Biomedicines

15 pages, 331 KiB

Open AccessReview

The Importance of Predictive Biomarkers and Their Correlation with the Response to Immunotherapy in Solid Tumors—Impact on Clinical Practice

by Raluca Ioana Mihaila, Adelina Silvana Gheorghe, Daniela Luminita Zob and Dana Lucia Stanculeanu

Biomedicines 2024, 12(9), 2146; https://doi.org/10.3390/biomedicines12092146 (registering DOI) - 22 Sep 2024

Abstract

Background/Objectives: Immunotherapy has changed the therapeutic approach for various solid tumors, especially lung tumors, malignant melanoma, renal and urogenital carcinomas, demonstrating significant antitumor activity, with tolerable safety profiles and durable responses. However, not all patients benefit from immunotherapy, underscoring the need for [...] Read more.

Background/Objectives: Immunotherapy has changed the therapeutic approach for various solid tumors, especially lung tumors, malignant melanoma, renal and urogenital carcinomas, demonstrating significant antitumor activity, with tolerable safety profiles and durable responses. However, not all patients benefit from immunotherapy, underscoring the need for predictive biomarkers that can identify those most likely to respond to treatment. Methods: The integration of predictive biomarkers into clinical practice for immune checkpoint inhibitors (ICI) holds great promise for personalized cancer treatment. Programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), microsatellite instability (MSI), gene expression profiles and circulating tumor DNA (ctDNA) have shown potential in predicting ICI responses across various cancers. Results: Challenges such as standardization, validation, regulatory approval, and cost-effectiveness must be addressed to realize their full potential. Predictive biomarkers are crucial for optimizing the clinical use of ICIs in cancer therapy. Conclusions: While significant progress has been made, further research and collaboration among clinicians, researchers, and regulatory institutes are essential to overcome the challenges of clinical implementation. However, little is known about the relationship between local and systemic immune responses and the correlation with response to oncological therapies and patient survival. Full article

(This article belongs to the Special Issue Modulation of Anti-tumor Immunity and Tumor Microenvironment)

25 pages, 1075 KiB

Open AccessArticle

Unraveling the Impact of COVID-19 on Rheumatoid Arthritis: Insights from Two Romanian Hospitals—Preliminary Results

by Andreea-Iulia Vlădulescu-Trandafir, Gelu Onose, Constantin Munteanu, Ioana Iancu, Andra-Rodica Bălănescu, Daniela Opriș-Belinski, Florian Berghea, Cristiana Prefac, Elena Grădinaru, Sorina Aurelian, Vlad Ciobanu and Violeta-Claudia Bojincă

Biomedicines 2024, 12(9), 2145; https://doi.org/10.3390/biomedicines12092145 (registering DOI) - 21 Sep 2024

Abstract

Background: Rheumatoid arthritis (RA) patients are at heightened risk of Coronavirus Disease—19 (COVID-19) complications due to immune dysregulation, chronic inflammation, and treatment with immunosuppressive therapies. This study aims to characterize the clinical and laboratory parameters of RA patients diagnosed with COVID-19, identify predictive [...] Read more.

Background: Rheumatoid arthritis (RA) patients are at heightened risk of Coronavirus Disease—19 (COVID-19) complications due to immune dysregulation, chronic inflammation, and treatment with immunosuppressive therapies. This study aims to characterize the clinical and laboratory parameters of RA patients diagnosed with COVID-19, identify predictive risk factors for severe forms of this infection for RA patients, and determine if any RA immunosuppressive therapy is associated with worse COVID-19 outcomes. Methods: A retrospective observational case-control study included 86 cases (43 diagnosed with RA and 43 cases without any inflammatory or autoimmune disease) that suffered from SARS-CoV-2 in two Romanian hospitals between March 2020 and February 2024. Data on demographics, RA disease characteristics, COVID-19 severity, treatment regimens, and outcomes were analyzed. Results: RA patients exhibited a distinct symptom profile compared to non-RA controls, with higher incidences of neurological, musculoskeletal, and gastrointestinal symptoms, while the control group showed more respiratory and systemic manifestations. Severe COVID-19 is correlated with age and laboratory markers like erythrocyte sedimentation rate (ESR), leucocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), aspartate aminotransferase (AST), serum creatinine, and urea. Additionally, RA treatments, particularly rituximab (RTX), were associated with more severe COVID-19 outcomes (but with no statistical significance), potentially due to the advanced disease stage and comorbidities in these patients. Post-infection, a significant number of RA patients experienced disease flares, necessitating adjustments in their treatment regimens. Conclusions: This study underscores the complex interplay between RA and COVID-19, highlighting significant clinical heterogeneity and the need for tailored management strategies. Limitations include sample size constraints, possible selection, and information bias, as well as the lack of adjustments for potential confounding variables that hinder the ability to formulate definitive conclusions. Future research plans to expand the research group size and further elucidate these relationships. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy (Volume II))

14 pages, 824 KiB

Open AccessArticle

Metabolic Dysfunction-Associated Steatotic Liver Disease: The Associations Between Inflammatory Markers, TLR4, and Cytokines IL-17A/F, and their Connections to the Degree of Steatosis and the Risk of Fibrosis

by Sorina-Cezara Coste, Olga Hilda Orășan, Angela Cozma, Vasile Negrean, Adela-Viviana Sitar-Tăut, Gabriela Adriana Filip, Adriana Corina Hangan, Roxana Liana Lucaciu, Mihaela Iancu and Lucia Maria Procopciuc

Biomedicines 2024, 12(9), 2144; https://doi.org/10.3390/biomedicines12092144 (registering DOI) - 21 Sep 2024

Abstract

Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease) is driven by environmental, genetic, metabolic, immune, and inflammatory factors. IL-17 and TLR4 determine hepatic steatosis, inflammation, and finally fibrosis. Objectives: To explore the associations between the plasma levels of inflammatory [...] Read more.

Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease) is driven by environmental, genetic, metabolic, immune, and inflammatory factors. IL-17 and TLR4 determine hepatic steatosis, inflammation, and finally fibrosis. Objectives: To explore the associations between the plasma levels of inflammatory markers, TLR4, and the cytokines IL17A/F, as well as their connections with the degree of hepatic steatosis and the risk of hepatic fibrosis (defined by the FIB-4 score) in MASLD patients. Methods: The study cohort included 80 patients diagnosed with MASLD. The IL-17A/F and TLR4 serum concentrations were determined using the ELISA method. Results: We found a significant difference in the CAR levels (C-reactive protein to albumin ratio) when comparing MASLD patients with severe steatosis to those with mild/moderate steatosis (Student’s t test, t (71) = 2.32, p = 0.023). The PIV (pan-immune inflammatory value) was positively correlated with the SII (systemic immune inflammation index), (r = 0.86, p < 0.0001) and the CAR (r = 0.41, p = 0.033) in MASLD patients with severe steatosis. In contrast, increased values of the LMR (lymphocyte to monocyte ratio) were significantly associated, with decreased levels of the SII (ρ = −0.38, p = 0.045). We also found a positive correlation between the CAR and the SII (r = 0.41, p = 0.028). In patients with mild/moderate steatosis, a significant positive correlation was observed between the SII and IL17A (r = 0.36, p = 0.010), the PIV and the CAR (r = 0.29, p = 0.011), the PIV and the SII (r = 0.87, p < 0.0001) and the PIV and IL17A (r = 0.3, p = 0.036). A negative correlation was observed between the LMR and the SII (r = −0.55, p < 0.0001) and the CAR and IL17F (r = −0.37, p = 0.011). Regarding the inflammatory markers, the PIV (336.4 vs. 228.63, p = 0.0107), and the SII (438.47 vs. 585.39, p = 0.0238) had significantly lower levels in patients with an intermediate–high risk of hepatic fibrosis as compared with the patients with a low risk of hepatic fibrosis. The PNI (prognostic nutritional index) (47.16 vs. 42.41, p = 0.0392) had significantly different levels in patients with the likelihood of hepatic fibrosis than those with a low risk of hepatic fibrosis. Conclusions: Regarding the inflammatory markers, the PIV and the SII hold promise as biomarkers for discriminating between MASLD patients with an intermediate–high risk and those with a low risk of hepatic fibrosis. Our findings underscore the role of IL-17A and its potential relationship with inflammatory markers in MASLD pathogenesis and the progression to hepatic fibrosis. Full article

(This article belongs to the Special Issue Pancreatic, Liver, Biliary Tract and Intestinal Diseases: Pathogenesis, Diagnostics and Therapy)

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21 pages, 902 KiB

Open AccessArticle

Reinforcement Learning: A Paradigm Shift in Personalized Blood Glucose Management for Diabetes

by Lehel Dénes-Fazakas, László Szilágyi, Levente Kovács, Andrea De Gaetano and György Eigner

Biomedicines 2024, 12(9), 2143; https://doi.org/10.3390/biomedicines12092143 (registering DOI) - 21 Sep 2024

Abstract

Background/Objectives: Managing blood glucose levels effectively remains a significant challenge for individuals with diabetes. Traditional methods often lack the flexibility needed for personalized care. This study explores the potential of reinforcement learning-based approaches, which mimic human learning and adapt strategies through ongoing interactions, [...] Read more.

Background/Objectives: Managing blood glucose levels effectively remains a significant challenge for individuals with diabetes. Traditional methods often lack the flexibility needed for personalized care. This study explores the potential of reinforcement learning-based approaches, which mimic human learning and adapt strategies through ongoing interactions, in creating dynamic and personalized blood glucose management plans. Methods: We developed a mathematical model specifically for patients with type IVP diabetes, validated with data from 10 patients and 17 key parameters. The model includes continuous glucose monitoring (CGM) noise and random carbohydrate intake to simulate real-life conditions. A closed-loop system was designed to enable the application of reinforcement learning algorithms. Results: By implementing a Policy Optimization (PPO) branch, we achieved an average Time in Range (TIR) metric of 73%, indicating improved blood glucose control. Conclusions: This study presents a personalized insulin therapy solution using reinforcement learning. Our closed-loop model offers a promising approach for improving blood glucose regulation, with potential applications in personalized diabetes management. Full article

(This article belongs to the Special Issue Diabetes: Pathogenesis, Therapeutics and Outcomes)

25 pages, 3094 KiB

Open AccessArticle

Exosome-like Nanoparticles, High in Trans-δ-Viniferin Derivatives, Produced from Grape Cell Cultures: Preparation, Characterization, and Anticancer Properties

by Yury Shkryl, Zhargalma Tsydeneshieva, Ekaterina Menchinskaya, Tatiana Rusapetova, Olga Grishchenko, Anastasia Mironova, Dmitry Bulgakov, Tatiana Gorpenchenko, Vitaly Kazarin, Galina Tchernoded, Victor Bulgakov, Dmitry Aminin and Yulia Yugay

Biomedicines 2024, 12(9), 2142; https://doi.org/10.3390/biomedicines12092142 (registering DOI) - 20 Sep 2024

Abstract

Background: Recent interest in plant-derived exosome-like nanoparticles (ENs) has surged due to their therapeutic potential, which includes antioxidant, anti-inflammatory, and anticancer activities. These properties are attributed to their cargo of bioactive metabolites and other endogenous molecules. However, the properties of ENs isolated [...] Read more.

Background: Recent interest in plant-derived exosome-like nanoparticles (ENs) has surged due to their therapeutic potential, which includes antioxidant, anti-inflammatory, and anticancer activities. These properties are attributed to their cargo of bioactive metabolites and other endogenous molecules. However, the properties of ENs isolated from plant cell cultures remain less explored. Methods: In this investigation, grape callus-derived ENs (GCENs) were isolated using differential ultracentrifugation techniques. Structural analysis through electron microscopy, nanoparticle tracking analysis, and western blotting confirmed that GCENs qualify as exosome-like nanovesicles. Results: These GCENs contained significant amounts of microRNAs and proteins characteristic of plant-derived ENs, as well as trans-δ-viniferin, a notable stilbenoid known for its health-promoting properties. Functional assays revealed that the GCENs reduced the viability of the triple-negative breast cancer cell line MDA-MB-231 in a dose-dependent manner. Moreover, the GCENs exhibited negligible effects on the viability of normal human embryonic kidney (HEK) 293 cells, indicating selective cytotoxicity. Notably, treatment with these GCENs led to cell cycle arrest in the G1 phase and triggered apoptosis in the MDA-MB-231 cell line. Conclusions: Overall, this study underscores the potential of grape callus-derived nanovectors as natural carriers of stilbenoids and proposes their application as a novel and effective approach in the management of cancer. Full article

(This article belongs to the Section Nanomedicine and Nanobiology)

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12 pages, 3844 KiB

Open AccessArticle

Cytocidal Effects of Interstitial Photodynamic Therapy Using Talaporfin Sodium and a Semiconductor Laser in a Rat Intracerebral Glioma Model

by Yuki Saito, Shinjiro Fukami, Kenta Nagai, Emiyu Ogawa, Masahiko Kuroda, Michihiro Kohno and Jiro Akimoto

Biomedicines 2024, 12(9), 2141; https://doi.org/10.3390/biomedicines12092141 (registering DOI) - 20 Sep 2024

Abstract

This preclinical study was conducted to investigate the efficacy of interstitial PDT (i-PDT) for malignant gliomas arising deep within the brain, which are difficult to remove. C6 glioma cells were implanted into the basal ganglia of rats, and 3 weeks later, the second-generation [...] Read more.

This preclinical study was conducted to investigate the efficacy of interstitial PDT (i-PDT) for malignant gliomas arising deep within the brain, which are difficult to remove. C6 glioma cells were implanted into the basal ganglia of rats, and 3 weeks later, the second-generation photosensitizer talaporfin sodium (TPS) was administered intraperitoneally. Ninety minutes after administration, a prototype fine plastic optical fiber was punctured into the tumor tissue, and semiconductor laser light was irradiated into the tumor from a 2-mm cylindrical light-emitting source under various conditions. The brain was removed 24 h after the i-PDT and analyzed pathologically. The optical fiber was able to puncture the tumor center in all cases, enabling i-PDT to be performed. Histological analysis showed that tumor necrosis was induced in areas close to the light source, correlating with the irradiation energy dose, whereas apoptosis was induced at some distance from the light source. Irradiation using high energy levels resulted in tissue swelling from strong tumor necrosis, and irradiation at 75 J/cm² was most suitable for inducing apoptosis. An experimental system of i-PDT using TPS was established using malignant glioma cells transplanted into the rat brain. Tumor cell death, which correlated with the light propagation, was induced in tumor tissue. Full article

(This article belongs to the Special Issue Photodynamic Therapy (3rd Edition))

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12 pages, 1330 KiB

Open AccessSystematic Review

Breaking the Cycle of Pain: The Role of Graded Motor Imagery and Mirror Therapy in Complex Regional Pain Syndrome

by Danilo Donati, Paolo Boccolari, Federica Giorgi, Lisa Berti, Daniela Platano and Roberto Tedeschi

Biomedicines 2024, 12(9), 2140; https://doi.org/10.3390/biomedicines12092140 (registering DOI) - 20 Sep 2024

Abstract

Background: Complex Regional Pain Syndrome (CRPS) is a chronic condition characterized by severe pain and functional impairment. Graded Motor Imagery (GMI) and Mirror Therapy (MT) have emerged as potential non-invasive treatments; this review evaluates the effectiveness of these therapies in reducing pain, improving [...] Read more.

Background: Complex Regional Pain Syndrome (CRPS) is a chronic condition characterized by severe pain and functional impairment. Graded Motor Imagery (GMI) and Mirror Therapy (MT) have emerged as potential non-invasive treatments; this review evaluates the effectiveness of these therapies in reducing pain, improving function, and managing swelling in CRPS patients. Methods: A systematic review was conducted including randomized controlled trials (RCTs) that investigated GMI and MT in CRPS patients. This review was registered in PROSPERO (CRD42024535972) to ensure transparency and adherence to protocols. This review included searches of PubMed, Cochrane, SCOPUS, and Web of Science databases. Out of 81 studies initially screened, 6 were included in the final review. Studies were assessed for quality using the PEDro and RoB-2 scales. The primary outcomes were pain reduction, functional improvement, and swelling reduction. Results: Graded Motor Imagery (GMI) and Mirror Therapy (MT) reduced pain by an average of 20 points on the Neuropathic Pain Scale (NPS) and resulted in functional improvements as measured by the Task-Specific Numeric Rating Scale (NRS). GMI also contributed to some reduction in swelling. MT, particularly in post-stroke CRPS patients, showed significant pain reduction and functional improvements, with additional benefits in reducing swelling in certain studies. However, the included studies had small sample sizes and mixed designs, which limit the generalizability of the findings. The studies varied in sample size and design, with some risk of bias noted. Conclusions: Graded Motor Imagery (GMI) and Mirror Therapy (MT) have proven to be effective interventions for managing Complex Regional Pain Syndrome (CRPS), with significant improvements in pain reduction and functional recovery. These non-invasive treatments hold potential for integration into standard rehabilitation protocols. However, the small sample sizes and variability in study designs limit the generalizability of these findings. Future research should focus on larger, more homogeneous trials to validate the long-term effectiveness of GMI and MT, ensuring more robust clinical application. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Pathophysiology to Clinics, Diagnostics and Treatment)

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17 pages, 1030 KiB

Open AccessArticle

Analysis of Brain Age Gap across Subject Cohorts and Prediction Model Architectures

by Lara Dular, Žiga Špiclin, for the Alzheimer’s Disease Neuroimaging Initiative and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing

Biomedicines 2024, 12(9), 2139; https://doi.org/10.3390/biomedicines12092139 (registering DOI) - 20 Sep 2024

Abstract

Background: Brain age prediction from brain MRI scans and the resulting brain age gap (BAG)—the difference between predicted brain age and chronological age—is a general biomarker for a variety of neurological, psychiatric, and other diseases or disorders. Methods: This study examined the differences [...] Read more.

Background: Brain age prediction from brain MRI scans and the resulting brain age gap (BAG)—the difference between predicted brain age and chronological age—is a general biomarker for a variety of neurological, psychiatric, and other diseases or disorders. Methods: This study examined the differences in BAG values derived from T1-weighted scans using five state-of-the-art deep learning model architectures previously used in the brain age literature: 2D/3D VGG, RelationNet, ResNet, and SFCN. The models were evaluated on healthy controls and cohorts with sleep apnea, diabetes, multiple sclerosis, Parkinson’s disease, mild cognitive impairment, and Alzheimer’s disease, employing rigorous statistical analysis, including repeated model training and linear mixed-effects models. Results: All five models consistently identified a statistically significant positive BAG for diabetes (ranging from 0.79 years with RelationNet to 2.13 years with SFCN), multiple sclerosis (2.67 years with 3D VGG to 4.24 years with 2D VGG), mild cognitive impairment (2.13 years with 2D VGG to 2.59 years with 3D VGG), and Alzheimer’s dementia (5.54 years with ResNet to 6.48 years with SFCN). For Parkinson’s disease, a statistically significant BAG increase was observed in all models except ResNet (1.30 years with 2D VGG to 2.59 years with 3D VGG). For sleep apnea, a statistically significant BAG increase was only detected with the SFCN model (1.59 years). Additionally, we observed a trend of decreasing BAG with increasing chronological age, which was more pronounced in diseased cohorts, particularly those with the largest BAG, such as multiple sclerosis (−0.34 to −0.2), mild cognitive impairment (−0.37 to −0.26), and Alzheimer’s dementia (−0.66 to −0.47), compared to healthy controls (−0.18 to −0.1). Conclusions: Consistent with previous research, Alzheimer’s dementia and multiple sclerosis exhibited the largest BAG across all models, with SFCN predicting the highest BAG overall. The negative BAG trend suggests a complex interplay of survival bias, disease progression, adaptation, and therapy that influences brain age prediction across the age spectrum. Full article

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

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14 pages, 1991 KiB

Open AccessArticle

COVID-19 Inflammatory Syndrome: Lessons from TNFRI and CRP about the Risk of Death in Severe Disease

by Thaís Soares Farnesi-de-Assunção, Ana Carolina de Morais Oliveira-Scussel, Wellington Francisco Rodrigues, Beatriz Sodré Matos, Djalma Alexandre Alves da Silva, Leonardo Eurípedes de Andrade e Silva, Fabiano Vilela Mundim, Fernanda Rodrigues Helmo, Anna Victória Bernardes e Borges, Chamberttan Souza Desidério, Rafael Obata Trevisan, Malu Mateus Santos Obata, Laís Milagres Barbosa, Marcela Rezende Lemes, Juliana Cristina Costa-Madeira, Rafaela Miranda Barbosa, Andrezza Cristina Cancian Hortolani Cunha, Loren Queli Pereira, Sarah Cristina Sato Vaz Tanaka, Fernanda Bernadelli de Vito, Ivan Borges Monteiro, Yulsef Moura Ferreira, Guilherme Henrique Machado, Hélio Moraes-Souza, Denise Bertulucci Rocha Rodrigues, Carlo José Freire de Oliveira, Marcos Vinicius da Silva and Virmondes Rodrigues Júnior Show full author list Hide full author list

Biomedicines 2024, 12(9), 2138; https://doi.org/10.3390/biomedicines12092138 (registering DOI) - 20 Sep 2024

Abstract

Background/Objectives: Cytokine storm in severe COVID-19 is responsible for irreversible tissue damage and death. Soluble mediators from the TNF superfamily, their correlation with clinical outcome, and the use of TNF receptors as a potent predictor for clinical outcome were evaluated. Methods: [...] Read more.

Background/Objectives: Cytokine storm in severe COVID-19 is responsible for irreversible tissue damage and death. Soluble mediators from the TNF superfamily, their correlation with clinical outcome, and the use of TNF receptors as a potent predictor for clinical outcome were evaluated. Methods: Severe COVID-19 patients had the levels of soluble mediators from the TNF superfamily quantified and categorized according to the clinical outcome (death versus survival). Statistical modeling was performed to predict clinical outcomes. Results: COVID-19 patients have elevated serum levels from the TNF superfamily. Regardless of sex and age, the sTNFRI levels were observed to be significantly higher in deceased patients from the first weeks following the onset of symptoms. We analyzed hematological parameters and inflammatory markers, and there was a difference between the groups for the following factors: erythrocytes, hemoglobin, hematocrit, leukocytes, neutrophils, band cells, lymphocytes, monocytes, CRP, IL-8, IFN-γ, IL-10, IL-6, IL-4, IL-2, leptin MIF sCD40L, and sTNFRI (p < 0.05). A post hoc analysis showed an inferential capacity over 70% for some hematological markers, CRP, and inflammatory mediators in deceased patients. sTNFRI was strongly associated with death, and the sTNFRI/sTNFRII ratio differed between outcomes (p < 0.001; power above 90%), highlighting the impact of these proteins on clinical results. The final logistic model, including sTNFRI/sTNFRII and CRP, indicated high sensitivity, specificity, accuracy, and an eight-fold higher odds ratio for an unfavorable outcome. Conclusions: The joint use of the sTNFRI/sTNFRII ratio with CRP proves to be a promising tool to assist in the clinical management of patients hospitalized for COVID-19. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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23 pages, 1543 KiB

Open AccessReview

Circulating Tumor Cells: Origin, Role, Current Applications, and Future Perspectives for Personalized Medicine

by Maria Cristina Rapanotti, Tonia Cenci, Maria Giovanna Scioli, Elisa Cugini, Silvia Anzillotti, Luca Savino, Deborah Coletta, Cosimo Di Raimondo, Elena Campione, Mario Roselli, Sergio Berardini, Luca Bianchi, Anastasia De Luca, Amedeo Ferlosio and Augusto Orlandi

Biomedicines 2024, 12(9), 2137; https://doi.org/10.3390/biomedicines12092137 - 20 Sep 2024

Abstract

Circulating tumor cells (CTCs) currently represent a revolutionary tool offering unique insights for the evaluation of cancer progression, metastasis, and response to therapies. Indeed, CTCs, upon detachment from primary tumors, enter the bloodstream and acquire a great potential for their use for personalized [...] Read more.

Circulating tumor cells (CTCs) currently represent a revolutionary tool offering unique insights for the evaluation of cancer progression, metastasis, and response to therapies. Indeed, CTCs, upon detachment from primary tumors, enter the bloodstream and acquire a great potential for their use for personalized cancer management. In this review, we describe the current understanding of and advances in the clinical employment of CTCs. Although considered rare and fleeting, CTCs are now recognized as key players favoring the development of cancer metastasis and disease recurrence, particularly in malignant melanoma, lung, breast, and colorectal cancer patients. To date, the advancements in technology and the development of several successful approaches, also including immunomagnetic enrichment allow for a reliable and reproducible detection and characterization of CTCs. Those innovative methodologies improved the isolation, quantification, and characterization of CTCs from the blood of cancer patients, providing extremely useful evidence and new insights into the nature of the tumor, its epithelial/mesenchymal profile, and its potential resistance to therapy. In fact, in addition to their prognostic and predictive value, CTCs could serve as a valuable instrument for real-time monitoring of treatment response and disease recurrence, facilitating timely interventions and thus improving patient outcomes. However, despite their potential, several challenges hinder the widespread clinical utility of CTCs: (i) CTCs’ rarity and heterogeneity pose technical limitations in isolation and characterization, as well as significant hurdles in their clinical implementation; (ii) it is mandatory to standardize CTC detection methods, optimize the sample processing techniques, and integrate them with existing diagnostic modalities; and (iii) the need for the development of new techniques, such as single-cell analysis platforms, to enhance the sensitivity and specificity of CTC detection, thereby facilitating their integration into routine clinical practice. In conclusion, CTCs represent a potential extraordinary tool in cancer diagnostics and therapeutics, offering unprecedented opportunities for personalized medicine and precision oncology. Moreover, their ability to provide real-time insights into tumor biology, treatment response, and disease progression underlines a great potential for their clinical application to improve patients’ outcomes and advance our understanding of cancer biology. Full article

(This article belongs to the Special Issue The Biology of Circulating Tumor Cells 2.0)

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13 pages, 2825 KiB

Open AccessArticle

Outcome Disparities in Patients with Early-Stage Laryngeal Cancer Depending on Localization, Tobacco Consumption, and Treatment Modality

by Theresa Wald, Tim-Jonathan Koppe, Markus Pirlich, Veit Zebralla, Viktor Kunz, Andreas Dietz, Matthaeus Stoehr and Gunnar Wichmann

Biomedicines 2024, 12(9), 2136; https://doi.org/10.3390/biomedicines12092136 - 20 Sep 2024

Abstract

Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is among most frequent malignancies of the head and neck. Recent oncologic research focusses on advanced rather than on early stages. Thus, we aimed to improve the knowledge concerning prognostic factors and survival in early glottic (GC) [...] Read more.

Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is among most frequent malignancies of the head and neck. Recent oncologic research focusses on advanced rather than on early stages. Thus, we aimed to improve the knowledge concerning prognostic factors and survival in early glottic (GC) and supraglottic cancer (SGC). Methods: We retrospectively investigated patients diagnosed in 2007 to 2020 with stage I or II GC (ICD-10-C32.0) or SGC (ICD-10-C32.1, C32.8 or C32.9). For precise discrimination of GC and SGC, pathology reports about biopsy and definitive excision were closely examined and information on clinical characteristics and risk factors were collected before analyzing patterns of risk factors for overall survival (OS) in multivariate Cox regression analyses (mvCox). Results: The cohort included 220 patients with early GC (n = 183) and SGC (n = 37). The GC patients showed significantly improved 5-year OS compared to SGC patients (83.6% vs. 64.9%; p = 0.004), whereas survival according to UICC stage (I vs. II) was not different (p = 0.177). Surgical resection was superior to definitive radiotherapy (RT) for 5-year OS (p < 0.001). Cumulative tobacco consumption of greater than 10 pack years drastically impaired OS (p = 0.024), especially in patients receiving RT (p < 0.001). Supraglottic localization, smoking, and re-resection after initial R1 status consistently were independent prognostic factors in mvCox. Conclusions: Our cohort of early LSCC patients demonstrates significant negative impact of supraglottic localization, older age, tobacco consumption, poor tumor differentiation, and re-resection on OS. Further research is required as there is still lack of evidence on optimal decision-making and therapeutic strategies. Full article

(This article belongs to the Special Issue Head and Neck Tumors, 3rd Edition)

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18 pages, 2917 KiB

Open AccessArticle

Elevated Cellular Uptake of Succinimide- and Glucose-Modified Liposomes for Blood–Brain Barrier Transfer and Glioblastoma Therapy

by Larissa J. Lubitz, Moritz P. Haffner, Harden Rieger and Gero Leneweit

Biomedicines 2024, 12(9), 2135; https://doi.org/10.3390/biomedicines12092135 - 20 Sep 2024

Abstract

The uptake of four liposomal formulations was tested with the murine endothelial cell line bEnd.3 and the human glioblastoma cell line U-87 MG. All formulations were composed of DPPC, cholesterol, 5 mol% of mPEG (2000 Da, conjugated to DSPE), and the dye DiD. [...] Read more.

The uptake of four liposomal formulations was tested with the murine endothelial cell line bEnd.3 and the human glioblastoma cell line U-87 MG. All formulations were composed of DPPC, cholesterol, 5 mol% of mPEG (2000 Da, conjugated to DSPE), and the dye DiD. Three of the formulations had an additional PEG chain (nominally 5000 Da, conjugated to DSPE) with either succinimide (NHS), glucose (PEG-bound at C-6), or 4-aminophenyl β-D-glucopyranoside (bound at C-1) as ligands at the distal end. Measuring the uptake kinetics at 1 h and 3 h for liposomal incubation concentrations of 100 µM, 500 µM, and 1000 µM, we calculated the liposomal uptake saturation S and the saturation half-time t_1/2. We show that only succinimide has an elevated uptake in bEnd.3 cells, which makes it a very promising and so far largely unexplored candidate for BBB transfer and brain cancer therapies. Half-times are uniform at low concentrations but diversify for high concentrations for bEnd.3 cells. Contrary, U-87 MG cells show almost identical saturations for all three ligands, making a uniform uptake mechanism likely. Only mPEG liposomes stay at 60% of the saturation for ligand-coated liposomes. Half-times are diverse at low concentrations but unify at high concentrations for U-87 MG cells. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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14 pages, 2995 KiB

Open AccessArticle

Comparison of Multiple Carbapenemase Tests Based on an Unbiased Colony-Selection Method

by Hsin-Yao Wang, Yi-Ju Tseng, Wan-Ying Lin, Yu-Chiang Wang, Ting-Wei Lin, Jen-Fu Hsu, Marie Yung-Chen Wu, Chiu-Hsiang Wu, Sriram Kalpana and Jang-Jih Lu

Biomedicines 2024, 12(9), 2134; https://doi.org/10.3390/biomedicines12092134 - 20 Sep 2024

Abstract

Carbapenemase-producing organisms (CPOs) present a major threat to public health, demanding precise diagnostic techniques for their detection. Discrepancies among the CPO tests have raised concerns, partly due to limitations in detecting bacterial diversity within host specimens. We explored the impact of an unbiased [...] Read more.

Carbapenemase-producing organisms (CPOs) present a major threat to public health, demanding precise diagnostic techniques for their detection. Discrepancies among the CPO tests have raised concerns, partly due to limitations in detecting bacterial diversity within host specimens. We explored the impact of an unbiased colony selection on carbapenemase testing and assessed its relevance to various tests. Using the FirstAll method for unbiased colony selection to reduce bias, we compared the results from different methods, namely the modified carbapenem inactivation method/EDTA-modified carbapenem inactivation method (mCIM/eCIM), the Carba5, the CPO panel, and the multiplex PCR (MPCR). We compared the FirstAll method to the conventional colony selection for MPCR with seven CPO species. In addition, we evaluated the test performance on seven CPO species using MPCR as a reference and the FirstAll method as the colony-selection method. The results revealed that the selections from the FirstAll method have improved rates of carbapenemase detection, in comparison to approximately 11.2% of the CPO isolates that were noted to be false negatives in the conventional colony-selection methods. Both the Carba5 test and the CPO panel showed suboptimal performance (sensitivity/specificity: Carba5 74.6%/89.5%, CPO panel 77.2%/74.4%) in comparison to the FirstAll method. The Carba5 test provided specific carbapenemase class assignments, but the CPO panel failed in 18.7% of the cases. The Carba5 test and the CPO panel results correlated well with ceftazidime–avibactam minimal inhibitory concentrations (MICs). The concordance for Class A/D with MICs was 94.7% for Carba5 and 92.7% for the CPO panel; whereas for Class B, it was 86.5% for Carba5 and 75.9% for the CPO panel. In conclusion, FirstAll, as the unbiased colony-selection method, was shown to impact carbapenemase testing. With FirstAll, the diagnostic performance of both the Carba5 and the CPO panel was found to be lower. Furthermore, the utilization of ceftazidime–avibactam guided by either the CPO panel or Carba5 was appropriate. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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16 pages, 506 KiB

Open AccessReview

Chemerin in the Spotlight: Revealing Its Multifaceted Role in Acute Myocardial Infarction

by Andreas Mitsis, Elina Khattab, Michael Myrianthefs, Stergios Tzikas, Nikolaos P. E. Kadoglou, Nikolaos Fragakis, Antonios Ziakas and George Kassimis

Biomedicines 2024, 12(9), 2133; https://doi.org/10.3390/biomedicines12092133 - 20 Sep 2024

Abstract

Chemerin, an adipokine known for its role in adipogenesis and inflammation, has emerged as a significant biomarker in cardiovascular diseases, including acute myocardial infarction (AMI). Recent studies have highlighted chemerin’s involvement in the pathophysiological processes of coronary artery disease (CAD), where it modulates [...] Read more.

Chemerin, an adipokine known for its role in adipogenesis and inflammation, has emerged as a significant biomarker in cardiovascular diseases, including acute myocardial infarction (AMI). Recent studies have highlighted chemerin’s involvement in the pathophysiological processes of coronary artery disease (CAD), where it modulates inflammatory responses, endothelial function, and vascular remodelling. Elevated levels of chemerin have been associated with adverse cardiovascular outcomes, including increased myocardial injury, left ventricular dysfunction, and heightened inflammatory states post-AMI. This manuscript aims to provide a comprehensive review of the current understanding of chemerin’s role in AMI, detailing its molecular mechanisms, clinical implications, and potential as a biomarker for diagnosis and prognosis. Additionally, we explore the therapeutic prospects of targeting chemerin pathways to mitigate myocardial damage and improve clinical outcomes in AMI patients. By synthesizing the latest research findings, this review seeks to elucidate the multifaceted role of chemerin in AMI and its promise as a target for innovative therapeutic strategies. Full article

(This article belongs to the Special Issue The Role of Chemerin in Human Disease—2nd Edition)

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16 pages, 2182 KiB

Open AccessArticle

Human Serum, Following Absorption of Fish Cartilage Hydrolysate, Promotes Dermal Fibroblast Healing through Anti-Inflammatory and Immunomodulatory Proteins

by Julie Le Faouder, Aurélie Guého, Régis Lavigne, Fabien Wauquier, Line Boutin-Wittrant, Elodie Bouvret, Emmanuelle Com, Yohann Wittrant and Charles Pineau

Biomedicines 2024, 12(9), 2132; https://doi.org/10.3390/biomedicines12092132 - 19 Sep 2024

Abstract

Background/Objectives: Marine collagen peptides (MCPs) and glycosaminoglycans (GAGs) have been described as potential wound-healing (WH) agents. Fish cartilage hydrolysate (FCH) is a natural active food ingredient obtained from enzymatic hydrolysis which combines MCPs and GAGs. Recently, the clinical benefits of FCH supplementation [...] Read more.

Background/Objectives: Marine collagen peptides (MCPs) and glycosaminoglycans (GAGs) have been described as potential wound-healing (WH) agents. Fish cartilage hydrolysate (FCH) is a natural active food ingredient obtained from enzymatic hydrolysis which combines MCPs and GAGs. Recently, the clinical benefits of FCH supplementation for the skin, as well as its mode of action, have been demonstrated. Some of the highlighted mechanisms are common to the WH process. The aim of the study is therefore to investigate the influence of FCH supplementation on the skin healing processes and the underlying mechanisms. Methods: To this end, an ex vivo clinical approach, which takes into account the clinical digestive course of nutrients, coupled with primary cell culture on human dermal fibroblasts (HDFs) and ultra-deep proteomic analysis, was performed. The effects of human serum enriched in circulating metabolites resulting from FCH ingestion (FCH-enriched serum) were assessed on HDF WH via an in vitro scratch wound assay and on the HDF proteome via diaPASEF (Data Independent Acquisition—Parallel Accumulation Serial Fragmentation) proteomic analysis. Results: Results showed that FCH-enriched human serum accelerated wound closure. In support, proteins with anti-inflammatory and immunomodulatory properties and proteins prone to promote hydration and ECM stability showed increased expression in HDFs after exposure to FCH-enriched serum. Conclusions: Taken together, these data provide valuable new insights into the mechanisms that may contribute to FCH’s beneficial impact on human skin functionality by supporting WH. Further studies are needed to reinforce these preliminary data and investigate the anti-inflammatory and immunomodulatory properties of FCH. Full article

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

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23 pages, 1415 KiB

Open AccessReview

Molecular, Pathophysiological, and Clinical Aspects of Corticosteroid-Induced Neuropsychiatric Effects: From Bench to Bedside

by Sara Sofía-Avendaño-Lopez, Angela Johanna Rodríguez-Marín, Mateo Lara-Castillo, Juanita Agresott-Carrillo, Luna Estefanía Lara-Cortés, Juan Felipe Sánchez-Almanzar, Sophya Villamil-Cruz, Luis Carlos Rojas-Rodríguez, Daniel Felipe Ariza-Salamanca, Mariana Gaviria-Carrillo, Carlos Alberto Calderon-Ospina and Jesús Rodríguez-Quintana

Biomedicines 2024, 12(9), 2131; https://doi.org/10.3390/biomedicines12092131 - 19 Sep 2024

Abstract

Corticosteroids are frequently prescribed across medical disciplines, yet they are associated with various adverse effects, including neuropsychiatric symptoms, documented since their introduction over 60 years ago. The cellular mechanisms underlying neuropsychiatric symptoms are complex and somewhat obscure, involving multiple pathways. Notably, they include [...] Read more.

Corticosteroids are frequently prescribed across medical disciplines, yet they are associated with various adverse effects, including neuropsychiatric symptoms, documented since their introduction over 60 years ago. The cellular mechanisms underlying neuropsychiatric symptoms are complex and somewhat obscure, involving multiple pathways. Notably, they include changes in excitability, cellular death of hippocampal and striatal neurons, and increased inflammation and oxidative stress. Clinical presentation varies, encompassing affective disorders (anxiety, euphoria, depression), psychotic episodes, and cognitive deficits. It is crucial to note that these manifestations often go unnoticed by treating physicians, leading to delayed detection of severe symptoms, complications, and underreporting. Discontinuation of corticosteroids constitutes the cornerstone of treatment, resolving symptoms in up to 80% of cases. Although the literature on this topic is scant, isolated cases and limited studies have explored the efficacy of psychotropic medications for symptomatic control and prophylaxis. Pharmacological intervention may be warranted in situations where corticosteroid reduction or withdrawal is not feasible or beneficial for the patient. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Action—2nd Edition)

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16 pages, 1256 KiB

Open AccessArticle

A Simple Score Scale Composed of Serum Inflammatory Factors Assists in Psoriasis Arthritis Prediction among Patients with Psoriasis Vulgaris

by Wanrong Huang, Yao Li, Yuanyuan Xu, Rui Gao and Long Geng

Biomedicines 2024, 12(9), 2130; https://doi.org/10.3390/biomedicines12092130 - 19 Sep 2024

Abstract

Aim: To compare the levels of serum inflammatory indicators in psoriasis vulgaris patients who progress to PsA and those not, as well as to establish and validate a simple score scale for predicting PsA for psoriasis vulgaris patients. Methods: A cross-sectional study was [...] Read more.

Aim: To compare the levels of serum inflammatory indicators in psoriasis vulgaris patients who progress to PsA and those not, as well as to establish and validate a simple score scale for predicting PsA for psoriasis vulgaris patients. Methods: A cross-sectional study was performed at a university hospital in China to recruit five hundred and seventy-seven patients who had been diagnosed with psoriasis vulgaris for at least 10 years. After evaluation, 86 were enrolled in the PsA group, and the others were selected as the control group. Eight serum inflammatory factors were detected and compared between the two groups. A simple score scale for PsA prediction was established and validated. Results: Serum CRP, IL-6, and TNF-α levels were significantly higher in the PsA group than in the control group. A simple score scale composed of CRP, IL-6, and TNF-α was established. The sensitivity was 59.30% and the specificity was 83.50% for predicting PsA among all psoriasis vulgaris patients when the cut-off value of the total score was set as 1.8 points. The simple score scale presented a predictive value for progressing to PsA among all psoriasis vulgaris patients internally (AUC = 0.788), and the performance was also conformed in psoriasis vulgaris patients receiving topical treatment (AUC = 0.746), systemic treatment (AUC = 0.747) and biological treatment (AUC = 0.808), respectively. The predictive performance of this scale was also validated by an external retrospective cohort (AUC = 0.686). Conclusions: CRP, IL-6, and TNF-α were potential indicators to recognize PsA risk in patients with psoriasis vulgaris. A simple score scale may provide new insights for early prediction of PsA among psoriasis vulgaris patients. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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55 pages, 3273 KiB

Open AccessReview

Adipokines in the Crosstalk between Adipose Tissues and Other Organs: Implications in Cardiometabolic Diseases

by Shaghayegh Hemat Jouy, Sukrutha Mohan, Giorgia Scichilone, Amro Mostafa and Abeer M. Mahmoud

Biomedicines 2024, 12(9), 2129; https://doi.org/10.3390/biomedicines12092129 - 19 Sep 2024

Abstract

Adipose tissue was previously regarded as a dormant organ for lipid storage until the identification of adiponectin and leptin in the early 1990s. This revelation unveiled the dynamic endocrine function of adipose tissue, which has expanded further. Adipose tissue has emerged in recent [...] Read more.

Adipose tissue was previously regarded as a dormant organ for lipid storage until the identification of adiponectin and leptin in the early 1990s. This revelation unveiled the dynamic endocrine function of adipose tissue, which has expanded further. Adipose tissue has emerged in recent decades as a multifunctional organ that plays a significant role in energy metabolism and homeostasis. Currently, it is evident that adipose tissue primarily performs its function by secreting a diverse array of signaling molecules known as adipokines. Apart from their pivotal function in energy expenditure and metabolism regulation, these adipokines exert significant influence over a multitude of biological processes, including but not limited to inflammation, thermoregulation, immune response, vascular function, and insulin sensitivity. Adipokines are pivotal in regulating numerous biological processes within adipose tissue and facilitating communication between adipose tissue and various organs, including the brain, gut, pancreas, endothelial cells, liver, muscle, and more. Dysregulated adipokines have been implicated in several metabolic diseases, like obesity and diabetes, as well as cardiovascular diseases. In this article, we attempted to describe the significance of adipokines in developing metabolic and cardiovascular diseases and highlight their role in the crosstalk between adipose tissues and other tissues and organs. Full article

(This article belongs to the Special Issue Recent Advances in Adipokines—2nd Edition)

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6 pages, 208 KiB

Open AccessOpinion

Structural Changes Likely Cause Chemical Differences between Empty and Full AAV Capsids

by Caryn L. Heldt, Molly A. Skinner and Ganesh S. Anand

Biomedicines 2024, 12(9), 2128; https://doi.org/10.3390/biomedicines12092128 - 19 Sep 2024

Abstract

Due to the success of adeno associated viruses (AAVs) in treating single-gene diseases, improved manufacturing technology is now needed to meet their demand. The largest challenge is creating a process to separate empty and full capsids. Patients received larger capsid doses than necessary [...] Read more.

Due to the success of adeno associated viruses (AAVs) in treating single-gene diseases, improved manufacturing technology is now needed to meet their demand. The largest challenge is creating a process to separate empty and full capsids. Patients received larger capsid doses than necessary due to the presence of empty capsids. By enabling the better separation of empty and full capsids, patients would receive the greatest therapeutic benefit with the least amount of virus capsids, thus limiting potential side effects from empty capsids. The two most common empty/full separation methods used in downstream processing are ultracentrifugation and anion exchange chromatography. Both processes have limitations, leading to a need for the identification of other structural differences that can be exploited to separate empty and full capsids. Here, we describe four possible theories of the structural changes that occur when AAV capsids envelop a genome. These theories include conformational changes occurring due to either the expansion or contraction of the capsid in the presence of nucleic acids, the constraining of the N-terminus into the five-fold pore when the genome is present, and the increased number of VP3 proteins in full capsids. These theories may reveal structural differences that can be exploited to separate full and empty capsids during manufacturing. Full article

(This article belongs to the Collection Feature Papers in Gene and Cell Therapy)

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