Biomedicines

19 pages, 2847 KiB

Open AccessArticle

Production of Reactive Oxygen Species by Epicardial Adipocytes Is Associated with an Increase in Postprandial Glycemia, Postprandial Insulin, and a Decrease in Serum Adiponectin in Patients with Severe Coronary Atherosclerosis

by Natalia V. Naryzhnaya, Olga A. Koshelskaya, Irina V. Kologrivova, Tatiana E. Suslova, Olga A. Kharitonova, Sergey L. Andreev, Alexander S. Gorbunov, Boris K. Kurbatov and Alla A. Boshchenko

Biomedicines 2022, 10(8), 2054; https://doi.org/10.3390/biomedicines10082054 - 22 Aug 2022

Cited by 12 | Viewed by 2430

Abstract

Purpose. This work investigates the relations between the production of reactive oxygen species (ROS) by epicardial adipose tissue (EAT) adipocytes and parameters of glucose/insulin metabolism, circulating adipokines levels, and severity of coronary atherosclerosis in patients with coronary artery disease (CAD); establishing significant determinants [...] Read more.

Purpose. This work investigates the relations between the production of reactive oxygen species (ROS) by epicardial adipose tissue (EAT) adipocytes and parameters of glucose/insulin metabolism, circulating adipokines levels, and severity of coronary atherosclerosis in patients with coronary artery disease (CAD); establishing significant determinants describing changes in ROS EAT in this category of patients. Material and methods. This study included 19 patients (14 men and 5 women, 53–72 y.o., 6 patients with diabetes mellitus type 2; 5 patients with prediabetes), with CAD, who underwent coronary artery bypass graft surgery. EAT adipocytes were isolated by the enzymatic method from intraoperative explants obtained during coronary artery bypass grafting. The size of EAT adipocytes and ROS level were determined. Results. The production of ROS by EAT adipocytes demonstrated a direct correlation with the level of postprandial glycemia (rs = 0.62, p < 0.05), and an inverse correlation with serum adiponectin (rs = −0.50, p = 0.026), but not with general and abdominal obesity, EAT thickness, and dyslipidemia. Regression analysis demonstrated that the increase in ROS of EAT adipocytes occurs due to the interaction of the following factors: postprandial glycemia (β = 0.95), postprandial insulin (β = 0.24), and reduced serum adiponectin (β = −0.20). EAT adipocytes in patients with diabetes and prediabetes manifested higher ROS production than in patients with normoglycemia. Although there was no correlation between the production of ROS by EAT adipocytes and Gensini score in the total group of patients, higher rates of oxidative stress were observed in EAT adipocytes from patients with a Gensini score greater than median Gensini score values (≥70.55 points, Gr.B), compared to patients with less severe coronary atherosclerosis (<70.55 points, Gr.A). Of note, the frequency of patients with diabetes and prediabetes was higher among the patients with the most severe coronary atherosclerosis (Gr.B) than in the Gr.A. Conclusions. Our data have demonstrated for the first time that systemic impairments of glucose/insulin metabolism and a decrease in serum adiponectin are significant independent determinants of oxidative stress intensity in EAT adipocytes in patients with severe coronary atherosclerosis. The possible input of the interplay between oxidative stress in EAT adipocytes and metabolic disturbances to the severity of coronary atherosclerosis requires further investigation. Full article

(This article belongs to the Special Issue Advances in Adipogenesis and Adipose Tissue Metabolism)

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12 pages, 666 KiB

Open AccessArticle

The Role of Immunoglobulin G (IgG), IgA and IgE—Antibodies against Helicobacter pylori in the Development of Oxidative Stress in Patients with Chronic Gastritis

by Olga Valentinovna Smirnova, Alexander Alexandrovich Sinyakov and Eduard Vilyamovich Kasparov

Biomedicines 2022, 10(8), 2053; https://doi.org/10.3390/biomedicines10082053 - 22 Aug 2022

Cited by 3 | Viewed by 2666

Abstract

Aim: To study the predominant serum responses (antibodies IgG, IgA, IgE) against H. pylori in relation to the indicators of the system “lipid peroxidation–antioxidant system” in various pathogenetic variants of chronic gastritis (CG). Materials and Methods: Sixty patients with CG, 33 [...] Read more.

Aim: To study the predominant serum responses (antibodies IgG, IgA, IgE) against H. pylori in relation to the indicators of the system “lipid peroxidation–antioxidant system” in various pathogenetic variants of chronic gastritis (CG). Materials and Methods: Sixty patients with CG, 33 patients with chronic atrophic gastritis (CAG) and 31 patients with chronic allergic gastritis (CALG) were examined. The values of the system of lipid peroxidation and antioxidant protection in plasma were determined in the serum of patients using a spectrophotometric method. Statistical data processing was carried out using the Statistica 7.0 software package (StatSoft, Tulsa, OK, USA). Results: With serum responses “antibodies IgG > IgA” and “high concentrations of IgE antibodies”, we found unidirectional changes in the form of an increase in the amount of diene conjugates, malondialdehyde and an increase in the activity of all enzymes: superoxide dismutase, catalase, glutathione-S-transferase and glutathione peroxidase. With a serum response with low concentrations of IgG, IgA antibodies, multidirectional changes were found in the form of an increase in the amount of diene conjugates, malondialdehyde and a decrease in the activity of all enzymes: superoxide dismutase, catalase, glutathione-S-transferase and glutathione peroxidase relative to the control group. Conclusions: The obtained data testify to the balance of lipid peroxidation and antioxidant system processes and depend on the characteristics of the immune response to H. pylori infection. Full article

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

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34 pages, 6238 KiB

Open AccessArticle

Mutational Slime Mould Algorithm for Gene Selection

by Feng Qiu, Pan Zheng, Ali Asghar Heidari, Guoxi Liang, Huiling Chen, Faten Khalid Karim, Hela Elmannai and Haiping Lin

Biomedicines 2022, 10(8), 2052; https://doi.org/10.3390/biomedicines10082052 - 22 Aug 2022

Cited by 10 | Viewed by 3581

Abstract

A large volume of high-dimensional genetic data has been produced in modern medicine and biology fields. Data-driven decision-making is particularly crucial to clinical practice and relevant procedures. However, high-dimensional data in these fields increase the processing complexity and scale. Identifying representative genes and [...] Read more.

A large volume of high-dimensional genetic data has been produced in modern medicine and biology fields. Data-driven decision-making is particularly crucial to clinical practice and relevant procedures. However, high-dimensional data in these fields increase the processing complexity and scale. Identifying representative genes and reducing the data’s dimensions is often challenging. The purpose of gene selection is to eliminate irrelevant or redundant features to reduce the computational cost and improve classification accuracy. The wrapper gene selection model is based on a feature set, which can reduce the number of features and improve classification accuracy. This paper proposes a wrapper gene selection method based on the slime mould algorithm (SMA) to solve this problem. SMA is a new algorithm with a lot of application space in the feature selection field. This paper improves the original SMA by combining the Cauchy mutation mechanism with the crossover mutation strategy based on differential evolution (DE). Then, the transfer function converts the continuous optimizer into a binary version to solve the gene selection problem. Firstly, the continuous version of the method, ISMA, is tested on 33 classical continuous optimization problems. Then, the effect of the discrete version, or BISMA, was thoroughly studied by comparing it with other gene selection methods on 14 gene expression datasets. Experimental results show that the continuous version of the algorithm achieves an optimal balance between local exploitation and global search capabilities, and the discrete version of the algorithm has the highest accuracy when selecting the least number of genes. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Advances in Genetic Research)

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10 pages, 1345 KiB

Open AccessArticle

Hashimoto’s Thyroiditis Minimizes Lymph Node Metastasis in BRAF Mutant Papillary Thyroid Carcinomas

by Peter P. Issa, Mahmoud Omar, Yusef Buti, Chad P. Issa, Bert Chabot, Christopher J. Carnabatu, Ruhul Munshi, Mohammad Hussein, Mohamed Aboueisha, Mohamed Shama, Ralph L. Corsetti, Eman Toraih and Emad Kandil

Biomedicines 2022, 10(8), 2051; https://doi.org/10.3390/biomedicines10082051 - 22 Aug 2022

Cited by 14 | Viewed by 2784

Abstract

Hashimoto’s thyroiditis (HT) (autoimmune thyroiditis) is a clinicopathological entity associated with chronic lymphocytic infiltration resulting in hypothyroidism. HT is a double-edged sword that increases the risk of papillary thyroid cancer (PTC), yet it serves as a protective factor for PTC progression. BRAF mutation [...] Read more.

Hashimoto’s thyroiditis (HT) (autoimmune thyroiditis) is a clinicopathological entity associated with chronic lymphocytic infiltration resulting in hypothyroidism. HT is a double-edged sword that increases the risk of papillary thyroid cancer (PTC), yet it serves as a protective factor for PTC progression. BRAF mutation in PTCs is associated with rapid cell growth, aggressive tumor characteristics, and higher mortality rates. Here, we aimed to analyze the influence of HT in patients with PTCs and its effect on lymph node metastasis (LNM) in BRAF mutant tumors. Adults diagnosed with PTC between 2008 and January 2021 were retrospectively included. A total of 427 patients, 128 of whom had underlying HT, were included. The HT group had significantly higher rates of microcarcinoma (49.2% vs. 37.5%, p = 0.025) and less lateral LNM (8.6% vs. 17.1%, p = 0.024). Interestingly, BRAF-mutated PTCs were found to have significantly less overall LNM (20.9% vs. 51%, p = 0.001), central LNM (25.6% vs. 45.1%, p = 0.040) and lateral LNM (9.3% vs. 29.4%, p = 0.010) in patients with HT when compared to those without underlying HT. HT was found to be an independent protective predictor of overall and lateral LNM. Altogether, HT was able to neutralize the effect of BRAF mutation and was determined to be an independent protective factor against LNM. Specifically, our work may influence treatment-aggressiveness decision making for endocrinologists, oncologists and surgeons alike. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Cancer: From Diagnosis to Treatment)

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96 pages, 1956 KiB

Open AccessReview

A Historical Review of Military Medical Strategies for Fighting Infectious Diseases: From Battlefields to Global Health

by Roberto Biselli, Roberto Nisini, Florigio Lista, Alberto Autore, Marco Lastilla, Giuseppe De Lorenzo, Mario Stefano Peragallo, Tommaso Stroffolini and Raffaele D’Amelio

Biomedicines 2022, 10(8), 2050; https://doi.org/10.3390/biomedicines10082050 - 22 Aug 2022

Cited by 16 | Viewed by 12206

Abstract

The environmental conditions generated by war and characterized by poverty, undernutrition, stress, difficult access to safe water and food as well as lack of environmental and personal hygiene favor the spread of many infectious diseases. Epidemic typhus, plague, malaria, cholera, typhoid fever, hepatitis, [...] Read more.

The environmental conditions generated by war and characterized by poverty, undernutrition, stress, difficult access to safe water and food as well as lack of environmental and personal hygiene favor the spread of many infectious diseases. Epidemic typhus, plague, malaria, cholera, typhoid fever, hepatitis, tetanus, and smallpox have nearly constantly accompanied wars, frequently deeply conditioning the outcome of battles/wars more than weapons and military strategy. At the end of the nineteenth century, with the birth of bacteriology, military medical researchers in Germany, the United Kingdom, and France were active in discovering the etiological agents of some diseases and in developing preventive vaccines. Emil von Behring, Ronald Ross and Charles Laveran, who were or served as military physicians, won the first, the second, and the seventh Nobel Prize for Physiology or Medicine for discovering passive anti-diphtheria/tetanus immunotherapy and for identifying mosquito Anopheline as a malaria vector and plasmodium as its etiological agent, respectively. Meanwhile, Major Walter Reed in the United States of America discovered the mosquito vector of yellow fever, thus paving the way for its prevention by vector control. In this work, the military relevance of some vaccine-preventable and non-vaccine-preventable infectious diseases, as well as of biological weapons, and the military contributions to their control will be described. Currently, the civil–military medical collaboration is getting closer and becoming interdependent, from research and development for the prevention of infectious diseases to disasters and emergencies management, as recently demonstrated in Ebola and Zika outbreaks and the COVID-19 pandemic, even with the high biocontainment aeromedical evacuation, in a sort of global health diplomacy. Full article

(This article belongs to the Special Issue Vaccines and Antibodies for Therapy and Prophylaxis)

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10 pages, 890 KiB

Open AccessArticle

Quantitative Measurement of Spinal Cerebrospinal Fluid by Cascade Artificial Intelligence Models in Patients with Spontaneous Intracranial Hypotension

by Jachih Fu, Jyh-Wen Chai, Po-Lin Chen, Yu-Wen Ding and Hung-Chieh Chen

Biomedicines 2022, 10(8), 2049; https://doi.org/10.3390/biomedicines10082049 - 22 Aug 2022

Cited by 4 | Viewed by 2446

Abstract

Cerebrospinal fluid (CSF) hypovolemia is the core of spontaneous intracranial hypotension (SIH). More than 1000 magnetic resonance myelography (MRM) images are required to evaluate each subject. An effective spinal CSF quantification method is needed. In this study, we proposed a cascade artificial intelligence [...] Read more.

Cerebrospinal fluid (CSF) hypovolemia is the core of spontaneous intracranial hypotension (SIH). More than 1000 magnetic resonance myelography (MRM) images are required to evaluate each subject. An effective spinal CSF quantification method is needed. In this study, we proposed a cascade artificial intelligence (AI) model to automatically segment spinal CSF. From January 2014 to December 2019, patients with SIH and 12 healthy volunteers (HVs) were recruited. We evaluated the performance of AI models which combined object detection (YOLO v3) and semantic segmentation (U-net or U-net++). The network of performance was evaluated using intersection over union (IoU). The best AI model was used to quantify spinal CSF in patients. We obtained 25,603 slices of MRM images from 13 patients and 12 HVs. We divided the images into training, validation, and test datasets with a ratio of 4:1:5. The IoU of Cascade YOLO v3 plus U-net++ (0.9374) was the highest. Applying YOLO v3 plus U-net++ to another 13 SIH patients showed a significant decrease in the volume of spinal CSF measured (59.32 ± 10.94 mL) at disease onset compared to during their recovery stage (70.61 ± 15.31 mL). The cascade AI model provided a satisfactory performance with regard to the fully automatic segmentation of spinal CSF from MRM images. The spinal CSF volume obtained through its measurements could reflect a patient’s clinical status. Full article

(This article belongs to the Topic Machine Learning Techniques Driven Medicine Analysis)

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10 pages, 540 KiB

Open AccessArticle

Adverse Neonatal Outcome of Pregnancies Complicated by Preeclampsia

by Piotr Tousty, Magda Fraszczyk-Tousty, Joanna Ksel-Hryciów, Beata Łoniewska, Joanna Tousty, Sylwia Dzidek, Kaja Michalczyk, Ewa Kwiatkowska, Aneta Cymbaluk-Płoska, Andrzej Torbé and Sebastian Kwiatkowski

Biomedicines 2022, 10(8), 2048; https://doi.org/10.3390/biomedicines10082048 - 22 Aug 2022

Cited by 6 | Viewed by 2605

Abstract

Despite many available treatments, infants born to preeclamptic mothers continue to pose a serious clinical problem. The present study focuses on the evaluation of infants born to preeclamptic mothers for the occurrence of early-onset complications and attempts to link the clinical status of [...] Read more.

Despite many available treatments, infants born to preeclamptic mothers continue to pose a serious clinical problem. The present study focuses on the evaluation of infants born to preeclamptic mothers for the occurrence of early-onset complications and attempts to link the clinical status of such infants to the angiogenesis markers in maternal blood (sFlt-1, PlGF). The study included 77 newborns and their mothers diagnosed with preeclampsia. The infants were assessed for their perinatal outcomes, with an emphasis on adverse neonatal outcomes such us infections, RDS, PDA, NEC, IVH, ROP, or BPD during the hospitalization period. The cutoff point was established using the ROC curve for the occurrence of any adverse neonatal outcome and it was 204 for the sFlt-1/PlGF and 32 birth week with AOC 0.644 and 0.91, respectively. The newborns born to mothers with high ratios had longer hospitalization times and, generally, were more frequently diagnosed with any of the aforementioned adverse neonatal outcomes. Also, the neonates born prior to or at 32 wkGA with higher sFlt-1/PlGF ratios were statistically significantly more common to be diagnosed with any of the adverse neonatal outcomes compared to those with lower ratio born prior to or at 32 wkGA. The sFlt-1/PlGF ratio can be a useful tool in predicting short-term adverse neonatal outcomes. Infants born after a full 33 weeks gestation developed almost no severe neonatal complications. Appropriate screening and preventive healthcare for preeclampsia can contribute significantly to reducing the incidence of neonatal complications. Full article

(This article belongs to the Special Issue Perinatal-Related Pathology)

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21 pages, 1919 KiB

Open AccessReview

Diagnostic and Therapeutic Potential of Circulating-Free DNA and Cell-Free RNA in Cancer Management

by Sadia Hassan, Adeeb Shehzad, Shahid Ali Khan, Waheed Miran, Salman Khan and Young-Sup Lee

Biomedicines 2022, 10(8), 2047; https://doi.org/10.3390/biomedicines10082047 - 22 Aug 2022

Cited by 16 | Viewed by 5125

Abstract

Over time, molecular biology and genomics techniques have been developed to speed up the early diagnosis and clinical management of cancer. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. Important advances [...] Read more.

Over time, molecular biology and genomics techniques have been developed to speed up the early diagnosis and clinical management of cancer. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. Important advances in applying molecular testing involve circulating-free DNA (cfDNA)- and cell-free RNA (cfRNA)-based liquid biopsies for the diagnosis, prognosis, prediction, and treatment of cancer. Both cfDNA and cfRNA are sensitive and specific biomarkers for cancer detection, which have been clinically proven through multiple randomized and prospective trials. These help in cancer management based on the noninvasive evaluation of size, quantity, and point mutations, as well as copy number alterations at the tumor site. Moreover, personalized detection of ctDNA helps in adjuvant therapeutics and predicts the chances of recurrence of cancer and resistance to cancer therapy. Despite the controversial diagnostic values of cfDNA and cfRNA, many clinical trials have been completed, and the Food and Drug Administration has approved many multigene assays to detect genetic alterations in the cfDNA of cancer patients. In this review, we underpin the recent advances in the physiological roles of cfDNA and cfRNA, as well as their roles in cancer detection by highlighting recent clinical trials and their roles as prognostic and predictive markers in cancer management. Full article

(This article belongs to the Special Issue Liquid Biopsy in Diseases)

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8 pages, 639 KiB

Open AccessArticle

Early Diagnosis in Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS) by Focusing on Major Clinical Clues: Beyond Ataxia and Vestibular Impairment

by Laurent Magy, Pauline Chazelas, Laurence Richard, Nathalie Deschamps, Simon Frachet, Jean-Michel Vallat, Corinne Magdelaine, Frédéric Favreau, Flavien Bessaguet, Anne-Sophie Lia and Mathilde Duchesne

Biomedicines 2022, 10(8), 2046; https://doi.org/10.3390/biomedicines10082046 - 22 Aug 2022

Cited by 10 | Viewed by 3689

Abstract

CANVAS, a rare disorder responsible for late-onset ataxia of autosomal recessive inheritance, can be misdiagnosed. We investigated a series of eight patients with sensory neuropathy and/or an unexplained cough, who appeared to suffer from CANVAS, and we emphasized the clinical clues for early [...] Read more.

CANVAS, a rare disorder responsible for late-onset ataxia of autosomal recessive inheritance, can be misdiagnosed. We investigated a series of eight patients with sensory neuropathy and/or an unexplained cough, who appeared to suffer from CANVAS, and we emphasized the clinical clues for early diagnosis. Investigations included clinical and routine laboratory analyses, skin biopsy, nerve biopsy and molecular genetics. The eight patients had clinical and/or laboratory evidence of sensory neuronopathy. All but one had neuropathic pain that had started in an asymmetric fashion in two patients. A chronic cough was a prominent feature in our eight patients and had started years before neuropathic symptoms in all but one. The course of the disease was slow, and ataxia remained mild in all. Five patients were initially thought to have immune-mediated sensory neuronopathy and received immunotherapy. Skin biopsies showed a near complete and non-length-dependent loss of intraepidermal nerve fibers. Moreover, nerve biopsy findings suggested a prominent involvement of small myelinated and unmyelinated fibers. The burden of CANVAS extends far beyond cerebellar ataxia and vestibular manifestations. Indeed, our study shows that a chronic cough and neuropathic pain may represent a major source of impairment in these patients and should not be overlooked to allow an early diagnosis and prevent unnecessary immunotherapy. Full article

(This article belongs to the Special Issue Early Diagnosis Research of Inherited Neuropathies)

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27 pages, 685 KiB

Open AccessSystematic Review

Systematic Review on the Use of Biosimilars of Trastuzumab in HER2+ Breast Cancer

by Eleni Triantafyllidi and John K. Triantafillidis

Biomedicines 2022, 10(8), 2045; https://doi.org/10.3390/biomedicines10082045 - 21 Aug 2022

Cited by 28 | Viewed by 4890

Abstract

Trastuzumab is a monoclonal antibody used in the treatment of breast cancer in cases where the tumor overexpresses the HER2 receptor, a cell membrane receptor activated by the epidermal growth factor. Intravenous and subcutaneous administration of trastuzumab have comparable clinical and pharmacological characteristics, [...] Read more.

Trastuzumab is a monoclonal antibody used in the treatment of breast cancer in cases where the tumor overexpresses the HER2 receptor, a cell membrane receptor activated by the epidermal growth factor. Intravenous and subcutaneous administration of trastuzumab have comparable clinical and pharmacological characteristics, but trastuzumab biosimilars are currently only available in intravenous form. Trastuzumab biosimilars are ultimately preferred by a proportion of patients, especially in cases where co-administration of other chemotherapeutic agents, such as trastuzumab and tucatinib, a small molecule of tyrosine kinase inhibitor, is required in patients with HER-positive metastatic breast cancer. Oncologists should be well-aware of the advantages of intravenously administered trastuzumab biosimilars over subcutaneous administration, certainly also taking into account the patient’s preferences. Further cost-effectiveness analyses will be very important, along with expectations regarding successful concomitant subcutaneous administration of trastuzumab with other anticancer drugs, such as pertuzumab. This systematic review describes and analyzes the so-far published studies concerning the use of the available trastuzumab biosimilars in HER-positive early and metastatic breast cancer in terms of efficacy, safety, and cost–benefit ratio. An attempt was also made to draw some conclusions and to comment on future needs and perspectives. Full article

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

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13 pages, 1243 KiB

Open AccessArticle

Identification of Germinal Neurofibromin Hotspots

by Sergio Lois, Juan Báez-Flores, María Isidoro-García, Jesus Lacal and Juan Carlos Triviño

Biomedicines 2022, 10(8), 2044; https://doi.org/10.3390/biomedicines10082044 - 21 Aug 2022

Cited by 4 | Viewed by 2856

Abstract

Neurofibromin is engaged in many cellular processes and when the proper protein functioning is impaired, it causes neurofibromatosis type 1 (NF1), one of the most common inherited neurological disorders. Recent advances in sequencing and screening of the NF1 gene have increased [...] Read more.

Neurofibromin is engaged in many cellular processes and when the proper protein functioning is impaired, it causes neurofibromatosis type 1 (NF1), one of the most common inherited neurological disorders. Recent advances in sequencing and screening of the NF1 gene have increased the number of detected variants. However, the correlation of these variants with the clinic remains poorly understood. In this study, we analyzed 4610 germinal NF1 variants annotated in ClinVar and determined on exon level the mutational spectrum and potential pathogenic regions. Then, a binomial and sliding windows test using 783 benign and 938 pathogenic NF1 variants were analyzed against functional and structural regions of neurofibromin. The distribution of synonymous, missense, and frameshift variants are statistically significant in certain regions of neurofibromin suggesting that the type of variant and its associated phenotype may depend on protein disorder. Indeed, there is a negative correlation between the pathogenic fraction prediction and the disorder data, suggesting that the higher an intrinsically disordered region is, the lower the pathogenic fraction is and vice versa. Most pathogenic variants are associated to NF1 and our analysis suggests that GRD, CSRD, TBD, and Armadillo1 domains are hotspots in neurofibromin. Knowledge about NF1 genotype–phenotype correlations can provide prognostic guidance and aid in organ-specific surveillance. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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NF1 germinal mutational spectrum and potential pathogenicity. A total of 2365 variants were classified in different categories including missense 165 (7%), 254 non-sense (10%), 520 frameshift (22%), 644 splicing alterations (27%), 770 synonymous (32%), and 12 are annotated as others (2%). They were also classified as (A) benign (913, 39%) or (B) pathogenic (1452, 61%) based on the annotation as reported in ClinVar. Full article ">Figure 2
Pathological proportion in neurofibromin domains. Based on the 0.52 threshold obtained as reported in M&M and using p-values up to 0.1 as the cut-off for significance, our analysis identified four hotspots. The RAS-GTPase domain p < 0.01 * (0.003), the CSRD domain and the Armadillo1 domain with p > 0.01 and p < 0.05 **, and the TBD with a p > 0.05 and < 0.1 *** (0.078). Full article ">Figure 3
Estimated pathological fraction across neurofibromin full length protein sequence. The continuous blue line corresponds to the predicted pathological fraction using the global model, whereas the red line indicates the proportion of pathological variants of each window. Neurofibromin domains are represented by different colors. Full article ">Figure 4
Variants distribution in neurofibromin. A total of 4610 variants annotated in ClinVar were used for the study. Different types of variants are represented by continuous lines using different colors. Neurofibromin protein domains are defined at the bottom. Full article ">Figure 5
Distribution of phenotypes across neurofibromin based on the sliding window test. The continuous line and colors indicate the distribution of variants according to their phenotype as annotated in ClinVar. Neurofibromin protein domains are defined at the bottom. Full article ">

21 pages, 1851 KiB

Open AccessReview

The Role of the NRF2 Pathway in Maintaining and Improving Cognitive Function

by Nora E. Gray, Marcelo Farina, Paolo Tucci and Luciano Saso

Biomedicines 2022, 10(8), 2043; https://doi.org/10.3390/biomedicines10082043 - 21 Aug 2022

Cited by 16 | Viewed by 3306

Abstract

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a redox-sensitive transcription factor that binds to the antioxidant response element consensus sequence, decreasing reactive oxygen species and regulating the transcription of a wide array of genes, including antioxidant and detoxifying enzymes, regulating genes involved in [...] Read more.

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a redox-sensitive transcription factor that binds to the antioxidant response element consensus sequence, decreasing reactive oxygen species and regulating the transcription of a wide array of genes, including antioxidant and detoxifying enzymes, regulating genes involved in mitochondrial function and biogenesis. Moreover, NRF2 has been shown to directly regulate the expression of anti-inflammatory mediators reducing the expression of pro-inflammatory cytokines. In recent years, attention has turned to the role NRF2 plays in the brain in different diseases such Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and others. This review focused on the evidence, derived in vitro, in vivo and from clinical trials, supporting a role for NRF2 activation in maintaining and improving cognitive function and how its activation can be used to elicit neuroprotection and lead to cognitive enhancement. The review also brings a critical discussion concerning the possible prophylactic and/or therapeutic use of NRF2 activators in treating cognitive impairment-related conditions. Full article

(This article belongs to the Special Issue Regulation of Keap1-Nrf2 Signaling in Health and Diseases)

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12 pages, 1812 KiB

Open AccessArticle

H3K27me3 Immunohistochemical Loss Predicts Lower Response to Neo-Adjuvant Chemo-Radiotherapy in Rectal Carcinoma

by Serena Ammendola, Nicolò Caldonazzi, Paola Chiara Rizzo, Giulia Turri, Corrado Pedrazzani and Valeria Barresi

Biomedicines 2022, 10(8), 2042; https://doi.org/10.3390/biomedicines10082042 - 21 Aug 2022

Cited by 2 | Viewed by 2498

Abstract

A watch-and-wait approach was suggested to avoid the possible complications related to surgery in patients with rectal carcinoma showing clinical complete response after neoadjuvant chemo-radiotherapy (CRT). Since clinical response may not correlate with pathological response, markers with higher accuracy are needed to identify [...] Read more.

A watch-and-wait approach was suggested to avoid the possible complications related to surgery in patients with rectal carcinoma showing clinical complete response after neoadjuvant chemo-radiotherapy (CRT). Since clinical response may not correlate with pathological response, markers with higher accuracy are needed to identify patients who are likely responders and could be spared surgery. This study aims to assess whether H3K27me3 immunohistochemical expression in pre-treatment rectal carcinoma predicts response to neoadjuvant CRT or shows prognostic relevance. We assessed H3K27me3 immunostaining in 46 endoscopic biopsies of rectal carcinomas treated with neoadjuvant CRT and surgery. H3K27me3 immunostaining was lost in 20, retained in 19, and inconclusive (absent in neoplastic and non-neoplastic cells) in 7 cases. Retained H3K27me3 immuno-expression was significantly associated with ypTNM stage 0 (p = 0.0111) and high tumor regression, measured using either five-tiered (p = 0.0042) or two-tiered Dworak tumor regression grade (p = 0.0009). Poor differentiation, determined counting the number of poorly differentiated clusters (PDC grade) or tumor budding (TB) foci (TB grade), in the pre-treatment biopsy, was significantly associated with a shorter time to progression after surgery (p = 0.008; p = 0.0093). However, only PDC grade (p = 0.0023), together with radial margin involvement (p = 0.0001), retained prognostic significance in the multivariate analysis. The assessment of H3K27me3 immunostaining in pre-treatment endoscopic biopsy of rectal carcinoma could be useful to predict response to neo-adjuvant CRT and to identify patients who could safely undergo watch-and-wait approach. PDC and TB grade in the pre-treatment biopsy could provide additional prognostic information in patients with rectal carcinoma treated with neoadjuvant CRT and surgery. Full article

(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 3.0)

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17 pages, 693 KiB

Open AccessCase Report

Juvenile Idiopathic Arthritis, Uveitis and Multiple Sclerosis: Description of Two Patients and Literature Review

by Cecilia Beatrice Chighizola, Matteo Ferrito, Luca Marelli, Irene Pontikaki, Paolo Nucci, Elisabetta Miserocchi and Roberto Caporali

Biomedicines 2022, 10(8), 2041; https://doi.org/10.3390/biomedicines10082041 - 21 Aug 2022

Cited by 2 | Viewed by 3004

Abstract

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood, while multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by remission and exacerbation phases. An association between MS and rheumatologic diseases, in particular rheumatoid arthritis, has [...] Read more.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood, while multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by remission and exacerbation phases. An association between MS and rheumatologic diseases, in particular rheumatoid arthritis, has been described and numerous studies acknowledge anti-TNF-α drugs as MS triggers. Conversely, the association between MS and JIA has been reported merely in five cases in the literature. We describe two cases of adult patients with longstanding JIA and JIA-associated uveitis, who developed MS. The first patient was on methotrexate and adalimumab when she developed dizziness and nausea. Characteristic MRI lesions and oligoclonal bands in cerebrospinal fluid led to MS diagnosis. Adalimumab was discontinued, and she was treated with three pulses of intravenous methylprednisolone. After a few months, rituximab was started. The second patient had been treated with anti-TNF-α and then switched to abatacept. She complained of unilateral arm and facial paraesthesias; brain MRI showed characteristic lesions, and MS was diagnosed. Three pulses of intravenous methylprednisolone were administered; neurological disease remained stable, and abatacept was reintroduced. Further studies are warranted to define if there is an association between JIA and MS, if MS represents JIA comorbidity or if anti-TNF-α underpins MS development. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Diagnostic in Juvenile Idiopathic Arthritis)

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3 pages, 180 KiB

Open AccessEditorial

Neutrophils, Fast and Strong

by Galina F. Sud’ina

Biomedicines 2022, 10(8), 2040; https://doi.org/10.3390/biomedicines10082040 - 21 Aug 2022

Viewed by 1786

Abstract

The history of medicine is also the history of our understanding of the role of neutrophils in protecting our bodies [...] Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

14 pages, 557 KiB

Open AccessViewpoint

Hidradenitis Suppurativa: A Perspective on Genetic Factors Involved in the Disease

by Chiara Moltrasio, Paola Maura Tricarico, Maurizio Romagnuolo, Angelo Valerio Marzano and Sergio Crovella

Biomedicines 2022, 10(8), 2039; https://doi.org/10.3390/biomedicines10082039 - 21 Aug 2022

Cited by 34 | Viewed by 3610

Abstract

Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease of the pilosebaceous unit, clinically consisting of painful nodules, abscesses, and sinus tracts mostly in, but not limited to, intertriginous skin areas. HS can be defined as a complex skin disease with multifactorial etiologies, [...] Read more.

Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease of the pilosebaceous unit, clinically consisting of painful nodules, abscesses, and sinus tracts mostly in, but not limited to, intertriginous skin areas. HS can be defined as a complex skin disease with multifactorial etiologies, including—among others—genetic, immunologic, epigenetic, and environmental factors. Based on genetic heterogeneity and complexity, three different forms can be recognized and considered separately as sporadic, familial, and syndromic. To date, several genetic variants associated to disease susceptibility, disease-onset, and/or treatment response have been reported; some of these reside in genes encoding the gamma-secretase subunits whereas others involve autoinflammatory and/or keratinization genes. The aim of this perspective work is to provide an overview of the contribution of several genetic studies encompassing family linkage analyses, target candidate gene studies, and -omic studies in this field. In our viewpoint, we discuss the role of genetics in Hidradenitis suppurativa considering findings based on Sanger sequencing as well as the more recent Next Generation Sequencing (i.e., exome sequencing or RNA Sequencing) with the aim of better understanding the etio-pathogenesis of the disease as well as identifying novel therapeutic strategies. Full article

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

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18 pages, 4956 KiB

Open AccessArticle

Genomic Aberrations Generate Fusion Gene FOXK2::TP63 and Activate NFKB1 in Cutaneous T-Cell Lymphoma

by Stefan Nagel, Claudia Pommerenke, Hilmar Quentmeier, Corinna Meyer, Maren Kaufmann and Roderick A. F. MacLeod

Biomedicines 2022, 10(8), 2038; https://doi.org/10.3390/biomedicines10082038 - 21 Aug 2022

Cited by 2 | Viewed by 2718

Abstract

Cutaneous T-cell lymphoma (CTCL) is a severe lymphoid malignancy with a worse prognosis lacking curative treatment regimens. Several gene mutations and deregulated pathways, including NFkB signaling, have been implicated in its pathogenesis. Accordingly, CTCL cell line HUT-78 reportedly contains mutated NFKB2, which is [...] Read more.

Cutaneous T-cell lymphoma (CTCL) is a severe lymphoid malignancy with a worse prognosis lacking curative treatment regimens. Several gene mutations and deregulated pathways, including NFkB signaling, have been implicated in its pathogenesis. Accordingly, CTCL cell line HUT-78 reportedly contains mutated NFKB2, which is constitutively activated via partial gene deletion, also demonstrating that genomic rearrangements cause driving mutations in this malignancy. Here, along with HUT-78, we analyzed CTCL cell line HH to identify additional aberrations underlying gene deregulation. Karyotyping and genomic profiling of HH showed several rearrangements worthy of detailed investigation. Corresponding to the established karyotype, RNA-seq data and PCR analysis confirmed the presence of t(3;17)(q28;q25), generating a novel fusion gene, FOXK2::TP63. Furthermore, chromosomal rearrangement t(1;4)(p32;q25) was connected to amplification at 4q24–26, affecting aberrant NFKB1 overexpression thereat. Transcription factor binding-site analysis and knockdown experiments demonstrated that IRF4 contributed to NFKB1 expression. Within the same amplicon, we identified amplification and overexpression of NFkB signaling activator CAMK2D (4q26) and p53-inhibitor UBE2D3 (4q24). Genomic profiling data for HUT-78 detailed a deletion at 10q25 underlying reported NFKB2 activation. Moreover, amplifications of ID1 (20q11) and IKZF2 (2q34) in this cell line drove overexpression of these NK cell differentiation factors and possibly thus formed corresponding lineage characteristics. Target gene analysis for NFKB1 via siRNA-mediated knockdown in HH revealed activation of TP63, MIR155, and NOTCH pathway component RBPJ. Finally, treatment of HH with NFkB inhibitor demonstrated a role for NFkB in supporting proliferation, while usage of inhibitor DAPT showed significant survival effects via the NOTCH pathway. Collectively, our data suggest that NFkB and/or NOTCH inhibitors may represent reasonable treatment options for subsets of CTCL patients. Full article

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

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3 pages, 191 KiB

Open AccessEditorial

Peptide-Based Drug Development

by William D. Lubell

Biomedicines 2022, 10(8), 2037; https://doi.org/10.3390/biomedicines10082037 - 21 Aug 2022

Cited by 15 | Viewed by 3077

Abstract

The celebration of one hundred years of insulin therapy in 2021 marked a milestone for the application of peptide-based therapeutics [...] Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

11 pages, 1476 KiB

Open AccessArticle

Prevention of Anti-HMGCR Immune-Mediated Necrotising Myopathy by C5 Complement Inhibition in a Humanised Mouse Model

by Sarah Julien, Douangsone Vadysirisack, Camil Sayegh, Sharan Ragunathan, Yalan Tang, Emma Briand, Marion Carrette, Laetitia Jean, Rachid Zoubairi, Henri Gondé, Olivier Benveniste, Yves Allenbach, Laurent Drouot and Olivier Boyer

Biomedicines 2022, 10(8), 2036; https://doi.org/10.3390/biomedicines10082036 - 20 Aug 2022

Cited by 14 | Viewed by 2927

Abstract

Introduction: immune-mediated necrotising myopathy (IMNM) is associated with pathogenic anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, at least partly through activation of the classical pathway of the complement. We evaluated zilucoplan, an investigational drug, and a macrocyclic peptide inhibitor of [...] Read more.

Introduction: immune-mediated necrotising myopathy (IMNM) is associated with pathogenic anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, at least partly through activation of the classical pathway of the complement. We evaluated zilucoplan, an investigational drug, and a macrocyclic peptide inhibitor of complement component 5 (C5), in humanized mouse models of IMNM. Methods: purified immunoglobulin G (IgG) from an anti-HMGCR⁺ IMNM patient was co-injected intraperitoneally with human complement in C57BL/6, C5-deficient B10 (C5^def) and Rag2 deficient (Rag2^−/−) mice. Zilucoplan was administered subcutaneously in a preventive or interventional paradigm, either injected daily throughout the duration of the experiment in C57BL/6 and C5^def mice or 8 days after disease induction in Rag2^−/− mice. Results: prophylactic administration of zilucoplan prevented muscle strength loss in C5^def mice (anti-HMGCR⁺ vs. anti-HMGCR⁺ + zilucoplan: p = 0.0289; control vs. anti-HMGCR⁺ + zilucoplan: p = 0.4634) and wild-type C57BL/6 (anti-HMGCR⁺ vs. anti-HMGCR⁺ + zilucoplan: p = 0.0002; control vs. anti-HMGCR⁺ + zilucoplan: p = 0.0939) with corresponding reduction in C5b-9 deposits on myofibres and number of regenerated myofibres. Interventional treatment of zilucoplan after disease induction reduced the complement deposits and number of regenerated myofibres in muscles of Rag2^−/− mice, although to a lesser extent. In this latter setting, C5 inhibition did not significantly ameliorate muscle strength. Conclusion: Early administration of zilucoplan prevents the onset of myopathy at the clinical and histological level in a humanized mouse model of IMNM. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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C5 inhibition prevents the development of IMNM in C5-deficient mice supplemented with human complement. (A) C57BL/10SnJ C5-deficient (C5def) mice (n = 8/group) were transiently immunosuppressed by a single injection of cyclophosphamide (CYC) and received injections of purified IgG from a patient suffering from anti-HMGCR+ IMNM with or without zilucoplan in conjunction with human complement. Control is IgG from normal serum in conjunction with human complement. (B) Circulating levels of anti-HMGCR aAb by addressable laser beads immunoassay (ALBIA) in the serum of mice at day 7. (C) Muscle strength was evaluated by measurement of gastrocnemius contraction upon electrostimulation (muscle strength). (D) Quantification of regenerative muscle fibres in all assessable frozen tibialis muscle biopsies from mice injected with control IgG or anti-HMGCR+ IgG with or without zilucoplan. (E) In vitro classical pathway complement-mediated haemolysis assay in serum from mice injected with control IgG or anti-HMGCR+ IgG with or without zilucoplan at day 0, 30 min, 5 h and day 7. (F,G) Quantification by ELISA of C5a and C5b-9 in serum from mice injected with control IgG or anti-HMGCR+ IgG with or without zilucoplan at day 0, 5 h. (H) H & E staining. Scale bar = 100 µm. (I) Immunodetection of regenerative myofibres after staining with mouse anti-foetal myosin heavy chain (My-HC) antibody followed by Alexa 647-labeled anti-mouse IgG antibody (red). Muscle fibres are made visible using rabbit anti-laminin antibody followed by Alexa 488-labeled anti-rabbit IgG (green) and DAPI (blue) for staining nuclei. Scale bar = 100 µm. (J) Complement deposits (red) on the surface of myofibres after staining with rabbit anti-C5b-9 antibody followed by Alexa 647-labeled anti-rabbit IgG and DAPI counterstaining (blue). Scale bar = 200 µm. Data are presented as mean ± SD; ns is for non-significant * p < 0.05, ** p < 0.01, *** p < 0.001 by Mann–Whitney two-tailed test. One out of two reproducible experiments is shown. Full article ">Figure 2
C5 inhibition prevents the development of IMNM in C57BL/6 mice supplemented with human complement. (A) C57BL/6 mice (n = 8/group) were transiently immunosuppressed by a single injection of cyclophosphamide (CYC) and received injections of purified IgG from a patient suffering from anti-HMGCR+ IMNM with or without zilucoplan in conjunction with human complement. Control is IgG from normal serum in conjunction with human complement. (B) Circulating levels of anti-HMGCR aAb by addressable laser beads immunoassay (ALBIA) in the serum of mice at day 7. (C) Muscle strength was evaluated by measurement of gastrocnemius contraction upon electrostimulation (muscle strength). (D) Quantification of regenerative muscle fibres in all assessable frozen tibialis muscle biopsies from mice injected with control IgG or anti-HMGCR+ IgG with or without zilucoplan. (E) H & E staining. Scale bar = 100 µm. (F) Immunodetection of regenerative myofibres after staining with mouse anti-foetal myosin heavy chain (My-HC) antibody followed by Alexa 647-labeled anti-mouse IgG antibody (red). Muscle fibres are made visible using rabbit anti-laminin antibody followed by Alexa 488-labeled anti-rabbit IgG (green) and DAPI (blue) for staining nuclei. Scale bar = 100 µm. (G) Complement deposits (red) on the surface of myofibres after staining with rabbit anti-C5b-9 antibody followed by Alexa 647-labeled anti-rabbit IgG and DAPI counterstaining (blue). Scale bar = 200 µm. Data are presented as mean ± SD; ns is for non-significant * p < 0.05, ** p < 0.01, *** p < 0.001 by Mann–Whitney two-tailed test. One out of two reproducible experiments is shown. Full article ">Figure 3
C5 inhibition partially ameliorates IMNM in Rag2−/− mice supplemented with human complement. (A) Rag2−/− mice (n = 8/group) received injections of purified IgG from a patient suffering from anti-HMGCR+ IMNM or purified IgG from normal serum in conjunction with human complement. Two groups were sacrificed at day 7 for assessing muscle strength. Moreover, three groups of Rag2−/− mice received injections of IgG purified from normal serum or from a patient suffering from anti-HMGCR+ IMNM with or without zilucoplan daily from day 8 in conjunction with human complement and were sacrificed at day 15. (B) Circulating levels of anti-HMGCR aAb by addressable laser beads immunoassay (ALBIA) in the serum of mice at day 15. (C) Muscle strength was evaluated by measurement of gastrocnemius contraction upon electrostimulation (muscle strength). (D) H & E staining. Scale bar = 100µm. (E) Immunodetection of regenerative myofibres after staining with mouse anti-foetal myosin heavy chain (My-HC) antibody followed by Alexa 647-labeled anti-mouse IgG antibody (red). Muscle fibres are made visible using rabbit anti-laminin antibody followed by Alexa 488-labeled anti-rabbit IgG (green) and DAPI (blue) for staining nuclei. Scale bar = 100 µm. (F) Complement deposits (red) on the surface of myofibres after staining with rabbit anti-C5b-9 antibody followed by Alexa 647-labeled anti-rabbit IgG and DAPI counterstaining (blue). Scale bar = 200µm. Data are presented as mean ± SD; ns is for non-significant * p < 0.05, ** p < 0.01 by Mann–Whitney two-tailed test. One out of two reproducible experiments is shown. Full article ">

16 pages, 990 KiB

Open AccessReview

Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease

by Robert W. M. Min, Filbert W. M. Aung, Bryant Liu, Aliza Arya and Sanda Win

Biomedicines 2022, 10(8), 2035; https://doi.org/10.3390/biomedicines10082035 - 20 Aug 2022

Cited by 14 | Viewed by 3349

Abstract

Non-alcoholic fatty liver (NAFL) is the most common chronic liver disease. Activation of mitogen-activated kinases (MAPK) cascade, which leads to c-Jun N-terminal kinase (JNK) activation occurs in the liver in response to the nutritional and metabolic stress. The aberrant activation of MAPKs, especially [...] Read more.

Non-alcoholic fatty liver (NAFL) is the most common chronic liver disease. Activation of mitogen-activated kinases (MAPK) cascade, which leads to c-Jun N-terminal kinase (JNK) activation occurs in the liver in response to the nutritional and metabolic stress. The aberrant activation of MAPKs, especially c-Jun-N-terminal kinases (JNKs), leads to unwanted genetic and epi-genetic modifications in addition to the metabolic stress adaptation in hepatocytes. A mechanism of sustained P-JNK activation was identified in acute and chronic liver diseases, suggesting an important role of aberrant JNK activation in NASH. Therefore, modulation of JNK activation, rather than targeting JNK protein levels, is a plausible therapeutic application for the treatment of chronic liver disease. Full article

(This article belongs to the Special Issue Drug-Induced Hepatotoxicity: From Pathology to Novel Therapeutic Approaches)

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10 pages, 744 KiB

Open AccessArticle

Serum Osmolarity and Vasopressin Concentration in Acute Heart Failure—Influence on Clinical Course and Outcome

by Mateusz Guzik, Mateusz Sokolski, Magdalena Hurkacz, Agata Zdanowicz, Gracjan Iwanek, Dominik Marciniak, Robert Zymliński, Piotr Ponikowski and Jan Biegus

Biomedicines 2022, 10(8), 2034; https://doi.org/10.3390/biomedicines10082034 - 20 Aug 2022

Cited by 6 | Viewed by 2146

Abstract

Neurohormone activation plays an important role in Acute Heart Failure (AHF) pathophysiology. Serum osmolarity can affect this activation causing vasopressin excretion. The role of serum osmolarity and vasopressin concentration and its interaction remain still unexplored in AHF. The objective of our study was [...] Read more.

Neurohormone activation plays an important role in Acute Heart Failure (AHF) pathophysiology. Serum osmolarity can affect this activation causing vasopressin excretion. The role of serum osmolarity and vasopressin concentration and its interaction remain still unexplored in AHF. The objective of our study was to evaluate the relationship of serum osmolarity with clinical parameters, vasopressin concentration, in-hospital course, and outcomes in AHF patients. The study group consisted of 338 AHF patients (male (76.3%), mean age of 68 ± 13 years) with serum osmolarity calculated by the equation: 1.86 × sodium [mmol/L] + (glucose [mg/dL]/18) + (urea [mg/dL]/2.8) + 9 and divided into osmolarity quartiles marked as: low: <287 mOsm/L, intermediate low: 287–294 mOsm/L, intermediate high: 295–304 mOsm/L, and high: >304 mOsm/L. There was an increasing age gradient in the groups and patients differed in the occurrence of comorbidities and baseline clinical and laboratory parameters. Importantly, analysis revealed that vasopressin presented a linear correlation with osmolarity (r = −0.221, p = 0.003) and its concentration decreased with quartiles (61.6 [44.0–81.0] vs. 57.8 [50.0–77.3] vs. 52.7 [43.1–69.2] vs. 45.0 [30.7–60.7] pg/mL, respectively, p = 0.034). This association across quartiles was observed among de novo AHF (63.6 [55.3–94.5] vs. 58.0 [50.7–78.6] vs. 52.0 [46.0–58.0] vs. 38.0 [27.0–57.0] pg/mL, respectively, p = 0.022) and was not statistically significant in patients with acute decompensated heart failure (ADHF) (59.5 [37.4–80.0] vs. 52.0 [38.0–74.5] vs. 57.0 [38.0–79.0] vs. 50.0 [33.0–84.0] pg/mL, respectively, p = 0.849). The worsening of renal function episodes were more frequent in quartiles with higher osmolarity (4 vs. 2 vs. 13 vs. 11%, respectively, p = 0.018) and patients that belonged to the quartiles with low and high osmolarity were characterized more often by incidence of worsening heart failure (20 vs. 9 vs. 10 vs. 22%, respectively, p = 0.032). There was also a U-shape distribution in relation to one-year mortality (31 vs. 19 vs. 23 vs. 37%, respectively, p = 0.022). In conclusion, there was an association of serum osmolarity with clinical status and both in-hospital and out-of-hospital outcomes. Moreover, the linear dependence between vasopressin concentration and serum osmolarity in the AHF population was identified and was driven mainly by patients with de novo AHF which suggests different pathophysiological paths in ADHF and AHF de novo. Full article

(This article belongs to the Special Issue Advances in Therapy for Heart Failure)

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17 pages, 662 KiB

Open AccessReview

Update on the Pharmacological Treatment of Primary Biliary Cholangitis

by Annarosa Floreani, Daniela Gabbia and Sara De Martin

Biomedicines 2022, 10(8), 2033; https://doi.org/10.3390/biomedicines10082033 - 20 Aug 2022

Cited by 8 | Viewed by 5995

Abstract

Ursodeoxycholic acid (UDCA) is the first-line therapy used for the treatment of PBC. In recent years, new pharmacological agents have been proposed for PBC therapy to cure UDCA-non-responders. Obeticholic acid (OCA) is registered in many countries for PBC, and fibrates also seem to [...] Read more.

Ursodeoxycholic acid (UDCA) is the first-line therapy used for the treatment of PBC. In recent years, new pharmacological agents have been proposed for PBC therapy to cure UDCA-non-responders. Obeticholic acid (OCA) is registered in many countries for PBC, and fibrates also seem to be effective in ameliorating biochemistry alteration and symptoms typical of PBC. Moreover, a variety of new agents, acting with different mechanisms of action, are under clinical evaluation for PBC treatment, including PPAR agonists, anti-NOX agents, immunomodulators, and mesenchymal stem cell transplantation. Since an insufficient amount of data is currently available about the effect of these novel approaches on robust clinical endpoints, such as transplant-free survival, their clinical approval needs to be supported by the consistent improvement of these parameters. The intensive research in this field will hopefully lead to a novel treatment landscape for PBC in the near future, with innovative therapies based on the combination of multiple agents acting on different pathogenetic mechanisms. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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22 pages, 3082 KiB

Open AccessReview

Role of Neuropilin 1 in COVID-19 Patients with Acute Ischemic Stroke

by Asma W. Al-Thomali, Hayder M. Al-kuraishy, Ali I. Al-Gareeb, Ali K. Al-buhadiliy, Michel De Waard, Jean-Marc Sabatier, Atif Ali Khan Khalil, Hebatallah M. Saad and Gaber El-Saber Batiha

Biomedicines 2022, 10(8), 2032; https://doi.org/10.3390/biomedicines10082032 - 20 Aug 2022

Cited by 37 | Viewed by 4641

Abstract

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can trigger the adaptive and innate immune responses, leading to uncontrolled inflammatory reactions and associated local and systematic tissue damage, along with thromboembolic disorders that may increase the risk of acute ischemic stroke (AIS) [...] Read more.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can trigger the adaptive and innate immune responses, leading to uncontrolled inflammatory reactions and associated local and systematic tissue damage, along with thromboembolic disorders that may increase the risk of acute ischemic stroke (AIS) in COVID-19 patients. The neuropilin (NRP-1) which is a co-receptor for the vascular endothelial growth factor (VEGF), integrins, and plexins, is involved in the pathogenesis of AIS. NRP-1 is also regarded as a co-receptor for the entry of SARS-CoV-2 and facilitates its entry into the brain through the olfactory epithelium. NRP-1 is regarded as a cofactor for binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2), since the absence of ACE2 reduces SARS-CoV-2 infectivity even in presence of NRP-1. Therefore, the aim of the present study was to clarify the potential role of NRP-1 in COVID-19 patients with AIS. SARS-CoV-2 may transmit to the brain through NRP-1 in the olfactory epithelium of the nasal cavity, leading to different neurological disorders, and therefore about 45% of COVID-19 patients had neurological manifestations. NRP-1 has the potential capability to attenuate neuroinflammation, blood–brain barrier (BBB) permeability, cerebral endothelial dysfunction (ED), and neuronal dysfunction that are uncommon in COVID-19 with neurological involvement, including AIS. Similarly, high NRP-1 serum level is linked with ED, oxidative stress, and the risk of pulmonary thrombosis in patients with severe COVID-19, suggesting a compensatory mechanism to overcome immuno-inflammatory disorders. In conclusion, NRP-1 has an important role in the pathogenesis of COVID-19 and AIS, and could be the potential biomarker linking the development of AIS in COVID-19. The present findings cannot provide a final conclusion, and thus in silico, experimental, in vitro, in vivo, preclinical, and clinical studies are recommended to confirm the potential role of NRP-1 in COVID-19, and to elucidate the pharmacological role of NRP-1 receptor agonists and antagonists in COVID-19. Full article

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

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24 pages, 735 KiB

Open AccessReview

The Role of Non-Coding RNAs in Glioma

by Anshika Goenka, Deanna Marie Tiek, Xiao Song, Rebeca Piatniczka Iglesia, Minghui Lu, Bo Hu and Shi-Yuan Cheng

Biomedicines 2022, 10(8), 2031; https://doi.org/10.3390/biomedicines10082031 - 20 Aug 2022

Cited by 21 | Viewed by 4665

Abstract

For decades, research in cancer biology has been focused on the protein-coding fraction of the human genome. However, with the discovery of non-coding RNAs (ncRNAs), it has become known that these entities not only function in numerous fundamental life processes such as growth, [...] Read more.

For decades, research in cancer biology has been focused on the protein-coding fraction of the human genome. However, with the discovery of non-coding RNAs (ncRNAs), it has become known that these entities not only function in numerous fundamental life processes such as growth, differentiation, and development, but also play critical roles in a wide spectrum of human diseases, including cancer. Dysregulated ncRNA expression is found to affect cancer initiation, progression, and therapy resistance, through transcriptional, post-transcriptional, or epigenetic processes in the cell. In this review, we focus on the recent development and advances in ncRNA biology that are pertinent to their role in glioma tumorigenesis and therapy response. Gliomas are common, and are the most aggressive type of primary tumors, which account for ~30% of central nervous system (CNS) tumors. Of these, glioblastoma (GBM), which are grade IV tumors, are the most lethal brain tumors. Only 5% of GBM patients survive beyond five years upon diagnosis. Hence, a deeper understanding of the cellular non-coding transcriptome might help identify biomarkers and therapeutic agents for a better treatment of glioma. Here, we delve into the functional roles of microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) in glioma tumorigenesis, discuss the function of their extracellular counterparts, and highlight their potential as biomarkers and therapeutic agents in glioma. Full article

(This article belongs to the Special Issue Glioma Metabolism, Epigenetics, and Microenvironment)

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14 pages, 1600 KiB

Open AccessArticle

MGMT Promoter Methylation as a Prognostic Factor in Primary Glioblastoma: A Single-Institution Observational Study

by Mateusz Szylberg, Paweł Sokal, Paulina Śledzińska, Marek Bebyn, Stanisław Krajewski, Łukasz Szylberg, Aneta Szylberg, Tadeusz Szylberg, Kamil Krystkiewicz, Marcin Birski, Marek Harat, Robert Włodarski and Jacek Furtak

Biomedicines 2022, 10(8), 2030; https://doi.org/10.3390/biomedicines10082030 - 20 Aug 2022

Cited by 32 | Viewed by 4149

Abstract

Glioblastoma is the most malignant central nervous system tumor, which represents 50% of all glial tumors. The understanding of glioma genesis, prognostic evaluation, and treatment planning has been significantly enhanced by the discovery of molecular genetic biomarkers. This study aimed to evaluate survival [...] Read more.

Glioblastoma is the most malignant central nervous system tumor, which represents 50% of all glial tumors. The understanding of glioma genesis, prognostic evaluation, and treatment planning has been significantly enhanced by the discovery of molecular genetic biomarkers. This study aimed to evaluate survival in patients with primary glioblastoma concerning O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation and other clinical factors. The study included 41 newly diagnosed glioblastoma patients treated from 2011 to 2014 in the 10th Military Research Hospital and Polyclinic, Poland. All patients underwent surgical resection followed by radiation and chemotherapy with alkylating agents. The MGMT promoter methylation was evaluated in all patients, and 43% were found to be methylated. In 26 and 15 cases, gross total resection and subtotal resection were conducted, respectively. Patients with a methylated MGMT promoter had a median survival of 504 days, while those without methylation had a median survival of 329 days. The group that was examined had a median age of 53. In a patient group younger than 53 years, those with methylation had significantly longer overall survival (639 days), compared to 433.5 days for patients without methylation. The most prolonged survival (551 days) was in patients with MGMT promoter methylation after gross total resection. The value of MGMT promoter methylation as a predictive biomarker is widely acknowledged. However, its prognostic significance remains unclear. Our findings proved that MGMT promoter methylation is also an essential positive prognostic biomarker. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology and Therapeutics in Poland)

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14 pages, 905 KiB

Open AccessReview

Biomarkers in Anal Cancer: Current Status in Diagnosis, Disease Progression and Therapeutic Strategies

by Maria Cecília Mathias-Machado, Renata D’Alpino Peixoto, Camila Motta Venchiarutti Moniz and Alexandre A. Jácome

Biomedicines 2022, 10(8), 2029; https://doi.org/10.3390/biomedicines10082029 - 20 Aug 2022

Cited by 5 | Viewed by 4143

Abstract

Squamous cell carcinoma of the anal canal (SCCA) is a rare neoplasm, but with rising incidence rates in the past few decades; it is etiologically linked with the human papillomavirus (HPV) infection and is especially prevalent in immunocompromised patients, mainly those infected with [...] Read more.

Squamous cell carcinoma of the anal canal (SCCA) is a rare neoplasm, but with rising incidence rates in the past few decades; it is etiologically linked with the human papillomavirus (HPV) infection and is especially prevalent in immunocompromised patients, mainly those infected with HIV. Fluoropyrimidine-based chemoradiotherapy remains the cornerstone of the treatment of non-metastatic disease, but the locally advanced disease still presents high rates of disease recurrence and systemic therapy of SCCA is an unmet clinical need. Despite sharing common molecular aspects with other HPV-related malignancies, such as cervical and head and neck cancers, SCCA presents specific epigenomic, genomic, and transcriptomic abnormalities, which suggest that genome-guided personalized therapies should be specifically designed for this disease. Actionable mutations are rare in SCCA and immune checkpoint inhibition has not yet been proven useful in an unselected population of patients. Therefore, advances in systemic therapy of SCCA will only be possible with the identification of predictive biomarkers and the subsequent development of targeted therapies or immunotherapeutic approaches that consider the unique tumor microenvironment and the intra- and inter-tumoral heterogeneity. In the present review, we address the molecular characterization of SCCA and discuss potential diagnostic, predictive and prognostic biomarkers of this complex and challenging disease. Full article

(This article belongs to the Special Issue Biomarkers in Anal Cancer: Current Status in Diagnosis, Disease Progression and Therapeutic Strategies)

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22 pages, 3414 KiB

Open AccessArticle

Machine Learning Data Analysis Highlights the Role of Parasutterella and Alloprevotella in Autism Spectrum Disorders

by Daniele Pietrucci, Adelaide Teofani, Marco Milanesi, Bruno Fosso, Lorenza Putignani, Francesco Messina, Graziano Pesole, Alessandro Desideri and Giovanni Chillemi

Biomedicines 2022, 10(8), 2028; https://doi.org/10.3390/biomedicines10082028 - 19 Aug 2022

Cited by 24 | Viewed by 4211

Abstract

In recent years, the involvement of the gut microbiota in disease and health has been investigated by sequencing the 16S gene from fecal samples. Dysbiotic gut microbiota was also observed in Autism Spectrum Disorder (ASD), a neurodevelopmental disorder characterized by gastrointestinal symptoms. However, [...] Read more.

In recent years, the involvement of the gut microbiota in disease and health has been investigated by sequencing the 16S gene from fecal samples. Dysbiotic gut microbiota was also observed in Autism Spectrum Disorder (ASD), a neurodevelopmental disorder characterized by gastrointestinal symptoms. However, despite the relevant number of studies, it is still difficult to identify a typical dysbiotic profile in ASD patients. The discrepancies among these studies are due to technical factors (i.e., experimental procedures) and external parameters (i.e., dietary habits). In this paper, we collected 959 samples from eight available projects (540 ASD and 419 Healthy Controls, HC) and reduced the observed bias among studies. Then, we applied a Machine Learning (ML) approach to create a predictor able to discriminate between ASD and HC. We tested and optimized three algorithms: Random Forest, Support Vector Machine and Gradient Boosting Machine. All three algorithms confirmed the importance of five different genera, including Parasutterella and Alloprevotella. Furthermore, our results show that ML algorithms could identify common taxonomic features by comparing datasets obtained from countries characterized by latent confounding variables. Full article

(This article belongs to the Special Issue Omics Data Analysis and Integration in Complex Diseases, 2nd Edition)

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Figure 1
Relative abundance of the genus identified in all the datasets. For each dataset, the mean relative abundance of the 85 genera has been evaluated for ASD patients and HC. The 20 most abundant genera are represented using different colors and the remaining genera are reported in the “Others” bin. Full article ">Figure 2
Principal Coordinate Analysis (PCoA) and Principal Component Analysis (PCA) were performed on microbial abundances. The phenotype variable is reported using a square or a circle for ASD and HC samples, respectively. Each color represents a different Project ID, namely one of the six datasets used in this study (AGP, Averina, Dan, Pulikkan, Vernocchi, Son and Zurita). (A) PCoA performed on original data; (B) PCoA performed after the removal of the batch effect using the ComBatfunction of the SVA package; (C) PCA performed on original data; (D) PCA performed after the removal of the batch effect using the ComBatfunction of the SVA package. Full article ">Figure 3
(A) Feature rank importance for all the 15 bacterial taxa identified by the feature selection procedure for the RF (green diamond), GBM (red circle) and SVM (orange triangle) algorithms. Feature selection for the (B) RF, (C) GBM and (D) SVM algorithms. On the y-axis, the mean precision value (evaluated on k = 5 fold) is reported. On the x-axis, the number of the n-th most relevant features used to train the algorithms is reported. Full article ">Figure 4
Results of the SHAP algorithm allow the visualization of the contribution of five features (bacterial genera) to classify a sample as ASD or HC. In this figure, each dot represents a sample, while the color indicates the microbial abundance. Red dots are samples for which a genus is abundant, while blue dots are genera that are poorly represented in a sample. Points that show an attribution greater than 0 are ASD samples, while points that show an attribution lower than 0 are HC samples. Full article ">

10 pages, 959 KiB

Open AccessArticle

TERT and TET2 Genetic Variants Affect Leukocyte Telomere Length and Clinical Outcome in Coronary Artery Disease Patients—A Possible Link to Clonal Hematopoiesis

by Trine B. Opstad, Svein Solheim, Alf-Åge R. Pettersen, Are A. Kalstad, Harald Arnesen and Ingebjørg Seljeflot

Biomedicines 2022, 10(8), 2027; https://doi.org/10.3390/biomedicines10082027 - 19 Aug 2022

Cited by 6 | Viewed by 2612

Abstract

Inherited and acquired mutations in hematopoietic stem cells can cause clonal expansion with increased risk of cardiovascular disease (CVD), a condition known for the clonal hematopoiesis of indeterminate potential (CHIP). Inherited genetic variants in two CHIP-associated genome loci, the telomerase gene telomerase enzyme [...] Read more.

Inherited and acquired mutations in hematopoietic stem cells can cause clonal expansion with increased risk of cardiovascular disease (CVD), a condition known for the clonal hematopoiesis of indeterminate potential (CHIP). Inherited genetic variants in two CHIP-associated genome loci, the telomerase gene telomerase enzyme reverse transcriptase (TERT) (rs7705526) and the epigenetic regulator ten–eleven translocation 2 (TET2) (rs2454206), were investigated in 1001 patients with stable coronary artery disease (CAD) (mean age 62 years, 22% women), with regards to cardiovascular outcome, comorbidities, and leukocyte telomere length. Over 2 years, mutated TERT increased the risk two-fold for major clinical events (MACEs) in all patients (p = 0.004), acute myocardial infarction (AMI) in male patients (p = 0.011), and stroke in female patients (p < 0.001). Mutated TET2 correlated with type 2 diabetes (p < 0.001), the metabolic syndrome (p = 0.002), as well as fasting glucose, HbA1c, and shorter telomeres (p = 0.032, p = 0.003, and p = 0.016, respectively). In conclusion, our results from stable CAD patients highlight TERTs’ role in CVD, and underline TET2s’ role in the epigenetic regulation of lifestyle-related diseases. Full article

(This article belongs to the Special Issue Atherosclerosis: Pathophysiology and Associations with Other Diseases)

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21 pages, 1130 KiB

Open AccessReview

Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology

by Alba Sebastián-Martín, Belén G. Sánchez, José M. Mora-Rodríguez, Alicia Bort and Inés Díaz-Laviada

Biomedicines 2022, 10(8), 2026; https://doi.org/10.3390/biomedicines10082026 - 19 Aug 2022

Cited by 27 | Viewed by 7291

Abstract

DPP4/CD26 is a single-pass transmembrane protein with multiple functions on glycemic control, cell migration and proliferation, and the immune system, among others. It has recently acquired an especial relevance due to the possibility to act as a receptor or co-receptor for SARS-CoV-2, as [...] Read more.

DPP4/CD26 is a single-pass transmembrane protein with multiple functions on glycemic control, cell migration and proliferation, and the immune system, among others. It has recently acquired an especial relevance due to the possibility to act as a receptor or co-receptor for SARS-CoV-2, as it has been already demonstrated for other coronaviruses. In this review, we analyze the evidence for the role of DPP4 on COVID-19 risk and clinical outcome, and its contribution to COVID-19 physiopathology. Due to the pathogenetic links between COVID-19 and diabetes mellitus and the hyperinflammatory response, with the hallmark cytokine storm developed very often during the disease, we dive deep into the functions of DPP4 on carbohydrate metabolism and immune system regulation. We show that the broad spectrum of functions regulated by DPP4 is performed both as a protease enzyme, as well as an interacting partner of other molecules on the cell surface. In addition, we provide an update of the DPP4 inhibitors approved by the EMA and/or the FDA, together with the newfangled approval of generic drugs (in 2021 and 2022). This review will also cover the effects of DPP4 inhibitors (i.e., gliptins) on the progression of SARS-CoV-2 infection, showing the role of DPP4 in this disturbing disease. Full article

(This article belongs to the Special Issue Past, Present and Future of COVID-19)

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12 pages, 1859 KiB

Open AccessArticle

Hemin Ameliorates the Inflammatory Activity in the Inflammatory Bowel Disease: A Non-Clinical Study in Rodents

by Inês Silva, Rita Correia, Rui Pinto and Vanessa Mateus

Biomedicines 2022, 10(8), 2025; https://doi.org/10.3390/biomedicines10082025 - 19 Aug 2022

Cited by 4 | Viewed by 2106

Abstract

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Currently, there is no cure, and pharmacological treatment aims to induce and maintain remission in patients, so it is essential to investigate new possible treatments. Hemin is a heme-oxygenase [...] Read more.

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Currently, there is no cure, and pharmacological treatment aims to induce and maintain remission in patients, so it is essential to investigate new possible treatments. Hemin is a heme-oxygenase inducer which can confer anti-inflammatory, cytoprotective, and antiapoptotic effects; therefore, it can be considered an asset for different gastrointestinal pathologies, namely for IBD. Aim: This experiment aims to evaluate the efficacy and safety of hemin, in a chronic 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rodents. Methods: The induction of chronic colitis consisted of five weekly intrarectal administrations of 1% TNBS. Then, the mice were treated daily with 5 mg/kg/day or 10 mg/kg/day of hemin, through intraperitoneal injections, for 14 days. Results: Hemin demonstrated an anti-inflammatory effect through the reduction in tumor necrosis factor (TNF)-? levels, fecal calprotectin, and fecal hemoglobin. It was also found to be safe in terms of extraintestinal manifestations, since hemin did not promote renal and/or hepatic changes. Conclusions: Hemin could become an interesting tool for new possible pharmacological approaches in the management of IBD. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases 2.0)

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