Biomedicines

15 pages, 4428 KiB

Open AccessArticle

The Effect of Radiotherapy on Cell Survival and Inflammatory Cytokine and Chemokine Secretion in a Co-Culture Model of Head and Neck Squamous Cell Carcinoma and Normal Cells

by Sybilla Matuszczak, Krzysztof Szczepanik, Aleksandra Grządziel, Alina Drzyzga, Tomasz Cichoń, Justyna Czapla, Ewelina Pilny and Ryszard Smolarczyk

Biomedicines 2023, 11(6), 1773; https://doi.org/10.3390/biomedicines11061773 - 20 Jun 2023

Cited by 1 | Viewed by 1404

Abstract

Radiotherapy (RT) is one of the main treatments for head and neck squamous cell carcinomas (HNSCCs). Unfortunately, radioresistance is observed in many cases of HNSCCs. The effectiveness of RT depends on both the direct effect inducing cell death and the indirect effect of [...] Read more.

Radiotherapy (RT) is one of the main treatments for head and neck squamous cell carcinomas (HNSCCs). Unfortunately, radioresistance is observed in many cases of HNSCCs. The effectiveness of RT depends on both the direct effect inducing cell death and the indirect effect of changing the tumor microenvironment (TME). Knowledge of interactions between TME components after RT may help to design a new combined treatment with RT. In the study, we investigated the effect of RT on cell survival and cell secretion in a co-culture model of HNSCCs in vitro. We examined changes in cell proliferation, colony formation, cell cycle phases, type of cell death, cell migration and secretion after irradiation. The obtained results suggest that the presence of fibroblasts and endothelial cells in co-culture with HNSCCs inhibits the function of cell cycle checkpoints G₁/S and G₂/M and allows cells to enter the next phase of the cell cycle. We showed an anti-apoptotic effect in co-culture of HNSCCs with fibroblasts or endothelial cells in relation to the execution phase of apoptosis, although we initially observed increased activation of the early phase of apoptosis in the co-cultures after irradiation. We hypothesize that the anti-apoptotic effect depends on increased secretion of IL-6 and MCP-1. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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28 pages, 1633 KiB

Open AccessSystematic Review

Update on Classic and Novel Approaches in Metastatic Triple-Negative Breast Cancer Treatment: A Comprehensive Review

by Salvatore Greco, Nicolò Fabbri, Riccardo Spaggiari, Alfredo De Giorgi, Fabio Fabbian and Antonio Giovine

Biomedicines 2023, 11(6), 1772; https://doi.org/10.3390/biomedicines11061772 - 20 Jun 2023

Cited by 4 | Viewed by 2194

Abstract

Triple-negative breast cancer (TNBC) accounts for almost 15% of all diagnosed breast cancers and often presents high rates of relapses and metastases, with generally poor prognosis despite multiple lines of treatment. Immunotherapy has radically changed the approach of clinicians towards TNBC in the [...] Read more.

Triple-negative breast cancer (TNBC) accounts for almost 15% of all diagnosed breast cancers and often presents high rates of relapses and metastases, with generally poor prognosis despite multiple lines of treatment. Immunotherapy has radically changed the approach of clinicians towards TNBC in the last two to three years, even if targeted and specific therapeutic options are still missing; this unmet need is further justified by the extreme molecular and clinical heterogeneity of this subtype of breast cancer and by the weak response to both single-agent and combined therapies. In March 2023, the National Comprehensive Cancer Network (NCCN), the main association of cancer centers in the United States, released the last clinical practice guidelines, with an update on classic and novel approaches in the field of breast cancer. The purpose of this comprehensive review is to summarize the latest findings in the setting of metastatic TNBC treatment, focusing on each category of drugs approved by the Food and Drug Administration (FDA) and included in the NCCN guidelines. We also introduce part of the latest published studies, which have reported new and promising molecules able to specifically target some of the biomarkers involved in TNBC pathogenesis. We searched the PubMed and Scopus databases for free full texts reported in the literature of the last 5 years, using the words “triple-negative breast cancer” or “TNBC” or “basal-like”. The articles were analyzed by the authors independently and double-blindly, and a total of 114 articles were included in the review. Full article

(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)

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17 pages, 8291 KiB

Open AccessArticle

Phytochemical Profiling and Anti-Fibrotic Activities of the Gemmotherapy Bud Extract of Corylus avellana in a Model of Liver Fibrosis on Diabetic Mice

by Cornel Balta, Hildegard Herman, Alina Ciceu, Bianca Mladin, Marcel Rosu, Alciona Sasu, Victor Eduard Peteu, Sorina Nicoleta Voicu, Mihaela Balas, Mihaela Gherghiceanu, Anca Dinischiotu, Neli Kinga Olah and Anca Hermenean

Biomedicines 2023, 11(6), 1771; https://doi.org/10.3390/biomedicines11061771 - 20 Jun 2023

Viewed by 1550

Abstract

In this study, we aimed to explore the hepatoprotective effects of the gemmotherapy bud extract of Corylus avellana in a model of liver fibrosis on diabetic mice. An evaluation of total flavonoids and polyphenols contents and LC/MS analyses were performed. Experimental fibrosis was [...] Read more.

In this study, we aimed to explore the hepatoprotective effects of the gemmotherapy bud extract of Corylus avellana in a model of liver fibrosis on diabetic mice. An evaluation of total flavonoids and polyphenols contents and LC/MS analyses were performed. Experimental fibrosis was induced with CCl₄ (2 mL/kg by i.p. injections twice a week for 7 weeks) in streptozotocin-induced diabetic mice. Our results showed a content of 6–7% flavonoids, while hyperoside and chlorogenic acids were highlighted in the bud extract. Toxic administration of CCl₄ increased oxidative stress, mRNA expression of the transforming growth factor-β1 (TGF-β1) and Smad 2/3, and reduced Smad 7 expression. Furthermore, up-regulation of α-smooth muscle actin (α-SMA) revealed an activation of hepatic stellate cells (HSCs), while collagen I (Col I) up-regulation and matrix metalloproteinases (MMPs) unbalance led to an altered extracellular matrix enriched in collagen, confirmed as well by a trichrome stain and electron microscopy analysis. Treatment with gemmotherapy extract significantly restored the liver architecture and the antioxidant balance, and significantly decreased collagen deposits in the liver and improved the liver function. Our results suggest that Corylus avellana gemmotherapy extract may have anti-fibrotic effects and could be useful in the prevention and treatment of liver fibrosis. The hepatoprotective mechanism is based on HSC inhibition, a reduction in oxidative stress and liver damage, a downregulation of the TGF-β1/Smad signaling pathway and a MMPs/TIMP rebalance. Full article

(This article belongs to the Special Issue New Strategies and Therapeutic Targets Involved in Liver Fibrosis Management)

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15 pages, 1180 KiB

Open AccessReview

The Role of the Microbiome in First Episode of Psychosis

by Lucero Nuncio-Mora, Nuria Lanzagorta, Humberto Nicolini, Emmanuel Sarmiento, Galo Ortiz, Fernanda Sosa and Alma Delia Genis-Mendoza

Biomedicines 2023, 11(6), 1770; https://doi.org/10.3390/biomedicines11061770 - 20 Jun 2023

Viewed by 3475

Abstract

The relationship between the gut-brain-microbiome axis has gained great importance in the study of psychiatric disorders, as it may represent a new target for their treatment. To date, the available literature suggests that the microbiota may influence the pathophysiology of several diseases, including [...] Read more.

The relationship between the gut-brain-microbiome axis has gained great importance in the study of psychiatric disorders, as it may represent a new target for their treatment. To date, the available literature suggests that the microbiota may influence the pathophysiology of several diseases, including psychosis. The aim of this review is to summarize the clinical and preclinical studies that have evaluated the differences in microbiota as well as the metabolic consequences related to psychosis. Current data suggest that the genera Lactobacillus and Megasphaera are increased in schizophrenia (SZ), as well as alterations in the glutamate-glutamine-GABA cycle, serum levels of tryptophan, kynurenic acid (KYNA), and short-chain fatty acids (SCFAs). There are still very few studies on early-onset psychosis, thus more studies are needed to be able to propose targeted therapies for a point when the disease has just started or has not yet progressed. Full article

(This article belongs to the Special Issue Biomarkers of Neurocognitive and Psychiatric Disorders: Focusing on Transdiagnostic Approaches)

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15 pages, 6092 KiB

Open AccessCase Report

Risankizumab: Daily Practice Experience of High Need Patients

by Alexandra M. G. Brunasso, Martina Burlando, Fabrizio Amoruso, Luisa Arancio, Giovanna Malara, Raffaella Manzo, Maria Antonia Montesu and Giacomo Caldarola

Biomedicines 2023, 11(6), 1769; https://doi.org/10.3390/biomedicines11061769 - 20 Jun 2023

Cited by 2 | Viewed by 1992

Abstract

Psoriasis is a chronic inflammatory disease which affects 29.5 million people worldwide and it can negatively impact quality of life, especially when it affects a special localization, such as nails, face, palms and soles, or intertriginous regions. Risankizumab is a humanized monoclonal antibody [...] Read more.

Psoriasis is a chronic inflammatory disease which affects 29.5 million people worldwide and it can negatively impact quality of life, especially when it affects a special localization, such as nails, face, palms and soles, or intertriginous regions. Risankizumab is a humanized monoclonal antibody which targets the p19 subunit of interleukin-23 and it is currently licensed also as systemic therapy for moderate to severe plaque psoriasis. Here, we present eight cases of patients with moderate to severe psoriasis treated with risankizumab with a significant efficacy in the remission of the disease. Our cases represent a real-world clinical setting and provide a valuable adjunct to results obtained in the selected patients usually included in controlled clinical trials. In our cases, risankizumab rapidly improved clinical manifestations and relieved symptoms in patients with moderate to severe psoriasis, regardless of the presence of comorbidities or the location of the plaques in special sites, and without any safety concerns. Full article

(This article belongs to the Special Issue Chronic Inflammatory Skin Diseases: From Bench to Bedside)

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15 pages, 324 KiB

Open AccessReview

Clinical Significance of PD-L1 Status in Circulating Tumor Cells for Cancer Management during Immunotherapy

by Areti Strati, Panagiota Economopoulou, Evi Lianidou and Amanda Psyrri

Biomedicines 2023, 11(6), 1768; https://doi.org/10.3390/biomedicines11061768 - 20 Jun 2023

Cited by 2 | Viewed by 1657

Abstract

The approval of monoclonal antibodies against programmed death-ligand 1 (PD-L1) and programmed cell death protein (PD1) has changed the landscape of cancer treatment. To date, many immune checkpoint inhibitors (ICIs) have been approved by the FDA for the treatment of metastatic cancer as [...] Read more.

The approval of monoclonal antibodies against programmed death-ligand 1 (PD-L1) and programmed cell death protein (PD1) has changed the landscape of cancer treatment. To date, many immune checkpoint inhibitors (ICIs) have been approved by the FDA for the treatment of metastatic cancer as well as locally recurrent advanced cancer. However, immune-related adverse events (irAEs) of ICIs highlight the need for biomarker analysis with strong predictive value. Liquid biopsy is an important tool for clinical oncologists to monitor cancer patients and administer or change appropriate therapy. CTCs frequently express PD-L1, and this constitutes a clinically useful and non-invasive method to assess PD-L1 status in real-time. This review summarizes all the latest findings about the clinical significance of CTC for the management of cancer patients during the administration of immunotherapy and mainly focuses on the assessment of PD-L1 expression in CTCs. Full article

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

11 pages, 960 KiB

Open AccessArticle

Acute Prosthetic Joint Infections with Poor Outcome Caused by Staphylococcus Aureus Strains Producing the Panton–Valentine Leukocidin

by Martina Maritati, Marco Manfrini, Maria Rosa Iaquinta, Alessandro Trentini, Silva Seraceni, Matteo Guarino, Anna Costanzini, Roberto De Giorgio, Gustavo Alberto Zanoli, Alessandro Borghi, Elisa Mazzoni, Giuseppe De Rito and Carlo Contini

Biomedicines 2023, 11(6), 1767; https://doi.org/10.3390/biomedicines11061767 - 20 Jun 2023

Viewed by 835

Abstract

The aim of this study was to investigate whether the presence of Staphylococcus aureus (SA) producing the Panton–Valentine leukocidin (PVL) affects the outcome of Prosthetic Joint Infection (PJI). Patients with acute and chronic PJI sustained by SA were prospectively enrolled at the orthopedic [...] Read more.

The aim of this study was to investigate whether the presence of Staphylococcus aureus (SA) producing the Panton–Valentine leukocidin (PVL) affects the outcome of Prosthetic Joint Infection (PJI). Patients with acute and chronic PJI sustained by SA were prospectively enrolled at the orthopedic unit of “Casa di Cura Santa Maria Maddalena”, from January 2019 to October 2021. PJI diagnosis was reached according to the diagnostic criteria of the International Consensus Meeting on PJI of Philadelphia. Synovial fluid obtained via joint aspirations was collected in order to isolate SA. The detection of PVL was performed via real-time quantitative PCR (RT-qPCR). The outcome assessment was performed using the criteria of the Delphi-based International Multidisciplinary Consensus. Twelve cases of PJI caused by SA were included. Nine (75%) cases were acute PJI treated using debridement, antibiotic and implant retention (DAIR); the remaining three (25%) were chronic PJI treated using two-stage (n = 2) and one-stage revision (n = 1), respectively. The SA strains that tested positive for PVL genes were 5/12 (41.6%,). Treatment failure was documented in three cases of acute PJI treated using DAIR, all supported by SA–PVL strains (p < 0.045). The remaining two cases were chronic PJI treated with a revision arthroplasty (one and two stage, respectively), with a 100% eradication rate in a medium follow-up of 24 months. Although a small case series, our study showed a 100% failure rate in acute PJI, probably caused by SA PVL-producing strains treated conservatively (p < 0.04). In this setting, toxin research should guide radical surgical treatment and targeted antibiotic therapy. Full article

(This article belongs to the Topic Biomarker Development and Application)

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12 pages, 749 KiB

Open AccessArticle

Vitamin D Supplementation and Adherence to World Cancer Research Fund (WCRF) Diet Recommendations for Colorectal Cancer Prevention: A Nested Prospective Cohort Study of a Phase II Randomized Trial

by Davide Serrano, Federica Bellerba, Harriet Johansson, Debora Macis, Valentina Aristarco, Chiara A. Accornero, Aliana Guerrieri-Gonzaga, Cristina M. Trovato, Maria Giulia Zampino, Emanuela Omodeo Salè, Bernardo Bonanni, Sara Gandini and Patrizia Gnagnarella

Biomedicines 2023, 11(6), 1766; https://doi.org/10.3390/biomedicines11061766 - 20 Jun 2023

Cited by 1 | Viewed by 1141

Abstract

Vitamin D and a healthy diet, based on World Cancer Research Fund (WCRF) recommendations, are considered key elements for colorectal cancer (CRC) prevention. In a CRC case-control study, we observed that CRC cases were often significantly Vitamin D deficient while subjects following WCRF [...] Read more.

Vitamin D and a healthy diet, based on World Cancer Research Fund (WCRF) recommendations, are considered key elements for colorectal cancer (CRC) prevention. In a CRC case-control study, we observed that CRC cases were often significantly Vitamin D deficient while subjects following WCRF recommendations significantly decreased their risk of developing CRC. We conducted a randomized phase-II trial (EudraCT number-2015-000467-14) where 74 CRC patients showed differences in response to Vitamin D supplementation, 2000 IU in average per day, according to gender and microbiota. The aim of this nested study is to correlate Vitamin D (supplementation, serum level and receptor polymorphisms), circulating biomarkers, and events (polyp/adenoma, CRC relapse and other cancers) in concomitant to WCRF recommendation adherence. Vitamin D supplementation did not modulate circulating biomarkers or follow-up events. FokI and TaqI VDR were associated with 25-hydroxyvitamin D (25OHD) levels. Patients following the WCRF recommendations had significantly lower leptin, significantly lower IL-6 (only in females), and significantly lower risk of events (HR = 0.41, 95%CI: 0.18–0.92; p = 0.03; median follow-up 2.6 years). Interestingly, no WCRF adherents had significantly more events if they were in the placebo (p < 0.0001), whereas no influence of WCRF was observed in the Vitamin D arm. While one-year Vitamin D supplementation might be too short to show significant preventive activity, a healthy diet and lifestyle should be the first step for preventive programs. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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27 pages, 1522 KiB

Open AccessReview

Move Your Body, Boost Your Brain: The Positive Impact of Physical Activity on Cognition across All Age Groups

by Felice Festa, Silvia Medori and Monica Macrì

Biomedicines 2023, 11(6), 1765; https://doi.org/10.3390/biomedicines11061765 - 20 Jun 2023

Cited by 6 | Viewed by 5836

Abstract

While the physical improvements from exercise have been well documented over the years, the impact of physical activity on mental health has recently become an object of interest. Physical exercise improves cognition, particularly attention, memory, and executive functions. However, the mechanisms underlying these [...] Read more.

While the physical improvements from exercise have been well documented over the years, the impact of physical activity on mental health has recently become an object of interest. Physical exercise improves cognition, particularly attention, memory, and executive functions. However, the mechanisms underlying these effects have yet to be fully understood. Consequently, we conducted a narrative literature review concerning the association between acute and chronic physical activity and cognition to provide an overview of exercise-induced benefits during the lifetime of a person. Most previous papers mainly reported exercise-related greater expression of neurotransmitter and neurotrophic factors. Recently, structural and functional magnetic resonance imaging techniques allowed for the detection of increased grey matter volumes for specific brain regions and substantial modifications in the default mode, frontoparietal, and dorsal attention networks following exercise. Here, we highlighted that physical activity induced significant changes in functional brain activation and cognitive performance in every age group and could counteract psychological disorders and neural decline. No particular age group gained better benefits from exercise, and a specific exercise type could generate better cognitive improvements for a selected target subject. Further research should develop appropriate intervention programs concerning age and comorbidity to achieve the most significant cognitive outcomes. Full article

(This article belongs to the Special Issue Genetic, Epigenetic, Environmental, and Pharmacological Models for Neuroscience, Neurologic Diseases, and Psychiatric Disorders: Advancement in Bench-to-Bedside Translational Research)

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12 pages, 1013 KiB

Open AccessArticle

High Rate of Mutations of Adhesion Molecules and Extracellular Matrix Glycoproteins in Patients with Adult-Onset Focal and Segmental Glomerulosclerosis

by Sara Marcos González, Emilio Rodrigo Calabia, Ignacio Varela, Michal Červienka, Javier Freire Salinas and José Javier Gómez Román

Biomedicines 2023, 11(6), 1764; https://doi.org/10.3390/biomedicines11061764 - 20 Jun 2023

Viewed by 1036

Abstract

(1) Background: Focal and segmental glomerulosclerosis (FSGS) is a pattern of injury that results from podocyte loss in the setting of a wide variety of injurious mechanisms. These include both acquired and genetic as well as primary and secondary causes, or a combination [...] Read more.

(1) Background: Focal and segmental glomerulosclerosis (FSGS) is a pattern of injury that results from podocyte loss in the setting of a wide variety of injurious mechanisms. These include both acquired and genetic as well as primary and secondary causes, or a combination thereof, without optimal therapy, and a high rate of patients develop end-stage renal disease (ESRD). Genetic studies have helped improve the global understanding of FSGS syndrome; thus, we hypothesize that patients with primary FSGS may have underlying alterations in adhesion molecules or extracellular matrix glycoproteins related to previously unreported mutations that may be studied through next-generation sequencing (NGS). (2) Methods: We developed an NGS panel with 29 genes related to adhesion and extracellular matrix glycoproteins. DNA was extracted from twenty-three FSGS patients diagnosed by renal biopsy; (3) Results: The average number of accumulated variants in FSGS patients was high. We describe the missense variant ITGB3c.1199G>A, which is considered pathogenic; in addition, we discovered the nonsense variant CDH1c.499G>T, which lacks a Reference SNP (rs) Report and is considered likely pathogenic. (4) Conclusions: To the best of our knowledge, this is the first account of a high rate of change in extracellular matrix glycoproteins and adhesion molecules in individuals with adult-onset FSGS. The combined effect of all these variations may result in a genotype that is vulnerable to the pathogenesis of glomerulopathy. Full article

(This article belongs to the Special Issue Genetic Research on Kidney Diseases)

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10 pages, 806 KiB

Open AccessReview

Low-Dose Estrogens as Neuroendocrine Modulators in Functional Hypothalamic Amenorrhea (FHA): The Putative Triggering of the Positive Feedback Mechanism(s)

by Christian Battipaglia, Tabatha Petrillo, Elisa Semprini, Francesco Ricciardiello, Maria Laura Rusce, Greta Prampolini, Fedora Ambrosetti, Alessandra Sponzilli and Alessandro D. Genazzani

Biomedicines 2023, 11(6), 1763; https://doi.org/10.3390/biomedicines11061763 - 20 Jun 2023

Viewed by 2068

Abstract

Functional hypothalamic amenorrhea (FHA) is a non-organic reversible chronic endocrine disorder characterized by an impaired pulsatile secretion of the gonadotropin-releasing hormone (GnRH) from the hypothalamus. This impaired secretion, triggered by psychosocial and metabolic stressors, leads to an abnormal pituitary production of gonadotropins. As [...] Read more.

Functional hypothalamic amenorrhea (FHA) is a non-organic reversible chronic endocrine disorder characterized by an impaired pulsatile secretion of the gonadotropin-releasing hormone (GnRH) from the hypothalamus. This impaired secretion, triggered by psychosocial and metabolic stressors, leads to an abnormal pituitary production of gonadotropins. As LH and FSH release is defective, the ovarian function is steadily reduced, inducing a systemic hypoestrogenic condition characterized by amenorrhea, vaginal atrophy, mood changes and increased risk of osteoporosis and cardiovascular disease. Diagnosis of FHA is made excluding other possible causes for secondary amenorrhea, and it is based upon the findings of low serum gonadotropins and estradiol (E2) with evidence of precipitating factors (excessive exercise, low weight, stress). Treatments of women with FHA include weight gain through an appropriate diet and physical activity reduction, psychological support, and integrative approach up to estrogen replacement therapy. If no spontaneous ovarian function is restored, assisted reproductive technologies may be used when pregnancy is desired. Because subjects with FHA are hypoestrogenic, the use of low-dose estrogens has been proposed as a putative treatment to positively modulate the spontaneous restart of gonadotropin secretion, counteracting the blockade of the reproductive axis triggered by stress acting through the neuroendocrine pathways at the basis of positive feedback of estrogens. The mechanism through which low-dose estrogens acts is still unknown, but kisspeptin-secreting neurons may be involved. Full article

(This article belongs to the Special Issue State-of-the-Art Endocrinology and Metabolism Research in Italy)

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13 pages, 328 KiB

Open AccessReview

Vitamin D: Can Gender Medicine Have a Role?

by Tiziana Ciarambino, Pietro Crispino, Giovanni Minervini and Mauro Giordano

Biomedicines 2023, 11(6), 1762; https://doi.org/10.3390/biomedicines11061762 - 19 Jun 2023

Cited by 2 | Viewed by 1298

Abstract

This narrative review aims to shed light on the role of gender differences, on the biological and molecular functions in the main pathological mechanisms that recognize the role of vitamin D. Vitamin D deficiency is widespread worldwide, but it is still very controversial [...] Read more.

This narrative review aims to shed light on the role of gender differences, on the biological and molecular functions in the main pathological mechanisms that recognize the role of vitamin D. Vitamin D deficiency is widespread worldwide, but it is still very controversial whether the amount of vitamin D taken daily is actually the only problem related to its biological functions. Currently, the plasma concentration of 25-hydroxyvitamin D represents the only indicator of the circulating blood quota. The concept is that the biological function of vitamin D is not only linked to its circulating levels, but it is hypothesized that its biological functions depend, above all, on its total bioavailability. In particular, vitamin D circulates for the most part linked to albumin and vitamin D binding protein (DBP), which depend on various pathological conditions and physiologically, above all, the function of the latter is regulated by estrogens, glucocorticoids, and inflammatory cytokines. During her life, women undergo various changes in the hormonal and sexual sphere concerning menarche, possible pregnancies, and breastfeeding but also the use of contraceptives and, finally, the transition from the period of fertility to menopause. Each of these phases presents specific needs and, consequently, sometimes also specific criticalities. Studies on young women have shown that vitamin D deficiency is present in 58 to 91% of cases. Obesity, metabolic disorders, and variation in estrogen contraction may affect vitamin D deficiency due to the decreased bioavailability from dietary sources due to deposition in body fat compartments. Full article

(This article belongs to the Special Issue Feature Reviews in Cerebrovascular Research)

34 pages, 786 KiB

Open AccessReview

Tumor Microenvironment Remodeling in Gastrointestinal Cancer: Role of miRNAs as Biomarkers of Tumor Invasion

by Valeria Lucarini, Daniela Nardozi, Valentina Angiolini, Monica Benvenuto, Chiara Focaccetti, Raffaele Carrano, Zein Mersini Besharat, Roberto Bei and Laura Masuelli

Biomedicines 2023, 11(6), 1761; https://doi.org/10.3390/biomedicines11061761 - 19 Jun 2023

Viewed by 1310

Abstract

Gastrointestinal (GI) cancers are the most frequent neoplasm, responsible for half of all cancer-related deaths. Metastasis is the leading cause of death from GI cancer; thus, studying the processes that regulate cancer cell migration is of paramount importance for the development of new [...] Read more.

Gastrointestinal (GI) cancers are the most frequent neoplasm, responsible for half of all cancer-related deaths. Metastasis is the leading cause of death from GI cancer; thus, studying the processes that regulate cancer cell migration is of paramount importance for the development of new therapeutic strategies. In this review, we summarize the mechanisms adopted by cancer cells to promote cell migration and the subsequent metastasis formation by highlighting the key role that tumor microenvironment components play in deregulating cellular pathways involved in these processes. We, therefore, provide an overview of the role of different microRNAs in promoting tumor metastasis and their role as potential biomarkers for the prognosis, monitoring, and diagnosis of GI cancer patients. Finally, we relate the possible use of nutraceuticals as a new strategy for targeting numerous microRNAs and different pathways involved in GI tumor invasiveness. Full article

(This article belongs to the Special Issue Recent Advances in Tumor Cell Migration)

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9 pages, 659 KiB

Open AccessReview

Laboratory Diagnosis of Antiphospholipid Syndrome in Anticoagulated Patients

by Armando Tripodi, Erica Scalambrino, Marigrazia Clerici and Flora Peyvandi

Biomedicines 2023, 11(6), 1760; https://doi.org/10.3390/biomedicines11061760 - 19 Jun 2023

Cited by 5 | Viewed by 3814

Abstract

The laboratory diagnosis of antiphospholipid syndrome (APS) requires the measurement of solid-phase antibodies to cardiolipin or β2-Glycoprotein-I and the search for lupus anticoagulant (LA). The diagnosis of patients whilst on anticoagulation is impaired by the difficult interpretation of results, at least for LA, [...] Read more.

The laboratory diagnosis of antiphospholipid syndrome (APS) requires the measurement of solid-phase antibodies to cardiolipin or β2-Glycoprotein-I and the search for lupus anticoagulant (LA). The diagnosis of patients whilst on anticoagulation is impaired by the difficult interpretation of results, at least for LA, owing to the fact that prolongations of clotting times induced by LA superimpose those induced by anticoagulants. This is a matter of concern as treating physicians very often need to know the APS status of their patients to make a decision on secondary antithrombotic prophylaxis. This article aims to review the effect brought about by anticoagulants on APS diagnosis and discuss the options that can be used to overcome such an effect. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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11 pages, 567 KiB

Open AccessArticle

Treatment with Myo-Inositol Does Not Improve the Clinical Features in All PCOS Phenotypes

by Vittorio Unfer, Michele Russo, Cesare Aragona, Gabriele Bilotta, Mario Montanino Oliva and Mariano Bizzarri

Biomedicines 2023, 11(6), 1759; https://doi.org/10.3390/biomedicines11061759 - 19 Jun 2023

Cited by 3 | Viewed by 4470

Abstract

Background: The aim of the present study is to investigate the effects produced by a treatment with myo-Inositol (myo-Ins) in women presenting polycystic ovary syndrome (PCOS) of different phenotypes. Methods: We performed a retrospective study to evaluate whether patients presenting different PCOS phenotypes, [...] Read more.

Background: The aim of the present study is to investigate the effects produced by a treatment with myo-Inositol (myo-Ins) in women presenting polycystic ovary syndrome (PCOS) of different phenotypes. Methods: We performed a retrospective study to evaluate whether patients presenting different PCOS phenotypes, treated for 6 months with myo-Ins, might exhibit a differential response to the treatment. On this premise, we clustered women with PCOS phenotypes A, B, and C in the first study group (hyperandrogenic PCOS or H-PCOS), and women presenting PCOS phenotype D in a separate study group (non-hyperandrogenic PCOS or NH-PCOS) to evaluate if the presence of hyperandrogenism, shared by H-PCOS, might imply a metabolic/endocrine condition rather than a gynecological issue. Results: The administration of myo-Ins induced a significant improvement in metabolic and endocrine parameters in H-PCOS, while the effects on NH-PCOS were negligible. Additionally, myo-Ins treatment improved the endometrial thickness of H-PCOS. Conclusions: Subjects selected for the study exhibited a differential response to myo-Ins therapy according to their PCOS phenotypes. The data suggest that the same treatment might not equally improve the parameters of the PCOS condition in each sub-group of patients. It is crucial to distinguish the various phenotypes to properly select the therapeutical approach. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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16 pages, 32659 KiB

Open AccessArticle

Chromosomal Aberration t(14;17)(q32;q21) Simultaneously Activates HOXB5 and miR10a in Triple-Hit B-Cell Lymphoma

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

Biomedicines 2023, 11(6), 1758; https://doi.org/10.3390/biomedicines11061758 - 19 Jun 2023

Viewed by 1106

Abstract

BCL2, BCL6 and MYC are major oncogenes in B-cell lymphoma. Their aberrant activation frequently occurs via chromosomal translocations which juxtapose light or heavy chain immunoglobulin (IG) genes to BCL2 and MYC or fuse diverse partner genes with BCL6. So-called double-hit lymphomas [...] Read more.

BCL2, BCL6 and MYC are major oncogenes in B-cell lymphoma. Their aberrant activation frequently occurs via chromosomal translocations which juxtapose light or heavy chain immunoglobulin (IG) genes to BCL2 and MYC or fuse diverse partner genes with BCL6. So-called double-hit lymphomas usually carry BCL2 and MYC rearrangements, while triple-hit lymphomas additionally bear BCL6-fusions. All these translocations are of diagnostic relevance and usually denote poor prognosis. Here, we genomically characterized classic follicular lymphoma (FL) cell line SC-1, thereby identifying t(14;18)(q32;q21) juxtaposing IGH and BCL2, t(8;14)(q24;q32) juxtaposing IGH and MYC, and t(3;3)(q25;q27) fusing MBNL1 to BCL6. In addition, we found that SC-1 carries a novel chromosomal rearrangement, t(14;17)(q32;q21), which, though present at establishment, has remained unreported until now. We further show that t(14;17)(q32;q21) juxtaposes IGH with the HOXB gene cluster at 17q21 and affect the oncogenic activation of both homeobox gene HOXB5 and neighboring micro-RNA gene miR10a. Moreover, we detected aberrant overexpression of HOXB5 in subsets of Burkitt lymphoma, FL, and multiple myeloma patients, confirming the clinical relevance of its deregulation. In SC-1, HOXB5 activation was additionally supported by co-expression of hematopoietic stem cell factor ZNF521, indicating an aberrant impact in cell differentiation. Functional investigations showed that HOXB5 represses the apoptotic driver BCL2L11 and promotes survival in the presence of etoposide, and that miR10a inhibits BCL6 and may thus play an oncogenic role in later stages of lymphomagenesis. Collectively, we characterize triple-hit B-cell line SC-1 and identify the aberrant expression of HOXB5 and miR10a, both novel oncogenes in B-cell lymphoma. Full article

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

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15 pages, 2014 KiB

Open AccessArticle

Efficacy of Early Optimization of Infliximab Guided by Therapeutic Drug Monitoring during Induction—A Prospective Trial

by Karoline Soares Garcia, Matheus Freitas Cardoso de Azevedo, Alexandre de Sousa Carlos, Luísa Leite Barros, Jane Oba, Carlos Walter Sobrado Junior, Aytan Miranda Sipahi, Olívia Duarte de Castro Alves, Tomás Navarro-Rodriguez, Rogério Serafim Parra, Júlio Maria Fonseca Chebli, Liliana Andrade Chebli, Cristina Flores, Andrea Vieira, Christianne Damasceno Arcelino do Ceará, Natália Sousa Freitas Queiroz and Aderson Omar Mourão Cintra Damião

Biomedicines 2023, 11(6), 1757; https://doi.org/10.3390/biomedicines11061757 - 19 Jun 2023

Cited by 1 | Viewed by 1431

Abstract

Therapeutic drug monitoring (TDM) during induction therapy with anti-tumor necrosis factor drugs has emerged as a strategy to optimize response to these biologics and avoid undesired outcomes related to inadequate drug exposure. This study aimed to describe clinical, biological, and endoscopic remission rates [...] Read more.

Therapeutic drug monitoring (TDM) during induction therapy with anti-tumor necrosis factor drugs has emerged as a strategy to optimize response to these biologics and avoid undesired outcomes related to inadequate drug exposure. This study aimed to describe clinical, biological, and endoscopic remission rates at six months in Brazilian inflammatory bowel disease (IBD) patients following a proactive TDM algorithm guided by IFX trough levels (ITL) and antibodies to IFX (ATI) levels during induction, at week six. A total of 111 IBD patients were prospectively enrolled, excluding those previously exposed to the drug. ITL ≥ 10 μg/mL was considered optimal. Patients with suboptimal ITL (<10 µg/mL) were guided according to ATI levels. Those who presented ATI ≤ 200 ng/mL underwent dose intensification in the maintenance phase, and patients with ATI > 200 ng/mL discontinued IFX. In our study, proactive TDM was associated with persistence in the IFX rate at six months of 82.9%. At that time, rates of clinical, biological, and endoscopic remission in patients under IFX treatment were 80.2%, 73.9%, and 48.1%, respectively. Applying a simplified TDM-guided algorithm during induction seems feasible and can help improve patients’ outcomes in clinical practice. Full article

(This article belongs to the Special Issue Advances in Therapeutic Drug Monitoring)

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14 pages, 8047 KiB

Open AccessArticle

A Deep-Learning-Based Method Can Detect Both Common and Rare Genetic Disorders in Fetal Ultrasound

by Jiajie Tang, Jin Han, Jiaxin Xue, Li Zhen, Xin Yang, Min Pan, Lianting Hu, Ru Li, Yuxuan Jiang, Yongling Zhang, Xiangyi Jing, Fucheng Li, Guilian Chen, Kanghui Zhang, Fanfan Zhu, Can Liao and Long Lu

Biomedicines 2023, 11(6), 1756; https://doi.org/10.3390/biomedicines11061756 - 19 Jun 2023

Cited by 5 | Viewed by 2132

Abstract

A global survey indicates that genetic syndromes affect approximately 8% of the population, but most genetic diagnoses can only be performed after babies are born. Abnormal facial characteristics have been identified in various genetic diseases; however, current facial identification technologies cannot be applied [...] Read more.

A global survey indicates that genetic syndromes affect approximately 8% of the population, but most genetic diagnoses can only be performed after babies are born. Abnormal facial characteristics have been identified in various genetic diseases; however, current facial identification technologies cannot be applied to prenatal diagnosis. We developed Pgds-ResNet, a fully automated prenatal screening algorithm based on deep neural networks, to detect high-risk fetuses affected by a variety of genetic diseases. In screening for Trisomy 21, Trisomy 18, Trisomy 13, and rare genetic diseases, Pgds-ResNet achieved sensitivities of 0.83, 0.92, 0.75, and 0.96, and specificities of 0.94, 0.93, 0.95, and 0.92, respectively. As shown in heatmaps, the abnormalities detected by Pgds-ResNet are consistent with clinical reports. In a comparative experiment, the performance of Pgds-ResNet is comparable to that of experienced sonographers. This fetal genetic screening technology offers an opportunity for early risk assessment and presents a non-invasive, affordable, and complementary method to identify high-risk fetuses affected by genetic diseases. Additionally, it has the capability to screen for certain rare genetic conditions, thereby enhancing the clinic’s detection rate. Full article

(This article belongs to the Special Issue New Challenges and Opportunities for Artificial Intelligence in Human Disease and Health)

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12 pages, 285 KiB

Open AccessReview

Better Safe than Sorry: Rheumatoid Arthritis, Interstitial Lung Disease, and Medication—A Narrative Review

by Iulia-Tania Andronache, Victoria-Cristina Şuţa, Maria Şuţa, Sabina-Livia Ciocodei, Liliana Vladareanu, Alina Doina Nicoara and Oana Cristina Arghir

Biomedicines 2023, 11(6), 1755; https://doi.org/10.3390/biomedicines11061755 - 19 Jun 2023

Cited by 1 | Viewed by 1836

Abstract

It is well known that rheumatoid arthritis (RA) patients are at an increased risk of developing non-infectious pulmonary complications, especially interstitial lung disease (ILD); however, the clinician must keep in mind that lung disease could not only be a manifestation of the underlying [...] Read more.

It is well known that rheumatoid arthritis (RA) patients are at an increased risk of developing non-infectious pulmonary complications, especially interstitial lung disease (ILD); however, the clinician must keep in mind that lung disease could not only be a manifestation of the underlying condition, but also a consequence of using disease-modifying therapies. New-onset ILD or ILD worsening has also been reported as a possible consequence of both conventional disease-modifying antirheumatic drugs (DMARDs) and biologic agents. This study is a narrative review of the current literature regarding the potential risk of developing interstitial lung disease along with the administration of specific drugs used in controlling rheumatoid arthritis. Its purpose is to fill knowledge gaps related to this challenging patient cohort by addressing various aspects of the disease, including prevalence, disease features, treatment strategies, and patient outcomes. Full article

(This article belongs to the Special Issue Molecular Mechanisms, Diagnoses, and Treatments of Respiratory Diseases)

12 pages, 1008 KiB

Open AccessArticle

Continuous Glucose Monitoring as an Additional Tool in Early Cystic Fibrosis-Related Diabetes Monitoring and in Evaluation of Short-Term Sitagliptin Response

by Fernando Sebastian-Valles, José Alfonso Arranz Martín, Rosa María Girón, Carolina Knott-Torcal, Miguel Antonio Sampedro-Nuñez, Jose Carlos Martin-Adan, Jessica Jiménez-Díaz and Mónica Marazuela

Biomedicines 2023, 11(6), 1754; https://doi.org/10.3390/biomedicines11061754 - 19 Jun 2023

Cited by 2 | Viewed by 1217

Abstract

Cystic fibrosis-related diabetes (CFRD) is a complication associated with a negative prognosis in patients with cystic fibrosis (CF). Although the oral glucose tolerance test (OGTT) is the widely recommended screening test for CFRD diagnosis, continuous glucose monitoring (CGM) is increasingly considered a useful [...] Read more.

Cystic fibrosis-related diabetes (CFRD) is a complication associated with a negative prognosis in patients with cystic fibrosis (CF). Although the oral glucose tolerance test (OGTT) is the widely recommended screening test for CFRD diagnosis, continuous glucose monitoring (CGM) is increasingly considered a useful and easy-to-perform test for diagnosis and follow-up in clinical practice. Regarding CFRD treatment, although insulin is the classic approved pharmacological option, incretins could also be a helpful alternative in early stages. CGM could be also a useful tool to measure the early response to this therapy. METHODS: We studied 25 CF patients with abnormal OGTT results and compared glucose and insulin levels during the OGTTs with CGM results as a tool for early CFRD diagnosis. In addition, we evaluated glycaemic control with CGM before and after treatment with sitagliptin. RESULTS: A correlation was found between lower plasma insulin levels during the OGTTs and higher average sensor glucose (p = 0.009) and hyperglycaemic excursions (p = 0.017). The CGM data on sitagliptin treatment (n = 25) showed an average glycaemic improvement from 124.2 to 117.2 mg/dL (p = 0.002) with a 5.6-point standard deviation of glucose decrease (p < 0.001). Hyperglycaemic excursions ≥200 mg/dL diminished 57.1% (p = 0.021). Both time in range and time above 180 mg/dL improved during treatment (p = 0.036 and p = 0.006, respectively). CONCLUSION: CGM is a useful tool that offers valuable information for both the diagnosis and the management of CFRD. Lower plasma insulin levels during OGTTs are associated with a poor ambulatory glucose profile in CGM. Sitagliptin could play an important role in the treatment of the early stages of CFRD. Full article

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

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10 pages, 433 KiB

Open AccessArticle

Association between Low-Density Lipoprotein Cholesterol and Vascular Biomarkers in Primary Prevention

by Michaela Kozakova, Carmela Morizzo, Giuli Jamagidze, Daniele Della Latta, Sara Chiappino, Dante Chiappino and Carlo Palombo

Biomedicines 2023, 11(6), 1753; https://doi.org/10.3390/biomedicines11061753 - 18 Jun 2023

Cited by 1 | Viewed by 1143

Abstract

Several noninvasive vascular biomarkers have been proposed to improve risk stratification for atherothrombotic events. To identify biomarkers suitable for detecting intermediate-risk individuals who might benefit from lipid-lowering treatment in primary prevention, the present study tested the association of plasma LDL-cholesterol with coronary artery [...] Read more.

Several noninvasive vascular biomarkers have been proposed to improve risk stratification for atherothrombotic events. To identify biomarkers suitable for detecting intermediate-risk individuals who might benefit from lipid-lowering treatment in primary prevention, the present study tested the association of plasma LDL-cholesterol with coronary artery calcification (CAC) Agatston score, high carotid and femoral intima-media thickness (IMT), low carotid distensibility and high carotid-femoral pulse-wave velocity in 260 asymptomatic individuals at intermediate cardiovascular risk and without diabetes and lipid-lowering treatment. High or low vascular biomarkers were considered when their value was above the 95th or below the 5th percentile, respectively, of the distribution in the healthy or in the study population. LDL-cholesterol was independently associated with the CAC score = 0 (OR 0.67; 95%CI 0.48–0.92, p = 0.01), CAC score > 100 (1.59; 1.08–2.39, p = 0.01) and high common femoral artery (CFA) IMT (1.89; 1.19–3.06, p < 0.01), but not with other biomarkers. Our data confirm that in individuals at intermediate risk, lipid-lowering treatment can be avoided in the presence of a CAC score = 0, while it should be used with a CAC score > 100. CFA IMT could represent a useful biomarker for decisions regarding lipid-lowering treatment. However, sex- and age-specific reference values should be established in a large healthy population. Full article

(This article belongs to the Special Issue Atherosclerotic Cardiovascular Disease (ASCVD), Dyslipidemia, and CV Residual Risk: From Mechanisms to Therapeutic Approaches 2.0)

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16 pages, 1053 KiB

Open AccessReview

Nanomedicine in the Management of Alzheimer’s Disease: State-of-the-Art

by Shehla Nasar Mir Najib Ullah, Obaid Afzal, Abdulmalik Saleh Alfawaz Altamimi, Hissana Ather, Shaheen Sultana, Waleed H. Almalki, Pragya Bharti, Ankit Sahoo, Khusbu Dwivedi, Gyas Khan, Shahnaz Sultana, Abdulaziz Alzahrani and Mahfoozur Rahman

Biomedicines 2023, 11(6), 1752; https://doi.org/10.3390/biomedicines11061752 - 18 Jun 2023

Cited by 10 | Viewed by 4750

Abstract

Alzheimer’s disease (AD) is a deadly, progressive, and irreversible brain condition that impairs cognitive abilities. Globally, it affects 32.6 million individuals, and if no viable therapies are available by 2050, that figure might rise to 139 million. The current course of treatment enhances [...] Read more.

Alzheimer’s disease (AD) is a deadly, progressive, and irreversible brain condition that impairs cognitive abilities. Globally, it affects 32.6 million individuals, and if no viable therapies are available by 2050, that figure might rise to 139 million. The current course of treatment enhances cognitive abilities and temporarily relieves symptoms, but it does not halt or slow the disease’s development. Additionally, treatments are primarily offered in conventional oral dosage forms, and conventional oral treatments lack brain specialization and cause adverse effects, resulting in poor patient compliance. A potential nanotechnology-based strategy can improve the bioavailability and specificity of the drug targeting in the brain. Furthermore, this review extensively summarizes the applications of nanomedicines for the effective delivery of drugs used in the management of AD. In addition, the clinical progress of nanomedicines in AD is also discussed, and the challenges facing the clinical development of nanomedicines are addressed in this article. Full article

(This article belongs to the Special Issue Targeted Drug Delivery in Immune Diseases)

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13 pages, 3572 KiB

Open AccessArticle

Effects of the Co-Overexpression of the BCL and BDNF Genes on the Gamma-Aminobutyric Acid-Ergic Differentiation of Wharton’s-Jelly-Derived Mesenchymal Stem Cells

by Paulina Borkowska, Julia Morys, Aleksandra Zielinska and Jan Kowalski

Biomedicines 2023, 11(6), 1751; https://doi.org/10.3390/biomedicines11061751 - 18 Jun 2023

Cited by 1 | Viewed by 1188

Abstract

One of the problems with using MSCs (mesenchymal stem cells) to treat different neurodegenerative diseases of the central nervous system is their low ability to spontaneously differentiate into functional neurons. The aim of this study was to investigate how the co-overexpression of the [...] Read more.

One of the problems with using MSCs (mesenchymal stem cells) to treat different neurodegenerative diseases of the central nervous system is their low ability to spontaneously differentiate into functional neurons. The aim of this study was to investigate how the co-overexpression of the BCL and BDNF genes affects the ability of genetically modified MSCs to differentiate into GABA-ergic neurons. A co-overexpression of two genes was performed, one of which, BCL, was supposed to increase the resistance of the cells to the toxic agents in the brain environment. The second one, BDNF, was supposed to direct the cells onto the neuronal differentiation pathway. As a result, the co-overexpression of both BCL2 + BDNF and BCLXL + BDNF caused an increase in the MAP2 gene expression level (a marker of the neuronal pathway) and the SYP gene that is associated with synaptogenesis. In both cases, approximately 18% of the genetically modified and then differentiated cells exhibited the presence of the GAD protein, which is characteristic of GABA-ergic neurons. Despite the presence of GAD, after both modifications, only the BCL2 and BDNF co-overexpression correlated with the ability of the modified cells to release gamma-aminobutyric acid (GABA) after depolarization. Our study identified a novel model of genetically engineered MSCs that can be used as a tool to deliver the antiapoptotic proteins (BCL) and neurotrophic factor (BDNF) directly into the brain microenvironment. Additionally, in the investigated model, the genetically modified MSCs could easily differentiate into functional GABA-ergic neurons and, moreover, due to the secreted BCL and BDNF, promote endogenous neuronal growth and encourage synaptic connections between neurons. Full article

(This article belongs to the Special Issue State-of-the-Art Gene-Target and Cell Therapy in Poland)

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15 pages, 1219 KiB

Open AccessReview

Wall Tension and Tubular Resistance in Kidney Cystic Conditions

by Michele Della Corte and Davide Viggiano

Biomedicines 2023, 11(6), 1750; https://doi.org/10.3390/biomedicines11061750 - 18 Jun 2023

Cited by 1 | Viewed by 1370

Abstract

The progressive formation of single or multiple cysts accompanies several renal diseases. Specifically, (i) genetic forms, such as adult dominant polycystic kidney disease (ADPKD), and (ii) acquired cystic kidney disease (ACKD) are probably the most frequent forms of cystic diseases. Adult dominant polycystic [...] Read more.

The progressive formation of single or multiple cysts accompanies several renal diseases. Specifically, (i) genetic forms, such as adult dominant polycystic kidney disease (ADPKD), and (ii) acquired cystic kidney disease (ACKD) are probably the most frequent forms of cystic diseases. Adult dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by multiple kidney cysts and systemic alterations. The genes responsible for the condition are known, and a large amount of literature focuses on the molecular description of the mechanism. The present manuscript shows that a multiscale approach that considers supramolecular physical phenomena captures the characteristics of both ADPKD and acquired cystic kidney disease (ACKD) from the pathogenetic and therapeutical point of view, potentially suggesting future treatments. We first review the hypothesis of cystogenesis in ADPKD and then focus on ACKD, showing that they share essential pathogenetic features, which can be explained by a localized obstruction of a tubule and/or an alteration of the tubular wall tension. The consequent tubular aneurysms (cysts) follow Laplace’s law. Reviewing the public databases, we show that ADPKD genes are widely expressed in various organs, and these proteins interact with the extracellular matrix, thus potentially modifying wall tension. At the kidney and liver level, the authors suggest that altered cell polarity/secretion/proliferation produce tubular regions of high resistance to the urine/bile flow. The increased intratubular pressure upstream increases the difference between the inside (Pi) and the outside (Pe) of the tubules (∆P) and is counterbalanced by lower wall tension by a factor depending on the radius. The latter is a function of tubule length. In adult dominant polycystic kidney disease (ADPKD), a minimal reduction in the wall tension may lead to a dilatation in the tubular segments along the nephron over the years. The initial increase in the tubule radius would then facilitate the progressive expansion of the cysts. In this regard, tubular cell proliferation may be, at least partially, a consequence of the progressive cysts’ expansion. This theory is discussed in view of other diseases with reduced wall tension and with cysts and the therapeutic effects of vaptans, somatostatin, SGLT2 inhibitors, and potentially other therapeutic targets. Full article

(This article belongs to the Special Issue Acute Kidney Injury and Chronic Kidney Disease: Pathophysiology and New Therapeutic Strategies)

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13 pages, 691 KiB

Open AccessArticle

Synthesizing Electronic Health Records for Predictive Models in Low-Middle-Income Countries (LMICs)

by Ghadeer O. Ghosheh, C. Louise Thwaites and Tingting Zhu

Biomedicines 2023, 11(6), 1749; https://doi.org/10.3390/biomedicines11061749 - 18 Jun 2023

Cited by 3 | Viewed by 1329

Abstract

The spread of machine learning models, coupled with by the growing adoption of electronic health records (EHRs), has opened the door for developing clinical decision support systems. However, despite the great promise of machine learning for healthcare in low-middle-income countries (LMICs), many data-specific [...] Read more.

The spread of machine learning models, coupled with by the growing adoption of electronic health records (EHRs), has opened the door for developing clinical decision support systems. However, despite the great promise of machine learning for healthcare in low-middle-income countries (LMICs), many data-specific limitations, such as the small size and irregular sampling, hinder the progress in such applications. Recently, deep generative models have been proposed to generate realistic-looking synthetic data, including EHRs, by learning the underlying data distribution without compromising patient privacy. In this study, we first use a deep generative model to generate synthetic data based on a small dataset (364 patients) from a LMIC setting. Next, we use synthetic data to build models that predict the onset of hospital-acquired infections based on minimal information collected at patient ICU admission. The performance of the diagnostic model trained on the synthetic data outperformed models trained on the original and oversampled data using techniques such as SMOTE. We also experiment with varying the size of the synthetic data and observe the impact on the performance and interpretability of the models. Our results show the promise of using deep generative models in enabling healthcare data owners to develop and validate models that serve their needs and applications, despite limitations in dataset size. Full article

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

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13 pages, 890 KiB

Open AccessArticle

Urodynamics Are Essential to Predict the Risk for Upper Urinary Tract Damage after Acute Spinal Cord Injury

by Veronika Birkhäuser, Collene E. Anderson, Marko Kozomara, Mirjam Bywater, Oliver Gross, Stephan Kiss, Stephanie C. Knüpfer, Miriam Koschorke, Lorenz Leitner, Ulrich Mehnert, Helen Sadri, Ulla Sammer, Lara Stächele, Jure Tornic, Martina D. Liechti, Martin W. G. Brinkhof and Thomas M. Kessler

Biomedicines 2023, 11(6), 1748; https://doi.org/10.3390/biomedicines11061748 - 17 Jun 2023

Cited by 1 | Viewed by 1073

Abstract

We used clinical parameters to develop a prediction model for the occurrence of urodynamic risk factors for upper urinary tract (UUT) damage during the first year after acute spinal cord injury (SCI). A total of 97 patients underwent urodynamic investigation at 1, 3, [...] Read more.

We used clinical parameters to develop a prediction model for the occurrence of urodynamic risk factors for upper urinary tract (UUT) damage during the first year after acute spinal cord injury (SCI). A total of 97 patients underwent urodynamic investigation at 1, 3, 6, and 12 months after acute SCI, within the framework of a population-based longitudinal study at a single university SCI center. Candidate predictors included demographic characteristics and neurological and functional statuses 1 month after SCI. Outcomes included urodynamic risk factors for UUT damage: detrusor overactivity combined with detrusor sphincter dyssynergia, maximum storage detrusor pressure (pDetmax) ≥ 40 cmH₂O, bladder compliance < 20 mL/cmH₂O, and vesicoureteral reflux. Multivariable logistic regression was used for the prediction model development and internal validation, using the area under the receiver operating curve (aROC) to assess model discrimination. Two models showed fair discrimination for pDetmax ≥ 40 cmH₂O: (i) upper extremity motor score and sex, aROC 0.79 (95% CI: 0.69–0.89), C-statistic 0.78 (95% CI: 0.69–0.87), and (ii) neurological level, American Spinal Injury Association Impairment Scale grade, and sex, aROC 0.78 (95% CI: 0.68–0.89), C-statistic 0.76 (95% CI: 0.68–0.85). We identified two models that provided fair predictive values for urodynamic risk factors of UUT damage during the first year after SCI. Pending external validation, these models may be useful for clinical trial planning, although less so for individual-level patient management. Therefore, urodynamics remains essential for reliably identifying patients at risk of UUT damage. Full article

(This article belongs to the Special Issue Bench to Bedside in Neuro-Urology)

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13 pages, 2798 KiB

Open AccessArticle

Carrier-Free Inhalable Dry Microparticles of Celecoxib: Use of the Electrospraying Technique

by Azin Jahangiri, Ali Nokhodchi, Kofi Asare-Addo, Erfan Salehzadeh, Shahram Emami, Shadi Yaqoubi and Hamed Hamishehkar

Biomedicines 2023, 11(6), 1747; https://doi.org/10.3390/biomedicines11061747 - 17 Jun 2023

Cited by 1 | Viewed by 1327

Abstract

Upregulation of cyclooxygenase (COX-2) plays an important role in lung cancer pathogenesis. Celecoxib (CLX), a selective COX-2 inhibitor, may have beneficial effects in COVID-19-induced inflammatory storms. The current study aimed to develop carrier-free inhalable CLX microparticles by electrospraying as a dry powder formulation [...] Read more.

Upregulation of cyclooxygenase (COX-2) plays an important role in lung cancer pathogenesis. Celecoxib (CLX), a selective COX-2 inhibitor, may have beneficial effects in COVID-19-induced inflammatory storms. The current study aimed to develop carrier-free inhalable CLX microparticles by electrospraying as a dry powder formulation for inhalation (DPI). CLX microparticles were prepared through an electrospraying method using a suitable solvent mixture at two different drug concentrations. The obtained powders were characterized in terms of their morphology, solid state, dissolution behavior, and aerosolization performance. Electrosprayed particles obtained from the ethanol–acetone solvent mixture with a drug concentration of 3 % w/v exhibited the best in vitro aerosolization properties. The value of the fine particle fraction obtained for the engineered drug particles was 12-fold higher than that of the untreated CLX. When the concentration of CLX was increased, a remarkable reduction in FPF was obtained. The smallest median mass aerodynamic diameter was obtained from the electrosprayed CLX at a 3% concentration (2.82 µm) compared to 5% (3.25 µm) and untreated CLX (4.18 µm). DSC and FTIR experiments showed no change in drug crystallinity or structure of the prepared powders during the electrospraying process. The findings of this study suggest that electrospraying has potential applications in the preparation of DPI formulations. Full article

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

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18 pages, 2351 KiB

Open AccessArticle

Rhythmic TMS as a Feasible Tool to Uncover the Oscillatory Signatures of Audiovisual Integration

by Riccardo Bertaccini, Giuseppe Ippolito, Luca Tarasi, Agnese Zazio, Antonietta Stango, Marta Bortoletto and Vincenzo Romei

Biomedicines 2023, 11(6), 1746; https://doi.org/10.3390/biomedicines11061746 - 17 Jun 2023

Cited by 3 | Viewed by 1046

Abstract

Multisensory integration is quintessential to adaptive behavior, with clinical populations showing significant impairments in this domain, most notably hallucinatory reports. Interestingly, altered cross-modal interactions have also been reported in healthy individuals when engaged in tasks such as the Sound-Induced Flash-Illusion (SIFI). The temporal [...] Read more.

Multisensory integration is quintessential to adaptive behavior, with clinical populations showing significant impairments in this domain, most notably hallucinatory reports. Interestingly, altered cross-modal interactions have also been reported in healthy individuals when engaged in tasks such as the Sound-Induced Flash-Illusion (SIFI). The temporal dynamics of the SIFI have been recently tied to the speed of occipital alpha rhythms (IAF), with faster oscillations entailing reduced temporal windows within which the illusion is experienced. In this regard, entrainment-based protocols have not yet implemented rhythmic transcranial magnetic stimulation (rhTMS) to causally test for this relationship. It thus remains to be evaluated whether rhTMS-induced acoustic and somatosensory sensations may not specifically interfere with the illusion. Here, we addressed this issue by asking 27 volunteers to perform a SIFI paradigm under different Sham and active rhTMS protocols, delivered over the occipital pole at the IAF. Although TMS has been proven to act upon brain tissues excitability, results show that the SIFI occurred for both Sham and active rhTMS, with the illusory rate not being significantly different between baseline and stimulation conditions. This aligns with the discrete sampling hypothesis, for which alpha amplitude modulation, known to reflect changes in cortical excitability, should not account for changes in the illusory rate. Moreover, these findings highlight the viability of rhTMS-based interventions as a means to probe the neuroelectric signatures of illusory and hallucinatory audiovisual experiences, in healthy and neuropsychiatric populations. Full article

(This article belongs to the Special Issue Emerging Trends in Brain Stimulation)

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11 pages, 250 KiB

Open AccessReview

Pathophysiology of Work-Related Neuropathies

by Tariq Malik, Ahmed Malik and Alaa Abd-Elsayed

Biomedicines 2023, 11(6), 1745; https://doi.org/10.3390/biomedicines11061745 - 17 Jun 2023

Cited by 3 | Viewed by 941

Abstract

Work-related injuries are common. The cost of these injuries is around USD 176 billion to USD 350 billion a year. A significant number of work-related injuries involve nerve damage or dysfunction. Injuries may heal with full recovery of function, but those involving nerve [...] Read more.

Work-related injuries are common. The cost of these injuries is around USD 176 billion to USD 350 billion a year. A significant number of work-related injuries involve nerve damage or dysfunction. Injuries may heal with full recovery of function, but those involving nerve damage may result in significant loss of function or very prolonged recovery. While many factors can predispose a person to suffer nerve damage, in most cases, it is a multifactorial issue that involves both intrinsic and extrinsic factors. This makes preventing work-related injuries hard. To date, no evidence-based guidelines are available to clinicians to evaluate work-related nerve dysfunction. While the symptoms range from poor endurance to cramping to clear loss of motor and sensory functions, not all nerves are equally vulnerable. The common risk factors for nerve damage are a superficial location, a long course, an acute change in trajectory along the course, and coursing through tight spaces. The pathophysiology of acute nerve injury is well known, but that of chronic nerve injury is much less well understood. The two most common mechanisms of nerve injury are stretching and compression. Chronic mild to moderate compression is the most common mechanism of nerve injury and it elicits a characteristic response from Schwann cells, which is different from the one when nerve is acutely injured. It is important to gain a better understanding of work-related nerve dysfunction, both from health and from regulatory standpoints. Currently, management depends upon etiology of nerve damage, recovery is often poor if nerves are badly damaged or treatment is not instituted early. This article reviews the current pathophysiology of chronic nerve injury. Chronic nerve injury animal models have contributed a lot to our understanding but it is still not complete. Better understanding of chronic nerve injury pathology will result in identification of novel and more effective targets for pharmacological interventions. Full article

(This article belongs to the Special Issue The Pathophysiology of Peripheral Nerve Injuries)

12 pages, 1196 KiB

Open AccessArticle

Carpal Tunnel Syndrome: Neuropathic Pain Associated or Not with a Nociplastic Condition

by César Fernández-de-las-Peñas, Stella Fuensalida-Novo, Jo Nijs, Annalie Basson, Gustavo Plaza-Manzano, Juan A. Valera-Calero, Lars Arendt-Nielsen and Ana I. de-la-Llave-Rincón

Biomedicines 2023, 11(6), 1744; https://doi.org/10.3390/biomedicines11061744 - 17 Jun 2023

Cited by 2 | Viewed by 2785

Abstract

Carpal tunnel syndrome (CTS) has been traditionally classified as primarily a neuropathic condition with or without pain. Precision medicine refers to an evidence-based method of grouping patients based on their susceptibility to biology, prognosis of a particular disease, or in their response to [...] Read more.

Carpal tunnel syndrome (CTS) has been traditionally classified as primarily a neuropathic condition with or without pain. Precision medicine refers to an evidence-based method of grouping patients based on their susceptibility to biology, prognosis of a particular disease, or in their response to a specific treatment, and tailoring specific treatments accordingly. In 2021, the International Association for the Study of Pain (IASP) proposed a grading system for classifying patients into nociceptive, neuropathic, or nociplastic phenotypes. This position paper presents data supporting the possibility of subgrouping individuals with specific CTS related-pain into nociceptive, neuropathic, nociplastic or mixed-type phenotypes. Carpal tunnel syndrome is a neuropathic condition but can also be comorbid with a nociplastic pain condition. The presence of extra-median symptoms and the development of facilitated pain processing seem to be signs suggesting that specific CTS cases can be classified as the nociplastic pain phenotype. The clinical responses of therapeutic approaches for the management of CTS are inconclusive. Accordingly, the ability to identify the predominant pain phenotype in patients with CTS could likely be problematic for producing efficient treatment outcomes. In fact, the presence of a nociplastic or mixed-type pain phenotype would explain the lack of clinical effect of treatment interventions targeting the carpal tunnel area selectively. We propose a clinical decision tree by using the 2021 IASP classification criteria for identifying the predominant pain phenotype in people with CTS-related pain, albeit CTS being a priori a neuropathic pain condition. The identification of a nociplastic-associated condition requires a more nuanced multimodal treatment approach to achieve better treatment outcomes. Full article

(This article belongs to the Special Issue The Pathophysiology of Peripheral Nerve Injuries)

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Biomedicines, Volume 11, Issue 6 (June 2023) – 271 articles

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