bluuebunny/crossref_metadata_2025 huggingface dataset:
NGR-Based Radiopharmaceuticals for Angiogenesis Imaging: A Preclinical Review
Authors: Trencsényi György , Enyedi Kata Nóra , Mező Gábor , Halmos Gábor , Képes Zita
Published: August 2023

Angiogenesis plays a crucial role in tumour progression and metastatic spread; therefore, the development of specific vectors targeting angiogenesis has attracted the attention of several researchers. Since angiogenesis-associated aminopeptidase N (APN/CD13) is highly expressed on the surface of activated endothelial cells of new blood vessels and a wide range of tumour cells, it holds great promise for imaging and therapy in the field of cancer medicine. The selective binding capability of asparagine-glycine-arginine (NGR) motif containing molecules to APN/CD13 makes radiolabelled NGR peptides promising radiopharmaceuticals for the non-invasive, real-time imaging of APN/CD13 overexpressing malignancies at the molecular level. Preclinical small animal model systems are major keystones for the evaluation of the in vivo imaging behaviour of radiolabelled NGR derivatives. Based on existing literature data, several positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radioisotopes have been applied so far for the labelling of tumour vasculature homing NGR sequences such as Gallium-68 (68Ga), Copper-64 (64Cu), Technetium-99m (99mTc), Lutetium-177 (177Lu), Rhenium-188 (188Re), or Bismuth-213 (213Bi). Herein, a comprehensive overview is provided of the recent preclinical experiences with radiolabelled imaging probes targeting angiogenesis.
OsMKK6 Regulates Disease Resistance in Rice
Authors: Jiang Ruirui , Zhou Shichen , Da Xiaowen , Yan Peng , Wang Kai , Xu Jiming , Mo Xiaorong
Published: August 2023

Mitogen-activated protein kinase cascades play important roles in various biological programs in plants, including immune responses, but the underlying mechanisms remain elusive. Here, we identified the lesion mimic mutant rsr25 (rust spots rice 25) and determined that the mutant harbored a loss-of-function allele for OsMKK6 (MITOGEN-ACTIVATED KINASE KINASE 6). rsr25 developed reddish-brown spots on its leaves at the heading stage, as well as on husks. Compared to the wild type, the rsr25 mutant exhibited enhanced resistance to the fungal pathogen Magnaporthe oryzae (M. oryzae) and to the bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo). OsMKK6 interacted with OsMPK4 (MITOGEN-ACTIVATED KINASE 4) in vivo, and OsMKK6 phosphorylated OsMPK4 in vitro. The Osmpk4 mutant is also a lesion mimic mutant, with reddish-brown spots on its leaves and husks. Pathogen-related genes were significantly upregulated in Osmpk4, and this mutant exhibited enhanced resistance to M. oryzae compared to the wild type. Our results indicate that OsMKK6 and OsMPK4 form a cascade that regulates immune responses in rice.
Clinical, Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania
Authors: Afrăsânie Vlad-Adrian , Marinca Mihai-Vasile , Gafton Bogdan , Alexa-Stratulat Teodora , Rusu Alexandra , Froicu Eliza-Maria , Sur Daniel , Lungulescu Cristian Virgil , Popovici Larisa , Lefter Andrei-Vlad , Afrăsânie Irina , Ivanov Anca-Viorica , Miron Lucian , Rusu Cristina
Published: August 2023

Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania to determine the frequency, distribution, coexistence, and clinicopathological and molecular correlations of these mutations. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). Patients with KRAS mutant tumors and wild-type TP53 genotype were found to have no personal history of gastrointestinal cancer (p = 0.02, p = 0.007). KRAS mutations in exon 3 were associated with the female gender (p = 0.02) and the absence of lymph node invasion (p = 0.02). PIK3CA mutations were linked to the absence of lymph node invasion (p = 0.006). TP53 mutations were associated with KRAS mutations in exon 2 (p = 0.006), ulcerated histopathologic type (p = 0.04), and G2 differentiation (p = 0.01). It provides novel insights into genetic variations specific to the population from Northeastern Romania, which has been underrepresented in previous studies within Eastern Europe. Furthermore, our findings enable the development of genetic profiles in a developing country with limited access to specialized genetic tests and facilitate comparisons with other populations.
Al-Doped Octahedral Cu2O Nanocrystal for Electrocatalytic CO2 Reduction to Produce Ethylene
Authors: Li Sanxiu , Sha Xuelan , Gao Xiafei , Peng Juan
Published: August 2023

Ethylene is an ideal CO2 product in an electrocatalytic CO2 reduction reaction (CO2RR) with high economic value. This paper synthesised Al-doped octahedral Cu2O (Al–Cu2O) nanocrystal by a simple wet chemical method. The selectivity of CO2RR products was improved by doping Al onto the surface of octahedral Cu2O. The Al–Cu2O was used as an efficient electrocatalyst for CO2RR with selective ethylene production. The Al–Cu2O exhibited a high % Faradic efficiency (FEC2H4) of 44.9% at −1.23 V (vs. RHE) in CO2 saturated 0.1 M KHCO3 electrolyte. Charge transfer from the Al atom to the Cu atom occurs after Al doping in Cu2O, optimizing the electronic structure and facilitating CO2RR to ethylene production. The DFT calculation showed that the Al–Cu2O catalyst could effectively reduce the adsorption energy of the *CHCOH intermediate and promote the mass transfer of charges, thus improving the FEC2H4. After Al doping into Cu2O, the center of d orbitals shift positively, which makes the d–band closer to the Fermi level. Furthermore, the density of electronic states increases due to the interaction between Cu atoms and intermediates, thus accelerating the electrochemical CO2 reduction process. This work proved that the metal doping strategy can effectively improve the catalytic properties of Cu2O, thus providing a useful way for CO2 cycling and green production of C2H4.
Characterization of the Heat Shock Transcription Factor Family in Medicago sativa L. and Its Potential Roles in Response to Abiotic Stresses
Authors: Liu Hao , Li Xianyang , Zi Yunfei , Zhao Guoqing , Zhu Lihua , Hong Ling , Li Mingna , Wang Shiqing , Long Ruicai , Kang Junmei , Yang Qingchuan , Chen Lin
Published: August 2023

Heat shock transcription factors (HSFs) are important regulatory factors in plant stress responses to various biotic and abiotic stresses and play important roles in growth and development. The HSF gene family has been systematically identified and analyzed in many plants but it is not in the tetraploid alfalfa genome. We detected 104 HSF genes (MsHSFs) in the tetraploid alfalfa genome (“Xinjiangdaye” reference genome) and classified them into three subgroups: 68 in HSFA, 35 in HSFB and 1 in HSFC subgroups. Basic bioinformatics analysis, including genome location, protein sequence length, protein molecular weight and conserved motif identification, was conducted. Gene expression analysis revealed tissue-specific expression for 13 MsHSFs and tissue-wide expression for 28 MsHSFs. Based on transcriptomic data analysis, 21, 11 and 27 MsHSFs responded to drought stress, cold stress and salt stress, respectively, with seven responding to all three. According to RT–PCR, MsHSF27/33 expression gradually increased with cold, salt and drought stress condition duration; MsHSF6 expression increased over time under salt and drought stress conditions but decreased under cold stress. Our results provide key information for further functional analysis of MsHSFs and for genetic improvement of stress resistance in alfalfa.
Expression Profiling along the Murine Intestine: Different Mucosal Protection Systems and Alterations in Tff1-Deficient Animals
Authors: Salm Franz , Znalesniak Eva B. , Laskou Aikaterini , Harder Sönke , Schlüter Hartmut , Hoffmann Werner
Published: August 2023

Tff1 is a typical gastric peptide secreted together with the mucin, Muc5ac. Tff1-deficient (Tff1KO) mice are well known for their prominent gastric phenotype and represent a recognized model for antral tumorigenesis. Notably, intestinal abnormalities have also been reported in the past in these animals. Here, we have compared the expression of selected genes in Tff1KO mice and their corresponding wild-type littermates (RT-PCR analyses), focusing on different mucosal protection systems along the murine intestine. As hallmarks, genes were identified with maximum expression in the proximal colon and/or the duodenum: Agr2, Muc6/A4gnt/Tff2, Tff1, Fut2, Gkn2, Gkn3, Duox2/Lpo, Nox1. This is indicative of different protection systems such as Tff2/Muc6, Tff1-Fcgbp, gastrokines, fucosylation, and reactive oxygen species (ROS) in the proximal colon and/or duodenum. Few significant transcriptional changes were observed in the intestine of Tff1KO mice when compared with wild-type littermates, Clca1 (Gob5), Gkn1, Gkn2, Nox1, Tff2. We also analyzed the expression of Tff1, Tff2, and Tff3 in the pancreas, liver, and lung of Tff1KO and wild-type animals, indicating a cross-regulation of Tff gene expression. Furthermore, on the protein level, heteromeric Tff1-Fcgbp and various monomeric Tff1 forms were identified in the duodenum and a high-molecular-mass Tff2/Muc6 complex was identified in the proximal colon (FPLC, proteomics).
Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells
Authors: Luffarelli Riccardo , Panarello Luca , Quatrana Andrea , Tiano Francesca , Fortuni Silvia , Rufini Alessandra , Malisan Florence , Testi Roberto , Condò Ivano
Published: August 2023

Friedreich’s ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA.
Neuroinflammatory Dysfunction of the Blood–Brain Barrier and Basement Membrane Dysplasia Play a Role in the Development of Drug-Resistant Epilepsy
Authors: Zabrodskaya Yulia , Paramonova Natalia , Litovchenko Anastasia , Bazhanova Elena , Gerasimov Aleksandr , Sitovskaya Darya , Nezdorovina Victoria , Kravtsova Svetlana , Malyshev Stanislav , Skiteva Ekaterina , Samochernykh Konstantin
Published: August 2023

Drug-resistance epilepsy (DRE) is a key problem in neurology. It is possible that damage to the blood–brain barrier (BBB) may affect resistance in DRE. The aim of this work was to assess the damage and dysfunction in the BBB in the area of epileptic foci in patients with DRE under conditions of neuroinflammation. The changes to the BBB in temporal lobe epilepsy (by immunohistochemistry and transmission electron microscopy), levels of neuroinflammatory proteins, and cytokine levels in the blood (by multiplex analysis) were studied. Increased levels of vascular endothelial growth factor (VEGF) and growth-regulated protein (GRO), and decreased levels of epidermal growth factor (EGF) in plasma, combined with overexpression of the VEGF-A receptor by endotheliocytes were detected. Malformation-like growths of the basement membrane of the capillaries of the brain complicate the delivery of antiepileptic drugs (AEDs). Dysplasia of the basement membrane is the result of inadequate reparative processes in chronic inflammation. In conclusion, it should be noted that damage to the microcirculatory network of the brain should be considered one of the leading factors contributing to DRE.
An Overall View of the Functional and Structural Characterization of Glucose-6-Phosphate Dehydrogenase Variants in the Mexican Population
Authors: Hernández-Ochoa Beatriz , Ortega-Cuellar Daniel , González-Valdez Abigail , Martínez-Rosas Víctor , Morales-Luna Laura , Rojas-Alarcón Miriam Abigail , Vázquez-Bautista Montserrat , Arreguin-Espinosa Roberto , Pérez de la Cruz Verónica , Castillo-Rodríguez Rosa Angélica , Canseco-Ávila Luis Miguel , Vidal-Limón Abraham , Gómez-Manzo Saúl
Published: August 2023

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, affecting an estimated 500 million people worldwide, is a genetic disorder that causes human enzymopathies. Biochemical and genetic studies have identified several variants that produce different ranges of phenotypes; thus, depending on its severity, this enzymopathy is classified from the mildest (Class IV) to the most severe (Class I). Therefore, understanding the correlation between the mutation sites of G6PD and the resulting phenotype greatly enhances the current knowledge of enzymopathies’ phenotypic and genotypic heterogeneity, which will assist both clinical diagnoses and personalized treatments for patients with G6PD deficiency. In this review, we analyzed and compared the structural and functional data from 21 characterized G6PD variants found in the Mexican population that we previously characterized. In order to contribute to the knowledge regarding the function and structure of the variants associated with G6PD deficiency, this review aimed to determine the molecular basis of G6PD and identify how these mutations could impact the structure, stability, and function of the enzyme and its relation with the clinical manifestations of this disease.
Amyloid-β Tetramers and Divalent Cations at the Membrane/Water Interface: Simple Models Support a Functional Role
Authors: Krupa Pawel , La Penna Giovanni , Li Mai Suan
Published: August 2023

Charge polarization at the membrane interface is a fundamental process in biology. Despite the lower concentration compared to the abundant monovalent ions, the relative abundance of divalent cations (Ca2+, Mg2+, Zn2+, Fe2+, Cu2+) in particular spaces, such as the neuron synapse, raised many questions on the possible effects of free multivalent ions and of the required protection of membranes by the eventual defects caused by the free forms of the cations. In this work, we first applied a recent realistic model of divalent cations to a well-investigated model of a polar lipid bilayer, di-myristoyl phosphatidyl choline (DMPC). The full atomistic model allows a fairly good description of changes in the hydration of charged and polar groups upon the association of cations to lipid atoms. The lipid-bound configurations were analyzed in detail. In parallel, amyloid-β 1–42 (Aβ42) peptides assembled into tetramers were modeled at the surface of the same bilayer. Two of the protein tetramers’ models were loaded with four Cu2+ ions, the latter bound as in DMPC-free Aβ42 oligomers. The two Cu-bound models differ in the binding topology: one with each Cu ion binding each of the monomers in the tetramer; one with pairs of Cu ions linking two monomers into dimers, forming tetramers as dimers of dimers. The models here described provide hints on the possible role of Cu ions in synaptic plasticity and of Aβ42 oligomers in storing the same ions away from lipids. The release of structurally disordered peptides in the synapse can be a mechanism to recover ion homeostasis and lipid membranes from changes in the divalent cation concentration.
Blood–Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models
Authors: Brandl Sarah , Reindl Markus
Published: August 2023

The blood–brain barrier, which is formed by tightly interconnected microvascular endothelial cells, separates the brain from the peripheral circulation. Together with other central nervous system-resident cell types, including pericytes and astrocytes, the blood–brain barrier forms the neurovascular unit. Upon neuroinflammation, this barrier becomes leaky, allowing molecules and cells to enter the brain and to potentially harm the tissue of the central nervous system. Despite the significance of animal models in research, they may not always adequately reflect human pathophysiology. Therefore, human models are needed. This review will provide an overview of the blood–brain barrier in terms of both health and disease. It will describe all key elements of the in vitro models and will explore how different compositions can be utilized to effectively model a variety of neuroinflammatory conditions. Furthermore, it will explore the existing types of models that are used in basic research to study the respective pathologies thus far.
Molecular Studies for the Early Detection of Philadelphia-Negative Myeloproliferative Neoplasms
Authors: Stuckey Ruth , Bilbao-Sieyro Cristina , Segura-Díaz Adrián , Gómez-Casares María Teresa
Published: August 2023

JAK2 V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN). JAK2 mutations are also frequent in clonal hematopoiesis of indeterminate potential (CHIP) in otherwise “healthy” individuals. However, the period between mutation acquisition and MPN diagnosis (known as latency) varies widely between individuals, with JAK2 mutations detectable several decades before diagnosis and even from birth in some individuals. Here, we will review the current evidence on the biological factors, such as additional mutations and chronic inflammation, which influence clonal expansion and may determine why some JAK2-mutated individuals will progress to an overt neoplasm during their lifetime while others will not. We will also introduce several germline variants that predispose individuals to CHIP (as well as MPN) identified from genome-wide association studies. Finally, we will explore possible mutation screening or interventions that could help to minimize MPN-associated cardiovascular complications or even delay malignant progression.
Isolation of Hepatic and Adipose-Tissue-Derived Extracellular Vesicles Using Density Gradient Separation and Size Exclusion Chromatography
Authors: Martínez-Greene Juan Alfonso , Gómez-Chavarín Margarita , Ramos-Godínez María del Pilar , Martínez-Martínez Eduardo
Published: August 2023

In recent years, the study of extracellular vesicles (EVs) in the context of various diseases has dramatically increased due to their diagnostic and therapeutic potential. Typically, EVs are isolated in vitro from the cell culture of primary cells or cell lines or from bodily fluids. However, these cell culture methods do not represent the whole complexity of an in vivo microenvironment, and bodily fluids contain a high heterogeneous population of vesicles since they originate from different tissues. This highlights the need to develop new methods to isolate EVs directly from tissue samples. In the present study, we established a protocol for isolating EVs from hepatic and adipose tissue of mice, using a combination of ultracentrifugation and iodixanol-sucrose density gradient separation. EV isolation was confirmed with EV protein marker enrichment in Western blot assays, total protein quantification, and transmission electron microscopy. Regarding the liver tissue, we additionally implemented size exclusion chromatography (SEC) to further increase the purity grade of the EVs. The successful isolation of EVs from tissue samples will allow us to uncover a more precise molecular composition and functions, as well as their role in intercellular communication in an in vivo microenvironment.
Dynamic Transcriptional Landscape of Mycobacterium smegmatis under Cold Stress
Authors: Grigorov Artem S. , Skvortsova Yulia V. , Bychenko Oksana S. , Aseev Leonid V. , Koledinskaya Ludmila S. , Boni Irina V. , Azhikina Tatyana L.
Published: August 2023

Bacterial adaptation to cold stress requires wide transcriptional reprogramming. However, the knowledge of molecular mechanisms underlying the cold stress response of mycobacteria is limited. We conducted comparative transcriptomic analysis of Mycobacterium smegmatis subjected to cold shock. The growth of M. smegmatis cultivated at 37 °C was arrested just after exposure to cold (acclimation phase) but later (by 24 h) was resumed at a much slower rate (adaptation phase). Transcriptomic analyses revealed distinct gene expression patterns corresponding to the two phases. During the acclimation phase, differential expression was observed for genes associated with cell wall remodeling, starvation response, and osmotic pressure stress, in parallel with global changes in the expression of transcription factors and the downregulation of ribosomal genes, suggesting an energy-saving strategy to support survival. At the adaptation phase, the expression profiles were recovered, indicating restoration of the processes repressed earlier. Comparison of transcriptional responses in M. smegmatis with those in other bacteria revealed unique adaptation strategies developed by mycobacteria. Our findings shed light on the molecular mechanisms underlying M. smegmatis survival under cold stress. Further research should clarify whether the discovered transcriptional mechanisms exist in other mycobacterial species, including pathogenic Mycobacterium tuberculosis, which could be important for transmission control.
Modeling Sarcoglycanopathy in Danio rerio
Authors: Dalla Barba Francesco , Soardi Michela , Mouhib Leila , Risato Giovanni , Akyürek Eylem Emek , Lucon-Xiccato Tyrone , Scano Martina , Benetollo Alberto , Sacchetto Roberta , Richard Isabelle , Argenton Francesco , Bertolucci Cristiano , Carotti Marcello , Sandonà Dorianna
Published: August 2023

Sarcoglycanopathies, also known as limb girdle muscular dystrophy 3-6, are rare muscular dystrophies characterized, although heterogeneous, by high disability, with patients often wheelchair-bound by late adolescence and frequently developing respiratory and cardiac problems. These diseases are currently incurable, emphasizing the importance of effective treatment strategies and the necessity of animal models for drug screening and therapeutic verification. Using the CRISPR/Cas9 genome editing technique, we generated and characterized δ-sarcoglycan and β-sarcoglycan knockout zebrafish lines, which presented a progressive disease phenotype that worsened from a mild larval stage to distinct myopathic features in adulthood. By subjecting the knockout larvae to a viscous swimming medium, we were able to anticipate disease onset. The δ-SG knockout line was further exploited to demonstrate that a δ-SG missense mutant is a substrate for endoplasmic reticulum-associated degradation (ERAD), indicating premature degradation due to protein folding defects. In conclusion, our study underscores the utility of zebrafish in modeling sarcoglycanopathies through either gene knockout or future knock-in techniques. These novel zebrafish lines will not only enhance our understanding of the disease’s pathogenic mechanisms, but will also serve as powerful tools for phenotype-based drug screening, ultimately contributing to the development of a cure for sarcoglycanopathies.
Biophysics in Membrane of Cells
Authors: Tan Songwen , Zhou Wenhu
Published: August 2023

The membrane of a cell, often compared to a dynamic city border, carries out an intricate dance of controlling entry and exit, guarding the valuable life processes occurring inside [...]
S100A4 Promotes BCG-Induced Pyroptosis of Macrophages by Activating the NF-κB/NLRP3 Inflammasome Signaling Pathway
Authors: Li Mengyuan , Liu Yueyang , Nie Xueyi , Ma Boli , Ma Yabo , Hou Yuxin , Yang Yi , Xu Jinrui , Wang Yujiong
Published: August 2023

Pyroptosis is a host immune strategy to defend against Mycobacterium tuberculosis (Mtb) infection. S100A4, a calcium-binding protein that plays an important role in promoting cancer progression as well as the pathophysiological development of various non-tumor diseases, has not been explored in Mtb-infected hosts. In this study, transcriptome analysis of the peripheral blood of patients with pulmonary tuberculosis (PTB) revealed that S100A4 and GSDMD were significantly up-regulated in PTB patients’ peripheral blood. Furthermore, there was a positive correlation between the expression of GSDMD and S100A4. KEGG pathway enrichment analysis showed that differentially expressed genes between PTB patients and healthy controls were significantly related to inflammation, such as the NOD-like receptor signaling pathway and NF-κB signaling pathway. To investigate the regulatory effects of S100A4 on macrophage pyroptosis, THP-1 macrophages infected with Bacillus Calmette-Guérin (BCG) were pre-treated with exogenous S100A4, S100A4 inhibitor or si-S100A4. This research study has shown that S100A4 promotes the pyroptosis of THP-1 macrophages caused by BCG infection and activates NLRP3 inflammasome and NF-κB signaling pathways, which can be inhibited by knockdown or inhibition of S100A4. In addition, inhibition of NF-κB or NLRP3 blocks the promotion effect of S100A4 on BCG-induced pyroptosis of THP-1 macrophages. In conclusion, S100A4 activates the NF-κB/NLRP3 inflammasome signaling pathway to promote macrophage pyroptosis induced by Mtb infection. These data provide new insights into how S100A4 affects Mtb-induced macrophage pyroptosis.
Changes in the Fibrinolytic System of Patients Infected with Severe Acute Respiratory Syndrome Coronavirus 2
Authors: Abudouleh Esra’a , Alhamlan Fatimah , Al-Qahtani Arwa A. , Bohol Marie Fe , Al Hazzani Amal , Khorfan Khadija , Alkaff Morad , Owaidah Tarek , Al-Qahtani Ahmed A.
Published: August 2023

Introduction: In this study, coagulation and fibrinolysis parameters and their association with disease severity were investigated in coronavirus disease (COVID-19) patients. Materials and Methods: COVID-19 patients (n = 446) admitted to our institute between 21 February 2021 and 17 March 2022, were recruited. Clinical data and staging were collected from all patients. Blood samples were collected and analyzed for several parameters of fibrinolysis and coagulation, including alpha-2-antiplasmin(α2AP) and plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), D-dimer, and fibrinogen levels. Results: The TAFI, fibrinogen, and tPA levels were significantly higher in participants who died compared to that of patients who recovered (p < 0.001). However, PAI-1, tPA, and TAFI were significantly higher in patients admitted to the ICU than those of the healthy controls (p < 0.001 for PAI-1 and tPA; p = 0.0331 for TAFI). Our results showed that stage C and D COVID-19 patients had significantly higher levels of PAI-1 (p = 0.003). Furthermore, stage D COVID-19 patients had significantly higher tPA and TAFI values (p = 0.003). Conclusions: Hypofibrinolysis was the most prevalent condition among patients with severe COVID-19. In this study, several coagulation markers were elevated, making them suitable prognostic markers for hypofibrinolysis.
Change in Androgenic Status and Cardiometabolic Profile of Middle-Aged Women with Polycystic Ovary Syndrome
Authors: van der Ham Kim , Koster Maria P. H. , Velthuis Birgitta K. , Budde Ricardo P. J. , Fauser Bart C. J. M. , Laven Joop S. E. , Louwers Yvonne V.
Published: August 2023

Understanding the cardiovascular disease (CVD) risk for women with polycystic ovary syndrome (PCOS) at reproductive age is crucial. To investigate this, we compared the cardiometabolic profiles of different PCOS groups over a median interval of 15.8 years. The study focused on three groups: (1) women with PCOS who were hyperandrogenic at both initial and follow-up screening (HA-HA), (2) those who transitioned from hyperandrogenic to normoandrogenic (HA-NA), and (3) those who remained normoandrogenic (NA-NA). At initial and follow-up screenings, both HA-HA and HA-NA groups showed higher body mass indexes compared to the NA-NA group. Additionally, at follow-up, the HA-HA and HA-NA groups exhibited higher blood pressure, a higher prevalence of hypertension, elevated serum triglycerides and insulin levels, and lower levels of HDL cholesterol compared to the NA-NA group. Even after adjusting for BMI, significant differences persisted in HDL cholesterol levels and hypertension prevalence among the groups (HA-HA: 53.8%, HA-NA: 53.1%, NA-NA: 14.3%, p < 0.01). However, calcium scores and the prevalence of coronary plaques on CT scans were similar across all groups. In conclusion, women with PCOS and hyperandrogenism during their reproductive years exhibited an unfavorable cardiometabolic profile during their post-reproductive years, even if they changed to a normoandrogenic status.
Evaluation of Retinal Blood Flow in Patients with Monoclonal Gammopathy Using OCT Angiography
Authors: Czakó Cecilia , Gerencsér Dóra , Kormányos Kitti , Kéki-Kovács Klaudia , Németh Orsolya , Tóth Gábor , Sándor Gábor László , Csorba Anita , Langenbucher Achim , Nagy Zoltán Zsolt , Varga Gergely , Gopcsa László , Mikala Gábor , Kovács Illés , Szentmáry Nóra
Published: August 2023

Background: Monoclonal gammopathy (MG) is characterized by monoclonal protein overproduction, potentially leading to the development of hyperviscosity syndrome. Objective: To assess retinal circulation using optical coherence tomography angiography (OCTA) parameters in patients with monoclonal gammopathy. Methods: OCTA measurements were performed using the Optovue AngioVue system by examining 44 eyes of 27 patients with MG and 62 eyes of 36 control subjects. Superficial and deep retinal capillary vessel density (VD SVP and DVP) in the whole 3 × 3 mm macular and parafoveal area, foveal avascular zone (FAZ) area, and central retinal thickness (CRT) were measured using the AngioAnalytics software. The OCTA parameters were evaluated in both groups using a multivariate regression model, after controlling for the effect of imaging quality (SQ). Results: There was no significant difference in age between the subjects with monoclonal gammopathy and the controls (63.59 ± 9.33 vs. 58.01 ± 11.46 years; p > 0.05). Taking into account the effect of image quality, the VD SVP was significantly lower in the MG group compared to the control group (44.54 ± 3.22% vs. 46.62 ± 2.84%; p < 0.05). No significant differences were found between the two groups regarding the other OCTA parameters (p > 0.05). Conclusions: A decreased superficial retinal capillary vessel density measured using OCTA in patients with MG suggests a slow blood flow, reduced capillary circulation, and consequent tissue hypoperfusion. An evaluation of retinal circulation using OCTA in cases of monoclonal gammopathy may be a sensitive method for the non-invasive detection and follow-up of early microcirculatory dysfunction caused by increased viscosity.
High-Power Short-Duration Lesion Index-Guided Posterior Wall Isolation beyond Pulmonary Vein Isolation for Persistent Atrial Fibrillation
Authors: Conti Sergio , Sabatino Francesco , Fortunato Fabrizio , Ferrara Giuliano , Cascino Antonio , Sgarito Giuseppe
Published: August 2023

Background: High-power short-duration (HPSD) radiofrequency (RF) ablation has been adopted to improve atrial fibrillation (AF) ablation. Although the role of HPSD is well-established in pulmonary vein isolation (PVI), fewer data have assessed the impact of HPSD when addressing extra-pulmonary veins (PVs) targets. Therefore, this study aims to determine the safety, effectiveness, and acute outcomes of HPSD lesion index (LSI)-guided posterior wall isolation (PWI) in addition to PVI as an initial strategy in persistent atrial fibrillation (Pe-AF). Methods: Consecutive patients who underwent ablation of Pe-AF in our center between August 2021 and January 2022 were retrospectively enrolled. All patients’ ablation strategy was PVI plus PWI using HPSD LSI-guided isolation. RF parameters included 50 W targeting LSI values of ≥5 on the anterior part of the PVs and anterior roofline and ≥4 for the posterior PVs aspect, bottom line, and within the posterior wall (PW). We compared the LSI values with and without acute conduction gaps after the initial first-pass PWI. Left atrial mapping was performed with the EnSite X mapping system and a high-density multipolar Grid-shaped mapping catheter. We compared the procedural characteristics using HPSD (n = 35) vs. a control group (n = 46). Results: Thirty-five consecutive patients were included in the study. PWI on top of PVI was achieved in all cases in the HPSD group. First-pass PVI was achieved in 93.3% of PVs (n = 126/135). First-pass roofline block was obtained in most patients (n = 31, 88.5%), while first-pass block of the bottom line was only achieved in 51.4% (n = 18). There were no significant differences compared to the control group; first-pass PVI was achieved in 94.9% of PVs (n = 169/178), first-pass roofline block in 89.1%, and bottom-line in 45.6% of patients. To achieve complete PWI with HPSD, scattered RF applications within the PW were necessary. No electrical reconnection of the PW was found after adenosine administration and the waiting period. The procedure and RF times were significantly shorter in the HPSD group compared to the control group, with values of 116.2 ± 10.9 vs. 144.5 ± 11.3 min, and 19.8 ± 3.6 vs. 26.3 ± 6.4 min, respectively, p < 0.001. Fluoroscopy time was comparable between both groups. No procedural complications were observed. At the 12-month follow-up, 71.4% of patients remained free from AF, with no differences between the groups. Conclusions: HPSD LSI-guided PWI on top of PVI seems effective and safe. Compared to a control group, HPSD is associated with similar rates of first-pass PWI and PVI but with a shorter procedural and RF time.
Risk Factors for Elevated D-Dimer Levels in Patients with Gastrointestinal Tumors Treated with Endoscopic Submucosal Dissection
Authors: Komatsuda Shogo , Kodashima Shinya , Ikusaka Ken , Aoki Naoaki , Shimizu Yuki , Oda Minoru , Harada Fumito , Honda Taku , Komazaki Shingo , Sakurai Miyoko , Yanagisawa Daisuke , Maruyama Kyohei , Aoyagi Hitoshi , Isono Akari , Miura Ryo , Abe Koichiro , Arizumi Toshihiko , Asaoka Yoshinari , Yamamoto Takatsugu , Tanaka Atsushi
Published: August 2023

Endoscopic submucosal dissection (ESD) is almost always performed with a sedative because of the longer procedure times involved. The risk of post-ESD deep vein thrombosis (DVT) has been reported as relatively high, and D-dimer levels are sometimes elevated after ESD. This retrospective study evaluated factors affecting changes in D-dimer levels from before to after ESD to identify causes of elevated D-dimer levels after ESD. This retrospective analysis included 117 patients with gastrointestinal tumors resected using ESD. After excluding eight patients with pre-ESD levels of D-dimer >1.5 μg/mL, factors correlating with changes in D-dimer from before to after ESD were analyzed using logistic regression analysis in 109 patients. Sedation was accomplished primarily using midazolam, but, because the sedative effect of midazolam shows marked inter-individual variability, a “corrected midazolam dose” was determined by dividing the total midazolam dose by the initial dose to correct for inter-individual differences in the sedative effect of midazolam. This value was used as one potential explanatory variable in the subgroup analysis of the 103 patients who received midazolam. In the subgroup analysis using the corrected midazolam dose as an explanatory variable, only the corrected midazolam dose correlated with a change in D-dimer ≥1.0 μg/mL in multivariate analysis (odds ratio (OR) = 1.5, 95% confidence interval (CI) 0.43–0.95; p = 0.030). The corrected midazolam dose correlated with increases in post-ESD D-dimer levels. This potential relationship indicates that patients undergoing ESD and requiring extended sedation may be at increased risk of DVT.
Biomarkers of the L-Arginine/Dimethylarginine/Nitric Oxide Pathway in People with Chronic Airflow Obstruction and Obstructive Sleep Apnoea
Authors: Hannemann Juliane , Thorarinnsdottir Elin H. , Amaral André F. S. , Schwedhelm Edzard , Schmidt-Hutten Lena , Stang Heike , Benediktsdottir Bryndis , Gunnarsdóttir Ingibjörg , Gislason Thórarinn , Böger Rainer
Published: August 2023

Background: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea (OSA) are common chronic diseases that are associated with chronic and intermittent hypoxemia, respectively. Patients affected by the overlap of COPD and OSA have a particularly unfavourable prognosis. The L-arginine/nitric oxide (NO) pathway plays an important role in regulating pulmonary vascular function. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) interfere with NO production. Methods: We analysed the serum concentrations of ADMA, SDMA, L-arginine, L-citrulline, and L-ornithine in a large sample of the Icelandic general population together with chronic airflow obstruction (CAO), a key physiological marker of COPD that was assessed by post-bronchodilator spirometry (FEV1/FVC < LLN). OSA risk was determined by the multivariable apnoea prediction (MAP) index. Results: 713 individuals were analysed, of whom 78 (10.9%) showed CAO and 215 (30%) had MAP > 0.5. SDMA was significantly higher in individuals with CAO (0.518 [0.461–0.616] vs. 0.494 [0.441–0.565] µmol/L; p = 0.005), but ADMA was not. However, ADMA was significantly associated with decreasing FEV1 percent predicted among those with CAO (p = 0.002). ADMA was 0.50 (0.44–0.56) µmol/L in MAP ≤ 0.5 versus 0.52 (0.46–0.58) µmol/L in MAP > 0.5 (p = 0.008). SDMA was 0.49 (0.44–0.56) µmol/L versus 0.51 (0.46–0.60) µmol/L, respectively (p = 0.004). The highest values for ADMA and SDMA were observed in individuals with overlap of CAO and MAP > 0.5, which was accompanied by lower L-citrulline levels. Conclusions: The plasma concentrations of ADMA and SDMA are elevated in COPD patients with concomitant intermittent hypoxaemia. This may account for impaired pulmonary NO production, enhanced pulmonary vasoconstriction, and disease progression.
The Impact of Microbiota on the Gut–Brain Axis: Examining the Complex Interplay and Implications
Authors: Chaudhry Tuba Shahid , Senapati Sidhartha Gautam , Gadam Srikanth , Mannam Hari Priya Sri Sai , Voruganti Hima Varsha , Abbasi Zainab , Abhinav Tushar , Challa Apurva Bhavana , Pallipamu Namratha , Bheemisetty Niharika , Arunachalam Shivaram P.
Published: August 2023

The association and interaction between the central nervous system (CNS) and enteric nervous system (ENS) is well established. Essentially ENS is the second brain, as we call it. We tried to understand the structure and function, to throw light on the functional aspect of neurons, and address various disease manifestations. We summarized how various neurological disorders influence the gut via the enteric nervous system and/or bring anatomical or physiological changes in the enteric nervous system or the gut and vice versa. It is known that stress has an effect on Gastrointestinal (GI) motility and causes mucosal erosions. In our literature review, we found that stress can also affect sensory perception in the central nervous system. Interestingly, we found that mutations in the neurohormone, serotonin (5-HT), would result in dysfunctional organ development and further affect mood and behavior. We focused on the developmental aspects of neurons and cognition and their relation to nutritional absorption via the gastrointestinal tract, the development of neurodegenerative disorders in relation to the alteration in gut microbiota, and contrariwise associations between CNS disorders and ENS. This paper further summarizes the synergetic relation between gastrointestinal and neuropsychological manifestations and emphasizes the need to include behavioral therapies in management plans.
Normative Data for Macular Thickness and Volume for Optical Coherence Tomography in a Diabetic Population without Maculopathies
Authors: Arruabarrena Carolina , Rodríguez-Miguel Antonio , de Aragón-Gómez Fernando , Escámez Purificación , Rosado Ingrid , Teus Miguel A.
Published: August 2023

Purpose: The purpose was to establish normative data for the macular thicknesses and volume using spectral-domain optical coherence tomography (SD-OCT) in a diabetic population without maculopathies for use as a reference in diabetic retinopathy (DR) and diabetic macular edema screening programs. Methods: This was an observational study nested in a cohort of diabetics from a telemedicine DR screening program. Each patient underwent SD-OCT centered on the fovea. Macular thickness and volume were described and compared using the built-in normative database of the device. Quantile regression models for the 97.5% percentile were fitted to evaluate the predictors of macular thickness and volume. Results: A total of 3410 eyes (mean age, 62.25 (SD, 0.22) years) were included. Mean (SD) central subfield thickness (CST) was 238.2 (23.7) µm, while center thickness (CT), average thickness (AT), and macular volume (MV) were 205.4 (31.6) µm, 263.9 (14.3) µm, and 7.46 (0.40) mm3, respectively. Para- and perifoveal thicknesses were clinically and statistically significantly thinner in our population than in the normative reference database. The 97.5% percentile of the thickness of all sectors was increased in males and in the para- and perifovea among those with DR. Conclusions: All ETDRS sectors were thinner in patients with diabetes than in the reference population, except for the CST, which was the most stable parameter that only changed with sex. The upper cutoff limit to detect diabetic macular edema (DME) was different from that of the reference population and was influenced by conditions related to diabetes, such as DR. Therefore, specific normative data for diabetic patients should be used for the screening and diagnosis of DME using SD-OCT.
Management of Coronary Artery Disease in Older Adults: Recent Advances and Gaps in Evidence
Authors: Cacciatore Stefano , Spadafora Luigi , Bernardi Marco , Galli Mattia , Betti Matteo , Perone Francesco , Nicolaio Giulia , Marzetti Emanuele , Martone Anna Maria , Landi Francesco , Asher Elad , Banach Maciej , Hanon Olivier , Biondi-Zoccai Giuseppe , Sabouret Pierre
Published: August 2023

Coronary artery disease (CAD) is highly prevalent in older adults, yet its management remains challenging. Treatment choices are made complex by the frailty burden of older patients, a high prevalence of comorbidities and body composition abnormalities (e.g., sarcopenia), the complexity of coronary anatomy, and the frequent presence of multivessel disease, as well as the coexistence of major ischemic and bleeding risk factors. Recent randomized clinical trials and epidemiological studies have provided new data on optimal management of complex patients with CAD. However, frail older adults are still underrepresented in the literature. This narrative review aims to highlight the importance of assessing frailty as an aid to guide therapeutic decision-making and tailor CAD management to the specific needs of older adults, taking into account age-related pharmacokinetic and pharmacodynamic changes, polypharmacy, and potential drug interactions. We also discuss gaps in the evidence and offer perspectives on how best in the future to optimize the global strategy of CAD management in older adults.
Clinical Outcome of TAVI vs. SAVR in Patients with Severe Aortic Stenosis
Authors: Krittanawong Chayakrit , Virk Hafeez Ul Hassan , Hahn Joshua , Wang Zhen , Al-Azzam Fu’ad , Alam Mahboob , Sharma Samin , Jneid Hani
Published: August 2023

The utilization of transcatheter aortic valve implantation (TAVI) has become the treatment of choice in patients with severe aortic stenosis (AS) with intermediate-to-high surgical risk for surgical aortic valve replacement (SAVR) [...]
Do More with Less? Lobectomy vs. Segmentectomy for Patients with Congenital Pulmonary Malformations
Authors: Marinucci Beatrice Trabalza , Menna Cecilia , Scanagatta Paolo , Fiorelli Silvia , Tiracorrendo Matteo , Naldi Giuseppe , Inserra Alessandro , Macchini Francesco , Rendina Erino Angelo , Ibrahim Mohsen
Published: August 2023

Background: Congenital Pulmonary Malformations (CPMs) are rare benign lesions potentially causing infective complications and/or malignant transformation, requiring surgery even when asymptomatic. CPMs are rare in adulthood but potentially detected at any age. There is not a consensus on the correct extent of resection in both adults and paediatrics. This retrospective multicentric study aims to identify the appropriate surgical resection to prevent the recurrence of the related respiratory symptoms. Methods: Between 2010 and 2020, a total of 96 patients (adults and pediatrics) underwent surgery for CPMs in 4 centers. A 2:1 propensity score matching (considering sex and lesion side) was performed, identifying 2 groups: 50 patients underwent lobectomy (group A) and 25 sub-lobar resections (group B). Clinical and histopathological characteristics, early and late complications, and symptom recurrence were retrospectively analyzed and compared between the two groups by univariate and multivariate analysis. Results: Patients who underwent lobectomy had a statistically significant lower rate of recurrence (4% vs. 24% of group B, p = 0.014) and a lower rate of intraoperative complications (p = 0.014). Logistic regression identified sub-lobar resection (p = 0.040), intra- and post-operative complications (p = 0.105 and 0.022),and associated developed neoplasm (p = 0.062) as possible risk factors for symptom recurrence after surgery. Conclusions: Pulmonary lobectomy seems to be the most effective surgical treatment for CPMs, guaranteeing the stable remission of symptoms and a lower rate of intra- and postoperative complications. To our knowledge, this is one of the largest studies comparing lobectomy and sub-lobar resections in patients affected by CPMs, considering the low incidence worldwide.