bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypothermic Oxygenated Machine Perfusion Promotes Mitophagy Flux against Hypoxia-Ischemic Injury in Rat DCD Liver
Authors: Luo Jia , Hu Yiqing , Qiao Yinbiao , Li Haoyu , Huang Jiacheng , Xu Kangdi , Jiang Li , Wu Hao , Hu Xiaoyi , Jia Junjun , Zhou Lin , Xie Haiyang , Li Jianhui , Zheng Shusen
Published: March 2023

Hypothermic oxygenated machine perfusion (HOPE) can enhance organ preservation and protect mitochondria from hypoxia-ischemic injury; however, an understanding of the underlying HOPE mechanism that protects mitochondria is somewhat lacking. We hypothesized that mitophagy may play an important role in HOPE mitochondria protection. Experimental rat liver grafts were exposed to 30 min of in situ warm ischemia. Then, grafts were procured, followed by cold storage for 3 or 4 h to mimic the conventional preservation and transportation time in donation after circulatory death (DCD) in clinical contexts. Next, the grafts underwent hypothermic machine perfusion (HMP) or HOPE for 1 h through portal vein only perfusion. The HOPE-treated group showed a better preservation capacity compared with cold storage and HMP, preventing hepatocyte damage, nuclear injury, and cell death. HOPE can increase mitophagy marker expression, promote mitophagy flux via the PINK1/Parkin pathway to maintain mitochondrial function, and reduce oxygen free radical generation, while the inhibition of autophagy by 3-methyladenine and chloroquine could reverse the protective effect. HOPE-treated DCD liver also demonstrated more changes in the expression of genes responsible for bile metabolism, mitochondrial dynamics, cell survival, and oxidative stress. Overall, HOPE attenuates hypoxia-ischemic injury in DCD liver by promoting mitophagy flux to maintain mitochondrial function and protect hepatocytes. Mitophagy could pave the way for a protective approach against hypoxia-ischemic injury in DCD liver.
Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles
Authors: Baykov Sergey V. , Shetnev Anton A. , Semenov Artem V. , Baykova Svetlana O. , Boyarskiy Vadim P.
Published: March 2023

1,2,4-Oxadiazole is an essential motif in drug discovery represented in many experimental, investigational, and marketed drugs. This review covers synthetic methods that allow the conversion of different types of organic compounds into 1,2,4-oxadiazole at ambient temperature and the practical application of the latter approaches for the preparation of pharmaceutically important molecules. The discussed methods are divided into three groups. The first combines two-stage protocols requiring the preliminary preparation of O-acylamidoximes followed by cyclization under the action of organic bases. The advantages of this route are its swiftness, high efficiency of the cyclization process, and uncomplicated work-up. However, it requires the preparation and isolation of O-acylamidoximes as a separate preliminary step. The second route is a one-pot synthesis of 1,2,4-oxadiazoles directly from amidoximes and various carboxyl derivatives or aldehydes in aprotic bipolar solvents (primarily DMSO) in the presence of inorganic bases. This recently proposed pathway proved to be highly efficient in the field of medicinal chemistry. The third group of methods consists of diverse oxidative cyclizations, and these reactions have found modest application in drug design thus far. It is noteworthy that the reviewed methods allow for obtaining 1,2,4-oxadiazoles with thermosensitive functions and expand the prospects of using the oxadiazole core as an amide- or ester-like linker in the design of bioactive compounds.
MYCN Amplification, along with Wild-Type RB1 Expression, Enhances CDK4/6 Inhibitors’ Efficacy in Neuroblastoma Cells
Authors: De Rosa Piergiuseppe , Severi Federica , Zadran Suleman Khan , Russo Marco , Aloisi Sara , Rigamonti Alberto , Capranico Giovanni , Milazzo Giorgio , Perini Giovanni
Published: March 2023

Neuroblastoma (NB) is one of the primary causes of death for pediatric malignancies. Given the high heterogeneity in NB’s mutation landscape, optimizing individualized therapies is still challenging. In the context of genomic alterations, MYCN amplification is the most correlated event with poor outcomes. MYCN is involved in the regulation of several cellular mechanisms, including cell cycle. Thus, studying the influence of MYCN overexpression in the G1/S transition checkpoint of the cell cycle may unveil novel druggable targets for the development of personalized therapeutical approaches. Here, we show that high expression of E2F3 and MYCN correlate with poor prognosis in NB despite the RB1 mRNA levels. Moreover, we demonstrate through luciferase reporter assays that MYCN bypasses RB function by incrementing E2F3-responsive promoter activity. We showed that MYCN overexpression leads to RB inactivation by inducing RB hyperphosphorylation during the G1 phase through cell cycle synchronization experiments. Moreover, we generated two MYCN-amplified NB cell lines conditionally knockdown (cKD) for the RB1 gene through a CRISPRi approach. Indeed, RB KD did not affect cell proliferation, whereas cell proliferation was strongly influenced when a non-phosphorylatable RB mutant was expressed. This finding revealed the dispensable role of RB in regulating MYCN-amplified NB’s cell cycle. The described genetic interaction between MYCN and RB1 provides the rationale for using cyclin/CDK complexes inhibitors in NBs carrying MYCN amplification and relatively high levels of RB1 expression.
The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy
Authors: Engel Tobias
Published: March 2023

Epilepsy, characterized by recurrent spontaneous seizures, is a heterogeneous group of brain diseases affecting over 70 million people worldwide. Major challenges in the management of epilepsy include its diagnosis and treatment. To date, video electroencephalogram (EEG) monitoring is the gold-standard diagnostic method, with no molecular biomarker in routine clinical use. Moreover, treatment based on anti-seizure medications (ASMs) remains ineffective in 30% of patients, and, even if seizure-suppressive, lacks disease-modifying potential. Current epilepsy research is, therefore, mainly focussed on the identification of new drugs with a different mechanism of action effective in patients not responding to current ASMs. The vast heterogeneity of epilepsy syndromes, including differences in underlying pathology, comorbidities and disease progression, represents, however, a particular challenge in drug discovery. Optimal treatment most likely requires the identification of new drug targets combined with diagnostic methods to identify patients in need of a specific treatment. Purinergic signalling via extracellularly released ATP is increasingly recognized to contribute to brain hyperexcitability and, consequently, drugs targeting this signalling system have been proposed as a new therapeutic strategy for epilepsy. Among the purinergic ATP receptors, the P2X7 receptor (P2X7R) has attracted particular attention as a novel target for epilepsy treatment, with P2X7Rs contributing to unresponsiveness to ASMs and drugs targeting the P2X7R modulating acute seizure severity and suppressing seizures during epilepsy. In addition, P2X7R expression has been reported to be altered in the brain and circulation in experimental models of epilepsy and patients, making it both a potential therapeutic and diagnostic target. The present review provides an update on the newest findings regarding P2X7R-based treatments for epilepsy and discusses the potential of P2X7R as a mechanistic biomarker.
Modulation of Melatonin in Pain Behaviors Associated with Oxidative Stress and Neuroinflammation Responses in an Animal Model of Central Post-Stroke Pain
Authors: Kaur Tavleen , Huang Andrew , Shyu Bai-Chuang
Published: March 2023

Central post-stroke pain is a severe persistent pain disease that affects 12% of stroke survivors (CPSP). These patients may have a cognitive impairment, depression, and sleep apnea, which leave them open to misdiagnosis and mistreatment. However, there has been little research on whether the neurohormone melatonin can effectively reduce pain in CPSP conditions. In the present study, we labeled melatonin receptors in various brain regions of rats. Later, we established a CPSP animal model by intra-thalamic collagenase lesions. After a rehabilitation period of three weeks, melatonin was administered using different doses (i.e., 30 mg/kg, 60 mg/kg, 120 mg/kg) for the following three weeks. Mechanical allodynia, thermal hyperalgesia, and cold allodynia behavioral tests were performed. Immediately after behavioral parameters were tested, animals were sacrificed, and the thalamus and cortex were isolated for biochemical (mitochondrial complexes/enzyme assays and LPO, GSH levels) and neuroinflammatory (TNF-α, IL-1β, IL-6) assessments. The results show that melatonin receptors were abundant in VPM/VPL regions. The thalamic lesion significantly induced pain behaviors in the mechanical, thermal planters, and cold allodynia tests. A significant decrease in mitochondrial chain complexes (C-I, II, III, IV) and enzymes (SOD, CAT, Gpx, SDH) was observed after the thalamic lesion. While there were significant increases in reactive oxygen species levels, including increases in LPO, the levels of reduced GSH were decreased in both the cortex and thalamus. Proinflammatory infiltration was noticed after the thalamic lesion, as there was a significant elevation in levels of TNF-α, IL-1β, and IL-6. Administration of melatonin has been shown to reverse the injury effect dose-dependently. Moreover, a significant increase in C-I, IV, SOD, CAT, and Gpx levels occurred in the CPSP group. Proinflammatory cytokines were significantly reduced by melatonin treatments. Melatonin seems to mediate its actions through MT1 receptors by preserving mitochondrial homeostasis, reducing free radical generation, enhancing mitochondrial glutathione levels, safeguarding the proton potential in the mitochondrial ETC by stimulating complex I and IV activities, and protecting the neuronal damage. In summary, exogenous melatonin can ameliorate pain behaviors in CPSP. The present findings may provide a novel neuromodulatory treatment in the clinical aspects of CPSP.
Temporins: Multifunctional Peptides from Frog Skin
Authors: D'Andrea Luca Domenico , Romanelli Alessandra
Published: March 2023

Temporins are short peptides secreted by frogs from all over the world. They exert antimicrobial activity, mainly against Gram-positive bacteria, including resistant pathogens; recent studies highlight other possible applications of these peptides as anticancer or antiviral agents. This review is meant to describe the main features of temporins produced by different ranid genera. Due to the abundance of published papers, we focus on the most widely investigated peptides. We report studies on their mechanism of action and three-dimensional structure in model systems mimicking bacterial membranes or in the presence of cells. The design and the antimicrobial activity of peptide analogues is also described, with the aim of highlighting elements that are crucial to improve the bioactivity of peptides while reducing their toxicity. Finally, a short section is dedicated to the studies aimed at applying these peptides as drugs, to produce new antimicrobial materials or in other technological uses.
Effect of Ovocystatin on Amyloid β 1-42 Aggregation—In Vitro Studies
Authors: Stańczykiewicz Bartłomiej , Goszczyński Tomasz M. , Migdał Paweł , Piksa Marta , Pawlik Krzysztof , Gburek Jakub , Gołąb Krzysztof , Konopska Bogusława , Zabłocka Agnieszka
Published: March 2023

Amyloid β peptides (Aβ) aggregating in the brain have a potential neurotoxic effect and are believed to be a major cause of Alzheimer’s disease (AD) development. Thus, inhibiting amyloid polypeptide aggregation seems to be a promising approach to the therapy and prevention of this neurodegenerative disease. The research presented here is directed at the determination of the inhibitory activity of ovocystatin, the cysteine protease inhibitor isolated from egg white, on Aβ42 fibril genesis in vitro. Thioflavin-T (ThT) assays, which determine the degree of aggregation of amyloid peptides based on fluorescence measurement, circular dichroism spectroscopy (CD), and transmission electron microscopy (TEM) have been used to assess the inhibition of amyloid fibril formation by ovocystatin. Amyloid beta 42 oligomer toxicity was measured using the MTT test. The results have shown that ovocystatin possesses Aβ42 anti-aggregation activity and inhibits Aβ42 oligomer toxicity in PC12 cells. The results of this work may help in the development of potential substances able to prevent or delay the process of beta-amyloid aggregation—one of the main reasons for Alzheimer’s disease.
MiRNAs in Hematopoiesis and Acute Lymphoblastic Leukemia
Authors: Mendiola-Soto Diana Karen , Bárcenas-López Diego Alberto , Pérez-Amado Carlos Jhovani , Cruz-Miranda Gabriela Marisol , Mejía-Aranguré Juan Manuel , Ramírez-Bello Julian , Hidalgo-Miranda Alfredo , Jiménez-Morales Silvia
Published: March 2023

Acute lymphoblastic leukemia (ALL) is the most common kind of pediatric cancer. Although the cure rates in ALL have significantly increased in developed countries, still 15–20% of patients relapse, with even higher rates in developing countries. The role of non-coding RNA genes as microRNAs (miRNAs) has gained interest from researchers in regard to improving our knowledge of the molecular mechanisms underlying ALL development, as well as identifying biomarkers with clinical relevance. Despite the wide heterogeneity reveled in miRNA studies in ALL, consistent findings give us confidence that miRNAs could be useful to discriminate between leukemia linages, immunophenotypes, molecular groups, high-risk-for-relapse groups, and poor/good responders to chemotherapy. For instance, miR-125b has been associated with prognosis and chemoresistance in ALL, miR-21 has an oncogenic role in lymphoid malignancies, and the miR-181 family can act either as a oncomiR or tumor suppressor in several hematological malignancies. However, few of these studies have explored the molecular interplay between miRNAs and their targeted genes. This review aims to state the different ways in which miRNAs could be involved in ALL and their clinical implications.
Interaction between Sulfate and Selenate in Tetraploid Wheat (Triticum turgidum L.) Genotypes
Authors: Coppa Eleonora , Celletti Silvia , Sestili Francesco , Mimmo Tanja , Garcia Molina Maria Dolores , Cesco Stefano , Astolfi Stefania
Published: March 2023

Selenium (Se) is an essential micronutrient of fundamental importance to human health and the main Se source is from plant-derived foods. Plants mainly take up Se as selenate (SeO42−), through the root sulfate transport system, because of their chemical similarity. The aims of this study were (1) to characterize the interaction between Se and S during the root uptake process, by measuring the expression of genes coding for high-affinity sulfate transporters and (2) to explore the possibility of increasing plant capability to take up Se by modulating S availability in the growth medium. We selected different tetraploid wheat genotypes as model plants, including a modern genotype, Svevo (Triticum turgidum ssp. durum), and three ancient Khorasan wheats, Kamut, Turanicum 21, and Etrusco (Triticum turgidum ssp. turanicum). The plants were cultivated hydroponically for 20 days in the presence of two sulfate levels, adequate (S = 1.2 mM) and limiting (L = 0.06 mM), and three selenate levels (0, 10, 50 μM). Our findings clearly showed the differential expression of genes encoding the two high-affinity transporters (TdSultr1.1 and TdSultr1.3), which are involved in the primary uptake of sulfate from the rhizosphere. Interestingly, Se accumulation in shoots was higher when S was limited in the nutrient solution.
Eptifibatide, an Older Therapeutic Peptide with New Indications: From Clinical Pharmacology to Everyday Clinical Practice
Authors: Tonin Gašper , Klen Jasna
Published: March 2023

Therapeutic peptides are oligomers or short polymers of amino acids used for various medical purposes. Peptide-based treatments have evolved considerably due to new technologies, stimulating new research interests. They have been shown to be beneficial in a variety of therapeutic applications, notably in the treatment of cardiovascular disorders such as acute coronary syndrome (ACS). ACS is characterized by coronary artery wall damage and consequent formation of an intraluminal thrombus obstructing one or more coronary arteries, leading to unstable angina, non-ST elevated myocardial infarction, and ST-elevated myocardial infarction. One of the promising peptide drugs in the treatment of these pathologies is eptifibatide, a synthetic heptapeptide derived from rattlesnake venom. Eptifibatide is a glycoprotein IIb/IIIa inhibitor that blocks different pathways in platelet activation and aggregation. In this narrative review, we summarized the current evidence on the mechanism of action, clinical pharmacology, and applications of eptifibatide in cardiology. Additionally, we illustrated its possible broader usage with new indications, including ischemic stroke, carotid stenting, intracranial aneurysm stenting, and septic shock. Further research is, however, required to fully evaluate the role of eptifibatide in these pathologies, independently and in comparison to other medications.
Using Small Non-Coding RNAs in Extracellular Vesicles of Semen as Biomarkers of Male Reproductive System Health: Opportunities and Challenges
Authors: Larriba Sara , Vigués Francesc , Bassas Lluís
Published: March 2023

Reproductive dysfunction and urogenital malignancies represent a serious health concern in men. This is in part as a result of the absence of reliable non-invasive tests of diagnosis/prognosis. Optimizing diagnosis and predicting the patient’s prognosis will affect the choice of the most appropriate treatment and therefore increase the chances of success and the result of therapy, that is, it will lead to a more personalized treatment of the patient. This review aims firstly to critically summarize the current knowledge of the reproductive roles played by extracellular vesicle small RNA components, which are typically altered in diseases affecting the male reproductive tract. Secondly, it aims to describe the use of semen extracellular vesicles as a non-invasive source of sncRNA-based biomarkers for urogenital diseases.
Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies
Authors: Baggio Chiara , Luisetto Roberto , Boscaro Carlotta , Scanu Anna , Ramonda Roberta , Albiero Mattia , Sfriso Paolo , Oliviero Francesca
Published: March 2023

Genome damage has been related to the induction of autoimmune processes, chronic inflammation, and apoptosis. Recent studies suggest that some rheumatological diseases are associated with overall genomic instability in the T cell compartment. However, no data regarding leucocyte abnormalities in synovial fluid (SF) and their relationship with inflammation are available. The aim of this study was to investigate cellular phenotypes in SF collected from patients with different inflammatory arthropathies, including rhematoid arthritis (RA), psoriatic arthritis (PsA), crystal-induced arthritis (CIA), and non-inflammatory arthropathies, such as osteoarthritis (OA). We found high percentage of micronuclei in SF from CIA compared to the other groups and a high frequency of pyknotic cell in RA and CIA patients. A correlation between pyknosis and immature polymorphonuclear cells with local inflammatory indices was observed. The study of the apoptosis process revealed an increased BAX expression in CIA and RA compared to OA and PsA, while Bcl-2 was higher in CIA. Caspase-3 activity was increased in SF from RA patients and correlates with inflammatory and anti-inflammatory cytokines. In conclusion, our results showed that inflammatory SF is associated with genomic instability and abnormal cell subsets.
Exostosin 1 Knockdown Induces Chemoresistance in MV3 Melanoma Cells by Upregulating JNK and MEK/ERK Signaling
Authors: Pfeifer Vladlena , Weber Heiko , Wang Yuanyuan , Schlesinger Martin , Gorzelanny Christian , Bendas Gerd
Published: March 2023

Heparan sulfate proteoglycans (HSPGs) possess various functions driving malignancy of tumors. However, their impact on tumor cell sensitivity to cytotoxic treatment is far less understood. Aiming to investigate this, we depleted HSPGs by downregulating Exostosin 1 (EXT1), a key enzyme in HS formation, or upregulating heparanase in human MV3 human melanoma cells, and investigated their response to cytotoxic drugs. Cytotoxicity of trametinib, doxorubicin, and mitoxantrone was detected by MTT assay. Insights into intracellular signaling was provided by kinome protein profiler array, and selected kinases were inhibited to investigate their impact on cell sensitization and migratory dynamics. EXT1 knockdown (EXT1kd) in MV3 cells affected the activity of doxorubicin and mitoxantrone, significantly increasing EC50 values two- or fourfold, respectively. Resistance formation was scarcely related to HSPG deficiency, suggested by enzymatic cleavage of HSPG in control cells. Notably, EXT1kd induced an upregulation of EGFR signaling via JNK and MEK/ERK, and hence blocking these kinases returned resistance to a sensitive level. JNK appeared as a key signal component, also inducing higher migratory activity of EXT1kd cells. Furthermore, EXT1kd upregulated thrombotic properties of MV3 cells, indicated by tissue factor and PAR-1 expression, functionally reflected by a stronger activation of platelet aggregation. EXT1 was confirmed to act as a tumor suppressor, shown here for the first time to affect chemosensitivity of melanoma cells.
Intrinsic Allergenicity Potential of Salt-Soluble Protein Extracts from the Diploid, Tetraploid and Hexaploid Wheats: Validation Using an Adjuvant-Free Mouse Model
Authors: Gao Haoran , Jorgensen Rick , Raghunath Rajsri , Chandra Shivam , Othman Aqilah , Olson Eric , Ng Perry K. W. , Gangur Venu
Published: March 2023

Wheat allergies are potentially life-threatening and, therefore, have become a major health concern at the global level. It is largely unknown at present whether genetic variation in allergenicity potential exists among hexaploid, tetraploid and diploid wheat species. Such information is critical in establishing a baseline allergenicity map to inform breeding efforts to identify hyper-, hypo- and non-allergenic varieties. We recently reported a novel mouse model of intrinsic allergenicity using the salt-soluble protein extract (SSPE) from durum, a tetraploid wheat (Triticum durum). Here, we validated the model for three other wheat species [hexaploid common wheat (Triticum aestivum), diploid einkorn wheat (Triticum monococcum), and the ancient diploid wheat progenitor, Aegilops tauschii], and then tested the hypothesis that the SSPEs from wheat species will exhibit differences in relative allergenicities. Balb/c mice were repeatedly exposed to SSPEs via the skin. Allergic sensitization potential was assessed by specific (s) IgE antibody responses. Oral anaphylaxis was quantified by the hypothermic shock response (HSR). The mucosal mast cell response (MMCR) was determined by measuring mast cell protease in the blood. While T. monococcum elicited the least, but significant, sensitization, others were comparable. Whereas Ae. taushcii elicited the least HSR, the other three elicited much higher HSRs. Similarly, while Ae. tauschii elicited the least MMCR, the other wheats elicited much higher MMCR as well. In conclusion, this pre-clinical comparative mapping strategy may be used to identify potentially hyper-, hypo- and non-allergenic wheat varieties via crossbreeding and genetic engineering methods.
Protein Unfolding—Thermodynamic Perspectives and Unfolding Models
Authors: Seelig Joachim , Seelig Anna
Published: March 2023

We review the key steps leading to an improved analysis of thermal protein unfolding. Thermal unfolding is a dynamic cooperative process with many short-lived intermediates. Protein unfolding has been measured by various spectroscopic techniques that reveal structural changes, and by differential scanning calorimetry (DSC) that provides the heat capacity change Cp(T). The corresponding temperature profiles of enthalpy ΔH(T), entropy ΔS(T), and free energy ΔG(T) have thus far been evaluated using a chemical equilibrium two-state model. Taking a different approach, we demonstrated that the temperature profiles of enthalpy ΔH(T), entropy ΔS(T), and free energy ΔG(T) can be obtained directly by a numerical integration of the heat capacity profile Cp(T). DSC thus offers the unique possibility to assess these parameters without resorting to a model. These experimental parameters now allow us to examine the predictions of different unfolding models. The standard two-state model fits the experimental heat capacity peak quite well. However, neither the enthalpy nor entropy profiles (predicted to be almost linear) are congruent with the measured sigmoidal temperature profiles, nor is the parabolic free energy profile congruent with the experimentally observed trapezoidal temperature profile. We introduce three new models, an empirical two-state model, a statistical–mechanical two-state model and a cooperative statistical-mechanical multistate model. The empirical model partially corrects for the deficits of the standard model. However, only the two statistical–mechanical models are thermodynamically consistent. The two-state models yield good fits for the enthalpy, entropy and free energy of unfolding of small proteins. The cooperative statistical–mechanical multistate model yields perfect fits, even for the unfolding of large proteins such as antibodies.
The Structural–Rhythmological Organization of Coelogyne (Orchidaceae Juss.) Inflorescences
Authors: Kolomeitseva Galina , Koval Vladimir , Ryabchenko Andrey
Published: March 2023

The morphostructure of inflorescences in the genus Coelogyne Lindl. was studied for the first time using a structural–rhythmological approach. Three species of Coelogyne were used to describe one-season, intercalary, and all-season inflorescences. In C. monilirachis, a new type of all-season inflorescence was identified, characterized by a prolonged sympodial growth of the rachis, lack of a pronounced dormant period, and thickening of all rachis internodes except the first. This inflorescence has been determined to be a compound monochasial cyme, with each floral unit represented by a separate flower. C. ovalis has a one-season inflorescence, with the floral unit being a determinate bracteous spike (stachyoid), and C. prolifera developed intercalary inflorescences united in an indeterminate bracteous spike.
Association of Major Adverse Cardiac Events and Beta-Blockers in Patients with and without Atherosclerotic Cardiovascular Disease: Long-Term Follow-Up Results of the T-SPARCLE and T-PPARCLE Registry in Taiwan
Authors: Liu Patrick Yan-Tyng , Lin Fang-Ju , Yeh Chih-Fan , Hsiao Yu-Chung , Hsuan Chin-Feng , Chang Wei-Tien , Kao Hsien-Li , Jeng Jiann-Shing , Wu Yen-Wen , Hsieh I-Chang , Fang Ching-Chang , Wang Kuo-Yang , Chang Kuan-Cheng , Lin Tsung-Hsien , Sheu Wayne Huey-Herng , Li Yi-Heng , Yin Wei-Hsian , Yeh Hung-I , Chen Jaw-Wen , Wu Chau-Chung
Published: March 2023

Beta-blockers are widely used, but the benefit is now challenged in patients at risk of atherosclerotic cardiovascular disease (ASCVD) in the present coronary reperfusion era. We aimed to identify the risk factors of a major adverse cardiac event (MACE) and the long-term effect of beta-blockers in two large cohorts in Taiwan. Two prospective observational cohorts, including patients with known atherosclerosis cardiovascular disease (T-SPARCLE) and patients with at least one risk factor of ASCVD but without clinically evident ASCVD (T-PPARCLE), were conducted in Taiwan. The primary endpoint is the time of first occurrence of a MACE (cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, and cardiac arrest with resuscitation). Between December 2009 and November 2014, with a median 2.4 years follow-up, 11,747 eligible patients (6921 and 4826 in T-SPARCLE and T-PPARCLE, respectively) were enrolled. Among them, 273 patients (2.3%) met the primary endpoint. With multivariate Cox PH model analysis, usage of beta-blocker was lower in patients with MACE (42.9% vs. 52.4%, p < 0.01). In patients with ASCVD, beta-blocker usage was associated with lower MACEs (hazard ratio 0.72; p < 0.001), but not in patients without ASCVD. The event-free survival of beta-blocker users remained higher during the follow-up period (p < 0.005) of ASCVD patients. In conclusion, in ASCVD patients, reduced MACE was associated with beta-blocker usage, and the effect was maintained during a six-year follow-up. Prescribing beta-blockers as secondary prevention is reasonable in the Taiwanese population.
EUS-Guided Vascular Interventions
Authors: Baliss Michelle , Patel Devan , Madi Mahmoud Y. , Bazarbashi Ahmad Najdat
Published: March 2023

Endoscopic ultrasound (EUS) has numerous advanced applications as a diagnostic and therapeutic modality in contemporary medicine. Through intraluminal placement, EUS offers a real-time Doppler-guided endoscopic visualization and access to intra-abdominal vasculature, which were previously inaccessible using historical methods. We aim to provide a comprehensive review of key studies on both current and future EUS-guided vascular applications. This review details EUS-based vascular diagnostic techniques of portal pressure measurements in the prognostication of liver disease and portal venous sampling for obtaining circulating tumor cells in the diagnosis of cancer. From an interventional perspective, we describe effective EUS-guided treatments via coiling and cyanoacrylate injections of gastric varices and visceral artery pseudoaneurysms. Specific attention is given to clinical studies on efficacy and procedural techniques described by investigators for each EUS-based application. We explore novel and future emerging EUS-based interventions, such as liver tumor ablation and intrahepatic portosystemic shunt placement.
Repeated Dose of Contrast Media and the Risk of Contrast-Induced Acute Kidney Injury in a Broad Population of Patients Hospitalized in Cardiology Department
Authors: Cichoń Małgorzata , Wybraniec Maciej T. , Okoń Oliwia , Zielonka Marek , Antoniuk Sofija , Szatan Tomasz , Mizia-Stec Katarzyna
Published: March 2023

Contrast-induced acute kidney injury (CI-AKI) can lead to the development of chronic kidney disease (CKD) and impaired in-hospital and long-term outcomes among cardiac patients. The aim of this study was to evaluate the impact of repeated contrast media (CM) administration during a single hospitalization on the rate of CI-AKI. The study group (n = 138) comprised patients with different diagnoses who received CM more than once during hospitalization, while the control group (n = 153) involved CAD patients subject to a single CM dose. Following propensity score matching (PSM), both groups of n = 84 were evenly matched in terms of major baseline variables. CI-AKI was defined by an absolute increase in SCr ≥ 0.3 mg/dL or >50% relative to the baseline value within 48–72 h from the last CM dose. Patients in the study group were older, had a higher prevalence of diabetes and CKD, received a higher total volume of CM, had a lower left ventricular ejection fraction, lower prevalence of multivessel coronary artery disease (MV-CAD), and a trend towards a lower prevalence of arterial hypertension and smoking. SCr did not differ between the study and control groups at 72 h after the CM use. CI-AKI occurred in 18 patients in the study (13.0%) and in 18 patients (11.8%) in the control group (p = 0.741). The rate of CI-AKI was also comparable following the PSM (13.1% vs. 13.1%, p = 1.0). Logistic regression analysis revealed that CKD, diabetes mellitus, MV-CAD, age, and non-steroidal anti-inflammatory drugs use, but not repeated CM use, were independent predictors of CI-AKI.
Examining Clinical Opinion and Experience Regarding Utilization of Plain Radiography of the Spine: Evidence from Surveying the Chiropractic Profession
Authors: Arnone Philip , Kraus Steven , Farmen Derek , Lightstone Douglas , Jaeger Jason , Theodossis Christine
Published: March 2023

Plain Radiography of the spine (PROTS) is utilized in many forms of healthcare including the chiropractic profession; however, the literature reflects conflicting opinions regarding utilization and value. Despite being an essential part of Evidence-Based Practice (EBP), few studies assess Doctors of Chiropractic (DCs) clinical opinions and experience regarding the utilization of (PROTS) in practice. In this study, DCs were surveyed regarding utilization of PROTS in practice. The survey was administered to an estimated 50,000 licensed DCs by email. A total of 4301 surveys were completed, of which 3641 were United States (US) DCs. The Clinician Opinion and Experience on Chiropractic Radiography (COECR) scale was designed to analyze survey responses. This valid and reliable scale demonstrated good internal consistency using confirmatory factor analysis and the Rasch model. Survey responses show that 73.3% of respondents utilize PROTS in practice and 26.7% refer patients out for PROTS. Survey responses show that, among US DCs, 91.9% indicate PROTS has value beyond identification of pathology, 86.7% indicate that PROTS is important regarding biomechanical analysis of the spine, 82.9% indicate that PROTS is vital to practice, 67.4% indicate that PROTS aids in measuring outcomes, 98.6% indicate the opinion that PROTS presents very low to no risk to patients, and 93.0% indicate that sharing clinical findings from PROTS studies with patients is beneficial to clinical outcomes. The results of the study indicated that based on clinical experience, the majority of DCs find PROTS to be vital to practice and valuable beyond the identification of red flags.
Trends in Net Survival from Vulvar Squamous Cell Carcinoma in Italy (1990–2015)
Authors: Mancini Silvia , Bucchi Lauro , Zamagni Federica , Baldacchini Flavia , Crocetti Emanuele , Giuliani Orietta , Ravaioli Alessandra , Vattiato Rosa , Preti Mario , Tumino Rosario , Ferretti Stefano , Biggeri Annibale , Ballotari Paola , Boschetti Lorenza , Brustolin Angelita , Caldarella Adele , Cavallo Rossella , Cirilli Claudia , Citarella Annarita , Contrino Maria L. , Dal Maso Luigino , Filiberti Rosa A. , Fusco Mario , Galasso Rocco , Lotti Fernanda L. , Magoni Michele , Mangone Lucia , Masanotti Giuseppe , Mazzoleni Guido , Mazzucco Walter , Melcarne Anna , Michiara Maria , Pesce Paola , Pinto Angela , Piras Daniela , Rizzello Roberto V. , Rognoni Magda , Rosso Stefano , Rugge Massimo , Sampietro Giuseppe , Scalzi Santo , Scuderi Tiziana , Tagliabue Giovanna , Toffolutti Federica , Vitarelli Susanna , Falcini Fabio
Published: March 2023

(1) Objective: In many Western countries, survival from vulvar squamous cell carcinoma (VSCC) has been stagnating for decades or has increased insufficiently from a clinical perspective. In Italy, previous studies on cancer survival have not taken vulvar cancer into consideration or have pooled patients with vulvar and vaginal cancer. To bridge this knowledge gap, we report the trend in survival from vulvar cancer between 1990 and 2015. (2) Methods: Thirty-eight local cancer registries covering 49% of the national female population contributed the records of 6274 patients. Study endpoints included 1- and 2-year net survival (NS) calculated using the Pohar-Perme estimator and 5-year NS conditional on having survived two years (5|2-year CNS). The significance of survival trends was assessed with the Wald test on the coefficient of the period of diagnosis, entered as a continuous regressor in a Poisson regression model. (3) Results: The median patient age was stable at 76 years. One-year NS decreased from 83.9% in 1990–2001 to 81.9% in 2009–2015 and 2-year NS from 72.2% to 70.5%. Five|2-year CNS increased from 85.7% to 86.7%. These trends were not significant. In the age stratum 70–79 years, a weakly significant decrease in 2-year NS from 71.4% to 65.7% occurred. Multivariate analysis adjusting for age group at diagnosis and geographic area showed an excess risk of death at 5|2-years, of borderline significance, in 2003–2015 versus 1990–2002. (4) Conclusions: One- and 2-year NS and 5|2-year CNS showed no improvements. Current strategies for VSCC control need to be revised both in Italy and at the global level.
Sacrospinous Hysteropexy Versus Prolapse Hysterectomy with Apical Fixation: A Retrospective Comparison over an 18 Year Period
Authors: Carlin Greta , Lange Sören , Ziegler Christina , Heinzl Florian , Bodner-Adler Barbara
Published: March 2023

Background. Pelvic organ prolapse (POP) is a common health problem, with a high lifetime risk for prolapse surgery. Uterine-preserving procedures such as vaginal sacrospinous hysteropexy (SSH) have become an increasingly utilized surgical option for the primary treatment of POP. We wanted to evaluate peri- and postoperative outcome parameters of SSH as an alternative to vaginal hysterectomy with apical fixation. Methods. A retrospective cohort study was conducted (2003–2021). All patients who underwent primary SSH (study group) for symptomatic POP were matched 1:1 by age and BMI with patients who underwent primary prolapse hysterectomy with apical fixation (control group). Results. A total of 192 patients were included with 96 patients in the each of the SSH and hysterectomy groups. There were no statistically significant differences in baseline characteristics. The SSH group show a significantly shorter mean surgery time (p < 0.001), significantly fewer hospitalization days (p < 0.001), and significantly less intraoperative blood loss (p = 0.033) in comparison to the control group. Neither group had any intraoperative complication, or an intraoperative conversion to other surgical management options. No statistically significant difference was found in postoperative complications as categorized by the Clavien–Dindo classification or in postoperative urogynecological issues (UTI, de-novo, incontinence, residual urine, voiding disorders). Through log regression, none of the confounding factors such as age, BMI, or preoperative POP-Q stage could be identified as independent risk factors for the occurrence of postoperative complications. Conclusions. Our results confirm that a uterus-preserving technique has many benefits and, thus, should be considered as an additional intermediate step in a long-term treatment plan of pelvic organ prolapse.
Dealing with the Persistent Pathogenic Issues of Dry Eye Disease: The Importance of External and Internal Stimuli and Tissue Responses
Authors: Rolando Maurizio , Barabino Stefano , Giannaccare Giuseppe , Aragona Pasquale
Published: March 2023

The immune system plays a central role in protecting the ocular surface from exogenous and endogenous insults, maintaining tissue homeostasis thanks to the mechanism of para-inflammation. This physiological adaptive response may induce resident macrophages/monocytes to produce cytokines and growth factors in order to promote epithelial cell recovery. In case of well-controlled para-inflammation, caused by a low amount of stress, cell viability and function are maintained. When stress becomes too intense, there is a response characterized by the activation of autophagic pathways and consequent cell death. Dysregulated homeostasis and chronic sub-clinical inflammation are the starting points for the development of a stable, chronic inflammatory disease, which leads to ocular surface damage, and, in turn, to the onset or progression of chronic dry eye disease (DED). The long-term management of DED should consider all of the pathogenic issues involved in the disease, including the control of persistent external or internal stresses that are capable of activating and maintaining the para-inflammatory adaptive mechanisms, potentially leading to full-blown inflammation. Dysregulated para-inflammation can be corrected by means of the prolonged use of tear substitutes containing minimal doses of safe corticosteroids or other anti-inflammatory molecules (e.g., corticosteroid, cyclosporine) in order to re-equilibrate ocular surface homeostasis.
Rats, Neuregulins and Radical Prostatectomy: A Conceptual Overview
Authors: Novacescu Dorin , Nesiu Alexandru , Bardan Razvan , Latcu Silviu Constantin , Dema Vlad Filodel , Croitor Alexei , Raica Marius , Cut Talida Georgiana , Walter James , Cumpanas Alin Adrian
Published: March 2023

In the contemporary era of early detection, with mostly curative initial treatment for prostate cancer (PC), mortality rates have significantly diminished. In addition, mean age at initial PC diagnosis has decreased. Despite technical advancements, the probability of erectile function (EF) recovery post radical prostatectomy (RP) has not significantly changed throughout the last decade. Due to virtually unavoidable intraoperative cavernous nerve (CN) lesions and operations with younger patients, post-RP erectile dysfunction (ED) has now begun affecting these younger patients. To address this pervasive limitation, a plethora of CN lesion animal model investigations have analyzed the use of systemic/local treatments for EF recovery post-RP. Most promisingly, neuregulins (NRGs) have demonstrated neurotrophic effects in both neurodegenerative disease and peripheral nerve injury models. Recently, glial growth factor 2 (GGF2) has demonstrated far superior, dose-dependent, neuroprotective/restorative effects in the CN injury rat model, as compared to previous therapeutic counterparts. Although potentially impactful, these initial findings remain limited and under-investigated. In an effort to aid clinicians, our paper reviews post-RP ED pathogenesis and currently available therapeutic tools. To stimulate further experimentation, a standardized preparation protocol and in-depth analysis of applications for the CN injury rat model is provided. Lastly, we report on NRGs, such as GGF2, and their potentially revolutionary clinical applications, in hopes of identifying relevant future research directions.
Effects of Pendrin Protein in Nasal Epithelial Cells on Mucin Production in the Context of Type 2 Inflammation
Authors: Zhong Nongping , Ai Honghui , Zhong Wei , Huang Xiaoyan , Wang Kai , Luo Qing , Yu Jieqing
Published: March 2023

Background: Chronic rhinosinusitis (CRS) is a heterogeneous disease. The pathogenesis of chronic sinusitis is still unclear; however, the nasal cavity and paranasal sinuses are commonly affected by type 2 inflammation, which is caused by Th2 cytokines such as interleukin (IL)-5, IL-4, and IL-13. Previous studies have shown that pendrin promotes local infiltration of neutrophils through the production of human neutrophil elastase (HNE), which is essential for the secretion of mucin 5AC (MUC5AC) in chronic inflammatory diseases of the lower respiratory tract. This study investigated pendrin expression and its relationship to mucin in type 2 inflammation. Methods: A total of 40 patients (10 CRS patients with nasal polyps,10 CRS patients without nasal polyps, and 20 nasal septum deviation patients) were included in this study and were divided into the CRS group and the NC group. A normal nasal mucosa tissue culture model was established in vitro. IL-13 was used to stimulate primary cultures of human nasal epithelial cells (HNECs). Western blot (WB), enzyme-linked immunosorbent assay (ELISA), and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of pendrin, MUC5AC, and MUC5B. After transfecting HNECs with siRNA pendrin or negative control (NC), EGF receptor (EGFR), HNE, MUC5AC, and MUC5B expression were analyzed using qRT-PCR, WB, or ELISA in terms of their relationships with pendrin. Pendrin expression in the tissue was also analyzed. Results: After IL-13 stimulation, pendrin, MUC5AC, and MUC5B expression levels were upregulated; the optimal concentration of IL-13 was 50 ng/mL. The expression levels of HNE, EGFR, MUC5AC, and MUC5B were downregulated after transfection with siRNA pendrin-1650. Pendrin expression in the NC group was lower than in the CRS group. Conclusion: IL-13 is implicated in the inflammation of nasal mucosa, and pendrin is closely related to the excessive secretion of mucin. The expression of mucin is downregulated after transfection with siRNA pendrin. There is a positive relationship between pendrin and EFGR/HNE. Moreover, pendrin plays an important role in type 2 inflammation.
Intra-Articular Injection of Autologous Micro-Fragmented Adipose Tissue for the Treatment of Knee Osteoarthritis: A Prospective Interventional Study
Authors: Yu Yang , Lu Qunshan , Li Songlin , Liu Mingxing , Sun Houyi , Li Lei , Han Kaifei , Liu Peilai
Published: March 2023

Background: To investigate the efficacy and safety of autologous micro-fragmented adipose tissue (MF-AT) for improving joint function and cartilage repair in patients with knee osteoarthritis. Methods: From March 2019 to December 2020, 20 subjects (40 knees) between 50 and 65 years old suffering from knee osteoarthritis were enrolled in the study and administered a single injection of autologous MF-A. The data of all patients were prospectively collected. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), knee society score (KSS), hospital for special surgery (HSS) score, visual analogue score (VAS) pain score, changes in cartilage Recht grade on magnetic resonance imaging (MRI) and adverse events were analyzed before and 3, 6, 9, 12 and 18 months after injection. Results: The WOMAC, VAS, KSS and HSS scores at 3, 6, 9, 12 and 18 months after injection were improved compared with those before injection (p < 0.05). There was no significant difference in WOMAC scores between 9 and 12 months after injection (p > 0.05), but the WOMAC score 18 months after injection was worse than that at the last follow-up (p < 0.05). The VAS, KSS and HSS scores 9, 12 and 18 months after injection were worse than those at the last follow-up (p < 0.05). The Recht score improvement rate was 25%. No adverse events occurred during the follow-up. Conclusions: Autologous MF-AT improves knee function and relieves pain with no adverse events. However, the improved knee function was not sustained, with the best results occurring 9–12 months after injection and the cartilage regeneration remaining to be investigated.