bluuebunny/crossref_metadata_2025 huggingface dataset:
High Temperatures and Cardiovascular-Related Morbidity: A Scoping Review
Authors: Cicci Kendra R. , Maltby Alana , Clemens Kristin K. , Vicedo-Cabrera Ana Maria , Gunz Anna C. , Lavigne Éric , Wilk Piotr
Published: September 2022

The primary objective of this review was to synthesize studies assessing the relationships between high temperatures and cardiovascular disease (CVD)-related hospital encounters (i.e., emergency department (ED) visits or hospitalizations) in urban Canada and other comparable populations, and to identify areas for future research. Ovid MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, and Scopus were searched between 6 April and 11 April 2020, and on 21 March 2021, to identify articles examining the relationship between high temperatures and CVD-related hospital encounters. Studies involving patients with pre-existing CVD were also included. English language studies from North America and Europe were included. Twenty-two articles were included in the review. Studies reported an inconsistent association between high temperatures and ischemic heart disease (IHD), heart failure, dysrhythmia, and some cerebrovascular-related hospital encounters. There was consistent evidence that high temperatures may be associated with increased ED visits and hospitalizations related to total CVD, hyper/hypotension, acute myocardial infarction (AMI), and ischemic stroke. Age, sex, and gender appear to modify high temperature-CVD morbidity relationships. Two studies examined the influence of pre-existing CVD on the relationship between high temperatures and morbidity. Pre-existing heart failure, AMI, and total CVD did not appear to affect the relationship, while evidence was inconsistent for pre-existing hypertension. There is inconsistent evidence that high temperatures are associated with CVD-related hospital encounters. Continued research on this topic is needed, particularly in the Canadian context and with a focus on individuals with pre-existing CVD.
The Current Status and Prevention of Antibiotic Pollution in Groundwater in China
Authors: Zeng Huiping , Li Jianxue , Zhao Weihua , Xu Jiaxin , Xu He , Li Dong , Zhang Jie
Published: September 2022

The problem of environmental pollution caused by the abuse of antibiotics has received increasing attention. However, only in recent years have antibiotic pollution and its risk assessment to the environment been deeply studied. Although there has been a large number of reports about the input, occurrence, destination, and influence of antibiotics in the past 10 years, systemic knowledge of antibiotics in the groundwater environment is still lacking. This review systematically expounds the sources, migration and transformation, pollution status, and potential risks to the ecological environment of antibiotics in groundwater systems, by integrating 10 years of existing research results. The results showed that 47 kinds of antibiotics in four categories, mainly sulfonamides and fluoroquinolones, have been detected; antibiotics in groundwater species will induce the production of resistance genes and cause ecological harm. In view of the entire process of antibiotics entering groundwater, the current antibiotic control methods at various levels are listed, including the control of the discharge of antibiotics at source, the removal of antibiotics in water treatment plants, and the treatment of existing antibiotic contamination in groundwater. Additionally, the future research direction of antibiotics in groundwater is pointed out, and suggestions and prospects for antibiotic control are put forward.
What Are More Efficient Transportation Services in a Rural Area? A Case Study in Yangsan City, South Korea
Authors: Roh Chang-Gyun , Kim Jiyoon
Published: September 2022

Population aging and population decline are experienced not only in South Korea but also in other countries around the world. In particular, public transportation operations, which have been centered on existing large buses, are struggling with a continuous deficit owing to the rapid population decline in rural areas, thus leading to a social issue. To address this issue, nations worldwide have attempted to find various alternatives. In South Korea, voucher taxis and city-type buses have been newly supplied in rural areas as alternatives. In this study, six city-type bus routes implemented in Yangsan-si, South Korea have been intensively reviewed in particular. The planned routes and operation status of each bus route were compared and reviewed based on geographic information systems. Six improved demand-responsive transport (DRT) operation methods were studied based on the operation patterns of city-type buses that were operated differently from the planed routes. Through this, a more suitable DRT small bus operation model for each route was proposed. Our study results will be a foundational proposal for policy makers concerned with improving public transport services and supplying new services in rural areas.
Exploring Factors That Affected Student Well-Being during the COVID-19 Pandemic: A Comparison of Data-Mining Approaches
Authors: Yürekli Hülya , Yiğit Öyküm Esra , Bulut Okan , Lu Min , Öz Ersoy
Published: September 2022

COVID-19-related school closures caused unprecedented and prolonged disruption to daily life, education, and social and physical activities. This disruption in the life course affected the well-being of students from different age groups. This study proposed analyzing student well-being and determining the most influential factors that affected student well-being during the COVID-19 pandemic. With this aim, we adopted a cross-sectional study designed to analyze the student data from the Responses to Educational Disruption Survey (REDS) collected between December 2020 and July 2021 from a large sample of grade 8 or equivalent students from eight countries (n = 20,720), including Burkina Faso, Denmark, Ethiopia, Kenya, the Russian Federation, Slovenia, the United Arab Emirates, and Uzbekistan. We first estimated a well-being IRT score for each student in the REDS student database. Then, we used 10 data-mining approaches to determine the most influential factors that affected the well-being of students during the COVID-19 outbreak. Overall, 178 factors were analyzed. The results indicated that the most influential factors on student well-being were multifarious. The most influential variables on student well-being were students’ worries about contracting COVID-19 at school, their learning progress during the COVID-19 disruption, their motivation to learn when school reopened, and their excitement to reunite with friends after the COVID-19 disruption.
Impact of Exercise Intensity on Systemic Oxidative Stress, Inflammatory Responses, and Sirtuin Levels in Healthy Male Volunteers
Authors: Cho Su-Youn , Chung Young-Soo , Yoon Hyoung-Ki , Roh Hee-Tae
Published: September 2022

Exercise can induce anti-inflammatory and antioxidant effects, for which regulation of sirtuins (SIRTs) may be a major consideration for exercise prescription. The purpose of this study was to investigate the effects of acute aerobic exercise, in particular its intensity, on systemic oxidative stress, inflammatory responses, and SIRT levels. Twenty healthy, untrained males were recruited and randomly assigned to moderate-intensity (MI, 65% VO2max, n = 10) and high-intensity (HI, 85% VO2max, n = 10) exercise. Blood samples were obtained pre-, immediately post-, and 1 h post-exercise for measurements of malonaldehyde (MDA), superoxide dis-mutase (SOD), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, SIRT-1, SIRT-2, and SIRT-3. Overall, MDA, SOD, IL-6, SIRT-1, and SIRT-3 levels were significantly increased at post-exercise compared with pre-exercise regardless of exercise intensity (p < 0.05). The HI group had significantly higher MDA, SOD, and IL-6 levels than the MI group at post-exercise (p < 0.05), whereas no significant differences were observed in the IL-1β, TNF-α, and SIRT-2 levels (p > 0.05). Altogether, these findings suggest that exercise-induced oxidative stress and inflammatory responses may be dependent on exercise intensity. Moreover, activation of inflammatory cytokines and SIRT family members may be dependent on the intensity of the exercise.
Urban Air Mobility Noise: Further Considerations on Indoor Space
Authors: Kim JungHoon
Published: September 2022

Various countries are preparing for the introduction of urban air mobility (UAM) vehicles, which move freely within the space above a city, as a new means of urban transportation. However, UAM vehicles present new forms of challenges to many urban residents. This study aims to propose newly sensory standards for the noise levels of UAM vehicles in urban indoor spaces based on two fundamental questions: (1) Would UAM vehicles not have a lower and wider impact on city residents than a commercial aircraft? (2) Should the flight of UAM vehicles not consider the sensory noise, like the conventional noise standard? UAM vehicles, unlike commercial aircrafts, will cause noise pollution in a broad area of the city. Therefore, expanded aircraft noise standards will be required. In addition, the hybridized noise generated by conventional vehicles in the ground and UAM vehicles in the air will affect urban residents. Furthermore, urban residents will be exposed to sensory noise from UAM vehicles, which fly directly above them but not within their line of sight. Therefore, the noise standards for UAM vehicles should include the sensory properties in addition to the physical properties in the existing noise standards.
Revisiting Standard and Novel Therapeutic Approaches in Halitosis: A Review
Authors: Izidoro Catarina , Botelho João , Machado Vanessa , Reis Ana Mafalda , Proença Luís , Alves Ricardo Castro , Mendes José João
Published: September 2022

Halitosis, or bad breath, is an oral health problem characterized by an unpleasant malodor emanating from the oral cavity. This condition can have different origins and causes a negative burden in social interactions, communication and quality of life, and can in uncommon cases be indicative of underlying non-oral non-communicable diseases. Most cases of halitosis are due to inadequate oral hygiene, periodontitis and tongue coating, yet the remaining proportion of cases are due to ear–nose–throat-associated (10%) or gastrointestinal/endocrine (5%) disorders. For this reason, the diagnosis, treatment and clinical management of halitosis often require a multidisciplinary team approach. This comprehensive review revisits the etiology of halitosis as well as standard and novel treatment that may contribute to higher clinical success.
Caring Ability and Professional Values of Polish Nursing Students—A Cross-Sectional Study
Authors: Machul Michał , Dziurka Magdalena , Gniadek Agnieszka , Gotlib Joanna , Gutysz-Wojnicka Aleksandra , Kotowski Michał , Kozieł Dorota , Krasucka Kamila , Obuchowska Anna , Ozdoba Patrycja , Panczyk Mariusz , Pydyś Aleksandra , Uchmanowicz Izabella , Dobrowolska Beata
Published: September 2022

Caring ability and professional values developed and shaped during nursing university studies are often recognised as fundamental components of education and professional nursing attitudes. The aim of this study was to analyse the relationship between caring ability and professional values among nursing students and their correlation with selected sociodemographic variables. A cross-sectional study was conducted among a convenience sample of 379 nursing students. During the research, the Polish versions of the Caring Ability Inventory and the Professional Values Scale were used. The overall result in the Professional Values Scale was 108.78 (SD = 16.17)—which is considered average, and in the Caring Ability Inventory 189.55 (SD = 18.77)—which is considered low. Age correlated negatively with the professional values of students in total and in the subscale “care”; in contrast, “gender”, “place of residence” and “financial situation” did not show any correlation with the level of students’ professional values and caring ability. The professional values and caring abilities of nursing students depended on the year and mode of study and the type of university. The results of the study revealed that the caring ability and professional values of nursing students undergo changes during their education.
Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases
Authors: Saito Satoshi , Ono Kenjiro , Tanaka Masashi
Published: September 2022

The rate of dementia continues to increase worldwide; however, there currently exist no therapeutic strategies for this condition [...]
Platelet-Derived S1P and Its Relevance for the Communication with Immune Cells in Multiple Human Diseases
Authors: Tolksdorf Céline , Moritz Eileen , Wolf Robert , Meyer Ulrike , Marx Sascha , Bien-Möller Sandra , Garscha Ulrike , Jedlitschky Gabriele , Rauch Bernhard H.
Published: September 2022

Sphingosine-1-phosphate (S1P) is a versatile signaling lipid involved in the regulation of numerous cellular processes. S1P regulates cellular proliferation, migration, and apoptosis as well as the function of immune cells. S1P is generated from sphingosine (Sph), which derives from the ceramide metabolism. In particular, high concentrations of S1P are present in the blood. This originates mainly from erythrocytes, endothelial cells (ECs), and platelets. While erythrocytes function as a storage pool for circulating S1P, platelets can rapidly generate S1P de novo, store it in large quantities, and release it when the platelet is activated. Platelets can thus provide S1P in a short time when needed or in the case of an injury with subsequent platelet activation and thereby regulate local cellular responses. In addition, platelet-dependently generated and released S1P may also influence long-term immune cell functions in various disease processes, such as inflammation-driven vascular diseases. In this review, the metabolism and release of platelet S1P are presented, and the autocrine versus paracrine functions of platelet-derived S1P and its relevance in various disease processes are discussed. New pharmacological approaches that target the auto- or paracrine effects of S1P may be therapeutically helpful in the future for pathological processes involving S1P.
The Proteoglycan Glypican-1 as a Possible Candidate for Innovative Targeted Therapeutic Strategies for Pancreatic Ductal Adenocarcinoma
Authors: Busato Davide , Mossenta Monica , Dal Bo Michele , Macor Paolo , Toffoli Giuseppe
Published: September 2022

Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers, with a 5-year survival rate of 7% and 80% of patients diagnosed with advanced or metastatic malignancies. Despite recent advances in diagnostic testing, surgical techniques, and systemic therapies, there remain limited options for the effective treatment of PDAC. There is an urgent need to develop targeted therapies that are able to differentiate between cancerous and non-cancerous cells to reduce side effects and better inhibit tumor growth. Antibody-targeted strategies are a potentially effective option for introducing innovative therapies. Antibody-based immunotherapies and antibody-conjugated nanoparticle-based targeted therapies with antibodies targeting specific tumor-associated antigens (TAA) can be proposed. In this context, glypican-1 (GPC1), which is highly expressed in PDAC and not expressed or expressed at very low levels in non-malignant lesions and healthy pancreatic tissues, is a useful TAA that can be achieved by a specific antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy. In this review, we describe the main clinical features of PDAC. We propose the proteoglycan GPC1 as a useful TAA for PDAC-targeted therapies. We also provide a digression on the main developed approaches of antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy, which can be used to target GPC1.
Stem Cell Therapy for Sequestration of Traumatic Brain Injury-Induced Inflammation
Authors: Borlongan Mia C. , Rosi Susanna
Published: September 2022

Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disabilities in the world. TBI is a signature disease for soldiers and veterans, but also affects civilians, including adults and children. Following TBI, the brain resident and immune cells turn into a “reactive” state, characterized by the production of inflammatory mediators that contribute to the development of cognitive deficits. Other injuries to the brain, including radiation exposure, may trigger TBI-like pathology, characterized by inflammation. Currently there are no treatments to prevent or reverse the deleterious consequences of brain trauma. The recognition that TBI predisposes stem cell alterations suggests that stem cell-based therapies stand as a potential treatment for TBI. Here, we discuss the inflamed brain after TBI and radiation injury. We further review the status of stem cells in the inflamed brain and the applications of cell therapy in sequestering inflammation in TBI.
Genetic Mechanism Study of Auditory Phoenix Spheres and Transcription Factors Prediction for Direct Reprogramming by Bioinformatics
Authors: Chen Jishizhan , Liu Ziyu , Chang Jinke
Published: September 2022

Background: Hearing loss is the most common irreversible sensory disorder. By delivering regenerative cells into the cochlea, cell-based therapy provides a novel strategy for hearing restoration. Recently, newly-identified phoenix cells have drawn attention due to their nearly unlimited self-renewal and neural differentiation capabilities. They are a promising cell source for cell therapy and a potential substitute for induced pluripotent stem cells (iPSCs) in many in vitro applications. However, the underlying genomic mechanism of their self-renewal capabilities is largely unknown. The aim of this study was to identify hub genes and potential molecular mechanisms between differentiated and undifferentiated phoenix cells and predict transcription factors (TFs) for direct reprogramming. Material and Methods: The datasets were downloaded from the ArrayExpress database. Samples of differentiated and undifferentiated phoenix cells with three biological replicates were utilised for bioinformatic analysis. Differentially expressed genes (DEGs) were screened and the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were investigated. The gene set enrichment analysis (GSEA) was conducted to verify the enrichment of four self-defined gene set collections, followed by protein-protein interaction (PPI) network construction and subcluster analysis. The prediction of TFs for direct reprogramming was performed based on the TRANSFAC database. Results: Ten hub genes were identified to be the key candidates for self-renewal. Ten TFs were predicted as the direct reprogramming factors. This study provides a theoretical foundation for understanding phoenix cells and clues for direct reprogramming, which would stimulate further experiments and clinical applications in hearing research and treatment.
Impact of Baseline Versus Intercurrent Steroids Administration on Upfront Chemo-Immunotherapy for Advanced Non-Small Cell Lung Cancer (NSCLC)
Authors: De Giglio Andrea , Aprile Marta , Di Federico Alessandro , Sperandi Francesca , Melotti Barbara , Gelsomino Francesco , Ardizzoni Andrea
Published: September 2022

The impact of baseline versus intercurrent steroids on the efficacy of upfront chemotherapy plus pembrolizumab (CT-ICI) for advanced non-small cell lung cancer (NSCLC) patients is unclear. We conducted a retrospective study on metastatic NSCLC patients treated with upfront CT-ICI at our institution between March 2020 and December 2021. The use of steroids was considered as the administration of at least 10 mg of prednisone equivalent. Of 101 patients, 36 (35.6%) received steroid therapy at baseline, and 18 (17.8%) started steroids on treatment. Overall, median progression-free survival (mPFS) was 6.5 months (95% CI, 5.9–8.9) and median overall survival (mOS) was 18.2 months (95% CI, 8.9-NR). Patients taking baseline steroids had significantly shorter survival than those not taking them and those assuming intercurrent steroids (mPFS 5.0 vs. 9.2 vs. 7.3 months, p < 0.001; mOS 7.0 months vs. not reached, p < 0.001). Baseline steroids were significantly associated with poorer survival outcomes in the multivariate model (OS HR 2.94, p = 0.02; PFS HR 3.84, p > 0.001). Conversely, intercurrent prescription did not reach a significant value regardless of other pivotal variables included in the model. Baseline steroid administration was associated with a detrimental effect on survival outcomes in NSCLC patients treated with CT-ICI. The role of intercurrent steroid administration should be further explored in larger studies.
The Relative Abundances of Human Leukocyte Antigen-E, α-Galactosidase A and α-Gal Antigenic Determinants Are Biased by Trichostatin A-Dependent Epigenetic Transformation of Triple-Transgenic Pig-Derived Dermal Fibroblast Cells
Authors: Samiec Marcin , Wiater Jerzy , Wartalski Kamil , Skrzyszowska Maria , Trzcińska Monika , Lipiński Daniel , Jura Jacek , Smorąg Zdzisław , Słomski Ryszard , Duda Małgorzata
Published: September 2022

The present study sought to establish the mitotically stable adult cutaneous fibroblast cell (ACFC) lines stemming from hFUT2×hGLA×HLA-E triple-transgenic pigs followed by trichostatin A (TSA)-assisted epigenetically modulating the reprogrammability of the transgenes permanently incorporated into the host genome and subsequent comprehensive analysis of molecular signatures related to proteomically profiling the generated ACFC lines. The results of Western blot and immunofluorescence analyses have proved that the profiles of relative abundance (RA) noticed for both recombinant human α-galactosidase A (rhα-Gal A) and human leukocyte antigen-E (HLA-E) underwent significant upregulations in tri-transgenic (3×TG) ACFCs subjected to TSA-mediated epigenetic transformation as compared to not only their TSA-unexposed counterparts but also TSA-treated and untreated non-transgenic (nTG) cells. The RT-qPCR-based analysis of porcine tri-genetically engineered ACFCs revealed stable expression of mRNA fractions transcribed from hFUT2, hGLA and HLA-E transgenes as compared to a lack of such transcriptional activities in non-transgenic ACFC variants. Furthermore, although TSA-based epigenomic modulation has given rise to a remarkable increase in the expression levels of Galα1→3Gal (α-Gal) epitopes that have been determined by lectin blotting analysis, their semi-quantitative profiles have dwindled profoundly in both TSA-exposed and unexposed 3×TG ACFCs as compared to their nTG counterparts. In conclusion, thoroughly exploring proteomic signatures in such epigenetically modulated ex vivo models devised on hFUT2×hGLA×HLA-E triple-transgenic ACFCs that display augmented reprogrammability of translational activities of two mRNA transcripts coding for rhα-Gal A and HLA-E proteins might provide a completely novel and powerful research tool for the panel of further studies. The objective of these future studies should be to multiply the tri-transgenic pigs with the aid of somatic cell nuclear transfer (SCNT)-based cloning for the purposes of both xenografting the porcine cutaneous bioprostheses and dermoplasty-mediated surgical treatments in human patients.
Strategies for Therapeutic Amelioration of Aberrant Plasma Zn2+ Handling in Thrombotic Disease: Targeting Fatty Acid/Serum Albumin-Mediated Effects
Authors: Regan-Smith Spencer , Fritzen Remi , Hierons Stephen J. , Ajjan Ramzi A. , Blindauer Claudia A. , Stewart Alan J.
Published: September 2022

The initiation, maintenance and regulation of blood coagulation is inexorably linked to the actions of Zn2+ in blood plasma. Zn2+ interacts with a variety of haemostatic proteins in the bloodstream including fibrinogen, histidine-rich glycoprotein (HRG) and high molecular weight kininogen (HMWK) to regulate haemostasis. The availability of Zn2+ to bind such proteins is controlled by human serum albumin (HSA), which binds 70–85% of plasma Zn2+ under basal conditions. HSA also binds and transports non-esterified fatty acids (NEFAs). Upon NEFA binding, there is a change in the structure of HSA which leads to a reduction in its affinity for Zn2+. This enables other plasma proteins to better compete for binding of Zn2+. In diseases where elevated plasma NEFA concentrations are a feature, such as obesity and diabetes, there is a concurrent increase in hypercoagulability. Evidence indicates that NEFA-induced perturbation of Zn2+-binding by HSA may contribute to the thrombotic complications frequently observed in these pathophysiological conditions. This review highlights potential interventions, both pharmaceutical and non-pharmaceutical that may be employed to combat this dysregulation. Lifestyle and dietary changes have been shown to reduce plasma NEFA concentrations. Furthermore, drugs that influence NEFA levels such as statins and fibrates may be useful in this context. In severely obese patients, more invasive therapies such as bariatric surgery may be useful. Finally, other potential treatments such as chelation therapies, use of cholesteryl transfer protein (CETP) inhibitors, lipase inhibitors, fatty acid inhibitors and other treatments are highlighted, which with additional research and appropriate clinical trials, could prove useful in the treatment and management of thrombotic disease through amelioration of plasma Zn2+ dysregulation in high-risk individuals.
Prognostic Value, Immune Signature, and Molecular Mechanisms of the PHLDA Family in Pancreatic Adenocarcinoma
Authors: Duan Yunjie , Du Yongxing , Gu Zongting , Zheng Xiaohao , Wang Chengfeng
Published: September 2022

Background: Increasing evidence supports the belief that the pleckstrin homology domain family A (PHLDA) family is associated with the development of a variety of cancers. However, the function of the PHLDA family members in PAAD is still unclear. Methods: Comprehensive bioinformatic analyses using R (version 3.6.3), Cytoscape (version 3.9.1), UALCAN, etc., were performed to study the clinicopathological characteristics, prognostic value, immune features, and functional mechanisms of the PHLDA family members in PAAD. Results: The PHLDA family members showed significantly elevated expression in PAAD compared with paracancerous or normal tissues. Their high expression or amplification were significantly correlated with worse clinicopathological characteristics and prognosis in PAAD patients. In addition, the role of the PHLDA family members in the immune regulation is diverse and complex. Mechanistically, TP53 mutations were significantly associated with the promoter methylation and expression levels of the PHLDA family members, which were activated in multiple oncogenic pathways, including the EMT, RAS/MAPK, and TSC/mTOR pathways. Moreover, we found that their expression levels were significantly correlated with the sensitivity of multiple traditional chemotherapeutic drugs and novel targeted MEK1/2 inhibitors. Conclusion: The PHLDA family members play an oncogenic role in the development of PAAD and might serve as new biomarkers or therapeutic targets.
Comparative Study on the Models of Thermoreversible Gelation
Authors: Tanaka Fumihiko
Published: September 2022

A critical survey on the various theoretical models of thermoreversible gelation, such as the droplet model of condensation, associated-particle model, site–bond percolation model, and adhesive hard sphere model, is presented, with a focus on the nature of the phase transition predicted by them. On the basis of the classical tree statistics of gelation, combined with a thermodynamic theory of associating polymer solutions, it is shown that, within the mean-field description, the thermoreversible gelation of polyfunctional molecules is a third-order phase transition analogous to the Bose–Einstein condensation of an ideal Bose gas. It is condensation without surface tension. The osmotic compressibility is continuous, but its derivative with respect to the concentration of the functional molecule reveals a discontinuity at the sol–gel transition point. The width of the discontinuity is directly related to the amplitude of the divergent term in the weight-average molecular weight of the cross-linked three-dimensional polymers. The solution remains homogeneous in the position space, but separates into two phases in the momentum space; particles with finite translational momentum (sol) and a network with zero translational momentum (gel) coexist in a spatially homogeneous state. Experimental methods used to detect the singularity at the sol–gel transition point are suggested.
Recent Advances in PROTACs for Drug Targeted Protein Research
Authors: Yao Tingting , Xiao Heng , Wang Hong , Xu Xiaowei
Published: September 2022

Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule. Typically, PROTAC consists of two terminals which are the ligand of the protein of interest (POI) and the specific ligand of E3 ubiquitin ligase, respectively, via a suitable linker. PROTAC degradation of the target protein is performed through the ubiquitin–proteasome system (UPS). The general process is that PROTAC binds to the target protein and E3 ligase to form a ternary complex and label the target protein with ubiquitination. The ubiquitinated protein is recognized and degraded by the proteasome in the cell. At present, PROTAC, as a new type of drug, has been developed to degrade a variety of cancer target proteins and other disease target proteins, and has shown good curative effects on a variety of diseases. For example, PROTACs targeting AR, BR, BTK, Tau, IRAK4, and other proteins have shown unprecedented clinical efficacy in cancers, neurodegenerative diseases, inflammations, and other fields. Recently, PROTAC has entered a phase of rapid development, opening a new field for biomedical research and development. This paper reviews the various fields of targeted protein degradation by PROTAC in recent years and summarizes and prospects the hot targets and indications of PROTAC.
Unraveling the Role of the Tyrosine Tetrad from the Binding Site of the Epigenetic Writer MLL3 in the Catalytic Mechanism and Methylation Multiplicity
Authors: Blanco-Esperguez Kevin , Tuñón Iñaki , Kästner Johannes , Mendizábal Fernando , Miranda-Rojas Sebastián
Published: September 2022

MLL3, also known as KMT2C, is a lysine mono-methyltransferase in charge of the writing of an epigenetic mark on lysine 4 from histone 3. The catalytic site of MLL3 is composed of four tyrosines, namely, Y44, Y69, Y128, and Y130. Tyrosine residues are highly conserved among lysine methyltransferases’ catalytic sites, although their complete function is still unclear. The exploration of how modifications on these residues from the enzymatic machinery impact the enzymatic activity of MLL3 could shed light transversally into the inner functioning of enzymes with similar characteristics. Through the use of QMMM calculations, we focus on the effect of the mutation of each tyrosine from the catalytic site on the enzymatic activity and the product specificity in the current study. While we found that the mutations of Y44 and Y128 by phenylalanine inactivated the enzyme, the mutation of Y128 by alanine reactivated the enzymatic activity of MLL3. Moreover, according to our models, the Y128A mutant was even found to be capable of di- and tri-methylate lysine 4 from histone 3, what would represent a gain of function mutation, and could be responsible for the development of diseases. Finally, we were able to establish the inactivation mechanism, which involved the use of Y130 as a water occlusion structure, whose conformation, once perturbed by its mutation or Y128 mutant, allows the access of water molecules that sequester the electron pair from lysine 4 avoiding its methylation process and, thus, increasing the barrier height.
Integrated Antitumor Activities of Cellular Immunotherapy with CIK Lymphocytes and Interferons against KIT/PDGFRA Wild Type GIST
Authors: Fiorino Erika , Merlini Alessandra , D’Ambrosio Lorenzo , Cerviere Ilaria , Berrino Enrico , Marchiò Caterina , Giraudo Lidia , Basiricò Marco , Massa Annamaria , Donini Chiara , Leuci Valeria , Rotolo Ramona , Galvagno Federica , Vitali Letizia , Proment Alessia , Ferrone Soldano , Pisacane Alberto , Pignochino Ymera , Aglietta Massimo , Grignani Giovanni , Mesiano Giulia , Sangiolo Dario
Published: September 2022

Gastrointestinal stromal tumors (GISTs) are rare, mesenchymal tumors of the gastrointestinal tract, characterized by either KIT or PDGFRA mutation in about 85% of cases. KIT/PDGFRA wild type gastrointestinal stromal tumors (wtGIST) account for the remaining 15% of GIST and represent an unmet medical need: their prevalence and potential medical vulnerabilities are not completely defined, and effective therapeutic strategies are still lacking. In this study we set a patient-derived preclinical model of wtGIST to investigate their phenotypic features, along with their susceptibility to cellular immunotherapy with cytokine-induced killer lymphocytes (CIK) and interferons (IFN). We generated 11 wtGIST primary cell lines (wtGISTc). The main CIK ligands (MIC A/B; ULBPs), along with PD-L1/2, were expressed by wtGISTc and the expression of HLA-I molecules was preserved. Patient-derived CIK were capable of intense killing in vitro against wtGISTc resistant to both imatinib and sunitinib. We found that CIK produce a high level of granzyme B, IFNα and IFNγ. CIK-conditioned supernatant was responsible for part of the observed tumoricidal effect, along with positive bystander modulatory activities enhancing the expression of PD-L1/2 and HLA-I molecules. IFNα, but not In, had direct antitumor effects on 50% (4/8) of TKI-resistant wtGISTc, positively correlated with the tumor expression of IFN receptors. wtGIST cells that survived IFNα were still sensitive to CIK immunotherapy. Our data support the exploration of CIK immunotherapy in clinical studies for TKI-resistant wtGIST, proposing reevaluation for IFNα within this challenging setting.
Editors Introduction to the Special Issue on Advances in Cognitive and Behaviour Therapies and Applications in Health Practices
Authors: McHugh Louise , Merwin Rhonda M.
Published: September 2022

The last thirty years have seen significant advances in cognitive and behavioural psychotherapies and their application in health care/clinical practices [...]
Massive Thrombosis of Mitral Bioprosthesis Due to SARS-CoV-2 Infection
Authors: Librera Mariateresa , Paolillo Stefania , Carlomagno Guido , Santise Gianluca , Mariniello Antonio , Nardella Saverio , Briguori Carlo , Maselli Daniele
Published: September 2022

Thromboembolic events have been reported as frequent and fearsome complications in patients affected by SARS-CoV-2 infection. Patients undergoing cardiac valve replacement exhibit an increased risk of valve thrombosis, even with prosthetic biological valves, and especially in the first period after surgery. The management of these patients is challenging and requires prompt interventions. We report the case of a young woman infected by SARS-CoV-2 three months after double cardiac valve replacement that developed a massive prosthetic biological valve thrombosis despite optimal anticoagulant therapy.
The Limits of Acute Anemia
Authors: Tomić Mahečić Tina , Brooks Roxane , Noitz Matthias , Sarmiento Ignacio , Baronica Robert , Meier Jens
Published: September 2022

For many years, physicians’ approach to the transfusion of allogeneic red blood cells (RBC) was not individualized. It was accepted that a hemoglobin concentration (Hb) of less than 10 g/dL was a general transfusion threshold and the majority of patients were transfused immediately. In recent years, there has been increasing evidence that even significantly lower hemoglobin concentrations can be survived in the short term without sequelae. This somehow contradicts the observation that moderate or mild anemia is associated with relevant long-term morbidity and mortality. To resolve this apparent contradiction, it must be recognized that we have to avoid acute anemia or treat it by alternative methods. The aim of this article is to describe the physiological limits of acute anemia, match these considerations with clinical realities, and then present “patient blood management” (PBM) as the therapeutic concept that can prevent both anemia and unnecessary transfusion of RBC concentrates in a clinical context, especially in Intensive Care Units (ICU). This treatment concept may prove to be the key to high-quality patient care in the ICU setting in the future.
Efficacy and Safety of Tacrolimus as Treatment for Bleeding Caused by Hereditary Hemorrhagic Telangiectasia: An Open-Label, Pilot Study
Authors: Hessels Josefien , Kroon Steven , Boerman Sanne , Nelissen Rik C. , Grutters Jan C. , Snijder Repke J. , Lebrin Franck , Post Marco C. , Mummery Christine L. , Mager Johannes-Jurgen
Published: September 2022

Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2–6.9) mmol/L at baseline (9.8 g/dL) to 6.7 (6.5–7.1) mmol/L (10.8 g/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (±9.2) to 1.9 (±3.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study.
Maternal Left Ventricular Function in Uncomplicated Twin Pregnancies: A Speckle-Tracking Imaging Longitudinal Study
Authors: Orabona Rossana , Sciatti Edoardo , Vizzardi Enrico , Bonadei Ivano , Metra Marco , Sartori Enrico , Frusca Tiziana , Pinna Antonio , Bellocco Rino , Prefumo Federico
Published: September 2022

Objective: The knowledge of maternal cardiovascular hemodynamic adaptation in twin pregnancies is incomplete. We aimed to longitudinally investigate maternal left ventricular (LV) function in uncomplicated twin pregnancies. Methods: 30 healthy and uncomplicated twin pregnant women and 30 controls with normal singleton pregnancies were prospectively enrolled to undergo transthoracic echocardiography at 10–15 week’s gestation (w) (T1), 19–26 w (T2) and 30–38 w (T3). LV dimensions and volumes, as well as LV ejection fraction (LVEF), mass (LVM) and diastolic parameters (at transmitral pulsed wave Doppler and mitral annular plane tissue Doppler), were calculated. Speckle-tracking imaging was also applied to evaluate LV global longitudinal (GLS), radial and circumferential 2D strains. Results: During twin pregnancy, maternal LV dimensions, volumes and LVM had an increasing trend from T1 to T3, similar to singletons, while LVEF remained stable. There was LV remodeling/hypertrophy in 50% of women at T2 and T3 in both groups. Diastolic function had a worsening trend from T1 to T3 with no differences between twins and singletons, except for higher LV filling pressure (i.e., E/E′) at T2 in twins. Two-dimensional strains did not vary during gestation in either group, except for a linear trend to increase (i.e., worsen) GLS in singletons. Radial and circumferential 2D strains were impaired in about half of the women at each trimester, while GLS was altered in one-fourth/one-third of them in both groups. Conclusion: Maternal LV geometry, dimensions and function are significantly impaired during twin pregnancies, in particular in the second half of gestation, with no significant differences compared to singletons.
Pediatric Anaphylaxis: A 20-Year Retrospective Analysis
Authors: De Filippo Maria , Votto Martina , Albini Maria , Castagnoli Riccardo , De Amici Mara , Marseglia Alessia , Pizzo Alessandro , Marseglia Gian Luigi , Licari Amelia
Published: September 2022

Background. Anaphylaxis is a steadily increasing global problem defined as an acute hypersensitivity multisystem reaction that is potentially fatal. In the pediatric age, the leading cause is food. In other allergic diseases, intrinsic heterogeneity has been reported in the clinical presentation, severity, and triggers of anaphylaxis. This study analyzes the features and management approach of the anaphylactic reactions in children evaluated at the pediatric clinic in Pavia. Materials and methods. A retrospective study was conducted on patients with anaphylaxis between 2001 and 2021. Results. A total of 148 patients with a median age of 5 years were enrolled, and 80% of the patients had other atopic comorbidities that were correlated with the severity of anaphylaxis. The main trigger of anaphylaxis was food. Most reactions involved mucocutaneous, respiratory, and gastrointestinal systems, and occurred at home. Adrenaline was administered only in a minority of cases. Conclusions. Considering that anaphylaxis is a potentially life-threatening condition requiring prompt management, the use of adrenaline should be implemented. Our data also suggest the importance of educating and spreading awareness of anaphylactic management within the medical community.
Reconstructive Surgery and Joint-Sparing Surgery in Valgus and Varus Ankle Deformities: A Comprehensive Review
Authors: Caravelli Silvio , Puccetti Giulia , Vocale Emanuele , Di Ponte Marco , Pungetti Camilla , Baiardi Annalisa , Grassi Alberto , Mosca Massimiliano
Published: September 2022

Osteoarthritis (OA) of the ankle affects about 1% of the world’s adult population, causing an important impact on patient lives and health systems. Most patients with ankle OA can show an asymmetrical wear pattern with a predominant degeneration of the medial or the lateral portion of the joint. To avoid more invasive ankle joint sacrificing procedures, joint realignment surgery has been developed to restore the anatomy of the joints with asymmetric early OA and to improve the joint biomechanics and symptoms of the patients. This narrative, comprehensive, all-embracing review of the literature has the aim to describe the current concepts of joint preserving and reconstructive surgery in the treatment of the valgus and varus ankle early OA, through an original iconography and clear indications and technical notes.
Hepatic Ly6CLo Non-Classical Monocytes Have Increased Nr4a1 (Nur77) in Murine Biliary Atresia
Authors: Mohamedaly Sarah , Levy Claire S. , Korsholm Cathrine , Alkhani Anas , Rosenberg Katherine , Ashouri Judith F. , Nijagal Amar
Published: September 2022

Biliary atresia (BA) is a rapidly progressive perinatal inflammatory disease, resulting in liver failure. Hepatic Ly6CLo non-classical monocytes promote the resolution of perinatal liver inflammation during rhesus rotavirus-mediated (RRV) BA in mice. In this study, we aim to investigate the effects of inflammation on the transcription factor Nr4a1, a known regulator of non-classical monocytes. Nr4a1-GFP reporter mice were injected with PBS for control or RRV within 24 h of delivery to induce perinatal liver inflammation. GFP expression on myeloid immune populations in the liver and bone marrow (BM) was quantified 3 and 14 days after injection using flow cytometry. Statistical significance was determined using a student’s t-test and ANOVA, with a p-value < 0.05 for significance. Our results demonstrate that non-classical monocytes in the neonatal liver exhibit the highest mean fluorescence intensity (MFI) of Nr4a1 (Ly6CLo MFI 6344 vs. neutrophils 3611 p < 0.001; macrophages 2782; p < 0.001; and Ly6CHi classical monocytes 4485; p < 0.0002). During inflammation, hepatic Ly6CLo non-classical monocytes showed a significant increase in Nr4a1 expression intensity from 6344 to 7600 (p = 0.012), while Nr4a1 expression remained unchanged on the other myeloid populations. These findings highlight the potential of using Nr4a1 as a regulator of neonatal hepatic Ly6CLo non-classical monocytes to mitigate perinatal liver inflammation.
Transdermal Maltose-Based Microneedle Patch as Adjunct to Enhance Topical Anesthetic before Intravenous Cannulation of Pediatric Thalassemic Patients Receiving Blood Transfusion: A Randomized Controlled Trial Protocol
Authors: Abdul Jalal Muhammad Irfan , Ooi Kai Shen , Foo Kai Cheong , Hamzah Azrul Azlan , Goh Chee Seong , Dee Chang Fu , Ooi Poh Choon , Buyong Muhamad Ramdzan , Low Teck Yew , Chua Xin Yun , Lau Doris Sie Chong , Abdul Latiff Zarina , Cheah Fook Choe
Published: September 2022

Intravenous cannulation is experientially traumatic to children. To minimize this, EMLA® is applied on the would-be-cannulated area before IV cannula insertion. However, the time to achieve its maximum efficacy may be affected due to incomplete cutaneous absorption and the duration of application. The latter may be a limiting factor in a busy healthcare facility. The usage of dissolvable maltose microneedles may circumvent this problem by introducing micropores that will facilitate EMLA® absorption. A randomized phase II cross-over trial will be conducted to compare the Visual Analogue Scale (VAS) pain scores and skin conductance algesimeter index between 4 different interventions (1 fingertip unit (FTU) of EMLA® with microneedle patch for 30 min before cannulation; 0.5 FTU of EMLA® with microneedle patch for 30 min; 1 FTU of EMLA® with microneedle for 15 min; 1 FTU of EMLA® with sham patch for 30 min). A total of 26 pediatric patients with thalassemia aged between 6 and 18 years old and requiring blood transfusion will be recruited in this trial. During the visits, the VAS scores and skin conductance algesimeter index at venous cannulation will be obtained using the VAS rulers and PainMonitor™ machine, respectively. The trial will commence in August 2021 and is anticipated to end by August 2022.