bluuebunny/crossref_metadata_2025 huggingface dataset:
Malondialdehyde, Antioxidant Defense System Components and Their Relationship with Anthropometric Measures and Lipid Metabolism Biomarkers in Apparently Healthy Women
Authors: Černiauskas Linas , Mažeikienė Asta , Mazgelytė Eglė , Petrylaitė Eglė , Linkevičiūtė-Dumčė Aušra , Burokienė Neringa , Karčiauskaitė Dovilė
Published: September 2023

Cardiovascular diseases are the leading cause of mortality worldwide. Since atherosclerosis, an inflammatory, lipid-driven disease, is an underlying basis for the development of cardiovascular disease, it is important to understand its relationship with confounding factors, such as oxidative lipid degradation. In contrast, circulating antioxidants prevent oxidative lipid damage, and therefore, may be associated with reduced development of atherosclerosis. We aimed to assess oxidative lipid degradation biomarker malondialdehyde (MDA) and antioxidant defense system components, total antioxidant capacity (TAC) and superoxide dismutase (SOD) inhibition rate levels, in healthy women and evaluate their relationships with age, anthropometric measures, and lipid metabolism biomarkers. The study included 86 healthy middle-aged women. MDA in human serum samples was evaluated by HPLC, and the TAC and SOD inhibition rates were measured by photometric methods. MDA was found to be associated with age, total cholesterol, non-HDL cholesterol, apolipoprotein B and triacylglycerols. TAC was shown to be associated with age, BMI, and waist circumference, as well as lipid metabolism biomarkers apolipoprotein B and triacylglycerol, while SOD inhibition rate was only associated with total cholesterol, apolipoprotein B and triacylglycerols. In conclusion, the association of oxidative status indices, MDA, TAC and SOD, with cardiovascular risk factors suggests that they could be additional useful biomarkers in the research of aging, obesity, and atherosclerosis pathogenesis.
Non-Lethal Doses of RSL3 Impair Microvascular Endothelial Barrier through Degradation of Sphingosie-1-Phosphate Receptor 1 and Cytoskeletal Arrangement in A Ferroptosis-Independent Manner
Authors: Baoyinna Boina , Miao Jiaxing , Oliver Patrick J. , Ye Qinmao , Shaheen Nargis , Kalin Timothy , He Jinshan , Parinandi Narasimham L. , Zhao Yutong , Zhao Jing
Published: September 2023

The excess microvascular endothelial permeability is a hallmark of acute inflammatory diseases. Maintenance of microvascular integrity is critical to preventing leakage of vascular components into the surrounding tissues. Sphingosine-1-phosphate (S1P) is an active lysophospholipid that enhances the endothelial cell (EC) barrier via activation of its receptor S1PR1. Here, we delineate the effect of non-lethal doses of RSL3, an inhibitor of glutathione peroxidase 4 (GPX4), on EC barrier function. Low doses of RSL3 (50–100 nM) attenuated S1P-induced human lung microvascular barrier enhancement and the phosphorylation of AKT. To investigate the molecular mechanisms by which RSL3 attenuates S1P’s effect, we examined the S1PR1 levels. RSL3 treatment reduced S1PR1 levels in 1 h, whereas the effect was attenuated by the proteasome and lysosome inhibitors as well as a lipid raft inhibitor. Immunofluorescence staining showed that RSL3 induced S1PR1 internalization from the plasma membrane into the cytoplasm. Furthermore, we found that RSL3 (100 and 200 nM) increased EC barrier permeability and cytoskeletal rearrangement without altering cell viability. Taken together, our data delineates that non-lethal doses of RSL3 impair EC barrier function via two mechanisms. RSL3 attenuates S1P1-induced EC barrier enhancement and disrupts EC barrier integrity through the generation of 4-hydroxynonena (4HNE). All these effects are independent of ferroptosis.
Combining Celiac and Hepatic Vagus Nerve Neuromodulation Reverses Glucose Intolerance and Improves Glycemic Control in Pre- and Overt-Type 2 Diabetes Mellitus
Authors: Waataja Jonathan J. , Asp Anders J. , Billington Charles J.
Published: September 2023

Neurological disorders and type 2 diabetes mellitus (T2DM) are deeply intertwined. For example, autonomic neuropathy contributes to the development of T2DM and continued unmanaged T2DM causes further progression of nerve damage. Increasing glycemic control has been shown to prevent the onset and progression of diabetic autonomic neuropathies. Neuromodulation consisting of combined stimulation of celiac vagal fibers innervating the pancreas with concurrent electrical blockade of neuronal hepatic vagal fibers innervating the liver has been shown to increase glycemic control in animal models of T2DM. The present study demonstrated that the neuromodulation reversed glucose intolerance in alloxan-treated swine in both pre- and overt stages of T2DM. This was demonstrated by improved performance on oral glucose tolerance tests (OGTTs), as assessed by area under the curve (AUC). In prediabetic swine (fasting plasma glucose (FPG) range: 101–119 mg/dL) the median AUC decreased from 31.9 AUs (IQR = 28.6, 35.5) to 15.9 AUs (IQR = 15.1, 18.3) p = 0.004. In diabetic swine (FPG range: 133–207 mg/dL) the median AUC decreased from 54.2 AUs (IQR = 41.5, 56.6) to 16.0 AUs (IQR = 15.4, 21.5) p = 0.003. This neuromodulation technique may offer a new treatment for T2DM and reverse glycemic dysregulation at multiple states of T2DM involved in diabetic neuropathy including at its development and during progression.
Identifying Aging-Related Biomarkers and Immune Infiltration Features in Diabetic Nephropathy Using Integrative Bioinformatics Approaches and Machine-Learning Strategies
Authors: Liu Tao , Zhuang Xing-Xing , Gao Jia-Rong
Published: September 2023

Background: Aging plays an essential role in the development of diabetic nephropathy (DN). This study aimed to identify and verify potential aging-related genes associated with DN using bioinformatics analysis. Methods: To begin with, we combined the datasets from GEO microarrays (GSE104954 and GSE30528) to find the genes that were differentially expressed (DEGs) across samples from DN and healthy patient populations. By overlapping DEGs, weighted co-expression network analysis (WGCNA), and 1357 aging-related genes (ARGs), differentially expressed ARGs (DEARGs) were discovered. We next performed functional analysis to determine DEARGs’ possible roles. Moreover, protein–protein interactions were examined using STRING. The hub DEARGs were identified using the CytoHubba, MCODE, and LASSO algorithms. We next used two validation datasets and Receiver Operating Characteristic (ROC) curves to determine the diagnostic significance of the hub DEARGs. RT-qPCR, meanwhile, was used to confirm the hub DEARGs’ expression levels in vitro. In addition, we investigated the relationships between immune cells and hub DEARGs. Next, Gene Set Enrichment Analysis (GSEA) was used to identify each biomarker’s biological role. The hub DEARGs’ subcellular location and cell subpopulations were both identified and predicted using the HPA and COMPARTMENTS databases, respectively. Finally, drug–protein interactions were predicted and validated using STITCH and AutoDock Vina. Results: A total of 57 DEARGs were identified, and functional analysis reveals that they play a major role in inflammatory processes and immunomodulation in DN. In particular, aging and the AGE-RAGE signaling pathway in diabetic complications are significantly enriched. Four hub DEARGs (CCR2, VCAM1, CSF1R, and ITGAM) were further screened using the interaction network, CytoHubba, MCODE, and LASSO algorithms. The results above were further supported by validation sets, ROC curves, and RT-qPCR. According to an evaluation of immune infiltration, DN had significantly more resting mast cells and delta gamma T cells but fewer regulatory T cells and active mast cells. Four DEARGs have statistical correlations with them as well. Further investigation revealed that four DEARGs were implicated in immune cell abnormalities and regulated a wide range of immunological and inflammatory responses. Furthermore, the drug–protein interactions included four possible therapeutic medicines that target four DEARGs, and molecular docking could make this association practical. Conclusions: This study identified four DEARGs (CCR2, VCAM1, CSF1R, and ITGAM) associated with DN, which might play a key role in the development of DN and could be potential biomarkers in DN.
Antidiabetic Molecule Efficacy in Patients with Type 2 Diabetes Mellitus—A Real-Life Clinical Practice Study
Authors: Salmen Teodor , Rizvi Ali Abbas , Rizzo Manfredi , Pietrosel Valeria-Anca , Bica Ioana-Cristina , Diaconu Cosmina Theodora , Potcovaru Claudia Gabriela , Salmen Bianca-Margareta , Coman Oana Andreia , Bobircă Anca , Stoica Roxana-Adriana , Pantea Stoian Anca
Published: September 2023

In this paper, we aim to evaluate the efficacy of antidiabetic cardioprotective molecules such as Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) and Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RAs) when used with other glucose-lowering drugs, lipid-lowering, and blood pressure (BP)-lowering drugs in a real-life setting. A retrospective, observational study on 477 patients admitted consecutively in 2019 to the outpatient clinic of a tertiary care unit for Diabetes Mellitus was conducted. Body mass index (BMI), blood pressure (BP) (both systolic and diastolic), and metabolic parameters, as well as A1c hemoglobin, fasting glycaemia and lipid profile, including total cholesterol (C), HDL-C, LDL-C and triglycerides), were evaluated at baseline and two follow-up visits were scheduled (6 months and 12 months) in order to assess the antidiabetic medication efficacy. Both SGLT-2i and GLP-1 RAs were efficient in terms of weight control reflected by BMI; metabolic control suggested by fasting glycaemia and A1c; and the diastolic component of BP control when comparing the data from the 6 and 12-month visits to the baseline, and when comparing the 12-month visit to the 6-month visit. Moreover, when comparing SGLT-2i and GLP-1 RAs with metformin, there are efficacy data for SGLT-2i at baseline in terms of BMI, fasting glycaemia, and HbA1c. In this retrospective study, both classes of cardioprotective molecules, when used in conjunction with other glucose-lowering, antihypertensive, and lipid-lowering medications, appeared to be efficient in a real-life setting for the management of T2DM.
Ghrelin Amplifies the Nicotine-Induced Release of Dopamine in the Bed Nucleus of Stria Terminalis (BNST)
Authors: Ayman Jázmin , Palotai Miklós , Dochnal Roberta , Bagosi Zsolt
Published: September 2023

Ghrelin is an orexigenic neuropeptide that is known for stimulating the release of growth hormone (GH) and appetite. In addition, ghrelin has been implicated in addiction to drugs such as nicotine. Nicotine is the principal psychoactive component in tobacco and is responsible for the reward sensation produced by smoking. In our previous in vitro superfusion studies, it was demonstrated that ghrelin and nicotine stimulate equally the dopamine release in the rat amygdala, and ghrelin amplifies the nicotine-induced dopamine release in the rat striatum. However, less attention was paid to the actions of ghrelin and nicotine in the bed nucleus of the stria terminalis (BNST). Therefore, in the present study, nicotine and ghrelin were superfused to the BNST of male Wistar rats, and the dopamine release from the BNST was measured in vitro. In order to determine which receptors mediate these effects, mecamylamine, a non-selective nicotinic acetylcholine receptor (nAchR) antagonist, and GHRP-6, a selective growth hormone secretagogue receptor (GHS-R1A) antagonist, were also superfused to the rat BNST. Nicotine significantly increased the release of dopamine, and this effect was significantly inhibited by mecamylamine. Ghrelin increased dopamine release even more significantly than nicotine did, and this effect was significantly inhibited by GHRP-6. Moreover, when administered together, ghrelin significantly amplified the nicotine-induced release of dopamine in the BNST, and this additive effect was reversed partly by mecamylamine and partly by GHRP-6. Therefore, the present study provides a new base of evidence for the involvement of ghrelin in dopamine signaling implicated in nicotine addiction.
Endothelial Dysfunction and Pregnant COVID-19 Patients with Thrombophilia: A Narrative Review
Authors: Sekulovski Metodija , Mileva Niya , Chervenkov Lyubomir , Peshevska-Sekulovska Monika , Vasilev Georgi Vasilev , Vasilev Georgi Hristov , Miteva Dimitrina , Tomov Latchezar , Lazova Snezhina , Gulinac Milena , Velikova Tsvetelina
Published: September 2023

Pregnancy with SARS-CoV-2 infection can raise the risk of many complications, including severe COVID-19 and maternal–fetal adverse outcomes. Additionally, endothelial damage occurs as a result of direct SARS-CoV-2 infection, as well as immune system, cardiovascular, and thrombo-inflammatory reactions. In this narrative review, we focus on endothelial dysfunction (ED) in pregnancy, associated with obstetric complications, such as preeclampsia, fetal growth retardation, gestational diabetes, etc., and SARS-CoV-2 infection in pregnant women that can cause ED itself and overlap with other pregnancy complications. We also discuss some shared mechanisms of SARS-CoV-2 pathophysiology and ED.
Circulating Soluble EPCR Levels Are Reduced in Patients with Ischemic Peripheral Artery Disease and Associated with Markers of Endothelial and Vascular Function
Authors: Krug Janina , Bochenek Magdalena L. , Gogiraju Rajinikanth , Laubert-Reh Dagmar , Lackner Karl J. , Münzel Thomas , Wild Philipp S. , Espinola-Klein Christine , Schäfer Katrin
Published: September 2023

(1) Background: Endothelial dysfunction initiates cardiovascular pathologies, including peripheral artery disease (PAD). The pathophysiology of impaired new vessel formation in the presence of angiogenic stimuli, such as ischemia and inflammation, is unknown. We have recently shown in mice that reduced endothelial protein C receptor (EPCR) expression results in defective angiogenesis following experimental hindlimb ischemia. (2) Purpose: To determine soluble (s)EPCR levels in the plasma of patients with PAD and to compare them with the protein C activity and biomarkers of endothelial function, inflammation, and angiogenesis. (3) Methods and Results: Clinical tests of vascular function and immunoassays of plasma from patients with PAD stage II were compared to age- and sex-matched individuals with and without cardiovascular risk factors or PAD stage III/IV patients. sEPCR levels were significantly lower in PAD stage II patients compared to subjects with risk factors, but no PAD, and further decreased in PAD stage III/IV patients. Plasma protein C activity or levels of ADAM17, a mediator of EPCR shedding, did not differ. Significant associations between sEPCR and the ankle-brachial index (p = 0.0359), age (p = 0.0488), body mass index (p = 0.0110), and plasma sE-selectin levels (p = 0.0327) were observed. High-sensitive CRP levels and white blood cell counts were significantly elevated in PAD patients and associated with serum glucose levels, but not sEPCR. In contrast, plasma TNFα or IL1β levels did not differ. Circulating levels of VEGF were significantly elevated in PAD stage II patients (p = 0.0198), but not associated with molecular (sE-selectin) or functional (ankle-brachial index) markers of vascular health. (4) Conclusions: Our findings suggest that circulating sEPCR levels may be useful as biomarkers of endothelial dysfunction, including angiogenesis, in persons older than 35 years and that progressive loss of endothelial protein C receptors might be involved in the development and progression of PAD.
Development of a Variable-Configuration Bionic Robotic Fish
Authors: Xia Dan , Li Yuyao , Li Zhihan , Tian Mengqian , Wang Xingsong
Published: September 2023

Bionic robotic fish have advantages over traditional underwater propulsion. Most of the existing studies have been conducted with only one type of fish as a bionic object, but a single propulsion mode may not be able to achieve the different needs of underwater operations. In this paper, we designed a pneumatic variable-configuration soft bionic fish and completed the overall structure design. It was built with a cownose ray as the main-configuration bionic object and a Caranx melampygus as the secondary-configuration bionic object. The base structure, actuators, and variable-configuration modules of the robot were made using flexible materials. After completing the design of the structure and control system of the robot, the prototype was manufactured and an underwater test was completed. The tests results indicated that the robot fish could achieve underwater linear propulsion and turning movements in both configurations. The maximum propulsion speed of the main configuration was 38.24 mm/s and the turning angle speed was 5.6°/s, and the maximum propulsion speed of its secondary configuration was 43.05 mm/s and the turning angle speed was 30°/s. The feasibility of the machine fish structure and control scheme were verified.
Bioactivity Features of a Zn-1%Mg-0.1%Dy Alloy Strengthened by Equal-Channel Angular Pressing
Authors: Martynenko Natalia , Anisimova Natalia , Shinkareva Maria , Rybalchenko Olga , Rybalchenko Georgy , Zheleznyi Mark , Lukyanova Elena , Temralieva Diana , Gorbenko Artem , Raab Arseny , Pashintseva Natalia , Babayeva Gulalek , Kiselevskiy Mikhail , Dobatkin Sergey
Published: September 2023

The structure, phase composition, corrosion and mechanical properties, as well as aspects of biocompatibility in vitro and in vivo, of a Zn-1%Mg-0.1%Dy alloy after equal-channel angular pressing (ECAP) were studied. The structure refinement after ECAP leads to the formation of elongated α-Zn grains with a width of ~10 µm and of Mg- and Dy-containing phases. In addition, X-ray diffraction analysis demonstrated that ECAP resulted in the formation of the basal texture in the alloy. These changes in the microstructure and texture lead to an increase in ultimate tensile strength up to 262 ± 7 MPa and ductility up to 5.7 ± 0.2%. ECAP slows down the degradation process, apparently due to the formation of a more homogeneous microstructure. It was found that the alloy degradation rate in vivo after subcutaneous implantation in mice is significantly lower than in vitro ones. ECAP does not impair biocompatibility in vitro and in vivo of the Zn-1%Mg-0.1%Dy alloy. No signs of suppuration, allergic reactions, the formation of visible seals or skin ulcerations were observed after implantation of the alloy. This may indicate the absence of an acute reaction of the animal body to the Zn-1%Mg-0.1%Dy alloy in both states.
Probing Biochemical Differences in Lipid Components of Human Cells by Means of ATR-FTIR Spectroscopy
Authors: Portaccio Marianna , Faramarzi Bahar , Lepore Maria
Published: September 2023

Infrared spectroscopy has emerged as a promising technique for studying the composition of biological samples like lipids that play important roles in cellular functions and are involved in various diseases. For this reason, lipids are a target of interest in many biomedical studies. The objective of the present study is to utilize Fourier-Transform Infrared (FT-IR) spectroscopy to examine the main lipid components of human cells (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, C18 ceramide, sphingosine-1-phosphate, ceramide-1-phosphate, sphingomyelin, cholesterol, and triolein). FT-IR analysis on the previously mentioned lipid samples was performed in Attenuated Total Reflection (ATR) mode. The obtained spectra clearly evidence the contributions of the different functional groups that are present in the examined samples. Detailed assignments of spectral features were carried out in agreement with the literature. Similarities and differences among the different types of commercial lipid samples are evidenced and discussed, with particular attention to phospholipid and sphingolipid components. A quantitative analysis of phosphatidylinositol and sphingomyelin spectra using a ratiometric approach is reported. Moreover, a reconstruction procedure of FT-IR spectra of complex lipids useful for chemometrics applications is described. These representative examples of the potential use of the results of the present study can certainly contribute to a larger use of FT-IR spectroscopy in lipidomics.
Photocatalytic Materials Based on g-C3N4 Obtained by the One-Pot Calcination Method
Authors: Shamilov Radik R. , Muzipov Zufar M. , Sagdeev Dmitriy O. , Kholin Kirill V. , Saifina Alina F. , Gubaidullin Aidar T. , Galyametdinov Yuriy G.
Published: September 2023

Photocatalysts based on graphitic carbon nitride (g-C3N4) attracted considerable attention due to their efficiency in hydrogen production and decomposition of organic pollutants in aqueous solutions. In this work, a new approach to synthesis of g-C3N4-based heterostructures with improved photocatalytic properties was proposed. The properties of two different CdZnS/g-C3N4 and ZnIn2S4/g-C3N4 heterostructures synthesized and studied in the same conditions were compared. Pure g-C3N4 photocatalysts as well as CdZnS/g-C3N4 and ZnIn2S4/g-C3N4 heterostructures were synthesized using a one-pot method by calcining the mixture of the initial components. Photocatalytic properties of the synthesized substances were evaluated in a model reaction of rhodamine B decomposition induced by visible light. It was shown that ultrasonic treatment in the presence of a nonionic surfactant enhances the photocatalytic activity of g-C3N4 structures as a result of a higher photocatalyst dispersity. The electronic structures of the CdZnS/g-C3N4 and ZnIn2S4/g-C3N4 heterostructures were analyzed in detail. The photocatalytic activity of heterostructures was found to be 2–3-fold higher as compared with an unmodified g-C3N4 due to formation of a type II heterojunction and Z-scheme structures. Decomposition of rhodamine B occurred mostly via formation of active oxygen radicals by irradiation.
A Grand Canonical Monte Carlo Simulation for the Evaluation of Pore Size Distribution of Nuclear-Grade Graphite from Kr Adsorption Isotherms
Authors: Laudone Giuliano M. , Jones Katie L.
Published: September 2023

Characterizing materials with low surface areas or with very small sample sizes requires innovative approaches beyond traditional N2 and Ar adsorption measurements. The measurement of Kr adsorption isotherms is often employed to serve this purpose, yet its potential remains limited by the lack of models for the interpretation of the experimental results in terms of pore size distribution. In this work, simulated adsorption isotherms of Kr onto graphite in slit-shaped pores are generated with a Grand Canonical Monte Carlo method. The pore size distributions of nuclear-grade graphite samples and activated carbon are modelled by fitting simulated isotherms to the experimental data. The resulting distributions are favourably compared with those generated by commercially available modelling packages, based on the use of N2 adsorption isotherms using GCMC and BJH methods. The new GCMC-Kr kernel developed in this study offers an alternative method for the evaluation of the distribution of pore sizes in nuclear graphite and other low surface area materials, which can be employed when N2 and Ar adsorption measurements cannot be carried out.
USP14 Positively Modulates Head and Neck Squamous Carcinoma Tumorigenesis and Potentiates Heat Shock Pathway through HSF1 Stabilization
Authors: Wang Jie , Xiang Yuandi , Xie Zhanghong , Fan Mengqi , Fang Shizhen , Wan Huanzhi , Zhao Rui , Zeng Feng , Hua Qingquan
Published: September 2023

The ubiquitin-proteasome system is a pivotal intracellular proteolysis process in posttranslational modification. It regulates multiple cellular processes. Deubiquitinating enzymes (DUBs) are a stabilizer in proteins associated with tumor growth and metastasis. However, the link between DUBs and HNSCC remains incompletely understood. In this study, therefore, we identified USP14 as a tumor proliferation enhancer and a substantially hyperactive deubiquitinase in HNSCC samples, implying a poor prognosis prediction. Silencing USP14 in vitro conspicuously inhibited HNSCC cell proliferation and migration. Consistently, defective USP14 in vivo significantly diminished HNSCC tumor growth and lung metastasis compared to the control group. Luciferase assays indicated that HSF1 was downstream from USP14, and an evaluation of the cellular effects of HSF1 overexpression in USP14-dificient mice tumors showed that elevated HSF1 reversed HNSCC growth and metastasis predominantly through the HSF1-HSP pathway. Mechanistically, USP14 encouraged HSF1 expression by deubiquitinating and stabilizing HSF1, which subsequently orchestrated transcriptional activation in HSP60, HSP70, and HSP90, ultimately leading to HNSCC progression and metastasis. Collectively, we uncovered that hyperactive USP14 contributed to HNSCC tumor growth and lung metastasis by reinforcing HSF1-depedent HSP activation, and our findings provided the insight that targeting USP14 could be a promising prognostic and therapeutic strategy for HSNCC.
Epidemiological Trends of Haematological Malignancies in Belgium 2004–2018: Older Patients Show the Greatest Improvement in Survival
Authors: Henau Kris , Tambuyzer Tim , Van Gool Bart , Van Eycken Liesbet , Poirel Hélène A.
Published: September 2023

(1) Background: Haematological malignancies (HMs) represent a heterogeneous group of mostly rare cancers that differ in pathophysiology, incidence, and outcome. (2) Methods: Our study aims to understand the epidemiological situation and trends of 24 main types of HMs in Belgium over a 15-year period, with a focus on the impact of age. Age-standardised incidence, average annual percentage change (AAPC), 5- and 10-year relative survival (RS) and RS trends were estimated for all HMs (N = 94,415) diagnosed between 2004 and 2018. (3) Results: Incidence rates of HM increased, mainly in the 70+ age group (AAPC: 3%). RS varied by age and HM type. For each HM type, outcome decreased with age. The greatest decrease with age in 5-year RS is observed for aggressive HM, acute myeloid leukaemia (AML), acute lymphoblastic leukaemia, and Burkitt lymphoma, from 67%, 90%, and 97% below 20 years, to 2%, 12%, and 16% above 80 years of age, respectively. The moderate improvement in 5-year RS over the 2004–2018 period for all HMs, of +5 percentage point (pp), masks highly heterogenous outcomes by HM type and age group. The most impressive improvements are observed in the 80+ group: +45, +33, +28, and +16 pp for Hodgkin lymphoma, immunoproliferative disorders, follicular lymphoma, and chronic myeloid leukaemia, respectively. (4) Conclusions: The increasing incidence and survival over the 2004–2018 period are likely explained by diagnostic and therapeutic innovations, which have spread to populations not targeted by clinical trials, especially older adults. This real-world population-based study highlights entities that need significant improvement, such as AML.
Urinary Continence Recovery after Retzius-Sparing Robot Assisted Radical Prostatectomy and Adjuvant Radiation Therapy
Authors: Olivero Alberto , Tappero Stefano , Maltzman Ofir , Vecchio Enrico , Granelli Giorgia , Secco Silvia , Caviglia Alberto , Bocciardi Aldo Massimo , Galfano Antonio , Dell’Oglio Paolo
Published: September 2023

Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) allows the preservation of the structures advocated to play a crucial role in the continence mechanism. This study aims to evaluate the association between adjuvant radiation therapy (aRT) and urinary continence (UC) recovery after RS-RARP. For the purpose of the current study, all patients submitted to RS-RARP for prostate cancer (PCa) at a single high-volume European institution between January 2010 and December 2021 were identified. Only patients that harbored pT2 stage with positive surgical margins or pT3/pN1 stage with or without positive surgical margins were included in the analyses. Two groups of patients were identified as follows: patients who had undergone aRT and patients submitted to observation (no-aRT patients). As per definition, aRT was delivered within 1–6 months after surgery. After 1:1 propensity score matching, 124 aRT patients were compared with 124 no-aRT patients who continued standard follow-up protocol after surgery. UC recovery was 81 vs. 84% in aRT vs. no-aRT patients (p = 0.7). In multivariable Cox regression analyses, aRT did not reach the independent predictor status for UC recovery at 12 months. In the subgroup analysis including only aRT patients, only the nerve-sparing technique was independently associated with UC recovery at 12 months. Conversely, the type of aRT (IMRT/VMAT vs. 3D-CRT) did not reach the independent predictor status for UC recovery at 12 months. The current study is the first to address the association between aRT and UC recovery in patients treated with RS-RARP for PCa. Based on our data, aRT is not associated with worse UC recovery. In the cohort of patients treated with aRT, the nerve-sparing technique independently predicted UC recovery.
Prognostic Role of Dynamic Changes in Serological Markers in Metastatic Hormone Naïve Prostate Cancer
Authors: Roy Soumyajit , Sun Yilun , Wallis Christopher J. D. , Kishan Amar U. , Morgan Scott C. , Spratt Daniel E. , Malone Shawn , Saad Fred
Published: September 2023

We investigated whether inter-patient variation in the dynamic trajectory of hemoglobin (Hb), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and prostate-specific antigen (PSA) can prognosticate overall survival (OS) in de novo mHSPC. This is a secondary analysis of the LATITUDE trial in which high-risk de novo mHSPC patients were randomly assigned to receive either androgen deprivation therapy (ADT) plus abiraterone or ADT plus placebo. We used a five-fold cross-validated joint model approach to determine the association of temporal changes in the serological markers with OS. Decision curve analysis was applied to determine the net benefit. When dynamic changes in Hb, LMR, NLR, PLR, and PSA were included in a multivariate joint model, an increase in the log of the current value of PSA (HR: 1.24 [1.20–1.28]) was associated with inferior OS. A multivariate joint model that captured dynamic trajectory of Hb, NLR, PLR, LMR, and PSA up to 24 months, showed a net benefit over the “treat all” strategy at a threshold of probability of approximately ≥30% while no net benefit was seen when dynamic change in PSA was omitted. Our joint model could be used for designing future adaptive trials investigating sequential treatment personalization.
Multi-omics Characterization of Response to PD-1 Inhibitors in Advanced Melanoma
Authors: Trilla-Fuertes Lucía , Gámez-Pozo Angelo , Prado-Vázquez Guillermo , López-Vacas Rocío , Soriano Virtudes , Garicano Fernando , Lecumberri M. José , Rodríguez de la Borbolla María , Majem Margarita , Pérez-Ruiz Elisabeth , González-Cao María , Oramas Juana , Magdaleno Alejandra , Fra Joaquín , Martín-Carnicero Alfonso , Corral Mónica , Puértolas Teresa , Ramos-Ruiz Ricardo , Dittmann Antje , Nanni Paolo , Fresno Vara Juan Ángel , Espinosa Enrique
Published: September 2023

Immunotherapy improves the survival of patients with advanced melanoma, 40% of whom become long-term responders. However, not all patients respond to immunotherapy. Further knowledge of the processes involved in the response and resistance to immunotherapy is still needed. In this study, clinical paraffin samples from fifty-two advanced melanoma patients treated with anti-PD-1 inhibitors were assessed via high-throughput proteomics and RNA-seq. The obtained proteomics and transcriptomics data were analyzed using multi-omics network analyses based on probabilistic graphical models to identify those biological processes involved in the response to immunotherapy. Additionally, proteins related to overall survival were studied. The activity of the node formed by the proteins involved in protein processing in the endoplasmic reticulum and antigen presentation machinery was higher in responders compared to non-responders; the activity of the immune and inflammatory response node was also higher in those with complete or partial responses. A predictor for overall survival based on two proteins (AMBP and PDSM5) was defined. In summary, the response to anti-PD-1 therapy in advanced melanoma is related to protein processing in the endoplasmic reticulum, and also to genes involved in the immune and inflammatory responses. Finally, a two-protein predictor can define survival in advanced disease. The molecular characterization of the mechanisms involved in the response and resistance to immunotherapy in melanoma leads the way to establishing therapeutic alternatives for patients who will not respond to this treatment.
Changes in the Number of Gastrointestinal Cancers and Stage at Diagnosis with COVID-19 Pandemic in Japan: A Multicenter Cohort Study
Authors: Kuzuu Kento , Misawa Noboru , Ashikari Keiichi , Tamura Shigeki , Kato Shingo , Hosono Kunihiro , Yoneda Masato , Nonaka Takashi , Matsushima Shozo , Komatsu Tatsuji , Nakajima Atsushi , Higurashi Takuma
Published: September 2023

This retrospective cohort study compared the number of newly diagnosed patients, stage at diagnosis, and detection process of gastrointestinal cancers based on hospital-based cancer registry data at two tertiary Japanese hospitals. The pre-COVID-19 period was from January 2017 to February 2020, with phase 1 (midst of COVID-19 pandemic) from March to December 2020 and phase 2 (the transition period to the “new normal”) from January to December 2021. Each month, the number of patients diagnosed with esophageal, gastric, colorectal, pancreatic, liver, and biliary tract cancers were aggregated, classified by stage and detection process, and compared, including a total of 6453 patients. The number of colorectal Stage 0-II patients decreased significantly in phase 1 and increased in phase 2. The total number of colorectal cancer patients returned to pre-COVID-19 levels (mean monthly patients [SD]: 41.61 [6.81] vs. 36.00 [6.72] vs. 46.00 [11.32]). The number of patients with gastric cancer Stage I significantly decreased in phase 2 following phase 1. The number of gastric cancer patients decreased significantly from pre-COVID-19 levels (30.63 [6.62] vs. 22.40 [5.85] vs. 24.50 [4.15]). During phase 2, the number of patients diagnosed after screening with colorectal cancer increased significantly, whereas that with gastric cancer remained considerably lower. The number of Stage III colorectal and gastric cancer patients increased significantly from the pre-COVID-19 levels. Thus, gastric cancer may not be optimally screened during phases 1 and 2. There was a significant increase in patients with Stage III colorectal and gastric cancers from the pre-COVID-19 period; hence, the stage at diagnosis may have progressed.
Improving Prediction of Cervical Cancer Using KNN Imputed SMOTE Features and Multi-Model Ensemble Learning Approach
Authors: Karamti Hanen , Alharthi Raed , Anizi Amira Al , Alhebshi Reemah M. , Eshmawi Ala’ Abdulmajid , Alsubai Shtwai , Umer Muhammad
Published: September 2023

Objective: Cervical cancer ranks among the top causes of death among females in developing countries. The most important procedures that should be followed to guarantee the minimizing of cervical cancer’s aftereffects are early identification and treatment under the finest medical guidance. One of the best methods to find this sort of malignancy is by looking at a Pap smear image. For automated detection of cervical cancer, the available datasets often have missing values, which can significantly affect the performance of machine learning models. Methods: To address these challenges, this study proposes an automated system for predicting cervical cancer that efficiently handles missing values with SMOTE features to achieve high accuracy. The proposed system employs a stacked ensemble voting classifier model that combines three machine learning models, along with KNN Imputer and SMOTE up-sampled features for handling missing values. Results: The proposed model achieves 99.99% accuracy, 99.99% precision, 99.99% recall, and 99.99% F1 score when using KNN imputed SMOTE features. The study compares the performance of the proposed model with multiple other machine learning algorithms under four scenarios: with missing values removed, with KNN imputation, with SMOTE features, and with KNN imputed SMOTE features. The study validates the efficacy of the proposed model against existing state-of-the-art approaches. Conclusions: This study investigates the issue of missing values and class imbalance in the data collected for cervical cancer detection and might aid medical practitioners in timely detection and providing cervical cancer patients with better care.
Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling
Authors: Angus Lindsay , Smid Marcel , Wilting Saskia M. , Bos Manouk K. , Steeghs Neeltje , Konings Inge R. H. M. , Tjan-Heijnen Vivianne C. G. , van Riel Johanna M. G. H. , van de Wouw Agnes J. ,   CPCT Consortium, Cuppen Edwin , Lolkema Martijn P. , Jager Agnes , Sleijfer Stefan , Martens John W. M.
Published: September 2023

Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of ESR1 target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of ESR1 and its target genes. Samples in this cluster were significantly enriched for mutations in ESR1 and amplifications in FGFR1 and TSPYL. Patients in the other cluster showed relatively lower expression levels of ESR1 and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including NF1, and ESR1 transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of ESR1 and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data.
mAb14, a Monoclonal Antibody against Cell Surface PCNA: A Potential Tool for Sezary Syndrome Diagnosis and Targeted Immunotherapy
Authors: Knaneh Jamal , Hodak Emmilia , Fedida-Metula Shlomit , Edri Avishay , Eren Rachel , Yoffe Yael , Amitay-Laish Iris , Prag Naveh Hadas , Lubin Ido , Porgador Angel , Moyal Lilach
Published: September 2023

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common types of primary cutaneous T-cell lymphoma (CTCL). Proliferating cell nuclear antigen (PCNA) is expressed on the cell surface of cancer cells (csPCNA), but not on normal cells. It functions as an immune checkpoint ligand by interacting with natural killer (NK) cells through the NK inhibitory receptor NKp44, leading to the inhibition of NK cytotoxicity. A monoclonal antibody (mAb14) was established to detect csPCNA on cancer cells and block their interaction with NKp44. In this study, three CTCL cell lines and peripheral blood mononuclear cells (PBMCs) from patients with SS and healthy donors were analyzed for csPCNA using mAb14, compared to monoclonal antibody PC10, against nuclear PCNA (nPCNA). The following assays were used: immunostaining, imaging flow cytometry, flow cytometry, cell sorting, cell cycle analysis, ELISA, and the NK-cell cytotoxic assay. mAb14 successfully detected PCNA on the membrane and in the cytoplasm of viable CTCL cell lines associated with the G2/M phase. In the Sézary PBMCs, csPCNA was expressed on lymphoma cells that had an atypical morphology and not on normal cells. Furthermore, it was not expressed on PBMCs from healthy donors. In the co-culture of peripheral blood NK (pNK) cells with CTCL lines, mAb14 increased the secretion of IFN-γ, indicating the reactivation of pNK activity. However, mAb14 did not enhance the cytotoxic activity of pNK cells against CTCL cell lines. The unique expression of csPCNA detected by mAb14 suggests that csPCNA and mAb14 may serve as a potential biomarker and tool, respectively, for detecting malignant cells in SS and possibly other CTCL variants.
Novel Function of Cancer Stem Cell Marker ALDH1A3 in Glioblastoma: Pro-Angiogenesis through Paracrine PAI-1 and IL-8
Authors: Chen Zhen , Will Rainer , Kim Su Na , Busch Maike Anna , Dünker Nicole , Dammann Philipp , Sure Ulrich , Zhu Yuan
Published: September 2023

Hyper-angiogenesis is a typical feature of glioblastoma (GBM), the most aggressive brain tumor. We have reported the expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in proliferating vasculature in GBM patients. We hypothesized that ALDH1A3 may act as an angiogenesis promoter in GBM. Two GBM cell lines were lentivirally transduced with either ALDH1A3 (ox) or an empty vector (ev). The angiogenesis phenotype was studied in indirect and direct co-culture of endothelial cells (ECs) with oxGBM cells (oxGBMs) and in an angiogenesis model in vivo. Angiogenesis array was performed in oxGBMs. RT2-PCR, Western blot, and double-immunofluorescence staining were performed to confirm the expression of targets identified from the array. A significantly activated angiogenesis phenotype was observed in ECs indirectly and directly co-cultured with oxGBMs and in vivo. Overexpression of ALDH1A3 (oxALDH1A3) led to a marked upregulation of PAI-1 and IL-8 mRNA and protein and a consequential increased release of both proteins. Moreover, oxALDH1A3-induced angiogenesis was abolished by the treatment of the specific inhibitors, respectively, of PAI-1 and IL-8 receptors, CXCR1/2. This study defined ALDH1A3 as a novel angiogenesis promoter. oxALDH1A3 in GBM cells stimulated EC angiogenesis via paracrine upregulation of PAI-1 and IL-8, suggesting ALDH1A3-PAI-1/IL-8 as a novel signaling for future anti-angiogenesis therapy in GBM.
Enhanced Modification between Glucose Dehydrogenase and Mediator Using Epoxy Silane Assembly for Monitoring Glucose
Authors: Seo Tae-Won , Jeon Won-Yong , Choi Young-Bong
Published: September 2023

Blood glucose monitoring (BGM) using disposable electrodes is commonly used in healthcare diagnosis. The BGM method is not suitable for people with diabetes requiring real-time monitoring who might experience sudden hypoglycemia or hyperglycemia owing to a single measurement at a specific moment. This study aimed to achieve an enhanced stability of glucose diagnosis for continuous glucose measurement systems (CGMs). A representative mediator of a second-generation glucose sensor was synthesized and coordinated with a polymer for immobilization on an indium tin oxide (ITO) electrode. For electrode immobilization, an electrode for enhanced stability was fabricated using the silanization method. The morphological properties of the electrodes were confirmed via cyclic voltammetry (CV), impedance spectroscopy, and SEM. The loss rate of the current density was only 10.11% of the initial current after 8 d. The electrode exhibited a coefficient of determination of R2 = 0.9924, sensitivity of 1.5454 μA/cm2·mM, limit of quantitation (LOQ) of 7.604 μM, and limit of detection (LOD) of 2.509 μM for glucose concentrations between 0.1 and 20.0 mM. The electrode system developed in this study is applicable to the CGM healthcare industry and is expected to be applicable to biofuel cells.
The Characteristics of Badminton-Related Pain in Pre-Adolescent and Adolescent Badminton Players
Authors: Zhou Xiao , Imai Kazuhiro , Chen Zhuo , Liu Xiaoxuan , Watanabe Eiji , Zeng Hongtao
Published: September 2023

Body pain, often considered as an early sign of injury in young players, warrants thorough study. This study aimed to examine the distribution of badminton-related pain and prevalence in pre-adolescent and adolescent badminton players. Profiles of badminton-related pain were surveyed using a questionnaire among 366 pre-adolescent and adolescent badminton players aged 7–12 years. The distribution of badminton-related pain was described, and the pain incidence was calculated. Proportions of pain per 1000-training-hour exposures were the main outcome measures. The analysis considered various age groups (7–8, 9–10, and 11–12 years) and years of badminton experience (≤2, 2–3, and > 3 years). In total, 554 cases of badminton-related pain were reported. The ankle was the most common site, followed by knee, plantar, shoulder, and lower back. The overall pain rate per 1000-training-hour exposure was 3.06. The 11–12-year-old group showed the highest pain rate, significantly greater than the 7–8-year-old group and the 9–10-year-old group. Additionally, the prevalence of pain exhibited an increasing trend with age. Finally, regardless of the age groups, participants with 2–3 years of badminton experience had the highest pain rate. These findings might help inform targeted interventions to reduce the high prevalence of pain in various body regions across pre-adolescent and adolescent badminton players.
Telesimulation for the Training of Medical Students in Neonatal Resuscitation
Authors: Mileder Lukas P. , Bereiter Michael , Schwaberger Bernhard , Wegscheider Thomas
Published: September 2023

Background: Telesimulation may be an alternative to face-to-face simulation-based training. Therefore, we investigated the effect of a single telesimulation training in inexperienced providers. Methods: First-year medical students were recruited for this prospective observational study. Participants received a low-fidelity mannequin and medical equipment for training purposes. The one-hour telesimulation session was delivered by an experienced trainer and broadcast via a video conference tool, covering all elements of the neonatal resuscitation algorithm. After the telesimulation training, each student underwent a standardized simulated scenario at our Clinical Skills Center. Performance was video-recorded and evaluated by a single neonatologist, using a composite score (maximum: 10 points). Pre- and post-training knowledge was assessed using a 20-question questionnaire. Results: Seven telesimulation sessions were held, with a total of 25 students participating. The median performance score was 6 (5–8). The median time until the first effective ventilation breath was 30.0 s (24.5–41.0) and the median number of effective ventilation breaths out of the first five ventilation attempts was 5 (4–5). Neonatal resuscitation knowledge scores increased significantly. Conclusions: Following a one-hour telesimulation session, students were able to perform most of the initial steps of the neonatal resuscitation algorithm effectively while demonstrating notable mask ventilation skills.