition known as long COVID or post-acute sequelae of COVID-19. Approved prevention and treatment options for long COVID are currently lacking. Given the heterogeneous nature of long [...] Read more.

Background/objectives: A significant number of COVID-19 cases experience persistent symptoms after the acute infection phase, a condition known as long COVID or post-acute sequelae of COVID-19. Approved prevention and treatment options for long COVID are currently lacking. Given the heterogeneous nature of long COVID, a personalized medicine approach is essential for effective disease management. This study aimed to describe trends in pharmacotherapy from pre-COVID to post-COVID phases to gain insights into COVID-19 treatment strategies and assess whether pre-COVID pharmacotherapy can predict long COVID symptoms as a health status indicator. Methods: In the Precision Medicine for more Oxygen (P4O2) COVID-19 study, 95 long COVID patients were comprehensively evaluated through post-COVID outpatient clinics and study visits. This study focused on descriptive analysis of the pharmacotherapy patterns across different phases: pre-COVID-19, acute COVID, and post-COVID. Furthermore, associations between pre-COVID medication and long COVID outcomes were analyzed with regression analyses. Results: We observed peaks in the use of certain medications during the acute infection phase, including corticosteroids and antithrombotic agents, with a decrease in the use of renin–angiotensin system inhibitors. Consistently high use of alimentary tract medications was found across all phases. Pre-COVID respiratory medications were associated with fatigue symptoms, while antiinfectives and cardiovascular drugs were linked to fewer persisting long COVID symptom categories. Conclusion: Our findings provide longitudinal, descriptive pharmacotherapy insights and suggest that medication history can be a valuable health status indicator in characterizing patients for personalized disease management strategies, considering the heterogeneous nature of long COVID. Full article

(This article belongs to the Special Issue Long COVID: Mechanisms, Biomarkers, and Treatment)

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