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Biomedicines, Volume 10, Issue 11 (November 2022) – 329 articles

Cover Story (view full-size image): Specialized pro-resolving molecules (SPMs) are endogenous mediators destined to resolve inflammation. Each sub-class, resolvins, maresins, lipoxins, and protectins, has a complex temporal and functional interdependence with the rest, which brings about the resolution of inflammation through various pathways. These include the following: (1) increasing the effectiveness of efferocytosis, a process of clearing apoptotic cells; (2) reducing the levels of pro-inflammatory molecules such as MCP-1, VCAM-1, and leukotriene B4, which recruit inflammatory cells to the plaque site, increasing its size and instability. By restricting inflammation, SPMs reduce plaque size and increase its stability, leading to the prevention of life-threatening events in cardiovascular disease. View this paper
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21 pages, 4002 KiB  
Article
Fecal Bacterial Community and Metagenome Function in Asians with Type 2 Diabetes, According to Enterotypes
by Xuangao Wu and Sunmin Park
Biomedicines 2022, 10(11), 2998; https://doi.org/10.3390/biomedicines10112998 - 21 Nov 2022
Cited by 6 | Viewed by 2233
Abstract
The role of gut microbes has been suggested in type 2 diabetes (T2DM) risk. However, their results remain controversial. We hypothesized that Asians with T2DM had different fecal bacterial compositions, co-abundance networks, and metagenome functions compared to healthy individuals, according to enterotypes. This [...] Read more.
The role of gut microbes has been suggested in type 2 diabetes (T2DM) risk. However, their results remain controversial. We hypothesized that Asians with T2DM had different fecal bacterial compositions, co-abundance networks, and metagenome functions compared to healthy individuals, according to enterotypes. This hypothesis was examined using the combined gut microbiota data from human fecal samples from previous studies. The human fecal bacterial FASTA/Q files from 36 different T2DM studies in Asians were combined (healthy, n = 3378; T2DM, n = 551), and operational taxonomic units (OTUs) and their counts were obtained using qiime2 tools. In the machine learning approaches, fecal bacteria rich in T2DM were found. They were separated into two enterotypes, Lachnospiraceae (ET-L) and Prevotellaceae (ET-P). The Shannon and Chao1 indices, representing α-diversity, were significantly lower in the T2DM group compared to the healthy group in ET-L (p < 0.05) but not in ET-P. In the Shapley additive explanations analysis of ET-L, Escherichia fergusonii, Collinsella aerofaciens, Streptococcus vestibularis, and Bifidobacterium longum were higher (p < 0.001), while Phocaeicola vulgatus, Bacteroides uniformis, and Faecalibacterium prausnitzii were lower in the T2DM group than in the healthy group (p < 0.00005). In ET-P, Escherichia fergusonii, Megasphaera elsdenii, and Oscillibacter valericigenes were higher, and Bacteroides koreensis and Faecalibacterium prausnitzii were lower in the T2DM group than in the healthy group. In ET-L and ET-P, bacteria in the healthy and T2DM groups positively interacted with each other within each group (p < 0.0001) but negatively interacted between the T2DM and healthy groups in the network analysis (p < 0.0001). In the metagenome functions of the fecal bacteria, the gluconeogenesis, glycolysis, and amino acid metabolism pathways were higher, whereas insulin signaling and adenosine 5′ monophosphate-activated protein kinase (AMPK) signaling pathways were lower in the T2DM group than in the healthy group for both enterotypes (p < 0.00005). In conclusion, Asians with T2DM exhibited gut dysbiosis, potentially linked to intestinal permeability and the enteric vagus nervous system. Full article
(This article belongs to the Special Issue Pathological Mechanisms in Diabetes)
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25 pages, 4844 KiB  
Review
Three-Dimensional Constructive Interference in Steady State (3D CISS) Imaging and Clinical Applications in Brain Pathology
by Marco Cavallaro, Alessandra Coglitore, Agostino Tessitore, Karol Galletta, Luciano Frosina, Antonino Cuffari, Roberta Ingrassia, Sarah Caroline Scarcella, Michele Caponnetto, Mirta Longo, Francesca Granata, Sergio Lucio Vinci and Enricomaria Mormina
Biomedicines 2022, 10(11), 2997; https://doi.org/10.3390/biomedicines10112997 - 21 Nov 2022
Cited by 5 | Viewed by 4205
Abstract
Three-dimensional constructive interference in steady state (3D CISS) is a steady-state gradient-echo sequence in magnetic resonance imaging (MRI) that has been used in an increasing number of applications in the study of brain disease in recent years. Owing to the very high spatial [...] Read more.
Three-dimensional constructive interference in steady state (3D CISS) is a steady-state gradient-echo sequence in magnetic resonance imaging (MRI) that has been used in an increasing number of applications in the study of brain disease in recent years. Owing to the very high spatial resolution, the strong hyperintensity of the cerebrospinal fluid signal and the high contrast-to-noise ratio, 3D CISS can be employed in a wide range of scenarios, ranging from the traditional study of cranial nerves, the ventricular system, the subarachnoid cisterns and related pathology to more recently discussed applications, such as the fundamental role it can assume in the setting of acute ischemic stroke, vascular malformations, infections and several brain tumors. In this review, after briefly summarizing its fundamental physical principles, we examine in detail the various applications of 3D CISS in brain imaging, providing numerous representative cases, so as to help radiologists improve its use in imaging protocols in daily clinical practice. Full article
(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy 2.0)
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16 pages, 1923 KiB  
Article
PET/CT with 18F-choline or 18F-FDG in Hepatocellular Carcinoma Submitted to 90Y-TARE: A Real-World Study
by Luca Filippi, Oreste Bagni, Ermanno Notarianni, Adelchi Saltarelli, Cesare Ambrogi and Orazio Schillaci
Biomedicines 2022, 10(11), 2996; https://doi.org/10.3390/biomedicines10112996 - 21 Nov 2022
Cited by 4 | Viewed by 1752
Abstract
Our aim was to assess the role of positron emission computed tomography (PET/CT) with 18F-choline (18F-FCH) or 18F-fluorodeoxyglucose (18F-FDG) in hepatocellular carcinoma (HCC) submitted to 90Y-radioembolization (90Y-TARE). We retrospectively analyzed clinical records of 21 [...] Read more.
Our aim was to assess the role of positron emission computed tomography (PET/CT) with 18F-choline (18F-FCH) or 18F-fluorodeoxyglucose (18F-FDG) in hepatocellular carcinoma (HCC) submitted to 90Y-radioembolization (90Y-TARE). We retrospectively analyzed clinical records of 21 HCC patients submitted to PET/CT with 18F-fluorocholine (18F-FCH) or 18F-fluodeoxyglucose (18F-FDG) before and 8 weeks after 90Y-TARE. On pre-treatment PET/CT, 13 subjects (61.9%) were 18F-FCH-positive, while 8 (38.1%) resulted 18F-FCH-negative and 18F-FDG-positive. At 8-weeks post 90Y-TARE PET/CT, 13 subjects showed partial metabolic response and 8 resulted non-responders, with a higher response rate among 18F-FCH-positive with respect to 18F-FDG-positive patients (i.e., 76.9% vs. 37.5%, p = 0.46). Post-treatment PET/CT influenced patients’ clinical management in 10 cases (47.6%); in 8 subjects it provided indication for a second 90Y-TARE targeting metabolically active HCC remnant, while in 2 patients it led to a PET-guided radiotherapy on metastatic nodes. By Kaplan–Meier analysis, patients’ age (≤69 y) and post 90Y-TARE PET/CT’s impact on clinical management significantly correlated with overall survival (OS). In Cox multivariate analysis, PET/CT’s impact on clinical management remained the only predictor of patients’ OS (p < 0.001). In our real-world study, PET/CT with 18F-FCH or 18F-FDG influenced clinical management and affected the final outcome for HCC patients treated with 90Y-TARE. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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15 pages, 4401 KiB  
Article
In Silico Identification of Genes Associated with Breast Cancer Progression and Prognosis and Novel Therapeutic Targets
by Shiro Uchida and Takashi Sugino
Biomedicines 2022, 10(11), 2995; https://doi.org/10.3390/biomedicines10112995 - 21 Nov 2022
Cited by 2 | Viewed by 2105
Abstract
Molecular mechanisms underlying breast cancer (BC) progression are complex and remain unclear. In this study, we used bioinformatic tools to identify genes associated with tumor progression mechanisms and novel therapeutic targets in BC. We identified genes with stepwise upregulated expression overlapping between the [...] Read more.
Molecular mechanisms underlying breast cancer (BC) progression are complex and remain unclear. In this study, we used bioinformatic tools to identify genes associated with tumor progression mechanisms and novel therapeutic targets in BC. We identified genes with stepwise upregulated expression overlapping between the T and N stages during BC progression using LinkedOmics. We compared the expression level of each gene in BC tissues with that in normal breast tissues and evaluated differences in expression in their intrinsic subtypes and their prognostic value using UALCAN and GEPIA2. We also investigated the dependency of BC cell lines on these genes and whether they are potential therapeutic targets using DepMap. SPDEF, TRIM3, ABCB9, HSPB1, RHBG, SPINT1, EPN3, LRFN2, and PRPH were found to be involved in BC progression. High expression of ABCB9 and SPINT1 was associated with a poor prognosis. SPDEF, TRIM3, ABCB9, RHBG, SPINT1, and PRPH were found to be essential for survival in some BC cell lines (gene effect score < −0.5). PRPH was newly discovered to be involved in the progression of BC and the growth and survival of BC cell lines. Hence, SPDEF, TRIM3, ABCB9, RHBG, SPINT1, and PRPH may serve as novel potential therapeutic targets in BC. Full article
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13 pages, 1884 KiB  
Article
Enhanced Efficacy of Radiopharmaceuticals When Using Technetium-99m-Labeled Liposomal Agents: Synthesis and Pharmacokinetic Properties
by Anfal M. Alkandari, Yasser M. Alsayed and Atallah M. El-Hanbaly
Biomedicines 2022, 10(11), 2994; https://doi.org/10.3390/biomedicines10112994 - 21 Nov 2022
Viewed by 1334
Abstract
Challenges posed by the retention of radiopharmaceuticals in unintended organs affect the quality of patient procedures when undergoing diagnostics and therapeutics. The aim of this study was to formulate a suitable tracer encapsulated in liposomes using different techniques and compounds to enhance the [...] Read more.
Challenges posed by the retention of radiopharmaceuticals in unintended organs affect the quality of patient procedures when undergoing diagnostics and therapeutics. The aim of this study was to formulate a suitable tracer encapsulated in liposomes using different techniques and compounds to enhance the stability, uptake, clearance, and cytotoxic effect of the radiopharmaceutical. Cationic liposomes were prepared by a thin-film method using dipalmitoyl phosphatidylcholine (DPPC) and cholesterol. Whole-body gamma camera images were acquired of intravenously injected New Zealand rabbits. Additionally, liposomes were assessed using stability, toxicity, zeta potential, and particle size tests. In the control cases, Technetium-99m (99mTc)-sestamibi exhibited the lowest heart uptake the blood pool and delayed images compared to both 99mTc-liposomal agents. Liver and spleen uptake in the control samples with 99mTc-sestamibi increased in 1-h-delayed images, unlike with 99mTc-liposomal agents, which were decreased in delayed images. The mean maximum count in the bladder for 99mTc-sestamibi loaded liposomes 1 h post-injection was 2354.6 (±2.6%) compared to 178.4 (±0.54%) for 99mTc-sestamibi without liposomes. Liposomal encapsulation reduced the cytotoxic effect of the sestamibi. 99mTc-MIBI-cationic liposomes exhibited excellent early uptake and clearance compared to 99mTc-MIBI without liposomes. Adding cholesterol during liposome formation enhanced the stability and specificity of the targeted organs. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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18 pages, 3608 KiB  
Article
Effect of Renal Ischemia Reperfusion on Brain Neuroinflammation
by Bina Lee, Ingabire Ines, Jihyun Je, Eun Jung Park, Hyemin Seong, Min Gi Jo, Hwajin Kim, Seon-Hee Kim, Seong Jae Kim, Hye Jung Kim, Minkyeong Kim, Sang Won Park and Seung Pil Yun
Biomedicines 2022, 10(11), 2993; https://doi.org/10.3390/biomedicines10112993 - 21 Nov 2022
Cited by 2 | Viewed by 1684
Abstract
Acute kidney injury (AKI) is an inflammatory sequence. It can lead to distant organ injury, including damage to the central nervous system (CNS), mediated by increased circulating cytokines and other inflammatory mediators. It can also lead to increased blood–brain barrier (BBB) permeability. However, [...] Read more.
Acute kidney injury (AKI) is an inflammatory sequence. It can lead to distant organ injury, including damage to the central nervous system (CNS), mediated by increased circulating cytokines and other inflammatory mediators. It can also lead to increased blood–brain barrier (BBB) permeability. However, the effect of AKI on the inflammatory response of the brain has not yet been investigated. Therefore, we observed the effect of AKI on BBB permeability, microglia and astrocyte activation, and neuronal toxicity in the brain. The striatum and ventral midbrain, known to control overall movement, secrete the neurotransmitter dopamine. The activation of microglia and astrocytes present in this area causes neuro-degenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The activation of astrocytes and microglia in the hippocampus and cerebral cortex, which are responsible for important functions, including memory, learning, concentration, and language, can trigger nerve cell apoptosis. The activation of astrocytes and microglia at this site is also involved in the inflammatory response associated with the accumulation of beta-amyloid. In the situation of kidney ischemia reperfusion (IR)-induced AKI, activation of microglia and astrocytes were observed in the striatum, ventral midbrain, hippocampus, and cortex. However, neuronal cell death was not observed until 48 h. Full article
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16 pages, 2508 KiB  
Article
Dienogest May Reduce Estradiol- and Inflammatory Cytokine-Induced Cell Viability and Proliferation and Inhibit the Pathogenesis of Endometriosis: A Cell Culture- and Mouse Model-Based Study
by Hyun Jin Kim, Sung Hoon Kim, Young Sang Oh, Sa Ra Lee and Hee Dong Chae
Biomedicines 2022, 10(11), 2992; https://doi.org/10.3390/biomedicines10112992 - 21 Nov 2022
Cited by 5 | Viewed by 1874
Abstract
Dienogest (DNG) is a therapeutic medication used in endometriosis treatment. Limited data are available regarding its mechanism of action on endometrial cells. Using in vivo and in vitro models, we investigated whether DNG treatment causes significant biological changes in human endometrial stromal cells [...] Read more.
Dienogest (DNG) is a therapeutic medication used in endometriosis treatment. Limited data are available regarding its mechanism of action on endometrial cells. Using in vivo and in vitro models, we investigated whether DNG treatment causes significant biological changes in human endometrial stromal cells (ESCs). The markers related to the pathogenesis of endometriosis in ESCs were evaluated using estradiol, tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and IL-32, administered alone or in combination with DNG. Implanted endometrial tissues were compared between C57BL/6 mice that did or did not receive DNG treatment by using size measurements and immunohistochemistry. A significant decrease in cell viability, protein kinase B (AKT) phosphorylation, and the expression of p21-activated kinase 4 and vascular endothelial growth factor were observed in ESCs treated with estradiol plus DNG. Cell viability, AKT phosphorylation, and proliferating cell nuclear antigen (PCNA) expression also decreased significantly after TNF-α plus DNG treatment. Treatment with IL-1β or IL-32 plus DNG significantly decreased cell viability or PCNA expression, respectively. The size of the implanted endometrial tissue significantly decreased in mice treated with DNG, accompanied by decreased PCNA expression. Thus, DNG may reduce cell viability and proliferation induced by estradiol, TNF-α, IL-1β, and IL-32, and inhibit the endometriosis pathogenesis by decreasing PCNA expression. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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16 pages, 3769 KiB  
Article
An Adapted Deep Convolutional Neural Network for Automatic Measurement of Pancreatic Fat and Pancreatic Volume in Clinical Multi-Protocol Magnetic Resonance Images: A Retrospective Study with Multi-Ethnic External Validation
by John Zhiyong Yang, Jichao Zhao, Reza Nemati, Xavier Yin, Kevin Haokun He, Lindsay Plank, Rinki Murphy and Jun Lu
Biomedicines 2022, 10(11), 2991; https://doi.org/10.3390/biomedicines10112991 - 21 Nov 2022
Cited by 1 | Viewed by 1426
Abstract
Pancreatic volume and fat fraction are critical prognoses for metabolic diseases like type 2 diabetes (T2D). Magnetic Resonance Imaging (MRI) is a required non-invasive quantification method for the pancreatic fat fraction. The dramatic development of deep learning has enabled the automatic measurement of [...] Read more.
Pancreatic volume and fat fraction are critical prognoses for metabolic diseases like type 2 diabetes (T2D). Magnetic Resonance Imaging (MRI) is a required non-invasive quantification method for the pancreatic fat fraction. The dramatic development of deep learning has enabled the automatic measurement of MR images. Therefore, based on MRI, we intend to develop a deep convolutional neural network (DCNN) that can accurately segment and measure pancreatic volume and fat fraction. This retrospective study involved abdominal MR images from 148 diabetic patients and 246 healthy normoglycemic participants. We randomly separated them into training and testing sets according to the proportion of 80:20. There were 2364 recognizable pancreas images labeled and pre-treated by an upgraded superpixel algorithm for a discernible pancreatic boundary. We then applied them to the novel DCNN model, mimicking the most accurate and latest manual pancreatic segmentation process. Fat phantom and erosion algorithms were employed to increase the accuracy. The results were evaluated by dice similarity coefficient (DSC). External validation datasets included 240 MR images from 10 additional patients. We assessed the pancreas and pancreatic fat volume using the DCNN and compared them with those of specialists. This DCNN employed the cutting-edge idea of manual pancreas segmentation and achieved the highest DSC (91.2%) compared with any reported models. It is the first framework to measure intra-pancreatic fat volume and fat deposition. Performance validation reflected by regression R2 value between manual operation and trained DCNN segmentation on the pancreas and pancreatic fat volume were 0.9764 and 0.9675, respectively. The performance of the novel DCNN enables accurate pancreas segmentation, pancreatic fat volume, fraction measurement, and calculation. It achieves the same segmentation level of experts. With further training, it may well surpass any expert and provide accurate measurements, which may have significant clinical relevance. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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14 pages, 1555 KiB  
Article
Anti-Inflammatory Activity of Olive Oil Polyphenols—The Role of Oleacein and Its Metabolites
by Vânia Costa, Marlene Costa, Romeu António Videira, Paula Branquinho Andrade and Fátima Paiva-Martins
Biomedicines 2022, 10(11), 2990; https://doi.org/10.3390/biomedicines10112990 - 21 Nov 2022
Cited by 8 | Viewed by 1942
Abstract
The anti-inflammatory potential of oleacein, the main polyphenolic compound found in olive oil, and its main metabolites were characterized by their effects on RAW 264.7 macrophages challenged with lipopolysaccharide (LPS), and by their ability to inhibit enzymes of the arachidonic acid metabolism with [...] Read more.
The anti-inflammatory potential of oleacein, the main polyphenolic compound found in olive oil, and its main metabolites were characterized by their effects on RAW 264.7 macrophages challenged with lipopolysaccharide (LPS), and by their ability to inhibit enzymes of the arachidonic acid metabolism with a key role in the synthesis of pro-inflammatory lipid mediators. Oleacein at 12.5 µM significantly decreased the amount of L-citrulline and NO generated by LPS-stimulated macrophages. Hydroxytyrosol, hydroxytyrosol acetate and hydroxytyrosol acetate sulfate were also able to reduce the cellular amount of NO, although to a lesser extent. In contrast, hydroxytyrosol glucuronide and sulfate did not show detectable effects. Oleacein was also able to inhibit the coupled PLA2 + 5-LOX enzyme system (IC50 = 16.11 µM), as well as the 5-LOX enzyme (IC50 = 45.02 µM). Although with lower activity, both hydroxytyrosol and hydroxytyrosol acetate were also capable of inhibiting these enzymes at a concentration of 100 µM. None of the other tested metabolites showed a capacity to inhibit these enzymes. In contrast, all compounds, including glucuronides and sulfate metabolites, showed a remarkable capacity to inhibit both cyclooxygenase isoforms, COX-1 and COX-2, with IC50 values lower than 3 µM. Therefore, oleacein and its metabolites have the ability to modulate NO- and arachidonic acid-dependent inflammatory cascades, contributing to the anti-inflammatory activity associated with olive oil polyphenols. Full article
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13 pages, 1014 KiB  
Article
Adjuvant Chemoradiotherapy Associated with Improved Overall Survival in Resected Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy in Intensity-Modulated Radiotherapy Era
by Wing-Keen Yap, Ming-Chieh Shih, Yu-Chen Chang, Chia-Hsin Lin, Shih-Ming Huang, Tsung-You Tsai, Ching-Fu Chang, Chih-Chung Hsu, Chen-Kan Tseng, Miao-Fen Chen, Din-Li Tsan, Chi-Ting Liau, Ming-Mo Hou, Yin-Kai Chao, Chien-Hung Chiu and Tsung-Min Hung
Biomedicines 2022, 10(11), 2989; https://doi.org/10.3390/biomedicines10112989 - 21 Nov 2022
Cited by 1 | Viewed by 1566
Abstract
Background: The prognosis of patients with resected esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy is particularly poor in those who were staged as ypT3/T4 and/or ypN+. This study investigated whether adjuvant chemoradiotherapy was associated with improved clinical outcomes in these patients. Methods: we [...] Read more.
Background: The prognosis of patients with resected esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy is particularly poor in those who were staged as ypT3/T4 and/or ypN+. This study investigated whether adjuvant chemoradiotherapy was associated with improved clinical outcomes in these patients. Methods: we identified patients with esophageal squamous cell carcinoma who were staged as ypT3/T4 and/or ypN+ after being treated with neoadjuvant chemoradiotherapy followed by esophagectomy between the years 2013 and 2019. Patients were divided into two groups based on whether they received adjuvant chemoradiotherapy. The Kaplan-Meier method and Cox regression modeling were performed for survival analyses and multivariable analysis, respectively. Results: 76 eligible patients were included in the analyses. The median follow-up for the study cohort was 43.4 months. On Kaplan-Meier analyses of the overall population, adjuvant chemoradiotherapy was associated with significantly improved median overall survival (31.7 months vs. 16.3 months, p = 0.036). On Kaplan-Meier analyses of the 35 matched pairs generated by propensity score matching, adjuvant chemoradiotherapy was associated with significantly longer median overall survival (31.7 months vs. 14.3 months; p = 0.004) and median recurrence-free survival (18.9 months vs. 11.7 months; p = 0.020). In multivariable analysis, adjuvant chemoradiotherapy was independently associated with a 60% reduction in mortality (p = 0.003) and a 48% reduction in risk of recurrence (p = 0.035) after adjusting for putative confounders. In addition, microscopic positive resection margin and Mandard tumor regression grade 3–4 were independently associated with increased mortality and risk of recurrence. While a greater number of lymph nodes dissected was independently associated with significantly improved overall survival, the number of positive lymph nodes was independently associated with significantly worse overall survival and a trend (p = 0.058) towards worse recurrence-free survival. Conclusions: This study demonstrated that adjuvant CRT was independently associated with a significantly improved survival and lower risk of recurrence than observation in esophageal squamous cell carcinoma patients staged as ypT3 and/or ypN+ after receiving neoadjuvant chemoradiotherapy and radical surgery. The results of this study have implications for the design of future clinical trials and may improve treatment outcomes of patients in this setting who cannot afford or are without access to adjuvant nivolumab. Full article
(This article belongs to the Special Issue Esophageal Cancer — Pathogenesis and Therapeutic Strategies)
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30 pages, 2420 KiB  
Review
Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment
by Ethan J. Kilmister, Sabrina P. Koh, Freya R. Weth, Clint Gray and Swee T. Tan
Biomedicines 2022, 10(11), 2988; https://doi.org/10.3390/biomedicines10112988 - 21 Nov 2022
Cited by 6 | Viewed by 2639
Abstract
Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)—a small population of highly tumorigenic cancer cells with [...] Read more.
Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)—a small population of highly tumorigenic cancer cells with pluripotency and self-renewal properties, at the apex of a cellular hierarchy. CSCs drive metastasis and treatment resistance and are sustained by a dynamic tumor microenvironment (TME). Numerous pathways mediate communication between CSCs and/or the surrounding TME. These include a paracrine renin-angiotensin system and its convergent signaling pathways, the immune system, and other signaling pathways including the Notch, Wnt/β-catenin, and Sonic Hedgehog pathways. Appreciation of the mechanisms underlying metastasis and treatment resistance, and the pathways that regulate CSCs and the TME, is essential for developing a durable treatment for cancer. Pre-clinical and clinical studies exploring single-point modulation of the pathways regulating CSCs and the surrounding TME, have yielded partial and sometimes negative results. This may be explained by the presence of uninhibited alternative signaling pathways. An effective treatment of cancer may require a multi-target strategy with multi-step inhibition of signaling pathways that regulate CSCs and the TME, in lieu of the long-standing pursuit of a ‘silver-bullet’ single-target approach. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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20 pages, 1563 KiB  
Article
Acetylcholine Reduces L-Type Calcium Current without Major Changes in Repolarization of Canine and Human Purkinje and Ventricular Tissue
by Arie O. Verkerk, Illés J. Doszpod, Isabella Mengarelli, Tibor Magyar, Alexandra Polyák, Bence Pászti, Igor R. Efimov, Ronald Wilders and István Koncz
Biomedicines 2022, 10(11), 2987; https://doi.org/10.3390/biomedicines10112987 - 21 Nov 2022
Cited by 3 | Viewed by 1903
Abstract
Vagal nerve stimulation (VNS) holds a strong basis as a potentially effective treatment modality for chronic heart failure, which explains why a multicenter VNS study in heart failure with reduced ejection fraction is ongoing. However, more detailed information is required on the effect [...] Read more.
Vagal nerve stimulation (VNS) holds a strong basis as a potentially effective treatment modality for chronic heart failure, which explains why a multicenter VNS study in heart failure with reduced ejection fraction is ongoing. However, more detailed information is required on the effect of acetylcholine (ACh) on repolarization in Purkinje and ventricular cardiac preparations to identify the advantages, risks, and underlying cellular mechanisms of VNS. Here, we studied the effect of ACh on the action potential (AP) of canine Purkinje fibers (PFs) and several human ventricular preparations. In addition, we characterized the effects of ACh on the L-type Ca2+ current (ICaL) and AP of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and performed computer simulations to explain the observed effects. Using microelectrode recordings, we found a small but significant AP prolongation in canine PFs. In the human myocardium, ACh slightly prolonged the AP in the midmyocardium but resulted in minor AP shortening in subepicardial tissue. Perforated patch-clamp experiments on hiPSC-CMs demonstrated that 5 µM ACh caused an ≈15% decrease in ICaL density without changes in gating properties. Using dynamic clamp, we found that under blocked K+ currents, 5 µM ACh resulted in an ≈23% decrease in AP duration at 90% of repolarization in hiPSC-CMs. Computer simulations using the O’Hara–Rudy human ventricular cell model revealed that the overall effect of ACh on AP duration is a tight interplay between the ACh-induced reduction in ICaL and ACh-induced changes in K+ currents. In conclusion, ACh results in minor changes in AP repolarization and duration of canine PFs and human ventricular myocardium due to the concomitant inhibition of inward ICaL and outward K+ currents, which limits changes in net repolarizing current and thus prevents major changes in AP repolarization. Full article
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19 pages, 1008 KiB  
Review
The Role of Cannabinoid Type 2 Receptors in Parkinson’s Disease
by Maria Sofia Basile and Emanuela Mazzon
Biomedicines 2022, 10(11), 2986; https://doi.org/10.3390/biomedicines10112986 - 20 Nov 2022
Cited by 1 | Viewed by 1837
Abstract
Parkinson’s disease (PD) is the second most frequent neurodegenerative disease and currently represents a clear unmet medical need. Therefore, novel preventive and therapeutic strategies are needed. Cannabinoid type 2 (CB2) receptors, one of the components of the endocannabinoid system, can regulate neuroinflammation in [...] Read more.
Parkinson’s disease (PD) is the second most frequent neurodegenerative disease and currently represents a clear unmet medical need. Therefore, novel preventive and therapeutic strategies are needed. Cannabinoid type 2 (CB2) receptors, one of the components of the endocannabinoid system, can regulate neuroinflammation in PD. Here, we review the current preclinical and clinical studies investigating the CB2 receptors in PD with the aim to clarify if these receptors could have a role in PD. Preclinical data show that CB2 receptors could have a neuroprotective action in PD and that the therapeutic targeting of CB2 receptors could be promising. Indeed, it has been shown that different CB2 receptor-selective agonists exert protective effects in different PD models. Moreover, the alterations in the expression of CB2 receptors observed in brain tissues from PD animal models and PD patients suggest the potential value of CB2 receptors as possible novel biomarkers for PD. However, to date, there is no direct evidence of the role of CB2 receptors in PD. Further studies are strongly needed in order to fully clarify the role of CB2 receptors in PD and thus pave the way to novel possible diagnostic and therapeutic opportunities for PD. Full article
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14 pages, 2568 KiB  
Article
Epithelial Cell Adhesion Molecule (EpCAM) Expression Can Be Modulated via NFκB
by Saadiya Zia, Komal Tehreem, Sidra Batool, Mehreen Ishfaq, Shaher Bano Mirza, Shahrukh Khan, Majed N. Almashjary, Mohannad S. Hazzazi, Husam Qanash, Ahmad Shaikh, Roua S. Baty, Ibrahim Jafri, Nouf H. Alsubhi, Ghadeer I. Alrefaei, Rokayya Sami and Ramla Shahid
Biomedicines 2022, 10(11), 2985; https://doi.org/10.3390/biomedicines10112985 - 20 Nov 2022
Cited by 3 | Viewed by 2342
Abstract
The epithelial cell adhesion molecule (EpCAM) is considered an essential proliferation signature in cancer. In the current research study, qPCR induced expression of EpCAM was noted in acute lymphoblastic leukemia (ALL) cases. Costunolide, a sesquiterpene lactone found in crepe ginger and lettuce, is [...] Read more.
The epithelial cell adhesion molecule (EpCAM) is considered an essential proliferation signature in cancer. In the current research study, qPCR induced expression of EpCAM was noted in acute lymphoblastic leukemia (ALL) cases. Costunolide, a sesquiterpene lactone found in crepe ginger and lettuce, is a medicinal herb with anticancer properties. Expression of EpCAM and its downstream target genes (Myc and TERT) wasdownregulated upon treatment with costunolide in Jurkat cells. A significant change in the telomere length of Jurkat cells was not noted at 72 h of costunolide treatment. An in silico study revealed hydrophobic interactions between EpCAM extracellular domain and Myc bHLH with costunolide. Reduced expression of NFκB, a transcription factor of EpCAM, Myc, and TERT in costunolide-treated Jurkat cells, suggested that costunolide inhibits gene expression by targeting NFκB and its downstream targets. Overall, the study proposes that costunolide could be a promising therapeutic biomolecule for leukemia. Full article
(This article belongs to the Special Issue Women’s Special Issue Series: Biomedicines)
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16 pages, 2094 KiB  
Article
Bacterial Urinary Tract Infection and Early Asymptomatic Bacteriuria in Kidney Transplantation Still Negatively Affect Kidney Transplant Outcomes in the Era of Modern Immunosuppression and Cotrimoxazole Prophylaxis
by Chayanan Santithanmakorn, Jakapat Vanichanan, Natavudh Townamchai, Kamonwan Jutivorakool, Salin Wattanatorn, Methee Sutherasan, Julin Opanuruk, Stephen J. Kerr, Kearkiat Praditpornsilpa, Yingyos Avihingsanon and Suwasin Udomkarnjananun
Biomedicines 2022, 10(11), 2984; https://doi.org/10.3390/biomedicines10112984 - 20 Nov 2022
Cited by 2 | Viewed by 1715
Abstract
Risk factors and consequences of urinary tract infection (UTI) post-kidney transplant have been variously reported by studies that were heterogenous in immunosuppressants and prophylactic protocols. We aimed to clarify the risks and consequences of UTI in kidney transplant recipients with post-transplantation cotrimoxazole prophylaxis [...] Read more.
Risk factors and consequences of urinary tract infection (UTI) post-kidney transplant have been variously reported by studies that were heterogenous in immunosuppressants and prophylactic protocols. We aimed to clarify the risks and consequences of UTI in kidney transplant recipients with post-transplantation cotrimoxazole prophylaxis in the context of modern immunosuppression. This retrospective cohort included kidney transplant recipients receiving tacrolimus, mycophenolate, prednisolone, and cotrimoxazole for bacterial UTI prophylaxis. Recipients were categorized into non-UTI and UTI groups. Asymptomatic bacteriuria (ASB) was screened in the first 3 months and was evaluated for association with UTI. Of 348 kidney transplant recipients, 129 were in the UTI group and 219 in the non-UTI group. UTI risk factors were female sex, body mass index ≥ 25 kg/m2, human leukocyte antigen mismatch, and panel reactive antibody ≥ 50%. Recipients with recurrent UTI had inferior allograft function compared with non-UTI recipients. Patient survival was significantly lower in recipients with UTI in the first post-transplant month. Higher degree of immunosuppressions was associated with recurrent UTI and drug-resistant organisms. In conclusion, UTI continues to negatively affect graft function and survival of kidney transplant recipients. Treating ASB in the first 3 months did not reduce the UTI incidence in the first transplantation year. Full article
(This article belongs to the Special Issue Emerging Issues in Immune Mechanism of Kidney Diseases)
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13 pages, 2490 KiB  
Article
Molecular Mechanisms Linking Empagliflozin to Renal Protection in the LLC-PK1 Model of Diabetic Nephropathy
by Vjera Mihaljević, Milorad Zjalić, Tomislav Kizivat, Tea Omanović Kolarić, Martina Smolić, Edi Rođak, Marina Čović, Lucija Kuna, Robert Smolić, Aleksandar Včev and Ines Bilić Ćurčić
Biomedicines 2022, 10(11), 2983; https://doi.org/10.3390/biomedicines10112983 - 20 Nov 2022
Cited by 5 | Viewed by 1686
Abstract
Aims: Chronic diabetes complications, including diabetic nephropathy (DN), frequently result in end-stage renal failure. This study investigated empagliflozin (SGLT2i) effects on collagen synthesis, oxidative stress, cell survival, and protein expression in an LLC-PK1 model of DN. Methods: Combinations of high glucose (HG) and [...] Read more.
Aims: Chronic diabetes complications, including diabetic nephropathy (DN), frequently result in end-stage renal failure. This study investigated empagliflozin (SGLT2i) effects on collagen synthesis, oxidative stress, cell survival, and protein expression in an LLC-PK1 model of DN. Methods: Combinations of high glucose (HG) and increasing empagliflozin concentrations (100 nM and 500 nM), as well as combinations of HG, H2O2, and empagliflozin, were used for cell culture treatment. The cell viability, glutathione (tGSH), ECM expression, and TGF-β1 concentration were measured. In addition, the protein expression of Akt, pAkt, GSK3, pGSK3, pSTAT3, and SMAD7 was determined. Results: The addition of both concentrations of empagliflozin to cells previously exposed to glucose and oxidative stress generally improved cell viability and increased GSH levels (p < 0.001, p < 0.05). In HG30/H2O2/Empa500-treated cells, significant increase in pSTAT3, pGSK3β, GSK3β, SMAD7, and pAKT levels (p < 0.001, p < 0.001, p < 0.05) was observed except for AKT. Lower drug concentrations did not affect the protein expression levels. Furthermore, empagliflozin treatment (100 nM and 500 nM) of HG30/H2O2-injured cells led to a decrease in TGF-β1 levels (p < 0.001). In cells exposed to oxidative stress and hyperglycemia, collagen production remained unchanged. Conclusion: Renoprotective effects of empagliflozin, in this LLC-PK1 cell model of DN, are mediated via activation of the Akt/GSK-3 signalling pathway, thus reducing oxidative stress-induced damage, as well as enhanced SMAD7 expression leading to downregulation of TGF-β1, one of the key mediators of inflammation and fibrosis. Full article
(This article belongs to the Section Cell Biology and Pathology)
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21 pages, 6555 KiB  
Article
Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia
by Xiaoyue Zhu, Joseph M. Schrader, Brandon A. Irizarry, Steven O. Smith and William E. Van Nostrand
Biomedicines 2022, 10(11), 2982; https://doi.org/10.3390/biomedicines10112982 - 19 Nov 2022
Cited by 2 | Viewed by 2018
Abstract
Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer’s disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number [...] Read more.
Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer’s disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number of cellular responses, including activation of astrocytes and microglia. In addition, fibril structures of the Aβ40 and Aβ42 peptides are known to be polymorphic, which poses a challenge for attributing the contribution of different Aβ sequences and structures to brain pathology. Here, we systematically treated primary astrocytes and microglia with single, well-characterized polymorphs of Aβ40 or Aβ42 fibrils, and performed bulk RNA sequencing to assess cell-specific changes in gene expression. A greater number of genes were up-regulated by Aβ42 fibril-treated glial cells (251 and 2133 genes in astrocyte and microglia, respectively) compared with the Aβ40 fibril-treated glial cells (191 and 251 genes in astrocytes and microglia, respectively). Immunolabeling studies in an AD rat model with parenchymal fibrillar Aβ42 plaques confirmed the expression of PAI-1, MMP9, MMP12, CCL2, and C1r in plaque-associated microglia, and iNOS, GBP2, and C3D in plaque-associated astrocytes, validating markers from the RNA sequence data. In order to better understand these Aβ fibril-induced gene changes, we analyzed gene expression patterns using the Ingenuity pathway analysis program. These analyses further highlighted that Aβ42 fibril treatment up-regulated cellular activation pathways and immune response pathways in glial cells, including IL1β and TNFα in astrocytes, and microglial activation and TGFβ1 in microglia. Further analysis revealed that a number of disease-associated microglial (DAM) genes were surprisingly suppressed in Aβ40 fibril treated microglia. Together, the present findings indicate that Aβ42 fibrils generally show similar, but stronger, stimulating activity of glial cells compared with Aβ40 fibril treatment. Full article
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12 pages, 5784 KiB  
Article
The Binding Specificity of PAB1 with Poly(A) mRNA, Regulated by Its Structural Folding
by Monikaben Padariya and Umesh Kalathiya
Biomedicines 2022, 10(11), 2981; https://doi.org/10.3390/biomedicines10112981 - 19 Nov 2022
Viewed by 1679
Abstract
The poly(A)-binding protein cytoplasmic 1 (PAB1 or PABPC1) protein is associated with the long poly(A) mRNA tails, inducing stability. Herein, we investigated the dynamics of the PABPC1 protein, along with tracing its mRNA binding specificity. During molecular dynamics simulations (MDS), the R176-Y408 amino [...] Read more.
The poly(A)-binding protein cytoplasmic 1 (PAB1 or PABPC1) protein is associated with the long poly(A) mRNA tails, inducing stability. Herein, we investigated the dynamics of the PABPC1 protein, along with tracing its mRNA binding specificity. During molecular dynamics simulations (MDS), the R176-Y408 amino acids (RRM3–4 domains; RNA recognition motifs) initiated a folded structure that resulted in the formation of different conformations. The RRM4 domain formed high-frequency intramolecular interactions, despite such induced flexibility. Residues D45, Y54, Y56, N58, Q88, and N100 formed long-lasting interactions, and specifically, aromatic residues (Y14, Y54, Y56, W86, and Y140) gained a unique binding pattern with the poly(A) mRNA. In addition, the poly(A) mRNA motif assembled a PABPC1-specific conformation, by inducing movement of the center three nucleotides to face towards RRM1–2 domains. The majority of the high-frequency cancer mutations in PAB1 reside within the RRM4 domain and amino acids engaging in high-frequency interactions with poly(A) mRNA were found to be preserved in different cancer types. Except for the G123C variant, other studied cancer-derived mutants hindered the stability of the protein. Molecular details from this study will provide a detailed understanding of the PABPC1 structure, which can be used to modulate the activity of this gene, resulting in production of mutant peptide or neoantigens in cancer. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease 2.0)
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9 pages, 401 KiB  
Article
Risk of Periodontitis in Patients with Gastroesophageal Reflux Disease: A Nationwide Retrospective Cohort Study
by Xin Li, Hitesh Singh Chaouhan, Yao-Ming Wang, I-Kuan Wang, Cheng-Li Lin, Te-Chun Shen, Chi-Yuan Li and Kuo-Ting Sun
Biomedicines 2022, 10(11), 2980; https://doi.org/10.3390/biomedicines10112980 - 19 Nov 2022
Cited by 4 | Viewed by 2990
Abstract
Background: Gastroesophageal reflux disease (GERD) is the most common digestive clinical problem worldwide that affects approximately 20% of the adult populations in Western countries. Poor oral hygiene has been reported to be associated with GERD as an atypical clinical complication. However, evidence showing [...] Read more.
Background: Gastroesophageal reflux disease (GERD) is the most common digestive clinical problem worldwide that affects approximately 20% of the adult populations in Western countries. Poor oral hygiene has been reported to be associated with GERD as an atypical clinical complication. However, evidence showing the relationship between GERD and the risk of periodontitis is less clear. The present study aimed to use a retrospective cohort study design to further clarify the association between GERD and the subsequent risk of periodontitis. Methods: The risk of periodontitis in patients with GERD was investigated by analyzing epidemiological data from the Taiwan National Health Insurance Research Database from 2008 to 2018. We selected 20,125 participants with a minimum age of 40 years in the GERD group and 1:1 propensity-matched these with non-GERD individuals by sex, age, and comorbidities. The incidence of periodontitis was determined at the end of 2018. A Cox proportional hazards regression model was used to evaluate the risk of periodontitis in patients with GERD. Results: The overall incidence rate of the periodontitis risk was 1.38-fold higher (30.0 vs. 21.7/1000 person years, adjusted hazard ratio (aHR) = 1.36, 95% confidence interval (CI) = 1.28–1.45) in patients with GERD than in those without GERD. After stratified analyses for sex, age, and comorbidity, patients with GERD had a higher risk of periodontitis for age (aHR = 1.31, 95% CI = 1.20–1.42 for 40–54 years and aHR = 1.42, 95% CI =1.28–1.57 for 55–69 years), sex (aHR = 1.40, 95% CI = 1.28–1.54 for men and aHR = 1.33, 95% CI = 1.23–1.45 for women), and presence (aHR = 1.36, 95% CI = 1.27–1.45) and absence (aHR = 1.40, 95% CI = 1.21–1.62) of comorbidity than those without GERD. Among the GERD cohort, the risk for periodontitis was increased with an increasing number of emergency room visits (≥ 1 vs. <1, aHR = 5.19, 95% CI = 2.16–12.5). Conclusions: Our results revealed that patients with GERD have a higher risk of periodontitis development than those without GERD. Clinicians should pay more attention to identifying and managing periodontitis in patients with GERD. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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14 pages, 5465 KiB  
Article
Leukotriene B4 Receptor 2 Mediates the Production of G-CSF That Plays a Critical Role in Steroid-Resistant Neutrophilic Airway Inflammation
by Dong-Wook Kwak, Donghwan Park and Jae-Hong Kim
Biomedicines 2022, 10(11), 2979; https://doi.org/10.3390/biomedicines10112979 - 19 Nov 2022
Cited by 1 | Viewed by 1361
Abstract
Granulocyte colony-stimulating factor (G-CSF) has been suggested to be closely associated with neutrophilic asthma pathogenesis. However, little is known about the factors regulating the production of G-CSF in neutrophilic asthma. We previously reported that a leukotriene B4 receptor 2, BLT2, played an [...] Read more.
Granulocyte colony-stimulating factor (G-CSF) has been suggested to be closely associated with neutrophilic asthma pathogenesis. However, little is known about the factors regulating the production of G-CSF in neutrophilic asthma. We previously reported that a leukotriene B4 receptor 2, BLT2, played an important role in neutrophilic airway inflammation. Therefore, in the current study, we investigated whether BLT2 plays a role in the production of G-CSF in lipopolysaccharide/ovalbumin (LPS/OVA)-induced steroid-resistant neutrophilic asthma. The data showed that BLT2 critically mediated G-CSF production, contributing to the progression of neutrophilic airway inflammation. We also observed that 12-lipoxygenase (12-LO), which catalyzes the synthesis of the BLT2 ligand 12(S)-HETE, was also necessary for G-CSF production. Together, these results suggest that the 12-LO-BLT2-linked signaling network is critical for the production of G-CSF, contributing to the development of neutrophilic airway inflammation. Our findings can provide a potential new target for the therapy of severe neutrophilic asthma. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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11 pages, 952 KiB  
Article
H19 and TUG1 lncRNAs as Novel Biomarkers for Irritable Bowel Syndrome in Diabetic Patients
by Marwa M. Esawy, Noorah Saleh Al-Sowayan, Maysa A. Mobasher, Amir Abd-elhameed, Elsayed S. Abd elbaser, Shereen A. Baioumy and Marwa A. Shabana
Biomedicines 2022, 10(11), 2978; https://doi.org/10.3390/biomedicines10112978 - 19 Nov 2022
Cited by 1 | Viewed by 1516
Abstract
Introduction: Irritable bowel syndrome (IBS) is a gastrointestinal disorder due to enteric nervous system impairment that produces different patterns of digestion. IBS is a common finding in diabetic patients. The functions of lncRNAs in IBS are still not clear and need to be [...] Read more.
Introduction: Irritable bowel syndrome (IBS) is a gastrointestinal disorder due to enteric nervous system impairment that produces different patterns of digestion. IBS is a common finding in diabetic patients. The functions of lncRNAs in IBS are still not clear and need to be further investigated. The aim of this study was to assess the diagnostic roles of lncRNA H19 and TUG1 for IBS associated with diabetes and to evaluate their association with clinical and laboratory findings. Subjects and Methods: Samples from 42 diabetic patients, 42 diabetic patients with IBS, and 42 healthy controls were obtained. The LncRNA H19 and TUG1 expressions were measured by quantitative real-time PCR. Results: The patients with IBS had significantly lower levels of lncRNA H19 and TUG1 expression than the healthy controls and diabetic-only patients (p < 0.001). LncRNA H19 and TUG1 can discriminate between diabetic-only patients and those with IBS (areas under the ROC curves of 0.95 and 0.722, respectively). The TUG1 expression levels were significantly different among types of IBS (IBS-D lower than IBS-M and IBS-C lower than IBS-M; p = 0.0165 and p = 0.043, respectively). H19 and TUG1 were downregulated in patients with poor glycemic control. lncRNA H19 and TUG1 expression in diabetic patients with IBS significantly negatively correlated with the IBS severity scoring system. Both lncRNAs’ expression significantly predicted the disease severity. LncRNA H19 expression can be an independent predictor for disease severity (adjusted odds ratio = 0.00001, 95% CI = 0–0.5, p = 0.045). Conclusions: Diabetic patients with IBS had significantly lower levels of lncRNA H19 and TUG1 expression than healthy controls and diabetic-only patients. LncRNA H19 had better diagnostic performance criteria for IBS. LncRNA H19 expression can be an independent predictor for IBS severity. Full article
(This article belongs to the Special Issue Diabetes and Enteric Nervous System)
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12 pages, 291 KiB  
Review
A Review of the Role of Stereotactic Radiosurgery and Immunotherapy in the Management of Primary Central Nervous System Tumors
by Eric J. Lehrer, Brianna M. Jones, Kunal K. Sindhu, Daniel R. Dickstein, Mira Cohen, Stanislav Lazarev, Alfredo Quiñones-Hinojosa, Sheryl Green and Daniel M. Trifiletti
Biomedicines 2022, 10(11), 2977; https://doi.org/10.3390/biomedicines10112977 - 19 Nov 2022
Cited by 3 | Viewed by 1816
Abstract
Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs) are widely used in the management of brain metastases. These therapies are commonly administered concurrently; as SRS may enhance anti-tumor immunity and responsiveness to ICIs. However, the use of ICIs with and without SRS in [...] Read more.
Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs) are widely used in the management of brain metastases. These therapies are commonly administered concurrently; as SRS may enhance anti-tumor immunity and responsiveness to ICIs. However, the use of ICIs with and without SRS in the management of primary brain tumors remains a controversial topic. Meningiomas are the most common nonmalignant and extra-parenchymal brain tumor, which often respond well to surgery and radiotherapy. However, higher grade meningiomas tend to be resistant to these treatments, and the use of chemotherapy and targeted agents in this setting have yielded disappointing results. Thus, there is heightened interest in the utilization of ICIs. Glioblastoma is the most common malignant primary intraparenchymal brain tumor. It is associated with a grim prognosis with a median overall survival of approximately 20 months, despite optimal therapy. While SRS in the adjuvant setting, and ICI in the recurrent setting, have failed to demonstrate a survival benefit, SRS in the preoperative setting has the potential to enhance anti-tumor immunity and responsiveness to ICIs. Thus, these treatments represent an attractive option to add to the armamentarium of meningioma and glioblastoma management. In this review, we provide a detailed overview of the evidence supporting the use of ICIs and SRS in each of these settings. Full article
(This article belongs to the Special Issue The Synergy of Radiotherapy and Immunotherapy)
18 pages, 2509 KiB  
Article
Multiple Head Rotations Result in Persistent Gait Alterations in Piglets
by Mackenzie Mull, Oluwagbemisola Aderibigbe, Marzieh Hajiaghamemar, R. Anna Oeur and Susan S Margulies
Biomedicines 2022, 10(11), 2976; https://doi.org/10.3390/biomedicines10112976 - 19 Nov 2022
Cited by 4 | Viewed by 1672
Abstract
Multiple/repeated mild traumatic brain injury (mTBI) in young children can cause long-term gait impairments and affect the developmental course of motor control. Using our swine model for mTBI in young children, our aim was to (i) establish a reference range (RR) for each [...] Read more.
Multiple/repeated mild traumatic brain injury (mTBI) in young children can cause long-term gait impairments and affect the developmental course of motor control. Using our swine model for mTBI in young children, our aim was to (i) establish a reference range (RR) for each parameter to validate injury and track recovery, and (ii) evaluate changes in gait patterns following a single and multiple (5×) sagittal rapid non-impact head rotation (RNR). Gait patterns were studied in four groups of 4-week-old Yorkshire swine: healthy (n = 18), anesthesia-only sham (n = 8), single RNR injury (n = 12) and multiple RNR injury (n = 11). Results were evaluated pre-injury and at 1, 4, and 7 days post-injury. RR reliability was validated using additional healthy animals (n = 6). Repeated mTBI produced significant increases in gait time, cycle time, and stance time, as well as decreases in gait velocity and cadence, on Day One post-injury compared to pre-injury, and these remained significantly altered at Day Four and Day Seven post-injury. The gait metrics of the repeated TBI group also significantly fell outside the healthy RR on Day One, with some recovery by Day Four, while many remained altered at Day Seven. Only a bilateral decrease in hind stride length was observed at Day Four in our single RNR group compared to pre-injury. In sum, repeated and single sagittal TBI can significantly impair motor performance, and gait metrics can serve as reliable, objective, quantitative functional assessments in a juvenile porcine RNR TBI model. Full article
(This article belongs to the Special Issue Porcine Models of Neurotrauma and Neurological Disorders)
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10 pages, 852 KiB  
Article
The TRACK-MS Test Battery: A Very Brief Tool to Track Multiple Sclerosis-Related Cognitive Impairment
by Daniela Taranu, Hayrettin Tumani, Jill Holbrook, Visal Tumani, Ingo Uttner and Patrick Fissler
Biomedicines 2022, 10(11), 2975; https://doi.org/10.3390/biomedicines10112975 - 18 Nov 2022
Cited by 5 | Viewed by 2190
Abstract
Tracking cognition in patients with multiple sclerosis (MS) is important for detection of disease progression but it is often not performed in routine settings due to time constraints. This exploratory cohort study aims to develop a very brief repeatable tracking tool with comparable [...] Read more.
Tracking cognition in patients with multiple sclerosis (MS) is important for detection of disease progression but it is often not performed in routine settings due to time constraints. This exploratory cohort study aims to develop a very brief repeatable tracking tool with comparable test quality criteria to the current gold standard, the Brief International Cognitive Assessment for MS (BICAMS). The study included 88 participants (22 healthy controls, 66 MS patients) who were examined at baseline and at one-year follow-up. As a validity criterion for the six administered cognitive tests, we assessed the difference between MS patients and HC, and the correlation with MS-related disability. Combining the two tests with the highest validity—the Controlled Oral Word Association Test and Symbol Digit Modalities Test—yielded an administration time of 5 min. Comparing this new TRACK-MS test battery with the 15 min BICAMS indicated that TRACK-MS showed larger differences between MS patients and healthy controls, a higher correlation with MS-related disability, smaller practice effects, and a good test–retest reliability. We provide evidence that TRACK-MS, although faster to administer, showed at least comparable quality criteria as the BICAMS. As the study was exploratory, replication of these results is necessary. Full article
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11 pages, 3471 KiB  
Article
Stroke-Prone SHR as Experimental Models for Cardiovascular Disease Risk Reduction in Humans
by Yukio Yamori, Miki Sagara, Hideki Mori and Mari Mori
Biomedicines 2022, 10(11), 2974; https://doi.org/10.3390/biomedicines10112974 - 18 Nov 2022
Cited by 2 | Viewed by 1470
Abstract
Since stroke-prone spontaneously hypertensive rats (SHRSP) develop hypertension and stroke without exception, the prevention or reduction of risk by various nutrients was tested on blood pressure and the mortality caused by stroke and cardiovascular diseases (CVD). In addition to sodium (Na) accelerating hypertension [...] Read more.
Since stroke-prone spontaneously hypertensive rats (SHRSP) develop hypertension and stroke without exception, the prevention or reduction of risk by various nutrients was tested on blood pressure and the mortality caused by stroke and cardiovascular diseases (CVD). In addition to sodium (Na) accelerating hypertension and stroke and potassium (K) counteracting the adverse effect of Na, taurine (Tau), rich in seafood, and magnesium (Mg) contained in soy, nuts, grains, etc., were proven to reduce stroke and CVD and improved survival. Therefore, the Cardiovascular Diseases and Alimentary Comparison Study was started in 1985 to explore the association of biomarkers of diet in 24 h urine(24U) with CVD risks, and about 100 males and 100 females aged 48–56 in each of 50 populations were studied until 1995. Linear regression analysis indicated that the 24U Tau/creatinine and Mg/creatinine ratios were inversely associated with body mass index, systolic and diastolic blood pressure, and total cholesterol. In comparison with six Euro-Western regions, 24U Tau and Mg collected from six regions, respectively, in Japan and the Mediterranean countries were significantly higher and were significantly associated with lower CVD risks. Diets rich in Tau and Mg were concluded to be contributory to the prevention of CVD in SHRSP and humans. Full article
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19 pages, 1312 KiB  
Review
Hidradenitis Suppurativa: The Influence of Gender, the Importance of Trigger Factors and the Implications for Patient Habits
by Elia Rosi, Maria Thais Fastame, Gianmarco Silvi, Prisca Guerra, Giulia Nunziati, Antonella Di Cesare, Ilaria Scandagli, Federica Ricceri and Francesca Prignano
Biomedicines 2022, 10(11), 2973; https://doi.org/10.3390/biomedicines10112973 - 18 Nov 2022
Cited by 2 | Viewed by 3097
Abstract
Hidradenitis suppurativa (HS) is a debilitating, chronic, inflammatory skin disease primarily affecting apocrine gland-rich areas of the body. On the one hand, the presence of triggering factors—some identified, others only hypothesized—may initiate or perpetuate the pathogenic process of HS. In addition to cigarette [...] Read more.
Hidradenitis suppurativa (HS) is a debilitating, chronic, inflammatory skin disease primarily affecting apocrine gland-rich areas of the body. On the one hand, the presence of triggering factors—some identified, others only hypothesized—may initiate or perpetuate the pathogenic process of HS. In addition to cigarette smoking and diet, other trigger factors, including choice of clothing, are frequently observed in clinical practice. On the other hand, the presence of disease may influence habits of HS patients. Indeed, high incidences of sexual and sleep impairment have been reported in these patients. Consequently, alcohol and substance abuse may be a coping strategy for the emotional and psychological disease burden. Furthermore, a greater awareness of gender differences in HS may be important for dermatologists in their own clinical practice (i.e., pregnancy and breastfeeding). Consequently, in this loop interaction, comprehensive knowledge of all factors involved is crucial for the management of HS patients. Thus, the objective of this review is to (i) discuss the influence of gender on HS, (ii) summarize the most frequent triggering factors of HS and (iii) analyze the impact of HS on patient habits. Full article
(This article belongs to the Special Issue New Advancements in Chronic Inflammatory Skin Disease)
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15 pages, 1538 KiB  
Article
Antipsychotic Abuse, Dependence, and Withdrawal in the Pediatric Population: A Real-World Disproportionality Analysis
by Diane Merino, Alexandre O. Gérard, Alexandre Destere, Florence Askenazy, Milou-Daniel Drici and Susanne Thümmler
Biomedicines 2022, 10(11), 2972; https://doi.org/10.3390/biomedicines10112972 - 18 Nov 2022
Cited by 2 | Viewed by 4152
Abstract
Antipsychotic drugs (APs) aim to treat schizophrenia, bipolar mania, and behavioral symptoms. In child psychiatry, despite limited evidence regarding their efficacy and safety, APs are increasingly subject to off-label use. Studies investigating addictology-related symptoms in young people being scarce, we aimed to characterize [...] Read more.
Antipsychotic drugs (APs) aim to treat schizophrenia, bipolar mania, and behavioral symptoms. In child psychiatry, despite limited evidence regarding their efficacy and safety, APs are increasingly subject to off-label use. Studies investigating addictology-related symptoms in young people being scarce, we aimed to characterize the different patterns of AP misuse and withdrawal in children and adolescents relying on the WHO pharmacovigilance database (VigiBase®, Uppsala Monitoring Centre, Sweden). Using the standardized MedDRA Query ‘drug abuse, dependence and withdrawal’, disproportionality for each AP was assessed with the reporting odds ratio and the information component. A signal was detected when the lower end of the 95% confidence interval of the information component was positive. Results revealed mainly withdrawal symptoms in infants (under 2 years), intentional misuse in children (2 to 11 years), and abuse in adolescents (12 to 17 years). Olanzapine, risperidone, aripiprazole, and quetiapine were disproportionately reported in all age groups, with quetiapine being subject to a specific abuse signal in adolescents. Thus, in adolescents, the evocation of possible recreational consumption may lead to addiction-appropriate care. Further, in young patients with a history of AP treatment, a careful anamnesis may allow one to identify misuse and its role in the case of new-onset symptoms. Full article
(This article belongs to the Special Issue Antipsychotics: 70 Years)
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23 pages, 3893 KiB  
Article
A Hybrid Workflow of Residual Convolutional Transformer Encoder for Breast Cancer Classification Using Digital X-ray Mammograms
by Riyadh M. Al-Tam, Aymen M. Al-Hejri, Sachin M. Narangale, Nagwan Abdel Samee, Noha F. Mahmoud, Mohammed A. Al-masni and Mugahed A. Al-antari
Biomedicines 2022, 10(11), 2971; https://doi.org/10.3390/biomedicines10112971 - 18 Nov 2022
Cited by 18 | Viewed by 3201
Abstract
Breast cancer, which attacks the glandular epithelium of the breast, is the second most common kind of cancer in women after lung cancer, and it affects a significant number of people worldwide. Based on the advantages of Residual Convolutional Network and the Transformer [...] Read more.
Breast cancer, which attacks the glandular epithelium of the breast, is the second most common kind of cancer in women after lung cancer, and it affects a significant number of people worldwide. Based on the advantages of Residual Convolutional Network and the Transformer Encoder with Multiple Layer Perceptron (MLP), this study proposes a novel hybrid deep learning Computer-Aided Diagnosis (CAD) system for breast lesions. While the backbone residual deep learning network is employed to create the deep features, the transformer is utilized to classify breast cancer according to the self-attention mechanism. The proposed CAD system has the capability to recognize breast cancer in two scenarios: Scenario A (Binary classification) and Scenario B (Multi-classification). Data collection and preprocessing, patch image creation and splitting, and artificial intelligence-based breast lesion identification are all components of the execution framework that are applied consistently across both cases. The effectiveness of the proposed AI model is compared against three separate deep learning models: a custom CNN, the VGG16, and the ResNet50. Two datasets, CBIS-DDSM and DDSM, are utilized to construct and test the proposed CAD system. Five-fold cross validation of the test data is used to evaluate the accuracy of the performance results. The suggested hybrid CAD system achieves encouraging evaluation results, with overall accuracies of 100% and 95.80% for binary and multiclass prediction challenges, respectively. The experimental results reveal that the proposed hybrid AI model could identify benign and malignant breast tissues significantly, which is important for radiologists to recommend further investigation of abnormal mammograms and provide the optimal treatment plan. Full article
(This article belongs to the Special Issue Artificial Intelligence in Biological and Biomedical Imaging 2.0)
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20 pages, 741 KiB  
Review
Role of Chemerin in Cardiovascular Diseases
by Mirjana T. Macvanin, Manfredi Rizzo, Jelena Radovanovic, Alper Sonmez, Francesco Paneni and Esma R. Isenovic
Biomedicines 2022, 10(11), 2970; https://doi.org/10.3390/biomedicines10112970 - 18 Nov 2022
Cited by 8 | Viewed by 2178
Abstract
(1) Background: Obesity is closely connected to the pathophysiology of cardiovascular diseases (CVDs). Excess fat accumulation is associated with metabolic malfunctions that disrupt cardiovascular homeostasis by activating inflammatory processes that recruit immune cells to the site of injury and reduce nitric oxide levels, [...] Read more.
(1) Background: Obesity is closely connected to the pathophysiology of cardiovascular diseases (CVDs). Excess fat accumulation is associated with metabolic malfunctions that disrupt cardiovascular homeostasis by activating inflammatory processes that recruit immune cells to the site of injury and reduce nitric oxide levels, resulting in increased blood pressure, endothelial cell migration, proliferation, and apoptosis. Adipose tissue produces adipokines, such as chemerin, that may alter immune responses, lipid metabolism, vascular homeostasis, and angiogenesis. (2) Methods: We performed PubMed and MEDLINE searches for articles with English abstracts published between 1997 (when the first report on chemerin identification was published) and 2022. The search retrieved original peer-reviewed articles analyzed in the context of the role of chemerin in CVDs, explicitly focusing on the most recent findings published in the past five years. (3) Results: This review summarizes up-to-date findings related to mechanisms of chemerin action, its role in the development and progression of CVDs, and novel strategies for developing chemerin-targeting therapeutic agents for treating CVDs. (4) Conclusions: Extensive evidence points to chemerin’s role in vascular inflammation, angiogenesis, and blood pressure modulation, which opens up exciting perspectives for developing chemerin-targeting therapeutic agents for the treatment of CVDs. Full article
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11 pages, 925 KiB  
Article
Evaluation of the Performance of an Indirect Immunofluorescence Assay for the Detection of Anti-MDA5 Antibodies
by Anaïs Nombel, Jean-Jacques Pin, Nicole Fabien, Pierre Miossec and Frédéric Coutant
Biomedicines 2022, 10(11), 2969; https://doi.org/10.3390/biomedicines10112969 - 18 Nov 2022
Cited by 1 | Viewed by 1641
Abstract
Anti-melanoma differentiation-associated protein 5 (MDA5) antibody (Ab) positive dermatomyositis (anti-MDA5 DM) is a rare systemic autoimmune disease; further, its prognosis can be rapidly fatal due to pulmonary involvement. The identification and quantification of anti-MDA5 Abs, which serve as a highly specific biomarker of [...] Read more.
Anti-melanoma differentiation-associated protein 5 (MDA5) antibody (Ab) positive dermatomyositis (anti-MDA5 DM) is a rare systemic autoimmune disease; further, its prognosis can be rapidly fatal due to pulmonary involvement. The identification and quantification of anti-MDA5 Abs, which serve as a highly specific biomarker of the disease, is a critical step for the establishing of both the diagnosis and monitoring of the disease’s activity. The development of a simple, fast, low-cost, and specific detection system of anti-MDA5 Ab is therefore highly desirable for the purposes of routine laboratory diagnosis. Here, we developed a human cell line that stably expresses MDA5 and evaluated its analytical performance in order to detect anti-MDA5 Abs by the utilization of indirect immunofluorescence (IIF). Serum samples from 23 anti-MDA5 DM patients and 22 anti-MDA5 Abs negative myositis readings, which were obtained at time of diagnosis, were analyzed by IIF on MDA5-transfected cells. The results were compared with those obtained with specific semi-quantitative (immunodot) and quantitative (ELISA) assays. A specific cytoplasmic pattern was found solely with the sera of anti-MDA5 DM patients. The sensitivity and specificity of IIF on MDA5-transfected cells were 96% and 100%, respectively, compared with ELISA. The anti-MDA5 Abs titers that were determined by this approach were consistent with the quantitative results obtained by ELISA. Baseline concentrations of anti-MDA5 Abs, either by ELISA or IIF, were not significantly different between surviving and deceased patients; further, they did not differ significantly according to clinical phenotypes. Overall, an IIF cell-based assay constitutes a simple, fast, and low-cost approach to identify and quantify anti-MDA5 Abs; moreover, it is as efficient as ELISA. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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