Biomedicines

13 pages, 3458 KiB

Open AccessArticle

Exercise-Induced Proteomic Profile Changes in Patients with Advanced Heart Failure

by Anna Drohomirecka, Joanna Waś, Ewa Sitkiewicz, Bianka Świderska, Anna Lutyńska, Tomasz Rywik and Tomasz Zieliński

Biomedicines 2024, 12(10), 2267; https://doi.org/10.3390/biomedicines12102267 (registering DOI) - 5 Oct 2024

Abstract

Background/Objectives: The pathophysiological background of the processes activated by physical activity in patients with heart failure (HF) is not fully understood. Proteomic studies can help to preliminarily identify new protein markers for unknown or poorly defined physiological processes. We aimed to analyse the [...] Read more.

Background/Objectives: The pathophysiological background of the processes activated by physical activity in patients with heart failure (HF) is not fully understood. Proteomic studies can help to preliminarily identify new protein markers for unknown or poorly defined physiological processes. We aimed to analyse the changes in the plasma proteomic profile of HF patients after a cardiopulmonary exercise test (CPET) to define pathways involved in the response to exercise. Methods: The study prospectively enrolled 20 male patients with advanced HF (aged 53.3 ± 8.3 years). Blood samples were taken from the patients before and immediately after the CPET to obtain plasma proteomic profiles. Two-sample t-tests (paired or non-paired) were performed with and without false discovery rate (FDR) correction for multiple testing. Enrichment analysis was performed to associate biological processes and pathways with the study results. Results: A total of 968 plasma proteins were identified, of which 722 underwent further statistical analysis. Of these, 236 proteins showed differential expression when comparing all plasma samples collected before and after CPT (p < 0.05), and for 86 of these the difference remained statistically significant after FDR correction. Proteins whose expression changed after exercise are mostly involved in immune response and inflammatory processes, coagulation, cell adhesion, regulation of cellular response to stimulus and regulation of programmed cell death. There were no differences in resting proteomics according to HF etiology (ischemic vs. non-ischemic). Conclusions: Changes in the proteomic profile revealed a complexity of exercise-induced processes in patients with HF, suggesting that few major physiological pathways are involved. Further studies focusing on specific pathways are needed. Full article

(This article belongs to the Special Issue Acute and Chronic Heart Failure: Pathophysiology and New Therapeutic Developments)

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20 pages, 5720 KiB

Open AccessReview

Cerebrospinal Fluid Total, Phosphorylated and Oligomeric A-Synuclein in Parkinson’s Disease: A Systematic Review, Meta-Analysis and Meta-Regression Study

by Ioanna Kapsali, Maria-Evgenia Brinia and Vasilios C. Constantinides

Biomedicines 2024, 12(10), 2266; https://doi.org/10.3390/biomedicines12102266 (registering DOI) - 5 Oct 2024

Abstract

Background: The diagnostic accuracy for Parkinson’s disease (PD), a synucleinopathy, based on diagnostic criteria is suboptimal. A biomarker for synucleinopathies is pivotal both from a clinical and from a research point of view. CSF a-synuclein has been extensively studied over the past [...] Read more.

Background: The diagnostic accuracy for Parkinson’s disease (PD), a synucleinopathy, based on diagnostic criteria is suboptimal. A biomarker for synucleinopathies is pivotal both from a clinical and from a research point of view. CSF a-synuclein has been extensively studied over the past two decades as a candidate biomarker of synucleinopathies. Herein, we present data on studies focusing on total, phosphorylated and oligomeric CSF a-synuclein in PD. Methods: Pubmed, Scopus and Web of Science were searched for studies with >10 PD patients and control subjects, with data (mean, SD) on total, phosphorylated or oligomeric a-synuclein. Cohen’s d, as a measure of effect size, was calculated for all a-synuclein forms. Subgroup analysis and meta-regression were performed in an effort to explain between-study heterogeneity. Results: Thirty studies on total, six studies on oligomeric and one study on phosphorylated a-synuclein were included. Total a-synuclein was decreased and oligomeric a-synuclein increased in PD patients vs. controls. The effect size was medium for total and high for oligomeric a-synuclein. A-syn forms provided suboptimal combined sensitivity/specificity for the differentiation of PD from controls. There was significant between-study heterogeneity. The PD cohort characteristics (sex, age, disease duration, UPDRS, H & Y) and study characteristics (study design, healthy vs. neurological controls, control for CSF blood contamination, method of a-syn measurement) could not account for between-study heterogeneity. Publication bias was limited. Conclusions: CSF a-synuclein levels lack sufficient accuracy to be used as biomarkers for PD. The standardization of (pre)analytical variables may improve the discriminatory power of a-synuclein forms in the future. Full article

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

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20 pages, 1280 KiB

Open AccessArticle

Establishment and Characterization of a Stable Producer Cell Line Generation Platform for the Manufacturing of Clinical-Grade Lentiviral Vectors

by Ane Arrasate, Igone Bravo, Carlos Lopez-Robles, Ane Arbelaiz-Sarasola, Maddi Ugalde, Martha Lucia Meijueiro, Miren Zuazo, Ana Valero, Soledad Banos-Mateos, Juan Carlos Ramirez, Carmen Albo, Andrés Lamsfus-Calle and Marie J. Fertin

Biomedicines 2024, 12(10), 2265; https://doi.org/10.3390/biomedicines12102265 - 4 Oct 2024

Abstract

Background/Objectives: To date, nearly 300 lentiviral-based gene therapy clinical trials have been conducted, with eight therapies receiving regulatory approval for commercialization. These advances, along with the increased number of advanced-phase clinical trials, have prompted contract development and manufacturing organizations (CDMOs) to develop innovative [...] Read more.

Background/Objectives: To date, nearly 300 lentiviral-based gene therapy clinical trials have been conducted, with eight therapies receiving regulatory approval for commercialization. These advances, along with the increased number of advanced-phase clinical trials, have prompted contract development and manufacturing organizations (CDMOs) to develop innovative strategies to address the growing demand for large-scale batches of lentiviral vectors (LVVs). Consequently, manufacturers have focused on optimizing processes under good manufacturing practices (GMPs) to improve cost-efficiency, increase process robustness, and ensure regulatory compliance. Nowadays, the LVV production process mainly relies on the transient transfection of four plasmids encoding for the lentiviral helper genes and the transgene. While this method is efficient at small scales and has also proven to be scalable, the industry is exploring alternative processes due to the high cost of GMP reagents, and the batch-to-batch variability predominantly attributed to the transfection step. Methods: Here, we report the development and implementation of a reliable and clinical-grade envisioned platform based on the generation of stable producer cell lines (SCLs) from an initial well-characterized lentiviral packaging cell line (PCL). Results: This platform enables the production of VSV-G-pseudotyped LVVs through a fully transfection-free manufacturing process. Our data demonstrate that the developed platform will facilitate successful technological transfer to large-scale LVV production for clinical application. Conclusions: With this simple and robust stable cell line generation strategy, we address key concerns associated with the costs and reproducibility of current manufacturing processes. Full article

(This article belongs to the Special Issue Gene Delivery and Gene Editing)

14 pages, 3089 KiB

Open AccessArticle

The Causal Relationship between Inflammatory Cytokines and Liver Cirrhosis in European Descent: A Bidirectional Two-Sample Mendelian Randomization Study and the First Conclusions

by Shiya Shi, Yanjie Zhou, He Zhang, Yalan Zhu, Pengjun Jiang, Chengxia Xie, Tianyu Feng, Yuping Zeng, He He, Yao Luo and Jie Chen

Biomedicines 2024, 12(10), 2264; https://doi.org/10.3390/biomedicines12102264 - 4 Oct 2024

Abstract

Background: Observational studies have highlighted the pivotal role of inflammatory cytokines in cirrhosis progression. However, the existence of a causal link between inflammatory cytokines and cirrhosis remains uncertain. In this study, we conducted a bidirectional Mendelian randomization (MR) analysis at a summarized level [...] Read more.

Background: Observational studies have highlighted the pivotal role of inflammatory cytokines in cirrhosis progression. However, the existence of a causal link between inflammatory cytokines and cirrhosis remains uncertain. In this study, we conducted a bidirectional Mendelian randomization (MR) analysis at a summarized level to illuminate the potential causal relationship between the two variables. Methods: This study utilized genetic variance in cirrhosis and inflammatory cytokines from a genome-wide association study (GWAS) of European descent. The MR-PRESSO outlier test, Cochran’s Q test, and MR-Egger regression were applied to assess outliers, heterogeneity, and pleiotropy. The inverse variance weighted method and multiple sensitivity analyses were used to evaluate causalities. Furthermore, the validation set was used for simultaneous data validation. Results: The inflammatory cytokine monocyte chemoattractant protein 3 (MCP-3) was supposedly associated with a greater risk of cirrhosis. And cirrhosis was significantly correlated with increased levels of hepatocyte growth factor (HGF). Conclusions: This study suggests that MCP-3 might be associated with the etiology of cirrhosis, while several inflammatory cytokines could potentially play a role in its downstream development. Additionally, the progression of cirrhosis was associated with elevated levels of HGF, suggesting a possible role for liver repair functions. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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15 pages, 2982 KiB

Open AccessArticle

The Association between the Firmicutes/Bacteroidetes Ratio and Body Mass among European Population with the Highest Proportion of Adults with Obesity: An Observational Follow-Up Study from Croatia

by Andrija Karačić, Ira Renko, Željko Krznarić, Sanja Klobučar and Ana-Marija Liberati Pršo

Biomedicines 2024, 12(10), 2263; https://doi.org/10.3390/biomedicines12102263 - 4 Oct 2024

Abstract

Background/Objectives: The phyla Firmicutes and Bacteroidetes are the main constituents of the gut microbiota. An imbalance in the gut microbiota is a sign of dysbiosis, and the Firmicutes-to-Bacteroidetes ratio has been proposed to be a marker of it, especially in the context [...] Read more.

Background/Objectives: The phyla Firmicutes and Bacteroidetes are the main constituents of the gut microbiota. An imbalance in the gut microbiota is a sign of dysbiosis, and the Firmicutes-to-Bacteroidetes ratio has been proposed to be a marker of it, especially in the context of obesity. Since Croatia is the country with one of the highest obesity rates in Europe, a pilot observational study was conducted. The aim of the study was to investigate the validity of this potential biomarker in a methodological study using sample processing, DNA sequence analysis and characterization of recruited participants, including various health factors. Methods: A study involving Croatian population was conducted. Participants age, body weight, gender, health history and lifestyle factors were recorded. Gut microbiota composition was analyzed using 16S rRNA sequencing. The F/B ratio was calculated and evaluated in the context of health factors. Statistical analysis was performed to detect the possible association of F/B ratio and excess body weight (kg) and possible impact of certain lifestyle factors. Results: No association between the F/B ratio and excess body weight (kg) was found. Excess body weight was significantly associated with higher age, male gender, and history of appendectomy. No significant health predictors of the F/B ratio were found, but weight gain was positively associated with a higher average F/B ratio. Conclusions: Although this study could not confirm the predictive value of the F/B ratio or any other phyla-related biomarker for excess body weight in the study population, it demonstrated interesting insights into the obesity-associated gut microbiota. Full article

(This article belongs to the Special Issue Biomarkers in Metabolic Disorders, Obesity and Type 2 Diabetes Mellitus)

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23 pages, 1181 KiB

Open AccessReview

Timing and Graded BMP Signalling Determines Fate of Neural Crest and Ectodermal Placode Derivatives from Pluripotent Stem Cells

by Keshi Chung, Malvina Millet, Ludivine Rouillon and Azel Zine

Biomedicines 2024, 12(10), 2262; https://doi.org/10.3390/biomedicines12102262 - 4 Oct 2024

Abstract

Pluripotent stem cells (PSCs) offer many potential research and clinical benefits due to their ability to differentiate into nearly every cell type in the body. They are often used as model systems to study early stages of ontogenesis to better understand key developmental [...] Read more.

Pluripotent stem cells (PSCs) offer many potential research and clinical benefits due to their ability to differentiate into nearly every cell type in the body. They are often used as model systems to study early stages of ontogenesis to better understand key developmental pathways, as well as for drug screening. However, in order to fully realise the potential of PSCs and their translational applications, a deeper understanding of developmental pathways, especially in humans, is required. Several signalling molecules play important roles during development and are required for proper differentiation of PSCs. The concentration and timing of signal activation are important, with perturbations resulting in improper development and/or pathology. Bone morphogenetic proteins (BMPs) are one such key group of signalling molecules involved in the specification and differentiation of various cell types and tissues in the human body, including those related to tooth and otic development. In this review, we describe the role of BMP signalling and its regulation, the consequences of BMP dysregulation in disease and differentiation, and how PSCs can be used to investigate the effects of BMP modulation during development, mainly focusing on otic development. Finally, we emphasise the unique role of BMP4 in otic specification and how refined understanding of controlling its regulation could lead to the generation of more robust and reproducible human PSC-derived otic organoids for research and translational applications. Full article

(This article belongs to the Special Issue Pluripotent Stem Cell: Current Understanding and Future Directions)

22 pages, 4031 KiB

Open AccessArticle

N-Pep-Zn Improves Cognitive Functions and Acute Stress Response Affected by Chronic Social Isolation in Aged Spontaneously Hypertensive Rats (SHRs)

by Mikhail Y. Stepanichev, Mikhail V. Onufriev, Yulia V. Moiseeva, Olga A. Nedogreeva, Margarita R. Novikova, Pavel A. Kostryukov, Natalia A. Lazareva, Anna O. Manolova, Diana I. Mamedova, Victoria O. Ovchinnikova, Birgit Kastberger, Stefan Winter and Natalia V. Gulyaeva

Biomedicines 2024, 12(10), 2261; https://doi.org/10.3390/biomedicines12102261 - 4 Oct 2024

Abstract

Background/Objectives: Aging and chronic stress are regarded as the most important risk factors of cognitive decline. Aged spontaneously hypertensive rats (SHRs) represent a suitable model of age-related vascular brain diseases. The aim of this study was to explore the effects of chronic isolation [...] Read more.

Background/Objectives: Aging and chronic stress are regarded as the most important risk factors of cognitive decline. Aged spontaneously hypertensive rats (SHRs) represent a suitable model of age-related vascular brain diseases. The aim of this study was to explore the effects of chronic isolation stress in aging SHRs on their cognitive functions and response to acute stress, as well as the influence of the chronic oral intake of N-Pep-Zn, the Zn derivative of N-PEP-12. Methods: Nine-month-old SHRs were subjected to social isolation for 3 months (SHRiso group), and one group received N-pep-Zn orally (SHRisoP, 1.5 mg/100 g BW). SHRs housed in groups served as the control (SHRsoc). The behavioral study included the following tests: sucrose preference, open field, elevated plus maze, three-chamber sociability and social novelty and spatial learning and memory in a Barnes maze. Levels of corticosterone, glucose and proinflammatory cytokines in blood plasma as well as salivary amylase activity were measured. Restraint (60 min) was used to test acute stress response. Results: Isolation negatively affected the SHRs learning and memory in the Barnes maze, while the treatment of isolated rats with N-Pep-Zn improved their long-term memory and working memory impairments, making the SHRisoP comparable to the SHRsoc group. Acute stress induced a decrease in the relative thymus weight in the SHRiso group (but not SHRsoc), whereas treatment with N-Pep-Zn prevented thymus involution. N-pep-Zn mitigated the increment in blood cortisol and glucose levels induced by acute stress. Conclusions: N-pep-Zn enhanced the adaptive capabilities towards chronic (isolation) and acute (immobilization) stress in aged SHRs and prevented cognitive disturbances induced by chronic isolation, probably affecting the hypothalamo–pituitary–adrenal, sympathetic, and immune systems. Full article

(This article belongs to the Special Issue Health-Related Applications of Natural Molecule Derived Structures)

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17 pages, 2622 KiB

Open AccessReview

Pigment Epithelial-Derived Factor in Pancreatic and Liver Cancers—From Inflammation to Cancer

by Sara Pączek, Monika Zajkowska and Barbara Mroczko

Biomedicines 2024, 12(10), 2260; https://doi.org/10.3390/biomedicines12102260 - 4 Oct 2024

Abstract

Gastrointestinal (GI) cancers are among the leading causes of mortality worldwide. Despite the emergence of new possibilities that offer hope regarding the successful treatment of these cancers, they still represent a significant global health burden. These cancers can arise from various cell types [...] Read more.

Gastrointestinal (GI) cancers are among the leading causes of mortality worldwide. Despite the emergence of new possibilities that offer hope regarding the successful treatment of these cancers, they still represent a significant global health burden. These cancers can arise from various cell types within the gastrointestinal tract and may exhibit different characteristics, behaviors, and treatment approaches. Both the prognosis and the outcomes of GI treatment remain problematic because these tumors are primarily diagnosed in advanced clinical stages. Current biomarkers exhibit limited sensitivity and specificity. Therefore, when developing strategies for the diagnosis and treatment of GI cancers, it is of fundamental importance to discover new biomarkers capable of addressing the challenges of early-stage diagnosis and the presence of lymph node metastases. Pigment epithelial-derived factor (PEDF) has garnered interest due to its inhibitory effects on the migration and proliferation of cancer cells. This protein has been suggested to be involved in various inflammation-related diseases, including cancer, through various mechanisms. It was also observed that reducing the level of PEDF is sufficient to trigger an inflammatory response. This suggests that PEDF is an endogenous anti-inflammatory factor. Overall, PEDF is a versatile protein with diverse biological functions that span across different tissues and organ systems. Its multifaceted activities make it an intriguing target for therapeutic interventions in various diseases, including cancer, neurodegeneration, and metabolic disorders. This review, for the first time, summarizes the role of PEDF in the pathogenesis of selected GI cancers and its potential utility in early diagnosis, prognosis, and therapeutic strategies for this malignancy. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 2nd Edition)

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40 pages, 2082 KiB

Open AccessReview

An Updated Comprehensive Review on Diseases Associated with Nephrotic Syndromes

by Ralph Wendt, Alina Sobhani, Paul Diefenhardt, Moritz Trappe and Alexander Völker Linus

Biomedicines 2024, 12(10), 2259; https://doi.org/10.3390/biomedicines12102259 - 4 Oct 2024

Abstract

There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and [...] Read more.

There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and sometimes also avoid unnecessary exposure to potentially toxic immunosuppression. New biomarkers have led to easier and more accurate diagnoses and more targeted therapeutic decisions. The treatment landscape is becoming wider with a pipeline of promising new therapeutic agents with more sophisticated approaches. This review focuses on all aspects of entities that are associated with nephrotic syndromes with updated information on recent advances in each field. This includes podocytopathies (focal segmental glomerulosclerosis and minimal-change disease), membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, fibrillary glomerulonephritis, amyloidosis, and monoclonal gammopathy of renal significance in the context of the nephrotic syndrome, but also renal involvement in systemic diseases, diabetic nephropathy, and drugs that are associated with nephrotic syndromes. Full article

(This article belongs to the Special Issue Nephrotic Syndrome: Pathomechanism, Diagnostics and Novel Treatment Options)

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13 pages, 7870 KiB

Open AccessArticle

Histopathological Characteristics of Percutaneous Endomyocardial Biopsy in Heart Transplant Rejection Surveillance: A Single Center Experience

by Anca Otilia Farcas, Mihai Ciprian Stoica, Septimiu Voidazan, Ioana Maria Maier, Adrian Cornel Maier, Horatiu Suciu and Anca Ileana Sin

Biomedicines 2024, 12(10), 2258; https://doi.org/10.3390/biomedicines12102258 - 4 Oct 2024

Abstract

Background: Heart transplantation (HT) remains the ultimate treatment for end-stage heart failure. An endomyocardial biopsy (EMB) is “the gold standard” diagnostic procedure used in HT rejection surveillance. The aim of this study is to provide a detailed analysis of the histopathological characteristics of [...] Read more.

Background: Heart transplantation (HT) remains the ultimate treatment for end-stage heart failure. An endomyocardial biopsy (EMB) is “the gold standard” diagnostic procedure used in HT rejection surveillance. The aim of this study is to provide a detailed analysis of the histopathological characteristics of the EMB and to investigate if there is a correlation between some histopathological changes, such as fibrosis, vasculitis, Quilty effect (Q.E.), myocytes damage, and the presence of episodes of acute rejection. Methods: In this retrospective study, 200 EMBs were included, coming from 65 patients transplanted in the Emergency Institute for Cardiovascular Diseases and Transplantation (ICvDT) Targu Mures between 2012 and 2024. Fibrosis, vasculitis, Q.E., myocyte damage, etc., were microscopically evaluated to see if these parameters correlate with rejection episodes. Results: The mean age was 38.18 years (SD 15.67), 25% of biopsies being recorded in the 41–50 age group. 77.14% of total acute cellular rejection (ACR) was of mild rejection, with most registered in the 11–20 age group; the cases of severe rejection being recorded in the 41–50 age group. Antibody-mediated rejection (AMR) was recorded more frequently in women with a representation of 23.4%, compared to 8.5% of men. 86.7% (39 cases) of the total number of EMBs with fibrosis score 3 and 71.4% (15 cases) of the total EMBs with fibrosis score 2 were recorded in men, compared to the 28.6% (6 cases) of fibrosis score 2 recorded in women (p = 0.013). 50.0% of all the EMB recorded in the 61–70 age group showed fibrosis score 3, compared to 34.8% of those from the 21–30 age group. The Q.E. was identified in 13% of the biopsies and, in some patients, it was observed across 3–4 successive biopsies. Mild vasculitis was associated in 34.9% of cases with ISHLT ≥ 1R and moderate vasculitis was associated in 87.5% of cases with ISHLT ≥ 1R. Conclusions: Fibrosis was detected much more frequently in men and in the 61–70 age group. In addition to the histopathological changes specific to acute rejection, there are other pathological changes, such as the Q.E., and vasculitis and myocytes damage and disarray, that seem to suggest a close connection with rejection, but extensive studies are needed to confirm this. Full article

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

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13 pages, 1073 KiB

Open AccessReview

Current Perspectives on Olfactory Loss in Atypical Parkinsonisms—A Review Article

by Katarzyna Bochniak, Mateusz Soszyński, Natalia Madetko-Alster and Piotr Alster

Biomedicines 2024, 12(10), 2257; https://doi.org/10.3390/biomedicines12102257 - 4 Oct 2024

Abstract

Introduction: Atypical parkinsonisms (APs) present various symptoms including motor impairment, cognitive decline, and autonomic dysfunction. Olfactory loss (OL), being a significant non-motor symptom, has emerged as an under-evaluated, yet potentially valuable, feature that might aid in the differential diagnosis of APs. State of [...] Read more.

Introduction: Atypical parkinsonisms (APs) present various symptoms including motor impairment, cognitive decline, and autonomic dysfunction. Olfactory loss (OL), being a significant non-motor symptom, has emerged as an under-evaluated, yet potentially valuable, feature that might aid in the differential diagnosis of APs. State of the art: The most pronounced OL is usually associated with Dementia with Lewy Bodies (DLB). While the view about the normosmic course of Multiple System Atrophy (MSA) remains unchanged, research indicates that mild OL may occur in a subset of patients with Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). This might be linked to the deposition of abnormal protein aggregates in the central nervous system. Clinical significance: The aim of this review is to discuss the role of OL and its degree and pattern in the pathogenesis and course of APs. Olfactory testing could serve as a non-invasive, quick screening tool to differentiate between APs and project disease progression. Future directions: There is a need for further evaluation of this topic. This may lead to the development of standardized olfactory testing protocols that could be implemented in clinical practice, making differential diagnosis of APs more convenient. Understanding differences in the sense of smell could create an avenue for more targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Parkinson's Disease)

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17 pages, 288 KiB

Open AccessArticle

CDKN2A Homozygous Deletion Is a Stronger Predictor of Outcome than IDH1/2-Mutation in CNS WHO Grade 4 Gliomas

by Sang Hyuk Lee, Tae Gyu Kim, Kyeong Hwa Ryu, Seok Hyun Kim and Young Zoon Kim

Biomedicines 2024, 12(10), 2256; https://doi.org/10.3390/biomedicines12102256 - 4 Oct 2024

Abstract

Background: We primarily investigated the prognostic role of CDKN2A homozygous deletion in CNS WHO grade 4 gliomas. Additionally, we plan to examine traditional prognostic factors for grade 4 gliomas and validate the findings. Materials: We conducted a retrospective analysis of the [...] Read more.

Background: We primarily investigated the prognostic role of CDKN2A homozygous deletion in CNS WHO grade 4 gliomas. Additionally, we plan to examine traditional prognostic factors for grade 4 gliomas and validate the findings. Materials: We conducted a retrospective analysis of the glioma cohorts at our institute. We reviewed medical records spanning a 15-year period and examined pathological slides for an updated diagnosis according to the 2021 WHO classification of CNS tumors. We examined the IDH1/2 mutation and CDKN2A deletion using NGS analysis with ONCOaccuPanel^®. Further, we examined traditional prognostic factors, including age, WHO performance status, extent of resection, and MGMT promoter methylation status. Results: The mean follow-up duration was 27.5 months (range: 4.1–43.5 months) and mean overall survival (OS) was 20.7 months (SD, ±1.759). After the exclusion of six patients with a poor status of pathologic samples, a total of 136 glioblastoma cases diagnosed by previous WHO classification criteria were newly classified into 29 (21.3%) astrocytoma, IDH-mutant, and CNS WHO grade 4 cases, and 107 (78.7%) glioblastoma, IDH-wildtype, and CNS WHO grade 4 cases. Among them, 61 (56.0%) had CDKN2A deletions. The high-risk group with CDKN2A deletion regardless of IDH1/2 mutation had a mean OS of 16.65 months (SD, ±1.554), the intermediate-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 21.85 months (SD, ±2.082), and the low-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 33.38 months (SD, ±2.946). Multifactor analysis showed that age (≥50 years vs. <50 years; HR 4.645), WHO performance (0, 1 vs. 2; HR 5.002), extent of resection (gross total resection vs. others; HR 5.528), MGMT promoter methylation, (methylated vs. unmethylated; HR 5.078), IDH1/2 mutation (mutant vs. wildtype; HR 6.352), and CDKN2A deletion (absence vs. presence; HR 13.454) were associated with OS independently. Conclusions: The present study suggests that CDKN2A deletion plays a powerful prognostic role in CNS WHO grade 4 gliomas. Even if CNS WHO grade 4 gliomas have mutant IDH1/2, they may have poor clinical outcomes because of CDKN2A deletion. Full article

(This article belongs to the Special Issue Glioblastoma: Pathogenetic, Diagnostic and Therapeutic Perspectives)

9 pages, 232 KiB

Open AccessArticle

Effect of Clinicopathological Characteristics on the Outcomes of Topical 5-Aminolevulinic Acid Photodynamic Therapy in Patients with Cervical High-Grade Squamous Intraepithelial Lesions (HSIL/CIN2): A Retrospective Cohort Study

by Yingting Wei, Jing Niu, Liying Gu, Zubei Hong, Zhouzhou Bao and Lihua Qiu

Biomedicines 2024, 12(10), 2255; https://doi.org/10.3390/biomedicines12102255 - 3 Oct 2024

Abstract

Background: Minimally-invasive 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is used for treating cervical high-grade squamous intraepithelial lesions (HSIL/CIN2). The purpose of this study was to analyze the factors affecting the efficacy of ALA-PDT in the treatment of cervical HSIL/CIN2 in order to guide physicians [...] Read more.

Background: Minimally-invasive 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is used for treating cervical high-grade squamous intraepithelial lesions (HSIL/CIN2). The purpose of this study was to analyze the factors affecting the efficacy of ALA-PDT in the treatment of cervical HSIL/CIN2 in order to guide physicians in making appropriate treatment decisions. Methods: A retrospective study including 69 female patients with pathologically diagnosed HSIL/CIN2 was conducted. Patients were given six doses of 20% ALA-PDT at 7–14-day intervals. Cytology, HPV testing, colposcopy, and pathology were performed before treatment and at 6-month follow-up after treatment to assess efficacy. The main outcome of this study was the regression of HSIL/CIN2 and the clearance of high-risk HPV (hrHPV) infection after ALA-PDT treatment. Clinicopathological characteristics were collected to analyze the factors affecting the effectiveness of ALA-PDT treatment for HSIL/CIN2. Results: Between the successful and failed lesion regression group, there was a significant difference in sleeping disorders (p < 0.05). Between the successful and failed hrHPV clearance group, no statistically significant factors were found. With sensitivity values of 0.556 and 0.778, respectively, multivariate analysis showed that current smoking and sleeping disorders were independent prognostics of failure in lesion regression after ALA-PDT treatment. Conclusions: Smoking and sleep disorders were independent risk factors for failure in HSIL/CIN2 regression following ALA-PDT, suggesting the need for careful consideration of ALA-PDT for patients with these conditions. Full article

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

11 pages, 1116 KiB

Open AccessArticle

Slow-Paced Breathing Intervention in Healthcare Workers Affected by Long COVID: Effects on Systemic and Dysfunctional Breathing Symptoms, Manual Dexterity and HRV

by Marcella Mauro, Elisa Zulian, Nicoletta Bestiaco, Maurizio Polano and Francesca Larese Filon

Biomedicines 2024, 12(10), 2254; https://doi.org/10.3390/biomedicines12102254 - 3 Oct 2024

Abstract

Background: Many COVID-19 survivors still experience long-term effects of an acute infection, most often characterised by neurological, cognitive and psychiatric sequelae. The treatment of this condition is challenging, and many hypotheses have been proposed. Non-invasive vagus nerve stimulation using slow-paced breathing (SPB) could [...] Read more.

Background: Many COVID-19 survivors still experience long-term effects of an acute infection, most often characterised by neurological, cognitive and psychiatric sequelae. The treatment of this condition is challenging, and many hypotheses have been proposed. Non-invasive vagus nerve stimulation using slow-paced breathing (SPB) could stimulate both central nervous system areas and parasympathetic autonomic pathways, leading to neuromodulation and a reduction in inflammation. The aim of the present study was to evaluate physical, cognitive, emotional symptoms, executive functions and autonomic cardiac modulation after one month of at-home slow breathing intervention. Methods: 6655 healthcare workers (HCWs) were contacted via a company email in November 2022, of which N = 58 HCWs were enrolled as long COVID (cases) and N = 53 HCWs as controls. A baseline comparison of the two groups was performed. Subsequently each case was instructed on how to perform a resonant SPB using visual heart rate variability (HRV) biofeedback. They were then given a mobile video tutorial breathing protocol and asked to perform it three times a day (morning, early afternoon and before sleep). N = 33 cases completed the FU. At T0 and T1, each subject underwent COVID-related, psychosomatic and dysfunctional breathing questionnaires coupled with heart rate variability and manual dexterity assessments. Results: After one month of home intervention, an overall improvement in long-COVID symptoms was observed: confusion/cognitive impairment, chest pain, asthenia, headache and dizziness decreased significantly, while only a small increase in manual dexterity was found, and no relevant changes in cardiac parasympathetic modulation were observed. Full article

(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications—2nd Edition)

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14 pages, 2555 KiB

Open AccessArticle

Associations between Disc Hemorrhage and Primary Open-Angle Glaucoma Based on Genome-Wide Association and Mendelian Randomization Analyses

by Je Hyun Seo, Young Lee and Hyuk Jin Choi

Biomedicines 2024, 12(10), 2253; https://doi.org/10.3390/biomedicines12102253 - 3 Oct 2024

Abstract

Background/Objectives: We aimed to investigate the genetic loci related to disc hemorrhage (DH) and the relationship of causation between DH and primary open-angle glaucoma (POAG) using a genome-wide association study (GWAS) in East Asian individuals. Methods: The GWAS included 8488 Koreans who underwent [...] Read more.

Background/Objectives: We aimed to investigate the genetic loci related to disc hemorrhage (DH) and the relationship of causation between DH and primary open-angle glaucoma (POAG) using a genome-wide association study (GWAS) in East Asian individuals. Methods: The GWAS included 8488 Koreans who underwent ocular examination including fundus photography to determine the presence of DH and POAG. We performed a GWAS to identify significant single-nucleotide polymorphisms (SNPs) associated with DH and analyzed the heritability of DH and genetic correlation between DH and POAG. The identified SNPs were utilized as instrumental variables (IVs) for two-sample Mendelian randomization (MR) analysis. The POAG outcome dataset was adopted from Biobank Japan data (n = 179,351). Results: We found that the rs62463744 (TMEM270;ELN), rs11658281 (CCDC42), and rs77127203 (PDE10A;LINC00473) SNPs were associated with DH. The SNP heritability of DH was estimated to be 6.7%, with an absence of a genetic correlation with POAG. MR analysis did not reveal a causal association between DH and POAG for East Asian individuals. Conclusions: The novel loci underlying DH in the Korean cohort revealed SNPs in the ELN, CCDC41, and LINC00473 genes. The absence of a causal association between DH and POAG implies that DH is a shared risk factor, rather than an independent culprit factor, and warrants further investigation. Full article

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

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13 pages, 1528 KiB

Open AccessSystematic Review

Dyslipidemia in Pregnancy: A Systematic Review of Molecular Alterations and Clinical Implications

by Agnesa Preda, Silviu-Daniel Preda, Maria Mota, Dominic Gabriel Iliescu, Lucian George Zorila, Alexandru Cristian Comanescu, Adina Mitrea, Diana Clenciu, Eugen Mota and Ionela Mihaela Vladu

Biomedicines 2024, 12(10), 2252; https://doi.org/10.3390/biomedicines12102252 - 3 Oct 2024

Abstract

Background: Dyslipidemia in pregnancy presents unique clinical challenges due to its effects on maternal and fetal health. This systematic review hypothesizes that molecular alterations in lipid metabolism during pregnancy contribute to adverse pregnancy outcomes and seeks to identify the clinical implications of these [...] Read more.

Background: Dyslipidemia in pregnancy presents unique clinical challenges due to its effects on maternal and fetal health. This systematic review hypothesizes that molecular alterations in lipid metabolism during pregnancy contribute to adverse pregnancy outcomes and seeks to identify the clinical implications of these changes. The rationale behind this review stems from the increased risk of complications such as preeclampsia, intrauterine growth restriction, and acute pancreatitis associated with dyslipidemia in pregnancy. The primary objective is to examine the interplay between lipid metabolism and pregnancy outcomes. Methods: To achieve this, a systematic review following PRISMA guidelines was conducted, with a comprehensive search of the PubMed database covering articles from January 2014 to June 2024. Inclusion criteria focused on studies assessing molecular alterations and clinical outcomes of dyslipidemia in pregnancy, while case reports and relevant clinical trials were analyzed to evaluate both maternal and fetal outcomes. A total of 12 studies were included in the final analysis. Results: This study provided evidence of the need for early detection and management strategies to reduce risks. The outcomes revealed significant associations between dyslipidemia and adverse maternal outcomes such as preeclampsia, gestational diabetes, and pancreatitis, as well as fetal outcomes like preterm birth and fetal distress. Conclusions: Early lipid monitoring and intervention are crucial in mitigating these risks and suggests that a multidisciplinary approach is necessary to improve maternal and fetal health in pregnancies complicated by dyslipidemia. Full article

(This article belongs to the Special Issue From Molecules to Medicine: Deciphering Obesity and Lipid Metabolism for Translational Insights)

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18 pages, 3196 KiB

Open AccessArticle

Impact of Stabilization Splint Therapy on Orthodontic Diagnosis in Patients with Signs and Symptoms of Temporomandibular Disorder

by Kenan Demirovic, Vildana Dzemidzic and Enita Nakas

Biomedicines 2024, 12(10), 2251; https://doi.org/10.3390/biomedicines12102251 - 3 Oct 2024

Abstract

Background/Objectives: The relation between the orthopedic temporomandibular joint (TMJ) instability and temporomandibular disorder (TMD) most commonly remain unrecognized by orthodontists. In this study we aimed to evaluate the dentofacial characteristics and temporomandibular disorder symptomatology of patients with orthopedic instability before and after deprogramming [...] Read more.

Background/Objectives: The relation between the orthopedic temporomandibular joint (TMJ) instability and temporomandibular disorder (TMD) most commonly remain unrecognized by orthodontists. In this study we aimed to evaluate the dentofacial characteristics and temporomandibular disorder symptomatology of patients with orthopedic instability before and after deprogramming with a stabilization splint. Methods: Sixty patients with the signs and symptoms of TMD were assessed using the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and underwent stabilization splint therapy to place the condyles in a more stable musculoskeletal position. The extent of condylar displacement was evaluated using the condylar position indicator (CPI). Sixteen angular and linear hard tissue landmarks were traced and compared from lateral cephalograms taken in the maximum intercuspation (MI) position before, and in the centric relation (CR) position after, the splint therapy. Results: Following the splint therapy, the signs and symptoms of TMD were significantly reduced or completely eliminated in more than 90% of patients. Compared with the values registered before the splint therapy, a significant reduction in the mean values of condylar displacement was observed on both sides of the vertical (p < 0.001), horizontal (p < 0.05), and transverse (p < 0.001) planes of space after the splint therapy. A comparison of pre- and post-splint lateral cephalograms revealed that, following the splint therapy, the mandible moved more posteriorly and rotated in a more clockwise direction. Conclusion: In patients with orthopedic instability and the signs and symptoms of TMD, muscle deprogramming with a stabilization splint therapy is highly recommended to improve the health of the temporomandibular joint and masticatory structures and contribute to a more correct orthodontic diagnosis. Full article

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

19 pages, 4778 KiB

Open AccessArticle

Development of a Competitive Nutrient-Based T-Cell Immunotherapy Designed to Block the Adaptive Warburg Effect in Acute Myeloid Leukemia

by Huynh Cao, Jeffrey Xiao, David J. Baylink, Vinh Nguyen, Nathan Shim, Jae Lee, Dave J. R. Mallari, Samiksha Wasnik, Saied Mirshahidi, Chien-Shing Chen, Hisham Abdel-Azim, Mark E. Reeves and Yi Xu

Biomedicines 2024, 12(10), 2250; https://doi.org/10.3390/biomedicines12102250 - 3 Oct 2024

Abstract

Background: T-cell-based adoptive cell therapies have emerged at the forefront of cancer immunotherapies; however, failed long-term survival and inevitable exhaustion of transplanted T lymphocytes in vivo limits clinical efficacy. Leukemia blasts possess enhanced glycolysis (Warburg effect), exploiting their microenvironment to deprive nutrients (e.g., [...] Read more.

Background: T-cell-based adoptive cell therapies have emerged at the forefront of cancer immunotherapies; however, failed long-term survival and inevitable exhaustion of transplanted T lymphocytes in vivo limits clinical efficacy. Leukemia blasts possess enhanced glycolysis (Warburg effect), exploiting their microenvironment to deprive nutrients (e.g., glucose) from T cells, leading to T-cell dysfunction and leukemia progression. Methods: Thus, we explored whether genetic reprogramming of T-cell metabolism could improve their survival and empower T cells with a competitive glucose-uptake advantage against blasts and inhibit their uncontrolled proliferation. Results: Here, we discovered that high-glucose concentration reduced the T-cell expression of glucose transporter GLUT1 (SLC2A1) and TFAM (mitochondrion transcription factor A), an essential transcriptional regulator of mitochondrial biogenesis, leading to their impaired expansion ex vivo. To overcome the glucose-induced genetic deficiency in metabolism, we engineered T cells with lentiviral overexpression of SLC2A1 and/or TFAM transgene. Multi-omics analyses revealed that metabolic reprogramming promoted T-cell proliferation by increasing IL-2 release and reducing exhaustion. Moreover, the engineered T cells competitively deprived glucose from allogenic blasts and lessened leukemia burden in vitro. Conclusions: Our findings propose a novel T-cell immunotherapy that utilizes a dual strategy of starving blasts and cytotoxicity for preventing uncontrolled leukemia proliferation. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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14 pages, 2083 KiB

Open AccessReview

Sex-Specific Insights into Etiology, Diagnosis, Treatment, and Prognosis in Significant Tricuspid Regurgitation: A Narrative Review

by Mariana Sousa Paiva, Rita Reis Santos, Sara Guerreiro and Regina Ribeiras

Biomedicines 2024, 12(10), 2249; https://doi.org/10.3390/biomedicines12102249 - 3 Oct 2024

Abstract

In recent decades, a burgeoning interest in tricuspid regurgitation (TR) has been prompted by a heightened awareness of its prevalence and the advent of dedicated percutaneous treatment approaches. Despite considerable understanding of its intricate anatomy and response to varying pressure and loading conditions, [...] Read more.

In recent decades, a burgeoning interest in tricuspid regurgitation (TR) has been prompted by a heightened awareness of its prevalence and the advent of dedicated percutaneous treatment approaches. Despite considerable understanding of its intricate anatomy and response to varying pressure and loading conditions, the impact of biological sex remains a subject of investigation. While TR typically afflicts more women, significant differences in TR etiology and post-treatment outcomes have not been conclusively established. This narrative review seeks to consolidate the latest evidence concerning sex-related nuances in anatomy, pathophysiology, diagnosis, treatment, and prognosis of significant tricuspid regurgitation. Through synthesizing this information, we aim to provide a comprehensive understanding of how sex may influence the management and prognosis of this condition. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapy for Heart Valve Diseases)

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