bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias
Authors: Sutanto Henry , Dobrev Dobromir , Heijman Jordi
Published: August 2021

The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.
From Fighting Critters to Saving Lives: Polyphenols in Plant Defense and Human Health
Authors: Stiller Amber , Garrison Kendall , Gurdyumov Karina , Kenner Jacob , Yasmin Farida , Yates Ping , Song Bao-Hua
Published: August 2021

Polyphenols, such as flavonoids and phenolic acids, are a group of specialized metabolites in plants that largely aid in plant defense by deterring biotic stressors and alleviating abiotic stress. Polyphenols offer a wide range of medical applications, acting as preventative and active treatments for diseases such as cancers and diabetes. Recently, researchers have proposed that polyphenols may contribute to certain applications aimed at tackling challenges related to the COVID-19 pandemic. Understanding the beneficial impacts of phytochemicals, such as polyphenols, could potentially help prepare society for future pandemics. Thus far, most reviews have focused on polyphenols in cancer prevention and treatment. This review aims to provide a comprehensive discussion on the critical roles that polyphenols play in both plant chemical defense and human health based on the most recent studies while highlighting prospective avenues for future research, as well as the implications for phytochemical-based applications in both agricultural and medical fields.
Insights into the Host Specificity of a New Oomycete Root Pathogen, Pythium brassicum P1: Whole Genome Sequencing and Comparative Analysis Reveals Contracted Regulation of Metabolism, Protein Families, and Distinct Pathogenicity Repertoire
Authors: Mohammadi Mojtaba , Smith Eric A. , Stanghellini Michael E. , Kaundal Rakesh
Published: August 2021

Pythium brassicum P1 Stanghellini, Mohammadi, Förster, and Adaskaveg is an oomycete root pathogen that has recently been characterized. It only attacks plant species belonging to Brassicaceae family, causing root necrosis, stunting, and yield loss. Since P. brassicum P1 is limited in its host range, this prompted us to sequence its whole genome and compare it to those of broad host range Pythium spp. such as P. aphanidermatum and P. ultimum var. ultimum. A genomic DNA library was constructed with a total of 374 million reads. The sequencing data were assembled using SOAPdenovo2, yielding a total genome size of 50.3 Mb contained in 5434 scaffolds, N50 of 30.2 Kb, 61.2% G+C content, and 13,232 putative protein-coding genes. Pythium brassicum P1 had 175 species-specific gene families, which is slightly below the normal average. Like P. ultimum, P. brassicum P1 genome did not encode any classical RxLR effectors or cutinases, suggesting a significant difference in virulence mechanisms compared to other oomycetes. Pythium brassicum P1 had a much smaller proportions of the YxSL sequence motif in both secreted and non-secreted proteins, relative to other Pythium species. Similarly, P. brassicum P1 had the fewest Crinkler (CRN) effectors of all the Pythium species. There were 633 proteins predicted to be secreted in the P. brassicum P1 genome, which is, again, slightly below average among Pythium genomes. Pythium brassicum P1 had only one cadherin gene with calcium ion-binding LDRE and DxND motifs, compared to Pythium ultimum having four copies. Pythium brassicum P1 had a reduced number of proteins falling under carbohydrate binding module and hydrolytic enzymes. Pythium brassicum P1 had a reduced complement of cellulase and pectinase genes in contrast to P. ultimum and was deficient in xylan degrading enzymes. The contraction in ABC transporter families in P. brassicum P1 is suggested to be the result of a lack of diversity in nutrient uptake and therefore host range.
Potential Roles of Extracellular Vesicles as Biomarkers and a Novel Treatment Approach in Multiple Sclerosis
Authors: Gutiérrez-Fernández María , de la Cuesta Fernando , Tallón Antonio , Puertas Inmaculada , Fernández-Fournier Mireya , Laso-García Fernando , Gómez-de Frutos Mari , Díez-Tejedor Exuperio , Otero-Ortega Laura
Published: August 2021

Extracellular vesicles (EVs) are a heterogeneous group of bilayer membrane-wrapped molecules that play an important role in cell-to-cell communication, participating in many physiological processes and in the pathogenesis of several diseases, including multiple sclerosis (MS). In recent years, many studies have focused on EVs, with promising results indicating their potential role as biomarkers in MS and helping us better understand the pathogenesis of the disease. Recent evidence suggests that there are novel subpopulations of EVs according to cell origin, with those derived from cells belonging to the nervous and immune systems providing information regarding inflammation, demyelination, axonal damage, astrocyte and microglia reaction, blood–brain barrier permeability, leukocyte transendothelial migration, and ultimately synaptic loss and neuronal death in MS. These biomarkers can also provide insight into disease activity and progression and can differentiate patients’ disease phenotype. This information can enable new pathways for therapeutic target discovery, and consequently the development of novel treatments. Recent evidence also suggests that current disease modifying treatments (DMTs) for MS modify the levels and content of circulating EVs. EVs might also serve as biomarkers to help monitor the response to DMTs, which could improve medical decisions concerning DMT initiation, choice, escalation, and withdrawal. Furthermore, EVs could act not only as biomarkers but also as treatment for brain repair and immunomodulation in MS. EVs are considered excellent delivery vehicles. Studies in progress show that EVs containing myelin antigens could play a pivotal role in inducing antigen-specific tolerance of autoreactive T cells as a novel strategy for the treatment as “EV-based vaccines” for MS. This review explores the breakthrough role of nervous and immune system cell-derived EVs as markers of pathological disease mechanisms and potential biomarkers of treatment response in MS. In addition, this review explores the novel role of EVs as vehicles for antigen delivery as a therapeutic vaccine to restore immune tolerance in MS autoimmunity.
Metalloproteinases 1 and 3 as Potential Biomarkers in Breast Cancer Development
Authors: Argote Camacho Angela Ximena , González Ramírez Amanda Rocío , Pérez Alonso Alejandro José , Rejón García Juan David , Olivares Urbano María Auxiliadora , Torné Poyatos Pablo , Ríos Arrabal Sandra , Núñez María Isabel
Published: August 2021

Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%–>50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity (p = 0.043) and MMP-3 percentage (p = 0.018) and intensity, (p = 0.025) present statistically significant associations with the variable group (control–case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis.
5-HT Receptors and the Development of New Antidepressants
Authors: Ślifirski Grzegorz , Król Marek , Turło Jadwiga
Published: August 2021

Serotonin modulates several physiological and cognitive pathways throughout the human body that affect emotions, memory, sleep, and thermal regulation. The complex nature of the serotonergic system and interactions with other neurochemical systems indicate that the development of depression may be mediated by various pathomechanisms, the common denominator of which is undoubtedly the disturbed transmission in central 5-HT synapses. Therefore, the deliberate pharmacological modulation of serotonergic transmission in the brain seems to be one of the most appropriate strategies for the search for new antidepressants. As discussed in this review, the serotonergic system offers great potential for the development of new antidepressant therapies based on the combination of SERT inhibition with different pharmacological activity towards the 5-HT system. The aim of this article is to summarize the search for new antidepressants in recent years, focusing primarily on the possibility of benefiting from interactions with various 5-HT receptors in the pharmacotherapy of depression.
Acute, Low-Dose Neutron Exposures Adversely Impact Central Nervous System Function
Authors: Klein Peter M. , Alaghband Yasaman , Doan Ngoc-Lien , Ru Ning , Drayson Olivia G. G. , Baulch Janet E. , Kramár Enikö A. , Wood Marcelo A. , Soltesz Ivan , Limoli Charles L.
Published: August 2021

A recognized risk of long-duration space travel arises from the elevated exposure astronauts face from galactic cosmic radiation (GCR), which is composed of a diverse array of energetic particles. There is now abundant evidence that exposures to many different charged particle GCR components within acute time frames are sufficient to induce central nervous system deficits that span from the molecular to the whole animal behavioral scale. Enhanced spacecraft shielding can lessen exposures to charged particle GCR components, but may conversely elevate neutron radiation levels. We previously observed that space-relevant neutron radiation doses, chronically delivered at dose-rates expected during planned human exploratory missions, can disrupt hippocampal neuronal excitability, perturb network long-term potentiation and negatively impact cognitive behavior. We have now determined that acute exposures to similar low doses (18 cGy) of neutron radiation can also lead to suppressed hippocampal synaptic signaling, as well as decreased learning and memory performance in male mice. Our results demonstrate that similar nervous system hazards arise from neutron irradiation regardless of the exposure time course. While not always in an identical manner, neutron irradiation disrupts many of the same central nervous system elements as acute charged particle GCR exposures. The risks arising from neutron irradiation are therefore important to consider when determining the overall hazards astronauts will face from the space radiation environment.
Insights into the Role of Membrane Lipids in the Structure, Function and Regulation of Integral Membrane Proteins
Authors: Renard Kenta , Byrne Bernadette
Published: August 2021

Membrane proteins exist within the highly hydrophobic membranes surrounding cells and organelles, playing key roles in cellular function. It is becoming increasingly clear that the membrane does not just act as an appropriate environment for these proteins, but that the lipids that make up these membranes are essential for membrane protein structure and function. Recent technological advances in cryogenic electron microscopy and in advanced mass spectrometry methods, as well as the development of alternative membrane mimetic systems, have allowed experimental study of membrane protein–lipid complexes. These have been complemented by computational approaches, exploiting the ability of Molecular Dynamics simulations to allow exploration of membrane protein conformational changes in membranes with a defined lipid content. These studies have revealed the importance of lipids in stabilising the oligomeric forms of membrane proteins, mediating protein–protein interactions, maintaining a specific conformational state of a membrane protein and activity. Here we review some of the key recent advances in the field of membrane protein–lipid studies, with major emphasis on respiratory complexes, transporters, channels and G-protein coupled receptors.
An Integrated Analysis of Intracellular Metabolites and Virulence Gene Expression during Biofilm Development of a Clinical Isolate of Candida tropicalis on Distinct Surfaces
Authors: Salvatore Maria Michela , Maione Angela , Albarano Luisa , de Alteriis Elisabetta , Carraturo Federica , Andolfi Anna , Salvatore Francesco , Galdiero Emilia , Guida Marco
Published: August 2021

Emergence of Candida tropicalis, which causes potential life-threatening invasive candidiasis, is often associated with colonization of medical devices as biofilm. Biofilm plays an important role in the virulence of the pathogen because of its complex structure, which provides resistance to conventional antimicrobials. In this study, the metabolic response of a clinical strain of C. tropicalis colonizing three distinct surfaces (polytetrafluoroethylene (PTFE), polystyrene, and polycarbonate) as well as the expression of virulence and stress related genes (ALS3, Hsp21, SAP1, SAP2, SAP3, and CYR1), were explored. Our results showed that lesser biofilm was developed on PTFE compared to polystyrene and polycarbonate. GS-MS metabolic analysis identified a total of 36 metabolites in the intracellular extract of cells grown on polystyrene, polycarbonate, and PTFE, essentially belonging to central carbon metabolism, amino acids, and lipids metabolism. The metabolic analysis showed that saturated and unsaturated fatty acids are preferentially produced during biofilm development on polycarbonate, whereas trehalose and vitamin B6, known as cellular protectors against a variety of stressors, were characteristic of biofilm on PTFE. The results of the transcriptomic analysis consider the different degrees of colonization of the three substrates, being CYR1, which encodes the component of signaling pathway of hyphal formation-cAMP-PKA, downregulated in PTFE biofilm compared to polycarbonate or polystyrene biofilms, while Hsp21 was upregulated in concomitance with the potential unfavorable conditions for biofilm formation on PTFE. Overall, this work provides new insights into the knowledge of C. tropicalis biofilm development on surfaces of medical relevance in the perspective of improving the management of Candida infections.
Proteomic and Biochemical Analyses of the Mechanism of Tolerance in Mutant Soybean Responding to Flooding Stress
Authors: Komatsu Setsuko , Yamaguchi Hisateru , Hitachi Keisuke , Tsuchida Kunihiro , Kono Yuhi , Nishimura Minoru
Published: August 2021

To investigate the mechanism of flooding tolerance of soybean, flooding-tolerant mutants derived from gamma-ray irradiated soybean were crossed with parent cultivar Enrei for removal of other factors besides the genes related to flooding tolerance in primary generated mutant soybean. Although the growth of the wild type was significantly suppressed by flooding compared with the non-flooding condition, that of the mutant lines was better than that of the wild type even if it was treated with flooding. A two-day-old mutant line was subjected to flooding for 2 days and proteins were analyzed using a gel-free/label-free proteomic technique. Oppositely changed proteins in abundance between the wild type and mutant line under flooding stress were associated in endoplasmic reticulum according to gene-ontology categorization. Immunoblot analysis confirmed that calnexin accumulation increased in both the wild type and mutant line; however, calreticulin accumulated in only the mutant line under flooding stress. Furthermore, although glycoproteins in the wild type decreased by flooding compared with the non-flooding condition, those in the mutant line increased even if it was under flooding stress. Alcohol dehydrogenase accumulated in the wild type and mutant line; however, this enzyme activity significantly increased and mildly increased in the wild type and mutant line, respectively, under flooding stress compared with the non-flooding condition. Cell death increased and decreased in the wild type and mutant line, respectively, by flooding stress. These results suggest that the regulation of cell death through the fermentation system and glycoprotein folding might be an important factor for the acquisition of flooding tolerance in mutant soybean.
Uncovering Microbial Composition in Human Breast Cancer Primary Tumour Tissue Using Transcriptomic RNA-seq
Authors: Hadzega Dominik , Minarik Gabriel , Karaba Marian , Kalavska Katarina , Benca Juraj , Ciernikova Sona , Sedlackova Tatiana , Nemcova Petra , Bohac Martin , Pindak Daniel , Klucar Lubos , Mego Michal
Published: August 2021

Recent research studies are showing breast tissues as a place where various species of microorganisms can thrive and cannot be considered sterile, as previously thought. We analysed the microbial composition of primary tumour tissue and normal breast tissue and found differences between them and between multiple breast cancer phenotypes. We sequenced the transcriptome of breast tumours and normal tissues (from cancer-free women) of 23 individuals from Slovakia and used bioinformatics tools to uncover differences in the microbial composition of tissues. To analyse our RNA-seq data (rRNA depleted), we used and tested Kraken2 and Metaphlan3 tools. Kraken2 has shown higher reliability for our data. Additionally, we analysed 91 samples obtained from SRA database, originated in China and submitted by Sichuan University. In breast tissue, the most enriched group were Proteobacteria, then Firmicutes and Actinobacteria for both datasets, in Slovak samples also Bacteroides, while in Chinese samples Cyanobacteria were more frequent. We have observed changes in the microbiome between cancerous and healthy tissues and also different phenotypes of diseases, based on the presence of circulating tumour cells and few other markers.
Bioactive Peptides as Potential Nutraceuticals for Diabetes Therapy: A Comprehensive Review
Authors: Antony Priya , Vijayan Ranjit
Published: August 2021

Diabetes mellitus is a major public health concern associated with high mortality and reduced life expectancy. The alarming rise in the prevalence of diabetes is linked to several factors including sedentary lifestyle and unhealthy diet. Nutritional intervention and increased physical activity could significantly contribute to bringing this under control. Food-derived bioactive peptides and protein hydrolysates have been associated with a number health benefits. Several peptides with antidiabetic potential have been identified that could decrease blood glucose level, improve insulin uptake and inhibit key enzymes involved in the development and progression of diabetes. Dietary proteins, from a wide range of food, are rich sources of antidiabetic peptides. Thus, there are a number of benefits in studying peptides obtained from food sources to develop nutraceuticals. A deeper understanding of the underlying molecular mechanisms of these peptides will assist in the development of new peptide-based therapeutics. Despite this, a comprehensive analysis of the antidiabetic properties of bioactive peptides derived from various food sources is still lacking. Here, we review the recent literature on food-derived bioactive peptides possessing antidiabetic activity. The focus is on the effectiveness of these peptides as evidenced by in vitro and in vivo studies. Finally, we discuss future prospects of peptide-based drugs for the treatment of diabetes.
Negative Influence by the Force: Mechanically Induced Hyperpolarization via K2P Background Potassium Channels
Authors: Lengyel Miklós , Enyedi Péter , Czirják Gábor
Published: August 2021

The two-pore domain K2P subunits form background (leak) potassium channels, which are characterized by constitutive, although not necessarily constant activity, at all membrane potential values. Among the fifteen pore-forming K2P subunits encoded by the KCNK genes, the three members of the TREK subfamily, TREK-1, TREK-2, and TRAAK are mechanosensitive ion channels. Mechanically induced opening of these channels generally results in outward K+ current under physiological conditions, with consequent hyperpolarization and inhibition of membrane potential-dependent cellular functions. In the past decade, great advances have been made in the investigation of the molecular determinants of mechanosensation, and members of the TREK subfamily have emerged among the best-understood examples of mammalian ion channels directly influenced by the tension of the phospholipid bilayer. In parallel, the crucial contribution of mechano-gated TREK channels to the regulation of membrane potential in several cell types has been reported. In this review, we summarize the general principles underlying the mechanical activation of K2P channels, and focus on the physiological roles of mechanically induced hyperpolarization.
Bordetella Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein
Authors: Malandra Anna , Rahman Waheed Ur , Klimova Nela , Streparola Gaia , Holubova Jana , Osickova Adriana , Bariselli Simone , Sebo Peter , Osicka Radim
Published: August 2021

The mucus layer protects airway epithelia from damage by noxious agents. Intriguingly, Bordetella pertussis bacteria provoke massive mucus production by nasopharyngeal epithelia during the initial coryza-like catarrhal stage of human pertussis and the pathogen transmits in mucus-containing aerosol droplets expelled by sneezing and post-nasal drip-triggered cough. We investigated the role of the cAMP-elevating adenylate cyclase (CyaA) and pertussis (PT) toxins in the upregulation of mucin production in B. pertussis-infected airway epithelia. Using human pseudostratified airway epithelial cell layers cultured at air–liquid interface (ALI), we show that purified CyaA and PT toxins (100 ng/mL) can trigger production of the major airway mucins Muc5AC and Muc5B. Upregulation of mucin secretion involved activation of the cAMP response element binding protein (CREB) and was blocked by the 666-15-Calbiochem inhibitor of CREB-mediated gene transcription. Intriguingly, a B. pertussis mutant strain secreting only active PT and producing the enzymatically inactive CyaA-AC– toxoid failed to trigger any important mucus production in infected epithelial cell layers in vitro or in vivo in the tracheal epithelia of intranasally infected mice. In contrast, the PT– toxoid-producing B. pertussis mutant secreting the active CyaA toxin elicited a comparable mucin production as infection of epithelial cell layers or tracheal epithelia of infected mice by the wild-type B. pertussis secreting both PT and CyaA toxins. Hence, the cAMP-elevating activity of B. pertussis-secreted CyaA was alone sufficient for activation of mucin production through a CREB-dependent mechanism in B. pertussis-infected airway epithelia in vivo.
Comment on Siracusa et al. Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update. Int. J. Mol. Sci. 2021, 22, 3891
Authors: Cuyul-Vásquez Iván , Araya-Quintanilla Felipe , Gutiérrez-Espinoza Héctor
Published: August 2021

We have read the study by Siracusa et al. [...]
The Effect of Modifiers on the Performance of Ni/CeO2 and Ni/La2O3 Catalysts in the Oxy–Steam Reforming of LNG
Authors: Mosinska Magdalena , Maniukiewicz Waldemar , Szynkowska-Jozwik Malgorzata I. , Mierczynski Pawel
Published: August 2021

This work interrogates for the first time the catalytic properties of various monometallic Ni catalysts in the oxy-steam reforming of LNG. Various research techniques, including X-ray diffraction (XRD), specific surface area and porosity analysis (BET method), scanning electron microscopy with X-ray microanalysis (SEM-EDS), temperature-programmed desorption of ammonia (TPD-NH3), temperature-programmed reduction (TPR-H2) and the FTIR method, were used to study their physicochemical properties. The mechanism of the oxy-steam reforming of LNG is also discussed in this paper. The high activity of monometallic catalysts supported on 5% La2O3–CeO2 and 5% ZrO2–CeO2 oxides in the studied process have been proven and explained on the basis of their acidity, specific surface area, sorption properties in relation to the reaction products, the crystallite size of the metallic nickel and their phase composition.
Bone Fracture-Treatment Method: Fixing 3D-Printed Polycaprolactone Scaffolds with Hydrogel Type Bone-Derived Extracellular Matrix and β-Tricalcium Phosphate as an Osteogenic Promoter
Authors: Yun Seokhwan , Choi Dami , Choi Dong-Jin , Jin Songwan , Yun Won-Soo , Huh Jung-Bo , Shim Jin-Hyung
Published: August 2021

Bone formation and growth are crucial for treating bone fractures. Improving bone-reconstruction methods using autologous bone and synthetic implants can reduce the recovery time. Here, we investigated three treatments using two different materials, a bone-derived decellularized extracellular matrix (bdECM) and β-tricalcium phosphate (β-TCP), individually and in combination, as osteogenic promoter between bone and 3D-printed polycaprolactone scaffold (6-mm diameter) in rat calvarial defects (8-mm critical diameter). The materials were tested with a human pre-osteoblast cell line (MG63) to determine the effects of the osteogenic promoter on bone formation in vitro. A polycaprolactone (PCL) scaffold with a porous structure was placed at the center of the in vivo rat calvarial defects. The gap between the defective bone and PCL scaffold was filled with each material. Animals were sacrificed four weeks post-implantation, and skull samples were preserved for analysis. The preserved samples were scanned by micro-computed tomography and analyzed histologically to examine the clinical benefits of the materials. The bdECM–β-TCP mixture showed faster bone formation and a lower inflammatory response in the rats. Therefore, our results imply that a bdECM–β-TCP mixture is an ideal osteogenic promoter for treating fractures.
Small Structural Proteins E and M Render the SARS-CoV-2 Pseudovirus More Infectious and Reveal the Phenotype of Natural Viral Variants
Authors: Wang Hsin-I , Chuang Zih-Shiuan , Kao Yu-Ting , Lin Yi-Ling , Liang Jian-Jong , Liao Chun-Che , Liao Ching-Len , Lai Michael M. C. , Yu Chia-Yi
Published: August 2021

The SARS-CoV-2 pseudovirus is a commonly used strategy that mimics certain biological functions of the authentic virus by relying on biological legitimacy at the molecular level. Despite the fact that spike (S), envelope (E), and membrane (M) proteins together wrap up the SARS-CoV-2 virion, most of the reported pseudotype viruses consist of only the S protein. Here, we report that the presence of E and M increased the virion infectivity by promoting the S protein priming. The S, E, and M (SEM)-coated pseudovirion is spherical, containing crown-like spikes on the surface. Both S and SEM pseudoviruses packaged the same amounts of viral RNA, but the SEM virus bound more efficiently to cells stably expressing the viral receptor human angiotensin-converting enzyme II (hACE2) and became more infectious. Using this SEM pseudovirus, we examined the infectivity and antigenic properties of the natural SARS-CoV-2 variants. We showed that some variants have higher infectivity than the original virus and that some render the neutralizing plasma with lower potency. These studies thus revealed possible mechanisms of the dissemination advantage of these variants. Hence, the SEM pseudovirion provides a useful tool to evaluate the viral infectivity and capability of convalescent sera in neutralizing specific SARS-CoV-2 S dominant variants.
Experimental Evidence of 2,3,7,8-Tetrachlordibenzo-p-Dioxin (TCDD) Transgenerational Effects on Reproductive Health
Authors: Gaspari Laura , Paris Françoise , Kalfa Nicolas , Soyer-Gobillard Marie-Odile , Sultan Charles , Hamamah Samir
Published: August 2021

Previous studies have demonstrated that endocrine disruptors (EDs) can promote the transgenerational inheritance of disease susceptibility. Among the many existing EDs, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) affects reproductive health, including in humans, following direct occupational exposure or environmental disasters, for instance the Agent Orange sprayed during the Vietnam War. Conversely, few studies have focused on TCDD multigenerational and transgenerational effects on human reproductive health, despite the high amount of evidence in animal models of such effects on male and female reproductive health that mimic human reproductive system disorders. Importantly, these studies show that paternal ancestral TCDD exposure substantially contributes to pregnancy outcome and fetal health, although pregnancy outcome is considered tightly related to the woman’s health. In this work, we conducted a systematic review of the literature and a knowledge synthesis in order (i) to describe the findings obtained in rodent models concerning TCDD transgenerational effects on reproductive health and (ii) to discuss the epigenetic molecular alterations that might be involved in this process. As ancestral toxicant exposure cannot be changed in humans, identifying the crucial reproductive functions that are negatively affected by such exposure may help clinicians to preserve male and female fertility and to avoid adverse pregnancy outcomes.
The Impact of Vitamin D on Skin Aging
Authors: Bocheva Georgeta , Slominski Radomir M. , Slominski Andrzej T.
Published: August 2021

The active metabolites of vitamin D3 (D3) and lumisterol (L3) exert a variety of antiaging and photoprotective effects on the skin. These are achieved through immunomodulation and include anti-inflammatory actions, regulation of keratinocytes proliferation, and differentiation programs to build the epidermal barrier necessary for maintaining skin homeostasis. In addition, they induce antioxidative responses, inhibit DNA damage and induce DNA repair mechanisms to attenuate premature skin aging and cancerogenesis. The mechanism of action would involve interaction with multiple nuclear receptors including VDR, AhR, LXR, reverse agonism on RORα and -γ, and nongenomic actions through 1,25D3-MARRS receptor and interaction with the nongenomic binding site of the VDR. Therefore, active forms of vitamin D3 including its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 derivatives as well as L3 derivatives are promising agents for the prevention, attenuation, or treatment of premature skin aging. They could be administrated orally and/or topically. Other forms of parenteral application of vitamin D3 precursor should be considered to avoid its predominant metabolism to 25(OH)D3 that is not recognized by CYP11A1 enzyme. The efficacy of topically applied vitamin D3 and L3 derivatives needs further clinical evaluation in future trials.
Incidence of Severe Hypothermia and Its Impact on Postoperative Surgical Complications and Time Delay to Adjunct Treatments in Breast Surgery Cancer Patients: A Case-Controlled Study
Authors: Motamed Cyrus , Weil Gregoire , Dridi Chaima , Bourgain Jean Louis
Published: August 2021

Introduction: Unintended postoperative hypothermia frequently occurs upon arrival in the post anesthesia care unit (PACU). As part of our quality assurance program in anesthesia, we regularly monitor the incidence of this complication through our anesthesia information management system (AIMS). In this case-controlled retrospective study, our goal was to detect the incidence of unintended severe hypothermia in our breast surgery cancer patients, and subsequently to analyze the consequence of this complication in terms postoperative cutaneous infection, as well as its impact on further complementary treatment, such as radiotherapy and chemotherapy. Methods: This study was a retrospective analysis conducted through our AIMS system from 2015 through 2019, with extraction criteria based on year, type of surgery (breast), and temperature upon arrival in PACU. A tympanic temperature of less than 36 °C was considered to indicate hypothermia. Severe hypothermia was considered for patients having a temperature lower than 35.2 °C (hypothermic) (n = 80), who were paired using a propensity score analysis with a control group (normothermic) (n = 80) of other breast cancer surgery patients. Extracted data included time of surgery, sex, age, ASA status, and type and duration of the intervention. Results: The mean incidence of hypothermia was 21% from 2015 through 2019. The body mass index (BMI) was significantly lower in the hypothermia group before matching, 23.5 ± 4.1 vs. 26.4 ± 6.1 kg/m2 in normothermic patients (p < 0.05). The hypothermia group also had significantly fewer monitoring and active warming devices. No difference was noted for wound complications. Time to complementary chemotherapy and or radiotherapy did not differ between groups (52 ± 21 days in group hypothermia vs 49 ± 22 days in the control group). Conclusion: Severe intraoperative hypothermia remains an important quality assurance issue in our breast surgery cancer patients, but we could not detect any long-term effect of hypothermia.
Beneficial Effects of Opioid Rotation to Buprenorphine/Naloxone on Opioid Misuse, Craving, Mental Health, and Pain Control in Chronic Non-Cancer Pain Patients with Opioid Use Disorder
Authors: Schellekens Arnt F. A. , Veldman Stijn E. , Suranto Eka S. D. , van Rijswijk Steffie M. , van der Wal Selina E. I. , Schene Aart H. , van Beek Marleen H. C. T.
Published: August 2021

Patients with chronic non-cancer pain (CNCP) often use opioids for long periods of time. This may lead to opioid use disorder (OUD) and psychiatric symptoms: mainly depression and anxiety. The current study investigated the effect of buprenorphine/naloxone (BuNa) rotation on opioid misuse, craving, psychiatric symptoms and pain in patients with CNCP and OUD. Forty-three participants with CNCP and OUD were converted from a full mu-receptor agonist opioid (mean morphine equivalent dose: 328.3 mg) to BuNa, in an inpatient setting. Opioid misuse, craving, co-occurring psychiatric symptoms, and pain perception were determined at baseline and after a two-month follow-up, using the following self-report questionnaires: Current Opioid Misuse Measurement (COMM), Visual Analog Scale (VAS-craving and VAS-pain) and Depression, Anxiety and Stress Scale (DASS), respectively. VAS-craving and VAS-pain were also determined immediately after conversion. A total of 37 participants completed the protocol. The mean COMM decreased from 17.1 to 6.7 (F = 36.5; p < 0.000), the mean VAS-craving decreased from 39.3 to 5.3 (−86.6%; F = 26.5, p < 0.000), the mean DASS decreased from 12.1 to 6.6 (F = 56.3, p < 0.000), and the mean VAS-pain decreased from 51.3 to 37.2 (−27.4%, F = 3.3; p = 0.043). Rotation to BuNa in patients with CNCP and OUD was accompanied by reductions in (i) opioid misuse, (ii) opioid craving, (iii) the severity of co-occurring psychiatric symptoms, and (iv) self-reported pain. BuNa as opioid agonist treatment may therefore be a beneficial strategy in CNCP patients with OUD. The limited sample size and the observational nature of this study underline the need for the replication of the current findings in large-scale, controlled studies.
Clinical Implications of Growth Hormone Deficiency for Oral Health in Children: A Systematic Review
Authors: Torlińska-Walkowiak Natalia , Majewska Katarzyna Anna , Kędzia Andrzej , Opydo-Szymaczek Justyna
Published: August 2021

Growth hormone (GH) is involved in the regulation of the postnatal dental and skeletal growth, but its effects on oral health have not been clearly defined. This paper aims to provide a review of current clinical knowledge of dental caries, tooth wear, developmental enamel defects, craniofacial growth and morphology, dental maturation, and tooth eruption in growth hormone deficient (GHD) children. A systematic review was carried out using Scopus, MEDLINE-EbscoHost and Web of Science from 2000 to May 2021. PRISMA guidelines for reporting systematic reviews were followed. All the selected studies involved groups under eighteen years of age, covering a total of 465 GHD patients. The studies that were selected provide reliable evidence for delayed dental maturity and orthodontic disturbances in GHD patients. Data on dental hard tissues pathology are scarce and are limited to occurrences of dental caries. GHD children showed abnormal craniofacial morphology with reduced mandibular dimensions, with a resulting tendency towards Angle’s Class II occlusion, which affected up to 31% of patients. Dental age has been shown to be delayed in GHD patients by about 1 to 2 years. Moreover, the risk of dental caries in children with GHD decreases with increasing levels of vitamin D. Hence, further studies would be valuable for evaluating the risk of various oral health problems and to organize targeted dental care for this vulnerable group.
Outcomes of Diabetic Retinopathy Post-Bariatric Surgery in Patients with Type 2 Diabetes Mellitus
Authors: Dascalu Ana Maria , Stoian Anca Pantea , Cherecheanu Alina Popa , Serban Dragos , Costea Daniel Ovidiu , Tudosie Mihail Silviu , Stana Daniela , Tanasescu Denisa , Sabau Alexandru Dan , Gangura Gabriel Andrei , Costea Andreea Cristina , Nicolae Vanessa Andrada , Smarandache Catalin Gabriel
Published: August 2021

Bariatric surgery is an emerging therapeutic approach for obese type 2 diabetes mellitus (T2DM) patients, with proven benefits for achieving target glucose control and even remission of diabetes. However, the effect of bariatric surgery upon diabetic retinopathy is still a subject of debate as some studies show a positive effect while others raise concerns about potential early worsening effects. We performed a systematic review, on PubMed, Science Direct, and Web of Science databases regarding the onset and progression of diabetic retinopathy in obese T2DM patients who underwent weight-loss surgical procedures. A total of 6375 T2DM patients were analyzed. Most cases remained stable after bariatric surgery (89.6%). New onset of diabetic retinopathy (DR) was documented in 290 out of 5972 patients (4.8%). In cases with DR at baseline, progression was documented in 50 out of 403 (12.4%) and regression in 90 (22.3%). Preoperative careful preparation of hemoglobin A1c (HbA1c), blood pressure, and lipidemia should be provided to minimize the expectation of DR worsening. Ophthalmologic follow-up should be continued regularly in the postoperative period even in the case of diabetic remission. Further randomized trials are needed to better understand the organ-specific risk factors for progression and provide personalized counseling for T2DM patients planned for bariatric surgery.
Hyperthyroidism in Pregnancy: The Delicate Balance between Too Much or Too Little Antithyroid Drug
Authors: Gheorghiu Monica Livia , Bors Roxana Georgiana , Gheorghisan-Galateanu Ancuta-Augustina , Pop Anca Lucia , Cretoiu Dragos , Varlas Valentin Nicolae
Published: August 2021

Overt hyperthyroidism (HT) during pregnancy is associated with a risk of maternal–fetal complications. Antithyroid drugs (ATD) have a potential risk for teratogenic effects and fetal–neonatal hypothyroidism. This study evaluated ATD treatment and thyroid function control during pregnancy, and pregnancy outcome in women with HT. Patients and methods: A retrospective analysis of 36 single fetus pregnancies in 29 consecutive women (median age 30.3 ± 4.7 years) with HT diagnosed before or during pregnancy; a control group of 39 healthy euthyroid pregnant women was used. Results: Twenty-six women had Graves’ disease (GD, 33 pregnancies), 1 had a hyperfunctioning autonomous nodule, and 2 had gestational transient thyrotoxicosis (GTT). Methimazole (MMI) was administered in 22 pregnancies (78.5%), Propylthiouracil (PTU) in 2 (7.1%), switch from MMI to PTU in 4 (14.2%), no treatment in 8 pregnancies (3 with subclinical HT, 5 euthyroid with previous GD remission before conception). In the 8 pregnancies of GD patients diagnosed during gestation or shortly before (<6 weeks), i.e., with fetal exposure to uncontrolled HT, there was 1 spontaneous abortion at 5 weeks (3.4% of all ATD-treated pregnancies), and 1 premature delivery at 32 weeks with neonatal death in 24 h (3.4%); 1 child had neonatal hyperthyroidism (3.3% of live children in GD women) and a small atrial sept defect (4% of live children in ATD treated women). In women treated more than 6 months until conception (20 pregnancies): (a) median ATD doses were lower than those in women diagnosed shortly before or during pregnancy; (b) ATD was withdrawn in 40% of pregnancies in trimester (T)1, all on MMI < 10 mg/day (relapse in 14.2%), and in up to 55% in T3; (c) TSH level was below normal in 37%, 35% and 22% of pregnancies in T1, T2 and T3 respectively; FT4 was increased in 5.8% (T1) and subnormal in 11.75% in T2 and T3; (d) no fetal birth defects were recorded; one fetal death due to a true umbilical cord knot was registered. Mean birth weight was similar in both ATD-treated and control groups. Hyperthyroidism relapsed postpartum in 83% of GD patients (at median 3 ± 2.6 months). Conclusion: In hyperthyroid women with long-term ATD treatment before conception, drugs could be withdrawn in T1 in 40% of them, the thyroid function control was better, and pregnancy and fetal complications were rarer, compared to women diagnosed during pregnancy. Frequent serum TSH and FT4 monitoring is needed to maintain optimal thyroid function during pregnancy.
Mortality after Use of Paclitaxel-Coated Balloons Correlates with Total Cumulative Dosage of Paclitaxel in Real-World Analysis
Authors: Heo Seon-Hee , Woo Shin-Young , Choi Seung-Hyuk , Park Taek-Kyu , Do Young-Soo , Park Kwang-Bo , Kim Dong-Ik , Kim Young-Wook , Park Yang-Jin
Published: August 2021

This study used independent, real-world, patient-level data to examine whether the dosage or frequency of paclitaxel exposure correlated with mortality during follow up. We conducted a retrospective analysis of patients treated with a drug-coated balloon (DCB) for an atherosclerotic femoropopliteal lesion from February 2013 to December 2018, excluding patients with non-atherosclerotic lesions or restenosis after DCB treatment in another hospital. We investigated the causes of death, comorbidities (including cancer status), and the initial and total cumulative dosages and frequency of paclitaxel use. To determine whether the dosage or frequency of paclitaxel exposure affected mortality during follow up, we analyzed the risk factors for all-cause death by conducting a time-dependent Cox regression analysis that considered demographics, comorbidities, lesion and procedural characteristics, and paclitaxel exposure data (dosage and frequency). Our analysis examined 225 patients (mean age 71 ± 9 years, range 38–93 years, male 81%). During a mean follow-up duration of 35 months (range 1–89 months), 56 patients (24.9%) died from cardiac disorders (16%, including acute myocardial infarction, heart failure, or sudden cardiac arrest), malignancy (14.3%), respiratory failure with pneumonia (12.5%), septic shock (12.5%), or another cause. Univariable and multivariable Cox regression analyses identified age (hazard ratio, HR, 1.057; 95% confidence interval, CI, 1019–1096; p = 0.0032), critical limb ischemia (CLI) (HR, 4135; 95% CI, 2171–7876; p < 0.0001), and the total dosage of paclitaxel (mg) (HR, 1.040; 95% CI, 1006–1074; p = 0.0210) as predictors of mortality during follow up. The subgroup analysis found that the total dosage of paclitaxel (mg) was also a predictor of mortality during follow up in the CLI group (HR, 1.046; 95% CI, 1007–1087, p = 0.0198). The estimated cut-off value of total cumulative paclitaxel dosage for predicting mortality was 12 mg as evaluated by minimum p value approach. This patient-level analysis identified the total cumulative dosage of paclitaxel as a predictor of mortality after the use of paclitaxel-coated balloons. Our results provide limited information about the potential dose–response relationship underlying paclitaxel-associated mortality concerns.
JAK Inhibition with Ruxolitinib in Patients with COVID-19 and Severe Pneumonia: Multicenter Clinical Experience from a Compassionate Use Program in Italy
Authors: Vannucchi Alessandro Maria , Mortara Andrea , D’Alessio Andrea , Morelli Mara , Tedeschi Alberto , Festuccia Moreno Benedetto , Monforte Antonella D’Arminio , Capochiani Enrico , Selleri Carmine , Simonetti Federico , Saracino Annalisa , Rapezzi Davide , Badagliacca Maria Rita , Falasca Katia , Molteni Alfredo , Palazzolo Roberto , Schettino Giuliano , Bocchia Monica , Turrini Mauro , Ascierto Paolo A. , Zuurman Mike , Paley Carole , Coco Paola , Saglio Giuseppe
Published: August 2021

Jak inhibitors are potent anti-inflammatory drugs that have the potential to dampen the hyperactive inflammatory response associated with severe COVID-19. We reviewed the clinical outcomes of 218 patients with COVID-19 hospitalized for severe pneumonia and treated with ruxolitinib through a compassionate use program. Data on the duration of treatment; outcomes at 4, 7, 14, and 28 days; oxygen support requirements; clinical status; and laboratory parameters were retrospectively collected. Overall, according to the physician evaluation, 66.5% of patients showed improvement at follow-up; of these, 83.5% showed improvement by day 7. Oxygen support status also showed improvement, and by day 7, 21.6% of patients were on ambient air, compared with 1.4% at baseline, which increased to 48.2% by day 28. Significant decreases in C-reactive protein and increases in the lymphocyte total count were already observed by day 4, which seemed to correlate with a positive outcome. At the end of the observation period, 87.2% of patients were alive. No unexpected safety findings were observed, and grade 3/4 adverse events were reported in 6.9% of patients.