bluuebunny/crossref_metadata_2025 huggingface dataset:
Looking at the Pathogenesis of the Rabies Lyssavirus Strain Pasteur Vaccins through a Prism of the Disorder-Based Bioinformatics
Authors: Dhulipala Surya , Uversky Vladimir N.
Published: October 2022

Rabies is a neurological disease that causes between 40,000 and 70,000 deaths every year. Once a rabies patient has become symptomatic, there is no effective treatment for the illness, and in unvaccinated individuals, the case-fatality rate of rabies is close to 100%. French scientists Louis Pasteur and Émile Roux developed the first vaccine for rabies in 1885. If administered before the virus reaches the brain, the modern rabies vaccine imparts long-lasting immunity to the virus and saves more than 250,000 people every year. However, the rabies virus can suppress the host’s immune response once it has entered the cells of the brain, making death likely. This study aimed to make use of disorder-based proteomics and bioinformatics to determine the potential impact that intrinsically disordered protein regions (IDPRs) in the proteome of the rabies virus might have on the infectivity and lethality of the disease. This study used the proteome of the Rabies lyssavirus (RABV) strain Pasteur Vaccins (PV), one of the best-understood strains due to its use in the first rabies vaccine, as a model. The data reported in this study are in line with the hypothesis that high levels of intrinsic disorder in the phosphoprotein (P-protein) and nucleoprotein (N-protein) allow them to participate in the creation of Negri bodies and might help this virus to suppress the antiviral immune response in the host cells. Additionally, the study suggests that there could be a link between disorder in the matrix (M) protein and the modulation of viral transcription. The disordered regions in the M-protein might have a possible role in initiating viral budding within the cell. Furthermore, we checked the prevalence of functional disorder in a set of 37 host proteins directly involved in the interaction with the RABV proteins. The hope is that these new insights will aid in the development of treatments for rabies that are effective after infection.
Sequential Hydrolysis of Chicken Feathers Composed of Ultrasound and Enzymatic Steps: An Enhanced Protein Source with Bioactive Peptides
Authors: Pedrosa Nely de Almeida , de Andrade Cristiano José , Petrus José Carlos Cunha , Monteiro Alcilene Rodrigues
Published: October 2022

Chicken feather is a massive by-product. Its incorrect disposal can lead to serious environmental impacts. However, chicken feather is a promising low-cost keratin source. Keratin products have a wide application in the food and pharmaceutical industry. Mostly, chicken feathers are hydrolyzed by hydrothermal processes, and then applied into animal feed formulations. Despite the low cost, the hydrothermal hydrolysis leads to uncontrolled and low hydrolysis yield. Therefore, the aim of this work was to develop and optimize a sequential strategy of chicken feathers hydrolysis composed of ultrasound and enzymatic hydrolysis (savinase®) steps. In the first research step an experimental design was built and the optimum hydrolysis condition was obtained at 50 °C and 12.5% (enzyme/chicken feather), using three integrated rectors containing enzyme/substrate and sodium disulfite. Then, the ultrasound probe was added in the experimental apparatus in order to investigate the enzymatic hydrolysis assisted by ultrasound treatment. The enzymatic hydrolysis assisted by ultrasound treatment led to high concentrations of peptides, including a dipeptide (245.1868 m/z). Thus, the sequential hydrolysis strategy composed by two green technologies proposed in this study, enhanced the degree of hydrolysis of chicken feathers, producing bioactive peptides that can be used as ingredients in food products and other sectors.
Critical Sites on Ostreolysin Are Responsible for Interaction with Cytoskeletal Proteins
Authors: Berke Nastacia Adler , Di Pizio Antonella , Vaden Timothy D. , Shoval Irit , Gover Ofer , Waiger Daniel , Solomon Gili , Sepčić Kristina , Schwartz Betty
Published: October 2022

We explored the structural features of recombinant ostreolysin A (rOlyA), a protein produced by Pleurotus ostreatus and responsible for binding to α/β-tubulin. We found that rOlyA cell internalization is essential for the induction of adipocyte-associated activity, which is mediated by the interaction of rOlyA and microtubule proteins. We created different point mutations at conserved tryptophan (W) sites in rOlyA and analyzed their biological activity in HIB-1B preadipocytes. We demonstrated that the protein’s cell-internalization ability and the differentiated phenotype induced, such as small lipid-droplet formation and gene expression of mitogenesis activity, were impaired in point-mutated proteins W96A and W28A, where W was converted to alanine (A). We also showed that an rOlyA homologue, OlyA6 complexed with mCherry, cannot bind to β-tubulin and does not induce mitochondrial biosynthesis-associated markers, suggesting that the OlyA6 region masked by mCherry is involved in β-tubulin binding. Protein–protein docking simulations were carried out to investigate the binding mode of rOlyA with β-tubulin. Taken together, we identified functional sites in rOlyA that are essential for its binding to β-tubulin and its adipocyte-associated biological activity.
FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology
Authors: Guettsches Anne-Katrin , Meyer Nancy , Zahedi René P. , Evangelista Teresinha , Muentefering Thomas , Ruck Tobias , Lacene Emmanuelle , Heute Christoph , Gonczarowska-Jorge Humberto , Schoser Benedikt , Krause Sabine , Hentschel Andreas , Vorgerd Matthias , Roos Andreas
Published: October 2022

Dominant VCP–mutations cause a variety of neurological manifestations including inclusion body myopathy with early–onset Paget disease and frontotemporal dementia 1 (IBMPFD). VCP encodes a ubiquitously expressed multifunctional protein that is a member of the AAA+ protein family, implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin–dependent protein degradation. The latter function accords with the presence of protein aggregates in muscle biopsy specimens derived from VCP–patients. Studying the proteomic signature of VCP–mutant fibroblasts, we identified a (pathophysiological) increase of FYCO1, a protein involved in autophagosome transport. We confirmed this finding applying immunostaining also in muscle biopsies derived from VCP–patients. Treatment of fibroblasts with arimoclomol, an orphan drug thought to restore physiologic cellular protein repair pathways, ameliorated cellular cytotoxicity in VCP–patient derived cells. This finding was accompanied by increased abundance of proteins involved in immune response with a direct impact on protein clearaqnce as well as by elevation of pro–survival proteins as unravelled by untargeted proteomic profiling. Hence, the combined results of our study reveal a dysregulation of FYCO1 in the context of VCP–etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre–clinical testing of this drug in fibroblasts.
Long-Term Response to Tyrosine Kinase Inhibitors for Metastatic Renal Cell Carcinoma
Authors: Catalano Martina , De Giorgi Ugo , Maruzzo Marco , Bimbatti Davide , Buti Sebastiano , Mazzaschi Giulia , Procopio Giuseppe , Santoni Matteo , Galli Luca , Conca Raffaele , Doni Laura , Antonuzzo Lorenzo , Roviello Giandomenico
Published: October 2022

Background: Tyrosine kinase inhibitors (TKIs) prolong progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC), some of which may achieve long-term responses. Herein, we report clinical and pathological characteristics of patients who achieved long-term responses during first-line TKI treatment. Methods: Patients receiving TKI as first-line therapy from January 2010 to December 2017 in seven Italian Oncology Centers were reviewed. Sixty-six patients were considered as long-term responders, as they remained progression-free for 36 months or more during TKI treatment. A logistic regression model was performed to evaluate the effect of each clinical-pathological variable on the probability of responding long-term. Results: A total of 335 patients with a median age of 66 years were included in the analysis. The median PFS and overall survival among the long-term responders was 70 and 106 months, respectively. At a landmark PFS analysis performed 36 months after the start of treatment, the median PFS was 34 months. Multivariate analysis from all patients identified previous nephrectomy, Eastern Cooperative Oncology Group Performance Status (ECOG PS) < 1, and lack of liver metastasis as favorable prognostic factors for long-term response. Female gender and lack of liver metastasis positively correlated with long-term responses in favorable-risk-score population, as well as ECOG PS < 1 in intermediate-poor risk score population. Patients Summary: Previous surgery, clinical condition, and lack of liver metastasis may predict long-term responses to tyrosine kinase inhibitors. Conclusions: TKIs can lead to a long-term response in a subset of patients with metastatic RCC. Previous nephrectomy, optimal performance status (ECOG PS = 0), and lack of liver metastasis may predict long-term responses.
Ultra-Hypofractionated Stereotactic Body Radiotherapy for Localized Prostate Cancer: Clinical Outcomes, Patterns of Recurrence, Feasibility of Definitive Salvage Treatment, and Competing Oncological Risk
Authors: Miszczyk Marcin , Szołtysik Monika , Hasterok Maja , Goldner Gregor , Rajwa Paweł , Namysł-Kaletka Agnieszka , Napieralska Aleksandra , Kraszkiewicz Małgorzata , Stąpór-Fudzińska Małgorzata , Tomasik Bartłomiej , Woźniak Grzegorz , Głowacki Grzegorz , Kaminiów Konrad , Moll Matthias , Magrowski Łukasz , Majewski Wojciech
Published: October 2022

A cohort of 650 patients treated for localized prostate cancer (PCa) with CyberKnifeTM ultra-hypofractionated radiotherapy between 2011 and 2018 was retrospectively analyzed in terms of survival, patterns of failure, and outcomes of second-line definitive salvage therapies. The analysis was performed using survival analysis including the Kaplan–Meier method and Cox regression analysis. At a median follow-up of 49.4 months, the main pattern of failure was local–regional failure (7.4% in low-, and 13% in intermediate/high-risk group at five years), followed by distant metastases (3.6% in low-, and 6% in intermediate/high-risk group at five years). Five-year likelihood of developing a second malignancy was 7.3%; however, in the vast majority of the cases, the association with prior irradiation was unlikely. The 5-year overall survival was 90.2% in low-, and 88.8% in intermediate/high-risk patients. The independent prognostic factors for survival included age (HR 1.1; 95% CI 1.07–1.14) and occurrence of a second malignancy (HR 3.67; 95% CI 2.19–6.15). Definitive local salvage therapies were feasible in the majority of the patients with local–regional failure, and uncommonly in patients with distant metastases, with an estimated second-line progression free survival of 67.8% at two years. Competing oncological risks and age were significantly more important for patients’ survival compared to primary disease recurrence.
Imaging Technologies for Cerebral Pharmacokinetic Studies: Progress and Perspectives
Authors: Ban Weikang , You Yuyang , Yang Zhihong
Published: October 2022

Pharmacokinetic assessment of drug disposition processes in vivo is critical in predicting pharmacodynamics and toxicology to reduce the risk of inappropriate drug development. The blood–brain barrier (BBB), a special physiological structure in brain tissue, hinders the entry of targeted drugs into the central nervous system (CNS), making the drug concentrations in target tissue correlate poorly with the blood drug concentrations. Additionally, once non-CNS drugs act directly on the fragile and important brain tissue, they may produce extra-therapeutic effects that may impair CNS function. Thus, an intracerebral pharmacokinetic study was developed to reflect the disposition and course of action of drugs following intracerebral absorption. Through an increasing understanding of the fine structure in the brain and the rapid development of analytical techniques, cerebral pharmacokinetic techniques have developed into non-invasive imaging techniques. Through non-invasive imaging techniques, molecules can be tracked and visualized in the entire BBB, visualizing how they enter the BBB, allowing quantitative tools to be combined with the imaging system to derive reliable pharmacokinetic profiles. The advent of imaging-based pharmacokinetic techniques in the brain has made the field of intracerebral pharmacokinetics more complete and reliable, paving the way for elucidating the dynamics of drug action in the brain and predicting its course. The paper reviews the development and application of imaging technologies for cerebral pharmacokinetic study, represented by optical imaging, radiographic autoradiography, radionuclide imaging and mass spectrometry imaging, and objectively evaluates the advantages and limitations of these methods for predicting the pharmacodynamic and toxic effects of drugs in brain tissues.
Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury
Authors: Quaglia Marco , Fanelli Vito , Merlotti Guido , Costamagna Andrea , Deregibus Maria Chiara , Marengo Marita , Balzani Eleonora , Brazzi Luca , Camussi Giovanni , Cantaluppi Vincenzo
Published: October 2022

Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.
Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury
Authors: Hsueh Shih Chang , Scerba Michael T. , Tweedie David , Lecca Daniela , Kim Dong Seok , Baig Abdul Mannan , Kim Yu Kyung , Hwang Inho , Kim Sun , Selman Warren R. , Hoffer Barry J. , Greig Nigel H.
Published: October 2022

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6′-dithiopomalidomide (F-3,6′-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6′-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6’-DP. F-3,6′-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6′-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6′-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.
Plasma and Peritoneal Poly (ADP-Ribose) Polymerase Levels in Patients with Endometriosis
Authors: Kacperczyk-Bartnik Joanna , Bartnik Paweł , Goławski Ksawery , Sierdziński Janusz , Mańka Grzegorz , Kiecka Mariusz , Lipa Michał , Warzecha Damian , Spaczyński Robert , Piekarski Piotr , Banaszewska Beata , Jakimiuk Artur , Issat Tadeusz , Rokita Wojciech , Młodawski Jakub , Szubert Maria , Sieroszewski Piotr , Raba Grzegorz , Szczupak Kamil , Kluz Tomasz , Kluza Marek , Czajkowski Krzysztof , Wielgoś Mirosław , Koc-Żórawska Ewa , Żórawski Marcin , Laudański Piotr
Published: October 2022

The evidence of poly (ADP-ribose) polymerase (PARP) association with the immune response could be coherent with the immunological theory of endometriosis and suggests the possibility of a new research direction. The aim of the study was to evaluate the levels of PARP in plasma and peritoneal fluid of patients with and without endometriosis. It was a multicenter, cross-sectional study. Plasma and peritoneal fluid samples were collected from patients with and without endometriosis during planned laparoscopic procedures in eight clinical centers. In total, 84 samples of plasma and 84 samples of the peritoneal fluid were included in the final analyses. Double-antibody sandwich enzyme-linked immunosorbent assay was performed in order to assess levels of PARP in collected samples. No statistically significant differences regarding the detected levels of PARP in plasma and peritoneal fluid comparing patients with and without endometriosis were observed. Patients with a history of infertility had significantly higher plasma PARP concentrations (p = 0.04). We have not observed the potential role of PARP concentration levels in plasma nor peritoneal fluid as an endometriosis biomarker. We have determined an association between a higher plasma PARP concentration and a history of infertility.
Updates on the Pivotal Roles of Mitochondria in Urothelial Carcinoma
Authors: Huang Chiang-Chi , Liu Hui-Ying , Hsu Tsuen-Wei , Lee Wen-Chin
Published: October 2022

Mitochondria are important organelles responsible for energy production, redox homeostasis, oncogenic signaling, cell death, and apoptosis. Deregulated mitochondrial metabolism and biogenesis are often observed during cancer development and progression. Reports have described the crucial roles of mitochondria in urothelial carcinoma (UC), which is a major global health challenge. This review focuses on research advances in the role of mitochondria in UC. Here, we discuss the pathogenic roles of mitochondria in UC and update the mitochondria-targeted therapies. We aim to offer a better understanding of the mitochondria-modulated pathogenesis of UC and hope that this review will allow the development of novel mitochondria-targeted therapies.
The Abundance of Tumor-Infiltrating CD8+ Tissue Resident Memory T Lymphocytes Correlates with Patient Survival in Glioblastoma
Authors: La Manna Marco Pio , Di Liberto Diana , Lo Pizzo Marianna , Mohammadnezhad Leila , Shekarkar Azgomi Mojtaba , Salamone Vincenzo , Cancila Valeria , Vacca Davide , Dieli Costanza , Maugeri Rosario , Brunasso Lara , Iacopino Domenico Gerardo , Dieli Francesco , Caccamo Nadia
Published: October 2022

Glial tumors alone account for 40% of all CNS tumors and present a low survival rate. The tumor microenvironment is a critical regulator of tumor progression and therapeutic effectiveness in glioma. Growing evidence from numerous studies of human solid tumor-infiltrating CD8+ T cells indicates that tissue-resident memory T cells (TRM) represent a substantial subpopulation of tumor-infiltrating lymphocytes (TILs). Although it is reported that some types of cancer patients with high immune infiltration tend to have better outcomes than patients with low immune infiltration, it seems this does not happen in gliomas. This study aimed to characterize TRMs cells in the glioma tumor microenvironment to identify their potential predictive and prognostic role and the possible therapeutic applications. Fluorescence activated cell sorting (FACS) analysis and immunofluorescence staining highlighted a statistically significant increase in CD8+ TRM cells (CD103+ and CD69+ CD8+ T cells) in gliomas compared to control samples (meningioma). In-silico analysis of a dataset of n = 153 stage IV glioma patients confirmed our data. Moreover, the gene expression analysis showed an increase in the expression of TRM-related genes in tumor tissues compared to normal tissues. This analysis also highlighted the positive correlation between genes associated with CD8+ TRM and TILs, indicating that CD8+ TRMs cells are present among the infiltrating T cells. Finally, high expression of Integrin subunit alpha E (ITGAE), the gene coding for the integrin CD103, and high CD8+ TILs abundance were associated with more prolonged survival, whereas high ITGAE expression but low CD8+ TILs abundance were associated with lower survival.
A Review on Increasing the Targeting of PAMAM as Carriers in Glioma Therapy
Authors: Li Xingyue , Ta Wenjing , Hua Ruochen , Song Jihong , Lu Wen
Published: October 2022

Glioma is an invasive brain cancer, and it is difficult to achieve desired therapeutic effects due to the high postoperative recurrence rate and limited efficacy of drug therapy hindered by the biological barrier of brain tissue. Nanodrug delivery systems are of great interest, and many efforts have been made to utilize them for glioma treatment. Polyamidoamine (PAMAM), a starburst dendrimer, provides malleable molecular size, functionalized molecular structure and penetrable brain barrier characteristics. Therefore, PAMAM-based nanodrug delivery systems (PAMAM DDS) are preferred for glioma treatment research. In this review, experimental studies on PAMAM DDS for glioma therapy were focused on and summarized. Emphasis was given to three major topics: methods of drug loading, linkers between drug/ligand and PAMAM and ligands of modified PAMAM. A strategy for well-designed PAMAM DDS for glioma treatment was proposed. Purposefully understanding the physicochemical and structural characteristics of drugs is necessary for selecting drug loading methods and achieving high drug loading capacity. Additionally, functional ligands contribute to achieving the brain targeting, brain penetration and low toxicity of PAMAM DDS. Furthermore, a brilliant linker facilitates multidrug combination and multifunctional PAMAM DDS. PAMAM DDS show excellent promise as drug vehicles and will be further studied for product development and safety evaluation.
Questions about Residual Cell Viability in Cryopreserved Human Amniotic Membrane and Its Impact on Clinical Applications
Authors: Gaudet Camille , Solecki Lauriana , Mathéaud Bastien , Odet Stephane , Meyer Christophe , Louvrier Aurélien , Gindraux Florelle
Published: October 2022

We questioned the relevance of evaluating residual cell viability in human amniotic membrane (hAM) after its cryopreservation since cell survival is controversial and its ability to act as a matrix (including the presence of growth factors and cytokines) appears to be most important for tissue regeneration purposes. We also discussed the usefulness of osteodifferentiating amniotic cells in whole hAM for bone repair applications. We have evidence that determining residual cell viability after cryopreservation and hAM osteodifferentiation is not justified.
Aminopeptidase Activities Interact Asymmetrically between Brain, Plasma and Systolic Blood Pressure in Hypertensive Rats Unilaterally Depleted of Dopamine
Authors: Banegas Inmaculada , Prieto Isabel , Segarra Ana Belén , Vives Francisco , Martínez-Cañamero Magdalena , Durán Raquel , Luna Juan de Dios , Domínguez-Vías Germán , Ramírez-Sánchez Manuel
Published: October 2022

Brain dopamine, in relation to the limbic system, is involved in cognition and emotion. These functions are asymmetrically processed. Hypertension not only alters such functions but also their asymmetric brain pattern as well as their bilateral pattern of neurovisceral integration. The central and peripheral renin-angiotensin systems, particularly the aminopeptidases involved in its enzymatic cascade, play an important role in blood pressure control. In the present study, we report how these aminopeptidases from left and right cortico-limbic locations, plasma and systolic blood pressure interact among them in spontaneously hypertensive rats (SHR) unilaterally depleted of dopamine. The study comprises left and right sham and left and right lesioned (dopamine-depleted) rats as research groups. Results revealed important differences in the bilateral behavior comparing sham left versus sham right, lesioned left versus lesioned right, and sham versus lesioned animals. Results also suggest an important role for the asymmetrical functioning of the amygdala in cardiovascular control and an asymmetrical behavior in the interaction between the medial prefrontal cortex, hippocampus and amygdala with plasma, depending on the left or right depletion of dopamine. Compared with previous results of a similar study in Wistar-Kyoto (WKY) normotensive rats, the asymmetrical behaviors differ significantly between both WKY and SHR strains.
Targeting Mitochondrial Function with Chemoptogenetics
Authors: Romesberg Amy , Van Houten Bennett
Published: October 2022

Mitochondria are ATP-generating organelles in eukaryotic cells that produce reactive oxygen species (ROS) during oxidative phosphorylation (OXPHOS). Mitochondrial DNA (mtDNA) is packaged within nucleoids and, due to its close proximity to ROS production, endures oxidative base damage. This damage can be repaired by base excision repair (BER) within the mitochondria, or it can be degraded via exonucleases or mitophagy. Persistent mtDNA damage may drive the production of dysfunctional OXPHOS components that generate increased ROS, or OXPHOS components may be directly damaged by ROS, which then can cause more mtDNA damage and create a vicious cycle of ROS production and mitochondrial dysfunction. If mtDNA damage is left unrepaired, mtDNA mutations including deletions can result. The accumulation of mtDNA mutations has been associated with conditions ranging from the aging process to cancer and neurodegenerative conditions, but the sequence of events leading to mtDNA mutations and deletions is yet unknown. Researchers have utilized many systems and agents for generating ROS in mitochondria to observe the downstream effects on mtDNA, ROS, and mitochondrial function; yet, there are various drawbacks to these methodologies that limit their precision. Here, we describe a novel chemoptogenetic approach to target oxidative damage to mitochondria and mtDNA with a high spatial and temporal resolution so that the downstream effects of ROS-induced damage can be measured with a high precision in order to better understand the mechanism of mitochondrial dysfunction in aging, cancer, and neurodegenerative diseases.
The Legacy of Parental Obesity: Mechanisms of Non-Genetic Transmission and Reversibility
Authors: Comas-Armangue Gemma , Makharadze Lela , Gomez-Velazquez Melisa , Teperino Raffaele
Published: October 2022

While a dramatic increase in obesity and related comorbidities is being witnessed, the underlying mechanisms of their spread remain unresolved. Epigenetic and other non-genetic mechanisms tend to be prominent candidates involved in the establishment and transmission of obesity and associated metabolic disorders to offspring. Here, we review recent findings addressing those candidates, in the context of maternal and paternal influences, and discuss the effectiveness of preventive measures.
The Role of [18F]F-Choline PET/CT in the Initial Management and Outcome Prediction of Prostate Cancer: A Real-World Experience from a Multidisciplinary Approach
Authors: Urso Luca , Rocca Giovanni Christian , Borgia Francesca , Lancia Federica , Malorgio Antonio , Gagliano Mauro , Zanetto Mauro , Uccelli Licia , Cittanti Corrado , Ippolito Carmelo , Evangelista Laura , Bartolomei Mirco
Published: October 2022

Initial staging of prostate cancer (PCa) is usually performed with conventional imaging (CI), involving computed tomography (CT) and bone scanning (BS). The aim of this study was to analyze the role of [18F]F-choline positron emission tomography (PET)/CT in the initial management and outcome prediction of PCa patients by analyzing data from a multidisciplinary approach. We retrospectively analyzed 82 patients who were discussed by the uro-oncology board of the University Hospital of Ferrara for primary staging newly diagnosed PCa (median age 72 (56–86) years; median baseline prostate specific antigen (PSA) equal to 8.73 ng/mL). Patients were divided into three groups based on the imaging performed: group A = only CI; group B = CI + [18F]F-choline PET/CT; group C = only [18F]F-choline PET/CT. All data on imaging findings, therapy decisions and patient outcomes were retrieved from hospital information systems. Moreover, we performed a sub-analysis of semiquantitative parameters extracted from [18F]F-choline PET/CT to search any correlation with patient outcomes. The number of patients included in each group was 35, 35 and 12, respectively. Patients with higher values of initial PSA were subjected to CI + PET/CT (p = 0.005). Moreover, the use of [18F]F-choline PET/CT was more frequent in patients with higher Gleason score (GS) or ISUP grade (p = 0.013). The type of treatment performed (surgery n = 33; radiation therapy n = 22; surveillance n = 6; multimodality therapy n = 6; systemic therapy n = 13; not available n = 2) did not show any relationship with the modality adopted to stage the disease. [18F]F-choline PET/CT induced a change of planned therapy in 5/35 patients in group B (14.3%). Moreover, patients investigated with [18F]F-choline PET/CT alone demonstrated longer biochemical recurrence (BCR)-free survival (30.8 months) in comparison to patients of groups A and B (15.5 and 23.5 months, respectively, p = 0.006), probably due to a more accurate selection of primary treatment. Finally, total lesion choline kinase activity (TLCKA) of the primary lesion, calculated by multiplying metabolic tumor volume and mean standardized uptake value (SUVmean), was able to more effectively discriminate patients who had recurrence after therapy compared to those without (p = 0.03). In our real-world experience [18F]F-choline PET/CT as a tool for the initial management of PCa had a relevant impact in terms of therapy selection and was associated with longer BCR-free survival. Moreover, TLCKA of the primary lesion looks a promising parameter for predicting recurrence after curative therapy.
Obeticholic Acid for Primary Biliary Cholangitis
Authors: Floreani Annarosa , Gabbia Daniela , De Martin Sara
Published: October 2022

Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease that may progress to fibrosis and/or cirrhosis. Treatment options are currently limited. The first-line therapy for this disease is the drug ursodeoxycholic acid (UDCA), which has been proven to normalize serum markers of liver dysfunction, halt histologic disease progression, and lead to a prolongation of transplant-free survival. However, 30–40% of patients unfortunately do not respond to this first-line therapy. Obeticholic acid (OCA) is the only registered agent for second-line treatment in UDCA-non responders. In this review, we focus on the pharmacological features of OCA, describing its mechanism of action of and its tolerability and efficacy in PBC patients. We also highlight current perspectives on future therapies for this condition.
Benign Metastasizing Leiomyoma of the Lung: Diagnostic Process and Treatment Based on Three Case Reports and a Review of the Literature
Authors: Wojtyś Małgorzata Edyta , Kacalska-Janssen Olga , Ptaszyński Konrad , Lisowski Piotr , Kunc Michał , Wójcik Janusz , Grodzki Tomasz
Published: October 2022

Uterine leiomyomas may occasionally spread to the lungs forming nodular lesions detectable on chest X-ray. This condition known as benign metastasizing leiomyoma (BML) usually occurs in females with a history of hysterectomy or myomectomy. We present three cases of BML demonstrating the diagnostic process and treatment approaches. Two patients presented with the more common multiple-nodule variant while the other had a single mass, but all were symptom-free. The age of presented patients at diagnosis of BML ranged from 46–53. The first patient was diagnosed with BML at the age of 50, and 12 years prior to the diagnosis, underwent a supracervical hysterectomy. The second patient had a myomectomy at 36, and BML was diagnosed 17 years later at the age of 53. The third patient had a hysterectomy with bilateral salpingo-oophorectomy at the age of 46, with lung lesions present before the hysterectomy. Immunohistochemical studies of postoperative materials showed positive staining of spindle cells with antibodies against desmin and smooth muscle actin, as well as estrogen and progesterone receptors. The final histopathological diagnoses were pulmonary BML. All patients are stable and symptom-free: two at two years follow-up and one at six months follow-up
Sex Differences in Oxycodone/Naloxone vs. Tapentadol in Chronic Non-Cancer Pain: An Observational Real-World Study
Authors: Barrachina Jordi , Margarit Cesar , Muriel Javier , López-Gil Vicente , López-Gil Santiago , Ballester Pura , Mira-Lorente Laura , Agulló Laura , Peiró Ana M.
Published: October 2022

Despite the large body of research on sex differences in pain, there is a lack of translation to real-world pain management. Our aim was to analyse the sex differences in the analgesic response to oxycodone/naloxone (OXN) and tapentadol (TAP), in comparison with other opioids (OPO) commonly prescribed for chronic non-cancer pain (CNCP). An observational and cross-sectional study was conducted on ambulatory CNCP patients (n = 571). Sociodemographic, clinical (pain intensity, relief, and quality of life), safety (adverse events (AEs), adverse drug reactions), hospital frequentations and pharmacological (morphine equivalent daily dose (MEDD)) variables were collected. Multiple linear regressions were carried out to assess the association between sex and outcomes. Sex differences were observed, with lower female tolerability and higher hospital frequentation, especially in the OXN group (OR AEs report = 2.8 [1.8–4.4], p < 0.001). Here, females showed higher hospital use (23% hospital admission, 30% prescription change, p < 0.05), requiring a higher MEDD (127 ± 103 mg/day, p < 0.05), compared to OXN men. Regardless of the opioid group, CNCP women were significantly older than men (three years), with significantly higher benzodiazepine use (OR = 1.6 [1.1–2.3]), more constipation (OR = 1.34 [0.93–1.90]) and headache (OR = 1.45 [0.99–2.13]) AEs, than men who were more likely to refer sexual dysfunction (OR = 2.77 [1.53–5.01]), and loss of libido (OR = 1.93 [1.22–3.04]). Sex-differences were found related to poorer female drug tolerability and higher hospital resources, even worst in OXN female users. Other differences related to older female ages and benzodiazepine prescription, need to be further analysed from a gender perspective.
Saliva Free Light Chains in Patients with Neuro-Sjögren
Authors: Konen Franz Felix , Seeliger Tabea , Schwenkenbecher Philipp , Gingele Stefan , Jendretzky Konstantin Fritz , Sühs Kurt-Wolfram , Ernst Diana , Witte Torsten , Skripuletz Thomas
Published: October 2022

Background: Sjögren’s syndrome (SS) is an autoimmune disease characterized by sicca symptoms and various extra-glandular manifestations. The diagnosis of SS requires sicca symptoms, anti-SSA(Ro)-antibody positivity, and/or pathological focus scores on a minor salivary gland biopsy. Previous studies have investigated different biomarkers in order to avoid invasive diagnostic procedures. It was found that kappa and lambda free light chains (KFLC and LFLC) in saliva are specific for SS. Methods: FLC concentrations in saliva and serum were determined in 130 patients—50 with SS and neurological involvement (Neuro-Sjögren) and 80 neurological controls. The EULAR SS disease activity index and patient reported index (ESSPRI) were determined in patients with SS. Results: Patients with SS revealed increased pain and decreased saliva production according to the ESSPRI and Saxon test, respectively, with increasing FLC concentrations in the saliva. No significant differences in serum and salivary protein concentrations were observed between patients with SS and controls. Conclusion: KFLC and LFLC concentrations in saliva are not suitable to distinguish patients with Neuro-Sjögren and neurological control subjects, thus a diagnostic biopsy is still required. The association of salivary KFLC and LFLC concentrations with saliva production and ESSPRI pain score suggests a complex relationship between dryness and pain in patients with SS.
Vericiguat in Heart Failure: Characteristics, Scientific Evidence and Potential Clinical Applications
Authors: Vannuccini Francesca , Campora Alessandro , Barilli Maria , Palazzuoli Alberto
Published: October 2022

Despite recent advances in heart failure (HF) management, the risk of death and hospitalizations remains high in the long term. HF is characterized by endothelial dysfunction, inflammation and increased oxidative stress, due to a reduction in the activity of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway. All these factors contribute to direct damage at the myocardial, vascular and renal level. Vericiguat restores the deficiency in this signaling pathway, through stimulation and activation of sGC, aiming to increase cGMP levels, with a reduction in HF-related oxidative stress and endothelial dysfunction. Two main clinical trials were developed in this setting: the SOCRATES-REDUCED phase II study and the VICTORIA phase III study. They found that vericiguat is safe, well tolerated and effective with an absolute event-rate reduction in patients affected by HF with reduced ejection fraction (HFrEF) and recent cardiac decompensation. In patients with HF with preserved ejection fraction (HfpEF), the SOCRATES-PRESERVED trial demonstrated an improvement in quality of life and health status, but the proven beneficial effects with vericiguat are still limited. Further studies are needed to correctly define the role of this drug in heart failure syndromes. Our paper reviews the potential applications and pharmacological characteristics of vericiguat in HFrEF and HFpEF.
Traumatic Brain Injury (TBI) Detection: Past, Present, and Future
Authors: Alouani Ali T. , Elfouly Tarek
Published: October 2022

Traumatic brain injury (TBI) can produce temporary biochemical imbalance due to leaks through cell membranes or disruption of the axoplasmic flow due to the misalignment of intracellular neurofilaments. If untreated, TBI can lead to Alzheimer’s, Parkinson’s, or total disability. Mild TBI (mTBI) accounts for about about 90 percent of all TBI cases. The detection of TBI as soon as it happens is crucial for successful treatment management. Neuroimaging-based tests provide only a structural and functional mapping of the brain with poor temporal resolution. Such tests may not detect mTBI. On the other hand, the electroencephalogram (EEG) provides good spatial resolution and excellent temporal resolution of the brain activities beside its portability and low cost. The objective of this paper is to provide clinicians and scientists with a one-stop source of information to quickly learn about the different technologies used for TBI detection, their advantages and limitations. Our research led us to conclude that even though EEG-based TBI detection is potentially a powerful technology, it is currently not able to detect the presence of a mTBI with high confidence. The focus of the paper is to review existing approaches and provide the reason for the unsuccessful state of EEG-based detection of mTBI.
Altered Extracellular Matrix as an Alternative Risk Factor for Epileptogenicity in Brain Tumors
Authors: de Jong Jody M. , Broekaart Diede W. M. , Bongaarts Anika , Mühlebner Angelika , Mills James D. , van Vliet Erwin A. , Aronica Eleonora
Published: October 2022

Seizures are one of the most common symptoms of brain tumors. The incidence of seizures differs among brain tumor type, grade, location and size, but paediatric-type diffuse low-grade gliomas/glioneuronal tumors are often highly epileptogenic. The extracellular matrix (ECM) is known to play a role in epileptogenesis and tumorigenesis because it is involved in the (re)modelling of neuronal connections and cell-cell signaling. In this review, we discuss the epileptogenicity of brain tumors with a focus on tumor type, location, genetics and the role of the extracellular matrix. In addition to functional problems, epileptogenic tumors can lead to increased morbidity and mortality, stigmatization and life-long care. The health advantages can be major if the epileptogenic properties of brain tumors are better understood. Surgical resection is the most common treatment of epilepsy-associated tumors, but post-surgery seizure-freedom is not always achieved. Therefore, we also discuss potential novel therapies aiming to restore ECM function.
Neuron Protection by EDTA May Explain the Successful Outcomes of Toxic Metal Chelation Therapy in Neurodegenerative Diseases
Authors: Ferrero Maria Elena
Published: October 2022

Many mechanisms have been related to the etiopathogenesis of neurodegenerative diseases (NDs) such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. In this context, the detrimental role of environmental agents has also been highlighted. Studies focused on the role of toxic metals in the pathogenesis of ND demonstrate the efficacy of treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (EDTA) in eliminating toxic metal burden in all ND patients, improving their symptoms. Lead, cadmium, aluminum, nickel, and mercury were the most important toxic metals detected in these patients. Here, I provide an updated review on the damage to neurons promoted by toxic metals and on the impact of EDTA chelation therapy in ND patients, along with the clinical description of a representative case.
Role of Matrix Metalloproteinases in Musculoskeletal Diseases
Authors: Kumar Lokender , Bisen Monish , Khan Azhar , Kumar Pradeep , Patel Sanjay Kumar Singh
Published: October 2022

Musculoskeletal disorders include rheumatoid arthritis, osteoarthritis, sarcopenia, injury, stiffness, and bone loss. The prevalence of these conditions is frequent among elderly populations with significant mobility and mortality rates. This may lead to extreme discomfort and detrimental effect on the patient’s health and socioeconomic situation. Muscles, ligaments, tendons, and soft tissue are vital for body function and movement. Matrix metalloproteinases (MMPs) are regulatory proteases involved in synthesizing, degrading, and remodeling extracellular matrix (ECM) components. By modulating ECM reconstruction, cellular migration, and differentiation, MMPs preserve myofiber integrity and homeostasis. In this review, the role of MMPs in skeletal muscle function, muscle injury and repair, skeletal muscle inflammation, and muscular dystrophy and future approaches for MMP-based therapies in musculoskeletal disorders are discussed at the cellular and molecule level.
Size Distribution of Inactivated Tick-Borne Encephalitis Virus Particles Revealed by a Comprehensive Physicochemical Approach
Authors: Moiseenko Andrey V. , Bagrov Dmitry V. , Vorovitch Mikhail F. , Uvarova Victoria I. , Veselov Maxim M. , Kashchenko Anastasia V. , Ivanova Alla L. , Osolodkin Dmitry I. , Egorov Alexey M. , Ishmukhametov Aydar A. , Shaitan Konstantin V. , Sokolova Olga S.
Published: October 2022

Tick-borne encephalitis virus (TBEV) is an enveloped RNA virus, a member of the genus Flavivirus (family Flaviviridae). Here, we provide a detailed analysis of the size and structure of the inactivated TBEV vaccine strain Sofjin-Chumakov. Four analytical methods were used to analyze individual TBEV particles—negative staining TEM, cryo-EM, atomic force microscopy (AFM), and nanoparticle tracking analysis (NTA). All methods confirmed that the particles were monodisperse and that their mean size was ~50 nm. Cryo-EM data allowed us to obtain a 3D electron density model of the virus with clearly distinguishable E protein molecules. STEM-EELS analysis detected phosphorus in the particles, which was interpreted as an indicator of RNA presence. Altogether, the described analytical procedures can be valuable for the characterization of inactivated vaccine virus samples.