bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Advances in Image-Guided Locoregional Therapies for Primary Liver Tumors
Authors: Criss Cody R. , Makary Mina S.
Published: July 2023

Primary liver cancer is the leading cause of cancer-related deaths worldwide. with incidences predicted to rise over the next several decades. Locoregional therapies, such as radiofrequency or microwave ablation, are described as image-guided percutaneous procedures, which offer either a curative intent for early-stage hepatocellular carcinoma or bridging/downstaging for surgical resection or transplantation. Catheter-driven locoregional therapies, such as transarterial chemoembolization and radioembolization, induce tumor hypoxia, can be palliative, and improve survival for early-to-intermediate hepatocellular carcinoma and unresectable intrahepatic cholangiocarcinoma. Herein, we provide a comprehensive overview of the antineoplastic mechanisms underpinning locoregional therapies, different treatment approaches, and the current state of the literature for the efficacy of locoregional therapies for primary liver cancer. We also discuss emerging advancements, such as the adjuvant use of immunotherapies and molecular targeting agents with locoregional therapy, for the treatment of primary liver cancer.
Comparative Genomic Analysis of Warthog and Sus Scrofa Identifies Adaptive Genes Associated with African Swine Fever
Authors: Feng Wen , Zhou Lei , Zhao Pengju , Du Heng , Diao Chenguang , Zhang Yu , Liu Zhen , Jin Wenjiao , Yu Jian , Han Jianlin , Okoth Edward , Mrode Raphael , Liu Jian-Feng
Published: July 2023

Background: As warthogs (Phacochoerus africanus) have innate immunity against African swine fever (ASF), it is critical to understand the evolutionary novelty of warthogs to explain their specific ASF resistance. Methods: Here, we present two completed new genomes of one warthog and one Kenyan domestic pig as fundamental genomic references to elucidate the genetic mechanisms of ASF tolerance. Results: Multiple genomic variations, including gene losses, independent contraction, and the expansion of specific gene families, likely molded the warthog genome to adapt to the environment. Importantly, the analysis of the presence and absence of genomic sequences revealed that the DNA sequence of the warthog genome had an absence of the gene lactate dehydrogenase B (LDHB) on chromosome 2 compared with the reference genome. The overexpression and siRNA of LDHB inhibited the replication of the African swine fever virus. Combined with large-scale sequencing data from 42 pigs worldwide, the contraction and expansion of tripartite motif-containing (TRIM) gene families revealed that TRIM family genes in the warthog genome are potentially responsible for its tolerance to ASF. Conclusion: Our results will help improve the understanding of genetic resistance to ASF in pigs.
The Lipid Phosphate Phosphatase Wunen Promotes Eggshell Formation and Is Essential for Fertility in Drosophila
Authors: Mukherjee Amrita , Schuppe Michaela , Renault Andrew D.
Published: July 2023

The eggshell that surrounds insect eggs acts as a barrier, protecting against biotic factors and desiccation. The eggshell is a multi-layered structure which is synthesised by the somatic follicle cells that surround the developing oocyte. Although the temporal order of expression of the protein eggshell components goes someway to explaining how the different layers are built up, but how the precise three-dimensional structure is achieved and how lipid components responsible for desiccation resistance are incorporated are poorly understood. In this paper, we demonstrate that wunen, which encodes a lipid phosphate phosphatase, is necessary for fertility in Drosophila females. Compared to sibling controls, females null for wunen lay fewer eggs which subsequently collapse such that no larvae emerge. We show that this is due to a requirement for wunen in the ovarian follicle cells which is needed to produce an ordered and functional eggshell. Knockdown of a septate junction component also results in collapsed eggs, supporting the idea that similar to its role in embryonic tracheal development, Wunen in follicle cells also promotes septate junction function.
N6-Methyladenosine Directly Regulates CD40L Expression in CD4+ T Lymphocytes
Authors: van Vroonhoven Ellen C. N. , Picavet Lucas W. , Scholman Rianne C. , van den Dungen Noortje A. M. , Mokry Michal , Evers Anouk , Lebbink Robert J. , Calis Jorg J. A. , Vastert Sebastiaan J. , van Loosdregt Jorg
Published: July 2023

T cell activation is a highly regulated process, modulated via the expression of various immune regulatory proteins including cytokines, surface receptors and co-stimulatory proteins. N6-methyladenosine (m6A) is an RNA modification that can directly regulate RNA expression levels and it is associated with various biological processes. However, the function of m6A in T cell activation remains incompletely understood. We identify m6A as a novel regulator of the expression of the CD40 ligand (CD40L) in human CD4+ lymphocytes. Manipulation of the m6A ‘eraser’ fat mass and obesity-associated protein (FTO) and m6A ‘writer’ protein methyltransferase-like 3 (METTL3) directly affects the expression of CD40L. The m6A ‘reader’ protein YT521-B homology domain family-2 (YTHDF2) is hypothesized to be able to recognize and bind m6A specific sequences on the CD40L mRNA and promotes its degradation. This study demonstrates that CD40L expression in human primary CD4+ T lymphocytes is regulated via m6A modifications, elucidating a new regulatory mechanism in CD4+ T cell activation that could possibly be leveraged in the future to modulate T cell responses in patients with immune-related diseases.
Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer’s Disease
Authors: Preziuso Alessandra , Piccirillo Silvia , Cerqueni Giorgia , Serfilippi Tiziano , Terenzi Valentina , Vinciguerra Antonio , Orciani Monia , Amoroso Salvatore , Magi Simona , Lariccia Vincenzo
Published: July 2023

Alzheimer’s disease (AD) is a widespread neurodegenerative disorder, affecting a large number of elderly individuals worldwide. Mitochondrial dysfunction, metabolic alterations, and oxidative stress are regarded as cooperating drivers of the progression of AD. In particular, metabolic impairment amplifies the production of reactive oxygen species (ROS), resulting in detrimental alterations to intracellular Ca2+ regulatory processes. The Na+/Ca2+ exchanger (NCX) proteins are key pathophysiological determinants of Ca2+ and Na+ homeostasis, operating at both the plasma membrane and mitochondria levels. Our study aimed to explore the role of NCX1 and NCX3 in retinoic acid (RA) differentiated SH-SY5Y cells treated with glyceraldehyde (GA), to induce impairment of the default glucose metabolism that typically precedes Aβ deposition or Tau protein phosphorylation in AD. By using an RNA interference-mediated approach to silence either NCX1 or NCX3 expression, we found that, in GA-treated cells, the knocking-down of NCX3 ameliorated cell viability, increased the intracellular ATP production, and reduced the oxidative damage. Remarkably, NCX3 silencing also prevented the enhancement of Aβ and pTau levels and normalized the GA-induced decrease in NCX reverse-mode activity. By contrast, the knocking-down of NCX1 was totally ineffective in preventing GA-induced cytotoxicity except for the increase in ATP synthesis. These findings indicate that NCX3 and NCX1 may differently influence the evolution of AD pathology fostered by glucose metabolic dysfunction, thus providing a potential target for preventing AD.
As Verified with the Aid of Biotinylated Spermine, the Brain Cannot Take up Polyamines from the Bloodstream Leaving It Solely Dependent on Local Biosynthesis
Authors: Weiss Torsten , Bernard René , Laube Gregor , Rieck Julian , Eaton Misty J. , Skatchkov Serguei N. , Veh Rüdiger W.
Published: July 2023

The importance of polyamines (PAs) for the central nervous system (CNS) is well known. Less clear, however, is where PAs in the brain are derived from. Principally, there are three possibilities: (i) intake by nutrition, release into the bloodstream, and subsequent uptake from CNS capillaries, (ii) production by parenchymatous organs, such as the liver, and again uptake from CNS capillaries, and (iii) uptake of precursors, such as arginine, from the blood and subsequent local biosynthesis of PAs within the CNS. The present investigation aimed to unequivocally answer the question of whether PAs, especially the higher ones like spermidine (SPD) and spermine (SPM), can or cannot be taken up into the brain from the bloodstream. For this purpose, a biotin-labelled analogue of spermine (B-X-SPM) was synthesized, characterized, and used to visualize its uptake into brain cells following application to acute brain slices, to the intraventricular space, or to the bloodstream. In acute brain slices there is strong uptake of B-X-SPM into protoplasmic and none in fibrous-type astrocytes. It is also taken up by neurons but to a lesser degree. Under in vivo conditions, astrocyte uptake of B-X-SPM from the brain interstitial fluid is also intense after intraventricular application. In contrast, following intracardial injection, there is no uptake from the bloodstream, indicating that the brain is completely dependent on the local synthesis of polyamines.
Evolutionary Study of Protein Short Tandem Repeats in Protein Families
Authors: Mier Pablo , Andrade-Navarro Miguel A.
Published: July 2023

Tandem repeats in proteins are patterns of residues repeated directly adjacent to each other. The evolution of these repeats can be assessed by using groups of homologous sequences, which can help pointing to events of unit duplication or deletion. High pressure in a protein family for variation of a given type of repeat might point to their function. Here, we propose the analysis of protein families to calculate protein short tandem repeats (pSTRs) in each protein sequence and assess their variability within the family in terms of number of units. To facilitate this analysis, we developed the pSTR tool, a method to analyze the evolution of protein short tandem repeats in a given protein family by pairwise comparisons between evolutionarily related protein sequences. We evaluated pSTR unit number variation in protein families of 12 complete metazoan proteomes. We hypothesize that families with more dynamic ensembles of repeats could reflect particular roles of these repeats in processes that require more adaptability.
Exome Survey and Candidate Gene Re-Sequencing Identifies Novel Exstrophy Candidate Genes and Implicates LZTR1 in Disease Formation
Authors: Köllges Ricarda , Stegmann Jil , Schneider Sophia , Waffenschmidt Lea , Fazaal Julia , Breuer Katinka , Hilger Alina C. , Dworschak Gabriel C. , Mingardo Enrico , Rösch Wolfgang , Hofmann Aybike , Neissner Claudia , Ebert Anne-Karolin , Stein Raimund , Younsi Nina , Hirsch-Koch Karin , Schmiedeke Eberhard , Zwink Nadine , Jenetzky Ekkehart , Thiele Holger , Ludwig Kerstin U. , Reutter Heiko
Published: July 2023

Background: The bladder exstrophy-epispadias complex (BEEC) is a spectrum of congenital abnormalities that involves the abdominal wall, the bony pelvis, the urinary tract, the external genitalia, and, in severe cases, the gastrointestinal tract as well. Methods: Herein, we performed an exome analysis of case-parent trios with cloacal exstrophy (CE), the most severe form of the BEEC. Furthermore, we surveyed the exome of a sib-pair presenting with classic bladder exstrophy (CBE) and epispadias (E) only. Moreover, we performed large-scale re-sequencing of CBE individuals for novel candidate genes that were derived from the current exome analysis, as well as for previously reported candidate genes within the CBE phenocritical region, 22q11.2. Results: The exome survey in the CE case-parent trios identified two candidate genes harboring de novo variants (NR1H2, GKAP1), four candidate genes with autosomal-recessive biallelic variants (AKR1B10, CLSTN3, NDST4, PLEKHB1) and one candidate gene with suggestive uniparental disomy (SVEP1). However, re-sequencing did not identify any additional variant carriers in these candidate genes. Analysis of the affected sib-pair revealed no candidate gene. Re-sequencing of the genes within the 22q11.2 CBE phenocritical region identified two highly conserved frameshift variants that led to early termination in two independent CBE males, in LZTR1 (c.978_985del, p.Ser327fster6) and in SLC7A4 (c.1087delC, p.Arg363fster68). Conclusions: According to previous studies, our study further implicates LZTR1 in CBE formation. Exome analysis-derived candidate genes from CE individuals may not represent a frequent indicator for other BEEC phenotypes and warrant molecular analysis before their involvement in disease formation can be assumed.
Molecular Evolutionary Landscape of the Immune Microenvironment of Head and Neck Cancer
Authors: Shao Baoyi , Ye Zheng , Sun Bo , Xiao Zhongdang
Published: July 2023

Head and neck cancer is a highly heterogeneous malignant tumor. Numerous studies have shown that the immune microenvironment of head and neck cancer has a significant impact on its occurrence and development, as well as its prognosis. However, there have been fewer studies related to the accurate immunophenotyping of head and neck cancer. In this study, we used gene expression profile information and clinical information from the TCGA-HNSC cohort (502 samples) and the GSE655858 cohort (270 samples) to identify and independently validate three immune subtypes (Cluster1–Cluster3) with different immune-related molecular profiles and clinical outcomes. Cluster2, which is mainly dominated by B-lymphocyte infiltration, was found to have the best prognosis. In addition, a support vector machine (SVM)-based classifier was constructed, which could accurately classify HNSC based on 19 genes. Furthermore, the results of the prognostic analysis showed activation of antibody-secreting B-lymphocyte function, which showed a good prognostic effect in all three immune subtypes of HNSC. Finally, the immune evolutionary landscape of HNSC was constructed in an attempt to explain the evolutionary pattern of the immune subtypes of HNSC. In summary, we provide a conceptual framework for understanding the tumor immune microenvironment in HNSC and demonstrate the importance of immune infiltration of B lymphocytes in HNSC. Further research is needed to assess the importance of these immunophenotypes in combination drug therapy and to provide a basis for screening appropriate patients for immunotherapy.
A Systematic Review on the Role of Matrix Metalloproteinases in the Pathogenesis of Inguinal Hernias
Authors: Bracale Umberto , Peltrini Roberto , Iacone Biancamaria , Martirani Mirko , Sannino Daniele , Gargiulo Antonio , Corcione Francesco , Serra Raffaele , Bracale Umberto Marcello
Published: July 2023

The recurrence rate in patients who undergo surgery for abdominal wall hernias (AWHs) is high. AWHs have been hypothesized to be a disease of the extracellular matrix, which is supported by evidence showing a high incidence of AWHs in patients with connective tissue disorders. This study aimed to investigate the most recent literature studies describing the levels of several matrix metalloproteinases (MMPs) in the blood and fascia, with the objective of better clarifying the pathogenetic role of matrix metalloproteinases (MMPs) and their inhibitors in inguinal hernias (IHs). A systematic literature search was conducted using the PubMed, Scopus, and Web of Science electronic databases to identify eligible studies. The identified studies were included in the analysis, and a qualitative synthesis of the results is provided to describe the most recent findings. Seventeen studies were included. An association between MMP-2 and direct IHs has also been demonstrated. MMP-1, MMP-2, MMP-9, MMP-12, and MMP-13 levels were increased in both the serum and fascia of patients with IHs. The analysis of inhibitors showed an increase in tissue inhibitors of metalloproteinases (TIMPs), specifically TIMP-1 in IHs, particularly in direct hernias, and a reduction in TIMP-2 in the biopsy samples of the transversalis fascia. In contrast, a reduction in TIMP-1 and an increase in TIMP-2 levels have been reported only in the serum of patients with IHs. Metalloproteinases play a crucial role in the pathogenesis of IHs. The analysis of other molecules, such as TIMPs or their correlation with specific genes, is enhancing our understanding of the pathophysiology of IHs. However, more prospective studies, including comprehensive clinical and laboratory data collection, are required to confirm the relationship between the studied biomarkers and the risk of IHs.
Effects of Antiplatelet Drugs on Platelet-Dependent Coagulation Reactions
Authors: Muravlev Ivan A. , Dobrovolsky Anatoly B. , Antonova Olga A. , Khaspekova Svetlana G. , Alieva Amina K. , Pevzner Dmitry V. , Mazurov Alexey V.
Published: July 2023

Activated platelets are involved in blood coagulation by exposing phosphatidylserine (PS), which serves as a substrate for assembling coagulation complexes. Platelets accelerate fibrin formation and thrombin generation, two final reactions of the coagulation cascade. We investigated the effects of antiplatelet drugs on platelet impact in these reactions and platelet ability to expose PS. Washed human platelets were incubated with acetylsalicylic acid (ASA), ticagrelor, ASA in combination with ticagrelor, ruciromab (glycoprotein IIb-IIIa antagonist), or prostaglandin E1 (PGE1). Platelets were not activated or activated by collagen and sedimented in multiwell plates, and plasma was added after supernatant removal. Fibrin formation (clotting) was monitored in a recalcification assay by light absorbance and thrombin generation in a fluorogenic test. PS exposure was assessed by annexin V staining using flow cytometry. Ticagrelor (alone and in combination with ASA), ruciromab, and PGE1, but not ASA, prolonged the lag phase and decreased the maximum rate of plasma clotting and decreased the peak and maximum rate of thrombin generation. Inhibition was observed when platelets were not treated with exogenous agonists (activation by endogenous thrombin) and pretreated with collagen. Ticagrelor (alone and in combination with ASA), ruciromab, and PGE1, but not ASA, decreased PS exposure on washed platelets activated by thrombin and by thrombin + collagen. PS exposure on activated platelets in whole blood was lower in patients with acute coronary syndrome receiving ticagrelor + ASA in comparison with donors free of medications. These results indicate that antiplatelet drugs are able to suppress platelet coagulation activity not only in vitro but also after administration to patients.
Effects of Bio-Aging on Mechanical Properties and Microbial Behavior of Different Resin Composites
Authors: Shou Yuke , Deng Lanzhi , Huang Xiaoyu , Peng Xinyu , Zhou Xinxuan , Wang Zheng , Huang Yannan , Yang Bina , Wang Haohao , Zhang Min , Cheng Lei
Published: July 2023

Under challenging oral environments, the overall performance of resin composites is affected by bio-aging. This study investigated the effects of saliva biofilm-induced bio-aging on the mechanical properties and microbial behavior of composites with different filler types. Microhybrid, nanohybrid, nano-filled and nano-filled flowable composites were bio-aged with saliva biofilm for 30 days. Surface morphology, roughness, mechanical and aesthetic properties were determined. A 48 h saliva biofilm model was used to evaluate the microbial behavior of different composites in vitro. Biofilm metabolic activity, lactic acid production and live/dead bacterial staining were tested. Six volunteers were selected to wear intra-oral appliances with composite slabs for 24 h and biofilms were collected and analyzed using 16S rRNA sequencing to assess the biofilm formation over those materials in situ. Although there were increasing trends, surface roughness, water resorption and material solubility had no significant changes for all groups after bio-aging (p > 0.05). There were no significant changes in elastic modulus for all groups after aging (p > 0.05). However, a decrease in flexural strength in all groups was observed (p < 0.05), except for the nanoflow composite group (p > 0.05). The Vickers hardness remained stable in all groups after aging (p > 0.05), except for the nano-filled group (p < 0.05). The nanoflow composite showed distinct color changes compared to the micro-hybrid group after aging (p < 0.05). Biofilm metabolic activity and lactic acid production in vitro increased slightly after bio-aging in all groups, but with no statistical significance (p > 0.05). The Shannon index diversity of biofilms in situ decreased after aging (p < 0.05), while no significant difference was shown in species composition at the genus level in all groups (p > 0.05). Resin composites with different sized fillers displayed a relatively stable mechanical performance and uncompromised microbial behavior both in vitro and in situ after 30 days of bio-aging. Based on the results, composites with different filler types can be selected flexibly according to clinical needs. However, a longer time for bio-aging is still needed to confirm the mechanical properties and microbial behaviors of composites in the long run.
Innovative Strategy for Aroma Stabilization Using Green Solvents: Supercritical CO2 Extracts of Satureja montana Dispersed in Deep Eutectic Solvents
Authors: Vladić Jelena , Kovačević Strahinja , Aladić Krunoslav , Jokić Stela , Radman Sanja , Podunavac-Kuzmanović Sanja , Duarte Ana Rita C. , Jerković Igor
Published: July 2023

The aim of this work was to establish the potential of natural deep eutectic solvents (NADES) for the stabilization of aroma volatile organic compounds from a natural source. Satureja montana was used as a source of volatile components, as it is rich in terpenes of great commercial and biological importance, such as carvacrol, thymol, and thymoquinone, among others. Supercritical CO2 was used to extract the lipophilic fraction of S. montana, which was further directly dispersed in NADES. The stabilizing capacity of seven different NADES based on betaine and glycerol was analyzed. The stability of the components in NADES was monitored by analyzing the headspace profile during 6 months of storage at room temperature. The changes in the headspace profile over time were analyzed by using different statistical and chemometric tools and the Wilcoxon matched pair test. It was determined that alterations over time occurred such as degradation and oxidation, and they were the most prominent in the control. In addition, the indicator of decreased stability of the control was the formation of the new compounds that could compromise the quality of the product. In the stabilized NADES samples, the changes were significantly less prominent, indicating that the NADES had a stabilizing effect on the volatile compounds. According to Wilcoxon matched pair test, the most efficient stability was achieved by using betaine/ethylene glycol, glycerol/glucose, and betaine/sorbitol/water. Therefore, by applying two green solvents, a sustainable approach for obtaining pure and high-quality S. montana extracts with extended stability at room temperature was established.
A Frame-by-Frame Glance at Membrane Fusion Mechanisms: From Viral Infections to Fertilization
Authors: Azimi Farshad C. , Dean Trevor T. , Minari Karine , Basso Luis G. M. , Vance Tyler D. R. , Serrão Vitor Hugo B.
Published: July 2023

Viral entry and fertilization are distinct biological processes that share a common mechanism: membrane fusion. In viral entry, enveloped viruses attach to the host cell membrane, triggering a series of conformational changes in the viral fusion proteins. This results in the exposure of a hydrophobic fusion peptide, which inserts into the host membrane and brings the viral and host membranes into close proximity. Subsequent structural rearrangements in opposing membranes lead to their fusion. Similarly, membrane fusion occurs when gametes merge during the fertilization process, though the exact mechanism remains unclear. Structural biology has played a pivotal role in elucidating the molecular mechanisms underlying membrane fusion. High-resolution structures of the viral and fertilization fusion-related proteins have provided valuable insights into the conformational changes that occur during this process. Understanding these mechanisms at a molecular level is essential for the development of antiviral therapeutics and tools to influence fertility. In this review, we will highlight the biological importance of membrane fusion and how protein structures have helped visualize both common elements and subtle divergences in the mechanisms behind fusion; in addition, we will examine the new tools that recent advances in structural biology provide researchers interested in a frame-by-frame understanding of membrane fusion.
Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders
Authors: Kuvarzin Savelii R. , Sukhanov Ilya , Onokhin Kirill , Zakharov Konstantin , Gainetdinov Raul R.
Published: July 2023

All antipsychotics currently used in clinic block D2 dopamine receptors. Trace amine-associated receptor 1 is emerging as a new therapeutic target for schizophrenia and several other neuropsychiatric disorders. SEP-363856 (International Nonproprietary Name: Ulotaront) is an investigational antipsychotic drug with a novel mechanism of action that does not involve antagonism of dopamine D2 receptors. Ulotaront is an agonist of trace amine-associated receptor 1 and serotonin 5-HT1A receptors, but can modulate dopamine neurotransmission indirectly. In 2019, the United States Food and Drug Administration granted Breakthrough Therapy Designation for ulotaront for the treatment of schizophrenia. Phase 2 clinical studies indicated that ulotaront can reduce both positive and negative symptoms of schizophrenia without causing the extrapyramidal or metabolic side effects that are inherent to most currently used antipsychotics. At present, it is in phase 3 clinical development for the treatment of schizophrenia and is expected to be introduced into clinical practice in 2023–2024. Clinical studies evaluating the potential efficacy of ulotaront in Parkinson’s disease psychosis, generalized anxiety disorder, and major depressive disorder have also been started. The aim of this scoping review is to summarize all currently available preclinical and clinical evidence on the utility of ulotaront in the treatment of schizophrenia. Here, we show the main characteristics and distinctive features of this drug. Perspectives and limitations on the potential use of ulotaront in the pharmacotherapy of several other neuropsychiatric disorders are also discussed.
Identifying Microbiome Dynamics in Pediatric IBD: More than a Family Matter
Authors: Dovrolis Nikolas , Moschoviti Anastasia , Fessatou Smaragdi , Karamanolis George , Kolios George , Gazouli Maria
Published: July 2023

Background: Pediatric inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disease that affects both children and adolescents. Symptoms can significantly affect a child’s growth, development, and quality of life, making early diagnosis and effective management crucial. This study focuses on treatment-naïve pediatric IBD patients and their immediate families to identify the role of the microbiome in disease onset. Methods: Nine families with pediatric IBD were recruited, comprising seven drug-naïve Crohn’s disease (CD) patients and two drug-naïve ulcerative colitis (UC) patients, as well as twenty-four healthy siblings/parents. Fecal samples were collected for 16S ribosomal RNA gene sequencing and bioinformatics analysis. Results: We identified patterns of dysbiosis and hallmark microbial taxa among patients who shared ethnic, habitual, and dietary traits with themselves and their families. In addition, we examined the impact of the disease on specific microbial taxa and how these could serve as potential biomarkers for early detection. Conclusions: Our results suggest a potential role of maternal factors in the establishment and modulation of the early life microbiome, consistent with the current literature, which may have implications for understanding the etiology and progression of IBD.
Subjective Sleep Quality Versus Objective Accelerometric Measures of Sleep and Systemic Concentrations of Sleep-Related Hormones as Objective Biomarkers in Fibromyalgia Patients
Authors: Hinchado María Dolores , Otero Eduardo , Gálvez Isabel , Martín-Cordero Leticia , Navarro María del Carmen , Ortega Eduardo
Published: July 2023

Poor quality of sleep leads to an increase in severity of the symptoms associated with fibromyalgia (FM) syndrome and vice versa. The aim of this study was to determine if the poor perceived sleep quality in FM patients could be corroborated by objective physiological determinations. Perceived sleep quality was evaluated (through the Pittsburgh Sleep Quality Index) in 68 FM patients compared to an age-matched reference group of 68 women without FM. Objective sleep quality (measured using accelerometry), and systemic concentrations of sleep-related hormones (catecholamines, oxytocin, serotonin, and melatonin) were evaluated in two representative groups from the reference control group (n = 11) and FM patients (n = 11). FM patients reported poorer subjective sleep quality compared to the reference group. However, no significant differences were found in accelerometry parameters, except for a delay in getting in and out of bed. In addition, FM patients showed no significant differences in oxytocin concentration and adrenaline/noradrenaline ratio, as well as a lower serotonin/melatonin ratio. Poor perception of sleep quality in FM patients does not correspond to objective determinations. A dysregulation of the stress response could be associated with the delay in their resting circadian rhythm and difficulty falling asleep. This would be the cause that justifies the perceived lack of rest and the fatigue they feel when waking up.
Preoperative C-Reactive Protein-to-Albumin Ratio and Its Ability to Predict Outcomes of Pancreatic Cancer Resection: A Systematic Review
Authors: Hajibandeh Shahin , Hajibandeh Shahab , Romman Saleh , Parente Alessandro , Laing Richard W. , Satyadas Thomas , Subar Daren , Aroori Somaiah , Bhatt Anand , Durkin Damien , Athwal Tejinderjit S. , Roberts Keith J.
Published: July 2023

Objectives. To evaluate the ability of the c-reactive protein-to-albumin ratio (CAR) in predicting outcomes in patients undergoing pancreatic cancer resection. Methods. A systematic search of electronic information sources and bibliographic reference lists was conducted. Survival outcomes and perioperative morbidity were the evaluated outcome parameters. Results. Eight studies reporting a total of 1056 patients undergoing pancreatic cancer resection were identified. The median cut-off value for CAR was 0.05 (range 0.0003–0.54). Using multivariate analysis, all studies demonstrated that a higher CAR value was an independent and significant predictor of poor overall survival in patients undergoing pancreatic cancer resection. The estimated hazard ratio (HR) ranged from 1.4 to 3.6. Although there was a positive correlation between the reported cut-off values for CAR and HRs for overall survival, it was weak and non-significant (r = 0.36, n = 6, p = 0.480). There was significant between-study heterogeneity. Conclusions. Preoperative CAR value seems to be an important prognostic score in predicting survival outcomes in patients undergoing pancreatic cancer resection. However, the current evidence does not allow the determination of an optimal cut-off value for CAR, considering the heterogeneous reporting of cut-off values by the available studies and the lack of knowledge of their sensitivity and specificity. Future research is required.
Development of a Transparent Transgenic Zebrafish Cellular Phenotype Tg(6xNF-kB:EGFP); Casper(roy−/−, nacre−/−) to Study NF-kB Activity
Authors: Rajpurohit Surendra K. , Ouellette Logan , Sura Suvarsha , Appiah Chelsea , O’Keefe Annabelle , McCarthy Katherine , Kandepu Umasai , Ye Mon May , Kimmerling Kirk , Arora Vishal , Lokeshwar Bal L.
Published: July 2023

NF-κB signaling has broad effects on cell survival, tissue growth, and proliferation activities. It controls many genes that are involved in inflammation and thus is a key player in many inflammatory diseases. The elevation of NF-κB activators is associated with elevated mortality, especially in cancer and cardiovascular diseases. The zebrafish has emerged as an important model for whole-organism in vivo modeling in translational research. In vertebrates, in-vivo spatial resolution is limited due to normal opacification of skin and subdermal structure. For in vivo imaging, skin transparency by blocking the pigmentation via chemical inhibition is required and the maintenance of this transparency is vital. The Casper(roy−/−, nacre−/−) mutant of zebrafish maintains this transparency throughout its life and serves as an ideal combination of sensitivity and resolution for in vivo stem cell analyses and imaging. We developed an NF-kB:GFP/Casper transparent transgenic zebrafish cellular phenotype to study inflammatory processes in vivo. We outline the experimental setup to generate a transparent transgenic NF-kB/Casper strain of zebrafish through the cross-breeding of Casper and NF-kB transgenic adult fish and have generated F01 in the form of heterozygous progeny. The transgenic F01 progeny was further inbred to generate heterozygous progenies from F1 to F4 generations. Furthermore, it continued to successfully develop the homozygous strain Tg(6xNF-kB:EGFP); Casper(roy−/−, nacre−/−) in the F05 generation. This novel strain of F05 generation showed 100% homozygosity in the transgenic transparent progeny of Tg(6xNF-kB:EGFP); Casper(roy−/−, nacre−/−). The strain has been confirmed by generating the F06 generation of homozygous progeny and again verified and validated for its homogeneity in the F07 generation. The newly developed novel transparent transgenic strain of the NF-kB reporter line has been coined as “Tg(6xNF-kB:EGFP); Casper(roy−/−, nacre−/−)gmc1”. We have established a newly generated phenotype of transparent transgenic zebrafish for time-lapse in vivo confocal microscopy to study the cellular phenotype and pathologies at the cellular level over time. This will allow for quantifying the changes in the NF-kB functional activities over time and allow the comparison of control and cardiac-oncology experimental therapeutics. We validated the newly developed Tg(6xNF-kB:EGFP); Casper(roy−/−, nacre−/−)gmc1 homozygous strain of zebrafish by studying the inflammatory response to bacterial lipopolysaccharide (LPS) exposure, tolerance, and the inhibitory role of a potential novel drug candidate against LPS-induced inflammation. The results establish the unique application of newly developed strains by identifying hit and lead drug candidates for experimental therapeutics.
Immunohistological Analysis of Lichen Sclerosus of the Foreskin in Pediatric Age: Could It Be Considered A Premalignant Lesion?
Authors: Arena Salvatore , Ieni Antonio , Currò Monica , Vaccaro Mario , Di Fabrizio Donatella , Cassaro Fabiola , Bonfiglio Roberta , Montalto Angela Simona , Tuccari Giovanni , Alibrandi Angela , Impellizzeri Pietro , Romeo Carmelo
Published: July 2023

Background: A major worry of juvenile penile LS is potential malignant degeneration to spinocellular carcinoma (SCC) in adulthood. LS is characterized by increased CD8+ and CD57+ cells, dermal sclerosis, epidermal atrophy, and hyperkeratosis. p53 and Ki67 are reliable premalignant markers. Our aim was to define the LS immunohistochemical profile of foreskin in children, focusing on tissue immune response and cell proliferation. Methods: Thirty specimens of foreskins removed from pediatric patients during circumcision were included: six from ritual operation (A), twelve from phimosis (B), and twelve from phimosis with LS (C). Formalin-fixed paraffin-embedded sections were stained for histomorphology and immunohistochemistry. A quantitative evaluation for CD8, CD57, p53, and Ki-67 and a statistical analysis were performed. Results: As compared to groups A and B, the samples from group C patients showed an acanthotic epidermis, a dermal band of lymphoid infiltrate with a significant enhancement of CD8+ CD57+ lymphocytes, and a keratinocytic hyperplasia with an overexpression of Ki67+ and p53+ cells. Conclusions: Immunohistological findings confirmed an immune reaction and proliferative behavior in juvenile LS of foreskin. We believe that radical circumcision should be the first treatment of choice in pediatric patients with clinical suspicious of LS for the potential risk of transformation to SCC in adulthood.
Indoleamine 2,3-Dioxygenase (IDO) Activity: A Perspective Biomarker for Laboratory Determination in Tumor Immunotherapy
Authors: Yang Pengbo , Zhang Junhua
Published: July 2023

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme involved in catalyzing the conversion of tryptophan (Trp) into kynurenine (Kyn) at the first rate-limiting step in the kynurenine pathway of L-tryptophan metabolism. It has been found to be involved in several biological functions such as aging, immune microorganism, neurodegenerative and infectious diseases, and cancer. IDO1 plays an important role in immune tolerance by depleting tryptophan in the tumor microenvironment and inhibiting the proliferation of effector T cells, which makes it an important emerging biomarker for cancer immunotherapy. Therefore, the research and development of IDO1 inhibitors are of great importance for tumor therapy. Of interest, IDO activity assays are of great value in the screening and evaluation of inhibitors. Herein, we mainly review the biological functions of IDO1, immune regulation, key signaling molecules in the response pathway, and the development of IDO1 inhibitors in clinical trials. Furthermore, this review provides a comprehensive overview and, in particular, a discussion of currently available IDO activity assays for use in the evaluation of IDO inhibitors in human blood. We believe that the IDO activity is a promising biomarker for the immune escape and laboratory evaluation of tumor immunotherapy.
A Preliminary Study Indicating Improvement in the Median Survival Time of Glioblastoma Multiforme Patients by the Application of Deuterium Depletion in Combination with Conventional Therapy
Authors: Somlyai Gábor , Kovács Beáta Zsuzsanna , Papp András , Somlyai Ildikó
Published: July 2023

Glioblastoma multiforme (GBM) and malignant gliomas are the most common primary malignant brain tumors. Temozolomide (TMZ) chemotherapy plus radiation therapy (RT), admi-mistered after debulking surgery, increased the median survival time (MST) from 12.1 months with RT alone merely to 14.6 months, respectively. In this study, the actions of deuterium-depleted water (DDW) on the survival of GBM patients who also received conventional therapies was investigated. Without changing the conventional treatment, the daily fluid intake of the patients was wholly replaced with DDW in 1.5–2 L per day volume to reduce the D concentration in their bodies. The primary endpoint was the MST. The 55 patients involved in this study, who received conventional treatment and consumed DDW, showed a longer MST (30 months) compared to the historical control (12.1–14.6 months). There was a massive difference between the two genders in the calculated MST values; it was 25 months in the male subgroup (n = 33) and 42 months in the female subgroup (n = 22), respectively. The MST was 27 months without TMZ treatment (38 patients) and 42 months in the TMZ-treated group (17 patients), respectively. For the selected 31 patients, who consumed DDW in the correct way in addition to their conventional treatments, their MST was calculated as 30 months. Within this group, the 20 subjects who had relapsed before DDW treatment had 30 months of MST, but in those 10 subjects who were in remission when DDW treatment started, their MST was 47 months. In the subgroup of patients who began their DDW treatment parallel with radiotherapy, their MST was again 47 months, and it was 25 months when their DDW treatment was started at 8 weeks or later after the completion of radiotherapy. Altogether, these survival times were substantially prolonged compared to the prospective clinical data of patients with primary GBM. Consequently, if conventional therapies are supplemented with D depletion, better survival can be achieved in the advanced stage of GBM than with the known targeted or combination therapies. Application of DDW is recommended in all stages of the disease before surgery and in parallel with radiotherapy, and repeated DDW courses are advised when remission has been achieved.
Senescence-Driven Inflammatory and Trophic Microenvironment Imprints Mesenchymal Stromal/Stem Cells in Osteoarthritic Patients
Authors: Fusi Giuseppe , Constantinides Michael , Fissoun Christina , Pichard Lydiane , Pers Yves-Marie , Ferreira-Lopez Rosanna , Pantesco Veronique , Poulet Christophe , Malaise Olivier , De Seny Dominique , Lemaitre Jean-Marc , Jorgensen Christian , Brondello Jean-Marc
Published: July 2023

Senescent cells promote progressive tissue degeneration through the establishment of a combined inflammatory and trophic microenvironment. The cellular senescence state has therefore emerged as a central driving mechanism of numerous age-related diseases, including osteoarthritis (OA), the most common rheumatic disease. Senescence hallmarks are detectable in chondrocytes, synoviocytes and sub-chondral bone cells. This study investigates how the senescence-driven microenvironment could impact the cell fate of resident osteoarticular mesenchymal stromal/stem cells (MSCs) that are hence contributing to OA disease progression. For that purpose, we performed a comparative gene expression analysis of MSCs isolated from healthy donors that were in vitro chronically exposed either to interferon-gamma (IFN-γ) or Transforming Growth Factor beta 1 (TGFβ1), two archetypical factors produced by senescent cells. Both treatments reduced MSC self-renewal capacities by upregulating different senescence-driven cycle-dependent kinase inhibitors. Furthermore, a common set of differentially expressed genes was identified in both treated MSCs that was also found enriched in MSCs isolated from OA patients. These findings highlight an imprinting of OA MSCs by the senescent joint microenvironment that changes their matrisome gene expression. Altogether, this research gives new insights into OA etiology and points to new innovative therapeutic opportunities to treat OA patients.
Cell Adhesion Molecules in Fibrotic Diseases
Authors: Hu Qianjiang , Saleem Komal , Pandey Jyotsana , Charania Arzoo N. , Zhou Yong , He Chao
Published: July 2023

Mechanisms underlying the pathogenesis of tissue fibrosis remain incompletely understood. Emerging evidence suggests that cell adhesion molecules (CAMs) are critical in fibrotic progression in many organs, including lung, kidney, skin, and liver. CAMs promote cell–cell and cell–extracellular matrix (ECM) interactions to maintain tissue architecture and normal function in homeostasis. However, dysregulated expression and function of CAMs can lead to chronic inflammation and tissue fibrosis. The major families of CAMs include integrins, cadherins, selectins, and immunoglobulins. Here, we review the role of the CAMs in fibrosis development across various organs with a focus on integrins and cadherins, and discuss their respective roles in the development of pulmonary fibrosis.
Detection and Dispersion Analysis of Water Globules in Oil Samples Using Artificial Intelligence Algorithms
Authors: Beskopylny Alexey N. , Chepurnenko Anton , Meskhi Besarion , Stel’makh Sergey A. , Shcherban’ Evgenii M. , Razveeva Irina , Kozhakin Alexey , Zavolokin Kirill , Krasnov Andrei A.
Published: July 2023

Fluid particle detection technology is of great importance in the oil and gas industry for improving oil-refining techniques and in evaluating the quality of refining equipment. The article discusses the process of creating a computer vision algorithm that allows the user to detect water globules in oil samples and analyze their sizes. The process of developing an algorithm based on the convolutional neural network (CNN) YOLOv4 is presented. For this study, our own empirical base was proposed, which comprised microphotographs of samples of raw materials and water–oil emulsions taken at various points and in different operating modes of an oil refinery. The number of images for training the neural network algorithm was increased by applying the authors’ augmentation algorithm. The developed program makes it possible to detect particles in a fluid medium with the level of accuracy required by a researcher, which can be controlled at the stage of training the CNN. Based on the results of processing the output data from the algorithm, a dispersion analysis of localized water globules was carried out, supplemented with a frequency diagram describing the ratio of the size and number of particles found. The evaluation of the quality of the results of the work of the intelligent algorithm in comparison with the manual method on the verification microphotographs and the comparison of two empirical distributions allow us to conclude that the model based on the CNN can be verified and accepted for use in the search for particles in a fluid medium. The accuracy of the model was AP@50 = 89% and AP@75 = 78%.
Profiles of University Students Who Graduate on Time: A Cohort Study from the Chilean Context
Authors: Moraga-Pumarino Ana , Salvo-Garrido Sonia , Polanco-Levicán Karina
Published: July 2023

Graduating from higher education on time is an important topic, given its relation to students’ academic success and the efficiency of the institutions. However, a low percentage of university students finish their studies on time, which poses a challenge that requires the identification of the factors that account for this phenomenon. This study aimed to identify and characterize profiles of students who graduate on time. The population is 514 university students (45% men, 55% women), with an average age of 19.5 years (SD= 1.9) studying business at a university in Chile who belong to four cohorts entering between 2011 and 2014. The results obtained from the Classification and Regression Tree (CART) technique demonstrate eight student profiles constructed considering different variables at the pre-university, transition-motivation, and university levels. As the primary outcome, the profile of the student who graduates on time is characterized by a good performance in the first year of university, enters university right after high school, and takes advantage of institutional support by participating in academic tutoring. These findings suggest that institutions can implement specific strategies from the beginning of the university journey to promote on-time graduation.